Drug-delivery stent formulations for restenosis and vulnerable plaque

Abstract

Drug-delivery stents capable of providing release of two or more drugs such as everolimus and estradiol are provided. The stents can be used for treating a disease such as restenosis and vulnerable plaque.

1 . A drug-delivery system, comprising an effective amount of everolimus, or derivatives thereof, and an effective amount of estradiol for the treatment or prevention of a vascular disorder or a related disorder.  
   
   
       2 . The drug-delivery system of  claim 1 , wherein estradiol is 17-beta-estradiol.  
   
   
       3 . The drug-delivery system of  claim 1 , wherein the system is a stent.  
   
   
       4 . The drug-delivery system of  claim 1 , wherein the disorder is restenosis.  
   
   
       5 . The drug-delivery system of  claim 1 , wherein the disorder is vulnerable plaque.  
   
   
       6 . The drug-delivery system of  claim 1 , wherein the system is a polymer or a polymeric coating.  
   
   
       7 . A method of treating restenosis of a blood vessel comprising administering to a patient an effective amount of everolimus, rapamycin, or derivatives of everolimus or rapamycin and an effective amount of estradiol, wherein the combination is for treatment or prevention of the vascular disorder.  
   
   
       8 . The method of  claim 7 , wherein estradiol is 17-beta-estradiol.  
   
   
       9 . The method of  claim 7 , wherein the combination of the drugs are administered by a drug-delivery stent.  
   
   
       10 . A method of treating vulnerable plaque of a blood vessel comprising administering to a patient an effective amount of everolimus, rapamycin, or derivatives of everolimus or rapamycin and an effective amount of estradiol, wherein the combination is for treatment or prevention of the vascular disorder.  
   
   
       11 . The method of  claim 10 , wherein estradiol is 17-beta-estradiol.  
   
   
       12 . The method of  claim 10 , wherein the combination of the drugs are administered by a drug-delivery stent.  
   
   
       13 . A drug-delivery stent comprising at least a drug selected from the group consisting of anti-proliferative drugs, immunosuppresant drugs, anti-inflammatory drugs, anti platelet drugs, antimigratory drugs, anti-thrombotic drugs, drugs that regress plaque, high density lipoprotein (HDL)-mimetics, prohealing drugs and combinations thereof; wherein the stent has a release profile that includes one or a combination of pulsed, burst and sustained release profile.  
   
   
       14 . The drug-delivery stent of  claim 13 , 
 wherein the anti-proliferative drugs have a sustained release over a period up to 30 days;    wherein the anti-inflammatory drugs and the anti platelet drugs have a sustained release over a period up to 2 months; and    wherein the antimigratory drugs have a sustained release over a period up to 4 weeks.    
   
   
       15 . The drug-delivery stent of  claim 13 , wherein a combination of the anti-proliferative and anti-inflammatory is used.  
   
   
       16 . The drug-delivery stent of  claim 13 , further comprising an additional drug selected from the group consisting of estradiol, idoxifene, and a combination thereof.  
   
   
       17 . The drug-delivery stent of  claim 13 , wherein the anti-proliferative is everolimus.  
   
   
       18 . The drug-delivery stent of  claim 17 , wherein everolimus is released at a rate of about 6 to 40 μg per day for at least one day after implantation and a rate of about 2 to 15 μg per day thereafter for a selected number of days.  
   
   
       19 . The drug-delivery stent of  claim 17 , wherein everolimus is released at a rate of about 45 μg to 120 μg within the first 3 days after implantation followed by a release at a rate of about 2 to 15 μg per day for a selected number of days.  
   
   
       20 . A drug-delivery stent comprising a first drug that reduces smooth muscle cell proliferation and a second drug that promotes endothelial cell growth, wherein the drug-delivery stent is capable of simultaneously releasing the first drug and the second drug.  
   
   
       21 . The drug-delivery stent of  claim 20 , wherein the first drug is everolimus and the second drug is estradiol, 17-beta-estradiol or idoxifene.  
   
   
       22 . The drug-delivery stent of  claim 20 , comprising: 
 a first layer that comprises the first drug and a first polymer, and a second layer that comprises the second drug and a second polymer, wherein the first polymer and the second polymer can be the same or different.    
   
   
       23 . A method of treating a disorder in a patient comprising implanting in the patient the stent of  claim 13 , wherein the disorder is selected from the group consisting of atherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, and combinations thereof.  
   
   
       24 . A method of treating a disorder in a patient comprising administering to the patient a formulation of  claim 20 , wherein the disorder is selected from the group consisting of atherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, and combinations thereof.  
   
   
       25 . A method of treating a disorder in a patient comprising administering to the patient a formulation of  claim 21 , wherein the disorder is selected from the group consisting of atherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, and combinations thereof.