WO2022253077A1 - 芬戈莫德药用盐、制备方法、含其的药物组合物及应用 - Google Patents

芬戈莫德药用盐、制备方法、含其的药物组合物及应用 Download PDF

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WO2022253077A1
WO2022253077A1 PCT/CN2022/095013 CN2022095013W WO2022253077A1 WO 2022253077 A1 WO2022253077 A1 WO 2022253077A1 CN 2022095013 W CN2022095013 W CN 2022095013W WO 2022253077 A1 WO2022253077 A1 WO 2022253077A1
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Prior art keywords
fingolimod
pamoate
crystal form
acid
powder diffraction
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PCT/CN2022/095013
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English (en)
French (fr)
Inventor
陈志祥
朱涛
刘璐
王婷婷
应述欢
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Shanghai Bocimed Pharmaceutical Co Ltd
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Shanghai Bocimed Pharmaceutical Co Ltd
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Priority to EP22815123.9A priority Critical patent/EP4353709A4/en
Priority to US18/565,928 priority patent/US20240262783A1/en
Priority to JP2023574191A priority patent/JP2024521882A/ja
Publication of WO2022253077A1 publication Critical patent/WO2022253077A1/zh
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
    • C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/105—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups polycyclic
    • C07C65/11—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups polycyclic with carboxyl groups on a condensed ring system containing two rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

  • the invention relates to a medicinal salt of fingolimod, a preparation method, a pharmaceutical composition containing it and application.
  • MS Multiple sclerosis
  • Fingolimod is a compound with strong immunosuppressive activity isolated from the fungus Sinclair Cordyceps and its close relative Cordyceps sinensis. It is a sphingosine 1-phosphate (S1PR) receptor modulator. Fingolimod (structural formula shown in formula II), named FTY 720.
  • Fingolimod Hydrochloride Capsules developed by Novartis is the world's first oral preparation (capsule) for the treatment of MS, and also the first drug for the treatment of MS in children. It has a significant effect in reducing the recurrence rate of MS patients.
  • Patent document WO2010055028A2 mentions a variety of crystal forms of fingolimod hydrochloride. These crystal forms will undergo crystal transformation due to temperature changes. Therefore, the crystal form of fingolimod hydrochloride has poor stability, and crystal form changes will affect the dissolution Speed, bioavailability and other aspects have an impact, which is not conducive to the processability and stability of the preparation.
  • the present invention provides a salt of fingolimod shown in formula I:
  • X is an organic acid with more than six carbons or an ester containing a hydroxyl group, and n is 0.5-2.0;
  • the salt is a pharmaceutically acceptable salt.
  • the organic acid with more than six carbons can be selected from C6-C30 organic acids, such as C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16 , C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30 organic acids.
  • C6-C30 organic acids such as C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16 , C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30 organic acids.
  • the X is selected from one or more of the following substances including but not limited to: hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, azelaic acid, capric acid, sebacic acid, Undecanoic Acid, Lauric Acid (Dodecanoic Acid), Tridecanoic Acid, Myristic Acid (Myristic Acid), Pentadecanoic Acid, Palmitic Acid (i.e.
  • Palmitic Acid or Palmitic Acid Heptadecanoic Acid Alkanoic acid, stearic acid (octadecanoic acid), nonadecanoic acid, eicosanoic acid (arachidic acid), oleic acid, eicosanoic acid, docosanoic acid, tricosanoic acid, eicosanoid Tetradecanoic acid, pentasanoic acid, hexacosanoic acid, heptacosanoic acid, octacosanoic acid, nonacosanoic acid, triacosanoic acid (melisic acid), glyceric acid, ligninic acid , pamoic acid (ie pamoic acid), 1-hydroxy-2 naphthoic acid and naphthoic acid derivatives (the naphthoic acid derivatives include but not limited to naphthoic acid esters).
  • the X is selected from one or more of pamoic acid, 1-hydroxy-2-naphthoic acid, lauric acid, palmitic acid, sebacic acid, undecanoic acid, and heptanoic acid kind.
  • said n is 0.5, 1.0 or 2.0.
  • fingolimod 1-hydroxy-2-naphthoate fingolimod laurate
  • fingolimod fingolimod palmitate
  • the salt of fingolimod may be in the form of single-phase crystals, amorphous or mixed crystals.
  • the single-phase crystal refers to a structure in which a large number of microscopic substance units (atoms, ions, molecules, etc.) are arranged in an orderly manner according to certain rules, which includes the non-solvate of the salt of fingolimod (such as anhydrate) and solvated (such as hydrate) crystal forms.
  • the term "mixed crystal” refers to different crystal forms and/or other solid molecular forms of the same compound, for example, two or more crystal forms comprising the salt of fingolimod solid and/or amorphous form.
  • the salt of fingolimod includes a solvate formed between the salt of fingolimod and a solvent.
  • the solvate includes the hydrate of the salt of fingolimod and the solvate of the salt of fingolimod with an organic solvent.
  • the "organic solvent” described in the "solvate of the salt of fingolimod and an organic solvent” includes, but is not limited to, one or more of ethanol, acetone, and dimethyl sulfoxide .
  • the present invention also provides a preparation method of the salt of fingolimod, the preparation method comprising the following steps: combining the free base of fingolimod with the X (that is, an organic acid with more than six carbons) A neutralization reaction is carried out to obtain the salt of fingolimod.
  • the preparation method of the salt of fingolimod can be carried out in a solvent or without a solvent.
  • the present invention also provides another preparation method of the salt of fingolimod, the preparation method comprising the following steps: forming a solution of fingolimod free base in an inorganic acid, and mixing the X (i.e. six An organic acid with more than one carbon) forms a solution in an inorganic base, and then mixes the two solutions to obtain the salt of fingolimod.
  • the preparation method comprising the following steps: forming a solution of fingolimod free base in an inorganic acid, and mixing the X (i.e. six An organic acid with more than one carbon) forms a solution in an inorganic base, and then mixes the two solutions to obtain the salt of fingolimod.
  • the organic acid with more than six carbons may be a C6-C30 organic acid.
  • the X is selected from one or more of the following substances including but not limited to: hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, azelaic acid, Capric Acid, Undecanoic Acid, Lauric Acid (Dodecanoic Acid), Tridecanoic Acid, Myristic Acid (Myristic Acid), Pentadecanoic Acid, Palmitic Acid (Hexadecanoic Acid), Heptadecanoic Acid , stearic acid (octadecanoic acid), nonadecanoic acid, eicosanoic acid (arachidic acid), oleic acid, arachidic acid, docosanoic acid, tricosanoic acid, tetradecanoic acid Acid, pentasanoic acid, hexacosanoic acid, heptacosanoic acid, oc
  • the pamoic acid is also called Pamoic acid, CAS No.130-85-8.
  • the present invention also provides a crystal form of a salt of fingolimod, such as a crystal form of fingolimod pamoate, a crystal form of fingolimod 1-hydroxy 2-naphthoate.
  • the crystal form of fingolimod pamoate is fingolimod pamoate crystal form B, and the crystal form of fingolimod pamoate
  • the X-ray powder diffraction pattern of B has characteristic peaks at 2 ⁇ values of 3.3° ⁇ 0.2°, 17.1° ⁇ 0.2°, 21.8° ⁇ 0.2°, etc.
  • the X-ray powder diffraction pattern of the fingolimod pamoate crystal form B has 2 ⁇ values of 3.3° ⁇ 0.2°, 17.1° ⁇ 0.2°, 18.7° ⁇ 0.2°, 19.1° ⁇ 0.2 °, 21.8° ⁇ 0.2°, 23.4° ⁇ 0.2°, etc. have characteristic peaks.
  • the X-ray powder diffraction pattern of the fingolimod pamoate crystal form B has a 2 ⁇ value of 3.3° ⁇ 0.2°, 17.1 ⁇ 0.2°, 17.7° ⁇ 0.2°, 18.7° ⁇ 0.2° , 19.1° ⁇ 0.2°, 20.6° ⁇ 0.2°, 21.8° ⁇ 0.2°, 23.4° ⁇ 0.2°, etc. have characteristic peaks.
  • the X-ray powder diffraction pattern of the fingolimod pamoate crystal form B has 2 ⁇ values of 3.3° ⁇ 0.2°, 7.1° ⁇ 0.2°, 9.8 ⁇ 0.2°, 11.2° ⁇ 0.2 °, 11.8° ⁇ 0.2°, 12.6° ⁇ 0.2°, 13.5° ⁇ 0.2°, 14.3° ⁇ 0.2°, 14.7° ⁇ 0.2°, 15.5° ⁇ 0.2°, 16.1° ⁇ 0.2°, 16.7° ⁇ 0.2°, 17.1° ⁇ 0.2°, 17.7° ⁇ 0.2°, 18.7° ⁇ 0.2°, 19.1° ⁇ 0.2°, 19.6° ⁇ 0.2°, 20.0° ⁇ 0.2°, 20.6° ⁇ 0.2°, 21.8° ⁇ 0.2°, 22.6° There are absorption peaks at ⁇ 0.2°, 23.4° ⁇ 0.2°, 23.8° ⁇ 0.2°, 25.2° ⁇ 0.2°, 26.5° ⁇ 0.2°, 27.5° ⁇ 0.2°, 30.1° ⁇ 0.2°, etc.
  • the X-ray powder diffraction pattern of the fingolimod pamoate crystalline form B is basically shown in FIG. 1 .
  • the crystalline form B of fingolimod pamoate has an X-ray powder diffraction spectrum as shown in Table 1.
  • thermogravimetric analysis chart of the fingolimod pamoic acid crystal form B is basically shown in FIG. 2 .
  • the NMR diagram of the fingolimod pamoic acid crystal form B is basically as shown in FIG. 3 .
  • the molar ratio of fingolimod to pamoic acid is 1:0.5.
  • the crystalline form B of fingolimod pamoate is a hydrate.
  • the preparation method of the fingolimod pamoate crystal form B is as follows:
  • the solvent 1 is an alkaline solution, such as an inorganic alkaline solution, preferably an aqueous potassium hydroxide solution;
  • the solvent 2 is water, methanol, ethanol, isopropanol, tetrahydrofuran, N,N-dimethylformamide, or a mixture of at least two of the aforementioned solvents, preferably water.
  • the crystalline form of fingolimod pamoate is crystalline form A of fingolimod pamoate.
  • the X-ray powder diffraction pattern of the fingolimod pamoate crystal form A has a 2 ⁇ value of 3.2° ⁇ 0.2°, 19.3° ⁇ 0.2°, 20.4° ⁇ 0.2°, etc. There are characteristic peaks.
  • the X-ray powder diffraction pattern of the fingolimod pamoate crystal form A has a 2 ⁇ value of 3.2° ⁇ 0.2°, 9.6° ⁇ 0.2°, 12.5° ⁇ 0.2°, 18.5° ⁇ 0.2 °, 19.3° ⁇ 0.2°, 20.4° ⁇ 0.2°, etc. have characteristic peaks.
  • the X-ray powder diffraction pattern of the fingolimod pamoate crystal form A has a 2 ⁇ value of 3.2° ⁇ 0.2°, 9.6° ⁇ 0.2°, 12.5° ⁇ 0.2°, 18.0° ⁇ 0.2 °, 18.5° ⁇ 0.2°, 19.3° ⁇ 0.2°, 20.4° ⁇ 0.2°, 24.3° ⁇ 0.2°, etc. have characteristic peaks.
  • the X-ray powder diffraction pattern of the fingolimod pamoate crystal form A has a 2 ⁇ value of 3.2° ⁇ 0.2°, 9.2° ⁇ 0.2°, 9.6° ⁇ 0.2°, 10.8° ⁇ 0.2°, 11.6° ⁇ 0.2°, 12.5° ⁇ 0.2°, 13.1° ⁇ 0.2°, 14.8° ⁇ 0.2°, 15.1° ⁇ 0.2°, 16.3° ⁇ 0.2°, 18.0° ⁇ 0.2°, 18.5° ⁇ 0.2° , 19.3° ⁇ 0.2°, 20.4° ⁇ 0.2°, 21.6° ⁇ 0.2°, 22.1° ⁇ 0.2°, 22.6° ⁇ 0.2°, 24.3° ⁇ 0.2°, 25.2° ⁇ 0.2°, etc. have characteristic peaks.
  • the X-ray powder diffraction pattern of the fingolimod pamoate crystalline form A is basically as shown in FIG. 4 .
  • the crystalline form A of fingolimod pamoate has an X-ray powder diffraction spectrum as shown in Table 2.
  • the differential scanning calorimetry diagram of the fingolimod pamoate crystalline form A is basically as shown in FIG. 5 .
  • the fingolimod pamoate crystalline form A has two endothermic peaks and one exothermic peak, for example, the peak temperature of the endothermic peak is 128 ⁇ 5°C, 180 ⁇ 5°C; for example, the peak temperature of the exothermic peak is 153 ⁇ 5°C.
  • thermogravimetric analysis chart of the fingolimod pamoate crystalline form A is basically shown in FIG. 6 .
  • the crystalline form A of fingolimod pamoate is an anhydrate or a tunnel hydrate.
  • the NMR image of the fingolimod pamoate crystalline form A is basically as shown in FIG. 7 .
  • the molar ratio of fingolimod to pamoic acid is 1:0.5.
  • the preparation method of the fingolimod pamoate crystalline form A is as follows:
  • the drying temperature is 25-50°C, such as 30°C, 40°C;
  • the drying is vacuum drying.
  • the crystalline form of fingolimod pamoate is crystalline form I of fingolimod pamoate.
  • the X-ray powder diffraction pattern of the fingolimod pamoate crystalline form I has a 2 ⁇ value of 3.0° ⁇ 0.2°, 8.9° ⁇ 0.2°, 19.9° ⁇ 0.2°, etc. There are characteristic peaks.
  • the X-ray powder diffraction pattern of the fingolimod pamoate crystal form I has a 2 ⁇ value of 3.0° ⁇ 0.2°, 3.3° ⁇ 0.2°, 5.6 ⁇ 0.2°, 5.9° ⁇ 0.2 °, 6.9° ⁇ 0.2°, 8.9° ⁇ 0.2°, 9.8° ⁇ 0.2°, 15.0° ⁇ 0.2°, 16.2° ⁇ 0.2°, 18.0° ⁇ 0.2°, 18.8° ⁇ 0.2°, 19.1° ⁇ 0.2°, There are characteristic peaks at 19.6° ⁇ 0.2°, 19.9° ⁇ 0.2°, 21.0° ⁇ 0.2°, 21.8° ⁇ 0.2°, 25.2° ⁇ 0.2°, etc.
  • the X-ray powder diffraction pattern of the fingolimod pamoate crystalline form I is basically shown in FIG. 8 .
  • the crystalline form I of fingolimod pamoate has an X-ray powder diffraction spectrum as shown in Table 3.
  • the preparation method of the fingolimod pamoate crystalline form I is as follows:
  • Pamoic acid is mixed with solvent 1 to obtain a pamoic acid solution
  • the solvent 1 is an alkaline solution, such as an inorganic alkaline solution, preferably an aqueous potassium hydroxide solution;
  • the solvent 2 is water, methanol, ethanol, isopropanol, tetrahydrofuran, N,N-dimethylformamide, or a mixture of at least two of the aforementioned solvents, preferably water.
  • the drying time is 2-7 days, preferably 2 days.
  • the crystalline form of fingolimod pamoate is crystalline form J of fingolimod pamoate.
  • the X-ray powder diffraction pattern of the fingolimod pamoate crystal form J has a 2 ⁇ value of 3.2° ⁇ 0.2°, 5.3° ⁇ 0.2°, 10.1° ⁇ 0.2°, There are characteristic peaks at 10.8° ⁇ 0.2°, 18.1° ⁇ 0.2°, 19.8° ⁇ 0.2°, 20.6° ⁇ 0.2°, 21.7° ⁇ 0.2°, etc.
  • the X-ray powder diffraction pattern of the fingolimod pamoate crystal form J has a 2 ⁇ value of 3.2° ⁇ 0.2°, 5.3° ⁇ 0.2°, 6.3 ⁇ 0.2°, 9.5° ⁇ 0.2 °, 10.1° ⁇ 0.2°, 10.8° ⁇ 0.2°, 13.5° ⁇ 0.2°, 17.0° ⁇ 0.2°, 17.8° ⁇ 0.2°, 18.1° ⁇ 0.2°, 19.8° ⁇ 0.2°, 20.6° ⁇ 0.2°, There are characteristic peaks at 21.7° ⁇ 0.2°, 22.0° ⁇ 0.2°, 24.5° ⁇ 0.2°, 25.5° ⁇ 0.2°, etc.
  • the X-ray powder diffraction pattern of the fingolimod pamoate crystalline form J is basically shown in FIG. 9 .
  • the fingolimod pamoate crystalline form J has an X-ray powder diffraction spectrum as shown in Table 4.
  • the preparation method of the fingolimod pamoate crystal form J is as follows:
  • the fingolimod pamoate crystalline form I was placed under dry conditions at room temperature to obtain the fingolimod pamoate crystalline form J.
  • the crystalline form of fingolimod pamoate is crystalline form C of fingolimod pamoate.
  • the X-ray powder diffraction pattern of the fingolimod pamoate crystal form C has a 2 ⁇ value of 3.2° ⁇ 0.2°, 6.4° ⁇ 0.2°, 19.8° ⁇ 0.2°, etc. There are characteristic peaks.
  • the X-ray powder diffraction pattern of the fingolimod pamoate crystal form C has a 2 ⁇ value of 3.2° ⁇ 0.2°, 6.4° ⁇ 0.2°, 9.6° ⁇ 0.2°, 15.1° ⁇ 0.2 °, 19.8° ⁇ 0.2°, 20.4° ⁇ 0.2°, etc. have characteristic peaks.
  • the X-ray powder diffraction pattern of the fingolimod pamoate crystal form C has a 2 ⁇ value of 3.2° ⁇ 0.2°, 6.4° ⁇ 0.2°, 9.6° ⁇ 0.2°, 13.6° ⁇ 0.2 °, 15.1° ⁇ 0.2°, 15.6° ⁇ 0.2°, 19.8° ⁇ 0.2°, 20.4° ⁇ 0.2°, etc. have characteristic peaks.
  • the X-ray powder diffraction pattern of the fingolimod pamoate crystal form C has 2 ⁇ values of 3.2° ⁇ 0.2°, 5.4° ⁇ 0.2°, 6.4° ⁇ 0.2°, 9.6° ⁇ 0.2 °, 12.8° ⁇ 0.2°, 13.6° ⁇ 0.2°, 14.3° ⁇ 0.2°, 15.1° ⁇ 0.2°, 15.6° ⁇ 0.2°, 16.7° ⁇ 0.2°, 17.3° ⁇ 0.2°, 17.7° ⁇ 0.2°, 18.3° ⁇ 0.2°, 18.6° ⁇ 0.2°, 19.0° ⁇ 0.2°, 19.8° ⁇ 0.2°, 20.4° ⁇ 0.2°, 22.7° ⁇ 0.2°, 23.1° ⁇ 0.2°, 23.5° ⁇ 0.2°, 25.9° There are characteristic peaks at ⁇ 0.2°, 29.2° ⁇ 0.2°, etc.
  • the X-ray powder diffraction pattern of the fingolimod pamoate crystalline form C is basically shown in FIG. 10 .
  • the fingolimod pamoate crystalline form C has an X-ray powder diffraction spectrum as shown in Table 5.
  • the preparation method of the fingolimod pamoate crystal form C is as follows:
  • the solvent 3 is a mixed solvent of n-heptane and ethyl acetate
  • the stirring crystallization temperature is 50-80°C, such as 60°C;
  • the stirring and crystallization time is 2-10 days, such as 7 days;
  • the preparation method further includes separation after stirring and crystallization, and drying the separated solid to obtain the crystalline form C of fingolimod pamoate.
  • the crystalline form of fingolimod pamoate is crystalline form D of fingolimod pamoate.
  • the X-ray powder diffraction pattern of the fingolimod pamoate crystalline form D has a 2 ⁇ value of 3.3° ⁇ 0.2°, 10.1° ⁇ 0.2°, 20.3° ⁇ 0.2°, etc. There are characteristic peaks.
  • the X-ray powder diffraction pattern of the fingolimod pamoate crystal form D has a 2 ⁇ value of 3.3° ⁇ 0.2°, 6.7° ⁇ 0.2°, 10.1° ⁇ 0.2°, 16.9° ⁇ 0.2 °, 18.8° ⁇ 0.2°, 20.3° ⁇ 0.2°, etc. have characteristic peaks.
  • the X-ray powder diffraction pattern of the fingolimod pamoate crystal form D has a 2 ⁇ value of 3.3° ⁇ 0.2°, 6.7° ⁇ 0.2°, 7.2° ⁇ 0.2°, 10.1° ⁇ 0.2 °, 16.9° ⁇ 0.2°, 18.8° ⁇ 0.2°, 20.3° ⁇ 0.2°, 23.8° ⁇ 0.2°, etc. have characteristic peaks.
  • the X-ray powder diffraction pattern of the fingolimod pamoate crystal form D has 2 ⁇ values of 3.3° ⁇ 0.2°, 5.0 ⁇ 0.2°, 6.7° ⁇ 0.2°, 7.3° ⁇ 0.2 °, 8.9° ⁇ 0.2°, 10.1° ⁇ 0.2°, 10.5° ⁇ 0.2°, 13.1° ⁇ 0.2°, 13.5° ⁇ 0.2°, 13.8° ⁇ 0.2°, 15.5° ⁇ 0.2°, 16.2° ⁇ 0.2°, 16.9° ⁇ 0.2°, 17.4° ⁇ 0.2°, 17.8° ⁇ 0.2°, 18.8° ⁇ 0.2°, 19.5° ⁇ 0.2°, 20.3° ⁇ 0.2°, 22.2° ⁇ 0.2°, 23.8° ⁇ 0.2°, 25.7° There are characteristic peaks at ⁇ 0.2°, 27.4° ⁇ 0.2°, 29.1° ⁇ 0.2°, etc.
  • the X-ray powder diffraction pattern of the fingolimod pamoate crystalline form D is substantially as shown in FIG. 11 .
  • the crystalline form D of fingolimod pamoate has an X-ray powder diffraction spectrum as shown in Table 6.
  • the preparation method of the fingolimod pamoate crystalline form D is as follows:
  • the crystalline form B of fingolimod pamoate was dissolved in good solvent 1, volatilized and crystallized to obtain the crystalline form D of fingolimod pamoate.
  • Described good solvent 1 is the mixed solvent of ethanol and water
  • the temperature of the volatilization and crystallization is room temperature.
  • the crystalline form of fingolimod pamoate is crystalline form E of fingolimod pamoate.
  • the X-ray powder diffraction pattern of the fingolimod pamoate crystalline form E has a 2 ⁇ value of 3.3° ⁇ 0.2°, 17.3° ⁇ 0.2°, 19.0° ⁇ 0.2°, etc. There are characteristic peaks.
  • the X-ray powder diffraction pattern of the fingolimod pamoate crystal form E has a 2 ⁇ value of 3.3° ⁇ 0.2°, 9.8° ⁇ 0.2°, 17.3° ⁇ 0.2°, 17.7° ⁇ 0.2 °, 19.0° ⁇ 0.2°, 21.8° ⁇ 0.2°, etc. have characteristic peaks.
  • the X-ray powder diffraction pattern of the fingolimod pamoate crystal form E has a 2 ⁇ value of 3.3° ⁇ 0.2°, 9.8° ⁇ 0.2°, 17.3° ⁇ 0.2°, 17.7° ⁇ 0.2 °, 19.0° ⁇ 0.2°, 19.3° ⁇ 0.2°, 20.0° ⁇ 0.2°, 21.8° ⁇ 0.2°, etc. have characteristic peaks.
  • the X-ray powder diffraction pattern of the fingolimod pamoate crystalline form E has a 2 ⁇ value of 3.3° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.5° ⁇ 0.2°, 8.6° ⁇ 0.2°, 8.9° ⁇ 0.2°, 9.1° ⁇ 0.2°, 9.8° ⁇ 0.2°, 10.1° ⁇ 0.2°, 10.5° ⁇ 0.2°, 11.9° ⁇ 0.2°, 13.1° ⁇ 0.2 °, 16.4° ⁇ 0.2°, 17.1° ⁇ 0.2°, 17.3° ⁇ 0.2°, 17.7° ⁇ 0.2°, 18.2° ⁇ 0.2°, 19.0° ⁇ 0.2°, 19.3° ⁇ 0.2°, 20.0° ⁇ 0.2°, There are characteristic peaks at 21.2° ⁇ 0.2°, 21.8° ⁇ 0.2°, 22.8° ⁇ 0.2°, 23.2° ⁇ 0.2°, 23.9° ⁇ 0.2°, 24.3° ⁇ 0.2°, etc.
  • the X-ray powder diffraction pattern of the fingolimod pamoate crystalline form E is substantially as shown in FIG. 12 .
  • the crystalline form E of fingolimod pamoate has an X-ray powder diffraction spectrum as shown in Table 7.
  • the preparation method of the fingolimod pamoate crystal form E is as follows:
  • the crystalline form B of fingolimod pamoate was dissolved in good solvent 2, volatilized and crystallized to obtain the crystalline form E of fingolimod pamoate.
  • Described good solvent 2 is dioxane
  • the volatilization and crystallization temperature is 50-80°C, such as 60°C.
  • the crystalline form of fingolimod pamoate is crystalline form F of fingolimod pamoate.
  • the X-ray powder diffraction pattern of the fingolimod pamoate crystalline form F has a 2 ⁇ value of 3.7° ⁇ 0.2°, 18.0° ⁇ 0.2°, 21.9° ⁇ 0.2°, etc. There are characteristic peaks.
  • the X-ray powder diffraction pattern of the fingolimod pamoate crystalline form F has 2 ⁇ values of 3.7° ⁇ 0.2°, 9.2° ⁇ 0.2°, 16.4° ⁇ 0.2°, 17.0° ⁇ 0.2 °, 18.0° ⁇ 0.2°, 19.7° ⁇ 0.2°, 20.1° ⁇ 0.2°, 21.9° ⁇ 0.2°, etc. have characteristic peaks.
  • the X-ray powder diffraction pattern of the fingolimod pamoate crystal form F has 2 ⁇ values of 3.7° ⁇ 0.2°, 8.0 ⁇ 0.2°, 9.2° ⁇ 0.2°, 11.3° ⁇ 0.2 °, 16.4° ⁇ 0.2°, 17.0° ⁇ 0.2°, 18.0° ⁇ 0.2°, 18.8° ⁇ 0.2°, 19.7° ⁇ 0.2°, 20.1° ⁇ 0.2°, 21.9° ⁇ 0.2°, etc. have characteristic peaks.
  • the X-ray powder diffraction pattern of the fingolimod pamoate crystalline form F is substantially as shown in FIG. 13 .
  • the fingolimod pamoate crystalline form F has an X-ray powder diffraction spectrum as shown in Table 8.
  • the preparation method of the fingolimod pamoate crystalline form F is as follows:
  • the solvent 3 is n-heptane, isopropyl acetate or mixed solvents thereof.
  • the stirring crystallization temperature is 50-80°C, such as 60°C.
  • the crystal form of fingolimod pamoate is fingolimod pamoate crystal form G.
  • the X-ray powder diffraction pattern of the fingolimod pamoate crystalline form G has a 2 ⁇ value of 3.6° ⁇ 0.2°, 7.2° ⁇ 0.2°, 19.9° ⁇ 0.2°, etc. There are characteristic peaks.
  • the X-ray powder diffraction pattern of the fingolimod pamoate crystalline form G has 2 ⁇ values of 3.6° ⁇ 0.2°, 7.2° ⁇ 0.2°, 18.1° ⁇ 0.2°, 18.4° ⁇ 0.2 °, 19.9° ⁇ 0.2°, 21.8° ⁇ 0.2°, 22.6° ⁇ 0.2°, 25.1° ⁇ 0.2°, etc. have characteristic peaks.
  • the X-ray powder diffraction pattern of the fingolimod pamoate crystalline form G has a 2 ⁇ value of 3.6° ⁇ 0.2°, 7.2° ⁇ 0.2°, 9.0 ⁇ 0.2°, 9.5° ⁇ 0.2°, 10.0° ⁇ 0.2°, 11.2° ⁇ 0.2°, 11.6° ⁇ 0.2°, 11.8° ⁇ 0.2°, 12.1° ⁇ 0.2°, 13.1° ⁇ 0.2°, 13.5° ⁇ 0.2° , 15.1° ⁇ 0.2°, 17.0° ⁇ 0.2°, 18.1° ⁇ 0.2°, 18.4° ⁇ 0.2°, 18.9° ⁇ 0.2°, 19.1° ⁇ 0.2°, 19.9° ⁇ 0.2°, 20.5° ⁇ 0.2°, 20.9 ° ⁇ 0.2°, 21.8° ⁇ 0.2°, 22.6° ⁇ 0.2°, 23.2° ⁇ 0.2°, 23.9° ⁇ 0.2°, 24.7° ⁇ 0.2°, 25.1° ⁇ 0.2°, 27.6° ⁇ 0.2°, 28.1° ⁇ There are characteristic peaks at 0.2° etc.
  • the X-ray powder diffraction pattern of the fingolimod pamoate crystalline form G is substantially as shown in FIG. 14 .
  • the fingolimod pamoate crystalline form G has an X-ray powder diffraction spectrum as shown in Table 9.
  • the preparation method of the fingolimod pamoate crystalline form G is as follows:
  • the solvent 5 is a mixed solvent of N,N-dimethylformamide and water.
  • the stirring crystallization temperature is 50-80°C, such as 60°C.
  • the crystalline form of fingolimod pamoate is crystalline form H of fingolimod pamoate.
  • the X-ray powder diffraction pattern of the fingolimod pamoate crystalline form H has a 2 ⁇ value of 3.3° ⁇ 0.2°, 10.1° ⁇ 0.2°, 17.2° ⁇ 0.2°, etc. There are characteristic peaks.
  • the X-ray powder diffraction pattern of the fingolimod pamoate crystalline form H has a 2 ⁇ value of 3.3° ⁇ 0.2°, 6.7° ⁇ 0.2°, 10.1° ⁇ 0.2°, 13.7° ⁇ 0.2 °, 17.2° ⁇ 0.2°, 20.3° ⁇ 0.2°, 20.6° ⁇ 0.2°, etc. have characteristic peaks.
  • the X-ray powder diffraction pattern of the fingolimod pamoate crystalline form H has a 2 ⁇ value of 3.3° ⁇ 0.2°, 5.0° ⁇ 0.2°, 6.7 ⁇ 0.2°, 7.3° ⁇ 0.2 °, 10.1° ⁇ 0.2°, 13.7° ⁇ 0.2°, 17.2° ⁇ 0.2°, 18.8° ⁇ 0.2°, 20.3° ⁇ 0.2°, 20.6° ⁇ 0.2°, 21.8° ⁇ 0.2°, 22.2° ⁇ 0.2°, There are characteristic peaks at 23.7° ⁇ 0.2°, 27.7° ⁇ 0.2°, etc.
  • the X-ray powder diffraction pattern of the fingolimod pamoate crystalline form H is substantially as shown in FIG. 15 .
  • the fingolimod pamoate crystalline form H has an X-ray powder diffraction spectrum as shown in Table 10.
  • the preparation method of the fingolimod pamoate crystalline form H is as follows:
  • the good solvent 3 is one or more of ethanol, isopropanol, dioxane and dimethyl sulfoxide, preferably ethanol;
  • the anti-solvent is water.
  • the crystalline form of fingolimod pamoate is crystalline form K of fingolimod pamoate.
  • the X-ray powder diffraction pattern of the fingolimod pamoate crystal form K has a 2 ⁇ value of 3.4° ⁇ 0.2°, 6.7° ⁇ 0.2°, 7.3° ⁇ 0.2°, There are characteristic peaks at 10.2° ⁇ 0.2°, 10.5° ⁇ 0.2°, 17.0° ⁇ 0.2°, 18.9° ⁇ 0.2°, 20.4° ⁇ 0.2°, etc.
  • the X-ray powder diffraction pattern of the fingolimod pamoate crystal form K has a 2 ⁇ value of 3.4° ⁇ 0.2°, 6.7° ⁇ 0.2°, 7.3 ⁇ 0.2°, 10.2° ⁇ 0.2 °, 10.5° ⁇ 0.2°, 13.1° ⁇ 0.2°, 13.8° ⁇ 0.2°, 16.3° ⁇ 0.2°, 17.0° ⁇ 0.2°, 17.4° ⁇ 0.2°, 17.9° ⁇ 0.2°, 18.2° ⁇ 0.2°, There are characteristic peaks at 18.9° ⁇ 0.2°, 20.4° ⁇ 0.2°, etc.
  • the X-ray powder diffraction pattern of the fingolimod pamoate crystalline form K is basically shown in FIG. 16 .
  • the crystalline form K of fingolimod pamoate has an X-ray powder diffraction spectrum as shown in Table 11.
  • the preparation method of the fingolimod pamoate crystal form K is as follows:
  • the solvent 6 is an alkyl acetate, for example, the alkyl group is a C1-C5 alkyl group; for example, the solvent 6 is one or more of ethyl acetate, isopropyl acetate, and n-butyl acetate, Preferred is n-butyl acetate.
  • the crystal form of fingolimod 1-hydroxy-2-naphthoate is crystal form 1 of fingolimod 1-hydroxy-2-naphthoate.
  • the X-ray powder diffraction pattern of the fingolimod 1-hydroxy-2-naphthoate crystal form 1 has a 2 ⁇ value of 3.2° ⁇ 0.2°, 12.9° ⁇ 0.2°, 19.4 ° ⁇ 0.2° and other places have characteristic peaks.
  • the X-ray powder diffraction pattern of the fingolimod 1-hydroxy-2-naphthoate crystal form 1 has a 2 ⁇ value of 3.2° ⁇ 0.2°, 9.6° ⁇ 0.2°, 12.9° ⁇ 0.2° , 16.1° ⁇ 0.2°, 19.4° ⁇ 0.2°, 25.9° ⁇ 0.2°, etc. have characteristic peaks.
  • the X-ray powder diffraction pattern of the fingolimod 1-hydroxy-2-naphthoate crystal form 1 has a 2 ⁇ value of 3.2° ⁇ 0.2°, 9.6° ⁇ 0.2°, 12.9° ⁇ 0.2° , 16.1° ⁇ 0.2°, 19.4° ⁇ 0.2°, 25.9° ⁇ 0.2°, 29.3° ⁇ 0.2°, 36.0° ⁇ 0.2°, etc. have characteristic peaks.
  • the X-ray powder diffraction pattern of the fingolimod 1-hydroxy-2-naphthoate crystal form 1 has a 2 ⁇ value of 3.2° ⁇ 0.2°, 6.4° ⁇ 0.2°, 9.6 ⁇ 0.2° , 12.9° ⁇ 0.2°, 13.9° ⁇ 0.2°, 14.4° ⁇ 0.2°, 15.7° ⁇ 0.2°, 16.1° ⁇ 0.2°, 16.5° ⁇ 0.2°, 17.4° ⁇ 0.2°, 18.3° ⁇ 0.2°, 19.4 ° ⁇ 0.2°, 20.0° ⁇ 0.2°, 21.0° ⁇ 0.2°, 21.6° ⁇ 0.2°, 22.4° ⁇ 0.2°, 23.5° ⁇ 0.2°, 24.1° ⁇ 0.2°, 25.1° ⁇ 0.2°, 25.9° ⁇ There are absorption peaks at 0.2°, 29.3° ⁇ 0.2°, 30.3° ⁇ 0.2°, 32.6° ⁇ 0.2°, 36.0° ⁇ 0.2°, etc.
  • the X-ray powder diffraction pattern of the fingolimod 1-hydroxy-2-naphthoate crystal form 1 is basically shown in FIG. 17 .
  • the fingolimod 1-hydroxy-2-naphthoate crystal form 1 has an X-ray powder diffraction spectrum shown in Table 12.
  • the differential scanning calorimetry diagram of the fingolimod 1-hydroxy-2-naphthoate crystal form 1 is basically as shown in Figure 18; in one embodiment, the Sufingolimod 1-hydroxy-2-naphthoate crystal form 1 has endothermic peaks at 125°C and 144°C.
  • thermogravimetric analysis chart of the fingolimod 1-hydroxy-2-naphthoic acid crystal form 1 is basically shown in FIG. 19 .
  • the fingolimod 1-hydroxy-2-naphthoic acid crystal form 1 has no weight loss before 120 ⁇ 5°C.
  • the fingolimod 1-hydroxy-2-naphthoic acid crystal form 1 is an anhydrous substance.
  • the NMR diagram of the fingolimod 1-hydroxy-2-naphthoic acid crystal form 1 is basically as shown in FIG. 20 .
  • the fingolimod 1-hydroxy-2-naphthoic acid crystal form 1 the molar ratio of fingolimod to 1-hydroxy-2-naphthoic acid is 1:1.
  • the preparation method of the fingolimod 1-hydroxy-2-naphthoate crystal form 1 is as follows:
  • the solvent 7 is an alkyl acetate, for example, the alkyl is C1 ⁇ C5 alkyl, preferably the solvent 7 is one of ethyl acetate, isopropyl acetate, n-butyl acetate, and isobutyl acetate or two or more, preferably ethyl acetate;
  • the stirring reaction temperature is 25-80°C, preferably 40-60°C, more preferably 60°C.
  • the stirring reaction refers to adding the fingolimod solution dropwise to the 1-hydroxy-2-naphthoic acid solution or adding the 1-hydroxy-2-naphthoic acid solution to the fingolimod solution dropwise.
  • the present invention also provides a pharmaceutical composition, which includes the salt of fingolimod and/or the crystal form of the salt, and pharmaceutically acceptable auxiliary materials.
  • the pharmaceutical composition includes but not limited to tablets, capsules, solutions, suspensions, (long-acting) injections and semi-solid preparations, the purpose of which is to promote the release of the compound (i.e. the active ingredient) to such as human or other Administration to a mammalian organism; preferably an injection, more preferably a long-acting injection.
  • the concentration of the salt of fingolimod and/or the crystalline form of the salt is not lower than 15 mg/mL.
  • the pharmaceutically acceptable adjuvant includes one or more of physiologically or pharmaceutically acceptable carriers, diluents, vehicles and/or excipients.
  • the pharmaceutically acceptable excipients can also be selected from one or more of suspending agents, wetting agents, osmotic pressure regulators, solvents, stabilizers, buffers and surfactants.
  • the concentration range of the suspending agent is 0-75 mg/mL, preferably 10 mg/mL-75 mg/mL, such as 30 mg/mL, 40 mg/mL, 50 mg/mL or 75 mg/mL.
  • the suspending agent is selected from one or more of sodium carboxymethylcellulose, methylcellulose, polyethylene glycol 4000 and polyvinylpyrrolidone, preferably polyethylene glycol 4000 .
  • the concentration range of the wetting agent is 1 mg/mL to 10 mg/mL, preferably 1 mg/mL to 5 mg/mL, such as 1 mg/mL, 1.5 mg/mL, 2.0 mg/mL, 2.5 mg/mL, 3.0 mg/mL, 3.5 mg/mL, 4.0 mg/mL, 4.5 mg/mL or 5.0 mg/mL, preferably 1 mg/mL.
  • the wetting agent is selected from one or more of Tween 20, Tween 80, and Poloxamer 188, preferably Poloxamer 188.
  • the buffer is selected from one or more of phosphoric acid, phosphate, citric acid, sodium citrate, hydrochloric acid and sodium hydroxide.
  • the solvent is water, such as water for injection.
  • the pharmaceutical composition may include:
  • the pharmaceutical composition may contain sodium hydroxide or hydrochloric acid.
  • the present invention also provides you with a preparation method of the pharmaceutical composition, comprising the following steps:
  • the solvent is water, such as water for injection.
  • the fingolimod solid particles may be selected from fingolimod, a pharmaceutically acceptable salt of fingolimod or a crystalline form of a salt thereof.
  • the fingolimod solid particles include but are not limited to fingolimod pamoate or its crystal form, fingolimod 1-hydroxy-2-naphthoate or its crystal form type.
  • the wetting agent, the buffering agent and the suspending agent may be successively dissolved in a solvent, such as dissolved in water for injection.
  • the fingolimod solid particles in step (2), can be sieved, for example, 400 mesh sieve.
  • the present invention also provides the use of the fingolimod pharmaceutical salt in the preparation of medicines for treating and/or preventing multiple sclerosis.
  • the present invention also provides a method for treating and/or preventing multiple sclerosis, which comprises administering the pharmaceutical composition or medicine to the administerer.
  • the present invention also provides the application of the composition in the preparation of medicines for treating and/or preventing multiple sclerosis.
  • the term "pharmaceutically acceptable”, “carrier”, “diluent”, “vehicle” or “excipient” refers to such a substance (or substances), which can It is included together with a specific agent (active ingredient) to form a pharmaceutical composition, and may be solid or liquid.
  • the solid carrier includes but not limited to starch, calcium sulfate dihydrate, terra alba, talc, lactose, sucrose, mica, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
  • the liquid carrier includes but not limited to syrup, peanut oil, olive oil, saline solution, water and the like.
  • the carrier or diluent may include delay or time release materials known in the art, such as monostearic acid alone or together with waxes, ethyl cellulose, hypromellose, methyl methacrylate, etc. Glycerides or Glyceryl Distearate.
  • the term "solvate” includes a molecular complex of a drug and one or more solvent molecules (such as ethanol) in stoichiometric or non-stoichiometric amounts.
  • solvent molecules such as ethanol
  • the resulting complex will have a well-defined stoichiometry independent of humidity.
  • the solvent content will depend on humidity and drying conditions. In such cases, the complex will generally be non-stoichiometric.
  • hydrate describes a solvate comprising a drug with a stoichiometric or non-stoichiometric amount of water.
  • relative humidity refers to the ratio, expressed as a percentage, of the amount of water vapor at a specified temperature to the maximum amount of water vapor that can be maintained at that temperature and pressure.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the room temperature refers to an ambient temperature of 10°C to 35°C.
  • the medicinal salt of fingolimod of the present invention has good solubility and stability, and has good market prospects.
  • the defects in the prior art such as unsatisfactory water solubility and stability of fingolimod hydrochloride are solved.
  • composition containing the pharmaceutically acceptable salt of fingolimod of the present invention has good stability, safety and long sustained drug release period.
  • Fig. 1 is the XRPD spectrum of fingolimod pamoate crystalline form B obtained in Example 1.
  • Fig. 2 is the TGA spectrum of fingolimod pamoate crystalline form B obtained in Example 1.
  • FIG. 3 is the 1 H-NMR spectrum of fingolimod pamoate crystal form B obtained in Example 1.
  • Fig. 4 is the XRPD pattern of fingolimod pamoate crystalline form A obtained in Example 3.
  • Fig. 5 is the DSC spectrum of fingolimod pamoate crystalline form A obtained in Example 3.
  • Fig. 6 is the TGA spectrum of fingolimod pamoate crystalline form A obtained in Example 3.
  • Fig. 7 is the 1 H-NMR spectrum of fingolimod pamoate crystalline form A obtained in Example 3.
  • Fig. 8 is the XRPD spectrum of fingolimod pamoate crystalline form I obtained in Example 4.
  • FIG. 9 is the XRPD pattern of fingolimod pamoate crystalline form J obtained in Example 5.
  • Fig. 10 is the XRPD pattern of fingolimod pamoate crystalline form C obtained in Example 6.
  • Fig. 11 is the XRPD pattern of fingolimod pamoate crystalline form D obtained in Example 7.
  • Fig. 12 is the XRPD pattern of fingolimod pamoate crystalline form E obtained in Example 8.
  • Fig. 13 is the XRPD pattern of fingolimod pamoate crystalline form F obtained in Example 9.
  • Fig. 14 is the XRPD pattern of fingolimod pamoate crystalline form G obtained in Example 10.
  • Fig. 15 is the XRPD pattern of fingolimod pamoate crystalline form H obtained in Example 11.
  • Fig. 16 is the XRPD pattern of fingolimod pamoate crystalline form K obtained in Example 13.
  • Fig. 17 is the XRPD pattern of fingolimod 1-hydroxy 2-naphthoate crystal form 1 obtained in Example 14.
  • Fig. 18 is the DSC spectrum of fingolimod 1-hydroxy 2-naphthoate crystal form 1 obtained in Example 14.
  • Fig. 19 is the TGA spectrum of fingolimod 1-hydroxy 2-naphthoate crystal form 1 obtained in Example 14.
  • Fig. 20 is the 1 H-NMR spectrum of fingolimod 1-hydroxy 2-naphthoate crystal form 1 obtained in Example 14.
  • Fig. 21 is a graph showing the relationship between the average blood drug concentration and time of the oral prescription samples of Example 21.
  • Fig. 22 is a graph showing the relationship between the average blood drug concentration and time of the sample of the suspension formulation in Example 21.
  • the 1 H-NMR test was carried out in a Bruker Advance III 500M nuclear magnetic resonance spectrometer with a measurement frequency of 400Mz and a solvent of deuterated DMSO.
  • XRPD measurements were performed on a Bruker model D8Advance X-ray powder diffractometer using a circular zero-background monocrystalline silicon sample stage.
  • the scanning parameters are as follows: voltage 40kv, current 40mA, scanning range 3° ⁇ 45°, scanning step size 0.02°, scanning mode is continuous scanning
  • the DSC measurement was carried out in a TA Instruments model Q2000 sealed pan device, the sample (about 1-2 mg) was weighed in an aluminum pan, and transferred to the instrument for measurement.
  • the test parameters are as follows: the instrument is balanced at 30°C, the temperature is raised at a rate of 10°C/min, and the experimental atmosphere is nitrogen.
  • the TGA measurement was carried out in a TA Instruments model Q2000 device.
  • the sample (about 2-5 mg) was weighed in a platinum pan and transferred to the instrument for measurement.
  • the test parameters are as follows: the temperature of the instrument is raised at a rate of 10°C/min, and the experimental atmosphere is nitrogen.
  • Step 1 Take 292 mg of potassium hydroxide and add 5 mL of water to obtain a potassium hydroxide solution.
  • Step 2 Take 78 mg of pamoic acid, add 1 mL of water, stir to disperse, add 0.4 mL of potassium hydroxide solution, stir, and filter to obtain pamoic acid solution.
  • Step 3 Take 68mg of fingolimod hydrochloride, add 1mL of water, stir to dissolve, add 0.6mL of pamoic acid solution obtained in step 2, stir to react, add 7mL of water, stir for 30 minutes, add 0.2mL The pamoic acid solution obtained in step 2 was continued to react for 30 minutes, and filtered to obtain fingolimod pamoate, which was detected as fingolimod pamoate crystal form B by XRPD.
  • Step 1 Take 5.84g of potassium hydroxide and add 100mL of water to obtain a potassium hydroxide solution.
  • Step 2 Take 15.6 g of pamoic acid, add 200 mL of water, stir to disperse, add 80 mL of potassium hydroxide solution, stir, and filter to obtain pamoic acid solution.
  • Step 3 Take 13.6g of fingolimod hydrochloride, add 200mL of water, stir to dissolve, add 120mL of pamoic acid solution obtained in step 2, stir for reaction, add 1400mL of water, stir for 30 minutes, add 40mL 2 The obtained pamoic acid solution was continued to react for 30 minutes, and filtered to obtain fingolimod pamoate, which was detected as fingolimod pamoate crystal form B by XRPD.
  • Step 1 Weigh 1192.23 mg of potassium hydroxide, add 20 mL of water to dissolve, and obtain an aqueous potassium hydroxide solution with a concentration of about 1.062 mmol/mL.
  • Step 2 Weigh 3124mg of pamoic acid, add 20mL of water, stir to disperse, add 16.725mL of potassium hydroxide aqueous solution, stir for 1h, filter and take the filtrate to obtain potassium pamoate solution.
  • Step 3 Preparation of fingolimod hydrochloride solution: Weigh 2721 mg of fingolimod hydrochloride, add 60 mL of water, stir, basically dissolve, and filter to get the filtrate.
  • Step 4 Slowly add 20.990 mL of potassium pamoate solution into the fingolimod hydrochloride solution under stirring, stir overnight at room temperature, recover by suction filtration, and vacuum-dry at 35°C for 2 days to obtain hemi-pamoate salt, which is tested by XRPD Detected as fingolimod pamoate crystalline form I.
  • the XRPD pattern of fingolimod pamoate crystalline form I is shown in FIG. 8 .
  • the fingolimod pamoate crystalline form I sample prepared in Example 4 was taken, and dried at room temperature for 10 days to obtain the fingolimod pamoate crystalline form J.
  • the XRPD pattern of fingolimod pamoate crystalline form J is shown in FIG. 9 .
  • the XRPD pattern of fingolimod pamoate crystalline form C is shown in FIG. 10 .
  • fingolimod pamoate crystal form B sample prepared in Example 3 Take 25 mg of the fingolimod pamoate crystal form B sample prepared in Example 3, add 0.3 mL of ethanol and 0.1 mL of water, and volatilize at room temperature to obtain fingolimod pamoate crystal form D.
  • fingolimod pamoate crystal form B sample prepared in Example 3 Take 25 mg of the fingolimod pamoate crystal form B sample prepared in Example 3, add 0.2mL 1,4-dioxane, and volatilize at 60°C to obtain fingolimod pamoate crystal form E .
  • fingolimod pamoate crystalline form B sample prepared in Example 3 Take 30 mg of the fingolimod pamoate crystalline form B sample prepared in Example 3, add 0.5 mL of n-heptane and 0.5 mL of isopropyl acetate to form a slurry, and stir at 60 ° C for 7 days to obtain fingolimod dihydroxy Naphthalate salt form F.
  • the XRPD pattern of fingolimod pamoate crystalline form F is shown in FIG. 13 .
  • fingolimod pamoate crystalline form B sample prepared in Example 3 Take 30 mg of fingolimod pamoate crystalline form B sample prepared in Example 3, add 0.1mL N,N-dimethylformamide and 1mL water to form a slurry, stir at 60°C for 7 days, and obtain fingolimod pamoate Hydroxynaphate salt form G.
  • fingolimod hydrochloride Take 12.6g of fingolimod hydrochloride, add 480mL of water, stir to dissolve, slowly add ammonia water dropwise, adjust the pH to 9-10, continue stirring for 1 hour, filter, and vacuum dry at room temperature for 3 hours to obtain 11.1g of free fingolimod alkali.
  • fingolimod free base prepared in Example 12, add 50mL of n-butyl acetate, stir at 60°C to dissolve, add 530mg of pamoic acid, stir for 4 hours, cool down to room temperature, stir overnight, filter, 40°C Drying in vacuo overnight gave fingolimod pamoate crystalline form K.
  • Step 1 Weigh 5500mg of 1-hydroxy-2-naphthoic acid, add 75mL of ethyl acetate, stir and dissolve in a water bath at 60°C, filter, and take the filtrate.
  • Step 2 Take 7230 mg of fingolimod free base of Example 12, add 250 mL of ethyl acetate, and dissolve in a water bath at 60°C.
  • Step 3 Slowly add the 1-hydroxy-2-naphthoic acid solution dropwise into the fingolimod solution under stirring at 60°C, add 17 mL of ethyl acetate to rinse, stir at room temperature overnight, filter, and wash the filter cake with 85 mL of ethyl acetate, After drying under vacuum at 35°C overnight, fingolimod 1-hydroxy-2-naphthoate was obtained, which was the crystalline form 1 of fingolimod 1-hydroxy-2-naphthoate by XRPD.
  • the prescription samples obtained from prescriptions 1 to 3 were taken to investigate the needle penetration and sedimentation ratio, and it was found that the prescription samples obtained from prescription 2 had good needle penetration and sedimentation ratio.
  • the dosage of polyethylene glycol 4000 in prescription 3 of Example 15 was adjusted to 200mg, 300mg, 400mg, 500mg and 600mg respectively, and then the prescription was prepared to obtain prescriptions 4, 5, 6, 7 and 8 . Samples of prescriptions 4 to 8 were taken to investigate the needle penetration and sedimentation ratio, and it was found that the needle penetration and sedimentation ratio of the obtained prescription samples were good.
  • fingolimod hydrochloride Take 3.676mg of fingolimod hydrochloride, dissolve it with water for injection, dilute, and set the volume to 100mL to obtain an oral prescription sample of fingolimod hydrochloride.
  • Embodiment 19 Solid State Stability Comparison
  • the fingolimod pamoate crystal form A and the fingolimod salt obtained in embodiment 3 respectively Salt under high temperature (60°C), high humidity (25°C/90%RH), accelerated (40°C/75%RH), light (1.2 ⁇ 106Lux ⁇ hr) and long-term (25°C/60%RH) conditions Place it, and take samples at 0 days, 5 days, and 10 days for HPLC detection of related substances.
  • Embodiment 20 Solubility comparison
  • the fingolimod 1-hydroxyl-2-naphthoate crystal form 1 prepared in Example 14 the fingolimod pamoate crystal form B and fingolimod salt obtained in Example 2 respectively acid salt and the fingolimod free base prepared in Example 12 were added to the following corresponding media respectively, shaken at 37°C for 24 hours, filtered through a 0.45 ⁇ m aqueous phase filter, and the filtrate was collected, and the high-efficiency liquid phase for solubility determination.
  • the corresponding medium is: pH3 and pH5 are acetate buffer solutions, pH7 and pH9 are phosphate buffer solutions, and the water is ultrapure water.
  • fingolimod 1-hydroxy-2-naphthalene Formate pamoate and their crystalline forms have slow-release effects, and at the same time have similar solubility in various pH media, and the release rate can be minimally dependent on pH, so as to avoid pH changes in different regions of the body.
  • the influence of the environment on its drug release rate can avoid sudden release phenomenon or excessive blood drug concentration in local areas of the body, and reduce the difference in drug release between individuals. Compliance, market prospect is good.
  • Embodiment 21 prescription stability contrast
  • Table 17 shows that the prescription samples prepared by the present invention are relatively stable under various conditions, and the sum of related substances does not change significantly after being placed for 10 days.
  • the prescription sample prepared in Example 18 has the same stability as the prescription sample in Example 15.
  • Embodiment 21 pharmacokinetic experiment
  • 6 male SD rats were divided into two groups, wherein a single dose of 3mg/kg was given to Fingolimod 1-hydroxyl-2-naphthoate crystal form prescription sample (embodiment 18) through intramuscular injection, and given Plasma was collected at 0, 1h, 3h, 7h, 24h, 4d, 7d, 11d, 15d, 20d, 25d, 30d, and 35d after the drug; the other group was given a single dose of 0.1mg/kg by oral gavage with fingolimod hydrochloride Salt samples (Example 17) and plasma were collected at 5 min, 15 min, 30 min, 1, 2, 3, 4, 6, 8, 12 and 24 hours after administration. Throughout the experiment, the animals in the intramuscular injection group had free access to food and water, and the animals in the oral gavage group fasted overnight before administration, and resumed diet 4 hours after administration.
  • Plasma sample collection About 150 ⁇ L of jugular vein blood (whole blood is centrifuged within 30 minutes to separate plasma) is placed in a test tube containing anticoagulant EDTA-K2, and the processed plasma is stored in a -70°C refrigerator until use.
  • Plasma sample pretreatment Add 200 ⁇ L internal standard solution (40ng/mL Glipizide acetonitrile solution) to 30 ⁇ L plasma sample, vortex and mix for 1 min, centrifuge at 5800 rpm for 10 min at 4 °C, transfer 100 ⁇ L supernatant to a new plate, and then take 5 ⁇ L of the solution was analyzed by LC-MS/MS.
  • the pharmacokinetic parameters of fingolimod in animals are shown in Tables 18 to 19, and the drug-time curves are shown in Figures 21 to 22.
  • the oral prescription group of fingolimod reached the peak blood concentration 12 hours after administration, and could maintain the blood concentration above 0.3ng/ml within 24 hours, and the MRT was only 12h.
  • the peak plasma concentration can be reached within 3 hours after administration, a relatively stable plasma concentration can be achieved within 1 day, and the plasma concentration can be maintained at 0.3ng for at least 15 days /ml or more, the MRT is as long as 12 days, indicating that the preparation has a quick onset of action and a long sustained drug release period; Cmax does not increase proportionally to the dose, and there is still a large safe distance from the toxic concentration, indicating that the safety is relatively high.
  • PK parameters unit Rat#1 Rat#2 Rat#3 mean SD CV(%) Tmax the day 0.0420 0.0420 0.292 0.125 0.144 115 Cmax ng/mL 4.36 2.45 2.93 3.25 0.994 30.6 T 1/2 the day 9.75 11.8 17.5 13.0 4.00 30.7 AUC last day*ng/mL 19.8 14.9 17.7 17.5 2.46 14.0 AUC INF day*ng/mL 23.9 16.7 28.1 22.9 5.80 25.3 MRT INF the day 17.3 17.4 29.7 21.5 7.12 33.2 MRT last the day 10.8 13.4 11.8 12.0 1.30 10.8
  • Rat#4 Rat#5 Rat#6 mean SD CV(%) Tmax hr 12.0 12.0 12.0 12.0 0.00 0.00 Cmax ng/mL 0.564 0.728 0.728 0.673 0.0947 14.1 T 1/2 hr NA NA NA NA NA NA AUC last hr*ng/mL 11.0 12.0 11.9 11.6 0.576 4.95 AUC INF hr*ng/mL NA NA NA NA NA NA MRT INF hr NA NA NA NA NA NA NA NA NA NA MRT last hr 12.2 13.2 12.0 12.5 0.649 5.21

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Abstract

提供了芬戈莫德药用盐、制备方法、含其的药物组合物及应用。芬戈莫德药用盐为芬戈莫德游离碱与六个碳以上的有机酸形成的盐。芬戈莫德药用盐溶解度和稳定性均较好，市场化前景良好。

Description

芬戈莫德药用盐、制备方法、含其的药物组合物及应用
本申请要求享有2021年5月31日向中国国家知识产权局提交的，专利申请号为202110601645.0，发明名称为“芬戈莫德药用盐、制备方法、含其的药物组合物及应用”的在先申请的优先权权益。所述在先申请的全文通过引用的方式结合于本申请中。
技术领域
本发明涉及芬戈莫德药用盐、制备方法、含其的药物组合物及应用。
背景技术
多发性硬化症(MS)是以中枢神经系统蛋白质炎性脱髓鞘病变为主要特点的自发免疫病，对患者的活动、心智、甚至精神状态均有严重不良影响。当前，MS全球范围发病率逐年上涨，患者人数超过250万人；女性患病率高于男性，患病人群涉及青年和儿童。
芬戈莫德最初是从真菌辛克莱虫草和其近亲冬虫夏草中分离出来的具有较强免疫抑制活性的化合物，是神经鞘氨醇1-磷酸(S1PR)受体调节剂，经过结构修饰得到盐酸芬戈莫德(结构式如式II所示)，命名为FTY 720。
Figure PCTCN2022095013-appb-000001
Novartis研发的盐酸芬戈莫德胶囊是全球首个治疗MS的口服制剂(胶囊剂)，也是首个治疗儿童MS的药物，在降低MS患者的复发率方面疗效显著。
本发明人在研究过程中发现，芬戈莫德盐酸盐水溶性高，导致其口服剂型的释放速度过快，需要频繁给药以维持血药浓度，使得患者的用药依从性差。专利文献WO2010055028A2提到了多种芬戈莫德盐酸盐的晶型，这些晶型会因温度的变化而发生转晶，故芬戈莫德盐酸盐晶型稳定性差，晶型变化会对溶出速率、生物利用度等方面产生影响，不利于制剂的可加工性和稳定性。
因此，寻找溶解度低且适宜缓释给药、稳定性高、临床效果好、适合于商品化的芬戈莫德药用盐型是目前急需解决的技术问题。
发明内容
本发明提供了一种式I所示的芬戈莫德的盐：
Figure PCTCN2022095013-appb-000002
其中，X为六个碳以上的有机酸或含有羟基的酯，n为0.5～2.0；
优选地，所述盐为药用盐。
根据本发明的实施方案，所述的六个碳以上的有机酸可以选自C6～C30的有机酸，例如为C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19、C20、C21、C22、C23、C24、C25、C26、C27、C28、C29、C30的有机酸。
根据本发明的实施方案，所述的X选自包括但不限于下述物质中的一种或多种：己酸、庚酸、辛酸、壬酸、壬二酸、癸酸、癸二酸、十一烷酸、月桂酸(十二烷酸)、十三烷酸、肉豆蔻酸(十四烷酸)、十五烷酸、软脂酸(即棕榈酸或十六烷酸)、十七烷酸、硬脂酸(十八烷酸)、十九烷酸、二十烷酸(花生酸)、油酸、二十一烷酸、二十二烷酸、二十三烷酸、二十四烷酸、二十五烷酸、二十六烷酸、二十七烷酸、二十八烷酸、二十九烷酸、三十烷酸(蜂花酸)、甘油酸、木质酸、双羟萘酸(即帕莫酸)、1-羟基-2萘甲酸以及萘酸衍生物(所述萘酸衍生物包括但不限于萘酸酯)。
根据本发明的实施方案，所述X选自双羟萘酸、1-羟基-2-萘甲酸、月桂酸、软脂酸、癸二酸、十一烷酸、庚酸中的一种或多种。
根据本发明的实施方案，所述n为0.5、1.0或2.0。
根据本发明的实施方案，所述的芬戈莫德的盐可以为芬戈莫德单帕莫酸盐(即n＝1.0，亦称芬戈莫德单双羟萘酸盐)、芬戈莫德半帕莫酸盐(即n＝0.5，亦称芬戈莫德半双羟萘酸盐)、芬戈莫德1-羟基-2-萘甲酸盐、芬戈莫德月桂酸盐、芬戈莫德软脂酸盐、芬戈莫德癸二酸盐、芬戈莫德十一烷酸盐或芬戈莫德庚酸盐。
根据本发明的实施方案，所述的芬戈莫德的盐可以为单相晶体、无定型或混合晶体的形式。
根据本发明的实施方案，所述的单相晶体是指由大量微观物质单位(原子、离子、分子等)按一定规则有序排列的结构，其包括芬戈莫德的盐的非溶剂合物(例如无水物)以及溶剂合物(例如水合物)的晶型形式。
根据本发明的实施方案，所述的术语“混合晶体”是指同一化合物的不同晶体形式和/或其他固态分子形式，例如包含所述的芬戈莫德的盐的两种或两种以上晶型和/或无定型形式的固体。
根据本发明的实施方案，所述的芬戈莫德的盐包括所述芬戈莫德的盐与溶剂形成的溶剂合物。例如，所述的溶剂合物包括芬戈莫德的盐的水合物和芬戈莫德的盐与有机溶剂形成的溶剂合物。优选地，所述的“芬戈莫德的盐与有机溶剂形成的溶剂合物”中所述 的“有机溶剂”包括但不限于乙醇、丙酮和二甲基亚砜中的一种或多种。
本发明还提供了所述的芬戈莫德的盐的一种制备方法，所述制备方法包括以下步骤：将芬戈莫德游离碱与所述的X(即六个碳以上的有机酸)进行中和反应，得到所述的芬戈莫德的盐。
根据本发明的实施方案，所述的芬戈莫德的盐的制备方法可以在溶剂中或无溶剂的条件下进行。
本发明还提供了所述的芬戈莫德的盐的另一种制备方法，所述制备方法包括以下步骤：将芬戈莫德游离碱在无机酸中形成溶液，将所述X(即六个碳以上的有机酸)在无机碱中形成溶液，再将两种溶液混合，得到所述的芬戈莫德的盐。
根据本发明的实施方案，上述两种制备方法中，所述的六个碳以上的有机酸可以为C6～C30的有机酸。
根据本发明的实施方案，上述两种制备方法中，所述的X选自包括但不限于下述物质中的一种或多种：己酸、庚酸、辛酸、壬酸、壬二酸、癸酸、十一烷酸、月桂酸(十二烷酸)、十三烷酸、肉豆蔻酸(十四烷酸)、十五烷酸、棕榈酸(十六烷酸)、十七烷酸、硬脂酸(十八烷酸)、十九烷酸、二十烷酸(花生酸)、油酸、二十一烷酸、二十二烷酸、二十三烷酸、二十四烷酸、二十五烷酸、二十六烷酸、二十七烷酸、二十八烷酸、二十九烷酸、三十烷酸(蜂花酸)、甘油酸、木质酸、双羟萘酸(帕莫酸)、1-羟基-2萘甲酸以及萘酸衍生物(所述萘酸衍生物包括但不限于萘酸酯)。
根据本发明的实施方案，所述的双羟萘酸又称帕莫酸(Pamoic acid)，CAS No.130-85-8。
本发明还提供芬戈莫德的盐的晶型，例如为芬戈莫德双羟萘酸盐的晶型、芬戈莫德1-羟基2-萘甲酸盐的晶型。
根据本发明的实施方案，所述的芬戈莫德双羟萘酸盐的晶型为芬戈莫德双羟萘酸盐晶型B，所述的芬戈莫德双羟萘酸盐晶型B的X射线粉末衍射图在2θ值为3.3°±0.2°、17.1°±0.2°、21.8°±0.2°等处有特征峰。
进一步地，所述的芬戈莫德双羟萘酸盐晶型B的X射线粉末衍射图在2θ值为3.3°±0.2°、17.1°±0.2°、18.7°±0.2°、19.1°±0.2°、21.8°±0.2°、23.4°±0.2°等处有特征峰。
进一步地，所述的芬戈莫德双羟萘酸盐晶型B的X射线粉末衍射图在2θ值为3.3°±0.2°、17.1±0.2°、17.7°±0.2°、18.7°±0.2°、19.1°±0.2°、20.6°±0.2°、21.8°±0.2°、23.4°±0.2°等处有特征峰。
更进一步地，所述的芬戈莫德双羟萘酸盐晶型B的X射线粉末衍射图在2θ值为3.3°±0.2°、7.1°±0.2°、9.8±0.2°、11.2°±0.2°、11.8°±0.2°、12.6°±0.2°、13.5°±0.2°、14.3°±0.2°、14.7°±0.2°、15.5°±0.2°、16.1°±0.2°、16.7°±0.2°、17.1°±0.2°、17.7°±0.2°、18.7°±0.2°、19.1°±0.2°、19.6°±0.2°、20.0°±0.2°、20.6°±0.2°、21.8°±0.2°、22.6°±0.2°、23.4°±0.2°、23.8°±0.2°、25.2°±0.2°、26.5°±0.2°、27.5°±0.2°、30.1°±0.2°等处有吸收峰。
根据本发明的实施方案，所述的芬戈莫德双羟萘酸盐晶型B的X射线粉末衍射图基本如图1所示。
根据本发明的一种实施方案，所述的芬戈莫德双羟萘酸盐晶型B具有如表1所示的X射线粉末衍射谱图。
根据本发明的实施方案，所述的芬戈莫德双羟萘酸晶型B的热重分析图基本如图2所示。
根据本发明的实施方案，所述的芬戈莫德双羟萘酸晶型B的核磁图基本如图3所示。
根据本发明的实施方案，所述的芬戈莫德双羟萘酸晶型B，芬戈莫德与双羟萘酸的摩尔比为1:0.5。
根据本发明的实施方案，所述的芬戈莫德双羟萘酸盐晶型B为水合物。
根据本发明的实施方案，所述的芬戈莫德双羟萘酸盐晶型B的制备方法如下：
将双羟萘酸与溶剂1混合，得到双羟萘酸溶液；将芬戈莫德盐酸盐与溶剂2混合，向其中加入所述双羟萘酸溶液，搅拌反应，得到所述的芬戈莫德双羟萘酸盐晶型B；
所述溶剂1为碱性溶液，例如为无机碱溶液，优选为氢氧化钾水溶液；
所述溶剂2为水、甲醇、乙醇、异丙醇、四氢呋喃、N,N-二甲基甲酰胺、或前述至少两种溶剂的混合物，优选为水。
根据本发明的实施方案，所述的芬戈莫德双羟萘酸盐的晶型为芬戈莫德双羟萘酸盐晶型A。
根据本发明的实施方案，所述的芬戈莫德双羟萘酸盐晶型A的X射线粉末衍射图在2θ值为3.2°±0.2°、19.3°±0.2°、20.4°±0.2°等处有特征峰。
进一步地，所述的芬戈莫德双羟萘酸盐晶型A的X射线粉末衍射图在2θ值为3.2°±0.2°、9.6°±0.2°、12.5°±0.2°、18.5°±0.2°、19.3°±0.2°、20.4°±0.2°等处有特征峰。
进一步地，所述的芬戈莫德双羟萘酸盐晶型A的X射线粉末衍射图在2θ值为3.2°±0.2°、9.6°±0.2°、12.5°±0.2°、18.0°±0.2°、18.5°±0.2°、19.3°±0.2°、20.4°±0.2°、24.3°±0.2°等处有特征峰。
更进一步地，所述的芬戈莫德双羟萘酸盐晶型A的X射线粉末衍射图在2θ值为3.2°±0.2°、9.2°±0.2°、9.6°±0.2°、10.8°±0.2°、11.6°±0.2°、12.5°±0.2°、13.1°±0.2°、14.8°±0.2°、15.1°±0.2°、16.3°±0.2°、18.0°±0.2°、18.5°±0.2°、19.3°±0.2°、20.4°±0.2°、21.6°±0.2°、22.1°±0.2°、22.6°±0.2°、24.3°±0.2°、25.2°±0.2°等处有特征峰。
根据本发明的实施方案，所述的芬戈莫德双羟萘酸盐晶型A的X射线粉末衍射图基本如图4所示。
根据本发明的一种实施方案，所述的芬戈莫德双羟萘酸盐晶型A具有如表2所示的X射线粉末衍射谱图。
根据本发明的实施方案，所述的芬戈莫德双羟萘酸盐晶型A的差式扫描量热分析图基本如图5所示。在一种实施方式中，所述芬戈莫德双羟萘酸盐晶型A具有两个吸热峰 和1个放热峰，例如，所述吸热峰的峰值温度为128±5℃、180±5℃；例如，所述放热峰的峰值温度为153±5℃。
根据本发明的实施方案，所述的芬戈莫德双羟萘酸盐晶型A的热重分析图基本如图6所示。
根据本发明的实施方案，所述的芬戈莫德双羟萘酸盐晶型A为无水物或隧道水合物。
根据本发明的实施方案，所述的芬戈莫德双羟萘酸盐晶型A的核磁图基本如图7所示。
根据本发明的实施方案，所述的芬戈莫德双羟萘酸晶型A，芬戈莫德与双羟萘酸的摩尔比1:0.5。
根据本发明的实施方案，所述的芬戈莫德双羟萘酸盐晶型A的制备方法如下：
将芬戈莫德双羟萘酸盐晶型B干燥，得到芬戈莫德双羟萘酸盐晶型A；
优选地，所述干燥的温度为25～50℃，例如30℃、40℃；
优选地，所述干燥为真空干燥。
根据本发明的实施方案，所述的芬戈莫德双羟萘酸盐的晶型为芬戈莫德双羟萘酸盐晶型I。
根据本发明的实施方案，所述的芬戈莫德双羟萘酸盐晶型I的X射线粉末衍射图在2θ值为3.0°±0.2°、8.9°±0.2°、19.9°±0.2°等处有特征峰。
更进一步地，所述的芬戈莫德双羟萘酸盐晶型I的X射线粉末衍射图在2θ值为3.0°±0.2°、3.3°±0.2°、5.6±0.2°、5.9°±0.2°、6.9°±0.2°、8.9°±0.2°、9.8°±0.2°、15.0°±0.2°、16.2°±0.2°、18.0°±0.2°、18.8°±0.2°、19.1°±0.2°、19.6°±0.2°、19.9°±0.2°、21.0°±0.2°、21.8°±0.2°、25.2°±0.2°等处有特征峰。
更进一步地，所述的芬戈莫德双羟萘酸盐晶型I的X射线粉末衍射图基本如图8所示。
根据本发明的一种实施方案，所述的芬戈莫德双羟萘酸盐晶型I具有如表3所示的X射线粉末衍射谱图。
根据本发明的实施方案，所述的芬戈莫德双羟萘酸盐晶型I的制备方法如下：
将双羟萘酸与溶剂1混合，得到双羟萘酸溶液；
将芬戈莫德盐酸盐与溶剂2混合，向其中加入所述双羟萘酸溶液，搅拌反应，过滤，干燥，得到所述的芬戈莫德双羟萘酸盐晶型I；
所述溶剂1为碱性溶液，例如无机碱溶液，优选为氢氧化钾水溶液；
所述溶剂2为水、甲醇、乙醇、异丙醇、四氢呋喃、N,N-二甲基甲酰胺、或前述至少两种溶剂的混合物，优选为水。
根据本发明的实施方案，所述干燥的时间为2～7天，优选为2天。
根据本发明的实施方案，所述的芬戈莫德双羟萘酸盐的晶型为芬戈莫德双羟萘酸盐晶型J。
根据本发明的实施方案，所述的芬戈莫德双羟萘酸盐晶型J的X射线粉末衍射图在2θ值为3.2°±0.2°、5.3°±0.2°、10.1°±0.2°、10.8°±0.2°、18.1°±0.2°、19.8°±0.2°、20.6°±0.2°、21.7°±0.2°等处有特征峰。
更进一步地，所述的芬戈莫德双羟萘酸盐晶型J的X射线粉末衍射图在2θ值为3.2°±0.2°、5.3°±0.2°、6.3±0.2°、9.5°±0.2°、10.1°±0.2°、10.8°±0.2°、13.5°±0.2°、17.0°±0.2°、17.8°±0.2°、18.1°±0.2°、19.8°±0.2°、20.6°±0.2°、21.7°±0.2°、22.0°±0.2°、24.5°±0.2°、25.5°±0.2°等处有特征峰。
更进一步地，所述的芬戈莫德双羟萘酸盐晶型J的X射线粉末衍射图基本如图9所示。
根据本发明的一种实施方案，所述的芬戈莫德双羟萘酸盐晶型J具有如表4所示的X射线粉末衍射谱图。
根据本发明的实施方案，所述的芬戈莫德双羟萘酸盐晶型J的制备方法如下：
将芬戈莫德双羟萘酸盐晶型I于室温干燥条件下放置，得到芬戈莫德双羟萘酸盐晶型J。
根据本发明的实施方案，所述的芬戈莫德双羟萘酸盐的晶型为芬戈莫德双羟萘酸盐晶型C。
根据本发明的实施方案，所述的芬戈莫德双羟萘酸盐晶型C的X射线粉末衍射图在2θ值为3.2°±0.2°、6.4°±0.2°、19.8°±0.2°等处有特征峰。
进一步地，所述的芬戈莫德双羟萘酸盐晶型C的X射线粉末衍射图在2θ值为3.2°±0.2°、6.4°±0.2°、9.6°±0.2°、15.1°±0.2°、19.8°±0.2°、20.4°±0.2°等处有特征峰。
进一步地，所述的芬戈莫德双羟萘酸盐晶型C的X射线粉末衍射图在2θ值为3.2°±0.2°、6.4°±0.2°、9.6°±0.2°、13.6°±0.2°、15.1°±0.2°、15.6°±0.2°、19.8°±0.2°、20.4°±0.2°等处有特征峰。
更进一步地，所述的芬戈莫德双羟萘酸盐晶型C的X射线粉末衍射图在2θ值为3.2°±0.2°、5.4±0.2°、6.4°±0.2°、9.6°±0.2°、12.8°±0.2°、13.6°±0.2°、14.3°±0.2°、15.1°±0.2°、15.6°±0.2°、16.7°±0.2°、17.3°±0.2°、17.7°±0.2°、18.3°±0.2°、18.6°±0.2°、19.0°±0.2°、19.8°±0.2°、20.4°±0.2°、22.7°±0.2°、23.1°±0.2°、23.5°±0.2°、25.9°±0.2°、29.2°±0.2°等处有特征峰。
更进一步地，所述的芬戈莫德双羟萘酸盐晶型C的X射线粉末衍射图基本如图10所示。
根据本发明的一种实施方案，所述的芬戈莫德双羟萘酸盐晶型C具有如表5所示的X射线粉末衍射谱图。
根据本发明的实施方案，所述的芬戈莫德双羟萘酸盐晶型C的制备方法如下：
将芬戈莫德双羟萘酸盐晶型J于溶剂3中形成混悬液，搅拌析晶，得到所述的芬戈莫德双羟萘酸盐晶型C；
所述溶剂3为正庚烷和乙酸乙酯的混合溶剂；
优选地，所述搅拌析晶的温度为50-80℃，例如60℃；
优选地，所述搅拌析晶的时间为2-10天，例如7天；
优选地，所述制备方法还包括搅拌析晶后分离，将分离得到的固体物干燥，得到所述芬戈莫德双羟萘酸盐晶型C。
根据本发明的实施方案，所述的芬戈莫德双羟萘酸盐的晶型为芬戈莫德双羟萘酸盐晶型D。
根据本发明的实施方案，所述的芬戈莫德双羟萘酸盐晶型D的X射线粉末衍射图在2θ值为3.3°±0.2°、10.1°±0.2°、20.3°±0.2°等处有特征峰。
进一步地，所述的芬戈莫德双羟萘酸盐晶型D的X射线粉末衍射图在2θ值为3.3°±0.2°、6.7°±0.2°、10.1°±0.2°、16.9°±0.2°、18.8°±0.2°、20.3°±0.2°等处有特征峰。
进一步地，所述的芬戈莫德双羟萘酸盐晶型D的X射线粉末衍射图在2θ值为3.3°±0.2°、6.7°±0.2°、7.2°±0.2°、10.1°±0.2°、16.9°±0.2°、18.8°±0.2°、20.3°±0.2°、23.8°±0.2°等处有特征峰。
更进一步地，所述的芬戈莫德双羟萘酸盐晶型D的X射线粉末衍射图在2θ值为3.3°±0.2°、5.0±0.2°、6.7°±0.2°、7.3°±0.2°、8.9°±0.2°、10.1°±0.2°、10.5°±0.2°、13.1°±0.2°、13.5°±0.2°、13.8°±0.2°、15.5°±0.2°、16.2°±0.2°、16.9°±0.2°、17.4°±0.2°、17.8°±0.2°、18.8°±0.2°、19.5°±0.2°、20.3°±0.2°、22.2°±0.2°、23.8°±0.2°、25.7°±0.2°、27.4°±0.2°、29.1°±0.2°等处有特征峰。
根据本发明的实施方案，所述的芬戈莫德双羟萘酸盐晶型D的X射线粉末衍射图基本如图11所示。
根据本发明的一种实施方案，所述的芬戈莫德双羟萘酸盐晶型D具有如表6所示的X射线粉末衍射谱图。
根据本发明的实施方案，所述的芬戈莫德双羟萘酸盐晶型D的制备方法如下：
将芬戈莫德双羟萘酸盐晶型B溶解于良溶剂1中，挥发析晶，得到所述的芬戈莫德双羟萘酸盐晶型D。
所述良溶剂1为乙醇与水的混合溶剂；
优选地，所述挥发析晶的温度为室温。
根据本发明的实施方案，所述的芬戈莫德双羟萘酸盐的晶型为芬戈莫德双羟萘酸盐晶型E。
根据本发明的实施方案，所述的芬戈莫德双羟萘酸盐晶型E的X射线粉末衍射图在2θ值为3.3°±0.2°、17.3°±0.2°、19.0°±0.2°等处有特征峰。
进一步地，所述的芬戈莫德双羟萘酸盐晶型E的X射线粉末衍射图在2θ值为3.3°±0.2°、9.8°±0.2°、17.3°±0.2°、17.7°±0.2°、19.0°±0.2°、21.8°±0.2°等处有特征峰。
进一步地，所述的芬戈莫德双羟萘酸盐晶型E的X射线粉末衍射图在2θ值为3.3°±0.2°、9.8°±0.2°、17.3°±0.2°、17.7°±0.2°、19.0°±0.2°、19.3°±0.2°、20.0°±0.2°、21.8°±0.2° 等处有特征峰。
更进一步地，根据本发明的实施方案，所述的芬戈莫德双羟萘酸盐晶型E的X射线粉末衍射图在2θ值为3.3°±0.2°、7.3°±0.2°、7.5°±0.2°、8.6°±0.2°、8.9°±0.2°、9.1°±0.2°、9.8°±0.2°、10.1°±0.2°、10.5°±0.2°、11.9°±0.2°、13.1°±0.2°、16.4°±0.2°、17.1°±0.2°、17.3°±0.2°、17.7°±0.2°、18.2°±0.2°、19.0°±0.2°、19.3°±0.2°、20.0°±0.2°、21.2°±0.2°、21.8°±0.2°、22.8°±0.2°、23.2°±0.2°、23.9°±0.2°、24.3°±0.2°等处有特征峰。
根据本发明的实施方案，所述的芬戈莫德双羟萘酸盐晶型E的X射线粉末衍射图基本如图12所示。
根据本发明的一种实施方案，所述的芬戈莫德双羟萘酸盐晶型E具有如表7所示的X射线粉末衍射谱图。
根据本发明的实施方案，所述的芬戈莫德双羟萘酸盐晶型E的制备方法如下：
将芬戈莫德双羟萘酸盐晶型B溶解于良溶剂2中，挥发析晶，得到所述的芬戈莫德双羟萘酸盐晶型E。
所述良溶剂2为二氧六环；
优选地，所述挥发析晶的温度为50-80℃，例如60℃。
根据本发明的实施方案，所述的芬戈莫德双羟萘酸盐的晶型为芬戈莫德双羟萘酸盐晶型F。
根据本发明的实施方案，所述的芬戈莫德双羟萘酸盐晶型F的X射线粉末衍射图在2θ值为3.7°±0.2°、18.0°±0.2°、21.9°±0.2°等处有特征峰。
进一步地，所述的芬戈莫德双羟萘酸盐晶型F的X射线粉末衍射图在2θ值为3.7°±0.2°、9.2°±0.2°、16.4°±0.2°、17.0°±0.2°、18.0°±0.2°、19.7°±0.2°、20.1°±0.2°、21.9°±0.2°等处有特征峰。
更进一步地，所述的芬戈莫德双羟萘酸盐晶型F的X射线粉末衍射图在2θ值为3.7°±0.2°、8.0±0.2°、9.2°±0.2°、11.3°±0.2°、16.4°±0.2°、17.0°±0.2°、18.0°±0.2°、18.8°±0.2°、19.7°±0.2°、20.1°±0.2°、21.9°±0.2°等处有特征峰。
根据本发明的实施方案，所述的芬戈莫德双羟萘酸盐晶型F的X射线粉末衍射图基本如图13所示。
根据本发明的一种实施方案，所述的芬戈莫德双羟萘酸盐晶型F具有如表8所示的X射线粉末衍射谱图。
根据本发明的实施方案，所述的芬戈莫德双羟萘酸盐晶型F的制备方法如下：
将芬戈莫德双羟萘酸盐晶型B在溶剂3中形成浆液，搅拌析晶，得到所述的芬戈莫德双羟萘酸盐晶型F；
所述溶剂3为正庚烷、乙酸异丙酯或其混合溶剂。
优选地，所述搅拌析晶的温度为50-80℃，例如60℃。
根据本发明的实施方案，所述的芬戈莫德双羟萘酸盐的晶型为芬戈莫德双羟萘酸盐 晶型G。
根据本发明的实施方案，所述的芬戈莫德双羟萘酸盐晶型G的X射线粉末衍射图在2θ值为3.6°±0.2°、7.2°±0.2°、19.9°±0.2°等处有特征峰。
进一步地，所述的芬戈莫德双羟萘酸盐晶型G的X射线粉末衍射图在2θ值为3.6°±0.2°、7.2°±0.2°、18.1°±0.2°、18.4°±0.2°、19.9°±0.2°、21.8°±0.2°、22.6°±0.2°、25.1°±0.2°等处有特征峰。
更进一步地，根据本发明的实施方案，所述的芬戈莫德双羟萘酸盐晶型G的X射线粉末衍射图在2θ值为3.6°±0.2°、7.2°±0.2°、9.0±0.2°、9.5°±0.2°、10.0°±0.2°、11.2°±0.2°、11.6°±0.2°、11.8°±0.2°、12.1°±0.2°、13.1°±0.2°、13.5°±0.2°、15.1°±0.2°、17.0°±0.2°、18.1°±0.2°、18.4°±0.2°、18.9°±0.2°、19.1°±0.2°、19.9°±0.2°、20.5°±0.2°、20.9°±0.2°、21.8°±0.2°、22.6°±0.2°、23.2°±0.2°、23.9°±0.2°、24.7°±0.2°、25.1°±0.2°、27.6°±0.2°、28.1°±0.2°等处有特征峰。
根据本发明的实施方案，所述的芬戈莫德双羟萘酸盐晶型G的X射线粉末衍射图基本如图14所示。
根据本发明的一种实施方案，所述的芬戈莫德双羟萘酸盐晶型G具有如表9所示的X射线粉末衍射谱图。
根据本发明的实施方案，所述的芬戈莫德双羟萘酸盐晶型G的制备方法如下：
将芬戈莫德双羟萘酸盐晶型B在溶剂5中形成浆液，搅拌析晶，得到所述的芬戈莫德双羟萘酸盐晶型G；
所述溶剂5为N,N-二甲基甲酰胺和水的混合溶剂。
根据本发明的实施方案，所述搅拌析晶的温度为50-80℃，例如60℃。
根据本发明的实施方案，所述的芬戈莫德双羟萘酸盐的晶型为芬戈莫德双羟萘酸盐晶型H。
根据本发明的实施方案，所述的芬戈莫德双羟萘酸盐晶型H的X射线粉末衍射图在2θ值为3.3°±0.2°、10.1°±0.2°、17.2°±0.2°等处有特征峰。
进一步地，所述的芬戈莫德双羟萘酸盐晶型H的X射线粉末衍射图在2θ值为3.3°±0.2°、6.7°±0.2°、10.1°±0.2°、13.7°±0.2°、17.2°±0.2°、20.3°±0.2°、20.6°±0.2°等处有特征峰。
更进一步地，所述的芬戈莫德双羟萘酸盐晶型H的X射线粉末衍射图在2θ值为3.3°±0.2°、5.0°±0.2°、6.7±0.2°、7.3°±0.2°、10.1°±0.2°、13.7°±0.2°、17.2°±0.2°、18.8°±0.2°、20.3°±0.2°、20.6°±0.2°、21.8°±0.2°、22.2°±0.2°、23.7°±0.2°、27.7°±0.2°等处有特征峰。
根据本发明的实施方案，所述的芬戈莫德双羟萘酸盐晶型H的X射线粉末衍射图基本如图15所示。
根据本发明的一种实施方案，所述的芬戈莫德双羟萘酸盐晶型H具有如表10所示的X射线粉末衍射谱图。
根据本发明的实施方案，所述的芬戈莫德双羟萘酸盐晶型H的制备方法如下：
将芬戈莫德双羟萘酸盐晶型B溶解于良溶剂3中，逐渐加入反溶剂，搅拌析晶，得到所述的芬戈莫德双羟萘酸盐晶型H。
所述良溶剂3为乙醇、异丙醇、二氧六环和二甲基亚砜中的一种或两种以上，优选为乙醇；
所述反溶剂为水。
根据本发明的实施方案，所述的芬戈莫德双羟萘酸盐的晶型为芬戈莫德双羟萘酸盐晶型K。
根据本发明的实施方案，所述的芬戈莫德双羟萘酸盐晶型K的X射线粉末衍射图在2θ值为3.4°±0.2°、6.7°±0.2°、7.3°±0.2°、10.2°±0.2°、10.5°±0.2°、17.0°±0.2°、18.9°±0.2°、20.4°±0.2°等处有特征峰。
更进一步地，所述的芬戈莫德双羟萘酸盐晶型K的X射线粉末衍射图在2θ值为3.4°±0.2°、6.7°±0.2°、7.3±0.2°、10.2°±0.2°、10.5°±0.2°、13.1°±0.2°、13.8°±0.2°、16.3°±0.2°、17.0°±0.2°、17.4°±0.2°、17.9°±0.2°、18.2°±0.2°、18.9°±0.2°、20.4°±0.2°等处有特征峰。
更进一步地，所述的芬戈莫德双羟萘酸盐晶型K的X射线粉末衍射图基本如图16所示。
根据本发明的一种实施方案，所述的芬戈莫德双羟萘酸盐晶型K具有如表11所示的X射线粉末衍射谱图。
根据本发明的实施方案，所述的芬戈莫德双羟萘酸盐晶型K的制备方法如下：
将芬戈莫德游离碱溶解于溶剂6中，加入双羟萘酸，搅拌反应，得到所述的芬戈莫德双羟萘酸盐晶型K；
所述溶剂6为乙酸烷基酯，例如所述烷基为C1～C5烷基；例如，所述溶剂6为乙酸乙酯、乙酸异丙酯、乙酸正丁酯中的一种或多种，优选为乙酸正丁酯。
根据本发明的实施方案，所述的芬戈莫德1-羟基-2-萘甲酸盐的晶型为芬戈莫德1-羟基-2-萘甲酸盐晶型1。
根据本发明的实施方案，所述的芬戈莫德1-羟基-2-萘甲酸盐晶型1的X射线粉末衍射图在2θ值为3.2°±0.2°、12.9°±0.2°、19.4°±0.2°等处有特征峰。
进一步地，所述的芬戈莫德1-羟基-2-萘甲酸盐晶型1的X射线粉末衍射图在2θ值为3.2°±0.2°、9.6°±0.2°、12.9°±0.2°、16.1°±0.2°、19.4°±0.2°、25.9°±0.2°等处有特征峰。
进一步地，所述的芬戈莫德1-羟基-2-萘甲酸盐晶型1的X射线粉末衍射图在2θ值为3.2°±0.2°、9.6°±0.2°、12.9°±0.2°、16.1°±0.2°、19.4°±0.2°、25.9°±0.2°、29.3°±0.2°、36.0°±0.2°等处有特征峰。
更进一步地，所述的芬戈莫德1-羟基-2-萘甲酸盐晶型1的X射线粉末衍射图在2θ值为3.2°±0.2°、6.4°±0.2°、9.6±0.2°、12.9°±0.2°、13.9°±0.2°、14.4°±0.2°、15.7°±0.2°、16.1°±0.2°、16.5°±0.2°、17.4°±0.2°、18.3°±0.2°、19.4°±0.2°、20.0°±0.2°、21.0°±0.2°、21.6°±0.2°、22.4°±0.2°、23.5°±0.2°、24.1°±0.2°、25.1°±0.2°、25.9°±0.2°、29.3°±0.2°、30.3°±0.2°、32.6°±0.2°、36.0°±0.2° 等处有吸收峰。
根据本发明的实施方案，所述的芬戈莫德1-羟基-2-萘甲酸盐晶型1的X射线粉末衍射图基本如图17所示。
根据本发明的一种实施方案，所述的芬戈莫德1-羟基-2-萘甲酸盐晶型1具有如表12所示的X射线粉末衍射谱图。
根据本发明的实施方案，所述的芬戈莫德1-羟基-2-萘甲酸盐晶型1的差式扫描量热分析图基本如图18所示；在一种实施方式中，所述芬戈莫德1-羟基-2-萘甲酸盐晶型1在125℃和144℃处有吸热峰。
根据本发明的实施方案，所述的芬戈莫德1-羟基-2-萘甲酸晶型1的热重分析图基本如图19所示。在一种实施方式中，所述芬戈莫德1-羟基-2-萘甲酸晶型1在120±5℃之前无失重。
根据本发明的实施方案，所述芬戈莫德1-羟基-2-萘甲酸晶型1为无水物。
根据本发明的实施方案，所述的芬戈莫德1-羟基-2-萘甲酸晶型1的核磁图基本如图20所示。
根据本发明的实施方案，所述芬戈莫德1-羟基-2-萘甲酸晶型1，芬戈莫德与1-羟基-2-萘甲酸的摩尔比为1:1。
根据本发明的实施方案，所述的芬戈莫德1-羟基-2-萘甲酸盐晶型1的制备方法如下：
将芬戈莫德与1-羟基-2-萘甲酸分别溶于溶剂7中，搅拌反应，得到所述的芬戈莫德1-羟基-2-萘甲酸盐晶型1；
所述溶剂7为乙酸烷基酯，例如所述烷基为C1～C5烷基，优选所述溶剂7为乙酸乙酯、乙酸异丙酯、乙酸正丁酯、乙酸异丁酯中的一种或两种以上，优选为乙酸乙酯；
优选地，所述搅拌反应的温度为25～80℃，优选为40～60℃，更优选为60℃。
优选地，所述搅拌反应是指将芬戈莫德溶液滴加至1-羟基-2-萘甲酸溶液中或将1-羟基-2-萘甲酸溶液滴加至芬戈莫德溶液。
本发明还提供了一种药物组合物，其包括所述的芬戈莫德的盐和/或盐的晶型，以及药学上可接受的辅料。
本发明中，所述的药物组合物包括但不限于片剂、胶囊、溶液剂、混悬剂、(长效)注射剂和半固体制剂，目的是促进化合物(即活性成分)向诸如人或其他哺乳动物的生物体的给药；优选为注射剂，更优选为长效注射剂。
根据本发明的实施方案，所述芬戈莫德的盐和/或盐的晶型的浓度不低于15mg/mL。
本发明中，所述的药学上可接受的辅料包括生理或药学上可接受的载体、稀释剂、媒介物和/或赋形剂中的一种或多种。
根据本发明的实施方案，所述药学上可接受的辅料还可以选自助悬剂、润湿剂、渗透压调节剂、溶剂、稳定剂、缓冲剂和表面活性剂中的一种或多种。
根据本发明的实施方案，所述助悬剂的浓度范围为0～75mg/mL，优选为10mg/ mL～75mg/mL，如30mg/mL、40mg/mL、50mg/mL或75mg/mL。
根据本发明的实施方案，所述助悬剂选自羧甲基纤维素钠、甲基纤维素、聚乙二醇4000和聚乙烯吡咯烷酮中的一种或多种，优选为聚乙二醇4000。
根据本发明的实施方案，所述润湿剂的浓度范围为1mg/mL～10mg/mL，优选为1mg/mL～5mg/mL，如1mg/mL、1.5mg/mL、2.0mg/mL、2.5mg/mL、3.0mg/mL、3.5mg/mL、4.0mg/mL、4.5mg/mL或5.0mg/mL，优选为1mg/mL。
根据本发明的实施方案，所述润湿剂选自吐温20、吐温80、泊洛沙姆188中的一种或多种，优选为泊洛沙姆188。
根据本发明的实施方案，所述缓冲剂选自磷酸、磷酸盐、枸橼酸、枸橼酸钠、盐酸和氢氧化钠中的一种或多种。
根据本发明的实施方案，所述溶剂为水，例如注射用水。
作为实例，所述药物组合物可以包括：
(a)芬戈莫德1-羟基-2-萘甲酸盐或其晶型，例如为芬戈莫德1-羟基-2-萘甲酸盐晶型1；
(b)聚乙二醇4000；
(c)泊洛沙姆；
(d)磷酸氢二钠；
(e)磷酸二氢钠；
(f)注射用水；
并且，可选地，所述药物组合物可以包含氢氧化钠或盐酸。
本发明还提供给你所述药物组合物的制备方法，包括下述步骤：
(1)将润湿剂、缓冲剂和助悬剂，溶解于溶剂中；
(2)往过筛后的芬戈莫德固体粒子加入适量溶剂，充分润湿，分散；
(3)用溶剂定容至目标体积，得到混悬液；
所述溶剂为水，例如注射用水。
根据本发明的实施方案，所述芬戈莫德固体粒子可以选自芬戈莫德、芬戈莫德药学上可接受的盐或其盐的晶型。
根据本发明的实施方案，所述芬戈莫德固体粒子包括但不限于芬戈莫德双羟萘酸盐或其晶型、芬戈莫德1-羟基-2-萘甲酸盐或其晶型。
根据本发明的实施方案，步骤(1)中，可将润湿剂、缓冲剂和助悬剂依次溶解于溶剂中，例如溶解于注射用水中。
根据本发明的实施方案，步骤(2)中，可将芬戈莫德固体粒子过筛，例如过400目筛。
本发明还提供了所述的芬戈莫德药用盐在制备治疗和/或预防多发性硬化症的药物中的应用。
本发明还提供了一种治疗和/或预防多发性硬化症的方法，其包括给施用者使用所述 的药物组合物或药物。
本发明还提供了所述的物组合物在制备治疗和/或预防多发性硬化症的药物中的应用。
除非另有说明，在本发明说明书和权利要求书中出现的以下术语具有下述含义：
本发明中，所述的术语“药学上可接受的”、“载体”、“稀释剂”、“媒介物”或“赋形剂”指这样的一种物质(或多种物质)，其可与特定药剂(活性成分)一起被包含从而形成药物组合物，并且可以是固体或液体。所述的固体载体包括但不限于淀粉、硫酸钙二水合物、石膏粉、滑石粉、乳糖、蔗糖、云母、明胶、琼脂、果胶、阿拉伯胶、硬脂酸镁、硬脂酸等。所述的液体载体包括但不限于糖浆、花生油、橄榄油、盐水溶液和水等。所述的载体或稀释剂可包括本领域已知的延时或定时释放材料，如单独或与蜡、乙基纤维素、羟丙甲纤维素、甲基丙烯酸甲酯等一起的单硬脂酸甘油酯或二硬脂酸甘油酯。
本发明中，所述的术语“溶剂合物”包含药物和化学计量或非化学计量量的一种或多种溶剂分子(如乙醇)的分子复合物。当溶剂与药物紧密结合时，所得的复合物会具有与湿度无关的明确限定的化学计量。然而，当溶剂与药物弱结合时，与在通道溶剂合物(channelsolvate)和吸湿性化合物中一样，溶剂含量会取决于湿度和干燥条件。在这样的情况下，复合物通常会是非化学计量性的。
本发明中，所述的术语“水合物”描述包含药物与化学计量或非化学计量量的水的溶剂合物。术语“相对湿度”指在指定温度下的水蒸气的量与在该温度和压力下可以保持的水蒸气的最大量的比率，以百分比表示。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明中，所述的室温是指环境温度为10℃～35℃。
本发明的有益效果：
本发明的芬戈莫德药用盐溶解度和稳定性均较好，市场化前景良好。解决了现有技术中芬戈莫德盐酸盐水溶性和稳定性均不够理想等缺陷。
含有本发明的芬戈莫德药用盐的组合物具有良好的稳定性、安全性和长的药物持续释放周期。
附图说明
图1为实施例1获得的芬戈莫德双羟萘酸盐晶型B的XRPD图谱。
图2为实施例1获得的芬戈莫德双羟萘酸盐晶型B的TGA图谱。
图3为实施例1获得的芬戈莫德双羟萘酸盐晶型B的 1H-NMR图谱。
图4为实施例3获得的芬戈莫德双羟萘酸盐晶型A的XRPD图谱。
图5为实施例3获得的芬戈莫德双羟萘酸盐晶型A的DSC图谱。
图6为实施例3获得的芬戈莫德双羟萘酸盐晶型A的TGA图谱。
图7为实施例3获得的芬戈莫德双羟萘酸盐晶型A的 1H-NMR图谱。
图8为实施例4获得的芬戈莫德双羟萘酸盐晶型I的XRPD图谱。
图9为实施例5获得的芬戈莫德双羟萘酸盐晶型J的XRPD图谱。
图10为实施例6获得的芬戈莫德双羟萘酸盐晶型C的XRPD图谱。
图11为实施例7获得的芬戈莫德双羟萘酸盐晶型D的XRPD图谱。
图12为实施例8获得的芬戈莫德双羟萘酸盐晶型E的XRPD图谱。
图13为实施例9获得的芬戈莫德双羟萘酸盐晶型F的XRPD图谱。
图14为实施例10获得的芬戈莫德双羟萘酸盐晶型G的XRPD图谱。
图15为实施例11获得的芬戈莫德双羟萘酸盐晶型H的XRPD图谱。
图16为实施例13获得的芬戈莫德双羟萘酸盐晶型K的XRPD图谱。
图17为实施例14获得的芬戈莫德1-羟基2-萘甲酸盐晶型1的XRPD图谱。
图18为实施例14获得的芬戈莫德1-羟基2-萘甲酸盐晶型1的DSC图谱。
图19为实施例14获得的芬戈莫德1-羟基2-萘甲酸盐晶型1的TGA图谱。
图20为实施例14获得的芬戈莫德1-羟基2-萘甲酸盐晶型1的 1H-NMR图谱。
图21为实施例21口服处方样品的平均血药浓度与时间的关系图。
图22为实施例21混悬剂处方样品的平均血药浓度与时间的关系图。
具体实施方式
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。
下述实施例中涉及的表征与测试：
分别采用核磁共振( 1H-NMR)对实施例的盐型化合物进行测试，测试参数如下：
1H-NMR测试在布鲁克型号为Bruker Advance III 500M核磁共振谱仪中进行，测量频率为400Mz，使用溶剂为氘代DMSO。
X射线粉末衍射仪(XRPD)
XRPD测量是在布鲁克型号为D8Advance X-射线粉末衍射仪中进行，并使用圆形零背景的单晶硅样品台。扫描参数如下：电压40kv，电流40mA，扫描范围3°～45°，扫描步长0.02°，扫描模式为连续扫描
差示扫描量热分析(DSC)
DSC测量在TA Instruments型号为Q2000的密封盘装置进行，将样品(约1～2mg)在铝盘中称量，转移至仪器中进行测量。测试参数如下：仪器在30℃平衡，以10℃/min的速率升温，实验气氛为氮气。
热重分析(TGA)
TGA测量在TA Instruments型号为Q2000装置中进行，将样品(约2～5mg)在铂金盘中称量，转移至仪器中进行测量。测试参数如下：仪器以10℃/min的速率升温，实验气氛为氮气。
HPLC检测有关物质的方法
Figure PCTCN2022095013-appb-000003
实施例1芬戈莫德双羟萘酸盐晶型B的制备
步骤1：取292mg氢氧化钾，加入5mL水，得到氢氧化钾溶液。
步骤2：取78mg双羟萘酸，加入1mL水，搅拌分散，加入0.4mL氢氧化钾溶液，搅拌，过滤，得双羟萘酸溶液。
步骤3：取68mg芬戈莫德盐酸盐，加入1mL水，搅拌溶清，加入0.6mL步骤2得到的双羟萘酸溶液，搅拌反应，补加7mL水，搅拌30分钟，补加0.2mL步骤2得到的双羟萘酸溶液，继续反应30分钟，过滤，得到芬戈莫德双羟萘酸盐，经XRPD检测为芬戈莫德双羟萘酸盐晶型B。
芬戈莫德双羟萘酸盐晶型B的XRPD图谱如图1所示；
芬戈莫德双羟萘酸盐晶型B的XRPD解析如表1所示：
表1
2θ/° 相对强度I/％
3.262 100
7.103 1.8
9.829 4.5
11.241 0.8
11.8 4.6
12.59 2.7
13.519 3.7
14.327 6
14.7 1.4
15.489 1.7
16.123 1.5
16.732 2.9
17.128 9.9
17.741 6.6
18.67 6.8
19.064 7.7
19.614 6
19.971 5
20.621 6.5
21.825 16.1
22.615 5.3
23.385 7.2
23.838 2.8
25.217 2.1
26.482 2.6
27.512 2.7
30.118 2
芬戈莫德双羟萘酸盐晶型B的TGA图谱如图2所示；
芬戈莫德双羟萘酸盐晶型B的 1H-NMR图谱如图3所示， 1H-NMR(400MHz,DMSO-d6)：δ8.21-8.16(t,2H)，7.83(s,3H)，7.62(d,2H)，7.10(m,5H)，6.99(m,1H)，5.46(s,2H)，4.67(s,1H)，3.55(s,4H)，2.56(m,2H)，1.79(m,2H)，1.52(m,2H)，1.24(d,10H)，0.86-0.83(t,3H)，显示芬戈莫德游离碱与双羟萘酸的摩尔比约为1:0.5。
实施例2芬戈莫德双羟萘酸盐晶型B的制备
步骤1：取5.84g氢氧化钾，加入100mL水，得到氢氧化钾溶液。
步骤2：取15.6g双羟萘酸，加入200mL水，搅拌分散，加入80mL氢氧化钾溶液，搅拌，过滤，得双羟萘酸溶液。
步骤3：取13.6g芬戈莫德盐酸盐，加入200mL水，搅拌溶清，加入120mL步骤2 得到的双羟萘酸溶液，搅拌反应，补加1400mL水，搅拌30分钟，补加40mL步骤2得到的双羟萘酸溶液，继续反应30分钟，过滤，得到芬戈莫德双羟萘酸盐，经XRPD检测为芬戈莫德双羟萘酸盐晶型B。
实施例3芬戈莫德双羟萘酸盐晶型A的制备
取10g实施例2制备的芬戈莫德双羟萘酸盐晶型B，40℃真空干燥过夜，得到芬戈莫德双羟萘酸盐晶型A。
芬戈莫德双羟萘酸盐晶型A的XRPD图谱如图4所示；
芬戈莫德双羟萘酸盐晶型A的XRPD解析如表2所示：
表2
2θ/° 相对强度I/％
3.158 100
9.197 1.3
9.55 2.9
10.754 0.7
11.604 1.6
12.492 1.9
13.104 1.7
14.84 1.8
15.136 1.1
16.302 1.3
17.957 2.8
18.489 3
19.339 4.8
20.424 7
21.61 1.4
22.064 1
22.594 0.5
24.253 2
25.182 1.2
芬戈莫德双羟萘酸盐晶型A的DSC图谱如图5所示；
芬戈莫德双羟萘酸盐晶型A的TGA图谱如图6所示；
芬戈莫德双羟萘酸盐晶型A的1H-NMR图谱如图7所示，显示芬戈莫德游离碱与双羟萘酸的摩尔比约为1:0.5。
实施例4芬戈莫德双羟萘酸盐晶型I的制备：
步骤1：称取1192.23mg氢氧化钾，加入20mL水溶解，得到浓度约为1.062mmol/mL的氢氧化钾水溶液。
步骤2：称取3124mg双羟萘酸，加入20mL水，搅拌分散，加入16.725mL氢氧化钾水溶液，搅拌1h，过滤取滤液，得到双羟萘酸钾溶液。
步骤3：盐酸芬戈莫德溶液制备：称取2721mg盐酸芬戈莫德，加入60mL水，搅拌，基本溶清，过滤取滤液。
步骤4：搅拌状态下将20.990mL双羟萘酸钾溶液缓缓加入盐酸芬戈莫德溶液中，室温搅拌过夜，抽滤回收，35℃真空干燥2天，得到半双羟萘酸盐，经XRPD检测为芬戈莫德双羟萘酸盐晶型I。
芬戈莫德双羟萘酸盐晶型I的XRPD图谱如图8所示。
芬戈莫德双羟萘酸盐晶型I的XRPD解析如表3所示：
表3
2θ/° 相对强度I/％
2.953 100
3.348 14.2
5.598 1.7
5.915 1.5
6.919 1.3
8.913 6.1
9.821 1.7
14.995 1.2
16.175 1.2
17.991 2.5
18.838 1.9
19.118 1.6
19.589 5.8
19.925 9.7
20.994 1.5
21.803 1.7
25.174 2.4
实施例5芬戈莫德双羟萘酸盐晶型J的制备
取实施例4制备得到的芬戈莫德双羟萘酸盐晶型I样品，室温干燥放置10天，得到芬戈莫德双羟萘酸盐晶型J。
芬戈莫德双羟萘酸盐晶型J的XRPD图谱如图9所示。
芬戈莫德双羟萘酸盐晶型J的XRPD解析如表4所示：
表4
Figure PCTCN2022095013-appb-000004
Figure PCTCN2022095013-appb-000005
实施例6芬戈莫德双羟萘酸盐晶型C的制备
取210mg实施例5制备的芬戈莫德双羟萘酸盐晶型J样品，加入3.5mL正庚烷和3.5mL乙酸乙酯，60℃搅拌7天，离心，40℃真空干燥4小时，得到芬戈莫德双羟萘酸盐晶型C。
芬戈莫德双羟萘酸盐晶型C的XRPD图谱如图10所示。
芬戈莫德双羟萘酸盐晶型C的XRPD解析如表5所示：
表5
Figure PCTCN2022095013-appb-000006
Figure PCTCN2022095013-appb-000007
实施例7芬戈莫德双羟萘酸盐晶型D的制备
取25mg实施例3制备的芬戈莫德双羟萘酸盐晶型B样品，加入0.3mL乙醇和0.1mL水，室温挥发，得到芬戈莫德双羟萘酸盐晶型D。
芬戈莫德双羟萘酸盐晶型D的XRPD图谱如图11所示。
芬戈莫德双羟萘酸盐晶型D的XRPD解析如表6所示：
表6
Figure PCTCN2022095013-appb-000008
Figure PCTCN2022095013-appb-000009
实施例8芬戈莫德双羟萘酸盐晶型E的制备
取25mg实施例3制备的芬戈莫德双羟萘酸盐晶型B样品，加入0.2mL 1,4-二氧六环，60℃挥发，得到芬戈莫双羟萘酸酸盐晶型E。
芬戈莫德双羟萘酸盐晶型E的XRPD图谱如图12所示。
芬戈莫德双羟萘酸盐晶型E的XRPD解析如表7所示：
表7
Figure PCTCN2022095013-appb-000010
Figure PCTCN2022095013-appb-000011
实施例9芬戈莫德双羟萘酸盐晶型F的制备
取30mg实施例3制备的芬戈莫德双羟萘酸盐晶型B样品，加入0.5mL正庚烷和0.5mL乙酸异丙酯形成浆液，60℃搅拌7天，得到芬戈莫德双羟萘酸盐晶型F。
芬戈莫德双羟萘酸盐晶型F的XRPD图谱如图13所示。
芬戈莫德双羟萘酸盐晶型F的XRPD解析如表8所示：
表8
2θ/° 相对强度I/％
3.709 100
8.03 1.8
9.176 2.6
11.307 1.9
16.379 2.1
17.046 2.1
18.016 3.7
18.829 1.2
19.696 2.8
20.05 2.1
21.885 3.9
。
实施例10芬戈莫德双羟萘酸盐晶型G的制备
取30mg实施例3制备的芬戈莫德双羟萘酸盐晶型B样品，加入0.1mLN,N-二甲基甲酰胺和1mL水形成浆液，60℃搅拌7天，得到芬戈莫德双羟萘酸盐晶型G。
芬戈莫德双羟萘酸盐晶型G的XRPD图谱如图14所示。
芬戈莫德双羟萘酸盐晶型G的XRPD解析如表9所示：
表9
Figure PCTCN2022095013-appb-000012
Figure PCTCN2022095013-appb-000013
实施例11芬戈莫德双羟萘酸盐晶型H的制备
取100mg实施例3制备的芬戈莫德双羟萘酸盐晶型B样品，加入0.5mL乙醇溶清，缓慢加入1mL水，搅拌析晶，得到芬戈莫德双羟萘酸盐晶型H。
芬戈莫德双羟萘酸盐晶型H的XRPD图谱如图15所示。
芬戈莫德双羟萘酸盐晶型H的XRPD解析如表10所示：
表10
Figure PCTCN2022095013-appb-000014
Figure PCTCN2022095013-appb-000015
实施例12芬戈莫德游离碱的制备
取12.6g盐酸芬戈莫德，加入480mL水，搅拌溶清，缓慢滴加氨水，调pH至9～10，继续搅拌1小时，过滤，室温真空干燥3小时，得到11.1g芬戈莫德游离碱。
实施例13芬戈莫德双羟萘酸盐晶型K的制备
取1000mg实施例12制备的芬戈莫德游离碱，加入50mL乙酸正丁酯，60℃搅拌溶清，加入530mg双羟萘酸，搅拌反应4小时，降至室温，搅拌过夜，过滤，40℃真空干燥过夜，得到芬戈莫德双羟萘酸盐晶型K。
芬戈莫德双羟萘酸盐晶型K的XRPD图谱如图16所示。
芬戈莫德双羟萘酸盐晶型K的XRPD解析如表11所示：
表11
2θ/° 相对强度I/％
3.393 100
6.693 0.2
7.284 0.4
10.161 1
10.501 0.2
13.142 0.1
13.798 0.1
16.279 0.1
16.989 0.2
17.425 0.1
17.858 0.1
18.219 0.1
18.942 0.4
20.403 0.5
。
实施例14芬戈莫德1-羟基-2-萘甲酸盐晶型1的制备
步骤1：称取5500mg 1-羟基-2-萘甲酸，加入75mL乙酸乙酯，水浴60℃搅拌溶解，过滤，取滤液。
步骤2：取7230mg实施例12的芬戈莫德游离碱，加入250mL乙酸乙酯，水浴60℃溶解。
步骤3：60℃搅拌状态下将1-羟基-2-萘甲酸溶液缓慢滴加入芬戈莫德溶液中，加入17mL乙酸乙酯冲洗，室温搅拌过夜，过滤，用85mL乙酸乙酯洗涤滤饼，35℃真空过夜干燥，得到芬戈莫德1-羟基-2-萘甲酸盐，经XRPD测试为芬戈莫德1-羟基-2-萘甲酸盐晶型1。
芬戈莫德1-羟基-2-萘甲酸盐晶型1的XRPD图谱如图17所示；
芬戈莫德1-羟基-2-萘甲酸盐晶型1的XRPD解析如表12所示：
表12
Figure PCTCN2022095013-appb-000016
Figure PCTCN2022095013-appb-000017
芬戈莫德1-羟基-2-萘甲酸盐晶型1的DSC图谱如图18所示；
芬戈莫德1-羟基-2-萘甲酸盐晶型1的TGA图谱如图19所示；
芬戈莫德1-羟基-2-萘甲酸盐晶型1的1H-NMR图谱如图20所示，显示芬戈莫德与1-羟基-2-萘甲酸以1:1成盐。
实施例15芬戈莫德1-羟基-2-萘甲酸盐晶型1的处方制备
表13
Figure PCTCN2022095013-appb-000018
制备过程：
(1)称取如表13所示的处方量泊洛沙姆188、羧甲基纤维素钠，聚乙二醇4000，磷酸氢二钠、磷酸二氢钠与约60％配制总量的注射用水中，搅拌溶解分散；
(2)加入如表13所示的处方量的过400目筛的芬戈莫德1-羟基-2-萘甲酸盐晶型1，充分润湿、分散；
(3)用注射用水定容至10mL，摇匀，即得芬戈莫德1-羟基-2-萘甲酸盐晶型1混悬液。
取处方1～3所得的处方样品，进行通针性和沉降比考察，发现处方2得到的处方样品通针性和沉降比良好。
实施例16芬戈莫德1-羟基-2-萘甲酸盐晶型1的处方制备
如表14所示，将实施例15处方3中的聚乙二醇4000用量分别调整为200mg、300mg、400mg、500mg和600mg，再进行处方配制，得到的处方4、5、6、7和8。取处方4～8样品进行通针性和沉降比考察，发现所得处方样品通针性和沉降比良好。
表14
Figure PCTCN2022095013-appb-000019
Figure PCTCN2022095013-appb-000020
实施例17盐酸芬戈莫德的口服处方样品的制备
取3.676mg盐酸芬戈莫德，用注射用水溶解、稀释、定容至100mL，得到盐酸芬戈莫德口服处方样品。
实施例18芬戈莫德1-羟基-2-萘甲酸盐晶型1处方样品的制备
(1)称取10mg泊洛沙姆188、750mg聚乙二醇4000、45mg磷酸氢二钠、9mg磷酸二氢钠与约6mL注射用水中，搅拌溶解分散；
(2)加入242.3mg过400目筛的芬戈莫德1-羟基-2-萘甲酸盐晶型1，充分润湿、分散；
(3)用注射用水定容至10mL，摇匀，即得芬戈莫德1-羟基-2-萘甲酸盐晶型1的混悬剂处方样品。
实施例19：固态稳定性对比
分别取实施例14制得的芬戈莫德1-羟基-2-萘甲酸盐晶型1、实施例3制得的芬戈莫德双羟萘酸盐晶型A和芬戈莫德盐酸盐于高温(60℃)，高湿(25℃/90％RH)，加速(40℃/75％RH)，光照(1.2×106Lux·hr)和长期(25℃/60％RH)条件下放置，于0天、5天、10天取样进行HPLC检测有关物质。
有关物质结果见表15，显示本发明的芬戈莫德1-羟基-2-萘甲酸盐晶型1较稳定，在各条件下放置10天，有关物质总和基本不变，而芬戈莫德双羟萘酸盐晶型A除光照条件下杂质略有增加外，其余条件下均较稳定。
表15.有关物质结果
Figure PCTCN2022095013-appb-000021
Figure PCTCN2022095013-appb-000022
实施例20：溶解度对比
分别取实施例14制得的芬戈莫德1-羟基-2-萘甲酸盐晶型1、实施例2制得的芬戈莫德双羟萘酸盐晶型B、芬戈莫德盐酸盐和实施例12制得的芬戈莫德游离碱，将其分别加入到下述相应介质中，在37℃条件下振荡24小时，0.45μm水相滤膜过滤，收集滤液，采用高效液相进行溶解度测定。其中，相应介质为：pH3和pH5为醋酸缓冲溶液、pH7和pH9为磷酸缓冲溶液，水为超纯水。
结果见表16，显示芬戈莫德游离碱和芬戈莫德盐酸盐在各介质中的溶解度相差较大，且芬戈莫德盐酸盐在高pH介质下会解离成芬戈莫德游离碱；而本发明制得的芬戈莫德1-羟基-2-萘甲酸盐、双羟萘酸盐及二者的晶型的溶解度在水中和低pH(pH不超过5)条件下均大幅降低，芬戈莫德1-羟基-2-萘甲酸盐在水中的溶解度为5.46μg/mL相当于芬戈莫德游离碱的四分之一至五分之一(约23μg/mL)，盐酸芬戈莫德的千分之一至二千六百分之一(约14mg/mL)，以及在各个pH介质中均较低，即芬戈莫德1-羟基-2-萘甲酸盐、双羟萘酸盐及二者的晶型本身就具有缓释作用，同时在各个pH介质中的溶解度相当，释放速度可以最小程度的依赖于pH，从而避免在体内不同区域的pH环境中对其释药速率的影响，避免造成突释现象或体内局部区域血药浓度过高，以及降低个体间释药差异性，，适合用于长效制剂，可减少用药次数，提高患者用药依从性，市场化前景良好。
表16.溶解度结果
Figure PCTCN2022095013-appb-000023
Figure PCTCN2022095013-appb-000024
实施例21处方稳定性对比
取实施例15制得的处方3样品，于高温(60℃)，加速(40℃/75％RH)，和长期(25℃/60％RH)条件下放置，于0天、5天、10天取样进行HPLC检测。
结果见表17，其显示本发明制得的处方样品在各条件下较稳定，放置10天后有关物质总和未发生明显变化。
表17.处方稳定性结果
Figure PCTCN2022095013-appb-000025
实施例18制备的处方样品具有与实施例15处方样品相同的稳定性。
实施例21：药代动力学实验
6只雄性SD大鼠分为两组，其中一组单剂量3mg/kg经肌肉注射给予芬戈莫德1-羟基-2-萘甲酸盐晶型处方样品(实施例18)，并于给药后0,1h,3h,7h,24h,4d,7d,11d,15d,20d,25d,30d,35d采集血浆；另一组单剂量0.1mg/kg经口服灌胃给予芬戈莫德盐酸盐样品(实施例17)，并于给药后5min,15min,30min,1,2,3,4,6,8,12和24小时，采集血浆。整个试验中，肌肉注射组动物自由饮食饮水，口服灌胃组给药前禁食过夜，给药后4小时恢复饮食。
血浆样品采集：颈静脉采血约150μL(全血在30分钟内离心分离血浆)置于内含抗凝剂EDTA-K2的试管内，经处理后血浆保存于-70℃冰箱待用。
血浆样品预处理：取30μL血浆样品中加入200μL内标溶液(40ng/mL Glipizide乙腈溶液)，涡旋混合1min，在4℃下以5800rpm离心10min，取100μL上清液转移至新板，后取5μL溶液进行LC-MS/MS分析。动物体内芬戈莫德的药代动力学参数见表18～表19，药时曲线见图21～图22。
结果显示：芬戈莫德口服处方组在给药后12小时达到血药浓度峰值，24小时内能维持血药浓度0.3ng/ml以上，MRT仅12h。芬戈莫德1-羟基-2-萘甲酸盐注射组给药后3小时即可达到血药浓度峰值，1天内能达到相对稳定的血药浓度，至少15天血药浓度维持在0.3ng/ml以上，MRT长达12天，表明该制剂起效快，药物持续释放周期长；Cmax未与剂量成正比增长，离中毒浓度还有较大安全距离，说明安全性较高。
表18.肌肉注射组药代动力学参数表
PK parameters Unit Rat#1 Rat#2 Rat#3 Mean SD CV(％)
T max day 0.0420 0.0420 0.292 0.125 0.144 115
C max ng/mL 4.36 2.45 2.93 3.25 0.994 30.6
T 1/2 day 9.75 11.8 17.5 13.0 4.00 30.7
AUC last day*ng/mL 19.8 14.9 17.7 17.5 2.46 14.0
AUC INF day*ng/mL 23.9 16.7 28.1 22.9 5.80 25.3
MRT INF day 17.3 17.4 29.7 21.5 7.12 33.2
MRT last day 10.8 13.4 11.8 12.0 1.30 10.8
表19.口服组药代动力学参数表
PK parameters Unit Rat#4 Rat#5 Rat#6 Mean SD CV(％)
T max hr 12.0 12.0 12.0 12.0 0.00 0.00
C max ng/mL 0.564 0.728 0.728 0.673 0.0947 14.1
T 1/2 hr NA NA NA NA NA NA
AUC last hr*ng/mL 11.0 12.0 11.9 11.6 0.576 4.95
AUC INF hr*ng/mL NA NA NA NA NA NA
MRT INF hr NA NA NA NA NA NA
MRT last hr 12.2 13.2 12.0 12.5 0.649 5.21

Claims (10)

  1. 一种式I所示的芬戈莫德的盐：
    Figure PCTCN2022095013-appb-100001
    其中，X为六个碳以上的有机酸或含有羟基的酯，n为0.5～2.0；
    优选地，所述盐为药用盐。
  2. 如权利要求1所述的芬戈莫德的盐，其特征在于：所述的六个碳以上的有机酸为C6～C30的有机酸。
  3. 如权利要求1或2所述的芬戈莫德的盐，其特征在于：所述的C6～C30的有机酸包括但不限于下述物质中的一种或多种：己酸、庚酸、辛酸、壬酸、壬二酸、癸酸、癸二酸、十一烷酸、月桂酸、十三烷酸、肉豆蔻酸、十五烷酸、棕榈酸、十七烷酸、硬脂酸、十九烷酸、二十烷酸、油酸、二十一烷酸、二十二烷酸、二十三烷酸、二十四烷酸、二十五烷酸、二十六烷酸、二十七烷酸、二十八烷酸、二十九烷酸、三十烷酸、甘油酸、木质酸、双羟萘酸、1-羟基-2萘甲酸以及萘酸衍生物；
    例如，所述的萘酸衍生物包括但不限于萘酸酯。
  4. 如权利要求1-3任一项所述的芬戈莫德的盐，其特征在于：所述的芬戈莫德的盐为单相晶体、无定型或混合晶体的形式；
    例如，所述的芬戈莫德盐包括其与溶剂形成的溶剂合物；
    优选地，所述的溶剂合物包括芬戈莫德的盐的水合物和芬戈莫德的盐与有机溶剂形成的溶剂合物；
    优选地，所述的有机溶剂包括但不限于乙醇、丙酮和二甲基亚砜中的一种或多种。
  5. 如权利要求1～4任一项所述的芬戈莫德的盐的制备方法，其特征在于包括以下步骤：将芬戈莫德游离碱与所述X(例如六个碳以上的有机酸)进行中和反应，得到所述的芬戈莫德的盐。
  6. 如权利要求1～4任一项所述的芬戈莫德盐的制备方法，其特征在于包括以下步骤：将芬戈莫德游离碱在无机酸中形成溶液，将六个碳以上的有机酸在无机碱中形成溶液，再将两种溶液混合，得到所述的芬戈莫德的盐。
  7. 权利要求1～4任一项所述的芬戈莫德的盐的晶型。
    优选地，所述晶型为芬戈莫德双羟萘酸盐的晶型、芬戈莫德1-羟基2-萘甲酸盐的晶型。
    优选地，所述的芬戈莫德双羟萘酸盐的晶型为芬戈莫德双羟萘酸盐晶型B，所述的 芬戈莫德双羟萘酸盐晶型B的X射线粉末衍射图在2θ值为3.3°±0.2°、17.1°±0.2°、21.8°±0.2°处有特征峰；
    优选地，所述的芬戈莫德双羟萘酸盐晶型B的X射线粉末衍射图在2θ值为3.3°±0.2°、17.1°±0.2°、18.7°±0.2°、19.1°±0.2°、21.8°±0.2°、23.4°±0.2°处有特征峰；
    优选地，所述的芬戈莫德双羟萘酸盐晶型B的X射线粉末衍射图在2θ值为3.3°±0.2°、17.1±0.2°、17.7°±0.2°、18.7°±0.2°、19.1°±0.2°、20.6°±0.2°、21.8°±0.2°、23.4°±0.2°处有特征峰；
    优选地，所述的芬戈莫德双羟萘酸盐晶型B的X射线粉末衍射图基本如图1所示；
    优选地，所述的芬戈莫德双羟萘酸晶型B，芬戈莫德与双羟萘酸的摩尔比为1:0.5。
    优选地，所述的芬戈莫德双羟萘酸盐晶型B的制备方法如下：
    将双羟萘酸与溶剂1混合，得到双羟萘酸溶液；将芬戈莫德盐酸盐与溶剂2混合，向其中加入所述双羟萘酸溶液，搅拌反应，得到所述的芬戈莫德双羟萘酸盐晶型B；
    所述溶剂1为碱性溶液；
    所述溶剂2为水、甲醇、乙醇、异丙醇、四氢呋喃、N,N-二甲基甲酰胺、或前述至少两种溶剂的混合物，优选为水。
    优选地，所述的芬戈莫德双羟萘酸盐的晶型为芬戈莫德双羟萘酸盐晶型A，其X射线粉末衍射图在2θ值为3.2°±0.2°、19.3°±0.2°、20.4°±0.2°处有特征峰；
    优选地，所述的芬戈莫德双羟萘酸盐晶型A的X射线粉末衍射图在2θ值为3.2°±0.2°、9.6°±0.2°、12.5°±0.2°、18.5°±0.2°、19.3°±0.2°、20.4°±0.2°处有特征峰；
    优选地，所述的芬戈莫德双羟萘酸盐晶型A的X射线粉末衍射图在2θ值为3.2°±0.2°、9.6°±0.2°、12.5°±0.2°、18.0°±0.2°、18.5°±0.2°、19.3°±0.2°、20.4°±0.2°、24.3°±0.2°处有特征峰；
    优选地，所述的芬戈莫德双羟萘酸盐晶型A的X射线粉末衍射图基本如图4所示；
    优选地，所述的芬戈莫德双羟萘酸盐晶型A为无水物或隧道水合物；
    优选地，所述的芬戈莫德双羟萘酸晶型A，芬戈莫德与双羟萘酸的摩尔比1:0.5；
    优选地，所述的芬戈莫德双羟萘酸盐晶型A的制备方法如下：
    将芬戈莫德双羟萘酸盐晶型B干燥，得到芬戈莫德双羟萘酸盐晶型A。
    优选地，所述的芬戈莫德双羟萘酸盐的晶型为芬戈莫德双羟萘酸盐晶型I，其X射线粉末衍射图在2θ值为3.0°±0.2°、8.9°±0.2°、19.9°±0.2°处有特征峰；
    优选地，所述的芬戈莫德双羟萘酸盐晶型I的X射线粉末衍射图在2θ值为3.0°±0.2°、3.3°±0.2°、5.6±0.2°、5.9°±0.2°、6.9°±0.2°、8.9°±0.2°、9.8°±0.2°、15.0°±0.2°、16.2°±0.2°、18.0°±0.2°、18.8°±0.2°、19.1°±0.2°、19.6°±0.2°、19.9°±0.2°、21.0°±0.2°、 21.8°±0.2°、25.2°±0.2°处有特征峰；
    优选地，所述的芬戈莫德双羟萘酸盐晶型I的X射线粉末衍射图基本如图8所示。
    优选地，所述的芬戈莫德双羟萘酸盐的晶型为芬戈莫德双羟萘酸盐晶型J，其X射线粉末衍射图在2θ值为3.2°±0.2°、5.3°±0.2°、10.1°±0.2°、10.8°±0.2°、18.1°±0.2°、19.8°±0.2°、20.6°±0.2°、21.7°±0.2°处有特征峰；
    优选地，所述的芬戈莫德双羟萘酸盐晶型J的X射线粉末衍射图在2θ值为3.2°±0.2°、5.3°±0.2°、6.3±0.2°、9.5°±0.2°、10.1°±0.2°、10.8°±0.2°、13.5°±0.2°、17.0°±0.2°、17.8°±0.2°、18.1°±0.2°、19.8°±0.2°、20.6°±0.2°、21.7°±0.2°、22.0°±0.2°、24.5°±0.2°、25.5°±0.2°处有特征峰；
    优选地，所述的芬戈莫德双羟萘酸盐晶型J的X射线粉末衍射图基本如图9所示。
    优选地，所述的芬戈莫德双羟萘酸盐的晶型为芬戈莫德双羟萘酸盐晶型C，其X射线粉末衍射图在2θ值为3.2°±0.2°、6.4°±0.2°、19.8°±0.2°处有特征峰；
    优选地，所述的芬戈莫德双羟萘酸盐晶型C的X射线粉末衍射图在2θ值为3.2°±0.2°、6.4°±0.2°、9.6°±0.2°、15.1°±0.2°、19.8°±0.2°、20.4°±0.2°处有特征峰；
    优选地，所述的芬戈莫德双羟萘酸盐晶型C的X射线粉末衍射图在2θ值为3.2°±0.2°、6.4°±0.2°、9.6°±0.2°、13.6°±0.2°、15.1°±0.2°、15.6°±0.2°、19.8°±0.2°、20.4°±0.2°处有特征峰；
    优选地，所述的芬戈莫德双羟萘酸盐晶型C的X射线粉末衍射图基本如图10所示。
    优选地，所述的芬戈莫德双羟萘酸盐的晶型为芬戈莫德双羟萘酸盐晶型D，其X射线粉末衍射图在2θ值为3.3°±0.2°、10.1°±0.2°、20.3°±0.2°处有特征峰；
    优选地，所述的芬戈莫德双羟萘酸盐晶型D的X射线粉末衍射图在2θ值为3.3°±0.2°、6.7°±0.2°、10.1°±0.2°、16.9°±0.2°、18.8°±0.2°、20.3°±0.2°处有特征峰；
    优选地，所述的芬戈莫德双羟萘酸盐晶型D的X射线粉末衍射图在2θ值为3.3°±0.2°、6.7°±0.2°、7.2°±0.2°、10.1°±0.2°、16.9°±0.2°、18.8°±0.2°、20.3°±0.2°、23.8°±0.2°处有特征峰；
    优选地，所述的芬戈莫德双羟萘酸盐晶型D的X射线粉末衍射图基本如图11所示。
    优选地，所述的芬戈莫德双羟萘酸盐的晶型为芬戈莫德双羟萘酸盐晶型E，其X射线粉末衍射图在2θ值为3.3°±0.2°、17.3°±0.2°、19.0°±0.2°处有特征峰；
    优选地，所述的芬戈莫德双羟萘酸盐晶型E的X射线粉末衍射图在2θ值为3.3°±0.2°、9.8°±0.2°、17.3°±0.2°、17.7°±0.2°、19.0°±0.2°、21.8°±0.2°处有特征峰；
    优选地，所述的芬戈莫德双羟萘酸盐晶型E的X射线粉末衍射图在2θ值为3.3°±0.2°、9.8°±0.2°、17.3°±0.2°、17.7°±0.2°、19.0°±0.2°、19.3°±0.2°、20.0°±0.2°、21.8°±0.2°处有特征峰；
    优选地，所述的芬戈莫德双羟萘酸盐晶型E的X射线粉末衍射图基本如图12所示。
    优选地，所述的芬戈莫德双羟萘酸盐的晶型为芬戈莫德双羟萘酸盐晶型F，其X射线粉末衍射图在2θ值为3.7°±0.2°、18.0°±0.2°、21.9°±0.2°处有特征峰；
    优选地，所述的芬戈莫德双羟萘酸盐晶型F的X射线粉末衍射图在2θ值为3.7°±0.2°、9.2°±0.2°、16.4°±0.2°、17.0°±0.2°、18.0°±0.2°、19.7°±0.2°、20.1°±0.2°、21.9°±0.2°处有特征峰；
    优选地，所述的芬戈莫德双羟萘酸盐晶型F的X射线粉末衍射图在2θ值为3.7°±0.2°、8.0±0.2°、9.2°±0.2°、11.3°±0.2°、16.4°±0.2°、17.0°±0.2°、18.0°±0.2°、18.8°±0.2°、19.7°±0.2°、20.1°±0.2°、21.9°±0.2°处有特征峰；
    优选地，所述的芬戈莫德双羟萘酸盐晶型F的X射线粉末衍射图基本如图13所示。
    优选地，所述的芬戈莫德双羟萘酸盐的晶型为芬戈莫德双羟萘酸盐晶型G，其X射线粉末衍射图在2θ值为3.6°±0.2°、7.2°±0.2°、19.9°±0.2°处有特征峰；
    优选地，所述的芬戈莫德双羟萘酸盐晶型G的X射线粉末衍射图在2θ值为3.6°±0.2°、7.2°±0.2°、18.1°±0.2°、18.4°±0.2°、19.9°±0.2°、21.8°±0.2°、22.6°±0.2°、25.1°±0.2°处有特征峰；
    优选地，所述的芬戈莫德双羟萘酸盐晶型G的X射线粉末衍射图在2θ值为3.6°±0.2°、7.2°±0.2°、9.0±0.2°、9.5°±0.2°、10.0°±0.2°、11.2°±0.2°、11.6°±0.2°、11.8°±0.2°、12.1°±0.2°、13.1°±0.2°、13.5°±0.2°、15.1°±0.2°、17.0°±0.2°、18.1°±0.2°、18.4°±0.2°、18.9°±0.2°、19.1°±0.2°、19.9°±0.2°、20.5°±0.2°、20.9°±0.2°、21.8°±0.2°、22.6°±0.2°、23.2°±0.2°、23.9°±0.2°、24.7°±0.2°、25.1°±0.2°、27.6°±0.2°、28.1°±0.2°处有特征峰；
    优选地，所述的芬戈莫德双羟萘酸盐晶型G的X射线粉末衍射图基本如图14所示。
    优选地，所述的芬戈莫德双羟萘酸盐的晶型为芬戈莫德双羟萘酸盐晶型H，其X射线粉末衍射图在2θ值为3.3°±0.2°、10.1°±0.2°、17.2°±0.2°处有特征峰；
    优选地，所述的芬戈莫德双羟萘酸盐晶型H的X射线粉末衍射图在2θ值为3.3°±0.2°、6.7°±0.2°、10.1°±0.2°、13.7°±0.2°、17.2°±0.2°、20.3°±0.2°、20.6°±0.2°处有特征峰；
    优选地，所述的芬戈莫德双羟萘酸盐晶型H的X射线粉末衍射图在2θ值为3.3°±0.2°、5.0°±0.2°、6.7±0.2°、7.3°±0.2°、10.1°±0.2°、13.7°±0.2°、17.2°±0.2°、18.8°±0.2°、20.3°±0.2°、20.6°±0.2°、21.8°±0.2°、22.2°±0.2°、23.7°±0.2°、27.7°±0.2°处有特征峰；
    优选地，所述的芬戈莫德双羟萘酸盐晶型H的X射线粉末衍射图基本如图15所示。
    优选地，所述的芬戈莫德双羟萘酸盐的晶型为芬戈莫德双羟萘酸盐晶型K，其X射线粉末衍射图在2θ值为3.4°±0.2°、6.7°±0.2°、7.3°±0.2°、10.2°±0.2°、10.5°±0.2°、17.0°±0.2°、18.9°±0.2°、20.4°±0.2°处有特征峰；
    优选地，所述的芬戈莫德双羟萘酸盐晶型K的X射线粉末衍射图在2θ值为3.4°±0.2°、6.7°±0.2°、7.3±0.2°、10.2°±0.2°、10.5°±0.2°、13.1°±0.2°、13.8°±0.2°、16.3°±0.2°、17.0°±0.2°、17.4°±0.2°、17.9°±0.2°、18.2°±0.2°、18.9°±0.2°、20.4°±0.2°处有特征峰；
    优选地，所述的芬戈莫德双羟萘酸盐晶型K的X射线粉末衍射图基本如图16所示。
    优选地，所述的芬戈莫德1-羟基-2-萘甲酸盐的晶型为芬戈莫德1-羟基-2-萘甲酸盐晶型1，其X射线粉末衍射图在2θ值为3.2°±0.2°、12.9°±0.2°、19.4°±0.2°处有特征峰；
    优选地，所述的芬戈莫德1-羟基-2-萘甲酸盐晶型1的X射线粉末衍射图在2θ值为3.2°±0.2°、9.6°±0.2°、12.9°±0.2°、16.1°±0.2°、19.4°±0.2°、25.9°±0.2°处有特征峰；
    优选地，所述的芬戈莫德1-羟基-2-萘甲酸盐晶型1的X射线粉末衍射图在2θ值为3.2°±0.2°、9.6°±0.2°、12.9°±0.2°、16.1°±0.2°、19.4°±0.2°、25.9°±0.2°、29.3°±0.2°、36.0°±0.2°处有特征峰；
    优选地，所述的芬戈莫德1-羟基-2-萘甲酸盐晶型1的X射线粉末衍射图基本如图17所示；
    优选地，所述芬戈莫德1-羟基-2-萘甲酸晶型1为无水物；
    优选地，所述芬戈莫德1-羟基-2-萘甲酸晶型1，芬戈莫德与1-羟基-2-萘甲酸的摩尔比为1:1。
    优选地，所述的芬戈莫德1-羟基-2-萘甲酸盐晶型1的制备方法如下：
    将芬戈莫德与1-羟基-2-萘甲酸分别溶于溶剂7中，搅拌反应，得到所述的芬戈莫德1-羟基-2-萘甲酸盐晶型1；
    所述溶剂7为乙酸烷基酯，所述烷基为C1～C5烷基。
  8. 一种药物组合物，其特征在于，包含治疗和/或预防有效量的选自权利要求1～4任一项所述的芬戈莫德盐或权利要求7所述的晶型，以及药学上可接受的辅料。
  9. 如权利要求8所述的药物组合物，其特征在于：所述药物组合物包括但不限于片剂、胶囊、溶液剂、混悬剂、长效注射剂和半固体制剂。
  10. 如权利要求1～4任一项所述的芬戈莫德盐、权利要求7所述的晶型或权利要求8-9任一项所述的药物组合物在制备治疗和/或预防多发性硬化症的药物中的应用。
PCT/CN2022/095013 2021-05-31 2022-05-25 芬戈莫德药用盐、制备方法、含其的药物组合物及应用 Ceased WO2022253077A1 (zh)

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EP22815123.9A EP4353709A4 (en) 2021-05-31 2022-05-25 FINGOLIMOD PHARMACEUTICAL SALT, ITS PREPARATION PROCESS, PHARMACEUTICAL COMPOSITION, CONTAINER AND ASSOCIATED USES
US18/565,928 US20240262783A1 (en) 2021-05-31 2022-05-25 Pharmaceutical salt of fingolimod, preparation method, pharmaceutical composition and use thereof
JP2023574191A JP2024521882A (ja) 2021-05-31 2022-05-25 フィンゴリモド薬用塩、製造方法、それを含む医薬組成物及び使用

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