Concentrated injectable tranexamic acid compositions and methods of use thereof

Abstract

Concentrated tranexamic acid compositions suitable for intramuscular administration via auto-injector are provided. Methods of treating non-compressible hemorrhage are also provided. Kits and auto-injectors comprising the tranexamic acid compositions are further provided.

1 . A ready-to-use injectable pharmaceutical composition comprising a therapeutically effective amount of tranexamic acid or a pharmaceutically acceptable salt thereof, the composition having a pH of no more than about pH 5.0. 
     
     
         2 . The pharmaceutical composition according to  claim 1 , having a pH in a range of from about pH 3.0 to about pH 5.0, from about pH 3.0 to about pH 4.5, or from about pH 3.0 to about pH 4.0. 
     
     
         3 . The pharmaceutical composition according to  claim 1 , comprising at least about 200 mg/mL of the tranexamic acid or pharmaceutically acceptable salt thereof. 
     
     
         4 . The pharmaceutical composition according to  claim 3 , comprising from about 200 mg/mL to about 600 mg/mL, about 300 mg/mL to about 550 mg/mL, about 400 mg/mL to about 550 mg/mL, about 450 mg/mL to about 550 mg/mL, about 475 mg/mL to about 525 mg/mL, or about 400 mg/mL, about 425 mg/mL, about 450 mg/mL, about 475 mg/mL, about 500 mg/mL, about 525 mg/mL, about 550 mg/mL, about 575 mg/mL, or about 600 mg/mL of the tranexamic acid or pharmaceutically acceptable salt thereof in solution. 
     
     
         5 . The pharmaceutical composition according to  claim 1 , wherein the composition is an aqueous solution that requires no dilution before administration. 
     
     
         6 . The pharmaceutical composition according to  claim 1 , comprising one or more additives selected from the group consisting of pH adjuster, tonicity agent, anesthetic, buffer, solvent, preservative, carrier, and colorant. 
     
     
         7 . The pharmaceutical composition according to  claim 6 , wherein the pH adjuster is hydrochloric acid. 
     
     
         8 . The pharmaceutical composition according to  claim 6 , wherein the tonicity agent is selected from the group consisting of sodium chloride, glycerin, mannitol, dextrose, and trehalose. 
     
     
         9 . The pharmaceutical composition according to  claim 8 , having a tonicity in a range of between about 270 to about 340 mOsm/kg. 
     
     
         10 . The pharmaceutical composition according to  claim 6 , wherein the anesthetic is benzyl alcohol. 
     
     
         11 . The pharmaceutical composition according to  claim 6 , wherein the solvent is selected from the group consisting of ethyl alcohol, isopropyl alcohol, methanol, polyethylene glycol, propylene glycol, benzyl benzoate, dimethyl sulfoxide, dimethyl formamide, acetone, acetonitrile, butanone, and solketal. 
     
     
         12 . The pharmaceutical composition according to  claim 6 , wherein the carrier is selected from an albumin, and a cyclodextrin. 
     
     
         13 . The pharmaceutical composition according to  claim 1 , wherein the composition does not include liposomes. 
     
     
         14 . A pharmaceutical composition for parenteral administration comprising a ready-to-use aqueous solution with a pH in a range of from about pH 3.0 to about pH 5.0 comprising: from 300 to about 600 mg/mL tranexamic acid or a pharmaceutically acceptable salt thereof; and a pH adjuster in an amount to provide initial pH from about pH 3.0 to about pH 5.0. 
     
     
         15 . The pharmaceutical composition according to  claim 14 , having a pH in a range of from about 3 to about 4.5, or about 3.0 to about 4.0, comprising: from about 450 to about 550 mg/mL tranexamic acid or a pharmaceutically acceptable salt thereof; and a pH adjuster in an amount to provide initial pH from about 3.5 to about 4.5. 
     
     
         16 . The pharmaceutical composition according to  claim 14 , further comprising a tonicity agent, optionally wherein the tonicity agent is about 0.9% (w/v) sodium chloride. 
     
     
         17 . The pharmaceutical composition according to  claim 14 , further comprising from about 2% to about 6%, about 3% to about 5%, or about 3.5% to about 4.5% (v/v) benzyl alcohol. 
     
     
         18 . The pharmaceutical composition according to  claim 14 , wherein the composition requires no dilution before administration. 
     
     
         19 . The pharmaceutical composition according to  claim 14 , wherein the composition when stored for 6 months at 25° C. at 60% RH is capable of maintaining:
 a pH within about ±0.5 points compared to starting pH at t=0; and 
 a concentration of tranexamic acid within ±10% of the starting concentration at t=0. 
 
     
     
         20 . The pharmaceutical composition according to  claim 14 , wherein the composition when stored for 6 months at 40° C. at 75% RH is capable of maintaining:
 a pH within about ±0.5 points compared to starting pH at t=0; and 
 a concentration of tranexamic acid within ±10% of the starting concentration at t=0. 
 
     
     
         21 . The pharmaceutical composition according to  claim 1 , wherein the pharmaceutical composition is an intramuscular pharmaceutical composition. 
     
     
         22 . Use of the pharmaceutical composition according to  claim 1  for manufacture of a medicament for treating hemorrhage in a subject in need thereof. 
     
     
         23 . A method of treating hemorrhage in a subject in need thereof, comprising parenterally administering an effective amount of the pharmaceutical composition according to  claim 1 . 
     
     
         24 . The method according to  claim 23 , wherein the administering comprises intramuscular administration. 
     
     
         25 . The method according to  claim 23 , wherein the subject exhibits onset of a tranexamic acid plasma concentration of at least about 15 ug/mL within about 7 minutes, or within about 10 minutes, following intramuscular administration of the composition comprising at least about 1.0 g of the tranexamic acid or a pharmaceutically acceptable salt thereof. 
     
     
         26 . The method according to  claim 23 , wherein the subject exhibits a tranexamic acid plasma concentration of at least about 15 ug/mL for at least about 100 min, at least about 110 min, or at least about 120 min following intramuscular administration of the composition comprising at least about 1.0 g of the tranexamic acid or a pharmaceutically acceptable salt thereof. 
     
     
         27 . The method according to  claim 23 , wherein the subject exhibits a tranexamic acid plasma Cmax of no more than about 40 ug/mL, or no more than about 37 ug/mL, following intramuscular administration of the composition comprising about 1.0 g of the tranexamic acid or a pharmaceutically acceptable salt thereof. 
     
     
         28 . An auto-injector arrangement, comprising:
 an auto-injector comprising an injector body housing the pharmaceutical composition according to  claim 1 .   
     
     
         29 .- 34 . (canceled) 
     
     
         35 . An auto-injector arrangement, comprising:
 an auto-injector comprising an injector body housing a ready-to-mix pharmaceutical composition comprising a therapeutically effective amount of tranexamic acid or a pharmaceutically acceptable salt thereof; and an aqueous diluent which when mixed with the ready-to-mix composition is capable of forming an injectable pharmaceutical composition according to  claim 21 .   
     
     
         36 .- 41 . (canceled) 
     
     
         42 . A kit comprising a prefilled aseptic primary container comprising the pharmaceutical composition according to  claim 1 , and optionally a sheet of instructions.