Sustained drug-releasing stent

Abstract

A stent includes a stent body of a cylindrical configuration having outer and inner surfaces, a first coated layer coating at least the outer surface, and a second coated layer coating substantially completely over the first coated layer. The first coated layer is prepared of a first composition comprising a polymer and a vascular intimal hyperplasia inhibitor (preferably argatroban) of a kind, which does not inhibit proliferation of endothelial cells, the weight compositional ratio of the polymer to the inhibitor being within the range of 8:2 to 3:7. On the other hand, the second coated layer is prepared of a polymer alone or a second composition comprising a polymer and a drug, the weight compositional ratio of the drug to 80% by weight of the polymer being less than 20% by weight.

1 . A stent comprising:
 a stent body of a cylindrical configuration having outer and inner surfaces without a diamond-like thin film coated on the surfaces;   a first coated layer coating at least the outer surface of the stent body; and   a second coated layer coating substantially completely over the first coated layer;   in which the first coated layer is prepared of a first composition comprising a polymer and a vascular intimal hyperplasia inhibitor of a kind, which does not inhibit proliferation of endothelial cells, the weight compositional ratio of the polymer to the vascular intimal hyperplasia inhibitor being within the range of 8:2 to 3:7; and   in which the second, coated layer is prepared of a polymer alone or a second composition comprising a polymer and a drug, the weight compositional ratio of the drug to 80% by weight of the polymer being less than 20% by weight.   
     
     
         2 . The stent as claimed in  claim 1 , in which the inhibitor comprises
 argatroban as an essential component.   
     
     
         3 . The stent as claimed in  claim 1 , in which the first coated layer has a thickness within the range of 1 to 20 μm and the second coated layer has a thickness within the range of 0.5 to 5 μm. 
     
     
         4 . The stent as claimed in  claim 2 , in which the argatroban contained in the first coated layer is microdispersed in the polymer. 
     
     
         5 . The stent as claimed in  claim 2 , in which the first coated layer contains no drug other than argatroban. 
     
     
         6 . The stent as claimed in  claim 1 , in which the second coated layer is prepared of the polymer alone. 
     
     
         7 . The stent as claimed in  claim 1 , in which the drug contained in the second composition is selected from the group consisting of argatroban, rapamycin, everolimus, biolimus A9, zotarolimus, tacrolimus, paclitaxel and statin. 
     
     
         8 . The stent as claimed in  claim 1 , in which the polymer forming a part of the first composition and/or the second coated layer is a biodegradable polymer. 
     
     
         9 . The stent as claimed in  claim 8 , in which the biodegradable polymer is selected from the group consisting of poly(lactic acid), poly(lactic acid-glycolic acid), poly(glycolic acid), poly(lactic acid-ε-caprolactone) and poly(glycolic acid-ε-caprolactone). 
     
     
         10 . The stent as claimed in  claim 1 , in which the stent body is made of a material selected from the group consisting of a metallic material, a ceramic material and a high molecular polymer material. 
     
     
         11 . A stent comprising:
 a stent body of a cylindrical configuration having outer and inner surfaces without a diamond-like thin film coated on the surfaces;   a first coated layer coating at least the outer surface of the stent body and having a thickness within the range of 1 to 15 μm; and   a second coated layer coating substantially completely over the first coated layer and having a thickness within the range of 0.5 to 5 μm;   in which the first coated layer is prepared of a first composition comprising a polymer and argatroban, the weight compositional ratio of the polymer to the argatroban being within the range of 8:2 to 3:7; and   in which the second coated layer is prepared of a polymer alone or a second composition comprising a polymer and a drug, the weight compositional ratio of the drug to 80% by weight of the polymer being less than 20% by weight.   
     
     
         12 . A method of making a stent, which comprises:
 preparing a solution containing a first composition, as defined in  claim 2 , dissolved in a solvent selected from the group consisting of a mixture of a lower alkyl ketone and methanol, a mixture of a lower alkyl ester and methanol or a mixture of a lower halogenated hydrocarbon and methanol;   coating at least an outer surface of a stent body; and   after the coating, removing the solvent to complete a first coated layer.   
     
     
         13 . A method of controlling the rate of release of argatroban from a stent as defined in  claim 2 , in which the rate of release of argatroban in a phosphate buffered saline at 37° C., which is measured on the first day and the second day subsequent to immersion of the stent in that phosphate buffered saline, is controlled to 3 μg/cm 2  per day or higher, by selecting a predetermined thickness of the second coated layer so as to fall within the range of 0.5 to 5.0 μm. 
     
     
         14 . A method of controlling the rate of release of argatroban from a stent as defined in  claim 2 , in which the rate of release of argatroban in a phosphate buffered saline at 37° C., which is measured on the second day subsequent to immersion of the stent in that phosphate buffered saline is controlled to a value within the range of 3 to 100 μg/cm 2  per day, by selecting a predetermined thickness of the second coated layer so as to fall within the range of 0.5 to 5.0 μm. 
     
     
         15 . A method of controlling the rate of release of argatroban from a stent as defined in  claim 2 , in which the rate of release of argatroban in the phosphate buffered saline at 37° C., which is measured on the third to seventh day subsequent to immersion of the stent in that phosphate buffered saline is controlled to a value within the range of 2 to 50 μg/cm 2  per day, by selecting a predetermined thickness of the second coated layer so as to fall within the range of 0.5 to 5.0 μm. 
     
     
         16 . The method of controlling the rate of release of argatroban from the stent as claimed in  claim 13 , in which the rate of release of argatroban contained in the first composition is controlled by microdispersing the argatroban in the polymer. 
     
     
         17 . The method of controlling the rate of release of argatroban from the stent as claimed in  claim 14 , in which the rate of release of argatroban contained in the first composition is controlled by microdispersing the argatroban in the polymer. 
     
     
         18 . The method of controlling the rate of release of argatroban from the stent as claimed in  claim 15 , in which the rate of release of argatroban contained in the first composition is controlled by microdispersing the argatroban in the polymer. 
     
     
         19 . The method of controlling the rate of release of argatroban from the stent as claimed in  claim 13 , in which the rate of release of argatroban is controlled by selecting a solvent for dissolving the first composition from the group consisting of a mixture of lower alkylketone and methanol, and a mixture of lower alkyl ester and methanol, coating a surface of the stent body with the use of a solution, in which the first composition has been dissolved by the use of the selected solvent, and removing the mixed solvent, after the coating, to thereby form the first coated layer. 
     
     
         20 . The method of controlling the rate of release of argatroban from the stent as claimed in  claim 14 , in which the rate of release of argatroban is controlled by selecting a solvent for dissolving the first composition from the group consisting of a mixture of lower alkylketone and methanol, and a mixture of lower alkyl ester and methanol, coating a surface of the stent body with the use of a solution, in which the first composition has been dissolved by the use of the selected solvent, and removing the mixed solvent, after the coating, to thereby form the first coated layer. 
     
     
         21 . The method of controlling the rate of release of argatroban from the stent as claimed in  claim 15 , in which the rate of release of argatroban is controlled by selecting a solvent for dissolving the first composition from the group consisting of a mixture of lower alkylketone and methanol, and a mixture of lower alkyl ester and methanol, coating a surface of the stent body with the use of a solution, in which the first composition has been dissolved by the use of the selected solvent, and removing the mixed solvent, after the coating, to thereby form the first coated layer. 
     
     
         22 . The method of controlling the rate of release of argatroban from the stent as claimed in  claim 13 , in which the polymer used to form the second coated layer is poly(lactic acid-glycolic acid) and in which the rate of release of argatroban is controlled by changing the copolymerization ratio between the lactic acid and the glycolic acid. 
     
     
         23 . The method of controlling the rate of release of argatroban from the stent as claimed in  claim 14 , in which the polymer used to form the second coated layer is poly(lactic acid-glycolic acid) and in which the rate of release of argatroban is controlled by changing the copolymerization ratio between the lactic acid and the glycolic acid. 
     
     
         24 . The method of controlling the rate of release of argatroban from the stent as claimed in  claim 15 , in which the polymer used to form the second coated layer is poly(lactic acid-glycolic acid) and in which the rate of release of argatroban is controlled by changing the copolymerization ratio between the lactic acid and the glycolic acid. 
     
     
         25 . A method of inhibiting vascular intimal hyperplasia, which comprises:
 placing a stent of a kind, as defined in  claim 2 , within a blood vessel; and   causing argatroban to be released from the stent to thereby inhibit the vascular intimal hyperplasia without inhibiting proliferation of endothelial cells.