JP5170474B2 - Vascular stent - Google Patents

Description

  The present invention relates to a vascular stent that is implanted in a blood vessel of a human body, a trachea, a bile duct, or the like and supports a lumen of the vessel from the inside.

  Conventionally, when a stenosis occurs in a blood vessel of a human body, for example, a blood vessel such as an artery, a percutaneous angioplasty (PTA) is performed, which is an operation for expanding the stenosis to improve blood flow. . In order to prevent restenosis from occurring in the PTA-applied portion, a tubular stent is implanted. This stent is inserted into the blood vessel in a reduced diameter state, and then expanded and implanted in the blood vessel, thereby supporting the blood vessel from the inside and preventing the restenosis from occurring in the blood vessel. I have to.

  As this type of stent, a cylindrical metal body is provided with a cut so that the diameter is increased or decreased.

  By the way, a metal stent may cause a foreign body reaction by being left in the human body for a long period of time, and it is not appropriate to place it in the human body semipermanently. Further, in order to remove the metal stent once implanted in the human body, a surgical operation is further required, and the burden on the patient becomes extremely large.

  And it has been reported that the incidence of restenosis in the part to which PTA has been applied decreases after 6 months from the operation.

  Therefore, a vascular stent used for supporting a stenotic blood vessel or other vascular vessel in an expanded state is a vascular vessel for a certain period, for example, about 6 months after being implanted in a human body. It is desirable that, after having the function of supporting the diameter expansion, the function disappears without being taken out from the human body after the function becomes unnecessary.

The inventors of the present invention have solved the problems of the metal stent as described above, and after implanting into the vascular vessel in the human body as a vascular stent that satisfies the desirable conditions required for the vascular stent , Proposes a product that eliminates the need for removal. This stent is formed using a biodegradable polymer . As this type of stent, WO92 / 15342 (Patent Document 1), WO00 / 13737 (Patent Document 2), and JP-A-11-57018. Is disclosed in Japanese Patent Publication (Patent Document 3).

WO92 / 15342 WO00 / 13737 Japanese Patent Laid-Open No. 11-57018

By the way, a stent using a biodegradable polymer is implanted into a blood vessel of a human body, is then decomposed by a body fluid, and is absorbed into the human body.

Therefore, in stents using biodegradable polymers , it is necessary to use materials that do not have adverse effects such as causing inflammation in the human body even if the constituent materials are decomposed and absorbed into the human body. There is.

Shape The stent for vascular, to prevent restenosis of PTA alms portions of vessels such as blood vessels, so as to maintain a state in which the vessels are enlarged, modeled after the lumen of the vessel It is desirable to have

Furthermore, stents for vascular, a portion subjected to PTA vascular, it is necessary to support the state of being expanded at constant intensity over a period of time.

An object of the present invention is to provide a vascular stent does not adversely affect the human body.

The present invention proposed to achieve the above-mentioned object is a vascular stent that is decomposed and disappears in vivo after being implanted in the living body, and the optical purity of L-body is 99.8. % Or more and the weight average molecular weight is formed from polylactic acid (PLLA) in the range of 80,000 to 300,000.

The polylactic acid (PLLA) used here has been removed to the extent that the residual material of the polymerization catalyst used when melt polymerizing L-lactide is not detected by atomic absorption spectrometry.

Since the D-isomer, which is an optical isomer of the L-isomer of polylactic acid, does not exist in the human body in a natural state, it is desirable not to remain in the human body in consideration of the safety of the human body. Vascular stents according to the present invention, since the optical purity of L- body naturally present in the human body is composed of polylactic acid and 99.8% or more, are degraded in the human body vessel, the body Even if absorbed into the body, it does not adversely affect the human body.

However, stents for vascular, necessary to maintain the structure and regardless of the state, a state in which a so a reduced diameter allowing insertion into the vessel, and a state of being expanded to support a vessel to expanded state There is.

Polylactic acid constituting the vascular stent according to the present invention, since the optical purity of L- body is 99.8% or more, it is possible to maintain a constant viscosity while realizing a high degree of crystallinity. As a result, a yarn obtained by melt spinning this material has high breaking strength and excellent workability such as bending or bending. A vascular stent formed into a cylindrical shape using such a thread has high mechanical strength, can guarantee good shape maintenance characteristics, and is in a reduced diameter state and a state in which the vascular is expanded. The expanded diameter state to be supported can be easily realized.

Also, the stent for vascular according to the present invention, since the one in which the content of impurities such as heavy metals other than polylactic acid consists of a very high purity polylactic acid in the range that is not detected by atomic absorption spectrometry, human intravascular Even if implanted in the body, impurities such as heavy metals remain in the human body and do not have an adverse effect.

Polylactic acid constituting the vascular stent according to the present invention, since the 300,000 or less a weight average molecular weight of 80,000 or more can be a yarn continuously reliably in series with the melt spinning . Furthermore, since this polylactic acid has a weight average molecular weight of 80,000 or more, it does not cause inflammation in the human body.

1 is a perspective view showing an example of a vascular stent according to the present invention. It is a top view which shows the state which bent the thread | yarn which comprises the vascular stent in zigzag shape. It is a top view which shows the state which joined the bending part of the thread | yarn bent in zigzag shape.

The yarn of polymer material and vascular stents vascular stent according to the present invention will be described.

Polymeric materials vascular stent according to the present invention, there is L- body optical purity 99.8% or more, the content of heavy metals, polylactic acid (PLLA) in the range that is not detected by atomic absorption spectrometry Become.

  Here, the impurities contained in the artificially produced polylactic acid (PLLA) include heavy metals such as tin that adversely affect the human body when present in a certain amount or more in the human body, more specifically, Tin or phosphorus used when polymerizing lactic acid to produce polylactic acid (PLLA).

  By the way, the polylactic acid (PLLA) used in the present invention is a polymerization raw material in which about 0.1 to 0.4 wt% of tin dioctylate is added as a polymerization catalyst to L-lactide having an optical purity of 99.8% or more. Produced by melt polymerization.

  The melt polymerization of the polymerization material is performed by heating and melting to a temperature equal to or higher than the melting point of the obtained polymer, and performing operations such as stirring, supply and discharge of inert gas, and vacuum as necessary. This melt polymerization is performed, for example, by mixing the raw materials for polymerization in advance and supplying them to an apparatus capable of reacting effectively, for example, a twin-screw kneader (polymerizer), and reacting while stirring and mixing therein. . Here, since the melting point of polylactic acid (PLLA) mainly composed of L-form is about 170 ° C., the polymerization temperature is preferably 180 to 230 ° C., particularly 190 to 220 ° C., and the polymerization time is 3 minutes to 2 hours. In particular, 5 minutes to 60 minutes is preferable. The weight average molecular weight of the obtained polymer is preferably in the range of 80,000 to 300,000.

  Then, polylactic acid (PLLA) melt-polymerized using a biaxial kneader as a polymerization machine is discharged from a nozzle of the biaxial kneader in a molten state and then cooled and solidified. The cooled and solidified polylactic acid (PLLA) is cut into chips having a thickness of about 3 to 5 mm and a length of about 3 to 5 mm.

  This chip is treated with an acetone solvent to remove lactic acid monomers and polymerization catalyst remaining in polylactic acid (PLLA). As the acetone solvent used for removing the lactic acid monomer and the residual catalyst, for example, a solvent containing 7% of 5N hydrochloric acid is used.

  The polylactic acid (PLLA) chip is treated with an acetone solvent, so that the lactic acid monomer remaining in the polylactic acid is removed to 0.8% by weight or less, and the remaining catalyst is not detected by the atomic absorption method. Removed. This residual catalyst is an impurity contained in the produced polylactic acid (PLLA). Here, since the dilactic acid tin is used for the polymerization catalyst of polylactic acid (PLLA), the residual catalyst is mainly composed of tin which is a heavy metal.

The chip of the polylactic acid-lactic acid monomer and residual catalyst has been removed (PLLA) is melt spun, the yarn constituting the vascular stent according to the present invention. This melt spinning is performed using, for example, a screw extruder.

  In order to perform melt spinning using a screw extruder, a polylactic acid (PLLA) chip produced through the above-described steps is dried under reduced pressure while being heated at a temperature of the melting point Tm or less. Thereafter, the chip is put into a hopper of a screw extruder and is compressed and melted while being heated to a temperature near the melting point Tm or above the melting point and below the thermal decomposition point in the cylinder. This molten polylactic acid material is extruded from a nozzle set at a temperature not higher than the melting point Tm and not lower than the glass transition point Tg. A linear body is formed by winding the extruded polymer with a winder. By further stretching this linear body, the thread of the vascular stent according to the present invention can be obtained.

  Here, the yarn is formed as a monofilament in which the polymer is continuous in series. By forming the yarn as a monofilament, the molecular orientation is almost uniform over the long axis direction of the monofilament, and the crystallinity can be easily and uniformly controlled over the entire length. It has uniform strength over the entire surface and can have uniform elasticity.

Yarn 1 formed as described above, as shown in FIG. 1, to form a tubular stent 3 by being spirally wound while being bent in a zigzag shape so as to form a V-shaped continuous . At this time, as shown in FIG. 2, the yarn 1 was spirally wound by setting one side of one bent portion 4 forming a V shape as a short line portion 4a and the other side as a long line portion 4b. A shape is obtained. The opening angle θ1 of the bent portion 4 formed in the middle portion of the yarn 1 is substantially the same, and the lengths of the short line portion 4a and the long line portion 4b between the bent portions 4 are substantially the same, so that FIG. As shown, the apexes of the bent portions 4 adjacent to each other come into contact with each other. Some or all of the vertices of the bent portions 4 that are in contact with each other are joined together. The yarn 1 forming the stent 3 is maintained in a state in which the tubular shape is reliably maintained by joining the portions of the bent portions 4 whose apexes are in contact with each other.

  In addition, joining of the bending part 4 which made the vertex contact | abut mutually is performed by heating a joining part to more than melting | fusing point Tm, and fuse | melting it.

  The stent 3 formed in a cylindrical shape as described above is shape-memorized in a size that can be implanted in a blood vessel, for example, by heat setting at a temperature not lower than the glass transition temperature Tg and not higher than the melting point Tm. Note that the shape-stored stent 3 is reduced in diameter and stored so as to be inserted into the blood vessel. This diameter reduction is performed by deforming the stent 3 while applying a mechanical pressure from the outer periphery of the stent 3 in a state where the stent 3 is cooled to the glass transition temperature Tg or lower.

  In addition, when the stent 1 reduced in diameter by applying external pressure was heated (above the glass transition temperature Tg), the strain applied to the bent portion 4 was released, and the stent 1 was bent to a small opening angle θ2. The bent portion 4 opens to the opening angle θ1 and recovers to the initial shape. That is, the diameter of the stent 1 in a reduced diameter state is expanded to a size memorized in an initial shape as shown in FIG. 1 by being implanted in a blood vessel of a human body and heated by body temperature. The stent 1 implanted and expanded in the blood vessel of the human body supports the inner wall of the blood vessel, and supports the blood vessel in an expanded state for a certain period.

As described above, the material for the vascular stent according to the present invention is composed of polylactic acid (PLLA) in which the optical purity of the L-body naturally present in the human body is 99.8% or more. That is, this material is composed of polylactic acid (PLLA) that hardly contains the D-isomer, which is an optical isomer of the L-isomer.

By the way, since the D-isomer, which is an optical isomer of the L-isomer of polylactic acid, does not exist in the human body, it is desirable not to remain in the human body in consideration of the safety of the human body. Therefore, as a material for a vascular stent to be implanted in a human vascular vessel, polylactic acid (PLLA) not containing D-body is desirable. However, it is extremely difficult to artificially produce polylactic acid (PLLA) with an L-form optical purity of 100%.

  The present inventors have obtained a yarn made of polylactic acid (PLLA) whose optical purity of the above L-form is 99.8% or more and whose heavy metal content is not detected by atomic absorption spectrometry. The stent 3 formed as shown in FIG. 1 was formed, and the stent 3 was implanted into the blood vessels of eight pigs and the progress of the implantation was observed.

  After 2 weeks have passed since the stent 3 has been implanted, and even after 4 weeks have passed, the blood vessel in which the stent 3 has been implanted has been observed to have adverse effects such as inflammation. There wasn't.

  From this experiment, it was concluded that by using polylactic acid (PLLA) whose optical purity of L-body was 99.8% or more as a material, a vascular stent that does not adversely affect the human body can be formed.

In addition, the material for the vascular stent according to the present invention is in a range in which the content of impurities other than polylactic acid (PLLA) is not detected by the atomic absorption method. In particular, tin and phosphorus, which are residual catalysts of the polymerization catalyst used for the production of polylactic acid (PLLA), have been removed to the extent that they cannot be detected by atomic absorption spectrometry. Even when a vascular stent formed using this material is implanted in a blood vessel such as a blood vessel of a human body, heavy metals such as tin and phosphorus contained as impurities in polylactic acid (PLLA) remain in the human body more than an allowable amount. Does not have a negative effect.

Further, polylactic acid that constitutes the material of the stent for vessel according to the present invention (PLLA), because the optical purity of L- body is 99.8% or more, it is possible to realize a high degree of crystallinity. According to the experiments by the present inventors, the crystallinity measured by differential scanning calorimetry could be controlled in the range of 15% to 60%.

  The material for the vascular stent according to the present invention was melt-spun using the above-described screw extruder to form a monofilament having a diameter of 0.08 mm to 0.3 mm and a crystallinity of 15% to 60%. However, the strength at break was 5.8N (Newton) to 17N. This breaking strength is a force when the monofilament is elongated from both sides and broken.

  As shown in FIG. 1, the stent 3 in which the yarn capable of obtaining such a breaking strength is formed into a cylindrical shape can guarantee a sufficiently large pressure strength against the pressing force from the outer peripheral side, and guarantees good shape maintenance characteristics. Then, when implanted in a blood vessel such as a blood vessel, the blood vessel can be reliably supported in an expanded state.

Then, the material of the stent for vessel according to the present invention, since the optical purity of L- body is 99.8% or more, it is possible to maintain a constant viscosity while realizing a high degree of crystallinity. As a result, the yarn 1 obtained by melt spinning this material is excellent in workability such as bending or bending while increasing the breaking strength. As shown in FIG. 1, the vascular stent 3 formed into a cylindrical shape using such a thread 1 has a large mechanical strength, can guarantee good shape maintenance characteristics, and is reduced in diameter. Along with the displacement to the expanded state, it is possible to easily perform the displacement to the expanded diameter state in which the vessel is supported in an expanded state.

By the way, when polylactic acid (PLLA) has a weight average molecular weight of 80,000 or less, it is difficult to spin it as a continuous yarn by a melt spinning method. Further, when the weight average molecular weight is 300,000 or more, the viscosity becomes high and it becomes difficult to perform melt spinning. Polylactic acid that constitutes the material of the stent for vessel according to the present invention (PLLA) is a weight average molecular weight since the 80,000 -, reliably and easily using a melt spinning method described above A series of continuous yarns can be spun.

In addition, polymers with a low weight average molecular weight have been reported to cause an inflammatory response in the human body when implanted in the human body ("Sustained Local Delivery of Dexamethasone by a Novel Intravascular Eluting Stent to Prevent Restenosis in the Porcine Coronary" Injury Model "A. Michael Lincoff, Joseph G. Furst, Stephen G. Ellis, Ronald J. Tuch, Eric J. Topol, JACC Vol29, No.4 March 15, 1997 P808). Polylactic acid that constitutes the material of the stent for vessel according to the present invention (PLLA), since then the weight-average molecular weight 80,000 or more, also implanted with stents formed by yarns spun the polylactic acid in the human body, It does not cause inflammation in the human body.

  The yarn obtained by melt spinning the polymer material according to the present invention is preferably a monofilament. A monofilament can have uniform characteristics over its entire length, and a vascular stent formed into a cylindrical shape using this monofilament can also have certain mechanical characteristics over its entire length. The inner wall of a blood vessel such as a blood vessel can be supported with a constant force.

  3 Vascular stent

Claims (2)

After being implanted in the living body, it is a vascular stent that degrades and disappears in the living body,
The stent is formed of polylactic acid (PLLA) having an optical purity of L-form of 99.8% or more and a weight average molecular weight in the range of 80,000 to 300,000. Vascular stent. 2. The vascular device according to claim 1, wherein the polylactic acid (PLLA) is removed to the extent that the residual material of the polymerization catalyst used when melt-polymerizing L-lactide is not detected by atomic absorption spectrometry . Stent.