WO2001034128A2 - Admixture for intravenous administration of linezolid and other antibacterial agents - Google Patents

Admixture for intravenous administration of linezolid and other antibacterial agents Download PDF

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Publication number
WO2001034128A2
WO2001034128A2 PCT/US2000/028872 US0028872W WO0134128A2 WO 2001034128 A2 WO2001034128 A2 WO 2001034128A2 US 0028872 W US0028872 W US 0028872W WO 0134128 A2 WO0134128 A2 WO 0134128A2
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Prior art keywords
pharmaceutical composition
linezolid
composition according
antibacterial agent
aqueous pharmaceutical
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PCT/US2000/028872
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French (fr)
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WO2001034128A3 (en
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Donald H. Batts
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Pharmacia & Upjohn Company
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Priority to AU15721/01A priority Critical patent/AU1572101A/en
Publication of WO2001034128A2 publication Critical patent/WO2001034128A2/en
Publication of WO2001034128A3 publication Critical patent/WO2001034128A3/en

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    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention is a mixture of sterile solutions of linezolid and particular antibacterial agents.
  • Also disclosed is a method of treating a human with a bacterial infection which comprises IVadministeration to the infected human an aqueous pharmaceutical composition of linezolid and one or more antibacterial agents selected from the group consisting of an aminoglycosides, cephalosporins, aztreonam, quinolones and penicillins and pharmaceutically acceptable salts thereof where such exist.
  • Linezolid (S)-N-[[3-[3-fluoro-4-(4-mo holinyl)phenyl]-2-oxo-5- oxazolidinyl]methyl]acetamide, is a known antibacterial agent, see US Patent 5,688,792 (EXAMPLE 5).
  • Linezolid can be used as an oral tablet, capsule or oral suspension or given by IV as a sterile solution.
  • Gentamicin is a known antibacterial agent, see page 964 of the 53 rd Edition of the PDR (1999) and can be given by TV as a sterile solution.
  • Tobramycin is a known antibacterial agent, see page 599 and 1562 of the 53 rd Edition of the PDR (1999) and can be given by IV as a sterile solution.
  • Aztreonam is a known antibacterial agent, see page 820 of the 53 rd Edition of the PDR (1999) and can be given by IV as a sterile solution.
  • Cefazolin is a known antibacterial agent, see page 3023 of the 53 rd Edition of the PDR (1999) and can be given by IV as a sterile solution.
  • Ceftazidime is a known antibacterial agent, see page 1100 of the 53 rd Edition of the PDR (1999) and can be given by IV as a sterile solution.
  • Piperacilhn is a known antibacterial agent, see page 1531 of the 53 rd Edition of the PDR (1999) and can be given by IV as a sterile solution.
  • Ciprofoxacin is a known antibacterial agent, see page 647 of the 53 rd Edition of the PDR (1999) and can be given by IV as a sterile solution.
  • Ofloxacin is a known antibacterial agent, see page 2180 of the 53 rd Edition of the PDR (1999) and can be given by IV as a sterile solution.
  • Levofloxacin is a known antibacterial agent, see page 2192 of the 53 rd Edition of the PDR (1999) and can be given by IV as a sterile solution.
  • Linezolid is a member of a new class of antibacterial agent known as an oxazolidinone and is useful in treating infections caused by gram positive bacteria including gram positive infections that are resistant to other gram positive antibacterial agents.
  • a physician does not know for sure whether or not a bacterial infection is caused by gram positive bacteria or gram negative bacteria or both. Therefore, often a physician desires to use an agent(s) which are effective against both gram positive and gram negative bacteria. Hence, often a physician will combine two agents, one useful against gram positive bacteria and the other useful against gram negative bacteria. The following agents are known to be useful against gram negative bacteria, gentamicin, tobramycin, aztreonam.
  • antibacterial agents are known as 'broad spectrum antibacterials" because they are active against both gram positive and gram negative bacteria, cefazolin, ceftazidime, piperacilhn, ciprofloxacin, ofloxacin and levofloxacin.
  • the antibacterial agent be selected from the group consisting of gentamicin, tobramycin, aztreonam, cefazolin, ceftazidime, piperacilhn, ciprofloxacin, ofloxacin and levofloxacin.
  • the concentration of both linezolid and the other antibacterial agents will be affected by a dilution factor as is well known to those skilled in the art.
  • the actual final concentration of linezolid and/or the other antibacterial agents is not very important. The concentration can vary considerably. What is critical is that the patient receive an antibacterial effective amount of linezolid and an antibacterial effective amount of the other antibacterial agent.
  • the effective amounts for each of these agents, for adults is as follows: linezolid (about 200 mg to about 600 mg/dose), gentamicin (about 1 mg/kg to about 7.5 mg/kg/dose), tobramycin (about 1 mg/kg to about 7.5 mg/kg/dose), aztreonam (about 500 mg to about 2 g/dose), ciprofloxacin (about 200 mg to about 400 mg/dose), ofloxacin (about 200 mg to about 400 mg/dose), levofloxacin (about 250 mg to about 500 mg/dose), piperacilhn sodium (about 2 g to about 4 g/dose), piperacillin/tazobactam (about 2 g to about 4 g/dose based on piperacilhn), ceftazidime (about 250 mg to about 2 g/dose) and cefazolin (about 500 mg to about 1 g/dose).
  • linezolid about 200 mg to about 600 mg/dose
  • gentamicin about 1 mg/kg to about
  • the aqueous pharmaceutical composition of the present invention be an aqueous solution. It is further preferred that the aqueous solution be a sterile solution.
  • an aqueous pharmaceutical composition of linezolid and an antibacterial agent selected from the group consisting of gentamicin, tobramycin, aztreonam, cefazolin, ceftazidime, piperacilhn, ciprofloxacin, ofloxacin and levofloxacin.
  • an aqueous pharmaceutical composition of linezolid and an aqueous pharmaceutical composition of one of the following agents gentamicin, tobramycin, aztreonam, cefazolin, ceftazidime, piperacilhn, ciprofloxacin, ofloxacin and levofloxacin.
  • each antibacterial agent is being diluted by the other as explained above.
  • solid antibacterial agent selected from the group consisting of gentamicin, tobramycin, aztreonam, cefazolin, ceftazidime, piperacilhn, ciprofloxacin, ofloxacin and levofloxacin to the linezolid aqueous pharmaceutical composition.
  • solid linezolid powder can be added to the aqueous pharmaceutical composition of one of the other antibacterial agents.
  • solid linezolid powder can be added to the aqueous pharmaceutical composition of one of the other antibacterial agents.
  • non-linezolid antibacterial agents it can be added in the same way.
  • the solid antibacterial agent or linezolid can be suspended or dissolved in an appropriate solvent such as water, ethanol, polyethylene glycol, propylene glycol, DMSO, DMAC, DMI, glycerine and M-pyrol and mixtures thereof.
  • the concentrate can then be added to the aqueous pharmaceutical composition.
  • the advantage of admixing is to lower the total volume administered and/or to use the same infusion line. The lowering of the total volume to be given to the patient is accomplished in a number of ways by using the admixing of the present invention. For example, an number of antibacterial agents come as concentrates to be diluted with acceptable diluents.
  • the diluent used is the linezolid sterile solution there by saving the volume of diluent normally used to dilute the other antibacterial agent.
  • other antibacterial agents are marketed as sterile powders which are then compounded into concentrates for dilution. With these sterile powders the first step is performed in making the concentrate. But rather then using a diluent that has no active ingredient, the concentrate is added to linezolid sterile solution (as described above). This reduces the overall volume of aqueous composition administered to the patient.
  • the antibacterial agent is marketed as a ready to use large volume parenteral sterile solution, there is no way to reduce the volume unless it is combined with linezolid in a concentrated form. If it is combined with sterile aqueous linezolid solution the advantage is that the same infusion line can be used for administering both the linezolid and the other antibacterial agent.
  • the linezolid TV solution is formulated by heating water for injection to 60°. Next the sodium citrate, citric acid and dextrose are added and stirred until dissolved. An aqueous slurry of linezolid is added to the previous mixture and stirred until dissolved. The mixture is cooled to 25° with stirring. The pH is measured and adjusted if necessary. Last the mixture is brought to volume, if necessary, with water for injection. The mixture is filtered, filled into infusion containers, over wrapped and terminally moist heat sterilized.
  • the aqueous solution for TV administration can be placed in the container which is selected from the group consisting of a bag, a bottle, a vial, a large volume parenteral, a small volume parenteral, a prefilled syringe and a cassette.
  • a vial is a bottle.
  • the container be a bag, a bottle, a vial or a prefilled syringe. It is more preferred that the container be a bag or bottle. It is most preferred that the container be a bag. The shape and/or size of the container is unimportant. It is preferred that the container be a bag sufficient to hold 25 to 2,000 mL of TV solution. It is preferred that the linezolid mixture be put in bags in amounts of 100, 200 or 300 mL of solution however smaller or larger volumes are acceptable.
  • the container-solution contact surface material be primarily a polyolefin; the remainder of the container can be made from polyolefin or other materials. It is preferred that the container-solution contact surface is made of from about 50 to about 100% polyolefin. It is more preferred that the container-solution contact surface is made of from about 70 to about 90% polyolefin. It is more preferred that the container-solution contact surface is made of from about 80% polyolefin. It is even more preferred that the container-solution contact surface is made of polyolefin.
  • Polyolefins include, for example, polyethylene, polypropylene, polybutenes, polyisoprenes and polypentenes and copolymers and mixtures thereof. It is preferred that the polyolefin be selected from the group consisting of polyethylene and polypropylene It is more preferred that the polyolefin be polypropylene or mixture of polypropylene and polyethylene
  • the exact dosage and frequency of administration of the aqueous pharmaceutical composition depends on the particular combination of linezolid and antibacterial agent used, the particular condition being treated, the severity ot the condition being treated, the age, weight, general physical condition of the particular patient, other medication the individual may be taking as is well known to those skilled in the art and can be more accurately determined by measuring the blood level or concentration of the antibacterial agents in the patient's blood and/or the patient's response to the particular condition being treated
  • Linezolid refers to (S)-N-[[3-[3-Fluoro-4-(4-morphohnyl)phenyl]-2-oxo-5- oxazohd ⁇ nyl]methyl]acetam ⁇ de and pharmaceutically acceptable salts thereof
  • Physiological saline refers to an aqueous 0 9% sodium chloride solution
  • Pharmaceutically acceptable refers to those properties and or substances which are acceptable to the patient from a pharmacological/toxicological point of view and to the manufacturing pharmaceutical chemist from a physical chemical point of view regarding composition, formulation, stability, patient acceptance and bioavailabi ty
  • the ratios of solvents used are volume/volume (v/v)
  • the solubility of a solid in a solvent is used the ratio of the solid to the solvent is weight/volume (wt/v)
  • qsad refers to addition of a sufficient quantity of that material to bring the final composition to the specified volume
  • DMSO dimethylsulfoxide [CH 3 -SO-CH 3 ]
  • DMAC dimethylacetamide [CH 3 -CO-N(CH 3 ) 2 ]
  • DMI refers to dimethyl isosorbide
  • M-PYROL refers to N-methyl-2-pyrrohdone
  • Linezolid sterile solution (PREPARATION 1) is admixed with commercial gentamicin concentrate. One admixture is stored at 4° and another at 23°. The admixtures were sampled at one, three, five days and seven days. The samples were tested for both chemical and physical stability. The results of the samples for both temperatures show there is good chemical and physical stability over 7 days at 4° and 5 days at 23°. It is concluded that the admixture of linezolid and commercial gentamicin concentrate is acceptable for human use.
  • Linezolid and Tobramycin Sulfate Following the general procedure of EXAMPLE 1 and making non-critical variations, Linezolid sterile solution (PREPARATION 1) is admixed with commercial tobramycin concentrate The results of the samples for both temperatures show there is good chemical and physical stability over 7 days at 4° and 1 day at 23° It is concluded that the admixture of linezolid and commercial tobramycin concentrate is acceptable for human use
  • Linezolid sterile solution PREPARATION 1
  • PREPARATION 1 Linezolid sterile solution
  • Linezolid sterile solution PREPARATION 1
  • PREPARATION 1 Linezolid sterile solution
  • results of the samples for both temperatures show there is good chemical and physical stability over 7 days at 4° and 3 day at 23°. It is concluded that the admixture of linezolid and commercial cefazolin concentrate is acceptable for human use.
  • Linezolid sterile solution PREPARATION 1
  • PREPARATION 1 Linezolid sterile solution
  • results of the samples for both temperatures show there is good chemical and physical stability over 7 days at 4° and 1 day at 23°. It is concluded that the admixture of linezolid and commercial ceftazidime concentrate is acceptable for human use.
  • EXAMPLE 6 Linezolid and Piperacilhn Sodium
  • Linezolid sterile solution PREPARATION 1
  • PREPARATION 1 Linezolid sterile solution
  • the results of the samples for both temperatures show there is good chemical and physical stability over 7 days at 4° and 3 days at 23°. It is concluded that the admixture of linezolid and commercial piperacilhn concentrate is acceptable for human use.
  • Linezolid sterile solution PREPARATION 1
  • PCTENT 1 Linezolid sterile solution
  • results of the samples show there is good chemical and physical stability over 7 days at 23°. It is concluded that the admixture of linezolid and commercial ciprofloxacin concentrate is acceptable for human use.
  • EXAMPLE 8 Linezolid and Ofloxacin Following the general procedure of EXAMPLE 1 and making non-c ⁇ tical variations, Linezolid sterile solution (PREPARATION 1) is admixed with commercial ofloxacin concentrate The results of the samples for both temperatures show there is good chemical and physical stability over 7 days at 4° and 7 days at 23° It is concluded that the admixture of linezolid and commercial ofloxacin concentrate is acceptable for human use.
  • PREPARATION 1 Linezolid and Ofloxacin
  • Linezolid sterile solution PREPARATION 1
  • PCL Linezolid sterile solution
  • results of the samples for both temperatures show there is good chemical and physical stability over 7 days at 4° and 7 days at 23° It is concluded that the admixture of linezolid and commercial levofloxacin concentrate is acceptable for human use

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Abstract

The present invention is an aqueous admixture of linezolid and an antibacterial agent selected from the group consisting of gentamicin, tobramycin, aztreonam, cefazolin, ceftazidime, piperacillin, ciprofloxacin, ofloxacin, levofloxacin for IV administration.

Description

ADMIXTURE OF LINEZOLID AND OTHER ANTIBACTERIAL AGENTS CROSS-REFERENCE TO RELATED APPLICATIONS
None.
BACKGROUND OF THE INVENTION 1. Field of the Invention
The present invention is a mixture of sterile solutions of linezolid and particular antibacterial agents.
2. Description of the Related Art US Patent 5,688,792 (EXAMPLE 5) discloses the antibacterial agent, linezolid.
The 53rd edition of the Physicians Desk Reference (PDR), Medical Economics Company, Montvale, NJ, 1999 discloses the other antibacterial agents of the invention. See for gentamicin (p. 964) , tobramycin (599, 1562), aztreonam (p.820), cefazolin (p. 3023), ceftazidime (p.l 100), piperacilhn (p. 1531), ciprofloxacin (p. 647), ofloxacin (p. 2180), and levofloxacin (2192).
It is known to those skilled in the art that mixing solutions of pharmaceutical agents can result in physical and/or chemical instability rendering the mixture unfit for pharmaceutical use.
US provisional patent application Serial No. 60/191,383 discloses a polyolefin lined container for linezolid IN pharmaceutical formulations.
SUMMARY OF INVENTION Disclosed is an aqueous pharmaceutical composition for TV administration of linezolid and one or more antibacterial agents selected from the group consisting of an aminoglycosides, cephalosporins, aztreonam, quinolones and penicillins and pharmaceutically acceptable salts thereof where such exist.
Also disclosed is a method of treating a human with a bacterial infection which comprises IVadministeration to the infected human an aqueous pharmaceutical composition of linezolid and one or more antibacterial agents selected from the group consisting of an aminoglycosides, cephalosporins, aztreonam, quinolones and penicillins and pharmaceutically acceptable salts thereof where such exist.
DETAILED DESCRIPTION OF THE INVENTION Linezolid, (S)-N-[[3-[3-fluoro-4-(4-mo holinyl)phenyl]-2-oxo-5- oxazolidinyl]methyl]acetamide,
Figure imgf000003_0001
is a known antibacterial agent, see US Patent 5,688,792 (EXAMPLE 5). Linezolid can be used as an oral tablet, capsule or oral suspension or given by IV as a sterile solution.
Gentamicin is a known antibacterial agent, see page 964 of the 53rd Edition of the PDR (1999) and can be given by TV as a sterile solution.
Tobramycin is a known antibacterial agent, see page 599 and 1562 of the 53rd Edition of the PDR (1999) and can be given by IV as a sterile solution. Aztreonam is a known antibacterial agent, see page 820 of the 53rd Edition of the PDR (1999) and can be given by IV as a sterile solution.
Cefazolin is a known antibacterial agent, see page 3023 of the 53rd Edition of the PDR (1999) and can be given by IV as a sterile solution.
Ceftazidime is a known antibacterial agent, see page 1100 of the 53rd Edition of the PDR (1999) and can be given by IV as a sterile solution.
Piperacilhn is a known antibacterial agent, see page 1531 of the 53rd Edition of the PDR (1999) and can be given by IV as a sterile solution.
Ciprofoxacin is a known antibacterial agent, see page 647 of the 53rd Edition of the PDR (1999) and can be given by IV as a sterile solution. Ofloxacin is a known antibacterial agent, see page 2180 of the 53rd Edition of the PDR (1999) and can be given by IV as a sterile solution.
Levofloxacin is a known antibacterial agent, see page 2192 of the 53rd Edition of the PDR (1999) and can be given by IV as a sterile solution.
Linezolid is a member of a new class of antibacterial agent known as an oxazolidinone and is useful in treating infections caused by gram positive bacteria including gram positive infections that are resistant to other gram positive antibacterial agents.
Often in medical treatment a physician does not know for sure whether or not a bacterial infection is caused by gram positive bacteria or gram negative bacteria or both. Therefore, often a physician desires to use an agent(s) which are effective against both gram positive and gram negative bacteria. Hence, often a physician will combine two agents, one useful against gram positive bacteria and the other useful against gram negative bacteria. The following agents are known to be useful against gram negative bacteria, gentamicin, tobramycin, aztreonam. The following antibacterial agents are known as 'broad spectrum antibacterials" because they are active against both gram positive and gram negative bacteria, cefazolin, ceftazidime, piperacilhn, ciprofloxacin, ofloxacin and levofloxacin.
If one combines sterile solutions of two different agents it is quite possible that there will not be chemical or physical compatibility between the two different sterile solutions and/or agents. In fact, for this very reason, the corporation conducting the clinical trials on linezolid specifically warned physicians against combining the sterile solution of linezolid and other antibacterial agents.
It now has been found that there is both chemical and physical stability between linezolid sterile solution and sterile solutions of the following antibacterial agents; aminoglycosides, cephalosporins, aztreonam, quinolones and penicillins and pharmaceutically acceptable salts thereof where such exist. It is preferred that the antibacterial agent be selected from the group consisting of gentamicin, tobramycin, aztreonam, cefazolin, ceftazidime, piperacilhn, ciprofloxacin, ofloxacin and levofloxacin.
When combining an aqueous composition of linezolid with an aqueous composition of the other antibacterial agents the concentration of both linezolid and the other antibacterial agents will be affected by a dilution factor as is well known to those skilled in the art. The actual final concentration of linezolid and/or the other antibacterial agents is not very important. The concentration can vary considerably. What is critical is that the patient receive an antibacterial effective amount of linezolid and an antibacterial effective amount of the other antibacterial agent. The effective amounts for each of these agents, for adults, is as follows: linezolid (about 200 mg to about 600 mg/dose), gentamicin (about 1 mg/kg to about 7.5 mg/kg/dose), tobramycin (about 1 mg/kg to about 7.5 mg/kg/dose), aztreonam (about 500 mg to about 2 g/dose), ciprofloxacin (about 200 mg to about 400 mg/dose), ofloxacin (about 200 mg to about 400 mg/dose), levofloxacin (about 250 mg to about 500 mg/dose), piperacilhn sodium (about 2 g to about 4 g/dose), piperacillin/tazobactam (about 2 g to about 4 g/dose based on piperacilhn), ceftazidime (about 250 mg to about 2 g/dose) and cefazolin (about 500 mg to about 1 g/dose). One skilled in the art would be able to calculate an effective amount for children (of various ages and weights) as well as the elderly.
It is preferred that the aqueous pharmaceutical composition of the present invention be an aqueous solution. It is further preferred that the aqueous solution be a sterile solution.
There are different ways that one skilled in the art could make an aqueous pharmaceutical composition of linezolid and an antibacterial agent selected from the group consisting of gentamicin, tobramycin, aztreonam, cefazolin, ceftazidime, piperacilhn, ciprofloxacin, ofloxacin and levofloxacin. First, one can combine an aqueous pharmaceutical composition of linezolid and an aqueous pharmaceutical composition of one of the following agents; gentamicin, tobramycin, aztreonam, cefazolin, ceftazidime, piperacilhn, ciprofloxacin, ofloxacin and levofloxacin. If this is done it must be realized that the concentration of each antibacterial agent is being diluted by the other as explained above. Alternatively, so as not to dilute the linezolid aqueous pharmaceutical composition, it is preferred to add solid antibacterial agent selected from the group consisting of gentamicin, tobramycin, aztreonam, cefazolin, ceftazidime, piperacilhn, ciprofloxacin, ofloxacin and levofloxacin to the linezolid aqueous pharmaceutical composition. Also so as not to dilute an aqueous pharmaceutical composition of one of the following antibacterial agents, gentamicin, tobramycin, aztreonam, cefazolin, ceftazidime, piperacilhn, ciprofloxacin, ofloxacin and levofloxacin, solid linezolid powder can be added to the aqueous pharmaceutical composition of one of the other antibacterial agents. In addition, should more than one of the non-linezolid antibacterial agents be desired for use with linezolid, it can be added in the same way. Besides adding solid antibacterial agent to a solution, to keep the dilution factor low, the solid antibacterial agent or linezolid can be suspended or dissolved in an appropriate solvent such as water, ethanol, polyethylene glycol, propylene glycol, DMSO, DMAC, DMI, glycerine and M-pyrol and mixtures thereof. The concentrate can then be added to the aqueous pharmaceutical composition. The advantage of admixing is to lower the total volume administered and/or to use the same infusion line. The lowering of the total volume to be given to the patient is accomplished in a number of ways by using the admixing of the present invention. For example, an number of antibacterial agents come as concentrates to be diluted with acceptable diluents. With these concentrates the diluent used is the linezolid sterile solution there by saving the volume of diluent normally used to dilute the other antibacterial agent. Alternatively, other antibacterial agents are marketed as sterile powders which are then compounded into concentrates for dilution. With these sterile powders the first step is performed in making the concentrate. But rather then using a diluent that has no active ingredient, the concentrate is added to linezolid sterile solution (as described above). This reduces the overall volume of aqueous composition administered to the patient. In situations where the antibacterial agent is marketed as a ready to use large volume parenteral sterile solution, there is no way to reduce the volume unless it is combined with linezolid in a concentrated form. If it is combined with sterile aqueous linezolid solution the advantage is that the same infusion line can be used for administering both the linezolid and the other antibacterial agent.
US Patent 5,688,792 discloses that oxazolidinones can be administered IV. The preferred formulation for linezolid IV solution is:
Linezolid 2.0 mg/mL
Sodium Citrate Dihydrate (USP) 1.64 mg/mL
Citric Acid Anhydrous (USP) 0.85 mg/mL
Dextrose Monohydrate (USP) 50.24 mg/mL Hydrochloric Acid (10%) q.s. to pH 4.8 (pH 4.6 to 5.0)
Sodium hydroxide (10%) q.s. to pH 4.8 (pH 4.6 to 5.0) Water for Injection (USP) q.s.ad l.O raL
The linezolid TV solution is formulated by heating water for injection to 60°. Next the sodium citrate, citric acid and dextrose are added and stirred until dissolved. An aqueous slurry of linezolid is added to the previous mixture and stirred until dissolved. The mixture is cooled to 25° with stirring. The pH is measured and adjusted if necessary. Last the mixture is brought to volume, if necessary, with water for injection. The mixture is filtered, filled into infusion containers, over wrapped and terminally moist heat sterilized. The aqueous solution for TV administration can be placed in the container which is selected from the group consisting of a bag, a bottle, a vial, a large volume parenteral, a small volume parenteral, a prefilled syringe and a cassette. It is realized that a vial is a bottle. However, those skilled in the art use the term "bottle" to refers to larger bottles and "vials" to refer to smaller bottles. It is preferred that the container be a bag, a bottle, a vial or a prefilled syringe. It is more preferred that the container be a bag or bottle. It is most preferred that the container be a bag. The shape and/or size of the container is unimportant. It is preferred that the container be a bag sufficient to hold 25 to 2,000 mL of TV solution. It is preferred that the linezolid mixture be put in bags in amounts of 100, 200 or 300 mL of solution however smaller or larger volumes are acceptable.
It is well known to those skilled in the art that pharmaceutical agents administered TV must be sterile. While there are a number of methods to sterilize an TV solution, it is preferred to terminally moist heat or steam sterilize IV solutions of oxazolidinones including those of linezolid. When the term terminally "moist heat sterilize" is used, it refers to and includes steam sterilization.
When terminally moist heat sterilizing an TV solution, the solution is placed in the container in which (1) it will be stored and then transferred to the container from which it will ultimately be administered, or (2) stored and then ultimately administered from the same container to deliver the TV solution to the patient. Therefore, it is imperative that the pharmaceutically active ingredient (oxazolidinone, linezolid) not react with the container in which it is to be terminally moist heat sterilized and stored/stored-administered. It has been found that when the container-solution contact surface is made of at least 50% polyolefin there is significantly much less loss of linezolid during and following terminal moist heat sterilization. What is essential is that the container- solution contact surface material be primarily a polyolefin; the remainder of the container can be made from polyolefin or other materials. It is preferred that the container-solution contact surface is made of from about 50 to about 100% polyolefin. It is more preferred that the container-solution contact surface is made of from about 70 to about 90% polyolefin. It is more preferred that the container-solution contact surface is made of from about 80% polyolefin. It is even more preferred that the container-solution contact surface is made of polyolefin. Polyolefins include, for example, polyethylene, polypropylene, polybutenes, polyisoprenes and polypentenes and copolymers and mixtures thereof. It is preferred that the polyolefin be selected from the group consisting of polyethylene and polypropylene It is more preferred that the polyolefin be polypropylene or mixture of polypropylene and polyethylene
The exact dosage and frequency of administration of the aqueous pharmaceutical composition depends on the particular combination of linezolid and antibacterial agent used, the particular condition being treated, the severity ot the condition being treated, the age, weight, general physical condition of the particular patient, other medication the individual may be taking as is well known to those skilled in the art and can be more accurately determined by measuring the blood level or concentration of the antibacterial agents in the patient's blood and/or the patient's response to the particular condition being treated
DEFINITIONS AND CONVENTIONS The definitions and explanations below are for the terms as used throughout this entire document including both the specification and the claims
DEFINITIONS All temperatures are in degrees Centigrade
Linezolid refers to (S)-N-[[3-[3-Fluoro-4-(4-morphohnyl)phenyl]-2-oxo-5- oxazohdιnyl]methyl]acetamιde and pharmaceutically acceptable salts thereof Physiological saline refers to an aqueous 0 9% sodium chloride solution Pharmaceutically acceptable refers to those properties and or substances which are acceptable to the patient from a pharmacological/toxicological point of view and to the manufacturing pharmaceutical chemist from a physical chemical point of view regarding composition, formulation, stability, patient acceptance and bioavailabi ty When solvent pairs are used, the ratios of solvents used are volume/volume (v/v) When the solubility of a solid in a solvent is used the ratio of the solid to the solvent is weight/volume (wt/v) qsad refers to addition of a sufficient quantity of that material to bring the final composition to the specified volume
DMSO refers to dimethylsulfoxide [CH3-SO-CH3] DMAC refers to dimethylacetamide [CH3-CO-N(CH3)2]
DMI refers to dimethyl isosorbide M-PYROL refers to N-methyl-2-pyrrohdone
EXAMPLES Without further elaboration, it is believed that one skilled in the art can, using the preceding description, practice the present invention to its fullest extent The following detailed examples describe how to prepare the various compounds and/or perform the various processes of the invention and are to be construed as merely illustrative, and not limitations of the preceding disclosure in any way whatsoever Those skilled in the art will promptly recognize appropriate variations from the procedures both as to reactants and as to reaction conditions and techniques PREPARATION 1 Linezolid sterile solution
Linezolid 2 0 mg/mL Sodium Citrate Dihydrate (USP) 1.64 mg/mL
Citric Acid Anhydrous (USP) 0.85 mg/mL
Dextrose Monohydrate (USP) 50.24 mg mL
Hydrochloric Acid (10%) q.s. to pH 4.8 (pH 4.6 to 5.0) Sodium hydroxide (10%) q.s. to pH 4.8 (pH 4.6 to 5.0) Water for Injection (USP) q.s.ad l.O mL
EXAMPLE 1 Linezolid and Gentamicin Sulfate
Linezolid sterile solution (PREPARATION 1) is admixed with commercial gentamicin concentrate. One admixture is stored at 4° and another at 23°. The admixtures were sampled at one, three, five days and seven days. The samples were tested for both chemical and physical stability. The results of the samples for both temperatures show there is good chemical and physical stability over 7 days at 4° and 5 days at 23°. It is concluded that the admixture of linezolid and commercial gentamicin concentrate is acceptable for human use. EXAMPLE 2 Linezolid and Tobramycin Sulfate Following the general procedure of EXAMPLE 1 and making non-critical variations, Linezolid sterile solution (PREPARATION 1) is admixed with commercial tobramycin concentrate The results of the samples for both temperatures show there is good chemical and physical stability over 7 days at 4° and 1 day at 23° It is concluded that the admixture of linezolid and commercial tobramycin concentrate is acceptable for human use
EXAMPLE 3 Linezolid and Aztreonam
Following the general procedure of EXAMPLE 1 and making non- critical variations, Linezolid sterile solution (PREPARATION 1) is admixed with commercial reconstituted aztreonam. The results of the samples for both temperatures show there is good chemical and physical stability over 7 days at 4° and 7 days at 23°.
It is concluded that the admixture of linezolid and commercial reconstituted aztreonam is acceptable for human use.
EXAMPLE 4 Linezolid and Cefazolin Sodium
Following the general procedure of EXAMPLE 1 and making non-critical variations, Linezolid sterile solution (PREPARATION 1) is admixed with commercial reconstituted cefazolin. The results of the samples for both temperatures show there is good chemical and physical stability over 7 days at 4° and 3 day at 23°. It is concluded that the admixture of linezolid and commercial cefazolin concentrate is acceptable for human use.
EXAMPLE 5 Linezolid and Ceftazidime
Following the general procedure of EXAMPLE 1 and making non-critical variations, Linezolid sterile solution (PREPARATION 1) is admixed with commercial reconstituted ceftazidime. The results of the samples for both temperatures show there is good chemical and physical stability over 7 days at 4° and 1 day at 23°. It is concluded that the admixture of linezolid and commercial ceftazidime concentrate is acceptable for human use. EXAMPLE 6 Linezolid and Piperacilhn Sodium
Following the general procedure of EXAMPLE 1 and making non-critical variations, Linezolid sterile solution (PREPARATION 1) is admixed with commercial reconstituted piperacilhn. The results of the samples for both temperatures show there is good chemical and physical stability over 7 days at 4° and 3 days at 23°. It is concluded that the admixture of linezolid and commercial piperacilhn concentrate is acceptable for human use.
EXAMPLE 7 Linezolid and Ciprofloxacin
Following the general procedure of EXAMPLE 1 and making non-critical variations, Linezolid sterile solution (PREPARATION 1) is admixed with commercial ciprofloxacin concentrate. The results of the samples show there is good chemical and physical stability over 7 days at 23°. It is concluded that the admixture of linezolid and commercial ciprofloxacin concentrate is acceptable for human use.
EXAMPLE 8 Linezolid and Ofloxacin Following the general procedure of EXAMPLE 1 and making non-cπtical variations, Linezolid sterile solution (PREPARATION 1) is admixed with commercial ofloxacin concentrate The results of the samples for both temperatures show there is good chemical and physical stability over 7 days at 4° and 7 days at 23° It is concluded that the admixture of linezolid and commercial ofloxacin concentrate is acceptable for human use EXAMPLE 9 Linezolid and Levofloxacin
Following the general procedure of EXAMPLE 1 and making non-cπtical variations, Linezolid sterile solution (PREPARATION 1) is admixed with commercial levofloxacin concentrate The results of the samples for both temperatures show there is good chemical and physical stability over 7 days at 4° and 7 days at 23° It is concluded that the admixture of linezolid and commercial levofloxacin concentrate is acceptable for human use
40

Claims

1 An aqueous pharmaceutical composition for IV administration of linezolid and one or more antibacterial agents selected from the group consisting of an aminoglycosides, cephalosporins, aztreonam, quinolones and penicillins and pharmaceutically acceptable salts thereof where such exist
2 An aqueous pharmaceutical composition according to claim 1 where the antibacterial agent is selected from the group consisting of gentamicin, tobramycin, aztreonam, cefazolin, ceftazidime, piperacilhn, ciprofloxacin, ofloxacin, levofloxacin
3 An aqueous pharmaceutical composition according to claim 1 where the antibacterial agent is gentamicin
4 An aqueous pharmaceutical composition according to claim 1 where the antibacterial agent is tobramycin
5 An aqueous pharmaceutical composition according to claim 1 where the antibacterial agent is aztreonam.
6. An aqueous pharmaceutical composition according to claim 1 where the antibacterial agent is cefazolin.
7 An aqueous pharmaceutical composition according to claim 1 where the antibacterial agent is ceftazidime
8 An aqueous pharmaceutical composition according to claim 1 where the antibacterial agent is piperacilhn
9 An aqueous pharmaceutical composition according to claim 1 where the antibacterial agent is ciprofloxacin
10. An aqueous pharmaceutical composition according to claim 1 where the antibacterial agent is ofloxacin.
41-
1 1. An aqueous pharmaceutical composition according to claim 1 where the antibacterial agent is levofloxacin
12 An aqueous pharmaceutical composition according to claim 1 where the aqueous composition is a solution
13 An aqueous pharmaceutical composition according to claim 12 where the solution is sterile
14 An aqueous pharmaceutical composition according to claim 1 where the linezolid-antibacterial agent mixture is made by combining an aqueous solution of linezolid and an aqueous solution of the antibacterial agent
15 An aqueous pharmaceutical composition according to claim 1 where the linezolid-antibacterial agent mixture is made by combining an aqueous solution of linezolid and solid antibacterial agent
16. An aqueous pharmaceutical composition according to claim 1 where the linezolid-antibacterial agent mixture is made by combining an aqueous solution of the antibacterial agent and solid linezolid
17 An aqueous pharmaceutical composition according to claim 1 where the linezolid-antibacterial agent mixture is made by combining an aqueous solution of linezolid and a concentrate of the antibacterial agent
18 An aqueous pharmaceutical composition according to claim 1 where the linezolid-antibacterial agent mixture is made by combining an aqueous solution of the antibacterial agent and a concentrate of linezolid
19. An aqueous pharmaceutical composition according to claim 1 where the rv pharmaceutical composition is in a container where the container-solution contact surface mateπal made of at least 50% polyolefin.
42
20. An aqueous pharmaceutical composition according to claim 19 where the container is selected from the group consisting of a bag, a bottle, a vial, a large volume parenteral, a small volume parenteral, a prefilled syringe and a cassette.
21. An aqueous pharmaceutical composition according to claim 20 where the container is a bag, a bottle, a vial and a prefilled syringe.
22. An aqueous pharmaceutical composition according to claim 19 where the container-solution contact surface is made of polyolefin or made primarily of polyolefin.
23. An aqueous pharmaceutical composition according to claim 22 where the container-solution contact surface is made of from about 50 to about 100% polyolefin.
24. An aqueous pharmaceutical composition according to claim 23 where the container-solution contact surface is made of from about 70 to about 90% polyolefin.
25. An aqueous pharmaceutical composition according to claim 22 where the container-solution contact surface is made of polyolefin.
26. An aqueous pharmaceutical composition according to claim 22 where the polyolefin is selected from the group consisting of polyethylene, polypropylene, polybutenes, polyisoprenes and polypentenes and copolymers and mixtures thereof.
27. A method of treating a human with a bacterial infection which comprises TV administration to the infected human an aqueous pharmaceutical composition of linezolid and one or more antibacterial agents selected from the group consisting of an aminoglycosides, cephalosporins, aztreonam, quinolones and penicillins and pharmaceutically acceptable salts thereof where such exist.
28. A method of treating a human with a bacterial infection according to claim 27 where the antibacterial agent is selected from the group consisting of gentamicin,
43 tobramycin, aztreonam, cefazolin, ceftazidime, piperacilhn, ciprofloxacin, ofloxacin, levofloxacin
29 A method of treating a human with a bacterial infection according to claim 17 s where the aqueous composition is a solution
30 A method of treating a human with a bacterial infection according to claim 29 where the solution is sterile
0 31 A method of treating a human with a bacterial infection according to claim 27 where TV pharmaceutical composition is in a container where the container-solution contact surface material made of at least 50% polyolefin
32 A method of treating a human with a bacterial infection according to claim 31 5 where the container-solution contact surface is made of polyolefin or made primarily of polyolefin
33. A method of treating a human with a bacterial infection according to claim 32 where the container-solution contact surface is made of polyolefin. 0
34 A method of treating a human with a bacterial infection according to claim 33 where the polyolefin is selected from the group consisting of polyethylene, polypropylene, polybutenes, polyisoprenes and polypentenes and copolymers and mixtures thereof 5
44
PCT/US2000/028872 1999-11-08 2000-11-02 Admixture for intravenous administration of linezolid and other antibacterial agents WO2001034128A2 (en)

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US60/163,990 1999-11-08

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WO2001070170A1 (en) * 2000-03-22 2001-09-27 Pharmacia & Upjohn Company Container for linezolid intravenous solution
US6605609B2 (en) 2000-06-16 2003-08-12 Pharmacia & Upjohn Company Thizaine oxazolidinone
WO2004052333A1 (en) * 2002-12-11 2004-06-24 Pari Gmbh Pharmaceutical compositions for the pulmonary delivery of aztreonam
WO2006064516A1 (en) * 2004-12-17 2006-06-22 Venus Remedies Limited Antibiotic combinations for providing total solution to the treatment of infections
WO2007086011A1 (en) * 2006-01-25 2007-08-02 Jegannathan Srinivas Formulation comprising cefepime, tazobactam and linezolid
WO2007086014A1 (en) * 2006-01-25 2007-08-02 Jegannathan Srinivas Formulation comprising cefpirome, tazobactam and linezolid
WO2007086013A1 (en) * 2006-01-25 2007-08-02 Jegannathan Srinivas Formulation comprising of ceftazidime, tazobactam and linezolid
WO2007086012A1 (en) * 2006-01-25 2007-08-02 Jegannathan Srinivas Formulation of cefpodoxime, clavulanic acid and linezolid
US7262293B2 (en) 2003-07-02 2007-08-28 Corus Pharma Aztreonam L-lysine and methods for the preparation thereof
CN102643251A (en) * 2012-04-17 2012-08-22 成都自豪药业有限公司 Linezolid degradation impurity and preparation method thereof
CN102973500A (en) * 2012-12-25 2013-03-20 江苏吴中苏药医药开发有限责任公司 Linezolid liquid preparation and preparation method thereof
US8921365B2 (en) 2007-07-23 2014-12-30 Biomet Deutschland Gmbh Pharmaceutical composition, substrate comprising a pharmaceutical composition, and use of a pharmaceutical composition

Family Cites Families (1)

* Cited by examiner, † Cited by third party
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US5688792A (en) * 1994-08-16 1997-11-18 Pharmacia & Upjohn Company Substituted oxazine and thiazine oxazolidinone antimicrobials

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6796975B2 (en) 2000-03-22 2004-09-28 Pharmacia & Upjohn Company Container for linezolid intravenous solution
WO2001070170A1 (en) * 2000-03-22 2001-09-27 Pharmacia & Upjohn Company Container for linezolid intravenous solution
US6605609B2 (en) 2000-06-16 2003-08-12 Pharmacia & Upjohn Company Thizaine oxazolidinone
WO2004052333A1 (en) * 2002-12-11 2004-06-24 Pari Gmbh Pharmaceutical compositions for the pulmonary delivery of aztreonam
US7262293B2 (en) 2003-07-02 2007-08-28 Corus Pharma Aztreonam L-lysine and methods for the preparation thereof
US7358093B2 (en) 2003-07-02 2008-04-15 Corus Pharma, Inc. Aztreonam L-lysine and methods for the preparation and analysis thereof
JP2008524204A (en) * 2004-12-17 2008-07-10 ヴィーナス・レメディーズ・リミテッド Combination of antibiotics to give a complete solution to the treatment of infection
WO2006064516A1 (en) * 2004-12-17 2006-06-22 Venus Remedies Limited Antibiotic combinations for providing total solution to the treatment of infections
US8178501B2 (en) 2004-12-17 2012-05-15 Venus Remedies Limited Antibiotic combinations for providing total solution to the treatment of infections
AU2005315140B2 (en) * 2004-12-17 2010-05-27 Venus Remedies Limited Antibiotic combinations for providing total solution to the treatment of infections
KR100900208B1 (en) 2004-12-17 2009-06-02 비너스 레머디스 리미티드 Antibiotic combinations for providing total solution to the treatment of infections
WO2007086011A1 (en) * 2006-01-25 2007-08-02 Jegannathan Srinivas Formulation comprising cefepime, tazobactam and linezolid
WO2007086012A1 (en) * 2006-01-25 2007-08-02 Jegannathan Srinivas Formulation of cefpodoxime, clavulanic acid and linezolid
WO2007086013A1 (en) * 2006-01-25 2007-08-02 Jegannathan Srinivas Formulation comprising of ceftazidime, tazobactam and linezolid
WO2007086014A1 (en) * 2006-01-25 2007-08-02 Jegannathan Srinivas Formulation comprising cefpirome, tazobactam and linezolid
US8921365B2 (en) 2007-07-23 2014-12-30 Biomet Deutschland Gmbh Pharmaceutical composition, substrate comprising a pharmaceutical composition, and use of a pharmaceutical composition
US9968710B2 (en) 2007-07-23 2018-05-15 Biomet Deutschland Gmbh Pharmaceutical composition, substrate comprising a pharmaceutical composition, and use of a pharmaceutical composition
CN102643251A (en) * 2012-04-17 2012-08-22 成都自豪药业有限公司 Linezolid degradation impurity and preparation method thereof
CN102643251B (en) * 2012-04-17 2016-08-10 四川美大康佳乐药业有限公司 degradation impurity of linezolid and preparation method thereof
CN102973500A (en) * 2012-12-25 2013-03-20 江苏吴中苏药医药开发有限责任公司 Linezolid liquid preparation and preparation method thereof

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WO2001034128A3 (en) 2001-11-22
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CO5251446A1 (en) 2003-02-28
PE20011006A1 (en) 2001-09-14

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