JPH06184266A - Antithrombogenic polyurethane elastomer and medical tool - Google Patents

Abstract

PURPOSE:To obtain the subject elastomer useful as a medical tool material such as artificial blood vessel, having excellent mechanical strength, flexibility, elasticity and durability by introducing a cross-linkable functional group to a main chain of a specific polyurethane. CONSTITUTION:(ii) A cross-linkable functional group such as cinnamoyl group is introduced to a main chain or side chain of (i) a polyurethane comprising an A-B-A type block copolymer of a polyoxyethylene (A) and a polyoxytetramethylene (B) as a polyether diol component to give the objective elastomer. A medical tool is obtained from this elastomer.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an antithrombogenic polyurethane elastomer useful as a material for a medical instrument that contacts blood such as artificial blood vessels and artificial organs, and a medical instrument comprising the polyurethane elastomer.

[0002]

2. Description of the Related Art Materials for medical devices that come into contact with blood have good mechanical properties such as flexibility, elasticity, durability and wet strength, and anti-thrombogenicity. It is necessary to have sex. Otherwise, blood will coagulate on the surface of the device to form a thrombus.

Conventionally, silicone and soft polyvinyl chloride have been mainly used as materials for medical devices requiring elasticity. However, when a device made of these materials is brought into direct contact with blood, the blood coagulates on the surface to form a thrombus, and therefore it is necessary to systemically administer an anticoagulant (such as heparin). In this case, if there is bleeding for some reason, there is a risk that hemostasis will not stop.

By the way, it has been proposed to use a polyurethane obtained from polyethylene glycol, an organic diisocyanate and an organic diamine as a medical material. However, this shows good antithrombotic property, but on the other hand, it becomes hydrophilic and therefore wet. Its strength is extremely low and it cannot be put to practical use.

As described above, generally, when the antithrombogenicity and other biocompatibility are improved by making hydrophilic, it is unavoidable that the mechanical strength is lowered. Therefore, it is possible to develop a material having a good balance between the two. It has become an important issue in medical materials.

Under such circumstances, polyoxyethylene (A) and polyoxytetramethylene (B) ABA are used as polyurethanes having both mechanical properties and antithrombotic properties which are sufficiently usable as medical materials. A polyurethane using a block copolymer as a polyether diol component has been proposed (Japanese Patent Laid-Open No. 61-204219). It has good antithrombotic properties, mechanical properties (especially good processability), but still lacks strength after molding.

Therefore, an object of the present invention is to provide an antithrombogenic polyurethane elastomer which has at least as good antithrombotic properties as conventional ones and is useful as a material for medical devices having further improved mechanical properties. . Another object of the present invention is to provide a medical device having an antithrombotic property at least as good as conventional ones and further improved mechanical properties.

[0008]

Means for Solving the Problems As a result of intensive studies by the present inventors, they have found that the present invention can achieve the above object. That is, the present invention provides a cross-linkable functional group in the main chain or side chain of a polyurethane containing an ABA type block copolymer of polyoxyethylene (A) and polyoxytetramethylene (B) as a polyether diol component. It is an antithrombogenic polyurethane elastomer having a group introduced therein. The present invention is also a medical device comprising the above antithrombogenic polyurethane elastomer.

The polyurethane elastomer of the present invention comprises a polyether diol component of an ABA type block copolymer of polyoxyethylene (A) and polyoxytetramethylene (B), an organic diisocyanate, an organic diamine or an organic diamine. It is a polyurethane composed of a diol and has a crosslinkable functional group introduced into its main chain or side chain. The polyurethane elastomer is AB-
Since the A-type block copolymer is used, it is easy to process, and thus easy to mold, and since a crosslinkable functional group is introduced, a crosslinking reaction proceeds after molding to improve strength. be able to.

The polyurethane elastomer of the present invention has, for example, the following formula

[0011]

[Chemical 1]

[Wherein n is an integer of 1 or more and R ₁ is

[0013]

[Chemical 2]

(A, b and c each represent an integer of 1 or more) or a structure having a crosslinkable functional group bonded thereto, R ₂ is an organic diisocyanate residue,
R ₃ represents an organic diamine or organic diol residue, or a residue having a crosslinkable functional group bonded thereto. ], Etc. (however, above-mentioned Chemical formula 1 is a structure before bridge construction) etc. are illustrated.

The polyoxyethylene (A) and polyoxytetramethylene (B) used in the present invention are
The A-type block copolymer has the general formula

[0016]

[Chemical 3]

(In the formula, a, b and c each represent an integer of 1 or more.) From the viewpoint of antithrombotic properties and mechanical properties, the number average molecular weight is usually 300 to 10,000, preferably 500 to. 8000, more preferably 1000-5
It is 000. When the number average molecular weight is less than 300, the antithrombogenicity and elastic properties of the resulting polyurethane elastomer tend to be lowered, and conversely, when it is more than 10,000,
The resulting polyurethane elastomer tends to have reduced mechanical strength and processability.

The polyoxyethylene content in the ABA type block copolymer is 5 to 95 mol%, preferably 10 to 70 mol%, and more preferably 20 to 60 mol%. When the polyoxyethylene content is less than 5 mol%, the resulting polyurethane elastomer tends to be inferior in antithrombogenicity, and when it exceeds 95 mol%, elasticity, flexibility and wet strength tend to be inferior.

The polyurethane elastomer of the present invention preferably has a number average molecular weight of about 1000 to 6000,
More preferably 1500-4500, polyoxyethylene content 10-70 mol%, more preferably 20-60.
Those having a molecular weight of about 20,000 to 60,000, obtained by using a mol% of polyether diol component, are particularly preferable.

The above polyether diol can be produced by anionic polymerization method or cationic polymerization method using polyoxytetramethylene glycol (PTMG) and ethylene oxide (EO).

As the organic diisocyanate, it is sufficient to use aliphatic, alicyclic and aromatic diisocyanates conventionally used in the production of polyurethane, and of course, they will be developed in the future as long as the object of the present invention can be achieved. You may use the thing. Specifically, for example, 4,4′-diphenylmethane diisocyanate (MDI), 2,4 (or 2,6) -tolylene diisocyanate (TDI), p
-Xylylene diisocyanate, hexamethylene diisocyanate, 4,4'-dicyclohexyl methane diisocyanate, etc. are mentioned, Preferably 4,4'-diphenyl methane diisocyanate is mentioned. These may be used alone or in combination of two or more.

As the organic diamine, it suffices to use one that is used as a chain extender in the usual production of polyurethane, and of course, one that will be developed in the future as long as the object of the present invention can be achieved. You may. Specific examples include alkylenediamines such as ethylenediamine, propylenediamine, and hexamethylenediamine, aromatic diamines such as p-xylylenediamine, p-diphenylmethanediamine, and the like, and ethylenediamine is preferable. These may be used alone or in combination of two or more.

As the organic diol, it is sufficient to use one which is used as a chain extender in the usual production of polyurethane, and of course, one which will be developed in the future as long as the object of the present invention can be achieved. You may. Specific examples include ethylene glycol, tetramethylene glycol, 1,6-hexanediol, 1,3-propanediol and the like, with ethylene glycol being preferred. These may be used alone or in combination of two or more.

The mixing ratio of each of the above components is usually about 2 mol of the organic diisocyanate component and about 1 mol of the organic diamine or organic diol component per mol of the polyether diol component, but when a hard polyurethane is required. For this purpose, the mixing ratio of the organic diisocyanate component and the organic diamine or organic diol component may be further increased. In such a case, the blending ratio of each component is appropriately selected within the range of 2 to 5 mol of the organic diisocyanate component and 1 to 4 mol of the organic diamine or organic diol component per 1 mol of the polyether diol component.

The polyurethane elastomer may be produced by a method known per se. For example, it is manufactured as follows. ABA of polyoxyethylene (A) and polyoxytetramethylene (B) which are polyether diol components
The mold block copolymer and the required amount of organic diisocyanate are added to the reaction solvent and heated to 50 to 100 ° C. for reaction. As the reaction solvent at this time, for example, N, N-dimethylacetamide, dimethylsulfoxide, dibutyl ether, dimethylformamide and the like are used. Also,
If a reaction accelerator such as 1,8-diazabicyclo [5.4.0] undecene-7 or dioctyltin dilaurate is used, the reaction can be carried out near room temperature. Then, a required amount of organic diamine or organic diol is added to the prepolymer thus obtained, and a chain extension reaction is carried out at around room temperature to obtain a polyurethane elastomer.

In the present invention, a crosslinkable functional group is introduced into polyurethane, but the crosslinkable functional group is not particularly limited as long as it is a functional group which can be crosslinked by any means such as ultraviolet irradiation and radiation irradiation. Examples thereof include a cinnamoyl group, a phenylazide group, a diacetylene group, a β-styrylacryl group, and the like, and a cinnamoyl group and a phenylazide group are preferable.

Examples of the method of introducing the crosslinkable functional group include the following methods. First, when synthesizing a polyether diol (ABA type block copolymer), a diol having a crosslinkable functional group (for example, PTMG having a crosslinkable functional group bonded thereto) is mixed. It is a method of synthesizing polyurethane from a polyether diol having a crosslinkable functional group. As another method, the polyether diol does not have a crosslinkable functional group, but an organic diamine or an organic diol having a crosslinkable functional group as a chain extender (the above-mentioned organic diamine or organic diol has a crosslinkable functional group There is a method of synthesizing polyurethane by using (bonded). These methods can be combined with the above-mentioned method for producing a polyurethane elastomer to produce the polyurethane elastomer of the present invention.

Even if a crosslinkable functional group is introduced into each component as described above, the mixing ratio of each component may be within the above range in total. The introduction ratio of the crosslinkable functional group in each component is usually 5 to 70 mol%.

After molding the above-mentioned polyurethane elastomer into a desired shape, irradiation of ultraviolet rays or the like is carried out to advance the crosslinking reaction, whereby a polyurethane molded article having high mechanical strength can be obtained.

An antithrombotic physiologically active substance or its derivative (heparin, heparin metal salt, etc.) may be bonded to the polyurethane elastomer. As the binding method, isocyanate, cyanuric chloride, thiophosgene, carbodiimide, cyanodiene bromide, a covalent bonding method using glutaraldehyde, or benzalkonium chloride, a basic surfactant such as tridodecylmethylammonium chloride is adsorbed, Examples thereof include an ionic bonding method in which heparin or the like is ionically bonded.

Examples of the medical device of the present invention include those that can preferably come into contact with blood. Specifically, for example, vascular catheters, artificial kidney AV shunts, artificial heart-lung membranes, artificial blood vessels, Examples include artificial heart blood pumps, aortic balloon pumps, heart catheters, blood bags, and the like.

[0032]

EXAMPLES Examples will be given below to explain the present invention in detail, but the present invention is not limited to these examples.

Example 1 0.2 mol of butandiol containing cinnamoyl group obtained by esterification reaction of 1,2,4-butanetriol and cinnamoyl chloride, and tetrahydrofuran 2
To the mol, 6 g of trifluoromethanesulfonic acid as a catalyst was added, and polymerization was carried out at 0 ° C. with vigorous stirring. The polymerization is stopped with a 2% aqueous sodium hydroxide solution. The polymerization flask was frozen with liquid nitrogen, ethylene oxide (EO) was charged so that the polyoxyethylene content in the polyether diol after polymerization would be 30 mol%, and the temperature was raised to 25 ° C. to perform polymerization. Polymerization was stopped with a 2% aqueous sodium hydroxide solution to obtain a polyether diol having a cinnamoyl group. 0.02 mol of this polyether diol having a cinnamoyl group and 0.04 mol of 4,4′-diphenylmethane diisocyanate were added to dimethyl sulfoxide 2
It was uniformly dissolved in 00 ml, and the mixture was reacted at 80 ° C. for 5 hours with stirring while introducing dry nitrogen gas, and then cooled. A solution of dimethyl sulfoxide containing 0.02 mol of ethylenediamine as a chain extender was added to this reaction solution.
ml was added dropwise, and the mixture was stirred at room temperature to 30 ° C for 7 hours for reaction. The reaction solution was poured into water to precipitate the formed polyurethane, which was filtered off. Further, a low molecular weight compound was removed with acetone using a Soxhlet extractor, and the rest was vacuum dried at room temperature to obtain a polyurethane elastomer.

Example 2 Except that ethylenediamine having a cinnamoyl group obtained by an esterification reaction of ethylenediamine-1-ol and cinnamoyl chloride was used as a chain extender instead of having a cinnamoyl group in a polyether diol. A polyurethane elastomer was obtained in the same manner as in Example 1.

Example 3 After ring-opening polymerization of p-dihydroxymethylphenylazide and tetrahydrofuran was carried out in place of the polyether diol having a cinnamoyl group, the content of polyoxyethylene in the polyether diol after the polymerization was 30 mol%. A polyurethane elastomer was obtained in the same manner as in Example 1, except that a polyether diol having a phenyl azide group obtained by adding ethylene oxide (EO) to the reaction system and polymerizing was used.

Example 4 A polyurethane elastomer was obtained in the same manner as in Example 2 except that p-diaminomethylphenylazide was used as the chain extender instead of ethylenediamine having a cinnamoyl group.

Comparative Example 1 Polyoxyethylene (A) and polyoxytetramethylene
Polyurethane having no crosslinkable functional group in the same manner as in Example 1 except that (B) the polyether diol consisting of the ABA type block copolymer, 4,4′-diphenylmethane diisocyanate and ethylenediamine were used. An elastomer was obtained.

Experimental Example 1 A 10% dimethylacetamide solution of the polyurethane elastomers obtained in the above Examples and Comparative Examples was poured into a horizontal Petri dish placed on a mercury plane, and the solvent was gradually evaporated under reduced pressure to obtain a uniform film. Was prepared. This was irradiated with ultraviolet rays to promote the crosslinking reaction (Examples 1 to 4 only).
Then, this film having a thickness of about 0.3 mm is cut into strips and subjected to JIS K63 at 20 ° C. and a pulling speed of 50 mm / min.
A tensile test was conducted according to the method described in No. 01, and the tensile strength and elongation at break of the film were measured. The results are shown in Table 1.

Experimental Example 2 1 ml of a 10% dimethylacetamide solution of the polyurethane elastomer obtained in the above Examples and Comparative Examples was placed in a test tube having an inner diameter of 10 mm and a length of 10 cm with a lapping lid, connected to a rotary evaporator, and depressurized. The inner wall is evenly coated under rotation. Then, Examples 1 to 4
For the above, the crosslinking reaction is advanced by irradiating with ultraviolet rays.
Make 2 tubes for each sample, put 1 ml each of the blood of healthy person immediately after collection into them, and keep them at 37 ° C for 5 minutes. Observe the flow state by inclining the blood sample, perform the same operation for the other one after the blood stops flowing at all, and use the elapsed time from the time when the blood in the test tube stops flowing to the coagulation time of the sample. To do. Further, when two glass test tubes not coated with polyurethane elastomer were evaluated for coagulation time on the glass surface by the same operation as above, it was usually 8 to 14 minutes although there were individual differences. The coagulation time is defined as the average value of the values obtained by testing the glass and each sample five times or more. As an index of antithrombogenicity, the coagulation time on the glass surface was set to 1 and the relative values of the coagulation time of each polyurethane elastomer were compared. The results are shown in Table 1.

[0040]

[Table 1]

Example 5 A polished stainless steel rod having a diameter of 4 mm was immersed in a 10% dimethylacetamide solution of the polyurethane elastomer of Example 1 and taken out, and dried at 60 ° C. to form a polyurethane film on the surface of the rod. Then, the polyurethane coating was irradiated with ultraviolet rays to have a desired thickness, and the crosslinking reaction was allowed to proceed. Then, the polyurethane coating was immersed in ethanol and the stainless steel rod was removed to obtain an antithrombogenic tube (artificial blood vessel).

Example 6 An antithrombogenic tube was obtained in the same manner as in Example 5 except that the polyurethane elastomer of Example 4 was used.

[0043]

EFFECTS OF THE INVENTION The antithrombogenic polyurethane elastomer of the present invention is easy to mold and has excellent mechanical strength, and its antithrombotic property is at least equivalent to that of conventional ones. Further, the medical device made of the polyurethane elastomer is easy to mold, has at least the same antithrombogenicity as the conventional one, and has mechanical strength several times better than the conventional one.

Claims (2)

[Claims] 1. A cross-linkable functional group is added to the main chain or side chain of a polyurethane containing an ABA type block copolymer of polyoxyethylene (A) and polyoxytetramethylene (B) as a polyether diol component. An antithrombogenic polyurethane elastomer characterized by being incorporated. 2. A medical device comprising the antithrombogenic polyurethane elastomer according to claim 1.