+

WO2018133109A1 - Liposome de ziyuglucoside ii de sanguisorba officinalis et son procédé de préparation - Google Patents

Liposome de ziyuglucoside ii de sanguisorba officinalis et son procédé de préparation Download PDF

Info

Publication number
WO2018133109A1
WO2018133109A1 PCT/CN2017/072229 CN2017072229W WO2018133109A1 WO 2018133109 A1 WO2018133109 A1 WO 2018133109A1 CN 2017072229 W CN2017072229 W CN 2017072229W WO 2018133109 A1 WO2018133109 A1 WO 2018133109A1
Authority
WO
WIPO (PCT)
Prior art keywords
saponin
liposome
carrier material
weight ratio
liposome according
Prior art date
Application number
PCT/CN2017/072229
Other languages
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.)
Filing date
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/CN2017/072229 priority Critical patent/WO2018133109A1/fr
Publication of WO2018133109A1 publication Critical patent/WO2018133109A1/fr

Links

Images

Classifications

    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • 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
    • A61K47/28—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
    • 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
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • 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 II liposome and a preparation method thereof, relating 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.
  • Diltiazem II is a mantle from the genus Rosaceae or A pharmacologically active compound is extracted from the roots of the longleaf mantle.
  • CN101119740A discloses the use of saponin II in the preparation of a medicament for increasing red blood cells and hemoglobin.
  • saponin II is not effective, and it is often difficult to obtain a better blood cell level and a bone marrow suppression treatment when used alone. Therefore, there is an urgent need to improve the efficacy of the saponin II and promote the clinical application of the drug.
  • the protective agent is selected from one or a mixture of two or more of glucose, sucrose, trehalose, fructose, mannitol or lactose.
  • the invention provides a preparation method of the liposome, comprising the following steps:
  • step b removing the organic solvent in the mixed solution of step a, and then adding a protective agent and water to the concentration of saponin II is 0.2 mg / mL;
  • the organic solvent is ethanol
  • the homogenization condition is: homogenization 4 times under a pressure of 1000 bar
  • the sterilization condition is: 0.22 ⁇ m microporous membrane filtration sterilization.
  • the invention provides the use of the liposomes in the manufacture of a medicament for the treatment and/or prevention of myelosuppression.
  • the present invention provides the liposome in the preparation of a drug for raising the number of blood cells and hemoglobin use.
  • the present invention provides a method of treating and/or preventing myelosuppression using the liposome.
  • the present invention provides a method of increasing the number of blood cells and hemoglobin using the liposome.
  • the reason that the effect of the saponin II on raising the blood cell level is poor is that the solubility is low and the gastrointestinal absorption rate is small, resulting in low bioavailability of the drug and limiting the exertion of its efficacy.
  • the mixed lipid of HSPC, DSPE-PEG 2000 and cholesterol is used as a carrier material, and the saponin II can be prepared into a liposome of better quality.
  • the saponin II liposome of the present invention can significantly increase the number of WBC, RBC, PLT, NEUT and HGB in the peripheral blood, and the drug effect is obviously superior to that of the saponin II drug, indicating that the present invention
  • the invention can improve the bioavailability of the main drug, and increase the blood cell number and prevent bone marrow suppression by preparing the saponin II into a liposome.
  • Figure 1 is a graph comparing the counts of bone marrow hematopoietic stem cells in mice of each experimental group.
  • 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.
  • Hydrogenated Soy Lecithin (HSPC), distearoylphosphatidylethanolamine-polyethylene glycol 2000 (DSPE-PEG 2000), cholesterol, and stigmasterol were purchased from Hangzhou Dayang Chemical Co., Ltd.; lecithin was purchased from Chubby Corporation of Japan.
  • Glucose, sucrose, trehalose, fructose, mannitol, lactose, starch, and cellulose were purchased from Jiangsu Manshi Biotechnology Co., Ltd.
  • Preparation method Mixing saponin II with total lipid (composed of HSPC, DSPE-PEG 2000 and cholesterol), dissolving in ethanol, removing ethanol by rotary evaporation under reduced pressure, adding sugar and water to make liposome suspension
  • concentration of the saponin II was 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 drug content was determined by HPLC-ELSD, and the particle size results were measured by a Malvern particle size analyzer.
  • the PDI is tested using a particle size analyzer.
  • the mixed lipids of 0.5mg of saponin II 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.
  • 5 mg of sucrose and water were used to make the concentration of saponin II in the liposome suspension 0.2 mg/mL, high pressure homogenization 4 times under a pressure of 1000 bar, and 0.22 ⁇ m microporous membrane filtration sterilization.
  • the entrapment efficiency, particle size distribution and dispersion index (PDI) of the saponin II in the liposome were measured. The results are shown in Table 1.
  • the quality of the saponin II 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 65%, the average particle size is below 220 nm, and the dispersion is The index (PDI) is less than 0.125; using the other two excipients, lecithin or stigmasterol, results in a significant decrease in the encapsulation efficiency and particle size uniformity of the drug, and the average particle size of the liposome is large.
  • the above results indicate that the mixed lipid of HSPC, DSPE-PEG 2000 and cholesterol is the most suitable carrier material for preparing the saponin II liposome.
  • HSPC DSPE-PEG 2000: cholesterol weight ratio of 5:1:1, the prepared saponin II liposome encapsulation efficiency, average particle size, dispersion index (PDI) and other indicators are the best.
  • the saponin II and total lipid were weighed according to the mass ratio shown in Table 2 (fixed saponin II mass 0.5 mg, total lipid) The mass is changed according to the ratio), dissolved in ethanol, and the ethanol is removed by rotary evaporation under reduced pressure. 5 mg of sucrose and water are added to make the concentration of saponin II in the liposome suspension 0.2 mg/mL, and the pressure is high pressure homogeneous under 1000 bar. The 0.22 ⁇ m microporous membrane was sterilized by filtration. The entrapment efficiency, average particle size and dispersion index (PDI) of the saponin II in the liposome were measured, and the results are shown in Table 2.
  • Table 2 The saponin II and total lipid
  • Test drug The saponin II liposome group (A, B, C, D, E, F) and the saponin II 10% DMSO-salt group prepared according to Example 1.
  • tool drugs cyclophosphamide.
  • mice All animals were adaptively fed for 1 week and were randomly divided into: blank group; model group; saponin II liposome group (A, B, C, D, E, F) prepared according to different prescriptions of Example 1, Formulated into 2.5mg ⁇ kg -1 suspension, prepared before use; saponin II group: saponin II powder, dissolved in 10% DMSO-physiological saline, formulated into 2.5mg ⁇ kg -1 suspension, Prepare 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.
  • the experimental groups were given the corresponding drugs by dose and tail vein 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 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 II liposome group of the present invention was significantly increased (P ⁇ 0.05), and there was no significant difference in the saponin II group; Compared with the group II, the number of hematopoietic stem cells in the saponin II liposome group of the present invention was significantly increased (P ⁇ 0.05).

Landscapes

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

Abstract

L'invention concerne un liposome de ziyuglucoside II 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 pourl la préparation d'un médicament indiqué pour augmenter le nombre de globules sanguins et le taux d'hémoglobine. Ce liposome de ziyuglucoside II de Sanguisorba officinalis comprend 1 partie de ziyuglucoside et 2-15 parties de vecteur caractérisé en ce qu'il est constitué partiellement des ingrédients suivants selon le rapport de poids qui suit : distéaroyl phosphatidylethanolamine-polyéthylène glycol 2000 : choléstérol = 5 : (1-4) : (1-2).
PCT/CN2017/072229 2017-01-23 2017-01-23 Liposome de ziyuglucoside ii de sanguisorba officinalis et son procédé de préparation WO2018133109A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/CN2017/072229 WO2018133109A1 (fr) 2017-01-23 2017-01-23 Liposome de ziyuglucoside ii de sanguisorba officinalis et son procédé de préparation

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2017/072229 WO2018133109A1 (fr) 2017-01-23 2017-01-23 Liposome de ziyuglucoside ii de sanguisorba officinalis et son procédé de préparation

Publications (1)

Publication Number Publication Date
WO2018133109A1 true WO2018133109A1 (fr) 2018-07-26

Family

ID=62907655

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2017/072229 WO2018133109A1 (fr) 2017-01-23 2017-01-23 Liposome de ziyuglucoside ii de sanguisorba officinalis et son procédé de préparation

Country Status (1)

Country Link
WO (1) WO2018133109A1 (fr)

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
CN106551907A (zh) * 2015-09-18 2017-04-05 四川英路维特医药科技有限公司 一种地榆皂苷ⅱ脂质体及其制备方法

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
CN106551907A (zh) * 2015-09-18 2017-04-05 四川英路维特医药科技有限公司 一种地榆皂苷ⅱ脂质体及其制备方法

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, 30 June 2016 (2016-06-30), pages 852 - 859, ISSN: 1001-6880 *

Similar Documents

Publication Publication Date Title
US20130190394A1 (en) Applications Of Arctigenin In Formulating Drugs For Preventing Or Treating Diseases Related To Red Blood Cell Reduction
EP4132548A1 (fr) Compositions comprenant des nanoparticules et leur procédé de préparation et d'utilisation
EP3500312B1 (fr) Administration d'urée à des cellules de la macula et de la rétine à l'aide de constructions de liposomes.
Luo et al. MPEG-PCL nanomicelles platform for synergistic metformin and chrysin delivery to breast cancer in mice
CN116474114A (zh) 一种载分子靶向药物聚合物囊泡及其制备方法与应用
CN108201540A (zh) 富勒烯结构在制备治疗白血病的药物中的应用
WO2018133109A1 (fr) Liposome de ziyuglucoside ii de sanguisorba officinalis et son procédé de préparation
CN106580881A (zh) 一种地榆苷元脂质体及其制备方法、用途
WO2018133113A1 (fr) Liposome d'aglycone de sanguisorba officinalis, son procédé de préparation et ses applications
US10493029B2 (en) Ziyuglycoside II polymer micelle and preparative methods thereof
WO2018133112A1 (fr) Injection d'aglycone de sanguisorba officinalis, son procédé de préparation et ses applications
WO2017181653A1 (fr) Micelle polymère à base de sapogénine de radix sanguisorbae, son procédé de préparation, et son utilisation pharmaceutique
WO2018133108A1 (fr) Émulsion de ziyuglucoside ii de sanguisorba officinalis et son procédé de préparation
CN106581692A (zh) 一种地榆皂苷i包合物及其制备方法
WO2018133106A1 (fr) Dispersion solide de ziyuglucoside ii de sanguisorba officinalis, son procédé de préparation et ses applications
Wang et al. As4S4 nanoparticles promote effective terminal erythropoiesis in bone marrow mononuclear cells from patients with myelodysplastic syndromes
CN114788811A (zh) 一种盐酸吉西他滨壳聚糖胶束及其制备方法
CN106551907A (zh) 一种地榆皂苷ⅱ脂质体及其制备方法
WO2018133105A1 (fr) COMPLEXE D'INCLUSION D'HYDROXYPROPYL-β-CYCLODEXTRINE DE ZIYUGLUCOSIDE II DE SANGUISORBA OFFICINALIS, SON PROCÉDÉ DE PRÉPARATION ET SES APPLICATIONS
CN106580882A (zh) 一种地榆皂苷i脂质体及其制备方法
WO2018133111A1 (fr) Injection de ziyuglucoside ii de sanguisorba officinalis, son procédé de préparation et ses applications
Daliri et al. Application of Golden Nanoparticles against Streptococcus Mutans for Prevention of Caries Lesions
CN109200098A (zh) 一种抑制耐多药结核杆菌的联合用药物
WO2018133110A1 (fr) Dispersion solide de ziyuglucoside ii de sanguisorba officinalis et son procédé de préparation
CN114042056B (zh) 雷公藤内酯甲吸入制剂在治疗肺炎药物中的应用

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17892188

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 17892188

Country of ref document: EP

Kind code of ref document: A1

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载