JP2001198209A - Material and instrument for intravascular treatment - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a material for intravascular treatment capable of suppressing restenosis after PTCA and having no side effects and an instrument for intravascular treatment using the same. SOLUTION: The material for intravascular treatment has an extracellular matrix containing a nitrogen monoxide donor and the instrument of intravascular treatment has the material for intravascular treatment and a holder for holding the same.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a material for endovascular treatment for inhibiting restenosis after percutaneous coronary angioplasty and a device for endovascular treatment using the same.

[0002]

2. Description of the Related Art Percutaneous coronary angioplasty (percutan)
eous transluminal coronary
angioplasty (PTCA))
Post-operative restenosis occurs at a frequency of 30-50%,
This has been the biggest problem with CA treatment. In contrast,
Although the restenosis rate was successfully reduced by introducing a stent having a metal mesh structure (Fishma).
n DL. et al, N.M. Engl. J. Med. ,
331, 496-501 (1994)), even after the introduction of a stent, restenosis was observed in about 20% of the lesions, and the problem of restenosis has not been solved.

[0003] For a long time, it has been generally assumed that the mechanism of restenosis is caused by intimal hyperplasia due to neointimal hyperplasia. In recent years, a vascular remodeling theory that a cavity is narrowed has also attracted attention (Gibbons GH. Et.
al. , N .; Engl. J. Med. , 330, 143
1-1438 (1994) and the like). In either theory, during the process leading to restenosis, smooth muscle cells in the vascular media undergo dedifferentiation from a contractile type to a synthetic type, migrate to the intima, proliferate, and synthesize a large amount of extracellular matrix. There is agreement on the fact that intimal hyperplasia occurs due to Therefore, by suppressing dedifferentiation and proliferation of vascular smooth muscle cells,
Various methods have been studied so far to prevent restenosis.

[0004] As one of them, the formation of mural thrombus is suppressed by administration of heparin and antiplatelet drugs (eg, aspirin and ticlopidine) which inhibit thrombus formation and coating on stents, and the like. -D, a growth factor of smooth muscle cells released from
enhanced growth factor (PDG
F) Attempts to suppress (Teomin
D. et al. , J. et al. Controlled Re
release, 60, 129-142 (1999), Ca
pron L. et al. , Arterioscle
r Thromb. Vasc. Biol. , 17,16
49-1656 (1997), Hardhammar
PA. et al. , Circulation, 93,
423-430 (1996)).

[0005] In addition, a peptide (eg, arginine) that inhibits the adhesion between cells such as platelets, leukocytes / macrophages, and smooth muscle cells or to the extracellular matrix by competitively inhibiting integrin, one of the cell adhesion molecules. Glycine-aspartic acid (RGD), tyrosine-isoleucine-glycine-serine-arginine (YIGS
R))) or inhibit it by holding it on a stent, PDGF or transforming g
There have also been attempts to suppress the production of smooth muscle cells by suppressing the production of cytokines such as row factor (TGF) (Srivatsa SS. et a).
l. , Cardiovasc. Res. , 36,408
-428 (1997); et a
l. , Circulation, 90, 2203-22.
06 (1994), Thyberg J. et al. et a
l. , J. et al. Histochem. Cytochem. ,
45, 837-846 (1997)).

[0006] However, at present it is considered that none of these measures is effective for restenosis (Frankli).
n SM. et al. , Coronary Arte
ryDisease, 4,232-242 (199
3)).

On the other hand, type IV collagen, laminin and heparan sulfate, and mouse En containing these components
A solubilized reconstituted basement membrane (Kleinma) extracted from gelbreth-Holm-Swarm (EHS) sarcoma
nH. et al. , Biochemistry, 2
1,6188-6193 (1982)) have been reported to suppress smooth muscle cell dedifferentiation in a culture system (Thyberg J., Interna).
tional Review of Cytolog
y, 169, 183-265 (1996), Haywa
rd IP. et al. , Cell Biology
International, 19, 727-734
(1995), Li X. et al. et al. , J. et al. Bio
l. Chem. , 269, 19653-19658 (1
994), etc.), which are only results in a culture system, and a means for suppressing restenosis using type IV collagen or the like in clinical practice has not yet been obtained.

Also, disodium nitroprusside includes:
It has been reported that it has an effect of suppressing the proliferation of vascular smooth muscle cells (Guh. JH. Et al., Mol. P.
Pharmacol. , 53, 467 (1998), and it has been reported that intravascular administration or administration of L-arginine is effective in inhibiting thickening (Tourne).
au TL. et al. , JACC, 33, 876-
882 (1999); et al. ,
J. Surg. Res. , 82, 17-23 (199
9), Severin P.S. , Circulatio
n, 95, 1863-1869 (1997)). However, administration of large amounts of L-arginine and the like into blood vessels decreases blood pressure (Nakai T. et al., Lancet, 3).
36, 696 (1990)) and platelet aggregation suppression (Ma
linsli T. , Biochem. Biophy
s. Res. Commun. , 194, 960-965
(1993)).
Means for inhibiting restenosis by intravascular administration of L-arginine or the like cannot be said to be actually usable.

[0009]

SUMMARY OF THE INVENTION It is an object of the present invention to provide an intravascular therapeutic material which can suppress restenosis after PTCA and has no side effects, and an endovascular therapeutic device using the same. As an issue.

[0010]

SUMMARY OF THE INVENTION The present invention provides an intravascular therapeutic material having an extracellular matrix containing a nitric oxide donor.

Preferably, the nitric oxide donor is L-arginine.

[0012] The extracellular matrix comprises at least
It is preferable that at least one selected from the group consisting of type IV collagen, laminin and heparan sulfate is used as a component.

The present invention also provides a device for endovascular treatment comprising the above-mentioned endovascular therapeutic material and a holder for holding the endovascular therapeutic material.

[0014] In one preferred embodiment, the holding body is a stent.

[0015]

DESCRIPTION OF THE PREFERRED EMBODIMENTS First, the material for endovascular treatment of the present invention will be described. The intravascular therapeutic material of the present invention has an extracellular matrix containing a nitric oxide donor. The nitric oxide donor used in the present invention is not particularly limited as long as it can provide nitric oxide.
L-arginine, nitroglycerin, isoamyl nitrite, erythrityl tetranitrate, isosorbide dinitrate, nicorandil, disodium nitroprusside, molsidomine. Among them, L-arginine is preferable because it can be obtained at low cost.

The extracellular matrix used in the present invention may be an in vivo extracellular matrix as it is, or may be a reconstituted in vivo extracellular matrix. The reconstituted product has advantages such as constant product quality and no risk of side effects. The reconstituted material is, for example, gelatin. In vivo, most cells in multicellular organisms are in contact with an extracellular matrix that has a complex network or fibrous structure, which organizes the intracellular skeleton, differentiates cells, And has the function of regulating the spatial organization of cells and tissues. Examples of components of the extracellular matrix include collagen, laminin, heparan sulfate, fibronectin, vitronectin, proteoglycan, glycosaminoglycan, chondroitin sulfate, heparin sulfate, hyaluron, dermatan sulfate, keratin sulfate, and elastin.

The extracellular matrix used in the present invention is not particularly limited as long as at least one of the above components is contained as a component.
It is preferable that at least one selected from the group consisting of type V collagen, laminin, and heparan sulfate is used as a component. Among them, it is preferable to use two or more types including collagen IV, and the most preferable configuration is to use these three types as components in terms of suppressing dedifferentiation of smooth muscle cells. It is also a preferred embodiment to use type IV collagen or the like together with type I collagen.

The structure of the extracellular matrix used in the present invention is not particularly limited, and can take various structures. For example, it may have a network structure or a fibrous structure, or may have a structure in which molecules of constituent components are arranged irregularly. The extracellular matrix used in the present invention may have any structure, but is preferably in a gel or paste form.

A preferred example of the extracellular matrix used in the present invention is a solubilized reconstituted basement membrane obtained by solubilizing and purifying mouse EHS sarcoma with uric acid, a surfactant and the like. Specifically, MATRIGEL (Becton D
Ickinson Labware (MA, USA)
Manufactured) can be suitably used.

In the intravascular therapeutic material of the present invention, the extracellular matrix contains the nitric oxide donor. The mode of inclusion is not particularly limited, and the nitric oxide donor may be present uniformly or heterogeneously dispersed in the extracellular matrix, or may be present locally in the extracellular matrix. Good. Although the nitric oxide donor suppresses intimal hyperplasia at the site of vascular injury, the effect of this effect is more pronounced. Preferably, they are uniformly dispersed.

The method for producing a material for endovascular treatment according to the present invention comprises:
There is no particular limitation. For example, when a solubilized reconstituted basement membrane is used as an extracellular matrix, a nitric oxide donor is dissolved in an aqueous solution of an ice-cooled solubilized reconstituted basement membrane, and then heated to form a gel. Thus, the intravascular therapeutic material of the present invention can be obtained in which the extracellular matrix contains the nitric oxide donor in a uniformly dispersed state. When gelatin is used as an extracellular matrix, a nitric oxide donor is dissolved in a heated aqueous solution of gelatin, and then cooled to a gel. Thereafter, the material is crosslinked by irradiation with ultraviolet rays or the like, whereby the material for endovascular treatment of the present invention in which the extracellular matrix contains the nitric oxide donor in a uniformly dispersed state can be obtained.

The method of using the endovascular therapeutic material of the present invention is as follows.
The method is not particularly limited as long as the method is directly applied to a vascular injury site. For example, a method of directly applying to a vascular injury site after PTCA using a catheter or a balloon provided with a material for endovascular treatment of the present invention on the surface, and a holder provided with the material for endovascular treatment of the present invention after PTCA. Examples include a method of indwelling at a vascular injury site and a method of directly injecting the intravascular therapeutic material of the present invention into a vascular injury site after PTCA using an intravascular drug infusion catheter. The method of direct application using a catheter or balloon provided with a material for endovascular treatment of the present invention,
It is suitable for treating complicated lesions where it is difficult to place a holder such as a stent. The method of indwelling the holder provided with the endovascular treatment material of the present invention is suitably used for vascular remodeling in which the entire blood vessel contracts and the blood vessel lumen narrows.

The material for endovascular treatment of the present invention can effectively prevent restenosis without side effects by directly applying to the site of vascular injury after PTCA. In the intravascular therapeutic material of the present invention, since a nitric oxide donor having an effect of suppressing hyperplasia is contained in a structure called extracellular matrix, it can be directly applied to a vascular injury site after PTCA. And restenosis can be prevented without causing side effects as in the case of intravascular administration or oral administration. In addition, by dispersing the nitric oxide donor inside the extracellular matrix, it is possible to give a sustained release of the nitric oxide donor, thereby also preventing side effects due to large dose administration. Furthermore, when the extracellular matrix used in the intravascular therapeutic material of the present invention contains at least one selected from the group consisting of type IV collagen, laminin and heparan sulfate, restenosis suppression is particularly effective. It is preferable because it has excellent effects. In this case, it is considered that not only the effect of inhibiting the intimal hyperplasia by the nitric oxide donor but also the effect of inhibiting the dedifferentiation of smooth muscle cells by the above-mentioned components are exerted.

Next, the endovascular treatment device of the present invention will be described. An endovascular treatment device of the present invention includes the above-described endovascular treatment material of the present invention, and a holder for holding the endovascular treatment material. The holding body used in the present invention is not particularly limited in its material, shape, size, etc., as long as it can hold the material for intravascular treatment and can be safely placed in the blood vessel. Examples of the material of the support include various inorganic compounds, various organic compounds, and composite materials thereof. The material of the support may or may not be biodegradable. Examples of the inorganic compound include metals such as stainless steel, nickel-titanium alloy, and tantalum; and ceramics. Examples of the organic compound include non-biodegradable materials such as polytetrafluoroethylene, polytrifluoroethylene, polyethylene, polyethylene terephthalate, and polypropylene.
Examples of the biodegradable material include polylactic acid, polyglycolic acid, polymalic acid, and poly α-amino acid.

The shape of the holder is not particularly limited as long as it has sufficient strength to be safely and stably placed on the inner wall of the blood vessel. For example, an arbitrary shape such as a cylindrical shape composed of a wire made of an inorganic compound wire or an organic compound fiber; and a cylindrical shape composed of an inorganic compound or an organic compound which may have pores. Preferred examples are given.

The endovascular treatment instrument of the present invention can use a stent, a catheter, a balloon, a vascular prosthesis, an artificial blood vessel or the like as a holder. Among them, one of the preferable embodiments is that the holding body is a stent. The stent is
For example, the shape may be a coil shape or a net tube shape.
In addition, any of a balloon expandable type and a self-expandable type may be used, and any of a rigid stent and a flexible stent may be used. The size of the stent may be appropriately selected depending on the application site. Usually, the inner diameter is 1.0 to 3.0m
m and the length are 5 to 50 mm.

[0027] The endovascular treatment device of the present invention comprises the above-mentioned endovascular therapeutic material of the present invention and the above-mentioned holder for holding the same. The mode of holding is not particularly limited, but the intravascular therapeutic material and the holding body are integrated with each other in terms of stability when transported to the site of vascular injury, stability in the state of being placed at the site of vascular injury, and the like. Is preferred.

The method for integrating the intravascular treatment material and the holder is not particularly limited. For example, when an intracellular therapeutic material whose extracellular matrix contains at least one selected from the group consisting of type IV collagen, laminin, and heparan sulfate as an intravascular therapeutic material is used. Is to add a nitric oxide donor such as L-arginine to one or more liquids selected from the group consisting of type IV collagen, laminin and heparan sulfate under ice cooling, and then immerse a support such as a stent. Then, the solution is heated to 37 ° C. to gel the liquid to integrate them. Further, in the above method,
Instead of heating to 37 ° C. to gel the liquid, instead of irradiating ultraviolet rays to gel the liquid to integrate them, or instead of heating to 37 ° C. to gel the liquid,
A method of integrating by gelling by adding glutaraldehyde is exemplified. Further, when the support is made of an organic compound fiber or the like, the support itself may contain the nitric oxide donor. For example, in the above-described method of integrating the intravascular treatment material and the support, when the support is immersed in a liquid of an extracellular matrix containing a nitric oxide donor, the liquid impregnates the support, and The nitric oxide donor may be supported on the support itself. In the intravascular therapeutic material of the present invention obtained by these methods, the nitric oxide donor is held in a gel-like extracellular matrix, exhibits activity in a living body, and effectively reduces restenosis. Can be deterred.

The intravascular therapeutic device of the present invention can be used by placing it at the site of vascular injury after PTCA. The indwelling method is not particularly limited, and examples thereof include a method using a balloon catheter. When the intravascular therapeutic device of the present invention is biodegradable, the decomposition rate can be appropriately selected by selecting the materials of the extracellular matrix and the support.

Since the endovascular therapeutic device of the present invention includes the above-described endovascular therapeutic material of the present invention and a holding body for holding the same, the device of the present invention can be obtained by placing it at a vascular injury site after PTCA. The intravascular therapeutic material can be stably applied to the site of vascular injury for a long period of time, and restenosis can be extremely effectively prevented without side effects.

The effects of the material for endovascular treatment and the device for endovascular treatment of the present invention can be obtained for the first time by the configuration of the present invention described above. For example, US Pat. No. 5,769,
No. 883 describes a stent wherein the cylindrical body has a biodegradable matrix containing type IV collagen and laminin and a biodegradable reinforcing material, the cylindrical body being saturated with a drug. However, this stent is
Restenosis after PTCA cannot be effectively suppressed. In contrast, in the endovascular treatment material and endovascular treatment device of the present invention, the extracellular matrix contains a nitric oxide donor. With the present invention, without side effects,
It is with this configuration that restenosis after PTCA can be very effectively suppressed. That is, the intravascular therapeutic material of the present invention, as shown in Comparative Examples later, whereas collagen alone cannot sufficiently suppress restenosis,
By supporting the nitric oxide donor on the extracellular matrix, the restenosis can be sufficiently suppressed by the synergistic action of the nitric oxide donor and the extracellular matrix. In particular, when the extracellular matrix contains at least one selected from the group consisting of type IV collagen, laminin, and heparan sulfate, the above components also sufficiently exert the effect of suppressing dedifferentiation of smooth muscle cells. Therefore, it is considered that the anti-restenosis effect is particularly excellent.

[0032]

EXAMPLES The present invention will be described more specifically with reference to the following examples, but the present invention is not limited to the following examples. 1. (Example 1) Extracellular matrix composed of type IV collagen / laminin / heparan sulfate (solubilized reconstituted basement membrane,
Growth Factor Reduced MAT
RIGEL (Becton Dickinson La
While a 10 mg / ml solution of Bware (MA, USA) was cooled on ice, L-arginine as a nitric oxide donor was dissolved in the solution to a concentration of 5 mg / ml. A cylindrical mesh stent having an inner diameter of 2 mm and a length of 1 cm made by knitting a stainless wire having a diameter of 50 μm was immersed in this solution. After 1 minute, the mesh stent is taken out, put in a thermostat at 37 ° C. for 10 minutes to be gelled, the extracellular matrix containing L-arginine and the mesh stent are integrated, and the endovascular therapeutic material of the present invention is used. A device for endovascular treatment of the present invention comprising a holder for holding the device was obtained (FIGS. 1 and 2).

Comparative Example 1 Extracellular matrix consisting of type IV collagen / laminin / heparan sulfate (solubilized reconstituted basement membrane, Growth Factor Reduc)
ed MATRIGEL) was chilled on a 10 mg / ml solution while ice-cooling the solution, and an inner diameter of 2 mm and a length of 1 cm were formed by knitting a 50 μm diameter stainless wire into the solution.
Was immersed. After one minute,
The mesh stent was taken out, placed in a thermostat at 37 ° C. for 10 minutes to gel, and the extracellular matrix and the mesh stent were integrated.

2. Test on Endovascular Treatment Effect Using Vascular Injury Model by Rat Carotid Artery Balloon Scratch Three Wistar rats (350 to 500 g) were anesthetized with ether and pentobarbital sodium 3 mg /
100 g was administered subcutaneously. A balloon catheter for removing thrombus from the right external carotid artery by surgically exposing the right common carotid artery (Fo)
garty2F catheter, Baxter heart
hcare (USA)) was inserted. The intima was released by repeating inflation of the balloon at about 1.5 atm and rubbing the right common carotid artery about 2 cm twice to create a vascular injury model. Immediately, the endovascular therapeutic device of the present invention was inserted into a blood vessel, and the peripheral 1 cm portion of the rubbed portion of about 2 cm was used to put the endovascular therapeutic device on the inner wall of the blood vessel using a balloon catheter. Detained. 14 days after the operation, 3 mg / 100 g of pentobarbital sodium was subcutaneously administered under ether anesthesia to open the abdomen. After blood was removed from the abdominal aortic blood vessel, an indwelling needle was inserted into the right atrium, and the intravascular perfusion washing with physiological saline was performed. And 10%
The right common carotid artery was removed by perfusion fixation with a formalin solution. 1 cm of the central side where nothing was done after the balloon was rubbed and 1 cm of the peripheral side where the intravascular treatment device of the present invention was placed were separately embedded in paraffin, and then sections were prepared and stained with hematoxylin and eosin. This was subjected to observation with an optical microscope, and the inner film thickness was measured.

The same test was carried out using the mesh stent integrated with the extracellular matrix obtained in Comparative Example 1 instead of the intravascular treatment device of the present invention.

3. Results The results of optical microscope observation are shown in FIG. The inner thickness of the normal blood vessel was 6 ± 5 μm (n = 3). When the device for endovascular treatment of the present invention was placed after the balloon injury, the carotid artery of 1 cm in the central side, which was not treated after the balloon injury, was 11 cm.
While it was thickened to 6 ± 16 μm (n = 3), the peripheral intima was 25 ± 8 μm (n = 3), which was significant (p <
At 0.05 (t-test), it can be seen that the intimal thickening was suppressed (Example 1). On the other hand, when the mesh stent integrated with the extracellular matrix was used after the balloon injury (Comparative Example 1), the central carotid artery of 1 cm which was not treated after the balloon injury was 125 ± 18.
The thickness of the intima on the peripheral side was 72 ± 16 μm (n = 3), whereas the thickness of the peripheral intima was 72 ± 16 μm (n = 3). .

[0037]

According to the present invention, an intravascular therapeutic material having an extracellular matrix containing a nitric oxide donor is PTC.
By directly applying to the site of vascular injury after A, restenosis can be effectively prevented without side effects,
Useful. In particular, when the extracellular matrix used for the intravascular therapeutic material of the present invention contains at least one selected from the group consisting of type IV collagen, laminin, and heparan sulfate, restenosis suppression is particularly effective. It is extremely useful because of its excellent effect. In addition, the device for endovascular treatment of the present invention can stably apply the intravascular therapeutic material of the present invention to a site of vascular injury for a long period of time by placing the device at the site of vascular injury after PTCA, Without this, restenosis can be prevented very effectively, which is extremely useful.

[Brief description of the drawings]

FIG. 1 is a side view showing one embodiment of the endovascular treatment device of the present invention.

FIG. 2 is a cross-sectional view showing one embodiment of the intravascular treatment device of the present invention.

FIG. 3 is a graph showing the effect of the endovascular treatment device of the present invention.

[Explanation of symbols]

 Reference Signs List 1 holder (mesh stent) 2 extracellular matrix (solubilized reconstituted basement membrane) 3 nitric oxide donor (L-arginine)

Continuation of front page (72) Inventor Jiro Sawamoto 1500 Inoguchi, Nakai-machi, Ashigara-gun, Kanagawa Prefecture Terumo F-term (reference) 4C081 AC06 AC09 CA021 CA131 CA161 CA171 CD051 CD061 CD121 CD171 CE02 CG03 CG05 CG06 DA03 DA06 DC03 DC13 DC14 EA06 4206 AA01 AA02 HA32 MA02 MA05 MA17 MA28 MA54 MA85 ZA39 ZA54

Claims (5)

[Claims] An intravascular therapeutic material having an extracellular matrix containing a nitric oxide donor. 2. The intravascular therapeutic material according to claim 1, wherein the nitric oxide donor is L-arginine. 3. The method according to claim 2, wherein the extracellular matrix comprises at least:
The material for endovascular treatment according to claim 1 or 2, comprising at least one selected from the group consisting of type IV collagen, laminin, and heparan sulfate. 4. A device for endovascular treatment comprising the material for endovascular treatment according to claim 1, and a holder for holding the material for endovascular treatment. 5. The endovascular treatment device according to claim 4, wherein the holder is a stent.