Controlled delivery of therapeutic agents by insertable medical devices

Abstract

A medical device and method for transportation and release of a therapeutic agent into a mammalian body are disclosed. The medical device is coated with alternating layers of a negatively charged therapeutic agent and a cationic polyelectrolyte, following a controlled adsorption technique. The method is simple, with minimal perturbation to the therapeutic agent and uses clinically acceptable biopolymers such as human serum albumin. The amount of the therapeutic agent that can be delivered by this technique is optimized by the number of the layers of the therapeutic agent adsorbed on the surface of medical device. There is a washing step between alternate layers of the therapeutic agent and cationic polyelectrolyte carrier, so that the amount of the therapeutic agent on the insertable medical device represents the portion that is stably entrapped and adsorbed on to the medical device. The insertable medical device and method according to this invention are capable of reproducibly delivering therapeutic agent to a site in a mammalian body, and allow for a highly reproducible and controllable release kinetics of the therapeutic agent.

1 - 46 . (canceled)  
     
     
         47 . A method of treating or preventing the course of a disease or tissue dysfunction comprising: 
 providing a medical device comprising: 
 an inner layer of a cationic polyelectrolyte carrier;  
 a layer of a negatively charged therapeutic agent adsorbed onto said inner layer of a cationic polyelectrolyte carrier; and  
 an additional layer of a cationic polyelectrolyte carrier and an additional layer of a negatively charged therapeutic agent adsorbed onto said additional layer of said cationic polyelectrolyte carrier, wherein said additional layer of a cationic polyelectrolyte carrier and said additional layer of a negatively charged therapeutic agent alternate;  
   implanting the medical device into a target location from which the negatively charged therapeutic agent can treat or prevent the course of the disease or tissue dysfunction.    
     
     
         48 . The method of  claim 47 , wherein treating or preventing tissue dysfunction comprises inhibiting angiogenesis.  
     
     
         49 . The method of  claim 48 , wherein treating or preventing tissue dysfunction comprises inducing angiogenesis.  
     
     
         50 . The method of  claim 49 , wherein treating or preventing the course of a disease or tissue dysfunction comprises treating or preventing restenosis; cardiomyopathy or other dysfunction of the heart; or cystic fibrosis or other dysfunction of the lung.  
     
     
         51 . The method of  claim 47 , wherein treating or preventing the course of a disease or tissue dysfunction comprises treating or inhibiting malignant cell proliferation.  
     
     
         52 . The method of  claim 47 , wherein treating or preventing the course of a disease or tissue dysfunction comprises inducing nerve, blood vessel, or tissue regeneration in a tissue.  
     
     
         53 . The method of  claim 47 , wherein the medical device is used in angioplasty.  
     
     
         54 . The method of  claim 47 , wherein the medical device further comprises an outermost layer of a cationic polyelectrolyte carrier which is the same or different from the inner or the additional layer of a cationic polyelectrolyte carrier.  
     
     
         55 . The method of  claim 47 , wherein the inner or the additional layer of a cationic polyelectrolyte carrier comprises human serum albumin, gelatin, chitosan, or a combination thereof.  
     
     
         56 . The method of  claim 47 , wherein the medical device is a stent or a catheter.  
     
     
         57 . The method of  claim 56 , wherein the catheter is a balloon catheter.  
     
     
         58 . The method of  claim 47 , wherein the negatively charged therapeutic agent is rapamycin or paclitaxel.  
     
     
         59 . The method of  claim 47 , wherein the negatively charged therapeutic agent comprises more than one negatively charged therapeutic agent.  
     
     
         60 . The method of  claim 47 , wherein the negatively charged therapeutic agent is selected from the group consisting of a: anti-thrombogenic protein, antioxidant compound, angiogenic protein, agent which blocks smooth muscle cell proliferation, anti-inflammatory agent, calcium entry blocker, antineoplastic/antiproliferative/anti-mitotic compound, anti-microbial compound, anesthetic agent, nitric oxide donor, anti-coagulant, vascular cell growth promoting protein, vascular cell growth protein inhibitor, vascular cell growth antibody inhibitor, cholesterol lowering drug, vasodilating drug, protein that protects against cell death, cell cycle CDK protein inhibitor, anti-restenosis protein, agent for treating malignancies, bone morphogenic protein, a polynucleotide encoding any of the above named proteins or protein inhibitors, and a vector comprising a polynucleotide encoding any of the above named proteins or protein inhibitors.  
     
     
         61 . A method of delivering a therapeutic agent to a target location comprising 
 providing a medical device comprising: 
 an inner layer of a cationic polyelectrolyte carrier;  
 a layer of a negatively charged therapeutic agent adsorbed onto said inner layer of a cationic polyelectrolyte carrier; and  
 an additional layer of a cationic polyelectrolyte carrier and an additional layer of a negatively charged therapeutic agent adsorbed onto said additional layer of said cationic polyelectrolyte carrier, wherein said additional layer of a cationic polyelectrolyte carrier and said additional layer of a negatively charged therapeutic agent alternate;  
   implanting the medical device into a target location to deliver the negatively charged therapeutic agent to the target location.    
     
     
         62 . The method of  claim 61 , wherein the target location is a brain, heart, liver, skeletal muscle, smooth muscle, kidney, bladder, intestine, stomach, pancreas, ovary, prostate, cartilage, bone, lung, blood vessel, ureter, urethra, or testes.  
     
     
         63 . The method of  claim 61 , wherein the at least one negatively charged therapeutic agent is selected from the group consisting of a: anti-thrombogenic protein, antioxidant compound, angiogenic protein, agent which blocks smooth muscle cell proliferation, anti-inflammatory agent, calcium entry blocker, antineoplastic/antiproliferative/anti-mitotic compound, anti-microbial compound, anesthetic agent, nitric oxide donor, anti-coagulant, vascular cell growth promoting protein, vascular cell growth protein inhibitor, vascular cell growth antibody inhibitor, cholesterol lowering drug, vasodilating drug, protein that protects against cell death, cell cycle CDK protein inhibitor, anti-restenosis protein, agent for treating malignancies, bone morphogenic protein, a polynucleotide encoding any of the above named proteins or protein inhibitors, and a vector comprising a polynucleotide encoding any of the above named proteins or protein inhibitors.