JP2001190687A - Stent and stent graft - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a stent and a stent graft which can synergistically utilize the effects of an antiplatelet agent and an antithrombin agent. SOLUTION: The stent is obtained by coating the outer peripheral surface and/or inner peripheral surface of a base material with a polymer containing the antiplatelet agent and antithrombin agent. The stent graft is obtained by putting a tubular body having one or two or more polymer layers containing the antiplatelet agent and/or antithrombin agent on the outer peripheral surface of a base material.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an improvement of a stent and a stent graft used for improvement of a stenosis formed in a living body such as a blood vessel, and more particularly, to an improvement of a stent and a thrombus which are covered with a polymer material containing a biologically active substance. The present invention relates to a stent and a stent-graft that provide a sexual surface and prevent restenosis.

[0002]

2. Description of the Related Art Most stents are made of metal such as stainless steel or Ti-Ni based shape memory metal, and are liable to form thrombus or blood clot, and the stent surface is covered with endothelial cells. About 2 days after surgery
During the week, it is necessary to administer an anticoagulant such as heparin for supplementary therapeutic purposes. For this reason, depending on the state of the patient, there is a risk that side effects may cause complications such as bleeding. Here, if it is possible to reduce the dose and the administration period of the anticoagulant, it is possible not only to reduce the complications but also to shorten the hospitalization period.

Attempts have also been made to supply drugs such as anticoagulants to stents. Examples of the use of anticoagulants and antiplatelet agents alone or in combination are disclosed in JP-A-8-224297 and JP-A-8-33.
718. However, an invention specifically utilizing the synergistic effect of the properties of each drug has not been disclosed yet. The inventor of the present invention has made intensive studies in order to solve the above-mentioned problems, and has arrived at the following invention.

[0004]

Means for Solving the Problems [1] The present invention is a stent in which a polymer containing an antiplatelet agent and an antithrombin agent is coated on the outer peripheral surface and / or the inner peripheral surface of a substrate. [2] The present invention is a stent having a first coating layer and a second coating layer containing an antiplatelet agent and / or an antithrombin agent formed on the outer peripheral surface of a substrate. [3] The present invention is a stent graft in which a single-layered or two- or more-layered tubular body made of a polymer containing an antiplatelet agent and / or an antithrombin agent is fitted on the outer peripheral surface of a substrate. [4] The present invention is the stent according to any one of [1] to [3], wherein the antiplatelet agent is cilostazol. [5] The present invention is the stent according to any one of [1] to [3], wherein the antithrombin agent is argatroban. [6] In the present invention, the polymer is a thermoplastic polyurethane;
The stent according to any one of [1] to [3], wherein the stent includes polyamide, polyester, polyethylene, polypropylene, and a mixture, blend, or copolymer of two or more of these polymers. In the present invention, “argatroban” means (2R, 4R) -4-methyl-1- [N ² -((RS)
-3-methyl-1,2,3,4-tetrahydro-8-quinolinsulfonyl) -L-arginyl] -2-piperidinecarboxylic acid monohydrate. In the present invention, "argatroban" is the argatroban described above. (2R, 4R) -4-methyl-1- [N ^2-
((RS) -3-methyl-1,2,3,4-tetrahydro-8-quinolinsulfonyl) -L-arginyl] -2
-Means also piperidinecarboxylic acid. Argatroban is classified as an antithrombin agent among anticoagulants, and has an effect of suppressing the initiation and progress of a blood coagulation reaction.
"Cilostazol" is 6- [4- (1-cyclohexyltetrazol-5-yl) butoxy] -3,4-dihydrocarbostyril. Cilostazol is an antiplatelet agent and has an effect of inhibiting platelet adhesion and aggregate formation.

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION A stent and a stent graft according to the present invention comprise a base material and a coating layer coated on the base material or a tubular body fitted on the outer periphery of the base material. The base material is, for example, SU
A pipe made of a material such as stainless steel such as S316 or Ni-Ti alloy, a substantially tubular body having a predetermined pattern formed on the surface thereof by laser processing a flat plate, or a substantially tubular body having a mesh shape formed by wires are used. However, the shape of the substantially tubular body is not particularly limited as long as desired physical properties can be obtained.

FIG. 1 is a schematic view showing an example of a stent according to the present invention. A stent 10 is made of a stainless steel base material 11.
, The outer surface of which is covered with a polymer layer 12 containing an antiplatelet agent and an antithrombin agent. FIG. 2 is a cross-sectional view of FIG. 1. The polymer layer 12 contains an antiplatelet agent 13 and an antithrombin agent 14 dispersed therein. As a coating method, an antiplatelet agent or an antithrombin agent and a polymer are dissolved and mixed in different solvents, and coating by spraying or coating by dipping is possible. The number of times of spraying and dipping may be one, but a method of dividing into plural times to adjust the thickness of the coating layer depending on the concentration of the polymer or the like is usually used.

The polymers used in the present invention include thermoplastic polyurethanes, polyamides, polyesters, polyethylenes, polypropylenes, and mixtures, blends and copolymers of two or more of these polymers.
The polymer is not limited to these, and any polymer having excellent biocompatibility can be used.

FIG. 3 shows a coating layer (inner layer 2) of a polymer containing an antiplatelet agent and an antithrombin agent on the inner and outer peripheral surfaces of a substrate 21.
2 and an example of a stent 20 provided with an outer layer 23). In order to coat the inner layer 22 and the outer layer 23 on both the inner and outer surfaces of the substrate 21, coating by dipping is effective.

In the stent 30 shown in FIG. 4, a polymer layer (first coating layer) 32 containing an antithrombin agent or an antiplatelet agent is coated on the outer peripheral surface of a substrate 31, and the outer peripheral surface thereof is further coated with an antiplatelet agent or an antithrombin agent. This is an example in which a polymer layer (second coating layer) 33 containing is coated. In this embodiment, the outer peripheral surface of the base material 31 is sprayed with a mixed solution of an antithrombin agent or an antiplatelet agent and a polymer to coat the polymer layer 32, and after drying, the antiplatelet agent or the antithrombin agent is mixed with the polymer. The outer periphery of the polymer layer 32 is coated with the polymer layer 33 by spraying the mixed solution. As the polymer used, thermoplastic polyurethane was used for both the polymer layer 32 and the polymer layer 33, and the same polymer was used. However, the polymer used for the polymer layer 32 and the polymer layer 33 was not limited as long as an adhesive force was obtained. Different types of combinations are also possible.

FIG. 5 shows an example of the stent graft 40 of the present invention. A tubular body 42 made of a polymer containing an antiplatelet agent and an antithrombin agent is fitted on the outer peripheral surface of the base material 41. The tubular body 42 can expand and contract from the size of the stent graft 40 when it is reduced to when it is expanded. The tubular member 42 may be a single layer or a multilayer of two or more layers.
In the case of a single layer, the tubular body 42 is formed of a polymer containing an antiplatelet agent and an antithrombin agent, whereas in the case of a multilayer, the tubular body 42 is formed of an inner layer of a polymer containing only an antiplatelet agent or an antithrombin agent, The outer layer may be formed of a polymer containing only an antithrombin agent or an antiplatelet agent.

[0011]

EXAMPLES Example 1 10% by weight solution of Tecoflex 100A (thermoplastic polyurethane) (solvent THF)
Was mixed with cilostazol and methanol in which argatroban was dissolved at 5% by weight, respectively, and sprayed on the outer peripheral surface of a SUS316 stent base material 11 by spraying, and drying was repeated five times to form a polymer layer 12 having a thickness of 70 μm. (Example 2) A mixed solution of a 7% by weight THF solution of bionate 80A (polycarbonate type thermoplastic polyurethane) and a 10% by weight methanol solution of argatroban is sprayed on the outer peripheral surface of a SUS316 stent base material 31 and dried. Is repeated five times to form a polymer layer 32, and then a 7% by weight THF solution of bionate 80A and 1% of cilostazol are applied to the outer peripheral surface of the polymer layer 32
A mixed solution of a 0 wt% methanol solution was sprayed on and sprayed, and drying was repeated five times to form a polymer layer 33 having a thickness of 70 μm. Example 3 Tecoflex 100A was compounded with cilostazol and argatroban in an amount of 5% by weight, respectively, and a total of 10% by weight at 190 ° C. using a small mixer, and then 1.45 mm × 1 with a 15 mm extruder. .50
mm of a tubular body 42 having a size of
, And fitted to a stent base material 41 to produce a stent graft 40. (Example 4) A compound in which cilostazol was mixed with Tecoflex 100A in an amount of 15% by weight and a compound in which Tecoflex 100A was mixed with Argatroban at 15% by weight were used with two 12 mm / 15 mm extruders. The thickness of each layer is 25 μm and 1.45 mm
× 1.50 mm two-layer tube is formed,
((Inner layer) Tecoflex 100A / Cilostazol 1
0% by weight, (outer layer) Tecoflex 100A / Argatroban 10% by weight), and
To produce a stent graft 40.

The prepared stent (Example 1) and the stent graft (Example 4) were immersed in a phosphate buffer at pH 37 ° C. and pH 7.4 and shaken 50 times over time, and then the amounts of cilostazol and argatroban eluted And the elution rate were measured. The results are shown in Table 1 (Example 1) and Table 2 (Example 4), respectively. In Example 1, there was almost no difference in the dissolution between cilostazol and argatroban.
In Example 4, the dissolution of cilostazol and argatroban has a time difference between a short period (three days from immediately after) and a long period (two weeks from immediately after), depending on the type of the coating layer, the composition, the manufacturing method, and the amount of the drug. It was confirmed that the sustained release of the drug could be adjusted.

[0013]

[Table 1]

[0014]

[Table 2]

[0015]

According to the stent and the stent graft of the present invention, the effects of the antiplatelet agent and the antithrombin agent can be used synergistically. That is, platelet adhesion is inhibited by the antiplatelet agent, and initiation and progress of the blood coagulation reaction can be suppressed by the antithrombin agent. In addition, by adjusting the thickness of the polymer layer coated or covered on the base material and the compounding amounts of the antiplatelet agent and the antithrombin agent, a long period of up to two weeks from immediate drug release immediately after stent placement to endothelial cell regeneration can be achieved. It is possible to control the drug to be released into the blood over a long period of time. In addition, the occurrence of side effects due to intravenous injection of an anticoagulant can be reduced, and a treatment with less burden on the patient can be realized. Furthermore, cilostazol used as an antiplatelet agent also has a smooth muscle cell proliferation inhibitory effect and an endothelial regeneration promoting effect, so that the risk of restenosis due to stent placement can be further reduced.

[Brief description of the drawings]

FIG. 1 is a schematic view of a stent of the present invention.

FIG. 2 is a cross-sectional view of the stent of FIG.

FIG. 3 is a schematic view of a stent of the present invention.

FIG. 4 is a schematic view of a stent of the present invention.

FIG. 5 is a schematic view of a stent graft of the present invention.

[Explanation of symbols]

 DESCRIPTION OF SYMBOLS 10, 20, 30 Stent 11, 21, 31 Base material 12 Polymer layer 13 Antiplatelet agent 14 Antithrombin agent 22 Inner layer 23 Outer layer 32 Polymer layer containing antithrombin agent (first coating layer) 33 Polymer layer containing antiplatelet agent (Second coating layer) 40 Stent graft 41 Base material 42 Tubular body

Claims (6)

[Claims] 1. A stent wherein a polymer containing an antiplatelet agent and an antithrombin agent is coated on the outer peripheral surface and / or the inner peripheral surface of a substrate. 2. A stent wherein a first coating layer and a second coating layer containing an antiplatelet agent and / or an antithrombin agent are formed on the outer peripheral surface of a substrate. 3. A stent graft comprising a single-layer or two-layer or more tubular body made of a polymer containing an antiplatelet agent and / or an antithrombin agent, fitted on the outer peripheral surface of a substrate. 4. The stent according to claim 1, wherein the antiplatelet agent is cilostazol. 5. The stent according to claim 1, wherein the antithrombin agent is argatroban. 6. The polymer according to claim 1, wherein said polymer is a thermoplastic polyurethane, polyamide, polyester, polyethylene, polypropylene, a mixture of two or more of these polymers, a blend,
The stent according to any one of claims 1 to 3, wherein the stent comprises a copolymer.