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WO2009100587A1 - Composition de médicament pour le traitement et la prévention d'un accident ischémique cérébral et ses procédés de préparation - Google Patents

Composition de médicament pour le traitement et la prévention d'un accident ischémique cérébral et ses procédés de préparation Download PDF

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Publication number
WO2009100587A1
WO2009100587A1 PCT/CN2008/000349 CN2008000349W WO2009100587A1 WO 2009100587 A1 WO2009100587 A1 WO 2009100587A1 CN 2008000349 W CN2008000349 W CN 2008000349W WO 2009100587 A1 WO2009100587 A1 WO 2009100587A1
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Prior art keywords
separation
extraction
kettle
oil
product
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Ceased
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PCT/CN2008/000349
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English (en)
Chinese (zh)
Inventor
Huiwan Han
Liang JI
Yanda Li
Mingyu Ding
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Tsinghua University
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Tsinghua University
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Priority to PCT/CN2008/000349 priority Critical patent/WO2009100587A1/fr
Priority to CN2008800014789A priority patent/CN101677989B/zh
Publication of WO2009100587A1 publication Critical patent/WO2009100587A1/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/23—Apiaceae or Umbelliferae (Carrot family), e.g. dill, chervil, coriander or cumin
    • A61K36/236—Ligusticum (licorice-root)
    • 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
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/898—Orchidaceae (Orchid family)
    • A61K36/8988—Gastrodia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin

Definitions

  • the invention belongs to a traditional Chinese medicine monomer composition, in particular to a pharmaceutical composition for preventing and treating ischemic stroke and a preparation method thereof.
  • Stroke is one of the leading causes of death and disability in middle-aged and elderly people. Nearly 80% of cases of ischemic stroke are caused by cerebral arterial embolism or atherothrombosis. According to clinical symptoms and duration, cerebral ischemia can be divided into transient ischemic attack (TIA) with complete remission of symptoms within 24 hours, reversible ischemic neurological deficit (RIND) with symptoms lasting for 6 weeks, and Symptoms persist in stroke. According to data released by the WHO, 40 of the 57 countries have listed the mortality rate of cerebrovascular disease in the top three causes of death, ranking first in Japan and China. However, the existing drug control effect is not good, so it is urgent to develop a clinical drug with better efficacy.
  • TIA transient ischemic attack
  • RIND reversible ischemic neurological deficit
  • Medicinal Chuanxiong is the rhizome of Ligusticum chuanxiong Hort, a perennial herb of the family Umbelliferae (English name Rhizoma chuanxiong).
  • the main chemical constituents are volatile oil, alkaloids, phenolic components, lactones, ferulic acid, etc.
  • the chemical component of the effective part of Chuanxiong, which improves cerebral ischemia in vivo, is a Chuanxiong lactone compound.
  • the lactone is cetanolactone (4,5-dihydro-3-butylbenzene peptide, 4, 5-dihydro- 3-butyl-phthalide ) (Formula ( I ) and Artemisactone (4, 5-dihydro-3-butylidene phenyl peptide, 4, 5-dihydro-3-buty 1 i dene-phthal ide ) Formula (11).
  • Medicinal Gastrodia (Gastrodia elata Blume, English name Rhizoma Gastrodiae) is a perennial orchid family high-grade fungus plant. Gastrodia contains gastrodin, vanillin, succinic acid, ⁇ -sitosterol, vitamin-like substances, terpenoids, Alkaloids, mucilage and gastrodia polysaccharides. Among them, gastrodin and gastrodia elata polysaccharide are the main components. It is now possible to artificially synthesize gastrodin (Tianma) (Zhou Shuzhen, etc., Chinese pharmaceutical industry miscellaneous Zhi, 1985, 05)
  • Gastrodin (English name is Gastrodin), its chemical name is 4-hydroxybenzene- ⁇ -D-glucopyranoside. The molecular formula is: C13H1807. Gastrodia has a variety of pharmacological effects. It can restore the imbalance between the excitatory and inhibitory processes in the cerebral cortex, and has central inhibition such as sedation, sleep and analgesia. The acute toxicity of gastrodin (tianzin) is small.
  • Tianzhu Soft Capsule Tianma and Rhubarb, and the ratio of Tianma and Rhubarb in the place is 3:1 (Guo Zengjun et al. Chinese patent medicine 2005, 27 (4), 467-468). Most of these prescriptions are mainly for the treatment of migraine, and the active ingredients are not used as indicators in the preparation process.
  • the above prior art has the following disadvantages: (1) The purity of the drug component is not high, and it cannot be made into a traditional Chinese medicine preparation with a clear chemical composition, in particular, it cannot be prepared into an injection having a clear chemical composition and a high purity; (2) The traditional Chinese medicine preparations for the prevention and treatment of stroke, which are mainly based on extracts of Chuanxiong, are all based on the chemically stable and stable artemisinone as the monitoring index, which affects the accuracy of the detection.
  • a pharmaceutical composition consisting of seledanolactone, artemisinide and gastrodin was not found by searching. Summary of the invention One of the objects of the present invention is to provide a pharmaceutical composition for preventing and treating ischemic stroke.
  • a second object of the present invention is to provide a process for the preparation of the above pharmaceutical composition.
  • Another object of the present invention is to provide the use of the above pharmaceutical composition for the preparation of a medicament for treating ischemic stroke.
  • a pharmaceutical composition for preventing and treating ischemic stroke the composition thereof and the weight percentage thereof are: Cetanolactone 19 ⁇ 72%
  • the solvent described in the above pharmaceutical composition means sodium carboxymethylcellulose, Tween-80 or vegetable oil and the like.
  • the vegetable oil refers to one or more of vegetable oils such as olive oil, peanut oil, corn oil, soybean oil, sunflower oil, sesame oil, castor oil, almond oil or peach kernel oil.
  • the dosage form prepared by the above pharmaceutical composition may be a pharmaceutically acceptable dosage form according to a usual method, and may be, for example, an injection, a spray, a capsule, a dropping tablet, a tablet, a granule, an emulsion, a dispersing agent, and a sustained release. Agents, etc.
  • compositions are all pure compounds of serranolol, artemisinide and gastrodin, all of which are more than 98% pure, and gastrodin is commercially available.
  • the preparation method of the above-mentioned pharmaceutical composition for preventing and treating ischemic stroke according to the ratio of cetanolactone, artemisinide, gastrodin and cosolvent, and then uniformly mixed.
  • the preparation method of the above-described seletanolactone comprises the following steps:
  • a step-by-step separation product of the Chuanxi lactone of the step (6) or a second-stage separation product of the Chuanxiong lactone or a mixture of the two products is added in an amount of 3 to 7 ml of petroleum ether: ethyl acetate (95: 5).
  • step (7) Repeat step (7) to sequentially elute the grade I and / or II separation products.
  • step (8) The eluate of step (8) is rotary evaporated in a water bath at 30 to 40 ° C to remove the solvent, thereby obtaining a primary purified product of seletanolactone;
  • the above extract was rotary evaporated in a water bath at 30 to 40 ° C to remove the solvent to obtain a cearyl lactone.
  • the preparation method of the artemisinone comprises the following steps:
  • Step (1) ⁇ (6) The same as the preparation method of the synthion lactone (1) ⁇ (6);
  • the solvent is removed by rotary evaporation in a water bath of 30 to 40 ° C, and the obtained product is artemisinide.
  • the supercritical carbon dioxide extraction tank described in the above preparation method step (1) may be
  • the gastrodin can be purchased directly from the market, such as gastrodin or acetyl gastrodin produced by Kunming Pharmaceutical Group Co., Ltd.
  • the active constituents extracted and purified by the method of the present invention have a purity of 98% or more.
  • the commercially available gastrodin or acetyl gastrodin
  • Correction page (fine 4 , rule 91)
  • the invention has the advantages and beneficial effects: (1) high drug efficacy, can effectively alleviate the pathological changes and behavioral disorders of ischemic stroke, and the drug effect is obviously better than the existing clinical drugs; (2) the pharmaceutical composition of the invention has exact efficacy , the dosage is small, the action is strong; (3) the purity is high, the components of the pharmaceutical composition of the invention are all pure, the purity is above 98%, and the preparation can be prepared including the injection; (4) the stability is good, The process of the invention reaches the level of the preparation standard; (5) The invention indicates that the chemical property of the cyanuric acid lactone is more stable than that of the artemisinol, and is more suitable as a monitoring index for the quality of the Chuanxiong oil product.
  • Figure 1 is a preparative spectrum of the artemispermide and the selenate lactone product isolated from the supercritical extract (forward HPLC method) (where QHNP-1 is artemisinide; QHNP-2 is in the seletanic acid) Ester)
  • Figure 2 shows the detection spectrum of artemisinide (reverse HPLC detection)
  • FIG. 3 shows the preparative spectrum of the primary purified product of seledanolactone (reverse HPLC method)
  • Figure 4 shows the detection spectrum of the final purified product of the seledanolactone (reverse HPLC detection).
  • Figure 5 shows the infrared identification spectrum of the seledanolide.
  • Figure 6 shows the infrared identification spectrum of artemisinide
  • Figure 7 shows the UV identification spectrum of the seletanide.
  • FIG 8 shows the UV identification spectrum of artemisinide
  • Figure 9 shows the mass spectrometric spectrum of the seletanide
  • Figure 10 shows the mass spectrometric spectrum of artemis lactone
  • Figure 11 shows the nuclear magnetic resonance spectrum of threonolactone (hydrogen spectrum)
  • Figure 12 shows the nuclear magnetic resonance spectrum of artemisinide (hydrogen spectrum)
  • Figure 13 shows the nuclear magnetic resonance spectrum of threonolactone (carbon spectrum)
  • Figure 14 shows the nuclear magnetic resonance spectrum of artemisinide (carbon spectrum)
  • step (10) Aspirate 5 ml of methanol from the product of step (9) and dissolve it into Shimadzu LC-8A reverse phase preparative liquid phase system; the column is Phenomenex Luna ⁇ , 250 mm 50 mm ID, and the mobile phase is A water B methanol.
  • the preparation of artemisinone comprises the following steps - (1) Weighing 30 kg of dried roots of Chuanxiong, pulverizing to particles of diameter 3, placed In the extraction tank of HA221-40-48;
  • Step (4) ⁇ (7) Same as step (4) of Example 2 ⁇ (7);
  • the cetyl lactones prepared in Examples 1 to 3 were collected in an amount of 4.2 g, ligustilide 1. Og (specific gravity 0.95, the same hereinafter), and gastrodin 0.6 g, To 20 g of pure olive oil, ultrasonically mixed uniformly to obtain a composition A 25.8 g of the present invention.
  • Example 5 0.6 g of cearyl lactone, 1.8 g of ligustilide, and 0.75 g of gastrodin were respectively added to 20 g of soybean oil, and ultrasonically mixed uniformly to obtain 23.15 g of the composition B of the present invention.
  • Example 7 - 2.8 g of cearyl lactone, 1.2 g of artemisinide, 0.08 g of gastrodin, respectively, and 0.5% sodium carboxymethylcellulose to 21.6 ml were added to obtain the composition D 25.68 of the present invention.
  • g. Taking propanol lactone 1.4g, ligustilide 3.0g, and gastrodin 0. l g , added to 2% sodium carboxymethylcellulose to 20ml, and ultrasonically mixed uniformly, the composition E 25.5g of the present invention was obtained. . Determined by high performance liquid chromatography (see Appendix VI of the Chinese Pharmacopoeia 2005 edition).
  • Preparation of the test solution Take the appropriate amount of the cetanolactone obtained in Example 1, accurately weighed, dissolved in methanol and quantitatively diluted to prepare a solution containing 0.08 mg per 1 ml, as a testosterone lactone for the test sample. Solution.
  • the measurement method is as follows: 10 ul of each of the standard sample of the seletanolactone and the test solution is accurately extracted, and injected into a liquid chromatograph, and the method can be determined according to the method described in the step (13) of the first embodiment.
  • test solution The appropriate amount of ligustilide obtained in Example 3 was accurately weighed, dissolved in methanol and quantitatively diluted to prepare a solution containing 0.4 mg per 1 ml, which was used as a sample solution for ligustilide.
  • the stability of the ligustilide of the present invention is mainly affected by light, temperature and oxidation; the purity falls from 98% to less than 95% after being placed at room temperature for 10 days. It is indicated that the ligustilide standard must be stored under nitrogen, light, refrigerated or frozen conditions. Must be freshly prepared. The amount of preparation per time does not exceed 5 days.
  • test method is carried out as follows:
  • the positive drug was selected from the traditional western medicine Mailuoning injection (lOrnl/branch, Jinling Pharmaceutical Co., Ltd. Nanjing Jinling Pharmaceutical Factory, batch number: 200503011) for clinical treatment of ischemic stroke.
  • the blank control group and the model control group were intraperitoneally injected with an equal volume of normal saline.
  • the preparation of the wire plug a nylon wire having a diameter of 0.23 mm made in Japan is formed into a straight line and cut into a 5 cm line segment, the front end is smoothed with a fine sandpaper, and the rubber is smoothed, at a distance of 1. 6 cin from the front end. 1. 8cm, 2. 0cm for labeling and spare, the helixin is taken from the front end of the nylon wire.
  • Model replication 400mg/kg intraperitoneal injection of 10% chloral hydrate anesthesia; neck median incision, exposure of the left common carotid artery (referred to as CCA), external carotid artery (ECA), internal carotid artery (referred to as ICA Ligation of the proximal end of the CCA, ECA root; at the end of the CCA ligation, cut a slant, insert a nylon thread, through the CCA bifurcation through the ICA into the cerebral artery (ACA), block the blood flow of MCA; The average insertion depth of the silk is 18. 5 ⁇ 0. 5 legs, ligation of ICA. The skin was sutured and the ends of the nylon filaments were exposed. After 2 hours of ischemia, the nylon filaments were pulled out to observe changes in different time courses after reperfusion; the sham operation group was not inserted with nylon filaments.
  • Neurobehavioral score A five-point scale (0-4 points) was used. Behavioral observations of animals were performed at the end of reperfusion. The rat tail was about 1 foot away from the ground, and the condition of the two forelimbs was observed. The rats were placed on the horizontal ground, and their shoulders were pushed to observe whether there was any difference in resistance between the two sides; the rats were placed on the ground to observe the walking. The higher the score, the more severe the neurobehavioral damage. (by the highest score)
  • Cerebral infarction volume (%) (the volume of the contralateral hemisphere of the operation - the uninfarcted part of the surgical side hemisphere Volume) I volume of the contralateral hemisphere X 100%
  • Brain water content is calculated according to the following formula:
  • Brain water content (wet weight to dry weight) / wet weight X 100 %
  • compositions A and B The three groups of pharmaceutical compositions A and B, and the positive drug group of the present invention all improved the area of focal cerebral ischemia and infarction in the middle cerebral artery of rats. Among them, the large dose of composition B (12mg/kg body weight) is the best, and the drug effect is better than the commonly used clinical drug Mailuoning injection. It is indicated that the pharmaceutical composition of the present invention can be used for treating ischemic stroke and reducing the area of cerebral infarction.
  • Grouping and administration 78 healthy male SD rats of 20 0 to 220 g were randomly divided into 6 groups, which were a normal control group, a model group, a positive control drug ligustrazine group, and Examples 4 to 6 of the present invention.
  • the positive control drug ligustrazine group is selected from the group consisting of ligustrazine phosphate tablets, 50 mg/tablet, 100 tablets/bottle, produced by Beijing Yanjing Pharmaceutical Factory, batch number: 040603.
  • the normal control group and the model group were given the same amount of normal saline.
  • results (see Table 4)
  • the oral administration of the three groups of pharmaceutical compositions A, B and C of the present invention and the positive drug group can improve the area of focal cerebral ischemia infarction of the middle cerebral artery in rats for 7 days;
  • the pharmacological effects of the three groups of B, C and C were significantly better than those of the commonly used clinical drug, Ligustrazine. It is indicated that the pharmaceutical composition of the invention can prevent and treat ischemic stroke and reduce the area of cerebral infarction.
  • the drug effect was significantly better than that of the commonly used clinical drug, Ligustic Acid Pyridazine (P ⁇ 0.01).
  • Grouping and administration 110 healthy male SD rats weighing 180 to 200 g were randomly divided into 9 groups according to body weight.
  • Oral administration once a day for 30 consecutive days, the blank group and the model control group were given an equal volume of edible oil.
  • mice of the pharmaceutical composition of the present invention Acute toxicity test of mice of the pharmaceutical composition of the present invention
  • the SPF Kunming mice were used for oral administration once.
  • the pretest result is the test dose, and the agent distance is 1:0.90.
  • the preparation method of the drug solution is as follows: Accurately weigh 2.601 g of seletanolactone, 2.502 g of artemispermide, and 0.7502 g of gastrodin, mix well and add appropriate amount of 2% sodium carboxymethylcellulose to dissolve the solution. A solution having a concentration of 0.0575 g/g was prepared; each dose was diluted with an aqueous solution of 2% sodium carboxymethylcellulose as shown in Table 7, and 0.8 ml was orally administered per 20 g of body weight; continuous observation was carried out for 48 hours.
  • the animals were randomly divided into 9 groups according to the body weight after fasting for 16 hours, 20 rats in each group, half male and half female; the distance between the groups was 1:0.9; the above-mentioned different concentrations of the test substances were administered by 0.8ml/20g.
  • the toxic reaction of each group of animals after administration of the test substance was immediately observed for 48 hours. Record the animal's toxicity and death.
  • Oral LD 5 was calculated in mice using the Bilss method. Dosage and 95% confidence limits.
  • the results show oral administration of LD 5 to mice of the pharmaceutical composition of the present invention.
  • the value is 0.7276 g /k g; LD 5 .
  • the 95% average confidence limit is 0, 7276 ⁇ 0.0470 g /k g (range: 0.6806-0.7746 g/kg); LD 5 .
  • the 99% average confidence limit is 0.7276 ⁇ 0.0616 g / kg (range: 0.6660-0 ⁇ 7892 g / kg).
  • the inter-group distance was 1:0.9.
  • This test is an acute toxicity test for chemical grade pure products. The results indicate that the pharmaceutical compositions of the present invention are safe and provide valuable reference data for clinical dosages.

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Abstract

L'invention porte sur une composition de médicament pour le traitement et la prévention d'un accident ischémique cérébral et sur ses procédés de préparation. La composition de médicament consiste en 19-72 % de Sédanolide, 17-67 % de Ligustilide, 2-29 % de Gastrodine et un solvant. Elle a une pureté élevée de plus de 98 %. La composition de médicament peut être préparée sous différentes formes de médicaments, comprenant une injection, et elle peut soulager de manière efficace les symptômes de la maladie.
PCT/CN2008/000349 2008-02-14 2008-02-14 Composition de médicament pour le traitement et la prévention d'un accident ischémique cérébral et ses procédés de préparation Ceased WO2009100587A1 (fr)

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PCT/CN2008/000349 WO2009100587A1 (fr) 2008-02-14 2008-02-14 Composition de médicament pour le traitement et la prévention d'un accident ischémique cérébral et ses procédés de préparation
CN2008800014789A CN101677989B (zh) 2008-02-14 2008-02-14 一种防治缺血性脑卒中的药物组合物及其制备方法

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PCT/CN2008/000349 WO2009100587A1 (fr) 2008-02-14 2008-02-14 Composition de médicament pour le traitement et la prévention d'un accident ischémique cérébral et ses procédés de préparation

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102626390A (zh) * 2012-04-19 2012-08-08 海南灵康制药有限公司 一种天麻素多相脂质体注射液
CN102688184A (zh) * 2012-05-15 2012-09-26 清华大学 改善大鼠血液流变障碍用的含有麻黄碱注射液的制备方法
CN102698089A (zh) * 2012-05-15 2012-10-03 清华大学 防治脑缺血用的含有麻黄碱提取物的口服液的制备方法
CN104415044A (zh) * 2013-08-30 2015-03-18 陈震 一种治疗中风及其后遗症的药物组合物及其制剂

Families Citing this family (1)

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CN102688253A (zh) * 2012-05-15 2012-09-26 清华大学 改善脑缺血用的含有麻黄碱的注射液的制备方法

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004017983A1 (fr) * 2002-08-20 2004-03-04 National University Of Singapore Procede de preparation d'extraits phytoprogestogeniques du rhizome de ligusticum chuanxiong et leurs utilisations
CN1559417A (zh) * 2004-03-05 2005-01-05 嵩 张 天麻素静脉注射液及其制备方法
CN1569848A (zh) * 2003-07-14 2005-01-26 中国中医研究院中药研究所 治疗缺血性心脏病的川芎内酯及其制备方法
CN1572310A (zh) * 2003-06-11 2005-02-02 山东绿叶天然药物研究开发有限公司 一种川芎挥发油软胶囊及其制备方法
CN1857622A (zh) * 2006-03-30 2006-11-08 欧苏 包含天麻和川芎有效成分的药物组合物及制剂
CN1883661A (zh) * 2006-05-31 2006-12-27 本溪市中心医院 大川芎干粉制剂及制备方法和用途
WO2007038610A2 (fr) * 2005-09-26 2007-04-05 President & Fellows Of Harvard College Utilisation de produits naturels pour le traitement de troubles neurologiques
CN1977839A (zh) * 2005-12-05 2007-06-13 江西青峰药业有限公司 一种治疗脑血管疾病的药物组合物及其制备方法
CN101015552A (zh) * 2006-12-29 2007-08-15 天津大学 一种川芎内酯提取物及其制备方法和应用

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004017983A1 (fr) * 2002-08-20 2004-03-04 National University Of Singapore Procede de preparation d'extraits phytoprogestogeniques du rhizome de ligusticum chuanxiong et leurs utilisations
CN1572310A (zh) * 2003-06-11 2005-02-02 山东绿叶天然药物研究开发有限公司 一种川芎挥发油软胶囊及其制备方法
CN1569848A (zh) * 2003-07-14 2005-01-26 中国中医研究院中药研究所 治疗缺血性心脏病的川芎内酯及其制备方法
CN1559417A (zh) * 2004-03-05 2005-01-05 嵩 张 天麻素静脉注射液及其制备方法
WO2007038610A2 (fr) * 2005-09-26 2007-04-05 President & Fellows Of Harvard College Utilisation de produits naturels pour le traitement de troubles neurologiques
CN1977839A (zh) * 2005-12-05 2007-06-13 江西青峰药业有限公司 一种治疗脑血管疾病的药物组合物及其制备方法
CN1857622A (zh) * 2006-03-30 2006-11-08 欧苏 包含天麻和川芎有效成分的药物组合物及制剂
CN1883661A (zh) * 2006-05-31 2006-12-27 本溪市中心医院 大川芎干粉制剂及制备方法和用途
CN101015552A (zh) * 2006-12-29 2007-08-15 天津大学 一种川芎内酯提取物及其制备方法和应用

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CAO JIANMIN ET AL.: "Study on extraction and separation method for lactone components in Chuanxiong", ANALYTICAL LABORATORY, vol. 24, no. 9, September 2005 (2005-09-01), pages 59 - 62 *
HU C. ET AL.: "Extraction, Isolation and Structure Identification ofLigustilide from Angelica sinensis", JOURNAL OF WUXI UNIVERSITY OF LIGHT INDUSTRY, vol. 22, no. 5, September 2003 (2003-09-01), pages 69 - 71 *
WU GUANGTONG ET AL.: "The determination of ligustilide in ligusticum chuanxiong hort. By supercritical fluid extraction", ACTA PHARMACEUTICA SINICA, vol. 33, no. 6, 1998, pages 457 - 460 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102626390A (zh) * 2012-04-19 2012-08-08 海南灵康制药有限公司 一种天麻素多相脂质体注射液
CN102626390B (zh) * 2012-04-19 2013-05-29 海南灵康制药有限公司 一种天麻素多相脂质体注射液
CN102688184A (zh) * 2012-05-15 2012-09-26 清华大学 改善大鼠血液流变障碍用的含有麻黄碱注射液的制备方法
CN102698089A (zh) * 2012-05-15 2012-10-03 清华大学 防治脑缺血用的含有麻黄碱提取物的口服液的制备方法
CN104415044A (zh) * 2013-08-30 2015-03-18 陈震 一种治疗中风及其后遗症的药物组合物及其制剂
CN104415044B (zh) * 2013-08-30 2018-10-16 陈震 一种治疗中风及其后遗症的药物组合物及其制剂

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