WO1999025351A1 - Compositions pharmaceutiques antipaludiques - Google Patents

Compositions pharmaceutiques antipaludiques Download PDF

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Publication number
WO1999025351A1
WO1999025351A1 PCT/CN1998/000274 CN9800274W WO9925351A1 WO 1999025351 A1 WO1999025351 A1 WO 1999025351A1 CN 9800274 W CN9800274 W CN 9800274W WO 9925351 A1 WO9925351 A1 WO 9925351A1
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Prior art keywords
trimethoprim
naphthoquine
dihydroartemisinin
malaria
phosphate
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PCT/CN1998/000274
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English (en)
French (fr)
Inventor
Guoqiao Li
Original Assignee
Guangzhou Kincare Technology Corp.
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Application filed by Guangzhou Kincare Technology Corp. filed Critical Guangzhou Kincare Technology Corp.
Priority to AU12227/99A priority Critical patent/AU1222799A/en
Publication of WO1999025351A1 publication Critical patent/WO1999025351A1/zh

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    • 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
    • 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 a pharmaceutical composition for treating or preventing malaria, in particular to a pharmaceutical composition containing naphthoquine.
  • Swiss NORVATIS pharmaceutical company is re-developing a technology purchased from China-compound artemether (consisting of artemisinic acid and benzyl alcohol), which may be better than existing antimalarial drugs, but its treatment still takes 3 days and costs Higher.
  • Malarone which is being developed by Glaxo Wellcome in the UK, consists of aphthoqinone and cyclochloroguanidine. There is no fast-acting drug in the formula. The course of treatment is 3 days, and the drug needs to be taken twice a day. If the daily dose is changed to one time, nausea and vomiting will have serious side effects.
  • the purpose of the present invention is to overcome the shortcomings of the prior art and provide a new anti-malaria medicine with high efficacy, fast speed, low toxicity and safety, and simple and convenient taking of protozoa. Summary of invention
  • the present invention relates to a pharmaceutical composition for treating or preventing malaria, which contains naphthoquine, Dihydroartemisinin, and trimethoprim or their antimalarial active derivatives, prodrugs, or Medicinal salts (referred to as N, D and T, respectively) as active ingredients.
  • the present invention relates to a pharmaceutical composition for treating or preventing malaria, which comprises Naphthoquine, dihydroartemisinin and trimethoprim or their antimalarial active derivatives or prodrugs or their pharmaceutically acceptable salts are used as active ingredients, and the weight ratio of the three active ingredients is Hydroartemisinin and trimethoprim are counted in the following ranges:
  • the present invention also relates to the use of naphthoquine, dihydroartemisinin and trimethoprim or their antimalarial active derivatives, prodrugs or pharmaceutically acceptable salts thereof in the preparation of a pharmaceutical composition for treating or preventing malaria.
  • the present invention also relates to a method for treating or preventing malaria, which comprises administering an effective amount of naphthoquine, dihydroartemisinin, and trimethoprim or their antimalarial active derivatives, prodrugs or medicinal products to a patient in need of treatment salt.
  • a method for treating or preventing malaria comprises administering an effective amount of naphthoquine, dihydroartemisinin, and trimethoprim or their antimalarial active derivatives, prodrugs or medicinal products to a patient in need of treatment salt.
  • the pharmaceutical composition and method of the present invention can be used to treat or prevent any type of malaria, such as Plasmodium falciparum, Plasmodium falciparum, Plasmodium falciparum, etc., especially drug-resistant Plasmodium falciparum.
  • any type of malaria such as Plasmodium falciparum, Plasmodium falciparum, Plasmodium falciparum, etc., especially drug-resistant Plasmodium falciparum.
  • prodrug refers to a derivative that can be converted into an active form by metabolism in the body.
  • Prodrugs of dihydroartemisinin include Artesunate, Arteether, Artemether, Artemisinin and other artemisinin derivatives. These drugs are ultimately metabolized into dihydroartemisinin through metabolism in the body to exert their killing effect on protozoa.
  • Pharmaceutically acceptable salts include salts of inorganic and organic acids.
  • Preferred pharmaceutically acceptable salts include salts of the following acids: methanesulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, stearic acid, citric acid, tartaric acid, fumaric acid, or maleic acid.
  • antimalarial active derivative refers to dihydroartemisinin, naphthoquinone and Trimethoprim or any derivative thereof.
  • N represents naproxen, its antimalarial active derivative, prodrug or its drug A salt is preferred, and naphthoquine phosphate is preferred.
  • D represents dihydroartemisinin, an antimalarial derivative or prodrug thereof. It is preferably dihydroartemisinin, or artesunate, artemisinin, artemisinic acid or artemisinin.
  • T represents trimethoprim or its antimalarial active derivative, prodrug or pharmaceutically acceptable salt thereof, preferably trimethoprim.
  • DNT in the present application represents a pharmaceutical composition of the present invention containing three active ingredients of 0, N, and T and a suitable pharmaceutical carrier,
  • each active compound in the composition or method of the present invention is given based on naphthoquinone gallate, dihydroartemisinin, and trimethoprim. If you choose other N, D and T, you need to consider the molecular weight for conversion.
  • Dihydroartemisinin the first antimalarial drug developed in China, was approved by the Ministry of Health of China in 1993 to be produced by the 6th Pharmaceutical Factory in Beijing, China (Product Name: Dihydroartemisinin, Address: 129 Xuanwumen West Street, Beijing ).
  • Naphthoquine phosphate is the earliest antimalarial drug developed in China and was approved by the Ministry of Health of China in 1993 to be produced by Shanghai No. 6 Pharmaceutical Factory (Product Name: Naphthoquine Phosphate, Address: 1290 Zhennan Road, Shanghai).
  • Trimethoprim which has been used as an antibacterial and antibacterial synergist in the 1970s, was produced by Shanghai Volkswagen Pharmaceutical Factory (Product name: Trimethoprim, Address: Jiangyin Road, Shanghai 152
  • the pharmaceutical composition of the present invention contains naphthoquine phosphate, dihydroartemisinin, and trimethoprim as active ingredients.
  • the pharmaceutical composition of the present invention contains naphthoquine phosphate, artesunate and trimethoprim as active ingredients.
  • the pharmaceutical composition of the present invention contains naphthoquine benzoate, artemisinic acid and trimethoprim as active ingredients.
  • the pharmaceutical composition of the present invention contains naphthoquine acid, artemisinin, and trimethoprim as active ingredients.
  • the pharmaceutical composition of the present invention contains naphthoquine phosphate, artemisinin, and trimethoprim as active ingredients.
  • the weight ratio of N: D: T in the pharmaceutical composition of the present invention is 5-8: 1-2: 2 -3.
  • the weight ratio of N: D: T in the pharmaceutical composition of the present invention is 6: 1: 2.
  • the pharmaceutical composition of the present invention contains a weight ratio of 6:
  • composition of the present invention is effective for oral or parenteral administration.
  • the N, D and T compounds can be administered orally in the form of solid dosage forms such as tablets, powders or capsules or liquid dosage forms such as elixirs, syrups or suspensions known to those skilled in the art.
  • the N, D and T compounds are preferably administered as a solid dosage form of the tablet.
  • the active ingredient of the composition of the present invention can be administered orally as an adult at 900 mg each time, once a day, twice a day, for a total amount of 1800 mg. It can also be administered twice a day, with an interval of about 8 hours between doses.
  • the preferred dose is a dose that can kill Plasmodium in the body in a short time and has a re-ignition rate of ⁇ 5%.
  • the short time is generally not more than 3 days, preferably not more than 2 days, and more preferably not more than 1 day. With a preferred oral dose of 1800 mg / day, any type of malaria can be controlled in one day.
  • composition of the invention may be in unit dosage form for administration to humans and other spinal propellants, such as tablets, powders, capsules, pills, powders, granules, sterile parenteral solutions or Suspensions, oral solutions or suspensions, oil-in-water or water-in-oil emulsions, suppositories and liquid suspensions or solutions.
  • spinal propellants such as tablets, powders, capsules, pills, powders, granules, sterile parenteral solutions or Suspensions, oral solutions or suspensions, oil-in-water or water-in-oil emulsions, suppositories and liquid suspensions or solutions.
  • solid or liquid unit dosage forms can be prepared.
  • solid compositions such as tablets
  • three compounds can be combined with common ingredients such as talc, magnesium stearate, dicalcium phosphate, magnesium aluminum silicate, calcium sulfate, starch, lactose, gum arabic, methyl cellulose, hydroxy Propyl cellulose is mixed with a functionally similar drug diluent or carrier material and then tabletted by conventional methods.
  • Capsules can be prepared by mixing the three compounds with an inert pharmaceutical diluent and filling the mixture by itself or after granulation into a hard gelatin capsule of suitable size.
  • Soft gelatin capsules are prepared by mechanically encapsulating a slurry of three compounds with an acceptable vegetable oil, light liquid paraffin, or other inert oil. It is also possible to combine the three compounds 0, N and T with, for example, sucrose, Insoluble carriers such as soluble starch are mixed to make powdered sugar.
  • Liquid unit dosage forms such as syrups, elixirs and suspensions can be prepared for oral administration. These dosage forms can be dissolved in an aqueous carrier with sugar, flavoring and preservatives to form a syrup.
  • Suspensions can be prepared using aqueous carriers and with the aid of suspending agents such as gum arabic, tragacanth, methyl cellulose and the like.
  • the three active ingredients can be molded into suppositories using conventional bases such as cocoa butter and semi-synthetic fatty acid glycerides.
  • three compounds and sterile carriers can be used to prepare liquid unit dosage forms.
  • the compound When preparing a solution, the compound can be dissolved in water for injection and filtered to sterilize, then filled into a suitable vial or ampoule and sealed. Additives such as local anesthetics, preservatives and buffers can be dissolved in the vehicle. After filling into the vial, the composition can be frozen and the water removed under vacuum. The freeze-dried powder can then be sealed in a vial and redissolved just before use.
  • the invention also relates to the use of compounds N, D and T in the manufacture of a medicament for the treatment or prevention of malaria.
  • the above discussion of the selection of the species and weight ratios of the compounds N, D and T in the pharmaceutical composition of the present invention is equally applicable to the use of the present invention.
  • the invention also relates to a method for treating or preventing malaria, which comprises administering to a patient in need of treatment an effective amount of compounds 1 ⁇ , 0 and 1 ⁇
  • the three compounds can be administered simultaneously (such as mixed or otherwise combined), or administered separately, or two of them can be administered simultaneously followed by a third compound or vice versa.
  • the two compounds administered simultaneously may be any two of the three compounds, but a combination of D and N or T is preferred.
  • the time interval between each dosing should be chosen to ensure that all three drugs are present in the plasma at the same time.
  • the three compounds N, D and T are administered to the patient simultaneously. More preferably, it is administered in the form of a pharmaceutical composition containing three compounds, D and T, and a pharmaceutically acceptable carrier.
  • test Example 1 ED 5 o and ED 9 of DNT against Plasmodium berghei. Determination
  • Naphthol quinophosphate dry powder (code N): molecular formula C 24 H 28 C1N 3 0 ⁇ 2H 3 P0 4 ⁇ 2H 2 0, molecular weight 641.98, free base content 64.77%, purity 99.1%, batch number: 950405, by Shanghai No. Six pharmaceutical factories.
  • Dihydroartemisinin powder (code D): molecular formula C 15 H 24 0 5 , molecular weight 284.35. The content is 98.0%, batch number: 960628, produced by Beijing No. 6 Pharmaceutical Factory.
  • Trimethoprim dry powder (TMP, code T): molecular formula C 14 H 18 N 4 0 8 , molecular weight 290.32. The content is 100.1%, batch number: 960601, produced by Shanghai Volkswagen Pharmaceutical Factory.
  • Drug preparation method According to the required dosage (MKD X 4), accurately weigh the test drugs, add appropriate amounts of polyethylene glycol 6000 and Tween-80, and mix them thoroughly to form a uniform suspension. 0.4ml / 20g mouse body weight was formulated with 0.9% physiological saline.
  • mice NIH inbred mice, half male and half male, were housed in separate cages and weighed 20 ⁇ 2g.
  • Qualification certificate for the quality and conditions of test animals Guangdong Medical Movement No. 26-97026 and Guangdong Inspection Certificate No. 97A009.
  • the mouse feed is a biscuit with multiple nutritional ingredients uniformly formulated by Guangzhou Experimental Animal Center. The mice were kept at room temperature of 22 ⁇ 2, relative humidity of 75 ⁇ 10%, and were exposed to light for 12 hours daily.
  • ANKA strain P. berghei ANKA strain (hereinafter abbreviated as ANKA strain). Shanghai Second Military Medical University was cited in 1981 from the London School of Hygiene and Tropical Medicine. In August 1996, it was introduced into the inventor's office by the Second Military Medical University.
  • composition DNT 13.41 9.12-19.71 47.16 32.08-69.33 Naphthoquine phosphate 59.34 44.33-79.60 139.45 104.07-186.86 It can be seen from Table 1 that the composition DNT of the present invention has an ED 50 against Plasmodium berghei ANKA strain And ED 9 Q are significantly lower than naphthoquine phosphate, that is, its titer is significantly higher than naphthoquine phosphate.
  • Test Example 3 Comparison of the efficacy of the composition DNT and the compatibility of single or two drugs
  • the antimalarial activity of the composition DNT, the compatibility of the two drugs, and the single drug was evaluated.
  • the protozoan negative rate of the mice was observed, and the negative dose (ED 50 ) and 90% of the mice were calculated.
  • the Berenbaum method was used to calculate the synergy coefficients.
  • the ED 5G of DNT was significantly lower than that of each single drug and lower than the combination of naphthoquine phosphate and dihydroartemisinin, and the resistance index was very low, and the synergy coefficients were significantly ⁇ 1, indicating that the three drugs are compatible Has a significant synergistic effect.
  • a split test was used to evaluate the potency of the composition DNT and its various components as a single drug or a combination of two drugs on malaria.
  • Plasmodium berghei strain K-173 was introduced in September 1996 from the Institute of Microbiology and Epidemiology, Beijing Academy of Military Medical Sciences.
  • Plasmodium berghei resistant to chloroquine RC strain was introduced in August 1996 from the Department of Parasitology, Shanghai Second Military Medical University.
  • the negative dose (ED 9 ) was significantly lower than that of each single drug (except for dihydroartemisinin for sensitive strains), and lower than the combination of naphthoquine phosphate + dihydroartemisinin; and resistance An index of 1.0 indicates that there is no cross-resistance between the composition and chloroquine.
  • Plasmodium berghei K-173 strain the source is the same as in Test Example 3.3.
  • mice were intraperitoneally infected K - 173 strains of Plasmodium 1 X 10 7 th parasitized erythrocytes, three hours after infection, the disposable gavage, the dose is the sum of the original dose of 4 days for each dose group.
  • Day 5 (D 4) mice were tail bled, the coating film is thin blood staining. 2 x 10 4 red blood cells were found to be negative if no protozoa were found.
  • the ED 5 of the composition and each test drug was obtained by the probability unit method. And ED 9 . And 95% confidence limit.
  • DNT tablets contain 450mg of biologically active ingredients.
  • the usage for treating malaria is 4 tablets (including 1800ng of biologically active ingredients) for adults. Take 2 tablets each time, once a day. Or two times a day, 8 hours apart.
  • Example 1 105 patients with P. falciparum were treated with DNT films, and all of them could quickly control the symptoms. No re-ignition cases were found. 6 cases of malignant or vomiting occurred in 105 cases, the incidence rate was 5.7%. Another case developed a local rash. The above results indicate that DNT is a highly effective, fast-acting and safe malaria treatment.
  • Example 5 75 g of artemisinic acid, 150 g of naphthoquine phosphate, 125 g of trimethoprim, and 125 g of methylcellulose were appropriately prepared into 1000 tablets, and tablets were prepared according to the method described in Example 1.
  • Example 5 75 g of artemisinic acid, 150 g of naphthoquine phosphate, 125 g of trimethoprim, and 125 g of methylcellulose were appropriately prepared into 1000 tablets, and tablets were prepared according to the method described in Example 1.

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Description

抗疟疾药物组合物 发明所属领域
本发明涉及一种治疗或预防疟疾的药物组合物，特别是一种含萘 紛喹的药物组合物。
发明背景
目前， 多重抗药性恶性疟疾正在全球蔓延， 东南亚尤为严重。 世 界卫生组织寄予很大希望的甲氟喹（ Mefloquine )及其复方法西密 ( Fansimef ) , 也由于其抗药性的迅速出现， 首先在泰国， 继而在 越南已经处于疗效很差的境地 [1，2】。七十年代以来， 中国研制发明的 青蒿素及其衍生物青蒿琥酯、 蒿甲醚、双氢青蒿素等具有高效速效的 优点， 但必须服药 7天才能达到高治愈率， 否则复燃率高 [3】， 不利 于疟疾传染源的控制。
瑞士 NORVATIS制药公司正在重新研制向中国购买的一项技 术-复方蒿甲醚（由蒿甲酸和本芴醇组成），有可能优于现有抗疟药， 但其疗程仍需 3天， 且成本较高。 英国 Glaxo Wellcome公司正在研 制的 Malarone , 由萘醍 ( aphthoqinone )和环氯胍组成， 其配方 中没有速效药物， 疗程 3天， 每天需服药 2次。 若将每天药量改为一 次服用， 则恶心、 呕吐副作用严重。
本发明的目的旨在克服现有技术的不足而提供一种杀灭原虫效 力高、速度快且毒副反应低、安全稳定，服用简单方便的抗疟疾新药。 发明概述
本发明涉及一种治疗或预防疟疾的药物组合物， 其含有萘酚喹 ( Naphthoquine )、 双氢青蒿素 ( Dihydroartemisinin )和甲氧 啶（ Trimethoprim )或它们的抗疟活性衍生物、 前药或药用盐（分 别称为 N , D和 T )作为活性成分。
更具体地， 本发明涉及一种治疗或预防疟疾的药物組合物， 其含 有萘紛喹、双氢青蒿素和甲氧苄嚏或它们的抗疟活性衍生物或前药或 其药用盐作为活性成分， 并且三种活性成分重量配比以磷酸萘紛喹、 双氢青蒿素和甲氧苄啶计在如下范围内：
N 5 - 8份
D 1 - 2份
T 2 - 3份。
本发明还涉及萘紛喹、双氢青蒿素和甲氧苄啶或它们的抗疟活性 衍生物、前药或其药用盐在制备用于治疗或预防疟疾的药物組合物中 的用途。
本发明还涉及一种治疗或预防疟疾的方法，包括给予需治疗的患 者有效量的萘紛喹、 双氢青蒿素和甲氧苄啶或它们的抗疟活性衍生 物、 前药或药用盐。 发明详述
本发明药物组合物和方法可用于治疗或预防任何类型的疟疾，如 恶性疟、 间日疟、 三日疟等， 特别是抗药性恶性疟。
本申请所述 "前药" 是指经体内代谢能转变成活性形式的衍生 物。 双氢青蒿素的前药例如有青蒿琥酯（ Artesunate ) 、 蒿乙醚 ( Arteether )、 蒿甲醚 ( Artemether )和青蒿素 ( Artemisinin ) 及其他青蒿素衍生物。这些药物经体内代谢最终均转化为双氢青蒿素 而发挥其杀灭原虫的作用。
药用盐包括无机和有机酸的盐。 优选的药用盐包括如下酸的盐： 甲磺酸、 盐酸、 氢溴酸、 硫酸、 磷酸、 硝酸、 笨甲酸、 柠檬酸、 酒石 酸、 富马酸或马来酸。
本申请所述 "抗疟活性衍生物"是指用本领域已确立的或本申请 详细描述的抗疟活性测定方法确定有杀死或抑制疟原虫作用的双氢 青蒿素、 萘紛喹和甲氧苄啶或其药用盐的任何衍生物。
本申请中 " N " 代表萘盼喹、 其抗疟活性衍生物、 前药或其药 用盐， 优选为磷酸萘盼喹。
本申请中 " D " 代表双氢青蒿素， 其抗疟活性衍生物或前药。 优选为双氢青蒿素， 或为青蒿琥酯、 蒿乙瞇、 蒿甲酸或青蒿素。
本申请中 " T " 代表甲氧苄啶或其抗疟活性衍生物、 前药或其 药用盐， 优选为甲氧苄啶。
本申请中 " DNT " 代表含有0、 N和 T三种活性成分和适当 的药物载体的本发明药物组合物，
本发明組合物或方法中各活性化合物的重量配比是以璘酸萘酚 喹、 双氢青蒿素和甲氧苄啶为基础给出的。 若选择其他的 N、 D和 T , 则需考虑分子量进行转换。
双氢青蒿素， 是最早由中国研制的抗疟药， 1993年经中国卫生 部批准由中国北京第 6制药厂生产（品名： 双氢青蒿素, 地址： 北京 市宣武门西大街 129号）。
磷酸萘紛喹， 是最早由中国研制的抗疟药， 1993年经中国卫生 部批准由中国上海第 6制药厂生产（品名： 磷酸萘酚喹, 地址： 上海 市真南路 1290号） 。
甲氧苄啶， 于 70年代已作为抗菌药和抗菌增效剂， 由中国上海 大众制药厂生产 （品名： 甲氧苄胺嘧啶, 地址： 上海市江阴路 152
±) 。
上述三药的结构式分别为：
双氢青蒿素（ DIHYDROARTEMISININ ) 的结构式：
Figure imgf000005_0001
- 3 - 替换页 (细则第 26条) 磷酸萘酚喹 ( NAPHTHOQUINE PHOSPHATE ) 结构式:
Figure imgf000006_0001
甲氧苄啶（ TRIMETHOPRIM ) 的结构式
Figure imgf000006_0002
C"H、eN4Ch 290.32 在一优选的实施方案中， 本发明的药物組合物含有磷酸萘酚喹、 双氢青蒿素和甲氧苄啶作为活性成分。
在另一优选实施方案中，本发明药物组合物含有磷酸萘紛喹、 青 蒿琥酯和甲氧苄啶作为活性成分。
.在另一实施方案中，本发明药物组合物含有碑酸萘紛喹、 蒿乙酸 和甲氧苄嚏作为活性成分。
在另一实施方案中，本发明药物组合物含有 酸萘盼喹、 蒿甲鲢 和甲氧苄嚏作为活性成分。
在另一实施方案中，本发明药物组合物含有磷酸萘酚喹、 青蒿素 和甲氧苄啶作为活性成分。
在一优选实施方案中， 本发明药物组合物中 N: D: T的重量 比为 5— 8: 1 - 2: 2 - 3。
在一更优选的实施方案中， 本发明药物组合物中 N: D: T的 重量比为 6: 1： 2.
在一最优选的实施方案中，本发明药物組合物含有重量比为 6:
替换页 (细则第 26糸) 1 : 2的磷酸萘酚喹、 双氢青蒿素和甲氧苄啶作为活性成分。
本发明组合物口服或胃肠外给药是有效的。 可将 N、 D和 T化 合物以本领域技术人员已知的固体剂型如片剂、粉剂或胶嚢或液体剂 型如酏剂、 糖浆或混悬剂的形式进行口服给药。 优选将 N、 D和 T 化合物以片剂的固体剂型给药。
通常， 可将本发明组合物活性成分按成人每次 900mg 口服给 药， 每日 1次， 连服 2次， 总量 1800mg。 亦可一日分二次给药， 两 次给药间隔约 8小时。
确切给药的剂量和频率取决于所用的具体组合物，所治疗的具体 疟疾类型， 所治疗疟疾的严重程度， 患者的年龄、 体重、 一般身体状 况， 患者可能使用的其它药物， 这些均是本领域技术人员熟知的， 并 可通过测量患者血液中活性化合物的浓度和 /或患者对所治疗的具体 疟疾的反应来更精确地确定。但优选的剂量是可在短时间内杀灭体内 疟原虫而复燃率 <5%的剂量。 所述短时间一般不大于 3 天， 优选不 大于 2天， 更优选不大于 1天。 在优选的口服剂量 1800mg/日下， 一 天内即可控制任何类型的疟疾。
本发明的組合物可以是用于向人和其它脊推动物给药的单位剂 量形式， 例如片剂、 粉剂、 胶嚢、 丸剂、 散剂、 颗粒剂、 无菌的胃肠 外给药用溶液或混悬液、 口服溶液或混悬液、 水包油或油包水乳液、 栓剂和液体混悬液或溶液。
对于口服给药， 可制备固体或液体单位剂型。为了制备固体组合 物如片剂，可将三种化合物与常用成分如滑石、硬脂酸镁、磷酸二钙、 硅酸镁铝、 硫酸钙、 淀粉、 乳糖、 阿拉伯胶、 甲基纤维素、 羟丙基纤 维素以及功能上相似的药物稀释剂或载体材料混合，然后用常规方法 压片。可通过将三种化合物与惰性药物稀释剂混合并将混合物本身或 经制粒后填充到适宜大小的硬明胶胶嚢中来制备胶嚢。通过机械包封 三种化合物与可接受的植物油、轻液体石蜡或其它惰性油形成的浆液 来制备软明胶胶嚢。 还可以将0、 N和 T三种化合物与诸如蔗糖、 可溶性淀粉等惰性载体混合制成糖粉剂。
可制备用于口服给药的液体单位剂型如糖浆、酏剂和混悬液。 可 将这些剂型与糖、 芳香矫味剂和防腐剂一起溶于水性载体中形成糖 浆。 可用水性载体并借助于悬浮剂如阿拉伯胶、 黄耆胶、 甲基纤维素 等来制备混悬液。
可用常规基质如可可脂、半合成脂肪酸甘油酯将三种活性成分模 制成栓剂。
为了进行胃肠外给药，可用三种化合物和无菌载体制备液体单位 剂型。 在制备溶液剂时， 可将化合物溶于注射用水并过滤灭菌， 然后 填充到适宜的小瓶或安瓿中并密封。 可将添加剂如局部麻醉剂、 防腐 剂和緩冲剂溶于溶媒中。在填充到小瓶中后， 可将組合物冷冻并真空 下除去水。然后可将冷冻干燥的粉末密封在小瓶中并在临用前重新溶 本发明还涉及化合物 N、 D和 T在制备用于治疗或预防疟疾的 药物中的用途。 上述对本发明药物组合物中化合物 N、 D和 T的种 类和重量配比选择的讨论同样适用于本发明的用途。
本发明还涉及一种治疗或预防疟疾的方法，其包括给予需要治疗 的患者有效量的化合物1\、 0和1\
在本发明的方法中，三种化合物可以同时给药（如混合或以其他 方式结合）， 或先后分别给药， 或其中两种同时给药随后再给予第三 种化合物或者相反。在分先后给药的情形中，对给药的先后顺序没有 限制。在两种化合物同时给药而随后给予第三种化合物的情形中， 同 时给药的两种化合物可以是三种化合物中的任意两者， 但优选是 D 与 N或 T的組合。 每两次给药之间的时间间隔的选择应确保三种药 物能同时在血浆中存在。分别给药时优选使用各单药的可在市场上购 得的制剂。 优选同时给予患者 N、 D和 T三种化合物。 更优选以含 有 、 D和 T三种化合物和药用载体的药物组合物的形式给药。
上述对本发明药物组合物中化合物 N、 D和 T的种类和重量配 比选择的讨论同样适用于本发明的方法。 下列试验例和实施例用于说明本发明药物组合物的抗疟疾活性 和制备方法， 但它们不限制本发明的范围。 试验例 1. DNT对伯氏疟原虫的 ED5o和 ED9。测定
1.1试验目的
以 4天抑制性试验测定 DNT对伯氏疟原虫 ANKA株的半数小 鼠原虫转阴和 90 %小鼠原虫转阴量（ ED5Q和 ED90 ) , 评价 DNT 对鼠疟的疗效。
1.2 受试药物、 试验动物、 鼠疟原虫
受试药物
磷 酸 萘 酚 喹 干 粉 （ 代 号 N ) ： 分 子 式 C24H28C1N30 · 2H3P04 · 2H20， 分子量 641.98 , 游离碱含量为 64.77%, 纯度为 99.1%， 批号： 950405 , 由上海第六制药厂生产。
双氢青蒿素干粉（代号 D )： 分子式 C15H2405， 分子量 284.35 。 含量为 98.0%， 批号： 960628， 由北京市第六制药厂生产。
甲氧苄啶干粉（ TMP， 代号 T ) : 分子式 C14H18N408， 分子 量 290.32。 含量为 100.1%, 批号： 960601 , 由上海大众制药厂生 产。
复方组合物干粉 (代号 DNT )： 由华灵医药研究所制剂研究室 提供， 内含各药配比为磷酸萘紛喹（ N ) ·· 双氢青蒿素（ D )： 甲 氧苄啶（ T ) = 6:1:2。 批号： 970401 。
药物配制方法： 按测定要求的剂量（ MKD X 4 )分别精确称取 受试药物， 加入适量的聚乙二醇 6000和 Tween-80充分研磨混合成 均匀的混悬液。 按 0.4ml/20g小鼠体重用 0.9%生理盐水配制。
试验动物
NIH近交系 （ Inbred )小鼠，雄雄各半，分笼飼养，体重 20±2g 。 试验动物质量和条件合格证书： 广东医动字第 26 - 97026号和粤检 证字 97A009号。 小鼠饲料为广州市实验动物中心统一配方的含有多 种营养成份的饼干。小鼠飼养室温为 22±2 ,相对湿度为 75±10 % , 每日光照 12小时。
鼠疟原虫
伯氏疟原虫 ANKA敏感株（ P. berghei ANKA strain , 以下简 称 ANKA株）。上海第二军医大学 1981年引自英国伦敦卫生与热带 医学院。 1996年 8月由第二军医大学引入本发明人处。
1.3试验方法
参考 Peters 四天抑制试验法 [4】， 每鼠腹腔接种 1 x 107个被伯 氏疟原虫寄生的红细胞。 DNT和对照药磷酸萘紛喹分别设 5 - 6个 剂量组， 随机分組。 每组 10只小鼠， 雌雄各半， 分笼飼养。 接种原 虫当天（ DO ) 于接种后 3小时， 及接种后连续 3天（ - D3 ) , 按 0.4ml/20g小鼠体重， 每天各灌胃给药一次。 D4取尾血涂薄血膜 用吉氏染色。 查 2 X 104个红细胞未见原虫者定为阴性， 得出每组的 原虫转阴率。 用直线回归法计算 ED5Q和 ED9。及其 95 %可信限。
1.4试验结果
DNT和磷酸萘酚喹对伯氏疟原虫 ANKA株的 EDso和 ED9()见下 表 1 。 表 1 DNT对伯氏疟原虫 ANKA株的 ED5。和 ED90
药物 ED50 ED90
MKD X 4 95%可信限 MKD X 4 95%可信限
DNT 13.41 9.12-19.71 47.16 32.08-69.33 磷酸萘酚喹 59.34 44.33-79.60 139.45 104.07-186.86 从表 1看出，本发明组合物 DNT对伯氏疟原虫 ANKA株的 ED50 和 ED9Q明显低于磷酸萘酚喹， 即其效价明显高于磷酸萘纷喹。
试验例 2组合物 DNT对伯氏疟原虫的杀虫速度
2.1试验目的
观察组合物 DNT对伯氏疟原虫 A KA株的杀虫速度， 并以磷 酸萘盼喹为已知阳性药对照。
2.2 受试药物、 试验动物、 鼠疟原虫
同试验例 1.2。
2.3试验方法
参照 WHO Tech Rep Ser No. 529(1973)的方法 [5】。 每鼠腹腔接 种 1 χ 107个被伯氏疟原虫感染的红细胞， 每組 10 - 20只小鼠。 当 实验鼠疟原虫红细胞感染率达到 10 %左右时开始给药。 DNT和磷 酸萘紛喹均以各该药 SD9。 X 100倍的剂量单次灌胃给药。 给药后 6 小时 1次取血片检查， 以连续观察原虫下降速度， 用直线回归方程计 算原虫下降回归系数（ b )和原虫下降 50 %和 90 %的时间 （ CT50 和 CT9() )及其 95%可信限。
2.4试验结果和结论
试验结果见表 2 。
表 2 DNT和磷酸萘紛喹对伯氏疟原虫 ANKA株的杀虫速度
药物 剂量 小鼠数给药前原 回归方程 CTso CT90 原虫下降回回归系数
(MKD X 1) (只） 虫平均感 (Y) (h) (h) 归系数 (b) (b)比值 染率 (％)
第 1次实验
DNT 181 15 14.60 -2.68X+103.18 19.8 34.7 2.68 1.60 磷酸萘酚喹 249 10 14.70 -1.67X+116.02 39.4 >63.3 1.67 1.00 第 2次实验
DNT 181 20 7.19 -2.90X+91.10 14.2 20.0 2.90 1.80 磷酸萘紛喹 249 20 6.38 -1.61X+96.78 29.0 >53.9 1.61 1.00 注： 各药剂量均相当于该药对伯氏疟原虫 ANKA株的 SD5o X 100倍。
从以上结果可以看出， 本发明组合物 DNT对伯氏疟原虫 ANKA株的杀虫速度（ CT5o=14.2h )明显快 于单药磷酸萘酚喹 ( CTso = 29.0h )
试验例 3 组合物 DNT与单药或二药配伍的药效比较
参考 Pelers的四天抑制试验法评价组合物 DNT、二药配伍及单 药的抗疟活性， 观察小鼠的原虫转阴率， 计算其半数小鼠转阴剂量 ( ED50 )和 90 %小鼠转阴剂量（ ED9Q )及其 95 %可信限。 再用 Berenbaum氏法分别计算其增效系数。 结果, DNT的 ED5G显著低 于各单药和低于磷酸萘酚喹 +双氢青蒿素二药联用， 且抗性指数甚 低， 其增效系数均显著 <1 , 说明三药配伍具有显著的增效作用。
3.1试验目的
用拆方试验评价组合物 DNT及其各种组分单药或二药联用对鼠 疟的效价。
3.2受试药物、 试验动物
同试验例 1.2 。
3.3鼠疟原虫
伯氏疟原虫 K - 173株， 1996年 9月引自北京中国人民解放军 军事医学科学院微生物流行病学研究所。
伯氏疟原虫抗氯喹 RC株， 1996年 8月引自上海第二军医大学 寄生虫教研室。
3.4试验方法
参考 Pelers 四天抑制试验法， 每鼠腹腔接种 1 x 107个被敏感 抹或抗氯喹株疟原虫寄生的红细胞。各混合物及各单药分别设 5 - 6 个剂量组， 随机分组， 每组 10只小鼠， 雄雄各半， 分笼饲养。 接种 原虫当天（ DO )于接种后 3小时，及接种后连续 3天（ - D3 ) , 按 0.4ml/20g小鼠体重， 每天各灌胃给药一次。 D4取尾血涂薄血膜 用吉氏染色， 查 2 X 104个红细胞未见原虫者定为原虫阴性。 用机率 单位法求出 DNT半数小鼠转阴剂量（ ED50 )和90 %小鼠转阴剂量 ( ED90 )及其 95 %可信限； 另用抗氯喹原虫株测试， 计算出抗性指 数； 用 Berenbaum氏法（ 1978 ) [6】按公式 Ac/Ae+Bc/Be+Cc/Ce计 算增效系数， 如系数值<1则为增效作用， - 1则为相加作用， >1则 为拮抗作用。
3.5结果与结论
试验结果见表 3、 表 4和表 5 。
表 3组合物 DNT及其组分对伯氏疟原虫 K - 173株的 ED50和 ED! 药物 ED50 ED90
MKD X 4 95%可信限 MKD X 4 95%可信限
DNT 52.94 42.35-66.18 134.12 107.30-167.65 磷酸萘酚喹 271.90 232.39-318.12 394.98 337.59-462.13 氲青蒿素 69.15 57.63-82.98 101.19 84.33-121.43 甲氧苄啶 271.53 222.57-331.27 429.18 351.79-523.60 磷酸萘酚喹 + 96.37 68.84-139.12 199.27 142.34-278.98 双氢青蒿素 表 4组合物 DNT及其组分对伯氏疟原虫抗氯喹 RC株的 ED5Q和 ED90 药物 ED n ED90 抗性指数
MKDx4 95%可信限 MKD x 4 95%可信限 I,
DNT 54.45 49.50-59.50 68.81 62.55-75.69 1.0 磷酸萘酚喹 459.23 389.18-541.89 595.47 504.64-702.65 1.7 双氢青蒿素 129.54 109.78-152.86 186.78 158.29-220.40 1.9
甲氧苄啶 577.36 524.80-635.10 723.32 657.56-795.65 2.1 磷酸萘酚喹 + 122.65 94.35-159.45 290.00 223.08-377.00 1.3 双氢青蒿素 表 5组合物 DNT对伯氏疟原虫 K - 173株和 RC株的增效作用 鼠疟原虫株 增效系数 数值
Ac/Ae+Bc/Be+Cc/Ce 意义
K-173株
以 ED50计 30.25/271.9+7.57/69.15+15.12/271.53=0.28 <1 增效 以 ED9Q计 76.64/394.98+19.16/101.19+38.32/429.18=0.47 <1 增效 RC株
以 ED50计 31.11/459.23+15.56/577.36+7.78/129.54=0.15 <1 增效 以 ED90计 39.32/595.47+19.66/723.32+9.83/186.78=0.15 <1 增效 注： 公式中 Ae、 Be、 Ce为各药单用时其 ED5o的用药量； Ac、 Be、 Cc则为药物配伍时产生同样效果（ ED50 ) 时 的用药量。 从表 3和表 4看出： 经拆方试验证明， 组合物 DNT对伯氏疟原 虫 K - 173株尤其是抗氯喹 RC抹的半数小鼠转阴剂量（ ED5。 )或 90 %小鼠转阴剂量（ ED9。）， 均显箸低于各单药（双氢青蒿素对敏 感株除外）， 也低于磷酸萘酚喹 +双氢青蒿素二药联用； 且抗性指数 为 1.0， 说明组合物和氯喹之间不存在交叉抗药性。
看出： 伯氏疟原虫 K - 173株或 RC株以 ED5o或 ED90 计， 其增效系数均明显 <1 , 说明三药配伍起到明显的增效作用。 试验例 4 用鼠疟一次性治疗进行组合物 DNT与各单药或二药 配伍的抗疟活性对比
用拆方试验和量效关系观察单次口服组合物 DNT及其各组分对 鼠疟药效学的影响，结果证明一次性口服复方萘酚喹远较各单药治疗 效果明显为优， 并证明甲氧苄嚏在此组合物中的增效作用十分明显。 为猴疟和进而为临床单次口服复方萘盼喹有效治疗疟疾提供了依 据。 4.1试验目的
用拆方试验观察单次口服本发明组合物及其各组分单药或二药 联用对鼠疟的疗效，为猴疟和进而为临庆单次口服复方萘紛喹有效治 疗疟疾提供依据。
4.2受试药物、 试验动物
同试验例 1.2 。
4.3鼠疟原虫
伯氏疟原虫 K - 173株， 来源同试验例 3.3 。
4.4试验方法
每鼠腹腔注射感染 K - 173株疟原虫 1 X 107个被寄生的红细 胞， 感染后 3小时， 一次性灌胃给药， 给药量为原各剂量组的 4天剂 量之总和。 第 5天（ D4 )从小鼠尾部取血， 涂薄血膜染色镜检。 查 2 X 104个红细胞未见原虫者定为阴性。 用机率单位法求出组合物和 各试验药的 ED5。和 ED9。及 95 %可信限。
4.5结果与结论
结果见表 6。
表 6 单次给药测定组合物 DNT及其各单药对伯氏疟原虫 K -
173株的 ED5。和 ED90
药物 ED50 ED90
MKD X 1 95%可信限 MKDxl 95%可信限
DNT 152.09 127.59-181.29 263.94 221.80-314.09 磷酸萘酴喹 754.87 656.41-868.10 1091.81 886.79-1172.78 双氬青蒿素 223.61 203.14-268.65 302.13 262.72-347.45 磷酸萘酚喹 + 407.90 339.92-489.48 801.34 667.78-961.61 氢青蒿素 从表 6看出： 1)組合物 DNT单次口服的疗效与 4天抑制疗法结 果相似， 组合物远较各单药或二药联用的治疗效果明显为优； 2)同 时表明甲氧苄啶在此组合物中的增效作用十分明显。 即組合物 DNT
(含甲氧苄啶） 的 ED5。 ( 152.09MKD )显著地低于磷酸萘紛喹 + 双氢青蒿素（不含甲氧苄啶） 的 ED5o ( 407.90MKD ) , 且两者的 95 %可信限并不重叠， 说明组合物中有无甲氧苄啶， 其效果相差显 著。
试验例 5 组合物 DNT与其各组分的毒性比较
对 DNT及其各单药同时进行小鼠 LD5o测定。 结果表明， 口服 磷酸萘酚喹、 双氢青蒿素和甲氧苄啶的 LD5G分别为 1070mg/kg 、 838mg/k 和 6184mg/kg , 而口服上述三种成分以 6 : 1 : 2重量比 的混合物测定的 LD5o为 1594mg/kg。 用 Finney公式 [7]计算该混合 物 LD5Q理论值和实测值的比值为 0.79 , 说明组合物 DNT的毒性仅 为相加性， 没有增毒作用。
试验例 6
DNT片含生物活性成分 450mg , 治疗疟疾的用法是成人总量 4 片 （含生物活性成分 1800ng )， 每次服 2片， 每天服一次。 或一天 分二次服， 间隔 8小时。
A. 在中国海南岛东方县抗氯喹恶性疟流行区用 DNT片治疗恶 性疟 74例。 全部病人住院治疗观察 7天， 追踪观察 28天， 于治疗后 14天， 21天和 28天随访涂血片， 了解病人出院后有无复燃。 住院 期间每 4小时查体温一次， 观察治疗后退热时间：每天涂血片二次检 查疟原虫， 以观察原虫转阴时间； 每天详细查询记录病人的症状， 评 价副反应情况。 74 例患者全部迅速临床治愈， 平均退热时间为 21.7±10.1 , 平均原虫转阴时间为 45.7±19.6小时； 其中 46例患者追 踪观察 28天无一例复燃。
B.在越南南方多重抗药性恶性疟流行区用 DNT片治疗恶性疟与 青蒿琥酯进行开放式随机比较， 两药分别治疗恶性疟 31例。 用药方 法和观察方法同前。 青蒿琥酯片每天服药一次 lOOmg , 连服 5天， 首剂加倍量， 5天总量 600mg。 退热时间 DNT组 24.0±17.0小时， 青蒿琥酯組 27.3±17.3小时； 原虫转阴时间 DNT組 70.0±19.7小时， 青蒿琥酯组 70.6±20.7小时。 DNT组观察 28天 31例无一例复燃， 青蒿琥酯組 6例复燃， 复燃率 19.4%, 两組比较（ X2 = 4.442， P<0.05 ) DNT组的治愈率显著高于青蒿琥酯組。
其 105例恶性疟患者接受 DNT片治疗， 均能快速控制症状， 未 见有复燃病例。 105例治疗过程中出现恶性或呕吐者 6例，发生率为 5.7%。 另有一例出现局部皮疹。 以上结果初步表明， DNT是一个高 效、 速效而安全的疟疾治疗药。 实施例 1
配方
磷酸萘酚喹 (C24H28C1N30 · 2H3P04) 300g
双氢青蒿素 (C15H2405) 50g
甲氧苄嚏 (C14B18H403) 100g
辅料（羟丙基纤维素) 适量
制成 1000片 制剂工艺
先对原料、 辅材料进行检测， 将合格之原料分别粉碎， 过 100 目筛， 然后， 按处方量准确称取原料及辅料。 将磷酸萘酚喹、 甲氧苄 啶、 双氢青蒿素和辅料羟丙基纤维素（ HPC )混合， 制粒， 烘干， 整粒， 压片， 用薄膜包衣， 包装， 即为成品。
实施例 2
配方
磷酸萘紛喹 250g 青蒿琥酯 100g 甲氧千啶 100g 甲基纤维素 适量 制成 1000片 按如实施例 1中所述方法制备片剂。 实施例 3
配方
蒿甲 50g 磷酸萘酚喹 300g 甲氧苄啶 150g 羟丙基纤维素 适量 制成 1000片 按实施例 1中所述方法制备片剂。 实施例 4
配方
蒿乙酸 75g 磷酸萘盼喹 150g 甲氧苄啶 125g 甲基纤维素 适量 制成 1000片 按实施例 1中所述方法制备片剂。 实施例 5
配方
青蒿素 400g 磷酸萘紛喹 350g 甲氧苄啶 50g 羟丙基纤维素 适量
1000片 按实施例 1中所述方法制备片剂,
参考文献：
1. Danai, Southease Asean J. Trop. Med. 1992; 4:762
2. Danai, Southease Asean J. Trop. Med. 1992; 3:337
3.符林春等。 广州中医药大学学报 1998; 15(2):81
4. Peters, W. "The 4-day suppressive test of blood schizontocidal actions" in Peters, W. 《 Chemotherapy and drug resistance in malaria 》 2nd Edition, Academic Press, 1987， P.lll-
115。
5. WHO Technical Report Series NO. 529, World Health Organization, Geneva, 1973.
6. Berenbaum M. G.， A method for testing for synergy with any number of agents. J. Inf. Dis. 1978, 137: 122-130。
7. Finney D. J: Statistical Method in Biological Assay, 3rd ed. 1978.

Claims

权 利 要 求
1. 一种治疗或预防疟疾的药物组合物， 其含有萘紛喹、 双氢青蒿 素和甲氧苄啶或它们的抗疟活性衍生物、 前药或药用盐（分别称为
N、 D和 T )作为活性成分和适当的药用载体。
2. —种治疗或预防疟疾的药物组合物， 其含有萘紛喹、 双氢青蒿 素和甲氧苄啶或它们的抗疟活性衍生物、前药或药用盐作为活性成分 和适当的药用载体， 其中三种活性成分的重量配比以磷酸萘紛喹、双 氢青蒿素和甲氧苄啶计在如下范围内：
N 5 - 8份
D 1 - 2份
T 2 - 3份。
3. 根据权利要求 2的组合物， 其中以磷酸萘紛喹、 双氢青蒿素和 甲氧苄啶计， N : D : T = 6： 1： 2 (重量）„
4. 根据权利要求 1 - 3任一项的组合物，其中 N为磷酸萘紛喹， D为双氢青蒿素， T为甲氧苄啶。
5. 根据权利要求 1 - 3任一项的组合物，其中 N为鱗酸萘紛喹， D为青蒿琥酯， T为甲氧苄啶。
6. 根据权利要求 1 - 3任一项的组合物，其中 N为磷酸萘紛喹， D为蒿甲醚， T为甲氧苄啶。
7. 根据权利要求 1 - 3任一项的组合物，其中 N为磷酸萘酚喹， D为蒿乙酸， T为甲氧苄啶。
8. 根据权利要求 1 - 3任一项的组合物，其中 N为磷酸萘酚喹， D为青蒿素， T为甲氧苄啶。
9. 萘紛喹、 双氢青蒿素和甲氧苄啶或它们的抗疟活性衍生物、 前 药或其药用盐在制备用于治疗或预防疟疾的药物组合物中的用途。
10. 一种治疗或预防疟疾的方法， 包括给予需治疗的患者有效量 的萘紛喹、双氢青蒿素和甲氧苄啶或它们的抗疟活生衍生物、前药或 药用盐。
11. 一种治疗或预防疟疾的方法， 包括给予需治疗的患者有效量 的权利要求 1 - 8任一项的药物组合物。
PCT/CN1998/000274 1997-11-18 1998-11-18 Compositions pharmaceutiques antipaludiques WO1999025351A1 (fr)

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CN104666300B (zh) * 2014-07-04 2017-01-18 昆药集团股份有限公司 一种磷酸萘酚喹的用途
CN111265527B (zh) * 2020-03-05 2021-04-23 中国人民解放军军事科学院军事医学研究院 萘酚喹及其药学上可接受的盐在制备抗冠状病毒药物中的用途

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WO2002026226A1 (fr) * 2000-08-23 2002-04-04 Chongqing Kincare Medicinal Development Co., Ltd. Composition pharmaceutique contenant de la dihydroartemisinine indiquee pour le traitement de la malaria

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