Ready-to-use bivalirudin compositions

Abstract

Ready-to-use bivalirudin compositions, methods of using the ready-to-use bivalirudin compositions, and methods of preparing the ready-to-use bivalirudin compositions. The ready-to-use bivalirudin compositions comprise bivalirudin and one or more stabilizing agents. The one or more stabilizing agents may be buffering agents having a pKa of about 2.5 to about 6.5, pH-adjusting agents, polymers, preservatives, antioxidants, sugars or polyols, or a combination thereof. The ready-to-use bivalirudin compositions may also comprise [9-10]-cycloimido bivalirudin, [11-12]-cycloimido bivalirudin, or a combination thereof. The method of using the ready-to-use bivalirudin compositions comprises administering the ready-to-use compositions to a patient in need thereof. Further, the method of preparing the ready-to-use bivalirudin compositions comprises mixing bivalirudin with one or more stabilizing agents.

1 - 20 . (canceled) 
     
     
         21 . A method of preparing an aqueous, injectable bivalirudin composition that has not been reconstituted from a lyophilizate comprising:
 (i) preparing a buffering agent having a pKa of about 2.5 to about 6.5;   (ii) mixing an amount of bivalirudin, or salts thereof, with the buffering agent to form a solution;   (iii) adding a pH-adjusting agent to the solution to adjust its pH to about 4 to less than 5;   (iv) transferring the solution into one or more containers, wherein the concentration of bivalirudin in the containers is about 1 mg/mL to about 10 mg/mL.   
     
     
         22 . The method of  claim 21 , wherein the bivalirudin in the containers is at a concentration of about 5 mg/mL. 
     
     
         23 . The method of  claim 21 , wherein the bivalirudin in the containers is at a concentration of about 10 mg/mL. 
     
     
         24 . The method of  claim 21 , wherein the buffering agent comprises acetate, tartrate, ascorbate, lactobionate, gentisate, succinate, lactate, α-lipoic acid, or any combination thereof. 
     
     
         25 . The method of  claim 24 , wherein the buffering agent is acetate. 
     
     
         26 . The method of  claim 21 , wherein the buffering agent has a pKa of about 3.5 to about 5. 
     
     
         27 . The method of  claim 26 , wherein the buffering agent has a pKa of about 4.2 to about 4.5. 
     
     
         28 . The method of  claim 21  wherein the pH-adjusting agent is an acid or base. 
     
     
         29 . The method of  claim 28 , wherein the pH-adjusting agent comprises acetic acid or sodium hydroxide. 
     
     
         30 . The method of  claim 21 , wherein the pH is adjusted to between about 4.2 and about 4.5. 
     
     
         31 . The method of  claim 21 , further comprising adding at least one preservative prior to transferring the solution in step (iv). 
     
     
         32 . The method of  claim 31 , wherein the preservative is methyl-paraben. 
     
     
         33 . The method of  claim 21 , further comprising adding at least one antioxidant prior to transferring the solution in step (iv). 
     
     
         34 . The method of  claim 33 , wherein the antioxidant is selected from a group consisting of histidine, methionine, and a combination thereof. 
     
     
         35 . The method of  claim 21 , further comprising sterilizing the solution prior to transferring the solution in step (iv). 
     
     
         36 . The method of  claim 35 , wherein the solution is sterilized through aseptic filtration. 
     
     
         37 . A method of preparing an aqueous, injectable bivalirudin composition that has not been reconstituted from a lyophilizate comprising:
 (v) dissolving a stabilizing agent selected from a group consisting of polymers, and sugars or polyols, in water;   (vi) mixing an amount of bivalirudin, or salts thereof, with the stabilizing agent to form a solution;   (vii) adding a pH-adjusting agent to the solution to adjust its pH to about 4 to less than 5;   (viii) transferring the solution into one or more containers, wherein the concentration of bivalirudin in the containers is about 1 mg/mL to about 10 mg/mL.   
     
     
         38 . The method of  claim 37 , wherein the bivalirudin in the containers is at a concentration of about 5 mg/mL. 
     
     
         39 . The method of  claim 37 , wherein the bivalirudin in the containers is at a concentration of about 10 mg/mL. 
     
     
         40 . The method of  claim 37 , wherein the polymers are selected from a group consisting of polyethylene glycol, poloxamer, polysorbates, hydroxyethyl starch, polyvinylpyrrolidone, and any combination thereof. 
     
     
         41 . The method of  claim 37 , wherein the sugars or polyols are selected from a group consisting of sucrose, dextrose, dextrin, propylene glycol, sorbitol, glycerol, and any combination thereof. 
     
     
         42 . The method of  claim 37 , wherein the pH-adjusting agent is an acid, base, or buffering agent. 
     
     
         43 . The method of  claim 42 , wherein the pH-adjusting agent comprises acetic acid or sodium hydroxide. 
     
     
         44 . The method of  claim 37 , wherein the pH is adjusted to between about 4.2 and about 4.5. 
     
     
         45 . The method of  claim 37 , further comprising adding at least one preservative prior to transferring the solution in step (iv). 
     
     
         46 . The method of  claim 45 , wherein the preservative is methyl-paraben. 
     
     
         47 . The method of  claim 37 , further comprising adding at least one antioxidant prior to transferring the solution in step (iv). 
     
     
         48 . The method of  claim 47 , wherein the antioxidant is selected from a group consisting of histidine, methionine, and a combination thereof. 
     
     
         49 . The method of  claim 37 , further comprising sterilizing the solution prior to transferring the solution in step (iv). 
     
     
         50 . The method of  claim 49 , wherein the solution is sterilized through aseptic filtration. 
     
     
         51 . Use of an aqueous, injectable composition that has not been reconstituted from a lyophilizate as an anticoagulant in a patient in need thereof, wherein the composition comprises:
 bivalirudin (SEQ ID NO: 1), or salts thereof, at a concentration of about 1 mg/mL to about 10 mg/mL;   (ii) one or more pharmaceutically acceptable stabilizing agents, wherein at least one of the stabilizing agents is a buffering agent having a pKa of about 2.5 to about 6.5;   (iii) a pH of about 4 to less than 5; and   (iv) total impurities in an amount less than about 15% area-under-the-curve (“AUC”) as determined by high performance liquid chromatography (“HPLC”) after storage at 25° C. for 1 month.   
     
     
         52 . The use of  claim 51 , wherein the patient is undergoing percutaneous coronary intervention (PCI). 
     
     
         53 . The use of  claim 52 , wherein the PCI is percutaneous transluminal coronary angioplasty. 
     
     
         54 . Use of an aqueous, injectable composition that has not been reconstituted from a lyophilizate for the prevention of venous thromboembolic disease, wherein the composition comprises:
 (i) bivalirudin (SEQ ID NO: 1), or salts thereof, at a concentration of about 1 mg/mL to about 10 mg/mL;   (ii) one or more pharmaceutically acceptable stabilizing agents, wherein at least one of the stabilizing agents is a buffering agent having a pKa of about 2.5 to about 6.5;   (iii) a pH of about 4 to less than 5; and   (v) total impurities in an amount less than about 15% area-under-the-curve (“AUC”) as determined by high performance liquid chromatography (“HPLC”) after storage at 25° C. for 1 month.   
     
     
         55 . Use of an aqueous, injectable composition that has not been reconstituted from a lyophilizate for the treatment of venous thromboembolic disease, wherein the composition comprises:
 (i) bivalirudin (SEQ ID NO: 1), or salts thereof, at a concentration of about 1 mg/mL to about 10 mg/mL;   (ii) one or more pharmaceutically acceptable stabilizing agents, wherein at least one of the stabilizing agents is a buffering agent having a pKa of about 2.5 to about 6.5;   (iii) a pH of about 4 to less than 5; and   (vi) total impurities in an amount less than about 15% area-under-the-curve (“AUC”) as determined by high performance liquid chromatography (“HPLC”) after storage at 25° C. for 1 month.   
     
     
         56 . Use of an aqueous, injectable composition that has not been reconstituted from a lyophilizate for the treatment in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty, wherein the composition comprises:
 (i) bivalirudin (SEQ ID NO: 1), or salts thereof, at a concentration of about 1 mg/mL to about 10 mg/mL;   (ii) one or more pharmaceutically acceptable stabilizing agents, wherein at least one of the stabilizing agents is a buffering agent having a pKa of about 2.5 to about 6.5;   (iii) a pH of about 4 to less than 5; and   (vii) total impurities in an amount less than about 15% area-under-the-curve (“AUC”) as determined by high performance liquid chromatography (“HPLC”) after storage at 25° C. for 1 month.   
     
     
         57 . Use of an aqueous, injectable composition that has not been reconstituted from a lyophilizate with a glycoprotein IIb/IIIa inhibitor for treating patients undergoing percutaneous coronary intervention, wherein the composition comprises:
 (i) bivalirudin (SEQ ID NO: 1), or salts thereof, at a concentration of about 1 mg/mL to about 10 mg/mL;   (ii) one or more pharmaceutically acceptable stabilizing agents, wherein at least one of the stabilizing agents is a buffering agent having a pKa of about 2.5 to about 6.5;   (iii) a pH of about 4 to less than 5; and   (viii) total impurities in an amount less than about 15% area-under-the-curve (“AUC”) as determined by high performance liquid chromatography (“HPLC”) after storage at 25° C. for 1 month.   
     
     
         58 . Use of an aqueous, injectable composition that has not been reconstituted from a lyophilizate for treating patients with, or at risk of, heparin-induced thrombocytopenia or heparin-induced thrombosis-thrombocytopenia syndrome undergoing percutaneous coronary intervention, wherein the composition comprises:
 (i) bivalirudin (SEQ ID NO: 1), or salts thereof, at a concentration of about 1 mg/mL to about 10 mg/mL;   (ii) one or more pharmaceutically acceptable stabilizing agents, wherein at least one of the stabilizing agents is a buffering agent having a pKa of about 2.5 to about 6.5;   (iii) a pH of about 4 to less than 5; and   (ix) total impurities in an amount less than about 15% area-under-the-curve (“AUC”) as determined by high performance liquid chromatography (“HPLC”) after storage at 25° C. for 1 month.