Medical implants and methods for regulating the tissue response to vascular closure devices

Abstract

Devices and methods for reducing, eliminating, preventing, suppressing, or treating tissue responses to hemostatic devices e.g., biological sealants or vascular procedures are disclosed. The invention employs a combination of resorbable, biocompatible matrix materials and a variety of therapeutic agents, such as antiproliferatives or antibiotics, applied to a vascular puncture or incision to achieve hemostasis following diagnostic or interventional vascular catheterizations and to treat neointimal hyperplasia and stenosis. A matrix of a material such as collagen provides a reservoir of a therapeutic agent such as rapamycin (sirolimus) and its derivatives and analogs for delivery at a tissue site at risk for vasculoproliferation, infection, inflammation, fibrosis or other tissue responses.

1 . A method of treating a site of vascular compromise to seal a puncture or opening, and to treat, suppress or prevent a tissue response at such site, comprising the steps of: 
 combining a tissue response regulating amount of a therapeutic agent and a hemostatic device or material; and    applying the combination to the site.    
     
     
         2 . The method of  claim 1 , wherein the therapeutic agent comprises a compound of formula I:  
       
         
           
           
               
               
           
         
       
       wherein R 1  is hydrogen, alkoxyhydroxyl, alkylalkoxycarbamoyl, tetrazolyl, or —OR 14  wherein R 14  is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, thioalkyl, hydroxyalkyl, hydroxyaryl, hydroxyarylalkyl, hydroxyalkoxyalkyl, hydroxyalkylarylalkyl, dihyroxyalkyl, dihyroxyalkylarylalkyl, alkoxyalkyl, acyloxyalkyl, alkylcarbonyloxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxycarbonylaminoalkyl, alkylcarbonylaminoalkyl, arylsulfonamidoalkyl, allyl, dihyroxyalkylallyl, dioxolanylallyl, carbalkoxyalkyl, or alkylsilyl, hydroxyl, carboxyl, cyano, halogen, epoxy, sulfohalo, sulfoalkyl, sulfoaryl, sulfoarylalkyl, sulfoheterocyclic, sulfoheterocyclicalkyl, sulfoamidoalkyl, sulfoamidoaryl, oxoalkyl, oxoaryl, oxocycloalkyl, oxoarylalkyl, oxoheterocyclic, oxoheterocyclicalkyl, carboxyl, carboxycycloalkyl, carboxyaryl, carboxyheterocyclic, carboxy(N-succinimidyl), alkylalkoxycarbonyl, carbamoylalkyl, alkylcarbamoylalkyl, carbamoylalkenyl, carbamoylalkynyl, alkoxycarbamoyl, carbamoylcycloalkyl, —N 3 , or —R 18 —R 15 —R 16 —R 17  wherein R 18  is oxo, alkyl, or amidoalkyl, R 15  is nitrogen, and R 16  and R 17  are independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, hydroxyl, carboxyl, cyano, aryl, heterocyclic, and arylalkyl; 
 R 2  is hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, aryl, acyl, acyloxy, aryloxy, alkylthio, alkylsulfinyl, oxo, or together with R 14  forms C 2-6  alkylene;  
 R 3 , R 5 , R 7 , R 9 , and R 10  are independently selected from hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, aryl, acyl, acyloxy, aryloxy, alkylthio, alkylsulfinyl, and oxo;  
 R 4  is hydrogen, hydroxyl, oxo, diazo, phenyl-substituted alkyl, ═CH 2 , —O—(CH 2 ) 2 —O—, —S—(CH 2 ) 2 —S—, —O—(CH 2 ) 3 —O—, —S—(CH 2 ) 3 —S—, or ═N—N(R 19 )(R 20 ) wherein R 19  and R 20  are independently selected from hydrogen, alkyl aryl, arylalkyl, heterocyclic, and heterocyclicalkyl;  
 R 6  is hydrogen, hydroxyl, oxo, phenyl-substituted alkyl, —OR 21  wherein R 21  is C 14  alkyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, hydroxyalkylcarbonyl, aminoalkylcarbonyl, formyl, or aryl;  
 R 8  is alkoxy, oxo, —OR 13 , —S(O)—R 13  or —NR 13  wherein R 13  is hydrogen, aryl, alkyl, alkenyl, alkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, benzyl, alkoxybenzyl, or chlorobenzyl and x is 0, 1, or 2; and  
 R 11  and R 12  are —CH 2 —, —S—, or >S═O.  
 
     
     
         3 . The method of  claim 1  wherein the therapeutic agent is rapamycin.  
     
     
         4 . The method of  claim 1 , wherein the therapeutic agent is an analogue of rapamycin.  
     
     
         5 . The method of  claim 1 , wherein the therapeutic agent is everolimus.  
     
     
         6 . The method of  claim 1 , wherein the therapeutic agent is dexamethasone.  
     
     
         7 . The method of  claim 1 , wherein the therapeutic agent is paclitaxel.  
     
     
         8 . The method of  claim 1 , wherein the therapeutic agent is tacrolimus.  
     
     
         9 . The method of  claim 1 , wherein the hemostatic material comprises collagen.  
     
     
         10 . The method of  claim 9 , wherein the collagen is Type I Bovine collagen.  
     
     
         11 . The method according to  claim 9 , wherein the collagen is selected from the group consisting of Type I, Type II, Type II, Type IV, Type XI, and mixtures thereof.  
     
     
         12 . The method of  claim 1 , wherein the hemostatic material comprises fibrin.  
     
     
         13 . The method of  claim 1 , wherein the hemostatic material comprises a polysaccharide.  
     
     
         14 . The method of  claim 13 , wherein the polysaccharide is chitosan.  
     
     
         15 . The method of  claim 1 , wherein the hemostatic material is selected from the group consisting of collagen, fibrin, chitosan and mixtures thereof.  
     
     
         16 . The method according to  9 - 15 , wherein the hemostatic material is biodegradable.  
     
     
         17 . The method according to  9 - 15 , wherein the hemostatic device is non-biodegradable.  
     
     
         18 . The method according to  claim 1 , wherein the hemostatic device comprises an adjuvant.  
     
     
         19 . The method according to  claim 18 , wherein the adjuvant inhibits calcification.  
     
     
         20 . The method according to  claim 18 , wherein the adjuvant is Vitamin K.