WO2007129779A1

WO2007129779A1 - The coating process of the stent for reopro

Info

Publication number: WO2007129779A1
Application number: PCT/KR2006/001741
Authority: WO
Inventors: Myung Ho Jeong; Dong Lyun Cho
Original assignee: Industry Foundation of Chonnam National University
Current assignee: Industry Foundation of Chonnam National University
Priority date: 2006-05-09
Filing date: 2006-05-10
Publication date: 2007-11-15
Anticipated expiration: 2008-11-09
Also published as: KR100778656B1; US20080038446A1; KR20070108974A; DE102007021601A1

Abstract

A method of coating a surface of a stent with abcixmab (Reopro) which is one of glycoprotein Ilb/IIIa receptor inhibitors is provided. In case of acute coronary occlusion, the stent made of a stainless steel treated with carbon is coated with the Reopro having an antiplatelet action against platelets, thereby remarkably preventing the stent restenosis. The coating method includes activating the surface through cleaning and plasma process, and coating the surface with a thin film having an amine radical. A process condition suitable for the feature of the carbon is induced at each process.

Description

THE COATING PROCESS OF THE STENT FOR REOPRO

BACKGROUND OF THE INVENTION

Field of the Invention [0001] The present invention relates to a method of coating a stent which is inser ted into narrowed or occluded blood vessels of a human body to vasodilate the blood ve ssel, with an anti-platelet agent, and more particularly, to a method of coating a surface of a stent with abcixmab (hereinafter referred to as "Reopro" (trademark)) which is one of glycoprotein Ilb/IIIa receptor inhibitors, so as to inhibit the stent restenosis after stenti ng operation, in case that the stent is made of a stainless steel treated with carbon.

Background of the Related Art

[0002] In general, if blood vessels, such as coronary artery, peripheral vascular sys tern, and so forth, are occluded due to deposition of cholesterol or the like, it blocks the flow of blood to induce a fatal disease.

[0003] In particular, a heart is the most major organ to control the flow of blood in a human body. If a problem arises in the cardiac blood vessel, it is difficult to cont rol the flow of blood which supplies the blood to all parts of the human body, and thus, it induces a serious problem. [0004] In case of a patient suffering from angina pectoris, for example, the patent feels a sever pain, or may suddenly die.

[0005] In case of the coronal occlusion of a heart, if the occlusion is not settled within about 90 minutes, a patient may die or may be suffered from a brain injury. [0006] In this instance, stenting operation using a stent is widely conducted recent

Iy, rather than conventional methods such as phlebotomy, arteriotomy, medication of medi cines to dissolving thrombus, and so forth.

[0007] More specifically, a guide catheter is inserted in a blood vessel through an inlet port of the blood vessel, and is traveled to a lesion in the blood vessel, and then a guide wire is inserted in the guide catheter positioned proximity to the lesion. The gu ide wire is guided by the guide catheter, and is positioned at the curved lesion of the bl ood vessel (see Fig. 3 a). After the guide wire is inserted in a bladder catheter, the blad der catheter is moved to the lesion of the blood vessel, and a bladder of the bladder cat heter is positioned at the lesion (see Fig. 3b). Finally, the bladder is inflated by supplyi ng air to the bladder with a pressing means coupled to a connector of the bladder cathet er, so that the lesion is expanded, with a blocking substance being compressed (see Fig.

3c).

[0008] Since the flexible bladder made of nylon material has a limit to compressi on of the blocking substance in the blood vessel, a stent made of a stainless steel mesh is mounted in the bladder. When the bladder is inflated, the stent is also expanded to i ncrease a compressing force against the blocking substance and also decrease coagulating action of blood on a surface of the stent due to Reopro coated on the surface of the ste nt.

[0009] The stent is left in the blood vessel after the stenting operation. In case t hat the surface of the stent is not smooth, some problems such as blood coagulation may occur. In order to solve the above problem, after the stent is subjected to polishing an d annealing, the stent is coated with carbon under conditions of a high pressure, thereby converting a coarse polished surface into a smooth coated surface. Also, since the stainl ess steel stent coated with the carbon should be further coated with Reopro, there is requ ired for a suitable coating method.

SUMMARY OF THE INVENTION

[0010] Accordingly, the present invention is directed to a method of coating a ste nt with Reopro that substantially obviates one or more problems due to limitations and di sadvantages of the related art.

[0011] An object of the present invention is to provide a method of coating a sur face of a stent with abcixmab (Reopro) which is one of glycoprotein Ilb/IIIa receptor inh ibitors, in which the stent made of a stainless steel treated with carbon is coated with th e Reopro having an antiplatelet action against platelets, thereby preventing the platelets from being coagulated on the surface of the stent by the action of the antiplatelet agent co ated on the stent and also preventing the coagulating action of blood on the surface of t he stent.

[0012] To achieve the object and other advantages, according to one aspect of the present invention, there is provided a method of coating a surface of a stent with a plat elet glycoprotein receptor inhibitor (Reopro), in which the stent is made of stainless steel implanted with carbon, comprising a wet cleaning process of eliminating alien substances from the surface of the stent; a surface activating process of activating the surface of th e stent, in which after the cleaned stent is fixed to a tubular reactor made of a Pyrex gl ass tube, an internal pressure of the reactor is lowered by atmospheric pressure of up to

0.01, and oxygen, argon, or a mixture gas of argon and hydrogen is introduced into the reactor and a discharge power of 5 to 200 W is applied to electrodes of the reactor duri ng 1 to 30 minutes to generate a plasma in the reactor; a coating process of coating the surface of the stent with a thin film having an amine radical, in which after the surface activating process is completed, the internal pressure of the reactor is lowered by atmos pheric pressure of up to 0.01, and diaminocyclo hexane (DACH) monomer is introduced into the reactor and a discharge power of 50 to 100 W is applied to the electrodes durin g 1 to 30 minutes to generate a plasma in the reactor; and a grafting process of grafting the stent with the Reopro, in which after the coating process is completed, the stent is withdrawn at air, and is immersed in a Reopro solution containing Reopro, sodium citrate, and cyamide at a temperature of 25 to 50 ^°C during 5 minutes to 80 minutes.

[0013] It is to be understood that both the foregoing general description and the f ollowing detailed description of the present invention are exemplary and explanatory and are intended to provide further explanation of the invention as claimed.

BRIEF DESCRIPTION OF THE DRAWINGS

[0014] The accompanying drawings, which are included to provide a further under standing of the invention and are incorporated in and constitute a part of this application, illustrate embodiment(s) of the invention and together with the description serve to expla in the principle of the invention, hi the drawings:

[0015] Fig. 1 is a diagram schematically depicting a coating process according to the present invention;

[0016] Fig. 2 is a perspective view of a vascular stent according to the present in vention; and

[0017] Fig. 3 is a view illustrating a process of expanding a blood vessel with a general stent. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] A preferred embodiment according to the present invention will now be ex plained with reference to the accompanying drawings.

[0019] Referring to Fig. 1 showing a coating apparatus of the present invention, t he coating apparatus includes a tubular reactor 11 made of a Pyrex glass tube, electrodes

21 installed on left and right sides of the reactor 11, an RF power supply source 13 fo r supplying an RF power to the electrodes, a pressure gauge 18 connected to the reactor

11 for controlling a pressure of the reactor, a vacuum pump 20 connected to the reactor

11 for controlling vacuum of the reactor using a valve 19, a stop valve 15 connected to the reactor 11 for controlling supply of a gas or liquid from a gas or liquid container 1

7, and a flow rate meter 16.

[0020] A sample support plate 12 is fixed to an inner portion of the reactor, and a stent is positioned on the sample support plate 12.

[0021] The coating apparatus illustrates one example of the present invention, and does not limit the scope of the present invention. Of course, an alteration or modificati on of a part of the coating apparatus to conduct a Reopro coating process is contained i n the scope of the present invention.

[0022] Fig. 2 is a perspective view of a vascular stent coated with carbon accordi ng to the present invention. The stent is made of a mesh of stainless steel to have resil ience and flexibility. Also, the stent has a feature of maintaining its shape.

[0023] Fig. 3 is a view illustrating a process of expanding a blood vessel with a general stent.

[0024] Fig. 3 a shows a first step that a wire passes through a lesion of the blood vessel. Fig. 3b shows a second step that a stent laid on a bladder is positioned in the lesion of the blood vessel. FIG. 3 c shows a third step that the bladder is inflated, and the stent expands the blood vessel strongly and effectively. Fig. 3d shows a fourth step that the bladder is deflated and extracted away from the blood vessel, and the expanded stent is left in the blood vessel. [0025] A method of coating the stainless steel implanted with carbon with Reopro will now be described with reference to the drawings. [0026] Cleaning process

[0027] A stent 22 is subjected to a wet cleaning to eliminate alien substances fro m a surface of the stent. For example, the stainless steel stent 22 implanted with carbon is immersed in a solution mixed with water and alcohol at a ratio of 1:1, and then is c leaned by use of an ultrasonic cleaning machine during 5 minutes or more. [0028] Surface activating process

[0029] After the cleaning process is completed, the stent 22 is treated by plasma t o eliminate molecular alien substances from the stent and simultaneously activate the surf ace of the stent 22 implanted with carbon. To the end, after the cleaned stent 22 is fix ed to the tubular reactor 11 made of Pyrex glass tube, the internal pressure of the reacto r 11 is lowered by atmospheric pressure of up to 0.01 by use of the vacuum pump 20, and oxygen, argon, or a mixture gas of argon and hydrogen is introduced into the reacto r 11 to maintain the pressure at 0.05 to 5.0 torr. [0030] The plasma is generated in the radiator by applying a discharge power of

5 to 200 W to the electrodes from the RF power supply source 13 during 1 to 30 minut es.

[0031] It is preferable that the discharge power is 50 W or more and the processi ng time is 10 minutes or more, in order to sufficiently clean and activate the surface of the stent 22.

[0032] Coating process

[0033] After the surface activating process is completed, the internal pressure of t he reactor is lowered by atmospheric pressure of up to 0.01, and diaminocyclo hexane (DACH) monomer is introduced into the reactor 11 to maintain the reactor 11 at atmosph eric pressure of 0.05 to 1.0.

[0034] The plasma is generated in the reactor by applying a discharge power of 5 0 to 100 W to the electrodes from the RF power supply source 13 during 1 to 30 minut es, preferably 15 to 20 minutes. [0035] Introduction of an amine radical is preferable above 15 minutes, but a thin film to be coated may be too thick if it is performed during above 20 minutes. In this instance, the internal stress in highly increased, and thus the coated thin film may be pe eled off from the surface of the stent 22.

[0036] It is preferable that the discharge power to generating the plasma is 40 to 60 W. The reason can be understood from the spectrum of the thin film which is analy zed by FTIR/ATR, as shown in Table 1. [0037] Graph 1

[0038] wavenumbeKcπf¹)

[0039] In Graph 1, a curve (a) indicates a surface of a stainless steel, a curve (b) indicates a surface of stainless steel treated by DACH plasma, and a curve (c) indicates a surface of a stainless steel treated by DACH plasma and then cleaned by water. It would be understood that an amine radical (1630 cm^"1 and 3300 cm^"1) is generated in th e curve (b) and the amine radical is still existed in the curve (c). [0040] Graph 2

4000 3500 3000 2500 2000 1500 1000

[0041] wavenumbeiW) [0042] Graph 3

wavenumbeKcm¹)

[0043]

[0044] Graphs 2 and 3 show variations of spectrums according to the discharge p ower before and after the water cleaning. It would be understood that when the discharg e power is 40 to 60 W, an intensity of a feature peak of an amine radical appeared at 1 630 cm^"1 and 3300 cm^"1 is the strongest. [0045] Grafting process

[0046] The coating process is completed, the stent 22 implanted with the amine ra dical is withdrawn at the air, and is immersed in a Reopro solution containing Reopro, s odium citrate, and cyamide at a temperature of 25 to 50 °C during 5 minutes to 80 min utes to graft the stent with the Reopro. In order to eliminate the Reopro weakly adhere d on the stent, the stent is cleaned with a deionized water during 1 to 5 minutes.

[0047] With the above description, according to the present invention, the surface of the stainless steel stent implanted with carbon is coated with the Reopro, thereby inhi biting coagulation of platelets onto the surface of the stent left in the blood vessel after t he stenting operation, and thus preventing the stent restenosis. [0048] The forgoing embodiment is merely exemplary and is not to be construed as limiting the present invention. The present teachings can be readily applied to other t ypes of apparatus. The description of the present invention is intended to be illustrative, and not to limit the scope of the claims. Many alternatives, modifications, and variatio ns will be apparent to those skilled in the art.

Claims

What is claimed is:

1. A method of coating a surface of a stent with a platelet glycoprotein receptor inh ibitor (Reopro), in which the stent is made of stainless steel implanted with carbon, com prising a wet cleaning process of eliminating alien substances from the surface of the ste nt; a surface activating process of activating the surface of the stent, in which after t he cleaned stent is fixed to a tubular reactor made of a Pyrex glass tube, an internal pre ssure of the reactor is lowered by atmospheric pressure of up to 0.01, and oxygen, argon, or a mixture gas of argon and hydrogen is introduced into the reactor and a discharge power of 5 to 200 W is applied to electrodes of the reactor during 1 to 30 minutes to g enerate a plasma in the reactor; a coating process of coating the surface of the stent with a thin film having an a mine radical, in which after the surface activating process is completed, the internal press ure of the reactor is lowered by atmospheric pressure of up to 0.01, and diaminocyclo he xane (DACH) monomer is introduced into the reactor and a discharge power of 50 to 10 0 W is applied to the electrodes during 1 to 30 minutes to generate a plasma in the rea ctor; and a grafting process of grafting the stent with the Reopro, in which after the coatin g process is completed, the stent is withdrawn at air, and is immersed in a Reopro soluti on containing Reopro, sodium citrate, and cyamide at a temperature of 25 to 50 ^°C durin g 5 minutes to 80 minutes.

2. The method as claimed in claim 1, wherein the discharge power for generate the plasma in the coating process is 4OW to 6OW.

3. The method as claimed in claim 1 or 2, wherein a processing time of the coatin g process is 15 minutes to 20 minutes.

4. The method as claimed in claim 1, wherein in the surface activating process, the discharge power to generate the plasma is 50W or above, and a processing time is 10 m inutes or above.