Patent Application
20080077232
The present invention relates to an almost tube-shaped stent, comprising a stent main body that is expandable toward outside in the radial direction of the tube and contains a material non-degradable in the body as the base stent material, a coating layer containing a polymer and a medicine on at least part of the stent main body surface, and an intermediate layer of a polymer having a weight-average molecular weight higher than the polymer between the coating layer and the stent surface. The base stent material according to the present invention means a material for the stent having no coating layer. The stent main body can be prepared by cutting a base stent material, such as a tube-shaped material, into the stent shape, for example by laser cutting.
The coating layer and the intermediate layer are preferably formed on almost entire surface of the external, internal, and side faces of the stent main body. The stent main body having the coating and intermediate layers on the almost entire surface is thus resistant to deposition of platelet on the surface of the stent placed in a body lumen, in particular in blood vessel, possibly preventing the occlusion of blood vessel by generation of an excessive amount of thrombus.
The “material non-degradable in the body” for use in the present invention is a material not easily degradable biologically; thus, it is not a material that no decomposition occurs at all in the body, but a material that can keep its original shape relatively for an extended period of time; and such a material is also included in the “material non-degradable in the body” according to the invention.
Examples of the materials non-degradable in the body according to the present invention, i.e., base stent materials, include inorganic materials such as stainless steel, Ni—Ti alloys, Cu—Al—Mn alloys, tantalum, Co—Cr alloys, iridium, iridium oxide, niobium, ceramics, and hydroxyapatite. The stent main body can be prepared by a method normally practiced by those who are skilled in the art, and, for example, it can be prepared by cutting a tube-shaped material tube of the base stent material into the stent shape for example by laser cutting, as described above. The stent may be polished electrically after the laser cutting. The material non-degradable in the body according to the present invention is not limited to an inorganic material, and a polymeric material such as polyolefin, polyolefin elastomer, polyamide, polyamide elastomer, polyurethane, polyurethane elastomer, polyester, polyester elastomer, polyimide, polyamide-imide, or polyether ether ketone may be used. The method of producing a stent main body by using such a polymeric material does not restenose the advantageous effects of the present invention, and any processing method may be used arbitrarily according to the material used. The stent according to present invention, which contains a material non-degradable in the body as its stent base material retains its favorable stent strength for a longer period of time and is extremely more effective in vasodilating the stenosed or occluded site of blood vessel than a stent having its stent main body made of a biodegradable material.
The stent main body surface preferably has at least partially a coating layer containing a polymer as the principal component and additionally a medicine and an intermediate layer of a polymer having a weight-average molecular weight of greater than that of the polymer above between the coating layer and the stent surface, and more preferably, the coating layer and the intermediate layer over the almost entire surface of the external, internal, and side faces of the stent main body. It is thus possible to reduce the exfoliation and cracking of the coating layer associated with stent expansion by forming the intermediate layer, and to prevent the exfoliation and cracking more effectively by making the weight-average molecular weight of the polymer for coating layer greater than that of the polymer for the intermediate layer.
The weight-average molecular weight of the polymer for the coating layer is preferably 10,000 or more and 50,000 or less, and the weight-average molecular weight of the polymer for the intermediate layer 80,000 or more and 200,000 or less. A coating layer of a polymer having a weight-average molecular weight of 10,000 or more and 50,000 or less, when it is formed directly on the stent main body surface, often results in cracking and exfoliation of the coating layer associated with stent expansion. If the coating layer of a polymer having a weight-average molecular weight of 10,000 or more and 50,000 or less contains a low-molecular weight compound such as medicine (molecular weight: ca. 5,000 or less), there are cracking and exfoliation of the coating layer associated with stent expansion at higher probability. In any case, it is possible to prevent exfoliation and cracking effectively by forming an intermediate layer between the stent main body surface and the coating layer and controlling the weight-average molecular weight of the polymer for the intermediate layer in the range of 80,000 or more and 200,000 or less.
Both of the polymers for the coating and intermediate layers are preferably biodegradable polymers. Generally if placement of the stent at blood vessel stenosis site is considered, the degradation products from the biodegradable polymer should be completely degraded and metabolized safely in the body. From the viewpoint above, the biodegradable polymer is more preferably selected from polylactic acid, polyglycolic acid, and lactic acid-glycolic acid copolymers. Polylactic acids are available in three kinds of structures depending on the optical activity of the lactic acid monomer: poly-L-lactic acid, poly-D-lactic acid, and poly-D,L-lactic acid, but polylactic acid in any structure shows the advantageous effects of the present invention. Use of a biodegradable polymer results in disappearance of all polymer by biodegradation in the chronic phase after stent placement and in residual only of the stent base material in the body. It is possible to provide a stent higher in stability and reliability also in the chronic phase, easily by using a reliable metal material, such as SUS316L, as the stent base material.
The biodegradable polymers exemplified above have a glass transition temperature not lower than the body temperature, although it may vary according to the composition, and thus, are in the rigid glass state at around body temperature. In addition, poly-L-lactic acid, poly-D-lactic acid, polyglycolic acid, and the like are known to show high crystallinity. For that reason, the biodegradable polymers exemplified above show a tensile strength higher and a tensile breaking elongation shorter than other polymers such as thermoplastic elastomers. Thus, use of such a biodegradable polymer in forming a coating layer on the surface of the stent main body, caused a problem that there was an extremely high possibility of cracking and exfoliation of the coating layer associated with stent expansion. The possibility of cracking, exfoliation, and the like becomes even greater when the coating layer contains a medicine. However, it is possible to reduce the possibility of the cracking and exfoliation of the coating layer associated with stent expansion significantly and to coat the biodegradable polymer exemplified above favorably, by forming the intermediate layer according to the invention between the stent main body surface and the coating layer.
The biodegradation period of biodegradable polymer for the coating layer is preferably shorter than that of the biodegradable polymer for the intermediate layer. When each of the coating and intermediate layers is made of a biodegradable polymer, the coating layer and the intermediate layer disappears by biodegradation in the chronic phase after placement of a stent in body lumen. The intermediate layer has a function to improve the adhesiveness between the coating layer and the stent surface, and thus, the intermediate layer should not be biodegraded sooner than the coating layer.
The biodegradation period of the biodegradable polymer is calculated by using the change in weight, strength, or molecular weight of the biodegradable polymer as an indicator. Generally, the biodegradation period calculated from the molecular weight change is shortest, that calculated from the strength change is second shortest, and that calculated from the weight change is longest. The biodegradation period, independent of the indicator used for calculation, does not restenose the advantageous effects of the present invention. Because the biodegradation periods of a single biodegradable polymer calculated from different indicators are different from each other, as described above, the biodegradation period of the biodegradable polymer for the intermediate layer and that of the biodegradable polymer for the coating layer should be the values calculated from the same indicator.
The method of forming the intermediate layer and the coating layer on the stent main body surface is not particularly limited. In a favorable method, a polymer for the intermediate layer is dissolved in a solvent; the polymer in the solution state is applied on the surface of a stent main body, and the solvent is removed: a polymer for the coating layer is dissolved in a solvent; and the polymer in the solution state applied on the surface of the intermediate layer and the solvent is removed. Alternatively, a film of the polymer for the intermediate layer may be prepared separately and bonded to the stent main body, and a film of the polymer for the coating layer bonded to the surface of the intermediate layer. Yet alternatively, a polymer for the intermediate layer may be dissolved in a solvent; the polymer in the solution state is applied on the surface of a stent main body, and the solvent removed; and then, a film of a polymer for the coating layer be prepared separately and bonded to the surface of the intermediate layer, and yet alternatively, a film of a polymer for the intermediate layer may be prepared separately and bonded to the stent main body, a polymer for the coating layer dissolved in a solvent; and the polymer in the solution state applied on the surface of the the intermediate layer and the solvent removed
The coating layer contains a medicine for reduction of the restenosis rate after stent placement. The medicine is preferably an immunosuppressive agent, favorably tacrolimus (FK506), cyclosporine, sirolimus (rapamycin), azathioprine, mycophenolate mofetil or the analog thereof, more preferably tacrolimus (FK506).
The medicine may be added to the coating layer, for example, by preparing an intermediate layer by the method described above, dissolving a polymer and a medicine for the coating layer in a solvent, applying the solution on the surface of the intermediate layer in the solution state and removing the solvent, or by preparing a film of a polymer for the coating layer separately, coating the film with a solution of the medicine dissolved in a solvent by dip coating, drying the resulting film, and bonding the film on the surface of the intermediate layer, or yet alternatively by preparing a film of a polymer for the coating layer, bonding it to the surface of the intermediate layer, and coating the film with a solution of the medicine by dip coating, and drying the resulting film.
The method of dissolving the polymer for the coating layer or/and polymer for the intermediate layer in a solvent and applying the polymers in the solution state or the method of dissolving the polymer and the medicine for the coating layer in a solvent and applying the slution in the solution state do not restenose the advantageous effects of the present invention. Thus, various methods, including the method of dipping the stent main body in each solution and the method of applying each solution on the stent main body by spraying, may be used. The solvent for use is not particularly limited. A solvent having a desirable solubility is favorably used, and two or more solvents may be used as a mixed solvent, for adjustment of volatility and others. The solute concentration is also not particularly limited, and the optimal concentration is determined, taking into consideration the surface smoothness or the like of the intermediate layer and the coating layer. For adjustment of the surface smoothness, an excessive amount of the solution may be removed during the process of dissolving the polymer for the coating layer or/and the polymer for the intermediate layer in a solvent or/and after application thereof, or alternatively, during the process of dissolving the polymer for the coating layer and a medicine in a solvent and applying the polymer in the solution state or/and after application thereof. The solvent-removing means include vibration, rotation, evacuation, and the like, and these means may be used in combination.
A stent main body was prepared by cutting a stainless steel tube (SUS316L) having an internal diameter of 1.50 mm and an external diameter of 1.80 mm into the stent shape by laser cutting and polishing it electrolytically, similarly to the method normally practiced by those who are skilled in the art.
A lactic acid-glycolic acid copolymer (product number: 85DG065, manufactured by Absorbable Polymers International, lactic acid/glycolic acid: 85/15, weight-average molecular weight: 85,000) was dissolved in chloroform (Wako Pure Chemical Industries Ltd.), to give a 0.5 wt % solution. A stainless steel wire having a diameter of 100 μm was connected to one end of the stent, and the other end was connected to a stainless steel rod having a diameter of 2 mm. The stent was held in the direction perpendicular to the length direction, by connecting the stent-unconnected sided terminal of the stainless steel rod to a motor. The stent was rotated with the motor at a frequency of 100 rpm, and the solution prepared was sprayed on the stent by using a spray gun having a nozzle diameter of 0.3 mm. The distance between the nozzle of spray gun and the stent was 75 mm, and the air pressure during spraying was 0.15 MPa. The stent was dried after spraying under vacuum at room temperature for 1 hour. An intermediate layer having a weight of the glycolic lactate acid copolymer per unit length of the stent main body in the axial direction at 4 μg/mm (52 μg per stent) was formed while the spraying period was adjusted.
A lactic acid-glycolic acid copolymer (product number: RG502H, manufactured by Boehringer Ingelheim, lactic acid/glycolic acid: 50/50, weight-average molecular weight: 11,000) was dissolved in chloroform, to give a 0.5 wt % solution. A stainless steel wire having a diameter of 100 μm was connected to one end of the stent, and the other end was connected to a stainless steel having a diameter of 2 mm. The stent was held in the direction perpendicular to the length direction, by connecting the stent-unconnected sided terminal of the stainless steel rod to a motor. The stent was rotated with the motor at a frequency of 100 rpm, and the solution prepared was sprayed by using a spray gun having a nozzle diameter of 0.3 mm on the stent carrying the formed intermediate layer, allowing deposition of the solution. The distance between the nozzle of spray gun and the stent was 75 mm, and the air pressure during spraying was 0.15 MPa. The stent was dried after spraying under vacuum at room temperature for 1 hour. A coating layer having a weight of the glycolic lactate acid copolymer per unit length of the stent main body in the axial direction at 40 μg/mm (520 μg per stent) was formed while the spraying period was adjusted.
A stent having intermediate and coating layers was prepared in a similar manner to Example 1, except that the weight of the intermediate layer was changed to 2 μg/mm (26 μg per stent), the polymer for the coating layer was changed to another lactic acid-glycolic acid copolymer (product number: RG504H, manufactured by Boehringer Ingelheim, lactic acid/glycolic acid: 50/50, weight-average molecular weight; 50,000), and the weight thereof per unit length of the stent main body in the axial direction was changed to 35 μg/mm (455 μg per stent).
A stent having intermediate and coating layers was prepared in a similar manner to Example 1, except that the weight of the intermediate layer was changed to 2 μg/mm (26 μg per stent), the polymer for the coating layer was changed to poly-D,L-lactic acid (product number: R202H, manufactured by Boehringer Ingelheim, weight-average molecular weight: 12,000), and the weight thereof per unit length of the stent main body in the axial direction was changed to 50 μg/mm (650 μg per stent).
A stent having intermediate and coating layers was prepared in a similar manner to Example 1, except that the weight of the intermediate layer was changed to 4 μpg/mm (52 μg per stent), the polymer for the coating layer was changed to poly-D,L-lactic acid (product number: R203H, manufactured by Boehringer Ingelheim, weight-average molecular weight: 22,000), and the weight thereof per unit length of the stent main body in the axial direction was changed to 42 μg/mm (546 μg per stent).
A stent having intermediate and coating layers was prepared in a similar manner to Example 1, except that the polymer for the intermediate layer was changed to poly-D, L-lactic acid (product number: 100D065, manufactured by Absorbable Polymers International, weight-average molecular weight: 83,000), the weight thereof per unit length of the stent main body in the axial direction was changed to 5 μg/mm (65 μg per stent), the polymer for the coating layer was changed to a lactic acid-glycolic acid copolymer (product number; RG502H, manufactured by Boehringer Ingelheim, lactic acid/glycolic acid: 50/50, weight-average molecular weight: 11,000), and the weight thereof per unit length of the stent main body in the axial direction was changed to 43 μg/mm (559 μg per stent).
A stent having intermediate and coating layers was prepared in a similar manner to Example 5, except that the weight of the intermediate layer was changed to 3 μg/mm (39 μg per stent), the polymer for the coating layer was changed to a lactic acid-glycolic acid copolymer (product number: RG504H, manufactured by Boehringer Ingelheim, lactic acid/glycolic acid: 50/50, weight-average molecular weight: 50,000), and the weight thereof per unit length of the stent main body in the axial direction was changed to 48 μg/mm (624 μg per stent).
A stent having intermediate and coating layers was prepared in a similar manner to Example 5, except that the weight of the intermediate layer was changed to 2 μg/mm (26 μg per stent), the polymer for the coating layer was changed to poly-D,L-lactic acid (product number: R202H, manufactured by Boehringer Ingelheim, weight-average molecular weight: 12,000), and the weight thereof per unit length of the stent main body in the axial direction was changed to 41 μg/mm (533 μg per stent).
A stent having intermediate and coating layers was prepared in a similar manner to Example 5, except that the weight of the intermediate layer was changed to 7 μg/mm (91 μg per stent), the polymer for the coating layer was changed to poly-D,L-lactic acid (product number; R203H, manufactured by Boehringer Ingelheim, weight-average molecular weight: 22,000), and the weight thereof per unit length of the stent main body in the axial direction was changed to 47 μg/mm (611 μg per stent).
A stent having intermediate and coating layers was prepared in a similar manner to Example 1, except that the polymer for the intermediate layer was changed to poly-L-lactic acid (product number: 100L105, manufactured by Absorbable Polymers International, weight-average molecular weight: 145,000), the weight thereof per unit length of the stent main body in the axial direction was changed to 3 μg/mm (per stent 39 μg), the polymer for the coating layer was changed to a lactic acid-glycolic acid copolymer (product number: RG502H, manufactured by Boehringer Ingelheim, lactic acid/glycolic acid: 50/50, weight-average molecular weight: 11,000), and the weight thereof per unit length of the stent main body in the axial direction was changed to 30 μg/mm (390 μg per stent).
A stent having intermediate and coating layers was prepared in a similar manner to Example 9, except that the weight of the intermediate layer was changed to 5 μg/mm (65 μg per stent), the polymer for the coating layer was changed to a lactic acid-glycolic acid copolymer (product number: RG504H, manufactured by Boehringer Ingelheim, lactic acid/glycolic acid: 50/50, weight-average molecular weight: 50,000), and the weight thereof per unit length of the stent main body in the axial direction was changed to 48 μg/mm (624 μg per stent).
A stent having intermediate and coating layers was prepared in a similar manner to Example 9, except that the weight of the intermediate layer was changed to 4 μg/mm (52 μg per stent), the polymer for the coating layer was changed to poly-D,L-lactic acid (product number: R202H, manufactured by Boehringer Ingelheim, weight-average molecular weight: 12,000), and the weight thereof per unit length of the stent main body in the axial direction was changed to 50 μg/mm (650 μg per stent).
A stent having intermediate and coating layers was prepared in a similar manner to Example 9, except that the weight of the intermediate layer was changed to 5 μg/mm (65 μg per stent), the polymer for the coating layer was changed to poly-D,L-lactic acid (product number: R203H, manufactured by Boehringer Ingelheim, weight-average molecular weight 22,000), and the weight thereof per unit length of the stent main body in the axial direction was changed to 39 μg/mm (507 μg per stent).
A stent main body was prepared by cutting a stainless steel tube (SUS316L) having an internal diameter of 1.50 mm and an external diameter of 1.80 mm into the stent shape by laser cutting and polishing it electrolytically, similarly to the method normally practiced by those who are skilled in the art.
A lactic acid-glycolic acid copolymer (product number: 85DG065, manufactured by Absorbable Polymers International, lactic acid/glycolic acid: 85/15, weight-average molecular weight: 85,000) was dissolved in chloroform (Wako Pure Chemical Industries Ltd.), to give a 0.5 wt % solution. A stainless steel wire having a diameter of 100 μm was connected to one end of the stent, and the other end was connected to a stainless steel rod having a diameter of 2 mm. The stent was held in the direction perpendicular to the length direction, by connecting the stent-unconnected sided terminal of the stainless steel rod to a motor. The stent was rotated with the motor at a frequency of 100 rpm, and the solution prepared was sprayed on the stent by using a spray gun having a nozzle diameter of 0.3 mm, allowing deposition of the solution. The distance between the nozzle of spray gun and the stent was 75 mm, and the air pressure during spraying was 0.15 MPa. The stent was dried after spraying under vacuum at room temperature for 1 hour. An intermediate layer having a weight of the glycolic lactate acid copolymer per unit length of the stent main body in the axial direction at 3 μg/mm (39 μg per stent) was formed while the spraying period was adjusted.
A lactic acid-glycolic acid copolymer (product number: RG502H, manufactured by Boehringer Ingelheim, lactic acid/glycolic acid: 50/50, weight-average molecular weight: 11,000) and a medicine tacrolimus (developed by Fujisawa Pharmaceutical Co., Ltd. and currently available from Astellas Pharma Inc.) were dissolved in chloroform, to give a mixed solution containing the lactic acid-glycolic acid copolymer at a concentration of 0.5 wt % and tacrolimus at a concentration of 0.19 wt %. A stainless steel wire having a diameter of 100 μm was connected to one end of the stent, and the other end was connected to a stainless steel rod having a diameter of 2 mm. The stent was held in the direction perpendicular to the length direction, by connecting the stent-unconnected sided terminal of the stainless steel rod to a motor. The stent was rotated with the motor at a frequency of 100 rpm, and the solution prepared was sprayed by using a spray gun having a nozzle diameter of 0.3 mm on the stent carrying the formed intermediate layer, allowing deposition of the solution. The distance between the nozzle of spray gun and the stent was 75 mm, and the air pressure during spraying was 0.15 MPa. The stent was dried after spraying under vacuum at room temperature for 1 hour. A coating layer having a weight of the glycolic lactate acid copolymer per unit length of the stent main body in the axial direction at 42 μg/mm (520 μg per stent) and a tacrolimus weight of 16 μg/mm (208 μg per stent) was formed while the spraying period was adjusted.
A stent having intermediate and coating layers was prepared in a similar manner to Example 13, except that the weight of the intermediate layer was changed to 7 μg/mm (91 μg per stent), the polymer for the coating layer was changed to a lactic acid-glycolic acid copolymer (product number: RG504H, manufactured by Boehringer Ingelheim, lactic acid/glycolic acid: 50/50, weight-average molecular weight: 50,000), and the weight of the lactic acid-glycolic acid copolymer per unit length of the stent main body in the axial direction was changed to 47 μg/mm (611 μg per stent) and the tacrolimus weight to 18 μg/mm (234 μg per stent).
A stent having intermediate and coating layers was prepared in a similar manner to Example 13, except that the polymer for the intermediate layer was changed to poly-D,L-lactic acid (product number: 100D065, manufactured by Absorbable Polymers International, weight-average molecular weight; 83,000), the weight of the poly-D,L-lactic acid per unit length of the stent main body in the axial direction was changed to 3 μg/mm (39 μg per stent), the polymer for the coating layer was changed to poly-D,L-lactic acid (product number: R202H, manufactured by Boehringer Ingelheim, weight-average molecular weight 12,000), and the weight of the poly-D,L-lactic acid per unit length of the stent main body in the axial direction was changed to 46 μg/mm (598 μg per stent) and the tacrolimus weight to 17 μg/mm (221 μg per stent).
A stent having intermediate and coating layers was prepared in a similar manner to Example 15, except that the weight of the intermediate layer was changed to 4 μg/mm (52 μg per stent), the polymer for the coating layer was changed to poly-D,L-lactic acid (product number: R203H, manufactured by Boehringer Ingelheim, weight-average molecular weight: 22,000), and the weight of the poly-D,L-lactic acid per unit length of the stent main body in the axial direction was changed to 42 μg/mm (546 μg per stent) and the tacrolimus weight to 16 μg/mm (208 μg per stent).
A stent having intermediate and coating layers was prepared in a similar manner to Example 13, except that the polymer for the intermediate layer was changed to poly-L-lactic acid (product number: 100L105, manufactured by Absorbable Polymers International, weight-average molecular weight 145,000), the weight of the poly-L-lactic acid per unit length of the stent main body in the axial direction was changed to 5 μg/mm (65 μg per stent), and the weight of the lactic acid-glycolic acid copolymer in the coating layer per unit length of the stent main body in the axial direction was changed to 40 μg/mm (520 μg per stent) and the tacrolimus weight to 15 μg/mm (195 μg per stent).
A stent having intermediate and coating layers was prepared in a similar manner to Example 13, except that the polymer for the intermediate layer was changed to poly-L-lactic acid (product number: 100L105, manufactured by Absorbable Polymers International, weight-average molecular weight 145,000), the weight of the poly-L-lactic acid per unit length of the stent main body in the axial direction was changed to 4 μg/mm (52 μg per stent), the polymer for the coating layer was changed to a lactic acid-glycolic acid copolymer (product number: RG504H, manufactured by Boehringer Ingelheim, lactic acid/glycolic acid: 50/50, weight-average molecular weight: 50,000), the weight of the lactic acid-glycolic acid copolymer per unit length of the stent main body in the axial direction was changed to 39 μg/mm (507 μg per stent), and the medicine was changed to sirolimus (manufactured by SIGMA) and the sirolimus weight to 15 μg/mm (195 μg per stent).
A stent having intermediate and coating layers was prepared in a similar manner to Example 13, except that the polymer for the intermediate layer was changed to a lactic acid-glycolic acid copolymer (product number: 85DG065, manufactured by Absorbable Polymers International, lactic acid/glycolic acid: 85/15, weight-average molecular weight 85,000), the weight of the lactic acid-glycolic acid copolymer per unit length of the stent main body in the axial direction was changed to 6 μg/mm (78 μg per stent), the polymer for the coating layer was changed to a lactic acid-glycolic acid copolymer (product number: RG502H, lactic acid/glycolic acid: 50/50, manufactured by Boehringer Ingelheim, weight-average molecular weight 11,000), the weight of the lactic acid-glycolic acid copolymer per unit length of the stent main body in the axial direction was changed to to 37 μg/mm (481 μg per stent), the medicine was changed to cyclosporine (manufactured by Japan Ciba-Geigy K.K. ), and the cyclosporine weight was changed to 14 μg/mm (182 μg per stent).
A stent having no intermediate but having a coating layer was prepared in a similar manner to Example 1, except that the polymer for the coating layer was changed to a lactic acid-glycolic acid copolymer (product number: RG502H, lactic acid/glycolic acid: 50/50, manufactured by Boehringer Ingelheim, weight-average molecular weight: 11,000), and the weight thereof per unit length of the stent main body in the axial direction was changed to 27 μg/mm (351 μg per stent)
A stent having no intermediate but having a coating layer was prepared in a similar manner to Comparative Example 1, except that the polymer for the coating layer was changed to a lactic acid-glycolic acid copolymer (product number: RG504H, lactic acid/glycolic acid; 50/50, manufactured by Boehringer Ingelheim, weight-average molecular weight; 50,000), and the weight thereof per unit length of the stent main body in the axial direction was changed to 45 μg/mm (585 μg per stent).
A stent having no intermediate but having a coating layer was prepared in a similar manner to Comparative Example 1, except that the polymer for the coating layer was changed to poly-D,L-lactic acid (product number: R202H, manufactured by Boehringer Ingelheim, weight-average molecular weight: 12,000), and the weight thereof per unit length of the stent main body in the axial direction was changed to 50 μg/mm (650 μg per stent).
A stent having no intermediate but having a coating layer was prepared in a similar manner to Comparative Example 1, except that the polymer for the coating layer was changed to poly-D,L-lactic acid (product number: R203H, manufactured by Boehringer Ingelheim, weight-average molecular weight 22,000), and the weight thereof per unit length of the stent main body in the axial direction was changed to 39 μg/mm (507 μg per stent)
A stent having no intermediate but having a coating layer was prepared in a similar manner to Example 13, except that the weight of the lactic acid-glycolic acid copolymer in the coating layer per unit length of the stent main body in the axial direction was changed to 40 μg/mm (520 μg per stent) and the tacrolimus weight to 15 μg/mm (195 μg per stent).
A stent having no intermediate but having a coating layer was prepared in a similar manner to Example 14, except that the weight of the lactic acid-glycolic acid copolymer in the coating layer per unit length of the stent main body in the axial direction was changed to 42 μg/mm (per stent 546 μg), the medicine was changed to cyclosporine (manufactured by Japan Ciba-Geigy K.K.), and the cyclosporine weight was changed to 16 μg/mm (208 μg per stent).
A stent having no intermediate but having a coating layer was prepared in a similar manner to Example 15, except that the weight of the poly-D,L-lactic acid in the coating layer per unit length of the stent main body in the axial direction was changed to 39 μg/mm (507 μg per stent), the medicine was changed to sirolimus (manufactured by SIGMA), and the sirolimus weight was changed to 15 μg/mm (195 μg per stent).
A stent having no intermediate but having a coating layer was prepared in a similar manner to Example 16, except that the weight of the poly-D-L-lactic acid in the coating layer per unit length of the stent main body in the axial direction was changed to 38 μg/mm (494 μg per stent) and the tacrolimus weight to 14 μg/mm (182 μg per stent).
A PTCA balloon catheter containing a balloon of 3.5×15 mm in dimension was prepared, and the stent described above was mounted on the balloon region. The balloon was inflated in air at room temperature at 8 atm (810 kPa), allowing expansion of the stent. The balloon was deflated after 1 minute and separated from the stent. The expanded stent was fixed on the test-piece stage of an electron microscope and vapor-deposited with a Pt-Pd alloy, and the surface thereof was observed under a scanning electron microscope (S-3000N, manufactured by Hitachi High-Technologies Corp.). The frequency of cracking and exfoliation on the coated film was evaluated qualitatively, and the results are summarized in Tables 1 to 3.
As shown in Tables 1 to 3, the stents according to the invention having intermediate and coating layers obtained in Examples 1 to 19 were resistant to cracking and exfoliation of the coated film. On the other hand, the stents obtained in Comparative Examples 1 to 4 having only a coating layer and no intermediate layer showed cracking of the film, and the stent obtained in Comparative Example 3 even showed exfoliation. In addition, all of the stents obtained in Comparative Examples 5 to 8 having only a coating layer containing a medicine showed cracking and exfoliation of the coated film.
As described above, the stent for placement in body according to the present invention, which has a stent base material containing a material non-degradable in the body, a coating layer of polymer formed on at least part of the stent main body, and an intermediate layer of a polymer having a weight-average molecular weight of greater than that of the polymer above between the coating layer and the stent main body surface, is effectively resistant to exfoliation and cracking of the coating layer associated with stent expansion.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2004-260793 | Sep 2004 | JP | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/JP05/16000 | 9/1/2005 | WO | 00 | 3/7/2007 |
