KR101253284B1 - Method for modifying surface of stent - Google Patents

Abstract

The present invention relates to a method of surface modification of a stent. Using the method for surface modification of the stent according to one embodiment, it is possible to more smoothly modify the surface of the stent coated with the biodegradable polymer.

Description

Method for modifying surface of stent

The present invention relates to a method of surface modification of a stent.

In order to reduce the restenosis rate of the stent, biodegradable polymers can be used instead of non-degradable polymers to suppress late thrombosis and inflammation, and also by forming a coating layer in several layers instead of stacking the biodegradable polymers in one layer. The timing of release can be controlled. Biodegradable polymers should be guaranteed for blood compatibility, tissue compatibility, nontoxicity, safety, and the like, in particular for stability in the body. Biodegradable synthetic polymers such as poly (lactic-co-glycolic acid) (PLGA), poly (L-lactic acid) (PLLA), poly (caprolactone) (PCL) to use materials that meet biocompatibility Has been used.

Commonly used coating methods are applied in a number of techniques. Currently known coating methods include dip coating (Whelan DM, et al., Heart Drug, 2000; 83: 338-345), electrospinning (Kuraishi K, et al., J. Biomed. Mater. Res. B Appl. Biomater., 2009; 88: 230-239), ink jet deposition, ultrasonic spray coating (Chen MC, et al., J. Control. Rel .. 2005; 108: 178-179), and the like. Although dip-coating is a common method that can be easily coated by a simple process, the fine tertiary structure such as stents can easily bond the coating to the spaces between the structures.

The simultaneous effect on uniform coating and productivity at the thin thickness required for coating is not expected. Electrospinning is not suitable for uniform, pore-free coatings as it is mainly used for making nanofibers, and it is not suitable for layer by layer (LBL, Jiyeon Choi, et al., Biomaterials, 2009, 88; 28: 5201-). 8) In the same case, each layer is connected to each other by electrostatic attraction, hydrogen bonding, or covalent bonding. It is possible to implement a multilayer ultra thin film without.

Thus, inserting materials with the desired properties into each layer could be used for a wider range of functionalities in drug release systems. On the other hand, since coating can be performed only through a repeated process, industrially, the productivity tends to be lower. In the case of electrospray technology, if a solution is applied from a microscopic nozzle by applying thousands of tens of thousands of high voltages to the solution, the sprayed solution can be easily microfabricated and microfabricated to easily prepare a nanostructure, thereby making a very simple equipment and coating process. This has the advantage that it is easily applicable to industrialization, and the equipment is also widely used because of its low cost. In the present invention, the ultrasonic coating machine was performed by focusing on a faster productivity with other technologies by minimizing the coating process through a simple equipment. When the stent is coated by various coating methods, the surface is not smooth. In addition, the stent coated with multiple layers may cause the drug release rate to be slow due to the too thick thickness of the coating supporting layer of the biodegradable polymer, and even the biodegradable polymer may have residual polymers and drugs and roughness of the surface of the polymer. The rougher it is, the more likely it is to cause inflammation of the walls of blood vessels. In particular, uneven and rough surfaces are more likely to cause wounds when endovascular stents are inserted. In previous experiments, inflammatory cells proliferated at the wound site of a metal stent, which were located in the endothelial cell (EC) layer located in the intima and in the media. A smooth muscle cell (SMC) layer is located in the interspace, and very active inflammatory cells are known to send biochemical signals to SMC. Upon receiving this signal, the SMC penetrates into the vascular lining and begins to proliferate. That is, the surface smoothness control is very important in the implant metal coating because the wound due to the rough surface may contribute to the SMC proliferation.

Therefore, there is a need for a stent coating method capable of improving the roughness of the stent to a smooth surface in a more effective manner, and also inhibiting neointimal proliferation through the effects of drugs.

One embodiment provides a method of surface modification of a stent.

One aspect is to form a coating layer by ultrasonically spraying a mixture of the first biodegradable polymer and drug on the surface of the stent; Contacting the stent and the solvent on which the coating layer is formed; And it provides a surface modification method of the stent comprising the step of evaporating the solvent at a temperature condition of 20 ℃ to 80 ℃.

The surface modification method of the stent will be described in detail for each step as follows.

First, the method may include forming a coating layer by ultrasonically spraying a mixture of the first biodegradable polymer and the drug on the surface of the stent.

The term "stent" is a tube used to insert a blood vessel or catheter to keep the inner diameter of the tube open and to facilitate fluid flow. A medical device for preventing closure due to stenosis. According to one embodiment, the stent may be, for example, a non-degradable metal material selected from the group consisting of stainless steel, cobalt-chromium, platinum-chromium, tantalum, titanium, nitinol, gold, platinum, silver and alloys thereof. have.

This step is a step of dissolving the first biodegradable polymer and drug in a solvent to form a uniform mixture, and then coating the mixture on a stent to form a coating layer, the solvent for preparing the mixture is acetone, chloroform, dioxane, One or more selected from the group consisting of tetrahydrofuran, acetonitrile, methylene chloride, carbon tetrachloride, toluene, xylene, benzene, dimethylformamide and hexafluoroisopropanol may be used, but is not limited thereto. The most important factor in determining the solvent is the solubility of the first biodegradable polymer and drug, and a high boiling point solvent may be used depending on the coating method. In order to make the multi-coated stent of the present invention, the mixed solution may be deposited on the surface of the stent using, for example, dip coating or spray coating. Most preferably, a spray coating method using an ultrasonic spray device can be used.

According to one embodiment, the first biodegradable polymer is polyglycolic acid, poly-L-lactic acid, poly-D-lactic acid, poly-D, L-lactic acid, poly-e-caprolactone, polylactic acid-glycolic acid aerial Copolymer (PLGA), poly-L-lactic acid-e-caprolactone copolymer (PLCL), polyethylene glycol, polyamino acid, polyanhydride, polyorthoester, polydioxanone, polyphosphagen, cellulose acetate butylate It may be at least one selected from the group consisting of cellulose tri acetate and copolymers thereof. In addition, the biodegradable polymer may have, for example, a molecular weight of 1,000 to 500,000 or a molecular weight of 2,000 to 200,000. If the molecular weight of the biodegradable polymer is too small, the surface of the stent is not well coated, the surface is not smooth, if the molecular weight is too high, it is difficult to dissolve in a solvent for spraying the surface of the stent, it is difficult to control the coating thickness As a result, the spray nozzles for the coating may be clogged, resulting in poor coating.

According to one embodiment, the biodegradable polymer, for example, may be included in the coating layer at a concentration of 0.001% to 40% by weight, or 0.01% to 20% by weight. The concentration of polymer contained in the coating layer is an important factor in determining the thickness of the coating. If the concentration of the biodegradable polymer is too low, the coating of the surface of the stent is not well coated, it takes a long time to coat, if the concentration of the biodegradable polymer is too high because the injection nozzle for the coating is blocked, the injection is not made The surface is not smoothed, and the coating film thickness can be difficult to control.

According to one embodiment, the drug may be, for example, but not limited to, chioctic acid, sirolimus, paclitaxel, liopuro, dexamethasone, tacrolimus, mycophenolylic acid, estradiol or nitric oxide. . The concentration of the drug is preferably 0.01% to 90% by weight of the biodegradable polymer concentration. If the concentration of the drug is less than 0.01% by weight of the biodegradable polymer concentration of the drug contained in the coating layer is less effective, the drug is less effective, when used in more than 90% by weight difficult to uniform coating on the surface of the stent, excessive drug Toxicity by release may result.

Thereafter, the method may include contacting the stent on which the coating layer is formed with a solvent and evaporating the solvent at a temperature condition of 20 ° C. to 80 ° C.

The solvent may be, for example, acetone, chloroform, ethyl acetate, toluene, benzene, methylene chloride, tetrahydrofuran, dioxane, acet nitrile or xylene, but not limited thereto, and modifying the surface of the stent by the above steps. The temperature range for this can be, for example, 1 ° C to 150 ° C, preferably 20 ° C to 80 ° C, most preferably 25 ° C to 40 ° C. If the temperature is too low, evaporation of the solvent does not occur, and if the temperature is higher than the melting point of the solvent, the biodegradable polymer is dissolved and flowed down. On the other hand, the time for evaporating the solvent in order to modify the surface of the stent by the step may be, for example, 1 second to 30 minutes, most preferably, 10 seconds to 300 seconds. Too much of this time causes the solvent to evaporate for too long, causing the coating on the stent surface to melt and flow down.

Another embodiment includes the steps of ultrasonically spraying a mixture of the first biodegradable polymer and drug on the surface of the stent to form a coating layer; And spraying a solution containing a second biodegradable polymer and a solvent on a surface of the stent on which the coating layer is formed.

Since the first step of the method is as described above, it is omitted to avoid excessive complexity of the specification.

Thereafter, the method may include spraying a solution including a second biodegradable polymer and a solvent on a surface of the stent on which the coating layer is formed.

According to one embodiment, the second biodegradable polymer is, for example, polylactide, polyglycolide, polycaprolactone, polylactide-co-glycolide, polylactide-co-caprolactone, polyglycolide Co-caprolactone, polydioxanone, polydioxanone, polytrimethylenecarbonate, polyglycolide-co-dioxanone, polyamide esters, polypeptides, polyorthoesters, polymaleic acid or polyanhydrides It may be, but is not limited thereto. In addition, the molecular weight of the second biodegradable polymer may be, for example, 1,000 to 500,000, most preferably 2,000 to 200,000. The solvent that may be used may be, for example, but not limited to acetone, chloroform, ethyl acetate, toluene, benzene, methylenechloride, tetrahydrofuran, dioxane, acetonitrile, xylene.

The sprayed solution may be a solution in which the second biodegradable polymer is dissolved in the solvent, for example, 0 wt% to 10 wt%, most preferably 0.01 wt% to 5 wt%, and the temperature during the spraying. The conditions may be 1 ° C to 150 ° C, preferably 20 ° C to 80 ° C, most preferably 25 ° C to 40 ° C. In addition, the injection time may be, for example, 1 second to 30 minutes, most preferably, 10 seconds to 180 seconds.

Another embodiment is to ultrasonically spray a mixture of the first biodegradable polymer and drug on the surface of the stent to form a coating layer; And heating the stent on which the coating layer is formed at a temperature condition of 50 ° C. to 80 ° C.

Since the first step of the method is as described above, it is omitted to avoid excessive complexity of the specification.

Thereafter, the method may include heating the stent on which the coating layer is formed to a temperature condition of 20 ℃ to 150 ℃.

According to one embodiment, the heating may be carried out by placing the stent on which the coating layer is formed in a sealed container and adjusting the temperature of the container. If the heating temperature is too low, the phase of the biodegradable polymer does not occur at all, and if the heating temperature is too high, the biodegradable polymer decomposes, and the temperature condition is considered in consideration of the glass transition temperature (Tg) and melting point (Tm) of the biodegradable polymer. You can decide. For example, the temperature may be 1 ° C to 250 ° C, preferably 20 ° C to 150 ° C, and most preferably 50 ° C to 80 ° C. The heating time may be for example 1 second to 30 minutes, most preferably 10 seconds to 300 seconds.

Using the method for surface modification of the stent according to one embodiment, it is possible to more smoothly modify the surface of the stent coated with the biodegradable polymer.

1 is a scanning electron micrograph showing that the surface of the stent is smoothly modified using the method of modifying the stent according to one embodiment.
2 is a scanning electron micrograph showing the surface of the stent without using the method of modifying the stent according to an embodiment.
FIG. 3 is a scanning electron micrograph showing that the solvent evaporation time is excessive in the method of reforming the stent according to one embodiment, the phenomenon of flowing down on the surface of the stent.

Hereinafter, one or more embodiments will be described in more detail by way of examples. However, these examples are provided to illustrate one or more embodiments by way of example, but the scope of the invention is not limited to these examples.

Example 1 Stent Surface Modification Using Solvent Evaporation (1)

The polylactic acid-glycolic acid copolymer (PLGA, molecular weight: 50,000 or less), a biodegradable polymer, was dissolved in a chloroform solvent at a concentration of 0.1% by weight in a cobalt-chromium stent, and then 20% by weight of sirolimus was completely dissolved. After the coating solution was prepared, the coating solution was coated on the stent to a thickness of 7 μm using an ultrasonic spray device. In order to smooth the surface of the coated stent, tetrahydrofuran solvent was placed in a sealed container, the temperature was fixed at 30 ° C., and the solvent was evaporated by solvent evaporation for 20 seconds, and then the surface was scanned with a scanning electron microscope. (scanning electron microscopy, SEM). As a result, as shown in Figure 1, it was confirmed that the surface of the coated stent was modified smoothly.

Example 2 Stent Surface Modification by Solvent Evaporation (2)

After dissolving poly-L-lactic acid (PLLA, molecular weight: 100,000 or more), a biodegradable polymer, in a chloroform solvent at a concentration of 0.1% by weight in a stainless steel stent, 20% by weight of paclitaxel was completely dissolved to prepare a coating solution. Next, the coating solution was coated on the stent to a thickness of 7 μm using an ultrasonic spray device. In order to smooth the surface of the coated stent, chloroform solvent was placed in an airtight container, the temperature was fixed at 25 ° C., the solvent was evaporated by solvent evaporation for 5 minutes, and then the surface was observed with a scanning electron microscope. It was. As a result, similar to Figure 1, it was confirmed that the surface of the coated stent was modified smoothly.

Example 3 Stent Surface Modification Using Solvent Evaporation (3)

After dissolving polycaprolactone (PCL, molecular weight: 80,000 or more), which is a biodegradable polymer, in a chloroform solvent at a concentration of 0.1% by weight in platinum-chromium stent, 20% by weight of chioctic acid was added to completely dissolve the coating solution. Next, the coating solution was coated on the stent to a thickness of 7 μm using an ultrasonic spray device. To smooth the surface of the coated stent, ethyl acetate solvent was placed in a sealed container, the temperature was fixed at 40 ° C., the solvent was evaporated by solvent evaporation for 20 seconds, and then the surface was scanned with a scanning electron microscope. Observed. As a result, similar to Figure 1, it was confirmed that the surface of the coated stent was modified smoothly.

Example 4 Stent Surface Modification Using Solution Spray (1)

After dissolving poly-D, L-lactic acid (PDLLA, molecular weight: 50,000 or more), which is a biodegradable polymer, in a chloroform solvent at a concentration of 0.1% by weight, nitronol stent was added to 20% by weight of a repro to completely dissolve the coating solution. After the preparation, the coating solution was coated on the stent to a thickness of 7 μm using an ultrasonic spray device. Thereafter, the coating solution prepared by dissolving PLGA having a molecular weight of 20,000 in a chloroform solvent at 0.01% by weight was slowly sprayed using an electric injector to coat the surface smoothly, and then the surface was observed with a scanning electron microscope. The injection was carried out at 30 ° C. for 90 seconds. As a result, similar to Figure 1, it was confirmed that the surface of the coated stent was modified smoothly.

Example 5 Stent Surface Modification Using Solution Spray (2)

Poly-L-lactic acid-caprolactone (PLCL, molecular weight: 130,000 or more), which is a biodegradable polymer, was dissolved in a magnesium stent at a concentration of 0.1% by weight in a chloroform solvent, and 20% by weight of estradiol was added to completely dissolve the coating solution. After the preparation, the coating solution was coated on the stent to a thickness of 7 μm using an ultrasonic spray device. Thereafter, the surface of the coating solution prepared by dissolving PDLLA having a molecular weight of 40,000 in methylene chloride solvent at 0.01% by weight was slowly sprayed using an ultrasonic nanocoating machine, and then the surface was observed with a scanning electron microscope. The injection was carried out at room temperature for 180 seconds. As a result, similar to Figure 1, it was confirmed that the surface of the coated stent was modified smoothly.

Example 6 Stent Surface Modification Using Solution Spray (3)

A polylactic acid-glycolic acid copolymer (PLGA, molecular weight: 50,000 or more) was dissolved in a chloroform solvent at a concentration of 0.1% by weight in a gold stent, and then 20% by weight of tacrolimus was completely dissolved to prepare a coating solution. Then, the coating solution was coated on the stent to a thickness of 7 μm using an ultrasonic spray device. Thereafter, the coating solution prepared by dissolving PCL having a molecular weight of 15,000 in an ethyl acetate solvent at 0.01% by weight was slowly sprayed using an electric injector to smoothly coat the surface, and then observed the surface by scanning electron microscope. The injection was carried out at 35 ° C. for 90 seconds. As a result, similar to Figure 1, it was confirmed that the surface of the coated stent was modified smoothly.

Example 7 Stent Surface Modification Using Heating Method (1)

After dissolving polyanhydride (molecular weight: 100,000 or more) in a chloroform solvent at a concentration of 0.1% by weight in silver stent, 20% by weight of mycophenolic acid was added to completely dissolve the coating solution, and then using an ultrasonic spray device. The coating solution was coated on the stent to a thickness of 7 μm. In order to smooth the surface of the coated stent was placed in an airtight container and heated for 300 seconds at a temperature of 50 ℃, the surface was observed with a scanning electron microscope. As a result, similar to Figure 1, it was confirmed that the surface of the coated stent was modified smoothly.

Example  8: by heating method Stent  Surface Modification Method (1)

After dissolving polyorthoester (molecular weight: 100,000 or more) in a tantalum stent at a concentration of 0.1% by weight in a chloroform solvent, 20% by weight of nitrogen oxide was added to completely dissolve the coating solution, and then using an ultrasonic spray device. The coating solution was coated on the stent to a thickness of 7 μm. In order to smooth the surface of the coated stent was placed in an airtight container and heated for 60 seconds at a temperature of 80 ℃, the surface was observed with a scanning electron microscope. As a result, similar to Figure 1, it was confirmed that the surface of the coated stent was modified smoothly.

Comparative Example 1: Observation of the surface of the stent without using the stent surface modification method

After dissolving PLGA (molecular weight; 50,000 or less), which is a biodegradable polymer, in a chloroform solvent at a concentration of 0.1% by weight, 20% by weight of sirolimus was added to dissolve the cobalt-chromium stent to prepare a coating solution. After the coating solution was coated on the stent to a thickness of 7 μm using an injector, the surface was observed by scanning electron microscopy. As a result, as shown in FIG. 2, the coated surface was not smooth and was found to be fairly rough.

Comparative Example 2: Observation of Surface Modification of Stents with Change of Solvent Evaporation Conditions by Solvent Evaporation

After dissolving PLGA (molecular weight; 50,000 or less), which is a biodegradable polymer, in a chloroform solvent at a concentration of 0.1% by weight, 20% by weight of sirolimus was added to dissolve the cobalt-chromium stent to prepare a coating solution. The coating solution was coated on the stent to a thickness of 7 μm using an injector. In order to smooth the surface of the coated stent, the tetrahydrofuran solvent was placed in a sealed container, the temperature was fixed at 30 ° C., the solvent was evaporated by solvent evaporation for 300 seconds, and then the surface was scanned with a scanning electron microscope. Observed by. As a result, as shown in Figure 3, the surface of the coated stent (webbing) was confirmed that the phenomenon appears.

Claims (11)

Ultrasonically spraying a mixture of the first biodegradable polymer and the drug on the surface of the stent to form a coating layer;
Contacting the stent and the chloroform solvent in which the coating layer is formed; And
Method for surface modification of the stent comprising evaporating the solvent at a temperature condition of 25 ℃ to 80 ℃. Ultrasonically spraying a mixture of the first biodegradable polymer and the drug on the surface of the stent to form a coating layer; And
And spraying a solution including a second biodegradable polymer and a solvent on a surface of the stent on which the coating layer is formed. Ultrasonically spraying a mixture of the first biodegradable polymer and the drug on the surface of the stent to form a coating layer;
Method for modifying the surface of the stent comprising the step of heating the stent on which the coating layer is formed at a temperature condition of 20 ℃ to 150 ℃. The metal material of claim 1, wherein the stent is selected from the group consisting of stainless steel, cobalt-chromium, platinum-chromium, tantalum, titanium, nitinol, gold, platinum, silver and alloys thereof. How to be. The method according to any one of claims 1 to 3, wherein the biodegradable polymer is polyglycolic acid, poly-L-lactic acid, poly-D-lactic acid, poly-D, L-lactic acid, poly-e-caprolactone, Polylactic acid-glycolic acid copolymer (PLGA), poly-L-lactic acid-e-caprolactone copolymer (PLCL), polyethyleneglycol, polyamino acid, polyanhydride, polyorthoester, polydioxanone, polyforce At least one selected from the group consisting of pargen, cellulose acetate butyrate, cellulose tri acetate, and copolymers thereof. The method of any one of claims 1 to 3, wherein the biodegradable polymer has a molecular weight of 2,000 to 200,000. The method of any one of claims 1 to 3, wherein the biodegradable polymer is at a concentration of 0.01% to 20% by weight. The drug according to any one of claims 1 to 3, wherein the drug is selected from the group consisting of chioctic acid, sirolimus, paclitaxel, liprolo, dexamethasone, tacrolimus, mycophenollylic acid, estradiol and nitric oxide. Which method is chosen. The method of claim 2, wherein the solvent is selected from the group consisting of acetone, chloroform, ethyl acetate, toluene, benzene, methylenechloride, tetrahydrofuran, dioxane, acetnitrile and xylene. Ultrasonically spraying a mixture of the first biodegradable polymer and the drug on the surface of the stent to form a coating layer;
Contacting the stent on which the coating layer is formed with a tetrahydrofuran solvent; And
Evaporating the solvent for 1 second to 200 seconds at a temperature condition of 25 ℃ to 80 ℃ method of surface modification of the stent. Ultrasonically spraying a mixture of the first biodegradable polymer and the drug on the surface of the stent to form a coating layer;
Contacting the stent on which the coating layer is formed with a solvent selected from the group consisting of acetone, ethyl acetate, toluene, benzene, methylene chloride, dioxane, acetnitrile and xylene; And
Method for surface modification of the stent comprising evaporating the solvent at a temperature condition of 25 ℃ to 80 ℃.

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