JP2013046829A - Polymer base stent assembly - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a polymer base stent which shows almost no or completely no negative reaction related to relaxation when implanted into the blood vessel or the lumen of a mammal.SOLUTION: There is provided a method for preparing a polymer base stent assembly including an inflatable balloon catheter and a polymer base stent resistant to relaxation-related negative reaction. The method includes: a step of heating a polymer cylindrical device having a predetermined final shape and diameter up to a temperature sufficiently higher than Tg of the polymer for a time sufficient for eliminating memory of prefabrication of the device; a step of, thereafter, quenching the device to provide the device trained to have memory of the predetermined final diameter and shape; and a step of attaching the trained cylindrical device to an inflatable balloon catheter.

Description

(Field of Invention)
The present invention relates to a tube, duct, or vessel (urethra, bile duct, blood vessel, lymphatic vessel, bronchi, or prostate duct) of a mammalian subject (preferably a human subject). (Including but not limited to) a polymer-based stent assembly, which includes an inflatable balloon catheter and a polymer-based stent. More specifically, the present invention is a degradable that exhibits little or no relaxation-related negative recoil when implanted in a tube, duct, or vessel of a mammalian subject. Relates to an assembly comprising a polymeric stent.

(background)
Atherosclerosis is a disease in which vascular lesions or plaques consisting of cholesterol crystals, necrotic cells, lipid pools, excess fibrous elements, and calcific deposits accumulate on the inner lining of an individual's artery. The presence of such plaque in the artery results in thickening of the arterial wall and stenosis of the lumen. Ultimately, such an increase in plaque can result in occlusion of the arterial lumen at the lesion site. One of the most successful treatments for treating coronary atherosclerosis is percutaneous transluminal coronary angioplasty (hereinafter referred to as "PTC angioplasty") ). PTC angioplasty involves introducing a deflated balloon into the lumen of an atherosclerotic artery; placing the balloon proximate to the site of a plaque or atherosclerotic lesion; Expanding to a pressure of about 6 atm to about 20 atm, thereby “breaking” the plaque and increasing the cross-sectional area of the arterial lumen.

  Unfortunately, the pressure exerted on the plaque during PTC angioplasty also damages the artery. In 30% to 40% of the cases, the vessels gradually restenose or reclose at the location of the original stenotic lesion. This gradual restenosis or reocclusion (hereinafter referred to as “chronic restenosis” herein) is only approximately during the first 3-6 months after angioplasty. It is a phenomenon that occurs. Studies of the mechanism of chronic restenosis have found that chronic restenosis is due in large part to chronic compression of the arteries at the site of pressure injury (hereinafter referred to as “constricted form of restenosis”) and To a lesser extent, it is attributed to smooth muscle cell proliferation (hereinafter referred to as “proliferation form of restenosis”) (Non-patent Document 1).

A number of approaches to prevent restenosis are currently used or tested. One approach involves the use of bioactive factors to prevent smooth muscle cell proliferation. To date, the use of only bioactive factors has proven unsuccessful. Another approach uses a metallic stent that is deployed at the site of a stenotic lesion after PTC angioplasty. Metallic stents have the mechanical strength necessary to prevent the restenotic form of restenosis, but the presence of metallic stents in arteries can include biological problems (vasospasm, compliance mismatches, and even occlusions) ). Sometimes technical difficulties (including distal movement and incomplete expansion) have also been observed with metallic stents. In addition, there are inherent and significant hazards (including vessel wall erosion) arising from the permanent implantation of metallic stents in arteries. Furthermore, steady exposure of this stent to blood can lead to embolization within the blood vessel.
Stents made from degradable polymers have also been suggested to prevent restenosis. Although generally an attractive alternative to metallic stents, animal studies have shown that degradable stents have multiple complications (relaxation-related negative recoil, and distant whole or part of the stent). Dislocation, as well as the formation of occlusive emboli within the stent lumen).

Lafont et al., Restenosis After Experimental Angiplasty, Circulation Res. (1995) 76: 996-1002.

  Therefore, it is desirable to have a new stent that overcomes the disadvantages of current stent designs. Polymer-based stents that exhibit little or no relaxation-related negative recoil when implanted in a mammalian vessel or duct are desirable. It is also desirable to have a stent assembly comprising an inflatable balloon catheter and a degradable polymer stent that is stably and snugly disposed on the inflatable balloon catheter. A polymer-based stent assembly that does not require mechanical restraints to prevent its stent from expanding when stored at room temperature or when exposed to physiological conditions found in the blood flow of human patients. Especially desirable. A method of preparing such stents and stent assemblies is also desirable.

(Summary of the present invention)
The present invention provides a method for preparing a polymer-based stent assembly comprising an inflatable balloon catheter and a polymer-based stent, wherein the polymer-based stent is a mammalian subject (particularly a human subject). It is resistant to relaxation-related negative recoil when implanted in the body's blood vessels or ducts. The polymer-based stent is in the form of a hollow cylindrical device with walls formed from a polymer (preferably a degradable and bioabsorbable polymer). Such a wall defines a first open end, a second open end, and a channel extending from the first open end to the second open end. The wall incorporates an open space or slit therein that allows the cylindrical device to decrease in diameter and increase in diameter without substantially changing the thickness of the wall.

  In one aspect, the method includes a polymeric cylindrical device having a predetermined final shape (ie, the desired final diameter, wall thickness, length, and design of the expanded stent). Heating for a sufficient time to erase any memory of the pre-processing of the polymeric cylindrical device to a temperature well above the glass transition temperature (Tg); then quenching the polymeric cylindrical device ( That is, the cylindrical device is rapidly cooled at a temperature below the Tg of the polymer to provide an educated polymeric cylindrical device having a predetermined final diameter and shape memory (herein). In the book, hereinafter referred to as “teaching cylindrical devices”). Preferably, the polymeric cylindrical device is attached in contact with the support during such an educational procedure. The method then attaches the educated cylindrical device to an inflatable balloon catheter; heating the polymer Tg temperature to or slightly above the Tg temperature while the cylindrical device wall Reducing the diameter of an educated cylindrical device by uniformly applying pressure to the outer surface of the substrate (a step referred to herein as “crimping into a cylindrical device”) Then the cylindrical device is cooled to below the Tg of the polymer, and an inflatable balloon catheter and an expandable educated polymer placed in a stable and snug manner on the inflatable balloon catheter Providing a stent assembly comprising a sexible stent. A slit or open space is allowed in the inflatable balloon catheter that allows the cylindrical device to decrease in diameter without substantially changing the wall thickness during crimping. Before the cylindrical device is crimped, it is incorporated into the cylindrical device. The temperature at which the cylindrical device is heated during crimping is high enough to allow a reduction in the diameter of the cylindrical device, but the memory of the predetermined final shape and diameter of the educated cylindrical device. Low enough not to erase. Thus, the temperature at which an educated cylindrical device is heated during crimping is lower than the temperature at which the cylindrical device is heated during education of the cylindrical device. Furthermore, the time that the cylindrical device is heated during crimping is shorter than the time that the cylindrical device is heated during the teaching of the cylindrical device. In accordance with the method of the present invention, expanding the polymeric stent to its predetermined final shape may include inflating a balloon catheter on which the polymeric stent is deployed at body temperature, or deploying the polymeric stent. Can be achieved by inflating the balloon catheter being heated while heating the stent to a temperature near, but not above, the Tg of the polymer.

  In another aspect, the method of the present invention begins with a polymeric tube that is initially smaller in diameter than the predetermined final diameter. Such a tube (which also has slits or open spaces in its wall to allow expansion of the tube without substantially changing the diameter of the tube) is first near the Tg of the polymer Is heated to a temperature equal to or higher than its Tg and expanded to provide a cylindrical device that is equal in diameter to the desired final diameter. The cylindrical device is then educated as described above, and an educated cylindrical device having a predetermined final shape and diameter memory is provided, and then crimped in a balloon catheter as described above, An assembly is provided comprising the balloon catheter described above and an expandable educated polymeric stent that is securely and securely disposed on the balloon catheter.

  The present invention also provides an assembly comprising an inflatable balloon catheter and a polymeric stent prepared according to the method of the present invention.

  In another aspect, the invention relates to an assembly comprising an inflatable balloon catheter and a polymer-based stent attached to the balloon catheter. The stent is a cylindrical device formed from a degradable and bioabsorbable polymeric material, the polymeric material having a Tg that is at least 8 ° C. above 37 ° C., preferably greater than 20 ° C. above 37 ° C. More preferably, it has a Tg of about 45 ° C to about 120 ° C. The cylindrical device includes a wall that defines a first open end, a second open end, and a channel extending from the first open end to the second open end. The wall contains the cylindrical device to a larger diameter and substantially the same wall thickness when the balloon catheter is inflated or when the cylindrical device is heated to a temperature above the Tg of the polymer. A void or open space is incorporated that allows it to expand. Advantageously, the stent of the present invention is expanded at 37 ° C. for 4 to 6 weeks or more when deployed in a subject's blood vessel or to a predetermined final shape and diameter. Show little or no relaxation-related negative recoil. Advantageously, the assembly of the present invention has a diameter that allows the assembly to be easily inserted into a subject's blood vessel and advanced to a target site. Advantageously, the stent of the present invention exhibits expansion (positive recoil) and fit to the outer diameter of the artery if the stent is not fully deployed to its final diameter during deployment. . Furthermore, the stent of the present invention is stably disposed on the balloon. This means that no mechanical restraint is required to prevent the stent from expanding rapidly to its final diameter during storage at room temperature. Thus, although not required, the assembly of the present invention also includes a retractable sheath that optionally covers the outer surface of the stent. Such a sheath serves to prevent stent deformation and slow expansion during storage.

  The present invention also relates to a method of making a stent that lacks prefabricated memory and has a memory of a predetermined final shape and diameter, and the invention also relates to a stent made by such a method. Such stents show little or no relaxation-related recoil when implanted in the duct, vessel, or lumen of a mammalian subject.

  The present invention also relates to a method of reducing the risk of chronic restenosis that may occur in a patient's artery after percutaneous transluminal coronary artery (PTC) surgery. This method uses the assembly of the present invention. The method includes delivering the stent assembly of the present invention to a stenotic lesion location; inflating the balloon catheter to expand the stent to a predetermined final diameter or less, wherein the stent is at the stenotic lesion location. Contacting the inner wall of the blood vessel or slowly expanding to come into contact; then, deflating and retrieving the balloon catheter. In accordance with the present invention, it has been determined that a stent of the present invention that has not been fully expanded to a predetermined final diameter by inflation of the balloon catheter will continue to expand after the balloon is retrieved. Since the stents of the present invention are trained to have the desired final diameter memory, the stents of the present invention exhibit little or no negative recoil after being implanted into the target site. .

(Detailed description of the invention)
(Definition)
A “bioabsorbable polymer” as used herein refers to a polymer whose degradation byproducts can be bio-analyzed or excreted through the natural route in the human body.

  “Crimping” as used herein to allow a reduction in diameter of the device without substantially affecting the wall thickness or struts of the polymeric cylindrical device. In particular, it relates to a process comprising radially pressing a polymeric cylindrical device having slits or openings in the wall. Such a process typically also results in an increase in the length of the cylindrical device.

  A “degradable polymer” as used herein is placed in the human body or in an aqueous solution and under conditions of temperature, osmolality, pH, etc. that mimic a physiological medium. When maintained, it preferably refers to a polymer that degrades into monomers and oligomers without enzymatic degradation to minimize the risk of having a human antigen-antibody defense system.

  “Predetermined final shape and diameter” as used herein refers to a vessel (particularly a blood vessel), duct, or tube in a mammalian subject (particularly a human subject). Refers to the desired diameter, length, design, and wall thickness of the stent deployed at the target site.

  “Negative recoil”, as used herein, refers to an undesirable diameter reduction of an expanded stent.

  “Positive recoil” refers to an increase in the diameter of a stent that has been trained to have the desired final diameter but has not fully expanded to that desired final diameter.

  “Relaxation-related recoil”, as used herein, is a polymer that results from a time-dependent slow reconstruction of molecular conformation that follows the well-known behavior of viscoelastic polymer materials. Refers to a slow change in device size. Such reconstitution refers to thermal motion that slowly guides the polymeric material to a thermodynamic equilibrium typified by its storage state when the polymeric material is processed under various environmental conditions. Relaxation is very slow at temperatures below Tg (ie, when the material is in the glassy state).

  “Tg” or “glass transition temperature” as used herein refers to the temperature at which a polymer changes from a rubbery state to a glassy state (and vice versa).

  In one aspect, the present invention provides an assembly that can be used to deliver a polymer-based stent to a region of a lumen, vessel, or vessel of a mammalian subject, particularly a human subject. I will provide a. The assembly includes an inflatable balloon catheter and a polymer stent that exhibits little or no negative recoil when expanded to a predetermined final shape and diameter. Accordingly, this assembly is particularly useful for delivering the stents of the present invention to lesions in blood vessels of human subjects that have undergone percutaneous transluminal coronary artery (PTC) surgery.

  The polymer stent of the present invention is tightly attached to the balloon catheter and has an inner diameter that matches the outer diameter of the deflated balloon catheter, and the inner diameter passes through the subject's tube, vessel, or duct. It is smaller than a predetermined final diameter so that the stent assembly can be easily inserted and passed. The polymer stent of the present invention is stably placed on a balloon catheter so that the stent does not expand when stored at room temperature or when inserted into a blood vessel of a mammalian subject, particularly a human subject. Has been. Although not necessary, the assembly of the present invention also optionally includes a retractable sheath disposed on the outer surface of the polymer stent.

(I. Stent)
The stent of the assembly of the present invention is formed from a degradable and bioabsorbable polymer having a Tg that is at least 8 ° C above 37 ° C, preferably at least 20 ° C above 37 ° C. The polymer that forms the wall of the stent may be a homopolymer or a copolymer. Preferably, the polymer is totally amorphous to minimize the risk of forming small inflammatory crystal residues during degradation. The polymer chains are not crosslinked. However, mild crosslinking is allowed under conditions that maintain the thermal and viscoelastic characteristics that allow the device to be taught, crimped, and deployed. In certain embodiments, the polymer has a Tg of about 45 ° C to about 120 ° C. Examples of suitable polymer types for the stents of the present invention include lactic acid based stereocopolymers (PLAx copolymers composed of L and D units, where X is the proportion of L-lactyl units) (55 <Tg < 60), a copolymer of lactic acid and glycolic acid (PLAxGAy (X (percentage of L-lactyl units) and Y (percentage of glycolyl units) such that the Tg of the copolymer is about 45 ° C.)), and poly (Lactic acid-co-glycolic acid-co-gluconic acid) (the OH group of the gluconyl unit can be somewhat substituted (PLAxGayGLx (X (ratio of L-lactyl unit) and Y (ratio of glycolyl unit) and Z (gluconyl unit) The unit ratio) is such that the Tg of the terpolymer is higher than 45 ° C)). Other suitable polymers include: polylactic acid (PLA), polyglycolic acid (PGA), polyglactin (PLAGA copolymer), polyglyconate (copolymer of trimethylene carbonate and glycolide, and polyglycolide or lactic acid or A copolymer of polylactic acid and ε-caprolactone), but is not limited thereto, provided that the polymer has a Tg of at least 45 ° C. or higher.

  The stent of the assembly of the present invention is a cylindrical device having a first open end, a second open end, a channel connecting the first open end and the second open end, and There are slits or openings in the wall of the cylindrical device. Such slits or openings allow crimping of the polymeric cylindrical device from a larger diameter to a smaller diameter without substantially changing the wall thickness of the device, and such Slits or openings can be made from a smaller diameter (eg, crimped diameter) without substantially changing the wall thickness upon inflation of a balloon catheter deployed inside the cylindrical device. Allows expansion of the polymeric cylindrical device to a large diameter. Such slits or openings can be formed by standard processing techniques (eg, by molding, cutting, engraving, or photolithography).

  The polymeric cylindrical device is made by standard techniques (eg, extrusion, molding, spinning, injection molding, or any other processing technique that converts a brut polymer into a hollow cylindrical device). It is formed. Although less desirable, the cylindrical device can also be formed by knitting polymer yarns or polymer fibers, although the mesh is then fused together to form a continuous polymer network and the slits. Alternatively, the opening is formed by a gap between the meshes. The initial polymeric cylindrical device formed by any of these processes can be configured to have a predetermined final shape, length, wall thickness, and diameter, all of which are Adjusted for the application to be utilized. For example, for cardiovascular applications, the initial polymeric device formed by these processes may have a predetermined final length ranging from 0.5 cm to about 3 cm. For certain applications, the initial polymeric cylindrical device may have a predetermined final diameter in the range of 0.50 mm to 8.0 mm, with a predetermined range of 0.05 mm to 0.5 mm. It may have a final wall thickness. Alternatively, the initial cylindrical device formed by any of these processes may have a diameter that is smaller than its predetermined final diameter.

The stents of the present invention can be formulated to be capable of carrying and delivering various substances or bioactive factors, provided that these substances or factors do not form a solid solution with the polymer, and It does not act as a plasticizer that reduces the Tg of the polymeric device to below 45 ° C. Such materials include opacifiers, natural factors (natural)
agent), and drug, but is not limited thereto. The polymer can be mixed with such materials or factors. For example, the substance or bioactive factor can be incorporated into the polymeric cylindrical device as a solid dispersion in a matrix. The matrix may be formed using a homogenous dispersion of particles in a biocompatible polymeric material of the type described herein above in connection with the stent of the present invention. Such particles must be small enough (eg, 1/5 to 1/10 of the column or wall of the cylindrical device) to not affect the continuity of the matrix. The substance or bioactive factor can also be placed on the exterior or interior surface of the cylindrical device, either by impacting or chemical coupling.

  The stent of the present invention lacks memory of previous processing and has a predetermined final shape and diameter memory.

II. Preparation of polymer-based stent assembly
In another aspect, the present invention relates to a method for preparing the polymer-based stents and stent assemblies of the present invention. If the initial polymeric cylindrical device has a diameter that is smaller than a predetermined final diameter, a slit or opening is formed in the cylindrical device, after which the cylindrical device has a final shape. And deformed or expanded to a diameter. This involves inserting a balloon into the polymeric cylindrical device (hereinafter referred to as a “pre-cut cylindrical device”), and the pre-cut cylindrical device is then pre-cut. Heated to a temperature above the Tg of the polymer used to form the cylindrical device, and until the size is approximately equal to or slightly larger than the predetermined final inner diameter of the implanted stent. This is accomplished by inflating the balloon. Maintaining the expanded pre-cut cylindrical device in a predetermined final shape, size and diameter, for example by attaching the pre-cut cylindrical device to a solid support, The cut cylindrical device is educated to erase the memory associated with any pre-process and gain a predetermined final shape, size, and diameter memory. In the case where the initial cylindrical device is formed in a given final shape, size and diameter, such a deformation or expansion step is not required. When the initial cylindrical device is formed in a predetermined final shape, size, and diameter, the slits or openings in the cylindrical device can be made before or after the educational process as described below.

  Although it is a given final shape, size and diameter, the cylindrical device will erase any memory associated with the pre-process up to a temperature well above the Tg of the polymer from which the device is formed. It is taught by heating the device for a time sufficient to give the polymeric cylindrical device a new memory of a given final shape and diameter. Such conditions relax the polymer chain, and the polymer chain reconfigures itself from the typical entanglement in the pre-processing stage to the typical entanglement at the high temperatures at which the cylindrical device is educated It is possible to make it possible. This final entanglement is cured by rapid cooling (rapid cooling below room temperature). When the polymeric cylindrical device is initially of a diameter smaller than the predetermined final diameter and heated to a temperature sufficiently higher than the Tg of the polymer, an extrusion or molding process (in the meantime, Memory associated with pre-processing of the polymer chain, as well as eliminating anisotropic internal stresses that are promoted by the polymer chain being somewhat oriented and non-uniformly quenched by contact with cold air or cold formwork Also erase. Good results have been obtained by heating a laser pre-cut polymeric cylindrical device formed from PLA 75 and deformed from 1.0 mm to 4 mm in diameter at a temperature of 80 ° C. for 30 minutes. Stents made from PLAx (0 <X <100), PLAxGAy (0 <X <25 and 75 <Y <100), or any PLAxGAyGLz at a temperature of about 45 ° C. to about 120 ° C. and a time of 5 minutes or longer Expected to be appropriate for educating.

  Still in its expanded state, the cylindrical device is then quenched or cooled to a temperature below the Tg of the polymer, preferably to a temperature below room temperature, more preferably to a temperature below room temperature. Such a cooling step equilibrates the entire polymer mass at a rate sufficiently fast to cure the cylindrical device to its new shape and at a temperature below the Tg without chain relaxation. Implemented at a rate slow enough to allow it to reach. Considering the thickness of the stent, this time is short compared to the time the polymer tube is educated.

  The educated polymeric cylindrical device described above is then attached to a deflated balloon catheter and uniformly crimped to reduce its diameter and the stent assembly of the present invention to a mammalian subject (particularly human). To be introduced into a subject). During crimping, the diameter of the cylindrical device is reduced by an appropriate amount (eg, 100% -400%) from the taught size. This crimping involves heating the trained cylindrical device to a temperature sufficient to allow deformation of the polymer matrix without erasing the memory imparted to the device during the teaching process. Thus, during crimping, the educated cylindrical device is uniformly pressured against the outer surface of the cylindrical device while being heated to a temperature at or slightly above the Tg of the polymer. Applies. Good results have been obtained by heating the cylindrical device to a temperature 5 ° C. higher than the Tg of the polymer. Such a crimping process reduces the diameter of the cylindrical device substantially uniformly so that the cylindrical device fits snugly onto the balloon. At the same time, the crimping process also allows the design to compress the slits, openings, or gaps of the cylindrical device and position the cylindrical device struts in close proximity to each other. Below, increase the length of the cylindrical device. In order to quench the polymer matrix of the cylindrical device, the stent assembly is then rapidly cooled to a temperature below the Tg of the polymer, preferably to room temperature, more preferably to a temperature below room temperature, , Pressure is maintained against the outer surface of the cylindrical device. The final product is a stent assembly that includes an inflatable balloon catheter that includes a snugly-fitting polymer stent that is stably positioned on the catheter. As used herein, the phrase “stablely placed” means that the stent is stored under normal storage conditions (ie, at or below room temperature) or feeding. It means not expanding during a short period of time allowing the physician to insert the assembly into the vessel of the animal subject.

(III. Procedures for determining the time and temperature for teaching and crimping the stent of the present invention)
Appropriate temperature and time to educate the device with the above cylindrical shape and thereby to develop a stent that is resistant to relaxation-related recoils will determine the balloon catheter of the stent assembly of the present invention for a given final Can be evaluated by inflating to a large diameter, removing the balloon catheter after deflation, and storing the expanded stent at 37 ° C. The stent shows little recoil when stored under these conditions for 4-6 weeks, or preferably for an estimated time to remove the arterial wall from percutaneous transluminal coronary artery (PTC) surgery The time and temperature used to educate the stent if it shows no or no recoil is appropriate. In the case where the polymer stent exhibits a slight recoil, the cylindrical device can be educated with a diameter slightly larger than the predetermined final diameter to compensate for the slight negative recoil.

  Appropriate time and temperature for crimping the stent to a reduced diameter can be assessed by allowing the balloon catheter fitted with the stent of the assembly of the present invention to remain at room or storage temperature. If the crimped stent remains collapsed at a small diameter corresponding to a deflated balloon under these conditions, the time and temperature used during crimping are appropriate.

(IV. Deployment of stent)
The polymer-based stent assembly of the present invention is introduced into a duct, vessel, or vessel (eg, a blood vessel) of a mammalian skin subject, preferably in combination with a guide catheter, and a target site (eg, a stenotic lesion). To the part). After the polymer-based stent assembly is placed at its target site, the balloon is rapidly inflated, so that the stent is brought to a desired final diameter or a diameter slightly smaller than the final diameter. Can be expanded. If necessary, the inflation fluid, balloon, and stent are heated to a temperature above body temperature to aid in expansion. During this process, the stent diameter increases, but the stent wall thickness remains substantially the same.

  The following examples included herein are intended to illustrate the invention but are not intended to limit the invention.

Example 1
The polymer tube is from PLA 75 (Mw = about 130,000, Mw / Mn = 1.8, Tg about 58 ° C. as determined by size exclusion chromatography) from 1.2 mm / 1.4 mm inside / outside diameter. Formed by extruding through a dye. A slit was then cut into the extruded tube using a femtosecond pulsed laser according to a design that allowed for the expansion of small diameter polymeric cylindrical devices without changing the wall thickness. The small diameter cylindrical device was attached to a deflated 4 mm balloon, heated to 65 ° C. in a heating bath, and expanded to 4 mm by inflating the balloon. The resulting assembly was then rapidly cooled to approximately room temperature. The balloon was removed and a 4 mm stainless steel support was inserted into the cylindrical device to secure the device to its predetermined final diameter and shape. In order to erase any memory of pre-processing and to give this cylindrical diameter device a memory of this final diameter, the device attached to the stainless steel support is placed in an oven preheated to 80 ° C. Heated for 30 minutes. The educated cylindrical device was then rapidly cooled to room temperature by insertion into running water at a temperature of 20 ° C. On the other hand, the device was still mounted on the support. This cooling has the effect of curing the polymeric device. The newly shaped stent was then attached to a new deflated balloon, after which both the balloon and stent were heated to 65 ° C. 65 ° C. is a temperature that is high enough to allow deformation of the device, but not high enough to reconstitute the chain in a short time. The stent was then crimped to the balloon by applying equal pressure against the outer surface of the stent. The stent was crimped to a deflated balloon by using a standard system typically used for crimping metal stents. Such a system applies a radial pressure equal to the external surface of the device. Once its diameter has been reduced to a size small enough to stably fit a deflated balloon, this pressure is maintained while the reduced attached stent is rapidly cooled to The stent was cured with a crimped shape and reduced diameter. This curing ensured a close fit of the stent in the balloon.

(Example 2)
The polymer tube is from PLA 75 (Mw = about 130,000, Mw / Mn = 1.8, Tg about 55 ° C. as determined by size exclusion chromatography) to 4.0 mm / 4.2 mm inner / outer diameter. Formed by extruding through a dye. The interstitial space was then extruded using a femtosecond pulsed laser according to a design that allowed the resulting educated polymeric cylindrical device to be reduced to a small diameter without altering the wall thickness. Cut into the tube. A 4 mm stainless steel support was inserted into the cylindrical device and secured so that the device had its predetermined final diameter and shape. In order to erase any memory of pre-processing and to give this cylindrical diameter device a memory of this final diameter, the device attached to the stainless steel support is placed in an oven preheated to 80 ° C. Heated for 30 minutes. The educated cylindrical device was then rapidly cooled to room temperature by insertion into running water at a temperature of 20 ° C. On the other hand, the device was still mounted on the support. This cooling has the effect of curing the polymeric device. The educated stent was then attached to a new deflated balloon, after which both the balloon and stent were heated to 65 ° C. 65 ° C. is a temperature that is high enough to allow deformation of the device, but not high enough to reconstitute the chain in a short time. The stent was then crimped to the balloon by applying equal pressure against the outer surface of the stent. Once its diameter has been reduced to a size small enough to stably fit a deflated balloon, this pressure is maintained while the reduced attached stent is rapidly cooled to The stent was cured with a crimped shape and reduced diameter. This curing ensured a close fit of the stent in the balloon.

(Example 3)
The polymer tube is from PLA 50 (Mw = about 145,000, Mw / Mn = 1.6, Tg about 58 ° C. as determined by size exclusion chromatography) from 1.2 mm / 1.4 mm inner / outer diameter. Formed by extruding through a dye. This tube was processed as described in Example 1 above to provide a stent assembly of the present invention.

Example 4
The polymer tube is from PLA 50 (Mw = about 145,000, Mw / Mn = 1.6, Tg about 55 ° C. as determined by size exclusion chromatography) to 4.0 mm / 4.2 mm inner / outer diameter. Formed by extruding through a dye. This tube was processed as described in Example 2 above to provide a stent assembly of the present invention.

(Example 5)
The polymer tubes were made from PLA 62.5 (Mw = about 165,000, Mw / Mn = 1.7, Tg about 56 ° C. as determined by size exclusion chromatography) from 1.2 mm / 1.4 mm ID / It was formed by extrusion through an outer diameter dye. This tube was processed as described in Example 1 above to provide a stent assembly of the present invention.

(Example 6)
The polymer tubes were made from PLA 62.5 (Mw = about 165,000, Mw / Mn = 1.7, Tg about 56 ° C. as determined by size exclusion chromatography) from 4.0 mm / 4.2 mm ID / It was formed by extrusion through an outer diameter dye. This tube was processed as described in Example 2 above to provide a stent assembly of the present invention.

(Example 7)
The polymer tubes are from PLA 96GA4 (Mw = about 185,000, Mw / Mn = 1.8, Tg about 51 ° C. as determined by size exclusion chromatography) from 1.2 mm / 1.4 mm ID / OD Formed by extruding through a dye. This tube was processed as described in Example 1 above to provide a stent assembly of the present invention.

(Example 8)
The polymer tube is from PLA 96G4 (Mw = about 185,000, Mw / Mn = 1.8, Tg about 51 ° C. as determined by size exclusion chromatography) from 4.0 mm / 4.2 mm ID / OD Formed by extruding through a dye. This tube was processed as described in Example 2 above to provide a stent assembly of the present invention.

  Stents made as described in Examples 1-8 were expanded to a predetermined final diameter and stored for more than 3 months at room temperature in a liquid environment. This showed no negative reaction.

From the above, it can be seen that a stent, an assembly comprising an inflatable balloon and the stent, and methods of use thereof are provided having a number of advantages. Since the stent of the present invention has a memory of a given final shape and diameter, it exhibits little or no relaxation-related recoil when implanted in the vessel of a mammalian subject. . Furthermore, when expanded by mechanical stress to a diameter that is smaller than a predetermined final diameter, the stent of the present invention can exhibit a positive reaction, which is the vessel in which the stent is deployed. Can be matched to the outer diameter of The stent of the present invention can be constructed and / or processed to deliver substances and bioactive factors to a target site.
The present invention also provides the following items.
(Item 1)
A method for preparing an assembly for delivering a degradable and bioabsorbable polymer stent that is resistant to relaxation-related recoil to a mammalian subject, the method comprising:
(A) To erase a polymeric cylindrical device having a predetermined final radius and wall thickness to a temperature well above the glass transition temperature (Tg) of the polymer Heating for a time sufficient for the polymeric cylindrical device to have a wall, the wall comprising a first open end, a second open end, and the first open end and the first open end. Defining a channel connecting the two open ends;
(B) rapidly cooling the polymeric cylindrical device at a temperature below the Tg of the polymer to quench the polymeric cylindrical device and storing the predetermined final diameter and shape memory Providing an educated polymeric cylindrical device having;
(C) forming a slit, gap, or open space in the wall of the polymeric cylindrical device before step (a) or after step (b), wherein the slit, gap, or open space is A configuration that allows for a reduction in the diameter of the device without substantially changing the wall thickness of the device;
(D) attaching the educated polymeric cylindrical device to an inflatable balloon catheter;
(E) applying the pressure uniformly to the outer surface of the wall of the cylindrical device while heating the cylindrical device to a temperature at or slightly above the Tg of the polymer; Reducing the diameter of the device; and (f) then cooling the cylindrical device rapidly to below the Tg of the polymer to provide an assembly comprising an inflatable balloon catheter and an expandable polymer stent. Providing the polymer stent when implanted in a lumen, vessel, or vessel lumen of the mammalian subject or expanded and stored at 37 ° C. for 4-6 weeks A process that is substantially resistant to relaxation-related reactions if
Including the method.
(Item 2)
The method of item 1, wherein the cylindrical device is attached to a support for maintaining the diameter and shape of the device during steps (a) and (b).
(Item 3)
2. The method according to item 1, wherein the stent is selected from PLA and stereocopolymer (a copolymer composed of L units and D units), PLAGA, and poly (lactic acid-co-glycolic acid-co-gluconic acid). Formed from the polymer formed.
(Item 4)
Item 2. The method of item 1, wherein the thickness of the cylindrical device is reduced during step (e) to a diameter that is smaller than the diameter of the target vessel, duct, or vessel lumen. ,Method.
(Item 5)
The method according to item 1, wherein the cylindrical device is substantially the same before and after step (e).
(Item 6)
A method for preparing an assembly for delivering a degradable and bioabsorbable polymeric stent into a lumen, vessel, or vessel lumen of a mammalian subject, the method comprising:
(A) providing a polymeric cylindrical device having a wall, the wall comprising a first open end, a second open end, and a channel connecting the first open end and the second open end The cylindrical device has a diameter and wall thickness comparable to the desired final diameter and wall thickness of the stent;
(B) educating the device by erasing the pre-fabricated memory of the polymeric device and establishing a memory of a desired diameter, wherein the education comprises the device over the Tg of the polymer Achieved by heating to a temperature at least 8 ° C higher;
(C) quenching the device to provide an educated polymeric cylindrical device having a memory of the predetermined final diameter and shape;
(D) forming slits, gaps or open spaces in the walls of the polymeric cylindrical device before or after the device is educated;
(E) attaching the educated polymeric cylindrical device to an inflatable balloon catheter;
(F) crimping the cylindrical device to the inflatable balloon catheter while heating the cylindrical device to a temperature at or slightly above the Tg of the polymer; and (g) thereafter Rapidly cooling the cylindrical device to below the Tg of the polymer to provide an assembly comprising an inflatable balloon catheter and an expandable polymer stent, the polymer stent comprising: Relief-related when implanted in the lumen of a mammalian subject's tube, duct, or vessel, or expanded to a predetermined final shape and diameter and stored at 37 ° C for 4 weeks or more A step that is substantially resistant to recoil;
Including the method.
(Item 7)
A method for preparing an assembly for delivering a degradable and bioabsorbable polymeric stent into a lumen, vessel, or vessel lumen of a mammalian subject, the method comprising:
(A) providing a hollow cylindrical device comprising a wall, wherein the wall has a slit, an opening, or a gap, the hollow cylindrical device being a predetermined final of the stent; Having a radius smaller than the diameter;
(B) heating the polymeric cylindrical device to a temperature near or above the Tg of the polymer while expanding the tube to the predetermined final diameter;
(C) attaching the cylindrical device to a support for maintaining the cylindrical device at the predetermined final diameter;
(D) heating the cylindrical device to a temperature sufficiently higher than the glass transition temperature (Tg) of the polymer for a time sufficient to erase the pre-processing memory of the polymer device;
(E) Educated with rapid cooling of the polymeric cylindrical device at a temperature below the Tg of the polymer, quenching the polymeric cylindrical device, and having a memory of the predetermined final diameter Providing a polymeric cylindrical device;
(F) attaching the educated polymeric cylindrical device to an inflatable balloon catheter;
(G) applying the pressure uniformly to the outer surface of the wall of the cylindrical device while heating the cylindrical device to a temperature at or slightly above the Tg of the polymer; Reducing the diameter of the device; and (h) then cooling the cylindrical device rapidly to below the Tg of the polymer to provide an assembly comprising an inflatable balloon catheter and an expandable polymer stent. Providing the polymer stent when expanded into a lumen, vessel, or vessel lumen of a mammalian subject or expanded to a predetermined final shape and diameter; A process that is substantially resistant to relaxation-related reactions when stored at 4 ° C. for more than 4 weeks;
Including the method.
(Item 8)
Item 7. The method according to Item 6, wherein the stent is selected from PLA and stereocopolymer (a copolymer composed of L and D units), PLAGA, and poly (lactic acid-co-glycolic acid-co-gluconic acid). Formed from the polymer formed.
(Item 9)
Item 7. The method of item 6, wherein the wall thickness of the cylindrical device is substantially the same before and after step (g).
(Item 10)
A method for preparing an assembly for delivering a degradable and bioabsorbable polymeric stent into a lumen, vessel, or vessel lumen of a mammalian subject, the method comprising:
(A) providing a polymeric cylindrical device comprising a wall, the wall comprising a first open end, a second open end, and a channel connecting the first open end and the second open end The wall has slits, gaps, or open spaces to allow expansion and contraction of the device without substantially changing the thickness of the wall, the cylindrical device comprising: Having a radius smaller than the desired final diameter of the stent;
(B) expanding the polymeric cylindrical device to the desired final diameter while heating to a temperature near or above the Tg of the polymer;
(C) educating the device by erasing the pre-fabricated memory of the polymeric device and establishing the memory of the desired diameter, wherein such education comprises removing the device from the Tg of the polymer Also achieved by heating to a temperature of at least 8 ° C., wherein the device is attached to a support;
(C) quenching the device to provide an educated polymeric cylindrical device having a predetermined final diameter and shape memory;
(D) attaching the educated polymeric cylindrical device to an inflatable balloon catheter;
(E) crimping the cylindrical device in the inflatable balloon catheter while heating to a temperature at or slightly above the Tg of the polymer; and (f) then the cylindrical device Is rapidly cooled to below the Tg of the polymer to provide an assembly comprising an inflatable balloon catheter and an expandable polymer stent, the polymer stent comprising a tube of a mammalian subject Substantial to relaxation-related reactions when implanted in the lumen of a duct, vessel, or vessel, or expanded to a predetermined final shape and diameter and stored at 37 ° C. for more than 4 weeks Resistant to the process;
Including the method.
(Item 11)
11. An assembly comprising an inflatable balloon and a polymer stent, prepared according to the method of item 1, 6, 7, or 10.
(Item 12)
An assembly for introducing a biodegradable and bioabsorbable stent into a vessel, vessel, or duct of a mammalian subject, the assembly comprising:
An inflatable balloon catheter; and a stent attached to the inflatable balloon catheter formed from a degradable polymer material having a Tg of at least 45 ° C;
The stent includes a first open end, a second open end, and a wall defining a channel connecting the first open end and the second open end, the wall of the stent comprising the balloon catheter When the stent expands or when the stent is heated to a temperature above the Tg of the polymer, the stent is expanded to a larger diameter, shorter length, and the same wall thickness. With gaps, open spaces, or slits to allow,
Does the stent exhibit little negative recoil when deployed in a subject's blood vessel or expanded to a predetermined final shape and diameter and stored at 37 ° C. for more than 4 weeks? Or not at all,
The assembly has a diameter that allows the assembly to be inserted into the subject's tube, vessel, or duct and advanced to a target site;
assembly.
(Item 13)
13. The assembly according to item 12, wherein the assembly has a diameter that allows the stent to be inserted into a blood vessel of a human subject and advanced into a stenotic lesion. (Item 14)
13. An assembly according to item 12, wherein the stent exhibits positive recoil and conformity to the arterial profile when the stent is not fully deployed to its final diameter during deployment. ,assembly.
(Item 15)
13. The assembly according to item 12, wherein the stent is selected from PLA and stereocopolymer (copolymer composed of L and D units), PLAGA, and poly (lactic acid-co-glycolic acid-co-gluconic acid). An assembly formed from the polymer to be made. (Item 16)
13. The assembly according to item 12, wherein the stent is stably attached to the balloon.
(Item 17)
13. The assembly according to item 12, further comprising a retractable sheath covering the outer surface of the stent.
(Item 18)
13. The assembly according to item 12, wherein a bioactive factor or tracking factor is disposed within the stent or on the surface of the stent.
(Item 19)
A method for preparing a degradable and bioabsorbable polymer stent for implantation into a lumen, vessel, or vessel lumen of a mammalian subject, the method comprising:
(A) To erase a polymeric cylindrical device having a predetermined final radius and wall thickness to a temperature well above the glass transition temperature (Tg) of the polymer Heating for a time sufficient for the polymeric cylindrical device to have a wall, the wall comprising a first open end, a second open end, and the first open end and the first open end. Defining a channel connecting the two open ends;
(B) rapidly cooling the polymeric cylindrical device to a temperature below the Tg of the polymer, quenching the polymeric cylindrical device, and storing the predetermined final diameter and shape memory Providing an educated polymeric cylindrical device having;
(C) forming slits, gaps or open spaces in the walls of the polymeric cylindrical device before step (a) or after step (b);
And when the stent is deployed in a subject's blood vessel or expanded to a predetermined final shape and diameter and stored at 37 ° C. for 4 weeks or more, a relaxation-related reaction A method that is resistant to.
(Item 20)
20. A method according to item 19, wherein the cylindrical device is attached to a support for maintaining the diameter and shape of the device during steps (a) and (b).
(Item 21)
Item 20. The method according to Item 19, wherein the stent is selected from PLA and stereocopolymer (a copolymer composed of L units and D units), PLAGA, and poly (lactic acid-co-glycolic acid-co-gluconic acid). Formed from the polymer formed.
(Item 22)
A method for preparing a degradable and bioabsorbable polymer stent, when the stent is implanted in a lumen, vessel, or vessel lumen of a mammalian subject or as defined When expanded to its final shape and diameter and stored at 37 ° C. for more than 4 weeks, it is resistant to relaxation-related reactions, the method comprising:
(A) providing a hollow cylindrical device comprising a wall, wherein the wall has a slit, an opening, or a gap, the hollow cylindrical device being a predetermined final of the stent; Having a radius smaller than the diameter;
(B) heating the polymeric cylindrical device to a temperature near or above the Tg of the polymer while expanding the tube to the predetermined final diameter;
(C) attaching the cylindrical device to a support for maintaining the cylindrical device at the predetermined final diameter;
(D) heating the attached cylindrical device to a temperature sufficiently higher than the glass transition temperature (Tg) of the polymer for a time sufficient to erase the pre-processing memory of the polymer device; ;
(E) Educated with rapid cooling of the polymeric cylindrical device at a temperature below the Tg of the polymer, quenching the polymeric cylindrical device, and having a memory of the predetermined final diameter Providing a polymeric cylindrical device;
Including the method.
(Item 23)
23. The method according to item 22, wherein the stent is selected from PLA and stereocopolymer (a copolymer composed of L units and D units), PLAGA, and poly (lactic acid-co-glycolic acid-co-gluconic acid). Formed from the polymer formed.
(Item 24)
A stent made according to the method of item 19 or item 22.
(Item 25)
Relaxed when implanted into the lumen of a mammalian subject's tube, duct, or vessel, or expanded to a predetermined final shape and diameter and stored at 37 ° C for more than 4 weeks A stent that is resistant to associated recoil,
The stent is formed from a polymer having a Tg of 45 ° C or higher;
The stent lacks processing memory, and the stent has a predetermined final shape and diameter memory;
Stent.
(Item 26)
A method of reducing the risk of chronic restenosis that may occur in a patient's artery after percutaneous transluminal coronary angioplasty comprising:
Delivering the assembly of item 12 to the location of a stenotic lesion;
Inflating the balloon to expand the stent to a diameter less than or equal to the predetermined final diameter; and deflating and retrieving the balloon;
Including the method.

Claims (1)

Invention described in this specification .