Process for formulation of carbapenem antibiotic compositions

CAFC
  • US 6,548,492 B1
  • Filed: 10/27/2000
  • Issued: 04/15/2003
  • Est. Priority Date: 10/29/1999
  • Status: Expired due to Term
First Claim
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1. 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 0°

    to about 10°

    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 0°

    to about 10°

    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 0°

    to about 10°

    C.;

    d. maintaining the carbonate solution at a temperature range of from about 0°

    to about 10°

    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 −

    20°

    C. to a temperature of from about 5°

    to about 25°

    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 0°

    to about 5°

    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 0°

    to about 5°

    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 0°

    to about 5°

    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 0°

    to about 5°

    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 −

    45°

    to about −

    40°

    C. to produce a frozen formulation;

    o. primary drying the frozen formulation at a temperature of from about −

    25 to about −

    15°

    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 40°

    to about 60°

    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 25°

    C.

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