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WO2018133108A1 - Émulsion de ziyuglucoside ii de sanguisorba officinalis et son procédé de préparation - Google Patents

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

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Publication number
WO2018133108A1
WO2018133108A1 PCT/CN2017/072228 CN2017072228W WO2018133108A1 WO 2018133108 A1 WO2018133108 A1 WO 2018133108A1 CN 2017072228 W CN2017072228 W CN 2017072228W WO 2018133108 A1 WO2018133108 A1 WO 2018133108A1
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WO
WIPO (PCT)
Prior art keywords
saponin
emulsion
parts
emulsion according
oil
Prior art date
Application number
PCT/CN2017/072228
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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/CN2017/072228 priority Critical patent/WO2018133108A1/fr
Publication of WO2018133108A1 publication Critical patent/WO2018133108A1/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
    • A61K31/70—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
    • A61K47/24—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
    • A61K47/44—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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • 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 emulsion and a preparation method 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.
  • 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 present invention provides a saponin II emulsion prepared by adding a raw material of the following weight ratio: 1 part of saponin II, 1-350 parts of oil phase, 0.5-40 parts of emulsifier.
  • the oil phase is selected from the group consisting of soybean oil, medium chain triglyceride, fish oil, olive oil, ethyl oleate, castor oil, or a mixture of two or more; the emulsifier is selected from the group consisting of egg yolk eggs.
  • the emulsifier is selected from the group consisting of egg yolk eggs.
  • it further comprises 0.5 to 5 parts of a stabilizer and 1 to 10 parts of an isotonicity adjusting agent.
  • the stabilizer is oleic acid; and the isotonicity adjusting agent is glycerin.
  • saponin II is prepared from the following raw materials by weight ratio: 1 part of saponin II, 300 parts of soybean oil, 20 parts of soybean phospholipid, 0.5 part of oleic acid, 1 part of glycerin, and water is added to the saponin II.
  • the concentration was 0.3 mg/mL.
  • the invention provides a preparation method of the emulsion, comprising the following steps:
  • step b removing the organic solvent in the mixed solution of step a, and then adding a stabilizer, glycerin and water;
  • the organic solvent is ethanol
  • the shearing condition is: shearing at 10,000 rpm for 5 min
  • the homogenizing condition is: homogenizing 4 times under a pressure of 800 bar.
  • the invention provides the use of the emulsion in the manufacture of a medicament for the treatment and/or prevention of myelosuppression.
  • the present invention provides the use of the emulsion in the manufacture of a medicament for increasing the number of blood cells and hemoglobin.
  • the present invention provides a method of treating and/or preventing myelosuppression using the emulsion.
  • the present invention provides a method of raising the number of blood cells and hemoglobin using the emulsion.
  • the invention adopts a specific kind and proportion of auxiliary materials, and can prepare the saponin II as a better quality emulsion.
  • the saponin II emulsion of the present invention can significantly increase the number of peripheral blood WBC, RBC, PLT, NEUT and HGB, and the drug effect is obviously superior to that of the saponin II drug, indicating the invention
  • the preparation of the saponin II as an emulsion can improve the bioavailability of the main drug, enhance its blood cell number, and prevent bone marrow suppression.
  • 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 commercially available through purchase. Product acquisition.
  • the preparation method comprises the following steps: mixing the saponin II, the oil and the phospholipid, dissolving in ethanol, and removing the ethanol by rotary evaporation under reduced pressure, and adding the oil according to the weight ratio of the saponin II: oleic acid: glycerin 1:0.5:1. Acid, glycerin, adding water to the emulsion, the concentration of saponin II is 0.3mg/mL, high-speed shearing at 10000rpm for 5min, high pressure homogenization at 800bar pressure for 4 times, autoclaving, that is.
  • the quality of the saponin II emulsion can be prepared, and the appearance of the emulsion has no delamination, flocculation, sticking, etc.
  • the experimental group 6 and other experimental groups The particle size and Ke value of the emulsion were significantly reduced (P ⁇ 0.05), indicating that the most suitable excipients for the preparation of the saponin II emulsion were: soybean oil as the oil phase, soybean phospholipid as the emulsifier, and oleic acid as the stabilizer.
  • Glycerin is an osmotic pressure regulator.
  • the saponin II soybean oil: soybean phospholipid weight ratio in the range of 1:1 ⁇ 350: 0.5 ⁇ 40, can produce better quality emulsion; among them, experimental group 6 compared with other experimental groups
  • Test drug The group of the saponin II fat emulsion solution (A, B, C, D, E, F, G) prepared according to Example 1, the saponin II 10% DMSO-salt group.
  • tool drugs cyclophosphamide.
  • mice All animals were fed ad libitum for 1 week and were randomly divided into: blank group; model group; different prescriptions of saponin II emulsion group (A, B, C, D, E, F, G), formulated into 2.5 mg ⁇ 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, prepared before use.
  • saponin II group saponin II powder, dissolved in 10% DMSO-physiological saline, formulated into 2.5mg ⁇ 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.
  • the blank group of mice was injected with an equal volume of normal saline in the tail vein.
  • Each experimental group was given the corresponding drug at the dose and iv 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 0.2% bovine serum albumin, and 106 cells were removed and centrifuged. 30 ⁇ L of normal mouse serum was added to block the non-specific binding site, 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 emulsion group of the present invention was significantly increased (P ⁇ 0.05), and there was no significant difference in the saponin II group; In comparison, the number of hematopoietic stem cells in the saponin II emulsion group of the present invention was significantly increased (P ⁇ 0.05).

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

Abstract

L'invention concerne une émulsion de ziyuglucoside II de Sanguisorba officinalis et son procédé de préparation, dont les excipients renferment : 1 partie de ziyuglucoside II de Sanguisorba officinalis, 1-350 parties de phase huileuse et 0,5-40 parties d'émulsifiant. L'émulsion selon l'invention trouve des applications dans la préparation d'un médicament pour le traitement et/ou la prophylaxie de la myélosuppression et dans la préparation d'un médicament destiné à augmenter les globules sanguins et le taux d'hémoglobine.
PCT/CN2017/072228 2017-01-23 2017-01-23 Émulsion de ziyuglucoside ii de sanguisorba officinalis et son procédé de préparation WO2018133108A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/CN2017/072228 WO2018133108A1 (fr) 2017-01-23 2017-01-23 Émulsion de ziyuglucoside ii de sanguisorba officinalis et son procédé de préparation

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2017/072228 WO2018133108A1 (fr) 2017-01-23 2017-01-23 Émulsion de ziyuglucoside ii de sanguisorba officinalis et son procédé de préparation

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WO2018133108A1 true WO2018133108A1 (fr) 2018-07-26

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103690618A (zh) * 2013-02-26 2014-04-02 江西本草天工科技有限责任公司 白头翁总皂苷口服乳剂及其制备方法
CN106551906A (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乳剂及其制备方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103690618A (zh) * 2013-02-26 2014-04-02 江西本草天工科技有限责任公司 白头翁总皂苷口服乳剂及其制备方法
CN106551906A (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乳剂及其制备方法

Non-Patent Citations (2)

* 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 DEVELOPMEN T, 7 April 2016 (2016-04-07), pages 852 - 859, ISSN: 1001-6880 *
YU , QI'NAN: "The Pharmaceutical Research of Sanguisorba Officinalis Dispersing Table t", MEDICINE & PUBLIC HEALTH, CHINA MASTER'S THESES FULL-TEXT DATABASE, 15 May 2016 (2016-05-15), pages E057 - 360, ISSN: 1674-0246 *

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