Method of drug delivery to interstitial regions of the myocardium

Abstract

A method of treating the heart and other body tissues by injecting a compound comprised of microsphere encapsulated macromolecule therapeutic agents into the myocardium, such that the microsphere size inhibits capillary transport of the compound but may permit lymphatic transport of the compound, and the compound releases therapeutic agents upon degradation of the microsphere. The compounds may be used in a method of treating the coronary arteries in which lymphatic transportable therapeutic agents are injected into the myocardium at a location distal to a target site in the coronary artery, after which they are taken up by the lymphatic vessels and transported proximally relative to the coronary artery, and migrate from the lymphatic vessel to the coronary blood vessel.

We claim:  
     
         1 . A system for delivering a drug to the heart of a patient, said system comprising: 
 a catheter capable of delivering a plurality of liposomes to the heart of the patient;    a source of liposomes adapted for fluid communication with the catheter, said source containing a plurality of liposomes, and wherein each of the plurality of liposomes has a half-life within the body of the patient of less than about sixty minutes; and    a drug encased within at least one of the plurality of liposomes.    
     
     
         2 . A system for delivering an agent to the heart of a patient, said system comprising: 
 a catheter capable of delivering a microsphere to the heart of the patient;    a source of microspheres adapted for fluid communication with the catheter, said source containing the microsphere;    wherein the agent is disposed within the microsphere;    wherein the agent is adapted to be taken-up by the lymphatic system of the heart, transported proximally relative to a coronary artery of the heart, and thereafter to migrate from the lymphatic system into the coronary artery at a site proximal from a location of injection.    
     
     
         3 . The system of  claim 2  wherein the agent comprises a liposome, wherein a drug is dispersed within the liposome.  
     
     
         4 . The system of  claim 2  wherein the agent comprises a drug.  
     
     
         5 . The system of  claim 2  wherein the agent comprises a therapeutic agent.  
     
     
         6 . The system of  claim 2  wherein the microsphere comprises a degradable material and wherein the agent comprises a drug dispersed within the degradable material, and wherein the microsphere is degradable within the myocardium, said microsphere being sized and dimensioned, at the time of injection, to inhibit take-up into the lymphatic system of the heart, said microsphere being degradable over time to release the drug into the myocardium, wherein the molecules of the drug are capable of take-up in the lymphatic system of the heart.  
     
     
         7 . The system of  claim 6  wherein the microsphere further comprises: 
 a first layer and a second layer, said first layer being at or near the surface of the microsphere, said second layer being inside the first layer;  
 wherein the drug comprises a first drug disposed within the first layer.  
 
     
     
         8 . The system of  claim 7  further comprising a second drug disposed within the second layer of the microsphere.  
     
     
         9 . The system of  claim 8  wherein the first drug comprises an anti-angiogenic agent and the second drug comprises an angiogenic agent.  
     
     
         10 . A system for delivering a therapeutic agent to the heart of a patient, said system comprising: 
 a catheter capable of delivering the therapeutic agent to the heart of the patient;    a source of agents adapted for fluid communication with the catheter, said source containing the therapeutic agent;    wherein the therapeutic agent is in the form of a plurality of microspheres which are degradable in the body, said plurality of microspheres comprising a first group of microspheres sized to permit entry into the lymphatic system in a first time period, and a second group of microspheres sized to inhibit entry into the lymphatic system in the first time period.    
     
     
         11 . The system of  claim 10  wherein the first group of microspheres is loaded with an anti-angiogenic agent and the second group of microspheres is loaded with an angiogenic agent.  
     
     
         12 . An infusion system for delivering a drug to the heart of a patient, said system comprising: 
 an infusion device adapted for implantation within the body of the patient, said infusion device capable of delivering a liposome to the heart of the patient, and said infusion system operably connected to the heart of the patient;    wherein the drug is encased within the liposome, the liposome having a half-life within the body of the patient of less than about sixty minutes, the liposome disposed such that the infusion device may deliver the liposome.    
     
     
         13 . The infusion system of  claim 12  wherein the liposome is sized and dimensioned to allow the liposome to be taken-up by the lymphatic system of the heart.  
     
     
         14 . A method of treating cardiac arrhythmia in a patient, said method comprising the steps of: 
 providing an infusion system for delivering an anti-arrhythmic agent to the heart of the patient, said system comprising: 
 an infusion device adapted for implantation within the body of the patient, said infusion device capable of delivering a liposome to the heart of the patient, and said infusion system operably connected to the heart of the patient;  
 wherein the anti-arrhythmic agent is encased within the liposome, the liposome having a half-life within the body of the patient of less than about sixty minutes, the liposome disposed such that the infusion device may deliver the liposome;  
   implanting the infusion device within the body of the patient; and    delivering the liposome to the heart of the patient with the infusion system.    
     
     
         15 . The method of  claim 14  wherein: 
 the step of providing an infusion system further comprises providing an infusion system wherein the liposome is sized and dimensioned to allow uptake of the liposome by the lymphatic system of the heart;  
 the step of delivering the liposome further comprises delivering the liposome to the wall of a ventricle of the heart; and  
 the method further comprises allowing the lymphatic system of the heart to transport the liposome to the wall of an atrium of the heart.  
 
     
     
         16 . A method of treating the heart of a patient, said method comprising the steps of: 
 delivering a dose of a first macromolecular agent to a depth within the heart muscle, said dose delivered in the form of a first plurality of microspheres encapsulating molecules of the first macromolecular agent; and    controlling the release of the molecules of the first macromolecular agent from the first plurality of microspheres.    
     
     
         17 . The method of  claim 16  wherein the step of delivering a dose of a first macromolecular agent comprises delivering a dose of an angiogenic agent.  
     
     
         18 . The method of  claim 16  comprising the further steps of: 
 delivering a dose of a second macromolecular agent to a depth within the heart muscle, said dose delivered in the form of a second plurality of microspheres encapsulating molecules of the second macromolecular agent; and  
 controlling the release of the molecules of the second macromolecular agent from the second plurality of microspheres.  
 
     
     
         19 . The method of  claim 18  wherein the step of delivering a dose of a first macromolecular agent comprises delivering a dose of an angiogenic agent and the step of delivering a dose of a second macromolecular agent comprises delivering a dose of an anti-inflammatory steroid.