Propofol formulations with non-reactive container closures

Abstract

A container storing a liquid anesthetic solution is disclosed. The container is sealed by a closure, and the liquid anesthetic solution includes an anesthetic being from 0.1% to 10% by weight of the liquid anesthetic solution, water, and a solvent. The container includes a material that is inert to the anesthetic, and the closure includes siliconized rubber, a fluoropolymer, or metal that is inert to the anesthetic. The concentration of the anesthetic in the liquid anesthetic solution stored in the container following a predetermined time period is at least 93% of a concentration of the anesthetic in the liquid anesthetic solution before the liquid anesthetic solution is stored in the container.

What is claimed is: 
     
         1 . A liquid anesthetic solution stored in a container, comprising:
 a container storing the liquid anesthetic solution, the container being sealed by a closure, the liquid anesthetic solution comprising:
 an anesthetic being from 0.1% to 10% by weight of the liquid anesthetic solution, 
 water, and 
 a solvent, wherein:
 the container comprises a material that is inert to the anesthetic, and 
 the closure comprises siliconized rubber, a fluoropolymer, or metal that is inert to the anesthetic, and 
 a concentration of the anesthetic in the liquid anesthetic solution stored in the container following a predetermined time period is at least 93% of a concentration of the anesthetic in the liquid anesthetic solution before the liquid anesthetic solution is stored in the container. 
 
   
     
     
         2 . The liquid anesthetic solution stored in the container of  claim 1 , wherein the anesthetic is propofol. 
     
     
         3 . The liquid anesthetic solution stored in the container of  claim 1 , wherein the solvent is a water-immiscible solvent. 
     
     
         4 . The liquid anesthetic solution stored in the container of  claim 3 , wherein the water-immiscible solvent is selected from the group consisting of soybean oil, safflower oil, cottonseed oil, corn oil, coconut oil, sunflower oil, arachis oil, castor sesame oil, orange oil, limonene oil, olive oil, hydrogenated castor oil, marine oil, fractionated oil, an ester of a medium-chain fatty acid, an ester of a long-chain fatty acid, a chemically modified palmitate, a glyceral ester, a polyoxyl, and mixtures thereof. 
     
     
         5 . The liquid anesthetic solution stored in the container of  claim 4 , wherein the water-immiscible solvent is soybean oil. 
     
     
         6 . The liquid anesthetic solution stored in the container of  claim 1 , wherein the liquid anesthetic solution further comprises a surfactant. 
     
     
         7 . The liquid anesthetic solution stored in the container of  claim 6 , wherein the surfactant is selected from the group consisting of phosphatides, synthetic phospholipids, natural phospholipids, lecithins, ethoxylated ethers, ethoxylated esters, tocopherol polyethylene glycol stearate, polypropylene-polyethylene block co-polymers, polyvinyl pyrrolidone, polyvinylalcohol, and combinations thereof. 
     
     
         8 . The liquid anesthetic solution stored in the container of  claim 7 , wherein the surfactant is selected from the group consisting of egg phosphatides, soya phosphatides, egg lecithins, soya lecithins, and combinations thereof. 
     
     
         9 . The liquid anesthetic solution stored in the container of  claim 1 , wherein the solvent is less than 10% by weight of the liquid anesthetic solution. 
     
     
         10 . The liquid anesthetic solution stored in the container of  claim 1 , wherein the liquid anesthetic solution further comprises a tonicity agent. 
     
     
         11 . The liquid anesthetic solution stored in the container of  claim 1 , wherein the container is selected from the group consisting of a vial, a bottle, a cartridge, a syringe, and a pre-filled syringe. 
     
     
         15 . The liquid anesthetic solution stored in the container of  claim 1 , wherein the closure is selected from the group consisting of a stopper, a plunger, a lid, and a top. 
     
     
         16 . The liquid anesthetic solution stored in the container of  claim 1 , wherein the material that is inert to the anesthetic is glass or plastic. 
     
     
         17 . A propofol emulsion stored in a container, comprising:
 a container storing the propofol emulsion, the container being sealed by a closure and comprising a plastic that is inert to propofol, and   the propofol emulsion comprising:
 propofol, 
 water, 
 a solvent, 
 a surfactant, and 
 a tonicity agent, wherein: 
 the closure comprises siliconized rubber, fluoropolymer, or metal that is inert to the propofol, and 
 a concentration of the propofol in the propofol emulsion stored in the container following a predetermined time period is at least 93% of a concentration of the propofol in the propofol emulsion before the propofol emulsion is stored in the container. 
   
     
     
         12 . The propofol emulsion stored in the container of  claim 11 , wherein the solvent is soybean oil. 
     
     
         13 . The propofol emulsion stored in the container of  claim 11 , wherein the surfactant is an egg phosphatide. 
     
     
         14 . The propofol emulsion stored in the container of  claim 11 , wherein the tonicity agent is glycerin. 
     
     
         18 . A sterile, injectable pharmaceutical composition in a container, comprising:
 a container which includes a closure and a composition in the container, the composition comprising   a) microdroplets having a mean size of from about 20 nanometers to about 1000 nanometers, the microdroplets comprising a sphere of propofol surrounded by a stabilizing layer comprising a phospholipid and devoid of oils capable of supporting bacterial growth; and   b) a pharmaceutically acceptable injectable carrier,   wherein when the composition in the container sealed with the closure is agitated at a frequency of 300-400 cycles/minute for 16 hours at room temperature, the composition maintains a propofol concentration (w/v) measured by HPLC that is at least 93% of the starting concentration (w/v) of the propofol.   
     
     
         19 . The sterile, injectable pharmaceutical composition in a container according to  claim 18 , where the closure is selected from the group consisting of siliconized bromobutyl rubber, a non-rubber selected from the group consisting of metal, plastics, and mixtures thereof, and siliconized chlorobutyl rubber. 
     
     
         20 . The sterile, injectable pharmaceutical composition in a container according to  claim 18 , wherein the closure is coated with a material inert to propofol.