Patent ID: 6548492
Filing Date: 2003-04-15
Classification: A61K,A61P,C07D

Abstract:
A process for stabililzing a beta-lactam carbapenem formulation for the treatment of bacterial infections in mammal patients, comprising the steps of:a. preparing a solution of about 1 to about 3N sodium hydroxide, chilling the solution to a temperature of from about 0Â° to about 10Â° C.; b. charging from about 40 to about 60% by wt., based on 100% by wt. total batch weight, of Water for Injection into a compounder having means for mixing, and cooling the water to a temperature of from about 0Â° to about 10Â° C.; c. charging 1 mole equivalent of carbonate/active beta-lactam carbapenem, wherein the carbonate are selected from sodium bicarbonate, sodium carbonate and mixtures thereof, into the compounder while mixing, to prepare a carbonate solution, while maintaining a temperature of from about 0Â° to about 10Â° C.; d. maintaining the carbonate solution at a temperature range of from about 0Â° to about 10Â° C., and a pH of from 7.5 to about 9.0; e. thawing a sufficient amount of a first beta-lactam carbapenem from a temperature of about âˆ’20Â° C. to a temperature of from about 5Â° to about 25Â° C. to prepare a final, formulation containing about 200 g/liter of active beta-lactam carbapenem, and charging at the same time into the compounder from about 0.7 to about 1.0 mole of sodium hydroxide/mole of active beta-lactam carbapenem, while mixing the carbonate solution to dissolve the beta-lactam carbapenem therein, and maintaining the compounder temperature of from about 0Â° to about 5Â° C. to produce a second beta-lactam carbapenem carbonate solution; f. adding the sodium hydroxide solution to the second beta-lactam carbapenem carbonate solution, as required, during step e. to maintain the pH of the solution of from about 7.0 to about 8.0; g. adding water, as required, to adjusting the second beta-lactam carbapenem carbonate solution to a range of about 95 to about 97 weight %, based on 100 total weight %, and maintaining a temperature of from about 0Â° to about 5Â° C.; h. adding the sodium hydroxide solution to the second beta-lactam carbapenem carbonate solution, as required, to maintain the solution in a pH of from about 7.2 to about 7.8; i. adding water, as required, to adjust the second beta-lactam carbapenem carbonate solution to 100 weight % total, and maintaining the temperature of from about 0Â° to about 5Â° C.; j. sealing the compounder containing the second beta-lactam carbapenem carbonate solution and pressurizing to from about 10 to about 30 psig to initialize filtration; k. filtering the second beta-lactam carbapenem carbonate solution through a sterilizing filter into a continuously cooled, sterile, receiving vessel exhibiting a temperature of from about 0Â° to about 5Â° C. to produce a final sterile, beta-lactam carbapenem formulation; l. aseptically filling the formulation into sterilized glass vials; m. partially sealing the glass vials with dry, sterilized stoppers; n. lyophilizing the solution by freezing in the glass vials at a temperature of from about âˆ’45Â° to about âˆ’40Â° C. to produce a frozen formulation; o. primary drying the frozen formulation at a temperature of from about âˆ’25 to about âˆ’15Â° C. for about 48 to 60 hours at a pressure of about 80 mTorr or lower; p. secondary drying the formulation at a temperature from about 40Â° to about 60Â° C. at pressure of about 80 mTorr or lower for from about 3 to about 10 hours; q. cooling the vials to ambient temperature; and r. sealing the vials under a partial vacuum, while maintaining a temperature of about 25Â° C.