Stabilized Aqueous Compositions of Neuromuscular Blocking Agents

Abstract

The present invention relates to an aqueous composition comprising: (i) a quaternary ammonium neuromuscular blocking agent; and (ii) an excipient selected from a polyhydroxy acid of the following formula: HO—CH 2 —[CH(OH)] n —COOH, wherein n is an integer from 1 to 8, an intramolecular lactone of said polyhydroxy acid or a mixture thereof. Furthermore the present invention relates to a liquid pharmaceutical composition comprising or consisting of said aqueous composition and a method for producing said aqueous composition comprising the steps of: a) providing a quaternary ammonium neuromuscular blocking agent wherein said quaternary ammonium neuromuscular blocking agent is optionally freeze-dried, b) providing an excipient selected from a polyhydroxy acid of the following formula: HO—CH 2 —[CH(OH)] n —COOH, wherein n is an integer from 1 to 8, an intramolecular lactone of said polyhydroxy acid or a mixture thereof, wherein said excipient is optionally freeze-dried, c) mixing the quaternary ammonium neuromuscular blocking agent of step a) and the excipient of step b) in water to give an aqueous composition. In addition, the present invention relates to the use of a polyhydroxy carboxylic acid of the following formula: HO—CH 2 —[CH(OH)] n —COOH, wherein n is an integer from 1 to 8, an intramolecular lactone of said polyhydroxy acid or a mixture thereof for stabilizing an aqueous composition comprising a quaternary ammonium neuromuscular blocking agent. The present invention also refers to a container containing the aqueous composition or the liquid pharmaceutical composition of the present invention. It furthermore relates to a kit comprising said compositions. Preferred embodiments are apparent from the dependent claims.

1 . An aqueous composition comprising:
 (i) a quaternary ammonium neuromuscular blocking agent; and   (ii) an excipient selected from a polyhydroxy acid of the following formula: HO—CH 2 —[CH(OH)] n —COOH, wherein n is an integer from 1 to 8, an intramolecular lactone of said polyhydroxy acid or a mixture thereof.   
     
     
         2 . The aqueous composition of  claim 1 , wherein the quaternary ammonium neuromuscular blocking agent is a compound of the following formula: 
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 3  are independently selected from tertiary amines and quaternary ammonium groups, preferably, R 1  and R 3  are independently selected from cyclic tertiary amines and cyclic quaternary ammonium groups wherein the cycle optionally further contains one or more heteroatoms selected from nitrogen, oxygen or sulfur, more preferably R 1  and R 3  are substituents of one of the following formulas: 
       
         
           
           
               
               
           
         
       
       wherein m is an integer from 1 to 5, X═CH 2 , NR 7 , N + R 7 R 8 , O or S (wherein R 7  and R 8  are independently H or C 1 -C 4  alkyl, preferably H or Me) and R 5 ═C 1 -C 10 -alkyl or C 2 -C 10 -alkenyl; preferably m=1 or 2, X═CH 2 , NR 7 , N + R 7 R 8  or O (wherein R 7  and R 8  are independently H or C 1 -C 4  alkyl) and R 5 =methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, vinyl, allyl or butenyl; R 2  and R 4  are independently selected from hydroxyl or 
       
         
           
           
               
               
           
         
       
       wherein R 6  is a C 1 -C 10  alkyl, with the proviso that at least one of R 2  or R 4  is 
       
         
           
           
               
               
           
         
       
     
     
         3 . The aqueous composition of  claim 1 , wherein the quaternary ammonium neuromuscular blocking agent is a Rocuronium salt and the excipient is selected from D-gluconic acid, an intramolecular lactone of D-gluconic acid, preferably D-glucono-delta-lactone, or a mixture thereof. 
     
     
         4 . The aqueous composition of  claim 1 , wherein the excipient is a mixture of D-gluconic acid and an intramolecular lactone thereof, preferably D-glucono-delta-lactone. 
     
     
         5 . The aqueous composition of  claim 1 , further comprising a buffering agent, wherein the buffering agent is preferably selected from a buffer based on citrate, acetate, phosphate or a combination thereof, preferably a buffer based on citrate and acetate. 
     
     
         6 . A liquid pharmaceutical composition comprising or consisting of the aqueous composition of  claim 1 . 
     
     
         7 . The liquid pharmaceutical composition of  claim 6  for use in anesthesia or for use as a muscle relaxant. 
     
     
         8 . A method for producing an aqueous composition of  claim 1  comprising the steps of:
 a) providing a quaternary ammonium neuromuscular blocking agent wherein said quaternary ammonium neuromuscular blocking agent is optionally freeze-dried, 
 b) providing an excipient selected from a polyhydroxy acid of the following formula: HO—CH 2 —[CH(OH)] n —COOH, wherein n is an integer from 1 to 8, an intramolecular lactone of said polyhydroxy acid or a mixture thereof, wherein said excipient is optionally freeze-dried, 
 c) mixing the quaternary ammonium neuromuscular blocking agent of step a) and the excipient of step b) in water to give an aqueous composition. 
 
     
     
         9 . The method of  claim 8 , wherein the concentration of the quaternary ammonium neuromuscular blocking agent is in the range of 1 to 100 mg/mL, preferably, 5 to 50 mg/mL, most preferably 5 to 15 mg/mL and the concentration of the excipient is in the range of 1 to 100 mg/mL, preferably 5 to 50 mg/mL, most preferably 15 to 30 mg/mL based on the total volume of the aqueous composition. 
     
     
         10 . The method of  claim 8  further comprising:
 adding a buffer agent, preferably a buffer based on citrate and acetate, 
 adjusting the pH value of the aqueous composition, preferably to a range of 2.0 to 7.0, more preferably from 3.0 to 5.0, most preferably from 3.8 to 4.0, and 
 optionally, adjusting the osmolality of the aqueous composition, preferably to a range of 270 to 340 mOsm/kg, more preferably from 285 to 315 mOsm/kg. 
 
     
     
         11 . The method of  claim 8 , wherein the quaternary ammonium neuromuscular blocking agent is a Rocuronium salt and the excipient is D-glucono-delta-lactone. 
     
     
         12 . Use of a polyhydroxy carboxylic acid of the following formula: HO—CH 2 —[CH(OH)] n —COOH, wherein n is an integer from 1 to 8, an intramolecular lactone of said polyhydroxy acid or a mixture thereof for stabilizing an aqueous composition comprising a quaternary ammonium neuromuscular blocking agent. 
     
     
         13 . The use of  claim 12 , wherein D-gluconic acid, an intramolecular lactone of D-gluconic acid, preferably D-glucono-delta-lactone, or a mixture thereof is used for stabilizing the aqueous composition comprising a Rocuronium salt. 
     
     
         14 . A container containing the composition according to  claim 1 , wherein the container is preferably made of an organic polymer or glass, more preferably made of a semipermeable plastic polyolefin, even more preferably made of polyethylene, polypropylene or a mixture thereof. 
     
     
         15 . A kit comprising the composition of  claim 1 , wherein the kit, optionally, further comprises an additional paralytic, a general anesthetic, a local anesthetic, a sedative, a hypnotic, and/or an analgesic.