JPH07328124A - Medicine dosing catheter - Google Patents

Abstract

PURPOSE:To make it possible to evenly inject a medicine without damaging an internal wall of a blood vessel and a tissue in the dosing of a medicine by covering the side of an external surface of the catheter tube or the balloon having the pore with a gelled layer. CONSTITUTION:A balloon catheter 1 is made up of a catheter tube comprising an inner tube 2 and an outer tube 3 and a balloon 4 and the inner tube 2 with the tip thereof opened has a first lumen 5 for inserting a guide wire. A second lumen 7 is formed between the outer tube 3 and the inner tube 2 to allow the inflow of a liquid for expanding the balloon 4, for example, an anti-thrombus agent and a blood vessel contrasting agent. The balloon 4 is provided with a pore 12 for dosing medicines and in this case, the surface of the pore 12 is covered with a gelled layer. The gelled layer herein used is, an amphiphatic polymer compound such as an acrylic amide based compound thereby enabling realization of gentle release of a chemical.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a drug catheter for treating blood vessels or other organs of the human body with drugs.

[0002]

2. Description of the Related Art In the treatment of various diseases, it is often desirable to administer a high concentration of a drug to a lesion site such as a human body organ or blood vessel. However, in general oral administration and intravenous administration, in order to secure an effective amount of drug for the lesion site, the human body may be injured at other sites that may be dangerous, or it may cause discomfort or pain. Some drugs have side effects such as Despite their excellent efficacy, these drugs often cannot be actually used for lesions.

In recent years, angioplasty using a dilatation balloon catheter has become widespread in cases of intrinsic intravascular stenosis, particularly coronary stenosis. (For example, by Gruntig, The New England Journal of Medicine.
d Journal of Medicicin), No. 301, Volume 2, 19
It was introduced on pages 61-68, June 12, 1979. This treatment method is a method of expanding the stenotic portion of the coronary artery by inflating the balloon attached to the catheter inserted percutaneously, which is less invasive than the surgical operation and is a physical burden on the patient. The feature is that there is little. A problem with this angioplasty is the high rate of reoccurrence of the dilated vessel stenosis. Therefore, to the lesion site and the inner wall of the expanded blood vessel, various anti-restenosis agents, antithrombotic agents, thrombolytic agents, calcium-dissolving agents, calcium-precipitation agents, administration of certain cytokines and cytostatics,
In recent years, gene therapy by introducing a foreign gene has been studied, and expectations for drug administration catheters are increasing.

A balloon having a medicine injection hole is disclosed in Japanese Patent Application Laid-Open No. HEI-2.
No. 283380. In a balloon catheter or a catheter that administers a drug through a drug injection hole, it is feared that the drug solution is vigorously released from the injection hole, damaging the inner wall of the blood vessel and the tissue and creating a new wound.

[0005]

SUMMARY OF THE INVENTION It is an object of the present invention to use a drug in the treatment or prevention of a disease in which it is desirable to administer a high concentration of the drug to a local blood vessel or organ having a lumen accessible by a catheter. A delivery catheter is provided. Further, an object of the present invention is to allow the drug to be uniformly injected without causing damage to the inner wall of the blood vessel or the tissue when the drug is administered, because the outer surface side (living body side) of the catheter or the balloon forms a gel layer during drug administration. To provide a catheter.

[0006]

The above problems can be solved by the present invention described below.

(1) Drug administration characterized in that in a catheter tube or balloon having pores, the outer surface side (living body side) of the catheter tube or balloon having pores is covered with a gelling layer. catheter.

(2) The drug administration catheter according to (1), wherein the gelled layer is an amphipathic polymer compound.

(3) The drug administration catheter according to (1), wherein the amphipathic polymer compound is an acrylamide compound or the like.

The present invention will be described by taking the vascular stenosis of coronary arteries as seen in ischemic heart disease such as myocardial infarction as an example. In the present invention, "lesion of blood vessel or living tissue" or "catheter system" is used. The “type” and the like are not limited to the following examples.

For prevention and treatment of vascular stenosis, antithrombotic therapy (thrombolytic therapy, anticoagulant therapy, antiplatelet therapy) and a method of expanding the stenosis with a balloon attached to the catheter tip [percutaneous coronary angioplasty] (PTCA)] is performed. The drug administration catheter of the present invention can be effectively used for expansion of these vascular stenosis and prevention or treatment of restenosis caused by administration of a drug solution. That is, the PTCA of the present invention
The dilatation catheter can expand the stenosis while releasing the drug solution through the gelling layer on the balloon surface by putting a liquid containing a thrombolytic agent or an antithrombotic drug inside the balloon. Further, since the drug solution for preventing restenosis is administered through the gel layer, the drug can be gradually transferred to the inner wall of the blood vessel without physically damaging the inner wall of the blood vessel.

That is, as shown in FIG. 1, the balloon catheter 1 comprises a catheter tube consisting of an inner tube 2 and an outer tube 3 and a balloon 4. The inner tube 2 has a first lumen 5 having an open tip. The first lumen 5 is a lumen for inserting a guide wire (not shown). The outer tube 3 is provided at a position where the inner tube 2 is inserted into the outer tube 3 and the tip is slightly retracted from the tip of the inner tube 2. The inner surface of the outer tube 3 and the outer surface of the inner tube 2 are
The lumen 7 is formed. The second lumen 7 is
The tip of the balloon communicates with a rear end of the balloon 4, which will be described later, and a liquid (for example, containing an antithrombotic drug and an angiographic agent) for inflating the balloon 4 is introduced. Then, the distal end portion of the outer tube 3 does not block the second lumen 7,
It is fixed to the inner pipe 2. Specifically, as shown in FIG. 2, it is fixed by a filling member 6 provided between the inner pipe 2 and the outer pipe 3, and this filling member 6 has a partially defective portion 6a. The second lumen 7 and the inside of the balloon 4 communicate with each other through the portion 6a.

The balloon 4 is foldable and can be folded around the outer circumference of the inner tube 2 when not expanded. Balloon 4
It has a substantially cylindrical portion 4a of substantially the same diameter, at least a portion of which has a substantially cylindrical shape so that the narrowed portion of the blood vessel can be easily expanded. The balloon 4 has the rear end 9 of the outer tube 3
Is liquid-tightly fixed to the tip of the inner tube 2, and the tip 8 is liquid-tightly fixed to the tip of the inner tube 2 to form an expansion space 10 between the inner surface of the balloon 4 and the outer surface of the inner tube 2. The rear end portion 10 communicates with the second lumen 7 via the defective portion 6 a of the filling member 6. In addition, the balloon surface has pores 12 for drug administration, and the surface of the pores 12 is covered with a gelling layer. When expanding the vascular stenosis, the pores 12 should be made small. When the balloon 4 is inflated by applying pressure to administer the drug to the vascular stenosis, the pores 12 are enlarged by the pressure to release the drug from the balloon surface into the blood vessel through the gel layer.

Further, a reinforcing member 11 is provided on the outer surface of the inner tube 2, and the reinforcing member 11 is composed of a coil spring, so that the position of the balloon 4 can be easily confirmed under fluoroscopy. Is located on the outer surface of the inner tube 2 near the center of the inner tube 2 and on the outer surface of the inner tube 2 near the tapered portion of the balloon 4 (near the tip of the outer tube 3). Instead of the coil spring, a radiopaque platinum marker or the like is also used.

The shape of the balloon portion is not particularly limited, and for example, the balloon may be a double balloon having a two-layer structure (double balloon) of a layer containing a drug solution and a layer containing a contrast agent.

The gelling layer covered on the outer surface (ecological side) of the catheter tube or balloon may be a layer in which a gel is formed by a liquid containing a drug. When the gelling layer contains an amphipathic polymer compound as a constituent component, a hydrophobic drug or solvent can be used, so that a wide range of drug administration is possible. The amphipathic polymer compound is a polymer compound having both a hydrophilic site and a hydrophobic site, and is characterized by being soluble in many organic solvents as well as water. As such an amphipathic polymer compound, N,
N-dimethylacrylamide, N-isopropylacrylamide, N, N-diethylacrylamide, N, N-
Homopolymers or copolymers of alkylacrylamides such as dimethylaminopropylacrylamide and acryloylmorpholine, copolymers of vinyl methyl ether and maleic anhydride derivatives, random and graft of hydrophilic and hydrophobic monomers, Block copolymer,
For example, as the hydrophilic monomer, N-vinylpyrrolidone,
(Meth) acrylic acid, N, N-dimethylaminoethyl acrylate, styrene sulfonic acid, copolymers such as (meth) acrylic acid esters as hydrophobic monomers,
Examples thereof include block copolymers of polyethylene glycol and polypropylene glycol. Moreover, the thickness of the gelled layer is 1 μm when dried in order to maintain the strength.
m or more is preferable.

The polymer compounds constituting these gels are
A structure that can be efficiently administered to the affected area can be selected in consideration of the affinity with each drug and the adsorptivity.

The drug used in the present invention is not particularly limited as long as it can be used for treating or preventing a lesion.
For example, thrombolytic agents such as urokinase, pro-urokinase, streptokinase, plasminogen activator, heparin, warfarin, aspirin, etc. are often used in the aforementioned vascular stenosis, but suppress the proliferation of smooth muscle cells. It is also possible to administer a drug or a vector for gene therapy. In addition, an anticancer drug is administered to malignant tumors.

The material of the catheter tube or balloon is not particularly limited. For example, olefin polymers include polyethylene, polypropylene, polybutene, polybutadiene and copolymers thereof, halides and ionomers, and condensation polymers include copolymers of various polyesters, polyamides and polyethers thereof. , Polyurethane, etc. can be exemplified. The catheter tube or balloon may include a coil made of a superelastic alloy or a coil made of metal or a mesh.

The shape of the catheter tube is also not particularly limited, but it can be used in combination with a guide wire that can smoothly advance the catheter tube to the lesion site, that a channel for storing or delivering the drug is secured, and the drug is administered. It is preferable that a pressurized liquid or a pressurized gas can be obtained and that the insertion site of the catheter tube can be confirmed (an impermeable platinum marker is used in an X-ray transmission image or the like).

The inner tube 2 which constitutes the catheter tube
Has an outer diameter of 0.30 to 2.50 mm, preferably 0.40
~ 2.40 mm, inner diameter 0.20 to 2.35 m
m, preferably 0.25 to 1.80 mm. Outer tube 3
Has an outer diameter of 0.50 to 4.30 mm, preferably 0.60
~ 4.00mm, inner diameter 0.40 ~ 3.80m
m, preferably 0.50 to 3.00 mm. The outer diameter of the balloon when expanded is 1.00-3
5.00 mm, preferably 1.50-30.00 mm, length 3.00-80.00 mm, preferably 1
0.00 to 75.00 mm, and the total length of the balloon 4 is 5.00 to 120.00 mm, preferably 15.
It is 00 to 100.00 mm.

Further, the filler 6 for the catheter tube is
A material having adhesiveness to the inner pipe 2 and the outer pipe 3 is preferably used. For example, when the inner pipe 2 and the outer pipe 3 are made of a polyolefin material, PE (polyethylene) or EVA is used.
(Ethylene vinyl acetate) is preferably used,
The length of the filler 6 is 1 to 10 mm, preferably 2 to
8 mm, and as shown in FIG. 2, 1/3 or more of the entire circumference,
It is preferable to have a thick portion of ½ or more.

The shape of the pores provided in the balloon of the present invention is not particularly limited, but a circle, an ellipse, a triangle, a quadrangle, a pentagon, a hexagon, a star shape, a slit shape and the like are suitable. The size of the pores required at the time of injecting the drug cannot be particularly limited because it depends on the purpose of use, the site to be administered, the concentration of the drug, the viscosity, etc., but is preferably 0.1.
It is about 1000 μm.

The method of forming pores in the balloon or the catheter tube is not particularly limited, such as laser processing method, accelerated particle processing method, electric discharge processing method, stretching method, phase separation method, and wet resolidification method. For example, by using an excimer laser, it is possible to freely form pores whose pore size is controlled at desired positions.

The method for providing the gelling layer on the surface of the balloon or catheter tube is a grafting method, a crosslink insolubilizing method,
It can be appropriately selected depending on the type of material such as a coating method and a surface polymerization method. For example, in the graft method,
There are a method of forming a polymerization initiation point on the material surface and then graft-polymerizing a monomer to form a gel layer, and a method of previously synthesizing a polymer and then binding it to the material surface. Further, as a method of bonding to the material surface with a crosslinking reaction between the polymers, there are a method of simultaneously performing polymerization and crosslinking on the material surface, a method of crosslinking the synthesized polymer, and the like. The degree of crosslinking and the strength of the gel are set according to the purpose by the molecular weight and electric charge of the drug to be administered.

[0026]

EXAMPLES The present invention will be described more specifically below with reference to examples. (Example 1) A balloon made of polyethylene terephthalate (PET) was molded. Balloon wall thickness is 12-16μ
The outer diameter of the balloon when an internal pressure of 4 m is applied is 2.
It was 5 mm. An excimer laser device (Lumonics manufactured by Sumitomo Heavy Industries, Ltd.) was used to open 100 square holes each having a side of 52 μm.

Radicals were generated in the region of the PET balloon where pores were formed by glow discharge treatment, and then graft polymerization was carried out in methacrylic acid (MAA) gas at 24 ° C. for 5 minutes. Then, a partial ring-opened product of a vinyl methyl ether-maleic anhydride copolymer containing 1% pyridine and a polyepoxy compound (Denacol E, Nagase & Co., Ltd.)
2% tetrahydrofuran solution of X313) (9: 1)
Was coated on a balloon and dried at 60 ° C. for 16 hours. This coating was repeated once more to obtain a balloon having a surface gelling layer. Using this balloon, a dilatation catheter as shown in FIG. 1 used for percutaneous coronary angioplasty (PTCA) was prepared.

Subsequently, from the second lumen 7 between the inner tube 2 and the outer tube 3 of the dilatation catheter 1 for injecting the normal contrast agent,
When a citrate buffer solution containing low molecular weight heparin adjusted to pH 8.0 is put and an internal pressure of 5 atm is applied, the balloon 4 swells and the surface hydrogels, and then the drug solution is discharged from the pores 12 of the balloon. It began to slowly exude. It was confirmed by observation with a microscope that the drug solution did not spout.
Sustained release of heparin is achieved by using a cellulose acetate membrane (pore size 0.22μ
m) was pressed against the surface of the balloon to absorb the liquid, dried, and then detected by staining with toluidine blue.

Example 2 On the surface of a polyethylene balloon (outer diameter φ2.5 mm), ethylene-acrylic acid ester-maleic anhydride terpolymer Bondine TX-8 was used.
A 0.5% toluene solution of 030 (Sumitomo Chemical Co., Ltd.) was coated and dried, and then an excimer laser device (Lumonics manufactured by Sumitomo Heavy Industries, Ltd.) was used to measure 120 per side.
80 μm square holes were opened. Then 3% of a block copolymer of glycidyl methacrylate and dimethyl acrylamide containing 1% pyridine (4.2: 1).
A gelled layer was obtained on the balloon surface by coating with a chloroform solution and drying. Subsequently, using this balloon, a dilatation catheter as shown in FIG. 1 used for percutaneous coronary angioplasty (PTCA) was produced. When physiological saline in which a drug (aspirin) is dissolved is put inside the balloon of the dilatation catheter 1 and an internal pressure of 6 atm is applied, the balloon 4 swells, and the drug solution becomes a pore of the balloon from the hydrogelized surface. It began to bleed out more slowly than 12. It was confirmed by observation with a microscope that the drug solution did not spout.

(Example 3) The balloon portion of the dilatation catheter prepared in Example 2 was dipped in a drug (low molecular weight heparin) solution to load the drug on the gel portion on the outer surface. Then, when a contrast medium solution was put inside the balloon and an internal pressure of 6 atm was applied, it was confirmed that the low molecular weight heparin slowly exudes in the same manner as in Example 1.

(Comparative Examples 1 and 2) The balloons having no surface gelation layer used as the substrate in Examples 1 and 2 were treated with a drug (low molecular weight heparin) solution when an internal pressure of 6 atm was applied to the inside of the balloon. It was confirmed using a microscope that the particles were ejected from the pores.

[0032]

INDUSTRIAL APPLICABILITY In the drug administration catheter of the present invention, since the drug is gradually released through the gelled layer, the vascular endothelium and the tissues are not damaged by the flow of the drug solution released from the pores. Further, the local administration of the drug can be evenly applied to the affected area, and the catheter is extremely effective for the treatment and prevention of the vascular stenosis.

[Brief description of drawings]

FIG. 1 is an enlarged cross-sectional view of a distal end portion of an embodiment of a drug delivery catheter of the present invention.

FIG. 2 is a sectional view taken along line AA in FIG.

[Explanation of symbols]

 DESCRIPTION OF SYMBOLS 1 catheter 2 inner tube of catheter tube 3 outer tube of catheter tube 4 balloon 5 first lumen 6 filler 6a filler defect 7 second lumen 8 balloon tip 9 balloon rear end 10 balloon expansion space 11 Coil spring 12 pore

Claims (3)

[Claims] 1. A catheter tube or balloon having pores, wherein the outer surface side (living body side) of the catheter tube or balloon having pores is covered with a gelling layer. . 2. The drug administration catheter according to claim 1, wherein the gelled layer is an amphipathic polymer compound. 3. The drug administration catheter according to claim 1, wherein the amphipathic polymer compound is an acrylamide compound.