Unit dose formulation of antidotes for factor xa inhibitors and methods of using the same

Abstract

The present invention relates unit dose formulations of antidotes to anticoagulants targeting factor Xa. Disclosed herein are methods of stopping or preventing bleeding in a patient that is currently undergoing anticoagulant therapy with a factor Xa inhibitor.

1 . A unit dose formulation comprising a pharmaceutically acceptable carrier and from about 10 milligrams to about 2 grams of a two-chain polypeptide comprising a first chain comprising the amino acid sequence of SEQ ID NO:14 or a first polypeptide having at least 90% sequence identity to SEQ ID NO:14, and a second chain comprising the amino acid sequence of SEQ ID NO:15 or a second polypeptide having at least 90% sequence identity to SEQ ID NO:15, wherein the two-chain polypeptide has reduced catalytic activity as compared to the wild-type factor Xa protein, and is capable to bind to the factor Xa inhibitor. 
     
     
         2 . The unit dose formulation of  claim 1 , having from about 100 milligrams to about 1.5 grams of the polypeptide. 
     
     
         3 . The unit dose formulation of  claim 2 , having from about 200 milligrams to about 1 gram of the polypeptide. 
     
     
         4 . The unit dose formulation of  claim 3 , having from about 400 milligrams to about 900 milligrams of the polypeptide. 
     
     
         5 . The unit dose formulation of  claim 1  wherein the polypeptide is effective in neutralizing a factor Xa inhibitor by at least about 20%. 
     
     
         6 . The unit dose formulation of  claim 5 , wherein the inhibitor is neutralized by at least about 50%. 
     
     
         7 . The unit dose formulation of  claim 6 , wherein the inhibitor is neutralized by at least about 75%. 
     
     
         8 . The unit dose formulation of  claim 7 , wherein the inhibitor is neutralized by at least about 90%. 
     
     
         9 . The unit dose formulation of  claim 8 , wherein the inhibitor is neutralized by at least about 95%. 
     
     
         10 . The unit dose formulation of  claim 5 , wherein the factor Xa inhibitor is selected from the group consisting of fondaparinux, idraparinux, biotinylated idraparinux, enoxaparin, fragmin, NAP-5, rNAPc2, tissue factor pathway inhibitor, DX-9065a, YM-60828, YM-150, apixaban, rivaroxaban, TAK-442, PD-348292, otamixaban, edoxaban, LY517717, GSK913893, razaxaban, low molecular weight heparin, betrixaban or a pharmaceutically acceptable salt thereof, and combinations thereof. 
     
     
         11 . The unit dose formulation of  claim 10 , wherein the factor Xa inhibitor is selected from the group consisting of betrixaban, rivaroxaban, apixaban, edoxaban, enoxaparin, low molecular weight heparin, and combinations thereof. 
     
     
         12 . The unit dose formulation of  claim 11 , wherein the factor Xa inhibitor is selected from the group consisting of betrixaban, rivaroxaban, apixaban, edoxaban, enoxaparin, and low molecular weight heparin. 
     
     
         13 - 14 . (canceled) 
     
     
         15 . The unit dose formulation of  claim 1 , wherein the carrier is saline. 
     
     
         16 . The unit dose formulation of  claim 15 , wherein the formulation has a concentration of from about 0.2 to about 10 milligrams of polypeptide per milliliter of saline. 
     
     
         17 . The unit dose formulation of  claim 16 , wherein the formulation has a concentration of about 2 to about 6 milligrams of polypeptide per milliliter of saline. 
     
     
         18 . The unit dose formulation of  claim 17 , wherein the formulation has a concentration of about 2 milligrams of polypeptide per milliliter of saline. 
     
     
         19 . The unit dose formulation of  claim 1  wherein the polypeptide is lyophilized. 
     
     
         20 - 31 . (canceled)