Ready-to-use co-solvents pharmaceutical composition in modified flexible plastic container

Abstract

A ready-to-use injectable, co-solvents (ternary mixture) pharmaceutical composition for the treatment of cardiac conditions and diagnosis applications, comprising methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate hydrochloride (Esmolol hydrochloride), a buffering agent, ethanol and propylene glycol which capable of been stored in modified flexible plastic container, heat-sterilized without deformation and/or integrity of the closure system been compromised, as well as method for its manufacture, is disclosed.

What is claimed is: 
     
         1 . A co-solvent sterile premixed pharmaceutical product stored in a non-PVC flexible plastic container, wherein said pharmaceutical product has a solution pH between 4.5 and 5.5 and comprises:
 a. 5 to 40 mg/mL methyl-3-[4-(2-hydroxy-3-isopropylamino) propoxy]phenylpropionate hydrochloride (esmolol hydrochloride),   b. a buffering agent to maintain a solution pH between 4.5 and 5.5,   c. 0.1% to 3 w/v % of ethyl alcohol, and   d. 0.1% to 3 w/v % of one of propylene glycol or glycerin; and   wherein said pharmaceutical product is contained in a sealed container and heat-moist sterilized for a period of time sufficient to render the composition sterile.   
     
     
         2 . The pharmaceutical product of  claim 1 , wherein the non-PVC flexible plastic container comprises a 3-7 multi-layer, polyolefin based co-extruded film, non-PVC, latex free, plasticizer free, tubing ports are made of a two layer material that is suitable for terminal sterilization. 
     
     
         3 . The pharmaceutical product of  claim 2 , wherein the polyolefin based co-extruded film is selected polypropylene, cycloolefin, polyethylene and copolymerized ethylene vinyl acetate. 
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein the non-PVC flexible plastic container comprises modified tubing ports and closure systems made of a material that is suitable for terminal sterilization. 
     
     
         5 . The pharmaceutical product of  claim 1 , wherein the buffering agent comprises at least one of acetate, tartrate, malate and furmarate. 
     
     
         6 . The pharmaceutical product of  claim 1 , wherein the buffering agent is sodium acetate. 
     
     
         7 . The pharmaceutical product of  claim 1 , wherein the buffering agent is sodium tartrate. 
     
     
         8 . The pharmaceutical product of  claim 1 , wherein the esmolol hydrochloride is contained in an amount ranging form 10 to 30 mg/mL. 
     
     
         9 . The pharmaceutical product of  claim 1 , wherein (d) is propylene glycol. 
     
     
         10 . The pharmaceutical product of  claim 1 , wherein (d) is glycerin. 
     
     
         11 . The pharmaceutical product of  claim 1 , wherein the container is made of ridge or flexible plastic container and exhibits (i) less than a 2% decrease in the concentration of Esmolol or pharmaceutically acceptable salt thereof after autoclaving (terminal sterilization) and (ii) having formation of related Esmolol esters less than about 0.5% (ii) having co-solvents composition between 0.15% to 5% stored in a non-PVC flexible plastic container and comprising wherein in at least the inner most layer which contacts the esmolol solution comprises a copolymer of ethylene and vinyl acetate. 
     
     
         12 . A method of controlling bradycardia and/or controlling hypotension in the diagnosis of cardiac conditions using computerized cardiac tomography in humans comprising administering to a subject in need thereof an effective amount of the pharmaceutical product of  claim 1 . 
     
     
         13 . A method of preparing a pharmaceutical product of  claim 1 , comprising preparing a composition comprising:
 a. 5 to 40 mg/mL methyl-3-[4-(2-hydroxy-3-isopropylamino) propoxy]phenylpropionate hydrochloride (esmolol hydrochloride),   b. a buffering agent to maintain a solution pH between 4.5 and 5.5,   c. 0.1% to 3 w/v % of ethyl alcohol, and   d. 0.1% to 3 w/v % of one of propylene glycol or glycerin;   adding said composition to a non-PVC flexible plastic container;   sealing said container; and   subjecting the sealed container to heat-moist sterilization for a period of time sufficient to render the composition sterile thereby forming said pharmaceutical product.   
     
     
         14 . The method of  claim 13 , wherein said heat-moist sterilization is autoclaving. 
     
     
         15 . The method of  claim 14 , wherein said autoclaving is at a temperature ranging from 110 to 130° C. for a period of time ranging from 7 to 60 minutes. 
     
     
         16 . A method of preparing a pharmaceutical product of  claim 1 , comprising preparing in a non-PVC flexible plastic container a composition comprising:
 a. 5 to 40 mg/mL methyl-3-[4-(2-hydroxy-3-isopropylamino) propoxy]phenylpropionate hydrochloride (esmolol hydrochloride),   b. a buffering agent to maintain a solution pH between 4.5 and 5.5,   c. 0.1% to 3 w/v % of ethyl alcohol, and   d. 0.1% to 3 w/v % of one of propylene glycol or glycerin;   sealing said container; and   subjecting the sealed container to heat-moist sterilization for a period of time sufficient to render the composition sterile thereby forming said pharmaceutical product.   
     
     
         17 . The method of  claim 16 , wherein said heat-moist sterilization is autoclaving. 
     
     
         18 . The method of  claim 17 , wherein said autoclaving is at a temperature ranging from 110 to 130° C. for a period of time ranging from 7 to 60 minutes.