WO2021217816A1 - 一种用于防治肺炎的组合物、组合物的制备方法及其在制备用于防治肺炎的药物中的应用 - Google Patents

一种用于防治肺炎的组合物、组合物的制备方法及其在制备用于防治肺炎的药物中的应用 Download PDF

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WO2021217816A1
WO2021217816A1 PCT/CN2020/096406 CN2020096406W WO2021217816A1 WO 2021217816 A1 WO2021217816 A1 WO 2021217816A1 CN 2020096406 W CN2020096406 W CN 2020096406W WO 2021217816 A1 WO2021217816 A1 WO 2021217816A1
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parts
composition
artemisinin
medicine
preventing
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PCT/CN2020/096406
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English (en)
French (fr)
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宋健平
王琪
邓长生
徐勤
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广州中医药大学科技产业园有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses

Definitions

  • the present disclosure relates to the field of medicine, in particular, to a composition for preventing and treating pneumonia, a preparation method of the composition and its application in preparing a medicine for preventing and treating pneumonia.
  • coronaviruses belong to the genus Coronavirus of the order Nidovirales, Coronaviridae (Coronaviridae).
  • Viruses of the genus Coronavirus are RNA viruses with an envelope and a linear single-stranded positive-stranded genome. They are a large group of viruses that exist widely in nature.
  • the diameter of the coronavirus is about 80-120nm, the 5'end of the genome has a methylated cap structure, and the 3'end has a poly(A) tail.
  • the full length of the genome is about 27-32kb. It is currently the largest virus in the genome of RNA viruses. .
  • Coronavirus was first isolated from chickens in 1937.
  • the diameter of the virus particles is 60-200nm, with an average diameter of 100nm. It is spherical or elliptical and has pleomorphism.
  • the virus has an envelope, and there are spinous processes on the envelope. The entire virus is like a corona. The spinous processes of different coronaviruses have obvious differences. Sometimes tubular inclusion bodies can be seen in coronavirus-infected cells.
  • Coronavirus family only infects vertebrates and is related to many diseases of humans and animals. In view of this, this disclosure is hereby provided.
  • the purpose of the present disclosure includes, for example, providing a composition for preventing and treating pneumonia and its application in preparing a medicine for preventing and treating pneumonia.
  • the embodiments of the present disclosure provide an application of a composition in the preparation of a medicine for preventing and treating pneumonia.
  • the composition includes 40.0-300.0 parts of artemisinin or an artemisinin derivative , And 200.0-400.0 parts of 4-aminoquinoline drugs.
  • the embodiments of the present disclosure provide a composition or medicine for preventing and treating pneumonia.
  • the composition or medicine includes 40.0-300.0 parts of artemisinin or artemisinin derivatives in parts by weight, and 200.0-400.0 parts of 4-aminoquinoline drugs.
  • the embodiments of the present disclosure provide a preparation method of a medicine for preventing and treating pneumonia, and the preparation method is as follows:
  • the dry granules obtained after granulation, sodium starch glycolate and magnesium stearate are uniformly mixed and then compressed.
  • the embodiments of the present disclosure provide a composition or medicine for preventing and treating pneumonia, in parts by weight, the composition or medicine includes 40.0 to 450.0 parts of artemisinin or artemisinin derivatives, and 50.0 ⁇ 450.0 parts of 4-aminoquinoline drugs.
  • the embodiments of the present disclosure provide a composition for the prevention and treatment of pneumonia and its application in the preparation of a medicine for prevention and treatment of pneumonia.
  • Drug development provides a new direction.
  • Fig. 1 shows the test results of the efficacy of the composition provided in Test Example 1 on the human coronavirus HcoV-229E.
  • Figure 2 shows the results of testing the efficacy of the drug for preventing and treating pneumonia provided in Example 4 on the novel coronavirus SARS-COV-2.
  • Fig. 3 shows the test results of the efficacy of the drug for preventing and treating pneumonia provided in Example 5 on the novel coronavirus SARS-COV-2.
  • Figure 4 shows the test results of the efficacy of the drug for preventing and treating pneumonia provided in Example 6 on the novel coronavirus SARS-COV-2.
  • Figure 5 shows the test results of the efficacy of the drug for preventing and treating pneumonia provided in Example 7 on the novel coronavirus SARS-COV-2.
  • Fig. 6 shows the test results of the efficacy of the drug for preventing and treating pneumonia provided in Example 8 on the novel coronavirus SARS-COV-2.
  • Fig. 7 shows the test results of the efficacy of the drug for preventing and treating pneumonia provided in Example 9 on the novel coronavirus SARS-COV-2.
  • Fig. 8 shows the test results of the efficacy of the drug for preventing and treating pneumonia provided in Example 10 on the novel coronavirus SARS-COV-2.
  • Fig. 9 shows the test results of the efficacy of the drug for preventing and treating pneumonia provided in Example 11 on the novel coronavirus SARS-COV-2.
  • Fig. 10 shows the test results of the efficacy of the drug for preventing and treating pneumonia provided in Example 12 on the new coronavirus SARS-COV-2.
  • Fig. 11 shows the test results of the efficacy of the drug for preventing and treating pneumonia provided in Example 13 on the novel coronavirus SARS-COV-2.
  • Fig. 12 shows the test results of the efficacy of the drug for preventing and treating pneumonia provided in Example 14 on the novel coronavirus SARS-COV-2.
  • Fig. 13 shows the test results of the efficacy of the drug for preventing and treating pneumonia provided in Example 15 on the novel coronavirus SARS-COV-2.
  • Fig. 14 shows the test results of the efficacy of the drug for preventing and treating pneumonia provided in Example 16 on the novel coronavirus SARS-COV-2.
  • Fig. 15 shows the test results of the efficacy of the drug for preventing and treating pneumonia provided in Example 17 on the novel coronavirus SARS-COV-2.
  • Figure 16 shows the test results of the efficacy of the drug for preventing and treating pneumonia provided in Example 18 on the novel coronavirus SARS-COV-2.
  • Prevention and treatment refers to prevention and/or treatment.
  • the embodiments of the present disclosure provide an application of a composition in the preparation of a medicine for preventing and treating pneumonia.
  • the composition includes 40.0-300.0 parts of artemisinin or artemisinin derivatives, and 200.0 ⁇ 400.0 parts of 4-aminoquinoline drugs.
  • the composition in parts by weight, includes 40.0-80.0 parts of artemisinin or artemisinin derivatives, and 350.0-400.0 parts of 4-aminoquinoline drugs.
  • the artemisinin derivative is selected from any one or more of the group consisting of dihydroartemisinin, artesunate and artemether;
  • the 4-aminoquinoline drugs are selected from any one or more of the group consisting of piperquine, hydroxychloroquine, chloroquine, amodiaquine and naphthoquine.
  • typical but non-limiting examples of artemisinin or its derivatives are, for example, 40.0 parts, 45.0 parts, 50.0 parts, 55.0 parts, 60.0 parts, 65.0 parts, 70.0 parts, 75.0 parts, 80.0 parts, 90.0 parts, 100.0 parts, 110.0 parts, 120.0 parts, 130.0 parts, 140.0 parts, 150.0 parts, 160.0 parts, 170.0 parts, 180.0 parts, 190.0 parts , 200.0 parts, 210.0 parts, 220.0 parts, 230.0 parts, 240.0 parts, 250.0 parts, 260.0 parts, 270.0 parts, 280.0 parts, 290.0 parts or 300.0 parts; typical but non-limiting examples of 4-aminoquinoline drugs are , For example, 200.0 parts, 210.0 parts, 220.0 parts, 230.0 parts, 240.0 parts, 250.0 parts, 260.0 parts, 270.0 parts, 280.0 parts, 290.0 parts, 300.0 parts, 310.0 parts, 320.0 parts, 330.0 parts, 340.0 parts, 350.0 parts , 36
  • artemisinin or its derivatives may be 40.0 parts, 45.0 parts, 50.0 parts, 55.0 parts, 60.0 parts, 65.0 parts, 70.0 parts by weight. Parts, 75.0 parts or 80.0 parts; 4-aminoquinoline drugs can be 350.0 parts, 360.0 parts, 370.0 parts, 380.0 parts, 390.0 parts or 400.0 parts.
  • the composition includes: 45.0-75.0 parts of artemisinin or artemisinin derivatives, and 360.0-390.0 parts of 4-aminoquinoline drugs.
  • the composition in parts by weight, includes: 52.5-72.5 parts of artemisinin or artemisinin derivatives, and 365.0-385.0 parts of 4-aminoquinoline drugs.
  • the composition further includes an adjuvant selected from the group consisting of pregelatinized starch, hydroxypropyl cellulose, hypromellose, sodium starch glycolate, and magnesium stearate A combination of at least one or more of the group.
  • the composition in parts by weight, includes: 52.5-72.5 parts of artemisinin or artemisinin derivatives, 365.0-385.0 parts of 4-aminoquinoline drugs, 20- 30 parts of pregelatinized starch, 20-25 parts of hypromellose, 10.0-16.0 parts of hypromellose, 20.0-25.0 parts of sodium starch glycolate, and 1.0-8.0 parts of magnesium stearate.
  • the composition in parts by weight, includes: 52.5-72.5 parts artemisinin, 365.0-385.0 parts piperaquine, 20-30 parts pregelatinized starch, and 20-25 parts Hydroxypropyl cellulose, 10.0 to 16.0 parts of hypromellose, 20.0 to 25.0 parts of sodium starch glycolate, and 1.0 to 8.0 parts of magnesium stearate.
  • typical but non-limiting examples of pregelatinized starch are, for example, 20 parts, 21 parts, 22 parts, 23 parts, 24 parts, 25 parts, 26 parts, 27 parts, 28 parts, 29 parts or 30 parts;
  • typical but non-limiting examples of hydroxypropyl cellulose are, for example, 20 parts, 21 parts, 22 parts, 23 parts, 24 parts or 25 parts;
  • Typical but non-limiting examples of propylmethyl cellulose are, for example, 10.0 parts, 11.0 parts, 12.0 parts, 13.0 parts, 14.0 parts, 15.0 parts or 16.0 parts;
  • typical but non-limiting examples of sodium starch glycolate are For example, 20.0 parts, 21.0 parts, 22.0 parts, 23.0 parts, 24.0 parts or 25.0 parts;
  • typical but non-limiting examples of magnesium stearate are, for example, 1.0 parts, 2.0 parts, 3.0 parts, 4.0 parts, 5.0 Parts, 6.0 parts, 7.0 parts or 8.0 parts.
  • the preparation method of the medicine is as follows:
  • the dry granules obtained after granulation, sodium starch glycolate and magnesium stearate are uniformly mixed and then compressed.
  • the particle size of the dry particles is 14-18 mesh; in one or more embodiments, a typical but non-limiting example of the particle size of the dry particles is: For example, 14 mesh, 15 mesh, 16 mesh, 17 mesh, or 18 mesh.
  • the preparation method of the composition further includes coating the tablet after compression.
  • the pneumonia is caused by a viral infection.
  • the virus includes: at least one of the new coronavirus 2019-nCoV and the coronavirus HCoV-229E.
  • the embodiments of the present disclosure also provide a composition or medicine for preventing and treating pneumonia.
  • the raw materials include 40.0-80.0 parts of artemisinin and 350.0-400.0 parts of piperaquine in parts by weight.
  • the components and proportions of the above-mentioned composition or medicine are the same as the components and proportions of the composition or medicine in the application provided in the above-mentioned embodiments, and will not be repeated here.
  • the above-mentioned pneumonia is caused by a viral infection
  • the virus is selected from at least one of the group consisting of the new coronavirus 2019-nCoV, coronavirus HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1 and SARS-CoV.
  • the embodiments of the present disclosure also provide a composition or medicine for preventing and treating pneumonia, which is characterized in that, in parts by weight, the composition or medicine includes 40.0-300.0 parts of artemisinin or artemisinin-derived And 200.0-400.0 parts of 4-aminoquinoline drugs.
  • the artemisinin derivative is selected from any one or more of the group consisting of dihydroartemisinin, artesunate and artemether;
  • the 4-aminoquinoline drugs are selected from any one or more of the group consisting of piperquine, hydroxychloroquine, chloroquine, amodiaquine and naphthoquine.
  • the raw materials include: 45.0-200.0 parts of artemisinin or artemisinin derivatives, and 260.0-390.0 parts of 4-aminoquinoline drugs.
  • the raw materials include: 52.5-72.5 parts of artemisinin or artemisinin derivatives, and 365.0-385.0 parts of 4-aminoquinoline drugs.
  • the composition or medicament further includes adjuvants selected from the group consisting of pregelatinized starch, hydroxypropyl cellulose, hypromellose, sodium starch glycolate, and magnesium stearate A combination of at least one or more of the constituent groups.
  • the composition or medicine in parts by weight, includes: 52.5-72.5 parts of artemisinin or artemisinin derivatives and 365.0-385.0 parts of 4-aminoquinoline drugs, 20-30 parts of pregelatinized starch, 20-25 parts of hypromellose, 10.0-16.0 parts of hypromellose, 20.0-25.0 parts of sodium starch glycolate, and 1.0-8.0 parts of magnesium stearate.
  • the composition in parts by weight, includes: 52.5-72.5 parts artemisinin, 365.0-385.0 parts piperaquine, 20-30 parts pregelatinized starch, and 20-25 parts Hydroxypropyl cellulose, 5.0 to 16.0 parts of hypromellose, 20.0 to 25.0 parts of sodium starch glycolate, and 1.0 to 8.0 parts of magnesium stearate.
  • the embodiments of the present disclosure also provide a method for preparing a medicine for preventing and treating pneumonia, and the preparation method is as follows:
  • the dry granules obtained after granulation, sodium starch glycolate and magnesium stearate are uniformly mixed and then compressed.
  • the particle size of the dry particles is 14-18 mesh.
  • the preparation method of the composition further includes coating the tablet after compression.
  • the embodiments of the present disclosure also provide a composition or medicine for preventing and treating pneumonia, which is characterized in that, in parts by weight, the composition or medicine includes 40.0 to 450.0 parts of artemisinin or artemisinin-derived And 50.0 ⁇ 450.0 parts of 4-aminoquinoline drugs.
  • the artemisinin derivative is selected from any one or more of the group consisting of dihydroartemisinin, artesunate and artemether;
  • the 4-aminoquinoline drugs are selected from any one or more of the group consisting of piperquine, hydroxychloroquine, chloroquine, amodiaquine and naphthoquine.
  • the raw materials include: 45.0-200.0 parts of artemisinin or artemisinin derivatives, and 260.0-390.0 parts of 4-aminoquinoline drugs;
  • the raw materials include: 52.5-72.5 parts of artemisinin or artemisinin derivatives, and 365.0-385.0 parts of 4-aminoquinoline drugs.
  • the composition or medicament further includes adjuvants selected from the group consisting of pregelatinized starch, hydroxypropyl cellulose, hypromellose, sodium starch glycolate, and magnesium stearate A combination of at least one or more of the constituent groups.
  • the composition or medicine in parts by weight, includes: 52.5-72.5 parts of artemisinin or artemisinin derivatives and 365.0-385.0 parts of 4-aminoquinoline drugs, 20-30 parts of pregelatinized starch, 20-25 parts of hypromellose, 10.0-16.0 parts of hypromellose, 20.0-25.0 parts of sodium starch glycolate, and 1.0-8.0 parts of magnesium stearate.
  • the composition in parts by weight, includes: 52.5-72.5 parts artemisinin, 365.0-385.0 parts piperaquine, 20-30 parts pregelatinized starch, and 20-25 parts Hydroxypropyl cellulose, 5.0 to 16.0 parts of hypromellose, 20.0 to 25.0 parts of sodium starch glycolate, and 1.0 to 8.0 parts of magnesium stearate.
  • This embodiment provides a composition for preventing and treating pneumonia.
  • the raw materials and auxiliary materials are as follows in parts by weight:
  • Raw materials including 62.5 parts of artemisinin and 375.0 parts of piperaquine;
  • Excipients 26 parts of pregelatinized starch, 22 parts of hypromellose, 7.0 parts of hypromellose, 20.0 parts of sodium starch glycolate, and 5.0 parts of magnesium stearate.
  • composition is applied to the preparation of drugs for preventing and treating pneumonia, and the preparation method is specifically as follows:
  • the mixed composition and the hypromellose pulp are mixed to form a soft material, which is granulated through a 12-mesh sieve, and then dried at 60°C ⁇ 2°C, and dried to obtain dry particles.
  • Coating solution (Opadry) preparation Add Opadry film coating material to 80% ethanol, stir and disperse evenly, and pass through a 100-mesh sieve for use.
  • Coating Put the tablets in the coating pan, preheat it to 45°C, adjust the air pressure of the spray gun and the flow rate of the coating liquid, spray the coating liquid at an appropriate speed, and dry it to prevent wrinkling or adhesion.
  • the film-coated tablets are bottled and packaged separately.
  • This example provides a composition for preventing and treating pneumonia, which is roughly the same as the composition provided in Example 1.
  • the difference lies in the different components and ratios of the raw materials and auxiliary materials. The differences are as follows:
  • This embodiment provides a composition for preventing and treating pneumonia.
  • the raw materials and auxiliary materials are as follows in parts by weight:
  • Raw materials including 218.75 parts of artemisinin and 218.75 parts of piperaquine;
  • Excipients 30 parts of pregelatinized starch, 25 parts of hypromellose, 10.0 parts of hypromellose, 22.0 parts of sodium starch glycolate, and 4.0 parts of magnesium stearate.
  • composition is applied to the preparation of drugs for preventing and treating pneumonia, and the preparation method is the same as that in Example 1.
  • This example provides a composition for preventing and treating pneumonia, which is roughly the same as the composition provided in Example 1.
  • the difference lies in the different components and ratios of the raw materials and auxiliary materials. The differences are as follows:
  • This embodiment provides a composition for preventing and treating pneumonia.
  • the raw materials and auxiliary materials are as follows in parts by weight:
  • Raw materials including 375.0 parts of artemisinin and 62.5 parts of piperaquine;
  • Excipients 25 parts of pregelatinized starch, 20 parts of hypromellose, 5.0 parts of hypromellose, 20.0 parts of sodium starch glycolate, and 5.0 parts of magnesium stearate.
  • composition is applied to the preparation of drugs for preventing and treating pneumonia, and the preparation method is the same as that in Example 1.
  • This example provides a composition for preventing and treating pneumonia, which is roughly the same as the composition provided in Example 1, except that the ratio of raw materials is different, and the differences are as follows:
  • This embodiment provides a composition for preventing and treating pneumonia.
  • the raw materials are as follows in parts by weight:
  • Raw materials including 250.0 parts of artemisinin and 250.0 parts of hydroxychloroquine sulfate.
  • This example provides a composition for preventing and treating pneumonia, which is roughly the same as the composition provided in Example 1, except that the ratio of raw materials is different, and the differences are as follows:
  • This embodiment provides a composition for preventing and treating pneumonia.
  • the raw materials are as follows in parts by weight:
  • Raw materials including 333.3 parts of artemisinin and 166.7 parts of hydroxychloroquine sulfate.
  • This example provides a composition for preventing and treating pneumonia, which is roughly the same as the composition provided in Example 1, except that the ratio of raw materials is different, and the differences are as follows:
  • This embodiment provides a composition for preventing and treating pneumonia.
  • the raw materials are as follows in parts by weight:
  • Raw materials including 400.0 parts of artemisinin and 100.0 parts of hydroxychloroquine sulfate.
  • This example provides a composition for preventing and treating pneumonia, which is roughly the same as the composition provided in Example 1, except that the ratio of raw materials is different, and the differences are as follows:
  • This embodiment provides a composition for preventing and treating pneumonia.
  • the raw materials are as follows in parts by weight:
  • Raw materials including 128.6 parts of artemisinin and 71.4 parts of hydroxychloroquine sulfate.
  • This example provides a composition for preventing and treating pneumonia, which is roughly the same as the composition provided in Example 1, except that the ratio of raw materials is different, and the differences are as follows:
  • This embodiment provides a composition for preventing and treating pneumonia.
  • the raw materials are as follows in parts by weight:
  • Raw materials including 444.5 parts of artemisinin and 55.6 parts of hydroxychloroquine sulfate.
  • This example provides a composition for preventing and treating pneumonia, which is roughly the same as the composition provided in Example 1, except that the ratio of raw materials is different, and the differences are as follows:
  • This embodiment provides a composition for preventing and treating pneumonia.
  • the raw materials are as follows in parts by weight:
  • Raw materials including 166.7 parts of artemisinin and 333.3 parts of hydroxychloroquine sulfate.
  • This example provides a composition for preventing and treating pneumonia, which is roughly the same as the composition provided in Example 1, except that the ratio of raw materials is different, and the differences are as follows:
  • This embodiment provides a composition for preventing and treating pneumonia.
  • the raw materials are as follows in parts by weight:
  • Raw materials including 83.3 parts of artemisinin and 416.7 parts of hydroxychloroquine sulfate.
  • This example provides a composition for preventing and treating pneumonia, which is roughly the same as the composition provided in Example 1, except that the ratio of raw materials is different, and the differences are as follows:
  • This embodiment provides a composition for preventing and treating pneumonia.
  • the raw materials are as follows in parts by weight:
  • Raw materials including 437.5 parts of artemisinin and 62.5 parts of hydroxychloroquine sulfate.
  • This example provides a composition for preventing and treating pneumonia, which is roughly the same as the composition provided in Example 1, except that the ratio of raw materials is different, and the differences are as follows:
  • This embodiment provides a composition for preventing and treating pneumonia.
  • the raw materials are as follows in parts by weight:
  • Raw materials including 125.0 parts of artemisinin and 375.0 parts of hydroxychloroquine sulfate.
  • This example provides a composition for preventing and treating pneumonia, which is roughly the same as the composition provided in Example 1, except that the ratio of raw materials is different, and the differences are as follows:
  • This embodiment provides a composition for preventing and treating pneumonia.
  • the raw materials are as follows in parts by weight:
  • Raw materials including 100.0 parts of artemisinin and 400.0 parts of hydroxychloroquine sulfate.
  • This example provides a composition for preventing and treating pneumonia, which is roughly the same as the composition provided in Example 1, except that the ratio of raw materials is different, and the differences are as follows:
  • This embodiment provides a composition for preventing and treating pneumonia.
  • the raw materials are as follows in parts by weight:
  • Raw materials including 50.0 parts of artemisinin and 450.0 parts of hydroxychloroquine sulfate.
  • This example provides a composition for preventing and treating pneumonia, which is roughly the same as the composition provided in Example 1, except that the ratio of raw materials is different, and the differences are as follows:
  • This embodiment provides a composition for preventing and treating pneumonia.
  • the raw materials are as follows in parts by weight:
  • Raw materials including 71.4 parts of artemisinin and 428.6 parts of hydroxychloroquine sulfate.
  • This example provides a composition for preventing and treating pneumonia, which is roughly the same as the composition provided in Example 1, except that the ratio of raw materials is different, and the differences are as follows:
  • This embodiment provides a composition for preventing and treating pneumonia.
  • the raw materials are as follows in parts by weight:
  • Raw materials including 55.6 parts of artemisinin and 444.5 parts of hydroxychloroquine sulfate.
  • This example provides a composition for preventing and treating pneumonia, which is roughly the same as the composition provided in Example 1, except that the ratio of raw materials is different, and the differences are as follows:
  • This embodiment provides a composition for preventing and treating pneumonia.
  • the raw materials are as follows in parts by weight:
  • Raw materials including 62.5 parts of artemisinin and 437.5 parts of hydroxychloroquine sulfate.
  • This example provides a composition for preventing and treating pneumonia, which is roughly the same as the composition provided in Example 1, except that the ratio of raw materials is different, and the differences are as follows:
  • This embodiment provides a composition for preventing and treating pneumonia.
  • the raw materials are as follows in parts by weight:
  • Raw materials including 450.0 parts of artemisinin and 50.0 parts of hydroxychloroquine sulfate.
  • Example 1 The inhibitory effect of the drug for preventing and treating pneumonia provided in Example 1 on the coronavirus (HcoV-229E) was verified.
  • a sterile 96-well culture plate add 100 ⁇ L of HuH-7 cells at a concentration of 2 x 10 -5 cells/mL to each well, and culture for 24 h at 37° C. and 5% CO 2. Both the experimental group and the virus control group of the culture plate were added with 100 ⁇ L/well of 100 TCID 50 virus solution, and adsorbed in a 37 °C, 5% CO 2 incubator for 2 hours. After 2 hours, discard the cell culture solution in the 96-well culture plate, and dilute the test drug to each concentration in Table 1, 3 replicate wells for each concentration, and add the above-mentioned drug solution at 100 ⁇ L/well.
  • a cell control group, a blank control group (solvent control group) and a virus control group (negative control group) are set up.
  • the cells were cultured in a 37°C, 5% CO 2 incubator for 3 days.
  • CPE cytopathic
  • Use Reed-Muench method or GraphPad Prism5.0 to calculate the half effective concentration (IC 50 ). Judging the drug standard: the concentration with 50% of the CPE inhibiting the virus is regarded as the effective concentration.
  • the drug prepared from the composition provided in Example 1 has an inhibitory effect on the cytopathic effect caused by the coronavirus infected cells when the maximum non-toxic concentration is 125 ⁇ g/mL.
  • Tested drugs 15 kinds, the names and concentrations of the drugs are shown in Table 3.
  • VeroE6 cells preserved by the Virus Room of the State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Health.
  • VeroE6 cells In a sterile 96-well culture plate, add 100 ⁇ L of VeroE6 cells at a concentration of 2 ⁇ 10 5 cells/mL to each well.
  • Example 4 Example 4, Example 5, Example 6, Example 7 and Example 8 at the maximum non-toxic concentration of 50 ⁇ g/mL, the new coronavirus (SARS-CoV-2 ) Cytopathies caused by infection of Vero E6 cells have an inhibitory effect.
  • SARS-CoV-2 new coronavirus
  • Example 9-11 and Figure 7-9 Example 9, Example 10, and Example 11 in the concentration range of 25-50 ⁇ g/mL, caused by the infection of Vero E6 cells with the new coronavirus (SARS-CoV-2)
  • SARS-CoV-2 new coronavirus
  • Example 12 From Table 12-14 and Figure 10-12, it can be seen that Example 12, Example 13, and Example 14 are in the concentration range of 6.25-12.5 ⁇ g/mL for the novel coronavirus (SARS-CoV-2) infection of Vero E6 cells.
  • SARS-CoV-2 novel coronavirus
  • the resulting cytopathic effect has an inhibitory effect.
  • Example 15 and Example 16 in the concentration range of 12.5-25 ⁇ g/mL, are effective against the cytopathic changes caused by the new coronavirus (SARS-CoV-2) infection of Vero E6 cells. Inhibition.
  • SARS-CoV-2 new coronavirus
  • Example 17 has an inhibitory effect on the cytopathic effect caused by the novel coronavirus (SARS-CoV-2) infection of Vero E6 cells.
  • SARS-CoV-2 novel coronavirus
  • Example 18 at the maximum non-toxic concentration of 100 ⁇ g/mL has an inhibitory effect on the cytopathic effect caused by the novel coronavirus (SARS-CoV-2) infection of Vero E6 cells.
  • SARS-CoV-2 novel coronavirus
  • Example 1 To verify the therapeutic effect of the drug for preventing and treating pneumonia provided in Example 1 on pneumonia caused by new coronavirus (2019-nCoV) infection.
  • This test case is based on the artemisinin-piperquine tablets for the treatment of mild and common new coronary pneumonia projects declared by the inventor, and has been in the special emergency project for the prevention and control of new coronavirus infection in Guangdong province.
  • Inclusion criteria patients with mild and common new coronavirus pneumonia with positive nucleic acid test, and asymptomatic patients with new coronavirus pneumonia;
  • Exclusion criteria severe cases of new coronavirus pneumonia, severe liver and kidney damage, pregnant women within 3 months, infants within 6 months;
  • Administration method take the medicine once a day, 1 tablet each time, double the first dose (2 tablets) for 5 days.
  • nucleic acid test the admission nucleic acid test was positive, and the time for the nucleic acid test to turn negative was 1-4 days. After taking the medicine, the nucleic acid test of 7 patients turned negative, of which 4 cases turned negative for 1 day, and 2 cases turned negative for 1 day Within 2 days, 1 case took 4 days to turn negative, with an average time of 1.7 days. The other 2 cases are still under hospital observation. Chest CT examination: 1 case of both lung nodules, granuloma; 1 case of right lung lobe slightly enlarged, the other 7 cases were normal. There was no significant change in the electrocardiogram during admission, hospitalization, and before discharge; no abnormal changes in laboratory blood routine, liver and kidney function monitoring, and no abnormalities in myocardial enzyme monitoring.
  • the embodiments of the present disclosure provide a composition for the prevention and treatment of pneumonia and its application in the preparation of a medicine for prevention and treatment of pneumonia.
  • Drug development provides a new direction.

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Abstract

公开了一种用于防治肺炎的组合物及其在制备用于防治肺炎的药物中的应用，涉及医药领域，所述组合物的原料包括40.0～300.0份青蒿素或青蒿素衍生物，和200.0～400.0份4-氨基喹啉类药物，其对于冠状病毒感染引发的肺炎具有很好的防治作用，为新冠肺炎的药物开发提供了一种新的方向。

Description

一种用于防治肺炎的组合物、组合物的制备方法及其在制备用于防治肺炎的药物中的应用
相关申请的交叉引用
本申请要求于2020年04月29日提交中国专利局的申请号为2020103586373、名称为“一种用于防治肺炎的组合物及其在制备用于防治肺炎的药物中的应用”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本公开涉及医药领域，具体而言，涉及一种用于防治肺炎的组合物、组合物的制备方法及其在制备用于防治肺炎的药物中的应用。
背景技术
冠状病毒在系统分类上属套式病毒目(Nidovirales)冠状病毒科(Coronaviridae)冠状病毒属(Coronavirus)。冠状病毒属的病毒是具囊膜(envelope)、基因组为线性单股正链的RNA病毒，是自然界广泛存在的一大类病毒。
冠状病毒直径约80～120nm，基因组5′端具有甲基化的帽状结构，3′端具有poly(A)尾，基因组全长约27-32kb，是目前已知RNA病毒中基因组最大的病毒。
冠状病毒最先于1937年从鸡身上分离出来，病毒颗粒的直径为60～200nm，平均直径为100nm，呈球形或椭圆形，具有多形性。病毒有包膜，包膜上存在棘突，整个病毒像日冕，不同的冠状病毒的棘突有明显的差异。在冠状病毒感染细胞内有时可以见到管状的包涵体。
目前所知，冠状病毒科只感染脊椎动物，与人和动物的许多疾病有关。鉴于此，特提出本公开。
发明内容
本公开的目的包括，例如提供一种用于防治肺炎的组合物及其在制备用于防治肺炎的药物中的应用。
本公开是这样实现的：
第一方面，本公开实施例提供了一种组合物在制备用于防治肺炎的药物中的应用，按重量份数计，所述组合物包括40.0～300.0份青蒿素或青蒿素衍生物，和200.0～400.0份4－氨基喹啉类药物。
第二方面，本公开实施例提供了一种用于防治肺炎的组合物或药物，按重量份数计，所述组合物或药物包括40.0～300.0份青蒿素或青蒿素衍生物，和200.0～400.0份4－氨基喹啉类药物。
第三方面，本公开实施例提供了一种用于防治肺炎的药物的制备方法，所述制备方法如下：
将粉碎后的青蒿素、预胶化淀粉、羟丙纤维素和哌喹混合均匀，并在得到的混合物中加入羟丙甲纤维素进行制粒；
将制粒后得到的干颗粒、羧甲淀粉钠和硬脂酸镁混合均匀后进行压片。
第四方面，本公开实施例提供了一种用于防治肺炎的组合物或药物，按重量份数计，所述组合物或药物包括40.0～450.0份青蒿素或青蒿素衍生物，和50.0～450.0份4－氨基喹啉类药物。
本公开具有以下有益效果：
本公开实施例提供了一种用于防治肺炎的组合物及其在制备用于防治肺炎的药物中的应用，该组合物对于冠状病毒感染引发的肺炎具有很好的防治作用，为新冠肺炎的药物开发提供了一种新的方向。
附图说明
为了更清楚地说明本公开实施例的技术方案，下面将对实施例中所需要使用的附图作简单地介绍，应当理解，以下附图仅示出了本公开的某些实施例，因此不应被看作是对范围的限定，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他相关的附图。
图1示出了试验例1提供的组合物对人冠状病毒HcoV-229E药效检测结果。
图2示出了实施例4提供的用于防治肺炎的药物对新型冠状病毒SARS-COV-2药效检测结果。
图3示出了实施例5提供的用于防治肺炎的药物对新型冠状病毒SARS-COV-2药效检测结果。
图4示出了实施例6提供的用于防治肺炎的药物对新型冠状病毒SARS-COV-2药效检测结果。
图5示出了实施例7提供的用于防治肺炎的药物对新型冠状病毒SARS-COV-2药效检测结果。
图6示出了实施例8提供的用于防治肺炎的药物对新型冠状病毒SARS-COV-2药效检测结果。
图7示出了实施例9提供的用于防治肺炎的药物对新型冠状病毒SARS-COV-2药效检测结果。
图8示出了实施例10提供的用于防治肺炎的药物对新型冠状病毒SARS-COV-2药效检测结果。
图9示出了实施例11提供的用于防治肺炎的药物对新型冠状病毒SARS-COV-2药效检测结果。
图10示出了实施例12提供的用于防治肺炎的药物对新型冠状病毒SARS-COV-2药效检测结果。
图11示出了实施例13提供的用于防治肺炎的药物对新型冠状病毒SARS-COV-2药效检测结果。
图12示出了实施例14提供的用于防治肺炎的药物对新型冠状病毒SARS-COV-2药效检测结果。
图13示出了实施例15提供的用于防治肺炎的药物对新型冠状病毒SARS-COV-2药效检测结果。
图14示出了实施例16提供的用于防治肺炎的药物对新型冠状病毒SARS-COV-2药效检测结果。
图15示出了实施例17提供的用于防治肺炎的药物对新型冠状病毒SARS-COV-2药效检测结果。
图16示出了实施例18提供的用于防治肺炎的药物对新型冠状病毒SARS-COV-2药效检测结果。
具体实施方式
为使本公开实施例的目的、技术方案和优点更加清楚，下面将对本公开实施例中的技术方案进行清楚、完整地描述。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市售购买获得的常规产品。
名词定义
本文中的“防治”是指预防和/或治疗。
以下结合实施例对本公开的特征和性能作进一步的详细描述。
本公开实施例提供了一种组合物在制备用于防治肺炎的药物中的应用，按重量份数计，所述组合物包括40.0～300.0份青蒿素或青蒿素衍生物，和200.0～400.0份4－氨基喹啉类药物。
在一种或多种实施方式中，按重量份数计，所述组合物包括40.0～80.0份青蒿素或青蒿素衍生物，和350.0～400.0份4－氨基喹啉类药物。
在一种或多种实施方式中，所述青蒿素衍生物选自由双氢青蒿素、青蒿琥酯和蒿甲醚组成的组中的任意一种或多种；
所述4－氨基喹啉类药物选自由哌喹、羟氯喹、氯喹、阿莫地喹和萘酚喹组成的组中的任意一种或多种。
经发明人研究发现，青蒿素或其衍生物，与4－氨基喹啉类药物的组合物对于冠状病毒引发的肺炎有很好的防治作用。
在一种或多种实施方式中，在上述组合物中，按重量份数计，青蒿素或其衍生物的典型但非限制性的实例为，例如，40.0份、45.0份、50.0份、55.0份、60.0份、65.0份、70.0份、75.0份、80.0份、90.0份、100.0份、110.0份、120.0份、130.0份、140.0份、150.0份、160.0份、170.0份、180.0份、190.0份、200.0份、210.0份、220.0份、230.0份、240.0份、250.0份、260.0份、270.0份、280.0份、290.0份或300.0份；4－氨基喹啉类药物的典型但非限制性的实例为，例如，200.0份、210.0份、220.0份、230.0份、240.0份、250.0份、260.0份、270.0份、280.0份、290.0份、300.0份、310.0份、320.0份、330.0份、340.0份、350.0份、360.0份、370.0份、380.0份、390.0份或400.0份。
在一种或多种实施方式中，在上述组合物中，按重量份数计，青蒿素或其衍生物可以为40.0份、45.0份、50.0份、55.0份、60.0份、65.0份、70.0份、75.0份或80.0份；4－氨基喹啉类药物可以为350.0份、360.0份、370.0份、380.0份、390.0份或400.0份。
在一种或多种实施方式中，按重量份数计，所述组合物包括：45.0～75.0份青蒿素或青蒿素衍生物，和360.0～390.0份4－氨基喹啉类药物。
在一种或多种实施方式中，按重量份数计，所述组合物包括：52.5～72.5份青蒿素或青蒿素衍生物，和365.0～385.0份4－氨基喹啉类药物。
在一种或多种实施方式中，所述组合物还包括辅料，所述辅料选自由预胶化淀粉、羟丙纤维素、羟丙甲纤维素、羧甲淀粉钠和硬脂酸镁组成的组中的至少一种或多种的组合。
在一种或多种实施方式中，按重量份数计，所述组合物包括：52.5～72.5份青蒿素或青蒿素衍生物和365.0～385.0份4－氨基喹啉类药物、20～30份预胶化淀粉、20～25份羟丙纤维素、10.0～16.0份羟丙 甲纤维素、20.0～25.0份羧甲淀粉钠和1.0～8.0份硬脂酸镁。
在一种或多种实施方式中，按重量份数计，所述组合物包括：52.5～72.5份青蒿素和365.0～385.0份哌喹、20～30份预胶化淀粉、20～25份羟丙纤维素、10.0～16.0份羟丙甲纤维素、20.0～25.0份羧甲淀粉钠和1.0～8.0份硬脂酸镁。
在一种或多种实施方式中，按重量份数计，预胶化淀粉的典型但非限制性的实例为，例如，20份、21份、22份、23份、24份、25份、26份、27份、28份、29份或30份；羟丙纤维素的典型但非限制性的实例为，例如，20份、21份、22份、23份、24份或25份；羟丙甲纤维素的典型但非限制性的实例为，例如，10.0份、11.0份、12.0份、13.0份、14.0份、15.0份或16.0份；羧甲淀粉钠的典型但非限制性的实例为，例如，20.0份、21.0份、22.0份、23.0份、24.0份或25.0份；硬脂酸镁的典型但非限制性的实例为，例如，1.0份、2.0份、3.0份、4.0份、5.0份、6.0份、7.0份或8.0份。
在一种或多种实施方式中，所述药物的制备方法如下：
将粉碎后的青蒿素、预胶化淀粉、羟丙纤维素和哌喹混合均匀，并在得到的混合中加入羟丙甲纤维素进行制粒；
将制粒后得到的干颗粒、羧甲淀粉钠和硬脂酸镁混合均匀后进行压片。
在一种或多种实施方式中，所述干颗粒的粒径为14～18目；在一种或多种实施方式中，所述干颗粒的粒径的典型但非限制性的实例为，例如，14目、15目、16目、17目或18目。
在一种或多种实施方式中，所述组合物的制备方法还包括对压片后的药片进行包衣。
在一种或多种实施方式中，所述肺炎由病毒感染所致。
在一种或多种实施方式中，所述病毒包括：新型冠状病毒2019-nCoV和冠状病毒HCoV-229E中的至少一种。
此外，本公开实施例还提供了一种用于防治肺炎的组合物或药物，按重量份数计，其原料包括40.0～80.0份青蒿素和350.0～400.0份哌喹。
具体地，上述组合物或药物的组分和配比同上述实施例提供的应用中的组合物或药物的组分和配比，在此不再赘述。
在一种或多种实施方式中，上述肺炎由病毒感染所致；
所述病毒选自由新型冠状病毒2019-nCoV、冠状病毒HCoV-229E、HCoV-OC43、HCoV-NL63、HCoV-HKU1和SARS-CoV组成的组中的至少一种。
此外，本公开实施例还提供了一种用于防治肺炎的组合物或药物，其特征在于，按重量份数计，所述组合物或药物包括40.0～300.0份青蒿素或青蒿素衍生物，和200.0～400.0份4－氨基喹啉类药物。
在一种或多种实施方式中，所述青蒿素衍生物选自由双氢青蒿素、青蒿琥酯和蒿甲醚组成的组中的任意一种或多种；
所述4－氨基喹啉类药物选自由哌喹、羟氯喹、氯喹、阿莫地喹和萘酚喹组成的组中的任意一种或多种。
在一种或多种实施方式中，按重量份数计，所述原料包括：45.0～200.0份青蒿素或青蒿素衍生物，和260.0～390.0份4－氨基喹啉类药物。
在一种或多种实施方式中，按重量份数计，所述原料包括：52.5～72.5份青蒿素或青蒿素衍生物，和365.0～385.0份4－氨基喹啉类药物。
在一种或多种实施方式中，所述组合物或药物还包括辅料，所述辅料选自由预胶化淀粉、羟丙纤维素、羟丙甲纤维素、羧甲淀粉钠和硬脂酸镁组成的组中的至少一种或多种的组合。
在一种或多种实施方式中，按重量份数计，所述组合物或药物包括：52.5～72.5份青蒿素或青蒿素衍生物和365.0～385.0份4－氨基喹啉类药物、20～30份预胶化淀粉、20～25份羟丙纤维素、10.0～16.0份羟丙甲纤维素、20.0～25.0份羧甲淀粉钠和1.0～8.0份硬脂酸镁。
在一种或多种实施方式中，按重量份数计，所述组合物包括：52.5～72.5份青蒿素和365.0～385.0份哌喹、20～30份预胶化淀粉、20～25份羟丙纤维素、5.0～16.0份羟丙甲纤维素、20.0～25.0份羧甲淀粉钠和1.0～8.0份硬脂酸镁。
此外，本公开实施例还提供了一种用于防治肺炎的药物的制备方法，所述制备方法如下：
将粉碎后的青蒿素、预胶化淀粉、羟丙纤维素和哌喹混合均匀，并在得到的混合物中加入羟丙甲纤维素进行制粒；
将制粒后得到的干颗粒、羧甲淀粉钠和硬脂酸镁混合均匀后进行压片。
在一种或多种实施方式中，所述干颗粒的粒径为14～18目。
在一种或多种实施方式中，所述组合物的制备方法还包括对压片后的药片进行包衣。
此外，本公开实施例还提供了一种用于防治肺炎的组合物或药物，其特征在于，按重量份数计，所述组合物或药物包括40.0～450.0份青蒿素或青蒿素衍生物，和50.0～450.0份4－氨基喹啉类药物。
在一种或多种实施方式中，所述青蒿素衍生物选自由双氢青蒿素、青蒿琥酯和蒿甲醚组成的组中的任意一种或多种；
所述4－氨基喹啉类药物选自由哌喹、羟氯喹、氯喹、阿莫地喹和萘酚喹组成的组中的任意一种或多种。
在一种或多种实施方式中，按重量份数计，所述原料包括：45.0～200.0份青蒿素或青蒿素衍生物，和260.0～390.0份4－氨基喹啉类药物；
在一种或多种实施方式中，按重量份数计，所述原料包括：52.5～72.5份青蒿素或青蒿素衍生物，和365.0～385.0份4－氨基喹啉类药物。
在一种或多种实施方式中，所述组合物或药物还包括辅料，所述辅料选自由预胶化淀粉、羟丙纤维素、羟丙甲纤维素、羧甲淀粉钠和硬脂酸镁组成的组中的至少一种或多种的组合。
在一种或多种实施方式中，按重量份数计，所述组合物或药物包括：52.5～72.5份青蒿素或青蒿素衍生物和365.0～385.0份4－氨基喹啉类药物、20～30份预胶化淀粉、20～25份羟丙纤维素、10.0～16.0份羟丙甲纤维素、20.0～25.0份羧甲淀粉钠和1.0～8.0份硬脂酸镁。
在一种或多种实施方式中，按重量份数计，所述组合物包括：52.5～72.5份青蒿素和365.0～385.0份哌喹、20～30份预胶化淀粉、20～25份羟丙纤维素、5.0～16.0份羟丙甲纤维素、20.0～25.0份羧甲淀粉钠和1.0～8.0份硬脂酸镁。
实施例1
本实施例提供了一种用于防治肺炎的组合物，按重量份数计，其原料和辅料如下：
原料：包括62.5份青蒿素、375.0份哌喹；
辅料：26份预胶化淀粉、22份羟丙纤维素、7.0份羟丙甲纤维素、20.0份羧甲淀粉钠和5.0份硬脂酸镁。
该组合物应用于防治肺炎的药物的制备，制备方法具体如下：
(1)原料准备
将青蒿素、哌喹、预胶化淀粉和羟丙纤维素分别粉碎后100目过筛；将过筛后的青蒿素、预胶化淀粉和羟丙纤维素混匀后，再与哌喹混合；
(2)制粒烘干
将混合后的组合物与羟丙甲纤维素浆混合制成软材，过12目筛制粒，随后于60℃±2℃烘干，烘干后得到干颗粒。
(3)整粒压片
干颗粒用16目筛整粒，然后加入干颗粒重量5％的羧甲淀粉钠及1.0％的硬脂酸镁，再充分混匀，精密称取适量混合物，测定药物含量，计算设定片重，选用条形异形冲模压片。
(4)包衣
包衣液(欧巴代)配制：将欧巴代薄膜包衣料加入80％乙醇中，搅拌分散均匀，过100目筛备用。
包衣：将药片放入包衣锅中，预热至45℃，调整喷枪空气压力及包衣液流量，以适当速度喷入包衣液，干燥，防止起皱或粘连。将薄膜衣片分别进行瓶装包装。
实施例2
本实施例提供了一种用于防治肺炎的组合物，其大致与实施例1提供的组合物相同，区别在于原料和辅料的组分和配比不同，区别如下：
本实施例提供了一种用于防治肺炎的组合物，按重量份数计，其原料和辅料如下：
原料：包括218.75份青蒿素、218.75份哌喹；
辅料：30份预胶化淀粉、25份羟丙纤维素、10.0份羟丙甲纤维素、22.0份羧甲淀粉钠和4.0份硬脂酸镁。
该组合物应用于防治肺炎的药物的制备，制备方法同实施例1。
实施例3
本实施例提供了一种用于防治肺炎的组合物，其大致与实施例1提供的组合物相同，区别在于原料和辅料的组分和配比不同，区别如下：
本实施例提供了一种用于防治肺炎的组合物，按重量份数计，其原料和辅料如下：
原料：包括375.0份青蒿素、62.5份哌喹；
辅料：25份预胶化淀粉、20份羟丙纤维素、5.0份羟丙甲纤维素、20.0份羧甲淀粉钠和5.0份硬脂酸镁。
该组合物应用于防治肺炎的药物的制备，制备方法同实施例1。
实施例4
本实施例提供了一种用于防治肺炎的组合物，其大致与实施例1提供的组合物相同，区别在于原料的配比不同，区别如下：
本实施例提供了一种用于防治肺炎的组合物，按重量份数计，其原料如下：
原料：包括250.0份青蒿素、250.0份硫酸羟氯喹。
实施例5
本实施例提供了一种用于防治肺炎的组合物，其大致与实施例1提供的组合物相同，区别在于原料的配比不同，区别如下：
本实施例提供了一种用于防治肺炎的组合物，按重量份数计，其原料如下：
原料：包括333.3份青蒿素、166.7份硫酸羟氯喹。
实施例6
本实施例提供了一种用于防治肺炎的组合物，其大致与实施例1提供的组合物相同，区别在于原料的配比不同，区别如下：
本实施例提供了一种用于防治肺炎的组合物，按重量份数计，其原料如下：
原料：包括400.0份青蒿素、100.0份硫酸羟氯喹。
实施例7
本实施例提供了一种用于防治肺炎的组合物，其大致与实施例1提供的组合物相同，区别在于原料的配比不同，区别如下：
本实施例提供了一种用于防治肺炎的组合物，按重量份数计，其原料如下：
原料：包括128.6份青蒿素、71.4份硫酸羟氯喹。
实施例8
本实施例提供了一种用于防治肺炎的组合物，其大致与实施例1提供的组合物相同，区别在于原料的配比不同，区别如下：
本实施例提供了一种用于防治肺炎的组合物，按重量份数计，其原料如下：
原料：包括444.5份青蒿素、55.6份硫酸羟氯喹。
实施例9
本实施例提供了一种用于防治肺炎的组合物，其大致与实施例1提供的组合物相同，区别在于原料的配比不同，区别如下：
本实施例提供了一种用于防治肺炎的组合物，按重量份数计，其原料如下：
原料：包括166.7份青蒿素、333.3份硫酸羟氯喹。
实施例10
本实施例提供了一种用于防治肺炎的组合物，其大致与实施例1提供的组合物相同，区别在于原料的配比不同，区别如下：
本实施例提供了一种用于防治肺炎的组合物，按重量份数计，其原料如下：
原料：包括83.3份青蒿素、416.7份硫酸羟氯喹。
实施例11
本实施例提供了一种用于防治肺炎的组合物，其大致与实施例1提供的组合物相同，区别在于原料的配比不同，区别如下：
本实施例提供了一种用于防治肺炎的组合物，按重量份数计，其原料如下：
原料：包括437.5份青蒿素、62.5份硫酸羟氯喹。
实施例12
本实施例提供了一种用于防治肺炎的组合物，其大致与实施例1提供的组合物相同，区别在于原料的配比不同，区别如下：
本实施例提供了一种用于防治肺炎的组合物，按重量份数计，其原料如下：
原料：包括125.0份青蒿素、375.0份硫酸羟氯喹。
实施例13
本实施例提供了一种用于防治肺炎的组合物，其大致与实施例1提供的组合物相同，区别在于原料的配比不同，区别如下：
本实施例提供了一种用于防治肺炎的组合物，按重量份数计，其原料如下：
原料：包括100.0份青蒿素、400.0份硫酸羟氯喹。
实施例14
本实施例提供了一种用于防治肺炎的组合物，其大致与实施例1提供的组合物相同，区别在于原料的配比不同，区别如下：
本实施例提供了一种用于防治肺炎的组合物，按重量份数计，其原料如下：
原料：包括50.0份青蒿素、450.0份硫酸羟氯喹。
实施例15
本实施例提供了一种用于防治肺炎的组合物，其大致与实施例1提供的组合物相同，区别在于原料的配比不同，区别如下：
本实施例提供了一种用于防治肺炎的组合物，按重量份数计，其原料如下：
原料：包括71.4份青蒿素、428.6份硫酸羟氯喹。
实施例16
本实施例提供了一种用于防治肺炎的组合物，其大致与实施例1提供的组合物相同，区别在于原料的配比不同，区别如下：
本实施例提供了一种用于防治肺炎的组合物，按重量份数计，其原料如下：
原料：包括55.6份青蒿素、444.5份硫酸羟氯喹。
实施例17
本实施例提供了一种用于防治肺炎的组合物，其大致与实施例1提供的组合物相同，区别在于原料的配比不同，区别如下：
本实施例提供了一种用于防治肺炎的组合物，按重量份数计，其原料如下：
原料：包括62.5份青蒿素、437.5份硫酸羟氯喹。
实施例18
本实施例提供了一种用于防治肺炎的组合物，其大致与实施例1提供的组合物相同，区别在于原料的配比不同，区别如下：
本实施例提供了一种用于防治肺炎的组合物，按重量份数计，其原料如下：
原料：包括450.0份青蒿素、50.0份硫酸羟氯喹。
试验例1
验证实施例1提供的用于防治肺炎的药物对冠状病毒(HcoV-229E)的抑制作用。
实验材料
细胞：HuH-7细胞，由广州呼吸健康研究所呼吸疾病国家重点实验室病毒式保存。
病毒：人冠状病毒HcoV-229E，滴度为TCID 50＝10 -5/100μL，由广州呼吸健康研究所呼吸疾病国家 重点实验室病毒-80℃保存；使用病毒滴度为100TCID 50。
实验方法
设置3组试验，具体的受试药物的信息请参照表1。
表1 药物信息
Figure PCTCN2020096406-appb-000001
在无菌96孔培养板中，每孔加入100μL浓度为2ⅹ10 -5细胞/mL的HuH-7细胞，在37℃、5％CO 2下培养24h。培养板实验组和病毒对照组均加入100TCID 50病毒液100μL/孔，并在37℃、5％CO 2培养箱吸附2h。2h后，弃去96孔培养板中细胞培养液，受试药物稀释成表1中的各个浓度，每个浓度3个复孔，并以100μL/孔加入上述药液。
同时设置细胞对照组、空白对照组(溶剂对照组)和病毒对照组(阴性对照组)。细胞在37℃、5％CO 2孵箱中培养3天。于光学显微镜下观察细胞病变(CPE)，细胞出现病变的程度按以下6级标准记录：“-”为无病变出现；“±”为细胞病变少于10％；“+”为细胞病变约25％；“++”为细胞病变约50％；“+++”为约75％的细胞出现病变；“++++”为75％以上的病变。采用Reed-Muench法或GraphPad Prism5.0计算半数有效浓度(IC 50)。判断药物标准：具有50％的抑制病毒CPE的浓度视为有效浓度。
实验结果
实验结果如表2和图1所示。
表2 组合物抗人冠状病毒HcoV-229E药效结果
药物浓度(μg/mL) 抑制率(％)
125.00 56.67±7.64
62.50 26.67±2.89
31.25 8.33±2.89
由表2和图1可知，实施例1提供的组合物制备的药物在最大无毒浓度为125μg/mL时对冠状病毒感染细胞所导致的细胞病变有抑制作用。
试验例2
验证实施例4-18提供的用于防治肺炎的药物对新型冠状病毒(SARS-COV-2)的抑制作用。
实验材料：
受试药物：15种，药物名称及浓度见表3。
细胞：VeroE6细胞，由广州呼吸健康研究院呼吸疾病国家重点实验室病毒室保存。
病毒：SARS-CoV-2，滴度为TCID 50＝10 -6/100μL，由广州海关技术中心卫生检疫研究所/国家生物安全检测重点实验室(呼吸疾病国家重点实验室高致病病原微生物研究室)于-80℃保存。使用病毒滴度为100TCID 50。
实验方法：
受试药物：
表3：药物名称、实验浓度和分组
在无菌96孔培养板中，每孔加入100μL浓度为2×10 5细胞/mL的VeroE6细胞，在37℃、5％
Figure PCTCN2020096406-appb-000002
CO 2下培养24小时；培养板实验组和病毒对照组加入100TCID 50病毒液100μL/孔，并在37℃、5％CO 2培养箱中吸附2h；2h后，弃去96孔培养板中细胞培养液；受试药物稀释成表3中的各个浓度，每个浓度3个复孔，以100μl/孔加入上述药液；
同时设立细胞对照组、空白对照组(溶剂对照组)、病毒对照组(阴性对照组)和阳性药物对照组；将细胞在37℃,5％CO 2孵箱中孵育3-4天；光学显微镜下观察细胞病变(CPE)，细胞出现病变的程度按以下6级标准记录：“-”无病变出现；“±”为细胞病变少于10％；“+”为细胞病变约25％；“++”为细胞病变约50％；“+++”为约75％的细胞出现病变：“++++”为75％以上病变。采用Reed-Muench法或GraphPad Prism5.0计算半数有效浓度(IC 50)。判断药效标准：具有50％的抑制病毒CPE的浓度视为有效浓度。
实验条件：以上实验操作均在BSL-3实验室内完成。
实验结果
实验结果如表4-18和图2-16所示。
表4 实施例4提供的药物的抗新型冠状病毒药效结果
药物浓度(μg/mL) 抑制率(％)
50 61.67±7.64
25 21.67±5.77
12.5 1.67±2.89
表5 实施例5提供的药物的抗新型冠状病毒药效结果
药物浓度(μg/mL) 抑制率(％)
50 56.67±7.64
25 18.33±5.77
12.5 3.33±2.89
表6 实施例6提供的药物的抗新型冠状病毒药效结果
药物浓度(μg/mL) 抑制率(％)
50 83.33±7.64
25 26.67±2.89
12.5 6.67±2.89
表7 实施例7提供的药物的抗新型冠状病毒药效结果
药物浓度(μg/mL) 抑制率(％)
50 65.00±8.67
25 26.67±7.63
12.5 3.33±2.89
表8 实施例8提供的药物的抗新型冠状病毒药效结果
药物浓度(μg/mL) 抑制率(％)
50 65.00±8.67
25 21.67±5.77
12.5 3.33±2.89
表9 实施例9提供的药物的抗新型冠状病毒药效结果
药物浓度(μg/mL) 抑制率(％)
50 91.67±2.89
25 66.67±10.41
12.5 21.67±5.77
6.25 1.67±2.89
表10 实施例10提供的药物的抗新型冠状病毒药效结果
药物浓度(μg/mL) 抑制率(％)
50 93.33±2.89
25 76.67±2.89
12.5 46.67±5.77
6.25 6.67±2.89
表11 实施例11提供的药物的抗新型冠状病毒药效结果
药物浓度(μg/mL) 抑制率(％)
50 65.00±8.67
25 53.33±7.64
12.5 20.00±8.67
表12 实施例12提供的药物的抗新型冠状病毒药效结果
药物浓度(μg/mL) 抑制率(％)
12.5 91.67±2.89
6.25 66.67±10.41
3.13 18.33±7.64
1.56 1.67±2.89
表13 实施例13提供的药物的抗新型冠状病毒药效结果
药物浓度(μg/mL) 抑制率(％)
12.5 91.67±2.89
6.25 53.33±7.64
3.13 15.00±5.00
表14 实施例14提供的药物的抗新型冠状病毒药效结果
药物浓度(μg/mL) 抑制率(％)
12.5 86.67±5.77
6.25 51.67±7.63
3.13 13.33±5.77
表15 实施例15提供的药物的抗新型冠状病毒药效结果
药物浓度(μg/mL) 抑制率(％)
25 93.33±2.89
12.5 71.67±14.43
6.25 23.33±2.89
3.13 3.33±2.89
表16 实施例16提供的药物的抗新型冠状病毒药效结果
药物浓度(μg/mL) 抑制率(％)
25 93.33±2.89
12.5 86.67±2.89
6.25 36.67±11.55
3.13 3.33±2.89
表17 实施例17提供的药物的抗新型冠状病毒药效结果
药物浓度(μg/mL) 抑制率(％)
6.25 86.67±2.89
3.13 35.00±8.67
表18 实施例18提供的药物的抗新型冠状病毒药效结果
药物浓度(μg/mL) 抑制率(％)
100 80.00±8.66
50 31.67±7.64
25 11.67±2.89
由表4-8和图2-6可知：实施例4、实施例5、实施例6、实施例7和实施例8在最大无毒浓度50μg/mL，对新型冠状病毒(SARS-CoV-2)感染Vero E6细胞所导致的细胞病变具有抑制作用。
由表9-11和图7-9可知：实施例9、实施例10和实施例11在25-50μg/mL的浓度范围，对新型冠状病毒(SARS-CoV-2)感染Vero E6细胞所导致的细胞病变具有抑制作用。
由表12-14和图10-12可知：实施例12、实施例13和实施例14在6.25-12.5μg/mL的浓度范围，对新型冠状病毒(SARS-CoV-2)感染Vero E6细胞所导致的细胞病变具有抑制作用。
由表15-16和图13-14可知：实施例15和实施例16在12.5-25μg/mL的浓度范围，对新型冠状病毒(SARS-CoV-2)感染Vero E6细胞所导致的细胞病变具有抑制作用。
由表17和图15可知：实施例17在最大无毒浓度6.25μg/mL，对新型冠状病毒(SARS-CoV-2)感染Vero E6细胞所导致的细胞病变具有抑制作用。
由表18和图16可知：实施例18在最大无毒浓度100μg/mL，对新型冠状病毒(SARS-CoV-2)感染Vero E6细胞所导致的细胞病变具有抑制作用。
试验例3
验证实施例1提供的用于防治肺炎的药物对新型冠状病毒(2019-nCoV)感染引发的肺炎的治疗效果。
本试验例基于发明人申报的青蒿素哌喹片治疗轻型和普通型新冠肺炎项目，已在广东省防控新型冠状病毒感染科技攻关应急专项。
纳入标准：核酸检测阳性者轻型、普通型新型冠状病毒肺炎患者，新型冠状病毒肺炎无症状感染者；
排除标准：新型冠状病毒肺炎重症病例，严重肝肾功能损害者，3个月内孕妇，6个月内婴儿；
给药方法：每天服药1次，每次1片，首剂加倍(2片)，连服5天。
11例患者经医生告知同意后服用实施例1提供的药物，其中，7例服用4次(5片)，3例服用2次(3片)，1例服用1次(2片)。由于2例患者在因服药前1天核酸检测转阴而不列入统计，纳入统计病例9例，男性7例，女性2例，年龄24-47岁，平均年龄31.1岁，平均体重为80kg，治疗前后体重无明显变化；食欲佳，二便正常。所有患者入院及住院期间生命体征平稳，入院及住院期间呼吸为18-20次/分；脉搏62-92次/分。
实验结果
对11例患者进行核酸检测、胸部CT检查、心电图、实验室血常规、肝肾功能以及心肌酶监测，11例病例的具体情况参照表3。
其中，核酸检测：入院核酸检测均为阳性，核酸检测转阴时间为1-4天，服药后，7例病人核酸检测转阴，其中4例转阴时间为1天，2例转阴时间为2天，1例转阴时间为4天，平均转阴时间1.7天，另外2例仍在住院观察中。胸部CT检查：1例双肺小结节，肉芽肿；1例右肺叶轻度肿大，另7例正常。心电图检查入院、住院期间、出院前均无明显变化；实验室血常规、肝肾功能监测无异常变化，心肌酶监测无异常。
表3 11例病例具体情况
Figure PCTCN2020096406-appb-000003
Figure PCTCN2020096406-appb-000004
Figure PCTCN2020096406-appb-000005
Figure PCTCN2020096406-appb-000006
由表3可知，总共11例患者使用过实施例1提供的药物。
其中，7例服用4次(5片)，3例服用2次(3片)，1例服用1次(2片)。由于2例患者在因服药前1天核酸检测转阴而不列入统计，纳入统计病例9例，服药后7例病人核酸检测转阴，其中1天转阴4例，2天转阴2例，4天转阴1例，平均转阴时间1.7天，另外2例仍在观察中。
以上所述仅为本公开的优选实施例而已，并不用于限制本公开，对于本领域的技术人员来说，本公开可以有各种更改和变化。凡在本公开的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本公开的保护范围之内。
工业实用性
本公开实施例提供了一种用于防治肺炎的组合物及其在制备用于防治肺炎的药物中的应用，该组合物对于冠状病毒感染引发的肺炎具有很好的防治作用，为新冠肺炎的药物开发提供了一种新的方向。

Claims (27)

  1. 组合物在制备用于防治肺炎的药物中的应用，其特征在于，按重量份数计，所述组合物的原料包括40.0～300.0份青蒿素或青蒿素衍生物，和200.0～400.0份4－氨基喹啉类药物。
  2. 根据权利要求1所述的组合物在制备用于防治肺炎的药物中的应用，其特征在于，按重量份数计，所述组合物包括40.0～80.0份所述青蒿素或青蒿素衍生物，和350.0～400.0份所述4－氨基喹啉类药物。
  3. 根据权利要求1或2所述的组合物在制备用于防治肺炎的药物中的应用，其特征在于，所述青蒿素衍生物选自由双氢青蒿素、青蒿琥酯和蒿甲醚组成的组中的任意一种或多种；
    所述4－氨基喹啉类药物选自由哌喹、羟氯喹、氯喹、阿莫地喹和萘酚喹组成的组中的任意一种或多种。
  4. 根据权利要求1所述的组合物在制备用于防治肺炎的药物中的应用，其特征在于，按重量份数计，所述原料包括：45.0～200.0份青蒿素或青蒿素衍生物，和260.0～390.0份4－氨基喹啉类药物；
    优选地，按重量份数计，所述原料包括：52.5～72.5份青蒿素或青蒿素衍生物，和365.0～385.0份4－氨基喹啉类药物。
  5. 根据权利要求1-4中任一项所述的组合物在制备用于防治肺炎的药物中的应用，其特征在于，所述组合物还包括辅料，所述辅料选自由预胶化淀粉、羟丙纤维素、羟丙甲纤维素、羧甲淀粉钠和硬脂酸镁组成的组中的至少一种或多种的组合。
  6. 根据权利要求5所述的组合物在制备用于防治肺炎的药物中的应用，其特征在于，按重量份数计，所述组合物包括：52.5～72.5份青蒿素或青蒿素衍生物和365.0～385.0份4－氨基喹啉类药物、20～30份预胶化淀粉、20～25份羟丙纤维素、10.0～16.0份羟丙甲纤维素、20.0～25.0份羧甲淀粉钠和1.0～8.0份硬脂酸镁。
  7. 根据权利要求5或6所述的组合物在制备用于防治肺炎的药物中的应用，其特征在于，按重量份数计，所述组合物包括：52.5～72.5份青蒿素和365.0～385.0份哌喹、20～30份预胶化淀粉、20～25份羟丙纤维素、5.0～16.0份羟丙甲纤维素、20.0～25.0份羧甲淀粉钠和1.0～8.0份硬脂酸镁。
  8. 根据权利要求5-7中任一项所述的组合物在制备用于防治肺炎的药物中的应用，其特征在于，所述药物的制备方法如下：
    将粉碎后的青蒿素、预胶化淀粉、羟丙纤维素和哌喹的混合均匀，并在得到的混合物中加入羟丙甲纤维素进行制粒；
    将制粒后得到的干颗粒、羧甲淀粉钠和硬脂酸镁混合均匀后进行压片；
    优选地，所述干颗粒的粒径为14～18目。
  9. 根据权利要求8所述的组合物在制备用于防治肺炎的药物中的应用，其特征在于，所述组合物的制备方法还包括对压片后的药片进行包衣。
  10. 根据权利要求1～9任一项所述的组合物在制备用于防治肺炎的药物中的应用，其特征在于，所述肺炎由病毒感染所致；
    优选地，所述病毒选自：新型冠状病毒2019-nCoV、冠状病毒HCoV-229E、HCoV-OC43、HCoV-NL63、HCoV-HKU1和SARS-CoV中的至少一种。
  11. 一种用于防治肺炎的组合物或药物，其特征在于，按重量份数计，其原料包括40.0～300.0份青蒿素和200.0～400.0份哌喹；
    优选地，按重量份数计，所述原料包括：45.0～200.0份青蒿素和260.0～390.0份哌喹；
    优选地，按重量份数计，所述原料包括：52.5～72.5份青蒿素和365.0～385.0份哌喹。
  12. 根据权利要求11所述的用于防治肺炎的组合物或药物，其特征在于，所述肺炎由病毒感染所致；
    所述病毒选自：新型冠状病毒2019-nCoV、冠状病毒HCoV-229E、HCoV-OC43、HCoV-NL63、HCoV-HKU1和SARS-CoV中的至少一种。
  13. 一种用于防治肺炎的组合物或药物，其特征在于，按重量份数计，所述组合物或药物包括40.0～300.0份青蒿素或青蒿素衍生物，和200.0～400.0份4－氨基喹啉类药物。
  14. 根据权利要求13所述的组合物或药物，其特征在于，所述青蒿素衍生物选自由双氢青蒿素、青 蒿琥酯和蒿甲醚组成的组中的任意一种或多种；
    所述4－氨基喹啉类药物选自由哌喹、羟氯喹、氯喹、阿莫地喹和萘酚喹组成的组中的任意一种或多种。
  15. 根据权利要求13或14所述的组合物或药物，其特征在于，按重量份数计，所述原料包括：45.0～200.0份青蒿素或青蒿素衍生物，和260.0～390.0份4－氨基喹啉类药物；
    优选地，按重量份数计，所述原料包括：52.5～72.5份青蒿素或青蒿素衍生物，和365.0～385.0份4－氨基喹啉类药物。
  16. 根据权利要求13-15中任一项所述的组合物或药物，其特征在于，所述组合物或药物还包括辅料，所述辅料选自由预胶化淀粉、羟丙纤维素、羟丙甲纤维素、羧甲淀粉钠和硬脂酸镁组成的组中的至少一种或多种的组合。
  17. 根据权利要求16所述的组合物或药物，其特征在于，按重量份数计，所述组合物或药物包括：52.5～72.5份青蒿素或青蒿素衍生物和365.0～385.0份4－氨基喹啉类药物、20～30份预胶化淀粉、20～25份羟丙纤维素、10.0～16.0份羟丙甲纤维素、20.0～25.0份羧甲淀粉钠和1.0～8.0份硬脂酸镁。
  18. 根据权利要求16或17所述的组合物或药物，其特征在于，按重量份数计，所述组合物包括：52.5～72.5份青蒿素和365.0～385.0份哌喹、20～30份预胶化淀粉、20～25份羟丙纤维素、5.0～16.0份羟丙甲纤维素、20.0～25.0份羧甲淀粉钠和1.0～8.0份硬脂酸镁。
  19. 一种用于防治肺炎的药物的制备方法，所述制备方法如下：
    将粉碎后的青蒿素、预胶化淀粉、羟丙纤维素和哌喹混合均匀，并在得到的混合物中加入羟丙甲纤维素进行制粒；
    将制粒后得到的干颗粒、羧甲淀粉钠和硬脂酸镁混合均匀后进行压片。
  20. 根据权利要求19所述的制备方法，其特征在于，所述干颗粒的粒径为14～18目。
  21. 根据权利要求19或20所述的制备方法，其特征在于，所述组合物的制备方法还包括对压片后的药片进行包衣。
  22. 一种用于防治肺炎的组合物或药物，其特征在于，按重量份数计，所述组合物或药物包括40.0～450.0份青蒿素或青蒿素衍生物，和50.0～450.0份4－氨基喹啉类药物。
  23. 根据权利要求22所述的组合物或药物，其特征在于，所述青蒿素衍生物选自由双氢青蒿素、青蒿琥酯和蒿甲醚组成的组中的任意一种或多种；
    所述4－氨基喹啉类药物选自由哌喹、羟氯喹、氯喹、阿莫地喹和萘酚喹组成的组中的任意一种或多种。
  24. 根据权利要求22或23所述的组合物或药物，其特征在于，按重量份数计，所述原料包括：45.0～200.0份青蒿素或青蒿素衍生物，和260.0～390.0份4－氨基喹啉类药物；
    优选地，按重量份数计，所述原料包括：52.5～72.5份青蒿素或青蒿素衍生物，和365.0～385.0份4－氨基喹啉类药物。
  25. 根据权利要求22-24中任一项所述的组合物或药物，其特征在于，所述组合物或药物还包括辅料，所述辅料选自由预胶化淀粉、羟丙纤维素、羟丙甲纤维素、羧甲淀粉钠和硬脂酸镁组成的组中的至少一种或多种的组合。
  26. 根据权利要求25所述的组合物或药物，其特征在于，按重量份数计，所述组合物或药物包括：52.5～72.5份青蒿素或青蒿素衍生物和365.0～385.0份4－氨基喹啉类药物、20～30份预胶化淀粉、20～25份羟丙纤维素、10.0～16.0份羟丙甲纤维素、20.0～25.0份羧甲淀粉钠和1.0～8.0份硬脂酸镁。
  27. 根据权利要求25或26所述的组合物或药物，其特征在于，按重量份数计，所述组合物包括：52.5～72.5份青蒿素和365.0～385.0份哌喹、20～30份预胶化淀粉、20～25份羟丙纤维素、5.0～16.0份羟丙甲纤维素、20.0～25.0份羧甲淀粉钠和1.0～8.0份硬脂酸镁。
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