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WO2022185240A1 - Formulation d'un antibiotique monobactame - Google Patents

Formulation d'un antibiotique monobactame Download PDF

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Publication number
WO2022185240A1
WO2022185240A1 PCT/IB2022/051871 IB2022051871W WO2022185240A1 WO 2022185240 A1 WO2022185240 A1 WO 2022185240A1 IB 2022051871 W IB2022051871 W IB 2022051871W WO 2022185240 A1 WO2022185240 A1 WO 2022185240A1
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WO
WIPO (PCT)
Prior art keywords
solid composition
composition
solid
active agent
liquid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2022/051871
Other languages
English (en)
Inventor
Sheng CUI
Dinesh Shyamdeo Mishra
Karl Bennett Hansen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bp Asset Vi Inc
Original Assignee
Bp Asset Vi Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bp Asset Vi Inc filed Critical Bp Asset Vi Inc
Publication of WO2022185240A1 publication Critical patent/WO2022185240A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • 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
    • A61K9/08—Solutions
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • 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 relates to stable pharmaceutical compositions comprising (1- (((Z)-(1-(2-aminothiazol-4-yl)-2-oxo-2-(((3S,4R)-2-oxo-4-((2-oxooxazolidin-3-yl) methyl)-1-sulfoazetidin-3-yl)amino)ethylidene)amino)oxy)cyclopropane carboxylic acid of the Formula (I), their use in medicine and method of preparing said pharmaceutical compositions.
  • nosocomial infections are thought to contribute to or cause more than 77,000 deaths per year and cost approximately $5 to $10 billion annually.
  • Resistance of Gram-negative bacteria against antibiotics may be caused by extended-spectrum beta-lactamases (ESBLs), serine carbapenemases (KPCs) and metallo-beta-lactamases (for example NDM-1 ) in Klebsiella pneumoniae, Escherichia coli, and Proteus mirabilis, high-level third-generation cephalosporin (AmpC) beta-lactamase resistance among Enterobacter species and Citrobacter freundii, and multidrug-resistance genes observed in Pseudomonas, Acinetobacter, and Stenotrophomonas.
  • ESBLs extended-spectrum beta-lactamases
  • KPCs serine carbapenemases
  • AmpC cephalosporin beta-lactamase resistance among Enterobacter species and Citrobacter freundii
  • multidrug-resistance genes observed in Pseudomonas, Acinetobacter, and Steno
  • Example 22 the preparation of 1 -(((Z)-(1 -(2-aminothiazol-4-yl)-2-oxo-2-(((3S,4R)-2-oxo-4-((2-oxo- oxazolidin-3-yl)methyl)-1-sulfoazetidin-3-yl)amino)ethylidene)amino)oxy)cyclo- propanecarboxylic acid (in the following compound (I)) is described.
  • compositions of compound (I) are disclosed in WO 2017/050218, the content of which is herein incorporated by reference. These compositions comprise large amounts of excipients such as sucrose for stabilizing the active agent compound (I). This makes preparing, handling and confectioning of these compositions cost-intensive, tedious and time-consuming. It would thus be beneficial to develop novel pharmaceutical compositions of compound (I).
  • the present invention is directed to new solid and liquid pharmaceutical compositions of compound (I) and kits containing such compositions, which can be prepared and used in a shorter time, and in an improved, economic and simplified fashion.
  • a first aspect of the present invention relates to a solid pharmaceutical composition essentially consisting of:
  • an active agent which is (1-(((Z)-(1-(2-aminothiazol-4-yl)-2-oxo-2-(((3S,4R)-2-oxo- 4-((2-oxooxazolidin-3-yl)methyl)-1-sulfoazetidin-3-yl)amino) ethylidene)amino)oxy)cyclopropane carboxylic acid) of the Formula (I): including any tautomeric species, solvate or hydrate thereof; and
  • a further aspect of the invention relates to a solid pharmaceutical composition essentially consisting of:
  • an active agent which is compound (I), including any tautomeric species, solvate or hydrate thereof;
  • a further aspect of the invention relates to a liquid composition essentially consisting of:
  • an active agent which is compound (I), including any tautomeric species, solvate or hydrate thereof;
  • a pharmaceutically acceptable aqueous liquid wherein the pH is in the range from about pH 4.0 to about pH 6.0.
  • a further aspect of the invention relates to a liquid composition essentially consisting of:
  • an active agent which is compound (I), including any tautomeric species thereof;
  • a further aspect of the invention relates to a kit comprising:
  • a further aspect of the invention relates to methods of preparing a solid pharmaceutical composition, a liquid pharmaceutical composition or a kit as described above.
  • a further aspect of the invention relates to the use of a solid pharmaceutical composition, a liquid pharmaceutical composition or a kit as described above in medicine, particularly for the treatment of a bacterial infection.
  • tautomeric species of compound (I) relates to compounds which differ from the depicted compound in that one or more H + ions are located at positions different from those indicated in the respective formula.
  • an NFh group may be in a protonated form, i.e. as an NH 3 + group
  • a CO 2 H group may be in a deprotonated form, i.e. as a CO 2 group
  • an SO 3 H group may be in a deprotonated form, i.e. as an SO 3 group.
  • compound (I) includes a plurality of different tautomeric species, which may be in an equilibrium with each other depending on the pH.
  • the term tautomeric species also includes zwitterionic species comprising both a protonated group and a deprotonated group.
  • solvate refers to a molecular complex of a compound of the present invention (including pharmaceutically acceptable salts thereof) with one or more solvent molecules, i.e. organic solvent molecules or water molecules.
  • solvent molecules i.e. organic solvent molecules or water molecules.
  • hydrate specifically refers to a complex where the solvent molecule is water.
  • a preferred hydrate of compound (I) is the trihydrate wherein compound (I) is bound to three molecules H 2 O per molecule. Suitable solvates and hydrates of compound (I) are described in WO 2017/050218, the content of which is herein incorporated by reference.
  • the present invention provides new stable solid compositions comprising compound (I) as an active agent, which are suitable for pharmaceutical use.
  • the compositions may only consist of compound (I), particularly in an anhydrous amorphous form, and a pH modifier, particularly L-arginine and/or sodium carbonate, and are free from further excipients, particularly carbohydrates such as sucrose. They may be prepared by lyophilization of highly concentrated aqueous solutions of compound (I). Before use, they are reconstituted with an aqueous liquid, particularly water, and then administered to a patient, particularly by injection or infusion.
  • the solid composition of the present invention comprises an active agent, which is compound (I) including any tautomeric species, solvate or hydrate thereof.
  • the active agent is the trihydrate of compound (I).
  • the active agent is an anhydrous form, particularly an anhydrous amorphous form of compound (I).
  • the solid composition of the present invention comprises a pH modifier, i.e. a compound, which is suitable to achieve a desired pH in an aqueous solution.
  • Suitable pH modifiers include sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium hydroxide, amines such as Tris (tris(hydroxymethyl)aminomethane), and amino acids, particularly basic amino acids such as arginine, lysine, and histidine.
  • the pH modifier is present in amount for adjusting a pH in the range from about pH 4.0 to about pH 6.0, and particularly for adjusting a pH of about 5.0, e.g. pH 5 +/- 0.5 or pH 5 +/- 0.25. in an aqueous solution.
  • the pH modifier is selected from the group consisting of a basic amino acid, a carbonate and any combination thereof.
  • the pH modifier is L-arginine.
  • the composition comprises the active agent and L-arginine in a molar ratio in the range of about 1.5:1 to about 2:1 .
  • the pH modifier is sodium carbonate.
  • the composition comprises the active agent and sodium carbonate in a molar ratio of about 0.7:1 to about 1 :1.
  • the solid composition of the present invention essentially consists of the active agent compound (I) and a pH modifier. Thus, the presence of substantial amounts of further constituents is excluded.
  • the solid composition contains about 10 wt-% or less, about 5 wt-% or less, about 2 w-% or less, or about 1 wt-% or less of further constituents.
  • the solid composition has a total water content of about 2 wt-% or less, of about 1 wt-% or less, or of about 0.5 wt-% or less.
  • the solid composition is essentially free from further excipients, e.g. essentially free from any carbohydrates and/or essentially free from sucrose.
  • the solid composition consists of the active agent and the pH modifier, i.e. it does not contain any other constituent possibly except residual water or solvent, e.g., in an amount of about 0.5 wt-% or less and/or unavoidable impurities.
  • the solid composition of the present invention is a lyophilized composition, i.e., a composition prepared by lyophilization.
  • the solid composition may be a composition prepared by spray drying.
  • the solid composition may be in present in any suitable container, particularly in a container suitable for pharmaceutical use, e.g., a vial.
  • the container may be a sterilized container, e.g., a sterilized vial.
  • the container optionally includes a stopper, e.g. a sterilized stopper, and/or a cap, e.g., a sterilized cap.
  • the container may be made of glass and/or plastic.
  • the container may have any suitable volume, e.g., from about 1 ml_ to about 1000 ml_. Typically, the volume of the container is from about 10 mL to about 200 ml_, e.g., about 50 mL.
  • the amount of the composition is adapted to its intended use, e.g. use as a pharmaceutical agent.
  • the composition may comprise about 1 g to about 50 g of the active agent, particularly about 2 g to about 6 g of the active agent and more particularly about 3 g of the active agent.
  • the solid composition of the present invention is typically adapted for reconstitution with a pharmaceutically acceptable liquid, particularly for reconstitution with water, particularly with water for injection.
  • the solid composition of the present invention is stable, i.e. it can be stored under suitable conditions without unacceptable degradation of the active agent, e.g. at a temperature of up to about 2-8°C for a time of at least 24 months of for at least 36 months.
  • a further aspect of the present invention is directed to a solid pharmaceutical composition essentially consisting of or consisting of:
  • an active agent which is compound (I), including any tautomeric species thereof, e.g. in an anhydrous amorphous form or in the form of a trihydrate;
  • a further aspect of the invention is directed to a liquid composition essentially consisting of:
  • an active agent which is compound (I), including any tautomeric species thereof,
  • a pharmaceutically acceptable aqueous liquid wherein the pH is in the range from about pH 4.0 to about pH 6.0, particularly of about pH 5.0, e.g. pH 5 +/- 0.5 or pH 5 +/- 0.25.
  • the liquid composition consists of the active agent, the pH modifier, and a pharmaceutically acceptable aqueous liquid.
  • the pharmaceutically acceptable aqueous liquid comprises at least about 50% (v/v) water, at least about 80% (v/v) water or at least about 95% (v/v) water.
  • the pharmaceutically acceptable aqueous liquid is water, particularly water for injection.
  • the liquid composition is a solution, i.e. it comprises the active agent and the pH modifier in a dissolved state.
  • the liquid composition comprises compound (I) in an amount, which is in the range of about 20 mg/mL to about 150 mg/mL, and which is particularly about 60 mg/mL.
  • the liquid composition can be obtained by combining the individual constituents, i.e. active agent, pH modifier, and pharmaceutically acceptable aqueous liquid in the required amounts and preparing a solution. From such a solution, a solid composition as described above may be prepared by drying, e.g., lyophilization.
  • liquid composition can be obtained by reconstituting a solid composition as described above with a pharmaceutically acceptable aqueous liquid. Such a composition is ready for administration to a patient.
  • a further aspect of the invention is directed to a liquid composition essentially consisting of or consisting of:
  • an active agent which is compound (I), including any tautomeric species thereof,
  • pH is in the range from about pH 4.0 to about pH 6.0.
  • a further aspect of the invention is directed to a kit comprising:
  • a further aspect of the invention is directed to a method for preparing a solid composition as described above, comprising the steps:
  • Filtration step (c) may comprise at least one filtration, e.g. two filtrations with a 0.22 urn filter.
  • Optional portioning step (d) may comprise portioning the solution into predetermined batch sizes .
  • the solvent may be removed by lyophilization or by spray drying.
  • Optional confectioning step (f) may comprise at least one of filling the solid composition into a sterilized vial, stoppering the vial using a sterilized stopper, and capping the vial using a sterilized cap.
  • the method may further comprise a quality control step, wherein the active agent and optionally of at least one impurity is quantitatively determined by suitable analytical methods including chromatographic methods such as HPLC.
  • a further aspect of the invention is directed to a method for preparing a liquid composition as described above, comprising reconstituting a solid composition, or a kit with a pharmaceutically acceptable aqueous liquid, particularly water.
  • the solid composition, the liquid composition or the kit are suitable for use in medicine, e.g. for use in human medicine, particularly for the treatment of a bacterial infection, e.g. a Gram-negative bacterial infection in a subject in need thereof.
  • the bacterial infection may be selected from a chronic urinary tract infection, particularly a Gram-negative urinary tract infection, including a complicated urinary tract infection, a bacterial pneumonia, particularly a Gram-negative pneumonia, including a hospital acquired and/or ventilator-associated pneumonia, and a bacterial intra abdominal infection, particularly a Gram-negative intra-abdominal infection, including a complicated intra-abdominal infection.
  • the bacterium causing the Gram negative bacterial infection may be selected from Citrobacter, Enterobacter, Escherichia, Haemophilus, Klebsiella, Morganella, Moraxella, Pseudomonas, Proteus, Salmonella, Serratia, Shigella, and Neisseria bacteria.
  • the solid composition or the kit may be reconstituted with a pharmaceutically acceptable aqueous liquid, particularly water, and administered to a subject in need thereof, e.g., a human subject.
  • the reconstituted composition may be administered by injection or infusion, particularly by intravenous infusion.
  • Other suitable routes include intramuscular, subcutaneous, intrathecal, and intraocular administration.
  • the reconstituted composition is administered within a time period of up to 24 hours after reconstitution.
  • the liquid composition may be administered to a subject in need thereof, e.g., a human subject, by injection or infusion.
  • the liquid composition is administered within a time period of up to 24 hours after preparation.
  • a further aspect of the invention is directed to a method for treating a bacterial infection in a subject in need thereof comprising administering an effective amount of compound (I), comprising reconstituting a solid composition as described above with a pharmaceutically acceptable aqueous liquid, particularly water, and administering the reconstituted composition to the subject, e.g., a human subject.
  • a further aspect of the invention is directed to a method for treating a bacterial infection in a subject in need thereof comprising administering an effective amount of compound (I), comprising administering a liquid composition as described above to the subject, a human subject.
  • the subject in need of treatment may suffer from a bacterial infection, e.g., from a Gram-negative bacterial infection as described above.
  • HPLC method can be used for the detection of compound (I) and other compounds as described herein.
  • Acetonitrile gradient grade, e.g. Merck LiChrosolv No. 100030
  • Methanol gradient grade, e.g. Merck LiChrosolv No. 106007
  • Tetrabutylammonium HPLC grade e.g. Sigma-Aldrich No. 86853 hydrogen sulphate (TBAHS)
  • Trifluoroacetic acid (TFA) HPLC grade e.g. Sigma-Aldrich No. 302031
  • Apparatus UHPLC system with gradient elution and UV detector e.g. Agilent 1290 with UV detector or equivalent
  • ⁇ 2 ml_ from each formulation were transferred into 48 vials, which were closed by a stopper.
  • Arg-1 Storage temperature 25°C/60% relative humidity (RH)

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Communicable Diseases (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Oncology (AREA)
  • Dermatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des compositions pharmaceutiques stables comprenant un antibiotique monobactame, leur utilisation en médecine et un procédé de préparation desdites compositions pharmaceutiques.
PCT/IB2022/051871 2021-03-04 2022-03-03 Formulation d'un antibiotique monobactame Ceased WO2022185240A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202163156518P 2021-03-04 2021-03-04
US63/156,518 2021-03-04

Publications (1)

Publication Number Publication Date
WO2022185240A1 true WO2022185240A1 (fr) 2022-09-09

Family

ID=80684927

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2022/051871 Ceased WO2022185240A1 (fr) 2021-03-04 2022-03-03 Formulation d'un antibiotique monobactame

Country Status (1)

Country Link
WO (1) WO2022185240A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015148379A1 (fr) 2014-03-24 2015-10-01 Novartis Ag Composés organiques monobactam pour le traitement d'infections bactériennes
WO2017050218A1 (fr) 2015-09-23 2017-03-30 Novartis Ag Sels et formes solides d'antibiotique monobactame

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015148379A1 (fr) 2014-03-24 2015-10-01 Novartis Ag Composés organiques monobactam pour le traitement d'infections bactériennes
WO2017050218A1 (fr) 2015-09-23 2017-03-30 Novartis Ag Sels et formes solides d'antibiotique monobactame

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