JP2744155B2 - Antithrombotic medical device having lubricity when wet and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a medical device having both lubricity and antithrombotic properties when wet and a method for producing the same, and particularly to catheters, guidewires, needles, and extracorporeal blood which come into contact with blood. This is a useful invention that can be widely used for tools and the like used in the system.

[0002]

2. Description of the Related Art With the improvement of medical device technology, medical devices having higher safety are required. In particular, there has been remarkable progress in catheters and guidewires used for angiography in recent years, as well as medical devices that come into contact with blood as tools not only by inspection but also by PTCA method and the like.

[0003] In order to further enhance the safety of medical devices used in these, it is necessary to satisfy two conditions. That is, the first is lubricity of the surface of the medical device for smoother usability, and the second is prevention of blood coagulation caused by contact with blood (antithrombotic property).

[0004] As a method for imparting lubricity to the surface of the first medical device, conventionally, a substrate having good slipperiness has been used, or silicone oil, olive oil or the like has been applied to the surface of the substrate. It is not enough in point.

As another method, a method using an interpolymer of polyvinylpyrrolidone, which is a hydrophilic compound, and polyurethane (JP-A-59-19852, US Pat. No. 4,100,309) is used to prepare a reactive functional group. A method using a copolymerized hydrophilic polymer and isocyanate (JP-A-59-81341) and a method of fixing polyethylene oxide using an isocyanate (JP-A-58-193766) are known. Although these methods have provided effective medical devices in terms of lubricity, they are not sufficient for antithrombotic properties.

As a method for imparting an antithrombosis to the surface of a second medical device, a medical device having antithrombotic properties uses a hydrophilic heparinized material (Japanese Patent Publication No. 54-1851).
No. 8, JP-A-60-12069, JP-A-62-381, and those using a linearly curable substance, and those using a graft / block copolymer having a microdomain structure.
71, JP-A-63-296762) and the like.
These methods use an antithrombotic material to change the substrate surface to a thrombus formation-inhibiting surface, and provide an effective antithrombotic medical device. However, lubricity was not sufficient.

[0007]

The combination of lubricating properties and antithrombotic properties is disclosed in Japanese Patent Laid-Open No. 2-144070.
Has been proposed. In this method, an acidic polysaccharide (among others, a heparin compound) is fixed to a base material by a covalent bond or an ionic bond to a hydrophilic copolymer by a conventional method. We provide excellent medical materials having antithrombotic properties by applying certain heparin compounds.

[0008] However, the acidic polysaccharide having an antithrombotic effect is said to have a mechanism of suppressing blood clot formation as a blood coagulation factor suppressing type, and is inactivated due to immobilization and inactivation during in vivo breeding. Is concerned. In addition, the fixing is complicated and the material is expensive.

SUMMARY OF THE INVENTION It is an object of the present invention to provide a medical device which can provide lubricating properties and antithrombotic properties to each other, enhance safety, and can be provided at low cost, and a method of manufacturing the same.

[0010]

SUMMARY OF THE INVENTION claims 1 invention, the base material surface of the medical device, as well as organic anti-thrombotic,
The gist of the present invention is to cover a copolymer having a hydrophilic / hydrophobic microdomain structure and to coat and fix a hydrophilic compound on the surface of a hydrophilic portion of the copolymer by a covalent bond.

The antithrombotic copolymer referred to in the present invention includes a graft copolymer or a block copolymer. The copolymer has a hydrophilic / hydrophobic microdomain structure having a function of inhibiting platelet contact activation, has a hydrolyzable silyl group, and is exposed to moisture on the surface of a medical device substrate. It is firmly fixed by silane cross-linking by hydrolysis of silyl groups to form a film of a copolymer having a microdomain structure, and then on the surface of the hydrophilic part of the copolymer to express lubricity when wet. Covalent bonding of a hydrophilic compound having lubricity when wet.

That is, by changing the hydrophilic portion of the hydrophilic / hydrophobic type microdomain structure into a microdomain structure comprising a hydrophilic portion and a hydrophobic portion having lubricity when wet, it has an antithrombotic and lubricity interaction. A manufacturing method characterized by the following.

The copolymer having a hydrophilic / hydrophobic microdomain structure used in the present invention is not particularly limited, but is preferably a copolymer derivative having a hydrolyzable silyl group.

The copolymer having a hydrolyzable silyl group is composed of a vinyl monomer unit (a) as a hydrophilic portion and a fluorine-containing vinyl monomer unit (b) as a hydrophobic portion.
A vinyl-based graft / block copolymer comprising a hydrolyzable silyl group (c) at least at one end.
Is a vinyl-based graft / block copolymer having

Alternatively, a vinyl monomer unit (a ′) as a hydrophilic portion, a fluorinated vinyl monomer unit (b ′) as a hydrophobic portion, and a monomer containing a hydrolyzable silyl group It is a graft / block copolymer composed of a body unit (c ′).

Acrylic acid is used as a monomer to be a vinyl monomer unit (a) or (a ') as a hydrophilic portion.
Methacrylic acid and its derivatives, specifically, acrylonitrile, methacrylonitrile, methyl acrylate, methyl methacrylate, n-butyl methacrylate, dimethylamino, vinyl alcohol, ethyl methacrylate, acrylamide, Preferred among acrylic acid amide, N-vinyl-2-pyrrolidone, 2-hydroxymethyl- (meth) acrylate and the like is methacrylic acid.

The monomers used as the fluorinated vinyl monomers (b) and (b ') as the hydrophobic portion include:
_{C 7 F 15 CH 2 OCO-} CH = CH 2, C 8 F 17 SO 2
_{N (Pr) CH 2 CH 2} OCO-CH = CH 2, C 8 F
₁₇ SO ₂ N (Me) CH ₂ CH ₂ OCO-C (Me) H
= CH ₂ ,

[0018]

Embedded image _{C 7 F 15 CON (Et)} CH 2 CH 2 OCO-C (M
e) = CH ₂ , CF ₃ (CF ₂ ) ₉ CH ₂ CH ₂ OCO
_{-CH = CH 2, C 8 F} 17 (CH 2) 11 OCO-C (M
_{e) = CH 2, C 8} F 17 CH 2 CH (OH) CH 2 OC
O-C (Me) = CH 2, C 8 F 17 SO 2 N (CH 2 C
_{H 2 OCO-CH = CH)} 2, C 8 F 17 SO 2 N (M
_{e) (CH 2) 10 OCO} -CH 2 CH = CH 2, C 8 F
_{17 SO 2 N (Et) CH} 2 CH 2 OCO-CH = CH-
COOEt, C ₆ F ₁₃ SO ₂ N (Me) CH ₂ CH ₂ O
_{CO-CH = CH 2, CF} 3 (CF 2) 2 CH 2 OCO
_{-C (Me) = CH 2,} CF 3 (CF 2) 4 CH 2 CH
₂ OCO-C (Me) = CH ₂ , HCF ₂ (CF ₂ ) ₇
CH ₂ OCO-CH = perfluoroalkyl group-containing CH _2, etc. (meth) acrylic acid esters; e.g. _{C 7 F 15 CH 2 OCH =} CH 2, C 7 F 15 CH 2 OCO
Vinyl ether or aryl ether having the same perfluoroalkyl group such as -CH = CH _2; for example _{C 8 F 17 (CH 2)} 11 -OCO-CH = CH-COOM
_{e, C 8 F 17 (CH} 2) 11 -OCO-CH = CH-CO
Maleic acid mono- or diesters having a perfluoroalkyl group similar to those of the above (meth) acrylates such as OCH ₂ C ₇ F ₁₅ ; for example, C ₈ F ₁₇ SO ₂ NHCH ₂ CH ₂ SO ₂ CH = CH ₂ Vinyl sulfonic acid having a perfluoroalkyl group as described above; and fluoroolefin monomers such as chlorotrifluoroethylene and tetrafluoroethylene.
In the above and the following, Me, Et, and Pr represent methyl, ethyl, and propyl groups, respectively.

Of these, preferred are those having 3 to 2 carbon atoms.
(Meth) acrylate containing one perfluoroalkyl group. Silyl mercaptan is used for the introduction of the hydrolyzable silyl group referred to in the present invention, and reacts with the above (a) and (b) to form a graft / block copolymer, which causes a hydrolysis reaction under moisture, Form silane crosslinks to form a strong film.

Examples of the monomer unit containing a silyl group (c ') include vinylsilane compounds such as vinylmethyldimethoxysilane and vinyltrimethoxysilane, hydrosilane compounds such as methyldimethoxysilane and methyldiacetoxysilane, and the like. Further, silyl group-containing vinyl vinyl polymer, silyl group-containing polyurethane and the like,
(A)-(b), (a ')-(b') and graft / block copolymerization, and (a)-(b)-(c), (a ')-
(B ′) − (c ′) are formed.

It is said that the surface expression of the antithrombotic property due to the microdomain structure is greatly influenced by the hydrophilic / hydrophobic lamella structure, and the molecular composition thereof is greatly reduced. It is possible to adjust the hydrophobic molecular structure.

Preferred compounds are: methyl methacrylate
_{CH 2 = C (Me) COOCH} 2 - (CF 2) 6 -CF
An organic solvent solution in which a ₃ -polyurethane-silyl graft / block copolymer is dissolved is exemplified.

Next, there are various kinds of known hydrophilic polymer compounds which form lubricity when wet, which are used in the present invention, but are not particularly limited. Examples are starch,
Cellulose, maleic anhydride, polyvinylpyrrolidone, polyvinyl alcohol and the like can be mentioned,
Preferably, maleic anhydride, polyvinyl alcohol-
A mixture of starch, polyvinylpyrrolidone and the like can be mentioned. The fixation of these hydrophilic high molecular compounds to the substrate surface can be applied to the graft / block copolymer previously fixed to the substrate by silane crosslinking by various conventionally known methods.

For example, a method in which a compound containing an isocyanate group or the like is previously coated and a hydrophilic polymer compound is fixed by a covalent bond is preferable. Examples of the compound containing an isocyanate group include toluene diisocyanate and 4,4′-diphenylmethane isocyanate.

The base material of the medical device may be various plastics, various inorganic materials, metal materials and the like. Specifically, polyurethane, polyamide nylon, vinyl chloride, polyester, polyurea, stainless steel, elastic metal, ceramics, Examples include wood and paper.

[0026]

According to the first aspect, the capping control function of the hydrophilic / hydrophobic microdomain structure itself is achieved without using a physiologically active substance such as a platelet activation inhibitor.
By inhibiting platelet contact activation, the surface of the medical device is surface-treated to exhibit antithrombotic properties with a graft-block copolymer having a hydrolyzable silyl group, and then wetted by a known method. The coated hydrophilic compound is fixed by a covalent bond.

According to the present invention, it is possible to obtain an antithrombotic medical device having lubricity when wet, regardless of the type of the base material of the medical device. That is, according to the conventional method, the base material of medical devices, metals, glass, and other inorganic materials are coated with an organic polymer compound on the surface of the base material in advance to form a reactive functional group. Although pretreatment for introducing or mixing a substance having a reactive functional group into the substrate was an essential condition, according to the present invention, there is no need for such a pretreatment, and production is easy.

[0028]

According to the invention of claims 1 to 4,
Medical devices have biological activities such as platelet activation inhibitors
Hydrophilic / hydrophobic microdomain structure itself without using substances
Platelet contact with capping control function
Activation can be prevented. Therefore, heparin compounds
Unlike acid polysaccharides such as substances, the thrombus formation suppression mechanism
Inactivation due to immobilization,
Lubricity and no risk of inactivation during in vivo breeding
To manufacture medical devices that have antithrombotic properties
Can be. According to the invention of claim 2, since it has a hydrolyzable silyl group, a copolymer having antithrombotic properties can be easily fixed regardless of the type of substrate surface (organic material, inorganic material). According to the invention of claim 3, the kind of the base material of the medical device
Anti-thrombotic that has lubricity when wet without being affected by
Sexual medical devices can be obtained.

The medical device according to claim 5 and claim 6
According to the report, use bioactive substances such as platelet activation inhibitor
Without capping the hydrophilic / hydrophobic microdomain structure itself
Activation control prevents platelet contact activation
Can be stopped. Therefore, acidic properties such as heparin compounds
Unlike polysaccharides, thrombus formation suppression mechanism suppresses blood coagulation factors
Inactivation due to immobilization and in vivo
Without lubrication and antithrombotic properties without the risk of inactivation during vo implantation
Can be held together. That is, the doctor
The medical device has not only antithrombotic properties but also lubricity when wet, and can be more safe and cheaper than conventional antithrombotic and lubricious ones.
Can be

[0030]

Embodiments will be described below. First, an example of a method for producing a copolymer having antithrombotic properties used in the following examples will be described.

100 parts of toluene was placed in a kolben, heated with stirring and heated to 100 ° C., 35 parts of methyl methacrylate was added, and CH ₂ ＣC (Me) COOCH ₂ (C
A mixed solution of 55 parts of F ₂ ) ₆ CF ₃ , 20 parts of styrene, 7 parts of γ-mercaptopropyltrimethoxysilane, 3 parts of azobisisobutyronitrile, and 5 parts of toluene was dropped over 2 hours. And at the same temperature for 2 hours.

Further, after adding 1 part of azobisisobutyronitrile, the mixture is reacted at the same temperature for 2 hours to obtain a polymer. To this, a mixed solution of 20 parts of a silyl group-containing polyurethane and 50 parts of toluene was added, 1 part of azobisisobutyronitrile was further added, and the mixture was reacted at the same temperature for 2 hours, and methyl methacrylate-CH ₂ ＣC (Me ) COOCH ₂ (C
F _{2) 6} CF ₃ - styrene - Polyurethane - obtaining trimethoxysilane reel copolymer. This polymer had no infrared absorption spectrum at 1648 cm ^-1 due to a fluorine-carbon double bond, and had a molecular weight measured by GPC of 1200.

(Example 1) Polyurethane (trade name "Pelesen", manufactured by Dow Chemical Company) Sheet 5 cm x 5 cm
× 0.5 tm / m on the surface, 10% methyl methacrylate-CH ₂ ＣC (Me) COOCH _2- (CF ₂ ) ₆ -C
Coating with a toluene solution of F ₃ -styrene-polyurethane-trimethoxyreel copolymer, 100 ° C., 1
Heat and dry in air for hours. 4,4'-Diphenylmethane diisocyanate 1% methyl ethyl ketone solution is coated and dried at 60 ° C. for 30 minutes, and then a 3% methyl ethyl ketone solution of methyl vinyl ether maleic anhydride copolymer is coated, dried at 60 ° C. for 30 minutes and humidified and heated. (100 WET%, 50 ° C) for 1 hour, then wash with purified water. Thereafter, the resultant was dried at 60 ° C. for 24 hours to obtain an antithrombotic angiographic polyurethane having wettability.

When this angiographic polyurethane was used, no thrombus was generated and excellent lubricity was obtained. (Example 2) 5Fr (outer diameter 1.67 m / m, inner diameter 1.1
m / m), 10% on the surface of an angiographic catheter made of nylon elastomer (trade name “Pebax”, manufactured by Toray Industries, Inc.).
% Methyl methacrylate-CH ₂ ＣC (Me) COOCH
_{2 - (CF 2) 6 -CF} 3 - styrene - Polyurethane -
Coating with a toluene solution of a trimethoxy reel copolymer, drying at 100 ° C. for 1 hour, coating with a 1% methyl ethyl ketone solution of 4,4′-diphenylmethane diisocyanate, drying at 60 ° C. for 30 minutes, and drying with methyl vinyl ether maleic anhydride The polymer is coated with a 3% methyl ethyl ketone solution, dried at 60 ° C. for 30 minutes, left for 1 hour in a humidified atmosphere, and washed with purified water.
Then, it was dried at 60 ° C. for 24 hours to obtain an antithrombotic angiographic catheter with wettability.

Using this angiographic catheter,
No thrombus was generated, and excellent lubricity was obtained. (Example 3) 4Fr (outer diameter 1.85 m / m, inner diameter 0.9)
m / m) and 10% methyl methacrylate-CH ₂ ＣC (Me) COO on the surface of a reservoir catheter made of polyurethane (trade name “Pelecene”, manufactured by Dow Chemical Company).
Coating with a toluene solution of CH _2- (CF ₂ ) ₆ CF ₃ -styrene-polyurethane-trimethoxy reel copolymer, drying at 100 ° C. for 1 hour, and coating with a 1% 4,4′-diphenylmethane diisocyanate 1% methyl ethyl ketone solution. After drying at 60 ° C. for 30 minutes, a 3% methyl ethyl ketone solution of a methyl vinyl ether maleic anhydride copolymer is coated, dried at 60 ° C. for 30 minutes, left for 1 hour in a humidified atmosphere, and washed with generated water. Thereafter, drying was performed at 60 ° C. for 24 hours to obtain a wettable reservoir catheter.

When this reservoir catheter was used, thrombus was not generated, and excellent lubricity was obtained. (Example 4) φ0.87 × 1500 m consisting of a polyurethane (trade name “Pelesen”, manufactured by Dow Chemical Co.)
A / m guidewire surface, 5% methyl methacrylate _{-CH 2 = C (Me) COOCH} 2 - (CF 2) 6 CF
It is coated with a toluene solution of ₃ -styrene-polyurethane-trimethoxyreel copolymer, and dried by heating at 100 ° C. for 1 hour in the air. 4,4'-diphenylmethane diisocyanate 1% methyl ethyl ketone solution is coated, dried at 60 ° C. for 30 minutes, further coated with a 3% methyl ethyl ketone solution of methyl vinyl ether maleic anhydride copolymer, dried at 80 ° C. for 2 hours, and humidified. After leaving for 1 hour at a temperature (100 WET%, 50 ° C.), it is washed with purified water. Thereafter, the guide wire was dried at 60 ° C. for 24 hours to obtain a guidewire having antithrombotic properties with wettability.

When this guide wire was used, thrombus was not generated for a long time, and excellent lubricity was obtained. (Example 5) φ0.87 × 1500 m made of a polyurethane (trade name “Pelesen” manufactured by Dow Chemical Co.)
A / m guidewire surface, 5% methyl methacrylate _{-CH 2 = C (Me) COOCH} 2 - (CF 2) 6 CF
Coating with a toluene solution of ₃ -styrene-polyurethane-trimethoxyreel copolymer, leaving it at room temperature for 10 minutes, coating with a 3% methyl ethyl ketone solution of methyl vinyl ether maleic anhydride copolymer, and drying at 80 ° C. for 12 hours After, humidification and heating (100WET
%, 50 ° C) for 1 hour, and then washed with purified water. Thereafter, the guide wire was dried at 60 ° C. for 24 hours to obtain a guide wire having antithrombotic properties with wettability.

Even when this guide wire was used, no thrombus was generated for a long time, and excellent lubricity was obtained.

 ────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Takeyasu Yamada Chiba Prefecture, Funabashi City, Wakamatsu 2-chome, 8-block, No. 4, Building 302 (56) References JP-A-3-184557 (JP, A) JP-A-61-45775 ( JP, A) JP-A-2-277458 (JP, A) JP-A-59-81341 (JP, A) JP-A-60-96259 (JP, A) JP-A-2-144070 (JP, A) JP Hei 1-250265 (JP, A) Special table Sho-59-500800 (JP, A)

Claims (6)

(57) [Claims] Respect 1. A substrate surface of the medical device, as well as organic anti-thrombotic, a hydrophilic-hydrophobic type microdomain structure
A method for producing an antithrombotic medical device having lubricity when wetted, comprising coating a copolymer having a hydrophilic compound on a surface of a hydrophilic portion of the copolymer by a covalent bond. Wherein said antithrombotic a having copolymer is a copolymer having a hydrolyzable silyl group in a humid, to form a coating layer by the silane crosslinking to a substrate surface of the medical device The method for producing an antithrombotic medical device having lubricity when wet according to claim 1, wherein the medical device is fixed. 3. The antithrombotic medical device having lubricity when wet according to claim 1 or 2, wherein the base material of the medical device is made of any one of a polymer resin compound, a metal, and an inorganic material. Production method. 4. The method for producing an antithrombotic medical device having lubricity when wet according to claim 1, wherein the hydrophilic compound is a compound having lubricity when wet. 5. A silane cross-linking on the surface of a substrate of a medical device.
With a hydrophilic / hydrophobic microdomain structure
On the other hand, for a coating layer made of a copolymer having antithrombotic properties ,
An antithrombotic medical device having lubricity when wet, characterized in that a hydrophilic compound is fixed on the surface of the hydrophilic portion of the copolymer by a covalent bond. 6. The antithrombotic medical device having lubricity when wet according to claim 5 , wherein the substrate of the medical device is made of one of a polymer resin compound, a metal, and an inorganic material.