CN108371945A - For in removing in uremic patient body, the adsorbent of macromolecular toxins and preparation method - Google Patents
For in removing in uremic patient body, the adsorbent of macromolecular toxins and preparation method Download PDFInfo
- Publication number
- CN108371945A CN108371945A CN201810417115.9A CN201810417115A CN108371945A CN 108371945 A CN108371945 A CN 108371945A CN 201810417115 A CN201810417115 A CN 201810417115A CN 108371945 A CN108371945 A CN 108371945A
- Authority
- CN
- China
- Prior art keywords
- adsorbent
- carrier
- blood
- chloromethylation
- aglucon
- 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
Classifications
-
- 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
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/22—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising organic material
- B01J20/26—Synthetic macromolecular compounds
- B01J20/265—Synthetic macromolecular compounds modified or post-treated polymers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
- A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
- A61M1/3687—Chemical treatment
-
- 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
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
- B01J20/28014—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their form
- B01J20/28016—Particle form
- B01J20/28021—Hollow particles, e.g. hollow spheres, microspheres or cenospheres
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M2202/00—Special media to be introduced, removed or treated
- A61M2202/04—Liquids
- A61M2202/0413—Blood
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Analytical Chemistry (AREA)
- Vascular Medicine (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Anesthesiology (AREA)
- Biomedical Technology (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Cardiology (AREA)
- General Chemical & Material Sciences (AREA)
- Solid-Sorbent Or Filter-Aiding Compositions (AREA)
- External Artificial Organs (AREA)
Abstract
For in removing in uremic patient body, the adsorbent of macromolecular toxins and preparation method.According in, macromolecular toxins such as β2Microglobulin (β2MG), parathormone (PTH), Advanced glycation endproducts (AGEs), homocysteine (Hcy) and interleukin 6 (IL 6) equimolecular size and its performance characteristic, utilization is devised using mesoporous polystyrene type hydrophobic resin as carrier, main β in energy high efficiency removing urotoxin blood samples of patients is prepared by being chemically crosslinked grafted ethene amine aglucon after chloromethylation activates2In MG, PTH, AGEs, Hcy and IL 6 etc., the functional adsorbent of macromolecular toxins, which has that adsorption capacity is big, mechanical strength is good, good biocompatibility and high adsorptive selectivity.The adsorbent is used for hemoperfusion treatment uremic mass formed by blood stasis, can take length mutually with the main blood filtering for removing small molecule toxins, combining hemoperfusion treatment uremia for haemodialysis provides a kind of new method.
Description
Technical field：
The invention belongs to biomedicine technical fields.More particularly to a kind of novel Medical Adsorbents, it is particularly suitable for
Blood perfusion remove in uremic patient body in, the adsorbents and preparation method thereof of macromolecular toxins.
Technical background：
Uremia is because the gradual irreversibility decline of renal function caused by the various kidney troubles of internal body, finally leads
It causes renal function to lose, prevents internal metabolic waste from the Comprehensive Clinical for a series of complex for being discharged, largely assembling and generating in time
Disease.Uremia may lead to patient's Water-Electrolyte and acid-base unbalance, angiocardiopathy, the nervous system disease, respiratory system
The complication such as disease and gastrointestinal tract disease, pruitus seriously affect the physical and mental health and life security of patient.It is currently known uremic
There are about the concentration ratio normal persons of 200 many kinds of substance to want high for disease patient's body, it has now been found that possibility there is uremia toxic effect
Substance just have as many as tens of kinds, be the pathogenic independent hazard factor of heart disease as AGEs, Hcy increase.β2- MG accumulation causes to form sediment
Powder sample becomes and carpal tunnel syndrome, and PTH accumulation causes renal osteodystrophy, the accumulation that increases of heterotopic calcification, IL-6 to lead to whole body chronic inflammation
Disease is reacted, and more and more that researches show that these inflammatory reactions is related with artery sclerosis, malnutrition.
Blood purification is still the uremic main method of current clinical treatment, haemodialysis (HD), blood perfusion (HP) and
Blood perfusion (HF+HP) etc. is combined in haemodialysis, and wherein haemodialysis is to apply disperse biological principle, is primarily used to remove and be suffered from
Small-molecule substance such as urea and creatinine etc. in person's body, but to big, middle molecule toxins elimination effect is bad.Blood perfusion is that blood is borrowed
Body aid outer circulation removes morbid substance in blood by specific adsorbent equipment, restores blood normal index, it is net to reach blood
A kind of therapy changed.Compared with the haemodialysis for mainly removing solute by diffusion way, blood perfusion is not only pair and egg
The white high poisonous substance of Percentage bound and fat-soluble poisonous substance have higher scavenging effect while also having certain free poisonous substance removed in blood
Effect, in can effectively removing in uremic patient body, macromolecular toxins such as β2- MG, PTH, AGEs, Hcy and IL-6
Deng, there is preferable application value, it is worth to carry out clinical expansion and application.
Blood perfusion require adsorbent blood compatibility is good, high specificity, large amount of adsorption etc., wherein key be aglucon and
The selection of carrier.It is mainly used for blood perfusion at this stage and removes the active charcoal of uremic adsorbent, chitosan (such as:
201410627562.9 wait) and polystyrene-divinylbenzene resin etc..But activated carbon class adsorbent and chitosan crosslinked resin
Selectivity it is poor, bad mechanical strength is broken, and pressure drop is big, not easy to operate, perfusing course resin possibly into blood, from
And cause the serious consequences such as blood coagulation, platelet adhesion reaction.In comparison polystyrene-divinylbenzene microspheres are a kind of widely applied
Bio-medical material has good blood compatibility, mechanical strength, chemical inertness, adjustable pore structure, big specific surface area
With the active group for coupling aglucon.At the same time in, macromolecular nosotoxin, in addition to requiring suitable specific surface
Product, it is necessary to there is larger aperture, usually 2-6 times of adsorption molecule diameter, it is freely in or out convenient for toxin to be adsorbed
Absorbent interior duct.In view of macromolecular toxins belong to albumin combination toxin more, and the molecular diameter of albumin is about
6.5nm, so, it is to grind to synthesize the polystyrene-divinylbenzene microspheres with abundant meso-hole structure to improve absorption property
The emphasis studied carefully.In addition, polystyrene adsorption resin synthesis technology is simple, it is used as blood perfusion adsorbent, can be effectively reduced
Whole treatment cost so that more patients can afford heavy expense.Therefore, the present invention has first tentatively synthesized and has had
The polystyrene-divinylbenzene microspheres of abundant meso-hole structure, while in view of the isoelectric point of lps molecule, then passing through function base
Change reaction and is prepared for a series of amino-containing polystyrene-divinylbenzene microspheres adsorbents.Pass through hydrophobic effect and electrostatic with this
Act on dual adsorption effect come efficiently remove in uremic patient body in, macromolecular toxins.
Invention content：
It is an object of the invention to overcome deficiencies of the prior art, a kind of removing urotoxin patient's body is provided
In, macromolecular toxins adsorbent and preparation method thereof, by the polystyrene type resin surface grafting aglucon in activation, specifically with
The polystyrene type resin of meso-hole structure is grafted vinylamine aglucon (polyethylene polyamine as carrier after chloromethylation activates
(HPAX), pentaethylene hexamine (PEHA), tetraethylenepentamine (TPA), triethylene tetramine (TTA), diethylenetriamine (ETA), second two
Amine (EDA) or aminoethylpiperazine (AEP) etc. are prepared into adsorbent.The adsorbent has good biocompatibility, chemistry steady
Qualitative, mechanical strength and higher absorption property and highly selective and specific, can be used for blood perfusion adsorbent.
Technical scheme of the present invention
For in removing in uremic patient body, macromolecular toxins adsorbent, be one kind by carrier and aglucon two parts group
At functional adsorbent, be using the styrene type resin of the meso-hole structure of activation as carrier, using vinylamine as aglucon, with chloromethane
Ether activated carrier makes carrier be made up of covalent coupling with aglucon, has higher adsorptive selectivity, which can be effective
Removing urotoxin blood samples of patients or blood plasma in, macromolecular toxins, be suitable for blood or plasma perfusion treatment uremic blood
Disease simultaneously can be used for whole blood perfusion.
The styrene type resin carrier of the meso-hole structure of the activation is spherical shape, and granularity is between 200-1000 μm, preferably
500-800μm；Chloromethylation content is between 3-8mmoL/g on carrier, preferably 4-7mmoL/g.
The carrier possesses flourishing meso-hole structure and possesses high-specific surface area simultaneously, and specific surface area is in 300-800m2/g
Between, preferably 600-750m2/g；Average pore size is between 5-50nm, preferably 20-50nm.
The vinylamine aglucon include polyethylene polyamine (HPAX), pentaethylene hexamine (PEHA), tetraethylenepentamine (TPA),
Triethylene tetramine (TTA), diethylenetriamine (ETA), ethylenediamine (EDA) or aminoethylpiperazine (AEP) etc., preferably five ethylene six
Amine (PEHA), diethylenetriamine (ETA) or ethylenediamine (EDA).
Provided by the present invention in removing in uremic patient body, the adsorbents of macromolecular toxins, preparation process packet
Include following steps：
1. the synthesis of carrier microballoons, that is, meso-hole structure polystyrene type resin：
By monomer styrene and crosslinking agent divinylbenzene by weight 1：2-6 is uniformly mixed, then accounts for list by weight addition
The pore-foaming agent of 1-5 times of body and crosslinking agent total weight, pore-foaming agent are 3 in mass ratio by toluene, ethyl acetate and gasoline：1：0.4-1
Mix, add in mass ratio account for reaction monomers, crosslinking agent and pore-foaming agent gross mass 0.5%-1.5% initiator peroxide
Change benzoyl, referred to as oil phase；Then the oil-based system solution is added to the polyvinyl alcohol that mass percent is 0.5%-2%
In the water phase of solution, wherein the mass ratio of water phase and oil phase is 1-2.5：1, stir speed (S.S.) is adjusted, after being warming up to 40-50 DEG C, with
3-5 DEG C/10min is warming up to 70-80 DEG C, continues to keep 3-5h at this temperature after sizing, then slow with the speed of 1-2 DEG C/5min
It is slow to be warming up to 90-95 DEG C, 3-8h is reacted, stops heating and stirring, reaction system is after filtering, extracting, carrying out washing treatment, in 4 DEG C
Hygrometric state preserves, spare, obtains meso-hole structure polystyrene type resin.
2. the chloromethylation of carrier microballoons：Chloromethylation is carried out to polymer microballoon with known reagent and method, specifically
Step is the carrier microballoons resin 20g (dry weight) for taking step 1 to prepare, and is added to the three-necked flask equipped with blender and thermometer
In, chloromethyl ether 80mL, CCl are added into reactor4Three-necked flask is placed in ultrasonic response by 300mL after standing swelling 12h
In device, the 5gAlCl of drying process is added into three-necked flask3, at 40 DEG C, after being stirred to react 12h, reaction was completed.Use ethyl alcohol
And deionized water washed product, until AgNO is added into cleaning solution3It is generated to get chloromethylation meso-hole structure without precipitation after solution
Polystyrene type carrier microballoons, chlorinity 3-8mmoL/g.
3. carrier conjugation aglucon：The polystyrene type carrier microballoons of chloromethylation meso-hole structure prepared by step 2 are added
Into DMF solution solution, after room temperature is swollen 8-12h, ethylenediamine solution, wherein polystyrene type carrier, DMF and vinylamine is added
Mass ratio be 0.1-0.2：1.9-5.69：Then 0.5-2 adds the NaOH solution of 30-50mL, 3mol/L in 60-80 DEG C
Lower reaction 6-10h is filtered, is fully cleaned with ethyl alcohol, deionized water successively, is preserved in 4 DEG C of hygrometric states, spare, obtains blood plasma or blood
In in perfusion uremic patient body, the adsorbent of macromolecular toxins.
Ethyl alcohol cleaning described in step 3 of the present invention refers to, and 3 times or more abundant cleanings is first carried out with ethyl alcohol, then dense with gradient
After spending the ethyl alcohol cleaning successively decreased, carry out with deionized water 3 times or more abundant cleanings again, in preferred technical solution, adsorbent
It first passes through after ethyl alcohol fully elutes, is eluted again with deionized water after being washed successively with 70%, 30%, 15% ethyl alcohol.
The advantages of the present invention
The present invention is according to big, middle molecule toxins such as β2- MG, PTH, AGEs, Hcy and IL-6 equimolecular size and its performance
Feature, and efficiency and strength problem existing for current adsorbent, design has been synthesized uses suspension copolymerization by monomer of styrene
The polystyrene type carrier microballoons of the synthesising mesoporous structure of method, fix vinylamine aglucon after chloromethyl activated, are prepared for having
The adsorbent of abundant meso-hole structure and high-specific surface area.The adsorbent can not only utilize the hydrophobic forces of styrene skeleton,
In alloing, macromolecular toxins are freely accessible to absorbent interior, and can utilize the electrostatic between vinylamine and lps molecule
Interaction force forms specific adsorption, to greatly improve the adsorption capacity of adsorbent centering, macromolecular toxins.Absorption is real
Test and show that adsorbent of the invention has excellent adsorption capacity to the big, middle molecule toxins in uremia blood, can safely,
It is effectively used for hemoperfusion treatment or blood filtering joint hemoperfusion treatment uremia etc..
Description of the drawings：
Fig. 1 adsorbents are to static state β in patients serum2The determining adsorption of-MG, PTH, AGEs, Hcy, IL-6 and total protein.
Fig. 2 adsorbents are to β in patients serum2The Dynamic Adsorption of-MG measures.
Fig. 3 adsorbents measure the Dynamic Adsorption of PTH in patients serum.
Fig. 4 adsorbents measure the Dynamic Adsorption of AGEs in patients serum.
Fig. 5 adsorbents measure the Dynamic Adsorption of Hcy in patients serum.
Fig. 6 adsorbents measure the Dynamic Adsorption of IL-6 in patients serum.
Specific implementation mode：
Embodiment 1
(1) prepared by carrier microballoons
15.4g styrene and 84.6g divinylbenzenes are added in the beaker of 1000mL, then 327.3g first is added thereto
Benzene, 109.1g ethyl acetate and 43.6g gasoline and 6.96g benzoyl peroxides, stir to dissolve, it is to be dissolved completely after, fill
Divide and be mixed, obtains organic phase.At normal temperatures, will be added in the three-necked flask of 2000mL 11.02g polyvinyl alcohol and 580mL go from
Sub- water, is made into the aqueous solution of the polyvinyl alcohol of 1.9% (mass fraction), and heating stirring keeps polyvinyl alcohol fully molten to 45 DEG C
Solution, obtains water phase, stops stirring, by obtain it is uniformly mixed it is organic be added in water phase, start blender, adjust stirring speed
Rate makes even droplet distribution, after being warming up to 50 DEG C, after being warming up to 80 DEG C with 5 DEG C/10min, drop is made to shape, after undetermined type
Continue to keep 3h at this temperature, then 95 DEG C are to slowly warm up to the speed of 1 DEG C/5min, reacts 5h, then stop experiment, mistake
Filter obtains the polystyrene type carrier microballoons of meso-hole structure with hot water wash ball after extracting pore-foaming agent.Grain size 0.5-0.8mm is put down
Equal aperture 11.2nm, specific surface area 769m2/g。
(2) chloromethylation of carrier microballoons
The polystyrene type carrier microballoons 20g (dry weight) for taking the meso-hole structure of step (1) preparation, is added to equipped with blender
In the three-necked flask of thermometer, chloromethyl ether 80mL, CCl are added into reactor4300mL, after standing swelling 12h, Jiang Sankou
Flask is placed in ultrasound reactor, and the 5gAlCl of drying process is wherein added to three-necked flask3, at 40 DEG C, it is stirred to react
After 12h, reaction was completed.With ethyl alcohol and deionized water washed product, until AgNO is added into cleaning solution3It is produced without precipitation after solution
The raw polystyrene-divinylbenzene carrier microballoons to get chloromethylation, chlorinity are finally 6.85mmoL/g.
(3) carrier conjugation aglucon
Take the polystyrene type carrier microballoons 5g that step (2) prepares chloromethylation meso-hole structure that 94.8gDMF solution is added,
After room temperature is swollen 12h, 87.4g pentaethylene hexamines (PEHA) are added, the NaOH solution of 48mL, 3mol/L are reacted at 80 DEG C
6.5h is filtered, and is first passed through after ethyl alcohol fully elutes, is washed with deionized water again after being eluted successively with 70%, 30%, 15% ethyl alcohol
Only, it is preserved in 4 DEG C of hygrometric states, spare, number PS-PEHA.
Embodiment 2
(1) prepared by carrier microballoons
30g styrene and 120g divinylbenzenes are added in the beaker of 1000mL, then be added thereto 189.5g toluene,
63.2g ethyl acetate and 47.3g gasoline and 4.5g benzoyl peroxides, stir to dissolve, it is to be dissolved completely after, it is fully mixed
, organic phase is obtained.At normal temperatures, 9g polyvinyl alcohol and 900mL deionized waters will be added in the three-necked flask of 2000mL, is made into
The aqueous solution of the polyvinyl alcohol of 1% (mass fraction), and heating stirring makes polyvinyl alcohol fully dissolve to 45 DEG C, obtains water phase,
Stop stirring, by obtain it is uniformly mixed it is organic be added in water phase, start blender, adjust stir speed (S.S.), make drop point
Cloth is uniform, after being warming up to 46 DEG C, after being warming up to 75 DEG C with 4 DEG C/10min, drop is made to shape, after undetermined type at this temperature after
4h is held in continuation of insurance, then is to slowly warm up to 92 DEG C with the speed of 2 DEG C/5min, is reacted 7.5h, is then stopped experiment, filter, use hot water wash
Ball obtains the polystyrene type carrier microballoons of meso-hole structure after extracting pore-foaming agent.Grain size 0.5-0.8mm, average pore size
12.8nm, specific surface area 754.9m2/g。
(2) chloromethylation of carrier microballoons
The polystyrene type carrier microballoons 20g (dry weight) for taking the meso-hole structure of step (1) preparation, is added to equipped with blender
In the three-necked flask of thermometer, chloromethyl ether 80.0mL, CCl are added into reactor4300mL, after standing swelling 12h, by three
Mouth flask is placed in ultrasound reactor, and the 5gAlCl of drying process is wherein added to three-necked flask3, at 40 DEG C, stirring is anti-
After answering 12h, reaction was completed.With ethyl alcohol and deionized water washed product, until AgNO is added into cleaning solution3It is produced without precipitation after solution
The raw polystyrene-divinylbenzene carrier microballoons to get chloromethylation, chlorinity are finally 6.51mmoL/g.
(3) carrier conjugation aglucon
Take the polystyrene type carrier microballoons 8g that step (2) prepares chloromethylation meso-hole structure that 209gDMF solution is added, often
After temperature swelling 10h, 76.7g diethylenetriamines (ETA) are added, the NaOH solution of 32mL, 3mol/L react 8h at 75 DEG C,
It filters, first passes through after ethyl alcohol fully elute, be washed with deionized water again after being eluted successively with 70%, 30%, 15% ethyl alcohol only, in 4
DEG C hygrometric state preserves, spare, number PS-ETA.
Embodiment 3
(1) prepared by carrier microballoons
28.6g styrene and 71.4g divinylbenzenes are added in the beaker of 1000mL, then 120g first is added thereto
Benzene, 30g ethyl acetate and 30g gasoline and 2g benzoyl peroxides, stir to dissolve, it is to be dissolved completely after, be fully mixed, obtain
To organic phase.At normal temperatures, 7.5g polyvinyl alcohol and 450mL deionized waters will be added in the three-necked flask of 2000mL, is made into
The aqueous solution of the polyvinyl alcohol of 1.5% (mass fraction), and heating stirring makes polyvinyl alcohol fully dissolve to 45 DEG C, obtains water
Phase stops stirring, by obtain it is uniformly mixed it is organic be added in water phase, start blender, adjust stir speed (S.S.), make drop
It is evenly distributed, after being warming up to 42 DEG C, after being warming up to 70 DEG C with 3 DEG C/10min, drop is made to shape, after undetermined type at this temperature
Continue to keep 3.5h, then 94 DEG C are to slowly warm up to the speed of 1 DEG C/5min, reacts 8h, then stop experiment, filter, use hot water
Ball is washed, after extracting pore-foaming agent, obtains the polystyrene type carrier microballoons of meso-hole structure.Grain size 0.5-0.8mm, average pore size
13.4nm, specific surface area 726.1m2/g。
(2) chloromethylation of carrier microballoons
The polystyrene type carrier microballoons 20g (dry weight) for taking the meso-hole structure of step (1) preparation, is added to equipped with blender
In the three-necked flask of thermometer, chloromethyl ether 80mL, CCl are added into reactor4300mL, after standing swelling 12h, Jiang Sankou
Flask is placed in ultrasound reactor, and the 5gAlCl of drying process is wherein added to three-necked flask3, at 40 DEG C, it is stirred to react
After 12h, reaction was completed.With ethyl alcohol and deionized water washed product, until AgNO is added into cleaning solution3It is produced without precipitation after solution
The raw polystyrene-divinylbenzene carrier microballoons to get chloromethylation, chlorinity are finally 5.91mmoL/g.
(3) carrier conjugation aglucon
Take the polystyrene type carrier microballoons 10g that step (2) prepares chloromethylation meso-hole structure that 285gDMF solution is added,
After room temperature is swollen 11h, 54g ethylenediamines (EDA) are added, the NaOH solution of 40mL, 3mol/L react 10h at 60 DEG C, take out
Filter is first passed through after ethyl alcohol fully elute, is washed with deionized water again after being eluted successively with 70%, 30%, 15% ethyl alcohol only, in 4 DEG C
Hygrometric state preserves, spare, number PS-EDA.
Embodiment 4
Adsorbent is to β in serum2The Static Adsorption experiment of-MG, PTH, AGEs, Hcy and IL-6
5mL urine is added in centrifuge tube in each 0.5mL of adsorbent PS-PEHA, PS-ETA, PS-EDA in Example 1,2,3
Blood serum sample (the β in sample of toxication patient2- MG concentration is about 55.28mg/L, a concentration of 245.28pg/mL of PTH, AGEs concentration
For μ × 10 760.17A-3/ mg, Hcy concentration are about 30.46 μm of oL/L, and IL-6 concentration is about 315.69pg/mL), sealed membrane is close
Envelope, in air table, 37 DEG C of concussion absorption 2h.After the completion of absorption, 1000rpm/min centrifuges 1min, and centrifugation takes upper liquid to survey
Its fixed concentration, absorption result are shown in attached drawing 1.
Embodiment 5
Measurement of the adsorbent to total protein in serum
In Example 1,2,3 in adsorbent PS-PEHA, PS-ETA, PS-EDA each 0.5mL of adsorbent in centrifuge tube,
The blood serum sample (total protein concentration is about 58.33mg/L in sample) of 5mL uremic patients, sealed membrane sealing, in air is added
In shaking table, 37 DEG C of concussion absorption 2h.After the completion of absorption, 1000rpm/min centrifuges 1min, and centrifugation takes upper liquid dense in measuring its
Degree.
Absorption result is shown in attached drawing 1.
Embodiment 6
Adsorbent is to β in serum2The dynamic adsorption test of-MG, PTH, AGEs, Hcy and IL-6
Adsorbent 2mL is in adsorption column in Example 3, connects the blood serum sample (β in sample of dialysis patient2- MG concentration
A concentration of μ × 10 760.17A about 55.28mg/L, PTH a concentration of 245.28pg/mL, AGEs-3/ mg, Hcy concentration is about
30.46 μm of oL/L, IL-6 concentration are about 315.69pg/mL) and constant flow pump, perfusion rate 1.0mL/min, Hemoperfusion time be
180min takes upper serum sample to survey in 10min, 30min, 60min, 90min, 120min, 150min and 180min respectively
Its fixed concentration.
Absorption result is shown in attached drawing 2,3,4,5 and 6 respectively.
Embodiment 7
The clotting assay of adsorbent
New southwestern White Rabbit is fixed, rapid heart blood sampling 6mL is distributed into rapidly 3.2% sodium citrate anticoagulant blood-collecting
Guan Zhong centrifuges 10min after mixing and obtains upper plasma at 3,000 rpm.1.5mL blood plasma is respectively taken to be added in 4 small test tubes, wherein three
Branch is separately added into each 0.15g of adsorbent PS-PEHA, PS-ETA, PS-EDA, mixing in embodiment 1,2,3 and is then filled all
The small test tube of blood plasma is totally submerged in 37 DEG C of water-bath, the blood plasma of sample of sorbent will be added to be sucked out after 1h, same not add adsorbent
Blood plasma measures Activated partial thromboplastin time (APTT) on automatic coagulation analyzer, prothrombin time (PT), coagulates together
Blood zymogen time international standardization ratio (PT-INR) and fibrinogen (FIB).
Coagulation results are shown in Table 1：
Table 1：The coagulant property of adsorbent is tested
It was found from haemolysis result in table：With after adsorbent effect, partial activation prothrombin time has obtained a little blood plasma
Extend, but within clinical reference range, thrombin time and prothrombin time international standardization ratio are also slightly prolonged
It is long.Show that adsorbent has preferable anti-freezing performance, is unlikely to cause Coagulation test.The level of fibrinogen slightly lowers, table
Bright adsorbent does not have apparent suction-operated to fibrinogen.
Embodiment 8
The static platelet adhesion reaction of adsorbent is tested
Each 0.1g of adsorbent PS-PEHA, PS-ETA, PS-EDA in embodiment 1,2,3 is weighed, it is abundant with sodium chloride injection
1mL is added after flushing and is rich in blood platelet rabbit blood blood plasma, after 37 DEG C of water-bath 1h, 20 μ L is taken to measure blood in blood cell analyzer respectively
Platelet index changes, and as a result see the table below 2：
Table 2：The platelet adhesion reaction performance of adsorbent is tested
。
Claims (9)
1. it is a kind of for remove in urotoxin patient's body, the adsorbent of macromolecular toxins, it is characterised in that the adsorbent is one
For kind by carrier and aglucon functional adsorbent dimerous, the carrier is the styrene type tree of the meso-hole structure of activation
Fat, the aglucon are vinylamine, and aglucon passes through covalent coupling with carrier in the adsorbent；The adsorbent prepares simple, cost
It is cheap, there is higher adsorptive selectivity, in capable of effectively removing in urotoxin blood samples of patients or blood plasma, macromolecular toxins, fit
Preferably it is used for blood or plasma perfusion treatment uremic mass formed by blood stasis.
2. adsorbent according to claim 1, which is characterized in that the carrier is the styrene of chloromethylation meso-hole structure
Type resin, for spherical shape, granularity is between 200-1000 μm, and chloromethylation content is between 3-8mmoL/g on carrier.
3. adsorbent according to claim 2, which is characterized in that preferred 500-800 μm of carrier fractions, chloromethyl on carrier
Change the preferred 4-7mmoL/g of content.
4. adsorbent according to claim 1, which is characterized in that the carrier possesses flourishing meso-hole structure and gathers around simultaneously
There is high-specific surface area, specific surface area is in 300-800m2Between/g, average pore size is between 5-50nm.
5. adsorbent according to claim 4, which is characterized in that the preferred 600-750m of carrier specific surface area2/ g is put down
Equal aperture is preferably in 20-50nm.
6. adsorbent according to claim 1, which is characterized in that the vinylamine aglucon includes polyethylene polyamine
(HPAX), pentaethylene hexamine (PEHA), tetraethylenepentamine (TPA), triethylene tetramine (TTA), diethylenetriamine (ETA), second two
Amine (EDA) or aminoethylpiperazine (AEP) etc..
7. adsorbent according to claim 6, which is characterized in that the preferred pentaethylene hexamine of vinylamine aglucon
(PEHA), diethylenetriamine (ETA) or ethylenediamine (EDA).
8. it is used to remove in urotoxin patient's body described in claim 1, the preparation method of the adsorbent of macromolecular toxins, it is special
Sign is that preparation includes the following steps：
The synthesis of 1st step, carrier microballoons meso-hole structure polystyrene type resin
By monomer styrene and crosslinking agent divinylbenzene by weight 1：2-6 be uniformly mixed, then by weight addition account for monomer and
The pore-foaming agent of 1-5 times of crosslinking agent total weight, pore-foaming agent are 3 in mass ratio by toluene, ethyl acetate and gasoline：1：0.4-1 is mixed
It forms, adds the initiator benzoyl peroxide first for accounting for reaction monomers, crosslinking agent and pore-foaming agent gross mass 0.4%-5% in mass ratio
Acyl stirs to dissolve, referred to as oil phase；Then it is the poly- of 0.5%-2% the system solution to be added to containing mass percent
In the water phase of glycohol solution, wherein the mass ratio of water phase and oil phase is 1-2.5：1, stir speed (S.S.) is adjusted, is warming up to 40-50 DEG C
Afterwards, it is warming up to 70-80 DEG C with 3-5 DEG C/10min, continues to be kept stirring 3-5h at this temperature after sizing, then with 1-2 DEG C/5min
Speed be to slowly warm up to 90-95 DEG C, react 3-8h, stop heating and stirring, reaction system is through filtering, extracting, carrying out washing treatment
Afterwards, it is preserved in 4 DEG C of hygrometric states, it is spare, obtain meso-hole structure polystyrene type resin.
2nd step, polymer microballoon chloromethylation
Chloromethylation is carried out to polymer microballoon with known reagent and method, uses ethyl alcohol and deionized water washed product successively,
And AgNO is added into cleaning solution3It is generated without precipitation after solution, obtains the mesoporous polystyrene support microballoon of chloromethylation；
3rd step, carrier microballoons are coupled aglucon
The polystyrene type carrier microballoons of chloromethylation meso-hole structure are added in DMF solution, after room temperature is swollen 8-12h, are added
Enter ethylenediamine solution, the wherein mass ratio of polystyrene type carrier, DMF and vinylamine is 0.1-0.2：1.9-5.69：0.5-2,
Then the NaOH solution for adding 30-50mL, 3mol/L reacts 6-10h at 60-80 DEG C, filters, and uses ethyl alcohol, deionization successively
Water fully cleans, and is preserved in 4 DEG C of hygrometric states, spare, in obtaining in blood plasma or blood perfusion uremic patient body, macromolecular toxins
Adsorbent.
9. the preparation method of adsorbent according to claim 8, which is characterized in that the ethyl alcohol cleaning described in the 3rd step refers to elder generation
3 times or more abundant cleanings are carried out with ethyl alcohol, then carried out after being cleaned with the ethyl alcohol that gradient concentration successively decreases, with deionized water 3 times with
On abundant cleaning；In preferred technical solution, adsorbent first passes through after ethyl alcohol fully elutes, with 70%, 30%, 15% ethyl alcohol
It is eluted again with deionized water after washing successively.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810417115.9A CN108371945B (en) | 2018-05-04 | 2018-05-04 | Adsorbent for eliminating middle and large molecular toxin in body of uremia patient and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810417115.9A CN108371945B (en) | 2018-05-04 | 2018-05-04 | Adsorbent for eliminating middle and large molecular toxin in body of uremia patient and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108371945A true CN108371945A (en) | 2018-08-07 |
| CN108371945B CN108371945B (en) | 2020-09-15 |
Family
ID=63033224
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810417115.9A Active CN108371945B (en) | 2018-05-04 | 2018-05-04 | Adsorbent for eliminating middle and large molecular toxin in body of uremia patient and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108371945B (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109758631A (en) * | 2019-01-28 | 2019-05-17 | 江苏关怀医疗科技有限公司 | A kind of absorption type haemodialyser |
| CN111701580A (en) * | 2019-12-26 | 2020-09-25 | 华中科技大学 | Middle molecular toxin adsorbent for removing beta 2 microglobulin in blood |
| CN112791712A (en) * | 2021-01-05 | 2021-05-14 | 南开大学 | Adsorbent for removing protein-bound uremic toxin through blood perfusion and preparation method thereof |
| CN113509919A (en) * | 2021-05-01 | 2021-10-19 | 南开大学 | Adsorbent for removing endotoxin and inflammatory factor in blood of sepsis patient and preparation method thereof |
| CN114405488A (en) * | 2022-01-12 | 2022-04-29 | 江苏贝美医疗科技有限公司 | Protein-bound toxoid blood perfusion adsorbent and preparation method and application thereof |
| CN114797800A (en) * | 2022-04-19 | 2022-07-29 | 江苏贝美医疗科技有限公司 | Adsorbent for removing toxin in body of uremia patient and preparation method |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3428684A (en) * | 1966-11-02 | 1969-02-18 | Commercial Solvents Corp | Purification of alkanol amines |
| CN101559245A (en) * | 2009-03-10 | 2009-10-21 | 李涛 | Application of using anion exchange resin to adsorb cell factor in blood/plasma perfusion device |
| CN103230781A (en) * | 2013-05-03 | 2013-08-07 | 重庆大学 | Heparin-phenylalanine adsorption material for blood purification method for removing endotoxin |
| CN103864973A (en) * | 2012-12-13 | 2014-06-18 | 中国科学院大连化学物理研究所 | Preparation method for polymer microspheres having mixed absorption mode |
| CN103980403A (en) * | 2014-05-16 | 2014-08-13 | 李涛 | Styrene system ion exchange resin as well as preparation method and application thereof |
| CN105085829A (en) * | 2015-08-17 | 2015-11-25 | 珠海健帆生物科技股份有限公司 | Preparation method of macroporous adsorbent resin for toxin substance adsorption |
| CN105504131A (en) * | 2016-01-26 | 2016-04-20 | 重庆希尔康血液净化器材研发有限公司 | Preparing method for resin for clearing away beta2-microglobulin in blood purification |
-
2018
- 2018-05-04 CN CN201810417115.9A patent/CN108371945B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3428684A (en) * | 1966-11-02 | 1969-02-18 | Commercial Solvents Corp | Purification of alkanol amines |
| CN101559245A (en) * | 2009-03-10 | 2009-10-21 | 李涛 | Application of using anion exchange resin to adsorb cell factor in blood/plasma perfusion device |
| CN103864973A (en) * | 2012-12-13 | 2014-06-18 | 中国科学院大连化学物理研究所 | Preparation method for polymer microspheres having mixed absorption mode |
| CN103230781A (en) * | 2013-05-03 | 2013-08-07 | 重庆大学 | Heparin-phenylalanine adsorption material for blood purification method for removing endotoxin |
| CN103980403A (en) * | 2014-05-16 | 2014-08-13 | 李涛 | Styrene system ion exchange resin as well as preparation method and application thereof |
| CN105085829A (en) * | 2015-08-17 | 2015-11-25 | 珠海健帆生物科技股份有限公司 | Preparation method of macroporous adsorbent resin for toxin substance adsorption |
| CN105504131A (en) * | 2016-01-26 | 2016-04-20 | 重庆希尔康血液净化器材研发有限公司 | Preparing method for resin for clearing away beta2-microglobulin in blood purification |
Non-Patent Citations (2)
| Title |
|---|
| 徐满才等: ""大孔交联聚苯乙烯的分形结构研究"", 《离子交换与吸附》 * |
| 高鸿宾: "《有机化学》", 30 November 1997, 化学工业出版社 * |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109758631A (en) * | 2019-01-28 | 2019-05-17 | 江苏关怀医疗科技有限公司 | A kind of absorption type haemodialyser |
| CN111701580A (en) * | 2019-12-26 | 2020-09-25 | 华中科技大学 | Middle molecular toxin adsorbent for removing beta 2 microglobulin in blood |
| CN111701580B (en) * | 2019-12-26 | 2022-02-15 | 华中科技大学 | Middle molecular toxin adsorbent for removing beta 2 microglobulin in blood |
| CN112791712A (en) * | 2021-01-05 | 2021-05-14 | 南开大学 | Adsorbent for removing protein-bound uremic toxin through blood perfusion and preparation method thereof |
| CN112791712B (en) * | 2021-01-05 | 2022-05-10 | 南开大学 | Adsorbent for removing protein-bound uremic toxin through blood perfusion and preparation method thereof |
| CN113509919A (en) * | 2021-05-01 | 2021-10-19 | 南开大学 | Adsorbent for removing endotoxin and inflammatory factor in blood of sepsis patient and preparation method thereof |
| CN113509919B (en) * | 2021-05-01 | 2023-01-10 | 南开大学 | Adsorbent for removing endotoxin and inflammatory factor in blood of sepsis patient and preparation method thereof |
| CN114405488A (en) * | 2022-01-12 | 2022-04-29 | 江苏贝美医疗科技有限公司 | Protein-bound toxoid blood perfusion adsorbent and preparation method and application thereof |
| CN114405488B (en) * | 2022-01-12 | 2023-08-25 | 江苏贝美医疗科技有限公司 | Protein-bound toxoid blood perfusion adsorbent and preparation method and application thereof |
| CN114797800A (en) * | 2022-04-19 | 2022-07-29 | 江苏贝美医疗科技有限公司 | Adsorbent for removing toxin in body of uremia patient and preparation method |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108371945B (en) | 2020-09-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108371945A (en) | For in removing in uremic patient body, the adsorbent of macromolecular toxins and preparation method | |
| CN104174385B (en) | A kind of adsorbent for bilirubin for blood perfusion | |
| CN104174386B (en) | A kind of for removing the adsorbent of B2M in blood | |
| EP2198901B1 (en) | Adsorption column for purifying body fluid | |
| EA002896B1 (en) | Method of removing beta-2 microglobulin from blood | |
| BR112013005793B1 (en) | size selective polymer system | |
| CN105709705B (en) | Remove molecular imprinting adsorbing agent of blood bilirubin and preparation method thereof | |
| CN108031454A (en) | Possesses blood-purifying adsorbing agent of physics specific selectivity and preparation method thereof | |
| CN109621912A (en) | A kind of coating method of blood perfusion acticarbon | |
| CN109092263B (en) | Low-density lipoprotein adsorbent and preparation method thereof | |
| CN107876031A (en) | A kind of uremia blood-purifying adsorbing agent and preparation method thereof | |
| EP3298129B1 (en) | Method of preparing universal blood product | |
| CN108855003A (en) | It is a kind of for removing the immunosorbent and preparation method thereof of inflammatory factor in blood | |
| CN104693332A (en) | Glycosylated medical macroporous adsorption resin | |
| Osman et al. | Molecularly imprinted composite cryogel for extracorporeal removal of uric acid | |
| CN106334541B (en) | A kind of adsorbent and preparation method thereof removing inflammatory factor in systemic inflammatory response blood samples of patients | |
| WO1997027889A1 (en) | Adsorbent for disease-related factors in body fluids, method of elimination by adsorption, body fluid purifier, and apparatus for purifying body fluids | |
| WO2009158027A1 (en) | Removal of myoglobin from blood and/or physiological fluids | |
| CN113509919B (en) | Adsorbent for removing endotoxin and inflammatory factor in blood of sepsis patient and preparation method thereof | |
| JPH0667472B2 (en) | Adsorbent for serum amyloid P protein | |
| CN109794172A (en) | A kind of preparation method of the antibacterial hollow-fibre membrane for blood purification | |
| JPH0622633B2 (en) | Adsorbent and removal device using the same | |
| JPH01181875A (en) | Adsorptive body of immune complex and removing device for immune complex with it | |
| CN203139198U (en) | Simple blood purifier | |
| CN114405488B (en) | Protein-bound toxoid blood perfusion adsorbent and preparation method and application thereof |
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 | ||
| TA01 | Transfer of patent application right | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20200702 Address after: 253000 No.7, lierkang Road, Dezhou Economic and Technological Development Zone, Shandong Province Applicant after: Shandong Zhuoyi Medical Technology Co., Ltd Address before: 300071 Tianjin City, Nankai District Wei Jin Road No. 94 Applicant before: NANKAI University |
|
| GR01 | Patent grant | ||
| GR01 | Patent grant |