Formulations of Terlipressin

Abstract

The disclosure provides pharmaceutical compositions comprising terlipressin having increased concentration with long term storage stability.

1 . An aqueous composition comprising terlipressin acetate or a pharmaceutically acceptable salt thereof in an amount of about 0.5 mg/mL to about 10.0 mg/mL and an aspartic acid stabilizing agent, wherein the pH of the composition is from about 3.4 to about 5.0. 
     
     
         2 . The composition of  claim 1 , wherein the composition has a sum of impurities of less than 5.0% of the total weight of the impurities and terlipressin in the composition. 
     
     
         3 . The composition of  claim 1 , wherein the composition is stable at about room temperature for about 12 months to about 24 months or longer. 
     
     
         4 . The composition of  claim 1 , wherein the composition is stable at about 25° C. to about 30° C. for about 6 months. 
     
     
         5 . The composition of  claim 1 , wherein the composition is stable at about 40° C. for about 3 months. 
     
     
         6 . The composition of  claim 1 , wherein the terlipressin acetate or a pharmaceutically acceptable salt thereof is in an amount of about 1.0 mg/mL. 
     
     
         7 . The composition of  claim 1 , wherein the aspartic acid is in an amount of about 0.1 mg/ml to about 2 mg/ml. 
     
     
         8 . The composition of  claim 1 , wherein the composition further comprises an isotonicity agent. 
     
     
         9 . The composition of  claim 8 , wherein the isotonicity agent is sodium chloride. 
     
     
         10 . The composition of  claim 1 , wherein the composition further comprises a pH adjusting agent. 
     
     
         11 . The composition of  claim 10 , wherein the pH adjusting agent is hydrochloric acid, potassium hydroxide, acetic acid, sodium hydroxide, or potassium hydroxide. 
     
     
         12 . The composition of  claim 1 , wherein the composition further comprises an anti-microbial preservative. 
     
     
         13 . A container comprising the composition of  claim 1 . 
     
     
         14 . The container of  claim 13 , wherein the container is a syringe, a vial, a bottle, an ampule, a cartridge, or a bag. 
     
     
         15 . The container of  claim 13 , wherein a head space within the container optionally comprises nitrogen. 
     
     
         16 . The container of  claim 14 , wherein the syringe is a pre-filled syringe. 
     
     
         17 . A kit comprising the composition of  claim 1 , wherein the kit comprises a container for the composition and instructions for administering the composition. 
     
     
         18 . The kit of  claim 17 , the container optionally has a means for injecting the composition into a subject. 
     
     
         19 . The kit of  claim 17 , wherein the container is a syringe, a vial, a bottle an ampule, a cartridge, or a bag. 
     
     
         20 . The kit of  claim 17 , wherein the instructions provide administering the composition by continuous infusion or as a bolus intravenous dose. 
     
     
         21 . An aqueous composition comprising terlipressin or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvent, an aspartic acid stabilizing agent, an isotonicity agent, an anti-microbial preservative, and one or more pH adjusting agents, wherein the composition comprises from 0.2 mg/mL to 10.0 mg/mL terlipressin or a pharmaceutically acceptable salt thereof, wherein the composition has a pH from about 3.4 to about 5.0, wherein the composition has a sum of impurities of less than about 5.0% of the total weight of the impurities and the terlipressin or a pharmaceutically acceptable salt thereof in the composition after storage at about 40° C. and about 75% relative humidity for 12 weeks. 
     
     
         22 . The composition of  claim 21 , wherein the pharmaceutically acceptable solvent is water. 
     
     
         23 . The composition of  claim 21 , wherein the pH adjusting agent is acetic acid, hydrochloric acid or sodium hydroxide. 
     
     
         24 . The composition of  claim 21 , wherein the aspartic acid is in an amount of about 0.1 mg/ml to about 2 mg/ml. 
     
     
         25 . The composition of  claim 21 , wherein the isotonicity agent is sodium chloride. 
     
     
         26 . An aqueous composition comprising from about 0.2 to about 10.0 mg/mL terlipressin acetate or a pharmaceutically acceptable salt thereof, an aspartic acid stabilizing agent, and a sum of impurities of less than 5.0% of the total weight of the impurities and terlipressin in the composition, wherein the pH of the composition is from about 3.4 to about 5.0. 
     
     
         27 . The composition of  claim 26 , wherein the aspartic acid is in an amount of about 0.1 mg/ml to about 2 mg/ml. 
     
     
         28 . The composition of  claim 26 , wherein the composition optionally comprises an isotonicity agent. 
     
     
         29 . The composition of  claim 26 , wherein the composition optionally comprises a pH adjusting agent. 
     
     
         30 . The composition of  claim 26 , wherein the composition further comprises an anti-microbial preservative.