WO2018133106A1 - Dispersion solide de ziyuglucoside ii de sanguisorba officinalis, son procédé de préparation et ses applications - Google Patents

Dispersion solide de ziyuglucoside ii de sanguisorba officinalis, son procédé de préparation et ses applications Download PDF

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Publication number
WO2018133106A1
WO2018133106A1 PCT/CN2017/072226 CN2017072226W WO2018133106A1 WO 2018133106 A1 WO2018133106 A1 WO 2018133106A1 CN 2017072226 W CN2017072226 W CN 2017072226W WO 2018133106 A1 WO2018133106 A1 WO 2018133106A1
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WIPO (PCT)
Prior art keywords
saponin
solid dispersion
povidone
solution
preparation
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Application number
PCT/CN2017/072226
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English (en)
Chinese (zh)
Inventor
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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Priority to PCT/CN2017/072226 priority Critical patent/WO2018133106A1/fr
Publication of WO2018133106A1 publication Critical patent/WO2018133106A1/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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • 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 solid dispersion, a preparation method thereof and a 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:
  • CN101119740A discloses the use of saponin II in the preparation of a medicament for increasing red blood cells and hemoglobin. In actual use, it was found that the saponin has poor efficacy, and when used alone, the effect of increasing blood cell level and treating bone marrow suppression is poor, which greatly limits the clinical application of saponin.
  • the object of the present invention is to provide a saponin solid dispersion, a preparation method thereof and use thereof.
  • the present invention provides a solid dispersion of saponin, which is prepared from a raw material of the following weight ratio: 1 part of saponin and 2 to 30 parts of povidone.
  • povidone is PVP K30.
  • the invention also provides a preparation method of the above solid dispersion, comprising the following steps:
  • the organic solvent described in the step a is anhydrous ethanol.
  • the invention also provides the use of a solid dispersion as described above 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 solid dispersion 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 invention also provides a method of treating and/or preventing myelosuppression, in particular using the solid dispersion described above.
  • 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 solid dispersion.
  • the present invention provides a saponin solid dispersion and a preparation method thereof.
  • the solid dispersion of saponin prepared by the invention can significantly improve the solubility and dissolution of the drug, and significantly increase the number of peripheral blood leukocytes, neutrophils, red blood cells, platelets, hemoglobin and bone marrow hematopoietic stem cells, and the effect is significantly better than the ground.
  • the original drug of saponin has obvious effects of treating and/or preventing myelosuppression.
  • 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 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 solid dispersion.
  • 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 solid dispersion.
  • 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 solid dispersion.
  • Dissolution method Take one tablet of each batch, according to the dissolution method ("Chinese Pharmacopoeia" Appendix XC second method), with pH 6.8PBS 1 000mL as the dissolution medium, the rotation speed is 100r ⁇ min -1 , temperature ( 37 ⁇ 0.5)°C, sample 5mL at 0, 5, 15, 20, 25min, filter with 0.45 ⁇ m microporous membrane, place the filtrate in a 100mL volumetric flask, dilute to the mark with pH 6.8PBS, shake well, and UV- Visible spectrophotometry (Chinese Pharmacopoeia Appendix IVA) measured absorbance at 345nm wavelength; after 25min sampling, the whole solution was transferred to a beaker, heated and stirred at 100 ° C for 2 ⁇ 3min, cooled to 37 ° C, according to the above method After sampling and dilution, the absorbance measured by the eluate after treatment at 100 ° C was the denominator, and the absorbance measured at each time point was taken as
  • the solubility of the original drug of the saponin was measured in the early stage of the experiment, which was only 0.021 mg/ml. It can be seen from Table 1 that when the solid dispersion of saponin is prepared by using the povidone of the present invention, the solubility and dissolution of the drug are the highest, which is significantly better than other carrier materials (P ⁇ 0.05); if other carrier materials, such as Pollock, are used, With sam, polyethylene glycol, etc., the dissolution rate of the solid dispersion is greatly reduced, and the solubility of the drug is not as obvious as that of PVP K30.
  • test drug saponin solid dispersion group prepared according to Example 2
  • saponin group saponin group
  • tool drugs cyclophosphamide.
  • mice All animals were fed ad libitum for 1 week and were randomly divided into: blank group; model group; saponin solid dispersion group, powder must be formulated into 0.5mg ⁇ kg -1 , 5mg ⁇ kg -1 , 10mg ⁇ kg -1 suspension, prepared before use; saponin group, formulated into 10mg ⁇ 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.
  • mice in the blank group and the model group were intragastrically administered with the same volume of normal 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 using an automatic blood cell counter. .
  • Bone marrow hematopoietic stem cell count (based on bone marrow cell CD34 + antigen expression), the right femur bone marrow cells were washed out with PBS buffer containing bovine serum albumin at a concentration of 0.2%, and 10 6 cells were removed and centrifuged. The supernatant was added with 30 ⁇ L of normal mouse serum to block the non-specific binding site, and then 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 incubated at 4 ° C for 30 min in the dark.
  • the number of hematopoietic stem cells in the saponin solid dispersion group of the present invention was significantly increased (P ⁇ 0.05), and there was no significant difference in the saponin group;
  • the number of hematopoietic stem cells in the saponin solid dispersion group of the present invention was significantly increased (P ⁇ 0.05).
  • the solid dispersion of saponin prepared by the invention effectively solves the problem of low solubility of the saponin, improves the bioavailability of the saponin, thereby improving the therapeutic effect of raising blood cells, and effectively preventing and treating bone marrow suppression. It is of great significance for the clinical application of saponin.

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

Abstract

L'invention concerne une dispersion solide de ziyuglucoside II de Sanguisorba officinalis, son procédé de préparation et ses applications, la formulation de la disperson solide de ziyuglucoside II de Sanguisorba officinalis étant constituée des excipients suivants, exprimés en poids : 1 partie de ziyuglucoside de Sanguisorba officinalis et 2-30 parties de polyvinylpyrrolidone.
PCT/CN2017/072226 2017-01-23 2017-01-23 Dispersion solide de ziyuglucoside ii de sanguisorba officinalis, son procédé de préparation et ses applications WO2018133106A1 (fr)

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PCT/CN2017/072226 WO2018133106A1 (fr) 2017-01-23 2017-01-23 Dispersion solide de ziyuglucoside ii de sanguisorba officinalis, son procédé de préparation et ses applications

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PCT/CN2017/072226 WO2018133106A1 (fr) 2017-01-23 2017-01-23 Dispersion solide 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
CN106580884A (zh) * 2015-10-16 2017-04-26 四川英路维特医药科技有限公司 一种地榆皂苷元固体分散体及其制备方法、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
CN106580884A (zh) * 2015-10-16 2017-04-26 四川英路维特医药科技有限公司 一种地榆皂苷元固体分散体及其制备方法、用途

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