Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-02-22
2001-03-27
Weddington, Kevin E. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06207661
ABSTRACT:
TECHNICAL FIELD
This invention relates to pharmaceutical compositions, and more specifically to a liquid premix formulation of piperacillin sodium and tazobactarn sodium. The liquid premix formulation is suitable for intravenous administration and has a viable shelf-life.
BACKGROUND ART
Polymicrobial infections often include pathogens that produce beta-lactamase enzymes. These enzymes commonly cause resistance to penicillins and cephalosporins. Without treatment these enzymes would multiply and thrive unimpeded, with serious or critical consequences to the patient.
To treat such infections, a product consisting of piperacillin sodium and tazobactam sodium in an 8 to 1 ratio (as free acids), is currently marketed under the tradename Zosyn®. This product is disclosed in U.S. Pat. No.4,562,073 to Micetich et al. However, because piperacillin is inherently unstable in solution at room temperature, like most penicillin compounds, Wyeth-Ayerst Research developed Zosyn® as a lyophilized vial product where the piperacillin is stored in the solid state.
In use, the piperacillin component offers the safety and efficacy of a broad-spectrum beta-lactam antibiotic. U.S. Pat. Nos. 4,477,452 and 4,534,977, both to Haeger, disclose a lyophilized form of piperacillin. Tazobactam reduces the vulnerability of the piperacillin to the bacteria that produce beta-lactamase enzymes. Basically, the tazobactam permanently inactivates beta-lactamases, allowing the piperacillin component to destroy susceptible bacteria. However, Zosyn® is supplied in a lyophilized form and therefore must be reconstituted prior to intravenous administration.
Zosyn® is a relatively potent antibiotic. It is used for the treatment of moderate to severe infections caused by piperacillin-resistant, piperacillin/tazobactam-susceptible beta-lactamase-producing strains of microorganisms in conditions such as nosocomial pneumonia due to
Staphylococcus aureits
; intra-abdominal infections, specifically appendicitis (complicated by rupture or abscess) and peritonitis due to
Escherichia coli
, skin and skin structure infections, including cellulitits, cutaneous abscesses and ischemic/diabetic foot infections due to
Staphylococcus acreus
; and gynecologic infections, specifically postpartum endometritis or pelvic inflammatory disease due to
Escherichia coli
. The seriousness of these infections highlights the need for a readily available and dependable treatment.
The admixing required by the lyophilized vial product is a skilled pharmaceutical procedure that must be performed using aseptic techniques to ensure product quality. This step creates the possibility of contamination and dosage miscalculation. It also adds to the cost of preparing the Zosyn® for administration. The laborious and difficult technique of lyophilizing and reconstituting the drug is addressed in U.S. Pat. No. 5,763,603 to Trickes. While the Trickes reference does teach a process of increasing the stability of tazobactam, such is accomplished by crystallization rather than in a buffered pH solution.
Another drawback of the reconstituted product is reflected in its short refrigerated shelf life. The reconstituted product remains stable and commercially viable for only seven days while refrigerated according to the manufacturer's product labeling (See also
Physicians' Desk Reference
, Medical Economics Company, Inc., pp. 1434-37 (52 ed., 1998)). The short shelf life and the reconstitution step may also lead to increased waste disposal as the components required to prepare the reconstituted solution, such as vials, needles and bags, as well as unused portions of the product, must be properly discarded.
Finally, another concern with the lyophilized powder vial product is that after reconstitution it has a pH more acidic than 6.5. This acidic condition increases the potential for hemolysis and pain to the patient during infusion.
The formulations of the present invention overcome the disadvantages of the reconstituted product as they are premixed and stable for longer periods at refrigerated temperature. Additionally, any potential for problems of contamination, needle sticks, increased waste, and dosage calculation errors are avoided, as medical personnel can simply use a prepared bag of the present formulations.
SUMMARY OF THE INVENTION
A new liquid form of premixed piperacillin for use in parenteral administration to fight polymicrobial infection in patients is disclosed. In providing the present premix many disadvantages of the prior art can be avoided. Such disadvantages include possible contamination, increased waste disposal, dosage calculation errors, and drug instability to name a few.
In one embodiment of the present invention the piperacillin, as piperacillin sodium, in a solution of suitable liquid, is brought within a suitable pH range. The pH, and therefore the stability of the solution, can be maintained by buffering the formulation with a suitable quantity of a citrate.
In another embodiment of the present invention, an effective amount of tazobactam, as tazobactam sodium, is included with the buffered piperacillin solution. The pH of this embodiment is also maintained within a particular range.
In still another embodiment, any of the previous embodiments may be made physiologically iso-osmotic (a.k.a., isosmotic) with the addition of dextrose hydrous or dextrose anhydrous.
The stability of the formulations allows the present invention to be stored for at least nine months at −20° C. or below. Before use the frozen formulation is thawed and remains viable for one day at room temperature. Alternatively, the formulations may be stored at a refrigerated temperature (5° C.±3° C.) for as long as 14 days and remain viable according to the premix product labeling. This is enhanced stability compared to the reconstituted vial product, which is only viable for seven (7) days while refrigerated according to the manufacturer's product labeling.
REFERENCES:
patent: 4452778 (1984-06-01), Brier
patent: 4477452 (1984-10-01), Haeger
patent: 4534977 (1985-08-01), Haeger
patent: 4535078 (1985-08-01), Fox, Jr. et al.
patent: 4552763 (1985-11-01), Brier
patent: 4562073 (1985-12-01), Micetich et al.
patent: 4594247 (1986-06-01), Brier
patent: 4837317 (1989-06-01), Ratti
patent: 5650421 (1997-07-01), Titus et al.
patent: 5763603 (1998-06-01), Trickes
patent: 0585987 (1994-03-01), None
patent: 2179348 (1987-03-01), None
patent: 2095551 (1982-10-01), None
Mathew, M., et al., “Stability of Piperacillin Sodium in the Presence of Tazobactam Sodium in 5% Dextrose and Normal Saline Injections,”Journal of Clinical Pharmacy and Therapeutics,vol. 19, 1994, pp. 397-399, XP00900664.
Bird, A., et al., “N-Formylpnicillamine and Penicillamine as Degradation Products of Penicillins in Solution,”Journal of Pharm. Pharmacol., vol. 38, No.12, 1986, pp. 913-916, XP000900666.
Yamana, T., et al., “Stability Kinetics of Piperacillin in Aqueous Solutions,”International Journal of Pharmaceutics, 11 (1982) pp. 71-80.
Chilamkurti Rao
Samuel Mary
Stephens Norma
Thompson Stacey S.
Baxter International Inc.
Buonaiuto Mark J.
Fuchs Joseph A.
Weddington Kevin E.
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