Formulations for Tailored Drug Release

Abstract

The present invention provides formulations comprising polymers and therapeutics and methods for their manufacture. The present invention also provides medical devices coated with such formulations and methods for their manufacture. The drug-loaded polymer formulations, solutions, and films tailor the drug release characteristics for medical devices.

We claim: 
     
         1 . A formulation comprising:
 a biocompatible hydrophilic polymer having a thickness of between about 1 μm and about 1 mm and an elastic modulus of between about 0.05 MPa and about 1000 MPa; and   a therapeutic disposed within the hydrophilic polymer,   wherein the polymer provides for release of about 0% to about 30% the therapeutic within about 1 minute after introduction of the formulation into physiological conditions, and wherein the polymer provides for release of at least about 50% to about 100% of the therapeutic within about 20 minutes after introduction of the formulation into physiological conditions.   
     
     
         2 . The formulation of  claim 1  wherein the release is measured using high performance liquid chromatography (HPLC). 
     
     
         3 . The formulation of  claim 1 , wherein the polymer comprises poly(ethylene oxide) (PEO), heparin, dextran, dextran sulfate (DS), polyethylene glycol (PEG), butyryl trihexyl citrate (BTC), heparin sulfate (HS), hyaluronic acid (HA), chondroitin sulfate (CS), or combinations thereof. 
     
     
         4 . The formulation of  claim 1 , wherein the polymer is present at a concentration of between about 1 μg/mm 2  and 2000 μg/mm 2 . 
     
     
         5 . The formulation of  claim 1 , wherein the polymer thickness is between about 50 μm and about 500 μm. 
     
     
         6 . The formulation of  claim 1 , wherein the polymer is PEO, and wherein the PEO has an average molecular weight range of between about 100 Da and about 10,000,000 Da. 
     
     
         7 . A formulation comprising:
 poly(ethylene oxide) (PEO) having (a) a thickness of between about 1 μm and about 1 mm; (b) an average molecular weight range of between about 50,000 and about 200,000; and (c) an elastic modulus of between about 0.05 MPa and about 1000 MPa; and   a therapeutic disposed within the PEO.   
     
     
         8 . The formulation of  claim 1 , wherein the polymer comprises DS, and wherein the DS has an average molecular weight of between about 100 Da and about 10,000,000 Da. 
     
     
         9 . The formulation of  claim 8 , wherein the DS has an average molecular weight of between about 100,000 Da and about 1,000,000 Da. 
     
     
         10 . A formulation comprising:
 dextran sulfate (DS) having (a) a thickness of between about 1 μm and about 1 mm; (b) an average molecular weight range of between about 100,000 Da and about 1,000,000 Da; and (c) an elastic modulus of between about 0.05 MPa and about 1000 MPa; and   a therapeutic disposed within the DS.   
     
     
         11 . The formulation of  claim 1 , wherein the polymer comprises a single polymer layer, and wherein the polymer provides for release of about 1% to about 30% of the therapeutic within about one minute after introduction of the formulation into physiological conditions, and release of at least about 50% to about 100% of the therapeutic within 4-12 minutes after introduction of the formulation into physiological conditions. 
     
     
         12 . The formulation of  claim 11 , wherein the polymer is between about 10 μm and about 500 μm in thickness. 
     
     
         13 . The formulation of  claim 1 , wherein the polymer comprises a plurality of polymer layers including at least a first polymer layer and a second polymer layer, wherein the first polymer layer provides for release of about 10% to about 60% of the therapeutic within about 4 minutes after introduction of the formulation into physiological conditions, and the second polymer layer provides for release of at least about another 10% to about 60% of the therapeutic within 8 minutes after introduction of the formulation into physiological conditions. 
     
     
         14 . The formulation of  claim 13 , wherein the polymer further comprises a third polymer layer, wherein the third polymer layer provides for release of at least about another about 10% to about 60% of the therapeutic within about 12 minutes after introduction of the formulation into physiological conditions. 
     
     
         15 . The formulation of  claim 13 , wherein each polymer layer comprises the same polymer. 
     
     
         16 . The formulation of  claim 15 , wherein each polymer layer comprises PEO or DS 
     
     
         17 . The formulation of  claim 11 , wherein the formulation further comprises an inert polymer layer disposed over the single polymer layer. 
     
     
         18 . The formulation of  claim 13 , wherein the formulation further comprises an inert polymer layer disposed between the first polymer layer and the second polymer layer. 
     
     
         19 . The formulation of  claim 17 , wherein the inert layer is between about 0.1 μm and about 50 μm in thickness. 
     
     
         20 . The formulation of  claim 1 , wherein the polymer further comprises a plasticizer and/or an excipient. 
     
     
         21 . The formulation of  claim 1 , wherein the therapeutic comprises paclitaxel and/or paclitaxel albumin bound particles. 
     
     
         22 . A medical device comprising the formulation of  claim 1  disposed on a surface of the medical device. 
     
     
         23 . A medical device comprising an array of the formulation of  claim 1  on a surface of the medical device, wherein the array comprises:
 one or more positions comprising a first formulation position; and 
 one or more positions comprising a second formulation position; 
 wherein the first formulation position provides for release of about 10% to about 60% of the therapeutic within about 4 minutes after introduction of the formulation into physiological conditions, and the second formulation position provides for release of at least about another about 10% to about 60% of the therapeutic within about 8 minutes after introduction of the formulation into physiological conditions. 
 
     
     
         24 . The medical device of  claim 23 , wherein the array further comprises one or more positions comprising a third formulation position, wherein third formulation position provides for release of at least about another 10% to about 60% of the therapeutic within about 12 minutes after introduction of the formulation into physiological conditions. 
     
     
         25 . The medical device of  claim 24 , wherein each formulation position comprises the same polymer, wherein the concentration of the polymer in the first formulation position is less than the concentration of the polymer in the second formulation position, and wherein the concentration of the polymer in the second formulation position is less than the concentration of the polymer in the third formulation position. 
     
     
         26 . The medical device of  claim 22 , wherein the medical device is selected from the group consisting of: balloon catheters, drug-eluting stents, vascular grafts, heart valves, pacemakers, artificial heart, ventricular assist devices, cardiopulmonary bypass, orthopedic devices, fracture fixation devices, dental devices, neural devices, stent grafts, heart-lung machines, hemodialysis machines, ocular implants and devices, and cochlear implants and devices. 
     
     
         27 . The medical device of  claim 22 , wherein the medical device comprises a balloon portion of a balloon catheter. 
     
     
         28 . The medical device of  claim 27 , wherein the polymer comprises a single layer of PEO or DS, and wherein the thickness of the PEO layer or the DS layer is between about 50 μm and about 500 μm, and wherein the therapeutic comprises paclitaxel and/or paclitaxel albumin bound particles. 
     
     
         29 . A method of using the medical device of  claim 27 , wherein the method comprises:
 inflating the balloon at a first location in a target blood vessel in a subject in need thereof for a first time period such that a first amount of the therapeutic is delivered to the first location in the target vessel;   deflating the balloon and moving the balloon catheter to a second location in the target blood vessel; and   inflating the balloon at the second location for a second time period such that a second amount of the therapeutic is delivered to the second location in the target vessel.   
     
     
         30 . The method of  claim 29 , wherein the subject is suffering from one or more of coronary artery disease, peripheral vascular disease, carotid artery disease, or cerebral artery disease.