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WO2018133105A1 - COMPLEXE D'INCLUSION D'HYDROXYPROPYL-β-CYCLODEXTRINE DE ZIYUGLUCOSIDE II DE SANGUISORBA OFFICINALIS, SON PROCÉDÉ DE PRÉPARATION ET SES APPLICATIONS - Google Patents

COMPLEXE D'INCLUSION D'HYDROXYPROPYL-β-CYCLODEXTRINE DE ZIYUGLUCOSIDE II DE SANGUISORBA OFFICINALIS, SON PROCÉDÉ DE PRÉPARATION ET SES APPLICATIONS Download PDF

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Publication number
WO2018133105A1
WO2018133105A1 PCT/CN2017/072225 CN2017072225W WO2018133105A1 WO 2018133105 A1 WO2018133105 A1 WO 2018133105A1 CN 2017072225 W CN2017072225 W CN 2017072225W WO 2018133105 A1 WO2018133105 A1 WO 2018133105A1
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WO
WIPO (PCT)
Prior art keywords
saponin
hydroxypropyl
cyclodextrin
solution
pharmaceutically acceptable
Prior art date
Application number
PCT/CN2017/072225
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English (en)
Chinese (zh)
Inventor
杨世林
Original Assignee
四川英路维特医药科技有限公司
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.)
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Publication date
Application filed by 四川英路维特医药科技有限公司 filed Critical 四川英路维特医药科技有限公司
Priority to PCT/CN2017/072225 priority Critical patent/WO2018133105A1/fr
Publication of WO2018133105A1 publication Critical patent/WO2018133105A1/fr

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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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • 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
    • 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 saponin hydroxypropyl ⁇ -cyclodextrin inclusion compound, 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.
  • the saponin is 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 technical proposal of the present invention provides a saponin hydroxypropyl ⁇ -cyclodextrin inclusion compound, a preparation method thereof and use thereof.
  • the present invention provides a saponin hydroxypropyl ⁇ -cyclodextrin inclusion compound prepared from the following stoichiometric starting materials plus a pharmaceutically acceptable solvent:
  • Hydroxypropyl ⁇ -cyclodextrin H- ⁇ -CD.
  • the pharmaceutically acceptable solvent is at least one of absolute ethanol, n-butanol and diethyl ether.
  • the present invention also provides a method of preparing the above clathrate, comprising the steps of:
  • the pharmaceutically acceptable solvent is at least one of absolute ethanol, n-butanol and diethyl ether;
  • the stirring time was 4 hours, and the evaporation to dryness was 60 °C.
  • the invention also provides the use of the above clathrate for the manufacture of a medicament for the treatment and/or prevention of myelosuppression.
  • the drug is a drug for treating and/or preventing bone marrow suppression caused by a chemical substance.
  • the present invention also provides the use of the above clathrate for the preparation of a medicament for increasing the number of one or more of peripheral blood leukocytes, neutrophils, red blood cells, platelets, hemoglobin, bone marrow hematopoietic stem cells.
  • the present invention also provides a saponin preparation which is prepared by using a saponin hydroxypropyl ⁇ -cyclodextrin inclusion compound as an active ingredient, adding a pharmaceutically acceptable auxiliary or auxiliary component. preparation.
  • the preparation is a powder, a tablet, a pill, a granule, a powder injection, an injection or a capsule.
  • the present invention also provides a method of treating and/or preventing myelosuppression, in particular, using the aforementioned clathrate.
  • the method is a method of treating and/or preventing bone marrow suppression caused by a chemical substance.
  • the present invention also provides a method for increasing the amount of one or more of peripheral blood leukocytes, neutrophils, red blood cells, platelets, hemoglobin, bone marrow hematopoietic stem cells, in particular, using the aforementioned clathrate.
  • the saponin hydroxypropyl ⁇ -cyclodextrin inclusion compound prepared by the invention can significantly improve the solubility and dissolution of the drug, and significantly increase the peripheral blood leukocytes, neutrophils, red blood cells, platelets, hemoglobin and bone marrow hematopoietic stem cells.
  • the quantity, with obvious therapeutic and/or prevention of myelosuppression, is of great significance for the clinical application of saponin.
  • the raw materials and equipment used in the specific embodiments of the present invention are known products and are obtained by purchasing commercially available products.
  • the preparation method is as follows:
  • the saponin was taken according to the ratio, and 50 ml of anhydrous ethanol was added thereto to ultrasonically dissolve to obtain a solution 1. Further, H- ⁇ -CD was taken according to the ratio, and 15 ml of absolute ethanol was added to ultrasonicate to dissolve to obtain a solution 2.
  • the solution 2 was stirred on a thermostatic magnetic stirrer while the solution 1 was slowly added to the solution 2 with a dropper. After the solution 1 was all added to the solution 2, the mixture was stirred on a thermostatic magnetic stirrer for four hours. The mixture was poured into an evaporating dish, placed in a 60 ° C water bath, evaporated to dryness, and the dried product was finely ground to obtain a clathrate.
  • the preparation method is as follows:
  • the saponin was taken according to the ratio, and 150 ml of absolute ethanol was added to dissolve to dissolve to obtain a solution 1.
  • Another H- ⁇ -CD was taken according to the ratio, and 50 ml of absolute ethanol was added to ultrasonicate to dissolve to obtain a solution 2.
  • the solution 2 was stirred on a thermostatic magnetic stirrer while the solution 1 was slowly added to the solution 2 with a dropper. After the solution 1 was all added to the solution 2, the mixture was stirred on a thermostatic magnetic stirrer for four hours.
  • the mixture was poured into an evaporating dish, placed in a 60 ° C water bath, evaporated to dryness, and the dried product was finely ground to obtain a clathrate.
  • the preparation method is as follows:
  • the saponin was taken according to the ratio, and 250 ml of absolute ethanol was added to dissolve to dissolve to obtain a solution 1. Further, H- ⁇ -CD was taken according to the ratio, and 100 ml of anhydrous ethanol was added thereto to ultrasonically dissolve to obtain a solution 2.
  • the solution 2 was stirred on a thermostatic magnetic stirrer while the solution 1 was slowly added to the solution 2 with a dropper. After the solution 1 was all added to the solution 2, the mixture was stirred on a thermostatic magnetic stirrer for four hours. The mixture was poured into an evaporating dish, placed in a 60 ° C water bath, evaporated to dryness, and the dried product was finely ground to obtain a clathrate.
  • the preparation method is as follows:
  • the saponin was taken according to the ratio, and 450 ml of anhydrous ethanol was added to dissolve to dissolve to obtain a solution 1. Further, H- ⁇ -CD was taken according to the ratio, and 450 ml of absolute ethanol was added to ultrasonicate to dissolve to obtain a solution 2.
  • the solution 2 was stirred on a thermostatic magnetic stirrer while the solution 1 was slowly added to the solution 2 with a dropper. After the solution 1 was all added to the solution 2, the mixture was stirred on a thermostatic magnetic stirrer for four hours. The mixture was poured into an evaporating dish, placed in a 60 ° C water bath, evaporated to dryness, and the dried product was finely ground to obtain a clathrate.
  • the preparation method is as follows:
  • the saponin was taken according to the ratio, and 650 ml of absolute ethanol was added to ultrasonicate to dissolve to obtain a solution 1. Further, H- ⁇ -CD was taken according to the ratio, and 165 ml of absolute ethanol was added to ultrasonicate to dissolve to obtain a solution 2.
  • the solution 2 was stirred on a thermostatic magnetic stirrer while the solution 1 was slowly added to the solution 2 with a dropper. After the solution 1 was all added to the solution 2, the mixture was stirred on a thermostatic magnetic stirrer for four hours. The mixture was poured into an evaporating dish, placed in a 60 ° C water bath, evaporated to dryness, and the dried product was finely ground to obtain a clathrate.
  • the preparation method is as follows:
  • the saponin was taken according to the ratio, and 850 ml of absolute ethanol was added to dissolve to dissolve to obtain a solution 1. Further, H- ⁇ -CD was taken according to the ratio, and 350 ml of absolute ethanol was added thereto to ultrasonically dissolve to obtain a solution 2.
  • the solution 2 was stirred on a thermostatic magnetic stirrer while the solution 1 was slowly added to the solution 2 with a dropper. After the solution 1 was all added to the solution 2, the mixture was stirred on a thermostatic magnetic stirrer for four hours. The mixture was poured into an evaporating dish, placed in a 60 ° C water bath, evaporated to dryness, and the dried product was finely ground to obtain a clathrate.
  • the preparation method is as follows:
  • the saponin was taken according to the ratio, and 1000 ml of absolute ethanol was added to ultrasonicate to dissolve to obtain a solution 1. Further, H- ⁇ -CD was taken according to the ratio, and 450 ml of absolute ethanol was added to ultrasonicate to dissolve to obtain a solution 2.
  • Stir the solution 2 on a constant temperature magnetic stirrer while slowly adding the solution 1 to the solution 2 with a dropper. After all of Solution 1 was added to Solution 2, the mixture was stirred on a thermostatic magnetic stirrer for four hours. The mixture was poured into an evaporating dish, placed in a 60 ° C water bath, evaporated to dryness, and the dried product was finely ground to obtain a clathrate.
  • the following materials were weighed and weighed: 5 g of saponin and 15 g of clathrate.
  • the preparation method is as follows:
  • the saponin was weighed and added with 100 times the amount of absolute ethanol to dissolve to obtain a solution 1.
  • the inclusion material was further taken, and 10 times of anhydrous ethanol was added thereto to ultrasonically dissolve to obtain a solution 2.
  • the solution 2 was stirred on a thermostatic magnetic stirrer while the solution 1 was slowly added to the solution 2 with a dropper. After the solution 1 was all added to the solution 2, the mixture was stirred on a thermostatic magnetic stirrer for four hours.
  • the mixture was poured into an evaporating dish, placed in a 60 ° C water bath, evaporated to dryness, and the dried product was finely ground to obtain a clathrate.
  • inclusion ratio mass of saponin in the inclusion compound / mass of saponin administration ⁇ 100%
  • the saponin hydroxypropyl ⁇ -cyclodextrin inclusion complex can be obtained only in the proportion of the saponin: hydroxypropyl ⁇ -cyclodextrin of the present invention; wherein, the saponin is used Element: Hydroxypropyl ⁇ -cyclodextrin is in the range of 1:1 to 1:20, and the inclusion ratio is over 90%, which is significantly different from that of hydroxypropyl ⁇ -cyclodextrin 1:0.5 (P ⁇ 0.05), indicating hydroxypropyl ⁇ -cyclodextrin to saponin pack The effect is good.
  • Test drug saponin-H- ⁇ -CD clathrate (prepared according to Examples 1 to 7), saponin, cyclophosphamide.
  • mice All animals were fed ad libitum for 1 week and were randomly divided into: blank group; model group; saponin-H- ⁇ -CD inclusion complex group, prepared according to Examples 1-7, formulated into 2.5 mg ⁇ kg - 1 suspension, set to sample groups 1 to 7, respectively, saponin group; dissolved in 10% DMSO-physiological saline, formulated into a 2.5mg ⁇ kg -1 suspension.
  • 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.
  • mice in the blank group and the model group were intragastrically administered with the same volume of physiological saline 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 saponin hydroxypropyl ⁇ -cyclodextrin inclusion compound group of the present invention was significantly increased (P ⁇ 0.05), and the saponin group was absent.
  • the number of hematopoietic stem cells in the saponin hydroxypropyl ⁇ -cyclodextrin inclusion compound group of the present invention was significantly increased (P ⁇ 0.05).
  • the saponin inclusion complex prepared by the invention effectively solves the problem of low solubility of the saponin, improves the bioavailability of the saponin, can effectively raise blood cells, and effectively prevent and treat bone marrow suppression.
  • the clinical application of sapogenin is of great significance.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Steroid Compounds (AREA)

Abstract

L'invention concerne un complexe d'inclusion d'hydroxypropyl-β-cyclodextrine de ziyuglucoside II de Sanguisorba officinalis, son procédé de préparation et ses applications, la formulation du complexe d'inclusion d'hydroxypropyl-β-cyclodextrine de ziyuglucoside II de Sanguisorba officinalis étant constituée des ingrédients suivants, exprimés en poids, pharmaceutiquement acceptables servant à la préparation d'un médicament : 0,5-10 parties de ziyuglucoside de Sanguisorba officinalis et 1-20 parties d'hydroxypropyl-β-cyclodextrine.
PCT/CN2017/072225 2017-01-23 2017-01-23 COMPLEXE D'INCLUSION D'HYDROXYPROPYL-β-CYCLODEXTRINE DE ZIYUGLUCOSIDE II DE SANGUISORBA OFFICINALIS, SON PROCÉDÉ DE PRÉPARATION ET SES APPLICATIONS WO2018133105A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/CN2017/072225 WO2018133105A1 (fr) 2017-01-23 2017-01-23 COMPLEXE D'INCLUSION D'HYDROXYPROPYL-β-CYCLODEXTRINE DE ZIYUGLUCOSIDE II DE SANGUISORBA OFFICINALIS, SON PROCÉDÉ DE PRÉPARATION ET SES APPLICATIONS

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2017/072225 WO2018133105A1 (fr) 2017-01-23 2017-01-23 COMPLEXE D'INCLUSION D'HYDROXYPROPYL-β-CYCLODEXTRINE DE ZIYUGLUCOSIDE II DE SANGUISORBA OFFICINALIS, SON PROCÉDÉ DE PRÉPARATION ET SES APPLICATIONS

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Citations (4)

* 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
CN103690549A (zh) * 2012-12-24 2014-04-02 江西本草天工科技有限责任公司 ɑ-常春藤皂苷固体分散体及其环糊精包合物的制备
CN106606504A (zh) * 2015-10-16 2017-05-03 四川英路维特医药科技有限公司 地榆皂苷元羟丙基β‑环糊精包合物及其制备方法和用途

Patent Citations (4)

* 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
CN103690549A (zh) * 2012-12-24 2014-04-02 江西本草天工科技有限责任公司 ɑ-常春藤皂苷固体分散体及其环糊精包合物的制备
CN106606504A (zh) * 2015-10-16 2017-05-03 四川英路维特医药科技有限公司 地榆皂苷元羟丙基β‑环糊精包合物及其制备方法和用途

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