JPS58203766A - Blood anti-coagulant material comprising amphoteric ion exchanger - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides polymer chains po17A-
The present invention relates to an anti-blood coagulant material comprising a linear or branched block copolymer in which a polymer chain pony B having an anion exchange group and a polymer chain pony B constitute all or part of the component block.

In recent years, Haruna's molecular materials have been used for artificial kidneys and artificial lungs.

They are used in artificial organs such as artificial blood vessels and medical devices such as syringes and blood bags, but the issue in this case is the biocompatibility of these molecular materials.

That is, it is required that contact between the material and the living body causes an undesirable foreign body reaction for the living body, and that contact with blood, for example, does not cause blood coagulation.

Such foreign body reactions are greatly influenced by the chemical and physical structure of polymeric materials, and many studies have been conducted to provide anticoagulant properties to the materials. However, satisfactory results are not always obtained, and various drawbacks and inconveniences arise in each case. For example, a method is known in which anticoagulants such as heparin are immobilized on polymer material table 111'+, but when used for a long time under physiological conditions, the heparin easily desorbs, resulting in poor anticoagulant properties. It may decrease. There is also a method of applying a negative charge to the surface of the material, but the anticoagulability is not improved as much as expected.

When using polyhedral polymers such as polyhedroxyethyl methacrylate or polyacrylamide, the drawback is poor mechanical properties, and when using materials with low surface energy such as silicone rubber, fibrin particles are formed. #'i cannot hear that it is easy to use and has good anticoagulant properties.

Under these circumstances, the surface gold heterogeneity is reduced by microphase separation.
Currently, active research and development is being carried out, including those in which a long-chain hydrophilic polymer with flexibility is bonded to the surface of the material.

Recently, the mechanism by which blood coagulates and causes ++ is being elucidated at the cellular or molecular level.According to these findings, when blood comes into contact with a foreign substance, platelet activation increases and the foreign substance becomes more active. It was found that the adhesion of the fibrino and the activation of the endogenous coagulation system occur in parallel, and the ribs interlock with each other to form fibrino, forming a frame. In addition, some facts show that platelets themselves have a negative charge as a whole, and therefore their adhesion to solid surfaces with the same negative fixed charge is quadrupled, and that the endogenous system On the contrary, it has been shown that the activation of the endovascular system is inhibited by the cationized surface.9 On the other hand, the heterogeneous microstructure of the blood vessel inner wall is also thought to be a factor in its antithrombotic properties. However, the introduction of a microdomain structure onto the surface of a molecular material is considered to be unsatisfactory in the sense of creating a geometrical structure similar to that of a living body. These recent research results suggest that there is an ability of af to obtain anti-coagulant properties that are superior to those associated with positive charges.

The present invention has been made in view of the above points, and aims to provide an excellent anticoagulant material and to provide a new use for block copolymers.

The present invention will be explained in detail below.

4- The anti-blood coagulant material of the invention is a linear or It consists of a branched block copolymer.

This material contains at least 5% by weight of a molecular block polyA capable of introducing cation exchange groups and a polymer block polyBA capable of introducing anion exchange groups at a weight ratio of 5% or more. No polymer block poly C
It is obtained by introducing a cation exchange group and an anion exchange group into polymer blocks po17 A and pony B, respectively, into a linear or branched original block copolymer containing 0 to 90% by weight of Generally, in the case of block copolymers, it is known that component blocks made of different monomers do not know each other in the solid state, and each block forms microdomains close to the size of the block.

The anti-blood coagulant material of the present invention is characterized in that it utilizes all of the microphase components, and simultaneously has domains with cation exchange groups and domains with anion exchange groups, and has excellent properties. Anticoagulant properties are expected from both the chemical and structural aspects due to the presence of these positive and negative fixed charges, and the geometrical and structural aspects of 111J[l due to microphase separation.

Usually, when a polymer with a positive fixed charge (a polycation) and a polymer with a negative fixed charge of gold (a polyanion) are mixed, a polymer electrolyte complex (polyion complex) is formed. In such a case, it is impossible for a polykanion domain and a polyanion domain to exist simultaneously. For this reason, the original block copolymer used in the present invention must have either positive or negative ion exchange groups, or neither ion exchange group, before molding. The remaining ion exchange group or positive and negative ion exchange groups are introduced after or simultaneously with molding.

As a result of intensive VC research, the present inventors have found that the amphoteric ion exchangers produced by these methods have excellent performance as anticoagulant materials.

The linear original block copolymer referred to in the present invention includes, for example,
In general, (polyA-polyB) n is a binary block copolymer in which n is 1 or more, or ld, generally (
polyA-polyB-poly(j)n, (
polyA-po'1yO-polyB)n, (
po'1yB-polyA-polyc)n, (
polyA-polyc-polyB-polycrin
, (polyB-polyc -0'1゜polyA-polyc) n is 1 or more ternary block copolymer, polyc-polyA-polyc
lyB-polyc.

poxyc-polyA-polyc-'po'17B
-polyc, po17A-polyB-poly
o-polyB-polyA, polyB-pol
yA-polyo-polyA-polyB, T)
017A-pO170-pOlFB-polyC! -p
olyA,, polyB-po'lyc-poly
It is a ternary block copolymer bonded by an A-polyc-polyB arrangement, and is branched; a block copolymer is, for example, polyB having polyA as a branch,
polyA, pony with polyB f branch
A and T) polyc with 017B as a branch.

(pony A-poly C) polyB, (p
polyA, polyc having a block copolymer in which n is 1 or more represented by olyB-polyO)n on a branch
! A block copolymer in which n is 1 or more, represented by (polyA-polyB) n, having (polyA-polyB) on its branches, (polyA-polyB)
lyB) Polyc having a block copolymer in its branches, where n is 1 or more.

'po17cmpolyA-polyc and polyBXT)0170 with branched block copolymers linked to polyc
-poly B-pol) r PolyA is connected to C and has a nine-block co-vehicle union on its branches.

Among the above block copolymers, in order to prevent the formation of a polyion complex in the boundary region between the domain with the cation exchange group and the four domains with the anion exchange group,
polyA and po17B do not match each other, and poly
It is preferable to use a frozen block copolymer body having a bonding mode separated by c. Such FEt-il
The shaped block copolymer includes (1) 017A-polyc
-polyB-pO17C)n, (pOlFB-p
olyC-polyA-polyc) n
is 1 or more ternary block copolymers and polyA-p
olyo-polyB, polyc-polyA
-polyc-polyB-polyc.

po17A-p0170-p017B-po17cmp
olym, T)017B-polyc-polyA
-po'1yc-polyB, etc., and branched block copolymers include polyA and polyB with p on the f branch.
olyc, (polyA-polyo)n(z91
) with branches polyB, (pollB-poly
crinrn>1) polyA, poly on the k branch
c-polyA-polyc f-branch with polyB,
The polyo-polyB-polyc f branch contains po17A, etc.

Furthermore, poly C-poly A-poly C-
poly B-poly O.

pol with branches polyc-polyA-polyc
yB.

Add polyc-polyB-polyc to the branch pol
Two or more ends are polymer blocks po1y like yA
c! and polyA and polyB are poly
c! In block copolymers that are separated from each other by poly CffB 5+, when cross-linked to poly CffB 5+, the microphase-separated structure is relatively less likely to change due to the introduction of ion-exchange groups, ultimately resulting in anti-blood coagulation properties with stable performance. It is expected that the materials will become easier to obtain.

Among the three types of polymers constituting the original block copolymer used in the present invention, the polymer p into which a cation exchange group can be introduced
It is necessary that a carboxyl group, a sulfone group, an ali/# group, etc. can be easily introduced into o17A. Among these, the carboxyl group is a non-anastomeric carboxylic acid ester (e.g. acrylic acid ester, methacrylic acid ester x tyl,
crotonyl ester, co-R diene carboxylic acid ester, etc.), or acrylonitrile, methacrylonitrile.

A monomer with a cyano group such as vinylidene cyanide, or an alkylidene malonzaki ester M-? It can be obtained by hydrolyzing a polymer such as α-cyanoacrylic ester, and the sulfone group can be obtained by hydrolyzing a polymer of styrene sulfonyl chloride or styrene, α
-Methylstyrene.

It can be obtained by sulfonating a polymer such as vinyltoluene or diphenylptadiene 7 by a known method.

Long-life molecule polyB Fi that can introduce L imaginary ion exchange group
, it is necessary to be able to introduce functional groups such as ammonium groups, sulfonium groups, or phosphonium groups.

These functionalities 4= are, for example, complex jj containing a nitrogen atom
Vinylpyridines (2-vinylpyridine, 4-vinylpyridine, 2-methyl-5-vinylpyridine, etc.), vinylpyrimidines, vinylquinolines, vinylcarbazoles, vinylimidazoles, etc., which are vinyl compounds with (n-' ~
5*RI r R2 is obtained by quaternizing a polymer of styrene derivative amines such as 'L mI p-vinylbenzyl dialkyl amines, each represented by an alkyl group having 1 to 12 carbon atoms.

(R, is hydrogen or an alkyl group having 1 to 12 carbon atoms, R
2e R3 is an alkyl group having 1 to 12 carbon atoms) or an alkylaminoacrylate (R14''! Hydrogen or an alkyl group having 1 to 12 carbon atoms, R2t Ra is an alkyl group having 1 to 12 carbon atoms, respectively) Quaternary amines can also be introduced by quaternizing a dialkylacrylamide polymer represented by an alkyl group).Furthermore, quaternary amines can be easily introduced into polymers of chloromethylsderene, including chloromethylated styrene, by known methods. can be introduced.

As the remaining monomer constituting the polymer polyC into which no ion exchange group is introduced, diene monomers are suitable, such as butadiene, isoprene, pentadiene, cyclohequinadiene, and the like.

In the case of a sample composed of such diene monomers and having a neutral block, this part is treated with peroxide, sulfur,
- Can be easily crosslinked by known methods using chloride fluoride, concentrated sulfuric acid, ultraviolet rays, etc. This increases the strength of the material.

Component polymers constituting the block copolymer used in the present invention: polyA, polyB, polyC
The molecular weight of is preferably 10 fathoms to 10·f/mol. More preferably 104 to 10 t/mol
It is.

As is generally well known, in a block copolymer, as the molecular weight decreases, the volume fraction of the compatible interface area generated between two adjacent domains formed by microphase separation increases. In samples with such good and low molecular weights, the formation of polyion complexes is large, and the effect of the simultaneous presence of cation domains and 7-ion domains due to microphase separation is weakened. According to the experimental facts published so far on various block copolymers, it is thought that a phase-separated structure is hardly formed when the molecular weight of each block is 10' or less. On the other hand, if the molecular tube is a large sample, the viscosity of the sample in its solid or liquid state increases, which may make molding difficult.

The original block copolymer must contain 5% or more of the component polymer polyA into which the cation exchange group is introduced and the component polymer p017B into which the anion exchange group is introduced in an amount of 5% or more, respectively. The reason for this is that when the number of component segments with cationic or Fi anionic symbiotic groups in the amphoteric ion exchanger obtained at the crossroads becomes less than 5, the effect of the simultaneous presence of amphoteric ions is significantly reduced. This is because it will be put away.

In addition, the neutral component polymer po17c does not necessarily need to be included, but if it is necessary to increase strength, the weight fraction is 3
It is desirable that the content be 0 or more.

The anti-blood coagulant material comprising the amphoteric ion exchanger of the present invention can be produced by, for example, forming an original block copolymer produced by living anionic polymerization, graft copolymerization, or a combination thereof into a desired shape, and then hydrolyzing it. If it is obtained by subjecting it to a sulfonation treatment, a sulfonation treatment, or a quaternization treatment, and it contains a neutral domain consisting of a boridiene system, it is also possible to add a partial bridge or a hydrogen atom depending on the requirements. It is.

As living anionic polymerization initiators, known butyrrhizium (n, sec, tsrt, etc.), 2-methylbutyrrhizium, sodium naphthalene, sodium anthracene, α-methylstere/tetramer sodium, sodium biphenyl, etc. are used. Aromatic hydrocarbons, cyclic ethers.

1 g of aliphatic hydrocarbon water (generally be/zene, toluene.

tetrahydrofuran, n-hexane, cyclohexane, etc.) in vacuum or nitrogen gas.

Polymerization is carried out under an inert gas atmosphere such as argon gas.

Graft copolymerization is, for example, the action of a homopolymer or block copolymer with a living anion terminal on a polymer having an active group (carboxylate, ester, carboxylic acid, amide, halide, etc.)'fr. Yosho is carried out.

It is also possible to cause the above-mentioned living anion polymerization initiator to act on a polymer of polyester or diphenylbutadiene.

Since the block coelectrolyte as described above is composed of a plurality of monomers having different polarities, it has excellent solubility in solvents and can be bathed in various solvents. Also polyethylene, polyvinyl chloride, polypropylene, Teflon, polysulfone, polyacrylonitrile, silicone rubber, polycarbonate.

It has excellent adhesion to many materials such as glass, and can be used as a thin coating on their surfaces. These properties are a great advantage in moldability when the block copolymer is used alone or as a composite material.

After molding this original block copolymer into any desired form alone or as a coating of other materials, or simultaneously with molding, the nitrogen portion is converted into a quaternary or tertiary ammonium salt, and then sulfonated, hydrolyzed, etc. give The quaternization of nitrogen is carried out by a known method, ie, by reacting it with an alkyl halide compound, but if a solvent containing an alkyl halide compound is used, the quaternization can be carried out simultaneously with film formation. Halomethylstyrene can be converted into a quaternary amine using trimethylamine or the like. Further, the nitrogen portion can also be converted into a tertiary ammonium salt using hydrochloric acid or the like.

For sulfonation of aromatic rings, use concentrated sulfuric acid and oleum.

lrl with sulfur trioxide, chlorosulfonic acid, etc. Ken Kagaku Koza, Vol. 14-1, P 1776), and the hydrolysis of carboxylic acid esters is carried out using an aqueous solution of t-17ium hydroxide, etc.
Each can be performed using a known method.

In the present invention, as described above, a material having good stability, e, formability, and high anticoagulability can be obtained from a suitable block copolymer. Due to these advantages, this material can be widely applied to various medical instruments or devices. Artificial blood vessels, sutures, ligatures, aortic balloons, especially those used in contact with blood.

Blood bag, catheter, caniere, shunt.

Blood transfusion tube, hemodialysis or #Li oxygen permeation membrane or hollow *! It is expected to be applicable to a, and to prevent blood coagulation over a long period of time.

In the original block copolymer used in the present invention, the positive and negative charges of the final material can be changed freely depending on its composition or the conditions for introducing ion exchange groups, and It is also possible to change the microdomain structure by changing the film forming conditions.
It becomes possible to control the way in which chestnuts and cells adhere to materials, opening up the possibility of application to bioseparators and cell culture beds.

The present invention will be explained below by way of examples.

Antithrombotic properties were evaluated using the method developed by Sakurai et al. (Sakurai, Akaike, Kataoka, Okano et al.
Polymers ”Academic Press
,N,! , p. 555 (1980)')
Therefore, I conducted several measurements.

All the results obtained in the experimental and comparative examples are summarized in Table 1.

Example 1 5ea-
Butyl lithium & 4 x 10-' mob initiator, styrene and 4-vinylbendi-2 dimethylamine (
Hereinafter abbreviated as 4-VBDMA) and imprene, isoprene 7? , styrene 15t, isoprene 7f, 4-V
BDMA 25 F, Isop vy7f in the order Ks. Polymerization is carried out by sequentially introducing monomers in 5 steps to form polyisoprene-polystyrene-polyisoprene-poly(4-VB
A five-block copolymer linked with DMA)-polyisoprene was obtained. Prior to polymerization, styrene was dried with calcium hydride, distilled under reduced pressure, and further purified with sodium benzophenone, followed by vacuum distillation. Isoprene was dried with calcium and sodium hydride and then distilled. 4-V
BDMA Fs was dried with calcium hydride, distilled under reduced pressure, and further purified using a triphenyl methylrhydium-rhydium bromide system and vacuum distilled. The polymerization yield was approximately 1.
00chi and 9.

A film prepared from a benzene solution of the obtained original block copolymer was stained with osmium tetroxide and observed with a transmission electron microscope, and each had a width of 1 oo;~150 mm.
It was confirmed that three layers of A grade were present in a lamellar shape.

This sample was coated on glass beads of f) 40 to 60 mesh by dipping method using a benzene bath solution of α2 heavy tS, treated with methyl iodide vapor, and then treated with a 20 wt% nitromethane solution of sulfur monochloride. crosslinked,
Furthermore, it was treated with a 3 wt % chloroform solution of chlorsulfo/acid at room temperature for 1 hour.

The sample thus obtained had an inner diameter of 31111. Packed into a column made of polyvinyl tetrachloride with a length of 10 mm, the fresh side of the adult dog was filled with a flow rate of 1
．． 2 + tg/min for 1 minute, and the number of platelets flowing out was counted using a phase contrast microscope.

As a result, this sample showed a significantly lower platelet adhesion rate than uncoated glass beads or polystyrene-coated samples.

Example 2 The glass beads coated with Samurai 9 amphoteric ion exchanger in Example 1 were treated with a 5% ferrous sulfate water bath solution and used to measure the adhesion rate of platelets.

As a result, the adhesion rate was even lower than in Example 1, and the adhesive ratio in the table also showed a low value.

Example 3 An experiment similar to Example 2 was conducted using cyclohexane as the dipping solvent, and fairly good results were obtained.

Example 4 An experiment similar to Example 2 was conducted using dioxane as the dipping solvent, and quite good results were obtained.

Example 5 Sodium #! 5 ec in thoroughly purified benzene
-Butyllithium 10X10-'mo15r used as initiator, styrene 5t, butadiene 50f.

8 fi of 4-vinylpyridine was sequentially added and polymerization was carried out in three stages to obtain a 3-block copolymer linked with polystyrene-polybutadiene-poly(4-vinylpyridine). Prior to polymerization, styrene was prepared in the same manner as in Example 1, and butadiene was prepared in the same manner as in Example 1 with isoprene.
After drying 4-vinylpyridine with calcium hydride,
Vacuum drying was performed. The polymerization yield was approximately 100%.

After coating glass beads, crosslinking, and introducing @ and anion ion exchange groups in the same manner as in Example 1, 5
When the adhesion rate of platelets was measured after treatment with % of acid Dai-Chichisui bath solution, good results were obtained.

Example 6 Same as Example 1, isopre/guanion polymerization method
8f, styrene 17t, and isoprene 8 were sequentially added in five stages to carry out polymerization. Initiator tVi52 x 1
It was set as 0-' mol. Then the molecular weight t 5 x 10
't/rno1 polychloromethylstyrene 2Bff
The benzene solution containing the polymer was poured into a polymerization tank to obtain polychloromethylstyrene having a block copolymer linked to polyisoprene-polystyrene-polyisopre/ on its branches. The polychloromethylstyrene used here was obtained by methylating polystyrene with chloro-methy≦-thi by a known method.

The polychloromethylstyrene moiety of the branched block copolymer thus obtained was quaternized using trimethylamine by a known method, and then
Using dioxane bath solution of S, 40 ~
60 mesh glass beads were coated and then cross-linked with a 20 wt 1 nitrometh/bath of sulfur monochloride, sulfonated with a 2 wt% chloroform bath of chlorosulfonic acid, and sulfonated with a 2 wt% chloroform bath of chlorosulfonic acid, and a 5% ferrous sulfate bath. Processed 3
, *As a result of evaluating the adhesion rate of platelets using the same method as in Example 1, it was found that this sample had almost the same anticoagulant properties as the linear block copolymer.

Comparative Example 1 The Kuhara block copolymer obtained in Example 1 was coated on 40 to 60 mesh glass beads by a dipping method using a benzene bath solution of α2vt, and then treated with methyl iodide vapor.

When the adhesion rate of platelets was measured in the same manner as in Example 1, a very high adhesion rate was observed.

Comparative Example 2 Same as Example 1, but 6t of isoprene, 12t of styrene, and 6t of isoprene were sequentially introduced in three stages using the pin anionic polymerization method to form a block copolymer linked with polyisoprene-polystyrene-polyimprene. Obtained. Amount of initiator used fl 2.8 x 10-'
I had sex with a mob.

This block copolymer was coated on 40 to 60 mesh glass beads by a dipping method from a 1 ka 2 vt% benzene solution, and -20 wt% of sulfur chloride was added.
After crosslinking with a nitromethane bath, chlorsulfonic acid
% chloroform solution tellulfonation, treated with 5% ferrous sulfate water bath solution.

When the adhesion rate of platelets was measured in the same manner as in Example 1, this sample showed a brighter value than the amphoteric ion exchanger of Example.

Comparative Example 3 Sodium polystyrene sulfonate and polyvinylbenzyltrimethylammonium chloride were prepared from water, sodium bromide, and acetone (3:1:1 by weight) in equal moles of 7 units (6). A solution having a polymer concentration of α5vt was prepared by dissolving the polymer in a mixed bath medium. 40～
60 meshes of glass beads were immersed in this bath solution and then in water at 0°C to obtain a sample whose surface was coated with a thin film consisting of a polyion complex.

When the adhesion rate of platelets was measured in the same manner as in Example 1, this sample showed a significantly high value as shown in Table 1.

Table 1 Sample Platelet adhesion rate Glass 42cm Polystyrene 7 55% Example 1 21- Example 2 5 whispers Example 3 20% Example 4 14% Example 5 13% Example 6 8% Comparative example 1 94% Comparative example 2 25% Comparative example 5 45% Patent applicant: Toyo Soda Kogyo Co., Ltd.

Claims (3)

[Claims] (1) An anti-blood product consisting of a linear or branched block copolymer in which the entire or part of the component block is a polymer chain poly A having a cation exchange group and a polymer chain pony B having an anion exchange group. Coagulable material. (2) Polymer block po into which cation exchange groups can be introduced
A polymer block pol containing ny A and a molecular block poly B into which an anion exchange group can be introduced at a weight ratio of 5 or more, and in which no ion exchange group is introduced.
yci weight ratio 0~? Polymer block pony
A K cation exchange fund is introduced to make it a polymer chain poly A having a cation exchange group, and an anion exchange group is introduced to the polymer block poly B to make it a polymer chain poly A having an anion exchange group: Anticoagulant material as Ly B . (3) The anti-blood coagulant material according to claim 2, which is formed by crosslinking a polymer block polyci.