CN100455349C - Absorbent for removing low-density lipoprotein by utilizing blood extracorporeal circulation and preparation method thereof - Google Patents
Absorbent for removing low-density lipoprotein by utilizing blood extracorporeal circulation and preparation method thereof Download PDFInfo
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- CN100455349C CN100455349C CNB2006100391320A CN200610039132A CN100455349C CN 100455349 C CN100455349 C CN 100455349C CN B2006100391320 A CNB2006100391320 A CN B2006100391320A CN 200610039132 A CN200610039132 A CN 200610039132A CN 100455349 C CN100455349 C CN 100455349C
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Abstract
The present invention relates to an adsorbent for removing low-density lipoprotein by utilizing blood extracorporeal circulation and the preparation method thereof. The adsorbent utilizes rigid cellulose gel particles or polyvinyl alcohol gel particles as carriers to react with ligand, such as activating vitriol dextran sodium salt, polyacrylic acid, poly (acrylic acid-co-2-propene amido group-2-methyl radical propanesulfonic acid) or chlorosulfonic acid, to produce. The adsorbent has negative charge, and is formed by the connection of the carriers and covalent bonds of the ligand. The adsorbent for removing low-density lipoprotein by utilizing blood extracorporeal circulation of the present invention can remove LDL-C of higher than 80 percent in blood, and the adsorbing rate of HDL is lower than 20 percent. The adsorbent is the adsorbent with high selectivity of the LDL-C. The present invention discloses the preparation method of the adsorbent.
Description
Technical field
The present invention relates to be used for the adsorbent that the harmful lipoprotein of blood is removed in the blood extracorporal circulatory system.Specifically, be that a kind of cellulose gel particle or polyvinyl alcohol gel particle are the adsorbent of carrier.
Background technology
Know that now lipid increases in the blood, particularly contain the low-density lipoprotein (LDL-C) and the VLDL (VLDL-C) of a large amount of cholesterol, can cause and quicken atherosclerotic and development, the result causes a series of diseases of blood circulation system.For example, the very high disease of the death rate such as miocardial infarction, cerebral embolism.Thereby, manage to remove the low-density lipoprotein (LDL-C) in the hyperlipemia disease human blood, slow down and quicken a kind of good method of the above-mentioned disease of treatment beyond doubt.The existing plasma exchange method of use, the plasma separation that is about in the patient body is come out, and with normal person's blood plasma or contain albuminous displacement liquid and exchange, this method curative effect is pretty good, and especially familial hyperlipemia patient only can effectively be treated with this method.But there is following shortcoming in the plasma exchange method:
1. fresh normal plasma or blood plasma components cost an arm and a leg.
2. abandon patient's blood plasma, also lost when removing harmful components as HDL beneficiating ingredients such as (HDL).
3. danger of the hepatitis viruse infectd or the like is arranged.
Latter half in last century, advanced countries such as Japan, the U.S. research and develop out the technology of removing LDL-C in the blood with absorption method, begin to have the LDL-C adsorbent at the last fixing heparin (part) of Ago-Gel (carrier) according to affine principle.Use the chromatography of Bio-Glas in addition.Though the former has preferably the performance of selecting absorption LDL-C, because of the mechanical strength of carrier-agarose is low, cause adsorbent in the middle distortion of disinfecting of high temperature and high pressure method, break, in use easily take place to stop up and do not have a practical value; The latter not only adsorptivity is poor, and selectivity is also poor, at all can't practicability.
Afterwards, develop various water-fast hard porous carriers again, delivered many patents, also produced as a trial, done clinical testing.For example, the Asahi chemical industry Co., Ltd of Japan and the Nobataka of the U.S. are carrier with polyvinyl alcohol and Toyogerd HW55gel respectively, and heparin is that part has been made the LDL-C adsorbent.This class connects heparin with carrier to be made the method for adsorbent and can remove LDL-C in the blood effectively, but often wants to have in the blood excusing from death to manage the C of concentration
a 2+Exist, this makes that process dialysis earlier is to reduce C before the defeated blood back pipe of the blood plasma that adsorption treatment is crossed
a 2+Concentration.This undoubtedly operation has not only increased expense but also increase the medical treatment time, is difficult for being accepted by doctor and patient.And for example, recently China's exploitation and the external plasma lipid filter of having test-manufactured, it is that this filter can make the triglycerides in patient's blood plasma, concentration and the blood fat viscosity of LDL-C descend 43%, 45% and 10～30% respectively with the complex filter of the multi-level combination of three kinds of filter membrane materials.But this filter does not have the selection adsorptivity, will human body beneficial's HDL-C have been removed when absorbing LDL-C yet.
Summary of the invention
The part that the inventor successfully develops a series of water-fast hard porous carriers and various electronegative functional groups reacts the LDL-C adsorbent that forms.
Technical scheme of the present invention is as follows:
A kind of adsorbent that is used for blood extracorporal circulatory system removal low-density lipoprotein, it is to be carrier with the cellulose gel particle of hard or polyvinyl alcohol gel particle, with make as the activation sulfuric acid dextran sodium salt of part, polyacrylic acid, poly-(acrylic acid-co-2-acrylamido-2-methyl propane sulfonic acid) or chlorosulfonic acid reaction, be the adsorbent that has negative electrical charge that carrier is connected with the part covalent bond.
The above-mentioned adsorbent that is used for blood extracorporal circulatory system removal low-density lipoprotein, it is that cellulose gel particle with hard is a carrier, be connected with expoxy propane by the oxygen carbon bond, be connected with hexamethylene diamine by carbonnitrogen bond again, at last by nitrogen carbon bond and adsorbent as the activation sulfuric acid dextran sodium salt low-density lipoprotein that be connected, that have negative electrical charge of part.
Above-mentioned adsorbent, the plain gel particles of described carrier fibre is grass cellulose gel particle preferably.
The carrier of adsorbent of the present invention, the cellulose gel particle or the polyvinyl alcohol gel particle that are above-mentioned hard are under the pressure reduction of 200mmHg, cubical contraction is less than or equal to 15% cellulose gel particle or polyvinyl alcohol gel particle, preferably under the pressure reduction of 200mmHg, cubical contraction is 12～10% cellulose gel particle or polyvinyl alcohol gel particle.
The carrier of adsorbent of the present invention is hard porous gel.So-called " hard " is meant that under external force its physical property can remain on more than the certain level.Adsorbent of the present invention reaches swelling equilibrium in normal saline solution after, under the pressure reduction of 200mmHg, cubical contraction is less than 15% o'clock, can stand autoclave sterilization and handle, in the adsorption column of packing into after, do not stop up at blood plasma by process.If cubical contraction was greater than 15% o'clock, adsorbent (mainly being its carrier) is too soft, and is yielding in autoclave sterilization is handled, and by in the process, flow velocity is slack-off with the compression of adsorbent layer at blood plasma, so that stop up fully.But less than 5%, then voidage is too low, and causes adsorption efficiency low as if adsorbent volume shrinkage factor.
The cubical contraction assay method is as follows: the adsorbent that will the wet internal diameter 10mm that packs into, the band scale of high 100mm, can connect in the glass pillar of leather hose up and down, when treating that adsorbent layer reaches the 50mm height, allow water pass through packed column, regulate the flow velocity of water, pressure differential maintain between making pillar inlet and exporting reads the adsorbent layer height drop-out value that is caused by pressure reduction at 200mmHg, can calculate the cubical contraction of adsorbent.The cubical contraction that this method is measured is " cubical contraction under 200mmHg pressure reduction ".
Above-mentioned adsorbent, the described amount that has negative electrical charge can be every milliliter of wet adsorbent and contain 1 μ eq～1meq, and preferred negative electrical charge content is 10 μ eq/ml～200 μ eq/ml, and most preferred negative electrical charge content is 50 μ eq/ml～130 μ eq/ml.
Adsorbent of the present invention adsorbs electropositive LDL-C and VLDL-C etc. according to Electrostatic Absorption mechanism, thereby, the factor of decision performance of the adsorbent, except that above-mentioned carrier structure factor, electronegative anionic type, quantity and distribution situation are most important factors on the adsorbent.
Adsorbent of the present invention is on above-mentioned carrier, will be keyed to as the little molecule of the electronegative group of part or macromolecular compound by chemical reaction to get on the carrier.
Be the chlorosulfonic acid that contains the negative electrical charge group, synthetic contain polyanionic polymer as the compound of adsorbent part among the present invention, as polyacrylic acid, poly-(acrylic acid-co-2-acrylamido-2-methyl propane sulfonic acid), or natural contain polyanionic polymer, as sulfuric acid dextran sodium salt etc.
Though the carboxyl electronegativity is weaker than sulfate or sulfonic group, but, the adsorbent that has a carboxyl presents atomic weak adsorptivity for the protein of useful lipoprotein such as albumin and blood clotting system and complement system, and, be difficult to cause the activation of these protein.With the natural polyanionic polymer phase ratio that contains, the synthetic polyanionic polymer that contains has the advantages that the molecular weight and the quantity of electric charge and electric charge intensity can artificially be controlled.The distribution of negative electrical charge group in carrier is evenly for well naturally, and this depends primarily on distribution situation, the active group steric hindrance size and the reaction condition on every side of in the carrier and the active group ligand activity radical reaction.
The negative electrical charge content x-ray fluorescence spectrometry of sulfur-bearing acidic group of the present invention, sulfonic adsorbent, promptly measure the sulfur content in the dried adsorbent of every gram, according to the swelling ratio of adsorbent, convert out every milliliter of wet adsorbent sulfur-bearing acidic group or sulfonic gram-equivalent number again.For being the adsorbent of part, because every root polypropylene acid molecule is not held and is-S-CH with polyacrylic acid
2-CH
2-NH
2Group can be measured polyacrylic weight average molecular weight by the GPC method, measures sulfur content in the adsorbent with x ray fluorescence spectrometry again, converts out every milliliter of contained carboxyl equivalent number of wet adsorbent then.
Adsorbing agent carrier of the present invention is spherical and granular.The average grain diameter size of ball or particle has certain influence to the adsorptivity and the dress post situation of adsorbent, and particle diameter is too big, has reduced specific area, is unfavorable for adsorption efficiency, also easily causes excessive intergranular gap during the dress post, also can reduce adsorption efficiency; If particle diameter is too little, fill in when using in the post, not only cause in the post density of adsorption layer big, plasma flow rate descends, and also has the danger of leaking by filter edge or some defective takes place.It is narrow more good more that particle diameter distributes because the adsorption layer each point situation that build-up of particles of uniform size becomes is identical, be beneficial to blood plasma evenly, speed stabilizing passes through.Adsorber particles particle diameter of the present invention between 10 μ m～200 μ m all can, better, and best between 60 μ m～100 μ m between 30 μ m～150 μ m.It is to observe with simple microscope that adsorbent particle diameter of the present invention and particle diameter distribute, and statistical computation obtains.
The gel of the carrier of adsorbent of the present invention is hard porous gel.This gellike both need be hard porous, had again to carry out chemical reaction with part, made the functional group of both covalent bonds, simultaneously, also will have the compatibility with blood or blood plasma.The carrier of adsorbent of the present invention--cellulose gel particle and polyvinyl alcohol gel particle all are the high polymers that has great amount of hydroxy group, thereby have well and the compatibility of blood or blood plasma, in handling blood plasma or blood process, seldom with LDL-C and VLDL-C beyond blood plasma in solutes such as other protein interact, therefore, the high adsorptive selectivity for adsorbent provides guarantee.
The carrier of adsorbent of the present invention is the polymer that contains great amount of hydroxy group, and hydroxyl can directly react with the ligand compound that contains negative electrical charge, introduces the sulfate radical negative electrical charge as directly reacting with chlorosulfonic acid.But, when containing polyanionic polymer and be part, must first activated carrier, allow the active group reactive activity base on easier and the part on the carrier band.Allow carrier (perhaps part) be called priming reaction with the reaction of going up active group, the carrier (or part) that has active group is called activated carrier (or activation part).The carrier of adsorbent of the present invention or part can be by being with epoxy radicals isoreactivity group with compound reactions such as diepoxides, epoxychloropropane.Can also utilize epoxy radicals very easily by the active hydrogen attack on the amino of diamine compounds and open loop connects diamine compound, thereby with having gone up active amino group.
A kind of method for preparing above-mentioned adsorbent, it is to carry out cross-linking reaction with having the cellulose gel particle of epoxide group or having the polyvinyl alcohol gel particle of epoxide group and have amino part in water under 70～80 ℃, obtain the adsorbent that low-density lipoprotein is removed in the blood extracorporal circulatory system that is used for of the present invention, described part is to have amino sulfuric acid dextran sodium salt, end to have amino polyacrylic acid or poly-(acrylic acid-co-2-acrylamido-2-methyl propane sulfonic acid).
The method of the above-mentioned adsorbent of another kind of preparation, it is with cellulose gel particle or polyvinyl alcohol gel particle and chlorosulfonic acid reaction under 40 ℃ in dimethyl formamide, obtains the adsorbent that low-density lipoprotein is removed in the blood extracorporal circulatory system that is used for of the present invention.
Of the present inventionly being used for the blood extracorporal circulatory system and removing LDL-C that the adsorbent of low-density lipoprotein can remove blood up to more than 80%, and HDL is removed below 20%, is a kind of adsorbent that LDL-C is had high selectivity.
The specific embodiment
Illustrate in greater detail the present invention with reference example and embodiment below, still, the present invention is not limited to these examples.
Embodiment 1. gossypin gel particles are carrier, and sulfuric acid dextran sodium salt is the preparation of the adsorbent CB-907b of part
A. the preparation of viscose
The 80g cotton linters cellulose paper pulp that shreds is added in the large beaker of sodium hydrate aqueous solution of 15% concentration that contains 1600ml, after soaking 2h, filter squeezing and remove part alkali lye, fully stir this alkali cellulose that looses, after being positioned over the 40h that wears out in 30 ℃ of insulating boxs, in aged alkali cellulose, add 40ml CS rapidly
2, seal up glass bottle opening after stirring slightly, under the room temperature, reaction 3h.In the course of reaction, cellulose is become light yellow by white, become crocus again after, pour in the large beaker, add the 5% concentration hydrogen aqueous solution of sodium oxide of 960ml again, beaker is placed ice-water bath, constantly after the stirred for several hour, sealing beaker mouth, dislocation is in 4 ℃ of refrigerators, make the former xanthate acid of cellulose continue dissolving, behind the placement diel, take out and carry out press filtration with filter press, the not molten residue of elimination, filtrate is the cellulose viscose, is placed in 4 ℃ of refrigerators, and is standby.The element of falling small amount of fibers viscose is in two glass culture dish of having weighed, after weighing, place 50 ℃ of oven dryings to constant weight, the concentration that calculates this batch viscose is 16.88%, and the viscosity that goes out 20 ℃ of following this batch cellulose viscoses with the NDJ-1 rotary viscosity design determining is 13175CP.
The preparation of b CB-907b gossypin gel particles:
Weighing potassium oleate 10g is dissolved in 50ml water, after treating to dissolve fully, pours the 5000ml glass reactor into, begins to stir.The dilution glue (concentration is 10%) 1000ml and the 50g calcium carbonate that add the viscose that makes by top a. in the 2000ml beaker, after mixing, add reactor simultaneously with the 3000ml Benzene Chloride, reinforced finishing, regulate mixing speed, the viscose glue drop that is suspended in the Benzene Chloride is fully disperseed, and particle diameter meets the requirements.Progressively be warming up to 90 ℃ then, stirring reaction 3h under this temperature.Cooling, discharging, with big water gaging flushing particle, make it to become white by yellow, pour into after draining in the saturated NaCl solution of 0.5N HCl of 4000ml, stirred for several minute, emit a large amount of bubbles after, leave standstill about 1h again, by the time calcium carbonate all decomposes, when not having bubble again and emerging, filter out acid solution, particulate is washed with massive laundering, drain, spend the night with alcohol immersion, water flushing is drained, standby again.
The activation of c.CB-907b gel particles
Take by weighing the gossypin CB-907b gel pellet 32g after above-mentioned the draining, add epoxychloropropane 13g, water 36ml soaked after 4 hours, added 1mol sodium hydrate aqueous solution 60ml, under 40 ℃, and stirring reaction 4h.Reactant is fallen in Buchner funnel, wash repeatedly, be dipped in the ethanol behind the suction filtration and spend the night, pour Buchner funnel again into, with the flushing of second alcohol and water repeatedly,, drain with the residual epoxychloropropane of thorough Ex-all with big water gaging, standby.
D. activate sulfuric acid dextran sodium salt
Add sulfuric acid dextran sodium salt 30g in the conical flask, add the NaOH aqueous solution 66ml of epoxychloropropane 2.g and 2% again, in 40 ℃, vibration down, react after 1 hour, add 1 of 2.8mol/l again, 6-hexamethylene diamine aqueous solution 18ml, vibration is reacted after 8 hours down, be stored in the closed container, standby.
C. cross-linking reaction
The activation sulfuric acid dextran sodium salt solution 9ml of activation cotton fiber gel particles 15g and 26% concentration above taking by weighing, after 70 ℃ reaction is spent the night down, fall and filter in Buchner funnel, wash adsorber particles repeatedly with purified water, drain, promptly get CB-907b adsorbent of the present invention.
The carrier of CB-907B adsorbent--the porosity of cotton fiber gel particles, negative electrical charge content, cubical contraction and the outward appearance of aperture and particle diameter, adsorbent are listed in table 1, and the adsorptivity sample measurement result of this adsorbent is listed in table 2.
Comparative example 1. is a carrier with the Ago-Gel particle, and sulfuric acid dextran sodium salt is that part prepares fine jade J27 adsorbent
Take by weighing 40g sulfuric acid dextran sodium salt, add 4.0gl, 1-carbonyl dimidazoles and 80ml 1,4-dioxane solvent, after room temperature fully stirs 1h, the elimination solvent.Place ventilation a period of time to guarantee to remain 1, the 4-dioxane vapors away fully, and is standby.
Take by weighing 4% Ago-Gel 10g (supply of Shanghai reagent company of Chinese Medicine group), adding 60ml contains the 2%NaOH solution of 0.5mol/L epoxychloropropane, behind the stir-activating 3h, with purified water flushing, suction filtration, adding concentration again is 1 of 2.8mol/L, and 6-hexamethylene diamine aqueous solution 9ml is in stirring reaction under the room temperature after 4 hours, with purified water flushing, suction filtration, standby.
The sulfuric acid dextran sodium salt 4g of aminated 4% Ago-Gel 10g of the face that deserves to be called and activation puts into taper also, adds the 2%NaOH solution of 60ml 0.5mol/L epoxychloropropane.Electromagnetic agitation, behind the cross-linking reaction 3h, repeatedly with purified water wash, drain, stand-by.
Negative electrical charge content, cubical contraction and the outward appearance of fine jade J27 are listed in table 1, and the sample adsorptivity is listed in table 2, and dress post absorption property is listed in table 7.
Comparative example 2～4. the gossypin gel particles is a carrier, and sulfuric acid dextran sodium salt is adsorbent CB-906a, the CB-906b of part and the preparation of CB-907a
Except that the cellulose viscose of using concentration 16.88%, 14% and 12% respectively replaces the cellulose viscose of concentration 10% among the embodiment 1, all the other every operations are all identical with embodiment 1.Obtain three kinds of adsorbents of CB-906a, CB-906b and CB-907a respectively.Their carrier characteristics and characterization of adsorption are listed in table 1 and table 2.
Carrier characteristics, cubical contraction, outward appearance and the negative electrical charge content of table 1.CB series adsorbent
| Project | Voidage (%) | Average pore size (NM) | Pore diameter range (NM) | Particle size range (μ m) | Cubical contraction (%) | Negative electrical charge content (ueq/ml wet adsorbent) | Outward appearance |
| Comparative example 1 fine jade J27 | --- | ---- | ---- | 64～200 | 30 | 100.4 | Rufous, spherical particle, the surface is more smooth |
| Comparative example 2 CB-906a | 80 | 700 | 30～1300 | 240～320 | 8.1 | 90 | Light yellow, surface irregularity, the irregularity bulky grain, |
| Comparative example 3 | 83 | 750 | 30～1500 | 30～150 | 10.0 | 97 | Light yellow, surface irregularity, |
| CB-906b | The irregularity particulate, | ||||||
| Comparative example 4 CB-907a | 86 | 820 | 3～1500 | 20～80 | 12.0 | 100 | Light yellow, surface irregularity, irregularity particulate and sheet and bar, |
| Embodiment 1 CB-907b | 90 | 960 | 30～2100 | 20～50 | 9.7 | 120 | Light yellow, irregularity particulate, concave-convex surface cellular |
The adsorptivity sample test result of table 2.CB series adsorbent
| Adsorbent | The CH clearance | The TG clearance | The HDL-C clearance | The LDL-C clearance |
| CB-906a (comparative example 2) | 6.94％ | 5.42％ | 13.48％ | 10.76％ |
| CB-906b (comparative example 3) | 33.12％ | 12.07％ | 15.73％ | 44.94％ |
| CB-907a (comparative example 4) | 49.21％ | 22.41％ | 15.73％ | 65.82％ |
| CB-907b (embodiment 1) | 54.57％ | 25.62％ | 17.98％ | 72.15％ |
| Fine jade J27 (comparative example 1) | 47.24％ | 46.75％ | 15.46％ | 69.89％ |
Annotate: data are to get the wet adsorbent of 1ml to put into the 4ml refrigerated plasma in the table 2, behind 30 ℃ of 1h that vibrate down, filter the numerical value (be difference dress column test, this method of testing gained result is called for short the sample test result) that filtrate obtains through the test of Olympus 2700 automatic clinical chemistry analyzers.
Embodiment 2. is that carrier, sulfuric acid dextran sodium salt are the WC-228a preparation of adsorbent of part with the lignose gel particles
A. the preparation of lignose viscose
The cotton linters cellulose paper pulp in a that replaces embodiment 1 with lignose paper pulp, all the other operations are described identical with a of embodiment 1.This that measure batch viscose glue concentration is 14.5%, and the viscosity that goes out 20 ℃ of following these viscoses with the NDJ-1 rotary viscosity design determining is 3410cp.
The preparation of b.WC-228a lignose gel particles:
Measure the four-hole glass reactor of 2850ml Benzene Chloride adding 5000ml earlier, take by weighing and be added in the reactor after the 5.9g potassium oleate is dissolved in the 44ml water, open agitator and begin slow stirring, again made viscose among a is diluted to 10% concentration, get 950ml and add 48g calcium carbonate, pour reactor after mixing into, operation is identical with the b of embodiment 1 later on.
The activation of c.WC-228a lignose gel particles:
Increase to scale outside (31.25 times) divided by 32gCB-907b gossypin particle, other priming reaction agents useful for same among the c of WC-228a lignose particle 1000g replacement embodiment 1, the c of all priming reaction steps and operation and embodiment 1 is identical.
D. the activation of sulfuric acid dextran sodium salt:
Except that each material quantity than all big 30 times of the d. of embodiment 1, every operation is identical with the d. of embodiment 1.
E. cross-linking reaction
Getting the activation sulfuric acid dextran sodium salt solution 300ml that makes among the activation WC-228a lignose particle 500g for preparing among the top c. and the d. adds in the reactor, add 1000ml water again, stir, be warming up to 70 ℃, behind the reaction 21h, cooling, discharging is filtered, drain after being soaked in water repeatedly, washing, promptly get WC-228a adsorbent of the present invention.
The negative electrical charge content of the carrier characteristics of WC-228a adsorbent and cubical contraction, adsorbent is listed in table 3, and absorption property sample test result is listed in table 4, and dress post absorption property test result is listed in table 5.
Comparative example 5. is a carrier with the lignose gel particles, and sulfuric acid dextran sodium salt is a part, with the adsorbent WC-1015b of glutaraldehyde as cross linker preparation
A. the preparation of lignose viscose:
Except that the alkali cellulose ageing time than the increase of a of embodiment 2 10 hours, all the other operations are identical with a of embodiment 2.This that measure batch viscose glue concentration is 14.5%, and viscosity is 1740cp.
The preparation of b.WC-1015b lignose gel particles:
Identical with the b of embodiment 2, it is 10% concentration (viscosity 216cp) that viscose also dilutes
The activation of c.WC-1015b lignose gel particles:
Get the WC-1015b lignose gel particles 130g that drains that makes among the top b, add epoxychloropropane 54g and water 150ml, soak after 10 hours, add 1mol sodium hydrate aqueous solution 240ml, under 40 ℃, stirring reaction 4h, be soaked in the alcohol after the water flushing again and spend the night, water washes once more, drains, and pours flask into, the amine aqueous solution 173ml and 90ml water in the sixth of the twelve Earthly Branches two that adds 2.8mol/l, under 40 ℃, stirring reaction 8h, water washes repeatedly, drain, stand-by.
D. the activation of sulfuric acid dextran sodium salt:
Identical with the d of embodiment 2.
E. cross-linking reaction:
The activared carbon sulfur dextran sodium salt solution 170ml that makes among aminated active WC-1015b lignose gel particles 130g and the d among the top c. is added in the conical flask, after stirring is spent the night, the glutaraldehyde solution 2ml that adds 25% concentration, behind 40 ℃ of following stirring reaction 3h, filter, move in the conical flask, glycine (containing 0.15mol/l NaCL) the solution soaked overnight that adds 0.2mol/l concentration refilters, washes, drains with big water gaging, makes the WC-1015b adsorbent.
The carrier characteristics of the WC-1015b adsorbent that makes and its outward appearance, cubical contraction and negative electrical charge content are listed in table 3, and sample adsorptivity test result is listed in table 4.
Comparative example 6. is a carrier with the lignose gel particles, and sulfuric acid dextran sodium salt is a part, with the adsorbent WC-1012a of glutaraldehyde as cross linker preparation
Remove former viscose (concentration 14.5%, viscosity 1740cp) replaces in the comparative example 5 outside 10% concentration, all the other are all identical with comparative example 5, and the carrier characteristics of the adsorbent WC-1012a that makes and its outward appearance, cubical contraction and negative electrical charge content are listed in table 3, and sample adsorptivity test result is listed in table 4.
Comparative example 7. is that carrier, sulfuric acid dextran sodium salt are the WC-228al and the WC-228a2 adsorbent of part preparation with the lignose gel particles
Be all the activation sulfuric acid dextran sodium salt solution and the 20ml water that prepare among the d of the activation lignose gel particles for preparing among the c of 10g embodiment 2 and 4ml embodiment 2 with two parts and carry out cross-linking reaction, a reaction temperature is 60 ℃, another part reaction temperature is 80 ℃, reaction time and post processing are all identical with embodiment 2, and the sample test result example of WC-228al that makes and WC-228a2 adsorbent is in table 4.
Embodiment 3. is a carrier with WC-228a lignose microgel particle, is " carboxylated WC-228a " preparation of adsorbent of part with the polyacrylic acid
The preparation of the activation WC-228a lignose gel particles of band epoxy radicals is same as embodiment 2 fully.
The polyacrylic preparation method of terminal band amino is as follows:
After in having four neck flasks of condenser pipe, dropping funel, electronic stirring and nitrogen ingress pipe, adding the 0.21g sodium pyrosulfite that is dissolved in the 70ml water, add acrylic acid 40g again.Pour in the dropping funel after being dissolved in 0.42g potassium peroxydisulfate and 0.2g mercaptoethylmaine in the 40ml water, start stirring, logical nitrogen, heating, when temperature in the reaction bulb rises to 65 ℃, begin to drip initator and chain-transferring agent solution, dropwise, be warmed up to 75 ℃ and react again about 2h, stop reaction, after the cooling, pour in the acetone, precipitation is pulled out, soluble in water again, add acetone again and make precipitation, like this after the repeatable operation three times, sediment is placed tetrafluoroethene garden dish, be dried to constant weight in 40 ℃ of baking ovens, be stored in the drier standby.
Measuring this polymer number-average molecular weight with titration is 20000.
Take by weighing activation WC-228a lignose gel particles 4g and add and be dissolved with the above-mentioned polyacrylic aqueous solution 27ml of 0.23g, under 70 ℃, stirring reaction 24h filters, big water gaging flushing, drains, and promptly gets " carboxylated WC-228a " adsorbent.
The carrier characteristics of this adsorbent and its outward appearance, cubical contraction and negative electrical charge content are listed in table 3, and sample adsorptivity test result is listed in table 4.
Embodiment 4.WC-228a lignose microgel particle is a carrier, is " carboxylic sulfo group WC-228a " preparation of adsorbent of part with poly-(acrylic acid-co-2-acrylamido-2-methyl propane sulfonic acid)
The preparation of the activation WC-228a lignose microgel particle of band epoxy radicals is same as embodiment 2 fully.
The preparation method of poly-(acrylic acid-co-2-acrylamido-2-methyl propane sulfonic acid) is as follows:
To contain the acrylic acid beaker of 15g and place ice-water bath, drip the NaOH aqueous solution of 60ml 16% concentration, pour in the four neck flasks that have condenser pipe, two dropping funels, electronic stirring and nitrogen ingress pipes after the dissolving fully, add the 0.1g sodium pyrosulfite that is dissolved in the 20ml water again.Pour in the dropping funel after being dissolved in 0.2g potassium peroxydisulfate and 0.05g mercaptoethylmaine in the 20ml water.15g 2-acrylamido-2-methyl propane sulfonic acid is dissolved in the NaOH aqueous solution of 20ml16% concentration, pours in another dropping funel.Start stirring, logical nitrogen, deoxygenation.Under the room temperature, simultaneously, slowly drip initator and chain-transferring agent solution and 2-acrylamido-2-methyl propane sulfonic acid solution, 1h dropwises, and is warmed up to 70 ℃ and reacts 2h again, stops reaction, after the cooling, pour in the acetone, precipitation is pulled out, soluble in water again, add acetone again and make precipitation, after the repeatable operation three times, sediment is placed tetrafluoroethene garden dish like this, be dried to constant weight in 40 ℃ of baking ovens, be stored in the drier standby.
Take by weighing activation WC-228a lignose microgel particle material 4g and add the aqueous solution 30ml that is dissolved with the above-mentioned copolymer of 0.25g, under 70 ℃, stirring reaction 24h filters, and big water gaging flushing is drained, and promptly gets " carboxylic sulfo group WC-228a " adsorbent.
The carrier characteristics of this adsorbent and its outward appearance, cubical contraction and negative electrical charge content are listed in table 3, and sample adsorptivity test result is listed in table 4.
Carrier characteristics, cubical contraction, outward appearance and the negative electrical charge content of table 3.WC series adsorbent
| Project | Hole rate (%) | Average pore size (nm) | Pore diameter range (nm) | Particle size range (μ m) | Cubical contraction (%) | Negative electrical charge content (ueq/ml) | The outward appearance heart, form |
| Embodiment 2 WC-228a | 92.7 | 1100 | 40-1500 | 70-100 | 12 | 101 | Light yellow, the particle majority is that how concavo-convex ellipticity, surface be |
| Embodiment 3 carboxylated WC-228a | 92.7 | 1100 | 40-1500 | 70-100 | 12 | 75 | The same |
| Embodiment 4 carboxylic sulfo group WC-228a | The same | The same | The same | The same | The same | 90 | The same |
| Comparative example 5 WC-1015b | 92.0 | 1100 | 40-1500 | 40-70 | 13.1 | 90 | Rufous, the particle majority is that how concavo-convex ellipticity, surface be |
| Comparative example 6 WC-1012a | 86.2 | 800 | 40-1300 | 40-120 | 10.0 | 81 | Rufous, the particle majority is a ball, how concavo-convex the surface is |
| Comparative example 7 WC-228a1 WC-228a2 | 92.7 | 1100 | 40-1500 | 70-100 | 12 | 101 | Light yellow, the particle majority is a ball, and how concavo-convex the surface is |
Table 4.WC series adsorbents adsorb sample test result
| Adsorbent | The CH clearance | The TG clearance | The HDL-C clearance | The LDL-C clearance |
| WC-228a (embodiment 2) | 73.24％ | 51.68％ | 14.07％ | 93.40％ |
| " carboxylated WC-228a " (embodiment 3) | 51.46％ | 22.66％ | 13.92％ | 68.66％ |
| Carboxylic sulfo group WC-228a (embodiment 4) | 69.60％ | 50.00％ | 13.50％ | 89.21％ |
| WC-1015b (comparative example 5) | 68.62％ | 47.58 | 14.77％ | 81.21％ |
| WC-1012a (comparative example 6) | 47.51％ | 23.64％ | 13.64％ | 58.79％ |
| WC-228a1 (comparative example 7) | 65.14％ | 50.61％ | 17.53％ | 88.49％ |
| WC-228a2 (comparative example 7) | 63.23％ | 50.65％ | 15.40％ | 88.50％ |
Embodiment 5. is a carrier with grass cellulose (being mainly reed, straw cellulose) gel particles, and sulfuric acid dextran sodium salt is the preparation of the adsorbent GC-421a of part.
A. the preparation of grass cellulose viscose:
Remove with the cotton linter fiber paper pulp among a of grass fibre pulp replacement embodiment 1, the alkali cellulose ageing time became outside 20 hours, and all the other operating procedures are identical with a of embodiment 1.The concentration of this grass cellulose viscose that makes is 14.6%, and the viscosity that goes out 20 ℃ of following these viscoses with the NDJ-1 rotary viscosity design determining is 390CP
B. the preparation of grass cellulose gel particle (GC-421a):
Identical with the b of embodiment 1.Wherein, the viscosity that gained grass cellulose viscose glue is diluted to the viscose of concentration 10% among a is 135cp.
The activation of c.GC-421a gel particles:
Identical with the C of embodiment 2.
D. the activation of sulfuric acid dextran sodium salt;
Identical with the d of embodiment 2.
E. cross-linking reaction:
Identical with the e of embodiment 2.
The carrier characteristics of this adsorbent, the cubical contraction under 0.026MPa pressure reduction, negative electrical charge content and outward appearance are listed in table 6; Sample absorption property test result is listed in table 7; Dress post characterization of adsorption is listed in table 5.
Comparative example 8. is a carrier with grass cellulose gel particle, and sulfuric acid dextran sodium salt is the GC-419a preparation of adsorbent of part
The GC-419a gel particles is to use and GC-421a gel particles batch grass fibre pulp together, removing the alkali fiber ageing time is 40h, the viscosity of the viscose (10% concentration) of preparation gel particles is outside the 114.35CP, and all the other operations are all described identical with embodiment 5.The characteristic of this adsorbing agent carrier, the cubical contraction under 0.026MPa pressure reduction, negative electrical charge content and outward appearance are listed in table 6; Sample absorption property test result is listed in table 7.
Embodiment 6. is a carrier with the GC-419a gel particles, is the preparation of the adsorbent " chlorosulfonation GC-419a " of part with the chlorosulfonic acid
The GC-419a gel particles is immersed in 2h in 50: 50 the ethanol-water mixed solvent earlier, is soaked in 2h, filtration in 70: 30 the ethanol-water mixed solvent after filtering, be soaked in 12h in the ethanol again, behind the suction filtration, in 40 ℃ of oven dry.Take by weighing the granules 8g of oven dry, in the 100ml four neck flasks of pack into band dropping funel, condenser pipe, thermometer and stirring rod, add 26mlN again, dinethylformamide slowly stirs.In dropping funel, add the 2ml chlorosulfonic acid.Flask is put in the ice-water bath, and when reaching 5 ℃, beginning slowly drips chlorosulfonic acid, dropwises in the 1h, and temperature must not be higher than 20 ℃ in the bottle.Continue reaction 1h again, remove ice bath, add 40 ℃ water-bath, reaction 1h left and right sides discharging after filtering, washing with big water gaging, is drained, and promptly gets " chlorosulfonation GC-419a " adsorbent.
This adsorbing agent carrier characteristic, the cubical contraction under 0.026MPa pressure reduction, negative electrical charge content and outward appearance are listed in table 6; The sample adsorptivity is listed in table 7.
Carrier characteristics, cubical contraction, negative electrical charge content and the outward appearance of table 6.GC series adsorbent
| Project | Voidage (%) | Average pore size (nm) | Pore diameter range (nm) | Particle size range (μ M) | Cubical contraction (%) | Negative electrical charge content (μ eq/ml) | Outward appearance, form |
| GC-421a | 93.4 | 500 | 40~1500 | 35~80 | 11.3 | 127 | Canescence, the garden is spherical and few |
| (implementing 5) | Number ellipticity, concave-convex surface | ||||||
| GC-419a (comparative example 8) | 94 | 500 | 40~1500 | 35~85 | 12.0 | 100 | The same |
| Chlorosulfonation GC-419a (embodiment 6) | 94 | 500 | 40~1500 | 35-85 | 12.0 | 22 | The same |
Table 7.GC series adsorbents adsorb sample test result
| Adsorbent | CH clearance (%) | TG clearance (%) | HDL clearance (%) | LDL clearance (%) |
| GC-421a (embodiment 5) | 77.1 | 57.4 | 13.2 | 94.8 |
| GC-419a (comparative example 8) | 74.3 | 56.25 | 15.66 | 92.45 |
| Chlorosulfonation GC-419a (embodiment 6) | 54.9 | 29.9 | 10.1 | 81 |
Respectively show the explanation of listed test data by above:
1.CB serial adsorbent is with the decline of short lint cellulose xanthate acid solution (being the cellulose viscose) concentration of preparation gel particles, voidage, aperture and the increase of negative electrical charge content are risen to the adsorption rate of LDL, TG thereupon, and the adsorption rate of HDL is descended thereupon; Cubical contraction then descends and rises slightly with viscose glue concentration, but all below 20%, and the J27 cubical contraction reaches 30%, color is dark.Though adsorptivity little sample testing result and the CB-907a of J27 are close, in the dress column test, because of the squeezing action that water and blood plasma pass through, the adsorbent distortion, adsorbent layer is compacting gradually, thereby has stopped up passage, and process can't be carried out again.
2. the same with CB series for WC series adsorbent, decline with lignose xanthate acid solution (the being viscose) concentration for preparing gel particles, voidage, aperture and negative electrical charge content increase, adsorption rate to LDL-C, TG rises thereupon, and the adsorption rate of HDL-C is changed not quite, cubical contraction also descends and rises slightly with viscose glue concentration.For identical carrier, the ability of adsorbents adsorb TG, LDL-C is sulfuric acid dextran sodium salt, poly-(acrylic acid-co-2-acrylamido-2-methyl propane sulfonic acid), the decline of polyacrylic order according to part, and the quantitative changeization that absorbs HDL-C is little, all about 15%.Use the ratio of glutaraldehyde cross-linking agent no, not only increase operation, appearance poor, the ability of absorption LDL-C is also poor.
3.GC serial adsorbent is the same with WC series adsorbent, the cubical contraction of carrier descends and rises slightly with viscose glue concentration, for identical carrier, the direct negative anionic amount of sulfate little than the multi-anion copolymer of keyed jointing sulfuric acid dextran sodium salt on the chlorosulfonation band, the ability of absorption LDL-C is also little.
4. the viscose with same concentrations prepares carrier, when all being part with sulfuric acid dextran sodium salt, the adsorption rate of cholesterol is descended in proper order according to CG, WC, CB.
5. by table 7 as seen: be better than refrigerated plasma to the treatment effect of fresh plasma, dress post adsorption efficiency is higher than sample.Find that also the adsorption capacity of the wet adsorbent of every gram of the present invention increases with the increase of CH contained in the blood plasma, TG, LDL-C content and the growth of attached adsorption time.
Embodiment 7. is carrier with the polyvinyl alcohol gel particle, and polyacrylic acid is a part " carboxylated PVA adsorbent " preparation
A. the preparation of polyvinyl alcohol gel particle:
In the 1000ml four neck flasks of being furnished with condenser pipe, two dropping funels, nitrogen ingress pipe, thermometer and agitators, add 100g vinyl acetate, 7g polyvinyl acetate (Mn=20000) and 100g ethyl acetate solvent, stirring, make be dissolved into homogeneous solution after, pour the 420ml aqueous solution that is dissolved with polyvinyl alcohol 4.38g, 0.18g sodium dihydrogen phosphate dihydrate and 5.25g sodium hydrogen phosphate dodecahydrate again into, stir fast.The 15g triallyl isocyanurate is dissolved in the 50g ethyl acetate solvent, pours in the dropping funel.In another dropping funel, add the 3.8g azodiisobutyronitrile that is dissolved in the 200ml ethyl acetate.Logical nitrogen, be warming up to 70 ℃ after, beginning drips crosslinking agent and initiator solution simultaneously, dropwises in 5h, continues reaction 5h down at 75～80 ℃ then, microgranular copolymer.Stop heating, after the cooling, filter, through water, alcohol flushing, drain, be dipped in again in the acetone after the night, after filtering, drain, blowing two hours in 40 ℃ of baking ovens, put into large beaker, pour 21 the methanol solution that contains 46.5g again into, seal in the beaker with film,, finish the ester exchange reaction (or claiming alcoholysis reaction) of copolymer in 40 ℃ of 20h that vibrate down.After filtration, the water flushing, use alcohol immersion, flushing, 40 ℃ of dry backs, standby again.
B. the priming reaction of polyvinyl alcohol gel particle:
Polyvinyl alcohol (PVA) the gel particles 20g that takes by weighing the drying that makes among a. pours the four neck flasks of adorning the 120ml methyl-sulfoxide into, the NaOH aqueous solution that adds 17.2ml epoxychloropropane and 20ml 30% concentration again, under 30 ℃, stirring reaction 5h, filtration, water and ethanol wash repeatedly, drain, and soak with methyl-sulfoxide again, suction filtration, drying must activate PVA gel pellet.
C. end is amino polyacrylic preparation:
Identical with method described in the embodiment 3, gained polyacrylic acid number-average molecular weight is 20000.
Table 5. dress post absorption result
D. cross-linking reaction:
Take by weighing activation PVA gel pellet 4g made among the top b and place four neck flasks, pour the 1.36g polyacrylic acid again into and be dissolved in the aqueous solution 40ml that contains 0.1mol/L concentration sodium carbonate, 70 ℃ of following stirring reactions one day filter, the water flushing, drain i.e. " carboxylated PVA adsorbent ".
Cubical contraction under 0.026MPa pressure reduction of carrier characteristics of this adsorbent " carboxylated PVA " and adsorbent, the test result of negative electrical charge content are listed in table 8, and sample adsorptivity testing result is listed in table 9.
Comparative example 9
With polyvinyl alcohol (PVA) gel particles is carrier, and poly-(acrylic acid-co-2-acrylamido-2-methyl propane sulfonic acid) [P (AA-AMPS)] is the preparation of " the carboxylic sulfo group PVA adsorbent " of part
The prepared activation polyvinyl alcohol gel of the b particle 4g that takes by weighing embodiment 7 puts into four neck flasks, claim that more poly-(acrylic acid-co-2-acrylamido-2-methyl propane sulfonic acid) 1.5g of prepared terminal band active group-amino pours four neck flasks into after being dissolved in the 40ml aqueous solution among the embodiment 4,70 ℃ of following stirring reaction diels, cooling, filtration, water repeatedly towards Xian, drain.
Cubical contraction under 0.026MPa pressure reduction of carrier characteristics that should " carboxylic sulfo group PVA adsorbent " and adsorbent, the test result of negative electrical charge content are listed in table 8, and sample adsorptivity testing result is listed in table 9.
Embodiment 8
With the polyvinyl alcohol gel particle is carrier, and sulfuric acid dextran sodium salt is the PVA-610 adsorbent that part makes.
Take by weighing activation sulfuric acid dextran sodium salt 12ml that the activation PVA gel pellet 4g that makes among the b of embodiment 7 and embodiment 2 make with method in four necks and in, 70 ℃ of following stirring reactions spend the night, cooling, filtration, water wash repeatedly, drain.
Cubical contraction under 0.026MPa pressure reduction of the carrier characteristics of this PVA-610 adsorbent and adsorbent, the test result of negative electrical charge content are listed in table 8, and sample adsorptivity testing result is listed in table 9.
Embodiment 9. is a carrier with the polyvinyl alcohol gel particle, and chlorosulfonic acid is the preparation of " the chlorosulfonation PVA adsorbent " of part
Take by weighing the PVA gel pellet that makes among a of embodiment 7 and be soaked in 12h in the ethanol, behind filtration, usefulness alcohol flushing, the suction filtration, in 10 ℃ of oven dry.Get the pellet 8g of 10g oven dry, 100ml four necks that are added to band dropping funel, condenser pipe, thermometer and stirring rod also in, add 26ml N, dinethylformamide again, reaction bulb adds ice-water bath, when reaching 5 ℃ in the bottle, stir down, the 2ml chlorosulfonic acid that is loaded in the dropping funel slowly is added dropwise to reaction bulb, temperature must not be higher than 20 ℃ in the bottle.After dropwising, continue reaction 1h, remove ice bath, modify-water stops reaction after bathing, be warming up to 40 ℃ of reaction 1h, discharging, filtration, wash, drain, promptly get " chlorosulfonation PVA adsorbent " with big water gaging.
The test result of the carrier characteristics of this " chlorosulfonation PVA adsorbent ", cubical contraction, negative electrical charge content is listed in table 8, and the sample adsorptivity is listed in table 9.
Carrier characteristics, cubical contraction, negative electrical charge content and the outward appearance of table 8.PVA series adsorbent
| Project | Voidage (%) | Average pore size (nm) | Pore diameter range (nm) | Particle size range (μ m) | Cubical contraction (%) | Negative electrical charge content (μ eq/ml) | Outward appearance, form |
| Carboxylated PVA (embodiment 7) | 68 | 1000 | 20～1500 | 50～100 | 76 | 41 | Canescence, the spherical and minority ellipticity in garden, concave-convex surface |
| Carboxylic sulfo group PVA (comparative example 9) | The same | The same | The same | The same | The same | 38 | The same |
| PVA-610 (embodiment 8) | The same | The same | The same | The same | The same | 30 | The same |
| Chlorosulfonation PVA (embodiment 9) | The same | The same | The same | The same | The same | 10 | The same |
Table 9.PVA series adsorbents adsorb sample test result
| Adsorbent | CH clearance (%) | TG clearance (%) | HDL clearance (%) | LDL clearance (%) |
| Carboxylated PVA (embodiment 7) | 31.55 | 44.77 | 12.20 | 34.78 |
| Carboxylic sulfo group PVA (comparative example 9) | 38.39 | 22.58 | 10.00 | 48.97 |
| PVA-610 (embodiment 8) | 60.19 | 68.83 | 13.41 | 69.57 |
| Chlorosulfonation PVA (embodiment 9) | 11.78 | 20.92 | 3.66 | 13.77 |
Table 8 and 9 data show:
1. in the PVA series adsorbent of the present invention, the same with cellulose series adsorbent, because of the part difference,, descend in proper order according to part dextran sulfuric ester sodium salt, poly-(acrylic acid-co-2-acrylic acid amido-methyl propane sulfonic acid), polyacrylic acid, chlorosulfonic acid to the adsorptivity difference of LDL-C.This is by their negative electrical charge content and the decision of anionic electronegativity, and when the anionic electrodeposition negativity was identical, negative electrical charge content was high more, and is strong more to the adsorptivity of LDL-C; And negative electrical charge content is when close, and anionic electronegativity is strong more, and is high more to the adsorption capacity of LDL-C.
2.. it is the cellulose series adsorbent of carrier with the cellulose fine particle that PVA of the present invention series adsorbent is lower than corresponding to the adsorption capacity of LDL-C.The porosity that this porosity with the carrier-PVA microballoon of PVA series adsorbent of the present invention is lower than cellulose fine particle of the present invention is relevant.Believe further effort, we can improve the porosity of PVA microballoon, are the adsorption capacity of the serial adsorbent of carrier thereby further improve with the PVA microballoon.
Claims (8)
1. one kind is used for the adsorbent that low-density lipoprotein is removed in the blood extracorporal circulatory system, it is characterized in that: it is that cellulose gel particle with hard is a carrier, be connected with expoxy propane by the oxygen carbon bond, be connected with hexamethylene diamine by carbonnitrogen bond again, by nitrogen carbon bond and adsorbent as the activation sulfuric acid dextran sodium salt low-density lipoprotein that be connected, that have negative electrical charge of part, the cellulose gel particle of described hard is a grass cellulose gel particle at last.
2. adsorbent according to claim 1 is characterized in that: the cellulose gel particle of described hard is under the pressure reduction of 200mmHg, and cubical contraction is less than or equal to 15% cellulose gel particle.
3. adsorbent according to claim 1 is characterized in that: the cellulose gel particle of described hard is under the pressure reduction of 200mmHg, and cubical contraction is 12～10% cellulose gel particle.
4. adsorbent according to claim 1 is characterized in that: the described adsorbent that has the low-density lipoprotein of negative electrical charge, its amount that has negative electrical charge are that every milliliter of wet adsorbent contains 1 μ eq～1meq.
5. adsorbent according to claim 1 is characterized in that: the described adsorbent that has the low-density lipoprotein of negative electrical charge, its amount that has negative electrical charge are that every milliliter of wet adsorbent contains 10 μ eq～200 μ eq.
6. adsorbent according to claim 1 is characterized in that: the particle diameter of the cellulose gel particle of hard is 10 μ m～200 μ m.
7. adsorbent according to claim 5 is characterized in that: the particle diameter of the cellulose gel particle of hard is 30 μ m～150 μ m.
8. method for preparing the described adsorbent of claim 1, it is characterized in that: the cellulose gel particle that will have epoxide group carries out cross-linking reaction with the part that has amino under 70～80 ℃ in water, promptly get and be used for the adsorbent that low-density lipoprotein is removed in the blood extracorporal circulatory system, described to have amino part be 1, that the 6-hexamethylene diamine connects, through the sulfuric acid dextran sodium salt of epoxychloropropane activation.
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