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WO2018169967A1 - Acorafloxacine dans le traitement d'infections oculaires - Google Patents

Acorafloxacine dans le traitement d'infections oculaires Download PDF

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Publication number
WO2018169967A1
WO2018169967A1 PCT/US2018/022197 US2018022197W WO2018169967A1 WO 2018169967 A1 WO2018169967 A1 WO 2018169967A1 US 2018022197 W US2018022197 W US 2018022197W WO 2018169967 A1 WO2018169967 A1 WO 2018169967A1
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Prior art keywords
acorafloxacin
pharmaceutically acceptable
treatment
acceptable salt
moxifloxacin
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.)
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PCT/US2018/022197
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English (en)
Inventor
Mohammed I. Dibas
John E. Donello
Miguel ALCANTARA
Ian A. Critchley
Michael R. Robinson
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Allergan Inc
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Allergan Inc
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Publication of WO2018169967A1 publication Critical patent/WO2018169967A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • 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
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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 subject matter described herein relates to use of the fluoroquinolone compound acorafloxacin for the treatment or control of ocular infections including, but not limited to, bacterial infections such as conjunctivitis, keratitis, vitritis, and endophthalmitis.
  • Bacterial conjunctivitis is the second most common cause of infectious conjunctivitis in humans and affects all ages and socioeconomic classes (Alfonso, S.A. et al., Prim. Care, 2015, 42:325-345). In the developed world, bacterial conjunctivitis is one of the primary causes of acute red eye, which in turn is responsible for 1-4% of primary care visits (Origlieri, C. et al., Expert Opirt. Emerg. Drugs, 2009, 14:523-536). The economic impact of bacterial conjunctivitis is significant, in terms of the cost of medical visits, cost of treatment, and lost work productivity (Smith, A.F.
  • a particular concern is that many of the methicillin-resistant isolates have a high probability of concurrent resistance to fluoroquinolones, aminoglycosides and macrolides. Multi- resistance to at least 3 additional antibiotic classes was identified among 428 methicillin-resistant S. aureus isolates (86.8%) and 381 methicillin-resistant coagulase-negative staphylococci (CoNS) isolates (77.3%) (Asbell, supra). There is an unmet need for new agents with potent antibacterial activity against ocular pathogens that includes contemporary resistant phenotypes that are resistant to existing fluoroquinolone drugs and/or other antimicrobial drugs.
  • a method for treating an ocular bacterial infection in a patient in recognized need of such treatment comprises administering to the patient in recognized need of such treatment a therapeutically effective amount of acorafloxacin.
  • administering comprises locally administering to an eye of the patient.
  • local administration to the eye comprises topical administration.
  • acorafloxacin is administered as a pharmaceutical composition comprising acorafloxacin and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition is a solution or a suspension.
  • the pharmaceutical composition is an ointment.
  • the pharmaceutical composition is a gel.
  • the therapeutically effective amount of acorafloxacin is at least about 4 times less than a therapeutically effective amount of one or more of besifloxacin, gatifloxacin, moxifloxacin, levofloxacin and ciprofloxacin.
  • the ocular infection comprises at least one bacterium selected from ophthalmic Staphylococcus aureus (MRSA) and ophthalmic Staphylococcus epidermidis (MRSE), and the administering is effective to resolve the infection at a dose of acorafloxacin that is at least about 4 times less than a dose of one or more of besifloxacin, gatifloxacin, moxifloxacin, levofloxacin and ciprofloxacin.
  • MRSA ophthalmic Staphylococcus aureus
  • MRSE ophthalmic Staphylococcus epidermidis
  • the ocular infection is bacterial conjunctivitis, bacterial blepharitis, bacterial keratitis, or bacterial endophthalmitis.
  • the method in another embodiment, is more effective than a corresponding method wherein acorafloxacin is replaced with at least one fluoroquinolone selected from besifloxacin, gatifloxacin, moxifioxacin, levofloxacin and ciprofloxacin.
  • the method is more effective than a corresponding method wherein acorafloxacin is replaced with moxifioxacin.
  • kits comprised of (i) a pharmaceutical composition comprising acorafloxacin, and a pharmaceutically acceptable excipient; and (ii) instructions for administering the composition topically to an eye with a bacterial infection is provided.
  • the pharmaceutical composition is a solution or a suspension administrable by drops.
  • the pharmaceutical composition is an ointment.
  • the pharmaceutical composition is a gel.
  • the pharmaceutical composition is provided in a container suitable for multidose administration.
  • the composition is provided in a container suitable for unit dose administration.
  • the container comprises a dropper to dispense the pharmaceutical composition as single drops.
  • the container comprises a tube that dispenses the pharmaceutical composition as an ointment.
  • the container comprises a tube that dispenses the pharmaceutical composition as an gel.
  • MRSA ophthalmic Staphylococcus aureus
  • MRSE ophthalmic Staphylococcus epidermidis
  • MRSA ophthalmic Staphylococcus aureus
  • MRSE ophthalmic Staphylococcus epidermidis
  • MRSA ophthalmic methicillin-resistant Staphylococcus aureus
  • MRSE ophthalmic methicillin-resistant Staphylococcus epidermidis
  • Example Embodiment 1 A method for treating an ocular bacterial infection in a patient in recognized need of such treatment, comprising:
  • acorafloxacin or a pharmaceutically acceptable salt thereof.
  • Example Embodiment 2 The method of example embodiment 1, wherein acorafloxacin, or a pharmaceutically acceptable salt thereof, is administered as a pharmaceutical composition comprising acorafloxacin, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • Example Embodiment 3 The method of example embodiment 2, wherein the pharmaceutical composition is a solution or a suspension.
  • Example Embodiment 4 The method of example embodiment 2, wherein the pharmaceutical composition is an ointment or a gel.
  • Example Embodiment 5 The method of any one of example embodiments 3 or 4, wherein the pharmaceutical composition comprises a preservative.
  • Example Embodiment 6 The method of any one of example embodiments 3 or 4, wherein the pharmaceutical composition is preservative-free.
  • Example Embodiment 7 The method of example embodiment 2, wherein the pharmaceutical composition is an ocular implant, intracameral implant, intravitreal implant, subconjunctival implant, sub-Tenon's implant, punctum plug, canicular eluting implant, or ocular ring.
  • Example Embodiment 8 The method of example embodiment 2, wherein the pharmaceutical composition is a microsphere.
  • Example Embodiment 9 The method of any one of example embodiments 1 to 8, wherein administering comprises locally administering to an eye of the patient in recognized need of such treatment.
  • Example Embodiment 10 The method of example embodiment 9, wherein the local administration to the eye comprises topical administration.
  • Example Embodiment 11 The method of example embodiment 9, wherein the local administration to the eye comprises intravitreal administration, intracameral administration, subconjunctival administration, or sub-Tenon' s administration.
  • Example Embodiment 12 The method of any one of example embodiments 1-11, wherein the therapeutically effective amount of acorafloxacin, or a pharmaceutically acceptable salt thereof, is at least about 4 times less than a therapeutically effective amount of one or more of besifloxacin, gatifloxacin, moxifloxacin, levofloxacin and ciprofloxacin.
  • Example Embodiment 13 The method of any preceding example embodiment, wherein the ocular infection comprises at least one bacterium selected from ophthalmic
  • MRSA Staphylococcus aureus
  • MRSE ophthalmic Staphylococcus epidermidis
  • Example Embodiment 14 The method of any preceding example embodiment, wherein the ocular infection is bacterial conjunctivitis, bacterial blepharitis, bacterial keratitis, or bacterial endophthalmitis.
  • Example Embodiment 15 The method of any one of example embodiments 1-14, wherein the method is more effective than a corresponding method wherein acorafloxacin, or a pharmaceutically acceptable salt thereof, is replaced with at least one fluoroquinolone selected from besifloxacin, gatifloxacin, moxifloxacin, levofloxacin and ciprofloxacin.
  • Example Embodiment 16 The method of any one of example embodiments 1-15, wherein the method is more effective than a corresponding method wherein acorafloxacin is replaced with moxifloxacin.
  • Example Embodiment 17 The method of any one of any one of example
  • embodiments 1-16 wherein the treatment is a prophylactic treatment.
  • Example Embodiment 18 A kit, comprising:
  • composition comprising acorafloxacin, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient;
  • Example Embodiment 19 The kit of example embodiment 18, wherein the composition is a solution or a suspension administrable by drops.
  • Example Embodiment 20 The kit of example embodiment 18, wherein the composition is an ointment or a gel.
  • Example Embodiment 21 The kit of any one of example embodiments 18-20, wherein the composition is provided in a container suitable for multidose administration.
  • Example Embodiment 22 The kit of example embodiment 21, wherein the container comprises a dropper to dispense the composition as single drops.
  • Example Embodiment 23 The kit of example embodiment 21, wherein the container comprises a tube that dispenses the composition as an ointment or a gel.
  • Example Embodiment 24 The kit of any one of example embodiments 18-23, wherein the composition comprises a preservative.
  • Example Embodiment 25 The kit of any one of example embodiments 18-23, wherein the composition is preservative-free.
  • Example Embodiment 26 The kit of example embodiment 18, wherein the composition is an ocular implant, intracameral implant, intravitreal implant, subconjunctival implant, sub-Tenon's implant, punctum plug, canicular eluting implant, or ocular ring.
  • Example Embodiment 27 The kit of example embodiment 18, wherein the composition is a microsphere.
  • Example Embodiment 28 A method of inhibiting growth of at least one bacterium selected from ophthalmic Staphylococcus aureus (MRSA) and ophthalmic Staphylococcus epidermidis (MRSE), comprising: contacting acorafloxacin, or a pharmaceutically acceptable salt thereof, with the at least one bacterium.
  • MRSA ophthalmic Staphylococcus aureus
  • MRSE ophthalmic Staphylococcus epidermidis
  • Example Embodiment 29 A method of treating an ocular infection comprising at least one bacterium in a patient in recognized need of such treatment, the method comprising:
  • Example Embodiment 30 The method of example embodiment 29, wherein the fluoroquinolone having the lowest MIC is acorafloxacin.
  • Example Embodiment 31 The method of example embodiment 29 or example embodiment 30, wherein the at least one bacterium is resistant to at least one fluoroquinolone selected from besifloxacin, gatifloxacin, moxifloxacin, levofloxacin and ciprofloxacin, or a pharmaceutically acceptable salt thereof.
  • Example Embodiment 32 The method of any one of example embodiments 29-31, wherein the at least one bacterium is resistant to moxifloxacin.
  • Example Embodiment 33 The method of any one of example embodiments 29-32, wherein the treatment is a prophylactic treatment.
  • Example Embodiment 34 A kit comprising acorafloxacin and instructions for measuring acorafloxacin MIC on at least one bacterium selected from ophthalmic
  • Example Embodiment 35 The kit of example embodiment 34, wherein the ophthalmic Staphylococcus aureus is methicillin-resistant.
  • Example Embodiment 36 The kit of example embodiment 34 or example
  • Example Embodiment 37 The kit of any one of example embodiments 34-35, wherein the at least one bacterium is resistant to at least one fluoroquinolone selected from besifloxacin, gatifloxacin, moxifloxacin, levofloxacin and ciprofloxacin, or a pharmaceutically acceptable salt thereof.
  • Example Embodiment 38 Use of acorafloxacin, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of an ocular bacterial infection.
  • Example Embodiment 39 The use of example embodiment 38 wherein the medicament is a pharmaceutical composition comprising acorafloxacin, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • Example Embodiment 40 The use of example embodiment 39, wherein the pharmaceutical composition is a solution or a suspension.
  • Example Embodiment 41 The use of example embodiment 39, wherein the pharmaceutical composition is an ointment or a gel.
  • Example Embodiment 42 The use of any one of example embodiments 39-41, wherein the composition comprises a preservative.
  • Example Embodiment 43 The use of any one of example embodiments 39-41, wherein the composition is preservative-free.
  • Example Embodiment 44 The use of example embodiment 39, wherein the pharmaceutical composition is an ocular implant, intracameral implant, intravitreal implant, subconjunctival implant, sub-Tenon's implant, punctum plug, canicular eluting implant, or ocular ring.
  • Example Embodiment 45 The use of example embodiment 39, wherein the pharmaceutical composition is a microsphere.
  • Example Embodiment 46 The use of any one of example embodiments 38-45, wherein the medicament, when used in the treatment of an ocular bacterial infection, is administered locally to an eye of a patient in recognized need of such treatment.
  • Example Embodiment 47 The use of example embodiment 46, wherein the local administration to the eye comprises topical administration.
  • Example Embodiment 48 The use of example embodiment 46, wherein the local administration to the eye comprises intravitreal administration, intracameral administration, subconjunctival administration, or sub-Tenon' s administration.
  • Example Embodiment 49 The use of any one of example embodiments 38-48, wherein the acorafloxacin, or a pharmaceutically acceptable salt thereof, is present in the medicament in a therapeutically effective amount that is at least about 4 times less than a therapeutically effective amount of one or more of besifloxacin, gatifloxacin, moxifloxacin, levofloxacin and ciprofloxacin.
  • Example Embodiment 50 The use of any one of example embodiments 38-49, wherein the ocular infection comprises at least one bacterium selected from ophthalmic
  • MRSA Staphylococcus aureus
  • MRSE ophthalmic Staphylococcus epidermidis
  • the medicament when administered a patient in recognized need of treatment for the ocular bacterial infection, is effective to resolve the infection at a dose of acorafloxacin, or a pharmaceutically acceptable salt thereof, that is at least about 4 times less than a dose of one or more of besifloxacin, gatifloxacin, moxifloxacin, levofloxacin and ciprofloxacin.
  • Example Embodiment 51 The use of any one of example embodiments 38-50, wherein the ocular infection is bacterial conjunctivitis, bacterial blepharitis, bacterial keratitis, or bacterial endophthalmitis.
  • Example Embodiment 52 The use of any one of example embodiments 38-51, wherein the treatment of the ocular infection is more effective than a corresponding treatment wherein acorafloxacin, or a pharmaceutically acceptable salt thereof, is replaced with at least one fluoroquinolone selected from besifloxacin, gatifloxacin, moxifloxacin, levofloxacin and ciprofloxacin.
  • Example Embodiment 53 The use of any one of example embodiments 38-52, wherein the treatment of the ocular infection is more effective than a corresponding treatment wherein acorafloxacin, or a pharmaceutically acceptable salt thereof, is replaced with moxifloxacin.
  • Example Embodiment 54 The use of any one of example embodiments 38-53, wherein the treatment is a prophylactic treatment.
  • Example Embodiment 55 Use of acorafloxacin, or a pharmaceutically acceptable salt thereof, in the treatment of an ocular bacterial infection in a patient in recognized need of such treatment.
  • Example Embodiment 56 The use of example embodiments 55, wherein the treatment comprises administering the acorafloxacin, or a pharmaceutically acceptable salt thereof, as a pharmaceutical composition comprising the acorafloxacin, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • Example Embodiment 57 The use of example embodiment 56, wherein the pharmaceutical composition is a solution or a suspension.
  • Example Embodiment 58 The use of example embodiment 56, wherein the pharmaceutical composition is an ointment or a gel.
  • Example Embodiment 59 The use of any one of example embodiments 56-58, wherein the composition comprises a preservative.
  • Example Embodiment 60 The use of any one of example embodiments 56-58, wherein the composition is preservative-free.
  • Example Embodiment 61 The use of example embodiment 56, wherein the pharmaceutical composition is an ocular implant, intracameral implant, intravitreal implant, subconjunctival implant, sub-Tenon's implant, punctum plug, canicular eluting implant, or ocular ring.
  • Example Embodiment 62 The use of example embodiment 56, wherein the pharmaceutical composition is a microsphere.
  • Example Embodiment 63 The use of any one of example embodiments 55-62, wherein the treatment comprises locally administering the acorafloxacin to an eye of the patient in recognized need of such treatment.
  • Example Embodiment 64 The use of example embodiment 63, wherein the local administration to the eye comprises topical administration,
  • Example Embodiment 65 The use of example embodiment 63, wherein the local administration to the eye comprises intravitreal administration, intracameral administration, subconjunctival administration, or sub-Tenon' s administration.
  • Example Embodiment 66 The use of any one of example embodiments 55-65, wherein the treatment comprises administering the acorafloxacin to the patient in recognized need thereof a therapeutically effective amount of acorafloxacin, or a pharmaceutically acceptable salt thereof, that is at least about 4 times less than a therapeutically effective amount of one or more of besifloxacin, gatifloxacin, moxifloxacin, levofloxacin and ciprofloxacin.
  • Example Embodiment 67 The use of any one of example embodiments 55-66, wherein the ocular infection comprises at least one bacterium selected from ophthalmic
  • MRSA Staphylococcus aureus
  • MRSE ophthalmic Staphylococcus epidermidis
  • pharmaceutically acceptable salt thereof is administered that is at least about 4 times less than a dose of one or more of besifloxacin, gatifloxacin, moxifloxacin, levofloxacin and ciprofloxacin.
  • Example Embodiment 68 The use of any one of example embodiments 55-67, wherein the ocular infection is bacterial conjunctivitis, bacterial blepharitis, bacterial keratitis, or bacterial endophthalmitis.
  • Example Embodiment 69 The use of any one of example embodiments 55-68, wherein the treatment is more effective than a corresponding treatment wherein acorafloxacin, or a pharmaceutically acceptable salt thereof, is replaced with at least one fluoroquinolone selected from besifloxacin, gatifloxacin, moxifloxacin, levofloxacin and ciprofloxacin.
  • Example Embodiment 70 The use of any one of example embodiments 55-69, wherein the treatment is more effective than a corresponding treatment wherein acorafloxacin, or a pharmaceutically acceptable salt thereof, is replaced with moxifloxacin.
  • Example Embodiment 71 The use of any one of example embodiments 55-70, wherein the treatment is a prophylactic treatment.
  • Example Embodiment 72 Acorafloxacin, or a pharmaceutically acceptable salt thereof, for use in the treatment of an ocular bacterial infection in a patient in recognized need of such treatment.
  • Example Embodiment 73 The acorafloxacin, or pharmaceutically acceptable salt thereof, for the use of example embodiments 72, wherein the treatment comprises administering the acorafloxacin as a pharmaceutical composition comprising the acorafloxacin and a pharmaceutically acceptable excipient.
  • Example Embodiment 74 The acorafloxacin, or pharmaceutically acceptable salt thereof, for the use of example embodiment 73, wherein the pharmaceutical composition is a solution or a suspension.
  • Example Embodiment 75 The acorafloxacin, or pharmaceutically acceptable salt thereof, for the use of example embodiment 73, wherein the pharmaceutical composition is an ointment or a gel.
  • Example Embodiment 76 The acorafloxacin, or pharmaceutically acceptable salt thereof, for the use of any one of example embodiments 73-75, wherein the pharmaceutical composition comprises a preservative.
  • Example Embodiment 77 The acorafloxacin, or pharmaceutically acceptable salt thereof, for the use of any one of example embodiments 73-75, wherein the pharmaceutical composition is preservative-free.
  • Example Embodiment 78 The acorafloxacin, or pharmaceutically acceptable salt thereof, for use according to example embodiment 73, wherein the pharmaceutical composition is an ocular implant, intracameral implant, intravitreal implant, subconjunctival implant, sub-Tenon's implant, punctum plug, canicular eluting implant, or ocular ring.
  • Example Embodiment 79 The acorafloxacin, or pharmaceutically acceptable salt thereof, for use according to example embodiment 73, wherein the pharmaceutical composition is a microsphere.
  • Example Embodiment 80 The acorafloxacin, or pharmaceutically acceptable salt thereof, for the use of any one of example embodiments 72-79, wherein the treatment comprises locally administering the acorafloxacin to an eye of the patient in recognized need of such treatment.
  • Example Embodiment 81 The acorafloxacin, or pharmaceutically acceptable salt thereof, for the use of example embodiment 80, wherein the local administration to the eye comprises topical administration.
  • Example Embodiment 82 The acorafloxacin, or pharmaceutically acceptable salt thereof, for the use of example embodiment 80, wherein the local administration to the eye comprises intravitreal administration, intracameral administration, subconjunctival
  • Example Embodiment 83 The acorafloxacin, or pharmaceutically acceptable salt thereof, for the use of any one of example embodiments 72-82, wherein the treatment comprises administering the acorafloxacin, or pharmaceutically acceptable salt thereof, to the patient in recognized need thereof a therapeutically effective amount of acorafloxacin, or pharmaceutically acceptable salt thereof, that is at least about 4 times less than a therapeutically effective amount of one or more of besifloxacin, gatifloxacin, moxifloxacin, levofloxacin and ciprofloxacin.
  • Example Embodiment 84 The acorafloxacin, or pharmaceutically acceptable salt thereof, for the use of any one of example embodiments 72-83, wherein the ocular infection comprises at least one bacterium selected from ophthalmic Staphylococcus aureus (MRSA) and ophthalmic Staphylococcus epidermidis (MRSE), and the treatment is effective to resolve the infection when a dose of acorafloxacin, or pharmaceutically acceptable salt thereof, is administered that is at least about 4 times less than a dose of one or more of besifloxacin, gatifloxacin, moxifloxacin, levofloxacin and ciprofloxacin.
  • MRSA ophthalmic Staphylococcus aureus
  • MRSE ophthalmic Staphylococcus epidermidis
  • Example Embodiment 85 The acorafloxacin, or pharmaceutically acceptable salt thereof, for the use of any one of example embodiments 72-84, wherein the ocular infection is bacterial conjunctivitis, bacterial blepharitis, bacterial keratitis, or bacterial endophthalmitis.
  • Example Embodiment 86 The acorafloxacin, or pharmaceutically acceptable salt thereof, for the use of any one of example embodiments 72-85, wherein the treatment is more effective than a corresponding treatment wherein acorafloxacin is replaced with at least one fluoroquinolone selected from besifloxacin, gatifloxacin, moxifloxacin, levofloxacin and ciprofloxacin.
  • Example Embodiment 87 The acorafloxacin, or pharmaceutically acceptable salt thereof, for the use of any one of example embodiments 72-86, wherein the treatment is more effective than a corresponding treatment wherein acorafloxacin is replaced with moxifloxacin.
  • Example Embodiment 88 The acorafloxacin, or pharmaceutically acceptable salt thereof, for the use of any one of 72-87, wherein the treatment is a prophylactic treatment.
  • Example Embodiment 89 Use of acorafloxacin, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of an ocular infection comprising at least one bacterium in a patient in recognized need of such treatment.
  • Example Embodiment 90 The use of example embodiment 89, wherein the treatment comprises:
  • Example Embodiment 91 The use of example embodiment 90, wherein the fluoroquinolone having the lowest MIC is acorafloxacin.
  • Example Embodiment 92 The of any one of example embodiments 89-91, wherein the at least one bacterium is resistant to at least one fluoroquinolone selected from besifloxacin, gatifloxacin, moxifloxacin, levofloxacin and ciprofloxacin, or a pharmaceutically acceptable salt thereof.
  • Example Embodiment 93 The use of any one of example embodiments 89-92, wherein the at least one bacterium is resistant to moxifloxacin.
  • Example Embodiment 94 The use of any one of example embodiments 89-93, wherein the treatment is a prophylactic treatment.
  • Example Embodiment 95 Use of acorafloxacin, or a pharmaceutically acceptable salt thereof, in the treatment of an ocular infection comprising at least one bacterium in a patient in recognized need of such treatment.
  • Example Embodiment 96 The use of example embodiment 95, wherein the treatment comprises:
  • Example Embodiment 97 The use of example embodiment 96, wherein the fluoroquinolone having the lowest MIC is acorafloxacin.
  • Example Embodiment 98 The use of any one of example embodiments 95-97, wherein the at least one bacterium is resistant to at least one fluoroquinolone selected from besifloxacin, gatifloxacin, moxifloxacin, levofloxacin and ciprofloxacin, or a pharmaceutically acceptable salt thereof.
  • Example Embodiment 99 The use of any one of example embodiments 95-98, wherein the at least one bacterium is resistant to moxifloxacin.
  • Example Embodiment 100 The use of any one of example embodiments 95-99, wherein the treatment is a prophylactic treatment.
  • Example Embodiment 101 Acorafloxacin, or a pharmaceutically acceptable salt thereof, for use in the treatment of an ocular infection comprising at least one bacterium in a patient in recognized need of such treatment.
  • Example Embodiment 102 Acorafloxacin, or a pharmaceutically acceptable salt thereof, for the use of example embodiment 101, wherein the treatment comprises:
  • Example Embodiment 103 Acorafloxacin for the use of example embodiment
  • Example Embodiment 104 Acorafloxacin for the use of any one of example embodiments 101-102, wherein the at least one bacterium is resistant to at least one
  • fluoroquinolone selected from besifloxacin, gatifloxacin, moxifloxacin, levofloxacin and ciprofloxacin, or a pharmaceutically acceptable salt thereof.
  • Example Embodiment 105 Acorafloxacin, or a pharmaceutically acceptable salt thereof, for the use of any one of example embodiments 101-104, wherein the at least one bacterium is resistant to moxifloxacin.
  • Example Embodiment 106 Acorafloxacin, or a pharmaceutically acceptable salt thereof, for the use of any one of example embodiments 101-105, wherein the treatment is a prophylactic treatment.
  • Example Embodiment 107 A method for treating an ocular bacterial infection in a patient substantially as described herein.
  • Example Embodiment 108 A method for treating an ocular bacterial infection in a patient in need thereof using acorafloxacin, or a pharmaceutically acceptable salt thereof, substantially as described herein.
  • Example Embodiment 109 The use of acorafloxacin, or a pharmaceutically acceptable salt thereof, substantially as described herein.
  • Example Embodiment 110 Acorafloxacin, or a pharmaceutically acceptable salt thereof, for use substantially as described herein.
  • FIG. 1 is a Finlandogram plot showing the cumulative percentage of ophthalmic
  • MIC minimum inhibitory concentration
  • FIG. 2 is a Finlandogram plot showing the cumulative percentage of ophthalmic
  • MIC minimum inhibitory concentration
  • a and “an,” such as in a pharmaceutically acceptable salt and a pharmaceutically acceptable excipient refers to one or more.
  • acorafloxacin includes acorafloxacin free form and/or a pharmaceutically acceptable salt thereof.
  • Such salts include, but are not limited to, acid addition salts, such as hydrochloride, hydrobromide, sulfurate, nitrate, phosphorate, acetate, propionate, glycolate, pyruvate, oxalate, malate, malonate, succinate, maleate, fumarate, tartarate, citrate, benzoate, cinnamate, mandelate, methanesulfonate, ethanesulfonate, p-toluene-sulfonate, salicylate and the like, and base addition salts, such as sodium, potassium, calcium, magnesium, lithium, aluminum, zinc, ammonium, ethylenediamine, arginine, piperazine and the like (see, e.g., Handbook of Pharmaceutical Salts, P. Heinrich Stahl & Camille G. Wermuth (Eds)
  • therapeutically effective amount refers to an amount that is effective, when administered to a patient in recognized need, such as human or non-human patient, to alleviate the symptoms or stop the progression of an ocular bacterial infection.
  • the therapeutically effective amount is an amount effective to alleviate the symptoms or stop the progression or cause disappearance of symptoms of an ocular bacterial infection caused at least in part by ophthalmic methicillin-resistant Staphylococcus aureus (MRSA) and/or ophthalmic methicillin-resistant Staphylococcus epidermidis (MRSE).
  • MRSA methicillin-resistant Staphylococcus aureus
  • MRSE ophthalmic methicillin-resistant Staphylococcus epidermidis
  • a therapeutically effective amount is an amount that would be effective to alleviate the symptoms or stop the progression or cause disappearance of symptoms of an ocular bacterial infection if the symptoms were to arise due to an infection that developed in a prophylactically treated subject at risk for such an infection even though said subject had not had any signs or symptoms of the infection at the time of administration of the compound.
  • treating means inhibiting the disease, i.e., arresting or reducing the progression of the disease or its clinical symptoms, or relieving the disease, i.e., causing regression or disappearance of the disease or its clinical symptoms.
  • the treatment can be prophylactic treatment.
  • prophylactic treatment means preventing the occurrence of a disease or condition (e.g. a bacterial infection) in a subject at risk for the disease or condition, but who has otherwise not yet manifested the disease or condition (e.g. a subject undergoing, or who had recently undergone ocular surgery).
  • a disease or condition e.g. a bacterial infection
  • keratitis and "bacterial keratitis” as used herein include corneal ulcer.
  • MIC refers to minimum inhibitory concentration. The MIC value is defined as the lowest concentration of antimicrobial agent that inhibits the visible growth of a given organism. MIC50 and MIC90 values were determined as the concentration of antibiotic that inhibited growth of 50% and 90% of an organism.
  • a bacterium is resistant to an antibiotic if the MIC on the bacterium meets the resistant definition according to Clinical & Laboratory Standards Institute (CLSI) breakpoint.
  • CLSI Clinical & Laboratory Standards Institute
  • a bacterium is resistant to ciprofloxacin if ciprofloxacin MIC on the bacterium is greater than or equal to 4 ⁇ g/mL.
  • a "corresponding method” refers to a method which is similar to the method provided herein but for administration of a different active ingredient.
  • a method is "more effective than a corresponding method" if the therapeutically effective amount of the active ingredient administered in the method is less than the therapeutically effective amount of the different active ingredient administered in the corresponding method.
  • a "pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes an excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • “A pharmaceutically acceptable excipient” as used in the specification and claims includes both one and more than one such excipient.
  • Exemplary pharmaceutically acceptable excipients can be pharmaceutically acceptable preservatives, surfactants, antioxidants, and stabilizers, etc.
  • a method for treating an ocular infection in a patient comprises administering to a patient in recognized need of treatment a therapeutically effective amount of acorafloxacin.
  • Acorafloxacin is 7-[(3E)-3-(2-amino-l- fluoroethylidene)-l- piperidinyl]- 1 -cyclopropyl-6-fluoro- 1 ,4-dihydro-8-methoxy-4-oxo 3- quinolinecarboxylic acid, which has a chemical structure of:
  • Acorafloxacin is also referred to as avarofloxacin and/or JNJ-Q2, and is a fluorinated 4-quinolone.
  • reference herein to 'acorafloxacin' includes reference to its pharmaceutically acceptable salts thereof.
  • acorafloxacin is administered to the eye as a topical pharmaceutical composition comprised of acorafloxacin and a pharmaceutically acceptable excipient.
  • a topical pharmaceutical composition comprised of acorafloxacin and a pharmaceutically acceptable excipient.
  • exemplary compositions, and excipients used to manufacture the compositions are set forth below.
  • acorafloxacin against ocular pathogens, such as methicillin resistant S. aureus and S. epidermidis (MRSA and MRSE, respectively).
  • MRSA and MRSE methicillin resistant S. aureus and S. epidermidis
  • Example 1 the antibiotic activity of acorafloxacin against an isolate panel of ophthalmic bacteria was evaluated and compared to other fluoroquinilone compounds.
  • the antibiotic activity of acorafloxacin was evaluated by assay for minimum inhibitory concentration (MIC) using a broth microdilution method and compared to besifloxacin, moxifloxacin, ciprofloxacin, gatifloxacin, and levofloxacin.
  • the various test compounds were tested for antibiotic activity against 262 bacteria strains, including 80 MRSA and 95 MRSE strains, isolated from ophthalmic specimen sources collected worldwide. For comparison, antibiotic activity of the compounds was also tested against 87 MRSA isolates from skin and respiratory infections.
  • FIG. 1 is a Finlandogram plot showing the cumulative percentage of ophthalmic MRSA isolates inhibited as a function of minimum inhibitory concentration (in ⁇ g/mL) for acorafloxacin (diamonds), besifloxacin (squares), moxifloxacin (triangles), gatifloxacin (X symbols), levofloxacin (inverted triangles) and ciprofloxacin (circles).
  • Acorafloxacin was more potent against the ophthalmic MRSA isolates than the other compounds, with a 4-fold lower MIC than besifloxacin.
  • Table 1 is a summary of the MICso and MIC90 values against ophthalmic MRSA for the compounds tested.
  • acorafloxacm was 8-fold to 32-fold more potent based on MIC90 values.
  • besifloxacin had a MIC90 of 2.0 ⁇ g/mL and acorafloxacin had an MIC90 of 0.25 ⁇ g/mL demonstrating that acorafloxacin was 8-fold more potent against ophthalmic MRSA bacterial isolates than besifloxacin.
  • Gatifloxacin had a MIC90 of >4 g/mL and acorafloxacin had an MIC90 of 0.25 g/mL demonstrating that acorafloxacin was 32-fold more potent against ophthalmic MRSA bacterial isolates than gatifloxacin.
  • Table 1 MIC Range, MIC50 and MIC90 Values of Antibiotic Agents Against
  • FIG. 2 is a Finlandogram plot showing the cumulative percentage of ophthalmic MRSE isolates inhibited as a function of minimum inhibitory concentration (in ⁇ g/mL) for acorafloxacin (diamonds), besifloxacin (squares), moxifloxacin (triangles), gatifloxacin (X symbols), levofloxacin (inverted triangles) and ciprofloxacin (circles).
  • Acorafloxacin was more potent against the ophthalmic MRSE isolates than the other compounds, with an 8-fold lower MIC than besifloxacin.
  • Table 2 is a summary of the MIC50 and MIC90 values against ophthalmic MRSE for the compounds tested.
  • acorafloxacin demonstrated potent activity with an MIC90 value of 0.5 ⁇ g mL, which is 8- to 16-fold more active in vitro than besifloxacin, gatifloxacin, moxifloxacin, levofloxacin, or ciprofloxacin, respectively.
  • Out of 95 MRSE strains 59% - 68% exhibited resistance to these fluoroquinolones according to CLSI breakpoints.
  • acorafloxacin was tested in comparison to other fluoroquinilones that are currently prescribed for ophthalmic bacterial infections, such as bacterial conjunctivitis, and the MIC90 values of acorafloxacin were found to be 4-32 times more potent against MRSA and MRSE ophthalmic bacteria isolates.
  • Acorafloxacin demonstrated potent in vitro activity against MRSA isolated from ophthalmic infections, and from skin and respiratory infections (See Example 1, below). Both MIC90 values were 0.25 ⁇ g/mL indicating acorafloxacin was equally active in vitro against MRSA from these specimen sources.
  • a method for treating a bacterial infection in the eye by locally administering acorafloxacin to the eye is provided.
  • the acorafloxacin is locally administered by topical application to an eye affected with a bacterial infection a pharmaceutical composition comprising acorafloxacin and a pharmaceutically acceptable excipient.
  • the method includes locally administering via topical application to both eyes of a patient the acorafloxacin composition, where one or both eyes are in need of treatment.
  • the treatment is a prophylactic treatment.
  • compounds described herein e.g. acorafloxacin
  • the prophylaxis obtained from the prophylactic treatments with the compounds described herein e.g.
  • acorafloxacin can include, for example, primary prophylaxis (prevention of an initial infection) and eradication prophylaxis (elimination of a colonized organism to prevent the development of an infection.) See, e.g., Bratzler, D. W., et al, American journal of health-system pharmacy 2013, 70 (3), 195-283.
  • compounds described herein can be administered intracamerally following cataract or other types of intraocular surgery to reduce the incidence of endophthalmitis (See, e.g., Javitt, J. C, Ophthalmology 2016, 123 (2), 226-231).
  • inoculation of bacteria at the time of intraocular surgery can occur with the insertion of instrumentation, e.g. during the removal of a cataract or during a glaucoma filtering procedure.
  • Small incision cataract surgery is minimally invasive and no sutures are placed to close the corneal incision. There is the potential for bacteria to enter the eye immediately postoperatively until the corneal incision is completely sealed.
  • prophylactic treatment with intracameral acorafloxacin at the end of the surgical procedure can potentially reduce the incidence of bacterial endophthalmitis, a condition that can lead to pain, vision loss, and the loss of the eye.
  • intravitreal acorafloxacin can also be used as a prophylactic strategy to prevent infection following vitrectomy procedures.
  • subconjunctival or sub-Tenon's injections of acorafloxacin can be used at the end of intraocular surgery for prophylaxis, and lastly, it is also contemplated that topical acorafloxacin therapy can also be used alone or in conjunction with injections in the subconjunctival, intracameral or intravitreal space for prophylaxis.
  • topical therapy can be done for a number of days post operatively, typically 5 to 14 days and can also be used for ocular surgeries that do not enter the anterior chamber or the vitreous, for example, pterygia surgery, excision of a conjunctival lesion, or procedures performed on the eyelid such as a chalazia incision and drainage.
  • a method of inhibiting bacterial growth or killing a bacterium where the bacterial growth or the bacterium to be killed is a bacterium selected from ophthalmic methicillin-resistant Staphylococcus aureus (MRSA) and ophthalmic methicillin-resistant Staphylococcus epidermidis (MRSE) comprising contacting the bacterium with acorafloxacin.
  • MRSA ophthalmic methicillin-resistant Staphylococcus aureus
  • MRSE ophthalmic methicillin-resistant Staphylococcus epidermidis
  • acorafloxacin is contacted with the bacterium in the form of a pharmaceutical composition comprising acorafloxacin and a pharmaceutically acceptable excipient.
  • the method is more effective than a corresponding method wherein acorafloxacin is replaced with at least one fluoroquinolone selected from besifloxacin, gatifloxacin, moxifloxacin, levofloxacin and ciprofloxacin.
  • the composition administered to the patient or contacted with the bacterium is administered at a dose of acorafloxacin that is 2, 4, 6, 8, 10, 12 or 16 times less than one or more of besifloxacin, gatifloxacin, moxifloxacin, levofloxacin and ciprofloxacin.
  • acorafloxacin in particular relative to other fluoroquinolone antibiotics
  • the inventors believe that the high potency of acorafloxacin (in particular relative to other fluoroquinolone antibiotics) described herein gives it the potential to interrupt biofilm production, which in turn give it the ability to treat chronic eye infections such as blepharitis in which biofilm formation may play a role.
  • Infections can be seen as acute or chronic.
  • acute infections include, e.g. conjunctivitis or postoperative endophthalmitis
  • chronic infections include, e.g. blepharitis, in which the infection can persist for years since the eyelid produces oils via the Meibomian glands and it is possible to have a scaffold for persistent growth.
  • bacteria form biofilms. Biofilms are thought to cause chronic infections such as with gingivitis and lately that have been linked to blepharitis.
  • the pharmaceutical composition is in the form of a solution for ophthalmic application.
  • the solution is prepared using a physiological saline solution as a major vehicle.
  • the pH of such ophthalmic solutions should for example be maintained from 4.5 to 8.0 with an appropriate buffer system, a neutral pH being preferred but not essential.
  • buffers include, but are not limited to, acetate buffers, citrate buffers, phosphate buffers and borate buffers. Acids or bases may be used to adjust the pH of these formulations as needed.
  • the formulations may also contain conventional, pharmaceutically acceptable preservatives, stabilizers and surfactants.
  • exemplary preservatives that may be used in the pharmaceutical compositions include, but are not limited to, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate and phenylmercuric nitrate.
  • Stabilizers include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, and hydroxyethyl cellulose cyclodextrin.
  • the formulations can also be devoid of preservatives.
  • the ophthalmic solution preparation may also include a surfactant.
  • Surfactants are useful to assist in dissolving an excipient or an active agent, dispersing a solid or liquid in a composition, enhancing wetting, modifying drop size, etc.
  • Useful surfactants include, but are not limited to surfactants of the following classes: alcohols; amine oxides; block polymers; carboxylated alcohol or alkylphenol ethoxylates; carboxylic acids/fatty acids; ethoxylated alcohols; ethoxylated alkylphenols; ethoxylated aryl phenols; ethoxylated fatty acids; ethoxylated; fatty esters or oils (animal & veg ); fatty esters; fatty acid methyl ester ethoxylates; glycerol esters; glycol esters; lanolin-based derivatives; lecithin and lecithin derivatives; lignin and lignin derivatives; methyl esters; monoglycerides and derivatives; polyethylene glycols; polymeric surfactants; propoxylated and ethoxylated fatty acids, alcohols, or alkyl phenols; protein-based surfactants; sarcosine derivative
  • Tonicity adjustors may be added as needed or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjustor.
  • An ophthalmically acceptable antioxidant may be included, and examples include sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.
  • chelating agents are chelating agents.
  • An exemplary chelating agent is edetate disodium, although other chelating agents are known and suitable, alone or in combination with edetate disodium.
  • composition also referred to herein as a preparation
  • acorafloxacin in an amount between about 0.1% and about 1% (w/v), or between about 0.1% and about 0.2% (w/v), about 0.1% and about 0.3% (w/v), about 0.1% and about 0.4% (w/v), about 0.1% and about 0.5% (w/v), about 0.1% and about 0.5% (w/v), about 0.1% and about 0.6% (w/v), about 0.1% and about
  • the composition may also comprise acorafloxacin in an amount between about 0.1% and about 0.2% (w/v), about 0.2% and about 0.3% (w/v), about 0.3% and about 0.4% (w/v), about 0.4% and about 0.5% (w/v), about 0.5% and about 0.6% (w/v), about 0.6% and about 0.7% (w/v), about 0.7% and about 0.8% (w/v), about 0.8% and about 0.9% (w/v), about 0.9% and about 1% (w/v). Additional amounts of acorafloxacin for the compositions described herein would be identifiable to a skilled person upon a reading of the present disclosure.
  • composition in one embodiment comprises an amount of acorafloxacin sufficient to provide a concentration in the aqueous humor and lacrimal fluid of the eye equal to or greater than the MIC90 (minimum inhibitory concentration levels to inhibit 90% growth) relative to gram- negative and gram-positive organisms commonly associated with ophthalmic infections.
  • a MIC90 of 0.25 ⁇ g/mL would correspond to an amount of 0.000025% (w/v) and a MIC90 of 0.5 ⁇ g/mL would correspond to an amount of 0.00005%) (w/v).
  • the composition may comprise acorafloxacin in an amount between about 0.000025% (w/v) to about 0.00005% (w/v), about 0.000025% (w/v) to about 0.00025% (w/v), about 0.000025% (w/v) to about 0.0025%% (w/v), about 0.000025% (w/v) to about 0.025% (w/v), about 0.000025% (w/v) to about 0.05% (w/v), about 0.000025% (w/v) to about 0.75% (w/v), about 0.000025% (w/v) to about 0.1% (w/v), about 0.000025% (w/v) to about 0.25% (w/v), about 0.00005% (w/v) to about 0.00025% (w/v), about 0.00025% (w/v) to about
  • the compounds described herein e.g. acorafloxacin
  • the compounds are the only active ingredients which have
  • antimicrobial activity such that would be of use for the treatment (including prophylactic treatment) or control of ocular infections (e.g. conjunctivitis, keratitis, vitritis, and
  • active ingredient refers to a component which is responsible for the antimicrobial biological effect of composition, whereas the other components of the composition (e.g. excipients, carriers, and diluents) are not responsible for the
  • compositions described herein in which the compound or compounds (e.g. acorafloxacin) are the only active ingredient or ingredient which have antimicrobial activity are compositions in which there are no other components which would be considered to have antimicrobial activity.
  • the ophthalmic formulation in another embodiment, is packaged in a form suitable for metered application, such as in a container equipped with a dropper, to facilitate application to the eye.
  • Containers suitable for drop wise application are usually made of suitable inert, non-toxic plastic material, and generally contain between about 0.5 and about 15 ml solution.
  • One package may contain one or more unit doses.
  • Preservative-free solutions are often formulated in non-resealable containers containing up to about ten, such as up to about five units doses, where a typical unit dose is from one to about 8 drops, such as from one to about 3 drops.
  • the volume of one drop usually is about 20-35 ⁇ ⁇ .
  • ocular delivery methods for administration to the eye are also contemplated for the compositions and/or compounds described herein.
  • ocular administration methods can include, for example, intravitreal administration, intracameral administration, and subconjunctival administration, and other ocular administration methods identifiable to a skilled person.
  • additional administration methods such as using ocular drug delivery systems (e.g.
  • ocular implants intracameral implants, intravitreal implants, subconjunctival implants, sub-Tenon' s implants, punctum plugs, canicular eluting implants, and ocular rings
  • injectable sustained-release formulations resulting in a depot, such as acorafloxacin in a PLGA-based microsphere, which can also be used in any of the intraocular compartments such as the subconjunctiva, sub-Tenon's, intracameral, and intravitreal spaces
  • Kuno Polymers 2011, 3, 193-221 US patents 9,289,413 and 9,504,653
  • US patent application publications 2011/0182966, 2016/0022695, and 2016/0296532 and Chee, S -P., Journal of Ocular
  • kits comprised of an ocular preparation comprising acorafloxacin and instructions for administering the preparation to the eye.
  • the ocular preparation is, in one embodiment, provided or packaged in multidose form.
  • the preparation preferably comprises acorafloxacin and a pharmaceutically acceptable excipient. Any of the excipients discussed herein are suitable for the ocular preparation.
  • the preparation comprises a preservative that prevents microbial contamination during use (i.e., repeated use).
  • Suitable preservatives include benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium, ascorbic acid, ONAMER® M, PURITE® or other agents known to those skilled in the art. In ophthalmic products, typically such preservatives are employed at a level of from 0.004% to 0.02%. In addition, the preparations can also be devoid of preservatives. Such preparations devoid of preservatives are said to be "preservative-free.”
  • the instructions for administration typically provide dosing instructions.
  • the instructions may be to administer the preparation once per day, twice per day or three times per day.
  • the administration may be to place one drop, two drops, or three drops in the infected eye or in both eyes (e.g., if one eye is infected, both eyes may be treated, or if both eyes are infected) once per day, twice per day, three times per day, or more.
  • the instructions may be to administer the ointment to the infected eye or in both eyes once per day, twice per day, three times per day, or more.
  • the preparation is a gel (e.g., a preparation with a viscosity at room temperature that is greater than saline but less than that of an ointment)
  • the instructions may be to administer the ointment to the infected eye or in both eyes once per day, twice per day, three times per day, or more.
  • the ocular infection contemplated for treatment by the methods and kits described herein is bacterial conjunctivitis.
  • the method of treatment is effective to inhibit growth of one or more of S. aureus, Streptococcus pneumoniae and Haemophilius influenza.
  • the composition is applied to the eye two or three times per day for 5, 6, 7, 8, 9, or 10 days.
  • the methods and kits described herein are contemplated for treating bacterial blepharitis, bacterial keratitis, or bacterial endophthalmitis.
  • one or more bacterium present at the site of infection is resistant to at least one fluoroquinolone selected from besifloxacin, gatifloxacin, moxifloxacin, levofloxacin and ciprofloxacin. In some embodiments, the at least one bacterium is resistant to moxifloxacin.
  • a method of treating an ocular infection comprising at least one bacterium, comprising:
  • each of the fluoroquinolone as described herein includes the free form and/or a pharmaceutically acceptable salt thereof.
  • the at least one bacterium is selected from ophthalmic
  • MRSA Staphylococcus aureus
  • MRSE ophthalmic Staphylococcus epidermidis
  • the MRSA and MRSE are methicillin-resistant.
  • the fluoroquinolone having the lowest MIC is acorafloxacin.
  • the manner of administration can be any described herein, such as administration of the fluoroquinolone in the form of a pharmaceutical composition to the eye.
  • Acorafloxacin, besifloxacin, moxifloxacin, ciprofloxacin, gatifloxacin and levofloxacin, and oxacillin were obtained from commercial vendors. All compounds tested were in free base form.
  • Acorafloxacin and besifloxacin stock solutions were diluted from 5 mg/mL and 3 mg/mL, respectively, in water and methanol into cation-adjusted Mueller-Hinton broth (MHB) to give a two-fold serial dilutions to cover the historical MIC data ranges (Haas, W. et al., Clinical Ophthalmology, 2011, 5 : 1359-1367).
  • Stock solution of moxifloxacin, ciprofloxacin, gatifloxacin, levofloxacin and oxacillin were prepared according to Clinical and Laboratory Standards Institute (CLSI) guidelines (CLSI M100-S26).
  • Ophthalmic MRSA and MRSE isolates tested in this study were purchased from International Health Management Associates, Inc. and were from ocular infection specimens collected during 2014 to 2015 in 13 countries in the regions of North America, Latin America, Europe, and Middle East. Skin and respiratory MRSA isolates tested in this study were collected from skin and respiratory infections in United States in 201 1 for Furiex Clinical Trials. Those ophthalmic MRSA and MRSE isolates were usually resistant to both Oxacillin and methicillin.
  • MIC determinations were performed according to CLSI guidelines (CLSI M100- S26). Cultures were streaked onto Mueller-Hinton agar (obtained from Hardy Diagnostics) from frozen stocks and incubated at 37 °C overnight. Antibiotic test plates were prepared in a 2-fold dilution series containing 10 ⁇ 10X the desired final concentration in 96-well round-bottom plates. Bacterial cell suspensions were made by picking colonies directly from the agar plate and suspending in saline. The cell density was adjusted until it reached an OD600 of 0.08 to 0.1 (equivalent to ⁇ 2 x 10 8 CFU/mL) as measured by a spectrophotometer.
  • Bacterial suspensions were diluted in cation-adjusted Mueller-Hinton broth so that the final culture density in the microtiter plates was equal to 5 x 10 5 CFU/mL. Bacteria (90 uL) were then added to the microtiter plates containing antibiotic and incubated for 18 hours at 37 °C. Plates were evaluated for growth and results were recorded. The MIC was recorded as the lowest concentration where there was no visible bacterial growth.
  • acorafloxacin MICs ranged from 0.004 to 0.5 ⁇ g/mL.
  • the MIC90 of acorafloxacin was 0.25 ⁇ g/mL, which was 8 times lower than that of besifloxacin where the MIC90 was 2 ⁇ g/mL and the MICs ranged from 0.016 ⁇ g/mL to >8 ⁇ g/mL.
  • Moxifloxacin MICs ranged from 0.03 to >8 ⁇ g/mL and MIC90 was >8 g mL.
  • Ciprofloxacin MICs ranged from 0.25 to >8 ⁇ g/mL and 70% of isolates were intermediate or resistant to ciprofloxacin according to CLSI breakpoint (2 ⁇ g/mL are intermediate; >4 ⁇ g/mL are resistant).
  • Gatifloxacin MICs ranged from 0.06 to >4 ⁇ g/mL and 65% of the isolates were intermediate or resistant to gatifloxacin according to CLSI breakpoint (1 ⁇ g/mL are intermediate; >2 ⁇ g/mL are resistant).
  • Levofloxacin MICs ranged from 0.125 to >4 ⁇ g/mL, and 65% of isolates were intermediate or resistant to levofloxacin according to CLSI breakpoint (4 ⁇ g/mL are intermediate; >8 ⁇ g/mL are resistant).
  • Acorafloxacin 18.8 31.3 35.0 - 46.3 67.5 93.8 100 - - - -
  • Organism No. of Isolates Compound MIC Range MICso MIC 90 S 1 R
  • MRSA ophthalmic 80 Acorafloxacin ⁇ 0.004 - 0.5 0.125 0.25 N/A N/A N/A
  • MRSA ophthalmic 55 Acorafloxacin 0.016-0.5 0.125 0.25 N/A N/A N/A
  • MRSA ophthalmic 53 Acorafloxacin 0.016-0.5 0.125 0.25 N/A N/A N/A
  • MRSA ophthalmic 40 Acorafloxacin 0.125 -0.5 0.25 0.5 N/A N/A N/A
  • acorafloxacin MICs ranged from 0.004 to 1 ⁇ g/mL.
  • the MIC90 of acorafloxacin was 0.5 ⁇ g/mL, which was eight times lower than that of besifloxacin where the MIC90 was >4 ⁇ g/mL and the MICs ranged from 0.016 to >8 ⁇ g/mL.
  • Moxifloxacin MICs ranged from 0.03 to >4 ⁇ g/mL and 56% of the isolates were intermediate or resistant to moxifloxacin according to CLSI breakpoint (1 ⁇ g/mL are intermediate; >2 are resistant).
  • Ciprofloxacin MICs ranged from 0.125 to >8 ⁇ g/mL and 63% of isolates were intermediate or resistant to ciprofloxacin according to CLSI breakpoint (2 ⁇ g/mL are intermediate; >4 ⁇ g/mL are resistant).
  • Gatifloxacin MICs ranged from 0.06 to >4 ⁇ g/mL and 61% of the isolates were intermediate or resistant to gatifloxacin according to CLSI breakpoint (1 ⁇ g/mL are intermediate; >2 ⁇ g/mL are resistant).
  • Levofloxacin MICs ranged from 0.125 to >4 ⁇ g/mL, and 61% of isolates were intermediate or resistant to levofloxacin according to CLSI breakpoint (4 ⁇ g/mL are intermediate; >8 are resistant).
  • Organism No. of Isolates Compound MIC Range MICso MIC90 S I R
  • MRSE (ophthalmic) 38 Acorafloxacin 0.06 - 1 0.5 1 N/A N/A N/A
  • MRSE (ophthalmic) 55 Acorafloxacin 0.03 - 1 0.06 1 N/A N/A N/A
  • MRSE (ophthalmic) 39 Acorafloxacin 0.06 - 1 0.125 1 N/A N/A N/A
  • the MICs of acorafloxacin ranged from 0.06 to 1 ⁇ g/mL.
  • the MIC90 of acorafloxacin was 0.25 g/mL, which was 4 times lower than that of besifloxacin where the MIC90 was 1 ⁇ g/mL and the MICs ranged from 0 5 ⁇ g/ L to >8 ⁇ g/mL.
  • Moxifloxacin MICs ranged from 1 to >4 ⁇ ⁇ and 90% of the isolates were intermediate or resistant to moxifloxacin according to CLSI breakpoint (1 ⁇ g/mL are intermediate; >2 are resistant).
  • Ciprofloxacin MICs were >8 ⁇ g/mL and 100% of isolates were intermediate or resistant to ciprofloxacin according to CLSI breakpoint (2 ⁇ g/mL are intermediate; >4 are resistant). Gatifloxacin MICs ranged from 2 to >4 ⁇ g/mL and 100% of the isolates were resistant to gatifloxacin according to CLSI breakpoint (1 ⁇ g/mL are intermediate, >2 are resistant). Levofloxacin MICs were >4 ⁇ g/mL, and 100% of the isolates were intermediate or resistant to levofloxacin according to CLSI breakpoint (4 ⁇ g/mL are intermediate; >8 are resistant).
  • Organism No. of Isolates Compound MIC Range MICso MIC90 S I R
  • MRSA skin & Respiratory
  • MRSA skin & Respiratory 85 Acorafloxacin 0.06 - 1 0.125 0.25 N/A N/A N/A
  • MRSA skin & Respiratory
  • MRSA skin & Respiratory
  • MRSA skin & Respiratory
  • MICs Minimum Inhibitory Concentrations
  • MICs were determined for the ocular bacterial isolates using the recommended Clinical and Laboratory Standards Institute (CLSI) protocols and methodology. All antibacterials were tested with eleven 2-fold dilutions from 32 to 0.03125 ⁇ g/ml. All testing was performed in fresh Mueller-Hinton medium except for Streptococcus species (3% lysed horse red blood cells were added to the Mueller-Hinton medium) and Haemophilus species (fresh Haemophilus Test Medium (remel)).
  • MRSA methicillin-resistant Staphylococcus aureus
  • MSSA methicillin-susceptible Staphylococcus aureus
  • MRCNS methicillin-resistant coagulase-negative Staphylococcus
  • MSCNS methicillin- susceptible coagulase-negative Staphylococcus
  • MIC concentration that inhibits the growth of 50% of the tested bacterial isolates
  • MIC90 concentration that inhibits the growth of 90% of the tested bacterial isolates
  • Table 3 The results are shown in table 3 below.
  • Streptococcus pneumoniae MOX 0.12 0.12 0.25 0.06-0.5 p 0.00001
  • the concentration of moxifloxacin in the assay was confirmed by comparing the MICs to a range of MICs predetermined to the following ATTC isolates: Staphylococcus aureus 29212, Enterococcus faecalis 29212, Escherichia coli 25922, and Pseudomonas aeruginosa 27853. There were no MIC ranges for the ATCC isolates to confirm the concentration of acorafloxacin.
  • the conjunctivitis isolates (SA, CNS, St. pneumoniae, Haemophilus sp., other Gram-positives and other Gram -negatives) were based on the incidence of occurrence from a University of Pittsburg laboratory and chosen consecutively over a time period.
  • the Pseudomonas aeruginosa isolated from keratitis were also consecutive isolates except for six that were chosen for fluoroquinolone resistance.
  • the six FQ resistant Pseudomonas aeruginosa isolates were obtained from Dr. David Ritterband (New York Eye & Ear Infirmary).
  • the MRSA and MSSA were isolated from endophthalmitis based on methicillin resistance (MR) and susceptibility (MS).
  • the MIC at the 50% rank was determined to be the MIC50.
  • the MIC50 and the median are often the same but can be different with even number of values. This is the concentration that inhibits the growth of 50% of the tested bacterial isolates.
  • the MIC at the 90% rank was determined to be the MICgo- This is the concentration that inhibits the growth of 50% of the tested bacterial isolates.
  • Range The range is the lowest MIC and the highest MIC.
  • acorafloxacin were significantly lower than the MICs to moxifloxacin, including isolates that are resistant to moxifloxacin using Clinical and Laboratory Standards Institute (CLSI) breakpoints.
  • CLSI Clinical and Laboratory Standards Institute
  • selected MIC90 values for acorafloxacin and moxifloxacin from this example were compared to selected literature values for other antibiotics.
  • the MIC90 values for acorafloxacin and moxifloxacin in the ophthalmic isolates of MRS A of this example are compared to selected literature MIC90 values of various antibiotics in ocular (for certain besifloxacin values) and non-ocular (for certain besifloxacin values and for cefuroxime and vancomycin values, as well as for non-MRSA acorafloxacin and moxifloxacin values) isolates of selected bacteria including some associated with ophthalmic infections (see, e.g., Morrow, B.
  • Results Slit lamp shows no particle formation post-injection, no AC cells or flare in all 3 dogs at each timepoint post-injection. Gross ocular shows trace to 1+ conjunctival hyperemia equal in both eyes, typical of what is observed with injection procedures, and less overall by 48 hours. No adverse effects observed.
  • ATOS acorafloxacin topical ophthalmic suspension
  • ATOS acorafloxacin topical ophthalmic suspension
  • 25 days dose levels of 1.4 and 0.7 mg/day, respectively.
  • Rabbits were sacrificed at the end of dosing (5/sex/group) or after a 14-day recovery period (2/sex/group).
  • clinical signs (cage side, detailed and veterinary examinations), body weights, food consumption, ophthalmology, tonometry, gross ocular examinations for irritation (redness, swelling, and discharge), corneal sensitivity, clinical pathology parameters (hematology, and clinical chemistry), toxicokinetic parameters, organ weights, and gross and microscopic pathology.
  • the no observable adverse effect level (NOAEL) in rabbits was considered to be 1.4 (3 days)/0.7 (25 days) mg/day acorafloxacin 0.5%.
  • the Cmax was 0.00628 ⁇ 0.00143 ⁇ g/mL and 0 0161 ⁇ 0.00386 ⁇ g/mL and AUCo-24hr values at day 1 were and 0.0139 ⁇ 0.000931 ⁇ g ⁇ hr/mL and 0.0450 ⁇ 0.0189 ⁇ g ⁇ hr/mL, respectively.
  • ATOS acorafloxacin topical ophthalmic suspension
  • the no observable adverse effect level (NOAEL)in dogs was considered to be 1.4 (3 days)/0.7 (25 days) mg/day 0.5% ATOS.
  • the C was 0.00249 ⁇ 0.00132 and 0.00237 ⁇ 0.000567 ⁇ g mL and AUCo-24hr was 0.00936 ⁇ 0.00372 and 0.00982 ⁇ 0.00188 g ⁇ hr/mL, respectively.
  • a 36-year old male patient presents to the ophthalmologist with sore, red eyes and a yellowish mucopurulent discharge.
  • the ophthalmologist determines that the condition is bacterial conjunctivitis.
  • the patient is instructed to administer moxifloxacin to his eyes daily in accordance with the package insert of the medication.
  • the patient's condition does not improve even after four days of administering the moxifloxacin and the ophthalmologist suspects a resistant strain of bacteria, likely a gram positive, is infecting the eye.
  • the patient is then instructed to discontinue the moxifloxacin administration and instead administer acorafloxacin eye drops to his eyes daily according to the package insert of the medication. After about three days of administering the eye drops daily, the signs and symptoms have rapidly subsided and the bacterial conjunctivitis is determined to have been resolved upon a follow up visit to the ophthalmologist.
  • a 28-year old female contact lens wearer presents complaining of ocular pain, eye redness, and decreased vison.
  • the patient reports that she has been spending large amounts of time working on a project at her work and as a result has been keeping her contact lenses in her eyes for prolonged periods of time and has not been able to be diligent in properly cleaning and replacing the lenses.
  • the physician finds corneal infiltrate upon slit lamp examinations and diagnoses the patient as suffering from bacterial keratitis.
  • the patient is instructed to administer moxifloxacin to her eyes daily in accordance with the package insert of the medication and refrain from wearing contact lenses for the time being.
  • the infection still persists after about 4 days and the ophthalmologist suspects a resistant strain of bacteria, likely a gram negative since the patient is wearing contact lenses.
  • the patient is then instructed to discontinue the moxifloxacin administration and instead administer acorafloxacin eye drops to her eyes daily according to the package insert of the medication.
  • the patient's symptoms have significantly subsided, and by a follow-up visit 10 days later, the infection appears to have resolved almost completely.
  • a 68-year old female with prior diagnosis of cataracts complains that her vison has steadily declined over the last year to the point of interfering with her daily activities thus impacting her quality of life.
  • Her ophthalmologist recommends that she consider cataract surgery in which her clouded lens is removed and replaced with an artificial lens, which she agrees to undergo. The case is referred to a surgeon, who is concerned that the patient might develop an infection leading to endophthalmitis as a result of the surgery since cataract surgery (and other ophthalmic surgical procedures) can in some cases put a patient at risk for ophthalmic infections such as endophthalmitis due to inadvertent bacterial contamination of the eye during the surgery.
  • the surgeon injects a solution comprising acorafloxacin into the anterior chamber of the surgically treated eye (i.e. intracameral injection) as a prophylactic measure against endophthalmitis.
  • a solution comprising acorafloxacin into the anterior chamber of the surgically treated eye (i.e. intracameral injection) as a prophylactic measure against endophthalmitis.
  • patient displays no signs or symptoms of endophthalmitis (or other ocular infections), and goes on to have a positive outcome from the surgery in the form of significantly restored vision in the treated eye.

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Abstract

La présente invention concerne des procédés de traitement (comprenant un traitement prophylactique) d'infections oculaires par administration d'acorafloxacine. Il a été démontré que l'acorafloxacine est plus puissante dans l'inhibition de Staphylococcus aureus résistant à la méthicilline (SARM) ophtalmique et Staphylococcus epidermidis résistant à la méthicilline (SERM) qu'au moins une fluoroquinolone choisie parmi la bésifloxacine, la gatifloxacine, la moxifloxacine, la lévofloxacine et la ciprofloxacine.
PCT/US2018/022197 2017-03-14 2018-03-13 Acorafloxacine dans le traitement d'infections oculaires Ceased WO2018169967A1 (fr)

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