JPH04197264A - Production of antithrombotic medical treating material and medical treating implement having antithrombotic medical treating material - Google Patents

Abstract

PURPOSE:To produce the antithrombotic material which maintains a stable antithrombotic property over a long period of time by covalent bonding the amino group of a polyvinyl chloride(PVC) polymer and the one terminal glycidyl group of polyethylene glycol diglycidyl ether, then covalent bonding the other terminal glycidyl group and the amino group of heparin. CONSTITUTION:The amino group of the PVC polymer introduced with the amino group and the one terminal glycidyl group of the polyethylene glycol diglycidyl ether are first covalent bonded in order to produce the antithrombotic medical treating material. The PVC polymer introduced with the amino group is brought into contact with an aq. soln. of the polyethylene glycol diglycidyl ether for this purpose. The soln. is thereafter brought into contact with the aq. heparin soln., by which the other terminal glycidyl group and the amino group of the heparin are covalent bonded. The resulted antithrombotic treating material has the excellent adhesiveness to the base material and exhibits the antithrombotic property over a long period of time. In addition, the elution of the heparin is obviated.

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to a method for producing an antithrombotic material and a medical device imparted with antithrombotic properties by the antithrombotic material obtained thereby.

<Prior art> Polyvinyl chloride is widely used as a molding material due to its excellent physical properties and low cost, or it is used in catheters that come into contact with blood, as it has poor antithrombotic properties required as a medical material. When used as a circuit or shunt, there is a risk that a blood clot may form, stopping blood flow and causing complications.

Various attempts have therefore been made to coat the polyvinyl chloride surface with non-thrombotic or antithrombotic materials or to bind anticoagulants such as heparin to the surface. However, conventional antithrombotic materials with a microphase-separated structure tend to crack due to poor compatibility with polyvinyl chloride, easily peel off when subjected to bending stress, and coat the surface of soft polyvinyl chloride. has the disadvantage that it has poor antithrombotic properties because it does not provide the original microphase-separated structure due to the transfer of plasticizer to the coating layer.

Regarding heparin-binding materials, a method has been disclosed in which heparin is bound to benzalkonium, a cationic surfactant, through ionic bonding. Sexuality is rapidly lost. Therefore, in order to have long-term antithrombotic properties, a heparinized hydrophilic polymer (Japanese Patent Application Laid-open No. 57-14358), in which heparin is ionically bonded in the polymer matrix, was developed, and it was possible to maintain a constant amount of heparin elution over a long period of time. Although it has become possible to maintain antithrombotic properties over a long period of time, there are concerns about abnormal bleeding and side effects due to eluted heparin.

A method of binding medical materials and heparin by forming a covalent bond (Japanese Patent Application Laid-Open No. 58-10053) has also been disclosed, but according to this method, the active site of heparin may also be involved in the covalent bond. , the anticoagulant activity of heparin may be impaired, leading to thrombus formation, which is undesirable.<Problems to be Solved by the Invention> Therefore, an object of the present invention is to solve the above-mentioned problems of the prior art, and to improve the effectiveness of heparin. The object of the present invention is to provide a method for producing an antithrombotic material that maintains stable antithrombotic properties over a long period of time due to anticoagulant action, and a medical device imparted with antithrombotic properties by the antithrombotic material obtained thereby.

<Means for solving the problem> According to the first aspect of the present invention, the amino group of the polyvinyl chloride polymer into which the amino group has been introduced and the glycidyl group at one end of the polyethylene glycol sidaline sol ether are combined. A method for producing an antithrombotic medical material is provided, which comprises covalently bonding the other terminal glycidyl group and the amine group of heparin after the covalent bonding.

According to a second aspect of the present invention, in a medical device having a part that comes into contact with blood, at least a part of the surface of the part that comes into contact with blood is made of the thrombogenic medical material. Medical equipment is provided.

The present invention will be explained in detail below.

In the present invention, the method for producing an antithrombotic medical material includes covalently bonding the amino group of a polyvinyl chloride polymer into which an amino group has been introduced and the glycidyl group at one end of polyethylene glycol cydarin sol ether, and then The other terminal glycidyl group and the amino group of heparin are covalently bonded. Figure 1 shows the outline.

Heparin is a type of polysaccharide containing ester-bonded sulfuric acid, and has functional groups such as amino groups, hydroxyl groups, and carboxyl groups.

Polyvinyl chloride-based polymers having amine groups can be synthesized by a polymer reaction between polyvinyl chloride and a low-molecular reagent, using conventionally known techniques (Okawara Shinkumi,
Polymer Reaction, Kyoritsu Shuppan, 1978, etc.) can be used.

An example of this is the reaction between polyvinyl chloride and a low-molecular reagent expressed by the following formula.

The ratio of amino group introduction is BOrnol 1% or less, preferably 0.05 to 40 mol 1%, more preferably 5 to 2
It is 0moρ%. The ratio of amino groups introduced into polyvinyl chloride can be arbitrarily changed by changing the reaction conditions. As a specific example, FIG. 2 shows the relationship between the reaction time of polyvinyl chloride and sodium azide and the rate of introduction of azide groups. As a result, polyvinyl chloride can be synthesized with the introduction rate of amine groups arbitrarily changed.

In order to covalently bond the amino group of the polyvinyl chloride polymer into which the amino group has been introduced and the glycidyl group at one end of the polyethylene glycol sidaline sol ether, as shown in Figure 1, the amino group This is achieved by bringing the polyvinyl chloride polymer into which has been introduced into contact with an aqueous solution of polyethylene glycol cydarine sol ether.

The concentration of polyethylene glycol cydarine sol ether is 0.05% to 5.0%, preferably 0.1% to 3%, and the reaction temperature is 20°C to 80°C, preferably 30°C to 6°C.
It is 0°C.

The reaction time varies depending on the conditions, but is generally 8 hours to 48 hours.
time, preferably 16 hours to 36 hours.

When the reaction temperature and reaction time are increased, one of the glycidyl groups at both ends of polyethylene glycol sidaline sol ether covalently bonds with the amino group of the polyvinyl chloride polymer into which an amino group has been introduced. However, the glycidyl groups at both ends may covalently bond with the amine groups of the polyvinyl chloride polymer into which amino groups have been introduced, or side reactions such as hydrolysis of the glycidyl groups may occur, resulting in covalent bonds with the amino groups of heparin. This is not preferable since it may become impossible to combine.

In the present invention, in order to covalently bond the other terminal glycidyl group and the amino group of heparin, the amino group of the polyvinyl chloride polymer into which the amino group has been introduced and the one terminal glycidyl group of polyethylene glycol sidaline sol ether are bonded together. This is achieved by covalently bonding and then contacting this with an aqueous heparin solution. Preferably, heparin is a sodium salt of heparin.

The heparin concentration at this time is 0.05% to 50%, preferably 0.1% to 3%, and the reaction temperature is 20°C to 80°C.
, preferably 30°C to 60°C. The reaction time varies depending on the conditions, but is generally 1 to 4 days, preferably 2 days.
The duration is between 1 and 3 days. If the reaction temperature and reaction time are made larger than this, the anticoagulant activity of heparin may be lost, which is not preferable.

As a method for manufacturing a medical device having a part that comes into contact with blood, at least a part of the surface of the part that comes into contact with blood is composed of the above-mentioned antithrombotic medical material, an amino group is introduced. After extruding the polyvinyl chloride polymer with other resins and additives to obtain medical moldings by injection molding, cast molding from a solution, wet molding using an appropriate coagulation bath, etc., polyethylene glycol diglycidyl There is a method of covalently bonding ether as a coupling agent.

These antithrombotic medical materials have excellent compatibility with the base material of the molded article, have good adhesive properties, and can form a heparin bonding layer without cracking or peeling.

The surface of the antithrombotic medical material thus obtained has long-term stable antithrombotic properties while maintaining the shape and physical properties of the base medical molded material, and can be used in indwelling vascular catheters, blood circuits, blood filters, etc. It is suitably used as a material for medical devices that come into contact with blood, such as plasma separators.

<Examples> The present invention will be explained below with reference to Examples, but the present invention is not limited thereto.

(Example 1) 1) Synthesis of polyvinyl chloride polymer with amino groups introduced Polyvinyl chloride (degree of polymerization 11000) 20 was dissolved in 400 mJ2 of N,N-dimethylformamide, and 20 g of sodium azide was added. , reacted at 60°C for 2 hours,
After reprecipitation in water, the mixture was washed with methanol and dried to obtain azidated polyvinyl chloride.

20 g of this azide polyvinyl chloride was dissolved in 660 mρ of tetrahydrofuran, and 8 g of lithium aluminum hydride was dissolved in 660 mρ of tetrahydrofuran.
g was added and reacted at 60°C for 2 hours under nitrogen atmosphere,
After the reaction was completed, 160 mρ of water was gradually added to decompose the remaining lithium aluminum hydride, and the inorganic salt was filtered and separated.

The filtrate was concentrated and dialyzed in dilute hydrochloric acid to obtain aminated polyvinyl chloride hydrochloride.

As a result of elemental analysis, the composition of this polymer was found to be vinyl chloride.
position 81, 6 mofL%, vinylamine unit 18.
It was 4moJ2%. In addition, according to flame light analysis and ICP emission analysis, Li was found to be 0.2% in aminated polyvinyl chloride.
Hereinafter, it was emphasized that the An content was 1% or less, and that the purification was sufficiently performed.

2) Production of antithrombotic medical material A sheet-like molded product was obtained by casting from a 5% by weight solution of the polyvinyl chloride polymer into which amine groups obtained in 1) had been dissolved in tetrahydrofuran.

Polyethylene glycol diglycidyl ether (number average molecular weight 1.too) o, tog was dissolved in 10 mJ2 of water, the sheet obtained earlier was immersed, and reacted at 45°C for 24 hours to form a polychloride into which amino groups were introduced. The amino group of the vinyl polymer and the glycidyl group at one end of polyethylene glycol sidaline sol ether were covalently bonded. Furthermore, the sheet was coated with 1.0 heparin sodium.
The other terminal glycidyl group and the amino group of heparin were covalently bonded by immersing it in a physiological saline solution containing wt% and reacting at 45° C. for 4 days. Uncovalently bound heparin was removed by washing with 2.0 M NaCβ, followed by washing with distilled water and drying.

The amount of sulfur derived from heparin in the heparin covalent bonding layer of the sheet was measured by X-ray photoelectron spectroscopy and was found to be 1.7.
The 5-atom IoOf was 1%.

(Example 2) 1) Manufacture of medical device equipped with antithrombotic medical material The polyvinyl chloride polymer into which amino groups were introduced obtained in Example 1, 1) was dissolved in 3% by weight of tetrahydrofuran. The inner and outer surfaces of a soft polyvinyl chloride sheet (plasticizer content of diethylhexyl phthalate: 45 parts) were coated by dipping.

0.10 g of polyethylene glycol diglycidyl ether (number average molecular weight 1.Zoo) was dissolved in TOMX water, and the previously obtained soft polyvinyl chloride sheet was immersed.
By reacting at 45° C. for 24 hours, the amino group of the polyvinyl chloride polymer into which amino groups had been introduced was covalently bonded to one terminal glycidyl group of polyethylene glycol sidaline sol ether. Furthermore, the sheet was immersed in physiological saline containing 1 wt% heparin sodium and heated at 45°C.
By reacting for 4 days, the other terminal glycidyl group and the amino group of heparin were covalently bonded. 2.0M
Uncovalently bound heparin was removed by washing with NaCn, followed by washing with distilled water and drying.

The amount of sulfur derived from heparin in the heparin covalent bonding layer of the sheet was measured by X-ray photoelectron spectroscopy and was found to be 1.2.
The moj per atom was 2%.

(Example 3) ■) Manufacturing of a medical device with antithrombotic properties Example 1-1)
The amino group-introduced polyvinyl chloride polymer obtained above was made into a 3% by weight solution in tetrahydrofuran, and a soft polyvinyl chloride tube (inner diameter 1.4 mm, length 200 mm
mm), and heparin was bound in the same manner as in Example 2.

The antithrombotic properties of the tube were determined by Chandler's rotating tube method (A, 8. Chandler, Labora
toryInvestigation, 7. pH0
(1958)). Fresh blood collected from the rabbit vein was injected into the tube, the tube was connected with a silicone tube, and the tube was rotated at a speed of 8 revolutions per minute. No thrombus was formed and the tube was occluded even after 90 minutes of rotation. That never happened.

Further, the antithrombotic properties of the tube were evaluated using the rabbit A-V shunt method. That is, a shunt between the rabbit neck and vein was formed using the tube, blood was collected at predetermined intervals, and fibrinogen, platelet count, ATm, and APTT were measured.

The results are shown in Figure 3 (a), (b), respectively.
Shown as (C) and (d). The blood circulating through the tube contains fibrinogen (Fig. 3(a)), ATIr
AP activity (Fig. 3 (C)) remains high and AP
No prolongation of TT (Figure 3(d)) was observed, indicating that activation of the coagulation system was suppressed.

(Comparative Example 1) The soft polyvinyl chloride tube used in Example 3 was not subjected to the treatment of the present invention, but was treated with Cha in the same manner as in Example 3.
When evaluated according to Ndler's rotating tube method, it was 6 ~
A thrombus formed and occluded after 9 minutes of rotation.

In addition, a rabbit cervical arterio-venous shunt was formed using the tube, blood was collected at predetermined intervals, and fibrinogen, platelet count, AT Hl, and APTT were measured. Figure 3 shows the results. The environmental blood from the tube contains fibrinogen (Fig. 3(a)), ATII+ activity (
Figure 3 (C)) decrease, APTT due to coagulation factor deficiency
The extension (Fig. 3(d)) became thicker, indicating that the coagulation system was activated.

<Effects of the present invention> The antithrombotic medical material obtained by the method of the present invention has excellent adhesion to the base material due to the polyvinyl chloride polymer into which amino groups have been introduced, and the anticoagulant activity of heparin bound to this material is excellent. It exhibits antithrombotic properties over a long period of time, and since there is no elution of heparin, there is no abnormal bleeding or side effects, and it is suitable for use as medical devices such as intravascular catheters, blood circuits, blood filters, and plasma separators. .

[Brief explanation of the drawing]

FIG. 1 is a diagram showing the procedure for carrying out the method of the present invention. FIG. 2 is a diagram showing changes over time in the introduction of an azide group into a polyvinyl chloride polymer. FIG. 3 is a diagram showing the antithrombotic properties in Examples and Comparative Examples, in which (a) is fibrinogen, (b) platelet count, (c) AT III, and (d) APTT.
It is a figure which shows the relationship with shunt time. F I G, 2 hours (hr) F I G, 3 Shunt Time (hr) Shunt Time (hr)

Claims (2)

[Claims] (1) After covalently bonding the amino group of the polyvinyl chloride polymer into which an amino group has been introduced and one terminal glycidyl group of polyethylene glycol sidaline sol ether, the other terminal glycidyl group and the amino group of heparin are bonded together. A method for producing an antithrombotic medical material characterized by covalent bonding. (2) In a medical device having a part that comes into contact with blood, at least a part of the surface of the part that comes into contact with blood is made of the antithrombotic medical material produced by the method according to claim 1. Characteristic medical equipment.