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WO2009076869A1 - Acide salvianolique de grande pureté, son procédé de préparation et son utilisation - Google Patents

Acide salvianolique de grande pureté, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2009076869A1
WO2009076869A1 PCT/CN2008/073365 CN2008073365W WO2009076869A1 WO 2009076869 A1 WO2009076869 A1 WO 2009076869A1 CN 2008073365 W CN2008073365 W CN 2008073365W WO 2009076869 A1 WO2009076869 A1 WO 2009076869A1
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WO
WIPO (PCT)
Prior art keywords
salvianolic acid
acid
injection
water
purity
Prior art date
Application number
PCT/CN2008/073365
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English (en)
Chinese (zh)
Inventor
Lichao Yuan
Original Assignee
Lichao Yuan
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from CN2007101447883A external-priority patent/CN101450051B/zh
Priority claimed from CN2008101368138A external-priority patent/CN101638405B/zh
Priority claimed from CN200810136811A external-priority patent/CN101638403A/zh
Application filed by Lichao Yuan filed Critical Lichao Yuan
Publication of WO2009076869A1 publication Critical patent/WO2009076869A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/86—Benzo [b] furans; Hydrogenated benzo [b] furans with an oxygen atom directly attached in position 7
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to a method for extracting and isolating salvianolic acid B from Chinese herbal medicine Salvia miltiorrhiza and a pharmaceutical composition of salvianolic acid B.
  • Salvianolic acid B is a water-soluble phenolic acid isolated from Salvia miltiorrhiza. Its molecular formula is
  • the method for extracting and separating salvianolic acid B in the prior art is to pulverize the medicinal material into a powder or a microwave to break or to extract or decoct, and further obtain the method by macroporous adsorption resin, polyamide chromatography or the like.
  • the disadvantage of the prior art is that the obtained salvianolic acid B has a purity of 92%, and the steps of obtaining more than 92% of salvianolic acid B are very high, the cost is very high, and it cannot be used for industrial production, and the part other than the active ingredient The ingredients are not clear and are prone to side effects.
  • the new preparation method of salvianolic acid B the obtained salvianolic acid B, has high purity and is suitable for industrial production.
  • a method for preparing high-purity salvianolic acid B, the composition thereof comprising: extraction,
  • the polyamide is chromatographed and collected to prepare a pharmaceutical preparation.
  • the extraction is carried out by pulverizing the Chinese medicinal material Salvia miltiorrhiza, and extracting with water at a pH of -1 to 7.0, the polyamide chromatography is first water and PH1-4.8 ⁇ The alcohols are deodorized separately, then desorbed with a lower alcohol of pH 1-4.8, and the components of greater than 98% salvianolic acid B are collected, concentrated under reduced pressure, adjusted to a pH of 3.5-6.5, and the extract is immediately filtered through a glucan gel column. , fractionally collect components containing salvianolic acid B, decompression Concentrated, lyophilized to give salvianolic acid 8 with a purity greater than 98%.
  • the extraction the first time, under the condition of 100 ° of deionized water, the smashed salvia miltiorrhiza is extracted under the condition of PH1-7.0 for 1 hour, and the weight of the salvia miltiorrhiza is 6 times the amount of water, and then the 2--- 4 times, 60 minutes each time, using 8 times the weight of Salvia miltiorrhiza; the extract is adjusted to PH1-4.8;
  • the polyamide chromatography is carried out by filtering the supernatant onto the polyamide column, first removing the impurities with water, and then removing the impurities with a C1-C5 lower alcohol having a cesium concentration of PH1-4.8, to a high concentration of C1-C5 of PH1-4.8.
  • Desorption of lower alcohol fractionally collect components of salvianolic acid B with a purity greater than 98%, concentrate under reduced pressure, and adjust pH to 3.5-6.5;
  • the C1-C5 lower alcohol is ethanol, the low concentration C1-C5 lower alcohol concentration is 10-80%, and the high concentration C1-C5 lower alcohol concentration is 80-99.99%
  • the pH adjusting substance is an inorganic acid or an organic acid or an acidic amino acid or a mixture thereof, or sodium hydroxide or sodium carbonate or sodium hydrogencarbonate
  • the salvianolic acid B injection prepared by the high-purity salvianolic acid B obtained by the above method comprises the following components: salvianolic acid B, pharmacological pH adjusting substance, stabilizer, excipient, and salvianolic acid B Concentration: lyophilized powder injection salvianolic acid B content is 2mg-400mg per branch, 3mg-1300mg per dry matter, the pH adjusting substance is adjusted to a pH of 2.5 to 6.5 ,, shaping The amount of the agent added is 0.05-0.7 g per branch, and the stabilizer is added in an amount of 10-800 mg per one.
  • the pH adjusting substance inorganic acid is hydrochloric acid, phosphoric acid, citric acid, wine Tritic acid, maleic acid, acidic buffer salt; acidic amino acids are L-lysine, L-leucine, L-glutathione
  • the stabilizer is disodium edetate, sodium edetate, sodium hydrogen sulfite, vitamin C, D-isoascorbic acid, L-cysteine Hydrochloride or nitrogen.
  • Salvianolic acid B is dissolved in the above solution, and 0.5-7 g of excipient is added.
  • 0.5% injection activated carbon 60 0.5% injection activated carbon 60. c Stir for 20 minutes, then filter, then make up the water for injection to 10-60ml, and make 10 pieces of film through 0.22 m, fill in the vial, freeze-dry by freeze-drying process.
  • a high-purity salvianolic acid B prepared by the method for the preparation of a medicinal solid preparation for treating cardiovascular and cerebrovascular diseases, liver diseases, tablets, capsules, and granular medicines.
  • the drug containing salvianolic acid B is present in the traditional Chinese medicine composition, and the content of the crude crude salvianolic acid B is generally below 80%, and the remaining 20% of the components are unclear.
  • the quality of the products caused by clinical application is unstable, the side effects are large, and it is easy to cause adverse reactions.
  • the purity of the salvianolic acid B monomer extracted from the plant is high, the effective pharmaceutical ingredient is clarified, the toxic and side effects are reduced, and a feasible way for the western medicine production of salvianolic acid B is provided.
  • the solvent used in the present invention is inexpensive, substantially non-toxic, and reduces the cost of the drug.
  • the process is simple, the equipment investment is small, the obtained salvianolic acid B has high purity, and the determined process route is suitable for industrial production.
  • the pharmaceutical preparation prepared by the invention has clear composition, controllable quality, good stability and small side effects, and is suitable for clinical use.
  • the final product of the present invention is a chemical injection prepared from a salvianolic acid B monomer, which has the characteristics of high purity, high pharmacological activity, less impurities, and side effects, and is more clinically useful than the corresponding traditional Chinese medicine compound preparation. Advantage.
  • L-Lysine Calcium edetate: Sodium bisulfite: Mannitol is 50: 25:1: 1:200.
  • the clinical dose of salvianolic acid B is 100 mg per intravenous injection, calculated as 70 kg body weight, 1.43 m g per kg, according to the above powder injection. the conversion ratio of salvianolic acid B, so that the dose per kg of taken Di 15m g, high doses of 45 kg and 150m g.
  • the positive reference substance is injected with Danshen powder needle (produced by Harbin Pharmaceutical Group Co., Ltd.).
  • the recommended dose is 400m g per day, the corresponding dose is 5.7m g per kg, and the dose of dog is 10m g per kg.
  • Positive control drug The dose is equivalent to the medium dose of the test drug, so it is 30m g per kilogram; the other positive control drug is injected with diltiazem hydrochloride powder (produced by Harbin Shengtai Pharmaceutical Co., Ltd.) at a dose of 0.5m g per kilogram.
  • the limbs are connected via the needle electrode 30.
  • the multi-conductivity switch was connected to a physiological recorder to record a 30-point outer membrane electrocardiogram.
  • the epicardial electrogram was scaled to 1 mm per mv and the recording speed was lk per second. Har Harris two-step ligation: 2 minutes before the first ligation, injection of lidocaine from the femoral vein 5m g per kg to prevent arrhythmia.
  • a lmm diameter wire was inserted into the first loose knot after ligation, the wire was ligated with the coronary artery, and the wire was withdrawn.
  • the second knot was completely ligated after 30 minutes.
  • the epicardial electrogram of lOm i after complete ligation was recorded as the pre-medication control value, and then the drug was injected from the femoral vein, the injection was performed for 1 minute, and the negative control group was injected with the same volume of physiological saline. Changes in epicardial electrograms were recorded at 10 min, 30 min, 60 min, 90 min, 120 min, and 180 min after dosing. Epicardial electrogram observation showed that the number of leads (N-ST) above the ST segment increased by 2 mV and the increase in ST segment elevation were used as indicators to observe changes before and after administration, and the degree and extent of myocardial ischemia were calculated.
  • the measured values of different daytimes after treatment were compared with those before administration, and the percentages of changes between different days after administration (100% before administration) were compared between groups.
  • After ligation for 3 hours take the heart and weigh the whole heart; cut off the atrium and right ventricle, weigh the left ventricle, and cut the left ventricle into equal thickness parallel to the coronary sulcus under the coronary ligature.
  • the tablets were washed with physiological saline and stained with 0.05% nitrotetrazolium chloride solution for 37 minutes at 37 degrees. During the staining process, the staining solution is shaken to make it fully contact with the myocardium.
  • the infarcted area was not stained, the non-infarcted area was dark blue, the stained part was cut, the uncolored infarcted area was weighed, and the infarct area was calculated to account for the whole heart and the left ventricle. percentage.
  • the 15, 30, and 150 mg groups were 27.4 ⁇ 6.3% lower than Ornin, respectively.
  • Salvianolic acid B powder can reduce the range of myocardial ischemia in a dose-dependent manner and reduce the N-ST value for 180 min.
  • the myocardial ischemia range of the injection of salvia miltiorrhiza and the diltiazem hydrochloride group was significantly lower than that of the normal saline group (P ⁇ 0.05).
  • Salvianolic acid B powder injection can reduce the range of myocardial infarction dose-dependently in an intravenous dose of 15-150 mg per kg.
  • the ratio of the infarct area to the whole heart and the ratio of the infarct area to the left ventricle were significantly lower than those in the saline group (P ⁇ 0.05).
  • the medium and high dose group 45 kg per kg
  • the ratio of 150 mg) decreased significantly (P ⁇ 0.01).
  • the positive control group with salvia miltiorrhiza injection and diltiazem hydrochloride for injection significantly reduced the range of myocardial infarction (P ⁇ 0.01).
  • the myocardial infarction area was significantly reduced, which proved that the intravenous injection of salvianolic acid B powder had a significant therapeutic effect on myocardial infarction caused by coronary artery ligation in dogs.
  • the results of this experiment also showed that salvianolic acid B powder injection can significantly reduce the ratio of serum LDH and reduce the LDH overflow of acute ischemic cardiomyocytes, indicating that the powder injection has protective effect on cardiomyocytes.
  • the main component of the sample of salvianolic acid B powder used in the test is salvianolic acid B: L-lysine: sodium calcium edetate: sodium hydrogen sulfite: mannitol is 50: 25:1: 1: 200.
  • the rats in the gavage group were intragastrically administered once a day for 3 consecutive days; the other groups were administered intravenously, and the sham-operated control group and the cerebral ischemia model group were given normal saline.
  • the rat middle cerebral artery occlusion (MCAO) model was prepared by the method of Longa et al. Rats were anesthetized with 10% hydrated trichloroacetaldehyde (300 mg/kg) ⁇ , a median incision in the neck of the supine thermostatic operating table, exposed to the right common carotid artery, outward traction of the abdominal muscles and sternocleidasis L.
  • the bifurcation of the common carotid artery is released to the head end in turn, and the branch of the external carotid artery is ligated and shortened: the suboccipital artery and the superior thyroid artery are ligated at the distal end of the external carotid artery, the external carotid artery is cut off, the trunk is freed, and then separated.
  • the internal carotid artery was wound with a silk thread at the base of the external carotid artery, and the common carotid artery and internal carotid artery were clamped. The nylon thread was incision through the main carotid artery, and slowly pushed into the internal carotid artery into the cranial direction.
  • the carotid artery bifurcation was used as a marker, and the resistance was felt after pushing about 20 mm, that is, the thinner brain was reached.
  • all sources of blood supply to the MCA were blocked, and the roots of the external carotid artery were tightened. After 1 hour, pull out the nylon thread and tighten the artery stump. The skin was sutured and the MCAO resulted in a focal cerebral ischemia-reperfusion model. After anesthesia in the sham-operated rats, only the internal and external carotid arteries were exposed, and MCA was not occluded.
  • Level 0 No neurological symptoms were observed.
  • Level 1 The tail is suspended, and the opposite side of the animal's operation shows flexion of the wrist and elbow, internal rotation of the shoulder, elbow abduction, and close to the chest wall.
  • Level 2 Place the animal on a smooth surface, push the side of the operation to the opposite side, and the resistance will drop.
  • Level 3 animals are free to walk or turn to the opposite side of the surgery.
  • Level 4 Soft palate, no physical activity of the limbs.
  • Salvianolic acid B powder can reduce the infarct size of rats with focal cerebral ischemia and improve the nerves caused by cerebral ischemia in rats Behavioral disorder. It can increase serum SOD activity and reduce MDA content. It can alleviate the pathological damage of brain tissue in rats with cerebral ischemia. It has a certain protective effect on cerebral ischemia and hypoxia in rats.
  • Fig. 1 is a structural formula of a danfenic acid B of the present invention.
  • the fraction of phenolic acid B was collected in sections with a purity greater than 98.5%, concentrated under reduced pressure, and adjusted to pH 4.8.
  • the concentrated solution is filtered through a glucan gel column, and the fraction having a purity greater than 98.5% is collected in stages, concentrated under reduced pressure, and lyophilized to obtain a high purity dansyl.
  • Example 13 The concentrated solution was passed through a Sephadex column, and the fraction having a purity greater than 98.5% was collected in stages, concentrated under reduced pressure, and immediately freeze-dried to obtain salvianolic acid 8 having a purity of 98.3%.
  • Example 16 All steps were adjusted to ⁇ 1 - 6.5 with a pH adjusting substance.
  • the preparation process comprises the following steps: taking 0.01 g of sodium hydrogen sulfite dissolved in 15 ⁇ water for injection, adding disodium edetate 10 ⁇ g , vitamin C 0.05 g, dissolving and mixing, and then taking salvianolic acid B.
  • O. lg is dissolved in the above solution, and then added with mannitol 1.0 g, and an appropriate amount of dilute hydrochloric acid solution is added to adjust pH 2.5, and then 0.01% of activated carbon 60 is added. c Stir for 20 minutes, then filter, then make up the injection water to 15ml and make a 0.22 m m film, fill it in a vial and freeze it by lyophilization.
  • the membrane is made into 10 pieces and filled in a vial and lyophilized according to the freeze-drying process.
  • Example embodiments of the injection 17 of salvianolic acid B, sodium-hydrogen sulfite 0.02 g, EDTA ON 20m g, L- lysine 0.5 g are dissolved in water for injection 25mr, then salvianolic Acid B
  • Example 22 Lg was dissolved in the above solution, 4.0 g of mannitol was added, and the pH was adjusted to 4.0 with an appropriate amount of citric acid solution, and 0.3% of activated carbon 60 was added. c Stir for 20 minutes, add water to the full amount of 30 ml, and pass through a 0.22 mm film to make 10 pieces. Fill in a vial and freeze-dry according to the freeze-drying process.
  • Membrane filtration make up the injection water to the full amount of 50ml, make 10 pieces, fill it in the vial and freeze it by freeze-drying process.
  • Example injection salvianolic acid B 17 take sodium hydrogen sulfite 0.04 g, EDTA ON 20m g, D- isoascorbic acid 0.5 g dissolved in water for injection 40 ⁇ , then Sal B
  • Membrane filtration make up the injection water to the full amount of 100ml, make 10 pieces, fill it in the vial and freeze it by freeze-drying process.
  • Salvianolic acid B tablets the preparation process is: salvianolic acid B 500g, sodium bisulfite 5 g ,
  • Salvianolic acid B capsule the preparation process is: salvianolic acid B 400g, sodium bisulfite 4 g , Fu L sugar

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines Containing Plant Substances (AREA)

Abstract

L'invention concerne l'acide salvianolique, son procédé de préparation et son utilisation. Les insuffisances des arts antérieurs reposent sur le fait que la pureté de l'acide salvianolique B obtenu est inférieure à 92 %. Pour obtenir de l'acide salvianolique B dont la pureté est supérieure à 92 %, de nombreuses étapes sont nécessaires et le coût est très élevé, ce qui ne rend donc pas possible son utilisation en vue d'une production industrielle. Le présent procédé inclut : l'extraction, la chromatographie sur polyamide, le recueil, la transformation en préparations pharmaceutiques. Ladite extraction consiste au broyage de la sauge, substance médicinale chinoise, à l'extraction avec de l'eau dans des conditions de pH de 1,7 à 0. Ladite chromatographie sur polyamide consiste en premier lieu à la suppression des impuretés avec de l'eau et un alcool inférieur, puis à l'élution avec un alcool inférieur, au recueil des constituants de l'acide salvianolique B dont la pureté est supérieure à 98 %, à la concentration sous vide, à l'ajustement de la valeur de pH à 1 à 6,5, à la filtration immédiate de l'éluant avec une colonne de gel sephadex, au recueil des constituants contenant l'acide salvianolique B par sections, à la lyophilisation, à l'obtention de l'acide salvianolique B dont la pureté est supérieure à 98 %. LE présent produit peut être utilisé comme substance destinée à la préparation de préparations pharmaceutiques pharmaceutiquement acceptables.
PCT/CN2008/073365 2007-12-07 2008-12-05 Acide salvianolique de grande pureté, son procédé de préparation et son utilisation WO2009076869A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
CN2007101447883A CN101450051B (zh) 2007-12-07 2007-12-07 单体丹酚酸b注射剂及其制备方法
CN200710144788.3 2007-12-07
CN2008101368138 2008-07-29
CN2008101368119 2008-07-29
CN2008101368138A CN101638405B (zh) 2008-07-29 2008-07-29 高纯度丹酚酸b、制备方法及应用
CN200810136811A CN101638403A (zh) 2008-07-29 2008-07-29 高纯度丹酚酸b、制备方法及应用

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WO2009076869A1 true WO2009076869A1 (fr) 2009-06-25

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Cited By (5)

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CN102335146A (zh) * 2010-07-19 2012-02-01 上海医药工业研究院 一种可注射用药用组合物及制备方法
CN108057038A (zh) * 2018-02-24 2018-05-22 上海中医药大学附属曙光医院 一种治疗肝纤维化的组合物及其应用
CN112870332A (zh) * 2016-04-12 2021-06-01 浙江艾杰斯生物科技有限公司 一种含有溶菌酶的治疗脂肪肝的片剂
CN114573455A (zh) * 2020-12-01 2022-06-03 江西青峰药业有限公司 一种丹酚酸a的制备方法
CN114848606A (zh) * 2019-08-23 2022-08-05 惠州市九惠制药股份有限公司 一种丹酚酸b及其粉雾剂胶囊和制备方法

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CN1508133A (zh) * 2002-12-13 2004-06-30 中国医科大学 丹参抗消化性溃疡有效部位及其制备工艺
CN1876641A (zh) * 2006-07-13 2006-12-13 大连理工大学 一种提取纯化丹酚酸b的方法

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CN1508133A (zh) * 2002-12-13 2004-06-30 中国医科大学 丹参抗消化性溃疡有效部位及其制备工艺
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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102335146A (zh) * 2010-07-19 2012-02-01 上海医药工业研究院 一种可注射用药用组合物及制备方法
CN112870332A (zh) * 2016-04-12 2021-06-01 浙江艾杰斯生物科技有限公司 一种含有溶菌酶的治疗脂肪肝的片剂
CN112870332B (zh) * 2016-04-12 2023-11-07 浙江艾杰斯生物科技有限公司 一种含谷胱甘肽的治疗脂肪肝的药物组合物
CN108057038A (zh) * 2018-02-24 2018-05-22 上海中医药大学附属曙光医院 一种治疗肝纤维化的组合物及其应用
CN114848606A (zh) * 2019-08-23 2022-08-05 惠州市九惠制药股份有限公司 一种丹酚酸b及其粉雾剂胶囊和制备方法
CN114848606B (zh) * 2019-08-23 2023-10-31 惠州市九惠制药股份有限公司 一种丹酚酸b及其粉雾剂胶囊和制备方法
CN114573455A (zh) * 2020-12-01 2022-06-03 江西青峰药业有限公司 一种丹酚酸a的制备方法

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