Process for formulation of carbapenem antibiotic compositions
DC CAFCFirst 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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Abstract
A novel process for preparing a stabilized, lyophilized carbapenem, antibiotic formulation suitable for intravenous administration to patients in need thereof, wherein the active ingredient is of formula II:
The process entails compounding a unstable, monosodium salt carbapenem with a sodium bicarbonate solution at a temperature range of from about 0° to about 5° C. while maintaining a pH between about 7.0 and about 8.0, filtering the resultant solution, bottling under sterile conditions, and lyophilizing to produce the formulation.
13 Citations
22 Claims
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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.- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14)
a. cooling the vials to a temperature of from about −
45°
to about −
40°
C. for about 2 hours;
b. heating the vials to a temperature of about −
20°
C. at a rate of about 0.5°
C./minute, and maintaining the vial temperature at about −
20°
C., while maintaining a pressure of from about 65 to about 95 mTorr for about 48 hours;
c. heating the vials to a temperature of about 10°
C. at a rate of about 0.1°
C./min;
d. heating the vials to a temperature of about 40°
C. at a rate of about 0.5°
C./min, and hold at about 40°
C., while maintaining a pressure of about 80 mTorr or lower for up to about 3 hours;
e. heating the vials to a temperature of about 60°
C. at a rate of about 0.5°
C./min, and hold at about 60°
C. and about 80 mTorr or lower for about 5 hours; and
f. cooling the vials to a temperature of from about 20°
to about 30°
C.
-
-
13. The process according to claim 10, wherein the vials are sealed under a partial vacuum of about 700 Torr or lower.
-
14. The process according to claim 11, wherein the final sterilized carbapenem of formula II exhibits a carbapenem concentration of 200 g/liter, and a sodium bicarbonate concentration of 35.0 g/liter.
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15. A process for converting a carbapenem compound of formula I:
-
into a carbapenem compound of formula II;
comprising the steps of; a. preparing a solution of from about 1 to about 3N of sodium hydroxide and chilling the solution to a temperature of from about 0°
to about 10°
C.;
b. charging a total of from about 40 to about 60% by wt., based on 100% by wt. total of the batch weight of Water for Injection exhibiting a temperature of from about 20 to about 85°
C. into a compounder having means for mixing, and cooling the water to a temperature of from about 0°
C. to about 5°
C.;
c. charging sufficient carbonate selected from sodium bicarbonate, sodium carbonate and mixtures thereof, into the compounder to prepare a final formulation exhibiting 1 mole equivalent of carbonate/active carbapenem, dissolving the same, and maintaining the solution at a temperature range of from about 0°
to about 5°
C. to prepare a carbonate solution;
d. maintaining the carbonate solution at a pH of from about 7.5 to about 9.0, and a temperature of about 0°
to about 5°
C.;
e. thawing a sufficient amount of bulk carbapenem of formula I to provide a formulation exhibiting a concentration of about 200 g/l from a temperature of about −
20°
C. to about temperature of from about 5 to about 25°
C., and slowly charging the same into the compounder with mixing of the carbonate solution to completely dissolve the bulk compound, while maintaining the compounder temperature of from about 0°
to about 5°
C. to produce an active carbapenem solution;
f. adding the sodium hydroxide solution to the active carbapenem, as required during step e., and maintaining a pH of from about 7.0 to about 8.0;
g. adjusting the active carbapenem solution to 95% by weight of the final product weight, based on 100 total weight percent, utilizing water for injection, as required and maintaining the bulk carbapenem of formula I solution in a temperature of from about 0°
to about 5°
C.;
h. adding the sodium hydroxide solution to the bulk carbapenem of formula I solution to maintain a pH of from about 7.2 to about 7.8;
i. adding Water for Injection, as required, to adjust the active carbapenem solution to q.s. of 100% by wt., based 100% by wt. total weight, and maintaining a temperature of from about 0 to about 5°
C.;
j. sealing and pressurizing the compounder containing the bulk compound of formula I solution to about 15 psig to initiate filtration;
k. filtering the bulk compound of formula I solution through a sterilizing filter into a continuously cooled, sterile, receiving vessel exhibiting a temperature of from about 0°
to about 5°
C. producing a final sterile beta-lactam carbapenem formulation; and
l. aseptically filling the final sterile beta-lactam carbapenem formulation into sterile glass vials, and partially sealing the vials with dry, sterilized, lyophilization stoppers;
m. lyophilizing the formulation by freezing in the glass vials at a temperature of from about −
45°
to about −
40°
C. to produce a frozen formulation;
n. 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;
o. secondary drying the formulation at a temperature of from about 40°
to about 60°
C. at a pressure of about 80 mTorr or lower for a time period of from about 3 to about 10 hours;
p. cooling the vials to ambient temperature; and
q. sealing the vials under a partial vacuum of about 0.9 bar/700 Torr or lower, while maintaining a temperature of about 25°
C.,wherein the final sterilized beta-lactam carbapenem antibiotic formulation of formula II exhibits a carbapenem concentration of about 200 g/l and a carbonate content of about 1 mole equivalent. - View Dependent Claims (16, 17, 18, 19, 20, 21, 22)
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Specification