JP2003033439A - Coating stent and method for producing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a stunt, having a good adhesion between a stent and medicine and capable of efficiently supplying the medicine to necessary sites. SOLUTION: The coating stent is produced by the steps of bringing the surface of the stent into contact with a polymer in a liquid state, rotating the stent, and fixing the polymer to the stent substantially, and a method for producing the same is also disclosed. A polymer material capable of releasing the medicine is joined to the stent, thus, the coating stent having a controlled film thickness can be obtained. The coating stent thus obtained can supply a predetermined amount of the medicine over a desired period of time.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a stent for indwelling a living body, which is used for ameliorating a stenotic portion generated in a living body such as a blood vessel, a bile duct, a trachea, an esophagus, a urethra, and other organs.
More particularly, the present invention relates to a coated stent having a surface coated with a polymer material capable of delivering and releasing a drug for reducing restenosis, and a method for manufacturing the same.

[0002]

2. Description of the Related Art Stents can be placed to expand the stenosis and secure an inner lumen in order to treat various diseases caused by the narrowing of the lumen in a living body such as a blood vessel. It is a tubular treatment tool. Most of them are medical devices made of metal materials or polymer materials. For example, a tubular body made of metal materials or polymer materials with pores, wires made of metal materials, and fibers of polymer materials are knitted. Various shapes such as a cylindrical shape have been proposed. Placement of a stent in a stenosis typically involves attaching the stent to the outside of the balloon of a balloon catheter and manipulating the balloon catheter through a lumen, such as a blood vessel, to position the stent in the stenosis. This is accomplished by inflating the balloon to expand the stent and bringing the stent into close contact with the lumen of the stenosis.
After confirming that the stent has been expanded to a target diameter (a diameter that can secure the lumen of the stenosis), the balloon is deflated and the balloon catheter is taken out of the stenosis, and the indwelling procedure is completed. The purpose of such stent placement is to prevent restenosis that occurs after performing a procedure such as percutaneous transluminal coronary angioplasty (PTCA), and to reduce it.
So far, restenosis has not been able to be significantly suppressed only by placement of a stent. Therefore, in recent years, by loading a drug on the stent,
There has been proposed an attempt to locally release the drug at the indwelling site for a predetermined period to reduce the restenosis rate. As a method for supporting such a drug on a stent, Japanese Patent Application Laid-Open No. 8-33718 discloses an example in which a polymer solution containing the drug is sprayed or dipped onto the surface of the stent to coat the drug. However, in the coating examples using various methods including dipping, spraying, and treating in the publication, a polymer is uniformly coated on the stent surface,
There are problems such as not providing an economical method for adding different kinds of polymers. Therefore, there is a need for new solutions for effectively and economically adding polymeric materials to stents.

[0003]

As described above, as a means for reducing the restenosis rate of a lumen in a living body such as a blood vessel, a stent carrying a drug is left in the stenosis portion and locally treated for a predetermined period. The method of releasing the drug effectively is regarded as promising. Therefore, the stent and the drug have good adhesiveness, the required drug can be more effectively supplied to a necessary site, and the stent surface is uniformly coated with a polymer capable of releasing the drug. It is an object of the present invention to provide Also, the coated polymer does not interfere with the placement of the stent, thus allowing the stent to expand freely.

[0004]

The present invention comprises the steps of contacting a stent surface with a polymer in a liquid state, rotating the stent to remove unwanted polymer, and substantially fixing the polymer to the stent. A manufacturing method having the method, and a coated stent manufactured by the manufacturing method, wherein a polymer material capable of releasing a drug is joined to the stent to obtain a coated stent having a controlled film thickness. The coated stent thus obtained can deliver a predetermined amount of drug over a desired period of time.

The method of manufacturing a coated stent as described above, wherein the structure of the stent is a substantially cylindrical stent having an inner surface and an outer surface.

The method for producing a coated stent as described above, wherein the polymer in a liquid state is a polymer dissolved in a solvent.

The method of producing a coated stent as described above, wherein the step of bringing the surface of the stent into contact with the liquid polymer is a step of immersing the stent in a polymer solution in which the polymer is dissolved in a solvent.

The method for producing a coated stent as described above, characterized in that the drug is contained in the polymer or the polymer solution.

[0009] In the method for producing a coated stent as described above, the drug is a drug for reducing restenosis.

[0010] The method for producing a coated stent as described above, wherein the polymer is multi-layer coated on the surface of the stent.

The method for producing a coated stent as described above, wherein the multilayer coating comprises a multilayer coating having at least a top coat and an undercoat.

A coated stent having a surface of the stent obtained by the above-mentioned manufacturing method coated with a polymer.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention is a coated stent having the above characteristics and a method for manufacturing the same. The present invention will be described in detail below. The shape of the coated stent of the present invention is generally a generally cylindrical shape having an inner surface and an outer surface. More specifically, for example, a tubular body made of a metal material or a polymer material provided with pores, a wire made of a metal material, or a fiber made of a polymer material braided into a cylindrical shape is used. These stents have an inner surface and an outer surface and are capable of contracting and expanding. Further, it may be a self-expanding type or a balloon type. For example, in the coated stent 17 shown in FIG. 4, the diamond-shaped components 18 which are long in the axial direction and open in the center are arranged on the circumference at substantially equal angular intervals with respect to the central axis of the stent, and , Component 1
An annular unit 20 is connected between adjacent portions (side portions) in the circumferential direction of 8 by a connecting portion 19, and a plurality of annular units 20, 20a, 20b are arranged in the axial direction of the stent 17. Further, the connecting portion 19a of one annular unit 20a and the connecting portion 19b of the adjacent annular unit 20b.
And are connected at least at one place by the connecting portion 21. In this stent 17, a diamond is used to apply pressure (expansion force) to the outside with respect to the central axis of the stent, so that the diamond-shaped openings of the constituent elements 18, 18a, and 18b expand. Then, the stent 17 is expanded outward with respect to the central axis.

The present invention comprises the step of rotating the stent after contact with the liquid polymer to remove unwanted polymer. As a device for rotating the stent, a centrifugal device,
There is a rotating device, but preferably a centrifugal device. Prior to contacting the stent with the liquid polymer, the stent is gripped with a jig that is the axis of its rotation. This part is approximately the center in the longitudinal direction of the stent, and at this part, the stent is hung in a direction perpendicular to the longitudinal direction of the stent using a rod-shaped jig, and the jig is lowered to bring it into contact with the liquid polymer. It is preferable that the jig is lifted to take out the stent from the polymer, and the jig is rotated to rotate the stent in a horizontal position about the center in the longitudinal direction. Thus, centrifugal force can be applied to the stent. Therefore,
In the present invention, after contact with the polymer, centrifugal force is applied in a state of not contacting the polymer to rotate the polymer, thereby removing excess polymer from the surface of the stent.

Next, the step of bringing the polymer into contact with the above-mentioned stent is a step of attaching the polymer in a liquid state to the stent. The liquid state may be a state in which the polymer itself is in a liquid state, but the polymer is dispersed or dissolved in an organic solvent, and may not be completely dissolved or may be in a molten state. Further, the polymer in the liquid state may contain a drug in the polymer. When the drug is contained in the polymer, it is preferable to disperse or dissolve the drug in the above solvent together with the polymer. The polymer in the liquid state may be brought into contact with the stent by dropping it, or the stent may be dipped in the solution. Further, the solution may be sprayed onto the stent, but in the step of contacting, any contact method among dropping, spraying and dipping can be used as a method for contacting the outer surface of the stent with the solution. However, since the inner surface can be sufficiently contacted by dipping, dipping is preferable as the step of attaching the liquid polymer to the stent.

The method for producing a coated stent of the present invention has a step of, when the stent is immersed in a polymer in a predetermined liquid state, pulling the stent out of the polymer after the immersion. Also, this step is performed before the step of rotating the stent to remove the unnecessary polymer.

As a device for rotating the stent, there are a device for holding the stent with a jig and rotating the jig, a device for inserting the stent in a rotating container and rotating it, and a case for rotating the stent itself with a magnet or the like. However, it is preferable to use the centrifugal device described later. The centrifugal device shown in FIG.
Immersion tank 16 for storing the drug-containing polymer solution 14 in the lower part
And a rod-shaped jig 15 is provided in the center of the dipping tank 16 perpendicularly to the liquid surface of the solution 14. The jig 15 is connected to an elevating device and a rotating means, and the stent 11c has a jig 15 at substantially the center thereof so that its longitudinal direction is horizontal.
I'm grabbed by. When the jig 15 is lowered by the elevating device, the stent 11c is immersed in the solution 14 in the immersion tank 16. When the jig 15 is lifted up, the stent 11c becomes the solution 1
Taken out from 4. When the jig 15 is rotated by the rotating means in this state, the stent 11c rotates around the jig 15 while maintaining the horizontal position. Using the centrifuge, on the above-mentioned rotation axis on the stent 11c, the stent 11c
The excess polymer in the liquid state is removed from the stent 11c by the centrifugal force by rotating the
Coating. The preferred rotation speed in this step is 1000 to 5000 rpm, and more preferably,
It is 2000-3000 rpm.

The method for producing a coated stent of the present invention includes the step of substantially fixing the polymer coated on the stent. As mentioned above, the polymer may contain a drug in the polymer. Preferably in this step,
This is a step of drying in an oven. More preferably,
It is a step of leaving it in an oven at 37 ° C. for 30 minutes to dry it. The drying step causes the solvent to evaporate, thereby coating the surface of the stent with the polymer to produce the coated stent of the present invention.

The coating on the stent may be only the polymer or only one layer of the polymer containing the drug, or may be a multi-layer coating in which these are separately coated. In the case of multi-layer coating, a layer containing only the drug may be provided. Since the coated stent of the present invention has the above-described rotation process of the stent, it is possible to form a multilayer coating in which a plurality of coating layers each have a uniform thickness. The layer thickness of the coating on the stent should be sufficiently thin. Therefore, the thickness is preferably 1 to 100 μm, more preferably 5 to 20 μm.

Further, the multilayer coating may have a top coat and an under coat. Here, the top coat is a paint having a protective function from the viewpoint of aesthetics and external factors, and required quality characteristics include hue, gloss, designability, weather resistance, adhesiveness, and the like. Therefore, the coated stent of the present invention relates to coating of the outer surface of the stent, and is preferably coated with a biocompatible material such as silicone resin, an antithrombotic material such as heparin, or a biodegradable polymer such as polylactic acid. , And more preferably polylactic acid. Further, the undercoat in the coated stent of the present invention relates to a coating that comes into contact with the surface of the stent, and is coated with a material having excellent adhesion between the stent and the polymer-only layer or the drug-containing polymer layer coated on the upper layer. Preferably.

In the coated stent of the present invention,
The coating method includes, but is not limited to, the patterns shown below. If the coating is a single layer, the surface of the stent is coated with the polymer in the liquid state. Further, the polymer in the liquid state may contain a drug in the polymer. In this case, after the stent is immersed in the polymer in the liquid state, the stent is pulled out from the polymer, and the excess polymer in the liquid state is removed from the stent by a centrifugal device for coating. When the drug is contained in the polymer in the liquid state, the release rate of the drug can be controlled by the ratio of the polymer to the drug in the solution, and appropriate bioabsorption is required to enhance the adhesion between the coating and the living body. Coat materials and polymers with high biostability. The drug to polymer ratio can range from about 1: 1000 to about 1:10 by weight. Also, the release rate can be controlled by varying the ratio of drug to polymer in the multiple layers. In the case of two-layer coating, two types are selected from a liquid-state polymer, a liquid-state polymer containing a drug, and a liquid-state drug, and each is coated. The first layer is coated on the stent by the method of the present invention, and after drying, the second layer is similarly coated.
The same applies to coating of three or more layers, and a coated stent is formed by a combination of a liquid polymer, a liquid polymer containing a drug, and a liquid drug. In each case, since the coating process has a rotation step, the unnecessary polymer or polymer solution is appropriately removed, and the thickness of each layer becomes uniform. For example, in the sectional view taken along the line AA of the coated stent of FIG. 4 shown in FIGS. 1 and 2, FIG. 1 shows a sectional view of the coated stent 10a in which only the first drug-containing polymer 12a is coated on the stent 11a. FIG. 3 is a cross-sectional view of a coated stent 10b in which the second drug-containing polymer 13 is coated on the stent 11b, dried, and then coated with the first drug-containing polymer 12b that is the second layer. Here, the first drug-containing polymer 12b and the second drug-containing polymer 13 are drug-containing polymers using different drugs or polymers, respectively.

Materials for forming the stent of the coated stent of the present invention include metals such as stainless steel, nickel titanium (NiTi), tantalum, titanium, gold and platinum. Among the metal materials, stainless steel is preferable. Further, the stent may be formed of a biodegradable polymer such as polylactic acid, polyhydroxybutyric acid, polyglycolic acid, a copolymer of lactic acid and glycolic acid, polyacetal, or polycaprolactone.

Next, the polymeric material coated on the surface of the stent in the present invention is preferably one having the ability to contain a drug therein and the ability to release the drug at a constant rate. The polymer material in the present invention includes polyglycolic acid, a copolymer of lactic acid and glycolic acid, and poly DL.
Examples thereof include biodegradable and bioabsorbable polymers capable of carrying and releasing drugs such as lactic acid (DL-PLA), poly-L-lactic acid (L-PLA), lactide, polycaprolactone (PCL) and gelatin. In addition, non-degradable polymers are also suitable. Examples of non-degradable polymers include parylene, parilast, polyurethane, polyethylene, polyethylene terephthalate, ethylene vinyl acetate, silicone, polyethylene oxide (PE
O), polybutylmethyl acrylate, polyacrylamide and the like. These non-degradable polymers can be used for the reason that drug release is possible. The polymer chosen is preferably biocompatible and, when the stent is implanted, a polymer that minimizes irritation to the walls of blood vessels.

Examples of agents that can be contained in the polymer material are antiplatelet agents, anticoagulants, antifibrin, antithrombin, antiproliferative agents, anticancer agents and HM.
An example is G-CoA reductase inhibitor statin. Examples of antiplatelet agents, anticoagulants, antifibrin, antithrombin are sodium heparin, low molecular weight heparin, hirudin, argatroban, forskolin, vapiprost, prostacyclin, prostacyclin congeners, dextran, D-fe-pro- Argu-chloromethyl ketone (synthetic antithrombin), dipyridamole, glycoprotein IIb / IIIa platelet membrane receptor antibody,
Examples include thrombin inhibitors. Examples of antiproliferative agents include angiotensin-converting enzyme inhibitors such as angiopeptin, captopril, cilazapril, lisinopril, calcium groove blocking antibodies, cortisine, fibroblast growth factor (FGF) antagonists, fish oil (omega-3-fatty acid ), A histamine antagonist, robastatin (an inhibitor of HMG-CoA reductase), methotrexate, nitroprusside, a phosphodiesterase inhibitor, a prostaglandin inhibitor,
Ceramine (PDGF antagonist), serotonin blocking antibody, steroid, thioprotease inhibitor, triazolopyrimidine (PDGF antagonist), nitric oxide, all trans
Examples include retinoic acid, 13-cis retinoic acid, and 9-cis retinoic acid (retinoindo). Other suitable agents include, for example, alpha interferon, genetically engineered epithelial cells. Examples of the anticancer agent include alkaloids such as taxol, taxotere, and topotecin, antibiotics such as adreacin and bleo, antimetabolites such as 5-FU, and alkylating agents such as nitromine and tespamin. While the agents described above are used to prevent or treat restenosis, these agents are exemplary and not limiting of the invention.

The above-mentioned polymer and drug may be brought into contact with the stent in a solution state, including a state in which they are dispersed or dissolved in an organic solvent, may not be completely dissolved, and may be in a molten state. Organic solvents that dissolve the polymer and drug include chloroform, dichloromethane, acetone, xylene, N-methylpyrrolidone, dimethylformamide (DMF), dimethylsulfoxide (DM).
SO). For example, when the polymer is polylactic acid, the organic solvent is preferably dichloromethane or chloroform.

[0026]

[Example 1] [Example 1] Stainless steel (SU
S316L) and a solution of 5 g of polylactic acid (molecular weight: 200,000) and 500 mg of vincristine (anticancer drug) dissolved in 100 ml of dichloromethane are prepared. The polylactic acid solution is placed in the solution bath in the dipping / spin coating apparatus shown in FIG. 3, and then the stent is immersed in the solution. Then, the stent is pulled out from the polylactic acid solution, the rotation speed of the spin coater is set to 2000 rpm, and the stent is rotated. The excess polymer attached to the stent was removed and a uniform drug-polymer coating was formed on the stent. Then, the coated stent was left in an oven at 37 ° C. for 30 minutes to be dried to obtain a coated stent.

[Embodiment 2] Stainless steel (S
A stent made of US316L), a solution of 5 g of polybutylmethyl acrylate (molecular weight: 20,000) dissolved in 100 ml of dichloromethane, and a solution of 10 g of all-trans retinoic acid dissolved in 100 ml of water are prepared. The dibutyl spin coating apparatus shown in FIG. 3 is filled with a polybutylmethyl acrylate solution in a solution bath, and then the stent is dipped in the solution. Then, pull up the stent from the polybutylmethyl acrylate solution, set the spin coater rotation speed to 2000 rpm,
Rotate the stent. Excess polymer attached to the stent was removed and a uniform polymer coating was formed on the stent. Then the coated stent
It was left to dry in a 37 ° C oven for 30 minutes. Further, the all-trans-retinoic acid solution is put into a solution tank in another dipping / spin coating apparatus, and the previously coated stent is immersed in the solution. Then, the stent is pulled out from the retinoic acid solution, the rotation speed of the spin coater is set to 2000 rpm, and the stent is rotated. Excess polymer retinoic acid attached to the stent was removed and a uniform drug-polymer coating was formed on the stent. Then, the coated stent was left to dry in an oven at 37 ° C. for 90 minutes to obtain a coated stent.

[Embodiment 3] The stainless steel (S
US316L) and a solution prepared by dissolving 5 g of polybutylmethyl acrylate (molecular weight: 20,000) in 100 ml of dichloromethane, all-trans.
Prepare a solution of 10 g of retinoic acid in 100 ml of water and a solution of silicone (molecular weight: 10,000) in 100 ml of hexane. The dibutyl spin coating apparatus shown in FIG. 3 is filled with a polybutylmethyl acrylate solution in a solution bath, and then the stent is dipped in the solution. Then, the stent is pulled out from the polybutyl methyl acrylate solution, the rotation speed of the spin coater is set to 2000 rpm, and the stent is rotated. Excess polymer attached to the stent was removed and a uniform polymer coating was formed on the stent. The coated stent is then left to dry in a 37 ° C oven for 30 minutes. Further, the all-trans-retinoic acid solution is put into a solution tank in another dipping / spin coating apparatus, and the previously coated stent is immersed in the solution. Then, the stent is pulled out from the retinoic acid solution, the rotation speed of the spin coater is set to 2000 rpm, and the stent is rotated. Excess polymer retinoic acid attached to the stent was removed and a uniform drug-polymer coating was formed on the stent. The coated stent is then left to dry in a 37 ° C oven for 90 minutes. Further, the silicone solution is placed in a solution bath in another dipping / spin coating apparatus, and the stent coated previously is immersed in the solution. Then, the stent is pulled out from the silicone solution, the rotation speed of the spin coater is set to 2000 rpm, and the stent is rotated. The excess silicone solution attached to the stent was removed and a uniform topcoat was formed on the stent. Then, the coated stent was left in an oven at 80 ° C. for 60 minutes to be dried to obtain a coated stent. (Comparative Example) In the conventional dipping coating method of Comparative Example, depending on the standing state after coating, the polymer moved downward due to the influence of gravity, and it was difficult to uniformly coat the entire surface of the stent. On the other hand, Examples 1 to 3
Stents coated with will remove excess polymer by rotating the stent,
It was possible to carry out a uniform coating of the polymer on the surface of the stent. Further, in the spray coating, since the polymer that is not coated on the stent by spraying is not used and is discarded, the coating must be performed using a large amount of the polymer as compared with the method of the present invention, which is a very economical loss. Is big.

[0029]

The coated stent of the present invention comprises the steps of bringing the surface of the stent into contact with a liquid polymer, rotating the stent to remove unwanted polymer, and substantially fixing the polymer to the stent. is doing. Therefore, it is possible to uniformly form a polymer containing a drug that reduces restenosis on the stent by a simple and economical method. The coated stent thus obtained can deliver a predetermined amount of drug over a desired period of time.

[Brief description of drawings]

FIG. 1 is a cross-sectional view showing a surface state of a stent according to the present invention.

FIG. 2 is a cross-sectional view showing a surface state of the stent according to the present invention.

FIG. 3 is an apparatus used to manufacture a stent according to the present invention.

FIG. 4 is a front view showing the entire stent according to the present invention.

[Explanation of symbols]

10a, 10b ... Coated stent 11a, 11b, 11c ... Stent 12a, 12b ... First drug-containing polymer 13 ... Second drug-containing polymer 14 ... Drug-containing polymer solution 15 ... Jig 16 ... Immersion tank 17 ... Coated stent 18, 18a, 18b ... Main components 19, 19a, 19b ... Connection part 20, 20a, 20b ... Annular unit 21 ... Connection part

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Claims (9)

[Claims] 1. A coated stent comprising the steps of contacting the surface of the stent with a liquid polymer, rotating the stent to remove unwanted polymer, and substantially fixing the polymer to the stent. Manufacturing method. 2. The method for producing a coated stent according to claim 1, wherein the structure of the stent is a substantially cylindrical stent having an inner surface and an outer surface. 3. The method for producing a coated stent according to claim 1, wherein the liquid polymer is a polymer dissolved in a solvent. 4. The method according to claim 1, wherein the step of bringing the surface of the stent into contact with a polymer in a liquid state is a step of immersing the stent in a polymer solution in which the polymer is dissolved in a solvent. A method for producing the coated stent described. 5. The method for producing a coated stent according to claim 1, wherein the polymer or the polymer solution contains a drug. 6. The method for producing a coated stent according to claim 5, wherein the drug is a drug that reduces restenosis. 7. The method for producing a coated stent according to claim 1, wherein the polymer is multi-layer coated on the surface of the stent. 8. The method of manufacturing a coated stent according to claim 7, wherein the multilayer coating comprises a multilayer coating having at least a topcoat and an undercoat. 9. A coated stent obtained by the production method according to claim 1, wherein the surface of the stent is coated with a polymer.