JPS6012069A - Guide wire having anti-thrombotic property imparted thereto and production thereof - 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 guide wire inserted into a blood vessel for intravascular catheterization or treatment, and in particular, its main purpose is to improve its antithrombotic properties and operability. A catheter company is used to inspect the condition of an affected area within a blood vessel of the human body and to transport a medicinal solution to the affected area.A guide wire is sent into the blood vessel in advance, and the catheter is inserted into the affected area using the outer wall of the catheter. The guidewires used for this purpose are coiled metal wires, which are devices composed of stainless steel wire and stainless steel wire coils.This guidewire has a surface roughness characteristic of coiled wires, which prevents blood clots. Because guidewires tend to stick to the guidewire and the metal wire is hard, it requires extremely complex operating procedures and skilled techniques such as pushing, pulling, and turning left and right to deliver the guidewire to the affected area within the blood vessel.
It has drawbacks such as the long time it takes to operate and the fact that it is a metal wire, so it can easily pass through the intima of blood vessels. Therefore, when using such a metal wire guide wire, it is always difficult to make the guide wire reach the target affected area within the blood vessel, and the pain and burden placed on the patient during treatment is also large. In recent years, treatment Although techniques using new catheters have been developed in conjunction with advances in methods, the demand for improvements in antithrombotic therapy is increasing. fc For example, a problem with the catheter method used to contrast the arteries of elderly people with X-rays is that the blood vessels of elderly people are markedly dilated and tortuous due to arteriosclerosis, etc. When introducing a catheter into the distal end of a blood vessel, it takes longer to introduce the guidewire than in younger patients, and as a result proteins in the blood and other substances that are prone to coagulation adhere to the surface of the guidewire. .

Such a phenomenon is also observed in silicone-coated lead wires that are applied to improve sliding, which requires rapid insertion of the guidewire to the distal end of the blood vessel, especially during dilation.

There is a drawback that considerable skill is required to introduce the tube into the distal end of an elderly patient's blood vessel, which has a marked meandering pattern.

The present inventors have improved the above-mentioned drawbacks of the conventional guidewire by covering the guidewire with an elastic material that has a smooth surface, flexibility, and high elasticity, and has improved the ease of operation. As a result of our research with the aim of providing a safe medical guidewire that does not cause pain to patients, we found that by applying a special treatment to the entire surface of the guidewire, the antithrombotic properties were significantly improved.
The present invention was achieved by discovering that the operability represented by sliding is also synergistically improved.

The present invention provides vasodilation for elderly patients.

When a guide wire is introduced into a blood vessel with significant tortuousness, or even when it is left in the blood vessel for a considerable period of time for monitoring purposes during heart surgery, it is necessary to avoid the adhesion of proteins, platelets, and other coagulable substances in the blood. The present invention provides a guide wire coated with an antithrombotic elastic material and a method for manufacturing a guidewire coated with an antithrombotic elastic material.The present invention provides a method for manufacturing a guidewire coated with an antithrombotic elastic material. First, the guide wire used will be explained.

Figure 1 shows an example of the basic structure of a guide wire, and shows a coiled spring wire 111 that forms the main body of the guide wire, a safety wire (2) that prevents the guide wire from bending or stretching, and kinking of the guide wire. Conventionally, such guide wires have been coated with Teflon or silicone to give them antithrombotic properties, but as shown in the comparative example below. However, the results are not as expected as the coating tends to peel off or crack.The present inventors have conducted extensive studies on antithrombotic materials to be coated on guidewires, and have found that coating them on guidewires provides excellent antithrombotic resistance. We have developed an anti-thrombotic material that not only provides thrombotic performance but also extremely advantageously improves operability, and based on this we have completed the present invention.
(2) have favorable elasticity and can follow the deformation of the guide wire; +3
) The surface is smooth and slippery, and (4) it does not scratch blood vessels.

The inventors have discovered that polyurethane and a composition material composed of polyurethane and polychloroxane, in which polyurethane forms a continuous phase and polynonoxane forms an independent phase, meet the above-mentioned objectives. 5 The present invention reached.

The polyurethane used here may be either polyether polyurethane or polyester 7N polyurethane. Further, these polyurethanes used diamine as a chain extender. 4) 1) Urethane Ureas may be used, including those produced by the known method described in Japanese Patent Publication No. 48-24518.

Examples of polyester polyurethanes include those obtained by esterifying glycols such as ethylene glycol and diethylene glycol, or polyhydric alcohols such as trimethylolpropane and glycerin with polycarboxylic acids such as adipic acid and succinic acid, and ethylene diisocyanate. , 2.
Included are those synthesized as prepolymers by condensation with incyanate group-containing compounds conventionally used in the production of polyurethanes, such as 4-tolylene diisocyanate and methylene diphenyl diisocyanate.

Examples of polyether polyurethanes include polymers of alkylene oxides such as ethylene oxide and 1,2-propylene oxide, tetramethylene glycol or its polymers, and polyhydric compounds such as alkylene oxide topropylene glycol and 1,2,6-hexanetriol. θ includes a prepolymer synthesized by condensing an alcohol with the above incyanate group-containing compound.

Polyurethanes that are particularly suitable for carrying out the present invention are so-called segmented polyurethanes, in which the polyethers constituting the soft segments include tetramethylene glycol, polytetramethylene glycol, polyethylene glycol, polypropylene glycol, and the aforementioned polyurethanes. A copolymer of ether is preferred, and a soft segment having a molecular weight of 1,000 to 2,500 is particularly preferable because it has excellent antithrombotic properties and is rich in elasticity.As the coating material made of polyurethane and polysiloxane, polyurethane and polysiloxane are preferred. and polyurethane forms a continuous phase and polysiloxane forms an independent phase, the polyurethane-polysiloxane copolymer (polyurethane/polysiloxane) 1.0 (weight ratio)), polyurethane-polysiloxane composition There are emulsion compositions and polyurethane-polysiloxane mixed compositions (polyurethane/polysiloxane>1 (weight ratio)) that have an interpenetrating network structure at least in part at the boundary between polysiloxane and polyurethane, but they have poor antithrombotic properties. So the first two are preferable.

Furthermore, compared to polyurethane alone, a coating made of a composition composed of polyurethane-polysiloxane is superior in terms of guide wire operability. Polyurethane has a somewhat sticky surface characteristic, which may cause slippage when inserting the catheter along the guidewire. However, it has been found that coatings containing polysiloxane components have extremely good slippage. The reason for this is not clear, but it is clearly thought to be due to the effect of polysiloxane. Polyurethane-polysiloxane copolymer is obtained by reacting polyurethane with polysiloxane having terminal acetate groups under anhydrous conditions. A compound having an interpenetrating network structure of polyurethane and polysilicone is composed of polyurethane and the general formula Rn5iR'a-3 [wherein R is an alkyloxy aryl group, al is a koxy group at 7, an acyloxy 7 group,
Halogen, vinyl group, hydrogen, etc., n is 0. or 1], such as methyltriacetoxysilane, ethyltriacetoxysilane, tetraacetoxysilane, phenyltriacetoxysilane, tetramethoxysilane, tetraethoxysilane, phenyltriethoxysilane, methyltrichlorosilane; Vinyltriacetoxysilane.

It is obtained by reacting a so-called 7-run cutting agent such as vinyltrimethoxysilane in the presence of a moderate amount of water and, if desired, in the presence of a polysiloxane having terminal hydroxyl groups or acetate groups.

Examples of the boria xane used in the above reaction include polydimethylsiloxane, polydiethylsiloxane, polymethylphenylsiloxane, dimethylsiloxane-diphenylsiloxane copolymer, polymethylvinylsiloxane, and polymethylphenylvinylsiloxane. Polydimethylsiloxene having an active group that crosslinks with a vulcanization (RTV) agent and/or an acetate group is easily available and most suitable, with a molecular weight of 300.
~160,000 range is good, 5,000~80,0
A range of 00 is even better. The treatment liquid of the present invention can be obtained by adding the aforementioned polyurethane or a composition containing polyurethane to an organic solvent, and reacting the mixture under appropriate conditions if desired.

As the organic solvent, dimethylformamide, dimethylacetamide, dioxane, tetrahydrofuran, or a mixture of these solvents can be used.

In the present invention, what is important about the material comprising polyurethane and polysiloxane is that the polyurethane phase forms a continuous phase. For this purpose, polyurethane must account for more than half of the weight of polysiloxane. By making polyurethane the majority of the weight composition, the coating material becomes a continuous phase of polyurethane. As a result, polyurethane is responsible for mechanical performance and exhibits excellent elasticity. This is an essential requirement for the present invention. This will be explained with reference to FIG.

The guide wire bends according to the curve of the blood vessel within the blood vessel and is introduced into a predetermined location. FIG. This figure also illustrates the behavior of the antithrombotic elastic body of the present invention. When the guide wire bends, it must on the one hand stretch considerably, and for this purpose it must have a certain degree of stretch, and it is necessary that the stretch does not affect the antithrombotic properties or the surface condition. For this reason, the base material must contain at least 500 liters of polyurethane by weight.

Conventionally known Teflon adhesive knee? In the case of silicone processing, if an elongated part is formed like this, the elasticity and elongation performance are insufficient, resulting in peeling and cracking of the coating film, and this part becomes a defect and triggers thrombus formation (Yumi 1 Kikin). It has become. Neither Teflon nor silicone inherently satisfy the desired antithrombotic properties, and such defects are a major problem as they occur during the introduction of the guidewire into the blood vessel or during its placement. .

The present invention provides a complete solution by coating the guidewire with the coating described above.

Next, the manufacturing method of the present invention will be explained. First, to prepare a solution for coating, an organic solvent containing the already applied polyurethane or polyurethane-polysiloxane (or its precursor) composition is prepared. In the case of polyurethane, it is a homogeneous solution, but in the case of polyurethane-Vorisilor #Sun (and other precursors of Q), it may be an emulsion. This emulsion has an independent phase of polysiloxane stably dispersed in a continuous phase of polyurethane. Those forming a grooved network are particularly preferred, and those having an average diameter of dispersed particles, that is, independent phases, of 60 μm or less, preferably 10 μm or less, and more preferably 5 μm or less are excellent from the viewpoint of antithrombotic properties. Typically, the independent phase particles are 20
A stable emulsion can be made between μ ~ [1.1 μ〇 The concentration of the polymer in the above solution or emulsion composition is 3
Weight - ~40% by weight used, preferably ~5% by weight
It is 60% by weight, more preferably 7% to 20% by weight. If the concentration is too low, the coating will be too thin and the strength will be unstable, and if the concentration is too high, the viscosity will be too high and the coating film after conniting will be too thick, which is not preferable.

The coating method is to pass the guide wire through the solution or emulsion liquid one or more times to coat the entire surface of the guide wire with the treatment liquid almost uniformly, evaporate the solvent, and then leave it in the air to coat the polysiloxane. Complete crosslinking. Crosslinking progresses under the action of moisture in the air, but in order to promote crosslinking, it may be immersed in water and then dried.

As shown in Figures 2 and 3, the metal coil of the guide wire has a coil-shaped constriction perpendicular to the length direction of the guide wire, and the coating film (4) is fitted along this constriction. Since the coating material is coated on the spring, there is almost no peeling, and even if the spring is stretched, the coating material of the present invention has elasticity and has a large elongation (400 to 600%), so it is thought that peeling and cracking will not occur. By increasing the number of times the guide wire is coated, or by increasing the solid content (polymer) concentration of the solution or emulsion, for example, 25%, the coating plane can be It can be smoothed and almost eliminate the constriction.In order to eliminate the difference in the constriction of the guide wire due to the coating by thinning the coating, it is better to increase the concentration of the treatment solution and reduce the number of coatings. It is better to reduce the concentration of the guide wire and increase the number of treatments.Furthermore, in order to reduce the waist of the spring wire by 3 degrees and coat it as thinly as possible, when coating the guide wire, after soaking it in the treatment solution, When pulling up the guide wire, the guide wire is passed through the orifice to squeeze out the excess treatment liquid, and by repeating this several times, the coated surface is squeezed out as shown in the partially enlarged view of Figure 413 (C). It is also possible to eliminate constrictions and create a smooth surface with a thin coating.

The guide wire obtained in this way is placed in the cervical region.

In addition to cerebrospinal vessels, it is used for contrast catheters in cardiac and visceral vessels, J-sadabe vessels, etc., and as intravascular indwelling catheters for monitoring. Although the present invention has been explained using a metal guide wire, it is obvious that the principle described above does not depend on the material of the guide wire.

For example, the present invention can of course be applied even if the guide wire is made of synthetic resin.

The present invention will be further explained below with reference to Examples.

Example 1 First, prepare guide wire treatment solutions A, B, and O. Treatment solution A: polyether polyurethane (Nisten 5714 manufactured by Gudrich) - polydimethylsiloxane block copolymer (weight composition ratio 90:10) Tokuko Sho 48-245
Synthesized by the method shown in Publication No. 18.

Processing solution B prepared by adding 12% by weight of the above copolymer in dioxane-tetrahydrofuran (volume ratio 1:2) Polyethylene glycol with a molecular weight of 1800 and having hydroxyl groups at both ends and methylene diphenyl diisocyanate were prepared by a conventional method. A prepolymer was prepared, and this was chain-extended with ethylene diamine to synthesize a segmented polyurethaneurea with a molecular weight of 18,600. This polyurethaneurea was dissolved in tetrahydrofuran that had been dehydrated with molecular sieves to a concentration of 30 ppm or less, and the concentration was adjusted to 10.5% by weight. , Purified methyltriacetoxysilane was added to this so that the concentration was 2 weight different.

Treatment liquid C Polytetramethylene glycol (molecule 11200) was used as the polyether component, and tolylene diisocyanate was reacted with this to create a prepolymer, and ethylene glycol was used as the chain extender to obtain an average molecular weight of 16,
000 polyether polyurethane was prepared by dissolving 2.5 parts of polydimethylsiloxane with a molecular weight of 16,000, which has hydroxyl groups at both ends, into 87 parts of tetrahydrofuran dehydrated with molecular sieves, and adding was adjusted to 1451)I'm.

Add 0 methyltriacetoxysilane just after distillation to this.
．． When 5 parts of silicone were added and reacted at 40C for 96 hours, an emulsion composition was obtained in which a silicone independent phase (average diameter 5μ) was stably dispersed in a polyurethane continuous phase (in the above description, parts refer to parts by weight). ).

The surface of these silicone independent phase particles is methyl) IJ
It is an extremely stable emulsion composition because it is crosslinked by a crosslinking reaction using a hydrolyzate of acetoxin, and the polyurethane molecules are transformed to form a spherical surface with an alternating network structure.

Next, we will discuss the linear guide wire (Fig. 4 (a)) and the three-shaped guide wire (Fig. 4 (b)), which are made of stainless steel and have the structure shown in Fig. 1. The coating treatment of the present invention was carried out using the above-mentioned prepared treatment solution under various conditions to obtain guidewires endowed with antithrombotic properties as shown in FIGS. 6(a) and 6(b).

These conditions and results are collectively shown in the table (!).

Table ti+ * Length direction KI of the spring coil 11 explained in the text + is present but extremely small; ± is very smooth (shape M as shown in the partial cross-sectional view of Figure 5 (b)) - is not noticeable (partial cross-sectional view of Figure 3 (C) ), respectively.

In addition, the coating thickness is the thickness from the outermost surface of the spring wire (
thinnest layer).

Example 2 and Comparative Example 1 Each of the 13 straight and three-shaped guidewires obtained in Example 1 was placed in the vein of an adult, and the 96-hour tube was cut and removed. The state of adhesion of blood, etc. on the guide wire surface was observed. Even after 96 hours, no blood clots were observed on the guide wire of the present invention.

On the other hand, as comparative examples, straight type (Fig. 4(a)) and three-shaped type (Fig. 4(b)) are shown, respectively, with untreated guide wire, dwarf wire, Teflon coated guide wire (stepped thickness 2μ) and silicone film coated guide wire. Guide wire (covering thickness 6μ)
), a comparative experiment was conducted using adults under exactly the same conditions.

For the untreated guide wire, a large amount of blood clots were observed to adhere to the entire surface of the guide wire after 8 hours, and for both the Teflon coated guide wire and the silicone coated guide wire, a large amount of blood clots were observed to adhere to the entire surface of the guide wire after 24 hours.

Regarding Teflon-coated guide wires and silicone film-coated guide wires, when we bent or stretched the tips of the straight type into a 3-shape and the 3-shape into a straight shape, we found that two types of Teflon film, Peeling of the coating and cracks were clearly observed in the covered portions of the bent or stretched portions of both types of silicone films.On the other hand, there were 4 types of straight and 3-shaped guide wires in experiments Na4 and 5 according to the present invention. When the film was similarly bent or stretched, no peeling or cracking was observed on the coated surface.

[Brief explanation of the drawing]

FIG. 1 is a partially cutaway cross-sectional view of the guide wire;
3 and 3 are plan views of a guide wire including a partially enlarged portion according to the present invention. Figure 4 shows the linear type ta+ before coating.
, is a plan view of the guide wire including a partially enlarged portion of the 3-shape (b). In the figure, numeral 1 is a spring wire in the guide wire, and 4 is a coating portion.

Claims (1)

Claims: 1. A guide wire characterized in that it is doped by a polyurethane or a polyurethane-polysiloxane composition in which the polyurethane forms a continuous phase. 2, (Treatment liquid A consisting of an organic solvent containing al polyurethane, (b) polyurethane and general formula Rn Si R'4-0
(In the formula, R is an alkyl group, aryl group R/ is an alkoxy group, acyloxy group, vinyl group, haloken or hydrogen, n
(C) is an organic solvent or emulsion containing a silicon-containing compound as an essential component, in which the weight ratio of polyurethane/silicon-containing compound is 1.0 or more; A treatment liquid C1 containing siloxane in an organic solvent with a polyurethane/polysiloxane weight ratio of 10 or more was prepared, and 5 these treatment liquids A were prepared.
, B, and C at least once to coat the guide wire with the treatment liquid, and then evaporate the solvent and coat the guide wire with antithrombotic properties. How to make wire.