WO2004098643A1 - Compositions d'injection contenant piperacilline et tazobactame - Google Patents

Compositions d'injection contenant piperacilline et tazobactame Download PDF

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Publication number
WO2004098643A1
WO2004098643A1 PCT/US2003/011340 US0311340W WO2004098643A1 WO 2004098643 A1 WO2004098643 A1 WO 2004098643A1 US 0311340 W US0311340 W US 0311340W WO 2004098643 A1 WO2004098643 A1 WO 2004098643A1
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Prior art keywords
pharmaceutical composition
composition according
piperacillin
tazobactam
pharmaceutically acceptable
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PCT/US2003/011340
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English (en)
Inventor
Jonathan Marc Cohen
Syed Muzafar Shah
Christian Luther Ofslager
Mahdi Bakir Fawzi
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Wyeth Holdings Corporation
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Priority to AU2003230899A priority Critical patent/AU2003230899A1/en
Priority to PCT/US2003/011340 priority patent/WO2004098643A1/fr
Publication of WO2004098643A1 publication Critical patent/WO2004098643A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A61K31/431—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems containing further heterocyclic rings, e.g. ticarcillin, azlocillin, oxacillin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame

Definitions

  • the invention relates to pharmaceutical compositions containing piperacillin (normally as piperacillin sodium) and tazobactam-(normally as tazobactam sodium) commercially available as Zosyn®.
  • Such compositions are useful for intravenous administration as antibiotics for hospitalized patients with serious infections.
  • this invention relates to a pharmaceutical composition further including an aminocarboxylic acid chelating agent, for example, ethylene diamine tetraacetic acid (EDTA), or a pharmaceutically acceptable salt thereof, and optionally citrate and optionally an aminoglycoside.
  • an aminocarboxylic acid chelating agent for example, ethylene diamine tetraacetic acid (EDTA), or a pharmaceutically acceptable salt thereof, and optionally citrate and optionally an aminoglycoside.
  • EDTA ethylene diamine tetraacetic acid
  • the pharmaceutical compositions described herein normally have enhanced resistance to particulate formation in solutions to be administered parenterally.
  • Zosyn® is an antibiotic marketed product containing piperacillin sodium and tazobactam sodium. The product is disclosed in U.S. Patent No. 4,562,073. U.S. Patent Nos. 4,477,452 and 4,534,977 disclose a lyophilized form of piperacillin.
  • Zosyn® is an antibiotic which is used in 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 aureus ; 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 aureus ; and gynecologic infections, specifically postpartum endometritis or pelvic inflammatory disease due to Escherichia coli .
  • Piperacillin is a broad-spectrum beta-lactam antibiotic which is inherently unstable in solution at room temperature. Adversely, instability in solution at room temperature further results in increased particulate formation.
  • 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.
  • Polymicrobial infections often include pathogens that produce beta-lactamase enzymes. These enzymes commonly cause resistance to penicillins and cephalosporins. Without treatment these microbes would multiply and thrive unimpeded, with serious or critical consequences to the patient.
  • Medicaments are formulated into not only emulsions, suspensions or solutions, but also as lyophilized preparations to be reconstituted before use.
  • lyophilized preparations are stable, can be stored and are easily reconstituted.
  • lyophilized preparations may be kept sterile and essentially free of insoluble matter.
  • Zosyn® is reconstituted or a frozen bag is thawed particulate matter formation begins.
  • Zosyn® is available as a powder (lyophilized product) which is reconstituted by addition of a compatible reconstitution diluent prior to intravenous administration.
  • Zosyn® is also available as a liquid premix formulation containing piperacillin sodium, tazobactam sodium and sodium citrate as buffer. Such a formulation is disclosed in U.S. Patent No. 6,207,661. This liquid premix is stored frozen and then parenterally administered to the patient after thawing and, if desired, adding a compatible diluent. The addition of citrate as buffer adjusts the pH to about 6.5.
  • aminoglycoside antibiotics may optionally be added to the frozen and thawed or reconstituted presentations. However, not without the disadvantage of particulate formation.
  • Zinc content of the reconstituted lyophilized product or frozen and thawed product optionally in the presence of aminoglycosides enhances the formation of particulates.
  • the presence of zinc in IV solutions is known to arise from plastic storage containers, septa and tubing.
  • the amount of zinc in IV bags can vary from lot to lot even when manufactured by the same manufacturer. Typically, the hospitals would not analyze the bags prior to use and therefore will be unaware of what level of zinc is present. Particulates are formed as reconstituted lyophilized formulations and thawed frozen formulations are readied and stored prior to patient administration. As the time increases from reconstitution or thawing and delivery to the patient so does formation of particulates. Storage after reconstitution or thawing also allows for the formation of unwanted particulates. It is recognized that the presence of particles in solution, particularly if injected intravenously, can be harmful.
  • compositions of the present invention overcome the disadvantages of pharmaceutical compositions known in the art.
  • decreased particulate formations in pharmaceutical compositions upon reconstitution and thawing is solved by the present invention.
  • pharmaceutical compositions of the invention which may optionally have an aminoglycoside also have decreased particulate formation.
  • Zosyn® has been found to be stable in glass and plastic containers (such as plastic syringes, and I.V. bags) when used with compatible diluents.
  • plastic containers such as plastic syringes, and I.V. bags
  • Various studies of the stability of Zosyn ® have been carried out. For example, Park TW et al.
  • Piperacillin and tazobactam were found to be stable in 2 CAPD solutions for at least 1 day when stored at 37 °C, 7 days at 23 °C, and 14 days at 4 °C.
  • the solutions were stored at room and refrigerator temperatures in plastic bags. They remained clear throughout the study. The solutions were stable for 2 days at 25 °C and for 28 days at 5 °C.
  • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever possible. Although existing Zosyn ® formulations exhibit satisfactory clarity when prepared in accordance with recommended manufacturer's instructions, it is desirable to minimize the particulate formations that occur in the pharmaceutical compositions upon reconstitution and thawing. Surprisingly it has been found that incorporation of an aminocarboxylic acid chelating agent, for example, ethylene diamine tetraacetic acid (EDTA) or diethylenetriamine pentaacetic acid (DTPA), or a suitable salt thereof into the composition can generally be used to inhibit particulate formation.
  • an aminocarboxylic acid chelating agent for example, ethylene diamine tetraacetic acid (EDTA) or diethylenetriamine pentaacetic acid (DTPA), or a suitable salt thereof into the composition can generally be used to inhibit particulate formation.
  • the present invention provides to the art a new pharmaceutical composition of premixed piperacillin or piperacillin-tazobactam which avoids the particulate formation of the prior art and is capable of being frozen and thawed and useful for the treatment or control of bacterial infections by parenteral administration, the composition comprising effective amounts of (a) piperacillin or a pharmaceutically acceptable salt thereof (normally as piperacillin sodium), (b) tazobactam or a pharmaceutically acceptable salt thereof (normally as tazobactam sodium), and, as particulate formation inhibitor, an aminocarboxylic acid chelating agent for example, ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), hydroxyethylenediaminetriacetic acid (HEDTA), nitrilotriacetic acid (NTA) or a pharmaceutically acceptable salt thereof (normally as a sodium salt).
  • EDTA ethylenediaminetetraacetic acid
  • DTPA di
  • the pharmaceutical composition according to the invention may be (A) in the form of a powder that can be reconstituted by addition of a compatible reconstitution diluent prior to parenteral administration, (B) in a form ready to use for parenteral administration or (C) in a form ready to use for parenteral administration.
  • the composition of the invention normally reduces the formation of particulates compared to the prior art. Particulates consist of mobile, randomly sourced, extraneous substances, other than gas bubbles, that cannot be quantitated by chemical analysis due to the small amount of material that represents and to its heterogeneous composition.
  • an effective amount of tazobactam as tazobactam sodium and piperacillin, as piperacillin sodium, is included in a buffered solution and further including an effective amount of a particulate formation inhibitor of the invention.
  • the pH of this embodiment may be maintained within a range of about 6.0 to 7.5.
  • the pH, and therefore the stability of the solution, can be maintained by buffering with, for instance, an effective amount of citrate.
  • Particulate formation inhibitors include ethylenediaminetetraacetic acid (EDTA) and salts thereof.
  • EDTA ethylenediaminetetraacetic acid
  • USP edetate disodium
  • any of the previous embodiments may be made physiologically iso-osmotic (a.k.a., isosmotic, isotonic) with the addition of dextrose hydrous or dextrose anhydrous.
  • One embodiment of the present invention is to further optionally include aminoglycosides in pharmaceutical compositions described herein.
  • This invention includes a solid lyophilized composition suitable for making a liquid useful for treatment of bacterial infections in mammals which when reconstituted generally has reduced particulate formation.
  • This invention is also includes an aqueous solution of a reconstituted lyophilized composition useful for the treatment of bacterial infections in mammals.
  • This invention also includes a process of making a lyophilized composition and other compositions of the invention.
  • the invention provides a process for the manufacture of a pharmaceutical composition useful for the treatment or control of bacterial infections preferably by parenteral administration, the pharmaceutical composition being in the form of a powder that can be reconstituted by addition of a compatible reconstitution diluent prior to parenteral administration or in the form of a frozen composition adapted to be thawed and, if desired, diluted with a compatible diluent prior to parenteral administration; which process comprises freezing or freeze- drying a solution containing effective amounts of (a) piperacillin or a pharmaceutically acceptable salt thereof, (b) tazobactam or a pharmaceutically acceptable salt thereof and, as particulate formation inhibitor, an aminocarboxylic acid chelating agent or a pharmaceutically acceptable salt thereof and optionally including an aminoglycoside antibiotic in an aqueous vehicle.
  • This invention also includes a method of treating bacterial infections in mammals using the composition of the invention.
  • This invention additionally includes an improved method of treating bacterial infections in mammals using the thawed composition of the invention.
  • This invention also includes a powder (lyophilized composition) dissolved in aqueous medium in a unit dosage IV bag or bottle at a concentration suitable for intravenous administration to a mammal for treatment of bacterial infections.
  • This invention further includes a powder (lyophilized composition) contained in a dose-concentrate sealed container.
  • a further aspect of this invention is a process for the preparation of a powder (lyophilized composition) and a process for the preparation of a liquid composition capable of being frozen and thawed.
  • the present inventive compositions offer a number of advantages over other forms of piperacillin and piperacillin-tazobactam for administration.
  • the solution for infusion may demonstrate a reduction in both the quantity of particulates and the rate of their formation whether derived from a reconstituted lyophilized or frozen and thawed pre-mixed dosage form.
  • Inhibiting particular formation may be achieved by buffering the pharmaceutical compositions of the invention with a buffer, for example, citrate to maintain the suitable pH range of about 6.0 to about 7.5 and further adding an aminocarboxylic acid chelating agent or a salt thereof as particulate formation inhibitor to limit particulate formation.
  • a preferred pH is about 6.5.
  • the presence of EDTA in the form of edetate disodium dihydrate as the particulate formation inhibitor significantly reduces the number of particles generated in 24 hours.
  • the particulate formation inhibitor may be added in a hospital setting before administration to a patient or may also be premixed in a ready to use pharmaceutical composition.
  • aminoglycosides may optionally be added to the pharmaceutical compositions of the invention. Further the aminoglycosides may optionally be admixed in a hospital setting by adding to the frozen bag on thawing or to the reconstituted lyophilized composition before administration to a patient or premixed in a lyophilized or frozen pharmaceutical composition. As shown in Table 1 the presence of the aminoglycoside amikacin increases the number of particles generated in 24 hours. However, the formation of particles is normally reduced in the presence of citrate and the particulate formation inhibitor EDTA in the form of edetate disodium dihydrate.
  • compositions of the present invention are premixed so they are ready for immediate use upon thawing or reconstitution which eliminates the requirement to form after thawing or reconstitution an admixture with a particle formation inhibitor and optionally an aminoglycoside.
  • particle formation inhibitor EDTA or other aminocarboxylic chelating agent
  • premixing before freezing or lyophilization has the advantage of preventing the inadvertent adding of the incorrect reagent or amount to the composition and allows for easier administration to the patient.
  • compositions of the present invention are premixed so they are ready for immediate use upon thawing or reconstitution which eliminates the requirement to form after thawing or reconstitution an admixture with an aminoglycoside.
  • aminoglycoside may optionally be added to the thawed or reconstituted pharmaceutical composition, preferably premixing before freezing or lyophilization has the advantage of preventing the inadvertent adding of the incorrect reagent or amount to the composition and allows for easier administration to the patient.
  • dose-concentrate refers to a solution of the pharmaceutical composition.
  • the dose-concentrate may be held in the container where it was formed by adding aqueous solvent or diluent to the pharmaceutical composition or it may be removed and held externally.
  • the dose-concentrate may be used as is, but is generally further diluted to a unit dosage concentration for administration to a mammal.
  • the entire volume of the dose-concentrate or aliquots thereof may be used in preparing unit dose(s) for treatment by the method of this invention.
  • Particulate formation inhibitor refers to a compound which has the desired property of inhibiting the formation of particles in parenteral compositions containing piperacillin and tazobactam.
  • Particulate formation inhibitors of the invention include ethylenediaminetetraacetic acid (EDTA) and salts thereof, for example, ethylenediaminetetraacetic acid, calcium disodium salt (preferably as the hydrate); ethylenediaminetetraacetic acid, diammonium salt (preferably as the hydrate); ethylenediaminetetraacetic acid, dipotassium salt (preferably as the dihydrate); ethylenediaminetetraacetic acid, disodium salt (preferably as the dihydrate and, if desired, as the anhydrous form); ethylenediaminetetraacetic acid, tetrasodium salt (preferably as the hydrate); ethylenediaminetetraacetic acid, tripotassium salt (preferably as the dihydrate); ethylenediaminetetraacetic acid, triso
  • Ethylenediaminetetraacetic acid disodium salt, USP is the preferred form for the particulate formation inhibitors used in the present invention.
  • the amount of particulate formation inhibitor such as ethylenediaminetetraacetic acid disodium salt USP is preferably within the range of about 0.01 to about 40 mg particulate formation inhibitor per gram of piperacillin, more preferably within the range of about 0.1 to about 0.5 mg particulate formation inhibitor per gram of piperacillin, or any range or subcombination of ranges therein.
  • Piperacillin sodium is the preferred form of piperacillin in the compositions of the present invention.
  • Piperacillin free acid is the preferred source of piperacillin for use in making the compositions of the present invention.
  • Piperacillin sodium is derived from D(-)- ⁇ -aminobenzylpenicillin.
  • the chemical name of piperacillin sodium is sodium (2S, 5R, 6R)-6-[(R)-2-(4-ethyl-2,3-dioxo-1- piperazinecarboxamido)-2- phenylacetamido]-5 3,3-dimethyl-7-oxo-4-thia-1- azabicyclo(3.2.0) heptane-2- carboxylate, with a chemical formula of C 23 H 26 N 5 O 7 SNa and a molecular weight of 539.6.
  • 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 about 8 to about 90 mg/ml, more preferably within the range of about 25 to about 85 mg/ml, and most preferably within the range of about 30 to about 80 mg/ml or any combination or subcombination of ranges therein.
  • 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 about 150 to about 500 mg/ml, more preferably within the range of about 200 to about 400 mg/ml, and most preferably within the range of about 220 to about 350 mg/ml or any combination or subcombination of ranges therein.
  • concentrations of solute can be processed successfully, but with the disadvantages of increasing production times and associated costs.
  • the concentration of the piperacillin in solution is within the preferred range of about 8 to about 90 mg/ml, more preferably within the range of about 25 to about 85 mg/ml, and most preferably within the range of about 30 to about 80 mg/ml or any combination or subcombination of ranges therein.
  • Tazobactam sodium is the preferred form of tazobactam in the compositions of the present invention.
  • Tazobactam free acid is the preferred source of tazobactam for use in making the compositions of the present invention. The free acid may be converted to the sodium salt during the process of forming the pharmaceutical compositions of the invention.
  • Tazobactam sodium, a derivative of the penicillin nucleus, is a penicillanic acid sulfone.
  • tazobactam free acid may be added to the piperacillin solution to create a concentration of tazobactam sodium to within a preferable range of about 0.1 to about 25 mg/ml, more preferably within the range of about 1.0 to about 22 mg/ml, and most preferably within the range of about 3 to about 20 mg/ml, or any range or subcombination of ranges therein.
  • tazobactam free acid may be to be added to the piperacillin solution to create a concentration of tazobactam sodium to within a preferable range of about 15 to about 125 mg/ml, more preferably within the range of about 2 to about 100 mg/ml, and most preferably within the range of about 27 to about 90 mg/ml, or any range or subcombination of ranges therein.
  • the concentration of tazobactam in the solution is within a preferable range of about 0.1 to about 25 mg/ml, more preferably within the range of about 1.0 to about 22 mg/ml, and most preferably within the range of about 3 to about 20 mg/ml, or any range or subcombination of ranges therein.
  • the total concentration of piperacillin sodium, tazobactam sodium, citrate as buffer and particulate formation inhibitor in solution when the dosage form is ready for patient use is preferably within the range of about 9 to about 125 mg/ml.
  • the total concentration is within the range of about 14 to about 115 mg/ml, and most preferably within the range of about 20 to about 105 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 about 50 to about 250 ml.
  • a suitable pH range is about 6.0 to about 7.5.
  • the resulting piperacillin or piperacillin /tazobactam solution may then be brought to within a preferred pH range of about 6.1 to about 6.9, and more preferably within the range of about 6.3 to about 6.7.
  • the pH of the solution is about 6.5. 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.
  • the solution may be 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.
  • the pH cannot be 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 O," 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.
  • Sodium citrate dihydrate also known as trisodium citrate dihydrate is the preferred form for the buffer used in the present invention.
  • the amount of sodium citrate dihydrate is preferably within the range of about 0.25 to about 5 mg/ml, more preferably within the range of about 0.6 to about 5 mg/ml, and most preferably within the range of about 1.0 to about 4.0 mg/ml or any range or subcombination of ranges therein. Ranges are for reconstituted and diluted or thawed for administration.
  • citrate is citric acid or salts thereof, preferably sodium citrate.
  • Sodium citrate includes: trisodium citrate anhydrous, trisodium citrate dihydrate, sodium citrate dihydrate and trisodium citrate pentahydrate.
  • Sodium citrate dihydrate is also know as trisodium citrate dihydrate and is preferred.
  • Physiologically acceptable diluents may optionally be added to improve cake characteristics of lyophilized products.
  • Acceptable diluents include but are not limited to sugars, inorganic salts and amino acids.
  • Representative examples of acceptable sugars include dextrose, mannitol, lactose, and sucrose and the like.
  • Representative examples of salts include sodium chloride, sodium phosphate, and calcium chloride and the like.
  • acceptable amino acids include arginine, tyrosine, and leucine, and the like.
  • dextrose hydrous or anhydrous can be used in the present invention.
  • concentration of the dextrose hydrous is within the preferred range of about 5 to about 30 mg/ml, and more preferably within the range of about 6 to about 22 mg/ml or any combination or subcombination or ranges therein.
  • Typical pharmaceutical compositions of the invention include the following ranges: Piperacillin in the range of about 8 mg/ml to about 500 mg/ml; more preferably about 12 mg/ml to about 300 mg/ml;
  • Tazobactam in the range of about 0.1 mg/ml to about 125 mg/ml; more preferably about 1.5 mg/ml to about 75 mg/ml;
  • Citrate in the range of about 0.25 mg/ml to about 25 mg/ml; more preferably about 0.6 mg/ml to about 15 mg/ml;
  • Particulate formation inhibitor in the range of about 0.002 mg/ml to about 10 mg/ml; more preferably about 0.003 to about 1 mg/ml;
  • compositions of the invention is dextrose in the range of about 5 mg/ml to about 100 mg/ml.
  • optionally added to pharmaceutical compositions of the invention are aminoglycosides in the range of about 0.1 mg/ml to about 75 mg/ml.
  • a non- limiting example of a pharmaceutical composition of the invention preferably in the case of a frozen composition, contains (a) piperacillin or a pharmaceutically acceptable salt thereof in an amount of about 4.0 g calculated as piperacillin free acid, (b) tazobactam or a pharmaceutically acceptable salt thereof in an amount of about 0.5 g calculated as tazobactam free acid, (c) about 1 mg of EDTA or of a pharmaceutically acceptable salt of EDTA and (d) about 100 ml of water for injection.
  • the composition may contain as optional further ingredients about 0.2 g of citrate as buffer, about 2.0 g of dextrose, about 500 mg amikacin, or about 160 mg of tobramycin.
  • the composition preferably includes (a) piperacillin sodium equivalent to about 4 g piperacillin free acid, (b) tazobactam sodium equivalent to about 0.5 g of tazobactam free acid and (c) substantially 1 mg of a sodium salt of EDTA and may include about 0.2 g of sodium citrate as buffer.
  • the particulate formation inhibitor may be added before freezing or after thawing.
  • an aminoglycoside may optionally be added before freezing or after thawing, in particular, for use in a hospital setting.
  • 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.
  • the containers may be refrigerated at about 5° ( ⁇ 3° C.) for as much as 14 days.
  • Optionally added aminoglycosides to both the lyophilized and reconstituted and frozen and thawed specifically for administration to a patient include amikacin and tobramycin in a range of about 0.1 to about 75 mg/ml, in a preferred range of about 0.1 to about 15 mg/ml and more preferred in a range of about 1 to about 10 mg/ml.
  • lyophilized composition(s) refers to the solid freeze-dried composition of matter prepared by the process of this invention and comprising as essential ingredients: (1) piperacillin; (2) tazobactam; further including (3) citrate and additionally including (4) a particulate formation inhibitor which further includes adjustment of the pH and optionally the addition of an aminoglycoside.
  • added aminoglycosides, including amikacin in a lyophilized composition are present in a preferred range of about 1 to about 100 mg/ml and more preferred in a range of about 5 to about 75 mg/ml.
  • lyophilization is a process of drying in which water is sublimed from the product after it is frozen, by optionally applying a vacuum.
  • lyophilizing or freeze-drying are described in Remington's Pharmaceutical Sciences, Chapter 84, page 1565, 18 th Edition, A.R. Gennaro, Editor, 1990, Mack Publishing Company.
  • techniques other than lyophilization which may also be used.
  • Non-limiting techniques to make the composition include: sterile powder filling of the components, singly, or as a complete blend.
  • Non-limiting techniques to prepare the powder prior to filling include: spray drying, tray drying, bulk lyophilization, sizing process including milling and/or screening and precipitation.
  • the lyophilized compositions of the present invention refer to a preparation prepared by freeze-drying a solution containing Zosyn®.
  • the solution containing all of the ingredients, which include, piperacillin, and tazobactam, and further including citrate, and additionally including a particulate formation inhibitor and optionally an aminoglycoside at a suitable pH are frozen, optionally being subjected to a heat treating process to improve cake characteristics, and then being dried in a high vacuum for sublimating water.
  • Such lyophilized preparations include lyophilized preparations for intravenous administration as mentioned above.
  • the lyophilized preparation may be produced by conventional methods including tray lyophilization, and vial lyophilization methods.
  • Vial lyophilization is advantageous for preparing multi-dosage units of the invention as described, infra.
  • a powdered form may be prepared directly by other techniques such as spray drying, or blending of dry powders of the appropriate salts of the individual or combined ingredients.
  • sodium citrate dihydrate is dissolved in a suitable amount of a solvent and mixed and stirred. Piperacillin acid and Tazobactam acid are added and stirring continued. The solution is neutralized with a sufficient quantity of sodium bicarbonate, to reach a pH of about 6.5 and the EDTA (particularly edetate disodium) is added to the aqueous solution followed by the optional addition of an aminoglycoside.
  • the solvent, standard solutions for injection or diluent are preferably an aqueous solvent such as water, purified water, water for injection, 5% dextrose in water or isotonic sodium chloride solution.
  • the processing solution before lyophilization may be subjected to a filtration process.
  • the filtration process includes, for example in the case of injection preparations, a sterilizing filtration and/or an ultra filtration of the processing solution before lyophilization to eliminate microorganisms or other contaminating matter from the processing solution before lyophilization.
  • the processing solution before lyophilization may be subjected to a distributing process.
  • the distributing process includes, for example in the case of vial lyophilizations, a process distributing a suitable volume of the processing solution before lyophilization into vials taking the concentration of piperacillin sodium/tazobactam sodium, citrate, particulate formation inhibitor and optionally an aminoglycoside into consideration in order that vial products carry a desired amount of piperacillin sodium/tazobactam sodium.
  • a lyophilization process is performed as follows:
  • the lyophilized composition is prepared by a controlled freeze-drying process.
  • the processing solution is first frozen, then subjected to a low pressure environment (a.k.a. vacuum) to facilitate sublimation, and gently heated to optimize the drying rate of the product.
  • a low pressure environment a.k.a. vacuum
  • a typical process for preparing a lyophilized composition comprises the sequential steps of:
  • composition ingredients comprising: Sodium Citrate Dihydrate, EDTA or other particulate formation inhibitor, Piperacillin Acid, Tazobactam Acid and optionally an aminoglycoside in an aqueous solvent; then adjusting pH to about 6.5;
  • step (b) cooling the processing solution of step (a) to a temperature below -35°C;
  • step (f) drying at about +45° C.
  • step (a) is conducted by dissolving in an aqueous solvent.
  • step (b) is performed for a time period of approximately 4 hours, and (e) is preferably conducted for a period of at about 35 hours and step (f) is performed at a subatmospheric pressure less than about (300 milliTorr) (40 pascals) and those conditions are maintained for 10 hours after the 45°C shelf temperature has been achieved.
  • the lyophilization process removes most of the water originally present, but the final product lyophilized composition may contain some free water.
  • the water content can range from about 0% to about 2% weight percent. More typically, the water content ranges from about 0% to about 1 %.
  • a dose-concentrate configuration of the pharmaceutical composition of the invention is a sealed container holding an amount of the lyophilized pharmaceutical composition of the invention to be employed over a standard treatment interval such as 7 days.
  • the dose-concentrate configuration is prepared by placing the lyophilized composition in a container (e.g., glass or plastic bottles, vials, ampoules) in sufficient amount to treat a mammal for a period ranging from 12 hours to 1 week, but preferably from 12 hours to 24 hours.
  • the container preferably also contains an empty space of sufficient size to permit (i) addition of aqueous solvent plus (ii) additional space as necessary to permit agitation and effect complete solution of the lyophilized composition in the added aqueous solvent.
  • the container may be equipped with a penetrable top, for example, a rubber seal, so that aqueous solvent may be added by penetrating the seal with a hypodermic syringe and the concentrate subsequently removed by the same means.
  • An example of a dose-concentrate configuration is a glass vial having a capacity of from about 250 to about 1000 milliliters containing about 25,000 to about 40,500 milligrams of lyophilized pharmaceutical composition of the invention.
  • a non-limiting specific example of an individual use configuration is a 50 mL glass bottle with a rubber seal having a lyophilized pharmaceutical composition containing about 4000 mg of piperacillin sodium, about 200 mg of sodium citrate, about 500 mg of tazobactam sodium and about 1 mg of EDTA (particularly as a sodium salt).
  • the empty space above the solid composition has ample room for addition of a solvent or diluent such as sterile water for injection plus room to agitate the total contents.
  • a further non-limiting specific example of a useable configuration is an approximately 100 ml glass bottle with a rubber seal having a lyophilized pharmaceutical composition containing about 40.5 g of piperacillin sodium, about 1.8 g of sodium citrate, about 4.5 g of tazobactam sodium and about 9 mg of EDTA (particularly as a sodium salt).
  • the empty space above the solid composition has ample room for addition of a solvent or diluent.
  • An additional non-limiting specific example of a useable configuration in an appropriately sized glass bottle with a rubber seal having a lyophilized pharmaceutical composition containing about 2000 mg of piperacillin sodium, about 100 mg of sodium citrate, about 250 mg of tazobactam sodium and about 0.5 mg of EDTA (particularly as a sodium salt).
  • the empty space above the solid composition has ample room for addition of a solvent or diluent such as sterile water for injection plus room to agitate the total contents.
  • aqueous solvent added to the dose-concentrate configuration results in a liquid concentrate which may then be conveniently used to form unit dosages of liquid pharmaceutical formulations by removing aliquot portions or entire contents for dilution as set out in the following section.
  • the concentrated solution of lyophilized composition formed in the dose-concentrate container is added to an IV (intravenous) container containing a suitable aqueous solvent.
  • Useful solvents are standard solutions for injection as previously described (e.g., 5% dextrose or sterile water etc.).
  • Typical unit dosage IV bags are conventional glass or plastic containers having inlet and outlet means and having standard (e.g., 50 ml, 100 ml and 150 ml) capacities.
  • the concentrated solution of lyophilized pharmaceutical formulation of the invention is added to the unit dose IV bag in an amount to achieve a concentration of about 8 to about 90 mg of Zosyn® per ml and preferably from about 20 to about 80 mg per ml.
  • other pharmaceutically acceptable additive agents may be added to the lyophilized preparations of the present invention.
  • Zosyn® 4.5 g as a frozen bag is first thawed or reconstituted, as appropriate:
  • a typical frozen bag of contains upon thawing the following ingredients:
  • Tazobactam Sodium about 5 mg/ml
  • Dextrose Hydrous USP about 20 mg/ml
  • Zosyn® containing solutions, other than frozen bags are prepared by reconstituting the lyophilized cake with a 20 ml portion of Dextrose 5% (water), transferring the resulting solution into the IV-bag through a 0.2 uM syringe filter, and then rinsing the vial with a second 20 ml portion of Dextrose 5% (water).
  • the rinse liquid is also recovered and added to the IV bag through a 0.2 uM syringe filter.
  • the fluid in the bag is mixed with gentle inversions for about 30 seconds.
  • aminoglycosides When added, aminoglycosides are added immediately. The fluid in the bag is mixed with gentle inversions for about 30 seconds.
  • a 50 ml sample is drawn with a 60 cc syringe fitted with a 21 -gauge needle.
  • a clean, particle free vial is rinsed with water for injection, and then filled with about 45 ml of the sample. HIAC testing is performed immediately. • Into a suitably sized sample vial, a 3 ml sample is prepared for HPLC testing.
  • HPLC testing is begun within an hour of sample preparation (Table 1).
  • the remainder of the Zosyn® admixture samples (about 50 ml) are stored in a closed cabinet in the laboratory, at ambient temperature and tested again 24 hours later (Table 1).
  • HPLC high pressure liquid chromatography
  • a typical lyophilized vial contains:
  • Tazobactam Sodium about 500 mg.
  • the following TABLE I has been divided into different sections (SUBTABLE IA, SUBTABLE IB, SUBTABLE IC, SUBTABLE ID AND SUBTABLE IE). Results shown in the same SUBTABLE represent experiments carried out on the same day with the same batch of Zosyn® containing solution.
  • SOLUTION A b) Adjust pH to 6.5 with sodium Bicarbonate, USP; c) Optionally adding an aminoglycoside; d) Adjust volume to 200 liters with additional water for injection, USP to give a bulk solution.
  • Process for Lyophilization a) The bulk solution is optionally passed through a 0.2uM filter; b) Approximately 16.9 ml are filled into each suitable lyophilization vial; c) Each vial is fitted with a suitable lyophilization stopper, inserted approximately half way to facilitate venting of water vapor; d) Vials are loaded on a lyophilizer shelf prechilled to 5° C; e) Vials are frozen to a temperature below -35°C , and held for 4 hours; f) The lyophilizer is evacuated to a pressure not exceeding 300 uM Hg (micrometers of mercury) (40 pascals); g) Shelf temperature is gradually raised to 5° C; h) The 5°C shelf temperature is maintained for about 30 hours; i) Shelf temperature is then increased to 45° C over a period of 18 hours; j) The 45°C shelf temperature is maintained for 10 hours; k) Shelf temperature is reduced to 30°C, and maintained for 1 hour; I) The chamber is repress

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Abstract

On a découvert qu'un agent chélatant d'acide aminocarboxylique, de préférence EDTA, ou un de ses sels, étaient efficaces pour inhiber la formation de particules dans des compositions de pipéracilline/tazobactame. Cette composition peut également contenir un tampon, de préférence citrate, et éventuellement un aminoglycoside. Ce produit peut se présenter sous la forme d'une composition congelée qu'on peut décongeler afin de l'utiliser. Ce produit peut également se présenter sous la forme d'une poudre cryodesséchée pouvant être reconstituée par apport d'un véhicule aqueux afin d'obtenir une nouvelle solution.
PCT/US2003/011340 2003-04-14 2003-04-14 Compositions d'injection contenant piperacilline et tazobactame WO2004098643A1 (fr)

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WO2005074925A1 (fr) * 2004-01-30 2005-08-18 Wyeth Compositions contenant de la piperacilline et du tazobactame
WO2006044600A1 (fr) * 2004-10-14 2006-04-27 Wyeth Préparations contenant de la pipéracilline, du tazobactam et un acide aminocarboxylique dilués dans du lactate de sodium
EP1759697A1 (fr) * 2005-09-02 2007-03-07 ACS DOBFAR S.p.A. Composition pharmaceutique contenant au mois deux principes actifs
EP1468697B1 (fr) * 2003-04-14 2007-12-26 Wyeth Holdings Corporation Compositions injectables contenant de la piperacilline et du tazobactame
EP1974721A1 (fr) * 2007-03-22 2008-10-01 ACS DOBFAR S.p.A. Composition pharmaceutique stérile injectable avec sodium de pipéracilline et sodium de tazobactan en tant que principes actifs
US8110209B2 (en) 2002-12-20 2012-02-07 Xeris Pharmaceuticals Inc. Intracutaneous injection
CN102716435A (zh) * 2012-05-05 2012-10-10 周士菊 一种治疗糖尿病足的中药泡足剂
CN102018713B (zh) * 2009-09-11 2013-01-23 北京四环新盛医药科技有限公司 一种药物组合物
US8476425B1 (en) 2012-09-27 2013-07-02 Cubist Pharmaceuticals, Inc. Tazobactam arginine compositions
US8697644B2 (en) 2011-03-10 2014-04-15 Xeris Pharmaceuticals, Inc. Stable formulations for parenteral injection of peptide drugs
US8906898B1 (en) 2013-09-27 2014-12-09 Calixa Therapeutics, Inc. Solid forms of ceftolozane
US8968753B2 (en) 2013-03-15 2015-03-03 Calixa Therapeutics, Inc. Ceftolozane-tazobactam pharmaceutical compositions
US9018162B2 (en) 2013-02-06 2015-04-28 Xeris Pharmaceuticals, Inc. Methods for rapidly treating severe hypoglycemia
US9044485B2 (en) 2013-03-15 2015-06-02 Calixa Therapeutics, Inc. Ceftolozane antibiotic compositions
US9125805B2 (en) 2012-06-27 2015-09-08 Xeris Pharmaceuticals, Inc. Stable formulations for parenteral injection of small molecule drugs
US9138479B2 (en) 2011-10-31 2015-09-22 Xeris Pharmaceuticals, Inc. Formulations for the treatment of diabetes
US9649364B2 (en) 2015-09-25 2017-05-16 Xeris Pharmaceuticals, Inc. Methods for producing stable therapeutic formulations in aprotic polar solvents
US9687527B2 (en) 2010-07-19 2017-06-27 The Regents Of The University Of Colorado, A Body Corporate Stable glucagon formulations for the treatment of hypoglycemia
US9872906B2 (en) 2013-03-15 2018-01-23 Merck Sharp & Dohme Corp. Ceftolozane antibiotic compositions
WO2018025248A1 (fr) * 2016-08-05 2018-02-08 Jodas Expoim Private Limited Injection d'edta et son procédé de fabrication.
US10376496B2 (en) 2013-09-09 2019-08-13 Merck, Sharp & Dohme Corp. Treating infections with ceftolozane/tazobactam in subjects having impaired renal function
CN112618486A (zh) * 2020-12-24 2021-04-09 浙江昂利康制药股份有限公司 一种注射用混悬油剂及其制备方法
US11020403B2 (en) 2017-06-02 2021-06-01 Xeris Pharmaceuticals, Inc. Precipitation resistant small molecule drug formulations
US11129940B2 (en) 2014-08-06 2021-09-28 Xeris Pharmaceuticals, Inc. Syringes, kits, and methods for intracutaneous and/or subcutaneous injection of pastes
CN115554298A (zh) * 2021-07-01 2023-01-03 北京诺康达医药科技股份有限公司 一种他唑巴坦和哌拉西林的联合制剂及其制备方法
US11590205B2 (en) 2015-09-25 2023-02-28 Xeris Pharmaceuticals, Inc. Methods for producing stable therapeutic glucagon formulations in aprotic polar solvents

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WO2003088914A2 (fr) * 2002-04-18 2003-10-30 The University Of Iowa Research Foundation Procede pour inhiber et traiter de films biologiques au moyen de chelateurs metalliques

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US8790679B2 (en) 2002-12-20 2014-07-29 Xeris Pharmaceuticals, Inc. Intracutaneous paste composition
US9314424B2 (en) 2002-12-20 2016-04-19 Xeris Pharmaceuticals, Inc. Pastes for injection of a therapeutic agent
US8110209B2 (en) 2002-12-20 2012-02-07 Xeris Pharmaceuticals Inc. Intracutaneous injection
EP1468697B1 (fr) * 2003-04-14 2007-12-26 Wyeth Holdings Corporation Compositions injectables contenant de la piperacilline et du tazobactame
WO2005074925A1 (fr) * 2004-01-30 2005-08-18 Wyeth Compositions contenant de la piperacilline et du tazobactame
WO2006044600A1 (fr) * 2004-10-14 2006-04-27 Wyeth Préparations contenant de la pipéracilline, du tazobactam et un acide aminocarboxylique dilués dans du lactate de sodium
US7964589B2 (en) 2005-09-02 2011-06-21 Acs Dobfar S.P.A. Injectable sterile pharmaceutical formulation containing at least two active principles
CN1923285B (zh) * 2005-09-02 2010-06-23 艾斯.多伯法股份公司 含有至少两种活性成分的注射用无菌药物制剂
EP1759697A1 (fr) * 2005-09-02 2007-03-07 ACS DOBFAR S.p.A. Composition pharmaceutique contenant au mois deux principes actifs
EP1974721A1 (fr) * 2007-03-22 2008-10-01 ACS DOBFAR S.p.A. Composition pharmaceutique stérile injectable avec sodium de pipéracilline et sodium de tazobactan en tant que principes actifs
US8765190B2 (en) 2007-03-22 2014-07-01 Acs Dobfar S.P.A. Injectable sterile pharmaceutical composition with piperacillin sodium and tazobactam sodium as active principles
CN102018713B (zh) * 2009-09-11 2013-01-23 北京四环新盛医药科技有限公司 一种药物组合物
US9687527B2 (en) 2010-07-19 2017-06-27 The Regents Of The University Of Colorado, A Body Corporate Stable glucagon formulations for the treatment of hypoglycemia
US9302010B2 (en) 2011-03-10 2016-04-05 Xeris Pharmaceuticals, Inc. Stable formulations for parenteral injection of peptide drugs
US10987399B2 (en) 2011-03-10 2021-04-27 Xeris Pharmaceuticals, Inc. Stable formulations for parenteral injection of peptide drugs
US9339545B2 (en) 2011-03-10 2016-05-17 Xeris Pharmaceuticals, Inc. Stable formulations for parenteral injection of peptide drugs
US8697644B2 (en) 2011-03-10 2014-04-15 Xeris Pharmaceuticals, Inc. Stable formulations for parenteral injection of peptide drugs
US9295724B2 (en) 2011-03-10 2016-03-29 Xeris Pharmaceuticals, Inc. Stable formulations for parenteral injection of peptide drugs
US9138479B2 (en) 2011-10-31 2015-09-22 Xeris Pharmaceuticals, Inc. Formulations for the treatment of diabetes
CN102716435A (zh) * 2012-05-05 2012-10-10 周士菊 一种治疗糖尿病足的中药泡足剂
US10765683B2 (en) 2012-06-27 2020-09-08 Xeris Pharmaceuticals, Inc. Stable formulations for parenteral injection of small molecule drugs
US9125805B2 (en) 2012-06-27 2015-09-08 Xeris Pharmaceuticals, Inc. Stable formulations for parenteral injection of small molecule drugs
US11446310B2 (en) 2012-06-27 2022-09-20 Xeris Pharmaceuticals, Inc. Stable formulations for parenteral injection of small molecule drugs
US8476425B1 (en) 2012-09-27 2013-07-02 Cubist Pharmaceuticals, Inc. Tazobactam arginine compositions
US9642894B2 (en) 2013-02-06 2017-05-09 Xeris Pharmaceuticals, Inc. Compositions for rapidly treating severe hypoglycemia
US9018162B2 (en) 2013-02-06 2015-04-28 Xeris Pharmaceuticals, Inc. Methods for rapidly treating severe hypoglycemia
US8968753B2 (en) 2013-03-15 2015-03-03 Calixa Therapeutics, Inc. Ceftolozane-tazobactam pharmaceutical compositions
US9320740B2 (en) 2013-03-15 2016-04-26 Merck Sharp & Dohme Corp. Ceftolozane-tazobactam pharmaceutical compositions
US9044485B2 (en) 2013-03-15 2015-06-02 Calixa Therapeutics, Inc. Ceftolozane antibiotic compositions
US9872906B2 (en) 2013-03-15 2018-01-23 Merck Sharp & Dohme Corp. Ceftolozane antibiotic compositions
US11278622B2 (en) 2013-03-15 2022-03-22 Merck Sharp & Dohme Corp. Ceftolozane antibiotic compositions
US9925196B2 (en) 2013-03-15 2018-03-27 Merck Sharp & Dohme Corp. Ceftolozane-tazobactam pharmaceutical compositions
US20150150883A1 (en) * 2013-03-15 2015-06-04 Calixa Therapeutics, Inc. Ceftolozane-tazobactam pharmaceutical compositions
US10420841B2 (en) 2013-03-15 2019-09-24 Merck, Sharp & Dohme Corp. Ceftolozane antibiotic compositions
US10376496B2 (en) 2013-09-09 2019-08-13 Merck, Sharp & Dohme Corp. Treating infections with ceftolozane/tazobactam in subjects having impaired renal function
US10933053B2 (en) 2013-09-09 2021-03-02 Merck Sharp & Dohme Corp. Treating infections with ceftolozane/tazobactam in subjects having impaired renal function
US8906898B1 (en) 2013-09-27 2014-12-09 Calixa Therapeutics, Inc. Solid forms of ceftolozane
US11129940B2 (en) 2014-08-06 2021-09-28 Xeris Pharmaceuticals, Inc. Syringes, kits, and methods for intracutaneous and/or subcutaneous injection of pastes
US10485850B2 (en) 2015-09-25 2019-11-26 Xeris Pharmaceuticals, Inc. Methods for producing stable therapeutic formulations in aprotic polar solvents
US9649364B2 (en) 2015-09-25 2017-05-16 Xeris Pharmaceuticals, Inc. Methods for producing stable therapeutic formulations in aprotic polar solvents
US11590205B2 (en) 2015-09-25 2023-02-28 Xeris Pharmaceuticals, Inc. Methods for producing stable therapeutic glucagon formulations in aprotic polar solvents
WO2018025248A1 (fr) * 2016-08-05 2018-02-08 Jodas Expoim Private Limited Injection d'edta et son procédé de fabrication.
US11020403B2 (en) 2017-06-02 2021-06-01 Xeris Pharmaceuticals, Inc. Precipitation resistant small molecule drug formulations
US11833157B2 (en) 2017-06-02 2023-12-05 Xeris Pharmaceuticals, Inc. Precipitation resistant small molecule drug formulations
CN112618486A (zh) * 2020-12-24 2021-04-09 浙江昂利康制药股份有限公司 一种注射用混悬油剂及其制备方法
CN112618486B (zh) * 2020-12-24 2023-07-18 浙江昂利康制药股份有限公司 一种注射用混悬油剂及其制备方法
CN115554298A (zh) * 2021-07-01 2023-01-03 北京诺康达医药科技股份有限公司 一种他唑巴坦和哌拉西林的联合制剂及其制备方法

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