JPS5832986B2 - medical equipment - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a medical device whose surface in contact with blood is made of a polyether/polyester block copolymer with improved hemolytic and blood coagulability properties.

Currently, polyvinyl chloride and silicone rubber, which are widely used as resin materials for medical devices such as blood transfusion containers and tubes, are known for their (1) safety, such as non-toxicity to living organisms, and (
It has the following problems in terms of 2) affinity with living bodies such as foreign body reactions, or (3) low cost.

In other words, there is a toxicity problem with polyvinyl chloride due to the plasticizer mixed into the material to make it soft, which migrates into the blood during use, and silicone rubber is not the main problem with plasticizers in polyvinyl chloride. However, safety issues remain regarding the various additives used for vulcanization.

Furthermore, silicone rubber is quite expensive due to the complexity of material processing, and it is still not sufficient in terms of safer and better quality materials, which is the essence of medical care.

As a result of intensive research to develop medical devices using materials free of such defects, the present inventor found that polyether/polyester block copolymers are sufficiently flexible without the use of plasticizers like polyvinyl chloride. In addition, since it can be injection molded, unlike silicone rubber, it does not require complicated molding processes such as vulcanization, is inexpensive, can be easily imparted with transparency, and is resistant to hemolysis and blood. We discovered that the coagulability properties are equivalent to those of silicone rubber, and that the blood coagulation and hemolytic properties were further improved by treating the polyether/polyester block copolymer with a specific solvent. This invention has been achieved.

That is, the present invention provides a medical device whose surface in contact with blood is made of a thermoplastic resin, wherein the thermoplastic resin has the formula and [where n is an integer of 1 to 6, ■ is an integer of 2 to 6, and m is 0 or An integer of 1 to 10, p is an integer of 1 to 10, and X is a halogen atom. The present invention relates to a medical device characterized by being made of a polymer.

The thermoplastic resin used in the present invention is a polyether/polyester block copolymer.

The polyester in the block copolymer means that the acid component (component A) is an aromatic dicarboxylic acid, substantially terephthalic acid, 2,6-naphthalene dicarboxylic acid, and/or an ester-forming derivative thereof (e.g., alkyl ester, aryl ester).

Other carboxylic acid components that can be used include:
Aromatic dicarboxylic acids other than terephthalic acid and 2,6-naphthalene dicarboxylic acid, aliphatic dicarboxylic acids, alicyclic dicarboxylic acids, etc., in an amount of 30 mol% or less, preferably 15 mol% or less of component A, such as isophthalic acid. acids, dicarboxylic acids such as methylterephthalic acid, diphenyldicarboxylic acid, diphenoxyethanedicarboxylic acid, diphenyl etherdicarboxylic acid, diphenylsulfonedicarboxylic acid, hexahydroterephthalic acid, adipic acid, sepatic acid, azelaic acid, succinic acid, oxalic acid, etc.; Oxy acids such as oxybenzoic acid, hydroxyethoxybenzoic acid, oxycaproic acid, and ester-forming derivatives thereof.

The glycol fraction (component B) includes glycols with a molecular weight of 400 or less, such as ethylene glycol, propylene glycol, tetramethylene glycol, hexamethylene glycol, pentamethylene glycol, decamethylene glycol, diethylene glycol, bishydroxyethoxybisphenol A1 bishydroxyethoxy It is derived from glycols such as diphenyl sulfone and xylylene glycol, and their ester-forming derivatives.

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

As will be described in more detail later, when attempting to impart transparency to a polyether/polyester flock copolymer, ethylene glycol, cyclohexane dimetatool, etc. may be mixed with tetramethylene glycol in an amount of 10 to 40 mol%. When used, favorable effects can be obtained.

The polyether of the polyether/polyester block copolymer used in the present invention mainly consists of poly(oxyalkylene) glycol (component C).

The poly(oxyalkylene) glycol has an average molecular weight of 500 to 5000 and a ratio of carbon atoms to oxygen atoms of 2.
0 to 4.5, and specific examples include polyethylene glycol, polypropylene glycol,
Examples include polytetramethylene glycol, polyethylene glycol-polyglopylene glycol copolymers, and ester-forming derivatives thereof.

Furthermore, in addition to the above-mentioned A, B, and C components, the polyether/polyester block copolymer may contain other compounds having two or more ester-forming functional groups for the purpose of modification (
component D) in the copolymer at 20% by weight or less, preferably 1
It can be contained in an amount of 0% by weight or less.

Examples include trimellitic acid, pyromellitic acid, naphthalene polycarboxylic acid, trimethylolpropane, pentaerythritol, glycerin, oxybenzoic acid, oxyterephthalic acid, oxycaproic acid, and ester-forming derivatives thereof.

When it is desired to impart transparency to a polyether/polyester block copolymer, this can be achieved by converting the polyester polymer portion into a copolymer.

In such a case, this can be achieved by using one or more of the components A, B, and C, or by adding and copolymerizing the component D.

To give a few examples of the embodiments, (1) terephthalic acid is selected as the A component and isophthalic acid is mixed therewith, (2) tetramethylene glycol is selected as the B component, and ethylene glycol or - A method such as mixing and using 4-cyclohexane dimetatool.

The preferred composition of the polyether/polyester block copolymer used in the present invention is terephthalic acid, tetramethylene glycol and polyoxytetramethylene glycol, or when imparting transparency, terephthalic acid,
These are tetramethylene glycol, 1,4-cyclohexane dimetatool (or ethylene glycol), and polyoxytetramethylene glycol.

The proportion of poly(oxyalkylene) glycol in the entire polymer is 40 to 80% by weight, and if it is less than 40% by weight, sufficient flexibility cannot be obtained.

If it exceeds 80% by weight, the softening point of the polymer will decrease,
It becomes impossible to withstand high-pressure steam sterilization (121°C, 1 hour), and at the same time, moldability deteriorates significantly.

Preferably it is 50 to 75% by weight.

The polyether/polyester block copolymer may be produced by any general method.

For example, (1) Prepare all three ingredients A, B and C,
A method of starting a polycondensation reaction, (2) A method of polycondensing both components A and B to a certain degree, and then adding a component C to copolymerize them; (3) A method of polycondensing both components A and C to a certain degree. After that, component B is added and copolymerized.

Conventionally known additives may be added to the polyether/polyester block copolymer used in the present invention at an appropriate time from the time of reaction to molding.

Examples of additives include polymerization accelerators and additives for physical and chemical modification, including various stabilizers and modifiers.

Examples include polymerization accelerators such as terephthaloyl-bisN-caprolactam, ultraviolet stabilizers,
For example, 2-(2/-hydroxy-3'.5'-ditertiarybutylphenyl)-5-chlorobenzotriazole and the like are shown.

These additives are added in an amount of 10% by weight or less, preferably 5% by weight or less, relative to the synthetic polymerization.

The polyether/polyester flock copolymer was prepared at 35°C in an orthochlorophenol solvent at C=1.2.
It is preferable to use one whose reduced viscosity (ηsp/c) measured in ff/dl satisfies the following formula.

[In the formula, Y is the value of reduced viscosity (ηsp/c), and M is the value expressed in weight percent of polyoxyalkylene glycol in the polyether/polyester block copolymer.]

Examples of embodiments in which the polyether/polyester block copolymer is used on the surface of a medical device that comes into contact with blood include (1)
) Medical devices, such as blood transfusion containers or tubes, are molded using the polyether/polyester flock copolymer as a material; (2) other materials such as,
There are cases where a polyether/polyester block copolymer is coated or laminated on the surface of a molded product made of silicone rubber, polyvinyl chloride, etc. that comes into contact with blood.

In either case, the present invention can be achieved by cleaning and extracting the surface of the molded product as a medical device that comes into contact with blood with a specific solvent shown below.

Solvent treatment extracts and removes unreacted monomers and/or oligomers near the surface of the polyether/polyester block copolymer that forms the surface that comes in contact with blood, and it is more desirable to extract them from within the polymer. That's true.

When extracting from inside the polymer, it can be carried out at the stage where the polymer is made into chips after completion of polymerization, or by increasing the processing time and number of times of processing of the molded product after molding.

Molded products here mean films, sheets, tubes, bottles, bags, and other molded products with a certain shape.
It also refers to coating and laminating molded products with other materials.

That is, the solvent treatment in the present invention may be carried out at any time after polymerization of the polyether/polyester floc copolymer, from the chip stage to immediately before use as a molded product, preferably immediately before sterilization.

The washing or extraction process may also include drying and expulsion of the solvent used.

The solvent has a boiling point of 50°C or higher at atmospheric pressure, and has the formula (However, n is an integer from 1 to 6.

Alcohols represented by the formula) (where l is an integer of 2 to 6, m is an integer of 0 or 1 to 10,
The compound is selected from the group consisting of ethers represented by the formula (X is a halogen atom) and epoxies represented by the formula (where l is an integer of 2 to 6, p is an integer of 1 to 10, and X is a halogen atom).

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

Examples of the alcohols shown in hole 1) include methanol, ethanol, propatool, butanol, pentanol, and hexanol.

Among these, methanol, ethanol, propatool, and butanol are particularly preferred.

Preferred ethers represented by force 2) include, for example, tetrahydrofuran, monochlorotetrahydrofuran, monofromtetrahydrofuran, and the like.

Furthermore, preferable epoxies represented by hole 3) include epichlorohydrin, epibromohydrin, and the like.

Such a solvent usually has the ability to quickly and sufficiently wash and extract monomers and/or oligomers remaining on the surface and/or inside of the polyether/polyester block copolymer.

Furthermore, alcohols and epoxies have little to no effect on the block copolymer, such as dissolution, swelling, or decomposition, or even if they do, they have very little effect, and they do not affect the inherent physical properties of the block copolymer. It has properties that do not substantially damage the shape of the molded product.

The amount of the solvent varies depending on the shape of the molded product, but it is generally sufficient that it is at least the amount that can immerse the molded product, and is preferably 0.2 rn1 or more per 1 c1ri of surface area of the molded product, for example.

The treatment is usually carried out at a temperature below the boiling point of the solvent; more specifically, when alcohols are used, the temperature is below the boiling point of the alcohol and above 0°C, and for alcohols with a boiling point exceeding 100°C, at 100°C. Hereinafter, it is desirable to conduct the reaction preferably at a temperature of 80°C or lower and 0°C or higher, particularly preferably at a temperature from room temperature to 80°C.

The treatment time is 5 minutes or more, preferably 30 minutes or more, until the purpose of washing and extraction is achieved.

Furthermore, when using epoxies, it is desirable to conduct the treatment at a temperature from 0° C. to its boiling point.

The treatment time is 10 minutes or more, preferably 30 minutes or more until the purpose of washing and extraction is achieved.

Furthermore, when using ethers, the temperature is between 0°C and 50°C.
C., preferably from room temperature to 40.degree. C., for at least 1 second, preferably at least 5 seconds, until the purpose of washing and extraction is achieved.

In the treatment, it is necessary to appropriately select conditions such as temperature and time depending on the type of solvent.

For example, incorrect selection of treatment conditions with ethers may damage the shape of the molded product.

Any processing operation such as batch type or continuous type may be employed, and the treatment may be carried out under normal pressure, increased pressure or reduced pressure.

It is desirable that the solvent be kept in a liquid state under reduced pressure.

The reason why the above-mentioned solvent used in the present invention has a preferable effect is not clear.

However, for polyesters such as polyethylene terephthalate, polytetramethylene terephthalate, polyethylene naphthalene dicarboxylate, etc., solvents such as dioxane and chloroform are usually used to extract the oligomers, and the specific solvent used in the present invention is not suitable for its purpose. is rarely achieved.

In addition, the polyether/polyester block copolymer used in the present invention exhibits the phenomenon of rapid swelling and dissolution in these dioxane and chloroform solvents, making it possible to extract the oligomer while maintaining the form of the molded product. The purpose of the invention is not achieved.

The medical device of the present invention has a surface that comes into contact with blood, and includes devices such as containers and tubes for blood transfusion, containers and tubes for blood collection, as well as devices such as artificial kidneys, heart-lung machines, artificial livers, and blood pumps. It also includes those having blood conduits such as.

As a method for molding molded products such as containers and tubes using the polyether/polyester block copolymer itself, melt injection molding or extrusion molding that takes advantage of its thermoplastic properties is generally preferred.

In addition, when coating or laminating the polyether/polyester block copolymer on the surface of a molded product made of other materials, such as a molded product made of silicone rubber, polyvinyl chloride metal, or glass, the block copolymer A method of dissolving it in a solvent and applying it and drying it, a method of adhering it using an adhesive, a method of melting it and applying it and adhering it, etc. are used.

When coating a polyether/polyester block copolymer on a molded product made of other materials, the solvent is one that can dissolve the block copolymer, and after coating, the used solvent can be removed by heating, drying, etc. is preferably used.

The medical device of the present invention has significantly improved hemolysis and blood coagulation properties because the surface in contact with blood is made of a polyether/polyester block copolymer treated with a specific solvent.

Furthermore, the polyether/polyester block copolymer has the advantage of being essentially plasticizer-free, biologically safe, flexible and transparent if desired, and a thermoplastic resin with good moldability. .

Hereinafter, aspects of the present invention will be illustrated by way of examples.

All "parts" in this work represent "parts by weight."

In addition, the measurement method for each test item in the work was as follows.

(1) Softening point: Measured by Vicat softening point measuring device.

(2) Reduced viscosity: Polymer 1.21 and orthochlorophenol 10077I
The viscosity was determined from the solution viscosity measured at 35°C.

(3) D hardness: Measured by Shore D hardness measuring device.

It is a measure of elasticity; the lower the value, the softer and more elastic the material is.

(4) Total light transmittance: Measured using a Gaitske integrating sphere microturbidity meter (manufactured by Nippon Seimitsu Kogaku Co., Ltd., model 5EP-TU).

This is a measure of transparency; the higher the value, the more transparent the substance is.

(5) Hemolytic test: According to the 8th revised Japanese Pharmacopoeia B, General Test Method 36 Plastic Container Test for Infusion 110) Hemolytic Test, the experiment was conducted using fresh pig ACD blood.

The evaluation was shown as -1 if there was no hemolysis, a condition in which it was difficult to judge, and a score of 1 if there was hemolysis.

(6) Blood coagulation test: 0, 1 M in a tube with one end closed in a constant temperature bath at 37°C.
of CaCl20.0251rLl, then 0.2
Add 5ml of fresh pig ACD blood and mix well with the blood.
Let stand for 10 minutes.

Then add water and remove the clot in the tube.
After being left in water for 5 minutes, it is transferred to approximately 2 ml of 37% formalin and left to stand for an additional 5 minutes.

After that, discard the formalin and store it in water.Weigh it by sandwiching it between sheets of paper or tissue paper to absorb the moisture and measure its weight.

The results are shown with the weight of the silicone rubber thrombus as 100%.

Examples 1 to 4 and Comparative Examples 1 to 4 A reactor equipped with a stirrer, a distillation device, and a nitrogen introduction tube was
The raw materials shown in the table were charged and heated to 180-220°C to distill out 90% of the theoretical amount of methanol produced, then the reaction temperature was raised to 245°C and the reaction was carried out for 30 minutes at normal pressure. In a weak vacuum of about 20mmHg abs, 3
React for 0 minutes and further increase 0.1 to 0.3 mmHg abs
Polymerization was carried out for 250 to 300 minutes under high vacuum of , to obtain a high molecular weight polymer, which was taken out as a chip with a diameter of 3 mm and a length of 3 mm.

The obtained chips were dried at 100°C for 2 hours using a hot air dryer, and then extruded into a tube shape with an outer diameter of 7 and an inner diameter of 5 using a melt extruder at a temperature 20 to 30°C higher than the softening point. It was cooled in a water layer and rolled up.

The physical properties of this tube are shown in Table 1.

Cut this tube to a length of 1 crIL and place it in a flask with ethanol (EtOH) or epichlorohydrin (EC).
H) for 30 minutes and 5 hours, respectively, and then the solvents EtOH and epichlorohydrin were expelled and dried to determine the weight of the residue, and the ratio to the initial weight was calculated as the extract percentage (%) in Table 1. I missed it.

In addition, for comparison, using polyvinyl chloride for blood pumps, the physical properties and the proportion of extractables were measured in the same manner as above, and the results are shown in Table 1.

A hemolytic test and a blood coagulability test were conducted using these tubes.

The results are shown in Table 2. Examples 5 to 9 and Comparative Example 5
．． 6 After washing the polyether/polyester block copolymer chips used in Examples 1 to 3 with the solvent shown in Table 3, dissolve them in the dissolution solvent shown in Table 3 to prepare a 5% by weight solution. Then, the coating material was immersed in the solution and dried to perform coating.

The material coated with the obtained polyether/polyester flock copolymer was tested for hemolysis and blood coagulation.

Claims (1)

[Scope of Claims] 1. A medical device whose surface in contact with blood is made of a thermoplastic resin, wherein the thermoplastic resin is formed by the formula [where n is an integer of 1 to 6, 1 is an integer of 2 to 6, and m is a 0 or an integer of 1 to 10, p is an integer of 1 to 10, and X is a halogen atom] Polyether/polyester treated with at least one solvent selected from the group consisting of alcohols, ethers, and epoxies A medical device characterized by being made of a block copolymer. 2. The medical device according to claim 1, wherein the polyether/polyester block copolymer is a block copolymer of aromatic polyester and poly(oxyalkylene) glycol. 3. The medical device according to claim 1, wherein the processing solvent is at least one type of alcohol represented by the formula CnH2n+tOH (n is an integer from 1 to 4).