AU2005201499B2

AU2005201499B2 - Premixed formulation of piperacillin sodium and tazobactam sodium injection

Info

Publication number: AU2005201499B2
Application number: AU2005201499A
Authority: AU
Inventors: Rao Chilamkurti; Stacey S Thompson
Original assignee: Baxter International Inc
Current assignee: Baxter International Inc
Priority date: 1999-02-22
Filing date: 2005-04-08
Publication date: 2007-03-08
Anticipated expiration: 2020-01-21
Also published as: AU2005201499A1

Description

00 SPREMIXED FORMULATION OF PIPERACILLIN SODIUM AND TAZOBACTAM SODIUM INJECTION Technical Field CI This invention relates to pharmaceutical compositions, and more specifically Sto a liquid premix formulation of piperacillin sodium and tazobactam sodium. The C 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. Patent 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 broadspectrum beta-lactam antibiotic. U.S. Patent 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.

2

O

SZosyn® is a relatively potent antibiotic. It is used for the treatment of moderate to severe infections caused by piperacillin-resistant, piperacillin/tazobactam- S susceptible beta-lactamase-producing strains of microorganisms in conditions such as nosocomial pneumonia due to Staphylococcus aureus; intra-abdominal infections, 5 specifically appendicitis (complicated by rupture or abscess) and peritonitis due to Escherichia coli; skin and skin structure infections, including cellulitits, cutaneous C abscesses and ischemic/diabetic foot infections due to Staphylococcus aureus; and gynecologic infections, specifically postpartum endometritis or pelvic inflammatory C 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. Patent 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 contamir sticks, increased waste, and dosage calculation errors are avoid personnel can simply use a prepared bag of the present formula Summary Of The Invention According to the present invention there is provided a phe composition according to claim 1 and a method of making a pha composition according to claim 19. A new liquid form of premixe for use in parenteral administration to fight polymicrobial infectiol disclosed. In providing the present premix many disadvantages o can be avoided. Such disadvantages include possible contamin waste disposal, dosage calculation errors, and drug instability to In one embodiment of the present invention the piperacilli piperacillin sodium, in a solution of suitable liquid, is brought witt pH range. The pH, and therefore the stability of the solution, is r buffering the formulation with a suitable quantity of a citrate.

In another embodiment of the present invention, an effect tazobactam, as tazobactam sodium, is included with the bufferec solution.

The pH of this embodiment is also maintained within a pa In still another embodiment, any of the previous embodim made physiologically iso-osmotic k. isosmotic) with the ad dextrose hydrous or dextrose anhydrous.

The stability of the formulations allows the present inventi for at least nine months at-20°C or below. Before use the frozen thawed and remains viable for one day at room temperature. Alt formulations may be stored at a refrigerated temperature (5°C± ation, needle d, as medical ions.

rmaceutical mTaceutical d piperacillin 1 in patients is )f the prior art ition, increased name a few.

i, as in a suitable naintained by ive amount of I piperacillin rticular range.

ents may be dition of on to be stored formulation is mrnatively, the 3 0 C) for as long 14/02/2007 as 14 days and remain viable according to the premix product lal enhanced stability compared to the reconstituted vial product, wl viable for seven days while refrigerated according to the man product labeling.

Other advantages and aspects of the present invention wi apparent upon reading the following detailed description of the in Detailed Disclosure While the invention is susceptible of embodiment in many forms, this disclosure will described in detail preferred embodime invention with the )eling. This is ich is only jfacturer's I become vention.

different nts of the 14/02/2007 understanding that the present disclosure is to be considered as an exemplification of the principles of the invention and is not intended to limit the broad aspect of the invention to the embodiments illustrated.

The present inventive formulations offer a number of advantages over other forms ofpiperacillin and piperacillin/tazobactam administration. For example, the premixed solution demonstrates long-term stability and enhanced shelf life when prepared at a physiologically suitable pH range. The long-term stability of piperacillin in solution was not known before the present invention. The stability of the formulation is achieved by buffering the solution with citrate to maintain the pH range.

Another example is that the formulations of the present invention are premixed so that they are ready for immediate use upon thawing. This eliminates the requirement to perform an admixture, along with the problems inherent to such a process.

Piperacillin free acid is the preferred source of piperacillin for use in the present invention. The free acid is converted to the sodium salt during the formulation process. Piperacillin sodium is derived from aminobenzylpenicillin. The chemical name ofpiperacillin sodium is sodium (2S, 6R)-6-[(R)-2-(4-ethyl-2,3-dioxo-l-piperazinecarboxamido)-2-phenylacetamido]-3,3dimethyl-7-oxo-4-thia-l-azabicyclo(3.2.0) heptane-2-carboxylate, with a chemical formula of C3H 2

N

5 Na07S and a molecular weight of 539.6. Piperacillin free acid was obtained in powder form from Wyeth-Ayerst. The piperacillin free acid is preferably mixed with a quantity of deionized water, and neutralized with sodium bicarbonate or other suitable agents, to bring the concentration of the solution within the preferred range of 20 to 80 mg/ml, more preferably within the range of 30 to mg/ml, and most preferably within the range of 38 to 62 mg/ml or any combination or subcombination of ranges therein.

Tazobactam free acid is the preferred source of tazobactam for use in the present invention. The free acid is converted to the sodium salt during the formulation process. Tazobactam sodium, a derivative of the penicillin nucleus, is a penicillanic acid sulfone. Its chemical name is sodium (2S, 3S, 5R)-3-methyl-7-oxo- O 3-(lH-1, 2, 3-triazol-l-ylmethyl)-4-thia-l-azabicyclo-(3.2.0)heptane-2-carboxylate- 4 4-dioxide. The chemical formula for tazobactam sodium is CoH,, N 4 NaO 5 S and the molecular weight is 322.3. The tazobactam free acid was supplied in powdered form 00 Othrough Wyeth-Ayerst. Tazobactam free acid is to be added to the piperacillin solution to create a concentration of tazobactam sodium to within a preferable range of 0.0 to 9.0 mg/ml, more preferably within the range of 4.0 to 8.0 mg/ml, and most preferably within the range of 4.8 to 7.8 mg/ml, or any range or subcombination of t ranges therein.

SThe total concentration of piperacillin sodium and tazobactam sodium in solution is preferably within the range of 20 to 89 mg/ml. More preferably the total concentration is within the range of 34 to 78 mg/ml, and most preferably within the range of 42.8 to 69.8 mg/ml, or any range or subcombination of ranges therein. These quantities allow for an effective amount of piperacillin or piperacillin/tazobactam to be delivered in common dosage amounts of 50 to 250 ml.

The resulting piperacillin or piperacillin/tazobactam solution is then brought to within a preferred pH range of 6.1 to 6.9, and more preferably within the range of 6.3 to 6.7. In a preferred form of the invention the pH of the solution is about Hydrochloric acid or other suitable acid can be used to adjust the pH downward, and sodium bicarbonate, or other suitable base, can be used to adjust the pH upward To maintain the pH within the preferred range, the solution is buffered with citrate or other suitable buffers. Citrate is the preferred buffer because it can maintain the pH of the solution without significant drug degradation. When using such buffers as phosphate, the pH cannotbe maintained in the frozen state (See "Effect Of Freezing On The pH And Composition Of Sodium And Potassium Phosphate Solutions: The reciprocal system KH 2

PO

4 -Na 2

HPO

4

-H

2 L. Van den Berg and D. Rose, Arch.

Biochem. Biophys., 81, p. 319 (1959)). The addition of a buffer is desired for controlling the pH to enhance stability. A suitable amount of sodium citrate used to buffer the formulation controls the pH for maximum stability without significantly catalyzing or degrading the drug, or causing pain to the patient upon infusion. [A clinical study was performed to confirm the absence of patient pain upon infusion.] SSodium citrate dihydrate is the preferred form for the buffer used in the present invention. The amount of sodium citrate dihydrate is preferably within the 00 O range of I to 4 mg/ml, more preferably within the range of 1.5 to 3.5 mg/ml, and most preferably within the range of 1.8 to 3.2 mg/ml or any range or subcombination of \N 5 ranges therein.

SIt may also be desirable to add dextrose to the solution to render the solution physiologically isosmotic (approximately 300 mOsmol/kg). Dextrose hydrous or Sanhydrous can be used in the present invention. The concentration of the dextrose t c hydrous is within the preferred range of 5 to 30 mg/ml, and more preferably within the range of 6 to 22 mg/ml or any combination or subcombination or ranges therein.

After complete formulation and mixing, the premixed piperacillin or piperacillin/tazobactam solution is placed into suitable dosage containers. Suitable containers include those sold by Baxter under the tradename GALAXY. The containers are then stored in a freezer at -20*C or lower. Studies have shown that the formulations of the present invention remain viable for at least nine months while frozen.

Before use the frozen containers should be thawed in a conventional manner.

The formulations will remain viable at room temperature for one day after removal from the freezer. Alternatively, the containers may be refrigerated at about 5 C) for as much as 14 days.

Under careful study, the stability of different formulations during long-term frozen and short-term thawed storage was assessed. Various formulations were evaluated to ascertain which combinations of components had long-term stability.

Parameters assessed included drug concentration, impurities, solution pH, solution color, visual appearance, osmolality, citrate concentration, and particulate matter.

Formulations were either unbuffered or buffered with sodium citrate dihydrate.

Various solution pHs were evaluated as well. Preferred formulations were stored for up to nine months frozen.

Illustrative, non-limiting examples of the present formulations are set out in TABLE 1 below. Numerous other examples can readily be envisioned in light of the

O

oo 0 guiding principles and teachings contained herein. For example, the solution pH could be varied, but remain in the zone of the desired long-term drug stability period; the dextrose concentration can be varied slightly and still allow the formulation to be isosmotic; and the citrate buffer concentration can be varied, but retain sufficient buffer capacity without causing pain on infusion. The examples given herein are intended to illustrate the invention and not in any sense to limit the manner in which the invention can be practiced.

TABLE 1 Dosage 2.25 g/50 mL 4.5 g/100 mL 3375 g/50 mL Component Contents per 50 Contents per 100 Contents per mL mL mL Piperacillin (as 2g 4g 3g piperacillin sodium) Tazobactam (as 0.25 g 0.5 g 0.375 g tazobactam sodium) Dextrose Hydrous, 1 g 2 g 350 mg

USP

Sodium Citrate 100 mg 200 mg 150 mg Dihydrate, USP Sodium for pH adjustment Bicarbonate, USP Hydrochloric for pH adjustment Acid, NF Water for Q.S. Q.S. Q.S.

Injection, USP While specific embodiments have been illustrated and described, numerous modifications are possible without departing from the spirit of the invention, and the scope of protection is only limited by the scope of the accompanying claims.

Claims

1. A pharmaceutical composition when used for parenteral a comprising a solution having an effective amount of piperacillin, having a pH adjusted to be in the range of from about 6.1 to aboi the composition further comprises an effective amount of a buffe maintaining the pH in the range of from about 6.1 to 6.9.

2. The pharmaceutical composition of claim 1 wherein the ef of piperacillin is provided in the form of piperacillin sodium, and v concentration of piperacillin is within the range of from about 20 1 mg/ml of solution.

3. The pharmaceutical composition of claim 2 wherein the cc piperacillin is within the range of about 30 to about 70 mg/ml of s

4. The pharmaceutical composition of claim 2 wherein the c piperacillin is within the range of about 38 to about 62 mg/ml of s The pharmaceutical composition of claim 1 wherein the p about Jministration, ,aid solution it 6.9, wherein -for fective amount therein the o about ncentration of olution. mncentration of olution. -I is adjusted to

6. The pharmaceutical composition of claim 1 wherein the buffer is a citrate.

7. The pharmaceutical composition of claim 6 wherein the buffer is sodium citrate. 14/02/07

8. The pharmaceutical composition of claim 7 wherein the cc the sodium citrate buffer is within the range of from about 1 to ab solution.

9. The pharmaceutical composition of claim 8 wherein the cc the sodium citrate buffer is within the range of from about 1.5 to mg/ml of solution. The pharmaceutical composition of claim 8 wherein the a the sodium citrate buffer is within the range of from about 1.8 to mg/ml of solution.

11. The pharmaceutical composition of claim 1 further compri effective amount of tazobactam.

12. The pharmaceutical composition of claim 11 wherein the amount of tazobactam is provided in the form of tazobactam sod wherein the concentration of tazobactam is within the range of fr to about 9.0 mg/ml of solution.

13. The pharmaceutical composition of claim 12 wherein the of tazobactam is preferably within the range of from about 4 to a solution. ncentration of out 4 mg/ml of ncentration of ibout ncentration of ibout 3.2 sing an ffective ium, and 3m about 0.0 moncentration bout 8 mg/ml of 14/02/07

14. The pharmaceutical composition of claim 12 wherein the of tazobactam is preferably within the range of from about 4.8 to mg/ml of solution. The pharmaceutical composition of claim 11 wherein the 1 to about

16. The pharmaceutical composition of claim 1 further compri effective amount of dextrose to render the composition physioloc isosmotic.

17. The pharmaceutical composition of claim 16 wherein the of dextrose is within the range of from about 5 to about 30 mg/m

18. The pharmaceutical composition of claim 17 wherein the I of dextrose is within the range of from about 6 to about 22 mg/m

19. A process of making a pharmaceutical composition includ the composition having a refrigerated shelf life in excess of 7 da' the steps of: oncentration about 7.8 >H is adjusted sing an ically concentration of solution. concentration Sof solution. piperacillin, comprising dissolving an effective amount of piperacillin into a suitable liquid forming a premixed solution; adjusting the pH of the premixed solution to a range of from about 6.1 to about 6.9; filling suitable containers with the premixed solution; and storing the containers of premixed solution in a suitable atmosphere at about 5 0 C 3 0 C, 14/02/07 wherein the process further comprises the step of providin amount of a buffer to maintain the pH in the range of from about I 6.9. The process of claim 19 further comprising the step of dis, effective amount of tazobactam into the premixed solution.

21. The process of claim 19 further comprising the step of stoi containers of premixed solution at -20 0 C or lower before storing in the suitable atmosphere.

22. The process of claim 19 further comprising the step of adi amount of dextrose to the premixed solution to make the compos physiologically isosmotic.

23. The process of claim 19 wherein the effective amount of p provided by piperacillin sodium at a concentration within the rang about 20 to about 80 mg/ml of suitable liquid.

24. The process of claim 23 wherein the concentration of the within the range of from about 30 to about 70 mg/ml of suitable li The process of claim 23 wherein the concentration of the within the range of from about 38 to about 62 mg/ml of suitable li j an effective .1 to about olving an ing the the containers ling an ition iperacillin is e of from )iperacillin is iuid. iperacillin is quid. 14/02/07

26. The process of claim 20 wherein the effective amount of provided by tazobactam sodium at a concentration within the rai about 0.0 to about 9.0 mg/ml of suitable liquid.

27. The process of claim 26 wherein the concentration of the within the range of from about 4 to about 8 mg/ml of suitable liqi

28. The process of claim 26 wherein the concentration of the within the range of from about 4.8 to about 7.8 mg/ml of suitable

29. The process of claim 19 wherein the step of buffering the solution includes the step of adding an effective amount of a citr premixed solution. The process of claim 29 wherein the citrate includes sodi is within the range of from about 1 to about 4 mg/ml of suitable I

31. The process of claim 29 wherein the citrate includes sodi is within the range of from about 1.5 to about 3.5 mg/ml of suital

32. The process of claim 29 wherein the citrate includes sodi is within the range of from about 1.8 to about 3.2 mg/ml of suital

33. The process of claim 19 wherein the pH of the premixed about :azobactam is ige of from tazobactam is lid. tazobactam is liquid. premixed ate to the Jm citrate and quid. Jm citrate and )le liquid. Jm citrate and )le liquid. solution is 14/02/07

34. A premixed pharmaceutical composition when used for pa administration substantially as hereinbefore described with refer( examples. A process of making a pharmaceutical composition includ the composition having a refrigerated shelf life in excess of 7 da) as hereinbefore described with reference to the examples. Dated this 14 t day of February 2007 renteral ince to the ng piperacillin, s substantially Baxter International Inc. Patent Attorneys for the Applicant PETER MAXWELL ASSOCIATES 14/02/07