CN109248668A - Adsorbent for blood extracorporeal circulation removal LDL and preparation method thereof and perfusion device - Google Patents
Adsorbent for blood extracorporeal circulation removal LDL and preparation method thereof and perfusion device Download PDFInfo
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- CN109248668A CN109248668A CN201811148278.8A CN201811148278A CN109248668A CN 109248668 A CN109248668 A CN 109248668A CN 201811148278 A CN201811148278 A CN 201811148278A CN 109248668 A CN109248668 A CN 109248668A
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- A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
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Abstract
The present invention relates to adsorbents that LDL is removed for blood extracorporeal circulation and preparation method thereof and perfusion device, the adsorbent reacted with polyanion by amino and be formed by introducing amino on carrier；Polyanion is at least one of polyacrylic acid, carbomer and dextran sulfate；Wherein polyacrylic acid be molecular weight be 5000 to 450000 polyacrylic acid or polyacrylic acid be at least two different molecular weights polyacrylic acid mixture；Carbomer be the single trade mark carbomer or carbomer be at least two different trades mark carbomer mixture；Dextran sulfate carries out aldehyde glycosylation reaction with periodate before reacting with amino, and reduction reaction is carried out after reacting with amino.Adsorbent of the invention is to LDL adsorption rate with higher and specific adsorption.
Description
Technical field
The present invention relates to extracorporeal blood purification techniques fields, and in particular to can be used for blood extracorporeal circulation removal low density lipoprotein
Processing mode before the adsorbent of albumen and cholesterol, preparation method and its use.
Background technique
Disorders of lipid metabolism is an important factor for causing athero- artery sclerosis, then lead to cardiovascular and cerebrovascular disease, the two
Correlation by a large amount of zoopery, human body atheromatous plaque histopathology and it is histochemical research and it is numerous
The investigation of epidemiology is confirmed.
Positive lipid-lowering therapy plays key player in cardiovascular and cerebrovascular disease.Most of disorders of lipid metabolism is suffered from
Person can control disease through positive diet control, sports appropriate and appropriate lipid-regulation medicine well, but congenital
Homozygote Familial HypercholesterolemicPatients Patients, need timing lipid-lowering therapy in time, otherwise coronary heart disease occur in one's early years, the service life is bright
It is aobvious to shorten.Merge the urgent need lipid-loweringing of serious disorders of lipid metabolism and microcirculation disorder for part of Acute ischemic angiopathy
Patient and cholesterolemia is especially high, blood lipid reduces undesirable or is not resistant to drug therapy and occurs tight after traditional treatment
The patient of side reaction again, these crowds need more effectively external lipid purification treatment, in this context, many external drops
Rouge therapy is come into being.
Hyperlipemic patients are treated by blood purification therapy, can fast and effeciently remove low-density lipoprotein (LDL),
Curative effect has been approved, and its technology is external very mature.Country's blood purification therapy removal LDL still locates at present
In the Popularization And Development stage.
The diameter of LDL is about 20nm to 27nm, and the apolipoprotein of LDL mainly has Apo-B.Apo-B is by 4536 amino acid
Composition, relative molecular weight 514kDa, it is residual which contains the basic amino acids such as a large amount of lysine, arginine and histidine
Base, residue is exposed to the surface of lipoprotein more so that albumen is positively charged under normal physiological pH environment, can with it is electronegative
Anion aglucon is combined by electrostatic interaction.Existing adsorbent utilizes this principle mostly, but since LDL is large biological molecule,
Planform is irregular, adsorbent pair more demanding to the amount of negative charge of the aperture of adsorbent, partial size and aglucon, different
The adsorption rate of target substance differs greatly, and suitable carrier, aglucon and preferable connection type can be improved to target substance
Adsorption rate.And since, containing other positively charged substances, such adsorbent is poor to the specific adsorption of LDL in blood plasma,
Other beneficiating ingredients such as metal cation etc. in blood of human body can be adsorbed, some adsorbents can also be to high-density lipoprotein, white
Albumen, total protein generate absorption, generate side effect.
In world wide all there is more problem and need to improve in commercialized LDL adsorbent at present.German Fresenius is public
The DALI product (immobilized polyacrylic acid on porous copolymer of acrylamide carrier) of department exists to the higher problem of adsorption of metal ions rate,
Lead to Ca2+It loses seriously, carries out long-term treatment using the product and require supplementation with electrolyte (2001T.Bosch Direct
Adsorption of Lipoproteins from Whole Blood by DALI), and the product cost is higher, disposably
It uses, can not regenerate.In addition the aglucon of a kind of commercialization adsorbent is the antibody of biogenic, and antibody cost is high, and storage is tired
It is difficult.Domestic DELP filter, the removal to LDL are using the mode of film filtering, and compared to absorbent-type product, filter membrane is to mesh
The adsorption rate of mark substance is low, safety is poor.Therefore, be badly in need of it is a kind of it is low in cost, preparation process is simple, selection adsorption capacity
By force, validity and the better adsorbent of safety.
Summary of the invention
Against the shortcomings and deficiencies of the above prior art, the first object of the present invention is to provide a kind of couple of LDL with higher
Adsorption rate and absorption specificity blood perfusion adsorbent.
The second object of the present invention is to provide a kind of for removing the preparation method of the blood perfusion adsorbent of LDL.
The third object of the present invention is to provide a kind of for removing the perfusion device of LDL.
The first purpose to realize the present invention, the present invention provides a kind of absorption for blood extracorporeal circulation removal LDL
Agent, the adsorbent are reacted with polyanion by amino and are formed by introducing amino on carrier；Polyanion is polypropylene
At least one of acid, carbomer and dextran sulfate；Wherein polyacrylic acid is the polypropylene that molecular weight is 5000 to 450000
Acid or polyacrylic acid are the mixtures of the polyacrylic acid of at least two different molecular weights；Carbomer is the card wave of the single trade mark
Nurse or carbomer are the mixtures of the carbomer of at least two different trades mark；Dextran sulfate before being reacted with amino with
Periodate carries out aldehyde glycosylation reaction, and reduction reaction is carried out after reacting with amino.
By above scheme as it can be seen that the present invention is anti-by the amino on carrier and the polyanion with carboxyl or sulfate group
It answers, so that carrier is connect with polyanion aglucon with amide group, the two is firmly combined, and advantageously ensures that the safety of adsorbent
Property.
Polyacrylic acid aglucon used in adsorbent can be the polyacrylic acid that molecular weight is 2,000 to 2,000,000.Polyacrylic acid
It can have more single molecular weight, i.e. the length of polyacrylic acid is almost the same.The polyacrylic acid of different molecular weight has not
Same molecular length and amount of charge, it is also different to the adsorption rate of LDL.Due to LDL be large biological molecule, adsorbent with biology
When macromolecular combines, largely to be influenced by space steric effect.When aglucon is smaller, carried due to being directly incorporated in
Small molecule aglucon on body is very close to carrier, and large biological molecule to be adsorbed is by steric restriction so that its with match base junction
The position of conjunction can not influence the combination of large biological molecule and aglucon close to aglucon, cause the reduction of adsorbance.It is this in order to reduce
Adverse effect, can choose suitable aglucon length, and aglucon flexes outward on carrier, when so that LDL and aglucon contacting, not allow
It is also easy to produce steric hindrance.For this purpose, the molecular weight of polyacrylic acid preferably 5,000 to 450,000, more preferable 5,000 to 250,000.
Polyacrylic acid aglucon can also be the combination of different molecular weight polyacrylic acid, the polyacrylic acid of different molecular weight press than
It is immobilized to form the branch with carboxyl different in size to after on resin after example mixing, with biology in irregular shape
When macromolecular LDL is contacted, LDL can be to the greatest extent in conjunction with the in picturesque disorder carboxyl with negative electricity, can to reduce
Carboxyl quantity in conjunction with metal ion, and then reduce the adsorption rate to metal cation.Wherein, lower molecular weight can be with
2,000 to 10,000 are selected, higher molecular weight can choose 20,000 to 250,000.
Adsorbent of the invention can also use carbomer as aglucon, and carbomer can be the single trade mark, can also be with
It is the mixture of a variety of trades mark.Use carbomer as aglucon, advantageously reduces adsorbent to the adsorption rate of metal ion, this is
By the electrically charged quantity of carbomer aglucon institute less than polyacrylic acid and negative electrical charge position it is irregular, cause and metal ion
In conjunction with melanoma cells.
Adsorbent of the invention can also use dextran sulfate as aglucon.Dextran sulfate is first before reacting with amino
Vicinal hydroxyl groups are aoxidized by periodate, are restored again after being reacted with amino, by aldehyde radical and reduction, change sulfuric acid
The structure of glucan.Dextran sulfate is firmly combined with carrier, highly-safe.
Further technical solution is, when polyanion is polyacrylic acid, be bonded on adsorbent calcium ion and magnesium from
At least one of son；When polyanion is carbomer or dextran sulfate, calcium is bonded with or is not bonded on adsorbent
At least one of ion and magnesium ion.
By above scheme as it can be seen that calcium ion or magnesium ion can be bonded on adsorbent of the invention, or it is bonded simultaneously
There are calcium ion and magnesium ion.The adsorbent of at least one of calcium ion and magnesium ion is bonded with when passing through blood plasma, due to aglucon
It is greater than aglucon to the binding force of metal cation with the binding force of LDL, aglucon can be less in conjunction with the LDL in blood plasma
In conjunction with metal cation, to be further reduced adsorbent to the adsorption rate of metal ion.When aglucon is carbomer and sulfuric acid
When glucan, since adsorption rate of the aglucon to metal ion itself is lower, adsorbent can also be without electrolyte before using
Solution rinses in advance.
Further technical solution is that at least one of calcium ion and magnesium ion rinse suction by electrolyte solution in advance
Attached dose and be bonded on the sorbent；Concentration of the calcium ion in electrolyte solution is 0.01mmol/L to 2mmol/L, and magnesium ion exists
Concentration in electrolyte solution is 0.01mmol/L to 1.05mmol/L.
By above scheme as it can be seen that adsorbent of the invention can be rushed before clinical use using electrolyte solution in advance
It washes, so that adsorbent be enable largely to be adequately bonded calcium ion and magnesium ion in advance.In electrolyte solution calcium ion and magnesium from
Son preferably uses above-mentioned concentration, to reduce adsorbent to the adsorption rate of calcium ion and magnesium ion.The concentration of calcium ion is more preferably
1.4mmol/L to 1.8mmol/L, the concentration of magnesium ion are more preferably 0.5mmol/L to 1mmol/L.Also contain in electrolyte solution
There is sodium chloride, sodium chloride plays the role of physiological saline, for making electrolyte solution that there is the osmotic pressure equal with blood of human body,
To improve the safety of adsorbent.Further technical solution is that carrier is in acrylic resin, cellulose or derivatives thereof
At least one；Carrier aperture is 50nm to 200nm, and partial size is 30 μm to 300 μm；Carrier elder generation epoxidation, then it is anti-with aminating agent
Amino or carrier should be introduced and react introducing amino with aminating agent.
As above scheme as it can be seen that blood perfusion resin carrier used in adsorbent of the invention can be acrylic resin,
Acrylic resin refers to the polymer containing acrylic acid, methacrylic acid or derivatives thereof as monomer, such as can be diformazan
The copolymer of base acrylic acid glycol ester (crosslinking agent) and methyl methacrylate (monomer).Blood perfusion absorption of the invention
Resin carrier used in agent can also be cellulose or derivatives thereof.These carriers are the common tree of biomedicine field all the time
Rouge, no particle and chemical residual have preferable blood compatibility, and mechanical strength with higher.Carrier has suitable
Aperture, macromolecular substances such as high-density lipoprotein, globulin, albumin etc. can be blocked in except carrier, only be closed
The target substance of suitable size could be by carrier, to improve the specific adsorption to LDL.It can be selected according to carrier institute band group
Reamination or direct aminatin after epoxidation are selected, to introduce amino on carrier.
The second purpose to realize the present invention, the present invention provides a kind of absorption for blood extracorporeal circulation removal LDL
The preparation method of agent, method includes the following steps:
Step 1: carrier and epoxidation reagent are subjected to epoxidation reaction, then carry out aminating reaction with aminating agent；Alternatively,
Carrier and aminating agent are subjected to aminating reaction；
Step 2: carrier and polyanion after the amination that step 1 is obtained carry out condensation reaction, obtain adsorbent；
Wherein polyanion is at least one of polyacrylic acid, carbomer and dextran sulfate；Polyacrylic acid is molecule
Polyacrylic acid or polyacrylic acid that amount is 5000 to 450000 are the mixing of the polyacrylic acid of at least two different molecular weights
Object；Carbomer be the single trade mark carbomer or carbomer be at least two different trades mark carbomer mixture；Sulfuric acid
Glucan carries out aldehyde glycosylation reaction with periodate before condensation reaction, and reduction reaction is carried out after condensation reaction.
Therefore sorbent preparation method of the invention is simple, reduces the dosage of chemical reagent, improves as suction
Attached dose of safety, while reducing production cost.Sorbent preparation method of the invention by control raw material type, dosage with
And process conditions, adjustable to match base unit weight in carrier surface, space bit when reducing adsorbent in conjunction with large biological molecule
Resistance influences simultaneously and provides enough anion, generates electrostatical binding with the target substance for carrying cation, reaches
To the optimal effectiveness of target substance absorption.
Further technical solution is that when polyanion is polyacrylic acid, preparation method further includes step 3: using electricity
Electrolyte solution rinses adsorbent in advance；When polyanion be carbomer or dextran sulfate when, preparation method include or
It does not include above-mentioned steps three.
Further technical solution is that electrolyte solution contains at least one of calcium ion and magnesium ion, calcium ion
Concentration is 0.01mmol/L to 2mmol/L, and the concentration of magnesium ion is 0.01mmol/L to 1.05mmol/L.
Further technical solution is, in step 1: carrier is in acrylic resin, cellulose or cellulose derivative
At least one；Carrier aperture is 50nm to 200nm, and partial size is 30 μm to 300 μm；Epoxidation reagent be epoxychloropropane, 1,
At least one of 4- butanediol diglycidyl ether；It is 8 to 11 that epoxidation reaction, which controls pH value,；Aminating agent is ammonium hydroxide, second two
At least one of amine, 1,2- propane diamine, 1,3- propane diamine；The volume ratio of carrier and aminating agent is 1:(2 to 6).
Further technical solution is that in step 2: condensation reaction carries out in the presence of condensing agent, and condensing agent is
At least one of EEDQ, HATU, DCC, DMAP, PyBOP；It is 3 to 7 that condensation reaction, which controls pH,；Carrier, polyanion after amination
Mass ratio with condensing agent is 10:(0.02 to 10): (0.01 to 10).The effect of condensing agent is that amino and carboxyl can be made to be condensed
Generate amide groups.The temperature of condensation reaction can be room temperature, and the reaction time can be 12h.
Further technical solution is that polyalcohol is added after reaction and removes excessive periodate for aldehyde radicalization；Reduction
Reaction is using sodium borohydride as reducing agent.Sodium metaperiodate progress can be added in aldehyde glycosylation reaction in dextran sulfate, to will match
Vicinal hydroxyl groups on base are oxidized to aldehyde radical.Dextran sulfate after aldehyde radical is mixed with the carrier after amination again, and it is anti-to carry out amination
It answers.It disperses product in sodium borohydride after aminating reaction and restores.
Further technical solution is, after epoxidation reaction, aminating reaction and condensation reaction, further include to product into
The step of row purification.
Third purpose to realize the present invention, the present invention provides a kind of perfusion device, which includes any of the above-described kind
It for the adsorbent of blood extracorporeal circulation removal LDL, or include removing LDL for blood extracorporeal circulation by any of the above-described kind
Adsorbent prepared by the preparation method of adsorbent.The adsorbent that the present invention is provided or is prepared can be used for blood extracorporeal circulation
Medical instrument, i.e. absorber or perfusion device etc..
In conclusion compared with prior art, the present invention can obtain it is following the utility model has the advantages that
(1) the present invention provides a kind of adsorbent for blood extracorporeal circulation, the adsorbent is mainly by carrier and aglucon
Two parts composition forms amide group and is covalently attached between carrier and aglucon, aglucon is not easily to fall off, guarantees the safety of use process
Property；And aglucon selects polyacrylic acid, carbomer or dextran sulfate, cost is relatively low for aglucon, and blood compatibility is good.
(2) adsorbent preparation process of the invention is simple, and reaction step is less, lower production costs.Can choose does not make
The low chemicals of threshold limit values is born with human bodies such as epoxychloropropane, is conducive to the safety for improving blood purification adsorbent.
(3) adsorbent of the invention is high to the adsorption rate of LDL, using the aglucon of suitable molecular weight, can increase substantially
To the adsorption rate of LDL；Or the combination of the aglucon of different molecular weight is immobilized on carrier, it is formed in carrier surface different in size
Polyanion group can also be improved the adsorption rate to LDL.
(4) adsorbent of the invention has the absorption specificity to LDL.To other cations in blood in addition to LDL
Substance, such as Ca ion, Mg ion, potassium ion etc., adsorption rate is lower, will not cause the loss of human electrolyte, has higher
Safety.By the suitable aglucon supported quantity of technology controlling and process, the aglucon and different molecular weight aglucon of suitable molecular weight are selected
Combination, or rinsed in advance using the electrolyte solution of suitable component, adsorbent can be made to the adsorption rate of metal cation
It is reduced to floor level, greatly improves the safety that human body uses.
(5) adsorbent of the invention can also adsorb cholesterol (TC), triglycerides (TG) and lipoprotein a (Lp (a)), have
Effect reduces concentration of these ingredients in body fluid, while hardly inhaling to benefit materials (including HDL, three, albumen, electrolyte)
Attached or adsorption rate is low.
Detailed description of the invention
Fig. 1 shows the adsorbents prepared respectively in the embodiment of the present invention 1 using different molecular weight polyacrylic acid aglucon to LDL
Adsorption rate.
Specific embodiment
LDL adsorbent and preparation method thereof of the invention is described further with reference to embodiments.
Embodiment 1
20mL polyacrylic acid vector resin is taken, carries out ring using epoxychloropropane or 1,4-butanediol diglycidyl ether
Oxidation, control pH are 8 to 11, react 3h at 30 DEG C, the carrier after obtaining epoxidation, by the carrier purified water after epoxidation
Purification is neutral to pH.Carrier after epoxidation is mixed with aminating agent by 1:(2 to volume ratio 6), reacts 1.5h at 30 DEG C,
Make carrier amination, aminating agent includes ammonium hydroxide, ethylenediamine, 1,2- propane diamine or 1,3- propane diamine.Carrier is washed using purified water
Purification is washed to pH neutrality.Carrier after amination is mixed with polyacrylic acid, EEDQ 10:0.2:0.1 in mass ratio, control pH is 3
To 7,12h is reacted under room temperature, polyacrylic acid aglucon is immobilized on carrier, by adsorbent cleaning, obtain LDL adsorbent.
Using different molecular weight, (the polyacrylic acid aglucon of 2,000 to 450,000, i.e. 2k to 45w) pass through above method system respectively
Standby adsorbent, the adsorption rate of these adsorbents is tested using plasma experiment method: taking the adsorbent of 1mL that the Healthy People of 8mL is added
In blood plasma, supernatant is taken after shaking 2h under conditions of revolving speed is 140rpm, temperature is 37 DEG C, using testing agency to object
Matter is detected.Adsorption rate calculation formula are as follows: adsorption rate=[(m1-m2)/m1] × 100%, wherein m1 is to adsorb in preceding blood plasma
The concentration of target substance, m2 are the concentration of target substance after blood plasma is adsorbed with adsorbent.Match with different molecular weight polyacrylic acid
The adsorbent of base is to the adsorption rate of target substance as shown in the following table 1 and Fig. 1.
The adsorption rate of 1 polyacrylic acid ligand molecule amount of table and its adsorbent
| Ligand molecule amount | LDL adsorption rate | Calcium ion adsorption rate | Magnesium ion adsorption rate |
| 2k | 23.9% | 54.5% | 33.2% |
| 3k | 27.7% | 56.9% | 34.6% |
| 5k | 63.7% | 55.8% | 34.2% |
| 5w | 62.5% | 58.8% | 45.7% |
| 8w | 55.1% | 48.2% | 35.2% |
| 12w | 59.5% | 45.6% | 36.8% |
| 25w | 63.1% | 44.2% | 35.2% |
| 45w | 42.2% | 43.1% | 38.6% |
As table 1 and Fig. 1 as it can be seen that adsorbent prepared by the aglucon with different molecular lengths, it is shown that not to LDL
Same adsorption rate.Preferable to the adsorptivity of LDL when the molecular weight of polyacrylic acid aglucon is 5,000 to 450,000, middle-molecular-weihydroxyethyl is 5,000
It is optimal to the adsorptivity of LDL when to 250,000.Adsorbent also changes the adsorption rate of calcium ion and magnesium ion with ligand molecule amount,
But compared to the variation of the adsorption rate to LDL, change smaller.
The polyacrylic acid aglucon that molecular weight is 5w is integrated to adsorbent prepared on carrier and is known as adsorbent 1, is used for
Follow-up test.
Embodiment 2
The polyacrylic acid aglucon of two kinds of different molecular weights is mixed in proportion, using the method synthetic adsorbent of embodiment 1.
Gained adsorbent is as shown in table 2 below to LDL and adsorption of metal ions rate.Mass ratio refers to poly- third with molecular weight 1 in table 2
Olefin(e) acid aglucon is with the polyacrylic acid aglucon with molecular weight 2 with mass ratio shared in based mixtures gross mass.
The ratio of 2 polyacrylic acid aglucon of table and its adsorption rate of adsorbent
Pass through the comparison of table 2 and table 1, it can be seen that aglucon is used as after mixing the polyacrylic acid of different molecular weight, it can
Adsorbent is improved to the adsorption rate of LDL or keeps the higher adsorption rate to LDL, while reducing adsorbent to metal ion
Adsorption rate even reduces about 50% to the adsorption rate of metal ion, improves the safety that adsorbent uses.This is because different
The polyacrylic acid of molecular weight is immobilized to form the aglucon branch with carboxyl different in size to after on carrier, with shape not
Rule large biological molecule LDL contact when, LDL can to the greatest extent in conjunction with the in picturesque disorder carboxyl with negative electricity, from
And reducing and then can reduce the adsorption rate to metal cation with the carboxyl quantity in conjunction with metal ion.
The adsorbent for the polyacrylic acid aglucon preparation combined by 4:6 for being 3k and 8w by molecular weight is known as adsorbent 2.It inhales
The adsorption rate of attached dose of 2 pairs of each target substances is as shown in table 3 below.
The adsorption rate of 3 adsorbent 2 of table
Seen from table 3, adsorbent 2 all has LDL, cholesterol (TC), triglycerides (TG) and lipoprotein a (Lp (a))
Higher adsorption rate, and to such as high-density lipoprotein of benefit materials in blood plasma (HDL), globulin, albumin and metal sun
The adsorption rate of ion is lower.The result shows that the such adsorbent of adsorbent 2 has good safety.
Evaluation of Biocompatibility is carried out to the resulting adsorbent 1 of embodiment 1 and the resulting adsorbent 2 of embodiment 2 below.
The biological safety testing result of adsorbent 1 and adsorbent 2 is as follows:
(1) prothrombin time
Prothrombin time is used for the activation capability of assessment material exogenous blood coagulation system.Prothrombin time is poor
Excessive tissue factor is added in the blood of blood platelet, conversion of prothrombin is fibrin ferment, when causing required for the clotting of plasma
Between.Prothrombin time is longer, and blood coagulation risk is lower.As shown in table 4, the prothrombin time of adsorbent 1 and adsorbent 2 and same
Class product is close or lower, and blood coagulation risk is low.
4 prothrombin time of table
| Adsorbent title | Prothrombin time (s) |
| Adsorbent 1 | 22.2 |
| Adsorbent 2 | 26.8 |
| The similar product of certain FDA approval | 26.1 |
| Blank control | 12.8 |
(2) complement (C3a) activation experiment
Complement C 3 is the typical sensitizer that complement activation generates, and the raising of expression may cause allergy etc. and exempt from
Epidemic disease stress enhancing, for the material directly contacted with blood, complement activation level is better closer to blank.It can from table 5
Adsorbent 1 and adsorbent 2 and blank control are close out, and activation risk is small.
5 complement of table (C3a) activation experiment result
(3) complement (SC5b-9) activation experiment
Complement SC5b-9 is the final membrane attack complex of complement system activity, activates degree and sensitization, haemolysis, blood coagulation etc.
Many index is closely related, and for the material directly contacted with blood, complement activation level is better closer to blank.It can from table 6
To find out, adsorbent 1 and adsorbent 2 and blank control are approached, and activation risk is small.
6 complement of table (SC5b-9) activation experiment result
(4) cell toxicity test
Cell toxicity test passes through cell with respect to appreciation rate reaction material to the toxic effect of cell, with blank control phase
Than cell opposite proliferation rate >=80% item shows that cytotoxicity is small.As can be seen from Table 7, adsorbent 1 and adsorbent 2 are to cell
The inhibiting effect of growth is small, and risk is smaller.
7 cell toxicity test result of table
By being tested above as it can be seen that adsorbent 1 and 2 biological safety of adsorbent are preferable, it may act on blood of human body and follow in vitro
Ring removes LDL etc..
Embodiment 3
It with the adsorbent of molecular weight 3k and 8w 4:6 in mass ratio the acrylic acid aglucon preparation mixed, that is, will be inhaled in embodiment 2
Attached dose 2, electrolyte is carried out by way of either statically or dynamically and is rushed in advance.Pre- punching can be carried out by either statically or dynamically two ways.
Wherein, static the step of rushing in advance includes the electrolyte solution in the adsorbent addition 1mL to 10mL of 1mL, will be electric after concussion 10min
Electrolyte solution is sucked out completely, and remaining adsorbent is carried out static plasma experiment；The pre- punching of dynamic includes putting the adsorbent of 100mL
It by direction from top to bottom, speed is that 30mL/min is carried out with the electrolyte solution of 50mL or more in the cylinder that diameter is 5cm
Pre- punching takes 1mL adsorbent to carry out static plasma experiment after pre- punching.Used electrolyte solution ingredient see the table below 8.
8 electrolyte solution of table
After rushing adsorbent in advance using different electrolyte, adsorption rate variation such as the following table 9 of the adsorbent to LDL and metal ion
It is shown.
9 adsorbent of table using different electrolytes rush in advance after adsorption rate
Absorption by table 9 as it can be seen that compared with the adsorbent not rushed in advance, after electrolyte solution A, B, C, D, E, F are rushed in advance
Agent is decreased obviously the adsorption rate of calcium and magnesium metal ion, and chlorine ion concentration variation is little, especially electrolyte solution A, C, E, F
Effect is more preferable after solution rushes in advance.C is compared with B solution or E is compared with solution D, to the adsorption rate of magnesium ion after addition magnesium ion
It reduces.
Therefore by being rushed in advance to adsorbent, preparatory bind metal ion on the sorbent, so that adsorbent is used
When extracorporal circulatory system adsorbing therapy, it is possible to reduce absorption of the adsorbent to metal ion in blood plasma.And matched as used in the present invention
The electrically charged intensity of base is suitable, under the liquid environment of blood plasma complexity, adsorbent to the binding force of LDL be better than metal from
Son, therefore the adsorbent by pre- punching processing reduces the adsorption rate to calcium ions and magnesium ions, and it is constant to the adsorption rate of LDL, thus
Greatly strengthen the safety that adsorbent uses.Moreover, because being come using electrolyte solution identical with concentration in human body fluid
Adsorbent is rushed in advance, the adsorbent after pre- punching can also be such that human body electrolyte concentration is located in normal range (NR), if electric in patients blood plasma
It is relatively low to solve matter concentration, which also has the function of supplementing human electrolyte, without increasing human body electrolyte concentration.It should
Adsorbent has good prospect of the application in circulation absorption treatment in vitro, greatly improves the safety of use, solves current
Adsorbent leads to the problem of absorption to metal ion.
Embodiment 4
The present embodiment is using the carbomer of the different trades mark as aglucon, using method same as Example 1, preparation absorption
Agent.Carbomer is the high molecular polymer of acrylic acid bonding allyl sucrose or pentaerythrite allyl ether, as polyacrylic acid
Containing carboxyl, it is usually used in food, in drug, is a kind of very important rheology control agent.The adsorbent of the present embodiment to LDL with
And the adsorption rate of metal ion is as shown in the following table 10, wherein a1 to a6 respectively represents the carbomer of the different existing trades mark.
Table 10 has the adsorption rate of the adsorbent of different trade mark carbomer aglucons
As can be seen from Table 10, the carbomer of the trade mark representated by a2, a3, a5 is relatively high to the adsorption rate of LDL.With polypropylene
Sour aglucon is compared, and carbomer aglucon is slightly lower to the adsorption rate of LDL, but the advantages of carbomer aglucon first is that the aglucon itself to calcium
The adsorption rate of magnesium ion is lower, this is because the polyacrylic acid in carbomer participates in crosslinking, it is less containing the carboxyl with negative electricity,
When LDL is in conjunction with the carboxyl of adsorbent surface, the aglucon branch terminals that adsorbent flexes outward are and golden in conjunction with large biological molecule
It is smaller to belong to ion volume, can be entered inside aglucon branch by the gap between LDL molecule, by institute's band on aglucon branch
Carboxyl-content it is less, to reduce absorption of the adsorbent to metal ion.
Embodiment 5
By the carboxyl or hydroxyl epoxychloropropane or 1,4- butanediol on polyacrylic acid or cellulose type carrier
Diglycidyl ether epoxidation, control pH is 8 to 11 in reaction process, the carrier after obtaining epoxidation.By the load after epoxidation
Body and aminating agent react 1.5h by 1:(2 to volume ratio hybrid reaction 6) at 30 DEG C, aminating agent include ammonium hydroxide, ethylenediamine,
1,2- propane diamine or 1,3- propane diamine make carrier amination.Aglucon dextran sulfate is reacted into 4h at 40 DEG C with sodium metaperiodate,
Vicinal hydroxyl groups are oxidized to aldehyde radical, polyhydric alcohols such as glycerine is added after reaction, 1h is reacted at 40 DEG C, polyalcohol is added
The purpose of reaction is the excessive sodium metaperiodate of consumption.The carrier microballoons for taking 20mL amination, the sulphur after pouring into the above-mentioned aldehyde radical of 10mL
Sour dextran solution, in 25 DEG C of stirring 12h, resin carrier, which is used, after the reaction was completed purifies Water warfare, and is scattered in 10mL 1%
NaBH4In, 15min is reacted at 25 DEG C, is used massive laundering after reaction, is obtained adsorbent.Gained adsorbent is carried out
Plasma experiment, as a result as shown in table 11 below.
Table 11 has the adsorption rate of the adsorbent of dextran sulfate aglucon
| Test item | LDL | Calcium ion | Magnesium ion |
| Adsorption rate (%) | 58% | 7% | 4.5% |
As can be seen from Table 11, which has good adsorptivity to LDL, and lower to adsorption of metal ions rate.
In conclusion absorption resin provided by the invention can also remove LDL adsorptivity with higher and specificity
Cholesterol, triglycerides and Lp (a) in blood etc. have preferable blood compatibility, are suitable for blood perfusion.And the present invention
Absorption resin preparation process it is simple, used cost of material is low.
It finally it is emphasized that the above is only a preferred embodiment of the present invention, is not intended to restrict the invention, for this
For the technical staff in field, the present invention can have various change and change, all within the spirits and principles of the present invention, done
Any modification, equivalent substitution, improvement and etc., should all be included in the protection scope of the present invention.
Claims (10)
1. the adsorbent for blood extracorporeal circulation removal LDL, it is characterised in that:
The adsorbent is reacted with polyanion by the amino and is formed by introducing amino on carrier；The poly- yin
Ion is at least one of polyacrylic acid, carbomer and dextran sulfate；
The polyacrylic acid is the polyacrylic acid that molecular weight is 5000 to 450000 or the polyacrylic acid is not at least two not
With the mixture of the polyacrylic acid of molecular weight；
The carbomer be the single trade mark carbomer or the carbomer be at least two different trades mark carbomer it is mixed
Close object；
The dextran sulfate carries out aldehyde glycosylation reaction with periodate before reacting with the amino, anti-with the amino
Reduction reaction should be carried out later.
2. the adsorbent according to claim 1 for blood extracorporeal circulation removal LDL, it is characterised in that:
When the polyanion is polyacrylic acid, at least one of calcium ion and magnesium ion are bonded on the adsorbent；
When the polyanion is carbomer or dextran sulfate, calcium ion is bonded with or is not bonded on the adsorbent
At least one of with magnesium ion.
3. the adsorbent according to claim 2 for blood extracorporeal circulation removal LDL, it is characterised in that:
At least one of the calcium ion and magnesium ion rinse the adsorbent by electrolyte solution in advance and are bonded in institute
It states on adsorbent；Concentration of the calcium ion in the electrolyte solution is 0.01mmol/L to 2mmol/L, the magnesium ion
Concentration in the electrolyte solution is 0.01mmol/L to 1.05mmol/L.
4. the adsorbent according to any one of claims 1 to 3 for blood extracorporeal circulation removal LDL, it is characterised in that:
The carrier is at least one of acrylic resin, cellulose or cellulose derivative；
The carrier aperture is 50nm to 200nm, and partial size is 30 μm to 300 μm；
Carrier elder generation epoxidation, then react with aminating agent and to introduce the amino or the carrier reacts introducing with aminating agent
The amino.
5. the preparation method of the adsorbent for blood extracorporeal circulation removal LDL, it is characterised in that the following steps are included:
Step 1: carrier and epoxidation reagent are subjected to epoxidation reaction, then carry out aminating reaction with aminating agent；Alternatively, will carry
Body and aminating agent carry out aminating reaction；
Step 2: carrier and polyanion after the amination that step 1 is obtained carry out condensation reaction, obtain adsorbent；
Wherein, the polyanion is at least one of polyacrylic acid, carbomer and dextran sulfate；
The polyacrylic acid is the polyacrylic acid that molecular weight is 5000 to 450000 or the polyacrylic acid is not at least two not
With the mixture of the polyacrylic acid of molecular weight；
The carbomer be the single trade mark carbomer or the carbomer be at least two different trades mark carbomer it is mixed
Close object；
The dextran sulfate carries out aldehyde glycosylation reaction with periodate before condensation reaction, is gone back after condensation reaction
Original reaction.
6. the preparation method of the adsorbent according to claim 5 for blood extracorporeal circulation removal LDL, feature exist
In:
When the polyanion is polyacrylic acid, the preparation method further includes step 3: using electrolyte solution to absorption
Agent is rinsed in advance；
When the polyanion is carbomer or dextran sulfate, the preparation method includes or does not include the step 3.
7. the preparation method of the adsorbent according to claim 6 for blood extracorporeal circulation removal LDL, feature exist
In:
The electrolyte solution contains at least one of calcium ion and magnesium ion, and the concentration of the calcium ion is 0.01mmol/L
To 2mmol/L, the concentration of the magnesium ion is 0.01mmol/L to 1.05mmol/L.
8. according to the preparation method of the described in any item adsorbents for blood extracorporeal circulation removal LDL of claim 5 to 7,
It is characterized by: in step 1:
The carrier is at least one of acrylic resin, cellulose or cellulose derivative；The carrier aperture is 50nm
To 200nm, partial size is 30 μm to 300 μm；
The epoxidation reagent is at least one of epoxychloropropane, 1,4- butanediol diglycidyl ether；The epoxidation
Reaction controlling pH value is 8 to 11；
The aminating agent is at least one of ammonium hydroxide, ethylenediamine, 1,2- propane diamine, 1,3- propane diamine；The carrier with it is described
The volume ratio of aminating agent is 1:(2 to 6).
9. according to the preparation method of the described in any item adsorbents for blood extracorporeal circulation removal LDL of claim 5 to 7,
It is characterized by: in step 2:
The condensation reaction carries out in the presence of condensing agent, the condensing agent be EEDQ, HATU, DCC, DMAP, PyBOP extremely
Few one kind；The condensation reaction control pH is 3 to 7；
The mass ratio of carrier, polyanion and condensing agent after amination is 10:(0.02 to 10): (0.01 to 10).
10. perfusion device, it is characterised in that described in any item for blood extracorporeal circulation removal LDL's including Claims 1-4
Adsorbent, or include by the system of the described in any item adsorbents for blood extracorporeal circulation removal LDL of claim 5 to 9
Adsorbent prepared by Preparation Method.
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| CN112569910A (en) * | 2020-11-11 | 2021-03-30 | 健帆生物科技集团股份有限公司 | Preparation method of adsorbent for removing LDL (low density lipoprotein) through blood extracorporeal circulation and perfusion device |
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