WO2018133112A1 - Ziyuglycogenin injection, preparation method therefor and use thereof - Google Patents

Ziyuglycogenin injection, preparation method therefor and use thereof Download PDF

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WO2018133112A1
WO2018133112A1 PCT/CN2017/072232 CN2017072232W WO2018133112A1 WO 2018133112 A1 WO2018133112 A1 WO 2018133112A1 CN 2017072232 W CN2017072232 W CN 2017072232W WO 2018133112 A1 WO2018133112 A1 WO 2018133112A1
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injection
aglycone
mantle
group
drug
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PCT/CN2017/072232
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French (fr)
Chinese (zh)
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杨世林
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四川英路维特医药科技有限公司
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/56Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44Oils, 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/08Solutions
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00Drugs for disorders of the blood or the extracellular fluid
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06Antianaemics

Definitions

  • the invention relates to a diterpene aglycone injection, a preparation method thereof and use thereof, and belongs to the field of medicine.
  • Myelosuppression is a clinically common hematopoietic disease that can occur in radiation therapy and/or chemotherapy of various systemic neoplastic diseases, radiation damage caused by ionizing radiation, viral hepatitis, parvovirus infection or drugs (chloramphenicol). , benzene, sulfonamides, anti-epileptic drugs, sedatives, anti-thyroid drugs, anti-diabetes drugs, anti-malaria, sleeping pills and other factors.
  • Myelosuppression can cause damage to the bone marrow microenvironment, hematopoietic stem cells, hematopoietic growth factors, etc., and the granulosa, red, and megakaryocyte systems are inhibited. Lack of granulocytes can cause serious infections; a marked reduction in red blood cells can cause severe anemia; a marked drop in platelets causes severe bleeding and even death.
  • the mantle aglycone is one of the roots extracted from the roots of Sanguisorba officinalis L. or S. officinalis L. var. longifolia (Bertol.) Yu et Li.
  • the active ingredient is an aglycon of saponin I and saponin II, chemical name: 3 ⁇ , 19 ⁇ -hydroxy-Uso-12--28-carboxylic acid, and its structural formula is as follows:
  • the present invention provides a diterpene aglycone injection, which is characterized in that it is a preparation comprising the following raw materials:
  • the weight ratio of the mantle aglycone to the solubilizer is 1:0.005-300.
  • solubilizing agent is Tween 80, polyoxyethylene castor oil EL or poloxamer 188; and the pH adjusting agent is sodium hydroxide.
  • the concentration of the indole aglycon in the injection was 0.2 mg/mL.
  • the injection is an injection, a powder injection, a water injection or a large infusion.
  • the genistein is weighed and dispersed in water for injection according to the ratio, and the corresponding ratio of solubilizer and pH adjuster is added, the pH is adjusted to 10, stirred and dissolved, and then water for injection is added, filtered, and sterilized to obtain the injection of the present invention.
  • the invention also provides the use of the injection for the preparation of a medicament for the treatment and/or prevention of myelosuppression.
  • the medicament is a medicament for treating and/or preventing bone marrow suppression caused by a chemical substance.
  • the drug is a drug that raises blood cells and/or bone marrow hematopoietic stem cells.
  • the drug is a drug that increases peripheral blood leukocytes, neutrophils, red blood cells, platelets, and/or hemoglobin.
  • the present invention also provides a method of treating and/or preventing myelosuppression by using the aforementioned injection
  • the agent is treated and/or prevented.
  • mantle aglycones have problems such as low solubility and low oral absorption rate, which results in low oral bioavailability of the component, which limits the effect of the component on blood cell growth.
  • the inventors have studied the dosage form and its formulation, and the mantle aglycone injection prepared by the invention solves the problem of low solubility of the mantle aglycone, improves the bioavailability of the mantle aglycone, and further improves the therapeutic effect of the blood cell. It is of great significance for the development of new dosage forms of geniposide and better clinical application.
  • Figure 1 is a comparison of bone marrow hematopoietic stem cell counts in mice of each experimental group.
  • the preparation method is as follows:
  • the aglycone was dispersed in 10 mL of water for injection, Tween 80 and sodium hydroxide were added, the pH was adjusted to 10, stirred and dissolved, and then water for injection was added to 7500 mL to make the concentration of the aglycone in the solution 0.2 mg/mL.
  • the injection of the present invention is obtained by filtration and sterilization with a 0.22 um microporous membrane.
  • the preparation method is as follows:
  • the mantle aglycone was dispersed in 10 mL of water for injection, polyoxyethylene castor oil EL and sodium hydroxide were added, the pH was adjusted to 10, stirred and dissolved, and then water for injection was added to 12500 mL to make the concentration of the aglycone in the solution 0.2 mg. /mL, filtered and sterilized with a 0.22 um microporous membrane to obtain the injection of the present invention.
  • the preparation method is as follows:
  • the mantle aglycone was dispersed in 10 mL of water for injection, poloxamer 188, sodium hydroxide was added, the pH was adjusted to 10, stirred and dissolved, and then water for injection was added to 50,000 mL to make the concentration of the aglycone in the solution 0.2 mg/ The mL was filtered and sterilized with a 0.22 um microporous membrane to obtain the injection of the present invention.
  • Tween 80 polyoxyethylene castor oil EL, poloxamer 188, propylene glycol and vitamin C were used as excipients to prepare scutellarin injection.
  • the preparation method is as follows: 0.2 g of mantle aglycone is dispersed in 100 mL of water for injection, and different auxiliary materials are added (Tween 80, polyoxyethylene castor oil EL, poloxamer 188, propylene glycol, vitamin C), sodium hydroxide. Adjust the pH to 10, stir and dissolve, then add water for injection to 1000 mL to make the concentration of the aglycone in the solution 0.2mg/mL, filter and sterilize with 0.22um microporous membrane to obtain the injection of the present invention. Table 1.
  • the pyrogen is determined according to the Chinese Pharmacopoeia (2010 edition) pyrogen inspection method.
  • the clarification degree can be checked by the light inspection method under the foreign matter inspection law.
  • the content of the aglycone was determined by HPLC. Chromatographic conditions: Agilent extend-C18 Column (250 x 4.6 mm, 5 ⁇ m); mobile phase: acetonitrile-0.5% phosphoric acid (70:30). Flow rate: 0.8 mL ⁇ min-1, column temperature: 40 ° C, detection wavelength: 205 nm, injection amount: 10 ⁇ L.
  • EXPERIMENTAL RESULTS The mantle aglycone injection prepared by using Tween 80, polyoxyethylene castor oil EL and poloxamer 188 of the invention was qualified for heat source examination, and the degree of clarity was checked. The content of mantle aglycone showed high content. It is indicated that the mantle aglycone injection prepared by using the excipient Tween 80, polyoxyethylene castor oil EL and poloxamer 188 of the invention meets the requirements of the preparation, and retains the aglycone component to the greatest extent.
  • the other two kinds of excipients, propylene glycol and vitamin C were prepared by geniposide injection, which was qualified by heat source, and the clarity of the test was unqualified. The content of genistein was low.
  • the preparation method is as follows: 0.2 g of mantle aglycone is dispersed in 100 mL of water for injection, and different amounts of solubilizing agent (Tween 80) and sodium hydroxide are added respectively, the pH is adjusted to 10, stirred and dissolved, and then water for injection is added to 1000 mL. The concentration of the indole aglycon in the solution was 0.2 mg/mL, and the mixture was filtered and sterilized by a 0.22 um microporous membrane to obtain the injection of the present invention. The results are shown in Table 2.
  • the present invention is a geniposide injection group A (prepared according to Example 1), group B (prepared according to Example 2), group C (prepared according to Example 3), mantle aglycone 10% DMSO-physiology Saline group, cyclophosphamide.
  • mice All animals were fed ad libitum for 1 week and were randomly divided into: blank group; model group; mantle aglycone injection group A, B, C, 2.5 mg ⁇ kg -1 suspension, prepared before use; Indole aglycone group: Mantle aglycone powder, dissolved in 10% DMSO-physiological saline, formulated into a 2.5 mg ⁇ kg -1 suspension, prepared before use.
  • the other groups of mice were intraperitoneally injected with cyclophosphamide physiological saline solution at a dose of 50 mg ⁇ kg -1 for 3 consecutive days, and the blank mice were injected with the same volume of normal saline in the tail vein.
  • Each experimental group was given the corresponding drug by dose and administration from the first day of the experiment.
  • the blank group and the model group were injected with the same volume of normal saline in the tail vein for 7 consecutive days.
  • Peripheral blood test Peripheral blood leukocytes (WBC), neutrophils (NEUT) red blood cells (RBC), platelets (PLT), and hemoglobin (HGB) were counted in each experimental group by an automatic blood cell counter.
  • WBC Peripheral blood leukocytes
  • NUT neutrophils
  • RBC red blood cells
  • PHT platelets
  • HGB hemoglobin
  • Bone marrow hematopoietic stem cell count (based on bone marrow cell CD34+ antigen expression), the right femur bone marrow cells were pulverized with PBS buffer containing 0.2% bovine serum albumin, 106 cells were removed, the supernatant was discarded, and 30 ⁇ L was added. Normal mouse serum was blocked with non-specific binding sites, 10 ⁇ L of FITC-labeled rat anti-mouse CD34+ antibody was added, 10 ⁇ L of the corresponding control antibody was added to the control tube, and the reaction was protected from light for 30 min at 4 °C.
  • the number of hematopoietic stem cells in the indole aglycone injection group of the present invention was significantly increased (P ⁇ 0.05), and there was no significant difference in the mantle aglycon group; In comparison, the number of hematopoietic stem cells in the inoculum aglycone injection group of the present invention was significantly increased (P ⁇ 0.05).
  • the mantle aglycone injection prepared by the invention solves the problem of low solubility of the mantle aglycone, improves the bioavailability of the mantle aglycone, and further improves the therapeutic effect of the blood cell, thereby improving the therapeutic effect of the cell aglycone.
  • Good clinical application is of great significance.

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Abstract

A ziyuglycogenin injection, a preparation method therefor and use thereof. The ziyuglycogenin injection comprises a formulation prepared from the following raw materials: 0.5-10 parts of ziyuglycogenin and 0.001-60 parts of solubilizer.

Description

一种地榆苷元注射剂及其制备方法和用途Mantle aglycone injection, preparation method and use thereof 技术领域Technical field
本发明涉及一种地榆苷元注射剂及其制备方法和用途,属药物领域。The invention relates to a diterpene aglycone injection, a preparation method thereof and use thereof, and belongs to the field of medicine.
背景技术Background technique
骨髓抑制是临床上常见的造血系统疾病,它可发生于各系统肿瘤性疾病的放射治疗及(或)化学治疗、电离辐射引起的放射损伤、病毒性肝炎、微小病毒感染或药物(氯霉素、苯、磺胺、抗癫痈药、镇静剂、抗甲状腺药、抗糖尿病药、抗疟疾、安眠药)等因素。骨髓抑制可引起骨髓微环境、造血干细胞、造血细胞生长因子等的损伤,粒、红、巨核细胞系统一系、二系或三系细胞受抑制。粒细胞缺乏会引起严重感染;红细胞明显减少会引起严重贫血;血小板明显下降引起严重出血,甚至导致死亡。Myelosuppression is a clinically common hematopoietic disease that can occur in radiation therapy and/or chemotherapy of various systemic neoplastic diseases, radiation damage caused by ionizing radiation, viral hepatitis, parvovirus infection or drugs (chloramphenicol). , benzene, sulfonamides, anti-epileptic drugs, sedatives, anti-thyroid drugs, anti-diabetes drugs, anti-malaria, sleeping pills and other factors. Myelosuppression can cause damage to the bone marrow microenvironment, hematopoietic stem cells, hematopoietic growth factors, etc., and the granulosa, red, and megakaryocyte systems are inhibited. Lack of granulocytes can cause serious infections; a marked reduction in red blood cells can cause severe anemia; a marked drop in platelets causes severe bleeding and even death.
目前,临床上对于骨髓抑制,尤其是放化疗引起的骨髓抑制,尚缺乏有效的治疗手段。因此,寻找到有效的药物来缓解骨髓抑制,成为了一个亟待解决的问题。At present, clinically, there is no effective treatment for myelosuppression, especially myelosuppression caused by radiotherapy and chemotherapy. Therefore, finding an effective drug to alleviate bone marrow suppression has become an urgent problem to be solved.
地榆苷元是从蔷薇科地榆属植物地榆(Sanguisorba officinalis L.)或长叶地榆[S.officinalis L.var.longifolia(Bertol.)Yu et Li]的根中提取得到的一种活性成分,是地榆皂苷I和地榆皂苷II的苷元,化学名:3β,19α-羟基乌索-12烯-28-羧酸,其结构式如下所示:The mantle aglycone is one of the roots extracted from the roots of Sanguisorba officinalis L. or S. officinalis L. var. longifolia (Bertol.) Yu et Li. The active ingredient is an aglycon of saponin I and saponin II, chemical name: 3β, 19α-hydroxy-Uso-12--28-carboxylic acid, and its structural formula is as follows:
Figure PCTCN2017072232-appb-000001
Figure PCTCN2017072232-appb-000001
然而,迄今尚未见以地榆苷元为活性成分制备注射剂,用于治疗和/或预防骨髓抑制的公开报道。However, to date, there has been no public report on the preparation of an injection using the indole aglycone as an active ingredient for the treatment and/or prevention of myelosuppression.
发明内容Summary of the invention
为解决上述问题,本发明提供了一种地榆苷元注射剂,其特征在于:它是包含下述原料制备而成的制剂:In order to solve the above problems, the present invention provides a diterpene aglycone injection, which is characterized in that it is a preparation comprising the following raw materials:
地榆苷元、增溶剂。Mantle aglycon and solubilizer.
进一步地,它是包含下述重量配比的原料制备而成的制剂:Further, it is a preparation prepared from a raw material having the following weight ratio:
地榆苷元0.5-10份、增溶剂0.001-60份。0.5-10 parts of mantle aglycone and 0.001-60 parts of solubilizer.
进一步地,所述地榆苷元与增溶剂的重量配比为1:0.005~300。Further, the weight ratio of the mantle aglycone to the solubilizer is 1:0.005-300.
进一步地,所述的增溶剂为吐温80、聚氧乙烯蓖麻油EL或泊洛沙姆188;所述的pH调节剂为氢氧化钠。Further, the solubilizing agent is Tween 80, polyoxyethylene castor oil EL or poloxamer 188; and the pH adjusting agent is sodium hydroxide.
进一步地,所述注射剂中地榆苷元的浓度为0.2mg/mL。Further, the concentration of the indole aglycon in the injection was 0.2 mg/mL.
进一步地,所述的注射剂是注射液、粉针剂、水针剂或大输液。Further, the injection is an injection, a powder injection, a water injection or a large infusion.
进一步地,包括下述步骤:Further, the following steps are included:
按配比称取地榆苷元分散于注射用水中,加入相应配比的增溶剂、pH调节剂,调节pH至10,搅拌溶解,再加入注射用水,过滤、灭菌,即得本发明注射剂。The genistein is weighed and dispersed in water for injection according to the ratio, and the corresponding ratio of solubilizer and pH adjuster is added, the pH is adjusted to 10, stirred and dissolved, and then water for injection is added, filtered, and sterilized to obtain the injection of the present invention.
本发明还提供了所述注射剂用于制备治疗和/或预防骨髓抑制的药物的用途。The invention also provides the use of the injection for the preparation of a medicament for the treatment and/or prevention of myelosuppression.
进一步地,所述的药物是治疗和/或预防化学物质导致的骨髓抑制的药物。Further, the medicament is a medicament for treating and/or preventing bone marrow suppression caused by a chemical substance.
进一步地,所述的药物是升高血细胞和/或骨髓造血干细胞的药物。Further, the drug is a drug that raises blood cells and/or bone marrow hematopoietic stem cells.
进一步地,所述的药物是升高外周血白细胞、中性粒细胞、红细胞、血小板和/或血红蛋白的药物。Further, the drug is a drug that increases peripheral blood leukocytes, neutrophils, red blood cells, platelets, and/or hemoglobin.
本发明还提供了一种治疗和/或预防骨髓抑制的方法,它是使用前述注射 剂进行治疗和/或预防。The present invention also provides a method of treating and/or preventing myelosuppression by using the aforementioned injection The agent is treated and/or prevented.
发明人前期研究发现,地榆苷元存在溶解度低、口服胃肠吸收率小等问题,造成该成分口服生物利用度低,限制了该成分升高血细胞效果的发挥。Previous studies by the inventors have found that mantle aglycones have problems such as low solubility and low oral absorption rate, which results in low oral bioavailability of the component, which limits the effect of the component on blood cell growth.
发明人经过对剂型及其配方的研究,通过本发明制备的地榆苷元注射剂解决了地榆苷元溶解度低的问题,提高了地榆苷元生物利用度,进而提高其升高血细胞的疗效,对地榆苷元的新剂型开发及更好的临床应用具有十分重要的意义。The inventors have studied the dosage form and its formulation, and the mantle aglycone injection prepared by the invention solves the problem of low solubility of the mantle aglycone, improves the bioavailability of the mantle aglycone, and further improves the therapeutic effect of the blood cell. It is of great significance for the development of new dosage forms of geniposide and better clinical application.
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。It is apparent that various other modifications, substitutions and changes can be made in the form of the above-described embodiments of the present invention.
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。The above content of the present invention will be further described in detail below by way of specific embodiments in the form of embodiments. However, the scope of the above-mentioned subject matter of the present invention should not be construed as being limited to the following examples. Any technique implemented based on the above description of the present invention is within the scope of the present invention.
附图说明DRAWINGS
图1为各实验组小鼠骨髓造血干细胞计数比较。Figure 1 is a comparison of bone marrow hematopoietic stem cell counts in mice of each experimental group.
具体实施方式detailed description
实施例1本发明注射剂的制备Example 1 Preparation of Injectable Agent of the Present Invention
按下述配比称取原料:Weigh the raw materials according to the following ratio:
地榆苷元1.5g、吐温80 10g、pH调节剂适量。1.5 g of mantle aglycone, 10 g of Tween 80, and an appropriate amount of pH adjuster.
制备方法如下:The preparation method is as follows:
取地榆苷元分散于10mL注射用水中,加入吐温80、氢氧化钠,调节pH至10,搅拌溶解,再加入注射用水至7500mL使溶液中地榆苷元的浓度为0.2mg/mL,用0.22um微孔滤膜过滤、灭菌,即得本发明注射剂。The aglycone was dispersed in 10 mL of water for injection, Tween 80 and sodium hydroxide were added, the pH was adjusted to 10, stirred and dissolved, and then water for injection was added to 7500 mL to make the concentration of the aglycone in the solution 0.2 mg/mL. The injection of the present invention is obtained by filtration and sterilization with a 0.22 um microporous membrane.
实施例2本发明注射剂的制备Example 2 Preparation of Injectable Agent of the Present Invention
按下述配比称取原料: Weigh the raw materials according to the following ratio:
地榆苷元2.5g、聚氧乙烯蓖麻油EL 60g、pH调节剂适量。2.5 g of mantle aglycone, 60 g of polyoxyethylene castor oil, and an appropriate amount of pH adjuster.
制备方法如下:The preparation method is as follows:
取地榆苷元分散于10mL注射用水中,加入聚氧乙烯蓖麻油EL、氢氧化钠,调节pH至10,搅拌溶解,再加入注射用水至12500mL使溶液中地榆苷元的浓度为0.2mg/mL,用0.22um微孔滤膜过滤、灭菌,即得本发明注射剂。The mantle aglycone was dispersed in 10 mL of water for injection, polyoxyethylene castor oil EL and sodium hydroxide were added, the pH was adjusted to 10, stirred and dissolved, and then water for injection was added to 12500 mL to make the concentration of the aglycone in the solution 0.2 mg. /mL, filtered and sterilized with a 0.22 um microporous membrane to obtain the injection of the present invention.
实施例3本发明注射剂的制备Example 3 Preparation of the Injection of the Invention
按下述配比称取原料:Weigh the raw materials according to the following ratio:
地榆苷元10g、泊洛沙姆188 60g、pH调节剂适量。10 g of mantle aglycone, 188 60 g of poloxamer, and an appropriate amount of pH adjuster.
制备方法如下:The preparation method is as follows:
取地榆苷元分散于10mL注射用水中,加入泊洛沙姆188、氢氧化钠,调节pH至10,搅拌溶解,再加入注射用水至50000mL使溶液中地榆苷元的浓度为0.2mg/mL,用0.22um微孔滤膜过滤、灭菌,即得本发明注射剂。The mantle aglycone was dispersed in 10 mL of water for injection, poloxamer 188, sodium hydroxide was added, the pH was adjusted to 10, stirred and dissolved, and then water for injection was added to 50,000 mL to make the concentration of the aglycone in the solution 0.2 mg/ The mL was filtered and sterilized with a 0.22 um microporous membrane to obtain the injection of the present invention.
以下通过具体实验证明本发明的有益效果。The beneficial effects of the present invention are demonstrated by specific experiments below.
实验例1采用不同辅料制备的地榆苷元注射剂的质量评价Experimental Example 1 Quality Evaluation of Mantle Aglycone Injection Prepared with Different Excipients
本研究根据地榆苷元的性质,选用吐温80、聚氧乙烯蓖麻油EL、泊洛沙姆188、丙二醇、维生素C为辅料,制成地榆苷元注射剂。According to the nature of mantle aglycones, Tween 80, polyoxyethylene castor oil EL, poloxamer 188, propylene glycol and vitamin C were used as excipients to prepare scutellarin injection.
制备方法如下:取地榆苷元0.2g分散于100mL注射用水中,分别加入不同的辅料(吐温80、聚氧乙烯蓖麻油EL、泊洛沙姆188、丙二醇、维生素C)、氢氧化钠,调节pH至10,搅拌溶解,再加入注射用水至1000mL使溶液中地榆苷元的浓度为0.2mg/mL,用0.22um微孔滤膜过滤、灭菌,即得本发明注射剂,结果见表1。The preparation method is as follows: 0.2 g of mantle aglycone is dispersed in 100 mL of water for injection, and different auxiliary materials are added (Tween 80, polyoxyethylene castor oil EL, poloxamer 188, propylene glycol, vitamin C), sodium hydroxide. Adjust the pH to 10, stir and dissolve, then add water for injection to 1000 mL to make the concentration of the aglycone in the solution 0.2mg/mL, filter and sterilize with 0.22um microporous membrane to obtain the injection of the present invention. Table 1.
热原按《中国药典》(2010年版)热原检查法测定。The pyrogen is determined according to the Chinese Pharmacopoeia (2010 edition) pyrogen inspection method.
澄明度按《中国药典》(2010年版)可见异物检查法项下的灯检法检查。According to the Chinese Pharmacopoeia (2010 edition), the clarification degree can be checked by the light inspection method under the foreign matter inspection law.
地榆苷元含量,采用HPLC法测定,色谱条件:Agilent extend-C18色 谱柱(250×4.6mm,5μm);流动相:乙腈-0.5%磷酸(70:30)。流速:0.8mL·min-1,柱温:40℃,检测波长:205nm,进样量:10μL。The content of the aglycone was determined by HPLC. Chromatographic conditions: Agilent extend-C18 Column (250 x 4.6 mm, 5 μm); mobile phase: acetonitrile-0.5% phosphoric acid (70:30). Flow rate: 0.8 mL·min-1, column temperature: 40 ° C, detection wavelength: 205 nm, injection amount: 10 μL.
表1 采用不同辅料制备的地榆苷元注射剂的质量评价Table 1 Quality evaluation of mantle aglycone injection prepared with different excipients
Figure PCTCN2017072232-appb-000002
Figure PCTCN2017072232-appb-000002
注:与吐温80组比较,*P<0.05。Note: Compared with Tween 80 group, *P<0.05.
实验结果:采用本发明辅料吐温80、聚氧乙烯蓖麻油EL、泊洛沙姆188制备的地榆苷元注射剂,热源检查合格,澄明度检查合格,地榆苷元含量测定显示含量较高,表明采用本发明辅料吐温80、聚氧乙烯蓖麻油EL、泊洛沙姆188制备的地榆苷元注射剂符合制剂要求,且最大程度保留地榆苷元成分。其它二种辅料丙二醇、维生素C制备的地榆苷元注射剂,热源检查合格,澄明度检查不合格,地榆苷元含量测定显示含量较低。EXPERIMENTAL RESULTS: The mantle aglycone injection prepared by using Tween 80, polyoxyethylene castor oil EL and poloxamer 188 of the invention was qualified for heat source examination, and the degree of clarity was checked. The content of mantle aglycone showed high content. It is indicated that the mantle aglycone injection prepared by using the excipient Tween 80, polyoxyethylene castor oil EL and poloxamer 188 of the invention meets the requirements of the preparation, and retains the aglycone component to the greatest extent. The other two kinds of excipients, propylene glycol and vitamin C, were prepared by geniposide injection, which was qualified by heat source, and the clarity of the test was unqualified. The content of genistein was low.
实验例2采用不同量辅料制备的地榆苷元注射剂的质量评价Experimental Example 2 Quality Evaluation of Mantle Aglycone Injection Prepared with Different Amounts of Excipients
制备方法如下:取地榆苷元0.2g分散于100mL注射用水中,分别加入不同量的增溶剂(吐温80)、氢氧化钠,调节pH至10,搅拌溶解,再加入注射用水至1000mL使溶液中地榆苷元的浓度为0.2mg/mL,用0.22um微孔滤膜过滤、灭菌,即得本发明注射剂,结果见表2。 The preparation method is as follows: 0.2 g of mantle aglycone is dispersed in 100 mL of water for injection, and different amounts of solubilizing agent (Tween 80) and sodium hydroxide are added respectively, the pH is adjusted to 10, stirred and dissolved, and then water for injection is added to 1000 mL. The concentration of the indole aglycon in the solution was 0.2 mg/mL, and the mixture was filtered and sterilized by a 0.22 um microporous membrane to obtain the injection of the present invention. The results are shown in Table 2.
表2 采用不同量增溶剂制备的地榆苷元注射剂的质量评价Table 2 Quality evaluation of mantle aglycone injection prepared with different amounts of solubilizer
Figure PCTCN2017072232-appb-000003
Figure PCTCN2017072232-appb-000003
注:与1.0mg组比较,*P<0.05。Note: *P<0.05 compared to the 1.0 mg group.
实验结果:仅在本发明地榆苷元0.2g和增溶剂用量为1.0mg-60g比例下制备的地榆苷元注射剂热源合格,澄明度符合要求,含量高,制剂最佳,可制备符合要求的地榆苷元注射剂。Experimental results: Only in the present invention, the aglycone 0.2g and the solubilizer dosage of 1.0mg-60g ratio prepared by the geniposide injection heat source qualified, the degree of clarity meets the requirements, the content is high, the preparation is the best, and the preparation can meet the requirements. A mantle aglycone injection.
实验例3本发明地榆苷元注射剂药效学研究Experimental Example 3 Pharmacodynamic study of the indole aglycone injection of the present invention
1实验材料1 experimental material
1.1受试药物本发明地榆苷元注射剂A组(按照实施例1制备)、B组(按照实施例2制备)、C组(按照实施例3制备)、地榆苷元10%DMSO-生理盐水组、环磷酰胺。1.1 Test drug The present invention is a geniposide injection group A (prepared according to Example 1), group B (prepared according to Example 2), group C (prepared according to Example 3), mantle aglycone 10% DMSO-physiology Saline group, cyclophosphamide.
1.2实验动物KM-小鼠:18.5~22.5g。1.2 Experimental animal KM-mouse: 18.5-22.5 g.
1.3实验仪器:全自动血球分析仪;BS-600L电子天平:规格:600g/0.1g,上海友声衡器有限公司。1.3 Experimental equipment: automatic blood cell analyzer; BS-600L electronic balance: Specifications: 600g/0.1g, Shanghai Yousheng Weighing Apparatus Co., Ltd.
1.4统计方法1.4 statistical methods
用SPSS 17.0软件进行统计分析。数据以均数±标准差(
Figure PCTCN2017072232-appb-000004
)表示,组间采用单因素方差分析,方差齐者组间进行LSD检验,方差不齐者进行Tamhane’s T2检验。
Statistical analysis was performed using SPSS 17.0 software. Data in mean ± standard deviation (
Figure PCTCN2017072232-appb-000004
), one-way analysis of variance was used between groups, LSD test was performed between groups with variance, and Tamhane's T2 test was performed for those with irregular variance.
2实验方法2 experimental methods
2.1实验动物分组及模型制备2.1 Experimental animal grouping and model preparation
所有动物适应性喂养1周后按体重随机分为:空白组;模型组;地榆苷元注射剂A、B、C组,制成2.5mg·kg-1混悬液,临用前配制;地榆苷元组:地榆苷元粉末,用10%DMSO-生理盐水溶解,配制成2.5mg·kg-1混悬液,临用前配制。实验第1天,除空白组外,其余各组小鼠按50mg·kg-1剂量腹腔注射环磷酰胺生理盐水溶液,连续3天,空白组小鼠尾静脉注射等体积生理盐水。All animals were fed ad libitum for 1 week and were randomly divided into: blank group; model group; mantle aglycone injection group A, B, C, 2.5 mg·kg -1 suspension, prepared before use; Indole aglycone group: Mantle aglycone powder, dissolved in 10% DMSO-physiological saline, formulated into a 2.5 mg·kg -1 suspension, prepared before use. On the first day of the experiment, except for the blank group, the other groups of mice were intraperitoneally injected with cyclophosphamide physiological saline solution at a dose of 50 mg·kg -1 for 3 consecutive days, and the blank mice were injected with the same volume of normal saline in the tail vein.
2.2给药2.2 administration
各实验组自实验第1天开始按剂量、给药方式给予相应药物,空白组和模型组小鼠尾静脉注射等体积生理盐水,连续7天。Each experimental group was given the corresponding drug by dose and administration from the first day of the experiment. The blank group and the model group were injected with the same volume of normal saline in the tail vein for 7 consecutive days.
2.3标本采集2.3 specimen collection
实验第8天,各实验组小鼠眼眶取血,用装有EDTA抗凝剂的0.5mlEP管收集待测。On the 8th day of the experiment, blood was taken from the eye of each experimental group and collected with a 0.5 ml EP tube containing EDTA anticoagulant.
2.4检测指标及方法2.4 Detection indicators and methods
外周血象检测:采用全自动血球计数仪对各实验组小鼠外周血白细胞(WBC)、中性粒细胞(NEUT)红细胞(RBC)、血小板(PLT)、血红蛋白(HGB)进行计数。Peripheral blood test: Peripheral blood leukocytes (WBC), neutrophils (NEUT) red blood cells (RBC), platelets (PLT), and hemoglobin (HGB) were counted in each experimental group by an automatic blood cell counter.
骨髓造血干细胞计数(以骨髓细胞CD34+抗原表达量计)用含牛血清白蛋白浓度为0.2%的PBS缓冲液冲出小鼠右侧股骨骨髓细胞,取出106个细胞离心,弃上清,加入30μL正常小鼠血清以封闭非特异结合位点,再加入10μL FITC标记的大鼠抗小鼠CD34+抗体,对照管加入10μL相应对照抗体,4℃避光反应30min。加入2mL红细胞裂解液,作用5min,洗细胞2次,加入终浓度为3μg/mL的PI染液,采用流式细胞仪检测骨髓细胞CD34+抗原表达。Bone marrow hematopoietic stem cell count (based on bone marrow cell CD34+ antigen expression), the right femur bone marrow cells were pulverized with PBS buffer containing 0.2% bovine serum albumin, 106 cells were removed, the supernatant was discarded, and 30 μL was added. Normal mouse serum was blocked with non-specific binding sites, 10 μL of FITC-labeled rat anti-mouse CD34+ antibody was added, 10 μL of the corresponding control antibody was added to the control tube, and the reaction was protected from light for 30 min at 4 °C. 2 mL of red blood cell lysate was added for 5 min, the cells were washed twice, and PI staining solution with a final concentration of 3 μg/mL was added, and the expression of CD34+ antigen in bone marrow cells was detected by flow cytometry.
3实验结果 3 experimental results
3.1外周血主要血细胞计数比较,见表3、表4。3.1 Comparison of the main blood cell counts of peripheral blood, see Table 3 and Table 4.
表3  各实验组小鼠外周血血细胞数量Table 3 Number of peripheral blood cells in each experimental group
Figure PCTCN2017072232-appb-000005
Figure PCTCN2017072232-appb-000005
注:与模型组比较,*P<0.05,**P<0.01;注:与地榆苷元组比较,P<0.05,△△P<0.01。Note: Compared with the model group, *P<0.05, **P<0.01; Note: Compared with the mantle aglycon group, P<0.05, △△ P<0.01.
结果显示,与模型组比较,地榆苷元注射剂A组、地榆苷元注射剂B组、地榆苷元注射剂C组小鼠造血干细胞数量均有显著升高(P<0.05),地榆苷元组无显著性差异;与地榆苷元组比较,地榆苷元注射剂A组、地榆苷元注射剂B组、地榆苷元注射剂C组小鼠外周血WBC、RBC、PLT数量均有显著升高(P<0.05)。The results showed that compared with the model group, the number of hematopoietic stem cells in the aglycone injection group A, the mantle aglycone injection group B, and the mantle aglycone injection group C were significantly increased (P<0.05). There was no significant difference in the tuple group. Compared with the mantle aglycone group, the number of WBC, RBC and PLT in the peripheral blood of the mice in the group A, the aglycone injection group B and the mantle aglycone injection group C were all different. Significantly elevated (P <0.05).
表4 各实验组小鼠外周血血细胞数量Table 4 Number of peripheral blood cells in each experimental group
Figure PCTCN2017072232-appb-000006
Figure PCTCN2017072232-appb-000006
注:与模型组比较,*P<0.05,**P<0.01;注:与地榆苷元组比较,P<0.05,△△P<0.01。 Note: Compared with the model group, *P<0.05, **P<0.01; Note: Compared with the mantle aglycon group, P<0.05, △△ P<0.01.
结果显示,与模型组比较,地榆苷元注射剂A组、地榆苷元注射剂B组、地榆苷元注射剂C组小鼠外周血NEUT和HGB数量均有显著升高(P<0.05),地榆苷元组无显著性差异;与地榆苷元组比较,地榆苷元注射剂A组、地榆苷元注射剂B组、地榆苷元注射剂C组组小鼠外周血NEUT和HGB数量均有显著升高(P<0.05)The results showed that compared with the model group, the number of NEUT and HGB in the peripheral blood of the mice treated with the aglycone injection group A, the mantle aglycone injection group B and the mantle aglycone injection group C were significantly increased (P<0.05). There was no significant difference in the mantle aglycon group; compared with the mantle aglycon group, the number of NEUT and HGB in peripheral blood of the mice in the group of the mantle aglycone injection group A, the mantle aglycone injection group B, and the mantle aglycone injection group C group There was a significant increase (P<0.05)
3.2、骨髓造血干细胞计数比较3.2, comparison of bone marrow hematopoietic stem cell count
从图1可知,与模型组比较,本发明地榆苷元注射剂组小鼠造血干细胞数量均有显著升高(P<0.05),地榆苷元组无显著性差异;与地榆苷元组比较,本发明地榆苷元注射剂组小鼠造血干细胞数量均有显著升高(P<0.05)。As can be seen from Fig. 1, compared with the model group, the number of hematopoietic stem cells in the indole aglycone injection group of the present invention was significantly increased (P<0.05), and there was no significant difference in the mantle aglycon group; In comparison, the number of hematopoietic stem cells in the inoculum aglycone injection group of the present invention was significantly increased (P<0.05).
以上实验结果表明,本发明地榆苷元注射剂可以有效升高血细胞,药效明显优于直接用地榆苷元原药给药。The above experimental results show that the indole aglycone injection of the present invention can effectively raise blood cells, and the drug effect is obviously superior to that of the direct use of the geniposide.
综上所述,本发明制备的地榆苷元注射剂解决了地榆苷元溶解度低的问题,提高了地榆苷元生物利用度,进而提高其升高血细胞的疗效,对地榆苷元更好的临床应用具有十分重要的意义。 In summary, the mantle aglycone injection prepared by the invention solves the problem of low solubility of the mantle aglycone, improves the bioavailability of the mantle aglycone, and further improves the therapeutic effect of the blood cell, thereby improving the therapeutic effect of the cell aglycone. Good clinical application is of great significance.

Claims (11)

  1. 一种地榆苷元注射剂,其特征在于:它是包含下述重量配比的原料制备而成的制剂:A mantle aglycone injection, which is prepared by preparing a raw material having the following weight ratio:
    地榆苷元0.5-10份、增溶剂0.001-60份。0.5-10 parts of mantle aglycone and 0.001-60 parts of solubilizer.
  2. 根据权利要求1所述的注射剂,其特征在于:所述地榆苷元与增溶剂的重量配比为1:0.005~300。The injection according to claim 1, wherein the weight ratio of the mantle aglycone to the solubilizer is 1:0.005 to 300.
  3. 根据权利要求1或2所述的注射剂,其特征在于:所述的增溶剂为吐温80、聚氧乙烯蓖麻油EL或泊洛沙姆188;所述的pH调节剂为氢氧化钠。The injection according to claim 1 or 2, wherein the solubilizing agent is Tween 80, polyoxyethylene castor oil EL or poloxamer 188; and the pH adjusting agent is sodium hydroxide.
  4. 根据权利要求1-3任意一项所述的注射剂,其特征在于:所述注射剂中地榆苷元的浓度为0.2mg/mL。The injection according to any one of claims 1 to 3, wherein the concentration of the indole aglycon in the injection is 0.2 mg/mL.
  5. 根据权利要求1-4任意一项所述的注射剂,其特征在于:所述的注射剂是注射液、粉针剂、水针剂或大输液。The injection according to any one of claims 1 to 4, wherein the injection is an injection, a powder injection, a water injection or a large infusion.
  6. 制备权利要求1-5任意一项所述注射剂的方法,其特征在于:包括下述步骤:A method of preparing an injection according to any one of claims 1 to 5, comprising the steps of:
    按配比称取地榆苷元分散于注射用水中,加入相应配比的增溶剂、pH调节剂,调节pH至10,搅拌溶解,再加入注射用水,过滤、灭菌,即得本发明注射剂。The genistein is weighed and dispersed in water for injection according to the ratio, and the corresponding ratio of solubilizer and pH adjuster is added, the pH is adjusted to 10, stirred and dissolved, and then water for injection is added, filtered, and sterilized to obtain the injection of the present invention.
  7. 权利要求1-6任意一项所述注射剂用于制备治疗和/或预防骨髓抑制的药物的用途。Use of the injection according to any one of claims 1 to 6 for the preparation of a medicament for the treatment and/or prevention of myelosuppression.
  8. 根据权利要求7所述的用途,其特征在于:所述的药物是治疗和/或预防化学物质导致的骨髓抑制的药物。The use according to claim 7, wherein the drug is a drug for treating and/or preventing a bone marrow suppression caused by a chemical substance.
  9. 根据权利要求7或8所述的用途,其特征在于:所述的药物是升高血细胞和/或骨髓造血干细胞的药物。Use according to claim 7 or 8, characterized in that the medicament is a medicament for raising blood cells and/or bone marrow hematopoietic stem cells.
  10. 根据权利要求9所述的用途,其特征在于:所述的药物是升高外周血白细胞、中性粒细胞、红细胞、血小板和/或血红蛋白的药物。 The use according to claim 9, characterized in that the drug is a drug for raising peripheral blood leukocytes, neutrophils, red blood cells, platelets and/or hemoglobin.
  11. 一种治疗和/或预防骨髓抑制的方法,其特征在于:它是使用权利要求1-6任意一项所述注射剂进行治疗和/或预防。 A method for treating and/or preventing myelosuppression, which is characterized in that it is treated and/or prevented by the injection according to any one of claims 1 to 6.
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CN106606474A (en) * 2015-10-16 2017-05-03 四川英路维特医药科技有限公司 3beta, 19alpha-hydroxy-urs-12-en-28-carboxylic acid injection, and preparation method and applications thereof

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPWO2019180946A1 (en) * 2018-03-23 2021-04-08 富山薬品工業株式会社 Non-aqueous electrolyte for power storage devices
JP7060777B2 (en) 2018-03-23 2022-04-27 富山薬品工業株式会社 Non-aqueous electrolyte for power storage devices

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