JPS6041947B2 - Method for imparting antithrombotic properties to the surface of polyester molded articles - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for imparting antithrombotic properties to the surface of a molded article containing polyester as a main component.

In recent years, polymer materials have come to be used in the field of medical materials.
When used in areas that come into direct contact with blood, such as artificial kidneys, artificial valves, artificial lungs, and sutures, there is a problem in that it may cause thrombus formation.

Various attempts have been made to develop antithrombotic materials to solve this problem. For example, it has been proposed to obtain an antithrombotic material by synthesizing a polyester containing quaternary nitrogen in its main chain and reacting it with hebalin (Japanese Patent Application Laid-open No. 139173/1983). In this case, a special monomer containing nitrogen must be used, and it has the disadvantage that it decomposes and becomes colored during the synthesis and molding process of polyester. In view of this problem, the present inventors investigated various methods for simply and effectively imparting antithrombotic properties to the surface of a molded article whose main component is a general polyester without synthesizing a special polyester. The surface of the molded product mainly composed of polyester is covered with at least one first
amination by treatment with a polyamine having a class or (and) a secondary amino group, then converting the resulting aminated surface into a quaternary salt, and then forming an antithrombotic compound having the quaternary salted surface and an anionic group. It has been found that antithrombotic properties can be imparted to the surface of a polyester molded article by reacting the polyester. The polyester in the present invention is a polymeric substance having an ester bond in its main chain, and is generally produced by polycondensation of a polybasic acid and a polyhydric alcohol, self-condensation of an oxycarboxylic acid, ring-opening polymerization of a lactone, or the like.

Examples of polybases include terephthalic acid, isophthalic acid, adipic acid, sebacic acid, diphenyl ether 4|4
'-dicarboxylic acid, diphenylsulfone, 4|4'-dicarboxylic acid, maleic acid, fumaric acid, trimellitic acid,
Pyromellitic acid etc. can be used. Examples of polyhydric alcohols include ethylene glycol, propylene glycol, butylene glycol, diethylene glycol, triethylene glycol, polyethylene glycol, polypropylene glycol, polybutylene glycol, pentaerythritol, and bisphenol A. Examples of the oxycarboxylic acid include ρ-oxybenzoic acid and ω-oxynonanoic acid. Examples of the lactone include ζ-valerolactone, γ-caprolactam, and vivalolactone. These monomers and their functional derivatives are homopolymerized or copolymerized by known methods. Furthermore, an unsaturated polyester resin can be obtained by adding a vinyl monomer such as styrene or (meth)acrylic acid ester to a polyester prepolymer made from an unsaturated monomer such as maleic anhydride or fumaric acid. Among the above polyesters, especially terephthalic acid and ethylene glycol and polyalkylene glycol, dimethyl terephthalate and ethylene glycol and polyalkylene glycol, bis(2-hydroxyethyl) terephthalate or its initial condensate and polyalkylene glycol, and terephthalic acid and polyalkylene glycol. Obtained by reacting 1,4-butanediol and polyalkylene glycol, dimethyl terephthalate, 1,4-butanediol and polyalkylene glycol, bis(4-hydroxybutyl) terephthalate or its initial condensate, and polykylene glycol. polyester is inexpensive and
Moreover, it is suitably used because it has a wide range of physical properties such as strength, moldability, and biocompatibility required as a medical polymer material.

The polyalkylene glycol mentioned here includes, for example, polyethylene glycol, poly(1,2-propylene glycol), polytrimethylene glycol, poly(1,2-butylene glycol), poly(1,3-butylene glycol), polytetramethylene glycol. , polypentamethylene glycol, etc., with an average molecular weight of 50
0 to 4000 is preferably used. These polyesters can be produced by known polymerization methods. Polyester can be processed and molded into various shapes such as powder, beads, fibers, films, tubes, and permeable membranes depending on the purpose.

Moreover, a polyester film can also be formed on the surface of a molded article made of a material other than polyester. Also,
Additives such as plasticizers, modifiers, and stabilizers may be added to the polyester as necessary. Furthermore, after processing and molding, surface roughening treatment and activation treatment with alkali, acid, etc. can be performed. The polyamine used in the present invention is
A low-molecular compound or a high-molecular compound having at least two amino groups, at least one of which must be a primary or (and) a secondary amino group. Examples of po-J amines having at least one primary or secondary amino group used in the present invention are listed below. 0 Low molecular polyamine ethylene diamine, trimethylene diamine 1,2-diaminopropane, tetramethylene diamine, 1,3-diaminobutane, 2,3-diaminobutane, pentamethylene diamine, 2,4-diaminopentane, hexamethylene diamine, octa Methylenediamine, nonamethylenediamine, decamethylenediamine, undecamethylenediamine, dodecamethylenediamine, tridecamethylenediamine, ocdecamethylenediamine, N,N-dimethylethylenediamine, N,N-diethylethylenediamine, N
, N-diethyltrimethylenediamine, N,N-dimethyltrimethylenediamine, N,N-dibutyltrimethylenediamine, N,N,N''-triethylethylenediamine, N-methyltrimethylenediamine, N,N-dimethyl-ρ- Phenylenediamine, N,N-dimethylhexamethylenediamine, diethylenetriamine, triethylenetetramine, tetraethylenepentamine, heptaethyleneoctamine, nonaethylenedecamine, 1,3-bis(7-aminoethylamino)propane, bis(3 -aminopropyl)amine, 1,3-bis(3″-aminopropylamino)propane, 1,2,3-triaminopropane, tris(2-aminoethyl)amine, tetra(aminomethyl)methane, methyliminobis propylamine,
Methyliminobisethylamine, ethyliminobisethylamine, N-aminopropyl-2-morpholine, N-
Aminopropyl-2-pipecoline, N-(2-hydroxyethyl)trimethylenediamine, xylenediamine,
Phenylenediamine, piperazine, N-methylpiperazine, N-(2-aminoethyl)ethanolamine, N-
Aminoethylpiperazine.

ζ) Polymeric polyamine (1) Poly(alkylene polyamine) synthesized from amine and alkylene dihalide or epichlorohydrin [EncyclOpediaOfPOlyTnerS
CieIlCeandTechnOlOgyllOvol.
616 pages] (2) Alkylene imine polymers obtained by ring-opening polymerization of alkylene imines such as ethyleneimine and propylene imine [EncyclOpediaOfP
OlyrTlerScience and Technol
Vol. Ogyll, p. 734] (3) Other polymeric polyamines such as polyvinylamine and polylysine Among these polyamines, polyethyleneimine is particularly preferably used because it is inexpensive and effective.

In the present invention, it is first necessary to treat the surface of a molded article containing polyester as a main component with the above polyamine to aminate it.

In order to treat the surface of a molded product whose main component is polyester with a polyamine, if the polyamine is a liquid, it is sufficient to bring the polyamine itself into contact with the surface of the molded product.
0.1% by weight, preferably 1% by weight of polyamine in methanol, ethanol, propanol, dioxane, tetrahydrofuran, water or a mixed solvent thereof.
It is also possible to dissolve the solution to the above concentration and bring the resulting solution into contact with the surface of the molded article. When the polyamine is solid, the solution obtained as described above may be brought into contact with the surface of the molded article. Processing temperature range is -20-100
'C1 is particularly preferably from 0 to 80°C, and the treatment time is preferably from 1 to 2 servings, particularly from 3 to 5 hours. During the polyamine treatment, a dehydration condensation agent can be used as necessary. As the dehydration condensation agent, for example, N, N''
-dicyclohexylcarposiimide, 1-cyclohexyl-3-[2-morpholino(4)-ethyl]-carposiimide-methop-toluenesulfonate, diphenylphosphoryl azide, N-ethyl-5-phenylisoxazolium-3''-sulfonate, Examples include diphenylketene-ρ-tolylimine, N,N″-carbonyldiimidazole, and 6-chloro-1-ρ-chlorobenzenesulfonyloxybenzotriazole. When the polyamine is brought into contact with the surface of the molded article, the surface can be renewed by methods such as stirring, shaking, and circulation as necessary. By the polyamine treatment as described above, the surface of the molded product containing polyester as a main component is aminated. That is, amino groups are introduced onto the solid surface. The reactions that occur during this polyamine treatment include (1) partial aminolysis of the ester bond by the primary or (and) secondary amino group of the polyamine, and (2) the reaction between the terminal carboxyl group of the polyester and the primary amino group of the polyamine. Alternatively, (and) an amide forming reaction between the secondary amino group and (3) an ion forming reaction between the terminal carboxyl group of the polyester and the polyamine. In the present invention, it is necessary to subsequently convert the aminated solid surface obtained as described above into a quaternary salt. The quaternary chloride on the aminated surface is a known quaternary chloride such as hydrogen halide or halogenated hydrocarbon.
This can be carried out by allowing a grading agent to act on the aminated surface. For example, by contacting an aminated solid surface with an aqueous solution of hydrogen chloride, hydrogen bromide, etc., or by contacting an aminated solid surface with an aqueous solution of hydrogen chloride, hydrogen bromide, etc. , methanol, ethanol, dimethylformamide, diethylacetamide, dimethyl sulfoxide, or a mixed solvent thereof can be brought into contact with a solution of the aminated solid surface to form a quaternary salt. The reaction temperature is O~90'C1 reaction time is 1~2
4 hours is a good guess. In the present invention, it is necessary to react the quaternary chlorinated surface obtained as described above with an antithrombotic compound having an anionic group.

The reaction between the quaternary chlorinated surface and the antithrombotic compound having anionic groups can be carried out, for example, in an amount of 0.01 to 10% by weight, preferably 0.5 to 10% by weight of the antithrombotic compound having anionic groups.
This can be carried out by bringing the solid surface into contact with 5 parts by weight of an aqueous solution.

The reaction temperature is preferably 10 to 100°C, particularly 30 to 90°C. Examples of antithrombotic compounds having anionic groups according to the present invention include natural substances such as hevarin and chondroitin sulfate, and synthetic substances such as homopolymers and copolymers such as vinylsulfonic acid and styrenesulfonic acid. Of these, hebalin is the most suitable.

These substances are usually used as their sodium salts, but other alkali metal salts can also be used in place of the sodium salts. The polyester material whose surface has been given antithrombotic properties by the method of the present invention not only has excellent antithrombotic properties, but also has a wide range of physical properties such as strength and biocompatibility required for medical polymer materials. ing.

EXAMPLES The present invention will be described in more detail below with reference to Examples.

The antithrombotic properties were evaluated using Chandler's rotating tube [A. B. Chandler. ．． LabOratOr
yInVeStlgatlOnl Volume 7, Page 110 (1
958)] (Injecting human citrate blood into a tube,
This was done by measuring the clot formation time using the clot formation time (after addition of Ca++). Example 1 Bis(4-hydroxybutyl)terephthalate (75g
), polytetramethylene glycol with a molecular weight of 2000 (
75g) and tetrabutyl titanate (4). 075
g) into a reactor and heated to 250°C11 while stirring.
A copolymer was obtained by carrying out a 9-powder polycondensation reaction under a high vacuum of Tf0ftHg or less.

After the reaction is completed, the copolymer is extruded into a tube with an inner diameter of 3WrIn having appropriate flexibility and good mechanical properties.
A polyester tube with an outer diameter of 5Tr$L was prepared.
The inside of this tube was flowed at a flow rate of 100rn1/min.
A mixed solution consisting of 0% polyethinimine aqueous solution 1001111 and methanol 500rT11 was circulated at room temperature for 2 hours.

Next, 200rr11 of a 5Wt% methanol solution of dicyclohexylcarbodiimide was added, followed by 100rr11.
It was circulated for 5 hours at a flow rate of n1/min. After draining the treatment liquid from the tube, the tube was washed by circulating methanol and then ion-exchanged water. Aqueous ethanol solution of ethyl bromide (equal weight mixture of ethanol and water with 3
．． % of ethyl bromide solution) and allowed to stand at 30°C for 4 hours, then washed with a mixture of equal weights of ethanol and water.
A grade chloride tube was obtained. The resulting quaternary chloride tube was filled with a 1% by weight aqueous sodium valine solution and heated to 40'C.
I let it stand for 2 minutes. When the thrombus formation time of the hevalinized tube obtained as described above was measured, it was found to be 4 or more times.

For comparison, when the clot formation time was measured for untreated tubes, there were 2 clots.

Example 2 The polyester tube obtained in Example 1 with an inner diameter of 3mm and an outer diameter of 5mm was filled with N,N-dimethyltrimethylenediamine, left to stand at 30°C for 5 hours, and then washed with ion-exchanged water. .

The obtained aminated tube was subjected to quaternary salt conversion in the same manner as in Example 1, and then reacted with hevalin sodium. The thrombus formation time of the obtained tube was 4 or more times. Example 3 Commercially available polyethylene terephthalate suture thread (thickness 5
No.-0) was treated in a boiling methanol solution containing 1% polyethyleneimine for 1 hour, then subjected to quaternary salting in the same manner as in Example 1, and then reacted with heparin sodium.

This suture was sterilized in ethylene oxide gas and then sewn to expose the inner surface of the dog's superior vena cava. When the body was examined one week later, no thrombus was observed on the surface of the suture. For comparison, untreated sutures were sewn into the superior vena cava in the same manner as above, and thrombus formation was observed.

Claims (1)

[Claims] 1. The surface of a molded article containing polyester as a main component is treated with a polyamine having at least one primary or (and) secondary amino group to be aminated, and then the resulting aminated surface is converted to a quaternary salt, A method for imparting antithrombotic properties to the surface of a polyester molded article, which comprises then reacting the quaternary chlorinated surface with an antithrombotic compound having an anionic group.