WO2019161761A1 - 一种治疗疟疾的药物组合物 - Google Patents

一种治疗疟疾的药物组合物 Download PDF

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WO2019161761A1
WO2019161761A1 PCT/CN2019/075418 CN2019075418W WO2019161761A1 WO 2019161761 A1 WO2019161761 A1 WO 2019161761A1 CN 2019075418 W CN2019075418 W CN 2019075418W WO 2019161761 A1 WO2019161761 A1 WO 2019161761A1
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artesunate
ligustrazine
pharmaceutical composition
polyethylene glycol
acid
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PCT/CN2019/075418
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English (en)
French (fr)
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朱晓新
李玉洁
沈硕
陈利娜
蔡维艳
翁小刚
谷丽维
杨庆
李凯
姜晓慧
郭媛
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中国中医科学院中药研究所
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Publication of WO2019161761A1 publication Critical patent/WO2019161761A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • 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
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • 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
    • A61P33/06—Antimalarials
    • 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 belongs to the field of pharmacy, and relates to a traditional Chinese medicine composition, in particular to a pharmaceutical composition for treating malaria.
  • Malaria is a major infectious disease that poses a serious threat to human health and life. It spreads in 108 countries and regions around the world. About half of the world's population is threatened by malaria and is one of the world's three major public health problems. According to the WHO World Malaria Report 2016, approximately 3.2 billion people worldwide (nearly half of the world's population) are at risk of malaria. In 2015, there were 214 million new malaria cases and approximately 438,000 people died of malaria. At the same time, the resistance of Plasmodium also poses a serious challenge to malaria drug treatment. In order to improve clinical efficacy and delay the development of drug resistance, WHO has promoted Artemisinin-based combination therapies (ACTs) since 2001, and prohibits the use of artemisinin alone against malaria.
  • ACTs Artemisinin-based combination therapies
  • Cerebral malaria is one of the most serious complications of falciparum malaria, with 74% of cases of cerebral malaria occurring in African children under five years of age with a mortality rate of 15-20% (WHO, World Malaria Report 2015) . Cerebral malaria may have hemiparesis, convulsions, ataxia, coma and disturbance of consciousness, and meningeal irritation. Most children with cerebral malaria die within one day of the onset of central nervous system symptoms, and 10-20% of surviving children develop neurological sequelae such as persistent neurological deficits, cognitive dysfunction, behavioral disorders, and motor impairment. At present, it is believed that the local microcirculation disorder and secondary immunopathological damage of brain tissue caused by erythrocytes infected with Plasmodium are the most important pathogenesis of cerebral malaria.
  • Artesunate is considered to be the most effective drug for the treatment of severe malaria. Intravenous artesunate is the preferred treatment for cerebral malaria recommended by WHO. As a first-line treatment, in addition to antimalarial activity, artesunate also has anti-inflammatory effects, but reburning rate after artesunate monotherapy Up to 10% -100%.
  • Ligustrazine is the main active ingredient of Chuanxiong. Modern research has found that ligustrazine mainly has the effects of treating ischemic stroke, headache, hypertension, coronary atherosclerotic heart disease (coronary heart disease), migraine, and ischemic encephalopathy.
  • the drug has the characteristics of good curative effect, quick effect, stable quality and can improve the symptoms of nerve damage.
  • the pharmaceutical composition of the present invention comprises artesunate, ligustrazine or a pharmaceutically acceptable salt thereof.
  • the weight ratio of artesunate: ligustrazine or a pharmaceutically acceptable salt thereof is 1-10:10-1;
  • the weight ratio of artesunate: ligustrazine or a pharmaceutically acceptable salt thereof is 1-2:2-1.
  • the weight ratio of artesunate: ligustrazine or a pharmaceutically acceptable salt thereof is 2:1.
  • the pharmaceutically acceptable salt of ligustrazine is preferably ligustrazine hydrochloride.
  • artesunate and ligustrazine or a pharmaceutically acceptable salt thereof are all existing products, which are commercially available or can be prepared by a conventional method.
  • Another object of the present invention is to provide a preparation of a pharmaceutical composition.
  • the preparation method of the invention comprises the following steps:
  • the preparation method of the present invention comprises the following steps:
  • Another object of the invention is to provide a pharmaceutical preparation.
  • compositions of the invention including pharmaceutical compositions, and pharmaceutically acceptable carriers.
  • the pharmaceutically acceptable carrier may be from 0.1 to 99.9% by weight based on the total weight of the preparation.
  • the pharmaceutical preparation of the invention can be prepared into any pharmaceutical dosage form, and the pharmaceutical dosage forms include: tablets, sugar-coated tablets, film-coated tablets, enteric coated tablets, capsules, hard capsules, soft capsules, oral liquids. Oral, granules, pills, powders, ointments, granules, suspensions, solutions, injections, suppositories, ointments, plasters, creams, sprays, patches, gels, microemulsions, fats Formulations for plastid and nasal administration.
  • a preferred dosage form is a nasal drop.
  • the administration mode of the present invention includes injection administration, oral administration, and nasal administration, and is preferably intranasal administration.
  • the pharmaceutically acceptable carrier comprises: mannitol, sorbitol, sorbic acid or potassium salt, sodium metabisulfite, sodium hydrogen sulfite, sodium thiosulfate, cysteine hydrochloride, thioglycolic acid, methionine, vitamin A , vitamin C, vitamin E, vitamin D, azone, EDTA disodium, EDTA calcium sodium, monovalent alkali metal carbonate, acetate, phosphate or its aqueous solution, hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid, amino acid, Sodium chloride, potassium chloride, sodium lactate, xylitol, maltose, glucose, fructose, dextran, glycine, starch, sucrose, lactose, mannitol, silicon derivatives, cellulose and its derivatives, alginate , gelatin, polyvinylpyrrolidone, glycerin, propylene glycol, ethanol, soil
  • Another object of the invention is to provide the use of the pharmaceutical composition.
  • composition of the present invention for the preparation of a medicament for treating cerebral malaria.
  • the pharmaceutical composition of the present invention has the effects of improving living conditions, reducing cerebral vascular occlusion and inflammatory cell invasion, and improving symptoms of nerve damage.
  • the invention also plays a role in improving a series of cerebral ischemic lesions and neurological damage caused by the accumulation of malaria parasites in the brain during cerebral malaria.
  • the invention can obviously alleviate the occurrence of cerebral malaria caused by infection of the Plasmodium berghei ANKA strain, prolong the survival time, and is more advantageous than the single use.
  • the invention can increase the blood supply to the brain of the brain malaria mice and alleviate the ischemia and hypoxia injury of the brain tissue.
  • the invention has a prominent effect on the improvement of microvascular obstruction in the cerebellum.
  • artesunate in clinical use for severe malaria such as cerebral malaria is intravenous injection, but in the high incidence of malaria in Africa, extremely backward medical conditions have largely restricted artesunate. Clinically timely and effective application.
  • artesunate has the common characteristics of artemisinin drugs, that is, there are problems such as rapid metabolism in the body, obvious first-pass effect, and low bioavailability. These factors also limit the exertion of antimalarial efficacy to some extent. Increased the re-ignition problem after treatment. If you simply increase the dose or increase the frequency of administration, it will promote the occurrence of drug resistance and may increase the side effects of the drug.
  • the invention effectively solves the problems existing in the prior art after nasal administration.
  • Drug absorption through the nasal mucosa can enter the brain through the olfactory nerve pathway, olfactory mucosal epithelial pathway, and blood circulation pathway. After absorption, it directly enters the systemic circulation, which can protect against the destruction of enzymes in the gastrointestinal tract and the first-pass effect of the liver on drugs.
  • the average bioavailability is high, and the nasal absorption rate of non-peptide drugs is close to that of intravenous injection; and because of the unique anatomical and physiological connection between the nasal cavity and the cranial cavity, the drug can bypass the blood-brain barrier and enter the brain to achieve brain-targeted therapy; It is convenient to use, and the patient has good compliance and is suitable for self-administration.
  • Artesunate and ligustrazine are chemically suitable for nasal administration, and have been reported in the literature, and absorption by nasal administration is faster.
  • the present invention combines artesunate with ligustrazine in a nasal administration manner, regardless of the need for targeted administration of cerebral malaria, the need for artesunate to improve the bioavailability of the drug, and the ease of administration.
  • the combination of the two needs to be treated with nasal administration for the treatment of cerebral malaria.
  • the results of the experiment showed that the combination of artesunate and ligustrazine was synergistic in the nasal administration, improved animal survival, reduced cerebral vascular occlusion and inflammatory cell invasion in cerebral malaria mice, and improved symptoms of nerve injury. Administered intraperitoneally.
  • FIG. 5A Control group brain microvessels (HE staining, 20x)
  • FIG. 5B Model group brain microvessels (HE staining, 20x)
  • Figure 10A model group brain microvessels (HE staining, 20x)
  • FIG 10B ARS (ip) brain microvessels (HE staining, 20x)
  • Figure 16A model group brain microvessels (HE staining, 20x)
  • FIG 16B ARS+CXQ (ip) brain microvessels (HE staining, 20x)
  • FIG 16C ARS+CXQ (IN) brain microvessels (HE staining, 20x)
  • mice 6-8 week old female healthy C57BL6 mice were intraperitoneally inoculated with 1 ⁇ 10 6 P. berghei ANKA strain-infected red blood cells (pRBC), which was recorded as day 0 of infection. Continuous observation for 16 days, observation of cerebral malaria symptoms and death.
  • pRBC red blood cells
  • mice C57BL6 mice were divided into two groups, one control group and two model groups (ANKA). Each mouse was intraperitoneally inoculated with 1 ⁇ 106 pRBC.
  • Survival rate survival experimental mice / total experimental mice.
  • protozoal rate the experimental mice began to calculate the protozoa rate every day after 3 days of infection, by: taking a small drop of blood from the tail vein of infected mice on a clean glass slide to make a thin blood film, methanol fixed air-dried, Giemsa dye staining for 15min Rinse and dry, count under 100X oil mirror.
  • Protozoa rate pRBC / total red blood cell count;
  • Brain tissue was taken 12 days after infection, and the tissue was cut into 4 ⁇ m sections by 4% neutral formalin fixation, and HE staining was observed. According to the severity of obstruction and micro-bleeding, the semi-quantitative scale (0-5) was used to score the vascular sites: 0, no obstruction; 1, partial obstruction; 2, there were white blood cells attached to the endothelium; Obstruction, white blood cells and red blood cells coexist; 4, completely blocked, no bleeding; 5, systemic obstruction. Data are expressed as the average score for each brain.
  • mice after modeling were tested for seven indicators in five aspects: coordination ability, exploration behavior, strength and bone, reflex and self-protection and health behavior, and scored 0 to 2 points.
  • the sum of the items was taken as the total score, and the total score of the seven items was 14 points. The lower the score, the more serious the neurological damage.
  • the survival time of the mice in the ANKA group was significantly shortened.
  • the red curve was the control group and the black curve was ANKA.
  • the weight of the mice in the ANKA group was significantly reduced, as shown in Fig. 2, the red curve was the control group, and the black curve was ANKA.
  • the protozoal blood rate of the ANKA group was significantly increased, as shown in Fig. 3, the red curve was the control group, and the black curve was ANKA.
  • the brain microvessels were blocked in the hippocampus and cerebellum of the ANKA group, as shown in Fig. 4.
  • ART artesunate
  • ART+CXQ artesunate + ligustrazine
  • mice were divided into 3 groups, which were 1 model control group 2 artesunate intraperitoneal injection group (ART ip) 3 artesunate + ligustrazine intraperitoneal injection group (ART+CXQ ip). After each mouse was intraperitoneally inoculated with 1 ⁇ 10 6 pRBC to establish cerebral malaria, the mice in the administration group were intraperitoneally administered 4 times on the day before, on the first day, the third day, and the fifth day of the inoculation.
  • ART ip artesunate intraperitoneal injection group
  • ART+CXQ ip artesunate + ligustrazine intraperitoneal injection group
  • mice 1. Observe the survival of mice day by day, and plot the survival curve and body weight after 12 days.
  • Brain tissue was taken 12 days after infection and fixed with 4% neutral formalin. The tissue was cut into 4 ⁇ m sections and stained with HE to observe cerebral microvascular obstruction.
  • the artesunate intraperitoneal injection group can significantly prolong the survival time of mice
  • artesunate + ligustrazine intraperitoneal injection group is superior to artesunate
  • the single-use group as shown in Fig. 6, the black curve was the control group, the green curve was the artesunate intraperitoneal injection group, and the blue curve was the artesunate + ligustrazine intraperitoneal injection group.
  • artesunate intraperitoneal injection group can significantly increase the body weight of mice, as shown in Figure 7, 12d end artesunate + ligustrazine intraperitoneal injection The weight gain of the group was significant.
  • the artesunate intraperitoneal injection group can reduce the protozoal blood rate in mice, as shown in Figure 8, the two groups are equivalent.
  • the artesunate + ligustrazine intraperitoneal injection group can reduce the serum inflammatory factor TNFa in mice, and the anti-inflammatory factor IL-4 has an increasing trend. As shown in Figure 9.
  • artesunate intraperitoneal injection group Compared with the model control group, artesunate intraperitoneal injection group, artesunate + ligustrazine intraperitoneal injection group can significantly reduce brain microvascular occlusion in hippocampus and cerebellum of mice, as shown in Figure 10, artesunate + The intraperitoneal injection group of ligustrazine was superior to the intraperitoneal injection group of artesunate.
  • mice were divided into 3 groups, 1 model control group (control) 2 artesunate + ligustrazine intraperitoneal injection group (ART + CXQ ip) 3 artesunate + ligustrazine nasal administration group (ART + CXQ IN).
  • Each mouse was intraperitoneally inoculated with 1 ⁇ 10 6 pRBC to establish cerebral malaria.
  • the mice in the drug-administered group were intraperitoneally injected or nasally administered 4 times on the day before, on the first day, the third day and the fifth day of the inoculation. .
  • mice 1. Observe the survival of mice day by day, and plot the survival curve and body weight after 12 days.
  • Brain tissue was taken 12 days after infection and fixed with 4% neutral formalin. The tissue was cut into 4 ⁇ m sections and stained with HE to observe cerebral microvascular obstruction.
  • the artesunate + ligustrazine nasal administration group can significantly prolong the survival time of mice, as shown in Figure 11, the black curve is the control group, and the blue curve is artesunate + ligustrazine.
  • the red curve was the artesunate + ligustrazine nasal administration group.
  • artesunate + ligustrazine intraperitoneal injection group can reduce the protozoal blood rate of mice, as shown in Figure 13, the two groups are equivalent.
  • artesunate + ligustrazine intraperitoneal injection group can significantly increase the behavioral score of mice, including artesunate + Chuanxiong after 10 days of administration.
  • the azine nasal administration group was superior to the artesunate + ligustrazine intraperitoneal injection group, as shown in FIG.
  • artesunate + ligustrazine intraperitoneal injection group can reduce the serum inflammatory factor TNFa in mice, and the anti-inflammatory factor IL-4 has an increasing trend. As shown in Figure 15.
  • the artesunate + ligustrazine nasal administration group had an outstanding effect on the microvascular occlusion and hemorrhage in the cerebellum.
  • Example 3 the pharmaceutical composition of the present invention
  • Example 4 the pharmaceutical composition of the present invention
  • Example 5 the pharmaceutical composition of the present invention
  • phase C into 500 ml beaker, ultrasonic treatment with probe, ultrasonic power 300w, ultrasonic time 15min, end of ultrasound Thereafter, the liposome was passed through a 0.22 ⁇ microporous membrane to obtain phase D; poloxamer 407 5 g, poloxamer 188 7 g, disodium edetate 0.5, sodium nepalate ethyl ester 0.2 g
  • the compound antimalarial liposome temperature-sensitive in situ gel was prepared by mixing 200 ml of physiological saline and 300 ml of D phase.
  • Example 7 the pharmaceutical composition of the present invention
  • phase C into 500 ml beaker, ultrasonic treatment with probe, ultrasonic power 300w, ultrasonic time 15min, end of ultrasound Thereafter, the liposome was passed through a 0.22 ⁇ micropore filter to obtain phase D; poloxamer 407 10 g, poloxamer 188 5 g, disodium edetate 0.5, sodium nepalate ethyl ester 0.2 g
  • the compound antimalarial liposome temperature-sensitive in situ gel was prepared by mixing 200 ml of physiological saline and 300 ml of D phase.
  • phase C into 500 ml beaker, ultrasonic treatment with probe, ultrasonic power 300w, ultrasonic time 15min, end of ultrasound After that, the liposome was passed through a 0.22 ⁇ microporous membrane to obtain phase D; poloxamer 407 5 g, poloxamer 188 7 g, disodium edetate 0.3, phenylethyl alcohol 0.2 g, 200 ml normal saline
  • Compound anti-malarial liposome temperature-sensitive in situ gel was prepared by mixing with 300 ml of D phase.
  • phase C into 500 ml beaker, ultrasonic treatment with probe, ultrasonic power 300w, ultrasonic time 15min, end of ultrasound
  • the liposome was passed through a 0.22 ⁇ microporous membrane to obtain phase D
  • the compound antimalarial liposome temperature-sensitive in situ gel was prepared by mixing 200 ml of physiological saline and 300 ml of D phase.
  • Example 10 the pharmaceutical composition of the present invention
  • phase A Phase A, hydration, hydration temperature 50 ° C, evaporation bottle rotation speed 180 rpm, hydration time 20 min, hydrated to obtain phase C; phase C was added to a 500 ml beaker, ultrasonic treatment with probe, ultrasonic power 300w, ultrasonic time 15min, after ultrasonic end
  • the liposome was passed through a 0.22 ⁇ microporous membrane to obtain phase D; poloxamer 407 10 g, poloxamer 1885 g, disodium edetate 0.5, sodium nepalate ethyl ester 0.2 g, 200 ml
  • the compound antimalarial liposome temperature-sensitive in situ gel was prepared by mixing physiological saline with 300 ml of D phase.

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Abstract

一种治疗疟疾的药物组合物，含有青蒿琥酯，和川芎嗪或其药用盐，它们的重量比为1-10:10-1，该药物组合物可改善神经损伤症状。

Description

一种治疗疟疾的药物组合物 技术领域
本发明属于药学领域，涉及一种中药组合物，具体涉及一种治疗疟疾的药物组合物。
背景技术
疟疾是严重威胁人类健康和生命安全的重大传染病，在全世界108个国家和地区传播流行，全球约半数人口受到疟疾的威胁，为世界三大公共卫生问题之一。根据WHO 2016年世界疟疾报告，全球约有32亿人(占全世界总人口近一半)面临疟疾风险，2015年共有2.14亿疟疾新病例，大约43.8万人死于疟疾。同时疟原虫的抗药性也使疟疾药物治疗面临的严重挑战。为提高临床疗效，延缓抗药性的产生，WHO自2001年开始推广基于青蒿素类抗疟药的联合治疗方案(Artemisinin-based combination therapies，ACTs)，同时禁止单独使用青蒿素类抗疟。2006年WHO发布的第1版疟疾治疗指南中明确推荐了5种以青蒿素类药物为基础的ACTs药物组合。联合药物治疗是当今抗击疟疾的主要方式，2015年全球ACT采购量达到3.11亿份，但近年新型药物组合的研发进展缓慢，2015年发布的第3版疟疾治疗指南中仍然是10年前的5种ACTs药物组合。一旦疟原虫在大范围内对目前的ACTs产生抗药性，疟疾将面临无药可治的困境，新型复方抗疟药物研制面临重大挑战。
脑型疟(cerebral malaria，CM)是恶性疟最严重的并发症之一，74％的脑型疟病例发生在五岁以下非洲儿童，死亡率为15-20％(WHO,World Malaria Report 2015)。脑型疟临床可出现轻偏瘫、抽搐、共济失调、昏迷及意识障碍、脑膜刺激征等。大多数儿童脑型疟患者在中枢神经系统症状发作后一天内死亡，幸存儿童中有10-20％出现持续性神经功能缺损、认知功能障碍、行为障碍以及运动功能损伤等神经系统后遗症。目前认为，感染疟原虫红细胞堵塞脑血管所致脑组织局部微循环障碍及继发免疫病理损伤是脑型疟最主要发病机制。
青蒿琥酯被认为是治疗严重疟疾最有效的药物。静脉注射青蒿琥酯是WHO推荐的脑型疟首选治疗方案，作为目前一线治疗药物，除抗疟活性外，青蒿琥酯 还具有抗炎作用，但青蒿琥酯单药治疗后再燃率可达10％-100％。
川芎嗪是川芎的主要活性成分，现代研究发现川芎嗪主要有治疗缺血性中风、头痛、高血压、冠状粥样硬化性心脏病(冠心病)、偏头痛、缺血性脑病等作用。
我们经过长时间的研究后，得到一种疗效更加显著的抗疟药物。
发明内容
本发明的目的在于提供一种治疗疟疾的药物组合物。该药物具有疗效好、见效快、质量稳定、可改善神经损伤症状的特点。
本发明所述的药物组合物，含有青蒿琥酯，川芎嗪或其药用盐。
具体的，青蒿琥酯：川芎嗪或其药用盐的重量比为1-10:10-1；
优选的，青蒿琥酯：川芎嗪或其药用盐的重量比为1-2:2-1。
进一步优选的，青蒿琥酯：川芎嗪或其药用盐的重量比为2:1。
其中，所述川芎嗪的药用盐优选为盐酸川芎嗪。
其中，青蒿琥酯和川芎嗪或其药用盐都属于现有产品，可以在市场上购买到，也可以通过常规方法制备得到。
本发明的另一个目的在于提供药物组合物的制备方。
本发明的制备方法，包括以下步骤：
(1)青蒿琥酯粉末，加入5％碳酸氢钠溶液振摇，待完全溶解后，加0.9％氯化钠注射液稀释，
(2)川芎嗪或其药用盐加0.9％氯化钠注射液振摇，至完全溶解，
(3)将上述两个步骤所得的溶液，混合均匀。
优选的，本发明的制备方法，包括以下步骤：
(1)青蒿琥酯，加0.9％氯化钠注射液，完全溶解，加0.9％氯化钠注射液稀释，
(2)盐酸川芎嗪加0.9％氯化钠注射液振摇，至完全溶解，
(3)将上述两个步骤所得的溶液，混合均匀。
本发明另一个目的在于提供一种药物制剂。
本发明的药物制剂，包括药物组合物，和药学上可接受的载体。
其中，药学上可接受的载体以重量计可以是制剂总重量的0.1-99.9％。
本发明的药物制剂，可以制备成任何药用剂型，药用剂型包括：片剂、糖衣 片剂、薄膜衣片剂、肠溶衣片剂、胶囊剂、硬胶囊剂、软胶囊剂、口服液、口含剂、颗粒剂、丸剂、散剂、膏剂、丹剂、混悬剂、溶液剂、注射剂、栓剂、软膏剂、硬膏剂、霜剂、喷雾剂、贴剂、凝胶、微乳、脂质体和经鼻给药的剂型。
优选剂型为滴鼻剂。
本发明的给药方式，包括：注射给药、口服给药和鼻腔给药，优选为鼻腔给药。
其中，所述药学上可接受的载体包括：甘露醇、山梨醇、山梨酸或钾盐、焦亚硫酸钠、亚硫酸氢钠、硫代硫酸钠、盐酸半胱氨酸、巯基乙酸、蛋氨酸、维生素A、维生素C、维生素E、维生素D、氮酮、EDTA二钠、EDTA钙钠，一价碱金属的碳酸盐、醋酸盐、磷酸盐或其水溶液、盐酸、醋酸、硫酸、磷酸、氨基酸、氯化钠、氯化钾、乳酸钠、木糖醇、麦芽糖、葡萄糖、果糖、右旋糖苷、甘氨酸、淀粉、蔗糖、乳糖、甘露糖醇、硅衍生物、纤维素及其衍生物、藻酸盐、明胶、聚乙烯吡咯烷酮、甘油、丙二醇、乙醇、土温60-80、司班-80、蜂蜡、羊毛脂、液体石蜡、十六醇、没食子酸酯类、琼脂、三乙醇胺、碱性氨基酸、尿素、尿囊素、碳酸钙、碳酸氢钙、表面活性剂、聚乙二醇、环糊精、β－环糊精、磷脂类材料、高岭土、滑石粉、硬脂酸钙、硬脂酸镁、微晶、泊洛沙姆407、泊洛沙姆188、苯乙醇、尼泊金甲酯、尼泊金乙酯、苯扎溴铵、山梨酸、丙二醇、聚乙二醇400、聚乙二醇2000、聚乙二醇4000、聚乙二醇6000、甘油，甘露醇、山梨醇、葡萄糖、氯化钠、氯化钾、乙二胺四乙酸二钠、二硬脂酰基磷脂酰乙醇胺-聚乙二醇2000、二硬脂酰基磷脂酰乙醇胺-聚乙二醇3000、二硬脂酰基磷脂酰乙醇胺-聚乙二醇4000、二硬脂酰基磷脂酰乙醇胺-聚乙二醇5000、蛋黄卵磷脂、大豆卵磷脂、氢化卵磷脂、胆固醇、聚氧乙烯蓖麻油、聚氧乙烯氢化蓖麻油、辛酸癸酸聚乙二醇甘油酯、油酸乙酯、烷基糖苷、癸酸甘油三酯、辛酸癸酸甘油三酯中一种或以上；优选所述的载体为微晶纤维素、乳糖、淀粉、羧甲基纤维素钠、低取代羟丙基纤维素、滑石粉中一种或以上。
本发明另一个目的在于提供该药物组合物的应用。
本发明的药物组合物在制备治疗疟疾的药物中的应用。
本发明的药物组合物在制备治疗脑型疟的药物中的应用。
本发明的药物组合物在制备治疗重症疟疾的药物中的应用。
本发明的药物组合物具有改善生存状态、降低脑血管堵塞及炎症细胞侵入，改善神经损伤症状等作用。
本发明还起到改善脑型疟过程中疟原虫在脑内蓄积引发的一系列脑缺血病变和神经功能损伤等兼变症状的作用。
本发明能够明显缓解伯氏疟原虫ANKA株感染导致的脑型疟的发生，延长生存时间，比单独使用更具优势。
本发明能够增加脑型疟小鼠脑部供血，减轻脑组织缺血缺氧性损伤。
本发明对小脑中微血管阻塞情况改善具有突出的作用。
青蒿琥酯在临床上用于脑型疟等重症疟疾的主要给药方法是静脉注射，但在非洲脑型疟高发地区，极端落后的医疗条件在很大程度上限制了青蒿琥酯的临床及时、有效应用。同时，青蒿琥酯具有青蒿素类药物共同的特点，即存在体内代谢快、首过效应明显、生物利用度低等问题，这些因素也在一定程度上限制了其抗疟药效的发挥，加重了治疗后的复燃问题。如果简单通过加大单次给药剂量或增加给药频次，则会促进耐药现象的发生、并可能增加药物的毒副作用。
本发明采用鼻腔给药后，有效解决现有技术中存在的问题。药物经鼻黏膜吸收可通过嗅神经通路、嗅黏膜上皮通路、血液循环通路这3条通路入脑，吸收后直接进入体循环，可免受胃肠道中酶的破坏和肝脏对药物的首过效应，平均生物利用度较高，非肽类药物的鼻腔吸收速度接近静注；且由于鼻腔与颅腔在解剖生理上的独特联系，使得药物可绕过血脑屏障进入大脑，实现脑靶向治疗；同时用药方便，患者顺应性好，适合自身给药。青蒿琥酯与川芎嗪从化学性质而言均适合鼻腔给药，且均已有文献报道，鼻腔给药吸收更快。故本发明将青蒿琥酯与川芎嗪配伍组合采用鼻腔给药的方式无论从针对脑型疟脑内靶向给药的需求、青蒿琥酯提高药物生物利用度的需求、用药方便角度的需求，两者组合后采用鼻腔给药治疗脑型疟均有很大意义。实验结果发现，青蒿琥酯与川芎嗪配伍组合鼻腔给药后在协同增效，改善动物生存状态、降低脑型疟小鼠脑血管堵塞及炎症细胞侵入，改善神经损伤症状等方面均优于腹腔给药。
附图说明
图1、模型小鼠生存时间
图2、模型小鼠体重增长
图3、模型小鼠虫血率
图4、模型小鼠行为学评分
图5A对照组脑微血管(HE染色，20x)
图5B模型组脑微血管(HE染色，20x)
图6、各组生长曲线
图7、各组体重增长曲线
图8、各组感染率
图9A、对血清炎症因子TNFa的作用，图9B对炎因子IL-4的作用
图10A、模型组脑微血管(HE染色，20x)
图10B、ARS(ip)脑微血管(HE染色，20x)
图10C、ARS+CXQ(ip)脑微血管(HE染色，20x)
图11、各组生长曲线
图12、各组体重增长曲线
图13、各组感染率
图14、各组RMCBS评分
图15A、对血清炎症因子TNFa的作用，图15B对炎因子IL-4的作用
图16A、模型组脑微血管(HE染色，20x)
图16B、ARS+CXQ(ip)脑微血管(HE染色，20x)
图16C、ARS+CXQ(IN)脑微血管(HE染色，20x)
具体实施方式
通过以下具体实施例对本发明作进一步的说明，但不作为本发明的限制。
实施例中的所有组分均可以在市场上购买到。
上述实施例只是用于对本发明的内容进行阐述，而不是限制，因此在与本发明的权利要求书相当的含义和范围内的任何改变，都应该认为是包括在权利要求书的范围内。
下述试验例中所用青蒿琥酯+川芎嗪为本发明实施例1，青蒿琥酯：川芎嗪＝2:1。
试验例1、
实验性脑型疟模型建立：
6-8周龄雌性健康C57BL6小鼠，腹腔接种1×10 6个伯氏疟原虫ANKA株感染的红细胞(pRBC)，记为感染第0天。连续观察16天，观察脑型疟症状及死亡情况。
实验分组：
C57BL6小鼠分为2组，分别为①对照组(control)，②模型组(ANKA)，每只小鼠腹腔接种1×106个pRBC。
评价指标：
1、生存曲线：逐日观察小鼠生存情况，12天后绘制生存曲线、体重变化。
存活率＝存活实验小鼠/总实验小鼠。
2、原虫率：实验小鼠感染3d后开始每天计算原虫率,方法为:取感染小鼠尾静脉血1小滴于洁净载玻片上制作薄血片，甲醇固定风干，Giemsa染液染色15min后冲洗晾干,于100X油镜下进行计数.原虫率＝pRBC/总红细胞数；
3、脑微血管阻塞评价：感染后12天后取脑组织，用4％中性福尔马林固定将组织切成4μm切片，HE染色，观察。根据梗阻的严重程度和微出血情况，使用半定量量表(0-5)对包含血管部位进行评分：0，无梗阻；1，部分阻塞；2，存在附着于内皮的白细胞；3，存在局部阻塞，白细胞和红细胞并存；4，完全阻塞，无出血；5，全身阻塞。数据表示为每个脑的平均分。
4、行为学评分将小鼠置于长×宽×高＝31.8×19.8×10.5cm白盒内(底面方格)，准备3mm直径的直杆用于触碰小鼠。采用下列标准进行评分。
RMCBS评分表：
Figure PCTCN2019075418-appb-000001
Figure PCTCN2019075418-appb-000002
根据RMCBS评分表对造模后的小鼠隔天对协调能力、探索行为、力量和骨骼、反射和自我保护和卫生行为五个方面共七项指标进行测试，并给予0～2分的评分。各项之和作为总评分，七项总分14分，分数越低表示神经功能损伤越严重。实验结果：
1、模型小鼠生存时间：
与对照组相比，ANKA组小鼠生存时间明显缩短，如图1所示，红色曲线为对照组，黑色曲线为ANKA。
2、模型小鼠体重增长：
与对照组相比，ANKA组小鼠体重明显减轻，如图2所示，红色曲线为对照组，黑色曲线为ANKA。
3、模型小鼠虫血率：
与对照组相比，ANKA组小鼠原虫血率显著增高，如图3所示，红色曲线为对照组，黑色曲线为ANKA。
4、模型脑微血管阻塞评价：
与对照组相比，ANKA组小鼠海马和小脑组织中脑微血管堵塞，如图4所示。
试验例2、
青蒿琥酯(ART)与青蒿琥酯+川芎嗪(ART+CXQ)对实验性脑疟的保护作用
实验分组：
C57BL6小鼠分为3组，分别为①模型对照组(control)②青蒿琥酯腹腔注射组(ART ip)③青蒿琥酯+川芎嗪腹腔注射组(ART+CXQ ip)。每只小鼠腹腔接种1×10 6个pRBC建立脑型疟后，给药组小鼠分别在接种的前一天、第一天、第三 天、第五天经腹腔注射给药4次。
评价指标：
1、逐日观察小鼠生存情况，12天后绘制生存曲线、体重变化
2、逐日取血涂血片，镜检计算感染率。
3、感染后12天后取血，离心取上清检测炎症因子。
4、感染后12天后取脑组织，用4％中性福尔马林固定。将组织切成4μm切片，HE染色，观察脑微血管阻塞情况。
实验结果：
1、对小鼠生存时间的影响：
与模型对照组相比，青蒿琥酯腹腔注射组、青蒿琥酯+川芎嗪腹腔注射组均能够显著延长小鼠生存时间，青蒿琥酯+川芎嗪腹腔注射组优于青蒿琥酯单用组，如图6所示，黑色曲线为对照组，绿色曲线为青蒿琥酯腹腔注射组，蓝色曲线为青蒿琥酯+川芎嗪腹腔注射组。
2、对小鼠体重增长的影响：
与模型对照组相比，青蒿琥酯腹腔注射组、青蒿琥酯+川芎嗪腹腔注射组均能够显著增加小鼠体重，如图7所示，12d末青蒿琥酯+川芎嗪腹腔注射组体重增加显著。
3、对小鼠虫血率的影响：
与模型对照组相比，青蒿琥酯腹腔注射组、青蒿琥酯+川芎嗪腹腔注射组均能够降低小鼠原虫血率，如图8所示，2组作用相当。
4、对小鼠血清炎症因子的影响：
与模型对照组相比，青蒿琥酯+川芎嗪腹腔注射组能够降低小鼠血清炎症因子TNFa，对抗炎因子IL-4有增高趋势。如图9所示。
5、对脑微血管阻塞的影响
与模型对照组相比，青蒿琥酯腹腔注射组、青蒿琥酯+川芎嗪腹腔注射组均能显著减轻小鼠海马和小脑组织中脑微血管堵塞，如图10所示，青蒿琥酯+川芎嗪腹腔注射组优于青蒿琥酯腹腔注射组。
试验例3、
青蒿琥酯+川芎嗪(ART+CXQ)不同给药途径对实验性脑疟的保护作用比较
实验分组：
C57BL6小鼠分为3组，分别为①模型对照组(control)②青蒿琥酯+川芎嗪腹腔注射组(ART+CXQ ip)③青蒿琥酯+川芎嗪鼻腔给药组(ART+CXQ IN)。每只小鼠腹腔接种1×10 6个pRBC建立脑型疟后，给药组小鼠分别在接种的前一天、第一天、第三天、第五天经腹腔注射或鼻腔给药4次。
评价指标：
1、逐日观察小鼠生存情况，12天后绘制生存曲线、体重变化
2、逐日取血涂血片，镜检计算感染率。
3、4天后进行小鼠行为学评分。
4、感染后12天后取血，离心取上清检测炎症因子。
5、感染后12天后取脑组织，用4％中性福尔马林固定。将组织切成4μm切片，HE染色，观察脑微血管阻塞情况。
实验结果：
1、对小鼠生存时间的影响：
与模型对照组相比，青蒿琥酯+川芎嗪鼻腔给药组均能够显著延长小鼠生存时间，如图11所示，黑色曲线为对照组，蓝色曲线为青蒿琥酯+川芎嗪腹腔注射组，红色曲线为青蒿琥酯+川芎嗪鼻腔给药组。
2、对小鼠体重增长的影响：
与模型对照组相比，青蒿琥酯+川芎嗪鼻腔给药组在染毒12天时的体重增加显著，如图12所示。
3、对小鼠虫血率的影响：
与模型对照组相比，青蒿琥酯+川芎嗪腹腔注射组、青蒿琥酯+川芎嗪鼻腔给药组均能够降低小鼠原虫血率，如图13所示，2组作用相当。
4、对小鼠行为学评分的影响
与模型对照组相比，青蒿琥酯+川芎嗪腹腔注射组、青蒿琥酯+川芎嗪鼻腔给药组均能显著增高小鼠行为学评分，其中给药10d后青蒿琥酯+川芎嗪鼻腔给药组优于青蒿琥酯+川芎嗪腹腔注射组，如图14所示。
5、对小鼠血清炎症因子的影响：
与模型对照组相比，青蒿琥酯+川芎嗪腹腔注射组、青蒿琥酯+川芎嗪鼻腔给药组均能够降低小鼠血清炎症因子TNFa，对抗炎因子IL-4有增高趋势。如图15所示。
6、对微血管阻塞的影响
如图16示，与模型对照组相比，青蒿琥酯+川芎嗪鼻腔给药组对小脑中微血管阻塞及出血改善作用突出。
上述仅列举本发明部分药物的药效实验，实际上，本发明其他药物也具有相同或者相似的药物效果，在此不一一列举。
虽然，上文中已经用一般性说明及具体实施方案对本发明作了详尽的描述，但在本发明基础上，可以对之作一些修改或改进，这对本领域技术人员而言是显而易见的。因此，在不偏离本发明精神的基础上所做的这些修改或改进，均属于本发明要求保护的范围。
实施例1、本发明的药物组合物
青蒿琥酯40mg，盐酸川芎嗪20mg
(1)取40mg青蒿琥酯，加1ml 0.9％氯化钠注射液，完全溶解，再加3ml 0.9％氯化钠注射液稀释，
(2)取20mg盐酸川芎嗪，加0.9％氯化钠注射液4ml振摇，至完全溶解，
(3)将上述两个步骤所得的溶液，混合均匀，即可。
实施例2、本发明的药物组合物
青蒿琥酯20mg，盐酸川芎嗪20mg
(1)取20mg青蒿琥酯，加1ml 0.9％氯化钠注射液，完全溶解，再加1ml 0.9％氯化钠注射液稀释，
(2)取20mg盐酸川芎嗪，加0.9％氯化钠注射液4ml振摇，至完全溶解，
(3)将上述两个步骤所得的溶液，混合均匀，即可。
实施例3、本发明的药物组合物
青蒿琥酯20mg，盐酸川芎嗪40mg
(1)取20mg青蒿琥酯，加1ml 0.9％氯化钠注射液，完全溶解，再加1ml 0.9％ 氯化钠注射液稀释，
(2)取40mg盐酸川芎嗪，加0.9％氯化钠注射液8ml振摇，至完全溶解，
(3)将上述两个步骤所得的溶液，混合均匀，即可。
实施例4、本发明的药物组合物
青蒿琥酯20mg，盐酸川芎嗪200mg
(1)取20mg青蒿琥酯，加1ml 0.9％氯化钠注射液，完全溶解，再加19ml0.9％氯化钠注射液稀释，
(2)取200mg盐酸川芎嗪，加0.9％氯化钠注射液20ml振摇，至完全溶解，
(3)将上述两个步骤所得的溶液，混合均匀，即可。
实施例5、本发明的药物组合物
青蒿琥酯200mg，盐酸川芎嗪20mg
(1)取200mg青蒿琥酯，加10ml 0.9％氯化钠注射液，完全溶解，再加10ml0.9％氯化钠注射液稀释，
(2)取20mg盐酸川芎嗪，加0.9％氯化钠注射液20ml振摇，至完全溶解，
(3)将上述两个步骤所得的溶液，混合均匀，即可。
实施例6、本发明的药物组合物
将青蒿琥酯1g和盐酸川芎嗪0.2g，25℃下溶解于300ml生理盐水中，做为A相；取磷脂5g、胆固醇0.3g和二硬脂酰基磷脂酰乙醇胺-聚乙二醇2000 0.5g，25℃下溶解于30ml无水乙醇中做为B相；将B相加入旋转蒸发仪2L的蒸发瓶中，在50℃下减压蒸干乙醇；待乙醇除净后，向蒸发瓶中加入A相，进行水合，水合温度50℃，蒸发瓶转速180rpm，水合时间20min，水合后得到C相；将C相加入500ml烧杯中，采用探头超声处理，超声功率300w，超声时间15min，超声结束后，将脂质体过0.22μ微孔滤膜，得到D相；将泊洛沙姆407 5g、泊洛沙姆188 7g、乙二胺四乙酸二钠0.5、尼泊金乙酯钠0.2g、200ml生理盐水和300ml D相混合，制得复方抗疟脂质体温敏原位凝胶剂。
实施例7、本发明的药物组合物
将青蒿琥酯1g和盐酸川芎嗪0.5g，25℃下溶解于300ml生理盐水中，做为A相；取磷脂5g、胆固醇0.5g和二硬脂酰基磷脂酰乙醇胺-聚乙二醇2000 0.5g，25℃下溶解于30ml无水乙醇中做为B相；将B相加入旋转蒸发仪2L的蒸发瓶中，在50℃下减压蒸干乙醇；待乙醇除净后，向蒸发瓶中加入A相，进行水合，水合温度50℃，蒸发瓶转速180rpm，水合时间20min，水合后得到C相；将C相加入500ml烧杯中，采用探头超声处理，超声功率300w，超声时间15min，超声结束后，将脂质体过0.22μ微孔滤膜，得到D相；将泊洛沙姆407 10g、泊洛沙姆188 5g、乙二胺四乙酸二钠0.5、尼泊金乙酯钠0.2g、200ml生理盐水和300ml D相混合，制得复方抗疟脂质体温敏原位凝胶剂。
实施例8、本发明的药物组合物
将青蒿琥酯1g和盐酸川芎嗪0.4g，25℃下溶解于300ml生理盐水中，做为A相；取磷脂5g、胆固醇0.3g和二硬脂酰基磷脂酰乙醇胺-聚乙二醇2000 0.5g，25℃下溶解于30ml无水乙醇中做为B相；将B相加入旋转蒸发仪2L的蒸发瓶中，在50℃下减压蒸干乙醇；待乙醇除净后，向蒸发瓶中加入A相，进行水合，水合温度50℃，蒸发瓶转速180rpm，水合时间20min，水合后得到C相；将C相加入500ml烧杯中，采用探头超声处理，超声功率300w，超声时间15min，超声结束后，将脂质体过0.22μ微孔滤膜，得到D相；将泊洛沙姆407 5g、泊洛沙姆188 7g、乙二胺四乙酸二钠0.3、苯乙醇0.2g、200ml生理盐水和300ml D相混合，制得复方抗疟脂质体温敏原位凝胶剂。
实施例9、本发明的药物组合物
将青蒿琥酯1.25g和盐酸川芎嗪1g，25℃下溶解于300ml生理盐水中，做为A相；取磷脂8g、胆固醇0.2g和二硬脂酰基磷脂酰乙醇胺-聚乙二醇4000 0.3g，25℃下溶解于40ml无水乙醇中做为B相；将B相加入旋转蒸发仪2L的蒸发瓶中，在50℃下减压蒸干乙醇；待乙醇除净后，向蒸发瓶中加入A相，进行水合，水合温度50℃，蒸发瓶转速180rpm，水合时间20min，水合后得到C相；将C相加入500ml烧杯中，采用探头超声处理，超声功率300w，超声时间15min，超 声结束后，将脂质体过0.22μ微孔滤膜，得到D相；将泊洛沙姆407 9g、泊洛沙姆188 6g、乙二胺四乙酸二钠0.5、尼泊金乙酯钠0.2g、200ml生理盐水和300ml D相混合，制得复方抗疟脂质体温敏原位凝胶剂。
实施例10、本发明的药物组合物
将青蒿琥酯1g和盐酸川芎嗪1g，25℃下溶解于300ml生理盐水中，做为A相；取磷脂5g、胆固醇0.5g和二硬脂酰基磷脂酰乙醇胺-聚乙二醇2000 0.5g，25℃下溶解于30ml无水乙醇中做为B相；将B相加入旋转蒸发仪2L的蒸发瓶中，在50℃下减压蒸干乙醇；待乙醇除净后，向蒸发瓶中加入A相，进行水合，水合温度50℃，蒸发瓶转速180rpm，水合时间20min，水合后得到C相；将C相加入500ml烧杯中，采用探头超声处理，超声功率300w，超声时间15min，超声结束后，将脂质体过0.22μ微孔滤膜，得到D相；将泊洛沙姆407 10g、泊洛沙姆1885g、乙二胺四乙酸二钠0.5、尼泊金乙酯钠0.2g、200ml生理盐水和300ml D相混合，制得复方抗疟脂质体温敏原位凝胶剂。

Claims (10)

  1. 一种治疗疟疾的药物组合物，含有青蒿琥酯，川芎嗪或其药用盐。
  2. 根据权利要求1所述的药物组合物，其特征在于，青蒿琥酯：川芎嗪或其药用盐的重量比为1-10:10-1。
  3. 根据权利要求1所述的药物组合物，其特征在于，青蒿琥酯：川芎嗪或其药用盐的重量比为1-2:2-1。
  4. 根据权利要求1所述的药物组合物，其特征在于，青蒿琥酯：川芎嗪或其药用盐的重量比为2:1。
  5. 根据权利要求1-4任一所述的药物组合物，其特征在于，川芎嗪的药用盐为盐酸川芎嗪。
  6. 一种药物制剂，包括权利要求1所述的药物组合物，和药学上可接受的载体。
  7. 根据权利要求6所述的药物制剂，其特征在于，所述药学上可接受的载体选自：甘露醇、山梨醇、山梨酸或钾盐、焦亚硫酸钠、亚硫酸氢钠、硫代硫酸钠、盐酸半胱氨酸、巯基乙酸、蛋氨酸、维生素A、维生素C、维生素E、维生素D、氮酮、EDTA二钠、EDTA钙钠，一价碱金属的碳酸盐、醋酸盐、磷酸盐或其水溶液、盐酸、醋酸、硫酸、磷酸、氨基酸、氯化钠、氯化钾、乳酸钠、木糖醇、麦芽糖、葡萄糖、果糖、右旋糖苷、甘氨酸、淀粉、蔗糖、乳糖、甘露糖醇、硅衍生物、纤维素及其衍生物、藻酸盐、明胶、聚乙烯吡咯烷酮、甘油、丙二醇、乙醇、土温60-80、司班-80、蜂蜡、羊毛脂、液体石蜡、十六醇、没食子酸酯类、琼脂、三乙醇胺、碱性氨基酸、尿素、尿囊素、碳酸钙、碳酸氢钙、表面活性剂、聚乙二醇、环糊精、β－环糊精、磷脂类材料、高岭土、滑石粉、硬脂酸钙、硬脂酸镁、微晶、泊洛沙姆407、泊洛沙姆188、苯乙醇、尼泊金甲酯、尼泊金乙酯、苯扎溴铵、山梨酸、丙二醇、聚乙二醇400、聚乙二醇2000、聚乙二醇4000、聚乙二醇6000、甘油，甘露醇、山梨醇、葡萄糖、氯化钠、氯化钾、乙二胺四乙酸二钠、二硬脂酰基磷脂酰乙醇胺-聚乙二醇2000、二硬脂酰基磷脂酰乙醇胺-聚乙二醇3000、二硬脂酰基磷脂酰乙醇胺-聚乙二醇4000、二硬脂酰基磷脂酰乙醇胺-聚乙二醇5000、蛋黄卵磷脂、大豆卵磷脂、氢化卵磷脂、胆固醇、聚氧乙烯蓖麻油、聚氧乙烯氢化蓖麻油、辛酸癸酸聚乙二醇甘油酯、油酸乙酯、烷基糖苷、癸 酸甘油三酯、辛酸癸酸甘油三酯中一种或多种。
  8. 根据权利要求6所述的药物制剂，其特征在于，该药物制剂的剂型为任何一种药用剂型，包括：片剂、糖衣片剂、薄膜衣片剂、肠溶衣片剂、胶囊剂、硬胶囊剂、软胶囊剂、口服液、口含剂、颗粒剂、丸剂、散剂、膏剂、丹剂、混悬剂、溶液剂、注射剂、栓剂、软膏剂、硬膏剂、霜剂、喷雾剂、贴剂、凝胶、微乳、脂质体和经鼻给药的剂型，优选的药用剂型为滴鼻剂。
  9. 权利要求1所述的药物组合物的制备方法，其特征在于，包括以下步骤：
    (1)青蒿琥酯粉末，加入5％碳酸氢钠溶液振摇，待完全溶解后，加0.9％氯化钠注射液稀释，
    (2)川芎嗪或其药用盐加0.9％氯化钠注射液振摇，至完全溶解，
    (3)将上述两个步骤所得的溶液，混合均匀，
    优选的制备方法，包括以下步骤：
    (1)青蒿琥酯，加0.9％氯化钠注射液，完全溶解，加0.9％氯化钠注射液稀释，
    (2)盐酸川芎嗪加0.9％氯化钠注射液振摇，至完全溶解，
    (3)将上述两个步骤所得的溶液，混合均匀。
  10. 权利要求1所述的药物组合物在制备治疗重症疟疾的药物中的应用。
PCT/CN2019/075418 2018-02-23 2019-02-19 一种治疗疟疾的药物组合物 WO2019161761A1 (zh)

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