Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-10-27
2003-04-15
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S350000
Reexamination Certificate
active
06548492
ABSTRACT:
BACKGROUND OF THE INVENTION
Betalactams, a broader class of antibiotics, further defined as carbapenems useful for the treatment of infectious diseases, including gram positive and negative, aerobic and anaerobic bacteria. U.S. application Nos. 08/926,915 and 09/060,691 to Almarsson et al, filed Sep. 10, 1997, and Apr. 15, 1998, respectively, now assigned to Merck & Co., Inc., teach a novel carbapenem antibiotic compound of formula I:
and a process for the preparation thereof. The compound of formula I, prepared by chemical synthesis, is a relatively unstable, monosodium salt at ambient conditions, i.e. 20° C. and 1 atmosphere, and remains unstable at temperatures above about −20° C., wherein it undergoes dimerization and hydrolysis to form undesirable dimers and open ring by-products. Ahnarsson suggests a method of carbonation to converting the compound of formula I to a stable compound of formula II:
The method of stabilization requires the use of carbon dioxide, i.e. potassium, magnesium, calcium or sodium carbonates and bicarbonates as suitable carbon dioxide sources, and water or saline solution as a suitable solvent to produce the compound of formula II.
U.S. Pat. No. 5,952,323, to Zimmerman et al, issued Sep. 14, 1999, assigned to Merck & Co., Inc., teaches a more detailed process for converting the carbapenem monosodium salt into a stable carbapenem carbon dioxide adduct. In accordance with Zimmerman, specific mole ratios of sodium carbonate and sodium bicarbonate to unstabilized carbapenem monosodium salt, as well as pH limitations are suggested. The reference also provides solubility data for intravenous formulation at fixed conditions.
While Almarsson teaches reaction synthesis and conditions for preparation of the bulk carbapenem of formula I, and Zimmerman suggests CO
2
concentrations, pH and solubility ranges, neither reference provide a detailed step-by-step method for preparing a carbapenem formulation containing a stabilized CO
2
adduct of formula II. Due to the instability of the compound at temperatures above about −20° C., as well as its sensitivity to pH fluctuation, processing conditions for converting the bulk drug of formula I to the formulation of formula II are critical to providing a sterile, finish product of high quality.
It is now desirable to provide a process for converting a bulk drug, unstabilized carbapenem antibiotic, requiring storage at low temperatures, to a stabilized, carbapenem antibiotic, formulation suitable for intravenous and intramuscular injection into a patient in need thereof. It is also desirable to provide a product with needed solid state stability at room temperature and reconstitution stability for dosing.
SUMMARY OF THE INVENTION
The present invention is directed to a novel process for converting an unstabilized beta-lactam compound, i.e. carbapenem compound, more particularly a monosodium salt of a carbapenem compound, into a stabilized, beta-lactam compound, more particularly a stabilized, carbon dioxide adduct of carbapenem, and formulations thereof suitable for the treatment of bacterial infections in mammal patients, comprising the steps of:
a. preparing from about 1 to about 3N solution of 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 carbonates/active beta-lactam, 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 unstabihized, beta-lactam from a temperature of about 20° C. to a temperature of from about 50 to about 25° C. to prepare a final, formulation containing about 200 g/liter of active beta-lactam, 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, while mixing the carbonate solution to dissolve the beta-lactam therein, and maintaining the compounder temperature of from about 0° to about 5° C. to produce a beta-lactam-carbonate solution;
f. adding the sodium hydroxide solution to the beta-lactam-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 beta-lactam-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 beta-lactam-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 beta-lactam-carbonate solution to 100 weight % total, and maintaining the temperature of from about 0° to about 5° C.;
j. sealing the compounder containing the beta-lactam-carbonate solution and pressurizing to from about 10 to about 40 psig to initialize filtration;
k. filtering the beta-lactam-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 sterile, stabilized beta-lactam 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 −105° 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 80mTorr or lower from about 3 to about 10 hours;
q. cooling the vials to ambient temperature; and
r. sealing the vials under partial vacuum, while maintaining a temperature of about 25° C.
REFERENCES:
patent: 5478820 (1995-12-01), Betts et al.
patent: 5652233 (1997-07-01), Betts et al.
patent: 5952323 (1999-09-01), Zimmerman et al.
patent: 6180783 (2001-01-01), Williams et al.
patent: 6297231 (2001-10-01), Almarsson et al.
patent: WO 93/15078 (1993-08-01), None
patent: WO 99/45010 (1999-09-01), None
Smith, Peter A. S., The Chemistry of Open-Chain Organic Nitrogen Compounds, vol. 1, p. 263, 1965.
Betts et al., Chem. Abs., 118:80721, 1992.
Al-Dehneh Anthony
Hunke William A.
Illig Kathleen J.
Kanike Anand
Patel Hiren
Ayler Sylvia A.
Camara Valerie J.
McKenzie Thomas C
Merck & Co. , Inc.
Shah Mukund J.
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