Classifications

• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
  • C07D215/50—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4
  • C07D215/52—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4 with aryl radicals attached in position 2

Definitions

• the invention recognizes that crystals of brequinar sodium salt exist in multiple polymorphic forms and that one of those forms, polymorphic form C, is most stable under ambient conditions. Therefore, the stable crystalline form of brequinar sodium salt described herein allows the drug to be formulated in pharmaceutical compositions (for example solid pharmaceutical compositions for oral administration) amenable to commercial production and distribution. Prior to the insight of this invention, manufacture of crystalline brequinar sodium salt was deemed too unpredictable for large-scale manufacture, such as for example manufacture of solid oral dosage forms (e.g., such as tablets and capsules).
• the compositions of the invention overcome prior stability and consistency issues in the manufacturing process to provide the most stable form of brequinar sodium.
• the combining step may include incubating the combined brequinar acid, NaOH, and solvent at from about 50 °C to about 70 °C, from about 55 °C to about 70 °C, from about 50 °C to about 65 °C, from about 55 °C to about 65 °C, about 55 °C, about 60 °C, or about 65 °C.
• the composition may contain all or nearly all of the brequinar sodium salt in polymorphic form C.
• the composition may contain a brequinar sodium salt in which at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% of the brequinar sodium salt is polymorphic form C.
• the composition may be formulated for administration via any route.
• the composition may be formulated for oral, intravenous, enteral, parenteral, dermal, buccal, topical, transdermal, subcutaneous, nasal, or pulmonarily administration.
• the composition may be formulated for administration by injection or with or on an implantable medical device.
• the composition for oral administration may be formulated as a caplet, capsule, pill, or tablet.
• the mixture may be heated, i.e., incubated at a first defined temperature.
• the mixture may be incubated at from about 60 °C to about 90 °C, from about 65 °C to about 90 °C, from about 70 °C to about 90 °C, from about 73 °C to about 90 °C, from about 60 °C to about 85 °C, from about 65 °C to about 85 °C, from about 70 °C to about 85 °C, from about 73 °C to about 85 °C, from about 60 °C to about 80 °C, from about 65 °C to about 80 °C, from about 70 °C to about 80 °C, from about 73 °C to about 80 °C, from about 60 °C to about 77 °C, from about 65 °C to about 77 °C, from about 70 °C to about 77 °C, from about 70 °C to about 77 °C,
• insoluble material may be removed by filtration.
• the crystallizing step may include incubating the seeded mixture at a defined temperature.
• the seeded mixture may be incubated at from about 15 °C to about 35 °C, from about 20 °C to about 35 °C, from about 15 °C to about 30 °C, from about 20 °C to about 30 °C, about 20 °C, about 25 °C, or about 30 °C.
• the crystallizing step may include adding an agent that facilitates precipitation of the brequinar sodium salt.
• the agent may be an organic compound, such as an alkane.
• the alkane may be n-heptane.
• the crystallizing step may include removing the solvent from the precipitated brequinar sodium salt. Removing the solvent may include filtering the brequinar sodium salt, drying the brequinar sodium salt, or both.
• the sample may also be a solid or semi-solid sample, such as a tissue sample, feces sample, or stool sample, that has been treated to take a liquid form by, for example, homogenization, sonication, pipette trituration, cell lysis etc.
• a sample is from plasma, serum, whole blood, or sputum.
• the dosing regimen may raise or maintain levels of the metabolite above the threshold level for not more than 24 hours, not more than 36 hours, not more than 48 hours, not more than 60 hours, not more than 72 hours, not more than 84 hours, not more than 96 hours, not more than 5 days, not more than 6 days, not more than 7 days, not more than 10 days, or not more than 2 weeks.
• the dosing regimen may raise or maintain levels of the metabolite above the threshold level for at least 72 hours but not more than 96 hours, for at least 72 hours but not more than 5 days, for at least 72 hours but not more than 6 days, for at least 72 hours but not more than 7 days, for at least 96 hours but not more than 7 days.
• the dosing regimen may ensure that levels of a metabolite, such as DHO, do not exceed or are maintained below a maximum threshold that is associated with toxicity. Levels of the metabolite above a maximum threshold may indicate that brequinar is causing or is likely to cause an adverse event in the subject.
• adverse events include abdominal pain, anemia, anorexia, blood disorders, constipation, diarrhea, dyspepsia, fatigue, fever, granulocytopenia, headache, infection, leukopenia, mucositis, nausea, pain at the injection site, phlebitis, photosensitivity, rash, somnolence, stomatitis, thrombocytopenia, and vomiting.
• the dosing regimen may include a time point for administration of one or more subsequent doses to raise or maintain levels of the metabolite, such as DHO, above a threshold level for a certain time period.
• the time point for administration of a subsequent dose may be relative to an earlier time point.
• the time point for administration of a subsequent dose may be relative to a time point when a previous dose was administered or a time point when a sample was obtained from a subject.
• the dosing regimen may include a schedule for administration of doses.
• the first phase and the second phase each comprise administering brequinar. In some embodiments, the first phase and the second phase are at different times. In some embodiments, the first phase and the second phase are on different days. In some embodiments, the first phase lasts for a period of time that is less than four days. In some embodiments, the first phase comprises administering brequinar, followed by a period of time in which no brequinar is administered. In some embodiments, the period of time in which no brequinar is administered is 3 to 7 days after the dose during the first phase. In some embodiments, the first phase comprises administering more than one dose.
• brequinar is administered during a second phase. In some embodiments, brequinar is administered sub-cell-lethal levels during the second phase. In some embodiments, the first phase is repeated after the second phase. In some embodiments, both the first and second phases are repeated.

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• Chemical & Material Sciences (AREA)
• Health & Medical Sciences (AREA)
• Organic Chemistry (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 2021
  • 2021-03-19 AU AU2021236757A patent/AU2021236757A1/en active Pending
  • 2021-03-19 CA CA3175964A patent/CA3175964A1/en active Pending
  • 2021-03-19 EP EP21770978.1A patent/EP4121050A4/en active Pending
  • 2021-03-19 WO PCT/US2021/023350 patent/WO2021189017A1/en not_active Ceased
  • 2021-03-19 JP JP2022556043A patent/JP2023518419A/ja active Pending

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