JP2007105368A - Medical material, other than tissue replacing and bonding material - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide medical material, which avoids semi-permanent mechanical stress or post-placement chronic inflammation, since it is decomposed in a living body, which is deformable with small force compared to conventional metal material, and which achieves high form setting performance and prevents re-narrowing of a vessel. <P>SOLUTION: This medical material, other than tissue replacing and bonding material, includes polymer composite containing polylactic acid, biodegradable aliphatic and aromatic copolymer, and biologically bioactive substance. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a medical material excluding a tissue replacement / joining material.

  In response to the rapid increase in the number of patients with ischemic heart disease (angina pectoris, myocardial infarction) due to the westernization of dietary habits in Japan, percutaneous transvascular coronary artery is a method for reducing coronary artery lesions. Plastic surgery (PTCA) has been performed and has become very popular. At present, the number of cases where PTCA is applied is increasing due to technical development. Specifically, it is more eccentric and calcified more distally from the one that is localized (one with a short lesion length) and one-branch lesion (one that has stenosis only at one site) at the time PTCA began. And the application of PTCA has been expanded to multi-branch lesions (lesions with stenosis at two or more sites).

The PTCA procedure involves first making a small incision in the patient's leg or arm artery, placing an introducer sheath (introducer), leading the guidewire through the lumen of the introducer sheath, A long hollow tube called is inserted into the blood vessel and placed at the entrance of the coronary artery. Thereafter, the guide wire is removed, another guide wire and a balloon catheter are inserted into the lumen of the guide catheter, and the balloon catheter is advanced to the lesion of the coronary artery of the patient under X-ray imaging while the guide wire is advanced. Is located within the lesion. At that position, the doctor inflates the balloon at a predetermined pressure, usually for 30-60 seconds, one or more times. Thereby, the blood vessel lumen of the lesioned part is expanded, and the blood flow through the blood vessel lumen is increased.
However, it has been reported that when the blood vessel wall is damaged by a catheter, the intima proliferates, which is a healing reaction of the blood vessel wall, and restenosis occurs at a rate of about 30 to 40%.

As a method for preventing this restenosis, a method using a device such as a stent or an atherectomy catheter has been studied, and some results have been achieved.
A stent as used herein is intended to treat various diseases caused by stenosis or occlusion of blood vessels or other lumens, in order to expand the stenosis or occlusion site and secure its lumen. It is a tubular medical device that can be placed. Most of them are made of metal material or polymer material. For example, a tubular body made of metal material or polymer material with pores, metal material wire or polymer material fiber braided into a cylindrical shape. Various shaped stents such as molded ones have been proposed. The purpose of stent placement is to prevent and reduce restenosis that occurs after procedures such as PTCA, but conventionally it has been difficult to sufficiently suppress stenosis with only a stent.

In recent years, a biological physiologically active substance such as an immunosuppressive agent or an anticancer agent is supported on a stent, and this biologically physiologically active substance is locally released over a long period of time at the indwelling site of the lumen. Many attempts have been made to reduce the amount.
For example, Patent Document 1 describes a stent in which the surface of a stent body is coated with a mixture of a therapeutic substance and a biodegradable polymer.

However, in the stent proposed in Patent Document 1, after the biodegradable polymer is decomposed in vivo, the stent body is indwelled semi-permanently in the living body, and intimal thickening due to proliferation of vascular smooth muscle cells and the like. Can happen.
This problem is not limited to the stent proposed in Patent Document 1, but is applicable to all stents using a metal material such as stainless steel.

  Further, in Non-Patent Document 1, there is a possibility that inflammation is sustained chronically when the polymer layer is left in the living body semipermanently, and restenosis is induced by degradation of the polymer. It has been reported that not only there is a fear, but there is also a risk of thrombosis.

  In order to solve the above-described problem, a stent formed of a biodegradable material has been proposed (see, for example, Patent Document 2). In this stent, after the biological physiologically active substance is released, the biodegradable material of the stent body can be decomposed and disappear from the stent placement portion. Accordingly, it is possible to avoid the occurrence of chronic inflammation due to the radial force (radial force) exerted on the blood vessel wall by the stent body in order to keep the stent in the blood vessel. In addition, blood vessels gradually meander with aging, but if the stent disappears, the remaining endothelial cell layer can follow this meandering motion well. Therefore, it is possible to provide an intravascular indwelling that has no burden on the living body or has a very small burden. Furthermore, since the radial force is smaller than that of the metal stent, damage to the blood vessel wall derived from the stent due to the high radial force and damage to the blood vessel wall derived from the balloon when expanding with the balloon can be suppressed.

  However, since conventional biodegradable materials did not have sufficient mechanical strength, stents formed from these biodegradable materials were difficult to expand with a balloon and were not practical.

On the other hand, biodegradable materials have been actively developed. In particular, in the medical field, a biodegradable material that can be plastically deformed and has stretchability and shape setting properties that can be substituted for conventionally used metal materials is desired.
Among biodegradable materials, polylactic acid has the advantage of being excellent in transparency, rigidity, workability, etc., but has a problem that mechanical strength and the like are not sufficient when used as a film.
Therefore, attempts have been made to improve the mechanical strength by using this polylactic acid as a copolymer with other polyester compounds, etc., and performing a biaxial stretching operation to form a film (for example, Patent Document 3). ).
However, these films are not sufficient in terms of tensile strength, breaking elongation, impact strength, and the like, and their shape setting properties are low.

JP-A-8-33718 Renu Virmani etc. Circulation 2002, 106, p. 2649-2651 JP 9-308693 A JP 2003-342391 A

  Therefore, the present invention can avoid semi-permanent mechanical stress and chronic inflammation after placement by being decomposed in vivo over time, and can be deformed with a smaller force than a conventional metal material. It is an object of the present invention to provide a medical material that has high properties and can prevent restenosis of blood vessels.

As a result of intensive studies, the present inventors have improved the toughness, flexibility, and impact resistance (impact strength), and the impact value is remarkably maintained while maintaining thermal stability as compared with the polylactic acid raw material. The polymer composition which improved and was excellent in the drawability and shape set property was discovered.
As a result of further intensive studies to solve the above problems, the present inventor has found that a medical material comprising a polymer composition containing polylactic acid and a biodegradable aliphatic / aromatic copolymer, and a biological physiologically active substance However, it has been found that semi-permanent mechanical stress and chronic inflammation after indwelling can be avoided, it can be deformed with less force than conventional metal materials, shape setting is high, and vascular restenosis can be prevented. The present invention has been completed.

That is, the present invention provides the following (1) to (11).
(1) A medical material excluding a tissue replacement / joining material, comprising a polymer composition containing polylactic acid and a biodegradable aliphatic / aromatic copolymer and a biological physiologically active substance.
(2) The medical material excluding the tissue replacement / joining material according to the above (1), wherein the mass ratio of the polylactic acid to the biodegradable aliphatic / aromatic copolymer is 50/50 to 99/1 .
(3) The tissue replacement / joining material according to (1) or (2) above, wherein the polymer composition is obtained by melt-kneading the polylactic acid and the biodegradable aliphatic / aromatic copolymer. Excluding medical materials.
(4) A medical material excluding the tissue replacement / joining material according to any one of (1) to (3), wherein the biological physiologically active substance is embedded or dispersed in the polymer composition.
(5) The tissue replacement and combination as described in any one of (1) to (4) above, which has a biological physiologically active substance layer composed of the biologically physiologically active substance on the surface of the base material containing the polymer composition. Medical materials excluding bonding materials.
(6) A medical material excluding the tissue replacement / joining material according to (5) above, which has a biodegradable polymer layer containing a biodegradable polymer outside the biological physiologically active substance layer.
(7) The above (1) to (1) having a biodegradable polymer layer composed of a composition containing the biological and physiologically active substance and a biodegradable polymer on the surface of a substrate containing the polymer composition. 4) A medical material excluding the tissue replacement / joining material according to any one of 4).
(8) The biodegradable aliphatic / aromatic copolymer is a copolymer obtained by copolymerizing butanediol, succinic acid, and phthalic acid, and is obtained by copolymerizing ethylene glycol, succinic acid, and phthalic acid. A copolymer obtained by copolymerizing butanediol, adipic acid and phthalic acid, a copolymer obtained by copolymerizing ethylene glycol, adipic acid and phthalic acid, ethylene glycol, glutaric acid and terephthalic acid A copolymer obtained by copolymerizing acid, a copolymer obtained by copolymerizing butanediol, glutaric acid and terephthalic acid, and a copolymer obtained by copolymerizing butanediol, succinic acid, adipic acid and phthalic acid. Any of the above (1) to (7), which is at least one selected from the group consisting of a polymer and a copolymer obtained by copolymerizing adipic acid, terephthalic acid and 1,4-butanediol Medical materials excluding tissue replacement and bonding material crab according.
(9) The biological and physiologically active substance is an anticancer agent, immunosuppressant, antibiotic, antirheumatic agent, antithrombotic agent, HMG-CoA reductase inhibitor, ACE inhibitor, calcium antagonist, antihyperlipidemia Drugs, integrin inhibitors, antiallergic agents, antioxidants, GPIIbIIIa antagonists, retinoids, flavonoids, carotenoids, lipid improvers, DNA synthesis inhibitors, tyrosine kinase inhibitors, antiplatelet agents, vascular smooth muscle growth inhibitors, anti Excluding the tissue replacement / joining material according to any one of the above (1) to (8), which is at least one selected from the group consisting of inflammatory agents, biological materials, angiographic agents, interferons, and NO production promoting substances Medical material.
(10) The biodegradable polymer is polylactic acid, polyglycolic acid, a copolymer of polylactic acid and polyglycolic acid, polyhydroxybutyric acid, polymalic acid, poly-α-amino acid, collagen, laminin, heparan sulfate, A medical material excluding the tissue replacement / joining material according to any one of the above (6) to (9), which is at least one selected from the group consisting of fibronectin, vitronectin, chondroitin sulfate, hyaluronic acid, and polycaprolactone.
(11) A medical material excluding the tissue replacement / joining material according to any one of (1) to (10), which is a stent.

  The medical material of the present invention can avoid semi-permanent mechanical stress and chronic inflammation after indwelling by being decomposed in vivo over time, and can be deformed with less force than conventional metal materials. It is highly settable and can prevent restenosis of blood vessels.

Hereinafter, the present invention will be described in more detail.
The medical material of the present invention is a medical material excluding a tissue replacement / joining material, comprising a polymer composition containing polylactic acid and a biodegradable aliphatic / aromatic copolymer and a biological physiologically active substance. . As an example of the preferable aspect of the medical material of this invention, the medical material which has the biological physiologically active substance layer which consists of the said biologically physiologically active substance on the surface of the base material containing the said polymer composition is mentioned. It is preferable that the medical material of the present invention further has a biodegradable polymer layer containing a biodegradable polymer on the outside of the biological physiologically active substance layer.
Moreover, as another example of the preferable aspect of the medical material of this invention, it consists of a composition containing the said biological physiologically active substance and biodegradable polymer | macromolecule on the surface of the base material containing the said polymer composition. Examples thereof include medical materials having a biodegradable polymer layer.

The medical material of the present invention is preferably a medical material that can be placed percutaneously at a target site, and specific examples include a stent, a catheter, an artificial blood vessel, and an artificial prosthetic material. . Among these, a stent is preferable. However, the tissue replacement and bonding material is excluded from the use of the medical material of the present invention.
The tissue replacement / joining material means a bone material such as a bone pin.

Hereinafter, the medical material of the present invention will be described in detail based on a preferred embodiment taking a stent shown in the drawing as an example. However, the present invention is not limited to this.
FIG. 1 is a front view showing an embodiment of the stent of the present invention, and FIGS. 2, 4 and 6 are enlarged cross-sectional views taken along line AA in FIG. 1, respectively. 5 is a partially enlarged longitudinal sectional view taken along line BB in FIG.

As shown in FIGS. 2 and 3, the first preferred embodiment of the stent 1 of the present invention includes a stent body 2, a biological physiologically active substance layer 3 provided on the surface of the stent body 2, The biodegradable polymer layer 4 is provided so as to cover the physiologically bioactive substance layer 3.
The stent body 2 corresponds to the base material.

  If the stent body 2 is composed of the polymer composition and can be placed in a lesion in a living body such as a blood vessel, bile duct, trachea, esophagus, urethra, etc., its material, shape, size, etc. Is not particularly limited. The stent body 2 may include a biological physiologically active substance 6 in addition to the polymer composition.

The shape of the stent body 2 is not particularly limited as long as it has sufficient strength to be stably placed in a lumen in a living body. For example, those formed by knitting fibers formed from the polymer composition into a cylindrical shape, and those obtained by forming pores in a tubular body formed from the polymer composition are preferable.
The stent body 2 may be either a balloon expansion type or a self-expansion type.
Further, the size of the stent body 2 may be appropriately selected according to the application location. For example, when used for a coronary artery of the heart, the outer diameter before expansion is preferably 1.0 to 3.0 mm, and the length is preferably 5 to 50 mm.

The polymer composition constituting the stent body 2 is a composition containing polylactic acid and a biodegradable aliphatic / aromatic copolymer.
The polylactic acid is a polymer of lactic acid. Lactic acid, which is a raw material monomer for polylactic acid, includes L-lactic acid and D-lactic acid as optical isomers, but the polylactic acid used in the present invention is not particularly limited, and either or both of them can be used. .
Usually, polylactic acid has a D-lactic acid unit of about 10% or less and an L-lactic acid unit of about 90% or more, or an L-lactic acid unit of about 10% or less and a D-lactic acid unit of about 90% or more. A polylactic acid having an optical purity of about 80% or more, a polylactic acid having 10 to 90% of D-lactic acid units and 90 to 10% of L-lactic acid units, and having an optical purity of about 80% or less. It is known that there is amorphous polylactic acid.
As the polylactic acid used in the present invention, known polylactic acid can be used without particular limitation. Specifically, crystalline polylactic acid having an optical purity of 85% or more, and crystallinity having an optical purity of 85% or more. Preferred examples include a mixture of polylactic acid and amorphous polylactic acid having an optical purity of 80% or less.

The weight average molecular weight of the polylactic acid used in the present invention is preferably 20,000 to 800,000. When the molecular weight is within this range, it is excellent in toughness, flexibility, impact resistance, stretchability, shape setting properties, and the like. In view of these characteristics, the polylactic acid has a weight average molecular weight of more preferably 60,000 to 700,000, and even more preferably 100,000 to 600,000.
In addition, the weight average molecular weight in this specification is a standard polystyrene conversion value by a gel permeation chromatography method.

The biodegradable aliphatic / aromatic copolymer used in the present invention is a copolymer of an aliphatic dicarboxylic acid, an aromatic dicarboxylic acid and a diol compound.
Specific examples of the aliphatic dicarboxylic acid include oxalic acid, succinic acid, adipic acid, sebacic acid, azelaic acid, dodecanedioic acid, maleic acid, fumaric acid, itaconic acid, citraconic acid, mesaconic acid, and glutaric acid. An acid etc. are mentioned.
Specific examples of the aromatic dicarboxylic acid include phthalic acid, isophthalic acid, terephthalic acid, 2,6-naphthalenedicarboxylic acid, and 5-sodium sulfoisophthalic acid.
Specific examples of the diol compound include propanediol such as ethylene glycol, diethylene glycol, and 1,3-propanediol, butanediol such as 1,4-butanediol, neopentyl glycol, and 1,6-hexanediol. , Cyclohexanedimethanol, triethylene glycol, polyethylene glycol, polypropylene glycol, polytetramethylene glycol, ethylene oxide adducts such as bisphenol A and bisphenol S, and the like.

The ratio of the aliphatic dicarboxylic acid to the total monomers used in the production of the biodegradable aliphatic / aromatic copolymer is preferably 20 to 80 mol%, more preferably 40 to 70 mol%.
20-80 mol% is preferable and, as for the ratio of the said aromatic dicarboxylic acid with respect to all the monomers used for manufacture of the said biodegradable aliphatic-aromatic copolymer, 30-60 mol% is more preferable.
The ratio of the diol compound to the total monomers used in the production of the biodegradable aliphatic / aromatic copolymer is preferably 20 to 80 mol%, and more preferably 40 to 70 mol%.

  In addition to the monomer component, the biodegradable aliphatic / aromatic copolymer is an oxycarboxylic acid such as 4-hydroxybenzoic acid, ε-caprolactone, and lactic acid as long as the effects of the present invention are not impaired. A trifunctional or higher functional polyol compound such as trimellitic acid, trimesic acid, pyromellitic acid, trimethylolpropane, glycerin, pentaerythritol may be used as the monomer component.

  The biodegradable aliphatic / aromatic copolymer can be obtained by copolymerizing the above monomers by a known method. For example, the biodegradable aliphatic / aromatic copolymer can be obtained by mixing the aliphatic dicarboxylic acid, aromatic dicarboxylic acid and diol compound and performing a polycondensation reaction. A small amount of an isocyanate compound may be added during the copolymerization.

  Specific examples of the biodegradable aliphatic / aromatic copolymer include, for example, a copolymer obtained by copolymerizing butanediol, succinic acid, and phthalic acid, and ethylene glycol, succinic acid, and phthalic acid. A copolymer formed by copolymerization of butanediol, adipic acid and phthalic acid, a copolymer formed by copolymerizing ethylene glycol, adipic acid and phthalic acid, ethylene glycol Copolymers of styrene, glutaric acid and terephthalic acid, copolymers of butanediol, glutaric acid and terephthalic acid, butanediol, succinic acid, adipic acid and phthalic acid. Preferable examples include a copolymer obtained by polymerization, a copolymer obtained by copolymerizing adipic acid, terephthalic acid, and 1,4-butanediol.

  Although the weight average molecular weight of the said biodegradable aliphatic-aromatic copolymer is not specifically limited, 20,000-300,000 are preferable and 50,000-300,000 are more preferable. When the molecular weight is within this range, the shape setting property is excellent.

  The mass ratio of the polylactic acid to the biodegradable aliphatic / aromatic copolymer (polylactic acid / biodegradable aliphatic / aromatic copolymer) in the polymer composition used in the present invention was 50/50. -99/1 are preferable, and 60 / 40-95 / 5 are more preferable. When the mass ratio is within this range, the shape setting property is particularly excellent.

The method for producing the polymer composition used in the present invention is not particularly limited. For example, the polymer composition is obtained by melt-kneading the polylactic acid and the biodegradable aliphatic / aromatic copolymer. Is preferred. Specifically, for example, the polylactic acid in the form of pellets and the biodegradable aliphatic / aromatic copolymer are charged into a kneading apparatus, and melt-kneaded at about 180 ° C. to 250 ° C. to obtain the polymer composition. be able to.
As the kneading apparatus, generally used kneading apparatuses such as a single or twin screw extruder and various kneaders can be used. Among these, a twin-screw extruder is preferable, and a polymer composition in which an aliphatic / aromatic copolymer is finely dispersed in a polylactic acid matrix can be easily obtained by melt-kneading.
At the time of melt kneading, the respective components may be mixed in advance with a tumbler, a Henschel mixer or the like and then supplied to the kneading apparatus, or a method in which each component is separately quantitatively supplied to the kneading apparatus may be used.
The temperature in the tumbler or Henschel mixer is preferably 180 ° C or higher, and more preferably about 210 ° C.

The biological physiologically active substance layer 3 is composed of a biological physiologically active substance.
The biological physiologically active substance used in the composition of the present invention is not particularly limited as long as it has an effect of suppressing restenosis, and specifically, for example, an anticancer agent, an immunosuppressant, an antibiotic, an antibacterial agent Rheumatism, antithrombotic, HMG-CoA reductase inhibitor, ACE inhibitor, calcium antagonist, antihyperlipidemic agent, integrin inhibitor, antiallergic agent, antioxidant, GPIIbIIIa antagonist, retinoid, flavonoid, Preferred examples include carotenoids, lipid improving agents, DNA synthesis inhibitors, tyrosine kinase inhibitors, antiplatelet agents, vascular smooth muscle growth inhibitors, anti-inflammatory agents, biomaterials, interferons, and NO production promoters.

  Specific examples of the anticancer agent include vincristine, vinblastine, vindesine, irinotecan, pirarubicin, paclitaxel, docetaxel, methotrexate and the like.

  Specific examples of the immunosuppressant include sirolimus, everolimus, biolimus, tacrolimus, azathioprine, cyclosporine, cyclophosphamide, mycophenolate mofetil, gusperimus, and mizoribine.

  Specific examples of antibiotics include mitomycin, adriamycin, doxorubicin, actinomycin, daunorubicin, idarubicin, pirarubicin, aclarubicin, epirubicin, pepromycin, and dinostatin styramer.

  Specific examples of the anti-rheumatic agent include methotrexate, sodium thiomalate, penicillamine, and robenzalit.

  Specific examples of the antithrombotic drug include heparin, aspirin, antithrombin preparation, ticlopidine, hirudin and the like.

  Specific examples of the HMG-CoA reductase inhibitor include cerivastatin, cerivastatin sodium, atorvastatin, nisvastatin, itavastatin, fluvastatin, fluvastatin sodium, simvastatin, lovastatin, pravastatin and the like.

  Specific examples of the ACE inhibitor include quinapril, perindopril erbumine, trandolapril, cilazapril, temocapril, delapril, enalapril maleate, lisinopril, captopril and the like.

  Specific examples of the calcium antagonist include, for example, hifedipine, nilvadipine, diltiazem, benidipine, nisoldipine and the like.

  Specific examples of antihyperlipidemic agents include, for example, probucol.

  Specific examples of the antiallergic agent include tranilast.

  Specific examples of the retinoid include, for example, all-trans retinoic acid.

  Specific examples of the antioxidant preferably include catechins, anthocyanins, proanthocyanidins, lycopene, β-carotene and the like. Among catechins, epigallocatechin gallate is particularly preferable.

  Specific examples of the tyrosine kinase inhibitor include genistein, tyrphostin, arbustatin and the like.

  Specific examples of the anti-inflammatory agent include steroids such as dexamethasone and prednisolone.

  Specific examples of the biological material include, for example, EGF (epidemal growth factor), VEGF (basic endorthous growth factor), HGF (hepatocyte growth factor), PDGF (platelet growth factor), PDGF (platelet growth factor), and PDGF (platelet growth factor). Etc. are preferable.

  The above biological and physiologically active substances may be used alone or in combination of two or more.

  The thickness of the biological physiologically active substance layer 3 is not particularly limited as long as it does not significantly impair the performance of the stent body 2 such as delivery to a lesioned part or irritation to a blood vessel wall, but preferably 1 to 100 μm. More preferably, it is 1-50 micrometers, More preferably, it is the range of 1-10 micrometers.

  A method for providing the biological physiologically active substance layer 3 on the surface of the stent body 2 is not particularly limited. For example, a method of melting the biological physiologically active substance and coating the surface of the stent body 2; A method in which a biological physiologically active substance is dissolved in a solvent to prepare a solution, and the stent body 2 is dipped in the solution and then dried; a solution in which the biological physiologically active substance is dissolved in the solvent is sprayed Examples of the method include spraying the surface of the stent body 2 and then drying. When the solvent can easily wet the surface of the stent body 2, a solution is prepared by dissolving the biological and biologically active substance in the solvent, and the stent body 2 is immersed in the solution and then dried. A method in which the above-described biological physiologically active substance is dissolved in a solvent is sprayed onto the surface of the stent body 2 using a spray and then dried.

The biodegradable polymer layer 4 is formed of a biodegradable polymer.
The biodegradable polymer used in the composition of the present invention is not particularly limited as long as it is a polymer that can be degraded in a living body, but a biodegradable polymer is preferable. Specifically, for example, polylactic acid, polyglycolic acid, copolymer of polylactic acid and polyglycolic acid, polyhydroxybutyric acid, polymalic acid, poly-α-amino acid, collagen, laminin, heparan sulfate, fibronectin, vitronectin, chondroitin Preferable examples include sulfuric acid, hyaluronic acid, polycaprolactone and the like. These may be used alone or in combination of two or more.
Among these, in view of being decomposed in vivo, a medically safe one is preferable, and specific examples include polylactic acid.
Examples of the polylactic acid include L-polylactic acid, D-polylactic acid, and D, L-polylactic acid. The polylactic acid is not particularly limited as long as it can follow the balloon expansion operation and has a certain degree of strength. However, D, L-polylactic acid is preferred.

  The thickness of the biodegradable polymer layer 4 is the same as that of the biological physiologically active substance layer 3 as long as it does not significantly impair the performance of the stent body 2 such as delivery to the lesioned part and irritation to the blood vessel wall. Although not particularly limited, it is preferably in the range of 1 to 75 μm, more preferably 1 to 25 μm, and most preferably 1 to 10 μm.

  A method for providing the biodegradable polymer layer 4 on the surface of the biological physiologically active substance layer 3 is not particularly limited. For example, the biologically bioactive substance layer 3 is melted by melting the biodegradable polymer. A method in which the biodegradable polymer is dissolved in a solvent to prepare a solution, the stent body 2 having the biological physiologically active substance layer 3 on the surface is immersed in the solution, and then the solvent is pulled up. A method in which the biodegradable polymer is dissolved in a solvent, sprayed onto the surface of the biological physiologically active substance layer 3 using a spray, and then the solvent is evaporated or other The method of removing by a method etc. are mentioned. When the solvent can easily wet the surface of the biological physiologically active substance layer 3, a solution is prepared by dissolving the biodegradable polymer in a solvent, and the biological physiology is added to the solution. The stent body 2 having the active substance layer 3 on the surface is dipped and then pulled up, and the solvent is evaporated or removed by another method, and the solution in which the biodegradable polymer is dissolved in the solvent is used to spray After spraying on the surface of the biologically physiologically active substance layer 3, a method of evaporating or removing the solvent by other methods is preferable from the viewpoint of simplicity.

As shown in FIGS. 4 and 5, the preferred second embodiment of the stent 1 of the present invention is a composition containing a biological physiologically active substance 6 and a biodegradable polymer 7 on the surface of the stent body 2. It has the biodegradable polymer layer 5 which consists of a thing.
The stent body 2, the biological physiologically active substance 6, and the biodegradable polymer 7 are the same as those described in the first aspect of the stent 1 described above.
The composition containing the biological physiologically active substance 6 and the biodegradable polymer 7 is a composition in which the biological physiologically active substance 6 is dispersed in the biodegradable polymer 7.
The method for producing the composition is not particularly limited, and examples thereof include a method of kneading the molten biological and biologically active substance 6 and the molten biodegradable polymer 7 to obtain the composition. .

A method for providing the biodegradable polymer layer 5 made of the composition containing the biological physiologically active substance 6 and the biodegradable polymer 7 on the surface of the stent body 2 is not particularly limited. A method of melting the degradable polymer 7 and the biological physiologically active substance 6 to obtain the above composition, and then coating the surface of the stent body 2; the biodegradable polymer 7 and the biological physiologically active substance 6; A solution is prepared by dissolving in a solvent, and the stent body 2 is dipped in this solution and then pulled up, and then the solvent is evaporated or otherwise removed, or the solution is sprayed onto the stent body 2 using a spray. And a method of removing the solvent by transpiration or other methods.
When the above-mentioned solvent can easily wet the surface of the stent body 2, the stent body 2 is dissolved in a solution obtained by dissolving the biodegradable polymer 7 and the biological physiologically active substance 6 in the solvent. The method of immersing and drying, or the method of spraying the solution onto the stent body 2 using a spray and drying is simple and most preferably applied.

  The thickness of the biodegradable polymer layer 5 made of a composition containing the biological physiologically active substance 6 and the biodegradable polymer 7 determines the reachability to the lesion (delivery property) and irritation to the blood vessel wall. It is not particularly limited as long as it does not significantly impair the performance of the stent body 2 such as sex, but it is preferably 1 to 100 μm, more preferably 1 to 50 μm, more preferably the effect of the biological physiologically active substance. Preferably it is the range of 1-10 micrometers.

A preferred third embodiment of the stent 1 of the present invention has a stent body 2 containing the polymer composition and a biological physiologically active substance 6 as shown in FIG.
The method of including the biological physiologically active substance 6 in the stent body 2 is not particularly limited, but a method that can be easily produced is preferable, for example, a method of kneading together at the time of melt molding, Examples thereof include a method of mixing a biological physiologically active substance. Thereby, it becomes possible to release the biological physiologically active substance 6 together with the decomposition of the polymer composition constituting the stent body 2 in vivo, and the inflammatory reaction associated with the biodegradation of the stent body is biologically physiological. It can be suppressed with an active substance.

  As an indwelling means of the stent 1 of the present invention, for example, a balloon expanding means can be used. However, if the stent body 2 is an elastic body, a self-expanding means using this elastic force can be used.

After the stent of the present invention is placed in a lesioned part in a living body, a biological physiologically active substance is released over time. Thus, after the purpose of suppressing the restenosis of the blood vessel is achieved, the stent 1 of the present invention is decomposed in the living body and eventually disappears from the living body. Can avoid chronic inflammation.
In addition, since the stent body of the present invention is formed of the above polymer composition, the stent body can be deformed with a smaller force than conventional metal materials, and is excellent in shape setting, so that the stent can be reliably attached to the lesion. In place.

Hereinafter, the present invention will be specifically described with reference to examples. However, the present invention is not limited to these.
<Example 1>
80 parts by mass of pellet-shaped polylactic acid (API, 100D040) and pellet-shaped Ecoflex (BASF, biodegradable aliphatic / aromatic copolymer consisting of adipic acid, terephthalic acid and 1,4-butanediol) 20 parts by mass of the polymer) is put into a mixer heated to 210 ° C. (laboratory plast mill roller-type mixer 60R type manufactured by Toyo Seiki Co., Ltd.) and melt-kneaded at 100 rpm for 8 minutes to obtain a polymer composition. Obtained.
The polymer composition was pressed on a hot press and rapidly cooled in ice water to form a press sheet having a thickness of 120 μm. The sheet was cut into a size of 50 mm × 7 mm, and the diameter was 2.4 mm and a length of 60 mm polytetrafluoroethylene. It was rolled into a (PTFE) shrink tube and inserted.
Further, a 70 mm long PTFE tube (manufactured by Chukoh, AWG-17) is inserted therein, heated in an oven heated to 200 ° C. for 2 minutes in advance, cooled at room temperature, and then a shrink tube and a PTFE tube. Was removed to obtain a pipe-shaped molded article having a diameter of 2.1 mm and a wall thickness of 120 μm composed of the polymer composition. The pipe-shaped molded product was processed into a stent shape with an excimer laser (manufactured by Sumitomo Heavy Industries, Ltd., SPL400H) to obtain a stent body.

  Next, rapamycin (manufactured by Nippon Bulk Pharmaceutical Co., Ltd., sirolimus 05310020) (hereinafter also referred to as “RM”) and polylactic acid (API, 100D040) (hereinafter referred to as “PLA”) which is a biodegradable polymer. ) Was dissolved in tetrahydrofuran (hereinafter referred to as “THF”) so that the mass ratio of RM and PLA was 1: 1 to prepare a solution having a mixture concentration of 1% by mass. This solution is sprayed onto the stent body by spray (NORDSON, Micro Spray Gun-II), and the solvent, THF, is dried to form a biodegradable polymer layer composed of RM and PLA. Thus, the stent (outer diameter: 2.1 mm) of Example 1 was obtained. At this time, the total mass of RM and PLA contained in the biodegradable polymer layer was about 600 μg.

In order to evaluate the shape setting property of the stent, the obtained stent having an outer diameter of 2.1 mm was expanded to 3.5 mm using a balloon catheter (made by Terumo, Arashi). The outer diameter after the minute was measured with a digital microscope (manufactured by Sonic), and the recoil rate was calculated based on the following formula.
In addition, it means that shape setting property is so high that a recoil rate is small.
The results are shown in Table 1 below.

  Recoil rate (%) = 100 × (outer diameter immediately after expansion−outer diameter after 5 minutes from balloon contraction) / (outer diameter immediately after expansion)

FIG. 7 shows a rabbit iliac artery indwelling pathological image of the stent of Example 1. FIG. 8 shows a porcine coronary artery indwelling pathological image of the stent of Example 1.
In order to evaluate the effect of the obtained stent to suppress vascular restenosis, a rabbit iliac artery implantation experiment and a porcine coronary artery implantation experiment were performed on the stent of Example 1 by the following method. The intimal thickening (% Area Stenosis (% AS)) was measured.
In addition, it means that the effect which suppresses restenosis is so high that intimal thickening degree (% AS) is small.
The results are shown in FIG. 7 and FIG.

  % AS = 100 × (neointimal area) / (vascular lumen area + neointimal area) (%)

  FIG. 9 is a schematic cross-sectional view of a blood vessel after a rabbit iliac artery implantation experiment or a porcine coronary artery implantation experiment. In FIG. 9, the vascular lumen area (A) is the cross-sectional area of the vascular lumen, and the neointimal area (B) is the cross-sectional area of the intima formed between the vascular thickness 8 and the vascular lumen. is there. The blood vessel thickness 8 is the blood vessel itself between the inner elastic plate 9 and the outer elastic plate 10.

(Rabbit iliac artery implantation experiment)
A PTCA balloon loaded with the obtained stent was inserted into the blood vessel through the carotid artery sheath line, introduced into the left iliac artery, and expanded and placed under a pressure of 10 MPa. After removing the balloon, the common carotid artery was sutured in three layers and left for 4 weeks.
After placement for 4 weeks, the left carotid artery was approached to the blood vessel in the same manner as when the stent was placed, and after imaging the iliac artery, the abdomen was opened to expose the abdominal vena cava. Perfusion with 2 U / ml of heparinized physiological saline was started from the carotid artery sheath line, and at the same time, the abdominal vena cava was excised and killed by blood removal. After systemic perfusion with heparinized physiological saline, systemic perfusion was performed with 10% neutral buffered formalin solution to fix the target blood vessel. The fixed sample was embedded in a resin according to a standard method to prepare a pathological section, and stained with hematoxylin and eosin (HE). This was subjected to observation with an optical microscope, and the neointimal area and vascular lumen area were measured. The intimal thickness (% AS) was calculated based on the above formula.

(Pig coronary artery implantation experiment)
The PTCA balloon loaded with the obtained stent was inserted into the blood vessel through the carotid artery sheath line, introduced into the left circumflex branch (LCX) of the coronary artery, and expanded and placed under a pressure of 10 MPa. After removing the balloon, the common carotid artery was sutured in three layers and left for 4 weeks.
After placement for 4 weeks, the left carotid artery was approached to the blood vessel in the same manner as when the stent was placed, and after coronary artery angiography, the abdomen was opened to expose the abdominal vena cava. Perfusion with 2 U / ml of heparinized physiological saline was started from the carotid artery sheath line, and at the same time, the abdominal vena cava was excised and killed by blood removal. After systemic perfusion with heparinized physiological saline, systemic perfusion was performed with 10% neutral buffered formalin solution to fix the target blood vessel. The fixed sample was embedded in a resin according to a standard method to prepare a pathological section, and stained with hematoxylin and eosin (HE). This was subjected to observation with an optical microscope, the neointimal area and the blood vessel lumen area were measured, and the intimal thickness (% AS) was calculated based on the above formula.

<Example 2>
Biodegradation of pellet-shaped polylactic acid (API, 100D040) from 80 parts by mass to 90 parts by mass, pellet-shaped Ecoflex (BASF, adipic acid, terephthalic acid and 1,4-butanediol Except that the amount of the aliphatic aliphatic / aromatic copolymer) was changed from 20 parts by mass to 10 parts by mass, a stent was formed in the same manner as in Example 1, and the recoil rate was the same as in Example 1. Was measured.
The results are shown in Table 1 below.

<Example 3>
In a twin screw extruder (Technobel, twin screw extruder KZW15-30MG, screw outer diameter 15 mm, segment type screw, L / D = 30) heated to 190-215 ° C with a vacuum vent. 80 parts by mass of polylactic acid (API, 100D040) and pellet-shaped Ecoflex (BASF, biodegradable aliphatic / aromatic copolymer comprising adipic acid, terephthalic acid and 1,4-butanediol ) 20 parts by mass were mixed and added. Next, the mixture was kneaded at a screw rotational speed of 200 to 300 rpm, the molten strand was discharged from the extruder, cooled in water, and then cut with a pelletizer to obtain pellets composed of the polylactic acid and the ecoflex.
Further, the pellet was pressed on a hot press and quenched in ice water to obtain a press sheet having a thickness of 120 μm. The sheet was cut into a size of 50 mm × 7 mm, and rolled and inserted into a PTFE shrink tube having a diameter of 2.4 mm and a length of 60 mm.
Furthermore, a 70 mm long PTFE tube (manufactured by Chukoh, AWG-17) was inserted therein, heated in an oven heated to 200 ° C. for 2 minutes in advance, cooled at room temperature, and then removed from the PTFE tube. A pipe-shaped molded product having a diameter of 2.1 mm and a wall thickness of 120 μm composed of the polymer composition was obtained. The pipe-shaped molded product was processed into a stent shape with an excimer laser (manufactured by Sumitomo Heavy Industries, Ltd., SPL400H) to obtain a stent body.

  Next, rapamycin (manufactured by Nippon Bulk Pharmaceutical Co., Ltd., sirolimus 05310020) and polylactic acid (API Co., 100D040), which is a biodegradable polymer, have a mass ratio of RM to PLA of 1: 1. As described above, a solution in which the concentration of the mixture was 1% by mass was prepared by dissolving in THF. This solution is sprayed onto the stent body by spray (NORDSON, Micro Spray Gun-II), and the solvent, THF, is dried to form a biodegradable polymer layer composed of RM and PLA. Thus, the stent (outer diameter: 2.1 mm) of Example 1 was obtained. At this time, the total mass of RM and PLA contained in the biodegradable polymer layer was about 600 μg.

About the obtained stent, the recoil rate was measured by the same method as Example 1.
The results are shown in Table 1 below.

<Example 4>
Biodegradation of pellet-shaped polylactic acid (API, 100D040) from 80 parts by mass to 90 parts by mass, pellet-shaped Ecoflex (BASF, adipic acid, terephthalic acid and 1,4-butanediol Except that the amount of the aliphatic aliphatic / aromatic copolymer) was changed from 20 parts by mass to 10 parts by mass, a stent was formed in the same manner as in Example 3, and the recoil rate was increased in the same manner as in Example 1. Was measured.
The results are shown in Table 1 below.

<Example 5>
Rapamycin (manufactured by Nippon Bulk Pharmaceutical Co., Ltd., sirolimus 0530020), which is an anticancer agent, was dissolved in THF to prepare a solution having an RM concentration of 1% by mass. This solution is sprayed onto the stent body prepared in the same manner as in Example 1 with a spray (manufactured by NORDSON, Micro Spray Gun-II), the solvent THF is dried, and the biological physiological activity composed of RM A material layer was formed. At this time, the thickness of the biological physiologically active substance layer was 5 μm, and the mass of RM was 300 μg.
Next, polylactic acid (API, 100D040), which is a biodegradable polymer, was dissolved in THF to prepare a solution having a PLA concentration of 1% by mass. This solution is sprayed on the stent body provided with the biological physiologically active substance layer by spray (Microspray Gun-II, manufactured by NORDSON), and the solvent, THF, is dried. A biodegradable polymer layer composed of PLA was formed outside the layer. At this time, the thickness of the biodegradable polymer layer was 5 μm, and the mass of PLA was 300 μg.
About the obtained stent, the recoil rate was measured by the same method as Example 1.
The results are shown in Table 1 below.

<Comparative Example 1>
The amount of pellet-shaped polylactic acid (API, 100D040) was changed from 80 parts by mass to 100 parts by mass, and pellet-shaped Ecoflex (BASF, adipic acid, terephthalic acid and 1,4-butanediol were used. A stent was formed by the same method as in Example 1 except that the biodegradable aliphatic / aromatic copolymer) was not used, and the recoil rate was measured by the same method as in Example 1.
The results are shown in Table 1 below.

<Comparative example 2>
The amount of pellet-shaped polylactic acid (API, 100D040) was changed from 80 parts by mass to 100 parts by mass, and pellet-shaped Ecoflex (BASF, adipic acid, terephthalic acid and 1,4-butanediol were used. A stent was formed by the same method as in Example 3 except that the biodegradable aliphatic / aromatic copolymer) was not used, and the recoil rate was measured by the same method as in Example 1.
The results are shown in Table 1 below.

<Comparative Example 3>
Without using pellet-shaped polylactic acid (API, 100D040), pellet-shaped Ecoflex (BASF, biodegradable aliphatic / aromatic copolymer consisting of adipic acid, terephthalic acid and 1,4-butanediol A stent was formed by the same method as in Example 1 except that the amount of coalescence was changed from 20 parts by mass to 100 parts by mass, and the recoil rate was measured by the same method as in Example 1.
The results are shown in Table 1 below.

<Comparative example 4>
As the stent body, an existing metal stent (Tsunami, manufactured by Terumo Corporation) was used. Further, rapamycin (Nippon Bulk Chemical Co., Sirolimus 05310020) as an anticancer agent and polylactic acid (API Co., 100D040) as a biodegradable polymer are added to the main stent body, and the mass ratio of RM and PLA is 1. : 1 was prepared by dissolving in THF so that the concentration of the mixture was 1% by mass. Then, this solution is sprayed on the stent body by spray (Microspray Gun-II, manufactured by NORDSON), and the solvent THF is dried to form a biodegradable polymer layer composed of RM and PLA. The stent (outer diameter 2.1 mm) of Comparative Example 4 was obtained. At this time, the total mass of RM and PLA contained in the biodegradable polymer layer was about 600 μg, and the thickness of the biodegradable polymer layer was about 10 μm.
About the obtained stent, the recoil rate was measured by the same method as Example 1.
The results are shown in Table 1 below.

In addition, with respect to the stent of Comparative Example 4, a porcine coronary artery implantation experiment was performed in the same manner as in Example 1, and the intimal thickness (% Area Stenosis (% AS)) was measured.
The results are shown in FIG.

As is clear from the results shown in Table 1, the stent (Comparative Examples 1 and 2) in which the polymer main body is formed only from polylactic acid has a recoil rate of 96.5 to 98.9% and has shape setting properties. Was low. Further, the stent (Comparative Example 3) in which the polymer main body is formed only from Ecoflex (biodegradable aliphatic / aromatic copolymer) has a recoil rate of 42.3%. The shape setting property was better than that.
On the other hand, the stents (Examples 1 to 5) of the present invention had a recoil rate of 5.8 to 9.2%, and were remarkably superior in shape setting properties as compared with the stents of Comparative Examples 1 to 3.
As is clear from the results shown in FIGS. 7 to 9, the stent of Example 1 was highly effective in preventing restenosis and had the same effect as the stent of Comparative Example 4.

FIG. 1 is a front view showing an embodiment of the stent of the present invention. FIG. 2 is an enlarged cross-sectional view taken along line AA in FIG. 3 is a partially enlarged longitudinal sectional view taken along line BB in FIG. 4 is an enlarged cross-sectional view taken along line AA in FIG. FIG. 5 is a partially enlarged longitudinal sectional view taken along line BB in FIG. 6 is an enlarged cross-sectional view taken along line AA in FIG. FIG. 7 is a pathological image of the rabbit iliac artery indwelling of the stent in Example 1. FIG. 8 is a porcine coronary artery indwelling pathological image of the stent in Example 1. FIG. 9 is a schematic cross-sectional view of a blood vessel after a rabbit iliac artery implantation experiment or a porcine coronary artery implantation experiment. FIG. 10 is a porcine coronary artery indwelling pathological image of the stent in Comparative Example 4.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 Stent of this invention 2 Stent body 3 Biological bioactive substance layer 4, 5 Biodegradable polymer layer 6 Biological bioactive substance 7 Biodegradable polymer 8 Vascular thickness 9 Inner elastic plate 10 Outer elastic plate (A) Vascular lumen area (B) Neointimal area

Claims (11)

  A medical material excluding a tissue replacement / joining material, comprising a polymer composition containing polylactic acid and a biodegradable aliphatic / aromatic copolymer and a biological physiologically active substance.   The medical material excluding the tissue replacement / joining material according to claim 1, wherein a mass ratio of the polylactic acid to the biodegradable aliphatic / aromatic copolymer is 50/50 to 99/1.   The medical material excluding the tissue replacement / joining material according to claim 1 or 2, wherein the polymer composition is obtained by melt-kneading the polylactic acid and the biodegradable aliphatic / aromatic copolymer.   The medical material excluding the tissue replacement / joining material according to any one of claims 1 to 3, wherein the biological physiologically active substance is embedded or dispersed in the polymer composition.   The medical material excluding the tissue replacement / joining material according to any one of claims 1 to 4, which has a biological physiologically active substance layer comprising the biologically physiologically active substance on the surface of a base material containing the polymer composition. .   The medical material excluding the tissue replacement / joining material according to claim 5, further comprising a biodegradable polymer layer containing a biodegradable polymer outside the biological physiologically active substance layer.   The surface of the base material containing the polymer composition has a biodegradable polymer layer composed of a composition containing the biological physiologically active substance and a biodegradable polymer. Medical materials excluding the tissue replacement and bonding materials described.   The biodegradable aliphatic / aromatic copolymer is a copolymer obtained by copolymerizing butanediol, succinic acid and phthalic acid, and a copolymer obtained by copolymerizing ethylene glycol, succinic acid and phthalic acid. A copolymer obtained by copolymerizing butanediol, adipic acid and phthalic acid, a copolymer obtained by copolymerizing ethylene glycol, adipic acid and phthalic acid, and ethylene glycol, glutaric acid and terephthalic acid. A copolymer formed by copolymerization, a copolymer formed by copolymerizing butanediol, glutaric acid, and terephthalic acid, a copolymer formed by copolymerizing butanediol, succinic acid, adipic acid, and phthalic acid, And at least one selected from the group consisting of copolymers obtained by copolymerizing adipic acid, terephthalic acid and 1,4-butanediol. Medical materials except woven substituted and bonding material.   The biological and physiologically active substance is an anticancer agent, immunosuppressive agent, antibiotic, antirheumatic agent, antithrombotic agent, HMG-CoA reductase inhibitor, ACE inhibitor, calcium antagonist, antihyperlipidemic agent, integrin Inhibitor, antiallergic agent, antioxidant, GPIIbIIIa antagonist, retinoid, flavonoid, carotenoid, lipid improver, DNA synthesis inhibitor, tyrosine kinase inhibitor, antiplatelet agent, vascular smooth muscle growth inhibitor, anti-inflammatory agent, The medical material excluding the tissue replacement / joining material according to any one of claims 1 to 8, which is at least one selected from the group consisting of a biological material, an angiographic agent, an interferon, and a NO production promoting substance.   The biodegradable polymer is polylactic acid, polyglycolic acid, a copolymer of polylactic acid and polyglycolic acid, polyhydroxybutyric acid, polymalic acid, poly-α-amino acid, collagen, laminin, heparan sulfate, fibronectin, vitronectin The medical material excluding the tissue replacement / joining material according to any one of claims 6 to 9, which is at least one selected from the group consisting of chondroitin sulfate, hyaluronic acid, and polycaprolactone.   A medical material excluding the tissue replacement / joining material according to any one of claims 1 to 10, which is a stent.

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