JP4236802B2 - Lubricating medical device and manufacturing method thereof - Google Patents

Description

[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a medical device used by being inserted into a living body, and more particularly to a medical device used by being inserted into a living body, which is coated with a lubricating coating, and a method for manufacturing the same.
[0002]
[Prior art]
In general, medical devices such as catheters, stents, and guide wires that are inserted into a living body are used to prevent damage to biological tissues such as blood vessels during insertion, and improve the operability of medical devices during insertion. For this purpose, a treatment for imparting lubricity to the surface of the medical device that comes into contact with the living tissue (this treatment is referred to as lubricity imparting treatment) is performed. As this lubricity imparting treatment, there are a method using a highly lubricating material as a base material, a method of coating a surface of the base material with a lubricant, a low friction resin, a water-swellable polymer, and the like. For example, there are a method using a lubricating material such as a fluororesin or a polyethylene resin as a base material, and a method of applying a lubricant such as a fluororesin, a silicon resin and silicon oil to the surface of the base material such as a metal.
[0003]
However, the surface obtained by these methods has a problem that the lubricating material itself used as the base material, the applied lubricant, and the like are detached, peeled off, or eluted from the base material surface. When peeling or the like of the lubricating material occurs in the living body, the living body tries to discharge the peeled material as a foreign substance to the outside of the body, which causes a safety problem such as placing an extra burden on the living body. Further, the surface obtained by these methods also has a problem that the lubricating effect does not last for a long time.
[0004]
In recent years, for the purpose of improving safety and practicality, a method of coating a water-soluble polymer (water-swellable polymer) on a substrate surface has been studied. For example, a method of coating a water-soluble polymer (water swellable polymer) such as polyvinyl pyrrolidone or polyethylene oxide on the surface of a substrate using an isocyanate has been reported.
[0005]
However, in these methods, since the bond between the base material and the water-swellable polymer is insufficient, elution and peeling occurred. In particular, the bonding to a substrate having no functional group that reacts with isocyanate, such as polyethylene and polypropylene, was poor. In addition, since the isocyanate does not directly react with a base material using metal and ceramics, it is necessary to previously coat a material that reacts with the isocyanate as a primer layer. In this case, the film thickness of the entire coating film is increased, eventually increasing the thickness of the medical device, and it becomes difficult to work in a narrow part in the living body. Furthermore, the new problem that adhesiveness of a primer layer and a base material is bad arises.
[0006]
[Problems to be solved by the invention]
Therefore, an object of the present invention is to solve the above problems. That is, there is no problem that a lubricating substance (which belongs to the category of a lubricating material) or the like does not detach from, peel off, and / or elute from the surface of the base material, and has a surface that can provide a higher lubricating effect for a long time. It is to provide a medical device and a manufacturing method thereof.
[0007]
An object of the present invention is to increase the thickness of a base material itself such as a medical device main body and to have excellent adhesion to the medical device main body, so that a lubricating material or the like is detached from the surface of the base material and peeled off. It is another object of the present invention to provide a medical device having a surface that does not cause a problem of elution and has a higher lubricating effect for a long period of time, and a method for manufacturing the same.
[0008]
[Means for Solving the Problems]
To achieve the above object, possess a substrate, a vapor deposition polymerization film formed on the substrate surface, a hydrophilic polymeric coating which is fixed to the vapor deposition polymerization on the film, the vapor deposition polymerization coating Is an active hydrogen-containing film, and the hydrophilic polymer film is formed of an isocyanate compound capable of reacting with active hydrogen in the vapor deposition polymerization film and an active hydrogen-containing water-soluble polymer. A lubricious medical device ,
In one aspect of the lubricating medical device, the vapor-deposited polymer film is at least one selected from the group consisting of polyurea, polyamic acid, and polyimide obtained by partial dehydration of the polyamic acid. ,
Another means for solving the above-mentioned problem is that a vapor-deposited polymerization film containing active hydrogen is formed on the surface of the substrate by vapor-deposition polymerization, and can react with the active hydrogen in the vapor-deposition-polymerized film on the vapor-deposition polymerization film. It is a method for producing a lubricious medical device characterized in that an isocyanate compound and an active hydrogen-containing water-soluble polymer are applied simultaneously or stepwise and reacted.
In one embodiment of the method for producing the lubricious medical device, an isocyanate group-containing vapor-deposited polymer film is formed on the surface of the substrate by vapor-deposition polymerization, and the water-soluble polymer is capable of reacting with the isocyanate group on the vapor-deposited polymer film. It is characterized by coating and reacting a functional polymer.
[0009]
DETAILED DESCRIPTION OF THE INVENTION
A medical device having lubricity according to the present invention (referred to as a lubricious medical device) includes a base material, a vapor deposition polymer film formed on the surface of the base material, and a hydrophilic surface fixed on the vapor deposition polymer film. And a functional polymer film.
[0010]
Considering the microscopic state of the hydrophilic polymer film, a hydrophilic polymer is lined up on the surface of the vapor deposition polymerization film, and a number of water molecules are held between the lined hydrophilic polymer. Yes. Therefore, in the medical device according to the present invention, a strong water fixing layer is formed on the surface of the vapor deposition polymerization film, and high affinity is exhibited for blood in blood vessels and blood vessel wall surfaces, and also exhibits low friction. . Therefore, the lubricating medical device according to the present invention, for example, a medical device such as a catheter, a stent, and a guide wire, can smoothly progress in a living body such as a blood vessel without damaging a living tissue such as a vascular endothelium.
[0011]
The base material of the lubricious medical device is a medical device conventionally referred to as a catheter, a stent, a guide wire, or the like. In other words, the base material in the present invention is a medical device itself conventionally referred to as a catheter, a stent, a guide wire or the like if the vapor-deposited polymer film and the hydrophilic polymer film are not formed.
[0012]
Therefore, the material of the base material in the present invention is the same as the material that forms a medical device conventionally called a catheter or the like, and even if the material is different from the conventional medical device, the object of the present invention is achieved. There is no particular limitation as long as it can be achieved, and examples include metals, ceramics, and resins. Moreover, the material may differ for each part of this medical instrument. For example, it may be made of a non-contrast metal such as a stainless alloy and a nickel-titanium alloy. Regarding the shape of the substrate, various shapes are adopted depending on the type. In any case, in the present invention, the base material is a member formed with a vapor deposition polymerization film and a hydrophilic polymer film and applied to a living tissue.
[0013]
The vapor deposition polymerization film is a film formed on the surface of a substrate by a vapor deposition polymerization method. The vapor-deposited polymer film is formed on the entire surface of the substrate or on the surface of the required site. Necessary parts include, for example, a surface that may come into contact with a living body and a surface that contacts parts of the lubricious medical device of the present invention.
[0014]
The vapor deposition polymerization film formed on the substrate surface serves as a primer. By forming the vapor deposition polymerized film, a material that cannot directly form a hydrophilic polymer film such as metal or ceramics can be selected as the substrate. Since the vapor-deposited polymer film has high adhesion to a base material such as metal or ceramic, peeling does not occur from the part of the base material and the vapor-deposited polymer film. Moreover, since the vapor deposition polymerization film can be formed uniformly and thinly on the surface of the base material, the thickness of the medical device does not increase and it does not become difficult to operate. Moreover, in order to ensure operability, the rigidity of the medical device does not decrease at the expense of the thickness of the base material itself.
[0015]
A polymer capable of fixing a hydrophilic polymer is used for the vapor deposition polymerization film. For example, if the hydrophilic polymer film is bonded to the vapor deposition polymerized film by coordination bond, chelate bond, covalent bond, cross-linking bond by metal salt, etc., depending on the type of hydrophilic polymer film and the type of each bond The type of polymer constituting the vapor deposition polymerization film is determined.
[0016]
A polymer that forms a vapor deposition polymerization film suitable for the present invention is a polymer that can bond and fix a water-soluble polymer by the various bonding modes described above. Considering the availability of materials and the like, the vapor deposition polymerization film includes an active hydrogen-containing film that can form a urethane bond with a hydrophilic polymer, and an isocyanate group-containing film.
[0017]
Suitable polymers for forming this active hydrogen-containing film include, for example, urea resins such as polyurea-formaldehyde, polyamic acid, polyimide obtained by partial dehydration of this polyamic acid, polyamide, polyamideimide, polyazomethine, and Examples include polyester. Among these, urea resin, polyamic acid, and polyimide are particularly preferable because of low friction, in other words, high lubricity and high compatibility with living tissues.
[0018]
Examples of the isocyanate group-containing coating include urea resins such as polyurea-formaldehyde.
[0019]
The vapor deposition polymer film needs to have a certain thickness or more in consideration of surroundings to complicated shapes. On the other hand, if the thickness of the vapor deposition polymer film is too large, the operability of the medical device is lowered. . For these reasons, the thickness of the vapor deposition polymerization film is preferably 0.1 to 10 μm. Furthermore, it is especially preferable that it is 0.5-2 micrometers. In addition, although it is desirable for the thickness of a vapor deposition polymerization film to be uniform, it does not necessarily need to be uniform.
[0020]
The vapor deposition polymerization film is formed by a vapor deposition polymerization method. The vapor deposition polymerization method is a method of forming a polymer thin film by evaporating a monomer in a vacuum, for example, and performing a polymerization reaction on the surface of an object. Specifically, for example, the heated monomer is introduced into a decompression chamber in which the medical device prior to the manufacture of the medical device for lubrication of the present invention is disposed, and the monomer is polymerized by bringing the evaporated monomer into contact with the surface of the medical device. .
[0021]
The monomer used for the vapor deposition polymerization is not particularly limited as long as it is a monomer capable of efficiently forming a vapor deposition polymerization film that can be used in the present invention. As a monomer, for example, in order to obtain a polyamic acid, there is a combination of an aromatic tetracarboxylic dianhydride such as pyromellitic anhydride and an aromatic diamine such as 4,4′-diaminodiphenyl ether, and a urea resin such as In order to obtain an aromatic polyurea, there is a combination of an aromatic diamine such as 4,4′-diaminodiphenylmethane and an aromatic diisocyanate such as 4.4′-diphenylmethane diisocyanate. There are combinations of diols such as hydroquinone and diacid chloride compounds such as terephthalic acid dichloride and 4,4′-biphenyldiacid chloride. To obtain polyamide, aromatic diamines such as paraphenylenediamine and terephthalic acid dichloride are used. Or aromatic dicarboxylic acids such as terephthalic acid or aromatic dicarboxylic acids There is a combination with id.
[0022]
In the vapor deposition polymerization, the heating temperature for evaporating the monomer is appropriately determined according to the type of the monomer, but is usually in the range of room temperature to 200 ° C. The temperature of the decompression chamber is usually in the range of 160 to 230 ° C.
[0023]
For example, when forming a vapor deposition polymerization film of polyimide, pyromellitic anhydride monomer is heated to 200 to 240 ° C., and 4,4′-diaminodiphenyl ether monomer is heated to 180 to 200 ° C. In addition, when the polyamic acid film formed by vapor deposition polymerization is further heated at 250 to 300 ° C., a dehydration cyclization reaction occurs to form a polyimide film.
[0024]
When a polyurea film is formed as a vapor deposition polymerization film having NCO active groups (isocyanate group-containing vapor deposition film), the heating temperature of 4,4′-diaminodiphenylmethane monomer and 4,4′-diphenylmethane diisocyanate monomer is usually 60-130 ° C.
[0025]
The hydrophilic polymer film is a polymer film that can be fixed to the vapor deposition polymer film, and may be any polymer that can ensure lubricity with a living tissue. Suitable hydrophilic polymer coatings can be formed from isocyanate compounds capable of reacting with the active hydrogen and the active hydrogen-containing water-soluble polymer when the vapor deposition polymerization coating is an active hydrogen-containing coating, and When the vapor deposition polymerization film contains an isocyanate group, it can be formed of an active hydrogen-containing water-soluble polymer capable of reacting with the isocyanate group.
[0026]
Examples of the water-soluble polymer containing active hydrogen include water-soluble polymers containing terminal hydroxyl groups and ether bonds such as polyethylene oxide, polymers containing terminal hydroxyl groups such as polyols, water-soluble polymers containing urethane bonds such as water-soluble polyurethanes, and polyethylene glycol derivatives. And water-soluble polymers containing carboxylic acid groups such as polycarboxylic acids such as polyacrylic acid and acid derivatives thereof, water-soluble polymers containing amine groups such as polyacrylamide , and cellulose and derivatives thereof such as CMC.
[0027]
The active hydrogen-containing water-soluble polymer may have an isocyanate group at both ends or may have a block isocyanate group. These groups react with the vapor-deposited polymer film and are covalently bonded, thereby being firmly fixed on the vapor-deposited polymer film. Examples of the water-soluble polymer having such a group include a water-soluble urethane prepolymer having an isocyanate group at both ends or a water-soluble urethane prepolymer having a blocked isocyanate group.
[0028]
Examples of the isocyanate compounds include diisocyanates and blocked isocyanates.
[0029]
The isocyanate compound and the active hydrogen-containing water-soluble polymer are applied to the vapor deposition polymerization film. In this case, the active hydrogen-containing water-soluble polymer and an isocyanate compound such as diisocyanate and blocked isocyanate may be applied as a mixture, or the isocyanate compound and the active hydrogen-containing water-soluble polymer. And may be applied separately.
[0030]
When applying the mixture, it is desirable to use a blocked isocyanate that does not react with the active hydrogen-containing water-soluble polymer at room temperature. The mixing ratio of the active hydrogen-containing water-soluble polymer and isocyanate compounds such as diisocyanate and blocked isocyanate is preferably in the range of 1:10 to 1: 1.
[0031]
Diisocyanates include aliphatic diisocyanates such as hexamethylene diisocyanate, aromatic diisocyanates such as 2,4-toluene diisocyanate, and 2,6-toluene diisocyanate, isophorone diisocyanate. Examples thereof include alicyclic diisocyanates such as nate and these polydiisocyanates.
[0032]
Blocked isocyanate is inactive at normal temperature by reacting the NCO group of isocyanate with a volatile active hydrogen compound. Examples of the isocyanate used as a raw material include the diisocyanate, and examples of the blocking agent include alcohols, phenols, ε-caprolactam, oximes, and active methylene compounds.
[0033]
As a coating method of the active hydrogen-containing water-soluble polymer, diisocyanate or blocked isocyanate, a general coating method such as a dipping method and a spray method can be used.
[0034]
The diisocyanate and blocked isocyanate are applied as they are or dissolved in an organic solvent. The blocked isocyanate can be made aqueous by making it into an emulsion or grafting with a water-soluble resin.
[0035]
The heating temperature varies depending on the type of the applied water-soluble polymer, diisocyanate, blocked isocyanate, etc., but is 50 to 200 ° C., preferably 100 to 200 ° C., particularly preferably 100 to 150 ° C. The time is the time required for the reaction to be substantially completed, and is usually within 1 hour.
[0036]
The thickness of the formed hydrophilic polymer film is not particularly limited as long as the object of the present invention can be achieved. For example, the thickness after drying can be 5 to 50 μm. When the thickness of the hydrophilic coating is within the above range, high lubricity can be maintained for a long time, and it is preferable in that the size of the lubricious medical device of the present invention is not affected. The hydrophilic polymer film does not necessarily have a uniform thickness.
[0037]
【Example】
Example 1
Pyromellitic anhydride and 4,4′-diaminodiphenylmethane are vacuum-deposited on the surface of a coil portion of a SUS301 guide wire (maximum diameter 0.014 inch, length 150 cm), which has been conventionally used as a medical device. A deposited film with a thickness of 0.1 μm was formed.
[0038]
On the other hand, blocked isocyanate (trade name: Elastron H-8) and polyethylene glycol (molecular weight 100,000) were mixed at a weight ratio of 1:10 to prepare a 10% aqueous solution. This 10% aqueous solution was applied to the surface of the coil of the guide wire on which the vapor-deposited film was formed, and then dried in a hot air circulating dryer at 50 ° C. for 2 hours, and then heat-treated at 120 ° C. for 20 minutes.
[0039]
After the heat treatment, the coated portion of the guide wire was immersed in warm water at 37 ° C. for 30 minutes, rinsed with running water and washed, and a coil portion having a length of about 20 mm was cut out from the coil portion of the guide wire and used as a sample. .
[0040]
This sample was placed in a wet state on an inclined table on which a polyethylene coating was applied and kept horizontal. The angle at which the sample slides was measured by gradually tilting the tilt table. The angle of the tilt table at which the sample began to slide was 5 degrees.
[0041]
Further, when the sample (guide wire) is inserted into a polyethylene tube having an inner diameter of 1.5 mm, which is wound in a coil shape so as to have a diameter of 30 mm, the insertion operation is smoothly performed without a sense of resistance. I was able to. After the insertion, the sample was removed from the polyethylene tube, and after removal, the sample was again inserted into the polyethylene tube. When such insertion and removal were repeated 100 times, the 100th insertion and removal of the sample could be performed smoothly and without resistance. When the coil portion of the sample after the 100th extraction was observed, no peeling of the hydrophilic polymer film constituting the outer layer was observed.
[0042]
(Comparative Example 1)
A coil portion of about 20 mm was cut out from the coil portion on which the vapor deposition film was formed in Example 1, and this was used as a sample. Using this sample, the sample was placed on the same tilt table as in Example 1, and the tilt angle of the tilt table was gradually tilted to measure the angle at which the sample started to slide. The angle of the tilt table at which the sample began to slide was 35 degrees.
[0043]
(Reference Example 1)
4,4′-diphenylmethane diisocyanate and 4,4′-diaminodiphenylmethane are formed on the surface of a SUS301 medical basket catheter wire (maximum diameter 0.010 inch, length 150 cm), which has been conventionally used as a medical device. Were vacuum-deposited to form a deposited film having a thickness of 0.1 μm.
[0044]
On the other hand, blocked isocyanate (trade name: Elastron H-8) and polyvinylpyrrolidone were mixed at a weight ratio of 1:10 to prepare a 10% aqueous solution. This 10% aqueous solution was applied to the surface of the medical basket catheter wire on which the vapor-deposited film was formed, then dried in a hot air circulating dryer at 50 ° C. for 2 hours, and then heat treated at 120 ° C. for 20 minutes. .
[0045]
After the heat treatment, the coated portion was immersed in warm water at 37 ° C. for 30 minutes, rinsed with running water, washed, connected to the basket, and assembled with an operation handle, a flush port and a catheter mantle tube in this order to form a basket catheter. The basket catheter was wound twice with a 50 mm diameter, and the operation handle was pulled to observe the operability of the basket. As a result, the handle operation was light and no sense of resistance was felt.
[0046]
Moreover, although the said handle operation was repeated 100 times, it was able to be performed without a feeling of resistance at all. When the coil portion of the sample was observed after the operation, no peeling of the hydrophilic polymer film was observed.
[0047]
(Comparative Example 2)
Using said medical basket catheter wire having a vapor deposited film in the same manner as in Reference Example 1 to form a basket catheter in the same manner as in Reference Example 1. When the operability of this basket catheter was evaluated in the same manner as in Reference Example 1 , it was difficult to use because of the large catch.
[0048]
(Comparative Example 3)
The surface of the coil part of the guide wire made of SUS301 used in Example 1 was coated with polyvinyl pyrrolidone using an isocyanate by a known method, and dried by heating to form a hydrophilic polymer film. When inserted and removed from the same polyethylene tube as in Example 1 using this guide wire, there was no resistance to the initial insertion and removal, but the resistance increased with each turn, Insertion has become difficult before 100 insertions and removals. When the coil portion of the guide wire that became difficult to insert was observed, most of the hydrophilic polymer film was peeled off.
[0049]
【The invention's effect】
The lubricious medical device according to the present invention has a vapor deposition polymer film with excellent adhesion to the substrate surface and a small thickness, and is chemically fixed to the vapor deposition polymer film to be easily detached, detached, It has a hydrophilic polymer film excellent in lubricity without being separated. Therefore, the lubricious medical device according to the present invention can be smoothly inserted into a living tissue, and the hydrophilic polymer substance is not peeled, detached, separated or eluted during use and is safe. .
[0050]
In the present invention, if the vapor deposition polymerization film is a film having a functional group capable of binding to a water-soluble polymer, the water-soluble polymer having excellent biocompatibility can be chemically bonded. The bond between the film and the hydrophilic polymer film is strong.
[0051]
When the vapor deposition polymerization film is an active hydrogen-containing film and the hydrophilic polymer film is formed of an isocyanate compound and an active hydrogen-containing water-soluble polymer, the vapor deposition polymerization film and the hydrophilic polymer are bonded via a urethane bond. The film is firmly bonded.
[0052]
If the vapor deposition polymerization film has an isocyanate group, the hydrophilic polymer film can be bonded to the vapor deposition polymerization film using an active hydrogen-containing water-soluble polymer without using an isocyanate compound.
[0053]
When the vapor deposition polymerization film is polyurea, polyamic acid, polyimide or the like, vapor deposition polymerization can be easily performed.
[0054]
According to this invention, without increasing the thickness, it has excellent adhesion to the substrate surface, and there is no detachment, exfoliation, elution, etc. of the coating, which is safe for the living body, and has excellent lubricity. It is possible to provide a method for easily manufacturing a sex medical device.

Claims (4)

A substrate, possess a vapor deposition polymerization film formed on the substrate surface, and a fixed hydrophilic polymer film on the vapor deposition polymerization on the film, the vapor deposition polymerization coating is an active hydrogen-containing coating, wherein the hydrophilic A lubricious medical device , wherein the functional polymer film is formed from an isocyanate compound capable of reacting with active hydrogen in the vapor deposition polymerization film and a water-soluble polymer containing active hydrogen . The lubricated medical treatment according to claim 1 , wherein the vapor deposition polymerization film is at least one selected from the group consisting of polyurea, polyamic acid, and polyimide obtained by partial dehydration of the polyamic acid. Tools.   An active hydrogen-containing vapor-deposited polymer film is formed on the surface of the substrate by vapor-deposition polymerization, and an isocyanate compound capable of reacting with active hydrogen in the vapor-deposited polymer film and an active hydrogen-containing water-soluble polymer The method for producing a lubricious medical device is characterized by applying and reacting with each other simultaneously or stepwise.   A vapor-deposition polymerization film containing an isocyanate group is formed on the substrate surface by vapor deposition polymerization, and a water-soluble polymer capable of reacting with the isocyanate group is coated on the vapor-deposition polymerization film and reacted. A method for producing a lubricious medical device.