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WO2018133113A1 - Liposome d'aglycone de sanguisorba officinalis, son procédé de préparation et ses applications - Google Patents

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

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Publication number
WO2018133113A1
WO2018133113A1 PCT/CN2017/072233 CN2017072233W WO2018133113A1 WO 2018133113 A1 WO2018133113 A1 WO 2018133113A1 CN 2017072233 W CN2017072233 W CN 2017072233W WO 2018133113 A1 WO2018133113 A1 WO 2018133113A1
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WO
WIPO (PCT)
Prior art keywords
liposome
carrier material
mantle
aglycone
weight ratio
Prior art date
Application number
PCT/CN2017/072233
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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
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Publication date
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Priority to PCT/CN2017/072233 priority Critical patent/WO2018133113A1/fr
Publication of WO2018133113A1 publication Critical patent/WO2018133113A1/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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • 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
    • A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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 mantle aglycone liposome, 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 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:
  • CN101119740A discloses the use of saponin II in the preparation of a medicament for increasing red blood cells and hemoglobin.
  • saponin II in the preparation of a medicament for increasing red blood cells and hemoglobin.
  • the geniposide 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 the geniposide.
  • An object of the present invention is to provide a guanosine aglycon liposome, a preparation method thereof and use thereof.
  • HSPC hydrogenated soybean lecithin
  • DSPE-PEG 2000 distearoylphosphatidylethanolamine-polyethylene glycol 2000.
  • the protective agent is selected from one or a mixture of two or more of glucose, sucrose, trehalose, fructose, mannitol or lactose.
  • the invention also provides a preparation method of the above liposome, comprising the following steps:
  • step b removing the organic solvent in the mixed solution of step a, and adding a protective agent and water;
  • the organic solvent described in the step a is ethanol; in the step b, after adding the protective agent and water, the concentration of the geniposide is 0.2 mg/mL; in the step c, the homogenous condition is: 1000 bar The mixture was homogenized 4 times under pressure; the sterilization condition was: 0.22 ⁇ m microporous membrane filtration sterilization.
  • the present invention also provides the use of the above liposome for the preparation of a medicament for the treatment and/or prevention of myelosuppression.
  • the present invention also provides the use of the above liposome for the preparation of a medicament for increasing the number of one or more of peripheral blood leukocytes, neutrophils, red blood cells, platelets, hemoglobin or bone marrow hematopoietic stem cells.
  • the invention also provides a method of treating and/or preventing myelosuppression, in particular using the aforementioned solid liposomes.
  • 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 liposomes.
  • the inventors found that the reason that the effect of the cellar aglycone on the elevated blood cell level is poor is that its solubility is low and the gastrointestinal absorption rate is small, which leads to low bioavailability of the drug and limits its efficacy.
  • the scorpion aglycone liposome prepared by the invention can significantly increase the number of peripheral blood leukocytes, neutrophils, red blood cells, platelets, hemoglobin and bone marrow hematopoietic stem cells, and the pharmacological effect is obviously superior to the scorpion aglycone original drug, indicating
  • the preparation of the diterpene aglycone into a liposome can improve the bioavailability of the main drug, enhance the blood cell number and prevent bone marrow suppression.
  • 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.
  • Prescription seven (G): 1 mg of mantle aglycon and 20 mg of carrier material (HSPC: DSPE-PEG 2000: cholesterol 5:1:1, ie, HSPC 14 mg, DSPE-PEG 2000 3 mg, cholesterol 3 mg), and sucrose 5 mg.
  • aglycone ie, saponin
  • total lipid composed of HSPC, PEG 2000-DSPE and cholesterol
  • sugar corresponding glucose, sucrose
  • trehalose fructose
  • mannitol mannitol or lactose
  • appropriate amount of water so that the concentration of the aglycone in the liposome suspension is 0.2 mg / mL
  • high pressure homogenization 4 times under 1000 bar pressure, 0.22 ⁇ m microporous membrane Filter and sterilize, that is.
  • the drug content was determined by HPLC-ELSD, the particle size was measured by a Malvern particle size analyzer, and the PDI was detected by a particle size analyzer.
  • the mixed lipids of 1mg of scutellarin and different carrier materials HSPC, DSPE-PEG 2000, cholesterol, lecithin and stigmasterol were mixed at a mass ratio of 1:20, dissolved in ethanol, and ethanol was removed by rotary evaporation under reduced pressure, and 5 mg was added.
  • Sucrose and water were used to make the concentration of the aglycone in the liposome suspension 0.2 mg/mL, and the pressure was high pressure 4 times under the pressure of 1000 bar, and the 0.22 ⁇ m microporous membrane was filtered and sterilized.
  • the encapsulation efficiency, particle size distribution and dispersion index (PDI) of the indole aglycone in the liposome were measured. The results are shown in Table 1.
  • the quality of the mantle aglycone liposome prepared by using the mixed lipid of HSPC, DSPE-PEG 2000 and cholesterol as the carrier material is better: the encapsulation efficiency is above 70%, and the average particle diameter is below 215 nm.
  • the dispersion index (PDI) is less than 0.127, the effect is significantly better than other excipients and proportioning group (P ⁇ 0.05); using the other two excipients lecithin or stigmasterol, the drug encapsulation rate and particle size uniformity are significantly reduced. And the average particle size of the liposome is large.
  • HSPC DSPE-PEG 2000: cholesterol weight ratio of 5:1:1, the prepared mantle aglycons liposome encapsulation efficiency, average particle size, dispersion index (PDI) and other indicators are the best.
  • the bacteria were sterilized by filtration through a 0.22 ⁇ m microporous membrane.
  • the encapsulation efficiency, average particle size and dispersion index (PDI) of the indole aglycone in the liposome were measured. The results are shown in Table 2.
  • test drug was prepared with different excipients to prepare the aglycone liposome solution group (A, B, C, D, E, F, G) and the mantle aglycone 10% DMSO-saline group.
  • tool drugs cyclophosphamide.
  • All animals were fed ad libitum for 1 week and were randomly divided into: blank group; model group; different prescriptions of mantle aglycone liposome group (A, B, C, D, E, F, G). 2.5mg ⁇ kg -1 suspension, prepared before use; mantle aglycone group: mantle aglycone powder, dissolved in 10% DMSO-physiological saline, formulated into 2.5mg ⁇ kg -1 suspension, use Pre-formulation.
  • mice 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.
  • Each experimental group was given the corresponding drug by dose and tail vein from the first day of the experiment, and the blank group and The model group mice were injected with an equal 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 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 scorpion aglycone liposome group of the present invention was significantly increased (P ⁇ 0.05), and there was no significant difference in the scutellarin group;
  • the number of hematopoietic stem cells in the scorpion aglycone liposome group of the present invention was significantly increased (P ⁇ 0.05).
  • the mantle aglycone liposome prepared by the invention effectively solves the problem of low solubility of the mantle aglycone, improves the bioavailability of the mantle aglycone, thereby improving the therapeutic effect of raising blood cells, and effectively preventing and preventing bone marrow suppression. It is of great significance for the clinical application of geniposide.

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

Abstract

L'invention concerne un liposome d'aglycone de Sanguisorba officinalis, son procédé de préparation et ses applications pour la préparation d'un médicament pour le traitement et/ou la prévention de la myélosuppression et indiqué pour augmenter les globules sanguins et le taux d'hémoglobine. Ce liposome d'aglycone de Sanguisorba officinalis comprend 1 partie d'aglycone de Sanguisorba officinalis et 2-40 parties d'un vecteur caractérisé en ce qu'il est constitué partiellement des ingrédients suivants selon le rapport de poids qui suit : lécithine de soja hydrogénée : distéaroyl phosphatidylethanolamine-polyéthylène glycol 2000 : choléstérol = 5 : (1-4) : (1-2).
PCT/CN2017/072233 2017-01-23 2017-01-23 Liposome d'aglycone de sanguisorba officinalis, son procédé de préparation et ses applications WO2018133113A1 (fr)

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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
CN1850098A (zh) * 2006-02-27 2006-10-25 杭州创新中药标准化研究所有限公司 原人参二醇脂质体及其制备方法
CN106580881A (zh) * 2015-10-16 2017-04-26 四川英路维特医药科技有限公司 一种地榆苷元脂质体及其制备方法、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
CN1850098A (zh) * 2006-02-27 2006-10-25 杭州创新中药标准化研究所有限公司 原人参二醇脂质体及其制备方法
CN106580881A (zh) * 2015-10-16 2017-04-26 四川英路维特医药科技有限公司 一种地榆苷元脂质体及其制备方法、用途

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DAI, LIANGMIN ET AL.: "Protective Effect of Tannins from Sanguisorba Officinalis on Cyclophosphamide-induced Myelosuppression in Mice", NATURAL PRODUCT RESEARCH AND DEVELOPMENT, vol. 6, 30 June 2016 (2016-06-30), pages 852 - 859, ISSN: 1001-6880 *

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