KR20210103996A - Drug eluting stent and manufacturing method of the same - Google Patents

Abstract

The present invention relates to a drug-releasing stent comprising a metal stent, and a coating layer coated on the metal stent, wherein the coating layer contains sertraline. By using the drug-releasing stent according to the present application, it is possible to suppress the occurrence of blood clots.

Description

DRUG ELUTING STENT AND MANUFACTURING METHOD OF THE SAME

The present application relates to a drug releasing stent and a method of making the same.

A stent is a device made of a biocompatible material such as metal or polymer, and is mainly used for the treatment of stenosis or aneurysms because it is inserted into a blood vessel and maintains its shape for a certain period of time. For example, when a stenosis occurs in a blood vessel such as a coronary artery, a balloon forming part of the catheter is inserted into the stenosis of the blood vessel, and the balloon of the catheter is expanded to expand the vascular stenosis to restore blood flow, etc. After this, a stent may be inserted to prevent restenosis of the blood vessel.

However, since the stent is a foreign substance made of metal or polymer, side effects such as restenosis and blockage of blood flow due to acute thrombosis in the stent after stent insertion, and interference with reendothelialization due to inflammation may occur.

In order to prevent the occurrence of side effects, a drug-releasing stent has been developed by coating the stent with a drug such as an anticancer agent or an immunosuppressant, and allowing it to slowly elute into the cells of the blood vessel. However, the drug-releasing stent coated with an anticancer agent or immunosuppressant inhibits the growth of vascular endothelial cells as well as vascular muscle cells, so it may interfere with the treatment of blood vessels, and there is a problem in that it is difficult to control the release of drugs from the outside. .

In addition, when a polymer material that can be decomposed in the human body is coated together so that the drug can be slowly released, the polymer is not coated with a uniform thickness on the entire stent structure, so there is a problem that the drug is not uniformly released. By overcoming these problems, studies related to a stent and a drug to be coated on the stent are being conducted for uniform discharge of the drug on the stent and selective treatment of the affected area.

Korea Patent Publication No. 10-1722036, which is the background technology of the present application, relates to a drug coating agent for a controlled drug release biodegradable stent, a method for manufacturing the same, and a biodegradable stent coated with the coating agent and a method for manufacturing the same. The registered patent discloses the use of an anticancer agent or an immunosuppressant in a stent as a drug for preventing restenosis of blood vessels.

The present application is intended to solve the problems of the prior art described above, and an object of the present application is to provide a drug-releasing stent.

Another object of the present application is to provide a method for manufacturing the drug-releasing stent.

However, the technical problems to be achieved by the embodiments of the present application are not limited to the technical problems as described above, and other technical problems may exist.

As a technical means for achieving the above technical problem, the first aspect of the present application is a metal stent, and in a drug-releasing stent comprising a coating layer coated on the metal stent, the coating layer is seltraline It provides a drug-releasing stent comprising:

According to one embodiment of the present application, the celltraline may inhibit the growth of vascular myocytes (SMC) and not simultaneously inhibit the growth of vascular endothelial cells, but is not limited thereto.

According to one embodiment of the present application, the coating layer may include a biodegradable polymer, but is not limited thereto.

According to one embodiment of the present application, the biodegradable polymer is polylactide, polyglycolide, polycaprolactone, polyethylene glycol, polyorthoester, poly It may include a material selected from the group consisting of amino acids (polyamino acid), and combinations thereof, but is not limited thereto.

According to one embodiment of the present application, the celtraline may be dispersed in the biodegradable polymer, but is not limited thereto.

According to one embodiment of the present application, the coating layer may be coated to a thickness of 5 μm to 10 μm, but is not limited thereto.

According to one embodiment of the present application, the metal stent may include a biocompatible metal selected from the group consisting of Cr, Co, Ti, Ni, Fe, and combinations thereof, but is not limited thereto.

A second aspect of the present application provides a method for manufacturing a drug-releasing stent comprising preparing a coating solution comprising celtraline and a biodegradable polymer, and coating a metal stent with the coating solution.

According to one embodiment of the present application, the coating solution may include one or more solvents selected from the group consisting of tetrahydrofuran, acetone, methylene chloride, chloroform, carbon tetrachloride, ethanol, and combinations thereof, but is limited thereto. it's not going to be

According to one embodiment of the present application, the coating is an ultrasonic coating method, a spin coating method, a cast method, a Langmuir-Blodgett (LB) method, an inkjet printing method, a nozzle printing method, a slot die coating method, a doctor It may be performed by a method selected from the group consisting of blade coating method, screen printing method, dip coating method, gravure printing method, reverse offset printing method, physical transfer method, spray coating method, and combinations thereof. It is not limited.

The above-described problem solving means are merely exemplary, and should not be construed as limiting the present application. In addition to the exemplary embodiments described above, additional embodiments may exist in the drawings and detailed description.

According to the above-described problem solving means of the present application, the drug-releasing stent according to the present application is to include celtraline. Accordingly, the stent inhibits the proliferation of vascular muscle cells and does not inhibit the growth of vascular endothelial cells, so that the stent-injected blood vessel can be easily treated, and restenosis of the blood vessel can be suppressed.

In addition, by using the drug-releasing stent according to the present application, it is possible to suppress the occurrence of thrombus, and may not affect reendothelialization.

However, the effects obtainable herein are not limited to the above-described effects, and other effects may exist.

1 is a cross-sectional view of a drug-releasing stent according to an embodiment of the present application.
2 is a flowchart illustrating a method for manufacturing a drug-releasing stent according to an embodiment of the present application.
3 is an SEM image of the drug-releasing stent according to an embodiment of the present application.
4 is a graph showing the activity of vascular muscle cells (SMC) and vascular endothelial cells (HUVEC) according to an experimental example of the present application.
5 is a diagram related to the performance evaluation of the drug-releasing stent according to an experimental example of the present application.
6 is a diagram related to the performance evaluation of the drug-releasing stent according to an experimental example of the present application.
7 is a cross-sectional image of a blood vessel according to an experimental example of the present application.

Hereinafter, embodiments of the present application will be described in detail with reference to the accompanying drawings so that those of ordinary skill in the art to which the present application pertains can easily implement them.

However, the present application may be implemented in several different forms and is not limited to the embodiments described herein. And in order to clearly explain the present application in the drawings, parts irrelevant to the description are omitted, and similar reference numerals are attached to similar parts throughout the specification.

Throughout this specification, when a part is said to be "connected" with another part, it includes not only the case where it is "directly connected" but also the case where it is "electrically connected" with another element interposed therebetween. do.

Throughout this specification, when it is said that a member is positioned "on", "on", "on", "under", "under", or "under" another member, this means that a member is positioned on the other member. It includes not only the case where they are in contact, but also the case where another member exists between two members.

Throughout this specification, when a part "includes" a component, it means that other components may be further included, rather than excluding other components, unless otherwise stated.

As used herein, the terms "about," "substantially," and the like are used in a sense at or close to the numerical value when the manufacturing and material tolerances inherent in the stated meaning are presented, and to aid in the understanding of the present application. It is used to prevent an unconscionable infringer from using the mentioned disclosure in an unreasonable manner. Also, throughout this specification, "step to" or "step to" does not mean "step for".

Throughout this specification, the term "combination of these" included in the expression of the Markush form means one or more mixtures or combinations selected from the group consisting of the components described in the expression of the Markush form, and the components It is meant to include one or more selected from the group consisting of.

Throughout this specification, reference to “A and/or B” means “A or B, or A and B”.

Hereinafter, the drug-releasing stent of the present application and a manufacturing method thereof will be described in detail with reference to embodiments and examples and drawings. However, the present application is not limited to these embodiments and examples and drawings.

1 is a cross-sectional view of a drug-releasing stent 10 according to an embodiment of the present application.

As a technical means for achieving the above technical problem, the first aspect of the present application is a drug-releasing stent 10 comprising a metal stent 100, and a coating layer 200 coated on the metal stent 100. In this case, the coating layer 200 provides a drug-releasing stent (10) comprising a celtraline (210, Sertraline).

According to one embodiment of the present application, the celltraline 210 may inhibit the growth of vascular muscle cells (SMC) and at the same time do not inhibit the growth of vascular endothelial cells, but is not limited thereto.

Celtraline is a type of selective serotonin reuptake inhibitors (SSRIs), and is known as a substance mainly used as an antidepressant and anxiolytic agent. The present inventors have confirmed that the celltraline has a property of inhibiting the growth of vascular muscle cells and not inhibiting the growth of vascular endothelial cells.

The vascular muscle cells are also referred to as vascular smooth muscle cells, and play a role in regulating the tension of blood vessels due to constriction of blood vessels, blood pressure, blood flow, and the like. In addition, the vascular endothelial cells (vascular endothelial cells) as cells constituting the endothelium of blood vessels, and serves as an interface between the blood and tissues and organs. When the vascular endothelial cells are damaged, blood vessels may leak into the underlying tissue, resulting in additional diseases.

Therefore, when the drug-releasing stent is inserted to prevent restenosis of the blood vessel, if the growth of the vascular endothelial cells is inhibited by the drug-releasing stent, additional diseases may occur. Therefore, by applying Celtraline, a drug that inhibits the growth of the vascular muscle cells and does not inhibit the growth of the vascular endothelial cells, to the stent according to the present disclosure, the above risk can be reduced.

According to one embodiment of the present application, the blood vessel into which the drug-releasing stent 10 coated with the celtraline 210 is inserted may suppress the occurrence of thrombus, but is not limited thereto.

According to one embodiment of the present application, the drug-releasing stent 10 may be inserted into the coronary artery, but is not limited thereto. For example, the coronary artery may include, but is not limited to, a left anterior descending artery, a left circumflex artery, and a right coronary artery.

As will be described later, as a criterion for evaluating the performance of the drug-releasing stent 10, the blood vessel wall damage index (injury score), inflammatory cell invasion index (inflammation score), endothelization index (endothelization score), and thrombus score (fibrin) score), etc.

According to one embodiment of the present application, the coating layer 200 may include the biodegradable polymer 220, but is not limited thereto.

According to one embodiment of the present application, the biodegradable polymer 220 is polylactide (polylactide), polyglycolide (polyglycolide), polycaprolactone (polycaprolactone), polyethylene glycol (polyethylene glycol), polyorthoester (polyorthoester) ), polyamino acids, and may include a material selected from the group consisting of combinations thereof, but is not limited thereto.

The biodegradable polymer 220 is coated on the metal stent 100 together with the celltraline 210 to suppress the release of a large amount of the celltraline 210 in a short period of time, and the cell It may serve to release the traline (210). Since the celtraline 210 is gradually released from the biodegradable polymer 220 or the coating layer 200 over time, it may interfere with the growth of blood vessels between the gaps of the metal stent 100 . Therefore, the problem of restenosis of blood vessels can be solved through the drug-releasing stent 10 .

According to one embodiment of the present application, the celtraline 210 may be dispersed on the biodegradable polymer 220, but is not limited thereto.

According to one embodiment of the present application, the coating layer 200 may be coated to a thickness of 5 μm to 10 μm, but is not limited thereto.

For example, when the coating layer 200 is coated on the metal stent 100 to a thickness of 5 μm or less, the release of the celtraline 210 on the coating layer 200 is accelerated, and the drug-releasing stent ( When 10) is expanded, cracks, peeling, etc. may occur in the coating layer 200 . In addition, for example, when the coating layer 200 is coated on the metal stent 100 to a thickness of 10 μm or more, the release of the celtraline 210 is slowed, so that the therapeutic effect by the drug-releasing stent 10 is reduced. is reduced, and the biodegradable polymer 220 on the coating layer 200 is decomposed, and inflammation may be further generated.

According to one embodiment of the present application, the metal stent 100 may include a biocompatible metal selected from the group consisting of Cr, Co, Ti, Ni, Fe, and combinations thereof, but is not limited thereto.

When the biodegradable polymer 220 on the coating layer 200 is decomposed in a blood vessel, the metal stent 100 may be exposed to blood. Therefore, the metal stent 100 should not corrode or react in the human body, and for this purpose, the metal stent 100 is made of a biocompatible metal such as Co-Cr alloy, Ni-Ti alloy, and stainless steel. can

2 is a flowchart showing a method of manufacturing the drug-releasing stent 10 according to an embodiment of the present application.

The second aspect of the present application is a drug-releasing stent comprising the steps of preparing a coating solution containing celtraline 210 and a biodegradable polymer 220, and coating the metal stent 100 by the coating solution The manufacturing method of (10) is provided.

With respect to the manufacturing method of the drug-releasing stent 10 according to the second aspect of the present application, detailed descriptions of parts overlapping with the first aspect of the present application are omitted, but even if the description is omitted, the contents described in the first aspect of the present application can be equally applied to the second aspect of the present application

First, a coating solution including celtraline 210 and biodegradable polymer 220 is prepared (S100).

According to one embodiment of the present application, the mass ratio of the celtraline 210 to the biodegradable polymer 220 may be 4:6 to 5:5, but is not limited thereto.

For example, when the mass ratio of the celltraline 210 to the biodegradable polymer 220 is greater than 5: 5, that is, when the celltraline 210 occupies 50% or more of the mass, the drug-releasing stent ( When 10) is expanded, cracks or peeling may occur in the coating layer 200 , and the celtraline 210 may be rapidly released. On the other hand, when the mass ratio of the celtraline 210 to the biodegradable polymer 220 is less than 4:6, that is, when the celtraline 210 occupies 40% or less by mass, the celtraline 210 ), it takes a lot of time to coat the desired amount, and the release period of the celtraline 210 may be longer than intended.

According to one embodiment of the present application, the coating solution may include one or more solvents selected from the group consisting of tetrahydrofuran, acetone, methylene chloride, chloroform, carbon tetrachloride, ethanol, and combinations thereof, but is limited thereto. it's not going to be

Then, the metal stent 100 is coated by the coating solution (S200).

Specifically, after the metal stent 100 is mounted on a jig, the metal stent 100 may be coated by the coating solution by using the coating solution.

According to one embodiment of the present application, the coating is an ultrasonic coating method, a spin coating method, a cast method, a Langmuir-Blodgett (LB) method, an inkjet printing method, a nozzle printing method, a slot die coating method, a doctor It may be performed by a method selected from the group consisting of blade coating method, screen printing method, dip coating method, gravure printing method, reverse offset printing method, physical transfer method, spray coating method, and combinations thereof. It is not limited.

The present invention will be described in more detail through the following examples, but the following examples are for illustrative purposes only and are not intended to limit the scope of the present application.

[Example]

A coating solution was prepared by mixing 20 mg of polylactide (PLA, molecular weight 100,000 or less) and 20 mg of celtraline in 20 ml of tetrahydrafuran (THF) solvent, and mixing for 1 hour. Then, the Co-Cr alloy stent was mounted on a jig, rotated at 125 rpm, and ultrasonically coated so that the gap between the stent and the nozzle through which the coating solution was discharged at a rate of 0.03 mL/min was 10 mm.

[Comparative Example 1]

A coating solution was prepared by mixing 20 mg of polylactide (PLA, molecular weight 100,000 or less) and 20 mg of sirolimus in 20 ml of tetrahydrafuran (THF) solvent, and mixing for 1 hour. Then, the Co-Cr alloy stent was mounted on a jig, rotated at 125 rpm, and ultrasonically coated so that the gap between the stent and the nozzle through which the coating solution was discharged at a rate of 0.03 mL/min was 10 mm.

[Comparative Example 2]

A coating solution was prepared by mixing 20 mg of polylactide (PLA, molecular weight 100,000 or less) and 20 mg of everolimus in 20 ml of tetrahydrafuran (THF) solvent and mixing for 1 hour. Then, the Co-Cr alloy stent was mounted on a jig, rotated at 125 rpm, and ultrasonically coated so that the gap between the stent and the nozzle through which the coating solution was discharged at a rate of 0.03 mL/min was 10 mm.

[Experimental Example 1]

Celltraline-injected vascular muscle cells (SMC) and vascular endothelial cells (HUVEC), sirolimus-injected vascular muscle cells (SMC) and vascular endothelial cells (HUVEC), and drug-free vascular muscle cells ( SMC) and vascular endothelial cells (HUVEC) were compared to measure the cell activity of the vascular muscle cells and the vascular endothelial cells.

4 is a graph showing the activity of vascular muscle cells (SMC) and vascular endothelial cells (HUVEC) according to an experimental example of the present application.

Referring to FIG. 4 , in the case of vascular muscle cells (SMC) and vascular endothelial cells (HUVEC) that are not injected with drugs, since the vascular muscle cells (SMC) and the vascular endothelial cells (HUVEC) have high activity, the Although the treatment is effective, the problem of restenosis of blood vessels may occur. In the case of vascular muscle cells (SMC) and vascular endothelial cells (HUVEC) injected with sirolimus, the activity of the vascular muscle cells is low, so that the problem of restenosis of blood vessels may not occur, but the activity of the vascular endothelial cells is also low. Treatment of blood vessels may be delayed.

However, in the case of vascular muscle cells (SMC) and vascular endothelial cells (HUVEC) injected with cetraline, the proliferation of the vascular muscle cells was inhibited, but the growth of the vascular endothelial cells was not inhibited. Therefore, when celtraline is used for the drug-releasing stent, it can be confirmed that the treatment of blood vessels can proceed quickly while solving the problem of restenosis of blood vessels.

[Experimental Example 2]

A balloon catheter was inserted into the porcine coronary artery and dilated to a pressure of 8 to 12 atm, resulting in a dilatation of 1.1 to 1.3 times the normal vessel size. Then, a stent according to an embodiment or a comparative example of the present application was inserted into the coronary artery. Then, the carotid artery of the pig was ligated, the sheath was removed, and the skin of the neck was sutured. Then, after transferring the pigs to the breeder, aspirin and clopidogrel were administered to the pigs for 4 weeks and observed.

After 4 weeks, the pigs were euthanized, and the heart was removed by incision of the side thorax, 4% formalin was flowed into the ascending aorta and pulmonary artery at a perfusion pressure of 70 mmHg, and perfusion-fixation was performed for more than 24 hours. Thereafter, a section of the coronary artery was excised with a margin of 1 cm above and below the stent, and the section was cut at an interval of 2 mm to 3 mm, and then the stent was removed. Then, a paraffin block was prepared from the section, and a fine section with a size of 5 μm was prepared by cutting the paraffin block.

The cross section of the coronary artery section was stained with hematoxylin and eosin staining method, and each section section was measured by calibrated digital microscope planimetry.

The measurement results were analyzed using the Visus 2000 Visual Image Analysis System, and the coronary artery restenosis rate, inflammation score, thrombus score, reendothelialization score, and the like were measured.

5 and 6 are diagrams related to the performance evaluation of the drug-releasing stent according to an experimental example of the present application. Specifically, FIG. 5 is a diagram related to the restenosis rate of the drug-releasing stent according to an experimental example of the present application, and FIG. 6 is a diagram showing the stage of the inflammation index of the drug-releasing stent according to an experimental example of the present application.

Referring to FIG. 5 , the restenosis rate means the ratio between the area of the neointima area and the area of the internal elastic lamina area. The area of the neointima can be obtained by excluding the area of the lumen area.

Referring to FIG. 6 , when no inflammatory cells are present around the strut of the drug-releasing stent, a score of 0, if the inflammatory cells are present in a low ratio but do not surround the strut, a score of 1, the inflammatory cells are By giving 2 points if present in an intermediate ratio but not surrounding the strut, and 3 points if the inflammatory cells are present at a high ratio and surround the strut, the degree of inflammation caused by the drug-releasing stent can be quantified. have.

A thrombus score can be determined through a cross-section of a section of the stained coronary artery. Specifically, 0 points if no stained area is visible in the cross section of the section of the stained coronary artery, 1 point if 25% or less of the area of the cut section, 2 points if 25% to 50% of the area of the cut section is 2 points, and If it is 50% or more of the area of the cut surface, by giving 3 points, it is possible to quantify the degree of thrombus generation by the drug-releasing stent.

When the cross section of the stained coronary artery section was observed, 3 points if the entire blood vessel was reendothelialized, 2 points if 50% or more of the circumference of the blood vessel was reendothelialized, 25% to 50% of the circumference of the blood vessel The degree of reendothelialization of the drug-releasing stent can be quantified by giving 1 point if reendothelialization is achieved, and 0 point if 25% or less of the circumference of the blood vessel is reendothelialized.

Evaluation items Example Comparative Example 1 restenosis rate
Area restenosis (%) 28.8±5.49 24.8±3.41 inflammation score
Inflammation score(0 ~ 3) 1.11
Mode: 1 1.01
Mode: 1 thrombus score
Fibrin score(0 ~ 3) 0.23
Mode: 0 1.43
Mode: 1 reendothelialization score
Endothelization score 1.25
Mode: 1 0.45
Mode: 0

In addition, referring to Table 1 and FIGS. 5 and 6 , the drug-releasing stent according to an embodiment of the present application has a similar degree of inflammation to the drug-releasing stent according to Comparative Example 1 of the present application, while thrombosis does not occur easily. It can be confirmed that the treatment effect of the blood vessel is high.

Referring to FIG. 7 , in the drug-releasing stent according to an embodiment of the present application, since the lumen area is not released to the adventitia, the drug-releasing stent will have a high therapeutic effect. On the other hand, in the drug-releasing stent according to Comparative Example 2 of the present application, since the lumen area is released to the adventitia beyond the drug-releasing stent, the therapeutic effect of the drug-releasing stent will be low. .

The above description of the present application is for illustration, and those of ordinary skill in the art to which the present application pertains will understand that it can be easily modified into other specific forms without changing the technical spirit or essential features of the present application. Therefore, it should be understood that the embodiments described above are illustrative in all respects and not restrictive. For example, each component described as a single type may be implemented in a distributed manner, and likewise components described as distributed may be implemented in a combined form.

The scope of the present application is indicated by the following claims rather than the above detailed description, and all changes or modifications derived from the meaning and scope of the claims and their equivalents should be construed as being included in the scope of the present application.

10: drug release stent
100: metal stent
200: coating layer
210: Celtraline
220: biodegradable polymer

Claims (7)

metal stents; and
a coating layer coated on the metal stent;
In the drug-releasing stent comprising a,
The coating layer includes Sertraline,
The celltraline inhibits the growth of vascular myocytes (SMC) and does not inhibit the growth of vascular endothelial cells at the same time,
The blood vessel into which the drug-releasing stent coated with the celtraline is inserted suppresses the occurrence of blood clots,
The coating layer contains a biodegradable polymer,
The celtraline is dispersed on the biodegradable polymer, the drug-releasing stent.
The method of claim 1,
The biodegradable polymer is polylactide, polyglycolide, polycaprolactone, polyethylene glycol, polyorthoester, polyamino acid, and these A drug-releasing stent comprising a material selected from the group consisting of combinations of
The method of claim 1,
Wherein the coating layer is coated to a thickness of 5 μm to 10 μm, the drug-releasing stent.
The method of claim 1,
Wherein the metal stent comprises a biocompatible metal selected from the group consisting of Cr, Co, Ti, Ni, Fe, and combinations thereof, the drug-releasing stent.
preparing a coating solution containing celtraline and a biodegradable polymer; and
coating the metal stent with the coating solution;
which includes,
A method of manufacturing a drug-releasing stent.
6. The method of claim 5,
The method of claim 1, wherein the coating solution comprises one or more solvents selected from the group consisting of tetrahydrofuran, acetone, methylene chloride, chloroform, carbon tetrachloride, ethanol, and combinations thereof.
6. The method of claim 5,
The coating is an ultrasonic coating method, a spin coating method, a casting method, a Langmuir-Blodgett (LB) method, an inkjet printing method, a nozzle printing method, a slot die coating method, a doctor blade coating method, a screen printing method, A method for manufacturing a drug-releasing stent, which is performed by a method selected from the group consisting of dip coating method, gravure printing method, reverse offset printing method, physical transfer method, spray coating method, and combinations thereof.

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