Drug-delivery endovascular stent and method for treating restenosis

Abstract

An intravascular stent and method for inhibiting restenosis, following vascular injury, is disclosed. The stent has an expandable, linked-filament body and a drug-release coating formed on the stent-body filaments, for contacting the vessel injury site when the stent is placed in-situ in an expanded condition. The coating releases, for a period of at least 4 weeks, a restenosis-inhibiting amount of a macrocyclic triene immunosuppressive compound having an alkyl group substituent at carbon position 40 in the compound. The stent, when used to treat a vascular injury, gives good protection against clinical restenosis, even when the extent of vascular injury involves vessel overstretching by more than 30% diameter. Also disclosed is a stent having a drug-release coating composed of (i) 10 and 60 weight percent poly-dl-lactide polymer substrate and (ii) 40-90 weight percent of an anti-restenosis compound, and a polymer undercoat having a thickness of between 1-5 microns.

It is claimed:  
     
         1 . An endovascular stent for placement at a vascular injury site, for inhibiting restenosis at the site, comprising 
 a body formed of one or more filaments,    carried on the one or more filaments, a bioerodable drug-release coating having a thickness of between 3-20 microns, and composed of (i) 20-60 weight percent poly-dl-lactide polymer substrate and (ii) 40-80 weight percent of an anti-restenosis compound, and    a polymer undercoat having a thickness of between 1-5 microns, disposed between the stent-body filaments and said coating,    said stent being expandable from a contracted condition in which the stent can be delivered to a vascular injury site via a catheter, and an expanded condition in which the stent coating can be placed in contact with the vessel at the injury site,    said coating being effective to release a restenosis-inhibiting amount of the compound over a period of at least 4 weeks after the stent is placed at the vascular injury site.    
     
     
         2 . The stent of  claim 2 , wherein said anti-restenosis compound is a macrocyclic triene immunosuppressive.  
     
     
         3 . The stent of  claim 2 , wherein the stent body is a metal-filament structure, the undercoat is formed of a parylene polymer and has a thickness between 1 and 3 microns, and the coating has a thickness between 2 and 15 microns.  
     
     
         4 . The stent of  claim 3 , wherein said compound is present in the coating in an amount between 50% and 75% by weight.  
     
     
         5 . The stent of  claim 2 , wherein said compound has the form  
       
         
           
           
               
               
           
         
       
       where (i) R is H or CH 2- —X—OH, and X is a linear or branched alkyl group containing 1 to 7 carbon atoms, when R′ is H (R′ is at the 28 position O) or (ii) at least one of R and R′ have the form  
       
         
           
           
               
               
           
         
       
       where m is an integer from 1 to 3 and R 1  and R 2  are each a hydrogen, or an alkyl radical having from one to three carbon atoms, or, alternatively, wherein R 1  and R 2  together with a nitrogen atom to which they are attached form a saturated heterocyclic ring having four carbon atoms.  
     
     
         6 . The stent of  claim 5 , where R′ is H and X is —CH 2 .  
     
     
         7 . A method for inhibiting restenosis in a vascular injury site, comprising delivering to the vascular injury site, an endovascular stent comprising 
 (a) a body formed of one or more filaments,    (b) carried on the one or more filament(s), a bioerodable drug-release coating having a thickness of between 3-20 microns, and composed of (i) 20 and 60 weight percent poly-dl-lactide polymer substrate and (ii) 40-80 weight percent of an anti-restenosis compound, and    (c) a polymer undercoat having a thickness of between 1-5 microns, disposed between the stent-body filaments and said coating, and    expanding the stent at the vascular injury site, to bring the stent coating in contact with the vessel at the injury site,    wherein said coating is effective to release a restenosis-inhibiting amount of the compound over a period of at least 4 weeks, thus to inhibit restenosis at the site.    
     
     
         8 . The method of  claim 7 , wherein the anti-restenosis compound is macrocyclic triene immunosuppressive compound.  
     
     
         9 . The method of  claim 8 , wherein the stent body is a metal-filament structure, the undercoat is formed of a parylene polymer having a thickness between 1 and 3 microns, and the coating has a thickness between 2 and 15 microns.  
     
     
         10 . The method of  claim 9 , wherein said compound is present in the coating in an amount between 50% and 75% by weight.  
     
     
         11 . The method of  claim 8 , wherein said compound has the form  
       
         
           
           
               
               
           
         
       
       where (i) R is H or CH 2- —X—OH, and X is a linear or branched alkyl group containing 1 to 7 carbon atoms, when R′ is H (R′ is at the 28 position O) or (ii) at least one of R and R′ have the form  
       
         
           
           
               
               
           
         
       
       where m is an integer from 1 to 3 and R 1  and R 2  are each a hydrogen, or an alkyl radical having from one to three carbon atoms, or, alternatively, wherein R 1  and R 2  together with a nitrogen atom to which they are attached form a saturated heterocyclic ring having four carbon atoms.  
     
     
         12 . The method of  claim 11 , where R′ is H and X is —CH 2 .  
     
     
         13 . The method of  claim 11 , for use where the vascular injury is produced during an angiographic procedure in which a vessel region is overstretched at least 30% in diameter.  
     
     
         14 . An endovascular stent for placement at a vascular injury site, for inhibiting restenosis at the site, comprising 
 a body having an open-lattice structure formed of linked filaments, and    carried on the one or more filaments, a drug-release coating having a thickness of between 3-30 microns, and composed of (i) 20 and 70 weight percent polymer substrate and (ii) 30-80 weight percent macrocyclic triene immunosuppressive compound having the form:                          where R is CH 2- —X—OH, and X is a linear alkyl group containing 1 to 7 carbon atoms,    said stent being expandable from a contracted condition in which the stent can be delivered to a vascular injury site via catheter, and an expanded condition in which the stent coating can be placed in contact with the vessel at the injury site,    said coating being effective to release said a restenosis-inhibiting amount of the compound over a period of at least weeks after the stent is placed at the vascular injury site.    
     
     
         15 . The stent of  claim 14 , wherein X is —CH 2 —.  
     
     
         16 . The stent of  claim 14 , wherein the stent body is a metal-filament structure, and the polymer substrate in the coating is selected from the group consisting of polymethylmethacrylate, ethylene vinyl alcohol, and poly-dl-lactide polymer.  
     
     
         17 . The stent of  claim 16 , wherein the polymer substrate in the coating is formed of a bioerodable poly-dl-lactide having a thickness between 3-20 microns and said compound is present in the coating at an initial concentration of between 35 and 80 weight percent of coating.  
     
     
         18 . The stent of  claim 17 , which further includes a parylene polymer undercoat having a thickness of between 1-3 microns, disposed between the filaments of the stent body and said poly-dl-lactide coating substrate.  
     
     
         19 . The stent of  claim 18 , wherein said coating includes the compound at an initial concentration of between 50 and 80 weight percent of coating.  
     
     
         20 . The stent of  claim 14 , wherein said stent body and coating substrate are both formed of a bioerodable polymer.  
     
     
         21 . The stent of  claim 20 , wherein said stent body is formed of a poly-l-or poly-dl-lactide acid, and the coating substrate is formed of poly-dl-lactide.  
     
     
         22 . The stent of  claim 14 , wherein said coating is constructed to contact blood flowing through the stent when the stent is placed at the site in its expanded condition, and said coating contains said macrocyclic triene and said polymer in the specified proportions, which is mixed with a bioactive agent selected from the group consisting of an antiplatelet, fibrinolytic, or thrombolytic agent in soluble crystalline form.  
     
     
         23 . The stent of  claim 22 , wherein wherein said antiplatelet, fibrinolytic, or thrombolytic agent is heparin, aspirin, hirudin, ticlopadine(sp), eptifibatide, urokinase, streptokinase, tissue plasminogen activator (TPA), or abciximab, or a mixture thereof.  
     
     
         24 . In a method for inhibiting restenosis at a vascular injury site, by placement at the site an intravascular stent designed to release a macrocyclic triene immunosuppressive compound over an extended period, an improvement comprising employing as the macrocyclic triene immunosuppressive compound, a compound having the formula:  
       
         
           
           
               
               
           
         
       
       where R is CH 2- —X—OH, and X is a linear alkyl group containing 1 to 7 carbon atoms.  
     
     
         25 . The method of  claim 24 , wherein X is —CH 2 —.  
     
     
         26 . An endovascular stent for placement at a vascular injury site, for inhibiting restenosis at the site, comprising 
 a body having an open-lattice structure formed of linked filaments, and    carried on the stent-body filaments, a drug-release coating having a thickness of between 3-30 microns, said coating containing a mixture of polymer and an agent effective for the control of restenosis, wherein said agent is present in a agent-to-polymer ratio of greater than 50% by weight and wherein said coating is attached to said filament using a polymer underlayer of between 1-5 microns.    
     
     
         27 . An endovascular stent for placement at a vascular injury site, for inhibiting restenosis at the site, comprising 
 a body having an open-lattice structure formed of linked filaments, and    carried on the stent-body filaments, a drug-release coating having a thickness of between 3-30 microns, said coating containing a mixture of polymer and an agent effective for the control of restenosis independent of the extent of vessel injury.