JPS58105759A - Anti-thromotic composition - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel antithrombotic composition, and more particularly to a composition having excellent antithrombotic and adhesive properties.

Medical devices that are used in direct contact with blood include various vascular cannulas, catheters, various monitoring tubes, extracorporeal circulation circuits, A-V shunts for artificial kidneys, and blood injection tubes, and each medical device has its own unique characteristics. The material constituting the device is required to have antithrombotic properties as well as mechanical properties closely related to the method and site of use.

Conventionally, the medical devices mentioned in item 1 have been made of soft vinyl chloride, polytetraferroethylene, polyethylene, polypropylene, polyester, and unmodified well-known polyesterimide resins, and their mechanical properties are generally satisfactory. However, thrombus formation upon contact with blood remains a major unresolved problem.

The present inventors conducted research to prevent thrombus formation at the interface with blood while maintaining the mechanical properties of the polymer material described above, and as a result, they arrived at the present invention. The present invention provides an antithrombotic composition in which heparin is bonded to a polyamide in which an 8th-class amine group or a quaternary amine group is introduced into the chain.

Since the antithrombotic composition of the present invention has excellent adhesive properties, it can easily impart antithrombotic properties to conventional medical devices made of various materials by coating the interface that comes into contact with blood. However, it is of course a preferred embodiment of the present invention that the antithrombotic composition itself constitutes a medical device.

Next, the present invention will be explained in more detail.

In the present invention, the polyamide having an octagrade amino group introduced into the side chain is particularly preferably one represented by the following general formula.

(7NH(OH,1)4CHOO9→NH(C!H2)
. C〇9 In the above general formula, R1, horse is CH,,0,1
%, n means 6 and/or 11, and a and b mean the molar ratio of each component. The polyamide is, for example, α
-(N-dimethylamino)-ε-caprolactam and ε-
That's caprolactam 41.

and ε-laurolactam through ring-opening copolymerization.

In the polyamide having tertiary amine groups, the substitution ratio (a/a+b The characteristics characterized by can be changed.

Furthermore, the degree of polymerization of the main chain poly-ε-capramide can also be arbitrarily selected depending on the polymerization conditions.

When the substitution rate is 88% or more, the polyamide becomes soluble in water and alcohol such as ethanol.

The polyamide into which the quaternary amino group of the present invention has been introduced is obtained by OH-coating the polyamide having the above-mentioned tertiary amine group.

It can be obtained by quaternization using a quaternization reagent represented by n = 0 to 15), which means a rogene atom.

A polyamide having a quaternary amino group has improved solubility in water, alcohol, etc. at the same substitution rate when compared with a polyamide having an octagrade amine group.

When coating the surface of a material to be coated with the composition of the present invention, the adhesion improves as the substitution rate increases, and the amount of heparin bonded to the polyamide is also proportional to the substitution rate. On the other hand, as the substitution rate increases, the solubility of the polyamide in water increases, giving rise to the possibility that the polyamide will dissolve in blood.

Therefore, it is preferable to crosslink the polyamide to make it insoluble in water. The most suitable method for crosslinking the polyamide to make it insoluble in water is intermolecular crosslinking using an epoxy compound.

Preferred examples of the epoxy compound include glycerol polyglycidyl ether, diglycerol polyglycidyl ether, and trimethylolprono-polyglycidyl ether. Here, the crosslinking by the epoxy compound is thought to proceed by reacting with the terminal hydrogen of the polyamide, and does not react with the 8th amine group in the polymer, and the tertiary amino group is the link between the epoxy compound and the polyamide. It is thought to act as an effective catalyst for the reaction, and is characterized by the fact that the 8th-class amine group necessary for heparin binding remains effectively even after the crosslinking reaction is completed.

However, the binding amount of heparin is closely related to the crosslinking density; if the crosslinking density is too high, heparin, a polymer (molecular weight approximately 15,000), cannot diffuse into the interior of the polymer, resulting in The amount of heparin binding is significantly reduced. Furthermore, if the crosslinking density is too high, the adhesion between the coated substrate and the polyamide will be significantly reduced.

Therefore, the crosslinking density is preferably within a range that prevents solubility of the polyamide in blood and does not hinder the diffusion of heparin into the polyamide.

An example of a method for coating the antithrombotic composition of the present invention on a surface that comes into contact with a medical device and blood will be specifically described below.

Dissolving the polyamide resin having an 8th class amino group with a substitution rate of preferably 80% to 100% in a solvent (water, alcohol or a mixed solvent thereof) at 01% to 20% by weight,
At the same time, glycerol polyglycidyl ether, dicrycerol h polyglycidyl ether or trimethylolpropane j polyglycidyl ether etc.

05% to 50% by weight of the boxy compound based on the polyamide
It is preferably added in an amount of 20% to 20% by weight. The coating solution can be applied to polyvinyl chloride, polytetra 70 roethylene, polypropyleno, polyethylene, polyester,
After coating the surface of a medical device made of polyamide resin or the like, removing the solvent at elevated temperature or under vacuum, heat treatment at a temperature of 40°C to 100°C for 5 minutes to 2 hours to cause a crosslinking reaction with the epoxy compound. Do the following. In order to improve the adhesion between the polyamide coating layer and the material to be coated, it is very effective to subject the surface of the material to be coated to prior corona discharge or plasma treatment or chemical or physical etching. Especially polypropylene, polyethylene, which has few active groups,
When coating the surface of 570 ethylene or polyester resin, it is preferable to carry out this treatment.Next, the coated material is immersed in methanol to sufficiently remove unreacted epoxy compounds, oligomers, etc. , the remaining methanol is extracted and removed by immersion in water.Then, in order to bind heparin to the coating layer, the coating material is immersed in water at a concentration of 0.1 wt% to 10 wt%.
]% heparin soda aqueous solution. The heparinization temperature is room temperature to 80℃, and the heparinization time is 5 minutes to 2
It is 4 hours.

Here, it is also possible to bind a large amount of heparin by quaternizing the tertiary amino groups in the polyamide before the heparinization treatment. After the heparinization treatment, unbound heparin is removed by washing with water, followed by drying.

This coated product passed the extract test, acute toxicity test, pyrogen test, sarcastic test, and hemolytic test of the Ministry of Health and Welfare Notification No. 801, "Standards for Disposable Blood Transfusion Sets and Infusion Sets."

Pan sterilization can be performed with ethylene oxide gas.

The present invention will be explained below by way of examples. However, the present invention is not limited thereto.

7 Example 1 5 wt of copolymerized polyamide of α-dimethyl ryomino ε-caprolactam and ε-caprolactam with a substitution rate of 52%
% ethanol solution and added and mixed glycerol polygrindyl ether (Bunacol EX 814, Nagashio Sangyo) at 10 wt %, 20 wt %, and 50 wt % based on the polymer to prepare 8 types of coating solutions. A polyester resin catheter is dipped into the coating solution and pulled up to coat the surface of the catheter with the polyamide.

Next, it was dried in an open air at 50° C. for 5 minutes to remove ethanol, and then heat-treated in a hot air dryer at 80° C. for 15 minutes to carry out a crosslinking reaction.

Thereafter, after passing through a methanol and water extraction step, heparinization was performed by immersing in 1 wt % heparin soda water at 60° C. for 2 hours. Table 1 shows the amount of epoxy compound added and the amount of heparin binding in the polyamide coating layer (
(quantified by an X-ray microanalyzer).

Insert the catheter of Sample θAl~8 and the uncoated catheter into the vena cava of an adult dog from the right femoral vein.
After being indwelled for a week, we observed thrombus formation on the outer surface of the non-coated catheter and A1 and A2 catheters, and found that thrombus formation was observed along the entire length of the catheter, whereas thrombus formation was observed on the 7f13 catheter. No formation was observed, and excellent antithrombotic properties were observed.

Example 2 Glycerol polycrystalline ether (Tenacol, EX81
4 Nagase Sangyo) per polymer and mix to make a homogeneous solution. Polypropylene/vascular indwelling needle (Argyle Medicut, 16 G'I) that has been previously treated with glow discharge in a Co2.N2 gas stream is coated with the coating. The outer and inner surfaces were coated by immersing the solution in a solution and pulling it up, and the ethanol was evaporated by drying in a dryer at 50°C for 5 minutes, followed by a crosslinking reaction by heat treatment at 80°C for 80 minutes. I did this.

Then, in a saturated aqueous solution of ethyl bromide at 60 °C,
After being immersed for 0 minutes and quaternized, it was subjected to an extraction process with methanol and water, and then heparinized by being immersed in a 0.5 wt % heparin soda aqueous solution at 60° C. for 10 minutes.

Table 2 shows the relationship between the substitution rate and the amount of heparin binding.

Table 2 Relationship between substitution rate and heparin binding amount where substitution rate 1
Sample A 1 and Samp where the heparin binding amount of SampleAa is 00% and the substitution rate is 52% and 63%.
The reason for the lower value compared to leA2 is thought to be due to the crosslinking density.

Uncoated vascular indwelling needles and coated vascular indwelling needles (Samples 1 to 3) were indwelled in the right and left femoral arteries, and pulse pressure was continuously monitored using a tractor/ducer. In contrast, in the case of coated indwelling needles, it was possible to monitor pulse pressure even after 3 hours had elapsed due to thrombus formation and it became impossible to measure pulse pressure after 20 minutes, showing excellent anti-thrombotic properties. It was found that it indicates gender.

Patent Applicant: Co., Ltd.

Claims (1)

[Claims] An antithrombotic composition comprising heparin bonded to a polyamide into which an octaminary amino group or a quaternary amine group has been introduced into the side chain.