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WO2018133112A1 - Injection d'aglycone de sanguisorba officinalis, son procédé de préparation et ses applications - Google Patents

Injection d'aglycone de sanguisorba officinalis, son procédé de préparation et ses applications Download PDF

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Publication number
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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WO
WIPO (PCT)
Prior art keywords
injection
aglycone
mantle
group
drug
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Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/CN2017/072232
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English (en)
Chinese (zh)
Inventor
杨世林
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sichuan Inlu Weite Pharmaceutical Technology Co Ltd
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Sichuan Inlu Weite Pharmaceutical Technology Co Ltd
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Filing date
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Priority to PCT/CN2017/072232 priority Critical patent/WO2018133112A1/fr
Publication of WO2018133112A1 publication Critical patent/WO2018133112A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/44—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
    • 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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics

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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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne une injection d'aglycone de Sanguisorba officinalis, son procédé de préparation et ses applications, la formulation de l'injection renfermant les excipients suivants : 0,5-10 parties d'aglycone de Sanguisorba officinalis et 0,001-60 parties d'agent de solubilisation.
PCT/CN2017/072232 2017-01-23 2017-01-23 Injection d'aglycone de sanguisorba officinalis, son procédé de préparation et ses applications Ceased WO2018133112A1 (fr)

Priority Applications (1)

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PCT/CN2017/072232 WO2018133112A1 (fr) 2017-01-23 2017-01-23 Injection d'aglycone de sanguisorba officinalis, son procédé de préparation et ses applications

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PCT/CN2017/072232 WO2018133112A1 (fr) 2017-01-23 2017-01-23 Injection d'aglycone de sanguisorba officinalis, son procédé de préparation et ses applications

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPWO2019180946A1 (ja) * 2018-03-23 2021-04-08 富山薬品工業株式会社 蓄電デバイス用非水電解液

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1593436A (zh) * 2003-09-08 2005-03-16 成都地奥制药集团有限公司 乌索烷型三萜皂苷在制备升高白细胞和/或血小板药物中的应用
CN1788758A (zh) * 2004-12-14 2006-06-21 成都地奥制药集团有限公司 中药地榆及其提取物在制备升高红细胞和血红蛋白药物中的应用
CN106606474A (zh) * 2015-10-16 2017-05-03 四川英路维特医药科技有限公司 一种地榆苷元注射剂及其制备方法和用途

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1593436A (zh) * 2003-09-08 2005-03-16 成都地奥制药集团有限公司 乌索烷型三萜皂苷在制备升高白细胞和/或血小板药物中的应用
CN1788758A (zh) * 2004-12-14 2006-06-21 成都地奥制药集团有限公司 中药地榆及其提取物在制备升高红细胞和血红蛋白药物中的应用
CN106606474A (zh) * 2015-10-16 2017-05-03 四川英路维特医药科技有限公司 一种地榆苷元注射剂及其制备方法和用途

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPWO2019180946A1 (ja) * 2018-03-23 2021-04-08 富山薬品工業株式会社 蓄電デバイス用非水電解液
JP7060777B2 (ja) 2018-03-23 2022-04-27 富山薬品工業株式会社 蓄電デバイス用非水電解液

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