JPS61204219A - Antithrombotic polyurethane elastomer - Google Patents

Abstract

PURPOSE:The titled novel elastomer useful as a medical material, having improved antithrombotic activity, affinity for organism, flexibility, and elasticity, obtained by reacting a specific polyether diol with an organic diisocyanate and an organic diamine. CONSTITUTION:(A) 1mol polyether diol shown by the formula (a, b, and c are >=1 integer), having about 500-8,000 number-average molecular weight and 10-50mol% polyoxyethylene content is reacted with (B) >=2mol organic diisocyanate, and (C) >=1mol organic diamine, to give the elastomer. Preferably the component A is obtained by anion polymerization method using polyoxytetramethylene glycol.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a novel polyurethane elastomer having antithrombotic properties and suitable as a medical material.

BACKGROUND OF THE INVENTION Medical materials that come into contact with blood, such as vascular catheters, artificial kidney A-V shunts, heart-lung membranes, artificial blood vessels, artificial heart blood pumps, and aortic balloon pumps, are flexible, elastic, and durable. In addition to mechanical properties such as strength and wet strength, it is also necessary to have biocompatibility such as antithrombotic properties.

Until now, silicone and soft polyvinyl chloride have been mainly used as medical materials that require elasticity. However, when these materials come into direct contact with blood, the blood coagulates on the surface, forming a thrombus. When using these materials, it is necessary to administer anticoagulants such as heparin systemically; The use of anticoagulants carries the risk that if bleeding occurs for some reason, the bleeding will not stop.

By the way, polyurethane and block copolymers of polyurethane and silicone are known to have better antithrombotic properties than other general-purpose polymer materials, and are commercially available as medical materials. Shi whose gender has changed,
In addition, there are problems such as the manufacturing process becoming complicated, and it cannot be said that it is necessarily satisfactory.

On the other hand, it has also been proposed to use polyurethane obtained from polyethylene glycol, organic diisocyanate, and organic diamine as a medical material;
Although it exhibits good antithrombotic properties, its wet strength is extremely low and it cannot be put to practical use.

In general, improving hydrophilicity, antithrombotic properties, and other biocompatibility inevitably reduces mechanical strength, so it is important to develop materials with a good balance between the two. This has become an important issue in materials.

Examples of polyurethanes that have both mechanical properties and antithrombotic properties that can be used as medical materials include polyoxyethylene (A) and polyoxypropylene (Bl).
A polyurethane using an A-B-A type block copolymer as a polyether diol component has been proposed (
Special Publication No. 5B-8700).

This material has antithrombotic properties and considerably high mechanical strength, so it can be widely used as a variety of medical materials, but even higher mechanical strength is required depending on the purpose of use.

Problems to be Solved by the Invention The purpose of the present invention is to further improve the antithrombotic properties and other biocompatibility of conventionally known medical polyurethanes, as well as further improve their mechanical properties. The goal is to further expand the field of use.

Means for Solving the Problems In order to achieve the above-mentioned object, the present inventors have conducted intensive research and found that an ABA type block of polyoxyethylene (A) and polyoxytetramethylene (in polyoxyethylene (A) and polyoxytetramethylene) copolymer,
It has been discovered that polyurethane as a polyether diol component exhibits better antithrombotic properties and mechanical properties than conventional ones, and the present invention has been completed based on this knowledge.

That is, the present invention has the general formula % () 1 mole of polyether diol having an oxyethylene content of 10 to 50 moles, 2 moles or more of an organic diisocyanate,
An antithrombotic polyurethane elastomer comprising a reaction product with one or more moles of an organic diamine is provided.

In the polyurethane of the present invention, the polyether diol component of general formula (I) has a number average molecular weight of about 500 to 80.
It must be in the range of 00. If a number average molecular weight smaller than this is used, the antithrombotic properties and elastic properties of the resulting polyurethane elastomer will be generally reduced, and if a number average molecular weight larger than this is used, the mechanical properties of the resulting polyurethane elastomer will be reduced. The strength is reduced and the workability is also poor.

Next, the polyoxyethylene content in this polyether diol, ie, the amount represented by (a+c), needs to be in the range of 10 to 50 molar ratios. If this amount is less than 10 mol, the resulting polyurethane will not exhibit sufficient antithrombotic properties, and if it exceeds 50 mol, the resulting polyurethane will have poor elasticity, flexibility and wet strength. For equipment materials that come into contact with blood for a long period of time, materials with a number average molecular weight of approximately 1000 to 60 are recommended.
00, polyoxyethylene content 10-40
Preferred are polyurethane disstomers obtained using Molch's.

The polyether diol of general formula +11 described above can be produced by either the anionic polymerization method or the cationic polymerization method shown below.

(1) Anionic polymerization method Polyoxytetramethylene glycol (PTMG).

PT obtained by reacting HO ((CH2)40)b-H, b is an integer of 1 or more) with metallic potassium under a nitrogen stream
MG potassium alcoholade (KO((”x)a 0)
b-'Q is produced, and using this as an anionic polymerization initiator, ethylene oxide (EO) is polymerized, and the polymerization is stopped with hydrochloric acidic inpropanol to produce a polyether diol of general formula (11). The chemical formula is as follows.

Ho-((”z)40)b-H+ 2→KQ-(((
:! H2)4Q), -K + nFJo-.

Ko-(CH2G(20)a-((CH2)40)B-
(C!H2”z O).-K”l.

HO-(':'H2''H2O)a-((CH2)40)
b-(0H2CH20) c-H (a, b, in the chemical formula
C, n are integers of 1 or more, and n:: IL + Q
and a = c. ) (2) Cationic polymerization method Ring-opening polymerization of tetrahydrofuran (TIIIF) is performed using trifluoromethanesulfonic anhydride ((OF, 3 E302) 20) as a cationic polymerization initiator, and then T! The chemical formula of these is as follows: Become.

bo+(cF, so, i→06(shima→廿CH,-)♂
O-+ uo+cu, cHt o-+(ax +4 o
-+(cnt a-0-)-Ha
l) (B (a, b and C in the formula
(has the same meaning as above) Next, as the organic diincyanate component to be reacted with such a polyether diol component, aliphatic, alicyclic and aromatic diisocyanates that have been used in the production of polyurethane can be used. Any one can be selected and used.

Examples of such are 4,4'-diphenylmethane diincyane) (MDI), 2,4 (or 2°6
)-tolylene diisocyanate) (TD Engineering), p-xylylene diisocyanate, hexamethylene diisocyanate, 4j4'-dicyclohexylmethane diisocyanate, and particularly preferred is 4°4'-diphenylmethane diisocyanate.

These may be used alone or in combination of two or more.

Furthermore, the organic diamine component can be arbitrarily selected from those used as chain extenders in the production of ordinary polyurethane.

Examples of such substances include alkylene diamines such as ethylene diamine, propylene diamine, and hexamethylene diamine, and aromatic diamines such as p-xylylene diamine and p-diphenylmethane diamine. Ethylenediamine.These may be used alone or in a mixture of two or more kinds.These organic diisocyanate components and organic diamine components are usually used per mole of polyether diol component.
They are used in a proportion of about 2 moles and about 1 mole, respectively, but if a hard polyurethane elastomer is required, the proportions of the organic dicyanate component and the organic diamine component are further increased.

In such a case, the ratio of each component is 2.1 to 2.1 to 1 mole of the organic diincyanate component per 1 mole of the polyether diol component.
5 mol, and the organic diamine component is appropriately selected in the range of 1.1 to 4 mol.

In order to produce the polyurethane of the present invention, for example, the general formula (
The required amounts of polyether diol and diisocyanate in I) are added to the reaction solvent and heated to 50-100°C to react. As a reaction solvent at this time, for example, N, N-
) Methylacetamide, dimethylsulfoxide, dibutyl ether, dimethylformamide, etc. are used.

Further, 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 at around room temperature.

Next, a required amount of organic diamine is added to the thus obtained prepolymer and a chain extension reaction is carried out at around room temperature to obtain the desired antithrombotic polyurethane elastomer.

Effects of the Invention The polyurethane distomer of the present invention has excellent antithrombotic properties, biocompatibility, flexibility, elasticity, durability, hydrolysis resistance, and wet toughness, and is suitable as a medical material, particularly as a material for blood contact devices. be. Further, as for its usage mode, for example, the polyurethane distomer of the present invention may be used as a base material and molded into the shape of various devices, or it may be dissolved in a soluble solvent such as dimethylformamide or dimethylacetamide and applied to various devices. It may also be used as a surface coating. Furthermore, it can be formed into a sheet or film and used as a secondary processed product.

Example Next, the present invention will be explained in more detail by way of examples.

Reference example (manufacture of polyether diol) a) Anionic polymerization method Commercially available polyoxytetramethylene glycol (PTMG)
, number average molecular weight 1850) is reacted with metallic potassium slightly in excess of the theoretical amount at 130° C. under a dry air stream for 4 hours to produce potassium alcoholade of PTMG. The reaction system solidifies when cooled. This (predetermined amount of ethylene oxide (EO) was charged during cooling, and PTMG potassium alcolanide was used as a polymerization initiator, and Eo
The polymerization time is usually 4 hours. Then, dilute with benzene and add hydrochloric acidic impropanol.
The polymerization is stopped, the potassium chloride produced is filtered, and the benzene, inpropanol,
Remove hydrochloric acid and water. The mixture is further extracted with diethyl ether to remove the EO homopolymer, and dried under reduced pressure to obtain the desired polyether diol. The results of the characterization of three types of polyether diols obtained in experiments conducted with varying amounts of Bo were shown in Table 1, experimental ratios 1.2 and 3.b) Cationic polymerization method Two-necked type In the flask, 150 ml of thoroughly dehydrated tetrahydrofuran (THF') was added.
) Add 2FI and polymerize for 10 minutes while stirring vigorously at Ao°C. Cool the flask to -64°C.
A portion of the reaction solution is withdrawn and added to a 2% aqueous sodium hydroxide solution to stop polymerization of the withdrawn solution. This is it, TH
A homopolymer of F (polyoxytetramethylene glycol) is obtained. On the other hand, the polymerization flask is frozen in liquid nitrogen, and the dehydrated and purified KOlooII is prepared by vacuum distillation.The flask is heated to 25°C and the polymerization of EO is continued.After a predetermined period of time, a large amount of EO is added to the reaction solution. Pour 2% sodium hydroxide aqueous solution to stop polymerization. This 1
The KO content in the polyether diol can be varied by lengthening or shortening the polymerization time.

It was found from NMR spectrum measurement that the polyether diol produced contained some THF units in its EO chain portion. This is probably because some copolymerization of EO and THF occurred (because THE' monomer remained during the polymerization of EO. However, in reality, the copolymerization of general formula (I) A polyether diol is obtained.

An example of the characterization of polyether diol obtained by this cationic polymerization method is shown in Experimental Ratio 4 in Table 1.

Table 1 0.02 mol of polyether diol obtained in Examples and Reference Examples and 4
,4'-diphenylmethane diisocyanate (0,04
mol) was uniformly dissolved in 200ff/dimethyl sulfoxide, and while introducing dry nitrogen gas, the reaction solution was poured into water to precipitate the produced polyurethane. The molecular compound was removed, and the residue was vacuum-dried at room temperature to obtain the desired polyurethane elastomer.

The thus obtained solution of the polyurethane elastomer in 15-tidimethylformamide was poured into a flat petri dish placed on a mercury plane, and the solvent was gradually vaporized under reduced pressure to prepare a uniform film. This film was cut into strips with a thickness of about 0.3 WIN, and the strength at break at 20°C was determined.
The elongation at break and 100 thymodiles were measured. The results are shown in Table 2.

Separately, for comparison, as a polyether component, PTM
G (average molecular weight 1830), polyoxyethylene (A
Polyurethane produced by the same method as in the above example using an A-B-A type block copolymer (abbreviated as KPK, see Japanese Patent Publication No. 58-8700) of polyoxypropylene (B) and polyoxypropylene (B) as a polyether component. The mechanical properties are listed in Table 2, and Biomer (
Ethicon (USA) is shown in Table 2. Table 2 shows that the mechanical strength of the polyurethane according to the present invention is equivalent to polyurethane made from PTMG and biomer, and superior to polyurethane made from ETE.

Note that polyurethane made using polyether diol with a number average molecular weight of 8,500 and an EO content of 74% had poor film forming properties, and the mechanical properties were not measured (-).

Furthermore, in order to evaluate the fatigue resistance of these polyurethane elastomer films, a fatigue test was carried out for two consecutive days at 37°C by elongating them by 50% and subjecting them to a stretching deformation of ±10% at a rate of 5 Hz. Physiological saline was used (repeated expansion/contraction deformation approximately 10 million times).

As a result, nothing broke.

From the above results, these polyurethane distomers have the mechanical strength, elasticity, and
It was found that it has excellent fatigue resistance when wet.

Next, each sample was examined for antithrombotic properties according to the following method.

1 zl of a solution of polyurethane entomer in 10% dimethylacetamide is placed in a test tube with a ground lid, 12 ff in diameter and 10 cM in length, connected to a rotary evaporator and rotated under reduced pressure to uniformly coat the inner wall of the tube.

Put 1 d of freshly collected healthy human blood into two test tubes,
While maintaining the temperature at 37°C, observe the flow state by tilting one of the test tubes at a 45 degree angle every 30 seconds after 5 minutes have elapsed, and after the blood stops flowing at all, repeat the same operation with the other test tube. The time elapsed until the blood in the test tube stops flowing at all is defined as the coagulation time of the sample. On the other hand, the solidification time of the glass was evaluated using the same procedure for two glass test tubes that were not coated with polyurethane elastomer. Although there are individual differences in the solidification time of glass,
Usually it takes 8 to 14 minutes. The solidification time is defined as the average value of the values obtained in five or more tests for the glass and sample polyurethane disstomer. As an index of antithrombotic properties, the relative values of the coagulation times of each polyurethane elastomer were compared, with the coagulation time of glass being taken as 1. These results are shown in Table 3.

For comparison, a polyurethane elastomer made from PTMG (number average molecule [1830) that does not contain EO, MDI and ethylenediamine, and a commercially available medical polyurethane and Biomer (manufactured by Ethicon, USA) were also tested. It is clear that the polyurethane elastomer of the present invention has excellent antithrombotic properties.

Furthermore, even when compared with the Leawhite test results of polyurethane made by EPK, it can be seen that the polyurethane of the present invention has equivalent antithrombotic properties.

Separately, a polished stainless steel rod with a diameter of 4 ff was immersed in a 10% by weight dimethylacetamide solution of the sample polyurethane elastomer, taken out, and dried at 60°C.
After repeating the process of forming a polyurethane coating on the surface of the stainless steel rod until the desired thickness is achieved, the stainless steel rod is immersed in an ethanol solution and removed to create a short tube.

A tube with a wall thickness of 0.5 ff, a length of 17 ff, and an inner diameter of 4 ttnm was implanted into the scapular vein and caudal vein of an adult dog,
The time it takes for an implanted tube to become occluded due to thrombus formation due to blood coagulation using a Doppler blood flow meter (patency time)
was measured. As an index of antithrombotic properties, polyoxytetramethylene glycol (PTMG), which was tested as a comparative example,
, number average molecular weight 11830) and the opening time (within 40 minutes) of polyurethane manufactured from MDI and ethylenediamine was compared based on a relative value of 1. These are shown in Table 3.

The above in vitro and in vivo test results show that the polyurethane elastomer of the present invention has excellent antithrombotic properties.

Claims (1)

[Claims] 1 General formula HO-(CH_2CH_2O)_a-[(CH_2)_
4O]_b-(CH_2CH_2O)_c-H (in the formula, a, b and c are integers of 1 or more), which has a number average molecular weight of about 500 to 8000 and has a polyoxyethylene content of 10 to 50 mol%. 1 mole of ether diol,
An antithrombotic polyurethane elastomer comprising a reaction product of 2 moles or more of an organic diisocyanate and 1 mole or more of an organic diamine.