WO2021185154A1 - 替唑尼特药物组合物及其医药用途 - Google Patents

替唑尼特药物组合物及其医药用途 Download PDF

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WO2021185154A1
WO2021185154A1 PCT/CN2021/080327 CN2021080327W WO2021185154A1 WO 2021185154 A1 WO2021185154 A1 WO 2021185154A1 CN 2021080327 W CN2021080327 W CN 2021080327W WO 2021185154 A1 WO2021185154 A1 WO 2021185154A1
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tizoxanide
formula
choline salt
drug
pharmaceutical composition
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French (fr)
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仲伯华
周明
李宏武
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北京君科华元医药科技有限公司
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Publication of WO2021185154A1 publication Critical patent/WO2021185154A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • 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
    • A61K31/14—Quaternary ammonium compounds, e.g. edrophonium, choline
    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/625—Salicylic acid; Derivatives thereof having heterocyclic substituents, e.g. 4-salicycloylmorpholine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
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    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07C215/40—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 with quaternised nitrogen atoms bound to carbon atoms of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/58—Nitro radicals
    • 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
    • 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 present invention relates to a tizoxanide pharmaceutical composition and its medical use, in particular to a pharmaceutical composition containing tizoxanide and choline and its medical use.
  • Nitazoxanide (chemical name: o-N-(5-nitrothiazol-2-yl)carbamoyl-phenol-acetate; English name: Nitazoxanide) is a nitrothiazole salicylic acid amide derivative , Has antiprotozoal, anti-intestinal parasites, antibacterial and other medicinal effects.
  • nitazoxanide also has broad-spectrum antiviral activity (Rossignol JF., Antiviral Research, 2014; 110:94-103), which is effective against influenza A virus, influenza B virus, avian influenza, and respiratory syndrome.
  • Cellular virus, parainfluenza virus, coronavirus, rotavirus, norovirus, hepatitis B virus, hepatitis C virus, dengue fever virus, yellow fever virus, Japanese encephalitis virus and human immunodeficiency virus have inhibitory effects.
  • Nitrazoxanide is also effective against Mycobacterium tuberculosis (Ranjbar S, et al., iScience, 2019; 22:299-313) and Helicobacter pylori (Basu PP, et al., Am J Gastroenterol, 2011; 106:1970-1975) Good inhibitory effect.
  • the Chinese invention patent application (CN109069648A) discloses the use of nitazoxanide to treat cholestasis and fibrotic diseases; the fibrotic diseases include liver fibrosis, pulmonary fibrosis and the like.
  • Nitrazoxanide also has anti-tumor effects (Di Santo N and Ehrisman J., Mutation Research, 2014; 768: 16-21), and has anti-tumor effects (Di Santo N and Ehrisman J., Cancers, 2013; 5: 1163- 1176) and colon cancer (Senkowski W, Zhang X, et al., Mol Cancer Ther, 2015; 14: 1504-1516) have strong inhibitory effects.
  • Nitrazoxanide is difficult to dissolve in water (the solubility in water is 0.000189mg/ml), the dosage is large (500mg/time, 2 times/day), the oral bioavailability is low, and it is difficult to achieve effective antiviral concentration in the lungs.
  • the therapeutic effect of oral administration on respiratory viral infections is limited.
  • nitazoxanide After oral administration of nitazoxanide, it is transformed into the active metabolite tizoxanide (English name: Tizoxanide) and the inactive metabolite glucuronic acid conjugate in the body:
  • nitazoxanide After oral administration of nitazoxanide, the original form of nitazoxanide cannot be detected in the blood, but only tizoxanide and glucuronic acid conjugates can be detected.
  • the systemic exposure of glucuronic acid conjugates is higher than that of tizoxanide.
  • the present invention provides a pharmaceutical composition containing tizoxanide and choline hydroxide.
  • the molar ratio of tizoxanide and choline hydroxide in the pharmaceutical composition is 1:4 to 1:0.25.
  • the molar ratio of tizoxanide and choline hydroxide in the pharmaceutical composition is 1:2 to 1:0.5.
  • the molar ratio of tizoxanide and choline hydroxide is 1:1, 1:0.5, 1:0.25, 1:2, 1:3, 1:4.
  • tizoxanide and choline hydroxide form a salt with a molar ratio of 1:1.
  • the pharmaceutical composition contains tizoxanide choline salt represented by formula (I):
  • the present invention also provides the tizoxanide choline salt of the above formula (I).
  • the tizoxanide choline salt of formula (I) may be in an amorphous form or a crystalline form; preferably in a crystalline form.
  • the present invention also provides a crystal form of tizoxanide choline salt of the above formula (I).
  • the tizoxanide choline salt of formula (I) is a crystalline form, and the powder X-ray diffraction pattern obtained by using Cu-K ⁇ radiation has characteristic peaks at the following 2 ⁇ angles (°) : 9.92 ⁇ 0.10, 15.10 ⁇ 0.10, 19.72 ⁇ 0.10, 20.69 ⁇ 0.10 and 25.66 ⁇ 0.10, of which the peak at 9.92 ⁇ 0.10 is the strongest peak.
  • the tizoxanide choline salt of formula (I) is a crystalline form
  • the powder X-ray diffraction pattern obtained by using Cu-K ⁇ radiation has characteristic peaks at the following 2 ⁇ angles (°) : 9.92 ⁇ 0.10, 15.10 ⁇ 0.10, 16.16 ⁇ 0.10, 19.72 ⁇ 0.10, 19.88 ⁇ 0.10, 20.69 ⁇ 0.10, 25.66 ⁇ 0.10 and 27.59 ⁇ 0.10, of which the peak at 9.92 ⁇ 0.10 is the strongest peak.
  • the tizoxanide choline salt of formula (I) is in crystalline form, and the powder X-ray diffraction pattern obtained by Cu-K ⁇ radiation has characteristic peaks at the following 2 ⁇ angles (°): 9.92 ⁇ 0.10 , 11.78 ⁇ 0.10, 15.10 ⁇ 0.10, 16.16 ⁇ 0.10, 19.72 ⁇ 0.10, 19.88 ⁇ 0.10, 20.69 ⁇ 0.10, 25.66 ⁇ 0.10, 27.59 ⁇ 0.10 and 28.88 ⁇ 0.10, of which the peak at 9.92 ⁇ 0.10 is the strongest peak.
  • the tizoxanide choline salt of formula (I) has a powder X-ray diffraction pattern substantially as shown in FIG. 1.
  • the pharmaceutical composition further contains a non-toxic pharmaceutically acceptable pharmaceutical carrier or excipient.
  • the pharmaceutical composition is a pharmaceutical composition containing tizoxanide and choline, and a non-toxic pharmaceutically acceptable pharmaceutical carrier or excipient.
  • the pharmaceutical composition may be a capsule, tablet, granule, powder, suspension, solution or lozenge.
  • the pharmaceutical composition can be administered orally or by injection.
  • the present invention provides the tizoxanide choline salt of the above formula (I), the crystal form of the tizoxanide choline salt of the above formula (I), or the use of the above pharmaceutical composition in the preparation of antiviral drugs.
  • the antiviral drug may be an anti-hepatitis virus drug and/or an anti-respiratory virus drug;
  • the anti-hepatitis virus drug may be an anti-hepatitis B virus drug and/or an anti-hepatitis C virus drug;
  • the anti-respiratory virus drug may be an anti-influenza virus drug and/or an anti-coronavirus drug.
  • the present invention also provides the tizoxanide choline salt of the above formula (I), the crystal form of the tizoxanide choline salt of the above formula (I), or the use of the above-mentioned pharmaceutical composition in the preparation of anti-fibrotic drugs.
  • the anti-fibrosis drug may be an anti-liver fibrosis drug and/or an anti-pulmonary fibrosis drug.
  • the present invention also provides the tizoxanide choline salt of the above formula (I), the crystal form of the tizoxanide choline salt of the above formula (I), or the use of the above pharmaceutical composition in the preparation of antibacterial drugs.
  • the antibacterial drug may be an anti- Helicobacter pylori drug and/or an anti-tuberculosis drug.
  • the present invention also provides the tizoxanide choline salt of the above formula (I), the crystal form of the tizoxanide choline salt of the above formula (I), or the use of the above-mentioned pharmaceutical composition in the preparation of anti-tumor drugs.
  • the anti-tumor drug may be an anti-ovarian cancer drug and/or an anti-colon cancer drug.
  • the present invention also provides the tizoxanide choline salt of the above formula (I), the crystal form of the tizoxanide choline salt of the above formula (I), or the use of the above pharmaceutical composition in the preparation of antiparasitic drugs.
  • the anti-intestinal parasite drug may be an anti-Cryptosporidium parvum drug and/or an anti-giardia lamblia drug.
  • the present invention also provides the tizoxanide choline salt of the above formula (I), the crystal form of the tizoxanide choline salt of the above formula (I), or the above pharmaceutical composition, which is used for the treatment of viral infections in patients, Fibrotic diseases, bacterial infections, cancer, parasitic infections and other diseases.
  • the viral infection may be a hepatitis virus infection or a respiratory virus infection.
  • the hepatitis virus may be hepatitis B virus or hepatitis C virus.
  • the respiratory virus may be influenza virus or coronavirus.
  • the fibrotic disease may be liver fibrosis and/or lung fibrosis.
  • the bacterial infection may be Helicobacter pylori infection and/or Mycobacterium tuberculosis infection.
  • the cancer may be ovarian cancer or colon cancer.
  • the parasitic infection may be Cryptosporidium parvum infection and/or anti-Giardia lamblia infection.
  • the present invention also provides a method for treating viral infectious diseases, which comprises the following steps: administering to a patient or subject in need a therapeutically effective amount of tizoxanide choline salt of the above formula (I), the above formula (I) ) The crystal form of tizoxanide choline salt or the above-mentioned pharmaceutical composition.
  • the viral infectious disease may be a hepatitis virus infection or a respiratory virus infection.
  • the hepatitis virus may be hepatitis B virus or hepatitis C virus.
  • the respiratory virus may be influenza virus or coronavirus.
  • the present invention also provides a method for treating fibrotic diseases, which comprises the following steps: administering to a patient or subject in need a therapeutically effective amount of tizoxanide choline salt of the above formula (I), the above formula (I) The crystal form of tizoxanide choline salt or the above-mentioned pharmaceutical composition.
  • the fibrotic disease may be liver fibrosis and/or lung fibrosis.
  • the present invention also provides a method for the treatment of bacterial infectious diseases, which comprises the following steps: administering to a patient or subject in need a therapeutically effective amount of tizoxanide choline salt of the above formula (I), the above formula (I) ) The crystal form of tizoxanide choline salt or the above-mentioned pharmaceutical composition.
  • the bacterial infectious disease may be Helicobacter pylori infection and/or Mycobacterium tuberculosis infection.
  • the present invention also provides a method for treating cancer, which comprises the following steps: administering to a patient or subject in need a therapeutically effective amount of tizoxanide choline salt of the above formula (I), and a substitute for the above formula (I)
  • a method for treating cancer which comprises the following steps: administering to a patient or subject in need a therapeutically effective amount of tizoxanide choline salt of the above formula (I), and a substitute for the above formula (I)
  • the crystalline form of zonide choline salt or the above-mentioned pharmaceutical composition is administered to a patient or subject in need a therapeutically effective amount of tizoxanide choline salt of the above formula (I), and a substitute for the above formula (I)
  • the cancer may be ovarian cancer and/or colon cancer.
  • the present invention also provides a method for treating parasitic infectious diseases, which comprises the following steps: administering to a patient or subject in need a therapeutically effective amount of tizoxanide choline salt of the above formula (I), the above formula ( I) the crystal form of tizoxanide choline salt or the above-mentioned pharmaceutical composition.
  • the parasitic infection may be Cryptosporidium parvum infection and/or anti-Giardia lamblia infection.
  • tizoxanide can form a mixture with a certain proportion of choline hydroxide, and the mixture can significantly improve the solubility and bioavailability of tizoxanide.
  • tizoxanide and choline hydroxide can form a salt at a molar ratio of 1:1, and the salt can also significantly improve the solubility and bioavailability of tizoxanide.
  • the mixture, the salt and the crystal form of the salt, and the pharmaceutical composition containing them have good effects in antiviral, anti-fibrotic, anti-bacterial, anti-tumor and/or anti-intestinal parasitic drugs.
  • Figure 1 is a powder X-ray diffraction pattern of tizoxanide choline salt of formula (I) measured in Example 3; the abscissa is the 2 ⁇ angle (°), and the ordinate is the intensity of the absorption peak.
  • the tizoxanide choline salt of formula (I) can be prepared according to the following synthetic route:
  • Nitrazoxanide is hydrolyzed and deacetylated under the action of hydrochloric acid to obtain deacetylated nitazoxanide, namely tizoxanide; tizoxanide reacts with choline hydroxide to obtain tizoxanide choline of formula (I) Salt.
  • the crystal form of tizoxanide choline salt of formula (I) prepared in Example 2 was characterized by powder X-ray diffraction method.
  • Powder X-ray diffraction test conditions and methods instrument model: DMAX-2500; experimental method: grind the sample to be tested to 200-300 meshes, scan angle range 3.0-60.0 degrees, scan speed 0.15 degrees per second counting.
  • Figure 1 is a powder X-ray diffraction pattern of tizoxanide choline salt of formula (I); the abscissa is the 2 ⁇ angle, and the ordinate is the intensity of the absorption peak.
  • the characterization results are as follows: The powder X-ray diffraction pattern has characteristic peaks at the following 2 ⁇ angles (°): 9.92 ⁇ 0.10, 11.78 ⁇ 0.10, 15.10 ⁇ 0.10, 16.16 ⁇ 0.10, 19.72 ⁇ 0.10, 19.88 ⁇ 0.10, 20.69 ⁇ 0.10, 25.66 ⁇ 0.10, 27.59 ⁇ 0.10 and 28.88 ⁇ 0.10, among which the peak of 9.92 ⁇ 0.10 is the strongest peak.
  • tizoxanide in plasma was determined by LC-MS/MS (instrument: LC-MS/MS-19, TQ5500 Triple quad); internal standard (IS): tolbutamide; mass spectrometry conditions: electrospray ion source, Negative ion multiple reaction detection (Tizoxanide: Q1/Q3 Mass: 263.80/217.00 Da, internal standard: Q1/Q3 Mass: 269.20/106.10 Da); liquid phase conditions: mobile phase A: 0.3% formic acid aqueous solution, mobile phase B: 0.1% Formic acid acetonitrile solution; Column: ACQUITY UPLC CORTECS T3 2.7 ⁇ m (2.1*100mm); Column temperature: 40°C; Flow rate: 0.6mL/min.
  • the ducks with vertical transmission infection and positive DHBV DNA test were randomly divided into groups, 8 in each group.
  • the compounds to be tested namely tizoxanide choline salt and nitazoxanide of formula (I) prepared in Example 2, were respectively formulated into suspensions with 0.1% sodium carboxymethyl cellulose and administered by gavage. Once a day. Blood was collected from vein before administration (T 0 ), 7 days (T 7 ), 14 days (T 14 ), 21 days (T 21 ), and 28 days (T 28) before administration (T 0 ), and separation Serum, frozen at -70°C for testing.
  • Dot hybridization assay method in serum DHBV DNA content take the above duck serum, while each batch of membranes point, measuring the change in serum DHBV DNA level in duck, nick translation kit according to the description method, with 32 P labeled DHBV DNA probe, And do the duck serum dot blot experiment (Dot Blot).
  • the spectral absorbance (filter wavelength is 490nm) OD 490 of the spots on the autoradiographic X film was measured with an enzyme-linked immunoassay. The higher the OD 490 value, the higher the virus content.
  • mice Male Kunming mice weighing 18-22 grams were randomly divided into a normal group, a model group, and an administration group, with 10 mice in each group. Model group and the treatment group of mice to 10 times the LD 50 dose of influenza A virus mouse lungs adapted strain A / PR / 8/34 by intranasal exposure; the test compound, i.e. nitazoxanide and Examples 2.
  • the prepared tizoxanide choline salt of formula (I) was prepared as a suspension with 0.1% sodium carboxymethyl cellulose, and was administered by gavage 1 hour after infection, twice a day, for continuous administration 5 days. Observe the death of mice and record for 14 consecutive days to investigate the survival rate.

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Abstract

包含替唑尼特和氢氧化胆碱的药物组合物，替唑尼特胆碱盐及其晶型，以及它们的医药用途。替唑尼特与氢氧化胆碱形成的混合物或者盐及盐的晶型可显著提高替唑尼特的溶解度和生物利用度，并且在抗病毒、抗纤维化、抗细菌、抗肿瘤和/或抗肠道寄生虫药物方面具有良好的效果。

Description

替唑尼特药物组合物及其医药用途
本申请要求于2020年3月16日向中国国家知识产权局提交的专利申请号为202010185575.0，发明名称为“替唑尼特药物组合物及其医药用途”的在先申请的优先权。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
本发明涉及替唑尼特药物组合物及其医药用途，具体涉及含有替唑尼特和胆碱的药物组合物及其医药用途。
背景技术
硝唑尼特(化学名：邻-N-(5-硝基噻唑-2-基)氨基甲酰基-苯酚-乙酸酯；英文名：Nitazoxanide)是一种硝基噻唑水杨酸酰胺衍生物，具有抗原虫、抗肠道寄生虫、抗菌等药效。
进一步的研究发现，硝唑尼特还具有广谱的抗病毒活性(Rossignol JF.,Antiviral Research,2014；110:94-103)，对甲型流感病毒、乙型流感病毒、禽流感、呼吸道合胞病毒、副流感病毒、冠状病毒、轮状病毒、诺如病毒、乙肝病毒、丙肝病毒、登革热病毒、黄热病病毒、乙型脑炎病毒及人免疫缺陷病毒等均有抑制作用。
硝唑尼特对结核杆菌(Ranjbar S,et al.,iScience,2019；22:299-313)和幽门螺旋杆菌(Basu PP,et al.,Am J Gastroenterol,2011；106:1970-1975)也有较好的抑制作用。
中国发明专利申请(CN109069648A)公开了硝唑尼特治疗胆汁淤积和纤维化疾病的用途；所述的纤维化疾病包括肝纤维化、肺纤维化等。
硝唑尼特还具有抗肿瘤作用(Di Santo N and Ehrisman J.,Mutation Research,2014；768:16-21)，对卵巢癌(Di Santo N and Ehrisman J.,Cancers,2013；5:1163-1176)和结肠癌(Senkowski W,Zhang X,et al.,Mol Cancer Ther,2015；14:1504-1516)等均有较强的抑制作用。
但是与大多数具有新用途前景的老药一样，硝唑尼特的这些新的药理作用的临床疗效还有待提高。硝唑尼特难溶于水(水中溶解度0.000189mg/ml)，剂量较大(500mg/次，2次/天)，口服生物利用度低，在肺中难以达到有效的抗病毒浓度，因此其口服给药对呼吸道病毒感染的治疗作用受到限制。
如何提高老药的疗效，成为制约其发挥新的药效用途的瓶颈。
硝唑尼特口服后，在体内转化为活性代谢产物替唑尼特(英文名：Tizoxanide)和非活性代谢产物葡萄糖醛酸结合物：
Figure PCTCN2021080327-appb-000001
人口服硝唑尼特后，血液中检测不出硝唑尼特原形，只能检测到替唑尼特和葡萄糖醛酸结合物，葡萄糖醛酸结合物的系统暴露高于替唑尼特。
发明内容
本发明提供一种药物组合物，所述药物组合物含有替唑尼特和氢氧化胆碱。
根据本发明的实施方案，所述药物组合物中替唑尼特和氢氧化胆碱的摩尔比例为1:4～1:0.25。
优选地，所述药物组合物中替唑尼特和氢氧化胆碱的摩尔比例为1:2～1:0.5。
例如，所述替唑尼特和氢氧化胆碱的摩尔比例为1:1、1:0.5、1:0.25、1:2、1:3、1:4。
根据本发明的实施方案，其中替唑尼特与氢氧化胆碱形成摩尔比例为1:1的盐。
根据本发明的示例性实施方案，所述药物组合物含有式(I)所示的替唑尼特胆碱盐：
Figure PCTCN2021080327-appb-000002
本发明还提供上述式(I)的替唑尼特胆碱盐。
根据本发明的实施方案，所述式(I)的替唑尼特胆碱盐可以为无定型形式，也可以为晶型形式；优选为晶型形式。
本发明还提供上述式(I)的替唑尼特胆碱盐的晶型。
根据本发明的实施方案，所述式(I)的替唑尼特胆碱盐为晶型，其使用Cu-Kα辐射获得的粉末X-射线衍射图谱在以下2θ角度(°)处具有特征峰：9.92±0.10，15.10±0.10，19.72±0.10，20.69±0.10和25.66±0.10，其中9.92±0.10的峰为最强峰。
根据本发明的实施方案，所述式(I)的替唑尼特胆碱盐为晶型，其使用Cu-Kα辐射获得的粉末X-射线衍射图谱在以下2θ角度(°)处具有特征峰：9.92±0.10，15.10±0.10，16.16±0.10，19.72±0.10，19.88±0.10，20.69±0.10，25.66±0.10和27.59±0.10，其中9.92±0.10的峰为最强峰。
优选地，所述式(I)的替唑尼特胆碱盐为晶型，其使用Cu-Kα辐射获得的粉末X-射线衍射图谱在以下2θ角度(°)处具有特征峰：9.92±0.10，11.78±0.10，15.10±0.10，16.16±0.10，19.72±0.10，19.88±0.10，20.69±0.10，25.66±0.10， 27.59±0.10和28.88±0.10，其中9.92±0.10的峰为最强峰。
根据本发明的实施方案，所述式(I)的替唑尼特胆碱盐具有基本如图1所示的粉末X-射线衍射图谱。
根据本发明的实施方案，所述药物组合物中还含有非毒性药学上可接受的药用载体或赋形剂。
优选地，所述药物组合物为含有替唑尼特和胆碱、以及非毒性药学上可接受的药用载体或赋形剂的药物组合物。
根据本发明的实施方案，所述药物组合物可以为胶囊剂、片剂、颗粒剂、散剂、混悬剂、溶液剂或锭剂。
根据本发明的实施方案，所述药物组合物可以通过口服或注射的途径给药。
本发明提供上述式(I)的替唑尼特胆碱盐，上述式(I)的替唑尼特胆碱盐的晶型，或者上述药物组合物在制备抗病毒药物中的用途。
优选地，所述的抗病毒药物可以为抗肝炎病毒药物和/或抗呼吸道病毒药物；
优选地，所述的抗肝炎病毒药物可以为抗乙肝病毒药物和/或抗丙肝病毒药物；
优选地，所述抗呼吸道病毒药物可以为抗流感病毒药物和/或抗冠状病毒药物。
本发明还提供上述式(I)的替唑尼特胆碱盐，上述式(I)的替唑尼特胆碱盐的晶型，或者上述药物组合物在制备抗纤维化药物中的用途。
优选地，所述的抗纤维化药物可以为抗肝纤维化药物和/或抗肺纤维化药物。
本发明还提供上述式(I)的替唑尼特胆碱盐，上述式(I)的替唑尼特胆碱盐的晶型，或者上述药物组合物在制备抗细菌药物中的用途。
优选地，所述的抗细菌药物可以为抗幽门螺旋杆菌药物和/或抗结核杆菌药物。
本发明还提供上述式(I)的替唑尼特胆碱盐，上述式(I)的替唑尼特胆碱盐的晶型，或者上述药物组合物在制备抗肿瘤药物中的用途。
优选地，所述的抗肿瘤药物可以为抗卵巢癌药物和/或抗结肠癌药物。
本发明还提供上述式(I)的替唑尼特胆碱盐，上述式(I)的替唑尼特胆碱盐的晶型，或者上述药物组合物在制备抗寄生虫药物中的用途。
优选地，所述的抗肠道寄生虫药物可以为抗微小隐孢子虫药物和/或抗蓝氏贾第鞭毛虫药物。
本发明还提供上述式(I)的替唑尼特胆碱盐，上述式(I)的替唑尼特胆碱盐的晶型，或者上述药物组合物，其用于治疗患者的病毒感染、纤维化疾病、细菌感染、癌症、寄生虫感染等疾病。
根据本发明的实施方案，所述病毒感染可以是肝炎病毒感染、呼吸道病毒感染。优选地，所述肝炎病毒可以是乙肝病毒或丙肝病毒。优选地，所述呼吸道病毒可以是流感病毒或冠状病毒。
根据本发明的实施方案，所述纤维化疾病可以是肝纤维化和/或肺纤维化。
根据本发明的实施方案，所述细菌感染可以是幽门螺杆菌感染和/或结核杆菌感染。
根据本发明的实施方案，所述癌症可以是卵巢癌或结肠癌。
根据本发明的实施方案，所述寄生虫感染可以是微小隐孢子虫感染和/或抗蓝氏贾第鞭毛虫感染。
本发明还提供一种治疗病毒感染性疾病的方法，其包括以下步骤：给予有需要的患者或受试者治疗有效量的上述式(I)的替唑尼特胆碱盐、上述式(I)的替唑尼特胆碱盐的晶型或者上述药物组合物。
根据本发明的实施方案，所述病毒感染性疾病可以是肝炎病毒感染、呼吸 道病毒感染。优选地，所述肝炎病毒可以是乙肝病毒或丙肝病毒。优选地，所述呼吸道病毒可以是流感病毒或冠状病毒。
本发明还提供一种治疗纤维化疾病的方法，其包括以下步骤：给予有需要的患者或受试者治疗有效量的上述式(I)的替唑尼特胆碱盐、上述式(I)的替唑尼特胆碱盐的晶型或者上述药物组合物。
根据本发明的实施方案，所述纤维化疾病可以是肝纤维化和/或肺纤维化。
本发明还提供一种治疗细菌感染性疾病的方法，其包括以下步骤：给予有需要的患者或受试者治疗有效量的上述式(I)的替唑尼特胆碱盐、上述式(I)的替唑尼特胆碱盐的晶型或者上述药物组合物。
根据本发明的实施方案，所述细菌感染性疾病可以是幽门螺杆菌感染和/或结核杆菌感染。
本发明还提供一种治疗癌症的方法，其包括以下步骤：给予有需要的患者或受试者治疗有效量的上述式(I)的替唑尼特胆碱盐、上述式(I)的替唑尼特胆碱盐的晶型或者上述药物组合物。
根据本发明的实施方案，所述癌症可以是卵巢癌和/或结肠癌。
本发明还提供一种治疗寄生虫感染性疾病的方法，其包括以下步骤：给予有需要的患者或受试者治疗有效量的上述式(I)的替唑尼特胆碱盐、上述式(I)的替唑尼特胆碱盐的晶型或者上述药物组合物。
根据本发明的实施方案，所述寄生虫感染可以是微小隐孢子虫感染和/或抗蓝氏贾第鞭毛虫感染。
本发明的有益效果
本发明意外地发现，替唑尼特可以与一定比例的氢氧化胆碱形成混合物，所述混合物可显著提高替唑尼特的溶解度和生物利用度。特别地，替唑尼特与氢氧化胆碱可以以1:1的摩尔比形成盐，所述盐也可显著提高替唑尼特的溶解度和生物利用度。并且，所述混合物、所述盐及盐的晶型、以及包含它们的药物 组合物在抗病毒、抗纤维化、抗细菌、抗肿瘤和/或抗肠道寄生虫药物方面具有良好的效果。
附图说明
图1为实施例3中测定的式(I)的替唑尼特胆碱盐的粉末X衍射图谱；横坐标为2θ角(°)，纵坐标为吸收峰的强度。
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。
如无特别说明，实施例中的“％”均为质量百分比。
式(Ⅰ)的替唑尼特胆碱盐可以按照如下合成路线制备：
Figure PCTCN2021080327-appb-000003
硝唑尼特在盐酸作用下水解脱去乙酰基，得到去乙酰化硝唑尼特即替唑尼 特；替唑尼特与氢氧化胆碱作用，得到式(Ⅰ)的替唑尼特胆碱盐。
实施例1 替唑尼特的制备
在500mL三口瓶中加入300毫升浓盐酸，搅拌下加入50克硝唑尼特；加完后，将反应混合物于50℃搅拌反应20小时。将反应混合物冷却至室温，过滤，滤饼依次用少量水和丙酮洗涤，抽干，于45℃干燥，得42.6克淡黄色粉末，即为替唑尼特。
实施例2 式(Ⅰ)的替唑尼特胆碱盐的制备
在1000毫升三口瓶中加入500毫升甲醇，搅拌下加入50克替唑尼特，搅拌均匀；于室温下搅拌，滴加57.2克40％的氢氧化胆碱水溶液；加毕，将体系升温至45℃搅拌反应1小时。趁热过滤，将滤液于-5℃下放置过夜；过滤，将滤饼用100mL甲醇淋洗，抽干，干燥，得到49.03克黄色结晶性粉末(纯度：98％)，即为式(Ⅰ)的替唑尼特胆碱盐。式(Ⅰ)的替唑尼特胆碱盐的核磁共振氢谱δ(ppm,DMSO-d6,600MHz):3.10(9H,s)；3.38-3.40(2H,dd)；3.81-3.85(2H,m)；5.26-5.27(1H,t)；6.79-6.82(2H,m)；7.29-7.32(1H,m)；7.90-7.91(1H,m)；8.50(1H,s)；14.70(1H,s)。
实施例3 结晶型的表征
采用粉末X-射线衍射法对实施例2制备的式(Ⅰ)的替唑尼特胆碱盐的结晶型进行表征。
粉末X-射线衍射测试条件及方法：仪器型号：DMAX-2500；实验方法：将待测样品研细为200-300目，扫描角度范围3.0-60.0度，扫描速度为0.15度/秒计数。
图1为式(Ⅰ)的替唑尼特胆碱盐的粉末X衍射图谱；横坐标为2θ角，纵坐标为吸收峰的强度。表征结果如下：其粉末X衍射图谱在以下的2θ角度(°)处 具有特征峰：9.92±0.10，11.78±0.10，15.10±0.10，16.16±0.10，19.72±0.10，19.88±0.10，20.69±0.10，25.66±0.10，27.59±0.10和28.88±0.10，其中9.92±0.10的峰为最强峰。
实施例4 大鼠口服药代动力学评价
将34.75mg硝唑尼特加于10mL 0.5％的羧甲基纤维素钠溶液中，混合均匀，备用；
将41.67mg实施例2制得的式(Ⅰ)的替唑尼特胆碱盐加于10mL 0.5％的羧甲基纤维素钠溶液中，混合均匀，备用；
将30mg替唑尼特加于5mL 0.5％的羧甲基纤维素钠溶液中，加入40％的氢氧化胆碱水溶液，混合均匀，然后再加入0.5％的羧甲基纤维素钠溶液至终体积10mL，得到替唑尼特胆碱混合物备用。调整氢氧化胆碱水溶液的加入量，分别得到替唑尼特与氢氧化胆碱的摩尔比为1:2、1:0.5、1:1的替唑尼特胆碱混合物。
SD雄性大鼠，体重为180至220g，每组3只；所有动物给药前禁食12小时。分别灌胃给予上述硝唑尼特、式(Ⅰ)的替唑尼特胆碱盐或替唑尼特胆碱混合物的溶液，给药量均为10mL/kg。于给药前和给药后15min，30min，1h，2h，4h，6h，8h，24h，经颈静脉采血，0.2mL/次，肝素钠抗凝，离心分离血浆，置于-80℃保存待测定。用LC-MS/MS测定血浆中替唑尼特的含量(仪器：LC-MS/MS-19，TQ5500 Triple quad)；内标(IS)：甲苯磺丁脲；质谱条件：电喷雾离子源，负离子多重反应检测(Tizoxanide:Q1/Q3 Masses:263.80/217.00 Da，内标:Q1/Q3 Masses:269.20/106.10 Da)；液相条件：流动相A:0.3％甲酸水溶液，流动相B:0.1％甲酸乙腈溶液；色谱柱:ACQUITY UPLC CORTECS T3 2.7μm(2.1*100mm)；柱温：40℃；流速：0.6mL/min。
通过不同时间点的血药浓度数据，运用WinNonlin计算药代动力学参数。结果见表1：
表1大鼠口服药代动力学评价结果
Figure PCTCN2021080327-appb-000004
实施例5 体内抗乙肝病毒作用的评价
将垂直传播感染、DHBV DNA检测阳性的麻鸭随机分组，每组8只。将待测化合物，即实施2制得的式(I)的替唑尼特胆碱盐以及硝唑尼特，分别以0.1％的羧甲基纤维素钠配制成悬浮液，灌胃给药，每天一次。分别在给药前(T 0)、给药7天(T 7)、给药14天(T 14)、给药21天(T 21)和给药28天(T 28)时静脉采血，分离血清，-70℃冻存待检。
应用斑点分子杂交法测定血清中DHBV DNA含量：取上述鸭血清，每批同时点膜，测定鸭血清中DHBV DNA水平的变化，按缺口翻译试剂盒说明书方法，用 32P标记DHBV DNA探针，并作鸭血清斑点杂交(Dot Blot)实验。放射自显影后，用酶联免疫测定仪测定放射自显影X胶片上斑点的光谱吸光度(滤光片波长为490nm)OD 490，OD 490值越高，说明病毒含量越高。
测定结果见表2：
表2体内抗鸭乙肝病毒作用的评价结果
Figure PCTCN2021080327-appb-000005
Figure PCTCN2021080327-appb-000006
注：药物组给药不同时间与给药前(T 0)比较：**P<0.01，*P<0.05；
药物组与对照组相同时间比较： △△P<0.01， △P<0.05。
实施例6 用小鼠模型评价抗流感病毒的作用
雄性昆明种小鼠，体重为18-22克，随机分为正常组、模型组和给药组，每组10只。将模型组和给药组小鼠以10倍LD 50剂量的甲型流感病毒小鼠肺适应株A/PR/8/34滴鼻染毒；将待测化合物，即硝唑尼特以及实施例2制得的式(I)的替唑尼特胆碱盐，分别以0.1％的羧甲基纤维素钠配制成悬浮液，在感染后1小时灌胃给药，每天2次，连续给药5天。观察小鼠死亡情况，连续记录14天，考察存活率。
实验结果见表3：
表3目标化合物对流感病毒感染小鼠的保护作用
Figure PCTCN2021080327-appb-000007
以上，对本发明的实施方式进行了说明。但是，本发明不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (10)

  1. 一种药物组合物，其含有替唑尼特和氢氧化胆碱；
    优选地，其中替唑尼特和氢氧化胆碱的摩尔比例为1:4～1:0.25，更优选为1:2～1:0.5，例如为1:1、1:0.5、1:0.25、1:2、1:3或1:4。
  2. 根据权利要求1所述的药物组合物，其中替唑尼特和氢氧化胆碱以1:1的摩尔比形成式(I)的替唑尼特胆碱盐：
    Figure PCTCN2021080327-appb-100001
    优选地，式(I)的替唑尼特胆碱盐为无定型形式或晶型形式，优选为晶型形式；
    优选地，式(I)的替唑尼特胆碱盐为晶型，其使用Cu-Kα辐射获得的粉末X-射线衍射图谱在以下2θ角度(°)处具有特征峰：9.92±0.10，15.10±0.10，19.72±0.10，20.69±0.10和25.66±0.10，其中9.92±0.10的峰为最强峰；
    优选地，式(I)的替唑尼特胆碱盐为晶型，其使用Cu-Kα辐射获得的粉末X-射线衍射图谱在以下2θ角度(°)处具有特征峰：9.92±0.10，15.10±0.10，16.16±0.10，19.72±0.10，19.88±0.10，20.69±0.10，25.66±0.10和27.59±0.10，其中9.92±0.10的峰为最强峰；
    优选地，式(I)的替唑尼特胆碱盐为晶型，其使用Cu-Kα辐射获得的粉末X-射线衍射图谱在以下2θ角度(°)处具有特征峰：9.92±0.10，11.78±0.10，15.10±0.10，16.16±0.10，19.72±0.10，19.88±0.10，20.69±0.10，25.66±0.10，27.59±0.10和28.88±0.10，其中9.92±0.10的峰为最强峰；
    优选地，式(I)的替唑尼特胆碱盐为晶型，其具有基本如图1所示的粉末X- 射线衍射图谱。
  3. 根据权利要求1或2所述的药物组合物，其中所述药物组合物中还含有非毒性药学上可接受的药用载体或赋形剂；
    优选地，所述药物组合物为胶囊剂、片剂、颗粒剂、散剂、混悬剂、溶液剂或锭剂；
    或优选地，所述药物组合物通过口服或注射的途径给药。
  4. 式(I)的替唑尼特胆碱盐，
    Figure PCTCN2021080327-appb-100002
    优选地，式(I)的替唑尼特胆碱盐为无定型形式或晶型形式，优选为晶型形式；
    优选地，式(I)的替唑尼特胆碱盐为晶型，其使用Cu-Kα辐射获得的粉末X-射线衍射图谱在以下2θ角度(°)处具有特征峰：9.92±0.10，15.10±0.10，19.72±0.10，20.69±0.10和25.66±0.10，其中9.92±0.10的峰为最强峰；
    优选地，式(I)的替唑尼特胆碱盐为晶型，其使用Cu-Kα辐射获得的粉末X-射线衍射图谱在以下2θ角度(°)处具有特征峰：9.92±0.10，15.10±0.10，16.16±0.10，19.72±0.10，19.88±0.10，20.69±0.10，25.66±0.10和27.59±0.10，其中9.92±0.10的峰为最强峰；
    优选地，式(I)的替唑尼特胆碱盐为晶型，其使用Cu-Kα辐射获得的粉末X-射线衍射图谱在以下2θ角度(°)处具有特征峰：9.92±0.10，11.78±0.10，15.10±0.10，16.16±0.10，19.72±0.10，19.88±0.10，20.69±0.10，25.66±0.10，27.59±0.10和28.88±0.10，其中9.92±0.10的峰为最强峰；
    优选地，式(I)的替唑尼特胆碱盐为晶型，其具有基本如图1所示的粉末X- 射线衍射图谱。
  5. 式(I)的替唑尼特胆碱盐的晶型，
    Figure PCTCN2021080327-appb-100003
    其使用Cu-Kα辐射获得的粉末X-射线衍射图谱在以下2θ角度(°)处具有特征峰：9.92±0.10，15.10±0.10，19.72±0.10，20.69±0.10和25.66±0.10，其中9.92±0.10的峰为最强峰；
    优选地，其使用Cu-Kα辐射获得的粉末X-射线衍射图谱在以下2θ角度(°)处具有特征峰：9.92±0.10，15.10±0.10，16.16±0.10，19.72±0.10，19.88±0.10，20.69±0.10，25.66±0.10和27.59±0.10，其中9.92±0.10的峰为最强峰；
    优选地，其使用Cu-Kα辐射获得的粉末X-射线衍射图谱在以下2θ角度(°)处具有特征峰：9.92±0.10，11.78±0.10，15.10±0.10，16.16±0.10，19.72±0.10，19.88±0.10，20.69±0.10，25.66±0.10，27.59±0.10和28.88±0.10，其中9.92±0.10的峰为最强峰；
    优选地，其具有基本如图1所示的粉末X-射线衍射图谱。
  6. 权利要求1-3任一项所述的药物组合物、权利要求4所述的式(I)的替唑尼特胆碱盐、或者权利要求5所述的式(I)的替唑尼特胆碱盐的晶型在制备治疗抗病毒药物中的用途；
    优选地，所述的抗病毒药物为抗肝炎病毒药物和/或抗呼吸道病毒药物；
    优选地，所述的抗肝炎病毒药物为抗乙肝病毒药物和/或抗丙肝病毒药物；
    优选地，所述抗呼吸道病毒药物为抗流感病毒药物和/或抗冠状病毒药物。
  7. 权利要求1-3任一项所述的药物组合物、权利要求4所述的式(I)的替唑尼特胆碱盐、或者权利要求5所述的式(I)的替唑尼特胆碱盐的晶型在制备治疗 抗细菌药物中的用途；
    优选地，所述的抗细菌药物为抗幽门螺旋杆菌药物和/或抗结核杆菌药物。
  8. 权利要求1-3任一项所述的药物组合物、权利要求4所述的式(I)的替唑尼特胆碱盐、或者权利要求5所述的式(I)的替唑尼特胆碱盐的晶型在制备治疗抗肿瘤药物中的用途；
    优选地，所述的抗肿瘤药物为抗卵巢癌药物和/或抗结肠癌药物。
  9. 权利要求1-3任一项所述的药物组合物、权利要求4所述的式(I)的替唑尼特胆碱盐、或者权利要求5所述的式(I)的替唑尼特胆碱盐的晶型在制备治疗抗纤维化药物中的用途；
    优选地，所述的抗纤维化药物为抗肝纤维化药物和/或抗肺纤维化药物。
  10. 权利要求1-3任一项所述的药物组合物、权利要求4所述的式(I)的替唑尼特胆碱盐、或者权利要求5所述的式(I)的替唑尼特胆碱盐的晶型在制备治疗抗肠道寄生虫药物中的用途；
    优选地，所述的抗肠道寄生虫药物为抗微小隐孢子虫药物和/或抗蓝氏贾第鞭毛虫药物。
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