JP3328367B2 - Antithrombotic catheter - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an antithrombotic catheter, and the catheter of the present invention is particularly suitable for indwelling and use in a blood vessel requiring antithrombotic properties.

[0002]

2. Description of the Related Art In recent years, many studies and developments have been made to impart antithrombotic properties to catheters. In this case, the method of imparting antithrombotic properties includes a method of imparting an antithrombotic substance consisting of a thrombolytic substance such as polysaccharide or prostaglandin, or a thrombolytic substance such as urokinase or streptokinase to a catheter by ionic or covalent bonding. A method of binding to a surface or a method of applying a solution containing an antithrombotic substance and a polymer binder to the surface of a catheter to form a coating film composed of the antithrombotic substance and a polymer is usually adopted.

However, a method of binding an antithrombotic substance to a catheter surface by ionic bonding or covalent bonding is as follows.
It is necessary to introduce ionic groups or covalently bondable groups on both the catheter surface and the antithrombotic substance, which requires extremely sophisticated and complicated processing operations, and furthermore, the catheter and the antithrombotic substance. Types are limited. In addition, in some cases, the antithrombotic substance is denatured by ionic or covalent bonds, and has a disadvantage of losing antithrombotic properties.

[0004] A method of applying a solution containing an antithrombotic substance and a polymer binder to the surface of a catheter to form a coating film is disclosed in US Pat. There are many problems, such as thickening, variations in inner and outer dimensions, and the risk of dissolution and erosion of the catheter due to the solvent for the polymer binder.

In recent years, (2R, 4R) -4-methyl-1- [N ^2- (RS) -3-methyl-1,2,3,4
-Tetrahydro-8-quinolinsulfonyl) -L-arginyl] -2-piperidinecarboxylic acid hydrate (hereinafter referred to as "argatroban") has been studied to obtain an antithrombotic material. The method of applying an organic solvent solution containing a polymer binder and argatroban to the surface of a catheter to form a coating film, or the method of covalently bonding argatroban to the catheter surface has been exclusively adopted, The method has the disadvantages of the conventional method or the covalent bonding method.

[0006]

SUMMARY OF THE INVENTION An object of the present invention is to provide a method for binding an antithrombotic substance to a catheter surface by an ionic bond or a covalent bond without the need for complicated and sophisticated techniques as in the above-mentioned conventional method. An object of the present invention is to simply provide a catheter having excellent antithrombotic properties. The object of the present invention is to remove the applied antithrombotic substance early, as in the conventional method of applying the antithrombotic substance to the catheter surface using a polymer binder, and to increase the thickness of the catheter by coating. It is an object of the present invention to provide a catheter having a predetermined and accurate shape and dimensions and having an antithrombotic substance firmly held therein, without causing problems such as variations in inner and outer dimensions. Furthermore, an object of the present invention is to gradually release the antithrombotic substance retained in the catheter without separating from the catheter in a short time,
An object of the present invention is to provide a catheter capable of maintaining its antithrombotic function for a long period of time.

[0007]

Means for Solving the Problems The present inventors have studied to solve the above-mentioned problems. As a result, among the many antithrombotic substances, argatroban is relatively heat-resistant and does not lose its antithrombotic function even when subjected to heat treatment.Additionally, argatroban is added to the thermoplastic polymer and melt molded. It has been found that when a catheter is manufactured by the method described above, a catheter having excellent antithrombotic properties can be extremely easily manufactured, and that the argatroban is gradually released from the catheter, thereby maintaining a good antithrombotic action over a long period of time. Thus, the present invention has been completed.

[0008] Accordingly, the present invention is an antithrombotic catheter, which is formed by melt-molding a thermoplastic polymer composition containing argatroban.

Argatroban used in the present invention comprises 13 kinds of blood coagulation factor precursors composed of proteases (eg, fibrinogen, prothrombin, tissue thromboplastin, plasma thromboplastin, prekallikrein, etc.), and activated coagulation produced from these precursors. It acts on at least one of the factors (thrombin, plasmin, kallikrein, etc.) to inhibit its activity, prevents or suppresses blood clotting, and has good antithrombotic properties.

Argatroban, unlike conventional mucopolysaccharides such as heparin, has heat stability in addition to its excellent antithrombotic function. Therefore, argatroban is blended in a thermoplastic polymer and heated and melt-molded. By doing so, the catheter of the present invention having good antithrombotic properties can be obtained. In that case, argatroban may be incorporated alone into the thermoplastic polymer or may be incorporated into the thermoplastic polymer along with other protease inhibitors.

As the thermoplastic polymer constituting the catheter, any polymer that can be melt-molded can be used. For example, polyester, polyamide, thermoplastic polyurethane, olefin-based polymers (polyethylene, polypropylene, ethylene-propylene copolymer) can be used. Polymers, ethylene-propylene-diene terpolymers, ethylene-vinyl acetate copolymers, ethylene-vinyl alcohol copolymers, ethylene-vinyl chloride copolymers, etc.), (meth) acrylate-based polymers, Examples include vinyl chloride-based polymers, polyvinyl acetate, styrene-butadiene copolymer, acrylonitrile-butadiene copolymer, natural rubber, synthetic rubber (such as isoprene rubber, butadiene rubber, chloroprene rubber, and butyl rubber), and silicone rubber. it can. The thermoplastic polymer may be used alone or as a blend of two or more.

Among the thermoplastic polymers described above, the thermoplastic polymer constituting the catheter has a melt molding temperature lower than the heat-resistant temperature of argatroban, has a good affinity for argatroban, and has argatroban in the polymer. It is particularly desirable that the argatroban added to the polymer can be gradually eluted from the surface of the catheter in an effective amount capable of preventing or suppressing blood coagulation from the surface of the catheter.

[0013] Such particularly desirable thermoplastic polymers include those having polyether chains such as polypropylene oxide chains, polyethylene oxide chains and polytetramethylene oxide chains in the molecule, and more specifically, Examples thereof include polyether polyurethane, polyether polyamide, and polyether polyester. In these thermoplastic polymers having a polyether bond in the molecule, argatroban added to the polymer is dissolved and trapped in the polyether chain part, while being released outside through the polyether chain part It is considered something.

The amount of argatroban added to the thermoplastic polymer depends on various requirements such as the elution rate of argatroban from the thermoplastic polymer catheter, the type of the thermoplastic polymer constituting the catheter, the shape and use of the catheter, and the like. Although it can vary, typically about 100 for the thermoplastic polymer
It is preferable that the concentration be in the range of about ppm to 20% by weight, and within such a range, an appropriate amount such that argatroban does not adversely affect blood vessels and blood while positively imparting antithrombotic properties to the catheter surface. It is better to choose. For example, the effective elution rate of argatroban from a catheter (artificial organ) is about 1.0 × 10 ^{-4 to} 1.0 × 10 ^-1 μg / cm ² ···
Min, preferably 2.5 × 10 ^{−4 to} 7.0 × 10 ⁻³ μg /
cm ² · min [artificial organ 14 (2), p679
682 (1985)], and in the present invention, the addition amount of argatroban may be selected so that the elution rate of argatroban is in such a range.

The thermoplastic polymer composition containing argatroban used in the present invention may be used in various thermoplastic polymers as long as it does not impair the antithrombotic properties of the catheter produced therefrom. May be contained as necessary.

In producing the catheter of the present invention, various molding methods can be adopted depending on the kind of the thermoplastic polymer to be used, and the molding method is not particularly limited.
For example, it can be manufactured by extrusion molding, injection molding, casting, sintering, and the like, and particularly easily and smoothly by extrusion or injection molding.

Further, in order to control the elution rate of argatroban from the surface of the catheter, a film made of a suitable material for controlling the elution rate may be further provided on the surface of the catheter by any method.

The antithrombotic catheter of the present invention may be a finished product or a raw material catheter for producing a finished product. Further, the catheter of the present invention may be one in which the entire catheter is formed from an organic polymer material, or one in which the organic polymer material is used only in a part of the product. The antithrombotic catheter of the present invention is particularly suitable for use as a catheter to be placed in a blood vessel requiring antithrombotic properties.

[0019]

EXAMPLES The present invention will be specifically described below with reference to examples and reference examples, but the present invention is not limited thereto.

Example 1 1% by weight of argatroban was added to polyurethane pandex T-5000 (polyether polyurethane manufactured by Dainippon Ink and Chemicals, Inc.), and an outer diameter of 1.10 mm and an inner diameter of 0 were measured by an extrusion molding machine. .78
After forming a tube of mm, the tip was processed to produce the catheter of the present invention. For comparison, an ethylene / tetrafluoroethylene copolymer (ETFE) catheter of the same size was prepared.

The left and right common jugular veins of the Japanese white rabbit were cut open, and the vein was closed by inserting the catheter of the present invention prepared above and the ETFE catheter for comparison respectively into each of them. 24 hours later, use heparin in rabbits for 1000 units
After administration at a rate of / kg body weight, blood was removed while administering physiological saline. When the blood vessel at the indwelling site was cut open and the portion was observed with the naked eye, no thrombus was formed in the blood vessel portion where the catheter of the present invention was inserted, and the catheter of the present invention exhibited an excellent antithrombotic effect. It became clear to have. On the other hand, in the blood vessel portion into which the ETFE catheter for comparison was inserted, a thrombus was formed at one end thereof, and there was no antithrombotic property.

Although the catheter was not directly manufactured, the following experiment was carried out using various thermoplastic polymers in order to clarify that the catheter of the present invention was excellent in sustained release of argatroban. went.

Reference Example 1 1% by weight of argatroban was added to Polyurethane Pandex T-5000 (polyether polyurethane manufactured by Dainippon Ink), and a twin-screw kneader (Laboplast manufactured by Toyo Seiki Co., Ltd.) was added. Then, the mixture was melt-kneaded at 180 ° C. by a mill and press-formed by a heat press at 175 ° C. to produce a 325 μm thick sheet. This sheet was cut into a circle having a diameter of 1 cm to obtain a test piece.

The test piece prepared as described above was used in a phosphate buffer (p
H7.4) Immerse in 5 ml and incubate at 37 ° C. for 14 days. It was measured by ion pair liquid chromatography (manufactured by Shimadzu Corporation; chromatography LC-6A). The mobile phase was 65% methanol containing 10 mM sodium heptanesulfonate, and the analytical column attached to the chromatography was Inertsil C ₈ (4.6 m diameter).
m, length 250 mm; GL Sciences Corporation;
(Temperature: 50 ° C.), and a 1N sodium hydroxide solution was fed into the eluate from the analytical column using a T-type joint, and a fluorescence detector (manufactured by Shimadzu Corporation; RF-53) was used.
The measurement was performed using excitation light of 325 nm and fluorescence of 400 nm using 5). The results are shown in Table 1 below.

Reference Example 2 A test piece was prepared in the same manner as in Reference Example 1 except that the amount of argatroban added to Polyurethane Pandex T-5000 was changed to 4% by weight. The sustained release rate was measured. Table 1 shows the results.

Reference Example 3 Polyamide Elastomer P
To AE1200 (Nylon having a polypropylene oxide chain in the molecule, manufactured by Ube Industries), 2% by weight of argatroban was added, melt-kneaded at 175 ° C. in the same manner as in Reference Example 1, and then press-formed by a heat press. Thus, a sheet having a thickness of 321 μm was manufactured. This sheet has a diameter of 1c.
The test piece was cut out into a circle of m. Thereafter, in the same manner as in Reference Example 1, the sustained release rate of argatroban from this test piece was measured. Table 1 shows the results.

Reference Example 4 Polyamide Elastomer P
EBAX3533 (manufactured by ATO CHIMIE; nylon containing a polytetramethylene oxide chain in the molecule)
After adding argatroban (wt%), the mixture was melt-kneaded at 165 ° C. in the same manner as in Reference Example 1, and then press-formed with a heat press to produce a 323 μm thick sheet. This sheet was cut into a circle having a diameter of 1 cm to obtain a test piece. In the same manner as in Reference Example 1, the sustained release rate of argatroban from this test piece was measured. Table 1 shows the results.

Reference Example 5 Polyamide Elastomer P
EBAX4033 (manufactured by ATO CHIMIE; nylon containing a polytetramethylene oxide chain in the molecule)
After adding argatroban (wt%), the mixture was melt-kneaded at 180 ° C. in the same manner as in Reference Example 1, and then press-formed with a heat press to produce a 321 μm-thick sheet. This sheet was cut into a circle having a diameter of 1 cm to obtain a test piece. Thereafter, in the same manner as in Reference Example 1, the sustained release rate of argatroban from this test piece was measured. Table 1 shows the results.

Reference Example 6: Polyurethane elastomer
2% by weight of argatroban was added to Tecoflex EG-80A (manufactured by Thermedics; a polyurethane elastomer containing a polytetramethylene oxide chain in the molecule) and melt-kneaded at 160 ° C. in the same manner as in Reference Example 1. Then, a sheet having a thickness of 360 μm was manufactured by press molding with a heat press. This sheet was cut into a circle having a diameter of 1 cm to obtain a test piece. Thereafter, in the same manner as in Reference Example 1, the sustained release rate of argatroban from this test piece was measured. Table 1 shows the results.

Reference Example 7 Polyurethane Elastomer
2% by weight of argatroban was added to Tecoflex EG-68D (manufactured by Thermedics; a polyurethane elastomer containing a polytetramethylene oxide chain in the molecule) and melt-kneaded at 175 ° C. in the same manner as in Reference Example 1. Then, a sheet having a thickness of 321 μm was manufactured by press molding with a heat press. This sheet was cut into a circle having a diameter of 1 cm to obtain a test piece. Thereafter, in the same manner as in Reference Example 1, the sustained release rate of argatroban from this test piece was measured. Table 1 shows the results.

Reference Example 8 2% by weight of argatroban was added to a polyester elastomer; Hytor 4057 (manufactured by Toray DuPont), melt-kneaded at 185 ° C. in the same manner as in Reference Example 1, and then heat pressed. To produce a sheet having a thickness of 320 μm. This sheet was cut into a circle having a diameter of 1 cm to obtain a test piece. Thereafter, in the same manner as in Reference Example 1, the sustained release rate of argatroban from this test piece was measured. Table 1 shows the results.

Reference Example 9 Ethylene-ethyl acrylate copolymer (manufactured by Nippon Unicar; NUC-6570)
Then, 4% by weight of argatroban was added thereto, and the mixture was melted and kneaded at 175 ° C. in the same manner as in Reference Example 1 and then press-molded with a heat press to produce a 333 μm thick sheet. This sheet was cut into a circle having a diameter of 1 cm to obtain a test piece. Thereafter, in the same manner as in Reference Example 1, the sustained release rate of argatroban from this test piece was measured. Table 1 shows the results.

[0033]

[Table 1] Slow release rate (μg / cm ² · min) 1st day 3rd day 7th day 14th day Reference example 1 6.25 × 10 ^-4 3.87 × 10 ^-4 3.36 × 10 ^-4 2.29 × 10 ^-4 Reference example 2 2.79 × 10 ^-3 1.91 × 10 ^-3 1.46 × 10 ^-3 1.09 × 10 ^-3 Reference example 3 1.49 × 10 ^-3 7.77 × 10 ^-4 4.99 × 10 ^-4 4.47 × 10 ^-4 Reference example 4 6.81 × 10 ^{− 3} 3.93 × 10 ^-3 2.34 × 10 ^-3 8.66 × 10 ^-4 Reference Example 5 5.62 × 10 ^-3 5.39 × 10 ^-3 1.65 × 10 ^-3 1.19 × 10 ^-3 Reference Example 6 5.48 × 10 ^-3 2.80 × 10 ^-3 1.69 × 10 ^-3 1.14 × 10 ^-3 Reference example 7 3.16 × 10 ^-4 2.32 × 10 ^-4 1.47 × 10 ^-4 1.07 × 10 ^-4 Reference example 8 2.28 × 10 ^-3 1.26 × 10 ^-3 7.56 × 10 ^-4 5.68 × 10 ^-4 Reference Example 9 1.09 × 10 ^-3 3.47 × 10 ^-4 1.97 × 10 ^-4 1.15 × 10 ^-4

From the results shown in Table 1 above, in all of Reference Examples 1 to 9, the sustained release rate (elution rate) of argatroban from the test piece was required for the artificial organ even on the 14th day. 0.0 × 10 ⁻⁴ μg / cm · min or more [“Artificial Organ” 14 (2), pp. 679-682 (198)
5)], indicating that the catheter of the present invention having excellent antithrombotic properties can be obtained from the thermoplastic polymer compositions of Reference Examples 1 to 9.

Reference Example 10 4% by weight of argatroban was added to 1,2-polybutadiene RB810 (manufactured by Nippon Synthetic Rubber Co., Ltd.) and melt-kneaded at 175 ° C.
A sheet having a thickness of 346 μm was produced by press molding with a heat press. This sheet was cut into a circle having a diameter of 1 cm to obtain a test piece. The test piece prepared above was immersed in 5 ml of a phosphate buffer (pH 7.4) in the same manner as in Reference Example 1 and incubated at 37 ° C. for 7 days.
The sustained release rate of argatroban from the test piece on day 3, day 3 and day 7 was measured in the same manner as in Reference Example 1.
The results are shown in Table 2 below.

[0036]

[Table 2] Slow release rate (μg / cm ² · min) 8 hours later Day 1 Day 3 Day 7 Reference example 10 9.48 × 10 ^-4 3.28 × 10 ^-4 1.73 × 10 ^-4 1.05 × 10 ^-4

From the results in Table 2 above, in Reference Example 10, the sustained release rate of argatroban from the test piece was about 1.0 × 10 ⁻⁴ μg / cm ·
Min or more, indicating that a catheter having excellent antithrombotic properties can be produced from the thermoplastic polymer composition used in Reference Example 10.

<< Reference Example 11 >> Soft polyvinyl chloride (D
2% by weight of argatroban was added to the mixture and melt-kneaded at 165 ° C., followed by press molding with a heat press to produce a 407 μm thick sheet. This sheet was cut into a circle having a diameter of 1 cm to obtain a test piece. The test piece prepared above was immersed in 5 ml of a phosphate buffer (pH 7.4) as in Reference Example 1, incubated at 37 ° C. for 24 hours, and after 1 hour, 4 hours, and 8 hours.
The sustained release rate of argatroban from the test piece after the time and after 24 hours was measured in the same manner as in Reference Example 1. The results are shown in Table 3 below.

Reference Example 12 Ethylene-vinyl alcohol copolymer (manufactured by Nippon Unicar; NUC-3195)
Was added with 4% by weight of argatroban,
After melting and kneading at ℃, press molding with heat press,
A 345 μm thick sheet was produced. This sheet was cut into a circle having a diameter of 1 cm to obtain a test piece. The sustained release rate of argatroban from the test piece prepared above was measured in the same manner as in Reference Example 11. The results are shown in Table 3 below.

[0040]

[Table 3] Slow release rate (μg / cm ² · min) 1 hour after 4 hours 8 hours after 24 hours Reference Example 11 3.88 × 10 ^-3 1.06 × 10 ^-3 6.10 × 10 ^-4 1.65 × 10 ^-4 Reference Example 12 2.76 × 10 ^-3 7.03 × 10 ^-4 3.83 × 10 ^-4 1.47 × 10 ^-4

From the results in Table 3 above, in Reference Examples 11 and 12, the sustained release rate of argatroban from the test piece was 1.0 × 10 ⁻⁴ μg required for the artificial organ even after 24 hours.
/ Cm ² · min or more, indicating that a catheter having excellent antithrombotic properties can be produced from the thermoplastic polymer compositions used in Reference Examples 11 and 12.

[0042]

According to the catheter of the present invention, argatroban is added to the thermoplastic polymer constituting the catheter, so that the antithrombotic substance is simply applied or bonded to the catheter surface. Alternatively, argatroban can be slowly released from the catheter without the premature withdrawal of the antithrombotic substance argatroban from the catheter. Since the catheter of the present invention can be obtained by adding argatroban to a thermoplastic polymer and melt-molding the same, its production is extremely simple, and there is no variation in dimensions and wall thickness, and the catheter has an extremely accurate shape. , Can be obtained in dimensions.

Furthermore, in the case of the catheter of the present invention, it is not necessary to use a binder for fixing the antithrombotic substance to the catheter, as in the prior art in which the antithrombotic substance is bound by an ionic bond or a covalent bond. No need to introduce ionic or covalently bondable groups on both the catheter surface and the antithrombotic substance, use solvents to dissolve or disperse the antithrombotic substance or binder, It is not necessary to remove the solvent after the application of the antithrombotic substance, and from this point, the production is extremely easy and the safety is high.

Continuation of front page (72) Inventor Susumu Tanabe 1500 Inoguchi, Nakai-machi, Ashigara-kami, Kanagawa Prefecture Inside Terumo Corporation (56) References JP-A-64-15059 (JP, A) JP-A-3-15478 (JP, A) JP-A-3-15479 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) A61L 29/00-33/18 A61M 25/00 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] 1. A method for preparing (2R, 4R) -4-methyl-1- [N
^2- (RS) -3-methyl-1,2,3,4-tetrahydro-8-quinolinsulfonyl) -L-arginyl]-
An antithrombotic catheter comprising a molded article obtained by melt-molding a thermoplastic polymer composition containing 2-piperidinecarboxylic acid hydrate.