JP2003299740A - Stent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a stent in which neither decomposition nor deterioration of a biological, physioactive material occurs, the material can be carried in stable state and after leaving it at a lesion site the material is released little by little over a long period of time without being rapidly released in a short time. <P>SOLUTION: The stent 1 has a stent body 2, a biological, physioactive material layer 3 made of at least one of the biological, physioactive material arranged on a surface of the stent body 2, and a polymer layer 4 completely covering the material layer 3. The polymer layer 4 has at least one recessed part 5 partially thinner than general thickness. A polymer forming the polymer layer 4 comprises a biodegradable polymer which slowly decomposed and is absorbed in a living body after being left in the lumen of the living body. Minute through holes penetrating from the recessed portions of the polymer layer to the biological, physioactive material layer are firstly formed after leaving the stent 1 in the lumen of the living body. The biological, physioactive material is slowly released into the living body from the minute through holes. <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a stent used for ameliorating a stenosis or an occlusion in a lumen of a living body such as a blood vessel, a bile duct, a trachea, an esophagus, a urethra.

[0002]

2. Description of the Related Art As an example, angioplasty applied to ischemic heart disease will be described.

Since the westernization of dietary habits in Japan has rapidly increased the number of patients with ischemic heart disease (angina pectoris, myocardial infarction), percutaneous is a method for reducing those coronary artery lesions. Transvascular coronary angioplasty (PTCA) has been performed and has become extremely popular. At present, the number of cases of application is increasing due to technological development, and from unilateral lesions (lesions with stenosis in only one site) that were localized (short lesion length) when PTCA began, More eccentric and calcified in the distal part, and PTC to multi-branch lesions (lesions with stenosis in more than one site)
The application of A is expanded. With PTCA, a small incision is made in an artery of a patient's leg or arm, an introducer sheath (introducer) is placed, and a guide wire is advanced through the lumen of the introducer sheath while a long hollow catheter called a guide catheter is placed. After inserting the tube into the blood vessel and placing it at the entrance of the coronary artery, pull out the guide wire, insert another guide wire and the balloon catheter into the lumen of the guide catheter, and radiograph the balloon catheter while the guide wire precedes Under this condition, the patient is advanced to the lesion of the coronary artery of the patient, and the balloon is positioned in the lesion.
It is a technique to inflate once or multiple times for 0 seconds. This dilates the vascular lumen in the lesion, thereby increasing blood flow through the vascular lumen. However, when the blood vessel wall is damaged by the catheter, the vascular intimal proliferation which is a healing reaction of the blood vessel wall occurs, and restenosis is reported at a rate of about 30 to 40%.

Although a method for preventing restenosis has not been established so far, a method using a device such as a stent or an atherectomy catheter has been studied, and some results have been achieved. The term "stent" as used herein means to expand the stenotic or occluded area and place it there to secure its lumen in order to treat various diseases caused by stenosis or occlusion of blood vessels or other lumens. It is a tubular medical device that can be used. Most of them are medical devices made of metal material or polymer material. For example, tubular material made of metal material or polymer material with pores, wire of metal material, or fiber of polymer material is knitted. Various shapes such as a cylindrical shape have been proposed. The purpose of stent placement is to prevent and reduce restenosis that occurs after performing procedures such as PTCA, but so far stent alone has not been able to significantly suppress stenosis. Is the actual situation.

Therefore, in recent years, by supporting a biophysiologically active substance such as an anti-cancer agent on this stent, the biophysiologically active substance is locally released at the indwelling site of the lumen for a long period of time, resulting in a restenosis rate. Attempts have been made to reduce the power consumption. For example, JP-A-8-33718
Japanese Patent Laid-Open No. 9-99056 discloses a stent in which a surface of a stent body is coated with a mixture of a therapeutic substance and a polymer, and Japanese Laid-Open Patent Publication No. 9-99056 provides a bioactive material layer on the surface of the stent body. A stent provided with a polymer porous material layer on the surface of the biologically active material layer,
Each has been proposed.

However, in the stent proposed in Japanese Unexamined Patent Publication No. 8-33718, the substance for treatment (biologically physiologically active substance) is completely mixed with the polymer, so that the polymer is biologically physiological. When chemically acting on the active substance, there arises a problem that the biologically physiologically active substance is decomposed and deteriorated, that is, the stability of the biologically physiologically active substance occurs. In addition, when a polymer that has a fast degradation rate in vivo is selected,
Within a few days), all the biologically / physiologically active substances are released, so that restenosis of the blood vessel lumen cannot be sufficiently suppressed. Therefore, in order to avoid the decomposition and deterioration of the biologically / physiologically active substance and to allow the biologically / physiologically active substance to be released for a long period of time (a few weeks to a few months after being placed), JP-A-8-33718. The stent of the type proposed in Japanese Patent Publication has a problem that the selection range is limited in terms of a combination of a polymer and a biologically / physiologically active substance.

On the other hand, in the stent proposed in Japanese Patent Application Laid-Open No. 9-99056, the bioactive material layer (biologically physiologically active substance layer) and the polymer layer are separated into different layers.
There is no concern about the decomposition and deterioration of biologically bioactive substances by polymers, but since a porous material is used for the polymer layer covering the biologically bioactive substances, one end to the other end of the polymer layer Since the passage is formed, the biologically / physiologically active substance layer has already been exposed to the outside-stent atmosphere (outside the polymer layer) from the time before being inserted into the living body, that is, the time when it is manufactured. . Therefore, in the stent having such a structure, the biologically / physiologically active substance may be released to the outside of the stent through the passage of the porous body before being placed in the lesion. In addition, even after being placed in the lesion area, the biologically / physiologically active substance remains for a short period of time (after placement,
There is also a phenomenon of rapid release within a few days), that is, an initial burst is likely to occur and it is difficult to release the biologically / physiologically active substance little by little over a long period (weeks to months after placement). It was

[0008]

SUMMARY OF THE INVENTION Therefore, an object of the present invention is to allow a biologically or physiologically active substance to be carried on a stent body in a stable state without decomposition or deterioration of the biologically / physiologically active substance, and to treat lesions. It is an object of the present invention to provide a stent in which a biologically / physiologically active substance is not rapidly released in a short period of time after being placed in a region, and is gradually released over a long period of time.

[0009]

These objects are achieved by the present invention described in (1) to (7) below.

(1) A stent for placement in a lumen of a living body, the stent comprising a main body of a stent and at least one biologically / physiologically active substance provided on a surface of the main body of the stent. It has a formed biologically / physiologically active substance layer and a polymer layer that completely covers the biologically / physiologically active substance layer, and the thickness of the polymer layer is partly thinner than the total thickness. A stent having at least one recess, wherein the polymer forming the polymer layer is a biodegradable polymer that is gradually decomposed after being left in a lumen of a living body and is absorbed in the living body.

(2) The stent according to (1) above, wherein the main stent body is made of a metal material.

(3) The stent according to (1) above, wherein the main stent body is made of a polymer material.

(4) The biologically / physiologically active substance layer comprises:
The stent according to (1) above, which is formed of only a biologically / physiologically active substance.

(5) The biologically / physiologically active substance layer comprises:
The stent according to (1) above, which is formed of a mixture of a biologically / physiologically active substance and a low molecular weight water-soluble substance.

(6) The biologically / physiologically active substance is an anticancer drug, an immunosuppressant, an antibiotic, an antirheumatic drug, an antithrombotic drug, an HMG-CoA reductase inhibitor, an ACE inhibitor, a calcium antagonist, or an antihypertensive agent. Lipemia, anti-inflammatory agent, integrin inhibitor, anti-allergic agent, antioxidant, GPIIbIIIa
Consisting of antagonists, retinoids, flavonoids, carotenoids, lipid improving agents, DNA synthesis inhibitors, tyrosine kinase inhibitors, antiplatelet agents, vascular smooth muscle growth inhibitors, anti-inflammatory agents, biological materials, interferons and NO production promoters The stent according to (1) above, which is at least one selected from the group.

(7) The biodegradable polymer is polyglycolic acid, polylactic acid, polycaprolactone, polyhydroxybutyric acid, cellulose, polyhydroxybutyrate-
The stent according to (1) above, which is either a polymer of valerate or polyorthoester or a composite of a copolymer or a mixture.

[0017]

BEST MODE FOR CARRYING OUT THE INVENTION The stent of the present invention will be described below in detail with reference to the preferred embodiments shown in the accompanying drawings.

FIG. 1 is a front view showing an embodiment of the stent of the present invention, FIG. 2 is an enlarged cross-sectional view taken along line AA of FIG. 1, and FIG. 3 is a polymer layer of the stent of FIG. FIG. 3 is an enlarged cross-sectional view showing a state in which a minute through hole that penetrates to a biologically / physiologically active substance layer is formed in a recess having a small thickness.

The stent 1 of the present invention shown in FIGS. 2 and 3.
Includes a main stent body 2, a biological and physiologically active substance layer 3 formed on the surface of the main stent body 2 and formed of at least one biologically and physiologically active substance, and a biological and physiologically active substance layer 3. With the polymer layer 4 completely covered, the thickness of the polymer layer 4 has at least one recess 5 that is partially thin relative to the total thickness, and the polymer forming the polymer layer 4 is It consists of a biodegradable polymer that is gradually decomposed after being placed in the lumen and is absorbed in the living body.

First, each constituent element of the stent 1 will be described in detail.

The stent body 2 is not particularly limited in its material, shape, size and the like as long as it can be placed in a lesion site formed in a lumen in a living body such as a blood vessel, a bile duct, a trachea, an esophagus, a urethra. The balloon expanding means as described above can be used as the indwelling means, but if the main stent body 2 is an elastic body, a self-expanding means utilizing this elastic force can be used.

The material for forming the main stent body 2 may be appropriately selected depending on the application site, and examples thereof include metal materials, polymer materials, and ceramics. When the stent body 2 is made of a metal material, the metal material is excellent in strength, so that the stent 1 can be reliably left in the lesion. In addition, when the stent body 2 is made of a polymeric material, the polymeric material is excellent in flexibility, and therefore exhibits an excellent effect in terms of reachability (delivery property) to the lesion site of the stent 1.

As the metal material, for example, stainless steel,
Examples thereof include Ni—Ti alloy, tantalum, titanium, gold, platinum, inconel, iridium, tungsten, and cobalt alloys. Among stainless steels, SUS316L, which has the best corrosion resistance, is suitable.

Many of the main stent bodies 2 made of a metal material can be expanded by using a balloon. Further, the stent body 2 is formed of a metal material called pseudoelasticity, for example, a metal material such as a Ni—Ti alloy whose stress is constant and whose strain changes greatly, or a metal material whose strain gradually increases and changes in response to an increase in stress. Is self-expandable, the stent main body 2 that has been compressed and held in advance is expanded by elastic force by releasing the compression at the lesion.

Examples of the polymeric material include polytetrafluoroethylene, polyethylene, polypropylene, polyethylene terephthalate, cellulose acetate, cellulose nitrate, biocompatible polymeric materials such as carbon or carbon fiber, polylactic acid, polyglycolic acid, lactic acid. And biodegradable polymer materials such as polycaprolactone, polyhydroxybutyrate-valerate and the like.

When the main stent body 2 is formed of a biodegradable polymer material, the main stent body 2 is decomposed in the living body and disappears from the lesion site with the passage of time. Therefore, even if the stent is to be placed in the lesion again, it can be treated in the same manner as the first placement.

The shape of the main stent body 2 is not particularly limited as long as it has sufficient strength to be stably placed in the lumen of the living body. For example, a wire made of a metal material or a fiber made of a polymer material is knitted into a cylindrical shape, or a tubular body made of a metal material or a polymer material is provided with pores.

The stent body 2 is a balloon expansion type,
It may be any of the self-expanding type. Further, the size of the main stent body may be appropriately selected according to the application site. For example, when used for the coronary artery of the heart, the outer diameter before expansion is usually 1.0 to 3.0 mm, and the length is 5 to 50 mm.
mm is preferred.

The surface of the main stent body 2 is provided with a biologically / physiologically active substance layer 3 formed of at least one biologically / physiologically active substance.

The method for providing the biologically / physiologically active substance layer 3 on the surface of the stent body 2 is not particularly limited. For example, a method of melting the biologically / physiologically active substance and coating the surface of the stent body 2 with In addition, a solution is prepared by dissolving a biologically / physiologically active substance in a solvent, and the main stent body 2 is dipped in this solution and then pulled up to remove the solvent by evaporation or another method, or by using a spray. Examples include a method in which the solution is sprayed onto the main stent body 2 to evaporate the solvent or remove the solvent by another method.

When it is considered that the adhesive force of the biologically / physiologically active substance to the main stent body 2 is insufficient, when the biologically / physiologically active substance is water-soluble, the low molecular weight of the water-soluble substance is used. If it is a substance, for example, saccharides such as monosaccharides, disaccharides, oligosaccharides, or water-soluble vitamins, and if it is a polymer substance, dextran, hydroxyethyl cellulose, etc. are mixed in water, and the mixture is coated on the main stent body 2 and dried. When the biologically / physiologically active substance is fat-soluble, higher molecular weight fatty acids such as fish oil, vegetable oil, fat-soluble vitamins such as vitamin A and vitamin E are mixed and coated on the main stent body 2. And then dried.

If the solvent that readily dissolves the biologically / physiologically active substance can easily wet the surface of the stent body 2, only the biologically / physiologically active substance is dissolved in the solvent. The method of immersing the stent body 2 in a solution and drying it, or the method of spraying the solution onto the stent body 2 by spraying to dry the solution is the simplest and most preferably applied.

The biologically / physiologically active substance is easily dissolved in body fluid such as blood even if it is water-soluble or fat-soluble. This is because most of body fluids such as blood are formed of water and also contain an oily component.

The thickness of the biologically / physiologically active substance layer 3 is such that the performance of the stent body 2 is not significantly impaired, such as reachability to the lesion (delivery) and irritation to the blood vessel wall.
Moreover, since the thickness should be set so as to confirm the effect of the biologically / physiologically active substance, it is preferably 1 to 10
The range is 0 μm, more preferably 1 to 50 μm, and most preferably 5 to 30 μm.

The biologically / physiologically active substance forming the biologically / physiologically active substance layer 3 is not particularly limited as long as it has an effect of suppressing restenosis when the stent 1 is left in the lesion of the lumen. Are, for example, anticancer agents, immunosuppressants, antibiotics, antirheumatic agents, antithrombotic agents, HMG-CoA reductase inhibitors, ACE inhibitors, calcium antagonists, antihyperlipidemic agents, antiinflammatory agents, integrin inhibitors , Anti-allergic agents,
Antioxidant, GPIIbIIIa antagonist, retinoid, flavonoid, carotenoid, lipid improving agent, DNA synthesis inhibitor, tyrosine kinase inhibitor, antiplatelet drug, vascular smooth muscle growth inhibitor, anti-inflammatory drug, biomaterial, interferon, NO Examples include production promoting substances.

Examples of the anticancer agent include vincristine,
Vinblastine, vindesine, irinotecan, pirarubicin, paclitaxel, docetaxel, methotrexate and the like are preferable.

Examples of immunosuppressants include sirolimus, tacrolimus, azathioprine, cyclosporine,
Cyclophosphamide, mycophenolate mofetil,
Gusperimus, mizoribine and the like are preferable.

Examples of antibiotics include mitomycin, adriamycin, doxorubicin, actinomycin, daunorubicin, idarubicin, pirarubicin,
Aclarubicin, epirubicin, peplomycin, dinostatin stimalamer and the like are preferable.

As the anti-rheumatic agent, for example, methotrexate, sodium thiomalate, penicillamine, lobenzarit and the like are preferable.

Preferred antithrombotic agents are, for example, heparin, aspirin, antithrombin preparations, ticlopidine, hirudin and the like.

As the HMG-CoA reductase inhibitor,
For example, cerivastatin, cerivastatin sodium,
Atorvastatin, nisvastatin, itavastatin,
Fluvastatin, fluvastatin sodium, simvastatin, lovastatin, pravastatin and the like are preferable.

Preferred ACE inhibitors are, for example, quinapril, perindopril erbumine, trandolapril cilazapril, temocapril, delapril, enalapril maleate, lisinopril, captopril and the like.

Examples of the calcium antagonist include, for example, hifedipine, nilvadipine, diltiazem, benidipine,
Nisoldipine and the like are preferred.

As the hyperlipidemic agent, for example, probucol is preferable.

As the antiallergic agent, for example, tranilast is preferable.

As the retinoid, for example, all-trans retinoic acid is preferable.

Antioxidants include, for example, catechins,
Anthocyanins, proanthocyanidins, lycopene, β
-Carotenes and the like are preferred. Among the catechins, epigallocatechin gallate is particularly preferable.

Preferred tyrosine kinase inhibitors are, for example, genistein, tyrphostin, arbstatin and the like.

As the anti-inflammatory agent, for example, steroids such as dexamethasone and prednisolone are preferable.

Examples of the biological material include EGF
(Epidermal growfactor),
VEGF (Vascular Endothelial)
growth factor), HGF (hepato)
cyte growth factor), PDGF
(Platelet delivered growhtf
actor), BFGF (basic fibrola)
st growth factor) and the like are preferable.

The biologically / physiologically active substance forming the biologically / physiologically active substance layer 3 preferably contains at least one of the above substances in view of surely suppressing restenosis. . Further, whether the biological physiologically active substance forming the biological physiologically active substance layer 3 should be one kind of biological physiologically active substance or whether two or more different biological physiologically active substances should be combined. Should be appropriately selected according to the case.

The surface of the biologically / physiologically active substance layer 3 is completely covered with the polymer layer 4, and the thickness of the polymer layer 4 is such that the concave portion 5 is partially thin with respect to the entire thickness. There is at least one place.

The method for covering the surface of the biologically / physiologically active substance layer 3 with the polymer layer 4 is not particularly limited, but for example, the polymer is dissolved in a solvent to prepare a solution, and the biologically / physiologically active substance layer is previously prepared. Method of immersing the stent body 2 provided with 3 in this solution and drying, or method of spraying the solution on the stent body 2 previously provided with the biologically / physiologically active substance layer 3 with a spray, and drying Is mentioned.

The polymer layer 4 has a partially thin recess 5
The method of producing the polymer is not particularly limited, but for example, a method of partially cutting the polymer by piercing the surface of the polymer layer 4 formed in advance on the surface of the stent body 2 with a needle or partially cutting the polymer beforehand. There is a method of irradiating the surface of the polymer layer 4 formed to have a constant thickness with an excimer laser at a pinpoint to partially cut the polymer.

The polymer forming the polymer layer 4 is not particularly limited as long as it is a biodegradable polymer which is gradually decomposed after being left in the lumen of the living body and is absorbed in the living body, but it has high biostability and is a tissue. It is preferably one having low irritation, for example, polyglycolic acid, polylactic acid, polycaprolactone, polyhydroxybutyric acid, cellulose, polyhydroxybutyrate-valerate, a single substance or a copolymer of polyorthoester, or Examples include a composite of a mixture.

The total thickness of the polymer layer 4 is set so that the performance of the main stent body 2 is not significantly impaired such as the delivery property to the lesion site and the stimulating property to the blood vessel wall, like the biologically / physiologically active substance layer 3. Therefore, the range is preferably 1 to 100 μm, more preferably 10 to 50 μm, and most preferably 20 to 30 μm.

When the thickness of the polymer layer 4 is less than 1 μm, it is feared that the function as a coating film that completely covers the biologically / physiologically active substance layer 3 cannot be achieved. Further, if the thickness of the polymer layer 4 exceeds 100 μm, the outer diameter of the stent 1 itself becomes too large, and it is easily expected that delivery to a lesion site will be particularly impaired.

The thickness of the recesses 5 of the polymer layer 4 should be specific to the total thickness of the polymer layer 4, so that the total thickness is preferably 1 to 50%, The range is more preferably 5 to 40%, most preferably 10 to 30%.

The disposition of the partially thin recesses 5 formed in the polymer layer 4 is not particularly limited, but it is preferable that the recesses 5 are located outside the stent that comes into contact with living tissue when placed in a living body, and are arranged only outside the stent. In this case, the amount of the biologically / physiologically active substance released into the body fluid on the lumen side of the stent can be suppressed to a small amount, and the biologically / physiologically active substance mounted on the stent can be efficiently used. Further, it is preferable that the elution concentration of the biologically / physiologically active substance is arranged so as to be uniform on the outer surface of the stent.

Next, the process when the biological / physiologically active substance forming the biological / physiologically active substance layer 3 is released from the stent 1 will be described.

After the stent 1 is left in the lesion of the lumen, the body fluid in the lumen comes into contact with the surface of the stent 1 (the surface of the polymer layer 4), whereby the polymer layer 4 is decomposed from the surface and polymer Layer 4 becomes thinner. And
In the polymer layer 4, a micro through hole 6 communicating with the biologically / physiologically active substance layer 3 is formed in a portion of the recess 5 which is partially thin in the polymer layer 4.

After that, the liquid such as the body fluid existing in the lumen comes into contact with the biologically / physiologically active substance layer 3 through the minute through holes 6. Then, the biologically / physiologically active substance is eluted into the liquid by coming into contact with the liquid. Then, the eluted biologically / physiologically active substance is released from the stent 1 through the minute through holes 6 formed in the polymer layer 4.

After that, the size of the micro through holes 6 formed in the polymer layer 4 increases, and the amount of the biologically / physiologically active substance eluted from the micro through holes 6 also increases. Since the amount of the biologically / physiologically active substance loaded on the stent 1 decreases with time, the amount of the biologically / physiologically active substance eluted from the stent 1 also gradually decreases.

Finally, the polymer layer 4 formed on the stent 1 is completely decomposed and absorbed in the living body, and the biologically / physiologically active substance layer 3 is entirely eluted in the living body.

As described above, the stent 1 of the present invention is inserted into a living body and is brought into contact with a body fluid such as blood until the surface of the biologically / physiologically active substance layer 3 and the stent 1 (the surface of the polymer layer 4). There is no passage to communicate with. Then, a passage is formed in the polymer layer 4 for the first time when it is left in the lesion of the lumen and comes into contact with body fluid. Therefore, the biologically / physiologically active substance can be used for a short period of time (after the stent 1 is placed in the lesion site,
It does not rapidly release within a few days) and can be released little by little over a long period of time (a few weeks to a few months after the stent 1 is left in the lesion site). In addition, the biologically / physiologically active substance is not released from the stent 1 before being inserted into the living body.

Further, in the stent 1 of the present invention, since the polymer layer 4 and the biologically / physiologically active substance layer 3 are separated into different layers, the biologically / physiologically active substance is decomposed and deteriorated by the action of the polymer. There is no problem. Therefore, the biologically / physiologically active substance can be carried in a stable state on the main stent body 2 until it is released from the stent 1. Further, the combination of the polymer and the biologically / physiologically active substance is not limited.

[0067]

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

(Example) Outer diameter 1.8 mm, length 30 mm
The cylindrical main body of the stent shown in FIG. 1 (material: SUS31
6L), an HMG-CoA reductase inhibitor simvastatin (hereinafter referred to as SV) dissolved in tetrahydrofuran, a solution having a concentration of SV of 5 wt% is sprayed by hand spraying (manufactured by HP-C IWATA), It was confirmed that about 0.3 mg of SV was applied to the outer surface of the main body of the stent (formation of the biologically / physiologically active substance layer).
The thickness of the biologically / physiologically active substance layer at this time is 5 μm on average.
It was m. After completely evaporating the solvent tetrahydrofuran, polyglycolic acid (RESOMER RG
503 Boehringer Ingelheim) was dissolved in dichloromethane to give a polyglycolic acid concentration of 10 wt.
% Spray solution (HP-C IWATA
It was confirmed that the polymer layer completely covered the biologically / physiologically active substance layer (formation of polymer layer). The thickness of the polymer layer was 50 μm on average. Then, a diameter of 0.56 mm and a length of 45.
A 5 mm sewing needle was pierced to a depth of about 40 μm and then pulled out to produce 232 recesses in which the polymer layer was partially thin (formation of polymer layer recesses).

Then, the amount of biologically physiologically active substance (SV) released from this stent was measured.

The measurement was carried out by immersing the above stent in 50 ml of a phosphate buffer solution (pH 7.4), and then applying the solution 37
The sample was allowed to stand in a constant temperature bath at 0 ° C., the phosphate buffer was sampled at predetermined intervals, and the SV release amount was measured.

The amount of SV contained in the collected phosphate buffer solution, that is, the amount of SV released from the stent was
Spectrophotometer (UV-2400PC Shimadzu
(Manufactured by K.K.) was used to measure the absorbance at the wavelength of 238.5 nm, and the absorbance was calculated from the calibration curve prepared in advance. The results are shown in Table 1. The amount of SV released in Table 1 is shown as a ratio (%) to the amount of SV applied to the main stent body.

As shown in Table 1, 1
It was confirmed that after a lapse of a week, SV started to be released, and thereafter, the amount of released SV increased with the lapse of time (day). In addition, a phenomenon in which SV was rapidly released in a short period of time (initial burst) was not observed, and it was confirmed that SV was gradually released over about 4 weeks.

(Comparative Example 1) Outer diameter 1.8 mm, length 30 m
m cylindrical main body of stent shown in FIG. 1 (material: SUS3
16 L), an HMG-CoA reductase inhibitor simvastatin (hereinafter referred to as SV) dissolved in tetrahydrofuran, a solution having a concentration of SV of 5 wt% is sprayed by hand spraying (manufactured by HP-C IWATA), It was confirmed that about 0.3 mg of SV was applied to the outer surface of the main body of the stent (formation of the biologically / physiologically active substance layer).
The thickness of the biologically / physiologically active substance layer at this time is 5 μm on average.
It was m. After completely evaporating the solvent tetrahydrofuran, polyglycolic acid (RESOMER RG
503 Boehringer Ingelheim) was dissolved in dichloromethane to give a polyglycolic acid concentration of 10 wt.
% Spray solution (HP-C IWATA
It was confirmed that the polymer layer completely covered the biologically / physiologically active substance layer (formation of polymer layer). The thickness of the polymer layer was 50 μm on average.

Then, with respect to this stent, the amount of biologically physiologically active substance (SV) released into the phosphate buffer was measured in the same manner as in the example.

The results are shown in Table 1. As shown in Table 1, in the system in which the polymer layer was not provided with the concave portion, SV started to be released after 2 weeks from being left in the constant temperature bath, and then 4
It was confirmed that SV was rapidly released until after a week.

(Comparative Example 2) Outer diameter 1.8 mm, length 30 m
m cylindrical main body of stent shown in FIG. 1 (material: SUS3
16 L), an HMG-CoA reductase inhibitor simvastatin (hereinafter referred to as SV) dissolved in tetrahydrofuran, a solution having a concentration of SV of 5 wt% is sprayed by hand spraying (manufactured by HP-C IWATA), It was confirmed that about 0.3 mg of SV was applied to the outer surface of the main body of the stent, and the solvent tetrahydrofuran was completely evaporated (formation of a biologically / physiologically active substance layer). At this time, the thickness of the biologically / physiologically active substance layer was 5 μm on average.

Then, the amount of biologically physiologically active substance (SV) released into the phosphate buffer was measured for this stent by the same method as in the example.

The results are shown in Table 1. As shown in Table 1, in the system in which the polymer layer was not provided, it was confirmed that SV was rapidly released in one day after being left in the constant temperature bath.

[0079]

[Table 1]

[0080]

INDUSTRIAL APPLICABILITY As described above, the present invention is a stent for placement in a lumen in a living body, which comprises a main stent body and at least one type of biological material provided on the surface of the main stent body. It has a biological and physiologically active substance layer formed of a physiologically active substance and a polymer layer which completely covers the biologically and physiologically active substance layer, and the thickness of the polymer layer is relative to the total thickness. There is at least one thin recessed portion, and the polymer forming the polymer layer is a biodegradable polymer that is gradually degraded after being left in the lumen of the living body and is absorbed in the living body. After being placed in the lumen of the body, a micro through hole penetrating from the concave portion of the polymer layer to the biologically and physiologically active substance layer is formed first, and the biologically and physiologically active substance enters the living body through the micro through hole. Gradually released Therefore, the biologically / physiologically active substance is not exposed to the outside air, and the biologically / physiologically active substance and the polymer are not in a mixed state, and the biologically / physiologically active substance layer and Since the contact is made only at the interface of the covering polymer layer, the biologically / physiologically active substance is not decomposed or deteriorated, and can be supported on the main stent body in a stable state. After the stent is placed in the lesion area, the biologically / physiologically active substance is not rapidly released in a short period of time but is gradually released over a long period of time. Further, the polymer layer is finally completely decomposed and absorbed in the living body and does not remain in the living body as a foreign substance.

When the main stent body is made of a metallic material, the metallic material is excellent in strength, so that the stent 1 can be reliably left in the lesion.

When the main stent body is made of a polymeric material, the polymeric material is excellent in flexibility, and therefore the reachability (delivery property) to the lesioned part of the stent is pointed out. Exerts an excellent effect on.

When the biologically / physiologically active substance layer is formed of only the biologically / physiologically active substance, the biologically / physiologically active substance layer is provided by a simple method. Is possible.

When the biologically / physiologically active substance layer is formed of a mixture of the biologically / physiologically active substance and a low-molecular water-soluble substance, the biologically / physiologically active substance is When water-soluble, it is possible to improve the adhesion of the biologically / physiologically active substance to the main stent body.

The biologically / physiologically active substance is an anticancer drug, an immunosuppressant, an antibiotic, an antirheumatic drug, an antithrombotic drug,
HMG-CoA reductase inhibitor, ACE inhibitor, calcium antagonist, antihyperlipidemic agent, anti-inflammatory agent, integrin inhibitor, antiallergic agent, antioxidant, GPIIbIIIa antagonist, retinoid, flavonoid, carotenoid, lipid At least one selected from the group consisting of an improving agent, a DNA synthesis inhibitor, a tyrosine kinase inhibitor, an antiplatelet agent, a vascular smooth muscle growth inhibitor, an anti-inflammatory agent, a biological material, interferon and an NO production promoter When it is characterized by, it is possible to suppress restenosis.

[Brief description of drawings]

FIG. 1 is a front view showing an aspect of a stent of the present invention.

FIG. 2 is an enlarged cross-sectional view taken along the line AA of FIG.

FIG. 3 is a partially enlarged cross-sectional view showing a state where minute through holes penetrating to a biologically / physiologically active substance layer are formed in a recess having a thin polymer layer in the stent of FIG.

[Explanation of symbols]

1 ... stent, 2 ... stent body, 3 ... Biologically bioactive agent layer, 4 ... Polymer layer, 5 ... recess, 6 ... Micro through holes.

   ─────────────────────────────────────────────────── ─── Continued front page    F-term (reference) 4C081 AC16 BA16 BB06 CA011                       CA152 CA172 CD022 CE02                       CG01 DA03 EA06                 4C167 AA42 AA44 AA50 AA52 AA54                       AA55 BB02 BB05 BB06 BB12                       BB14 BB26 BB31 BB40 CC09                       DD01 GG01 GG16 GG21 GG42                       GG43

Claims (7)

[Claims] 1. A stent for placement in a lumen in a living body, the stent comprising a main body of a stent and at least one biologically / physiologically active substance provided on a surface of the main body of the stent. And a polymer layer that completely covers the biologically / physiologically active substance layer, the thickness of the polymer layer is a recess that is partially thin with respect to the entire thickness. There is at least one site, and the polymer forming the polymer layer is a biodegradable polymer that is gradually decomposed after being left in the lumen of the living body and is absorbed in the living body. 2. The stent according to claim 1, wherein the main stent body is made of a metal material. 3. The stent according to claim 1, wherein the main stent body is made of a polymer material. 4. The stent according to claim 1, wherein the biologically / physiologically active substance layer is formed only of the biologically / physiologically active substance. 5. The stent according to claim 1, wherein the biologically / physiologically active substance layer is formed of a mixture of a biologically / physiologically active substance and a low-molecular water-soluble substance. 6. The biologically / physiologically active substance is an anticancer drug,
Immunosuppressants, antibiotics, antirheumatic agents, antithrombotic agents, HM
G-CoA reductase inhibitor, ACE inhibitor, calcium antagonist, antihyperlipidemic agent, anti-inflammatory agent, integrin inhibitor, antiallergic agent, antioxidant, GPIIbIIIa antagonist, retinoid, flavonoid, carotenoid, lipid At least one selected from the group consisting of an improving agent, a DNA synthesis inhibitor, a tyrosine kinase inhibitor, an antiplatelet agent, a vascular smooth muscle growth inhibitor, an anti-inflammatory agent, a biological material, interferon and an NO production promoter The stent according to claim 1, wherein 7. The biodegradable polymer is a monoglyceride, a copolymer or a mixture of polyglycolic acid, polylactic acid, polycaprolactone, polyhydroxybutyric acid, cellulose, polyhydroxybutyrate-valerate and polyorthoester. The stent according to claim 1, wherein the stent is any one of polymers including the composite of