JPS60240725A - Medical polyester copolymer composition - Google Patents

Abstract

PURPOSE:The titled composition suitable for use as a material for, for example, medical instruments in direct contact with blood, obtained by reacting an acid component essentially consisting of terephthalic acid with a glycol component containing a low-MW glycol and a polyalkylene glycol. CONSTITUTION:The purpose medical polyester copolymer composition is prepared by reacting an acid component containing terephthalic acid as an essential component and 20-50mol% acid components other than terephthalic acid (e.g., isophthalic acid) with a glycol component containing a low-MW glycol of an MW<=250 (e.g., ethylene glycol) and 5-40wt%, based on the total polymer, polyalkylene glycol (e.g., polypropylene glycol) of a number-average MW of about 300-60,000. When this material is in contact with blood, no thrombus forms, so that it can be suitably used as a material for catheters, blood bags, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a novel medical polyester copolymer composition.

More specifically, the present invention relates to a polyester copolymer composition suitable for medical devices or various separation membranes that are used in direct contact with blood components.

[Conventional technology]

In recent years, as the use of polymeric materials in the medical industry has progressed, various types of polymers have been used as medical materials that are used in direct contact with biological components such as blood.

Examples of medical devices include various blood vessel cannulas, catheters, various monitoring tubes, extracorporeal circulation blood circuits, blood bypass tubes, and blood bags.

Also included are various separation membranes that are permeable to substances used in artificial kidneys, blood vessel separation, and the like.

Further examples include embedding materials for enzymes and pharmaceuticals, and modifying materials for cosmetics.

Each constituent material is required to have biocompatibility such as antithrombotic properties as well as mechanical properties depending on the intended use.

Traditionally, medical materials used include soft vinyl chloride, polyethylene, polypropylene, silicone, polycarbonate, polyethylene terephthalate, polytetrafluoroethylene, ABS resin polymethyl methacrylate, polyvinyl alcohol, and cellulose diacetate.
Although its mechanical properties are mostly satisfied, biocompatibility, such as thrombus formation that occurs when it comes into contact with blood, remains a major unresolved issue.

[Problem that the invention seeks to solve]

An object of the present invention is to provide a medical composition that does not form a thrombus when it comes into contact with blood, while maintaining the permeability and mechanical properties of conventional polymeric materials.

[Means for solving problems]

The present invention contains 20 to 50 mol% of an acid component other than terephthalic acid in the acid component of a polyester copolymer mainly composed of terephthalic acid and a low molecular weight glycol having a molecular weight of 250 or less, and a glycol component other than low molecular weight glycol. 5 to 40% by weight of polyalkylene glycol having a number average molecular weight of about 300 to 60,000 based on the total amount of the polymer.
The present invention provides a medical polyester copolymer composition containing the following. A more preferred composition of this polyester copolymer composition is one in which the low molecular weight glycol is ethylene glycol, and the most preferred composition is:
The low molecular weight glycol is ethylene glycol, and the number average molecular weight of the polyalkylene glycol is about 6,000 ~
This is the case when it is approximately 60,000.

The acid component of the polyester copolymer of the present invention includes terephthalic acid as an essential component, and 20 to 50 mol%, preferably 25 to 40 mol% of acid components other than terephthalic acid. The acid component other than terephthalic acid is preferably a dicarboxylic acid such as an aromatic dicarboxylic acid other than terephthalic acid or an aliphatic dicarboxylic acid. Examples of aromatic dicarboxylic acids other than terephthalic acid include isophthalic acid, naphthalene dicarboxylic acid, diphenyl dicarboxylic acid, diphenyl ether dicarboxylic acid, methyl terephthalic acid, and methyl isophthalic acid.

Among these, isophthalic acid is particularly preferred.

It is also possible to use a small amount (usually 5 mol % or less) of a dicarboxylic acid containing a group represented by -303M (M is an alkali metal) in the molecule, such as sodium 5-sulfoisophthalate.

Aliphatic dicarboxylic acids include malonic acid, glutaric acid,
Adipic acid, sebacic acid, dodecanedioic acid, succinic acid, 1
．． Examples include 3-cyclopentadicarboxylic acid and 1,4-cyclohexanedicarboxylic acid.

Among these, adipic acid is particularly preferably used.

By adding these aromatic dicarboxylic acids and aliphatic dicarboxylic acids other than terephthalic acid, it becomes possible to increase the solubility in polar organic solvents without significantly reducing the film strength.

Next, as the glycol component used in the present invention,
In addition to low molecular weight glycols such as ethylene glycol, polyalkylene glycols having a number average molecular weight of about 300 to 60,000 are essential components. Glycols with a molecular weight of 250 or less are used as low molecular weight glycols,
Ethylene glycol, trimethylene glycol, 1,4
Compounds such as -butanediol, 1,4-cyclohexane dimetatool, neopentyl glycol, and 2,2-bis(4-hydroxyphenyl)propane can be used.

Among these, ethylene glycol is particularly preferred.

Examples of the polyalkylene glycol include polyethylene glycol, polypropylene glycol, polytetramethylene glycol, and a copolymer of ethylene oxide and propylene oxide, each having a number average molecular weight of about 300 to about 60.0.
00 is mentioned.

Among these, polyethylene glycol is particularly preferably used, and among these, those with a number average molecular weight of about 3,000 or more are preferable in terms of solute permeability balance and blood compatibility, and more preferably those with a molecular weight of about 6,000 or more. Particularly preferred are those.

The content of these polyalkylene glycols in the polyester polymer depends on the type of polyalkylene glycol and the type and content of the aliphatic dicarboxylic acid, but generally 5
-40% by weight, more preferably 15-25% by weight.

If it is less than 5% by weight, the antithrombotic properties and permeability of the membrane will be significantly reduced, and if it is more than 40% by weight, the strength will be reduced, which is not preferable.

The degree of polymerization of the polyester copolymer is preferably 15 or more, more preferably 22 or more when expressed in terms of relative viscosity.

The value of relative viscosity is determined by pulverizing polyester cooled with dry ice, and dissolving 8 g of it in 100 ml of O-chlorophenol at 100°C for 30 minutes, and calculating the viscosity of this polymer solution and that of O-chlorophenol itself. Viscosity is expressed as a ratio of values measured in the same unit at 25°C.

The method for polymerizing the polyester copolymer is, for example: The transesterification reaction is carried out by heating to 140 to 240°C in the presence of a transesterification catalyst and distilling off the methanol produced, and then using a known polymerization catalyst such as antimony dioxide, germanium dioxide, tetrabutyl titanate, etc. If necessary, add polyalkylene glycol in the presence of a phosphorus compound such as phosphorous acid or phosphoric acid (and/or its esterified product), and heat at 200 to 290°C, 0.0
A method of polycondensation by distilling off glycol at 1 to 50+b,
■Dicarboxylic acid and glycol are esterified at 150 to 250°C under normal pressure or under pressure while distilling off the water produced, and then polyalkylene glycol is added in the presence of a polycondensation catalyst and, if necessary, a phosphorus compound. Obtained by polycondensation method.

Although the polyalkylene glycol can be added at any stage before the transesterification reaction, before the esterification reaction, or during the polycondensation reaction, it is generally preferable to add it after the transesterification reaction or after the esterification reaction.

Application examples of the present invention include a method for manufacturing semipermeable membranes used in artificial kidneys, etc. using the material of the present invention, and imparting antithrombotic properties by coating conventionally used medical materials with the composition of the present invention. This will be explained in detail.

Many materials have been provided for semipermeable membranes, and they are used in fields such as the food industry, wastewater treatment, and medical care.
Their required performance varies depending on the application, and there are many problems in terms of performance and manufacturing technology.

One of the objects of the present invention is to provide a membrane whose permeability characteristics can be varied over a wide range depending on the purpose of use, and a method for producing the same.

According to the method of the present invention, membranes with various permeability properties can be obtained from stock solutions with similar polymer concentrations through a fixed membrane forming process.

Another object of the present invention is to provide a membrane that is easy to handle and has high strength and elongation in both dry and hydrated states, and furthermore, when used for medical purposes, it is free from the adhesion of blood components such as proteins and platelets. It provides a membrane with excellent compatibility with small blood.

Regarding semipermeable membranes made of polyester polymers by wet or wet-dry membrane formation, a polyester membrane containing polyethylene terephthalate as the main component and a large amount of polyethylene glycol relative to the total amount of the polymer is known from D. J. Lyman et al. The only thing that can be done is

(Biochemistry Vol-3+ No. 7
+985 (1964)) Lyvaan et al.'s membrane required copolymerization of a large amount of polyethylene glycol to increase its solubility in organic solvents, and as a result, the strength of the membrane became extremely low and it could not be put to practical use. Ta.

In the present invention, solubility in organic solvents is adjusted by copolymerization of acids other than terephthalic acid, and permeation performance such as water permeability and solute dialysis is adjusted by copolymerization of polyethylene glycol. The purpose is to obtain a semipermeable membrane that has high strength and elongation even in the state.

In the case of artificial kidneys, the required performance of the membrane is solute permeability, ultrafiltration capacity (UFR), and blood compatibility of the membrane, as well as:
Its mechanical strength.

It is desirable that the solute permeability be high enough to prevent plasma proteins (particularly albumin) from permeating, but the ultrafiltration rate is determined by the ultrafiltration rate (U F R ) is preferably adjustable over a wide range.

In addition to regular dialysis therapy, hemofiltration therapy (t
There has also been development into portable artificial kidneys and wearable artificial kidneys based on the lemoftltratton.
Semipermeable membranes with very high UFRs are also desired.

When the polyester copolymer composition of the present invention is used as such a semipermeable membrane, albumin does not substantially permeate and the water permeation rate (UFR) is 0.1 to 1,000.
111#/hr, +y? , n++nj1g, preferably 0.5-200m 12 /hr, cd, mmH
g- is good.

That is, for normal dialysis therapy applications, a material that does not substantially permeate albumin and has a water permeation rate (ultrafiltration rate, UFR) of 0.1 to 10 ++ lIL/hr, rrf
.

tawIHg, preferably 0.5-3 m j! /hr
, rd, mmHg is required, and for hemofiltration therapy, etc., a UFR of 20 val/hr, rd, mmHg or higher is required,
UFR as high as possible without penetrating albumin
A membrane that exhibits the following is desired.

The semipermeable membrane of the present invention is a membrane that satisfies these required permeation performance.

The water permeability (UFR of water) and albumin permeability were measured using conventional methods; water permeability was measured using distilled water, and albumin permeability was measured using bovine albumin (Fr/V) (e.g., Seikagaku Corporation, Sigma Co., Ltd.). ) is dissolved in distilled water to a concentration of 0.2 g/d1.

If the separation membrane is a flat membrane, use a normal stirring cell (for example,
In the case of hollow fibers, use a module with an effective length of 5ca+ or more made by bundling 10 or more fibers, stir in a stirring cell at 25°C and under a pressure of 50 mmHg, and in the case of hollow fibers, stir in a stirring cell. Linear velocity at 5cm
/sec, and the filtrate amount becomes stable for 30 minutes to 6.
Calculated from the 30 minute filtrate between 0 minutes.

X100 (%) The solvent used to form a film or to prepare a spinning dope needs to be one that can dissolve the polyester copolymer and can finally be replaced with water.

Preferred examples of solvents include polar organic solvents such as dimethyl sulfoxide, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, and dichloromethane.

Among these, dimethyl sulfoxide has good film-forming and thread-spinning properties, has extremely low toxicity, and is a preferable solvent for medical purposes.

The concentration of the raw material polymer in the membrane forming stock solution is a major factor in controlling water permeability, but it is usually 20 to 70% by weight, preferably 40% by weight.
~60% by weight.

The membrane-forming stock solution thus obtained can be formed into a membrane or spun into hollow fibers by various known methods. For example, the stock solution can be cast onto a flat plate such as a glass plate or a metal plate, and then immersed in a coagulation bath to solidify it, or it can be extruded into a coagulation bath through a nozzle with long and narrow holes to form a film.

In this case, it is also possible to apply it onto a supporting fabric such as polyester taffeta. In addition to flat membranes, membranes of various shapes can be formed by spinning from a spinneret with concentric circular holes and forming them into a cylindrical or hollow fiber shape, or by spreading them on convex, concave, or other irregularly shaped surfaces and solidifying them. can be obtained.

Among these various shapes, hollow fiber molded products are most suitable for medical applications and the like because they have a small filling liquid volume (priming volume) and a high linear velocity when modularized.

Depending on the composition of the film-forming stock solution made from the material of the present invention (mainly due to the solvent), it may gel in a low temperature range, so heating may be required when preparing the stock solution.

Especially when dimethyl sulfoxide is used as a solvent, 110
Since it becomes gel-like and solidifies at temperatures between ℃ and 50℃, it is possible to form membranes on hollow fibers by gas injection without using an internal coagulating liquid as a core liquid in the so-called dry-wet spinning method. Become. It goes without saying that a core liquid can be used in the same manner as in the usual dry-wet spinning or wet spinning method.

As the coagulation bath, water, aliphatic lower alcohols, or a mixture thereof is generally used.

Furthermore, in order to adjust the coagulation ability, it is also possible to use a mixture of water or alcohol to which the solvent used in the stock solution or inorganic salts is added.

However, when dimethyl sulfoxide is used as the solvent, it is generally preferable to use a mixture of dimethyl sulfoxide and water as the coagulation bath.

Further, the temperature of the coagulation bath at that time is 0°C to around 95°C, usually around 4°C to 40°C.

In the case of obtaining a semipermeable membrane in the form of hollow fibers, any spinneret used for spinning ordinary hollow fibers can be used, but a spinneret consisting of an annular orifice with a hollow capillary in the spinneret hole is preferably used. .

When spinning hollow fibers using such a spinneret, spinning is performed while quantitatively injecting gas or liquid as a core liquid from a hollow tube located in the center of the spinneret.

There are no particular restrictions on the gas, but air, nitrogen, or the like is usually used. The core liquid can be the solvent used in the spinning stock solution or a mixture of the solvent and water, alcohols such as isopropyl alcohol, polyhydric alcohols such as ethylene glycol and glycerin, higher fatty acid esters such as isopropyl myristate, higher fatty acids. A mixture of alcohol and alcohol is used.

Even when the membrane of the present invention is dried, the mechanical properties do not change significantly, but there are cases where the permeation performance changes.

In that case, by attaching a wetting agent such as hydrous glycerin or ethylene glycol, there will be no major change in permeation performance or mechanical properties over a long period of time.

Furthermore, it is also possible to change the permeation performance and mechanical properties (strength, dimensional stability, etc.) of the membrane by heat treatment or stretching treatment after membrane formation.

The semipermeable membrane of the present invention is most suitable as a medical material for artificial kidneys and the like, but it can of course also be applied as a separation membrane in fields such as the food industry and wastewater treatment.

Next, as another specific example of the present invention, the provision of antithrombotic properties to conventionally used medical materials by coating them with the composition of the present invention will be described.

For this purpose, hydrogels made of synthetic polymers containing hydrophilic components such as 2-hydroxyethyl methacrylate, N-vinylpyrrolidone, acrylamide, or vinyl alcohol have conventionally been used.

However, it is generally believed that synthetic polymers containing such hydrophilic monomers with a molecular weight of 200 or less still have insufficient antithrombotic properties.

When these come into contact with blood, body fluids, or biological tissues, they may adsorb various humoral components such as proteins, platelets,
Adhesion of formed particles such as white blood cells, red blood cells, and fibroblasts occurs, which can lead to thrombus formation on the material surface, tissue degeneration, and
It is thought to cause necrosis.

Furthermore, in the case of separation membranes, it has been reported that substance permeability decreases due to the adhesion of these biological components.

The polyester copolymer composition of the present invention has a strong effect of suppressing adsorption and adhesion of the above-mentioned biological components, has biocompatibility,
For example, it is a material with excellent antithrombotic properties, and can be applied to the surface of other materials such as vinyl chloride, polycarbonate, polysulfone, ABS resin, methacrylic resin, polyester resin, and cellulose resin to impart antithrombotic properties. .

The method for coating the medical material polymer is carried out by dissolving the polyester copolymer composition of the present invention in a solvent, and dipping it in the solution or applying the solution.

Any solvent that can dissolve the composition of the present invention can be used as the solvent, and is appropriately selected depending on the composition of the material polymer to be coated and the copolymer composition of the present invention.

Further, the concentration of the solution is also appropriately selected between about 0.5 and 40%. For example, a mixed solvent of dimethylformamide and tetrahydrofuran is preferably used for vinyl chloride, polycarbonate, polyethylene terephthalate, etc., which are widely used as medical polymers.

An example of the method is to immerse the composition of the present invention in a solution for a short time, dry it, and if necessary wash it with methanol, ethanol, water, or a mixture thereof.
The solvent and the like are removed by drying again.

Through such simple operations, it is possible to impart excellent biocompatibility such as antithrombotic properties to conventional general-purpose medical material polymers.

Of course, medical devices with excellent antithrombotic properties can also be manufactured by molding the composition of the present invention.

Regarding the attachment of various biological components to the polyester copolymer composition of the present invention, methods such as scanning or transmission electron microscopy, amino acid analysis, electrophoresis, and Fourier exchange infrared absorption spectroscopy can be used to detect attached blood cell components and It can be quantified by measuring attached protein components.

On the other hand, regarding the evaluation of medical applications, such as antithrombotic properties, various in vitro and eXVivo methods such as the Lee-White method, extracorporeal bypass circulation method, and intravascular indwelling method are used.
Alternatively, it can be evaluated by in vivo testing.

As a result of evaluation using such a method, it was found that the polyester copolymer composition of the present invention inhibits the adhesion of human and animal cells, such as platelets, leukocytes, lymphocytes, and tissue cells, and also inhibits the adhesion of proteins, etc. It has been found that it has low adsorption of body fluid components and has practical mechanical properties such as strength, elongation, and flexibility, making it suitable for medical use.

Such materials that do not adhere to biological components include, for example, vascular cannulas, catheters, monitoring tubes, blood circuits, bypass tubes, blood bags, artificial kidneys, membrane materials for plasma separation, contact lenses, wound protection materials, and drugs. It is suitable as an embedding material for cosmetics or as a modifying material for cosmetics.

As for its application, it can be usefully used alone, in a blend with other synthetic resins, or as a coating on the surface of other materials.

〔Effect of the invention〕

The polyester copolymer composition of the present invention has permeability properties,
It has excellent mechanical properties and does not form thrombi.

In addition, the composition of the present invention can be used to make medical devices and separation membranes by itself, and since it has excellent adhesive properties, by coating it on the interface that comes into contact with blood,
Antithrombotic properties can be easily imparted to conventional medical devices made of various materials.

Furthermore, the composition of the present invention can be easily prepared from industrial monomers used in large quantities for clothing, and can be supplied at a lower cost than blood-compatible polymers that have been studied in the past.

Examples of the present invention are shown below, but the present invention is not limited to these Examples.

Note that parts in the examples indicate parts by weight.

Example 1 81.8 parts of dimethyl terephthalate, 39.5 parts of dimethyl adipate, 80.4 parts of ethylene glycol, and 0.108 parts of calcium acetate were mixed and transesterified while distilling methanol off at 140 to 225°C. After the reaction, 0.05 part of trimethyl phosphate, 0 part of antimony dioxide
．． 0.4 parts, 30 parts of polyethylene glycol with an average molecular weight of 20,000 was added to produce 270"C, 0.2 mdg.
A polycondensation reaction was carried out for 4.5 hours to obtain a block polyether ester (copolymer I).

The obtained copolymer (■) has a relative viscosity of 32, and its approximate composition is 65 mol% of terephthalic acid component and 35% of adipine M component.
The mol% and polyethylene glycol content were 20% by weight.

Ethylene glycol was used as the low molecular weight glycol in the following examples as well.

As for the composition, the glycol components other than polyethylene glycol are ethylene glycol components.

Copolymer (1) was dissolved in dimethyl sulfoxide at 120"c so that the polymer concentration in the solution was 40% by weight to obtain a film-forming stock solution.

The solution was poured at approximately 110°C with a 100μ spacer placed between glass plates, cooled to room temperature to gel, and then one of the glass plates was removed and placed in water to replace the solvent with water, resulting in a film thickness of 10/2. A transparent film A with μ and a water content of 52% was obtained.

Table 1 shows the permeation characteristics of this membrane.

Here, P + (g -' ・c + J-5ec) is the pressure permeation constant, which represents the unit area of the membrane, the unit pressure difference per unit membrane thickness, and the volume of permeate per unit time, and P z
(ell/5ec) represents the solute permeation constant due to the concentration gradient per unit area of the membrane and unit membrane thickness when there is no volumetric flow of liquid.

In the same manner, a film was formed using a 100μ spacer from a film-forming stock solution with a concentration of Copolymer I reduced to 50% by weight, and the film thickness was 93.
A transparent film B with μ and water content of 43% was obtained.

Further, as a comparative example, polymethyl methacrylate membrane C for artificial kidneys (film thickness 106μ, water content 50%, obtained by mixing 5 parts of active PMMA and 1 part of isotactic PMMA and using the same method from a dimethyl sulfoxide solution)
A transparent film) was prepared.

Table 1 shows the permeation characteristics of these membranes.

Table 1 In other words, at the same water content, the polyester semipermeable membrane has better solute permeability than the comparative example.
This shows that when the solute permeability is kept at the same level, the membrane becomes stronger and thinner, making it possible to create a more efficient dialyzer.

Furthermore, polyester semipermeable membranes have high elongation and are therefore resistant to bending, making them excellent in terms of ease of handling.

Note that the albumin permeability of all membranes was 0.5% or less.

Example 2 When forming the membrane B of Example 1, the membrane was placed in water for 10 seconds, then stretched approximately three times and placed in water again to obtain a transparent membrane with a thickness of 30μ and a water content of 41%. It was done.

Furthermore, as a comparative example, a commercially available cellulose membrane for artificial kidneys ("Cuprophan membrane") E (film thickness 24 μm, water content 42%) was prepared.

Table 2 shows the permeation characteristics of these membranes.

Table 2 In other words, the polyester semipermeable membrane could be made into a membrane with high strength by stretching.

Note that the albumin permeability of these membranes was 0.5% or less.

Example 3 Dimethyl terephthalate (TPA), dimethyl isophthalate (IPA), dimethyl adipate (AA) as acid components
), and polyethylene glycol (PEG4000) with an average molecular weight of 4000 was used as the polyalkylene glycol.
The following five types of copolymers ■～
I got ■. The relative viscosities and approximate compositions of these copolymers are shown in Table 3.

Table 3 These copolymers (1) to (2) were each dissolved in dimethyl sulfoxide at a polymer concentration of 40% by weight, and films were formed in the same manner as in Example 1 to obtain five types of films F, G, H, J, and K.

Table 4 shows the permeation characteristics of these membranes.

Table 4 Example 4 (Reference Example) In the copolymer polymerization of Example 3, only dimethyl terephthalate was used as the acid component, and the amount of polyethylene glycol added was 10 to 35% by weight. ) was obtained.

These copolymers were dissolved in dimethyl sulfoxide, dimethylformamide, dimethylacetamide, and N-methylpyrrolidone at a polymer concentration of 40% at a melting temperature of 130°C.
I tried to dissolve it, but was unable to obtain a solution that could be used for film formation.

Example 5 The following polymerization method was carried out in the same manner as in Example 1 using dimethyl terephthalate and dimethyl adipate as acid components and five types of polyethylene glycols with different average molecular weights of 300 to 20,000 as polyalkylene glycols. Five types of copolymers (1) to (XI) were obtained.

The relative viscosities and approximate compositions of these copolymers are shown in Table 5.

Table 5 Each of these copolymers ■ to XI has a polymer concentration of 40
It was dissolved in dimethyl sulfoxide in weight percent, and films were formed in the same manner as in Example 1 to obtain five types of films, M, N, 0, and P.

Table 6 shows the permeation characteristics of these membranes.

Table 6 Example 6 Polymerization method similar to Example 1 using dimethyl terephthalate and dimethyl adipate as acid components, and a small amount of dimethyl sodium 5-sulfoisophthalate, and using polyethylene glycol with an average molecular weight of 4000 as the polyalkylene glycol. Copolymer XII was obtained.

The obtained copolymer XII has a relative viscosity of 36, and has an approximate composition of 70 mol% of terephthalic acid component, 28 mol% of adipic acid component, 2 mol% of 5-sulfoisophthalic acid component, and 15% by weight of polyethylene glycol. there were.

Polymer concentration in solution of copolymer Xll is 40% by weight
Example 1
A film was formed using a similar method to obtain a film thickness of 105.-10.

The water permeability of this membrane is 4.2ml/hr -rrr -mm
) Ig, and urea P2 is 4. I Xl0-6cal/
sec・Also, the strength of this membrane is 64Kg7cm
", the elongation was 460x, the water content was 46%, and the albumin permeability was 0.5% or less.

Example 7 A copolymer III was obtained by the same polymerization method as in Example 1 using dimethyl terephthalate and dimethyl sebacate as the acid components and polyethylene glycol having an average molecular weight of 1t20.000 as the polyalkylene glycol.

The relative viscosity of copolymer
The mol% and polyethylene glycol content were 20% by weight.

1 liter of copolymer X was dissolved in dimethyl sulfoxide to a polymer concentration of 40% by weight, and a film was formed in the same manner as in Example 1 to obtain a film R having a thickness of 81 μm.

The water permeability of this membrane is 1.25 ++ l/hr -% ・v
amHg and urea P2 is 3.8 X 1O-bc+
J/sec.

In addition, the strength of this membrane is 52 Kg7cm2, and the elongation is 54
oz, water content is 51%, and albumin permeability is 0.
．． It was less than 5%.

Example 8 Using a membrane forming stock solution with a concentration of 50% by weight of Copolymer I prepared in Example 1, the spinneret temperature was 105°C from the annular spinning hole.
The fibers were spun while injecting isopropyl alcohol into the inside of the hollow fibers, and introduced into a coagulation bath at about 5° C. consisting of an aqueous solution containing about 10% dimethyl sulfoxide to obtain hollow fibers.

The inner diameter of this hollow fiber was about 250μ, and the membrane thickness was about 20μ.

Thirty of these hollow fibers were housed in a small glass case with an effective length of 12 CI11 to produce a test module with an effective area of about 28 CI11.

The water permeability (UFR) of this hollow fiber module is 1.4
m1l/a”・hr-tataHg, 0.2%
When an aqueous albumin solution was flowed at 25°C under a pressure of 5 OmmHH at a linear velocity of 5 cm/sec at the inlet, the permeation rate of albumin into the filtrate was 0.5% or less, and the amount of filtration (albumin solution UFR) is 1.3 mR7m2・h
+”mmHg.

Example 9 In order to check the blood compatibility of the polyester membrane A obtained in Example 1, the amount of platelets attached was measured.

As a comparative example, the cuprophane membrane E and the glass plate (Pyrex 7740) used in Example 2 were used.
They were cut out into a circle with a diameter of 15 mm and used.

Blood-rich blood plasma (P
RP) and poor plasma plate blood-+1 (PPP) were prepared, a membrane was placed in each, and after soaking at 37°C for 3 hours, it was washed with phosphate buffer and fixed with 3% glutaraldehyde solution.

The amount of protein was calculated from the amount of amino acids obtained by observing these membranes with an electron microscope and decomposing the deposits with hydrochloric acid.

Only a few platelets are found in membrane A, and PR
The amount of platelet-derived protein obtained by subtracting PPP from P is 2.0
It was as low as μg/-.

Platelets are seen attached to the entire surface of membrane E, and the protein amount is 1.
It was 4.2 μg/ad.

Platelets adhered to the entire surface of the glass plate and were scattered in a deformed form, and the protein amount was 7.4 μg/cd.

Example 10 Copolymer 1 prepared in Example 1 was dissolved in a solvent prepared by mixing dimethylformamide and tetrahydrofuran in equal weights at 50°C at a polymer concentration of 10% to prepare a solution for coating.

Add to this solution a 2 cm x 20 cm strip-shaped vinyl chloride sheet (for blood bags), polyethylene terephthalate film (Toshi Lumirror, li thickness 75μ),
A method of dipping a polycarbonate sheet (Mitsubishi Gas Chemical, Nipiron, thickness 0.5 mm) for a short time and pulling it up (
coating by dipping method).

The coating thickness is 8 microns for vinyl chloride.
It was about 5 microns for polyethylene terephthalate and about 10 microns for polycarbonate.

After drying these at 50°C in a stream of dry nitrogen, they were washed in a 30% ethyl alcohol aqueous solution for 6 hours, and then washed with water for 6 hours.
It was washed for hours and dried at 50°C.

The amount of platelets attached to these three types of coated materials was measured in the same manner as in Example 9.

As a comparative example, three types of uncoated materials and a glass plate were used.

The results are shown in Table 7.

Table 7 That is, no platelets were observed on the surface coated with the polyester copolymer composition of the present invention, and the adhesion of platelets, which can cause blood clots, was suppressed.

Example 11 A soft vinyl chloride tube having a length of 30cm111 and an outer diameter of 2.5+am, which was used in Example 10 and was closed at both ends with the coating solution, was coated in the same manner as in Example 10.

Using two adult mongrel dogs (approximately 13 kg), the right inferior vein was incised under anesthesia, and this coated tube and an uncoated vinyl chloride tube as a comparative example were inserted from the incision near the right atrium inflow of the vena cava. After insertion and indwelling for 5 days, blood was removed, laparotomy was performed to open the vena cava, and the thrombus adhered and softened on the tube surface, and almost no thrombus was observed on the surface of the coated tube of the present invention.

Furthermore, the part to which no thrombus was attached was cut out, and μg/c
d, and the amount of adhesion to the coating tube of the present invention was 0.4 μgocd, which showed a large difference between the two.
That is, the polyester copolymer composition of the present invention exhibited excellent antithrombotic properties and biocompatibility even when coated.

Patent applicant: Toshi Co., Ltd.

Claims (3)

[Claims] (1) The acid component of a polyester copolymer mainly composed of terephthalic acid and a low molecular weight glycol with a molecular weight of 250 or less contains 20 to 50 mol% of an acid component other than terephthalic acid, and contains a glycol component other than a low molecular weight glycol. 11% of polyalkylene glycol with a number average molecular weight of about 300 to 60,000 based on the total amount of the polymer.
A medical polyester copolymer composition containing: (2) The medical polyester copolymer composition according to claim 1, wherein the low molecular weight glycol is ethylene glycol. (3) The low molecular weight glycol is ethylene glycol, and the number average molecular weight of polyalkylene glycol