JPS6023626B2 - Method for producing novel antithrombotic material - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a novel antithrombotic material with excellent mechanical properties.

In recent years, many polymeric materials have come into use as medical materials, but when they are used in areas that come into direct contact with blood, the blood coagulates and forms thrombi, so the antithrombotic properties of polymeric materials are limited. Improving this is an important challenge in this field.

As a method to improve the antithrombotic properties of this polymer material,
There are known methods of making the material itself less likely to generate blood clots, and of mixing natural anticoagulants such as heparin into the material or chemically bonding them to prevent the formation of blood clots.

Examples of the former include certain polyurethane compounds made hydrophobic or hydrophilic to increase antithrombotic properties, which are used in artificial hearts, and hydrogels or hydrophilic polymers used as base polymers. There is something that is combined with
However, although these polymeric materials exhibit fairly high antithrombotic properties, they are still insufficient for practical use, and no satisfactory material has yet been obtained. On the other hand, as an example of the latter method, there is a method in which a vinyl compound having a tertiary amino group is graft-polymerized onto a Motomura polymer, the amino groups in the grafted polymer are quaternized, and then the amino groups are heparinized. . However, the polymeric material heparinized in this way deteriorates the desirable mechanical properties originally possessed by the base polymer,
There is a drawback that the strength and durability necessary for practical use cannot be obtained. In addition, a so-called ionene polymer containing quaternary ammonium ions necessary for heparinization in its main chain is manufactured, and heparin is bonded to this polymer to form a reaction product of ricinoleic acid, glycerin, and tolylene diisocyanate. Journal of the Macromolecular Science-Chemistry (J. Nnecro.Mol., Sci-C
hem), A4'3', pages 715-738 (1
97th King)]. However, such polymeric materials have poor hydrophilicity, are not compatible with blood, and have the disadvantage that it is difficult to obtain sufficient mechanical properties for practical use. The present inventors have conducted extensive research in order to overcome the drawbacks of conventional medical polymer materials and develop polymer materials with excellent antithrombotic properties and mechanical properties. It was discovered that the object could be achieved by forming a urethane ionene containing a polyether as a component in the main chain and converting it into heparin, and based on this knowledge, the present invention was accomplished.

That is, the present invention is based on the general formula (1, m and n in the formula are each an integer of 1 or more)
A polyether diol with an average molecular weight of 500 to 390 or more and a polyoxyethylene content of 10 to 5% by weight is first reacted with a diisocyanate and then with a dialkylaminoalkanol to form a polyether diol having a tertiary amino group at both ends. It is characterized by producing a prepolymer, then reacting it with a dihalogen compound in the presence or absence of a small amount of polyvalent tertiary amine to produce polyether urethane ionene, and then converting it into heparin. The present invention provides a method for producing an antithrombotic material.

The method of the present invention involves the first step of producing a polyether urethane having isocyanate groups at both ends by reacting a specified polyether diol with a diisocyanate. The second step is to react to produce a polyether urethane prepolymer having dialkylamino groups at both ends, in which this prepolymer is reacted with a dihalogen compound in the presence or absence of a small amount of polyvalent tertiary amine. to elongate the main chain,
The process consists of a third step of producing polyether urethane ionene having a quaternary ammonium group in its main chain, and a fourth step of converting this polyether urethane ionene into heparin.

The general formula (1) used as a raw material in the method of the present invention
) has an average molecular weight of 5
00 to 3900, and the polyoxyethylene content is in the range of 10 to 5% by weight.

If the average molecular weight is less than 500, the physical properties such as elasticity are generally low, while if it exceeds 3,900, the strength decreases and it becomes difficult to process, which is not preferable. Furthermore, polyoxyethylene content less than 1% by weight has poor hydrophilicity and therefore cannot be adequately heparinized, whereas polyoxyethylene content exceeding 5% by weight has poor flexibility, elasticity and wet strength. I don't like it because it's inferior.

In particular, materials for equipment that come into contact with blood for a long period of time are preferably those having an average molecular weight in the range of 1000 to 3000 and a polyoxyethylene content in the range of 10 to 3% by weight. Such polyenal diols are well known and are usually commercially available as surfactants or emulsifiers. In the first step, the diisocyanate to be reacted with the polyether diol can be arbitrarily selected from diisocyanates commonly used in the production of polyurethane.

Suitable diisocyanates have the general formula OCN-R'-NC
○ ... (b) A compound represented by (R' in the formula is a divalent aliphatic, alicyclic or aromatic hydrocarbon group).

Examples of such diisocyanates include aliphatic diisocyanates such as hexamethylene diisocyanate and octamethylene diisocyanate; alicyclic diisocyanates such as methylcyclohexane diisocyanate and 4,4'-dicyclohexylmethane diisocyanate; (or 2,6)-tolylene diisocyanate, diphenylmethane-4,4'-diisocyanate,
Aromatic diisocyanates such as p-xylylene diisocyanate and 1,5-naphthylene diisocyanate can be mentioned. The first step of the method of the present invention can be carried out according to known methods commonly used in the production of polyurethane.

For example, the polyether diol represented by the general formula (1) and a predetermined diisocyanate are reacted in a suitable organic solvent in the presence of a catalyst if necessary. Examples of organic solvents used in this case include tetrahydrofuran, dimethyl sulfoxide, and dibutyl ether, and examples of catalysts used include dibutyltin dilaurate and 1,8-diazabicyclo[5,4,0]undecene-7. Usually, the diisocyanate is used in an excess amount of two or more molar equivalents of the polyether diol, and the reaction is carried out at a temperature ranging from room temperature to 100°C. In this first step, the reaction proceeds according to the following reaction formula, and a polyether urethane having isocyanate groups at both ends is obtained.

HO-A-OH+OCN-RI-NCO→OCN-RI
-NHCO○tA-OCONH-RI-NHCOOnax
-A-OCONH-RI-NC○ (A in the formula is a polyether residue, x is an integer of 0 or 1 or more, RI has the same meaning as above) ☆☆However, this polyether urethane is As a result of analysis by migration chromatography, x was 0 in approximately 95% of the samples, and x was 1 in most of the remaining samples.

Therefore, in the following explanation, x will be described as 0 for simplicity. In the second step of the present invention, the polyether urethane having isocyanate groups at both ends obtained in the first step and the dialkylaminoalkanol are mixed in the solvent used in the first step. A polyether urethane having dialkylamino groups at both ends is produced by reacting under the same temperature conditions.

Therefore, it is usually preferable to add the dialkyl alkanol immediately after the reaction in the first step is completed without separating the reaction product from the reaction solvent, and to continue the reaction. The dialkylaminoalkanol used here includes those represented by the general formula (in which R2 and R3 are an alkyl group and R4 is a linear or branched alkylene group), such as 2-dimethylaminoethanol. , 3-dimethylamino-1-propanol, 3-dimethylamino-2
-propanol, 2-dimethylamino-isobutanol, 2-diethylaminoethanol, 2-diethylamino-1-propanol, 2-diethylamino-2-propanol
Although examples include Gnol, 2 is preferable.
-dimethylaminoethanol.

In this second step, the reaction proceeds according to the reaction formula shown below, and a urethane prepolymer having tertiary amino groups at both ends is obtained.

In the third step of the method of the present invention, the polyether urethane having tertiary amino groups at both ends obtained in the second step is reacted with a dihalogen compound to convert the tertiary amino group into a tertiary amino group. The primary mirror is extended in the form of a quaternary ammonium salt,
Obtain polyether urethane ionene.

That is, the polyether urethane having tertiary amino groups at both ends obtained in the second step is dissolved in a suitable solvent, a small amount of polyvalent tertiary amino is added in some cases, and then,
A solution of a dihalogen compound dissolved in the same solvent is added dropwise to react. In this case, the dihalogen compound may be added dropwise to the reaction solution without isolating the reaction product obtained in the second step. This reaction proceeds relatively easily, so
It can be carried out within a few hours at a temperature of 60 oo. The dihalogen compound used in this third step has the general formula x-R5-x...(N) (R in the formula
5 is a divalent aliphatic, alicyclic or aromatic hydrocarbon group, x
is a halogen atom), and examples of such compounds include 1,2-dibromoetaso, 1,3-dibromopropane, 1,4-dibromoptane, 1,6-dibromohexane, 1,10 Examples include -dibromodecane, 1,4-dichlorobutene-2,1,4-dibromocyclohexane, and Q,Q'-dichloro-p-xylene.

Examples of the solvent used in this third step include dimethylformhumide, dimethylacetamide, tetrahydrofuran, and chloroform. Preferably, those having a molecular weight of 8 to 0, such as tetrahydrofuran.

In addition, in this third step, a small amount of polyvalent tertiary amine is used as desired, but its primary purpose is to reduce the amount of polyether urethane produced by adding it. The purpose is to increase the concentration of nitrogen cations in the structure of the quaternary ammonium salt in Nene, and to facilitate subsequent heparinization.The second purpose is to add a tertiary amine with a valence of 3 or more, In addition to increasing the concentration of nitrogen cations in the quaternary ammonium salt structure, the present invention aims to increase the strength of the material by forming a network structure by crosslinking between molecules.

However, adding too much of this polyvalent tertiary amine will affect the basic physical properties of the material, so it is desirable to add a small amount. A preferable range is 5 to 15% by weight. The polyvalent tertiary amine used in this case is not particularly limited as long as it can participate in the formation of quaternary ammonium salts, such as N, N, N',
N'-tetramethyl-1,3-diaminopro/f, N
, N,N',N'-tetramethyl-1,3-diaminobutane, N,N,N',N'-tetramethyl-1,6-diaminohexane, or divalent tertiary amines such as 1,
3,5-tris(3-dimethylaminopropyl)hexahydro S-triazine and the like are used.

In this third step, the reaction proceeds according to the reaction formula shown below to obtain polyether urethane ionene.

(n in the formula is an integer of 2 or more) The polyether urethane ionene obtained in this way can be formed into a sheet or tube shape, or coated on a suitable surface and However, in order to obtain a sheet-like molded product of polyether urethane iones,
The reaction solution obtained in the third step was cast onto a Teflon mold or a glass petri dish, and the solvent was evaporated at room temperature for about 4 hours, and then heated for 100 minutes under a nitrogen stream.
q○: After heating for several hours, sheet-like polyether uretasoionene is obtained.

After further cooling under reduced pressure, unreacted raw materials are extracted using methanol. In order to obtain a tubular molded article, a stainless steel rod of an appropriate thickness is inserted into the reaction solution, pulled up and dried.

After repeating this operation, remove the stainless steel rod to obtain a tube of appropriate thickness. Furthermore, in order to coat the surface, an object with a suitable surface is dipped into the reaction solution and pulled up and dried, or the reaction solution is applied to the surface of the object and then dried.

In the fourth step of the present invention, the polyether urethane ionene obtained in the third step is made into a molded object such as a sheet, or applied to another molded object, and brought into contact with an aqueous heparin solution. and perform heparinization.

This heparinization is carried out, for example, in an aqueous heparin solution with a heparin alkali salt (usually heparin sodium salt) concentration of 0.5% by weight or more, preferably 0.5 to 5% by weight.
Room temperature to 90qo, preferably 50 to 80°C for several hours to 2
This is carried out by soaking the molded body or coated body of the polyether urethane ionene for 0 days. In this case, the heparin aqueous solution is o. It is preferable that the amount of salt is less than 30%. After this heparinization, it is washed with water or physiological saline, and then vacuum dried at room temperature. The heparinized polyether urethane ionene of the present invention has excellent antithrombotic properties and mechanical properties, and can be used as a molded body such as a sheet or a tube, or as a composite of other base materials. By applying it to a molded body, it can be widely used as a medical antithrombotic material.

Next, the present invention will be explained in more detail with reference to Examples.

Example 1 A round bottom flask equipped with a vacuum stirrer, a dropping funnel, and a three-way cock was charged with 94.8 g of tolylene-2,4-diisocyanate, 50 g of tetrahydrofuran as a solvent, and 0.095 g of dibutyltin dilaurate as a catalyst, and the mixture was replaced with nitrogen. did.

While stirring at room temperature, an A-B-A type polyether consisting of a polyoxyethylene block block and a polyoxypropylene block 'B', having a polyethylene oxide block content of 10%, an average molecular weight of 1940, and having hydroxyl groups at both ends. Diol (hereinafter referred to as polyether diol).
A solution prepared by dissolving 100 ml (referred to as 61) in 25 ml of tetrahydrofuran was added dropwise from the dropping funnel over a period of about 2 hours.
Thereafter, the mixture was heated to 50 oo and continued to be stirred for 1 hour. At this point, a portion of the reaction solution was taken out, and the disappearance of the absorption of the hydroxyl group of polyether diol was confirmed using an infrared absorption spectrum.
Next, 193.9 evening dimethylaminoethanol was added to 10
The solution was added dropwise over a period of minutes, and after stirring for 1 hour while maintaining the temperature at 50 oo, the reaction solution was taken out and the disappearance of absorption of isocyanate groups was confirmed by infrared absorption spectrum. The produced polyether urethane having dimethylamino groups at both ends was taken out using a water-methanol mixed solvent (mixing ratio 2:1) as a precipitant. This was made into a tetrahydrofuran solution of about 3% by weight, and a dihalogen compound dissolved in a small amount of tetrahydrofuran was added dropwise while stirring.

The amount of the dihalogen compound used was approximately 1.2 times the excess number of moles of dimethylamino groups in the polyether urethane having dimethylamino groups at both ends. After stirring for a while, this was cast onto a Teflon mold. After evaporating the tetrahydrofuran at room temperature for about 4 hours, it was heated at 100°C for 2 hours in a nitrogen stream to form a sheet of polyether urethane ionene with a thickness of 0.1 to 0.2 feet. Got the film. As the dihalogen compound, 1,3-dibromopropane (OBP),
1,4-dibromobutane (DBB), 1,6-dibromohexane (DBH), 1,10-dibromodecane (DB
D), Q,Q'-dichloro-p-xylene (DCX),
Six kinds of 1,4-dichloroptene-2 (DCB) were used.

In order to investigate the mechanical properties of these films, tensile tests were conducted using punched or ring-shaped samples with an inner diameter of 11.6 legs and an outer diameter of 13.6 legs.

The results are summarized in Table 1. All of these six types of films have practically sufficient mechanical properties. 1st
These films were soaked in a 1% aqueous solution of heparin sodium (powder containing 162 international units per female) at 5 and 0.
After soaking for a day, rinse with water, and then soak with physiological saline for 2 days.
The sample soaked for a certain period of time was used as a heparinized sample.

The antithrombotic properties of this product were evaluated by the following method (Imai method).

In other words, a watch glass with a lid on which the film to be tested is placed is
Maintain the temperature at 7q0, add 0.25 ml of fresh large ACD blood on top of it, add 0.025 ml of 0.1 N calcium chloride aqueous solution to initiate blood coagulation, and after a certain period of time have passed. This was diluted with water to stop the blood clotting reaction. The generated clot was washed with water, fixed with formalin, washed again with water, air-dried overnight, and weighed. The measured weight of the obtained blood clot was determined as a coagulation rate (%) with respect to the measured weight of the blood clot obtained on a simple clean glass watch glass (15 minutes of blood contact time). The above test was carried out for six types of films according to the invention for a blood contact time of 3
When the test was carried out for 0 minutes, all the films either showed no blood clots or only a trace of blood clots formed. That is, the coagulation rate was 0%. Example 2 Various polyether urethane ionenes were produced in exactly the same manner as in Example 1, except that the type of polyether diol used as the raw material in Example 1 was changed.

Table 2 shows the types of polyether diols used. Further, Table 3 summarizes the mechanical properties of polyether urethane ionene produced from each of these polyether diols by changing the dihalogen compound. Note that the abbreviations in Table 3 are the same as in Example 1. Furthermore, among these Table 3, No. 3 has excellent mechanical properties. Example 1 Regarding films of three types of polyether urethane ionene produced using polyether diols of Example 1.
Heparinization was performed in the same manner as above, and antithrombotic properties were evaluated.

At a blood contact time of 30 minutes, all films showed either no blood clotting or only a trace of blood clots.
Table 2 Table 3 It is generally believed that the expression of antithrombotic properties of heparinized materials is based on the elution of heparin from the heparinized material into the contact blood, and in the above-mentioned evaluation of antithrombotic properties, If all the heparin bound to the film were eluted into the blood in a single test, the antithrombotic properties would no longer last.

Therefore, the film evaluated for antithrombotic properties was washed five times with physiological saline to wash away the blood, and the coagulation test was repeated for each flow of blood contact time until a clot that could be weighed was produced. I asked for the number of times. As a sample,
Polyether diol NO. in Table 3. A polyether urethane ionene film prepared from No. 3 and DCX was immersed in a 1% aqueous heparin solution at 5000 °C to heparinize it.

The number of repetitions of the above procedure was then investigated for samples whose immersion time in the heparin solution was varied. At the same time, Example 1
In polyether diol No. The number of repetitions was also investigated for polyether urethane ionene prepared from No. 1 and DCX. The results are shown in Table 4. Table 4 As clearly seen from Table 4, the heparinized polyether urethane ionene film according to the present invention has excellent antithrombotic properties.

On the other hand, for comparison, a similar blood coagulation test was conducted on polyether urethane ionene film and polyethylene film that were not heparinized.
When tested in minutes, the coagulation rate was 100%, that is, no antithrombotic properties were shown. Example 3 Polyether diol shame. 3,4,4'-diphenylmethane diisocyanate\diethylaminoethanol and dibromo-1,10-decane were used as raw materials in the same manner as in Example 2 (however, the diisocyanate was
Prepare a tetrahydrofuran solution (approximately 10% solution) of polyether urethane ionene synthesized with 500% tetrahydrofuran, and insert this into a stainless steel rod with a diameter of 5 ribs and a polished surface. The coating and drying process was repeated for about one cycle to form a polyether urethane coating on the surface of the stainless steel.

When this was immersed in water and the coating was removed, a tube with a thickness of about 300 Am was obtained. This tube was cut into a length of 2 mm (this is referred to as tube A). Separately, a European polyvinyl chloride blood circuit (5 inner ribs, 7 outer ribs) was cut into two lengths, and the tetrahydrofuran solution of the bolyether urethane ionene was applied to the inner and outer surfaces of the circuit.
Coating and drying were repeated to create a coated sample tube (this will be referred to as tube B). The tubes A and B were soaked in 60% water for 1 day to extract residual solvent and impurities, and then soaked in 5% by weight heparin aqueous solution.
00 for 5 days to perform heparinization, and further soaked in ion-exchanged water, washed, and vacuum-dried at room temperature.

The tube obtained in this way is
One tube was implanted into each of the left and right jugular veins of 0k9), left for 4 hours, and then removed, and the state of thrombus formation in the tubes was observed.

As a result, no thrombus was observed in tubes A and B. For comparison, an uncoated polyvinyl chloride tube was implanted into the same femoral vein, but it was completely occluded with thrombus within 4 hours.

Example 4 Polyether diol fabric. 3. 100 parts by weight of polyether urethane having dimethylamino groups at both ends, which was produced in the same manner as in Example 1 using tolylene-2,4-diisocyanate and dimethylaminoethanol as raw materials,
9. Dissolve in tetrahydrofuran to make a 20% solution, and add trivalent tertiary amine, i.e., 1,3,5-tris(3-dimethylaminopropyl)hexahydro-S-triazine (hereinafter abbreviated as TDHT)9. The mother weight part was added and stirred.

Next, 21 parts by weight of Q-Q'-dichloro-p-xylene was added thereto, stirred at room temperature for 5 minutes, cast on a glass petri dish, and after evaporating the solvent, a crosslinking reaction was carried out at 100 qo for 6 hours. The thickness thus obtained is approximately 0
．． When a tensile test was performed on the film on the second side,
Breaking strength 26. The base MPa was 60%, and the elongation at break was 60%. That is, the addition of trifunctional amino showed an increase in strength and a decrease in elongation, indicating that crosslinking had occurred. This film was heparinized in the same manner as in Example 1 and then subjected to a blood coagulation test.

Claims (1)

[Claims] 1 1 General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼ (l, m, and n in the formula are each an integer of 1 or more)
A polyether diol having an average molecular weight of 500 to 3900 and a polyoxyethylene content of 10 to 50% by weight is first reacted with a diisocyanate and then a dialkylaminoalkanol to produce a prepolymer having tertiary amino groups at both ends. Next, a method for producing an antithrombotic material, which comprises reacting this with a dihalogen compound to form polyether urethane ionene, and then converting it into heparin. 2 General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼ (l, m, and n in the formula are each an integer of 1 or more)
A polyether diol having an average molecular weight of 500 to 3900 and a polyoxyethylene content of 10 to 50% by weight is first reacted with a diisocyanate and then a dialkylaminoalkanol to produce a prepolymer having tertiary amino groups at both ends. and then reacting this with a dihalogen compound in the presence of a small amount of polyvalent tertiary amine to form polyether urethane ionene, and then converting it into heparin.