JPH07242723A - Antithrombogenic polyurethane elastomer and medical supply - Google Patents

Abstract

PURPOSE:To obtain an antithrombogenic polynrthane elastomer by using a specific reaction product obtained from a specific polyoxyethylene/ polyoxytetramethylene block copolymer as a polyether-diol ingredient, an organic diisocyanate, and an organic diamine. CONSTITUTION:A polyether-diol ingredient comprising an A-B-A type block copolymer of polyoxyethylene (A) and polyoxytetramethylene (B) (in which the content of the blocks A is 20-40mol% based on the whole diol ingredient) is reacted with an organic diisocyanate (e.g. 2,4-tolylene diisocyanate) and an organic diamine as a chain extender (e.g. ethylenediamine) under such conditions as to result in hard segments having a heat of fusion of 25mJ/mg or higher. This elastomer is preferably used as a material for a medical supply.

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 comprising a block copolymer, an organic diisocyanate, and an organic diol chain extender (the molar ratio of these three components is 1: 2: 1) is known [Japan Rubber Association, 62, 242 (1989)]. It has excellent antithrombogenicity and hydrolysis resistance, but further excellent antithrombogenicity is required.

Accordingly, it is an object of the present invention to provide an antithrombogenic polyurethane elastomer which has a further improved antithrombotic property and is useful as a material for medical devices. Another object of the present invention is to provide a medical device having an improved antithrombotic property.

[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 comprises a polyether diol component of an ABA type block copolymer of polyoxyethylene (A) and polyoxytetramethylene (B), an organic diisocyanate, and an organic diamine as a chain extender. The polyoxyethylene (A) content is 20 to 40 mol% of the total polyether diol component, and the heat of fusion of the hard segment is 25 mJ / mg or more, which is an antithrombogenic polyurethane elastomer. The present invention is also a medical device comprising the above antithrombogenic polyurethane elastomer.

In the present invention, in the polyurethane elastomer, the polyoxyethylene content is set to 20 to 40 mol% of the whole polyether diol component, and the heat of fusion of the hard segment is set to 25 mJ / mg or more, whereby antithrombogenicity is improved. Can be improved.

The polyurethane elastomer in the present invention is a polyurethane comprising a polyether diol component of an ABA type block copolymer of polyoxyethylene (A) and polyoxytetramethylene (B), and an organic diisocyanate and an organic diamine. It is an elastomer.

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

[0012]

[Chemical 1]

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

[0014]

[Chemical 2]

(A, b and c each represent an integer of 1 or more), the polyether diol residue represented by R is
₂ represents an organic diisocyanate residue, and R ₃ represents an organic diamine residue. ] The thing etc. which have a structure represented by these are illustrated.

The polyoxyethylene (A) and polyoxytetramethylene (B) AB- used in the present invention
The A-type block copolymer (hereinafter sometimes referred to as polyether diol) has the following formula (I):

[0017]

[Chemical 3]

(In the formula, a, b and c each represent an integer of 1 or more.) From the viewpoint of antithrombotic property and mechanical property, 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 must be 20 to 40 mol%, preferably 25 to 35 mol%. When the polyoxyethylene content is less than 20 mol%, the polyurethane elastomer obtained tends to be inferior in antithrombotic property, and when it exceeds 40 mol%, elasticity, flexibility and wet strength tend to be inferior.

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

Anionic Polymerization Method Polyoxytetramethylene glycol was added under a nitrogen stream,
Forming a potassium alcoholate of polyoxytetramethylene glycol obtained by reacting with metal potassium,
Using this as an anionic polymerization initiator, ethylene oxide is polymerized and terminated with hydrochloric acid isopropanol.
Process for producing a polyether diol of formula (I). This is the following formula

[0022]

[Chemical 4]

Is represented by

Cationic Polymerization Method Using trifluoromethanesulfonic anhydride as a cationic polymerization initiator, ring-opening polymerization of tetrahydrofuran is carried out, ethylene oxide is further added to the polymerization reaction system for polymerization, and then diluted aqueous sodium hydroxide solution is added for polymerization. Stopping the production of the polyether diol of the formula (I).
This is the following formula

[0025]

[Chemical 5]

Is represented by

As the organic diisocyanate, it suffices to use aliphatic, alicyclic and aromatic diisocyanates conventionally used for the production of polyurethane, which 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, tolidine diisocyanate, naphthylene diisocyanate, isophorone diisocyanate, etc. are mentioned, Preferably 4,4'-diphenylmethane diisocyanate is mentioned. These may be used alone,
Moreover, you may use it in mixture of 2 or more types.

As the organic diamine, it suffices 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 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.

In the polyurethane elastomer of the present invention, the hard segment means a hydrogen-bonding portion containing urethane and urea bonds, an organic diisocyanate,
The organic diamine portion corresponds to this. The soft segment refers to a rubber-like matrix portion having no hydrogen bonding property, and the polyether diol portion corresponds to this.

In the polyurethane elastomer of the present invention, the heat of fusion of the hard segment must be 25 mJ / mg or more, preferably 25 to 50 mJ / mg, and more preferably 25 to 40 mJ / mg. The heat of fusion is 2
If it is less than 5 mJ / mg, the microphase-separated structure exhibiting antithrombotic property is insufficiently developed, and the antithrombotic property tends to be poor.

The heat of fusion is measured by thermal analysis (DSC). Specifically, a polyurethane elastomer film produced by a solvent evaporation method was shredded and sealed in an aluminum sample pan.
Measured by a thermal analyzer at ˜350 ° C., temperature rising rate of 10 ° C./min, and N ₂ gas atmosphere (50 ml / min).

The heat of fusion can vary depending on various factors such as polyoxyethylene content, average molecular weight, molecular weight distribution and reaction conditions in the polyurethane elastomer. In the present invention, the polyoxyethylene is mainly used. The ethylene content is 20 to 40 mol% of the whole polyether diol component, and the ethylene content is 25 mJ / mg or more by producing under the following conditions (reaction temperature, reaction time, etc.).

In the polyurethane elastomer of the present invention, the value of the molar ratio of hard segment / soft segment is 3 to 100 from the viewpoint of mechanical strength and antithrombotic property.
Is preferable, and 4-20 is more preferable. By changing the value of the molar ratio of the hard segment / soft segment within the above range, it is possible to optimize the mechanical properties required by the site where the medical device is used.

In the known polyurethane, the mixing ratio of the above-mentioned components is usually about 2 mol of the organic diisocyanate component and about 1 mol of the organic diamine component per 1 mol of the polyether diol component (in this case, hard segment / The molar ratio of the soft segment is about 3, but in the present invention, it is preferable that the organic diisocyanate component is 2 to 90 mol and the organic diamine component is 1 to 90 mol per 1 mol of the polyether diol component. It is more preferable that the diisocyanate component is 2.5 to 20 mol and the organic diamine component is 1.5 to 20 mol.

The polyurethane elastomer of the present invention is preferably a polyurethane elastomer having a polyoxyethylene content of 25 to 35 mol% of the total polyether diol component and a heat of fusion of the hard segment of 25 to 40 mJ / mg. The molecular weight of the polyurethane elastomer is preferably 20,000 to 60,000,
It is more preferably 30,000 to 50,000.

The polyurethane elastomer is manufactured, for example, as follows. Required ABA type block copolymer of polyoxyethylene (A) and polyoxytetramethylene (B) which are polyether diol components (polyoxyethylene content is 20 to 40 mol%) and organic diisocyanate The amount is added to the reaction solvent (for example, N, N-dimethylacetamide, dimethylsulfoxide, dibutyl ether, dimethylformamide, etc.), and then 1,8-diazabicyclo [5.4.0] undecene-7 or dioctyltin dilaurate is added. Reaction accelerator (catalyst)
Is added and reacted at 25 to 35 ° C. for about 1 to 4 hours. Then, the required amount of organic diamine is added to the prepolymer thus obtained, and the mixture is added at 30 to 50 ° C. for about 0.5 to 3.5 hours.
When the chain extension reaction is carried out, the desired polyurethane elastomer is obtained. In the chain extension reaction, 30
If the reaction is carried out at a temperature lower than ° C, the chain extension reaction is difficult to proceed and the heat of fusion of the hard segment tends to be less than 25 mJ / mg. If the reaction is carried out at a temperature higher than 50 ° C., the crosslinking reaction tends to proceed too much and the reaction solution tends to gel.

The polyurethane elastomer of the present invention may be used in the form of various medical devices using the polyurethane elastomer as a base material, or the polyurethane elastomer may be soluble in dimethylformamide, dimethylacetamide or the like. It may be dissolved in a solvent and applied to various medical devices to form its surface film. Further, it can be formed into a sheet or film and used as a secondary processed product.

The medical instrument of the present invention obtained as described above is preferably one that can be brought into contact with blood. Specifically, for example, a vascular catheter, artificial kidney A
-V shunt, artificial heart-lung membrane, artificial blood vessel, artificial heart blood pump, aortic balloon pump, heart catheter, blood bag and the like are exemplified.

[0039]

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

Reference Example (Production of Polyetherdiol) 1) Anionic Polymerization Method Commercially available polyoxytetramethylene glycol (PTM)
G, number average molecular weight 1830) and metallic potassium in a slight excess over the theoretical amount are reacted at 130 ° C. for 4 hours in a dry air flow, and P
The potassium alcoholate of TMG was produced. The reaction system solidified when cooled. To this, ethylene oxide (EO) was charged during cooling so that the polyoxyethylene content in the polyether diol after polymerization would be the value shown in Table 1, and 4 hours at 45 ° C. using PTMG potassium alcoholate as a polymerization initiator. EO was polymerized. afterwards,
After diluting with benzene and adding hydrochloric acid isopropanol to terminate the polymerization, potassium chloride produced was filtered, and benzene, isopropanol, hydrochloric acid and water were removed by a rotary evaporator. Further extraction with diethyl ether,
The EO homopolymer was removed and dried under reduced pressure to obtain a polyether diol.

2) Cationic Polymerization Method In a two-necked flask, 150 g of sufficiently dehydrated and purified tetrahydrofuran (THF) and 6.2 g of trifluoromethanesulfonic anhydride as a catalyst were added, and the mixture was vigorously stirred at 0 ° C. for 10 hours. Polymerized for minutes. Then, the flask is cooled to −64 ° C., a part of the reaction liquid is extracted and added to a 2% aqueous sodium hydroxide solution to stop the polymerization of the extracted liquid. From this, a homopolymer of THF (polyoxytetramethylene glycol) is obtained. On the other hand, EO100 dehydrated and purified by freezing a polymerization flask in liquid nitrogen
g was vacuum distilled. The flask was heated to 25 ° C. to continue the polymerization of EO, and after a predetermined time, a large amount of a 2% sodium hydroxide aqueous solution was poured into the reaction solution to terminate the polymerization, followed by purification to obtain a polyether diol. The EO content in the polyether diol was adjusted to the value shown in Table 1 by adjusting the charged amount of EO and the polymerization time.

Examples 1 to 2 0.02 mol of polyether diol prepared in Reference Example so that the polyoxyethylene content becomes the value shown in Table 1, and 4,4'-diphenylmethane diisocyanate
06 mol of 1500 ml of N, N-dimethylacetamide
Uniformly dissolved in 1,8-diazabicyclo [5.
4.0] 60 mg of undecene-7 was added, and after reacting for 3.5 hours with stirring at 30 ° C. while introducing dry nitrogen gas, the mixture was cooled. To this reaction solution, 230 ml of a solution of N, N-dimethylacetamide containing 0.04 mol of ethylenediamine was added dropwise, and the mixture was stirred at 30 to 50 ° C. (gradual heating) for 1.5 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 3 0.02 mol of the polyether diol prepared in Reference Example so that the polyoxyethylene content becomes the value shown in Table 1, and 4,4'-diphenylmethane diisocyanate of 0.
06 mol of 1500 ml of N, N-dimethylacetamide
Uniformly dissolved in 1,8-diazabicyclo [5.
4.0] 60 mg of undecene-7 was added, and after reacting for 2.5 hours while stirring at 30 ° C. while introducing dry nitrogen gas, the mixture was cooled. To this reaction liquid, 230 ml of a solution of N, N-dimethylacetamide containing 0.04 mol of ethylenediamine was added dropwise, and the mixture was stirred at 30 to 50 ° C. (gradual heating) for 2 hours for reaction. Pour this reaction into water,
The generated polyurethane was precipitated and filtered off, the 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.

Comparative Examples 1 and 2 Example 1 was carried out by using the polyether diol prepared in Reference Example so that the polyoxyethylene content became the value shown in Table 1.
Polyurethane elastomers were obtained in the same manner as described above.

Comparative Example 3 0.02 mol of the polyether diol prepared in Reference Example so that the polyoxyethylene content becomes the value shown in Table 1, and 4,4'-diphenylmethane diisocyanate of 0.
06 mol of 1500 ml of N, N-dimethylacetamide
Uniformly dissolved in 1,8-diazabicyclo [5.
4.0] 60 mg of undecene-7 was added, and after reacting for 3.5 hours with stirring at 30 ° C. while introducing dry nitrogen gas, the mixture was cooled. To this reaction solution, 230 ml of a solution of N, N-dimethylacetamide containing 0.04 mol of ethylenediamine was added dropwise, and the mixture was stirred at 25 ° 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.

Comparative Example 4 0.02 mol of polyether diol prepared in Reference Example so as to have a polyoxyethylene content of 25 mol%, and 0.04,4'-diphenylmethane diisocyanate.
6 mol was uniformly dissolved in 1500 ml of N, N-dimethylacetamide, and 1,8-diazabicyclo [5.4.
0] Undecene-7 (60 mg) was added, and the mixture was reacted at 80 ° C. for 5 hours with stirring while introducing dry nitrogen gas, and then cooled. Ethylenediamine 0.0
A solution of N, N-dimethylacetamide containing 4 mol 23
Add 0 ml dropwise and heat at 30-50 ° C (gradual heating) for 1.5
When the reaction was carried out with stirring for a time, the reaction solution gelled, and the target polyurethane elastomer could not be obtained.

Comparative Example 5 0.02 mol of polyether diol prepared in Reference Example so that the polyoxyethylene content was 35 mol%, and 0.04 of 4,4'-diphenylmethane diisocyanate.
6 mol was uniformly dissolved in 1500 ml of N, N-dimethylacetamide, and 1,8-diazabicyclo [5.4.
0] Undecene-7 (60 mg) was added, and the mixture was reacted at 80 ° C. for 5 hours with stirring while introducing dry nitrogen gas, and then cooled. Ethylenediamine 0.0
A solution of N, N-dimethylacetamide containing 4 mol 23
When 0 ml was added dropwise and the reaction was carried out by stirring at 25 ° C. for 7 hours, the reaction solution gelated and the target polyurethane elastomer could not be obtained.

The polyurethane elastomers obtained in the above Examples and Comparative Examples were subjected to thermal analysis (DSC) as follows. The results are shown in Table 1. The sample is
A film prepared by solvent evaporation method from a N, N-dimethylacetamide solution of polyurethane elastomer was shredded and sealed in an aluminum sample pan. The measurement uses SSC-5020 (DSC-200) manufactured by Seiko Denshi Kogyo, -150 to 350 ° C., heating rate 10 ° C./min, N
_It was carried out under a ₂ gas atmosphere (50 ml / min).

The polyurethane elastomers obtained in the above Examples and Comparative Examples were subjected to an ex vivo test (dog AV shunt method, extracorporeal circulation test) as follows. The results are shown in Table 1. The inner surface of a soft vinyl chloride tube having an inner diameter of 5 mm and a length of 50 cm was coated with the above polyurethane elastomer by a solvent evaporation method, and the blood was circulated by connecting it from the carotid artery of the dog to the jugular vein. A component test was performed on blood collected at regular intervals during circulation to evaluate destruction and abnormalities of platelets and the like, abnormalities of coagulation factors, and the like. The tube was removed after 3 hours of circulation and the thrombus adhering to the inner surface of the tube was observed.

Further, 1 ml of a 10% dimethylacetamide solution of the polyurethane elastomers obtained in the above Examples and Comparative Examples was placed in a test tube with an inner lid of 10 mm and a length of 10 cm and equipped with a lapping lid, which was connected to a rotary evaporator and rotated under reduced pressure. Bottom, its inner wall is coated uniformly.
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.

[0051]

[Table 1]

From the above results, the polyoxyethylene content is 20 to 40 mol% of the whole polyether diol component,
Further, it was found that the polyurethane elastomer having a heat of fusion of hard segment of 25 mJ / mg or more has less platelet adhesion, suppression of activation of coagulation factor, and excellent antithrombotic property.

EXAMPLE 4 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. After adjusting the thickness to a desired thickness, the stainless steel rod was removed by immersing in ethanol to obtain an antithrombogenic tube (artificial blood vessel).

Example 5 An antithrombogenic tube was obtained in the same manner as in Example 4 except that the polyurethane elastomer of Example 2 was used.

Example 6 A vinyl chloride catheter tube was immersed in a 10% dimethylacetamide solution of the polyurethane elastomer of Example 3 and taken out, and dried under reduced pressure at 50 ° C. to form a polyurethane film on the tube surface, and antithrombogenicity. A catheter tube was obtained.

[0056]

The antithrombogenic polyurethane elastomer of the present invention and the medical device comprising the polyurethane elastomer have excellent antithrombogenicity.

Claims (2)

[Claims] 1. A polyether diol component of an ABA type block copolymer of polyoxyethylene (A) and polyoxytetramethylene (B), an organic diisocyanate, and an organic diamine as a chain extender, An antithrombogenic polyurethane elastomer having a polyoxyethylene (A) content of 20 to 40 mol% of the total polyether diol component and a heat of fusion of the hard segment of 25 mJ / mg or more. 2. A medical device comprising the antithrombogenic polyurethane elastomer according to claim 1.