WO2010146478A1 - Parenteral composition comprising a fluoroquinolone compound and a nitroimidazole compound - Google Patents

Parenteral composition comprising a fluoroquinolone compound and a nitroimidazole compound Download PDF

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Publication number
WO2010146478A1
WO2010146478A1 PCT/IB2010/052037 IB2010052037W WO2010146478A1 WO 2010146478 A1 WO2010146478 A1 WO 2010146478A1 IB 2010052037 W IB2010052037 W IB 2010052037W WO 2010146478 A1 WO2010146478 A1 WO 2010146478A1
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Prior art keywords
compound
composition
fluoroquinolone
nitroimidazole
composition according
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PCT/IB2010/052037
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French (fr)
Inventor
Bhaskar Chauhan
Jyoti Srivastava
Vinod Arora
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Ranbaxy Laboratories Limited
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Publication of WO2010146478A1 publication Critical patent/WO2010146478A1/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
    • 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
    • A61K31/4164—1,3-Diazoles
    • 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
    • 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
    • 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

Definitions

  • the present invention relates to a novel parenteral composition
  • a novel parenteral composition comprising at least one fluoroquinolone compound and at least one nitroimidazole compound.
  • Anaerobes are an important component of many serious infections, especially complicated intra-abdominal (IAI) and acute pelvic (PI) infections in addition to aerobes.
  • Treatment regimen should adequately cover anaerobic, microaerophillic and aerobic organisms in such mixed infections.
  • Appropriate management of mixed aerobic and anaerobic infections requires administration of antimicrobials that are effective against both aerobic and anaerobic components of the infection in addition to surgical intervention where indicated.
  • Regimens can be selected on the basis of the usual bacteriology and how that bacteriology may have been modified by specific circumstances (e.g., hospitalization, antimicrobial therapy, resistance patterns). There are usually several options available.
  • Drugs providing coverage against anaerobes include penicillin G, chloramphenicol, imipenem, ampicillin-sulbactam, clindamycin, cefoxitin, piperacillin, cefotaxime, ceftizoxime, cefoperazone, moxalactam, cefotetan, cefipime or a combination of antibiotics.
  • the fluoroquinolones exhibit concentration-dependent bactericidal activity by inhibiting the activity of DNA gyrase and topoisomerase, enzymes essential for bacterial DNA replication.
  • the fluoroquinolones are active against Neisseria , Haemophilus influenzae , Moraxella catarrhalis , Mycoplasma , Chlamydia and Chlamydophila , Legionella , Enterobacteriaceae, Pseudomonas aeruginosa.
  • the fluoroquinolones are also active against Mycobacterium tuberculosis, some atypical mycobacteria, and methicillin- sensitive staphylococci, but nosocomial methicillin-resistant staphylococci are usually resistant.
  • the older fluoroquinolones have poor activity against streptococci and anaerobes.
  • Newer fluoroquinolones have reliable activity against streptococci (including Streptococcus pneumoniae with reduced penicillinsensitivity) and some anaerobes. As use has increased, resistance is developing among Enterobacteriaceae, P. aeruginosa, S. pneumoniae, and Neisseria, particularly among older fluoroquinolones. Ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, ofloxacin, and trovafloxacin can be administered orally and parenterally; gemifloxacin and norfloxacin are available only orally.
  • Nitroimidazoles derivatives include metronidazole, tinidazole, ornidazole, nimorazole, secnidazole, azanidazole and propenidazole.
  • Ornidazole is a nitroimidazole derivative active against several protozoa and several strains of anaerobic bacteria. Ornidazole is effective against Trichomonas vaginalis, Entamoeba histolytica and Giardia lamblia. It also covers certain anaerobic bacteria such as Bacteroides, Clostridium spp., Fusobacterium spp., and anaerobic cocci.
  • Ornidazole is indicated for treatment of bacterial vaginosis (non-specific vaginitis), trichomoniasis (genitourinary infections in women and men due to Trichomonas vaginalis), amoebiasis, giardiasis (lambliasis), infections due to anaerobic bacteria, and prophylaxis during surgical interventions, particularly those involving the colon, and in gynecological operations.
  • Injectables or infusions containing ofloxacin, ofloxacin hydrochloride, ciprofloxacin or ornidazole are available in the market that can be useful in acute conditions.
  • U.S. Patent No. 4,957,922 relates to infusion solutions of ciprofloxacin which contain 0.015 to 0.5g of the active compound per 100ml of aqueous solution and an amount of physiologically tolerated acid sufficient to dissolve the active compound and to stabilize the solution.
  • the infusion solutions are found to have a low toxicity and a broad spectrum of antibacterial activity against gram-positive and gram-negative microbes, in particular against Enterobacteriaceae; especially including those which are resistant to various antibiotics such as, for example, penicillins, cephalosporins, aminoglycosides, sulphonamides and tetracyclines.
  • U.S. Patent Nos. 4,705,789 and 4,808,583 relate to storage stable solutions containing piperazinyl-quinolone- or piperazinyl-azaquinolone-carboxylic acids (ciprofloxacin) with lactic acid.
  • U.S. Patent Publication No. 2003/0073646 Al discloses a composition having synergistic effective amounts of one or more antibacterial agents, a nitroimidazole, and an antifungal agent effective against a Candida species. The compositions are particularly useful in the treatment of genitourinary infections.
  • U.S. Patent No. 7,304,075 relates to an aqueous solution consisting of sitafloxacin, sodium chloride, and a pH adjusting agent selected from the group consisting of one or both of hydrochloric acid and sodium hydroxide.
  • Russian Patent No. RU 2245134C1 discloses an antibacterial composition containing ofloxacin for injection, in which trilon-B and sodium chloride were used as additives.
  • aqueous formulations containing fluoroquinolones lack stability to light. Specifically, in aqueous solution fluoroquinolones undergo decomposition on being irradiated with light, resulting in reductions of active content, change in pH and generating related substances. It is therefore desirable to have a stable formulation containing combination of fluoroquinolones and nitroimidazoles with faster onset of action, for treating patients in acute mixed infection conditions. Further it advantageous to have a synergistic combination therapy to reduce the dosage required for a given therapeutic effect compared to those required using treatment with fluoroquinolone or a nitroimidazole alone, thereby minimizing possibly undesirable side effects.
  • the present invention relates to an aqueous parenteral composition
  • aqueous parenteral composition comprising:
  • composition may include one or more of the following features.
  • the pH of the composition may be in the range of 3 to 6.
  • fluoroquinolone compound of the composition may include, but are not limited to, compounds such as alatrofloxacin, balofloxacin, ciprofloxacin, clinafloxacin, danofloxacin, difloxacin, enoxacin, enrofloxacin, garenoxacin, gatifloxacin, gemifloxacin, grepafloxacin, levofloxacin, lomefloxacin, marbofloxacin, moxifloxacin, nadifloxacin, norfloxacin, ofloxacin, orbifloxacin, pefloxacin, sitafloxacin, sparfloxacin, tosufloxacin and trovafloxacin. More preferably the fluoroquinolone is ofloxacin.
  • nitroimidazole compound of the composition may include, but are not limited to, compounds such as metronidazole, tinidazole, ornidazole, nimorazole, secnidazole, azanidazole and propenidazole. More preferably the nitroimidazole is ornidazole.
  • It is another aspect to provide a process for preparing an aqueous parenteral composition comprising the steps of:
  • the pharmaceutically acceptable excipients may be one or more of other formulating agents such as complexing agents, antioxidants, tonicity agents and/or agents to adjust the pH. It is yet another aspect to provide a method for treating acute condition of mixed infections, especially like mixed intra-abdominal and pelvic infections or in surgical prophylaxis, by administering an aqueous parenteral composition comprising:
  • agents having broad coverage for both gram-positive and gram- negative aerobes and anaerobes are usually desired.
  • Dosage form containing combination of fluoroquinolones and nitroimidazoles with faster onset of action would be preferred over single agents in such acute conditions.
  • the half- lives of some fluoroquinolones and nitroimidazoles fall in the same range and hence, the time course of action of the two drugs would be similar, which is an important criterion for the selecting two different drugs for treating acute conditions.
  • Further studies show when fluoroquinolones and nitroimidazoles taken together show synergistic effect against some species of anaerobic bacteria such as B. fragilis.
  • the inventors have developed a stable aqueous parenteral composition comprising: (a) at least one fluoroquinolone compound; (b) at least one nitroimidazole compound and
  • composition one or more pharmaceutically acceptable excipients wherein the pH of the aqueous composition between 3 to 6.
  • composition aqueous parenteral composition (herein referred as "composition") of the present invention with the pH range of 3 to 6 found to be stable against light and does not led to change in active content or pH or generating related substances, during storage.
  • the concentration of fluoroquinolone compound and nitroimidazole compound (herein referred as "actives") in the aqueous solution is not particularly limited and can be selected according to the purpose of use and method of use within a range of solubility of actives in water (or water at a particular pH).
  • a suitable concentration of actives may range from 0.01 to 20 mg/ml.
  • composition of the present invention may be of infusion, in the form of dosage units suitable with extractable contents of from, 10 to 1000ml, preferably 50 to 500ml.
  • the dosage units may be dispensed in a single-dose or multiple-dose containers.
  • the composition of the present invention may be isotonic with the tissue fluid of the human or is slightly hypo or hypertonic.
  • the osmolality of the composition may be 0.20 to 0.70 Osm/kg, preferably 0.26 to 0.39 Osm/kg and is adjusted by isotonicizing agents such as, but limited not to, sodium chloride, sorbitol, mannitol, glucose, D-glucose, sucrose, xylitol, fructose and glycerol or mixtures of such substances. It is also possible where appropriate to employ for this purpose substances which are present in conventional, commercially available infusion vehicle solutions.
  • Customary infusion vehicle solutions include infusions with addition of electrolytes without carbohydrates, such as sodium chloride solution, potassium chloride solution, Ringer's lactate solution and others, and those with carbohydrates, and solutions to supply amino acids, in each case with or without carbohydrate content.
  • carbohydrates such as sodium chloride solution, potassium chloride solution, Ringer's lactate solution and others, and those with carbohydrates, and solutions to supply amino acids, in each case with or without carbohydrate content.
  • composition of the present invention may also be prepared as lyophilizates which can be prepared by customary techniques and which are converted into the infusion solutions by dissolution in solvents suitable for this purpose such as, for example, conventional infusion vehicle solutions. Lyophilizates of this type can be obtained by freeze-drying of various starting solutions such as, for example, the infusion solutions according to the invention. It is likewise possible to freeze-dry considerably more dilute solutions as well as considerably more concentrated solutions than the infusion solutions according to the invention.
  • composition of the present invention may also contain other pharmaceutically acceptable excipients in the capacity of thickeners, resorbents, light-protection agents, absorption inhibitors, crystallization accelerators, absorption accelerators, crystallization retardants, complexing agents, antioxidants, isotonicizing agents and/or agents to adjust the pH.
  • pH adjusting agents include, but are not limited to, hydrochloric acid, sulfuric acid, and phosphoric acid; inorganic acid salts such as sodium hydrogencarbonate, sodium carbonate, sodium hydrogenphosphate, sodium dihydrogenphosphate, trisodium phosphate, dipotassium phosphate, potassium dihydrogenphosphate, sodium sulfite, sodium hydrogensulfite, and sodium thiosulfate; organic acids such as acetic acid, lactic acid, succinic acid, maleic acid, tartaric acid, citric acid, ascorbic acid, salicylic acid, benzoic acid, methanesulfonic acid, and thioglycolic acid; organic acid esters such as ethyl lactate; organic acid salts such as sodium citrate, disodium citrate, sodium gluconate, calcium citrate, sodium lactate, sodium acetate, sodium pyrophosphate, sodium benzoate, sodium caprylate, and sodium thioglycolate; inorganic salts such as sodium hydrogen
  • suitable buffer system may include, but are not limited to, phosphoric acid; glycine; sodium citrate; histidine; citric acid; acetic acid; tromethamine; ammonium sulfate; and combinations thereof.
  • the aforementioned components are understood to include the salts, hydrates and solvates thereof.
  • phosphoric acid includes the sodium phosphate or potassium phosphate salts, among other salts.
  • Preferred buffer systems include sodium phosphate monobasic, sodium phosphate dibasic, or a combination thereof. More preferred buffer systems include sodium phosphate monobasic monohydrate, sodium phosphate dibasic anhydrous, or a combination thereof.
  • organic buffer refers to a buffer comprising at least one organic compound.
  • suitable organic buffers include: glycine; sodium citrate; histidine; citric acid; acetic acid; and combinations thereof.
  • Suitable examples of antioxidants may include, but are not limited to, propyl gallate, butylated hydroxytoluene, and alpha-D-tocopherol.
  • the composition can be sterilized by usual manner, for example, filtration or heating. Sterilization may be preceded or followed by packing into containers. If desired, the composition of the present invention can contain pharmaceutically acceptable additives, such as dissolving aids, buffering components, stabilizers, and the like.
  • the composition can be dispensed into suitable container for a single dose or for multiple dose. Without intending to effect a restriction hereby, in general glass bottles or bags made of plastic sheets which are suitable for medical use are employed for this purpose. Polyolefin-based PVC-free bags are particularly preferred. To improve storability, these bags can, where appropriate, be provided with a further outer packaging.
  • composition of the present invention may be administered to any part, organ, interstice or cavity of a patient's body that is subject to an infection.
  • the composition may be administered by, but not limited to, intravenously, intramuscularly, subcutaneously, ophthalmically, subconjuctivally, intraocularly, via anterior eye chamber injection, intravitreally, intraperitoneally, intrathecally, intracystically, intrapleurally, intranasally, topically, via wound irrigation, intradermally, intrabuccally, intra- abdominally, intra-articularly, intra- aurally, intrabronchially, intracapsularly, intrameningeally, intrapulmonarilly, via inhalation, via endotracheal or endobronchial installation, via direct installation into pulmonary cavities, intraspinally, intrasynovially, intrathoracic ally, via thoracostomy irrigation, vaginally, epidurally, rectally, intracistemally, intravascularly, intraventricularly, intraosseously
  • step 2 To the solution of step 1, ofloxacin and ornidazole were added and stirred.
  • compositions prepared in above examples were subjected to various stability studies like, degradation study, photostability study and multiple autoclave study.
  • Example 1 The composition of Example 1 and 2 were kept at 60 C for 15 days to check the degradation of actives. The results are summarized in Table 1. Table 1
  • Example 1 and 2 were exposed to light providing an overall illumination of not less than 1.2 million lux hours and an integrated near ultraviolet energy of not less than 200 watt hours/square meter in a photo stability chamber. The results are summarized in Table 2.
  • Example 1 The composition of Example 1 and 2 were subjected to multiple autoclave study at 121 0 C for 20 min. The results are summarized in Table 3. Table 3

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Abstract

The present invention relates to novel parenteral compositions comprising at least one fluoroquinolone compound and at least one nitroimidazole compound. It further relates to processes for preparing such compositions. It also relates to method of treating acute condition of mixed infections using compositions of the present invention.

Description

PARENTERAL COMPOSITION COMPRISING A FLUOROQUINOLONE COMPOUND AND A NITROIMIDAZOLE COMPOUND
Field of the Invention
The present invention relates to a novel parenteral composition comprising at least one fluoroquinolone compound and at least one nitroimidazole compound.
Background of the Invention
Anaerobes are an important component of many serious infections, especially complicated intra-abdominal (IAI) and acute pelvic (PI) infections in addition to aerobes. Treatment regimen should adequately cover anaerobic, microaerophillic and aerobic organisms in such mixed infections. Appropriate management of mixed aerobic and anaerobic infections requires administration of antimicrobials that are effective against both aerobic and anaerobic components of the infection in addition to surgical intervention where indicated. Regimens can be selected on the basis of the usual bacteriology and how that bacteriology may have been modified by specific circumstances (e.g., hospitalization, antimicrobial therapy, resistance patterns). There are usually several options available. Drugs providing coverage against anaerobes include penicillin G, chloramphenicol, imipenem, ampicillin-sulbactam, clindamycin, cefoxitin, piperacillin, cefotaxime, ceftizoxime, cefoperazone, moxalactam, cefotetan, cefipime or a combination of antibiotics. The fluoroquinolones exhibit concentration-dependent bactericidal activity by inhibiting the activity of DNA gyrase and topoisomerase, enzymes essential for bacterial DNA replication. The fluoroquinolones are active against Neisseria , Haemophilus influenzae , Moraxella catarrhalis , Mycoplasma , Chlamydia and Chlamydophila , Legionella , Enterobacteriaceae, Pseudomonas aeruginosa. The fluoroquinolones are also active against Mycobacterium tuberculosis, some atypical mycobacteria, and methicillin- sensitive staphylococci, but nosocomial methicillin-resistant staphylococci are usually resistant. The older fluoroquinolones have poor activity against streptococci and anaerobes. Newer fluoroquinolones have reliable activity against streptococci (including Streptococcus pneumoniae with reduced penicillinsensitivity) and some anaerobes. As use has increased, resistance is developing among Enterobacteriaceae, P. aeruginosa, S. pneumoniae, and Neisseria, particularly among older fluoroquinolones. Ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, ofloxacin, and trovafloxacin can be administered orally and parenterally; gemifloxacin and norfloxacin are available only orally.
The antimicrobial activity of nitroimidazole is due to the reduction of the nitro group to a more reactive amine that attacks microbial DNA, brings about loss of helical structure of DNA and subsequent DNA breakage thus inhibiting further synthesis and causing degradation of existing DNA. Nitroimidazoles derivatives include metronidazole, tinidazole, ornidazole, nimorazole, secnidazole, azanidazole and propenidazole.
Ornidazole is a nitroimidazole derivative active against several protozoa and several strains of anaerobic bacteria. Ornidazole is effective against Trichomonas vaginalis, Entamoeba histolytica and Giardia lamblia. It also covers certain anaerobic bacteria such as Bacteroides, Clostridium spp., Fusobacterium spp., and anaerobic cocci. Ornidazole is indicated for treatment of bacterial vaginosis (non-specific vaginitis), trichomoniasis (genitourinary infections in women and men due to Trichomonas vaginalis), amoebiasis, giardiasis (lambliasis), infections due to anaerobic bacteria, and prophylaxis during surgical interventions, particularly those involving the colon, and in gynecological operations.
Injectables or infusions containing ofloxacin, ofloxacin hydrochloride, ciprofloxacin or ornidazole are available in the market that can be useful in acute conditions. U.S. Patent No. 4,957,922 relates to infusion solutions of ciprofloxacin which contain 0.015 to 0.5g of the active compound per 100ml of aqueous solution and an amount of physiologically tolerated acid sufficient to dissolve the active compound and to stabilize the solution. The infusion solutions are found to have a low toxicity and a broad spectrum of antibacterial activity against gram-positive and gram-negative microbes, in particular against Enterobacteriaceae; especially including those which are resistant to various antibiotics such as, for example, penicillins, cephalosporins, aminoglycosides, sulphonamides and tetracyclines.
U.S. Patent Nos. 4,705,789 and 4,808,583 relate to storage stable solutions containing piperazinyl-quinolone- or piperazinyl-azaquinolone-carboxylic acids (ciprofloxacin) with lactic acid. U.S. Patent Publication No. 2003/0073646 Al discloses a composition having synergistic effective amounts of one or more antibacterial agents, a nitroimidazole, and an antifungal agent effective against a Candida species. The compositions are particularly useful in the treatment of genitourinary infections. U.S. Patent No. 7,304,075 relates to an aqueous solution consisting of sitafloxacin, sodium chloride, and a pH adjusting agent selected from the group consisting of one or both of hydrochloric acid and sodium hydroxide.
Russian Patent No. RU 2245134C1 discloses an antibacterial composition containing ofloxacin for injection, in which trilon-B and sodium chloride were used as additives.
In treating mixed infections, no single antimicrobial agent would be adequate to provide desired coverage for both gram-positive and gram-negative aerobes and anaerobes. A combination of at least two antimicrobials is required. A variety of oral formulations containing combination of fluoroquinolone and nitroimidazole in the form of tablet, suspension and syrup, and are currently commercially available for the treatment of mixed infections. For instance combination of ofloxacin and tinidazole, ofloxacin and metronidazole, ofloxacin and ornidazole, gatifloxacin and ornidazole, norfloxacin and ornidazole, levofloxacin and ornidazole, ciprofloxacin and ornidazole, norfloxacin and metronidazole, ciprofloxacin and tinidazole, norfloxacin and tinidazole, metronidazole and nalidixic acid are available.
However, none of the available oral formulations can be used for treating patients with acute conditions. In treating patients with acute condition of mixed infections, especially like mixed intra-abdominal and pelvic infections or in surgical prophylaxis, parenteral formulations containing combination of fluoroquinolones and nitroimidazoles are needed to provide faster onset of action.
It is also known that aqueous formulations containing fluoroquinolones lack stability to light. Specifically, in aqueous solution fluoroquinolones undergo decomposition on being irradiated with light, resulting in reductions of active content, change in pH and generating related substances. It is therefore desirable to have a stable formulation containing combination of fluoroquinolones and nitroimidazoles with faster onset of action, for treating patients in acute mixed infection conditions. Further it advantageous to have a synergistic combination therapy to reduce the dosage required for a given therapeutic effect compared to those required using treatment with fluoroquinolone or a nitroimidazole alone, thereby minimizing possibly undesirable side effects.
Summary of the Invention In one aspect, the present invention relates to an aqueous parenteral composition comprising:
(a) at least one fluoroquinolone compound;
(b) at least one nitroimidazole compound, and
(c) one or more pharmaceutically acceptable excipients. Embodiments of the composition may include one or more of the following features. For example, the pH of the composition may be in the range of 3 to 6.
In one embodiment, fluoroquinolone compound of the composition may include, but are not limited to, compounds such as alatrofloxacin, balofloxacin, ciprofloxacin, clinafloxacin, danofloxacin, difloxacin, enoxacin, enrofloxacin, garenoxacin, gatifloxacin, gemifloxacin, grepafloxacin, levofloxacin, lomefloxacin, marbofloxacin, moxifloxacin, nadifloxacin, norfloxacin, ofloxacin, orbifloxacin, pefloxacin, sitafloxacin, sparfloxacin, tosufloxacin and trovafloxacin. More preferably the fluoroquinolone is ofloxacin.
In another embodiment, nitroimidazole compound of the composition may include, but are not limited to, compounds such as metronidazole, tinidazole, ornidazole, nimorazole, secnidazole, azanidazole and propenidazole. More preferably the nitroimidazole is ornidazole.
It is another aspect to provide a process for preparing an aqueous parenteral composition comprising the steps of:
(a) preparing an aqueous solution having dissolved therein - at least one fluoroquinolone compound,
- at least one nitroimidazole compound,
- one or more pharmaceutically acceptable excipients; and
(b) adjusting the pH of the aqueous solution between 3 to 6.
The pharmaceutically acceptable excipients may be one or more of other formulating agents such as complexing agents, antioxidants, tonicity agents and/or agents to adjust the pH. It is yet another aspect to provide a method for treating acute condition of mixed infections, especially like mixed intra-abdominal and pelvic infections or in surgical prophylaxis, by administering an aqueous parenteral composition comprising:
(a) at least one fluoroquinolone compound; (b) at least one nitroimidazole compound, and
(c) one or more pharmaceutically acceptable excipients wherein the pH of the aqueous composition between 3 to 6. The method may further include administering other antibacterial or pharmaceutical agents. The details of one or more embodiments of the inventions are set forth in the description below. Other features and objects of the invention will be apparent from the description and examples.
Detailed Description of the Invention
In treating acute condition of mixed infections, agents having broad coverage for both gram-positive and gram- negative aerobes and anaerobes are usually desired. Dosage form containing combination of fluoroquinolones and nitroimidazoles with faster onset of action would be preferred over single agents in such acute conditions. The half- lives of some fluoroquinolones and nitroimidazoles fall in the same range and hence, the time course of action of the two drugs would be similar, which is an important criterion for the selecting two different drugs for treating acute conditions. Further studies show when fluoroquinolones and nitroimidazoles taken together show synergistic effect against some species of anaerobic bacteria such as B. fragilis.
The inventors have developed a stable aqueous parenteral composition comprising: (a) at least one fluoroquinolone compound; (b) at least one nitroimidazole compound and
(c) one or more pharmaceutically acceptable excipients wherein the pH of the aqueous composition between 3 to 6. The aqueous parenteral composition (herein referred as "composition") of the present invention with the pH range of 3 to 6 found to be stable against light and does not led to change in active content or pH or generating related substances, during storage.
The concentration of fluoroquinolone compound and nitroimidazole compound (herein referred as "actives") in the aqueous solution is not particularly limited and can be selected according to the purpose of use and method of use within a range of solubility of actives in water (or water at a particular pH). A suitable concentration of actives may range from 0.01 to 20 mg/ml.
The composition of the present invention may be of infusion, in the form of dosage units suitable with extractable contents of from, 10 to 1000ml, preferably 50 to 500ml. The dosage units may be dispensed in a single-dose or multiple-dose containers.
The composition of the present invention may be isotonic with the tissue fluid of the human or is slightly hypo or hypertonic. The osmolality of the composition may be 0.20 to 0.70 Osm/kg, preferably 0.26 to 0.39 Osm/kg and is adjusted by isotonicizing agents such as, but limited not to, sodium chloride, sorbitol, mannitol, glucose, D-glucose, sucrose, xylitol, fructose and glycerol or mixtures of such substances. It is also possible where appropriate to employ for this purpose substances which are present in conventional, commercially available infusion vehicle solutions. Customary infusion vehicle solutions include infusions with addition of electrolytes without carbohydrates, such as sodium chloride solution, potassium chloride solution, Ringer's lactate solution and others, and those with carbohydrates, and solutions to supply amino acids, in each case with or without carbohydrate content.
The composition of the present invention may also be prepared as lyophilizates which can be prepared by customary techniques and which are converted into the infusion solutions by dissolution in solvents suitable for this purpose such as, for example, conventional infusion vehicle solutions. Lyophilizates of this type can be obtained by freeze-drying of various starting solutions such as, for example, the infusion solutions according to the invention. It is likewise possible to freeze-dry considerably more dilute solutions as well as considerably more concentrated solutions than the infusion solutions according to the invention.
The composition of the present invention may also contain other pharmaceutically acceptable excipients in the capacity of thickeners, resorbents, light-protection agents, absorption inhibitors, crystallization accelerators, absorption accelerators, crystallization retardants, complexing agents, antioxidants, isotonicizing agents and/or agents to adjust the pH.
Suitable examples of pH adjusting agents include, but are not limited to, hydrochloric acid, sulfuric acid, and phosphoric acid; inorganic acid salts such as sodium hydrogencarbonate, sodium carbonate, sodium hydrogenphosphate, sodium dihydrogenphosphate, trisodium phosphate, dipotassium phosphate, potassium dihydrogenphosphate, sodium sulfite, sodium hydrogensulfite, and sodium thiosulfate; organic acids such as acetic acid, lactic acid, succinic acid, maleic acid, tartaric acid, citric acid, ascorbic acid, salicylic acid, benzoic acid, methanesulfonic acid, and thioglycolic acid; organic acid esters such as ethyl lactate; organic acid salts such as sodium citrate, disodium citrate, sodium gluconate, calcium citrate, sodium lactate, sodium acetate, sodium pyrophosphate, sodium benzoate, sodium caprylate, and sodium thioglycolate; inorganic salts such as sodium hydroxide; and organic amine compounds such as monoethanolamine, diethanolamine, triethanolamine, ethylenediamine, meglumine, and trometamol.
In order to maintain the pH, suitable buffer system may be used. Examples of buffer system may include, but are not limited to, phosphoric acid; glycine; sodium citrate; histidine; citric acid; acetic acid; tromethamine; ammonium sulfate; and combinations thereof. The aforementioned components are understood to include the salts, hydrates and solvates thereof. Thus, for example, phosphoric acid includes the sodium phosphate or potassium phosphate salts, among other salts. Preferred buffer systems include sodium phosphate monobasic, sodium phosphate dibasic, or a combination thereof. More preferred buffer systems include sodium phosphate monobasic monohydrate, sodium phosphate dibasic anhydrous, or a combination thereof. As used herein, the phrase "organic buffer" refers to a buffer comprising at least one organic compound. Non-limiting examples of suitable organic buffers include: glycine; sodium citrate; histidine; citric acid; acetic acid; and combinations thereof.
Suitable examples of antioxidants may include, but are not limited to, propyl gallate, butylated hydroxytoluene, and alpha-D-tocopherol.
The composition can be sterilized by usual manner, for example, filtration or heating. Sterilization may be preceded or followed by packing into containers. If desired, the composition of the present invention can contain pharmaceutically acceptable additives, such as dissolving aids, buffering components, stabilizers, and the like. The composition can be dispensed into suitable container for a single dose or for multiple dose. Without intending to effect a restriction hereby, in general glass bottles or bags made of plastic sheets which are suitable for medical use are employed for this purpose. Polyolefin-based PVC-free bags are particularly preferred. To improve storability, these bags can, where appropriate, be provided with a further outer packaging. The composition of the present invention may be administered to any part, organ, interstice or cavity of a patient's body that is subject to an infection. For example the composition may be administered by, but not limited to, intravenously, intramuscularly, subcutaneously, ophthalmically, subconjuctivally, intraocularly, via anterior eye chamber injection, intravitreally, intraperitoneally, intrathecally, intracystically, intrapleurally, intranasally, topically, via wound irrigation, intradermally, intrabuccally, intra- abdominally, intra-articularly, intra- aurally, intrabronchially, intracapsularly, intrameningeally, intrapulmonarilly, via inhalation, via endotracheal or endobronchial installation, via direct installation into pulmonary cavities, intraspinally, intrasynovially, intrathoracic ally, via thoracostomy irrigation, vaginally, epidurally, rectally, intracistemally, intravascularly, intraventricularly, intraosseously, via irrigation of infected bone, and via application as part of any admixture with cement for prosthetic devices. The present invention is illustrated below by reference to the following examples.
However, one skilled in the art will appreciate that the specific methods and results discussed are merely illustrative of the invention, and not to be construed as limiting the invention.
Examples: Composition
Figure imgf000010_0001
Procedure
1. Sodium chloride/Dextrose was dissolved in water for injection and purged with nitrogen gas.
2. To the solution of step 1, ofloxacin and ornidazole were added and stirred.
3. The pH of the above solution is adjusted to desired pH range.
4. The final solution is filtered and filled in USP type I glass vials and terminally autoclaved.
Stability studies:
The compositions prepared in above examples were subjected to various stability studies like, degradation study, photostability study and multiple autoclave study.
Degradation study
The composition of Example 1 and 2 were kept at 60 C for 15 days to check the degradation of actives. The results are summarized in Table 1. Table 1
Figure imgf000011_0001
Photostability study
The composition of Example 1 and 2 were exposed to light providing an overall illumination of not less than 1.2 million lux hours and an integrated near ultraviolet energy of not less than 200 watt hours/square meter in a photo stability chamber. The results are summarized in Table 2.
Table 2
Figure imgf000011_0002
Multiple autoclave study
The composition of Example 1 and 2 were subjected to multiple autoclave study at 1210C for 20 min. The results are summarized in Table 3. Table 3
Figure imgf000012_0001
While several particular forms of the invention have been illustrated and described, it will be apparent that various modifications and combinations of the invention detailed in the text can be made without departing from the spirit and scope of the invention. Accordingly, it is not intended that the invention be limited, except as by the appended claims.

Claims

We Claim: 1. An aqueous parenteral composition comprising: (a) at least one fluoroquinolone compound, (b) at least one nitroimidazole compound and (c) one or more pharmaceutically acceptable excipients.
2. The composition according to claim 1, wherein the pH of the composition is in the range of 3 to 6.
3. The composition according to claim 1, wherein the fluoroquinolone compound is selected from alatrofloxacin, balofloxacin, ciprofloxacin, clinafloxacin, danofloxacin, difloxacin, enoxacin, enrofloxacin, garenoxacin, gatifloxacin, gemifloxacin, grepafloxacin, levofloxacin, lomefloxacin, marbofloxacin, moxifloxacin, nadifloxacin, norfloxacin, ofloxacin, orbifloxacin, pefloxacin, sitafloxacin, sparfloxacin, tosufloxacin and tovafloxacin.
4. The composition according to claim 1, wherein the fluoroquinolone compound is ofloxacin.
5. The composition according to claim 1, wherein the nitroimidazole compound is selected from ronidazole, tinidazole, ornidazole, nimorazole, secnidazole, azanidazole and propenidazole.
6. The composition according to claim 1, wherein the nitroimidazole compound is ornidazole.
7. The composition according to claim 1, wherein the actives are present in a concentration of 0.01 to 20mg/ml.
8. The composition according to claim 1, wherein the pharmaceutically acceptable excipients comprises one or more of complexing agents, antioxidants, tonicity agents and/or pH adjusting agents.
9. A process for preparing an aqueous parenteral composition comprising the steps of: (a) preparing an aqueous solution having dissolved therein - at least one fluoroquinolone compound, _ at least one nitroimidazole compound, - one or more pharmaceutically acceptable excipients; and (b) adjusting the pH of the aqueous solution between 3 to 6.
10. A method for treating acute condition of mixed infections, especially like mixed intra-abdominal and pelvic infections or in surgical prophylaxis, by administering an aqueous parenteral composition comprising: (a) at least one fluoroquinolone compound; (b) at least one nitroimidazole compound and (c) one or more pharmaceutically acceptable excipients wherein the pH of the aqueous composition between 3 to 6.
11. A method according to claim 10, comprising further administration of other antibacterial or pharmaceutical agents.
12. An aqueous parenteral composition comprising at least one fluoroquinolone compound, at least one nitroimidazole compound and one or more pharmaceutically acceptable excipients, substantially as described and illustrated herein.
PCT/IB2010/052037 2009-05-08 2010-05-08 Parenteral composition comprising a fluoroquinolone compound and a nitroimidazole compound WO2010146478A1 (en)

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