WO2012138184A2

WO2012138184A2 - Drug-eluting stent comprising chitosan coating layer, and preparation method thereof

Info

Publication number: WO2012138184A2
Application number: PCT/KR2012/002642
Authority: WO
Inventors: 김헌영; 현창백; 유혁상; 이승열; 한숙희; 손영주; 김영희; 윤수진; 노형진; 김영완; 이광호; 박현식
Original assignee: 강원대학교산학협력단
Priority date: 2011-04-08
Filing date: 2012-04-06
Publication date: 2012-10-11
Also published as: WO2012138184A3; KR101064214B1

Abstract

The present invention relates to a stent, and more specifically, to a drug-eluting stent comprising a chitosan coating layer. According to the present invention, provided is a drug-eluting stent, comprising: a stent framework; and a chitosan coating layer coated on the stent framework and comprising a chitosan coating layer in which a restenosis preventing material is distributed. The stent framework comprises: a plurality of rings which have the axial direction, the circumferential direction and the radial direction, form a cylindrical shape before and after the expansion in the radial direction, and are arranged along the axial direction and the circumferential direction; a plurality of first flexible links which link two rings adjacent along the circumferential direction among the plurality of rings, and are expanded along the circumferential direction; and a plurality of second flexible links which link two rings adjacent along the axial direction among the plurality of rings, and are expanded along the axial direction.

Description

Drug-eluting stent with chitosan coating layer and preparation method

The present invention relates to a stent, and more particularly to a drug-eluting stent having a chitosan coating layer.

Stent is a medical device for restoring the flow to the normal lumen when the flow of blood or body fluids such as blood vessels, gastrointestinal tract, biliary tract is abnormally narrowed or blocked by the disease. In vascular diseases, stents are installed when blood flow is not smooth due to narrowing of the inner diameter of arteries due to the deposition of blood clots and lipids in the arteries. The stent has a cylindrical shape that can be expanded from a small diameter to a large diameter.

The stent may be inserted into the artery through a catheter and move inwards through the arterial path of the patient until the unexpanded stent is positioned where desired. Once the stent is in the desired position, a balloon or other inflation mechanism is used to inflate the stent outward to engage the artery. This expandable stent must retain sufficient rigidity even after it is inflated, and the rigidity must be maintained even after the catheter is removed.

The stent is composed of various shapes and structures to provide proper performance for various environments. Stents are easily found in many patent documents, including US Pat. Nos. 6,261,318, 5,868,782, and 5,514,154. The stent of these patent documents is configured to be inserted into the lumen and to expand and contract. It is very important that the stent be positioned exactly at the desired location of the lumen. If the length of the stent varies before and after expansion, it is very difficult to position the stent exactly at the desired location. This problem of incorrect positioning is difficult to reverse due to the fact that the stent not only expands easily, but also does not shrink once expanded.

The development of these stents contributed to making the intervention a safe and generalized procedure by quickly and safely overcoming the acute closure caused by endothelial detachment. There was a problem.

First, when the stent of the patent documents as described above is expanded in the radial direction, there is a problem that the length in the axial direction is reduced. The stent disclosed in US Pat. No. 5,514,154 has a structure for limiting the contraction in the axial direction, but there is a problem in that the contraction in the axial direction occurs at the end and it is difficult to position the stent at a desired place after expansion.

Second, there was a problem that restenosis is likely to occur within one year after the procedure. In order to prevent such restenosis, a drug eluting stent (DES) for coating a polymer layer containing a drug to prevent restenosis on the stent surface is mainly used, but the surface of a conventional drug eluting stent is coated. The polymer is a synthetic polymer, the molecular structure is different from the human tissue, there was a problem that the rejection may occur when inserted into the human body.

It is an object of the present invention to provide a stent that does not contract in the axial direction even if it expands in the radial direction and has a strong bearing force after the procedure.

It is another object of the present invention to provide a drug-eluting stent in which the molecular structure is very similar to human tissue and thus does not cause rejection when inserted into the human body.

According to the present invention, a plurality of rings having an axial direction, a circumferential direction and a radial direction, having a cylindrical shape before and after expansion in the radial direction, and arranged along the axial direction and the circumferential direction, Connecting two adjacent rings along the circumferential direction of the rings, connecting the plurality of first flexible links expanded along the circumferential direction, and connecting two adjacent rings along the axial direction among the plurality of rings A drug dissolution comprising a stent skeleton comprising a plurality of second flexible links expanded along the axial direction and a chitosan coating layer coated on the stent skeleton and including a chitosan coating layer on which a restenosis prevention material is distributed. Type stents are provided.

In addition, a plurality of rings having an axial direction, a circumferential direction and a radial direction, having a cylindrical shape before and after expansion in the radial direction, and arranged along the axial direction and the circumferential direction, Connecting two adjacent rings along the circumferential direction, connecting the plurality of first flexible links expanded along the circumferential direction, and two adjacent rings along the axial direction among the plurality of rings, Preparing a stent skeleton comprising a plurality of second flexible links expanded along the axial direction, preparing a solution in which a solvent, dexamethasone and acetic acid are mixed, and adding chitosan to the solution to form a chitosan solution And dipping the stent skeleton into the chitosan solution and drying to form a chitosan coating layer on the stent skeleton. There is provided a method for producing a drug-eluting stent having a chitosan coating layer comprising.

The drug-eluting stent having a chitosan coating layer according to the present invention is coated with chitosan, which is a biocompatible natural material, and thus does not cause rejection when inserted into the human body. In addition, since chitosan has a sustained release rate, the release rate of the anti-resorption drug distributed in the chitosan coating layer can be sustained to prevent prolonged restenosis.

In addition, the drug-eluting stent having a chitosan coating layer according to the present invention has an excellent effect of positioning the stent in the correct position, such as lumen, because the contraction in the axial direction is minimized by the rings during expansion. In addition, the longitudinal change is minimized, and the reaction force is small when the longitudinal compression force is applied, and the interference between the first and second flexible links is minimized during bending deformation, so that the amount of bending increases and can be easily and accurately installed. It works.

1 is a conceptual diagram of a drug-eluting stent having a chitosan coating layer according to the present invention.

Figure 2 is a perspective view showing a configuration in which the drug-eluting stent with a chitosan coating layer according to the invention is contracted.

Figure 3 is a perspective view showing a configuration in which the drug-eluting stent with the chitosan coating layer is expanded according to the present invention.

Figure 4 is a front view showing a developed configuration in which the drug-eluting stent with a chitosan coating layer according to the invention is contracted.

Figure 5 is a front view showing a developed configuration in which the drug eluting stent with a chitosan coating layer is expanded according to the present invention.

6 and 7 are diagrams for explaining the operation of the first flexible link in the drug-eluting stent having a chitosan coating layer according to the present invention.

8 and 9 are views for explaining the operation of the second flexible link in the drug-eluting stent having a chitosan coating layer according to the present invention.

Hereinafter, preferred embodiments of the expandable stent according to the present invention will be described in detail with reference to the accompanying drawings.

1 is a conceptual diagram of a drug-eluting stent having a chitosan coating layer according to the present invention. As shown in FIG. 1, the present invention includes a stent skeleton 10 and a chitosan coating layer 11 formed on the surface of the stent skeleton 10. First, the structure of the stent skeleton 10 will be described in detail, and then the chitosan coating layer 11 will be described.

First, referring to FIGS. 2 to 5, the stent skeleton 10 according to the present invention has a front open end 20 and a rear open end 22 on both sides, and includes a closed configuration for insertion into the lumen. Consists of a grid-shaped cylinder that can move between open configurations. The cylindrical stent skeleton 10 has an axial direction i, a radial direction j and a circumferential direction k, the diameter of which extends or contracts along the radial direction j.

4 to 7, the stent skeleton 10 includes a plurality of rings 30 arranged at intervals along the axial direction i and the circumferential direction k. The rings 30 are aligned along the axial direction i and the circumferential direction k and are formed in a rectangle. The rings 30 are connected to both ends of the first and

second struts

32a and 32b and the first and

second struts

32a and 32b which are arranged in parallel along the circumferential direction k. It consists of a 1st and 2nd loop (Loop: 34a, 34b). The length of the first and

second struts

32a and 32b is longer than the gap between the first and

second struts

32a and 32b. The first and

second loops

34a and 34b are bent outwardly of the first and

second struts

32a and 32b. In this embodiment, the rings 30 may be configured as elliptical as necessary.

Two rings 30 adjacent to each other along the circumferential direction k of the rings 30 are connected by a plurality of first flexible links 40 that can expand along the circumferential direction k. have. 6 and 7, the first flexible link 40 is shown as hatched portions.

The first flexible links 40 are composed of a plurality of third struts 42a through 42c and a plurality of

third loops

44a and 44b connecting both ends of the third struts 42a through 42c. The third struts 42a to 42c before the expansion of the first flexible links 40 are arranged in parallel along the circumferential direction k. Three to third struts 42a to 42c are shown in FIGS. 4 to 7, and two to three

third loops

44a and 44b are shown. This is illustrative and the third struts 42a to 42c and the third are shown. The number of three

loops

44a and 44b can be appropriately increased or decreased as necessary.

The first flexible links 40 may include a first finger 46a and a first finger extending from the first strut 42a and the last strut 44c disposed on both sides of the third struts 42a to 42c. 2 fingers 46b are provided. The first finger 46a is connected to the upper one of the two adjacent rings 30 along the circumferential direction k, and the second finger 46b is the two adjacent ones along the circumferential direction k. It is connected to the lower one of the rings 30. The first finger 46a is connected to the first loop 34a and the second finger 46b is connected to the second loop 34b. The first and second ends of the first and

second fingers

46a and 46b are close to the portions where the first and

second struts

32a and 32b and the first and

second loops

34a and 34b are respectively connected. The

loops

34a and 34b are alternately connected.

As shown in FIGS. 4 and 6, the axial length L ₁ of the rings 30 is formed longer than the axial length L ₂ of the first flexible links 40. Although the first flexible links 40 are shown in which the third struts 42a to 42c are arranged in parallel, this is exemplary and the first flexible links 40 are formed in a sinusoidal or "S" shape. S-link, "J" shaped J-link, "N" shaped N-link, "M" shaped M-link, "W" shaped W-link, etc. Can be. In addition, these shaped first flexible links 40 may be arranged inverted.

2 to 5, 8 and 9, two rings 30 adjacent to each other along the longitudinal direction i of the rings 30 may be formed of a plurality of agents that can be expanded along the longitudinal direction i. It is connected by two flexible links 50. 8 and 9 show the second flexible link 50 as a hatched portion.

The second flexible links 50 are composed of a plurality of fourth struts 52a through 52c and a plurality of

fourth loops

54a and 54b connecting both ends of the fourth struts 52a through 52c. In FIGS. 4, 5, 8 and 9 three fourth struts 52a to 52c are shown and two

fourth loops

54a and 54b are shown, but this is illustrative and the fifth strut ( The number of 52a to 52c and the number of

fourth loops

54a and 54b may be appropriately increased or decreased as necessary.

The second flexible links 50 have a third finger 56a and a fourth finger extending from the first strut 52a and the last strut 52c disposed on both sides of the fourth struts 52a to 52c. 56b is provided. The first finger 56a connects the first fourth strut 52a to the left of the two adjacent rings 30 along the axial direction i, and the fourth finger 56b is the last The fourth strut 52c is connected to the ring on the right side of two adjacent rings 30 along the axial direction i.

The third finger 56a is connected to the second loop 34b, and the fourth finger 56b is connected to the first loop 34a. The first and second ends of the third and

fourth fingers

56a and 56b are close to the portions where the first and

second struts

32a and 32b and the first and

second loops

34a and 34b are respectively connected. The

loops

34a and 34b are alternately connected. The second flexible links 50 may be formed in various shapes like the first flexible links 40. Meanwhile, two rings 30 adjacent along the longitudinal direction i and adjacent along the axial direction i by the arrangement of the rings 30, the first and second

flexible links

40, 50. A plurality of cells is closed between the two second flexible links 50. Although the second flexible links 50 are formed of S-links that are formed in a sinusoidal or "S" shape, it is illustrated that the first flexible links 50 are first flexible links ( Like 40), it may be formed in various shapes.

The stent skeleton 10 according to the present invention having such a configuration can easily and accurately approach the passage of the lumen during the expansion of the stent by the elastic deformation of the first and second flexible links 50. The radial j expansion of the stent skeleton 10, ie the expansion of the diameter, is smoothly achieved by the elastic deformation of the first flexible links 40. 6 shows the pre-expansion length L ₃ of the first flexible links 40 and the post-expansion length L ₄ of the first flexible links 40 in FIG. 7.

In addition, the longitudinal j expansion of the stent skeleton 10 is smoothly performed by the elastic deformation of the second flexible links 50. 8 shows the pre-expansion length L ₅ of the second flexible links 50 and the post-expansion length L ₆ of the second flexible links 50 is illustrated by way of example.

On the other hand, the closed ring 30 has a small expansion rate even if it is not expanded or expanded by the structural shape. That is, the substantial deformation of the rings 30 is made by plastic deformation. Due to the properties of these rings 30, for example, the anti-pressure resistance and radiological support of the stent skeleton 10 with respect to the stenosis of blood vessels is improved. Therefore, the contraction of the stent skeleton 10 can be prevented after the procedure to minimize restenosis of blood vessels.

In addition, the change in the longitudinal direction (i) of the stent 10 is minimized by the rings 30 of the closed structure, and the reaction force is generated small when the stent skeleton 10 receives the compressive force in the longitudinal direction (i). Therefore, when bending deformation of the stent skeleton 10, the interference between the first and second flexible (40, 50) can be minimized to increase the amount of bending, and furthermore, the longitudinal change is minimized and the longitudinal compression force is applied. In this case, a small reaction force is generated so that interference between the first and second flexible links may be minimized during bending deformation, and thus it may be easily and accurately installed.

Hereinafter, referring to FIG. 1, the chitosan coating layer 11 will be described in detail.

Chitosan is a deacetylate obtained by heating chitin with a concentrated alkaline solution. It is a biocompatible material that does not cause rejection when inserted in vivo because its molecular structure is very similar to that of human tissue.

Since the chitosan coating layer 11 has a sustained release type, it slowly releases dexamethasone (12), which is an anti-vascular restenosis material, to maintain a constant blood concentration, thereby preventing an inflammatory reaction or restenosis reaction caused by a stent for a long time. .

Dexamethasone (12), a restenosis prevention material, is a synthetic component of the glucocorticoid family of steroid hormones. Dexamethasone has 25 times the anti-inflammatory effect of hydrocortisone, so it is possible to treat inflammation by stents in a small amount.

The method for preparing a drug-eluting stent having a chitosan coating layer 11 includes preparing a stent skeleton, preparing a solution in which a solvent, dexamethasone, and acetic acid are mixed, and adding a chitosan to the mixed solution to form a chitosan solution. , Dipping the stent skeleton into the chitosan solution and drying to form a chitosan coating layer on the stent skeleton.

The step of preparing the stent skeleton is a step of manufacturing a stent skeleton 10 having the shape as described above by processing a cylindrical cylinder made of metal such as stainless steel, gold, titanium using a laser.

The next step is to add dexamethasone and acetic acid to distilled water and then mix to prepare a solution.

The preparing of the chitosan solution is a step in which chitosan is added to the prepared mixed solution and then dissolved to make a chitosan solution. After chitosan was added to the mixed solution, the mixture was firstly mixed at 200 to 500 rpm at room temperature using a stirrer and mixed for 12 hours or more in a roller mixer. The amount of chitosan added is preferably 0.5 to 3% by weight.

Finally, the stent skeleton is dipped in the chitosan solution for 10 minutes and then dried in an oven at 100 ° C. for 1 hour to form a chitosan coating layer. During drying, the solvent is removed by evaporation and only chitosan and dexamethasone remain on the surface to form a thin coating layer.

The surface of the stent skeleton prepared by processing stainless steel was washed with distilled water and dried in a vacuum dryer for 30 minutes. 0.2 mg acetic acid solution was prepared by mixing 1 mg of dexamethasone and 1.2 ml of acetic acid in 98.8 ml of distilled water. A chitosan solution was prepared by adding 0.015, 0.03, 0.06, and 0.09 g of Wako chitosan powder having a molecular weight of 100,000 to 3 ml of the solution, respectively. Each of the chitosan solutions was immersed in the dried stent skeleton for 12 hours or more, and then placed in a drying oven and dried at 100 ° C for one hour.

Example 2 is the same as Example 1 until the process of first coating the stent skeleton using a chitosan solution. In Example 2, the first coated stent skeleton was again immersed in the chitosan solution for 10 minutes, then placed in a drying oven and dried at 100 ° C. for 1 hour to coat the stent skeleton with secondary.

Comparative Example 1

A stent skeleton was prepared in the same manner as in Example 1, 1 mg of dexamethasone and 1.2 ml of acetic acid were mixed with 98.8 ml of distilled water to prepare a 0.2 M acetic acid solution. The dried stent skeleton was immersed in 3 ml of acetic acid solution for at least 12 hours, and then placed in a drying oven and dried at 100 ° C. for one hour. The first coated stent skeleton was again immersed in an acetic acid solution for 10 minutes, then placed in a drying oven and dried at 100 ° C. for one hour to coat the stent skeleton with a second coating.

The stents of Examples 1 and 2 and Comparative Example 1 were immersed in phosphate buffered saline (PBS), and the amount of drug released was examined. As a result of the investigation, the stent of Comparative Example 1 had an initial rapid release, and Examples 1 and 2 did not have an initial rapid release, and confirmed that the drug was continuously released even after 15 days or more. This means that when the stent with the chitosan coating layer is inserted, the drug can be prevented from being initially released and the drug is released at a constant level for a long time to reduce vascular restenosis.

The embodiments described above are merely illustrative of the preferred embodiments of the present invention, the scope of the present invention is not limited to the described embodiments, those skilled in the art within the spirit and claims of the present invention It will be understood that various changes, modifications, or substitutions may be made thereto, and such embodiments are to be understood as being within the scope of the present invention.

10: stent skeleton 11: chitosan coating layer

12: dexamethasone 30: ring

32a: first strut 32b: second strut

34a: first loop 34b: second loop

40: first flexible link 50: second flexible link

Claims

A plurality of rings having an axial direction, a circumferential direction and a radial direction, having a cylindrical shape before and after expansion in the radial direction, and arranged along the axial direction and the circumferential direction, and the circumferential direction of the plurality of rings Connecting two adjacent rings along the circumferential direction, connecting the plurality of first flexible links extending along the circumferential direction, and the two adjacent rings along the axial direction among the plurality of rings. A stent skeleton comprising a plurality of second flexible links expanded along a direction; And

A drug-eluting stent having a chitosan coating layer coated on the stent skeleton and including a chitosan coating layer in which a restenosis prevention material is distributed.
The method of claim 1,

The restenosis prevention material is a drug dissolution type stent having a chitosan coating layer is dexamethasone.
A plurality of rings having an axial direction, a circumferential direction and a radial direction, having a cylindrical shape before and after expansion in the radial direction, and arranged along the axial direction and the circumferential direction, and the circumferential direction of the plurality of rings Connecting two adjacent rings along the circumferential direction, connecting the plurality of first flexible links extending along the circumferential direction, and the two adjacent rings along the axial direction among the plurality of rings. Preparing a stent skeleton comprising a plurality of second flexible links expanding along a direction;

Preparing a mixture of a solvent, dexamethasone and acetic acid,

Adding chitosan to the solution to make a chitosan solution;

Dipping the stent skeleton in the chitosan solution and then drying to form a chitosan coating layer on the stent skeleton, wherein the stent skeleton has a chitosan coating layer.
The method of claim 3,

In the step of making the chitosan solution,

The chitosan addition amount is 0.5 to 3% by weight manufacturing method of drug eluting stent having a chitosan coating layer.