WO2022042642A1 - 卡利拉嗪药物组合物、制备方法及应用 - Google Patents

卡利拉嗪药物组合物、制备方法及应用 Download PDF

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WO2022042642A1
WO2022042642A1 PCT/CN2021/114754 CN2021114754W WO2022042642A1 WO 2022042642 A1 WO2022042642 A1 WO 2022042642A1 CN 2021114754 W CN2021114754 W CN 2021114754W WO 2022042642 A1 WO2022042642 A1 WO 2022042642A1
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cariprazine
pamoate
crystal form
pharmaceutical composition
characteristic peaks
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PCT/CN2021/114754
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English (en)
French (fr)
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应述欢
陈志祥
张贤
朱涛
王婷婷
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上海博志研新药物技术有限公司
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Priority to EP21860476.7A priority Critical patent/EP4205745A1/en
Priority to US18/043,201 priority patent/US20230414504A1/en
Priority to JP2023513714A priority patent/JP2023539298A/ja
Publication of WO2022042642A1 publication Critical patent/WO2022042642A1/zh

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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to the field of chemical medicine, in particular to a cariprazine pharmaceutical composition, a preparation method and an application.
  • Cariprazine hydrochloride (chemical structure shown in formula I) is a novel atypical antipsychotic drug, which has antagonistic effects on dopamine D3, dopamine D2 and serotonin 2B receptors. It can be used for the treatment of schizophrenia and type 1 double disorder.
  • Cariprazine hydrochloride capsules are currently on the market. This product is an oral preparation and needs to be administered daily to maintain its blood drug concentration. However, due to the need for frequent administration, the patient's medication compliance is poor.
  • Patent document CN108261394A discloses injection preparations of cariprazine hydrochloride, including aqueous suspensions and lyophilized formulations, which can obtain sustained release for at least 1 week or longer.
  • the inventors found in the research process: the stability of the aqueous solution of cariprazine hydrochloride is not ideal, and dissociation will occur under weakly acidic to alkaline conditions, so there is a risk of dissociation in the aqueous suspension solution, which is easy to cause product properties and Changes in quality lead to changes in drug dissolution and absorption, which affect drug efficacy and patient safety.
  • the cariprazine concentration administration concentration and the blood drug concentration in the animal pK experiment are too high. Large (approximately 2 to 4 hours for rats, 3 to 9 days for humans), high blood drug concentrations may lead to greater toxic and side effects and excessive drug accumulation in the human body.
  • the present invention provides a cariprazine pharmaceutical composition, which comprises cariprazine solid particles, and the particle size of the cariprazine solid particles Dv(10) ⁇ 30 microns , Dv(50) ⁇ 50 ⁇ m and Dv(90) ⁇ 100 ⁇ m, preferably ⁇ 10 ⁇ m.
  • the solid particles of cariprazine may be selected from solid particles of cariprazine, pharmaceutically acceptable salts of cariprazine, and solvates thereof.
  • the solvate may be selected from hydrates.
  • the pharmaceutically acceptable salt of cariprazine includes, but is not limited to, cariprazine pamoate.
  • the pamoic acid is also called Pamoic acid, CAS No. 130-85-8.
  • the cariprazine solid particles may be in crystalline or amorphous form.
  • the cariprazine pamoate is Cariprazine pamoate crystal form A.
  • the X-ray powder diffraction pattern of the cariprazine pamoate crystalline form A has 2 ⁇ values of 13.1° ⁇ 0.2°, 18.7° ⁇ 0.2°, 21.0° ⁇ 0.2°, etc. There are characteristic peaks.
  • the X-ray powder diffraction pattern of the crystal form A of cariprazine pamoate has 2 ⁇ values of 4.8° ⁇ 0.2°, 13.1° ⁇ 0.2°, 18.7° ⁇ 0.2°, 20.1° ⁇ There are characteristic peaks at 0.2°, 21.0° ⁇ 0.2°, 26.1° ⁇ 0.2°, etc.
  • the X-ray powder diffraction pattern of the crystal form A of cariprazine pamoate has 2 ⁇ values of 4.8° ⁇ 0.2°, 9.7 ⁇ 0.2°, 12.3° ⁇ 0.2°, 13.1° ⁇ 0.2 There are characteristic peaks at °, 18.7° ⁇ 0.2°, 20.1° ⁇ 0.2°, 21.0° ⁇ 0.2°, 26.1° ⁇ 0.2°, etc.
  • the X-ray powder diffraction pattern of the cariprazine pamoate crystal form A has 2 ⁇ values of 4.8° ⁇ 0.2°, 8.2° ⁇ 0.2°, 9.7 ⁇ 0.2°, 11.6° ⁇ 0.2 °, 12.3° ⁇ 0.2°, 13.1° ⁇ 0.2°, 14.7° ⁇ 0.2°, 15.1° ⁇ 0.2°, 16.6° ⁇ 0.2°, 18.7° ⁇ 0.2°, 20.1° ⁇ 0.2°, 20.7° ⁇ 0.2°, There are absorption peaks at 21.0° ⁇ 0.2°, 21.6° ⁇ 0.2°, 22.1° ⁇ 0.2°, 24.1° ⁇ 0.2°, 26.1° ⁇ 0.2°, etc.
  • the X-ray powder diffraction pattern of the cariprazine pamoate crystal form A is basically as shown in FIG. 2 .
  • the differential scanning calorimetry analysis diagram of the cariprazine pamoate crystal form A is basically as shown in FIG. 3 , showing that the melting point is about 166.5°C.
  • thermogravimetric analysis diagram of the described cariprazine pamoic acid crystal form A is basically as shown in Figure 4, showing that there are two stages of weight loss before 115 ° C, due to the loss of surface solvent and channel water, at 115 ⁇ 165 At °C, there is a weight loss of about 1.1%, which is attributed to the loss of crystal water.
  • the NMR chart of the described cariprazine pamoic acid crystal form A is basically as shown in FIG. 5 , which shows that cariprazine and pamoic acid form a salt in a molar ratio of 1:1.
  • the preparation method of described cariprazine pamoate crystal form A is as follows:
  • the solvent is methanol
  • the good solvent is dibutyl ketone
  • the anti-solvent is n-heptane.
  • the cariprazine pamoate salt is the crystalline form F of cariprazine pamoate salt.
  • the X-ray powder diffraction pattern of the cariprazine pamoate crystalline form F has 2 ⁇ values of 4.9° ⁇ 0.2°, 19.2° ⁇ 0.2°, 21.0° ⁇ 0.2°, etc. There are characteristic peaks.
  • the X-ray powder diffraction pattern of the cariprazine pamoate crystal form F has 2 ⁇ values of 4.9° ⁇ 0.2°, 13.6° ⁇ 0.2°, 19.2° ⁇ 0.2°, 21.0° ⁇ 0.2 There are characteristic peaks at °, 24.0° ⁇ 0.2°, 26.3° ⁇ 0.2°, etc.
  • the X-ray powder diffraction pattern of the cariprazine pamoate crystal form F has 2 ⁇ values of 4.9° ⁇ 0.2°, 12.8° ⁇ 0.2°, 13.6° ⁇ 0.2°, 19.2° ⁇ 0.2 There are characteristic peaks at °, 20.3° ⁇ 0.2°, 21.0° ⁇ 0.2°, 24.0° ⁇ 0.2°, 26.3° ⁇ 0.2°, etc.
  • the X-ray powder diffraction pattern of the cariprazine pamoate crystalline form F has 2 ⁇ values of 4.9° ⁇ 0.2°, 8.4° ⁇ 0.2°, 9.7 ⁇ 0.2°, 10.4° ⁇ 0.2°, 11.6° ⁇ 0.2°, 12.8° ⁇ 0.2°, 13.3° ⁇ 0.2°, 13.6° ⁇ 0.2°, 15.0° ⁇ 0.2°, 15.4° ⁇ 0.2°, 16.8° ⁇ 0.2° , 17.0° ⁇ 0.2°, 18.5° ⁇ 0.2°, 18.8° ⁇ 0.2°, 19.2° ⁇ 0.2°, 19.5° ⁇ 0.2°, 20.3° ⁇ 0.2°, 21.0° ⁇ 0.2°, 21.9° ⁇ 0.2°, 22.2 ° ⁇ 0.2°, 22.5° ⁇ 0.2°, 24.0° ⁇ 0.2°, 25.1° ⁇ 0.2°, 25.7° ⁇ 0.2°, 26.3° ⁇ 0.2°, 26.8° ⁇ 0.2°, 28.8° ⁇ 0.2°, 29.6° ⁇ There are characteristic peaks at 0.2° and so on.
  • the X-ray powder diffraction pattern of the cariprazine pamoate crystal form F is basically shown in FIG. 6 .
  • the differential scanning calorimetry analysis diagram of the cariprazine pamoate crystalline form F is basically as shown in FIG. 7 , showing that the melting point is about 166.6°C.
  • thermogravimetric analysis diagram of the described cariprazine pamoic acid crystal form F is basically as shown in Figure 8, showing that there is about 1.3% weight loss before 115 ° C, which is due to the loss of channel water; at 115 ⁇ 175 ° C There is a weight loss of about 1.3% due to the loss of crystal water.
  • the NMR image of the described cariprazine pamoic acid crystal form F is basically as shown in FIG. 9 , which shows that cariprazine and pamoic acid form a salt in a molar ratio of 1:1.
  • the preparation method of described cariprazine pamoate crystal form F is as follows:
  • the cariprazine pamoate crystal form A is formed into a slurry in a solvent, and the crystal form F is obtained by stirring and crystallization;
  • the solvent is ethyl acetate, isopropyl acetate, methyl tert-butyl ether or n-heptane.
  • the cariprazine pamoate salt is the crystalline form D of cariprazine pamoate salt.
  • the X-ray powder diffraction pattern of the cariprazine pamoate crystalline form D has 2 ⁇ values of 9.6° ⁇ 0.2°, 11.9° ⁇ 0.2°, 20.4° ⁇ 0.2°, etc. There are characteristic peaks.
  • the X-ray powder diffraction pattern of the cariprazine pamoate crystal form D has 2 ⁇ values of 9.6° ⁇ 0.2°, 11.9° ⁇ 0.2°, 16.6° ⁇ 0.2°, 20.4° ⁇ 0.2 There are characteristic peaks at °, 24.5° ⁇ 0.2°, 25.3° ⁇ 0.2°, etc.
  • the X-ray powder diffraction pattern of the cariprazine pamoate crystal form D has 2 ⁇ values of 9.6° ⁇ 0.2°, 11.9° ⁇ 0.2°, 15.2° ⁇ 0.2°, 16.6° ⁇ 0.2 There are characteristic peaks at °, 20.4° ⁇ 0.2°, 20.7° ⁇ 0.2°, 24.5° ⁇ 0.2°, 25.3° ⁇ 0.2°, etc.
  • the X-ray powder diffraction pattern of the cariprazine pamoate crystal form D has 2 ⁇ values of 9.6° ⁇ 0.2°, 10.1° ⁇ 0.2°, 10.5 ⁇ 0.2°, 11.9° ⁇ 0.2°, 13.2° ⁇ 0.2°, 14.5° ⁇ 0.2°, 15.2° ⁇ 0.2°, 16.6° ⁇ 0.2°, 20.4° ⁇ 0.2°, 20.7° ⁇ 0.2°, 21.1° ⁇ 0.2° , 21.9° ⁇ 0.2°, 23.5° ⁇ 0.2°, 24.5° ⁇ 0.2°, 25.3° ⁇ 0.2°, etc. have characteristic peaks.
  • the X-ray powder diffraction pattern of the cariprazine pamoate crystal form D is basically shown in FIG. 10 .
  • the differential scanning calorimetry analysis diagram of the cariprazine pamoate crystal form D is basically as shown in FIG. 11 , showing that the melting point is about 164.6°C.
  • thermogravimetric analysis diagram of the described cariprazine pamoic acid crystal form D is basically as shown in FIG. 12 , which shows that there is about 4% weight loss before 190° C., which is due to the loss of water and ethanol.
  • the NMR image of the described cariprazine pamoic acid crystal form D is basically as shown in FIG. 13 , which shows that cariprazine and pamoic acid form a salt in a molar ratio of 1:1.
  • the preparation method of described cariprazine pamoate crystal form D is as follows:
  • the cariprazine pamoate crystal form D is obtained by stirring and crystallization of cariprazine pamoate in ethanol.
  • the cariprazine pamoate salt is the crystal form B of cariprazine pamoate salt.
  • the X-ray powder diffraction pattern of the cariprazine pamoate crystalline form B has 2 ⁇ values of 5.2° ⁇ 0.2°, 10.5° ⁇ 0.2°, 14.0° ⁇ 0.2°, There are characteristic peaks at 14.4° ⁇ 0.2°, 17.5° ⁇ 0.2°, 21.3° ⁇ 0.2°, 21.9° ⁇ 0.2°, 22.9° ⁇ 0.2°, 26.2° ⁇ 0.2°, etc.
  • the X-ray powder diffraction pattern of the cariprazine pamoate crystal form B is basically as shown in FIG. 14 .
  • the cariprazine pamoate salt is the crystal form C of cariprazine pamoate salt.
  • the X-ray powder diffraction pattern of the cariprazine pamoate crystalline form C has 2 ⁇ values of 8.6° ⁇ 0.2°, 13.0° ⁇ 0.2°, 16.8° ⁇ 0.2°, There are characteristic peaks at 17.3° ⁇ 0.2°, 18.2° ⁇ 0.2°, 18.5° ⁇ 0.2°, 19.8° ⁇ 0.2°, 22.1° ⁇ 0.2°, 23.5° ⁇ 0.2°, etc.
  • the X-ray powder diffraction pattern of the cariprazine pamoate crystal form C is basically shown in FIG. 15 .
  • the cariprazine pamoate salt is the crystal form E of cariprazine pamoate salt.
  • the X-ray powder diffraction pattern of the cariprazine pamoate crystalline form E has 2 ⁇ values of 11.0° ⁇ 0.2°, 12.8° ⁇ 0.2°, 13.8° ⁇ 0.2°, There are characteristic peaks at 15.5° ⁇ 0.2°, 15.9° ⁇ 0.2°, 17.9° ⁇ 0.2°, 18.4° ⁇ 0.2°, 20.7° ⁇ 0.2°, 23.4° ⁇ 0.2°, etc.
  • the X-ray powder diffraction pattern of the cariprazine pamoate crystal form E is basically shown in FIG. 16 .
  • the cariprazine pamoate salt is the crystal form G of cariprazine pamoate salt.
  • the X-ray powder diffraction pattern of the cariprazine pamoate crystalline form G has 2 ⁇ values of 8.7° ⁇ 0.2°, 10.0° ⁇ 0.2°, 13.6° ⁇ 0.2°, There are characteristic peaks at 14.3° ⁇ 0.2°, 17.5° ⁇ 0.2°, 18.0° ⁇ 0.2°, 20.3° ⁇ 0.2°, 23.2° ⁇ 0.2°, 25.1° ⁇ 0.2°, etc.
  • the X-ray powder diffraction pattern of the cariprazine pamoate crystal form G is basically as shown in FIG. 17 .
  • the cariprazine pamoate salt is the crystal form I of cariprazine pamoate salt.
  • the X-ray powder diffraction pattern of the cariprazine pamoate crystalline form I has 2 ⁇ values of 10.0° ⁇ 0.2°, 14.9° ⁇ 0.2°, 16.3° ⁇ 0.2°, There are characteristic peaks at 17.7° ⁇ 0.2°, 18.5° ⁇ 0.2°, 19.0° ⁇ 0.2°, 21.1° ⁇ 0.2°, 22.1° ⁇ 0.2°, 24.5° ⁇ 0.2°, etc.
  • the X-ray powder diffraction pattern of the cariprazine pamoate crystal form I is basically as shown in FIG. 18 .
  • the cariprazine pharmaceutical composition may further include excipients, which may be selected from suspending agents, wetting agents, osmotic pressure regulators, solvents, stabilizers, buffers and surfactants one or more of.
  • the concentration of the suspending agent ranges from 0 to 10 mg/mL, preferably from 3.5 mg/mL to 5 mg/mL, such as 3.5 mg/mL, 4.0 mg/mL, 4.5 mg/mL or 5.0 mg/mL. mg/mL.
  • the suspending agent is selected from one or more of sodium carboxymethylcellulose, methylcellulose and polyvinylpyrrolidone, preferably sodium carboxymethylcellulose.
  • the concentration of the wetting agent is in the range of 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 mg/mL, 3.0 mg/mL, 3.5 mg/mL, 4.0 mg/mL, 4.5 mg/mL, or 5.0 mg/mL.
  • the wetting agent is selected from one or more of Tween 20, Tween 80, and Poloxamer 188, preferably Tween 20.
  • the concentration of the osmotic pressure regulator ranges from 20 to 30 mg/mL, preferably from 23 mg/mL to 26 mg/mL, such as 23 mg/mL, 24.7 mg/mL or 26 mg/mL.
  • the osmotic pressure regulator is selected from one or more of sodium chloride, mannitol and sucrose.
  • the concentration of the stabilizer ranges from 0 to 30 mg/mL, preferably 1 to 10 mg/mL, such as 1 mg/mL, 3 mg/mL, 5 mg/mL or 7.0 mg/mL.
  • the stabilizer is PVP K12.
  • the buffer is selected from one or more of phosphoric acid, phosphate, citric acid, sodium citrate, hydrochloric acid and sodium hydroxide.
  • the surfactant is sodium deoxycholate.
  • the solvent is water, such as water for injection.
  • the cariprazine composition may include:
  • the cariprazine composition may contain sodium hydroxide or hydrochloric acid.
  • the cariprazine composition is a cariprazine injection, such as a cariprazine long-acting injection.
  • the concentration of the cariprazine solid particles is not less than 15 mg/mL.
  • the preparation method of the cariprazine composition comprises the following steps:
  • the wetting agent, the buffering agent and the osmotic pressure regulator can be dissolved in a solvent in sequence, for example, dissolved in water for injection.
  • the adjusted pH may be 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5 or 9.0.
  • the invention provides the application of the cariprazine pharmaceutical composition in the preparation of medicines for treating and/or preventing psychosis, bipolar disorder and acute mania.
  • the present invention also provides a method of treating and/or preventing psychosis, bipolar disorder or acute mania, comprising administering the cariprazine pharmaceutical composition to a patient in need.
  • the "Dv(10)", “Dv(50)” and “Dv(90)” refer to the volume-weighted particle diameter, wherein the cumulative 10v/v%, 50v, respectively, when measured /v% or 90v/v% of the particles have equal or smaller diameters. For example, if the Dv(50) of a population of particles is about 25 microns, then 50% of the particles by volume have a diameter of less than or equal to about 25 microns.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the room temperature refers to an ambient temperature ranging from 10°C to 35°C.
  • cariprazine pamoate in the insoluble salt of cariprazine meets the advantages of long-acting sustained-release preparations, and can be developed into a suspension injection. It can overcome the risk of dissociation of cariprazine hydrochloride and achieve the effect of long-term administration, as well as the lower blood drug concentration in rats, which greatly improves the patient's compliance, the bioavailability of the drug and the drug safety.
  • the cariprazine pharmaceutical composition of the present invention has the characteristics of sustained release, high bioavailability, good solution stability, small administration volume and the like, and can continuously release cariprazine for at least one week or longer after one administration, and is marketable Prospects are good.
  • Fig. 1 is the XRPD spectrum of cariprazine pamoate amorphous
  • Fig. 2 is the XRPD spectrum of cariprazine pamoate crystal form A
  • Fig. 3 is the DSC spectrum of cariprazine pamoate crystal form A
  • Fig. 4 is the TGA spectrum of cariprazine pamoate crystal form A
  • Fig. 5 is the 1 H-NMR spectrum of cariprazine pamoate crystal form A
  • Fig. 6 is the XRPD spectrum of cariprazine pamoate crystal form F
  • Fig. 7 is the DSC spectrum of cariprazine pamoate crystal form F
  • Fig. 8 is the TGA spectrum of cariprazine pamoate crystal form F
  • Fig. 9 is the 1 H-NMR spectrum of cariprazine pamoate crystal form F.
  • Fig. 10 is the XRPD spectrum of cariprazine pamoate crystal form D
  • Fig. 11 is the DSC spectrum of cariprazine pamoate crystal form D;
  • Fig. 12 is the TGA spectrum of cariprazine pamoate crystal form D;
  • Figure 13 is the 1 H-NMR spectrum of cariprazine pamoate crystal form D;
  • Figure 14 is the XRPD pattern of cariprazine pamoate crystal form B
  • Fig. 15 is the XRPD pattern of cariprazine pamoate crystal form C
  • Figure 16 is the XRPD pattern of cariprazine pamoate crystal form E
  • Figure 17 is the XRPD pattern of cariprazine pamoate crystal form G
  • Figure 18 is the XRPD pattern of cariprazine pamoate crystal form I;
  • Figure 19 is the XRPD pattern of cariprazine hydrochloride crystal form I;
  • Figure 20 is a graph showing the results of the in vitro dissolution simulation experiment ( ⁇ is the amorphous form of cariprazine pamoate; ⁇ is the crystalline form A of cariprazine pamoate; ⁇ is cariprazine pamoate Crystal form B; ⁇ is cariprazine pamoate crystal form G);
  • Figure 21 is the XRPD spectrum overlay of cariprazine pamoate and cariprazine hydrochloride under the condition of pH 7.4 in Comparative Example 4 (A is cariprazine free base; B is cariprazine free base; Hydrochloride Form I; C: Cariprazine Hydrochloride Form I after shaking in pH 7.4; D: Cariprazine Pamoate Form A; E: Cariprazine Pamoate Naphthoate crystal form A after shaking in pH 7.4 medium).
  • Figure 22 depicts the relationship between the average blood concentration of cariprazine and time in the oral sample of the preparation of Example 44 of the present invention in rats;
  • Figure 23 depicts the relationship between the average blood concentration of cariprazine and time in the injection samples of the preparations of Examples 40-43 of the present invention in rats ( ⁇ is cariprazine pamoate amorphous; ⁇ is Cariprazine pamoate crystal form A; ⁇ is cariprazine pamoate crystal form B; ⁇ is cariprazine pamoate crystal form E);
  • Figure 24 Partial magnified view of Figure 23 (the relationship between the average blood concentration of cariprazine and time from 0 to 24 hours) ( ⁇ is cariprazine pamoate amorphous; ⁇ is cariprazine Pamoate crystalline form A; ⁇ is cariprazine pamoate crystalline form B; ⁇ is cariprazine pamoate crystalline form E).
  • the TGA measurement was performed in a TA Instruments model Q500 device, and the sample (about 2-5 mg) was weighed in an aluminum pan and transferred to the instrument for measurement.
  • the test parameters are as follows: the instrument is heated to 350°C at a rate of 10°C/min, data is collected, and the experimental atmosphere is nitrogen.
  • XRPD measurements were performed in a Bruker model D8Advance X-ray powder diffractometer using a circular zero-background single crystal silicon sample stage.
  • the scanning parameters are as follows: voltage 40kv, current 40mA, scanning range 3°-45°, scanning step size 0.02°, and scanning mode is continuous scanning.
  • the PLM measurement was carried out in a hot-stage polarizing microscope with Shanghai Dianying Optical Instrument Model DYP990/TPH350, and a small amount of samples were dispersed in a glass slide and photographed in a 10x eyepiece and a 5-40x objective.
  • the detection conditions of the particle size detection instrument for the suspension aqueous solution of cariprazine pharmaceutical composition are as follows:
  • solution B Dissolve 4000mg (9.36mmol) cariprazine in 200mL (5.4mg/mL) phosphoric acid solution to obtain solution A; dissolve 3634mg (9.36mmol) pamoic acid in 100mL (7.5mg/mL) sodium hydroxide solution , solution B was obtained. Under stirring, 100 mL of solution B was added to 200 mL of solution A within 30 minutes, and the product was isolated by filtration and washed with water, and dried under vacuum at 40° C. for 12 hours to obtain 5840 mg of pale yellow solid with a yield of 76% (based on free base).
  • cariprazine pamoate of the present invention was confirmed by proton nuclear magnetic resonance spectrum.
  • solution A Dissolve 200 mg (0.468 mmol) of cariprazine in 10 mL (5.4 mg/mL) of phosphoric acid solution to obtain solution A; dissolve 90.85 mg (0.234 mmol) of pamoic acid in 2.5 mL (7.5 mg/mL) of hydrogen peroxide In sodium solution, solution B was obtained. Under stirring, 2.5 mL of solution B was added to 10 mL of solution A within 30 minutes, the product was isolated by filtration, washed with water, and dried under vacuum at 40° C. for 12 hours to obtain 204 mg of pale yellow solid with a yield of 70%.
  • cariprazine pamoate of the present invention was confirmed by proton nuclear magnetic resonance spectrum.
  • cariprazine laurate 50 mg (0.117 mmol) of cariprazine and 23.7 mg (0.118 mmol) of lauric acid were added to 5 mL of methanol, dissolved at 50 °C, stirred at room temperature for 12 hours, added with 2 times the volume of water, filtered, and the solid was heated at 40 °C Dry under vacuum for 12 hours to obtain cariprazine laurate.
  • Example 7 Cariprazine Sebacate, Cariprazine Succinate, Cariprazine Malate, Cariprazine Lactate, Cariprazine Undecanoate, Cariprazine Preparation of azine heptanoate
  • Cariprazine and acid were weighed in a molar ratio of 1:1.1.
  • Various acids were dissolved in methanol solvent respectively, and the obtained acidic reagent was added to cariprazine methanol solution at room temperature to carry out salt-forming reaction. After stirring at room temperature for 12 hours, it was evaporated and dried at room temperature to obtain the corresponding cariprazine salt.
  • cariprazine pamoate prepared in Example 1 Take 2000 mg of cariprazine pamoate prepared in Example 1, add it to 20 mL of methanol, stir and crystallize at room temperature for 24 hours, filter, and vacuum dry at 55 °C to obtain 1900 mg of cariprazine pamoate crystal form A, the yield is 95%.
  • thermogravimetric analysis diagram is shown in Figure 4, which shows that there are two stages of weight loss before 115 °C, which is due to the loss of surface solvent and channel water. loss.
  • cariprazine pamoate crystal form A prepared in Example 8, add it to 2 mL of ethanol, stir and crystallize at room temperature for 48 hours, filter, and vacuum dry at 55 °C to obtain 190 mg of cariprazine pamoic acid.
  • Salt crystal form D the yield is 95%.
  • thermogravimetric analysis profile is shown in Figure 12, showing a weight loss of about 4% before 190°C, due to the loss of water and ethanol.
  • cariprazine pamoate crystal form A obtained in Example 8 Take the cariprazine pamoate crystal form A obtained in Example 8 to form a slurry in an acetonitrile solvent, and the weight-to-volume ratio of cariprazine pamoate crystal form A to the solvent is 40 mg/mL, and stir for 3
  • the crystal form E of cariprazine pamoate is obtained by crystallization.
  • cariprazine pamoate crystalline form A prepared in Example 8, add it to 20 mL of isopropyl acetate, stir and crystallize at room temperature for 12 hours, filter, and vacuum dry at 55 °C to obtain 180 mg of cariprazine bisulfite. Hydroxynaphthate crystal form F, the yield is 90%.
  • thermogravimetric analysis diagram is shown in Figure 8, which shows that there is about 1.3% weight loss before 115°C, which is due to the loss of channel water; about 1.3% weight loss at 115-175°C, which is due to the loss of crystal water.
  • cariprazine pamoate crystal form A obtained in Example 8, add 5 mL of acetonitrile to form a slurry, and stir for 5 days for crystallization to obtain cariprazine pamoate crystal form G.
  • Comparative Example 1 Comparison of the stability of related substances and crystal forms
  • cariprazine pamoate amorphous form prepared in Example 1 Take the cariprazine pamoate amorphous form prepared in Example 1, the cariprazine pamoate crystal form A prepared in Example 8, and the cariprazine pamoate crystalline form A prepared in Example 10, respectively.
  • the crystalline form B of cariprazine pamoate, the crystalline form F of cariprazine pamoate prepared in Example 16, the crystalline form G of cariprazine pamoate prepared in Example 17, and the crystalline form G of cariprazine pamoate prepared in Example 19 The obtained cariprazine hydrochloride crystal form I was exposed to high temperature (60°C), high humidity (25°C/90%RH), accelerated (40°C/75%RH), light (1.2 ⁇ 10 6 Lux ⁇ hr) Placed under conditions, samples were taken at 0 days, 5 days, 7 days and 10 days for HPLC or XRPD detection.
  • the crystal form stability results are shown in Table 2, which shows that compared with the known cariprazine hydrochloride crystal form I, the cariprazine pamoate crystal form A of the present invention has more excellent crystal form stability When placed under various conditions for 10 days, the crystal form does not change, and the crystallinity does not change significantly; the cariprazine pamoate crystal form F of the present invention is relatively stable under high temperature and light conditions, and the crystal form does not occur. changes, will convert to Cariprazine Pamoate Form A under high humidity and accelerated conditions.
  • cariprazine pamoate amorphous prepared in Example 1 Take the cariprazine pamoate amorphous prepared in Example 1, the cariprazine semi-pamoate amorphous prepared in Example 3, and the cariprazine lauric acid prepared in Example 5.
  • Salt Cariprazine Palmitate prepared in Example 6, Cariprazine Sebacate prepared in Example 7, Cariprazine Succinate, Cariprazine Malate, Cariprazine Perazine Lactate, Cariprazine Undecanoate, Cariprazine Enanthate, Cariprazine Pamoate Crystal Form A Prepared in Example 8, Cariprazine Pamoate Crystal Form A Prepared in Example 10
  • Cariprazine pamoate crystal form B Cariprazine pamoate crystal form F prepared in Example 16
  • Cariprazine pamoate crystal form G prepared in Example 17, Cariprazine hydrochloride crystal form I and cariprazine prepared in Example 19 were respectively added to the corresponding medium, shaken at 37° C.
  • pH3, pH4, pH5 and pH6 are acetate buffer solutions, and pH7, pH7.4, pH8 and pH9 are phosphate buffer solutions.
  • cariprazine pamoate amorphous form prepared in Example 1 Take the cariprazine pamoate amorphous form prepared in Example 1, the cariprazine pamoate crystal form A prepared in Example 8, and the cariprazine pamoate crystalline form A prepared in Example 10, respectively.
  • the cariprazine pamoate crystalline form B and the cariprazine pamoate crystalline form G prepared in Example 17 were respectively added to the pH 7.4 phosphate buffer solution medium, shaken at 37°C, and heated at 1 , 3, 5, 7, and 24 hours to check the solubility.
  • the results show that cariprazine pamoate crystal form A has not changed, while cariprazine The hydrochloride salt crystal form I dissociates into cariprazine free base, and the comparison results at pH 7.4 are shown in Figure 21 (the rest are not shown). It can be seen that the cariprazine pamoate crystal form A is in the solution. Compared with cariprazine hydrochloride crystal form I, it is more stable, can effectively avoid the change of drug effect caused by the change of crystal form after administration, and improve the safety of medication.
  • Example 20-25 Cariprazine Pamoate Suspension Aqueous Solution with Different Suspending Agent Amounts
  • the mixed aqueous solution of the same recipe and the same grinding parameters are applicable to different crystal forms of cariprazine pamoate.
  • Example 38 Aqueous suspension of cariprazine hydrochloride
  • Example 39 Stability of Cariprazine Pamoate and Cariprazine Hydrochloride Suspension Aqueous Solution at 60°C
  • the cariprazine pamoate suspension solution is significantly better than the cariprazine hydrochloride suspension solution in terms of the stability of impurities and particle size.
  • (1) take by weighing recipe quantity Tween 20, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol, sodium carboxymethyl cellulose and the water for injection of about 60% preparation total amount, stir, dissolve and disperse;
  • 15 male SD rats were divided into five groups, of which four groups were given a single dose of 9 mg/kg by intramuscular injection with different formulations of cariprazine pamoate crystal forms, and the samples were administered at 0, 1h, 3h, and 7h after administration. , 24h, 4d, 7d, 11d, 15d, 20d, 25d, 30d to collect plasma; the remaining group of single-dose 0.3 mg/kg oral gavage was given the prescription sample of cariprazine pamoate crystal form A, and the Plasma was collected at 5 min, 15 min, 30 min, 1, 2, 3, 4, 6, 8, 12 and 24 hours after administration.
  • the animals in the intramuscular injection group were allowed to eat and drink freely, while the animals in the oral gavage group fasted overnight before administration, and resumed their diet 4 hours after administration.
  • Plasma sample collection About 150 ⁇ L of blood was collected from the jugular vein (the whole blood was centrifuged to separate the plasma within 30 minutes) and placed in a test tube containing the anticoagulant EDTA-K2.
  • Plasma sample pretreatment add 200 ⁇ L of internal standard solution (40ng/mL Glipizide acetonitrile solution) to 30 ⁇ L of plasma sample, vortex for 1 min, centrifuge at 5800 rpm for 10 min at 4°C, transfer 100 ⁇ L of supernatant to a new plate, and take 1 ⁇ L The solution was subjected to LC-MS/MS analysis.
  • internal standard solution 40ng/mL Glipizide acetonitrile solution
  • Mobile phase composition Mobile phase A: 0.025% formic acid in water - 1 mM ammonium acetate
  • Injection volume 1 ⁇ L
  • Retention time Cariprazine: 1.16min; Glipizide: 1.22min.
  • the electrospray ion source (Turbo spray) was used in the positive ion detection mode, and the multi-channel reaction monitoring (MRM) mode was selected for secondary mass spectrometry analysis.
  • MRM multi-channel reaction monitoring
  • the oral cariprazine pamoate group was rapidly absorbed within 24 hours after administration, while the cariprazine pamoate injection group was significantly better than the oral group after administration. Sustained release for at least 11 days, combined with species differences, is expected to deliver at least 30 days in humans. At the same time, among the various crystal forms of cariprazine pamoate, the release time of cariprazine pamoate crystal form A is the best.
  • the cariprazine pamoate injection preparation provided by the present invention is prepared into an aqueous suspension
  • the cariprazine pamoate has small particle size, uniform distribution, and good performance. Injectable, and has the characteristics of long-term sustained drug release (at least one week in SD rats).

Abstract

一种包含卡利拉嗪的药物组合物、制备方法及应用。药物组合物包括：卡利拉嗪双羟萘酸盐固体粒子，所述卡利拉嗪固体粒子的粒径为Dv(10)小于等于30微米、Dv(50)小于等于50微米且Dv(90)小于等于100微米。包含卡利拉嗪的药物组合物使用时为混悬水溶液，其中卡利拉嗪游离碱浓度适中，在一定给药体积内注射可达到长效的作用，减少用药次数，提高患者用药依从性，且生物利用度高，市场化前景良好。

Description

卡利拉嗪药物组合物、制备方法及应用
本申请要求享有如下在先申请的优先权权益：2020年8月26日向中国国家知识产权局提交的申请号为202010870701.6的中国发明专利申请；2020年8月26日向中国国家知识产权局提交的申请号为202010869671.7的中国发明专利申请；2021年3月26日向中国国家知识产权局提交的申请号为202110324874.2的中国发明专利申请；和2021年3月26日向中国国家知识产权局提交的申请号为202110330670.X的中国发明专利申请。上述在先申请的全文以引用的方式结合至本文。
技术领域
本发明涉及化学医药领域，特别是包含卡利拉嗪药物组合物、制备方法及应用。
背景技术
盐酸卡利拉嗪(化学结构如式I所示)是一种新型非典型抗精神病药，对多巴胺D3、多巴胺D2和5-羟色胺2B受体有拮抗作用。可用于精神分裂症及1型双障碍的治疗。目前上市的是盐酸卡利拉嗪胶囊，该产品为口服制剂，需要每日给药，以维持其血药浓度，但由于需要频繁给药，使得患者的用药依从性差。
Figure PCTCN2021114754-appb-000001
专利文献CN108261394A公开了盐酸卡利拉嗪注射制剂，包括混悬水溶液和冻干剂的形式，可获得至少1周或更长时间的持续释放。但是，本发明人在研究过程中发现：盐酸卡利拉嗪水溶液稳定性不够理想，弱酸性至碱性条件下会发生解离，故在混悬水溶液中存在解离风险，容易造成产品性质与质量的变化，导致药物溶解与吸收的改变，影响药物的疗效与患者的用药安全。而且，专利文献CN108261394A公开的盐酸卡利拉嗪注射制剂中卡利拉嗪浓度给药浓度以及动物pK实验中血药浓度过高，结合原研数据中卡利拉嗪的消除在种属间差异较大(大鼠约2～4小时，人体为3～9天)，过高的血药浓度可 能导致较大的毒副作用以及过多的药物在人体内堆积。
目前未发现有性能改善的卡利拉嗪难溶性盐的注射制剂报道。
发明内容
为改善现有技术存在的问题，本发明提供了一种卡利拉嗪药物组合物，其包含卡利拉嗪固体粒子，所述卡利拉嗪固体粒子的粒径Dv(10)≤30微米、Dv(50)≤50微米且Dv(90)≤100微米，优选≤10微米。
根据本发明的实施方案，所述卡利拉嗪固体粒子可以选自卡利拉嗪、卡利拉嗪药学上可接受的盐及其溶剂合物的固体粒子。
根据本发明的实施方案，所述溶剂合物可以选自水合物。
根据本发明的实施方案，所述卡利拉嗪药学上可接受的盐包括但不限于卡利拉嗪双羟萘酸盐。
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。
根据本发明的实施方案，所述卡利拉嗪固体粒子可以为晶体或无定型形式。
根据本发明的实施方案，所述的卡利拉嗪双羟萘酸盐为卡利拉嗪双羟萘酸盐晶型A。
根据本发明的实施方案，所述的卡利拉嗪双羟萘酸盐晶型A的X射线粉末衍射图在2θ值为13.1°±0.2°、18.7°±0.2°、21.0°±0.2°等处有特征峰。
进一步地，所述的卡利拉嗪双羟萘酸盐的晶型A的X射线粉末衍射图在2θ值为4.8°±0.2°、13.1°±0.2°、18.7°±0.2°、20.1°±0.2°、21.0°±0.2°、26.1°±0.2°等处有特征峰。
进一步地，所述的卡利拉嗪双羟萘酸盐的晶型A的X射线粉末衍射图在2θ值为4.8°±0.2°、9.7±0.2°、12.3°±0.2°、13.1°±0.2°、18.7°±0.2°、20.1°±0.2°、21.0°±0.2°、26.1°±0.2°等处有特征峰。
更进一步地，所述的卡利拉嗪双羟萘酸盐晶型A的X射线粉末衍射图在2θ值为4.8°±0.2°、8.2°±0.2°、9.7±0.2°、11.6°±0.2°、12.3°±0.2°、13.1°±0.2°、14.7°±0.2°、15.1°±0.2°、16.6°±0.2°、18.7°±0.2°、20.1°±0.2°、20.7°±0.2°、21.0°±0.2°、21.6°±0.2°、22.1°±0.2°、 24.1°±0.2°、26.1°±0.2°等处有吸收峰。
更进一步地，所述的卡利拉嗪双羟萘酸盐晶型A的X射线粉末衍射图基本如图2所示。
所述的卡利拉嗪双羟萘酸盐晶型A的差式扫描量热分析图基本如图3所示，显示熔点约为166.5℃。
所述的卡利拉嗪双羟萘酸晶型A的热重分析图基本如图4所示，显示在115℃之前有两段失重，归结于表面溶剂和通道水的损失，在115～165℃时，有约1.1％的失重，归结于结晶水的损失。
所述的所述的卡利拉嗪双羟萘酸晶型A的核磁图基本如图5所示，显示卡利拉嗪与双羟萘酸以摩尔比1:1成盐。
根据本发明的实施方案，所述的卡利拉嗪双羟萘酸盐晶型A的制备方法如下：
(1)将卡利拉嗪双羟萘酸盐加入溶剂中，搅拌析晶，得到所述的卡利拉嗪双羟萘酸盐晶型A；
所述溶剂为甲醇；
(2)将卡利拉嗪双羟萘酸盐溶解于良溶剂中，逐渐加入反溶剂，搅拌析晶，得到所述的卡利拉嗪双羟萘酸盐晶型A。
所述良溶剂为二丁酮；
所述反溶剂为正庚烷。
根据本发明的实施方案，所述的卡利拉嗪双羟萘酸盐为卡利拉嗪双羟萘酸盐晶型F。
根据本发明的实施方案，所述的卡利拉嗪双羟萘酸盐晶型F的X射线粉末衍射图在2θ值为4.9°±0.2°、19.2°±0.2°、21.0°±0.2°等处有特征峰。
进一步地，所述的卡利拉嗪双羟萘酸盐晶型F的X射线粉末衍射图在2θ值为4.9°±0.2°、13.6°±0.2°、19.2°±0.2°、21.0°±0.2°、24.0°±0.2°、26.3°±0.2°等处有特征峰。
进一步地，所述的卡利拉嗪双羟萘酸盐晶型F的X射线粉末衍射图在2θ值为4.9°±0.2°、12.8°±0.2°、13.6°±0.2°、19.2°±0.2°、20.3°±0.2°、21.0°±0.2°、24.0°±0.2°、26.3°±0.2°等处有特征峰。
更进一步地，根据本发明的实施方案，所述的卡利拉嗪双羟萘酸盐晶型F的X射线粉末衍射图在2θ值为4.9°±0.2°、8.4°±0.2°、9.7±0.2°、10.4°±0.2°、11.6°±0.2°、12.8°±0.2°、 13.3°±0.2°、13.6°±0.2°、15.0°±0.2°、15.4°±0.2°、16.8°±0.2°、17.0°±0.2°、18.5°±0.2°、18.8°±0.2°、19.2°±0.2°、19.5°±0.2°、20.3°±0.2°、21.0°±0.2°、21.9°±0.2°、22.2°±0.2°、22.5°±0.2°、24.0°±0.2°、25.1°±0.2°、25.7°±0.2°、26.3°±0.2°、26.8°±0.2°、28.8°±0.2°、29.6°±0.2°等处有特征峰。
更进一步地，所述的卡利拉嗪双羟萘酸盐晶型F的X射线粉末衍射图基本如图6所示。
所述的卡利拉嗪双羟萘酸盐晶型F的差式扫描量热分析图基本如图7所示，显示熔点约为166.6℃。
所述的卡利拉嗪双羟萘酸晶型F的热重分析图基本如图8所示，显示在115℃之前有约1.3％的失重，归结于通道水的损失；在115～175℃有约1.3％的失重，归结于结晶水的损失。
所述的所述的卡利拉嗪双羟萘酸晶型F的核磁图基本如图9所示，显示卡利拉嗪与双羟萘酸以摩尔比1:1成盐。
根据本发明的实施方案，所述的卡利拉嗪双羟萘酸盐晶型F的制备方法如下：
将卡利拉嗪双羟萘酸盐晶型A在溶剂中形成浆液，搅拌析晶，得到所述的卡利拉嗪双羟萘酸盐晶型F；
所述溶剂为乙酸乙酯、乙酸异丙酯、甲基叔丁基醚或正庚烷。
根据本发明的实施方案，所述的卡利拉嗪双羟萘酸盐为卡利拉嗪双羟萘酸盐晶型D。
根据本发明的实施方案，所述的卡利拉嗪双羟萘酸盐晶型D的X射线粉末衍射图在2θ值为9.6°±0.2°、11.9°±0.2°、20.4°±0.2°等处有特征峰。
进一步地，所述的卡利拉嗪双羟萘酸盐晶型D的X射线粉末衍射图在2θ值为9.6°±0.2°、11.9°±0.2°、16.6°±0.2°、20.4°±0.2°、24.5°±0.2°、25.3°±0.2°等处有特征峰。
进一步地，所述的卡利拉嗪双羟萘酸盐晶型D的X射线粉末衍射图在2θ值为9.6°±0.2°、11.9°±0.2°、15.2°±0.2°、16.6°±0.2°、20.4°±0.2°、20.7°±0.2°、24.5°±0.2°、25.3°±0.2°等处有特征峰。
更进一步地，根据本发明的实施方案，所述的卡利拉嗪双羟萘酸盐晶型D的X射线粉末衍射图在2θ值为9.6°±0.2°、10.1°±0.2°、10.5±0.2°、11.9°±0.2°、13.2°±0.2°、 14.5°±0.2°、15.2°±0.2°、16.6°±0.2°、20.4°±0.2°、20.7°±0.2°、21.1°±0.2°、21.9°±0.2°、23.5°±0.2°、24.5°±0.2°、25.3°±0.2°等处有特征峰。
更进一步地，所述的卡利拉嗪双羟萘酸盐晶型D的X射线粉末衍射图基本如图10所示。
所述的卡利拉嗪双羟萘酸盐晶型D的差式扫描量热分析图基本如图11所示，显示熔点约为164.6℃。
所述的卡利拉嗪双羟萘酸晶型D的热重分析图基本如图12所示，显示在190℃之前有约4％的失重，归结于水和乙醇的损失。
所述的所述的卡利拉嗪双羟萘酸晶型D的核磁图基本如图13所示，显示卡利拉嗪与双羟萘酸以摩尔比1:1成盐。
根据本发明的实施方案，所述的卡利拉嗪双羟萘酸盐晶型D的制备方法如下：
将卡利拉嗪双羟萘酸盐于乙醇中搅拌析晶，得到所述的利拉嗪双羟萘酸盐晶型D。
根据本发明的实施方案，所述的卡利拉嗪双羟萘酸盐为卡利拉嗪双羟萘酸盐晶型B。
根据本发明的实施方案，所述的卡利拉嗪双羟萘酸盐晶型B的X射线粉末衍射图在2θ值为5.2°±0.2°、10.5°±0.2°、14.0°±0.2°、14.4°±0.2°、17.5°±0.2°、21.3°±0.2°、21.9°±0.2°、22.9°±0.2°、26.2°±0.2°等处有特征峰。
进一步地，所述的卡利拉嗪双羟萘酸盐晶型B的X射线粉末衍射图基本如图14所示。
根据本发明的实施方案，所述的卡利拉嗪双羟萘酸盐为卡利拉嗪双羟萘酸盐晶型C。
根据本发明的实施方案，所述的卡利拉嗪双羟萘酸盐晶型C的X射线粉末衍射图在2θ值为8.6°±0.2°、13.0°±0.2°、16.8°±0.2°、17.3°±0.2°、18.2°±0.2°、18.5°±0.2°、19.8°±0.2°、22.1°±0.2°、23.5°±0.2°等处有特征峰。
进一步地，所述的卡利拉嗪双羟萘酸盐晶型C的X射线粉末衍射图基本如图15所示。
根据本发明的实施方案，所述的卡利拉嗪双羟萘酸盐为卡利拉嗪双羟萘酸盐晶型E。
根据本发明的实施方案，所述的卡利拉嗪双羟萘酸盐晶型E的X射线粉末衍射图在2θ值为11.0°±0.2°、12.8°±0.2°、13.8°±0.2°、15.5°±0.2°、15.9°±0.2°、17.9°±0.2°、18.4°±0.2°、20.7°±0.2°、23.4°±0.2°等处有特征峰。
进一步地，所述的卡利拉嗪双羟萘酸盐晶型E的X射线粉末衍射图基本如图16所示。
根据本发明的实施方案，所述的卡利拉嗪双羟萘酸盐为卡利拉嗪双羟萘酸盐晶型G。
根据本发明的实施方案，所述的卡利拉嗪双羟萘酸盐晶型G的X射线粉末衍射图在2θ值为8.7°±0.2°、10.0°±0.2°、13.6°±0.2°、14.3°±0.2°、17.5°±0.2°、18.0°±0.2°、20.3°±0.2°、23.2°±0.2°、25.1°±0.2°等处有特征峰。
进一步地，所述的卡利拉嗪双羟萘酸盐晶型G的X射线粉末衍射图基本如图17所示。
根据本发明的实施方案，所述的卡利拉嗪双羟萘酸盐为卡利拉嗪双羟萘酸盐晶型I。
根据本发明的实施方案，所述的卡利拉嗪双羟萘酸盐晶型I的X射线粉末衍射图在2θ值为10.0°±0.2°、14.9°±0.2°、16.3°±0.2°、17.7°±0.2°、18.5°±0.2°、19.0°±0.2°、21.1°±0.2°、22.1°±0.2°、24.5°±0.2°等处有特征峰。
进一步地，所述的卡利拉嗪双羟萘酸盐晶型I的X射线粉末衍射图基本如图18所示。
根据本发明的实施方案，所述卡利拉嗪药物组合物还可以包括辅料，所述辅料可以选自助悬剂、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0～10mg/mL，优选为3.5mg/mL～5mg/mL，如3.5mg/mL、4.0mg/mL、4.5mg/mL或5.0mg/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、甲基纤维素和聚乙烯吡咯烷酮中的一种或多种，优选为羧甲基纤维素钠。
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。
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，优选为吐温20。
根据本发明的实施方案，所述渗透压调节剂的浓度范围为20～30mg/mL，优选为23mg/mL～26mg/mL，如23mg/mL、24.7mg/mL或26mg/mL。
根据本发明的实施方案，所述渗透压调节剂选自氯化钠、甘露醇和蔗糖中的一种或多种。
根据本发明的实施方案，所述稳定剂的浓度范围为0～30mg/mL，优选为1mg/mL～10mg/mL，如1mg/mL、3mg/mL、5mg/mL或7.0mg/mL。
根据本发明的实施方案，所述稳定剂为PVP K12。
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，所述表面活性剂为脱氧胆酸钠。
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，所述卡利拉嗪组合物可以包括：
(a)卡利拉嗪双羟萘酸盐；
(b)羧甲基纤维素钠；
(c)吐温20；
(d)磷酸氢二钠；
(e)磷酸二氢钠；和
(f)甘露醇；
并且，可选地，所述卡利拉嗪组合物可以包含氢氧化钠或盐酸。
根据本发明的实施方案，所述卡利拉嗪组合物为卡利拉嗪注射剂，如卡利拉嗪长效注射剂。
根据本发明的实施方案，所述卡利拉嗪组合物或卡利拉嗪长效注射剂中，所述卡利拉嗪固体粒子的浓度不低于15mg/mL。
根据本发明的实施方案，所述卡利拉嗪组合物的制备方法包括下列步骤：
(1)将润湿剂、缓冲剂、渗透压调节剂，溶解于溶剂中；
(2)加入卡利拉嗪固体粒子，得到粗颗粒的混悬水溶液；
(3)将上述粗颗粒混悬水溶液使用球磨机研磨，得到混悬液；
(4)将助悬剂加入上述混悬液中，混匀，可选地用氢氧化钠或盐酸调节pH为4.0～9.0， 定容，即得混悬水溶液。
根据本发明制备方法的实施方案，步骤(1)中，可将润湿剂、缓冲剂和渗透压调节剂依次溶解于溶剂中，例如溶解于注射用水中。
根据本发明制备方法的实施方案，步骤(4)中，调节后的pH可以为4.0、4.5、5.0、5.5、6.0、6.5、7.0、7.5、8.0、8.5或9.0。
本发明提供了所述卡利拉嗪药物组合物在制备治疗和/或预防精神病、双相性障碍、急性躁狂症的药物中的应用。
本发明还提供一种治疗和/或预防精神病、双相性障碍或急性躁狂症的方法，包括将所述卡利拉嗪药物组合物施用于有需要的患者。
根据本发明的实施方案，所述“Dv(10)”、“Dv(50)”和“Dv(90)”是指体积加权的粒子直径，其中在测量时分别有累积10v/v％、50v/v％或90v/v％的粒子具有相等或较小的直径。例如，如果粒子群的Dv(50)为约25微米，则50％体积的粒子具有小于或等于约25微米的直径。
在不违背本发明精神的基础上，本领域技术人员可以对上述各优选条件进行组合，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。
根据本发明的实施方案，所述室温是指环境温度为10℃～35℃。
有益效果
本发明人通过不断的研究、筛选与尝试，最终发现卡利拉嗪难溶性盐中的卡利拉嗪双羟萘酸盐符合长效缓释制剂的优点，并可以开发成混悬注射剂，同时可以克服盐酸卡利拉嗪解离的风险和可以达到长效给药的作用，以及大鼠中较低的血药浓度，大大提高了患者的依从性以及药物的生物利用度与用药安全性。
本发明的卡利拉嗪药物组合物具有持续释放作用，生物利用度高，溶液稳定性好，给药体积小等特点，给药一次可持续释放卡利拉嗪至少一周或更久，市场化前景良好。
附图说明
图1为卡利拉嗪双羟萘酸盐无定型的XRPD图谱；
图2为卡利拉嗪双羟萘酸盐晶型A的XRPD图谱；
图3为卡利拉嗪双羟萘酸盐晶型A的DSC图谱；
图4为卡利拉嗪双羟萘酸盐晶型A的TGA图谱；
图5为卡利拉嗪双羟萘酸盐晶型A的 1H-NMR图谱；
图6为卡利拉嗪双羟萘酸盐晶型F的XRPD图谱；
图7为卡利拉嗪双羟萘酸盐晶型F的DSC图谱；
图8为卡利拉嗪双羟萘酸盐晶型F的TGA图谱；
图9为卡利拉嗪双羟萘酸盐晶型F的 1H-NMR图谱；
图10为卡利拉嗪双羟萘酸盐晶型D的XRPD图谱；
图11为卡利拉嗪双羟萘酸盐晶型D的DSC图谱；
图12为卡利拉嗪双羟萘酸盐晶型D的TGA图谱；
图13为卡利拉嗪双羟萘酸盐晶型D的 1H-NMR图谱；
图14为卡利拉嗪双羟萘酸盐晶型B的XRPD图谱；
图15为卡利拉嗪双羟萘酸盐晶型C的XRPD图谱；
图16为卡利拉嗪双羟萘酸盐晶型E的XRPD图谱；
图17为卡利拉嗪双羟萘酸盐晶型G的XRPD图谱；
图18为卡利拉嗪双羟萘酸盐晶型I的XRPD图谱；
图19为卡利拉嗪盐酸盐晶型I的XRPD图谱；
图20为体外溶出模拟实验结果图(■为卡利拉嗪双羟萘酸盐无定型；◆为卡利拉嗪双羟萘酸盐晶型A；●为卡利拉嗪双羟萘酸盐晶型B；▲为卡利拉嗪双羟萘酸盐晶型G)；
图21为对比例4中pH7.4条件下卡利拉嗪双羟萘酸盐与卡利拉嗪盐酸盐的XRPD图谱叠图(A为卡利拉嗪游离碱；B为卡利拉嗪盐酸盐晶型I；C为卡利拉嗪盐酸盐晶型I在pH7.4介质振荡后；D为卡利拉嗪双羟萘酸盐晶型A；E为卡利拉嗪双羟萘酸盐晶型A在pH7.4介质振荡后)。
图22：描述在大鼠体中本发明实施例44制剂口服样品，卡利拉嗪的平均血药浓度与时间的关系图；
图23：描述在大鼠体内本发明实施例40-43制剂注射样品，卡利拉嗪的平均血药浓 度与时间的关系图(■为卡利拉嗪双羟萘酸盐无定型；◆为卡利拉嗪双羟萘酸盐晶型A；●为卡利拉嗪双羟萘酸盐晶型B；▲为卡利拉嗪双羟萘酸盐晶型E)；
图24：图23的局部放大图(0～24小时卡利拉嗪的平均血药浓度与时间的关系图)(■为卡利拉嗪双羟萘酸盐无定型；◆为卡利拉嗪双羟萘酸盐晶型A；●为卡利拉嗪双羟萘酸盐晶型B；▲为卡利拉嗪双羟萘酸盐晶型E)。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明拘囿于所述实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
除非另有说明，下文实施例中的原料和试剂可通过商购获得，或由本领域技术人员根据本领域已知的方法制备获得。
分别采用核磁共振( 1H-NMR)、X-射线粉末衍射(XRPD)、差示扫描量热法(DSC)、热重分析(TGA)、热台偏正光显微镜(PLM)、高效液相色谱(HPLC)对实施例的盐型化合物进行测试，测试参数如下：
(1) 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。
(2)DSC测量在TA Instruments型号Q2000中密封盘装置进行，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的速率升温至300℃，收集数据，实验气氛为氮气。
(3)TGA测量在TA Instruments型号Q500装置中进行，将样品(约2～5mg)在铝盘中称量，转移至仪器中进行测量。测试参数如下：仪器以10℃/min的速率升温至350℃，收集数据，实验气氛为氮气。
(4)XRPD测量在布鲁克型号为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。
(5)PLM测量在上海点应光学仪器型号为DYP990/TPH350的热台偏光显微镜中进行，取少量样品分散在载玻片中于10倍目镜以及5-40倍物镜中拍照。
(6)HPLC含量和有关物质检测方法：
含量方法：
Figure PCTCN2021114754-appb-000002
含量梯度洗脱程序表：
时间(min) 流动相A(％) 流动相B(％)
0 60 40
2 40 60
5 15 85
5.1 60 40
10 60 40
有关物质方法：
Figure PCTCN2021114754-appb-000003
有关梯度洗脱程序表：
Figure PCTCN2021114754-appb-000004
Figure PCTCN2021114754-appb-000005
除非另有说明，本发明上下文中卡利拉嗪药物组合物混悬水溶液粒度检测仪器的检测条件如下：
进样器名称：SCF-105B                   物质名称：卡利拉嗪组合物
颗粒折射率：1.595                      分散剂折射率：1.333
分散剂：水                             背景测试时间：10s
样品测试时间：10s                      遮光度：10-20％
搅拌速度：700-2000r/min                分析模型：通用
测量范围：0.02-2100μm                 颗粒吸收率：0.1
重复测量三次，创建平均值。
实施例1：卡利拉嗪双羟萘酸盐的制备
将4000mg(9.36mmol)卡利拉嗪溶于200mL(5.4mg/mL)磷酸溶液中，得到溶液A；将3634mg(9.36mmol)双羟萘酸溶于100mL(7.5mg/mL)氢氧化钠溶液中，得到溶液B。搅拌下将100mL溶液B于30分钟内加入200mL溶液A中，过滤分离产物并用水冲洗，40℃真空干燥12小时，得到5840mg浅黄色固体，收率为76％(以游离碱计)。
通过核磁共振氢谱证实了本发明所述的卡利拉嗪双羟萘酸盐的结构及摩尔比。
1H-NMR(400MHz,DMSO-d6)：δ8.38(s,2H)，8.16(d,2H)，8.80(d,2H)，7.39-7.13(m,7H)，5.86(d,1H)，4.76(s,2H)，3.40-3.32(m,3H)，3.22-3.18(m,4H)，2.75(s,6H)，1.76(t,4H)，1.63-1.57(m,2H)，1.25-1.16(m,3H)，1.04-0.96(m,2H)。
核磁结果显示卡利拉嗪和双羟萘酸以摩尔比为1:1成盐。
上述样品进行固相表征检测，XRPD图谱见图1，检测结果显示为无定型。
实施例2：卡利拉嗪双羟萘酸盐无定型的制备
60℃条件下，将20g(46.8mmol)卡利拉嗪与18.17g(46.8mmol)双羟萘酸溶解于170mL THF:MeOH(2:1)混合溶剂中，过滤，减压浓缩除去溶剂，再加入300mL 甲醇，60℃溶解，减压浓缩除去溶剂，40℃真空干燥12小时，得到36.6g卡利拉嗪双羟萘酸盐无定型。
实施例3：卡利拉嗪半双羟萘酸盐的制备
将200mg(0.468mmol)卡利拉嗪溶于10mL(5.4mg/mL)磷酸溶液中，得到溶液A；将90.85mg(0.234mmol)双羟萘酸溶于2.5mL(7.5mg/mL)氢氧化钠溶液中，得到溶液B。搅拌下将2.5mL溶液B于30分钟内加入10mL溶液A中，过滤分离产物并用水冲洗，40℃真空干燥12小时，得到204mg浅黄色固体，收率为70％。
通过核磁共振氢谱证实了本发明所述的卡利拉嗪双羟萘酸盐的结构及摩尔比。
1H-NMR(400MHz,DMSO-d6)：δ8.25(s,1H)，8.18(d,1H)，7.69(d,1H)，7.38-7.31(m,2H)，7.22-7.14(m,2H)，7.05(t,1H)，5.86(d,1H)，4.71(s,1H)，3.39-3.22(m,5H)，2.75(s,6H)，1.75(t,4H)，1.59-1.54(m,2H)，1.25-1.15(m,3H)，1.04-0.95(m,2H)。
核磁结果显示卡利拉嗪和双羟萘酸以摩尔比为2:1成盐。
上述样品进行PLM检测，显示该样品为无偏光固体，为无定型。
实施例4：卡利拉嗪1-羟基-2-萘甲酸盐的制备
将100mg(0.234mmol)卡利拉嗪与45mg(0.234mmol)1-羟基-2-萘甲酸加入8mL甲醇中，搅拌溶清，过滤，加入3倍体积的正庚烷，室温挥发至溶剂干，为油状物，40℃真空干燥4小时，得到固体。
PLM检测发现该固体具有偏光，在约200℃开始熔融。
1H-NMR(400MHz,DMSO-d6)：δ8.23(d,1H)，7.80-7.74(m,2H)，7.57-7.53(m,1H)，7.48-7.44(m,1H)，7.38-7.31(m,2H)，7.20-7.16(m,2H)，5.86(d,1H)，3.36-3.09(m,10H)，2.75(s,6H)，1.74(t,4H)，1.61-1.56(m,2H)，1.33-1.15(m,5H)，1.02-0.83(m,3H)。
核磁结果显示卡利拉嗪与1-羟基-2-萘甲酸以摩尔比为1:1成盐。
实施例5：卡利拉嗪月桂酸盐的制备
将50mg(0.117mmol)卡利拉嗪与23.7mg(0.118mmol)月桂酸加入5mL甲醇中，置于50℃条件下溶解，室温搅拌12小时，加入2倍体积的水，过滤，固体于40℃条件下真空干燥12小时，得到卡利拉嗪月桂酸盐。
实施例6：卡利拉嗪软脂酸盐的制备
将50mg(0.117mmol)卡利拉嗪与30.3mg(0.118mmol)软脂酸加入5mL甲醇中，置于50℃条件下溶解，室温搅拌12小时，加入1倍体积的水，过滤，固体于40℃条件下真空干燥12小时，得到卡利拉嗪软脂酸盐。
实施例7：卡利拉嗪癸二酸盐、卡利拉嗪琥珀酸盐、卡利拉嗪苹果酸盐、卡利拉嗪乳酸盐、卡利拉嗪十一烷酸盐、卡利拉嗪庚酸盐的制备
按照1:1.1的摩尔比称量卡利拉嗪与酸。将各种酸分别溶于甲醇溶剂，所得酸性试剂于室温条件下加入卡利拉嗪甲醇溶液中进行成盐反应。室温搅拌12小时后并置于室温下挥发、干燥得到相应的卡利拉嗪盐。
实施例8：卡利拉嗪双羟萘酸盐晶型A的制备
取2000mg实施例1制备得到的卡利拉嗪双羟萘酸盐，加入20mL甲醇中，室温搅拌析晶24小时，过滤，55℃真空干燥，得到1900mg卡利拉嗪双羟萘酸盐晶型A，收率为95％。
其X射线粉末衍射图如图2所示。
其差式扫描量热分析图如图3所示，显示熔点为166.5℃。
其热重分析图如图4所示，显示在115℃之前有两段失重，归结于表面溶剂和通道水的损失，在115～165℃时，有约1.1％的失重，归结于结晶水的损失。
其核磁图如图5所示，显示卡利拉嗪与双羟萘酸以摩尔比1:1成盐。
实施例9：卡利拉嗪双羟萘酸盐晶型A的制备
取30g实施例2制备得到的卡利拉嗪双羟萘酸盐无定型固体样品，加入300mL甲醇中，10℃搅拌析晶24小时，过滤，55℃真空干燥，得到28.5g卡利拉嗪双羟萘 酸盐晶型A。
实施例10：卡利拉嗪双羟萘酸盐晶型B的制备
取200mg实施例9所得的卡利拉嗪双羟萘酸盐晶型A在甲醇溶剂中形成浆液，卡利拉嗪双羟萘酸盐晶型A与溶剂的重量体积比为40mg/mL，搅拌3天析晶，得到180mg卡利拉嗪双羟萘酸盐晶型B。
其X射线粉末衍射图如图14所示。
核磁结果显示其为甲醇溶剂合物。
实施例11：卡利拉嗪双羟萘酸盐晶型B的制备
取2g实施例9制备得到的卡利拉嗪双羟萘酸盐晶型A，加入50mL甲醇中，室温搅拌析晶72小时，过滤，55℃真空干燥，得到1.9mg卡利拉嗪双羟萘酸盐晶型B。
实施例12：卡利拉嗪双羟萘酸盐晶型C的制备
取实施例8所得的卡利拉嗪双羟萘酸盐晶型A在丙酮溶剂中形成浆液，卡利拉嗪双羟萘酸盐晶型A与溶剂的重量体积比为40mg/mL，搅拌3天析晶，得到卡利拉嗪双羟萘酸盐晶型C。
其X射线粉末衍射图如图15所示。
核磁结果显示其为丙酮溶剂合物。
实施例13：卡利拉嗪双羟萘酸盐晶型D的制备
取200mg实施例8制备得到的卡利拉嗪双羟萘酸盐晶型A，加入2mL乙醇中，室温搅拌析晶48小时，过滤，55℃真空干燥，得到190mg卡利拉嗪双羟萘酸盐晶型D，收率为95％。
其X射线粉末衍射图如图10所示。
其差式扫描量热分析图如图11所示，显示熔点为164.6℃。
其热重分析图如图12所示，显示在190℃之前有约4％的失重，归结于水和乙醇的损失。
其核磁图如图13所示，显示卡利拉嗪与双羟萘酸以摩尔比1:1成盐，含约0.67个乙醇分子。
实施例14：卡利拉嗪双羟萘酸盐晶型E的制备
取实施例8所得的卡利拉嗪双羟萘酸盐晶型A在乙腈溶剂中形成浆液，卡利拉嗪双羟萘酸盐晶型A与溶剂的重量体积比为40mg/mL，搅拌3天析晶，得到卡利拉嗪双羟萘酸盐晶型E。
其X射线粉末衍射图如图16所示。
实施例15：卡利拉嗪双羟萘酸盐晶型E的制备
取2g实施例9制备得到的卡利拉嗪双羟萘酸盐晶型A，加入50mL乙腈中，室温搅拌析晶72小时，过滤，55℃真空干燥，得到1.8g卡利拉嗪双羟萘酸盐晶型E。
实施例16：卡利拉嗪双羟萘酸盐晶型F的制备
取200mg实施例8制备得到的卡利拉嗪双羟萘酸盐晶型A，加入20mL乙酸异丙酯中，室温搅拌析晶12小时，过滤，55℃真空干燥，得到180mg卡利拉嗪双羟萘酸盐晶型F，收率为90％。
其X射线粉末衍射图如图6所示。
其差式扫描量热分析图如图7所示，显示熔点约为166.6℃。
其热重分析图如图8所示，显示在115℃之前有约1.3％的失重，归结于通道水的损失；在115～175℃有约1.3％的失重，归结于结晶水的损失。
其核磁图如图9所示，显示卡利拉嗪与双羟萘酸以摩尔比1:1成盐。
实施例17：卡利拉嗪双羟萘酸盐晶型G的制备
取200mg实施例8所得的卡利拉嗪双羟萘酸盐晶型A，加入5mL乙腈形成浆液，搅拌5天析晶，得到卡利拉嗪双羟萘酸盐晶型G。
其X射线粉末衍射图如图17所示。
核磁结果显示其为乙腈溶剂合物。
实施例18：卡利拉嗪双羟萘酸盐晶型I的制备
取15mg实施例1所得的卡利拉嗪双羟萘酸盐无定型固体样品于光照条件下10天，得到卡利拉嗪双羟萘酸盐晶型I。
其X射线粉末衍射图如图18所示。
实施例19：卡利拉嗪盐酸盐晶型I的制备
根据卡利拉嗪盐酸盐原研专利制备卡利拉嗪盐酸盐晶型I样品：
1g市售卡利拉嗪游离碱加入25mL圆底烧瓶，加入2mL甲醇与8mL水，70℃油浴锅搅拌0.5h，加入0.226mL浓盐酸与0.35mL水的混合溶液，溶清后趁热过滤，关闭加热自然冷却过夜，收得0.8g类白色固体。
其X射线粉末衍射图如图19所示，显示为卡利拉嗪盐酸盐晶型I。
对比例1：有关物质与晶型稳定性对比
分别取实施例1制得的卡利拉嗪双羟萘酸盐无定型、实施例8制得的卡利拉嗪双羟萘酸盐晶型A、实施例10制得的卡利拉嗪双羟萘酸盐晶型B、实施例16制得的卡利拉嗪双羟萘酸盐晶型F、实施例17制得的卡利拉嗪双羟萘酸盐晶型G、实施例19制得的卡利拉嗪盐酸盐晶型I于高温(60℃)，高湿(25℃/90％RH)，加速(40℃/75％RH)，光照(1.2×10 6Lux·hr)条件下放置，于0天、5天、7天、10天取样进行HPLC或XRPD检测。
有关物质结果见表1，显示本发明的卡利拉嗪双羟萘酸盐晶型A、卡利拉嗪双羟萘酸盐晶型B和卡利拉嗪双羟萘酸盐晶型G，卡利拉嗪双羟萘酸盐晶型A较稳定，在各条件下放置10天，有关物质总和基本不变，而卡利拉嗪双羟萘酸盐无定型在高温条件下不稳定，杂质增长较多。
晶型稳定性结果见表2，其显示与已知的卡利拉嗪盐酸盐晶型I相比，本发明的卡利拉嗪双羟萘酸盐晶型A具有更优异的晶型稳定性，在各条件下放置10天，晶型未变，结晶度也未明显变化；本发明的卡利拉嗪双羟萘酸盐晶型F在高温和光照条件下较稳定，晶型未发生变化，在高湿和加速条件会向卡利拉嗪双羟萘酸盐晶型A转变。
表1有关物质结果
Figure PCTCN2021114754-appb-000006
表2晶型稳定性结果
Figure PCTCN2021114754-appb-000007
对比例2：溶解度对比
分别取实施例1制得的卡利拉嗪双羟萘酸盐无定型、实施例3制得的卡利拉嗪半双羟萘酸盐无定型、实施例5制得的卡利拉嗪月桂酸盐、实施例6制得的卡利拉嗪软脂酸盐、实施例7制得的卡利拉嗪癸二酸盐、卡利拉嗪琥珀酸盐、卡利拉嗪苹果酸盐、卡利拉嗪乳酸盐、卡利拉嗪十一烷酸盐、卡利拉嗪庚酸盐、实施例8制得的卡利拉嗪双羟萘酸盐晶型A、实施例10制得的卡利拉嗪双羟萘酸盐晶型B、实施例16制得的卡利拉嗪双羟萘酸盐晶型F、实施例17制得的卡利拉嗪双羟萘酸盐晶型G、实施例19制备的卡利拉嗪盐酸盐晶型I、卡利拉嗪将其分别加入到相应介质中，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，pH3、pH4、pH5和pH6为醋酸缓冲溶液、pH7、pH7.4、pH8和pH9为磷酸缓冲溶液。
结果见表3，显示本发明制得的卡利拉嗪双羟萘酸盐及其晶型与半双羟萘酸盐的溶解度均大幅低，卡利拉嗪双羟萘酸盐在水中的溶解度为3～10μg/mL相当于卡利拉嗪的十八分之一至六十分之一(约180μg/mL)，盐酸卡利拉嗪的千分之一至三千六百分之一(约11mg/mL)，以及在各个pH介质中均较低，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，且卡利拉嗪双羟萘酸盐的晶型稳定性较好，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3溶解度结果
Figure PCTCN2021114754-appb-000008
对比例3：体外溶出模拟实验
分别取实施例1制得的卡利拉嗪双羟萘酸盐无定型、实施例8制得的卡利拉嗪双羟萘酸盐晶型A、实施例10制得的卡利拉嗪双羟萘酸盐晶型B、实施例17制得的卡利拉嗪双羟萘酸盐晶型G，将其分别加入到pH7.4磷酸缓冲溶液介质中，在37℃条件下振荡，于1、3、5、7、24小时取点检测溶解度。
结果见表4与图20，其显示本发明制得的卡利拉嗪双羟萘酸盐晶型A与卡利拉嗪双羟萘酸盐晶型B两种晶型化合物样品较卡利拉嗪双羟萘酸盐无定型样品在pH7.4条件下 溶出更平缓且24小时溶解度小，说明晶型化合物更适合作为药用盐，避免血药浓度过高。
表4体外溶出模拟实验结果
Figure PCTCN2021114754-appb-000009
对比例4：溶液稳定性对比
分别取实施例8制得的卡利拉嗪双羟萘酸盐晶型A、实施例19制得的卡利拉嗪盐酸盐晶型I，将其分别加入到pH6、pH7、pH7.4、pH8、pH9等相应介质中，在37℃条件下振荡4小时，离心，对残渣进行XRPD检测，结果显示卡利拉嗪双羟萘酸盐晶型A并未发生变化，而卡利拉嗪盐酸盐晶型I解离为卡利拉嗪游离碱，pH7.4对比结果见图21(其余未示出)，由此可见，卡利拉嗪双羟萘酸盐晶型A在溶液中较卡利拉嗪盐酸盐晶型I更稳定，可有效避免给药后因晶型的变化引起的药效改变，提高用药的安全性。
实施例20-25：不同助悬剂用量的卡利拉嗪双羟萘酸盐混悬水溶液
Figure PCTCN2021114754-appb-000010
制备过程：
(1)称取处方量吐温20、磷酸氢二钠、磷酸二氢钠、甘露醇与约60％配制总量的注射用水中，搅拌溶解分散；
(2)加入处方量的卡利拉嗪双羟萘酸盐晶型A，得到粗颗粒的混悬水溶液；
(3)将上述粗颗粒混悬水溶液使用球磨机研磨，得到Dv(90)小于等于10微米的混悬液；
(4)分别加入处方量的羧甲基纤维素钠至上述混悬液中，搅拌至完全分散，可选地用氢氧化钠或盐酸调节pH为4.0～9.0，定容，即得实施例20-25混悬液。
分别取实施例20-25所制得的处方样品，进行通针性、混悬性、沉降比以及重分散性考察，发现上述混悬液样品均可通过0.45*15mm注射器针头，混悬性良好，实施例22-25样品24小时沉降比及重分散性良好。
实施例26-30：不同润湿剂用量的卡利拉嗪双羟萘酸盐混悬水溶液
Figure PCTCN2021114754-appb-000011
制备过程：
(1)称取处方量吐温20、磷酸氢二钠、磷酸二氢钠、甘露醇与约60％配制总量的注射用水中，搅拌溶解分散；
(2)加入处方量的卡利拉嗪双羟萘酸盐晶型A，得到粗颗粒的混悬水溶液；
(3)分别将上述粗颗粒混悬水溶液使用球磨机研磨，得到Dv(90)小于等于10微米的混悬液；
(4)分别加入处方量的羧甲基纤维素钠至上述混悬液中，搅拌至完全分散，可选地用氢氧化钠或盐酸调节pH为4.0～9.0，定容，即得实施例26-30混悬液。
分别取实施例26-30所制得的处方样品，进行通针性、混悬性、沉降比以及润湿性考察，发现上述混悬液样品均可通过0.45*15mm注射器针头，混悬性、沉降比以及润湿性均良好。
实施例31-34：不同粒径卡利拉嗪双羟萘酸盐混悬水溶液
Figure PCTCN2021114754-appb-000012
制备过程：
(1)称取处方量吐温20、磷酸氢二钠、磷酸二氢钠、甘露醇与约60％配制总量的注射用水中，搅拌溶解分散；
(2)加入处方量的卡利拉嗪双羟萘酸盐晶型A，得到粗颗粒的混悬水溶液；
(3)分别将上述实施例31-34所得粗颗粒混悬水溶液使用球磨机研磨分散；
(4)分别加入处方量的羧甲基纤维素钠至上述混悬液中，搅拌至完全分散，定容，即得pH7.4±0.2的实施例32-35混悬液；
(5)采用OMEC LS-909粒度测定仪测定研磨后实施例样品粒度分布，结果见下表：
Figure PCTCN2021114754-appb-000013
Figure PCTCN2021114754-appb-000014
根据上表结果可知，同样处方的混悬水溶液中，通过控制研磨参数，可制备出不同粒径大小(Dv90)颗粒的混悬水溶液。
实施例35-37：不同晶型卡利拉嗪双羟萘酸盐混悬水溶液
Figure PCTCN2021114754-appb-000015
制备过程：
(1)称取处方量吐温20、磷酸氢二钠、磷酸二氢钠、甘露醇与约60％配制总量的注射用水中，搅拌溶解分散；
(2)分别加入处方量的卡利拉嗪双羟萘酸盐相应样品，得到粗颗粒的混悬水溶液；
(3)分别将上述实施例35-37所得粗颗粒混悬水溶液使用球磨机研磨分散；
(4)分别加入处方量的羧甲基纤维素钠至上述混悬液中，搅拌至完全分散，定容，即得pH7.4±0.2的实施例35-37混悬液；
(5)采用OMEC LS-909粒度测定仪测定研磨后实施例样品粒度分布，结果见下表：
Figure PCTCN2021114754-appb-000016
分别取实施例35-37所制得的处方样品，进行通针性、混悬性、沉降比以及润湿性考察，发现上述混悬液样品均可通过0.45*15mm注射器针头，混悬性、沉降比以及润湿性 均良好。
根据上表结果以及通针性、混悬性、沉降比与润湿性考察，同样处方的混选水溶液中以及相同研磨参数，对于卡利拉嗪双羟萘酸盐的不同晶型均适用。
实施例38：卡利拉嗪盐酸盐混悬水溶液
Figure PCTCN2021114754-appb-000017
制备过程：
(1)称取处方量吐温20、磷酸氢二钠、磷酸二氢钠、甘露醇与约60％配制总量的注射用水中，搅拌溶解分散；
(2)加入处方量的卡利拉嗪盐酸盐，得到粗颗粒的混悬水溶液；
(3)将上述所得粗颗粒混悬水溶液使用球磨机研磨分散；
(4)加入处方量的羧甲基纤维素钠至上述混悬液中，搅拌至完全分散，定容，即得pH7.4±0.2的实施例38混悬液；
(5)采用OMEC LS-909粒度测定仪测定研磨后实施例样品粒度分布，结果见下表：
Figure PCTCN2021114754-appb-000018
实施例39：卡利拉嗪双羟萘酸盐与卡利拉嗪盐酸盐混悬水溶液60℃稳定性考察
取实施例33制备所得卡利拉嗪双羟萘酸盐以及实施例38制备所得卡利拉嗪盐酸盐混悬水溶液于60℃条件下检测0、5、10天的粒径与有关，结果见下表：
Figure PCTCN2021114754-appb-000019
根据上表结果可知，同样处方的混悬水溶液中，卡利拉嗪双羟萘酸盐混悬水溶液在杂质以及粒径的稳定性方面均明显优于卡利拉嗪盐酸盐混悬水溶液稳定。
实施例40-44：卡利拉嗪双羟萘酸盐混悬液处方在大鼠体内的药物动力学研究
Figure PCTCN2021114754-appb-000020
1、实施例40-43混悬注射液制备过程：
(1)称取处方量吐温20、磷酸氢二钠、磷酸二氢钠、甘露醇、羧甲基纤维素钠与约60％配制总量的注射用水中，搅拌溶解分散；
(2)分别加入处方量的卡利拉嗪双羟萘酸盐相应样品，搅拌至完全分散，定容，即得pH7.4±0.2的实施例40-43混悬注射液；
(3)采用OMEC LS-909粒度测定仪测定实施例41-43样品粒度分布，结果见下表：
Figure PCTCN2021114754-appb-000021
2、实施例44口服混悬液制备过程：
(1)称取处方量的吐温20、羧甲基纤维素钠与约60％配制总量的注射用水中，搅拌溶解分散；
(2)加入处方量的卡利拉嗪双羟萘酸盐，得到粗颗粒的混悬水溶液，用盐酸调节pH为5.0至5.5，定容，得到最终实施例44的混悬口服液。
实施例45：药代动力学实验
选择实施例40-44制备所得不同浓度卡利拉嗪双羟萘酸盐处方样品，进行大鼠体内实验，实验如下：
15只雄性SD大鼠分为五组，其中四组单剂量9mg/kg经肌肉注射给予不同卡利拉嗪双羟萘酸盐晶型处方样品，并于给药后0,1h,3h,7h,24h,4d,7d,11d,15d,20d,25d,30d采集血浆；剩余一组单剂量0.3mg/kg经口服灌胃给予卡利拉嗪双羟萘酸盐晶型A处方样品，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，取1μL溶液进行LC-MS/MS分析。
色谱条件：
流动相组成：流动相A：0.025％甲酸水-1mM乙酸铵
流动相B：0.025％甲酸甲醇-1mM乙酸铵
梯度洗脱：
时间(分钟) Pump B(％)
初始 10
0.20 10
0.70 95
1.30 95
1.31 10
1.80 10
色谱柱：Waters ACQUITY UPLC BEH C18(2.1×50mm,1.7μm)；
流速：0.60mL/min；
进样体积：1μL；
柱温箱：60℃；
保留时间：卡利拉嗪：1.16min；Glipizide：1.22min。
质谱条件：
采用电喷雾离子源(Turbo spray)，在正离子检测模式下，选择多通道反应监测(MRM)模式进行二级质谱分析。质谱检测工作参数及离子源参数见下表。
Figure PCTCN2021114754-appb-000022
从图22-24中可以看出，卡利拉嗪双羟萘酸盐口服组在给药后24小时内快速吸收，而卡利拉嗪双羟萘酸盐注射组给药后较口服组均达到至少11天的持续释放，结合种属间差异，预计在人体中可达至少30天释放。同时，在卡利拉嗪双羟萘酸盐各晶型之间以卡利拉嗪双羟萘酸盐晶型A释放时长为最优。
根据本发明的实验结果可知，本发明提供的卡利拉嗪双羟萘酸盐注射制剂在制备成混悬水溶液后，其中卡利拉嗪双羟萘酸盐粒度较小，分布均匀，具有良好的可注射性，同时具有长时间持续释放药物的特征(在SD大鼠体内至少一周时间)。

Claims (10)

  1. 一种卡利拉嗪药物组合物，其特征在于，所述卡利拉嗪药物组合物包含卡利拉嗪固体粒子，其中所述卡利拉嗪固体粒子的粒径Dv(10)≤30微米、Dv(50)≤50微米且Dv(90)≤100微米，优选≤10微米；
    所述卡利拉嗪固体粒子可以选自卡利拉嗪、卡利拉嗪药学上可接受的盐及其溶剂合物的固体粒子；
    优选地，所述卡利拉嗪固体粒子为卡利拉嗪双羟萘酸盐的固体粒子。
  2. 根据权利要求1所述的卡利拉嗪药物组合物，其特征在于，所述的卡利拉嗪双羟萘酸盐选自卡利拉嗪双羟萘酸盐晶型A、F、D、B、C、E、G、I中的一种或多种，其中：
    所述的卡利拉嗪双羟萘酸盐晶型A的X射线粉末衍射图在2θ值为13.1°±0.2°、18.7°±0.2°、21.0°±0.2°等处有特征峰，优选在2θ值为4.8°±0.2°、13.1°±0.2°、18.7°±0.2°、20.1°±0.2°、21.0°±0.2°、26.1°±0.2°等处有特征峰；更优选在2θ值为4.8°±0.2°、9.7±0.2°、12.3°±0.2°、13.1°±0.2°、18.7°±0.2°、20.1°±0.2°、21.0°±0.2°、26.1°±0.2°等处有特征峰；
    所述的卡利拉嗪双羟萘酸盐晶型F的X射线粉末衍射图在2θ值为4.9°±0.2°、19.2°±0.2°、21.0°±0.2°等处有特征峰；优选在2θ值为4.9°±0.2°、13.6°±0.2°、19.2°±0.2°、21.0°±0.2°、24.0°±0.2°、26.3°±0.2°等处有特征峰；更优选在2θ值为4.9°±0.2°、12.8°±0.2°、13.6°±0.2°、19.2°±0.2°、20.3°±0.2°、21.0°±0.2°、24.0°±0.2°、26.3°±0.2°等处有特征峰；
    所述的卡利拉嗪双羟萘酸盐晶型D的X射线粉末衍射图在2θ值为9.6°±0.2°、11.9°±0.2°、20.4°±0.2°等处有特征峰；优选在2θ值为9.6°±0.2°、11.9°±0.2°、16.6°±0.2°、20.4°±0.2°、24.5°±0.2°、25.3°±0.2°等处有特征峰；更优选在2θ值为9.6°±0.2°、11.9°±0.2°、15.2°±0.2°、16.6°±0.2°、20.4°±0.2°、20.7°±0.2°、24.5°±0.2°、25.3°±0.2°等处有特征峰；
    所述的卡利拉嗪双羟萘酸盐晶型B的X射线粉末衍射图在2θ值为5.2°±0.2°、10.5°±0.2°、14.0°±0.2°、14.4°±0.2°、17.5°±0.2°、21.3°±0.2°、21.9°±0.2°、22.9°±0.2°、26.2°±0.2°等处有特征峰；
    所述的卡利拉嗪双羟萘酸盐晶型C的X射线粉末衍射图在2θ值为8.6°±0.2°、13.0°±0.2°、16.8°±0.2°、17.3°±0.2°、18.2°±0.2°、18.5°±0.2°、19.8°±0.2°、22.1°±0.2°、 23.5°±0.2°等处有特征峰；
    所述的卡利拉嗪双羟萘酸盐晶型E的X射线粉末衍射图在2θ值为11.0°±0.2°、12.8°±0.2°、13.8°±0.2°、15.5°±0.2°、15.9°±0.2°、17.9°±0.2°、18.4°±0.2°、20.7°±0.2°、23.4°±0.2°等处有特征峰；
    所述的卡利拉嗪双羟萘酸盐晶型G的X射线粉末衍射图在2θ值为8.7°±0.2°、10.0°±0.2°、13.6°±0.2°、14.3°±0.2°、17.5°±0.2°、18.0°±0.2°、20.3°±0.2°、23.2°±0.2°、25.1°±0.2°等处有特征峰；
    所述的卡利拉嗪双羟萘酸盐晶型I的X射线粉末衍射图在2θ值为10.0°±0.2°、14.9°±0.2°、16.3°±0.2°、17.7°±0.2°、18.5°±0.2°、19.0°±0.2°、21.1°±0.2°、22.1°±0.2°、24.5°±0.2°等处有特征峰。
  3. 根据权利要求1或2所述的卡利拉嗪药物组合物，其特征在于，所述组合物为注射制剂；
    优选地，所述组合物还包括辅料，所述辅料包括但不限于助悬剂、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。
  4. 根据权利要求3所述的卡利拉嗪药物组合物，其特征在于，所述助悬剂的浓度范围为0～10mg/mL，优选为3.5mg/mL～5mg/mL；
    优选地，所述助悬剂选自羧甲基纤维素钠、甲基纤维素和聚乙烯吡咯烷酮中的一种或多种，优选为羧甲基纤维素钠。
  5. 根据权利要求3所述的卡利拉嗪药物组合物，其特征在于，所述润湿剂的浓度范围为1mg/mL～10mg/mL，优选为1mg/mL～5mg/mL；
    优选地，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，优选为吐温20。
  6. 根据权利要求3所述的卡利拉嗪药物组合物，其特征在于，
    根据本发明的实施方案，所述渗透压调节剂的浓度范围为20～30mg/mL，优选为 23mg/mL～26mg/mL；
    和/或，
    所述渗透压调节剂选自氯化钠、甘露醇和蔗糖中的一种或多种；
    和/或，
    所述稳定剂的浓度范围为0～30mg/mL，优选为1mg/mL～10mg/mL；
    和/或，
    所述稳定剂为PVP K12；
    和/或，
    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；
    和/或，
    所述表面活性剂为脱氧胆酸钠。
    和/或，
    所述溶剂为注射用水。
  7. 根据权利要求3所述的卡利拉嗪药物组合物，其特征在于，所述组合物包括：
    (a)卡利拉嗪双羟萘酸盐；
    (b)羧甲基纤维素钠；
    (c)吐温20；
    (d)磷酸氢二钠；
    (e)磷酸二氢钠；和
    (f)甘露醇；
    并且，可选地，所述卡利拉嗪组合物可以包含氢氧化钠或盐酸。
  8. 根据权利要求7所述的卡利拉嗪药物组合物，其特征在于，所述卡利拉嗪双羟萘酸盐固体粒子的浓度不低于15mg/mL。
  9. 如权利要求1-8任一项所述的卡利拉嗪药物组合物的制备方法，包括如下步骤：
    (1)将润湿剂、缓冲剂、渗透压调节剂，任选的，依次溶解于注射用水中；
    (2)加入卡利拉嗪双羟萘酸盐固体粒子，得到粗颗粒的混悬水溶液；
    (3)将上述粗颗粒混悬水溶液使用球磨机研磨，得到混悬液；
    (4)加入一定浓度的助悬剂至上述混悬液中，混匀，可选地用氢氧化钠或盐酸调节pH为4.0～9.0，定容，即得混悬水溶液。
  10. 如权利要求1-8任一项所述的卡利拉嗪药物组合物在制备治疗和/或预防精神病、双相性障碍和/或急性躁狂症的药物中的应用。
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