System and method for delivering protease inhibitors

Abstract

The disclosed invention provides a system and method of artificially retarding fibrin-based blood clot degradation via the sustained release of a protease inhibitor, such as, for example, aprotinin or tranexamic acid (“TA”). The sustained release of the protease inhibitor is accomplished through incorporation within a biodegradable polymer microsphere to produce a protease inhibitor formulation. Next, the formulation along with fibrinogen and thrombin is applied to a wound site where an outer surface of the polymer microsphere degrades in a proteolytic environment to expose and release the incorporated protease inhibitor to the surrounding hydrogel or sealant or clot matrix at the wound site.

The embodiment of the invention in which an exclusive property or privilege is claimed is defined as follows: 
     
         1 . A system for delaying fibrinolytic degradation of a hydrogel or sealant at a surgical wound site in presence of fibrinogen and thrombin, the system comprising:
 a.) a protease inhibitor; and   b.) an injectable biodegradable microsphere which provides a sustained release mechanism of said protease inhibitor in a proteolytic environment.   
     
     
         2 . The system of  claim 1  wherein the protease inhibitor is an organic compound selected from the group consisting of aprotinin, tranexamic acid, salts of tranexamic acid, and combinations thereof. 
     
     
         3 . The system of  claim 1  wherein the microsphere is a polymer selected from the group consisting of lactic acid, glycolic acid, caprolactone, and combinations thereof. 
     
     
         4 . The system of  claim 1  wherein the protease inhibitor is a calcium salt of tranexamic acid. 
     
     
         5 . An in vivo method for delaying fibrin-based blood clot degradation, the method comprising the steps of:
 a.) substantially encapsulating a protease inhibitor formulation within a biodegradable microsphere;   b.) combining the microsphere with fibrinogen and thrombin to form a mixture; and   c.) contacting the mixture to a surgical wound site, for a time sufficient to degrade the microsphere and cause the inhibitor to release the encapsulated protease inhibitor from the microsphere, whereby the site defines a proteolytic environment.   
     
     
         6 . The method claimed in  claim 5 , wherein the biodegradable microsphere is a polymer of monomers selected from the group consisting of lactic acid, glycolic acid, caprolactone and combinations thereof. 
     
     
         7 . The method of  claim 5 , wherein microsphere powder is delivered concomitant with a blend of fibrinogen powder and thrombin powder. 
     
     
         8 . The method as recited in  claim 5  wherein the fibrinogen and thrombin powder preexist at the surgical wound site. 
     
     
         9 . The method of  claim 5 , wherein the protease inhibitor is tranexamic acid. 
     
     
         10 . The method of  claim 5 , wherein the protease inhibitor is aprotinin. 
     
     
         11 . The method of  claim 5 , wherein the protease inhibitor formulation is a powder and is applied to the surgical wound site through a non-woven surgical mesh. 
     
     
         12 . The method of  claim 11 , wherein the protease inhibitor formulation powder is hydrated from water found in blood to form a clot. 
     
     
         13 . The method of  claim 5 , wherein the protease inhibitor formulation is a powder suspended in a thrombin solution and is applied to the wound site through a syringe. 
     
     
         14 . The method claimed in  claim 8 , wherein tranexamic acid comprises an organic-acid salt of tranexamic acid containing a cation selected from the group consisting of calcium, strontium, barium, zinc, and ferrous ions. 
     
     
         15 . The method claimed in  claim 8  wherein application of calcium tranexamate to a bleeding site contributes to swelling of a surrounding matrix thereby assisting improved hemostasis. 
     
     
         16 . The method claimed in  claim 6 , wherein an absorbable biodegradable polymer degradation time may be modified by altering a ratio of original monomers units in the polymer. 
     
     
         17 . The method claimed in  claim 5 , wherein release rate may be influenced by adjusting percent loading of the protease inhibitor in the absorbable polymer microsphere. 
     
     
         18 . A process for producing a calcium tranexamate comprising: mixing a methanolic solution of calcium nitrate and a solution of potassium tranexamate. 
     
     
         19 . The process claimed in  claim 18 , wherein the produced calcium tranexamate is made from tranexamic acid and solid potassium hydroxide dissolved in anhydrous methanol. 
     
     
         20 . The process claimed in  claim 18 , wherein the produced calcium tranexamate compound is a water soluble white powder.