JP2002193838A - Medical material for implantation and medical appliance for implantation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a medical material for implantation directly applicable to a damaged region of blood vessel and the like, surely suppressing proliferation of smooth muscle cells with a little medicinal amount and capable of preventing restenosis of the blood vessel, and to provide medical appliances for implantation using the medical material. SOLUTION: This medical material for implantation is characterized by comprising a biocompatible material or a biodegradable material each containing a HMG-CoA reductase inhibitor having <=0.1 μM human vasucular smooth muscle cell-proliferation 50%-suppressing concentration, and the other objective medical appliances for implantation each comprises the medical material and a support for supporting the medical material.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an implantable medical material used for improving a stenosis in a lumen in a living body such as a blood vessel, a bile duct, a trachea, an esophagus, and a urethra and an implantable medical material using the same Equipment related.

[0002]

2. Description of the Related Art A stent is a tubular device for maintaining a stenosis created in a blood vessel or other lumen in a living body in an expanded state, and is, for example, a percutaneous coronary angioplasty (P).
It is used to improve stenosis after TCA). PTCA
In the case of (1), after the stenosis was expanded with a balloon, the restenosis rate was successfully reduced by placing a stent made of a metal mesh structure.
Restenosis was observed at a rate of about 0%, and the problem of restenosis has not been solved.

[0003] Although various theories have been considered as to the cause of restenosis, at present, after a stent is placed,
The mainstream idea is that the phenotype of the smooth muscle cells around the stent changes from a contraction type to a synthetic type and migrates and proliferates toward the lumen of the stent, resulting in intimal thickening and consequent restenosis.

[0004] Therefore, various studies have been made to prevent restenosis by mounting an agent capable of suppressing the migration and proliferation of smooth muscle cells on a stent.

[0005] Specific examples of the above drugs are disclosed in
Japanese Patent Application Laid-Open No. Hei 9-56-503488 discloses a taxol.
No. 807 discloses mitomachine C, adriamycin, genistein, and tilphostin.
No. 00635 discloses cytochalasin, respectively.

On the other hand, HMG-CoA reductase inhibitors are
Conventionally, it is used as a therapeutic agent for hyperlipidemia because it blocks cholesterol synthesis in the liver.
It has been reported that direct application to the vascular wall has an effect related to suppression of intimal thickening. Specifically, NO-producing effects (Laufs U., et al.,
Circulation, 97, 1129-1135.
(1998)), suppression of oxidation of LDL (Massy Zi
ad A. , Et al. , Biochem Biop
hys Res Commun 267 536-54
0 (2000)), suppression of inflammatory response (Sakai
M. , Et al. , Atherosclerosis
133 51-59 (1997)), suppression of foaming of smooth muscle cells and macrophagy (Bellosta S.,
et al. , Atherosclerosis 13
7 Suppl. S101-S109 (1998))
And other effects have been reported.

Although the exact cause of the effects of these HMG-CoA reductase inhibitors on the inhibition of intimal hyperplasia is unknown, the HMG-CoA reductase inhibitors inhibit the synthesis of isoprenyl groups to inhibit cell growth. Have been reported to inhibit the growth and activity of (Kearney D., e.
t al. , Journal of American
College of Cardiology 33
1305-1307 (1999)). The isoprenyl group modifies the structure and function of various proteins, and is considered to lead to the proliferation and activity of smooth muscle cells.

[0008] Among such HMG-CoA reductase inhibitors, lovastatin and simvastatin are disclosed in
JP-56-80707 discloses a drug capable of suppressing intimal hyperplasia of blood vessels when mounted on a stent.

[0009] However, lovastatin and simvastatin do not inhibit human vascular smooth muscle cell proliferation by 50% (IC5
0) are 0.36 μM and 0.38 μM (Dor
othea I. Axel, et al. , Journ
al of Cardiovascular Phar
macology, 35, 619-629 (200
0)), which indicates a high value, it is necessary to mount a large amount on a stent in order to reliably suppress intimal thickening of blood vessels. On the other hand, the amount (volume) of a drug that can be loaded on a stent is physically limited, so a drug with low cytostatic ability, such as lovastatin or simvastatin, is required for a stent with a small diameter or a stent with a short length. In addition, there is a problem that a sufficient amount for suppressing intimal hyperplasia of blood vessels cannot be mounted.

[0010]

Therefore, an object of the present invention is to apply directly to an injured site such as a blood vessel, and to suppress the proliferation of smooth muscle cells with a small amount of a drug, and to obtain a blood vessel. It is an object of the present invention to provide an implantable medical material capable of preventing restenosis, and the like, and an implantable medical device using the same.

[0011]

This and other objects are achieved by the present invention which is defined below as (1) to (5).

(1) It is composed of a biocompatible material or a biodegradable material containing an HMG-CoA reductase inhibitor having a 50% inhibitory concentration of human vascular smooth muscle cell proliferation of 50% or less. And implantable medical materials.

(2) The implantable medical material according to (1), wherein the HMG-CoA reductase inhibitor is cerivastatin or a derivative thereof.

(3) The biodegradable material is one of polylactic acid, polyglycolic acid, a copolymer of polylactic acid and polyglycose acid, and polyhydroxybutyric acid. The implantable medical material according to (1).

(4) An implantable medical device comprising: the implantable medical material according to any one of (1) to (3); and a holder for holding the implantable medical material.

(5) The implantable medical device according to (4), wherein the holding body is a stent.

[0017]

DESCRIPTION OF THE PREFERRED EMBODIMENTS First, a medical material to be implanted in the body of the present invention will be described.

The implantable medical material of the present invention has a human vascular smooth muscle cell proliferation 50% inhibitory concentration (IC50) of 0.1.
It is composed of a biocompatible material or a biodegradable material containing an HMG-CoA reductase inhibitor of not more than μM.

The HMG-CoA reductase inhibitor of the present invention has a human vascular smooth muscle cell proliferation inhibitory concentration (IC5
0) is 0.1 μM or less, but is not particularly limited. Examples thereof include cerivastatin, cerivastatin sodium, nisvastatin and the like. Among them, human vascular smooth muscle cell proliferation 50% inhibitory concentration (IC50) is 0.037 μM (Do).
rothea I. Axel, et al. , Jour
nal of Cardiovascular Pha
rmology, 35, 619-629 (200
Cerivastatin, which is as low as 0) and can suppress intimal hyperplasia with a small amount, is particularly preferable.

The 50% inhibitory concentration (IC50) of human vascular smooth muscle cell proliferation is defined as 50% inhibition of human vascular smooth muscle cell proliferation.
It is the concentration required for suppression and is a term commonly used in biology and pharmacy. Note that the concentration is measured by an ELISA method.

The biocompatible material of the present invention is not particularly limited as long as platelets are essentially not adhered thereto, do not show irritation to tissues, and can elute the HMG-CoA reductase inhibitor. Although not limited, for example, various synthetic polymers such as a blend or block copolymer of polyether polyurethane and dimethyl silicon, polyurethane such as segmented polyurethane, polyacrylamide, polyethylene oxide, polyethylene carbonate, and polycarbonate such as polypropylene carbonate are exemplified. .

The biodegradable material of the present invention is one which is degraded enzymatically and non-enzymatically in vivo, the degradation product does not show toxicity and the HMG-CoA reductase inhibitor can be released. Although not particularly limited, for example, polylactic acid, polyglycolic acid, polylactic acid-polyglycolic acid copolymer, polyhydroxybutyric acid, polymalic acid, polyα-amino acid, collagen, laminin, heparan sulfate, fibronectin, vitronectin, chondroitin sulfate , Hyaluronic acid and the like.
Polylactic acid capable of releasing a CoA reductase inhibitor is particularly preferred.

In the implantable medical material of the present invention, the biocompatible material or the biodegradable material contains the HMG-CoA reductase inhibitor. The mode of inclusion is not particularly limited, and the HMG-CoA reductase inhibitor may be present uniformly or heterogeneously in the biocompatible or biodegradable material, or may be present locally. In order to increase the action of the HMG-CoA reductase inhibitor to suppress the growth of smooth muscle cells, HMG-CoA is preferably added to a portion of a biocompatible material or a biodegradable material that contacts an injury site such as a blood vessel. Preferably, the reductase inhibitor is uniformly dispersed.

The method for producing the implantable medical material of the present invention is not particularly limited. For example, in the case of using polylactic acid as a biodegradable material and cerivastatin sodium as an HMG-CoA reductase inhibitor, a solution in which polylactic acid was dissolved in dichloroethane and a solution in which cerivastatin sodium was dissolved in ethanol were mixed. After that, by dropping it into water stirred at high speed, it is possible to produce polylactic acid fine particles containing cerivastatin sodium in a uniformly dispersed state, and thereafter, by washing with water, the implantable medical device of the present invention can be produced. Material can be obtained.

The method for using the implantable medical material of the present invention is not particularly limited as long as it is a method directly applied to an injured site such as a blood vessel. For example, using a catheter or balloon provided with the implantable medical material of the present invention on its surface,
A method of directly applying to the injured site after expanding the stenosis,
A method of indwelling the holding body provided with the implantable medical material of the present invention at an injured site after the stenotic part is expanded is exemplified.

The method of direct application using a catheter or balloon provided with the implantable medical material of the present invention is suitable for treating a complex injured site where it is difficult to place a support such as a stent. . The method of placing the holder provided with the implantable medical 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 implantable medical material of the present invention is HMG
Since the CoA reductase inhibitor is contained in a biocompatible material or a biodegradable material, it can be directly applied to an injured site such as a blood vessel.

When the HMG-CoA reductase inhibitor is contained in the biocompatible material, the HMG-CoA reductase inhibitor is eluted from the outer surface of the biocompatible material, thereby inhibiting the HMG-CoA reductase inhibitor. Since the agent is directly released to an injury site such as a blood vessel, it is possible to surely suppress the proliferation of smooth muscle cells and prevent restenosis. Also, H
By dispersing the MG-CoA reductase inhibitor into the interior of the biocompatible material, the HMG-CoA reductase inhibitor can be given a sustained release property, whereby the HMG-CoA reductase inhibitor is gradually added. Can be eluted continuously for a long period of time.

Further, when the HMG-CoA reductase inhibitor is contained in the biodegradable material, the HMG-CoA reductase inhibitor is decomposed into the injured site such as a blood vessel by decomposing the biodegradable material. Since it is directly released, it is possible to reliably suppress the proliferation of smooth muscle cells and prevent restenosis. Further, by dispersing the HMG-CoA reductase inhibitor inside the biodegradable material, HMG-CoA
A sustained release of the A reductase inhibitor can be imparted, whereby the HMG-CoA reductase inhibitor can be gradually released over a long period of time.

Next, the medical device to be implanted in the body of the present invention will be described.

An implantable medical device of the present invention includes the above-described implantable medical material of the present invention, and a holder for holding the implantable medical material.

The holder of the present invention is not particularly limited in its material, shape, size, etc., as long as it can hold a medical material to be implanted in the body and can be safely placed in a lumen such as a blood vessel.

Examples of the material of the support include various inorganic compounds, various organic compounds, and composite materials thereof.

Examples of the inorganic compound include various metal materials such as stainless steel, Ni-Ti alloy, and tantalum, and ceramics. Examples of the organic compound include polytetrafluoroethylene, polyethylene, polypropylene, polyethylene terephthalate, and the like.

The shape of the holder is not particularly limited as long as it has sufficient strength to be stably placed in a lumen such as a blood vessel. For example, an arbitrary shape such as a cylindrical shape composed of a network formed of wires of an inorganic compound or fibers of an organic compound, and a cylindrical shape composed of an inorganic compound or an organic compound having pores are preferably mentioned. Can be

Further, the medical device for implantation in the body of the present invention comprises:
A stent, a catheter, a balloon, a vascular prosthesis, an artificial blood vessel, or the like can be used as the holding body, and in one of the preferred embodiments, the holding body is a stent.

The stent can be formed into a coil shape or a mesh tube shape, for example. In addition, any of a balloon expandable type and a self-expandable type may be used.
Any of a flexible stent may be used. Further, the size of the stent may be appropriately selected depending on the application site. Usually, the inner diameter is preferably 1.0 to 3.0 mm, and the length is preferably 5 to 50 mm.

The mode of holding the medical material to be implanted in the body is not particularly limited. However, in terms of stability when transported to an injured site such as a blood vessel, stability in a state where the medical material is indwelled at the injured site, etc.
Preferably, the implantable medical material and the holder are integrated.

The method for integrating the implantable medical material and the holder is not particularly limited. For example, polylactic acid is used as a biodegradable material constituting an implantable medical material, and HMG is used.
-When cerivastatin sodium is used as the CoA reductase inhibitor, in each case, a solution in which polylactic acid is dissolved in dichloroethane and a solution in which cerivastatin sodium is dissolved in ethanol are mixed. And a method of spraying and integrating them on the surface of the substrate.

The implantable medical device of the present invention obtained by these methods can be used by directly placing it at an injured site such as a blood vessel. The method of indwelling at this time is not particularly limited, and examples thereof include a method using a balloon catheter.

When the HMG-CoA reductase inhibitor is contained in the biocompatible material,
Since the HMG-CoA reductase inhibitor is directly released to the injury site by eluting the G-CoA reductase inhibitor from the outer surface of the biocompatible material, the proliferation of smooth muscle cells is surely suppressed, and It is possible to prevent stenosis.

When an HMG-CoA reductase inhibitor is contained in a biodegradable material, the biodegradable material is decomposed at an injured site such as a blood vessel after the indwelling, so that H
Since the MG-CoA reductase inhibitor is released directly to the site of injury, it is possible to reliably suppress the proliferation of smooth muscle cells and prevent restenosis.

Further, since the implantable medical device of the present invention has a holder for holding the implantable medical material, the implantable medical material can be stably applied to an injured site such as a blood vessel for a long period of time. Thus, the HMG-CoA reductase inhibitor can be released to the site of injury for a long period of time.

[0044]

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples. In addition, this invention is not limited to a following example.

1. Production of Medical Device for Implantation in the Body (Example 1) A solution of 5 mg of cerivastatin sodium dissolved in 1 ml of ethanol and a solution of 40 mg of polylactic acid dissolved in 4 ml of dichloroethane were mixed. Then, the mixed solution was knitted with a stainless wire having a diameter of 50 μm, and the inner diameter was 2 mm and the length was 1 mm.
cm is sprayed on a mesh stent having a cylindrical diameter to integrate the polylactic acid containing cerivastatin sodium and the mesh stent, and the implantable medical material of the present invention including the medical material for implantable implant of the present invention and a holding body holding the same. A medical device was obtained (FIGS. 1 and 2).

Comparative Example 1 1 ml of ethanol and a solution of 40 mg of polylactic acid dissolved in 4 ml of dichloroethane were mixed. Then, the mixed solution was used for a diameter of 50 μm.
Was sprayed onto a cylindrical mesh stent having an inner diameter of 2 mm and a length of 1 cm produced by knitting a stainless steel wire to integrate the polylactic acid and the mesh stent.

2. Test on therapeutic effect using vascular injury model by rubbing rabbit iliac artery balloon Kbs: 30 mg of ketamine in muscle of 3 JW rabbits
/ Kg and xylazine 3 mg / kg were administered to perform anesthesia. Then, the left and right femoral arteries were separated from the tissue, and about 150 U / kg of heparin was introduced from the auricular artery. Then, under X-ray fluoroscopy, a PTCA balloon pre-loaded with a guide wire is inserted into the blood vessel by the Seldinger method and carried to the proximal part of the iliac artery, and the balloon is brought to a prescribed pressure in the proximal part of the iliac artery. Expanded. Then, the balloon was pushed to the distal part of the iliac artery with the balloon being expanded, and the inside of the blood vessel was scraped. The rubbing with the balloon was repeated three times. In addition, abrasion with a balloon was performed on both blood vessels of the right and left iliac arteries per rabbit. After removing the balloon from the blood vessel, the femoral artery was ligated and sutured in three layers. Then, the rabbit was continuously fed a diet supplemented with 1% cholesterol for 2 weeks to induce intimal hyperplasia in the iliac artery. Two weeks after the blood vessels were rubbed, 30 mg / kg of ketamine and 3 mg / kg of xylazine were intramuscularly administered again to perform anesthesia. Then, the right common jaw artery was exfoliated from the tissue, and about 150 U / kg of heparin was introduced from the auricular artery. Thereafter, a PTCA balloon pre-loaded with a guidewire was inserted into the blood vessel by the Seldinger method and carried to the distal part of the iliac artery, where the balloon was expanded to a specified pressure at the distal part of the iliac artery. Then, the balloon was pulled to the proximal part of the iliac artery with the balloon being expanded, and the inside of the blood vessel was scraped. At this time, rubbing with a balloon was repeated three times. Subsequently, the mesh stent obtained in Example 1 and integrated with polylactic acid containing cerivastatin sodium was introduced into the right iliac artery, and was left. Further, the mesh stent integrated with polylactic acid obtained in Comparative Example 1 was introduced into the left iliac artery, and was placed. Then, for 4 weeks after the stent placement, the rabbit was continuously fed a diet supplemented with 0.5% cholesterol. Four weeks after placing the mesh stent, a contrast catheter was inserted into the blood vessel from the left maxillary artery, and the left and right iliac arteries were imaged to check the condition. afterwards,
The abdomen was opened to expose the abdominal aorta. Then, perfusion with 2 U / ml of heparinized saline was started from the carotid artery sheath line, and at the same time, the abdominal aorta was excised and killed by blood removal. After systemic perfusion with heparinized saline, 1
The whole body was perfused with 0% neutral buffered formalin solution to fix the target blood vessels (left and right iliac arteries). Then, the fixed blood vessel was embedded in resin according to a standard method to prepare a pathological section, and stained with hematoxylin and eosin. Further, this was subjected to observation with an optical microscope, and the inner film thickness was measured.

3. Results The inner thickness of the left iliac artery in which the mesh stent integrated with polylactic acid obtained in Comparative Example 1 was placed was 667 ± 11.
In contrast to 3 μm (n = 3), the inner thickness of the right iliac artery in which the mesh stent integrated with polylactic acid containing cerivastatin sodium obtained in Example 1 was placed was 107 ± 25 μm. (N = 3). From these results, it was confirmed that the incorporation of cerivastatin sodium into polylactic acid can significantly (p <0.05) significantly suppress the intimal thickening of the blood vessel.

[0049]

As described above, the implantable medical material of the present invention is biocompatible with an HMG-CoA reductase inhibitor having a 50% inhibitory concentration of human vascular smooth muscle cell proliferation of 0.1 μM or less. Since it is characterized by being composed of a material or a biodegradable material, it can be directly applied to an injured site such as a blood vessel, and can be treated with a small amount of a drug (HMG-CoA reductase inhibitor) to produce smooth muscle. Cell proliferation can be reliably suppressed, and restenosis can be prevented. In addition, the use of a small amount of drug leads to safety for the living body.

When the HMG-CoA reductase inhibitor is characterized by being cerivastatin or a derivative thereof, the proliferation of smooth muscle cells can be reduced with a smaller amount of the drug (HMG-CoA reductase inhibitor). Can be suppressed.

In the case where the biodegradable material is any of polylactic acid, polyglycolic acid, a copolymer of polylactic acid and polyglycolic acid, and polyhydroxybutyric acid, While showing excellent safety,
It is possible to release the HMG-CoA reductase inhibitor over a long period.

Further, when the present invention is characterized in that it comprises the implantable medical material and a holder for holding the implantable medical material, the implantable medical material can be stably applied to the blood vessel for a long period of time. And the like, it is possible to reliably release the HMG-CoA reductase inhibitor to the injury site.

Further, when the holding body is a stent, the medical material to be implanted in a living body can be securely fixed to an injured site such as a blood vessel.

[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 endovascular treatment device of the present invention.

[Explanation of symbols]

Reference Signs List 1 holder (mesh stent) 2 biodegradable material (polylactic acid) 3 HMG-CoA reductase inhibitor (cervastatin sodium)

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 9/10 101 A61P 9/10 101 29/00 29/00 43/00 111 43/00 111

Claims (5)

[Claims] 1. A biocompatible material or a biodegradable material containing an HMG-CoA reductase inhibitor having a 50% inhibitory concentration of human vascular smooth muscle cell proliferation of 50% or less. Implantable medical material. 2. The implantable medical material according to claim 1, wherein the HMG-CoA reductase inhibitor is cerivastatin or a derivative thereof. 3. The method according to claim 1, wherein the biodegradable material is selected from the group consisting of polylactic acid, polyglycolic acid, a copolymer of polylactic acid and polyglycose acid, and polyhydroxybutyric acid. Implantable medical material. 4. An implantable medical device comprising: the implantable medical material according to claim 1; and a holder for holding the implantable medical material. 5. The medical device according to claim 4, wherein the holder is a stent.