JP3476604B2 - Method for manufacturing stent with drug attached / coated - Google Patents

Description

Detailed Description of the Invention

[0001]

The present invention relates to medicine agents, more particularly to a method for a drug capable of suppressing intimal hyperplasia adhering and coating the stent.

[0002]

2. Description of the Related Art In recent years, ischemic heart diseases (angina pectoris, myocardial infarction) are rapidly increasing in Japan as well as westernization of lifestyle habits. Ischemic heart disease is mainly caused by arteriosclerosis of a large coronary artery running on the surface of the heart, and is accompanied by coronary thrombosis and coronary spasm. Today, coronary angioplasty (perc
utaneous transuluminal coronary angioplasty, hereinafter abbreviated as PTCA. However, restenosis occurs in about 30 to 40% of the cases in which PTCA succeeded in opening the coronary stenotic lesion. This restenosis is re-PT
Since CA is required, establishment of preventive method and therapeutic method thereof is an urgent global task.

In order to solve this problem, an intravascular stent has been recently developed. "Stent" here
Includes any device that is inserted into a blood vessel and held in the desired location. BACKGROUND ART A stent is a device made of metal or polymer, and various forms such as a metal crown-shaped one, a metal or polymer thread braided into a tubular shape, and the like are known. A stent is implanted in a peripheral or coronary artery in a bulged form. The purpose of the stent is to prevent stenosis of blood vessels, but in the clinical results so far, the stenosis cannot be significantly suppressed by the stent alone.

[0004] To date, in order to prevent restenosis after PTCA, various trials of various drugs have been conducted all over the world. For example, antiplatelet drugs (aspirin, dipyrimidamol, heparin, antithrombin preparations, fish oil, etc.), growth inhibitors (low molecular weight heparin, angiotensin converting enzyme inhibitors, etc.), inflammatory changes from the viewpoint of vascular smooth muscle proliferation From an important point of view, anti-inflammatory drugs (steroids, etc.),
From the standpoint of emphasizing the role of calcium ions, calcium antagonists have been tried, and from the standpoint of emphasizing the role of lipids, lipid improving agents (lovastatin, fish oil, etc.) have been tried to be used.
Currently, many of these clinical trials do not give satisfactory results regarding treatment. The reason why these drugs do not exert sufficient therapeutic effect is not clear, but when a sufficient amount of the drug cannot be administered due to side effects, or the concentration of the drug at the vascular local level cannot exert sufficient effect. It is estimated that there are cases. In view of such circumstances, if the drug can be delivered locally where restenosis of the blood vessel occurs, it is expected that the effectiveness of the drug will be improved and the toxicity will be reduced. Based on such an idea, Wolfrodney et al. Of the US have proposed a device for delivering a required amount of a drug to a vascular site in need of treatment by attaching or coating the drug on a stent. Adhesion of drugs to stents, as suggested by them,
As a method of coating, a method of linking a drug to a functional group of a polymer substance, a method of impregnating, adhering or coating a drug with a biodegradable or biocompatible polymer substance, and the like are disclosed. (Special table 5-
No. 502179).

[0005]

DISCLOSURE OF THE INVENTION The present inventors have been continuing research on the mechanism of arterial intimal thickening and its preventive / therapeutic methods, and the 3-phenylthiomethylstyrene derivative has already been used for the intimal thickening of arteries. It has prophylactic and therapeutic effects, and has been found to be useful in the prevention and treatment of coronary atherosclerosis, especially coronary restenosis after PTCA (The 59th Japanese Circulation Society,
Lecture number 250). Furthermore, in order to establish a method for delivering this drug to the vascular local area, a method for adhering or coating this drug on a stent was examined. As a result, in the known method, the amount of the drug that could be adhered or coated on the stent was extremely small. It was revealed that the drug adhered to and / or coated on the stent was easily detached from the stent and peeled off, so that it was extremely difficult to handle the drug-impregnated, adhered or coated stent. Further, in the known method, the attached or coated drug is rapidly eluted in body fluids such as serum,
It has proved difficult to elute continuously for a long time.

Therefore, an object of the present invention is to firmly attach a drug having a preventive or therapeutic effect on intimal thickening of an artery and to release the drug slowly in a body fluid. It is to provide a method for producing a stearate <br/> down bets coated with a biodegradable polymer.

[0007]

[Means for Solving the Problems] As a result of intensive studies to overcome these problems, the present inventors have found that
In particular, drugs that can suppress the intimal thickening of arteries, more specifically 3-
By reinforcing the adherence of the phenylthiomethylstyrene derivative and its salt-forming salts to the stent by using a biocompatible polymer or biodegradable polymer, the drug holding power of the stent can be improved and the amount of drug adhering can be significantly improved. The present invention has been completed by discovering that the release rate of the drug can be increased and that the release of the drug can be sustained release, and further studies have been carried out.

That is, the gist of the present invention is (1) a biocompatible polymer and / or a biodegradable polymer.
A solution obtained by dissolving or suspending a drug in a solution of limer
Apply the stent and dry it
Repeat the operation of dipping and drying at least once.
Or at least once more
After applying the drug solution to the stent and drying or
After dipping and drying the stent in the solution of
Immersion of polymer and / or biodegradable polymer in solution
To the stent by drying at least once
Drug attachment and biocompatible polymer and / or
Characterized by coating with biodegradable polymer
Manufacture of drug-coated / coated stents
Method, (2) The drug is of the general formula (I)

[0009]

[Chemical formula 3]

[Wherein x is a hydrogen atom, -OR ⁵ (provided that
R ⁵ represents a C ₁ -C ₃ alkyl group. ), An alkoxy group represented by), a C _{1 to} C ₅ alkyl group, a nitro group, an amino group, a hydroxyl group, a halogen atom, or —COOR ⁶ (provided that R ⁶ represents a C _{1 to} C ₃ alkyl group). Represents an alkoxycarbonyl group represented by, R ¹ is a hydrogen atom, C
_{1 to} C ₃ alkyl group, or an acyl group represented by R ⁷ CO— (provided that R ⁷ phenyl group or C _{1 to} C ₃ alkyl group is shown), and R ² is a hydrogen atom, or C _{1 to} C
₅ represents an alkyl group, and R ³ represents —COOR ⁸ (provided that R 3
⁸ represents a hydrogen atom or a C ₁ -C ₄ alkyl group. )
Or a amide, R ⁴ represents a cyano group, or an alkylsulfonyl group represented by R ⁹ SO ₂ — (wherein R ⁹ represents a C _{1 to} C ₄ alkyl group).
Alternatively, R ³ and R ⁴ are bonded to each other to -CO-Y-CH (R
¹⁰⁾ -CH ₂ - or _-CO-Y-CH 2 -CH
(R ¹⁰ )-(wherein R ¹⁰ is a hydrogen atom, or C ₁ -C
_{4 represents} an alkyl group, and Y represents an oxygen atom or an NH group. ), Or _{-CO-N (C 6 H 5} ) represents -NH-CO-, n when x is a halogen atom, represents an integer of 1 to 5, it represents 1 when x is other group, m represents an integer of 0 to 3. 3-phenylthiomethyl styrene derivative represented by], or a manufacturing method of (1) Symbol mounting a salt of the salt formation can ones, (3) the drug is the general formula (II)

[0011]

[Chemical formula 4]

(Wherein x, R ² , n and m have the same meanings as x, R ² , n and m in the general formula (I)) and α-cyano-4-hydroxycinnamic acid. acid amide derivatives, or a manufacturing method of (1) Symbol mounting a salt of the salt formation can ones,

( 4 ) The production method according to ( 1 ) above, wherein the drug is α-cyano-3-ethoxy-4-hydroxy-5-phenylthiomethylcinnamic acid amide, ( 5 ) the biocompatible polymer is polyurethane , polyacrylamide, polyethylene oxide, polyethylene carbonate, a method for manufacturing according to polypropylene car Bo sulfonate, and 1 or higher is said to be selected from the group consisting of fibrin (1) to (3) either, and (6) biodegradation Polymers are polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, collagen, gelatin, chitin, chitosan, hyaluronic acid,
One or more selected from the group consisting of poly-L-glutamic acid, starch, poly-ε-caprolactone, polyethylene succinate, poly-β-hydroxyalkanoate, polyamino acid, and epoxide copolymer ( 1 )
To ( 3 ) The production method according to any one of the items.

[0014]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention is described in detail below.
As the drug capable of suppressing the intimal thickening of the artery used in the present invention, any drug can be applied as long as it is a drug capable of substantially suppressing the intimal thickening in human, and it may be used alone or in combination. The above agents can also be used in appropriate combination. Examples of agents capable of suppressing the intimal thickening of the arteries include, for example, antiplatelet drugs (aspirin, dipyrimidamol, heparin, antithrombin preparations, which have already been reported to suppress the intimal thickening in humans and / or experimental animals).
Fish oil, etc., vascular smooth muscle growth inhibitor (low molecular weight heparin,
Angiotensin converting enzyme inhibitors, etc.), anti-inflammatory drugs (steroids, etc.), calcium channel blockers (nifedipine, etc.),
Lipid improving agents (lovastatin, simvastatin, fish oil, etc.), antiallergic agents (tranilast, etc.), and DNA synthesis inhibitors (mitomycin C) that have been shown to suppress vascular smooth muscle proliferation or chemotaxis in vitro. ,
Adriamycin, etc.), tyrosine kinase inhibitors (genistein, tyrphostin, arbstatin, etc.),
Furthermore, a 3-phenylthiomethylstyrene derivative represented by the general formula (I) or a salt of a salt-forming compound thereof, preferably an α-cyano-4-hydroxycinnamic acid amide derivative represented by the general formula (II), Or a salt of a salt-forming compound thereof, more preferably α-cyano-3-ethoxy-4
-Hydroxy-5-phenylthiomethylcinnamic acid amide (hereinafter abbreviated as ST638) and the like.

The above-mentioned antiplatelet drugs (aspirin, dipyrimidamol, heparin, antithrombin preparations, fish oil, etc.),
Vascular smooth muscle growth inhibitors (low molecular weight heparin, angiotensin converting enzyme inhibitors, etc.), anti-inflammatory drugs (steroids, etc.), calcium antagonists (nifedipine, etc.), lipid improvers (lovastatin, simvastatin, fish oil, etc.), antiallergic agents (Tranilast etc.), DNA synthesis inhibitor (mitomycin C, adriamycin etc.), tyrosine kinase inhibitor (genistein, tyrphostin etc.) are available as commercial drugs or reagents. In addition, the derivatives represented by the general formulas (I) and (II) and ST
The manufacturing method of 638 is described in JP-A-62-111962.
JP-A-62-29570, JP-A-62-
No. 39564, and Chem. Pharm. Bull. 36 , 974-981, 1988.

The stent used in the present invention, whether it is made of metal or made of a polymer, may be any device as long as it is a device for assisting the opening of a blood vessel by being left in the blood vessel, and its form is a coronal shape. Various shapes such as those formed by knitting threads into a tubular shape are used. Typical examples of such stents are Palmaz-Schatz stents, Strecker
Examples thereof include stents and Wallstents.

The biocompatible polymer used in the present invention is essentially any biocompatible polymer as long as it is difficult for platelets to adhere to it, does not exhibit irritation to tissues, and can elute drugs. Although it can be used as a polymer, for example, as the synthetic polymer, a blend or block copolymer of polyether type polyurethane and dimethyl silicone, polyurethane such as segmented polyurethane, polyacrylamide, polyethylene oxide, polyethylene carbonate, polycarbonate such as polypropylene carbonate, etc. However, fibrin, gelatin, collagen and the like can be used as the natural biocompatible polymer. These polymers may be used alone or in appropriate combination.

The biodegradable polymer used in the present invention can be any biodegradable polymer as long as it is enzymatically or non-enzymatically degraded in vivo, the degradation product does not show toxicity, and the drug can be released. Degradable polymers are also available. For example, polylactic acid, polyglycolic acid, a copolymer of polylactic acid and polyglycolic acid, collagen, gelatin, chitin, chitosan, hyaluronic acid, poly-L-glutamic acid, poly-L.
A polyamino acid such as lysine, starch, poly-ε-caprolactone, polyethylene succinate, poly-β-hydroxyalkanoate, and the like can be appropriately selected. These polymers may be used alone or in appropriate combination.

In the present invention, the drug can be attached to the stent by adding the drug in a solution state to the stent and then removing the solvent. Biocompatible and biodegradable polymers can be liquid or suitable solvents such as
It is possible to coat the stent with the drug by contacting the stent with water, a buffer solution, an acid solution such as acetic acid or hydrochloric acid, a solution of methanol, ethanol, acetone, acetonitrile, methylene chloride, etc., and then removing the solvent. it can. Specifically, biocompatible polymers and /
Alternatively, an operation of coating and drying a stent with a liquid obtained by dissolving or suspending a drug in a solution prepared by dissolving a biodegradable polymer in a low boiling point solvent, or an operation of immersing and drying the stent in the liquid is performed at least once. Prepared by repeating the above or at least once more times after applying and drying the drug solution on the stent or after dipping and drying the stent in the drug solution, and then dissolving it in a low boiling point solvent in which the drug is difficult to dissolve Biocompatible polymer and /
Alternatively, by immersing the biodegradable polymer in a solution and drying it at least once, the drug can be attached to the stent and coated with the biocompatible polymer and / or the biodegradable polymer.

The active ingredient of the agent for preventing thickening of the intimal artery used in the present invention is a dose that is not toxic to patients (animals and humans) in need of treatment and adversely affects the original function of the stent. If there is no amount, an arbitrary amount can be attached and coated on the stent, but it is preferable that the amount is 0.1 to 100 mg per stent, more preferably 0.1 to 10 mg per stent. . In addition, the biodegradable polymer used in the present invention is a dose that is not toxic to patients (animals and humans) in need of treatment, and substantially prevents the adhesion of the preventive agent for intimal thickening to the stent. Amounts that can be enhanced can be used, but it is desirable to use in the range of 0.1 to 100 mg per stent, preferably 0.1 to 10 mg per stent.

The active ingredients of the agent for preventing arterial intimal thickening used in the present invention can be used alone or in appropriate combination. In addition, the agent for preventing intimal arterial thickening may be adhered / coated on the stent alone, or may be adhered / coated with an auxiliary agent such as a stabilizer for the agent for preventing intimal arterial thickening and a preservative.

[0022]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

Example 1 α-Cyano-3-ethoxy-4-hydroxy-5-phen
Nylthiomethylcinnamic acid amide (ST638) attached
Preparation of coated stents 10 μl of an acetone solution (20 mg / ml) of α-cyano-3-ethoxy-4-hydroxy-5-phenylthiomethylcinnamic acid amide (ST638) was added to a stainless steel stent (Palmatz-Schatz stent, Johnson & USA).
It was placed on the surface (manufactured by Johnson Co.) and quickly dried with hot air, which was repeated 10 times. By this operation, ST638 was deposited and adhered on the stent. Then, after immersing the polylactic acid / polyglycolic acid (1/1) copolymer LGA5005 (average molecular weight 5000, manufactured by Wako Pure Chemical Industries, Ltd.) in a methylene chloride solution (40 mg / ml), quickly take out, air-dry and then dry under reduced pressure. Thus, a stent coated with ST638 was obtained.

The stent thus obtained was immersed in 1 ml of dimethylsulfoxide and stirred, whereby ST638 and LGA500 coated on the stent were coated.
5 was solubilized, and the amount of ST638 in the solution was quantified using high performance liquid chromatography (column: Cosmosil 5).
C18-AR, mobile phase solvent: 60% (v / v) acetonitrile aqueous solution, flow rate: 1 ml / ml, detection: 253n
m). As a result, the amount of ST638 attached / coated on the stent was 1.5 mg. In addition, after drying the substance that is attached to or coated on the stent, the total weight is
Weight less 638 (LGA500 attached
(Corresponding to 5 amounts) was 0.9 mg. LG as a control
A stent without the A5005 treatment was similarly prepared.

Example 2 ST638 was deposited and coated using polylactic acid.
Preparation of Stent In the same manner as in Example 1, after attaching ST638 to a Palmatz-Schatz stent, polylactic acid LA-0005 (average molecular weight of 5000, in place of LGA5005,
Wako Pure Chemical Industries, Ltd.), polylactic acid LA-0015 (average molecular weight 15,000, manufactured by Wako Pure Chemical Industries), or polylactic acid L
A stent coated with ST638 was obtained by treatment with A-0020 (average molecular weight 20000, manufactured by Wako Pure Chemical Industries, Ltd.). The amount of ST638 deposited obtained in the same manner as in Example 1 was 1.
It was 4 mg, 1.3 mg, and 1.4 mg.

Example 3 Adhesion and coating of ST638 using polyglycolic acid
Preparation of Stented As in Example 1, after attaching ST638 to the Palmatz-Schatz stent, polyglycolic acid (polyglycolide, dissolved in hexafluoropropanol)
Sigma, average molecular weight 100,000 to 125,000
Attach ST638 by coating 0)
A coated stent was obtained. The amount of ST638 deposited obtained in the same manner as in Example 1 was 1.0 per stent.
It was mg.

Example 4 In an ST638 acetone solution prepared in the same manner as in Example 1,
Palmats-Schatz Stent, Strecker
er) Stent and Wallstent 5
The dipping and drying process was repeated. The amount of ST638 deposited on each stent was 2.5 mg, 2.0 mg, and 1.8, respectively.
It was mg. Then, the same LGA500 as in Example 1
The objective ST638-attached and coated stent was obtained by repeating dipping and drying twice in a methylene chloride solution.

Example 5 In Example 1, instead of ST638, 4- (3-
Ethoxy-4-hydroxy-5-phenylthiomethylbenzylidene) -1-phenylpyrazolidine-3,5-dione, 3- (3-ethoxy-4-hydroxy-5-phenylthiomethylbenzylidene) -2-pyrrolidine Using these agents, these agents were impregnated and adhered in the same manner as in Example 1, and then LGA5005 was coated to obtain Palmat-Schatz stents on which these agents were adhered and coated. 4- (3 to each stent
-Ethoxy-4-hydroxy-5-phenylthiomethylbenzylidene) -1-phenylpyrazolidine-3,5-
Dione and 3- (3-ethoxy-4-hydroxy-5
-Phenylthiomethylbenzylidene) -2-pyrrolidine was attached in amounts of 1.8 mg and 1.6 mg.

Example 6 In Example 1, instead of ST638, genistein (Cosmo Bio Inc., Tokyo), tyrphostin A
1 (Cosmo Bio Inc., Tokyo), Tylfostin A
9 (Cosmo Bio Inc., Tokyo), Tylfostin A
46 (Cosmo Bio Co., Ltd., Tokyo), Tylfostin B42 (Cosmo Bio Co., Ltd., Tokyo), and Tylfostin 50 (Cosmo Bio Co., Ltd., Tokyo) were used to adhere the respective agents in the same manner as in Example 1, and further LGA500.
5 was coated to obtain Palmatz-Schatz stents. Genistein, tyrphostin A1, tyrphostin A9, tyrphostin A46, tilfostin B
42 and tyrphostin 50 were adhered to the stent at 1.2 mg, 1.3 mg, and
1.5 mg, 1.4 mg, 1.3 mg, and 1.0 m
It was g.

Example 7 Palmatz-Schatz stents were dipped in an aqueous suspension of mitomycin C (10 mg / ml) or an ethanol solution of adriamycin (10 mg / ml), taken out and dried, and then a 1% aqueous gelatin solution (40 ° C.). By immersing in and drying it, a stent having mitomycin C or adriamycin attached and coated was obtained. The amount of mitomycin C and adriamycin deposited on the stent was 0.2 mg and 0.3 mg per stent, respectively.

Example 8 Polylactic acid, polyglycolic acid, or polylactic acid-poly
ST638 retention force of glycolic acid copolymer-treated stent
The effect of LGA5005 treatment on the retention property of ST638 was evaluated using the stent obtained in Example 1. LGA
The 5005 treated stent and the LGA5005 untreated stent were naturally dropped onto the glass plate from 1 m above,
The degree of peeling of ST638 due to impact was determined by quantifying the amount of ST638 remaining on the stent and visually determining it. The amount of ST638 remaining on the stent was quantified by immersing the stent in 1 ml of dimethylsulfoxide and quantifying the amount of solubilized ST638 using high performance liquid chromatography (column: Cosmosil 5C18-
AR, mobile phase solvent: 60% (v / v) acetonitrile aqueous solution, flow rate: 1 ml / ml, detection: 253 nm). As a result, in the stent without LGA5005 treatment, ST638 was clearly peeled off and retained in ST63.
8 amount was reduced by about 75%. On the other hand, in the case of the stent treated with LGA5005, no change was observed in the weight and the amount of remaining ST638 adhering even after the drop treatment, and the S was visually confirmed.
No flaking of T638 was observed.

Similarly, polylactic acid LA-0005 prepared in Examples 2 and 3 (average molecular weight 5000,
Wako Pure Chemical Industries, Ltd.), polylactic acid LA-0015 (average molecular weight 15000, manufactured by Wako Pure Chemical Industries), polylactic acid LA-00
20 (average molecular weight 20000, manufactured by Wako Pure Chemical Industries) and polyglycolic acid (polyglycolide, manufactured by Sigma, average molecular weight 100,000 to 125,000) using S
The T638-coated stent was naturally dropped from above 1 m onto a glass plate, and the amount of ST638 remaining on the stent was measured (however, the stent treated with polyglycolic acid was treated with hexafluoroisopropanol 1 m).
ST638 was solubilized and quantified). As a result, in any of the polymers used, ST638 was hardly peeled off from the stent.

Example 9 Polylactic acid, polyglycolic acid, or polylactic acid-poly
To the sustained release of ST638 treated with glycolic acid copolymer
ST effect from the stent when the stent is held in serum
The 638 elution rates were compared and examined. L prepared in Example 1
GA5005 treated stent and LGA5005 untreated stent were treated with 1 ml of fetal bovine serum (manufactured by Flow).
It was immersed therein and left at room temperature for 12 hours. After that, the stent was taken out, washed with a small amount of the same serum, and fresh serum 1m
It was immersed in 1 and left in the same manner. ST eluted in serum
The amount of 638 was determined by measuring the absorbance at 352 nm. As a result, without LGA5005 treatment,
90% or more of ST638 was eluted on the first day, and almost no elution was observed on the fifth day, whereas LGA
With the 5005 treated stent, the elution of ST638 remained at 30% on the first day, and the elution of ST638 was continuously observed even after 1 week. This result shows that the method of the present invention makes the drug release from the stent sustained-release.

Similar experiments were examined using the stents obtained in Example 2 and Example 3. As a result, it was confirmed that in any of the stents treated with any of the polymers, the elution of ST638 into serum was sustained release, almost in the same manner as in the case of using LGA5005.

Example 10 of stent coated with drug using fibrin
Preparation ST638 crystals were suspended (20 mg / ml) in a calcium chloride solution in a physiological tissue adhesive Veriplus ^R P (Behring Berke) and set to 0.5 ml of the suspension.
Was added to a vial containing thrombin (150 units) powder, then added to a fibrinogen (40 mg) solution to which aprotinin (500 KIE) solution had been added in advance, and immediately coated on a Palmaz-Schatz stent,
The fibrin solidified. After that, water was removed by air drying to obtain a stent coated with ST638. The amount of ST638 attached to the stent was 0.5 mg per stent.

Similarly, instead of ST638, ST6
38-analog 4- (3-ethoxy-4-hydroxy-5-phenylthiomethylbenzylidene) -1-phenylpyrazolidine-3,5-dione or 3- (3-ethoxy-4-hydroxy-5-phenyl Thiomethylbenzylidene) -2-pyrrolidine was used to obtain a Palmatz-Schatz stent in which each drug was coated with fibrin. 4- (3-Ethoxy-4-hydroxy-5-phenylthiomethylbenzylidene) -1-phenylpyrazolidine-3,5-dione and 3- (3-ethoxy-4-hydroxy-5-phenylthiomethylbenzylidene) The amount of 2-pyrrolidine deposited on the stent was 0.6 mg and 0.4 mg per stent, respectively. The stents thus obtained were tested in the same manner as described in Example 8 and Example 9 with ST638, 4- (3-ethoxy-4-hydroxy-5), respectively.
-Phenylthiomethylbenzylidene) -1-phenylpyrazolidine-3,5-dione or 3- (3-ethoxy-4-hydroxy-5-phenylthiomethylbenzylidene) -2-pyrrolidine retention and serum The sustained release of these drugs was improved.

Example 11 ST638 (100 mg) sufficiently ground in a mortar was added to 5 ml of a 1% (w / w) hyaluronic acid aqueous solution, and after sufficiently stirring, 20 μl thereof was adhered to the surface of Palmatz-Schatz stent and dried. . The amount of ST638 deposited was 0.4 mg per stent. The stent thus obtained was tested in the same manner as in Example 8 to obtain ST63.
8 did not show flaking. Similarly, 1% (w / w) collagen aqueous solution, 1% (w / w) gelatin aqueous solution, 1
% (W / w) poly-L-glutamic acid aqueous solution, or 1
% (W / w) chitosan acetic acid aqueous solution was added with ST638 fine powder and stirred, and then a part of the suspension was attached to the surface of the stent and dried to obtain a stent coated with ST638. The amount of ST638 attached was 0.3 m per stent for each of collagen treatment, gelatin treatment, poly-L-glutamic acid treatment, and chitosan treatment.
It was g, 0.4 mg, 0.3 mg, and 0.3 mg. The thus-obtained stent did not show ST638 flaking in the same test as in Example 8.

Example 12 10 μl of ST638 acetone solution (20 mg / ml)
Was placed on the Palmatz-Schatz stent and quickly dried with hot air was repeated 10 times. By this operation, ST638 was deposited on the stent. Thus S
A polyethylene carbonate solution in methylene chloride (40 mg / ml) or a polypropylene carbonate solution in methylene chloride (5 m
20 μl of (g / ml) was gently added and air-dried to obtain a stent to which ST638 was attached and coated. The adhesion amount of ST638 was 0.2 mg and 0.1 mg per stent for the polyethylene carbonate treatment and the polypropylene carbonate treatment, respectively. The thus-obtained stent did not show ST638 flaking in the same test as in Example 8.

Example 13 30% (w / w) acrylamide and 0.8% (w / w)
To 3.3 ml of an aqueous solution in which N, N-methylenebis (acrylamide) was dissolved, 1.75 ml of water, ST638 (200 mg) sufficiently ground in a mortar, 0.5% (w / w) N,
N, N, N-tetramethylethylenediamine aqueous solution 0.
5 ml and 25 mg of ammonium persulfate were sequentially added, and after sufficiently stirring, 20 μl was attached to the surface of the stent to cause gelation and then air-dried to obtain a ST638-coated stent. The amount of ST638 deposited was 0.4 mg per stent. The thus-obtained stent did not show ST638 flaking in the same test as in Example 8.

Example 14 10 μl of ST638 acetone solution (20 mg / ml)
Was placed on the Palmatz-Schatz stent and quickly dried with hot air was repeated 10 times. By this operation, ST638 was deposited on the stent. This ST63
A ST638-coated stent was obtained by repeatedly spraying a 5% (w / v) polyurethane solution in chloroform / dioxane (1 volume / 1 volume) on the stent to which 8 was attached. The amount of ST638 attached was 1.6 mg per stent. The thus-obtained stent did not show ST638 flaking in the same test as in Example 8. The polyurethane used was polyethylene glycol (average molecular weight: 2000) / propylene glycol = 50/50 (w / w) with 3.5 mol% of m, m′-dihydroxyazobenzene added to it by a bulk polymerization method (Kamihara). Weekly, polycondensation and polyaddition reaction, Kyoritsu Publishing,
It was prepared according to p.327 (1958).

[0041]

Industrial Applicability According to the present invention, it is possible to provide a stent on which a therapeutically necessary amount of a drug capable of suppressing the intimal thickening of an artery is firmly adhered / coated. Further, since the drug coated on the stent is gradually released from the stent, the stent of the present invention is also excellent as a means for providing a sustained release drug.

─────────────────────────────────────────────────── ─── Continuation of the front page (58) Fields surveyed (Int.Cl. ⁷ , DB name) A61L 31/00 A61F 2/06 A61K 9/00

Claims (6)

(57) [Claims] 1. At least an operation of coating and drying a stent with a liquid obtained by dissolving or suspending a drug in a solution of a biocompatible polymer and / or a biodegradable polymer or an operation of immersing and drying the stent in the liquid. A biocompatible polymer and / or a biodegradable polymer after repeating once or more or at least once more after applying and drying the solution of the drug on the stent or dipping and drying the stent in the solution of the drug. Of the drug on the stent and biocompatible polymer and / or
Alternatively, a method for producing a drug-coated / coated stent is characterized by coating with a biodegradable polymer. 2. The drug has the general formula (I): [In the formula, x is a hydrogen atom, -OR ⁵ (provided that R ⁵ is C ₁ to
An alkyl group of C ₃ is shown. ) An alkoxy group represented by
A C ₁ -C ₅ alkyl group, a nitro group, an amino group, a hydroxyl group, a halogen atom, or —COOR ⁶ (wherein R ⁶ is C
An alkyl group having ₁ -C _3. ) Represents an alkoxycarbonyl group, and R ¹ represents a hydrogen atom, a C ₁ -C ₃ alkyl group, or R ⁷ CO— (however, R ⁷ phenyl group or a C ₁ -C ₃ alkyl group). .), R ² represents a hydrogen atom or a C ₁ -C ₅ alkyl group, R ³ represents —COOR ⁸ (provided that R ⁸ represents a hydrogen atom, or C ₁ -C _4). Represents an alkyl group of), or an amide, and R ⁴ is a cyano group or R ⁹ SO
_2- (provided that R ⁹ represents a C ₁ -C ₄ alkyl group)
Or an alkylsulfonyl group represented by the formula, or R ³ and R ⁴ are bonded to each other to -CO-Y-CH (R ¹⁰ ) -C.
H ₂ - or ^{_{-CO-Y-CH 2 -CH (}} R 10) -
(However, R ¹⁰ represents a hydrogen atom or a C _{1 to} C ₄ alkyl group, and Y represents an oxygen atom or an NH group.), Or-
_{CO-N (C 6 H 5} ) represents -NH-CO-, n when x is a halogen atom, represents an integer of 1 to 5, represents 1 when x is other groups, m is 0 Represents an integer of 3. 3-phenylthiomethyl styrene derivative represented by], or method according to claim 1 Symbol placement is a salt of the salt formation can ones. 3. The drug has the general formula (II): [In the formula, x is a hydrogen atom, -OR ⁵ (provided that R ⁵ is C ₁ to
An alkyl group of C ₃ is shown. ) An alkoxy group represented by
A C ₁ -C ₅ alkyl group, a nitro group, an amino group, a hydroxyl group, a halogen atom, or —COOR ⁶ (wherein R ⁶ is C
An alkyl group having ₁ -C _3. ) Represents an alkoxycarbonyl group, and R ¹ represents a hydrogen atom, a C ₁ -C ₃ alkyl group, or R ⁷ CO— (however, R ⁷ phenyl group or a C ₁ -C ₃ alkyl group). .), R ² represents a hydrogen atom or a C _{1 to} C ₅ alkyl group, n represents an integer of 1 to 5 when x is a halogen atom, and x represents another. When it is a group, it represents 1, and m is 0 to 3.
Represents the integer. Α- cyano-4-hydroxycinnamic acid amide derivative represented by], or method according to claim 1 Symbol placement is a salt of the salt formation can ones. 4. The drug is α-cyano-3-ethoxy-4.
- The process according to claim 1 Symbol placement is hydroxy-5-phenylthiomethyl-cinnamic acid amide. 5. The biocompatible polymer is polyurethane,
Polyacrylamide, polyethylene oxide, polyethylene carbonate, polypropylene car Bo sulfonate, and 1 or higher is claim 1-3 manufacturing method according to any one selected from the group consisting of fibrin. 6. The biodegradable polymer is polylactic acid, polyglycolic acid, a copolymer of polylactic acid and polyglycolic acid, collagen, gelatin, chitin, chitosan, hyaluronic acid, polyamino acid, starch, poly-ε- The method according to claim 1, wherein the number is at least one selected from the group consisting of caprolactone, polyethylene succinate, poly-β-hydroxyalkanoate, and epoxide copolymer.