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WO2015188428A1 - Médicament pour le traitement du syndrome métabolique - Google Patents

Médicament pour le traitement du syndrome métabolique Download PDF

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Publication number
WO2015188428A1
WO2015188428A1 PCT/CN2014/083363 CN2014083363W WO2015188428A1 WO 2015188428 A1 WO2015188428 A1 WO 2015188428A1 CN 2014083363 W CN2014083363 W CN 2014083363W WO 2015188428 A1 WO2015188428 A1 WO 2015188428A1
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WIPO (PCT)
Prior art keywords
metabolic syndrome
medicament
group
treatment
curcumin
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Ceased
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PCT/CN2014/083363
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English (en)
Chinese (zh)
Inventor
刘丽宏
宫丽丽
吕亚丽
刘河
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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

Definitions

  • the present invention relates to the field of medical technology, and mainly relates to a medicament for treating metabolic syndrome. Background technology
  • Metabolic syndrome is characterized by a group of metabolic risk factors, including abdominal obesity, insulin resistance or glucose intolerance, atherogenic dyslipidemia, prethrombotic state.
  • the Adult Treatment Panel is defined as the metabolic syndrome: waist circumference measures at least 40 inches for men and 35 inches for women; serum triglyceride levels are at least 150 mg/dl; HDL cholesterol levels are lower for men. 40mg/dl, women below 50mg/dl, blood pressure at least 135/80mm Hg and blood glucose (serum glucose) at least 110mg/dl. It is estimated that up to 25% of the population in the United States suffers from metabolic syndrome. The underlying cause of the metabolic syndrome is insulin resistance, in which insulin's ability to take up glucose in the blood is impaired.
  • metabolic syndrome significantly increases the risk of type 2 diabetes, cardiovascular disease, and other diseases involving atherosclerotic plaque buildup in the arterial wall.
  • drugs for the treatment of metabolic syndrome generally focus on the treatment of one of the metabolic disorders.
  • the present invention provides a medicament for use in the treatment of metabolic syndrome, characterized in that the pharmaceutical composition thereof is expressed by mass percentage, and includes:
  • the medicinal ingredients are expressed by mass percent, including:
  • the medicament for use in the treatment of metabolic syndrome can be formulated as a tablet, a capsule or an injection.
  • a drug is used to treat metabolic syndrome.
  • the medicament is for the treatment and prevention of diabetes, obesity, insulin resistance, hypercholesterolemia and hypertension.
  • the medicament is for the treatment and prevention of hyperlipidemia.
  • the medicament is for the treatment and prevention of increased serum triacylglycerol concentrations.
  • the diabetic patient has a fasting blood glucose level between 125 mg/dl and 200 mg/dl.
  • the drug reduces the fasting blood glucose level of the patient to below 11 mg/dl.
  • the drug For people defined as having metabolic syndrome, they must have:
  • TG Elevated triglyceride
  • HDL high-density lipoprotein
  • Elevated blood pressure (BP) contraction of BP 130 or diastolic BP 85 mm Hg, or treatment of previously diagnosed hypertension;
  • Elevated fasting blood glucose 100 mg/dL (5.6 mmol/L), or previously diagnosed type 2 diabetes, if higher than 5.6 mmol/L or 100 mg/dL.
  • the saponin D has the effect of lowering blood lipids.
  • Curcumin is a yellow pigment extracted from the rhizome of the ginger family, such as turmeric. It is an acidic polyphenolic substance, and the main chain is an unsaturated aliphatic and aromatic group. It is commonly used as a coloring agent for meat products and an acid-base indicator, and has pharmacological effects such as anti-inflammatory and anti-oxidation.
  • the beneficial effects of the invention are that the medicament of the invention can regulate the metabolic process of protein, lipid and carbohydrate of the patient, and has a good preventive and therapeutic effect on the metabolic syndrome, and the medicinal component of the medicament of the invention
  • the saponins D and curcumin are obtained from natural Chinese medicines.
  • the refining method is relatively simple.
  • the saponins D and curcumin are less toxic and meet the national safety standards.
  • curcumin is internationally recognized.
  • Food coloring, good development prospects, and these two medicinal ingredients can be purchased at ordinary pharmacies, the price is moderate, according to the mass percentage ratio of the medicine according to the invention, the effect is good for treating metabolic syndrome, and is suitable for ordinary patients. , can be mass produced.
  • Figure 1 is a graph showing the effect of a drug for treating metabolic syndrome on liver cell viability according to the present invention.
  • Figure 2 is a graph showing the effects of the drug for treating metabolic syndrome on the lipid deposition induced by palmitic acid PA in the present invention (Fig. 2a is a standard group, Fig. 2b model group, Fig. 2c-2e are a drug group).
  • Fig. 3 is a graph showing the change of lipid content in hepatocytes induced by PA for the treatment of metabolic syndrome according to the present invention (Fig. 3a is a standard group, Fig. 3b model group, Fig. 3c - Fig. 3e are a drug group).
  • Fig. 5 is a bar graph of the effect of PA-induced hepatocyte apoptosis rate in the treatment of metabolic syndrome according to the present invention.
  • Figure 6 is a graph showing the effect of the drug of the present invention for treating metabolic syndrome on serum transaminase levels in mice.
  • Figure 7 is a graph showing the effect of the drug for treating metabolic syndrome on hepatic steatosis in fatty liver mice.
  • Fig. 8 is a pharmacodynamic study of a medicament for treating metabolic syndrome according to the present invention for preventing insulin resistance.
  • Figure 9 is a graph showing the effect of the drug for treating metabolic syndrome on the glucose metabolism of adipocytes according to the present invention.
  • the medicament for treating metabolic syndrome is characterized in that the medicinal component thereof is in mass percentage, and includes: saponin D 70%, curcumin 30%.
  • a medicament for treating metabolic syndrome characterized in that its medicinal component is in mass percentage, including: saponin D 80%, curcumin 20%.
  • the medicament for treating metabolic syndrome is characterized in that the medicinal component thereof is in mass percentage, and includes: saponin D 90%, curcumin 10%.
  • the drug for treating metabolic syndrome of the present invention is used according to the mass percentage of the drug in Example 3.
  • Formulating the basic drug and applying the test method to detect the therapeutic effect of the drug for treating metabolic syndrome The cell experiment is to dissolve the drug in the above ratio in dimethyl sulfoxide (DMSO) for dosing, and the mouse experiment is to use the above ratio drug A suspension is prepared for oral gavage.
  • DMSO dimethyl sulfoxide
  • FBS fetal bovine serum
  • DMSO dimethyl sulfoxide
  • MTT tetramethyl azozolium salt
  • Method Take the logarithmic growth phase BRL cells, digest and make a single cell suspension, and adjust the cell concentration of 5 ⁇ 10 4 /mL cells to culture in 96-well plate. After the cells are attached, change the medium to the medium. The mixed drug of saponin D and curcumin was added to make the final concentration of the mixed drug in the medium 25, 50, 100, 200, 400, 800 ⁇ /L, and after incubation for 48 h, 10 MTT was added to each well.
  • Fig. 1 show that as the drug concentration is gradually decreased, the cell viability is gradually decreased, and the cell survival rate is gradually decreased, indicating that the drug for treating metabolic syndrome of the present invention has a significant influence on cell protein metabolism.
  • the logarithmic phase cells were counted and seeded in 6-well plates at 10,000 per well.
  • the cells were grouped into: normal group (cultured in normal medium), model group (induced by palmitic acid PA), saponin D and Curcumin combined with low, medium and high concentrations (25, 50, 100 ⁇ / L) pre-protection group.
  • the medium was discarded, phosphate buffer PBS was washed 3 times, 4% neutral formaldehyde was fixed for 30 min, boron fluoride dipyrrole (Bodipy) 493/503 was fluorescently stained for 30 min, PBS was washed 3 times, and fluorescence was observed. Under the microscope, observe the intracellular lipid deposition.
  • the OD value of the model group 3b was significantly increased (PO.05); compared with the model group, the saponin
  • the OD values of the D and curcumin combination dose groups (Fig. 3c, Fig. 3d and Fig. 3e) were all decreased, and the high dose group was statistically significant (PO.05) (see Fig. 3), indicating that the saponin D Combined with curcumin can inhibit lipid deposition in hepatocytes.
  • the logarithmic phase cells were counted and seeded in 6-well plates at 10,000 per well.
  • the cells were grouped into: normal group (cultured in normal medium), model group (induced by PA), saponin D and curcumin Combination therapy low, medium and high concentration (25, 50, 100 ⁇ / L) pre-protection group.
  • the medium was discarded, washed 3 times with PBS, and collected by trypsin digestion without ethylenediaminetetraacetic acid (EDTA); the cells were washed twice with PBS (centrifugation at 2000 rpm for 5 min). l ⁇ 5xl0 was collected.
  • the apoptosis rate of the intervention protection group was 1.00 ⁇ 0.10, 6.80 ⁇ 0.45, 6.60 ⁇ 0.10, 4.90 ⁇ 0.15, 1.70 ⁇ 0.10.
  • the apoptosis rate of BRL cells induced by palmitic acid PA was significantly higher than that of the normal control group (p ⁇ 0.05).
  • the apoptosis rate of the cells treated with the combination of Mutong saponin D and curcumin was higher than that of the PA group.
  • mice Thirty-one ob/ob mice, weighing 37 ⁇ 2 g, were randomly divided into 4 groups, namely the model group, the saponins D low, medium and high dose treatment groups, 9 in each group.
  • the mice in the normal control group were C57BL/6J wild type mice, 9 rats weighing 20 ⁇ 2 g.
  • the mice were housed in SPF laboratory animals and fed freely. After the mice were fed with the basic diet for one week, the normal mice continued to feed the basal diet, and the other experimental mice were fed with high-fat diet, and the high-fat diet was administered with the intervention treatment.
  • the mice in the normal group and the model group were given the same amount of normal saline by intraperitoneal injection.
  • the low, medium and high doses of the combination of saponin D and curcumin were administered intraperitoneally with 30, 60, 120 mg/kg saponins D and turmeric.
  • the drug is dissolved in physiological saline.
  • One injection per day was given intraperitoneally for 4 weeks.
  • the rats were fasted for 24 hours, and the body weight was weighed.
  • the mice were sacrificed by taking the eyeballs and the mice were sacrificed by centrifugation.
  • the serum was separated by centrifugation.
  • the total cholesterol (TC), triglyceride (TG) and low density lipid were determined by the kit. Protein cholesterol
  • LDL-C high-density lipoprotein cholesterol
  • HDL-C high-density lipoprotein cholesterol
  • AST aspartate aminotransferase
  • ALT alanine aminotransferase
  • the results in Table 3 showed that compared with the model group mice, the levels of GSH-PX and SOD in the mice of the combination of saponins D and curcumin were significantly increased, and the levels of MDA were significantly decreased, and the dose was present.
  • Dependence P ⁇ 0.05.
  • the results in Figure 7 show that the liver of the normal group is dark red, the surface is smooth, the edges are sharp, and the texture is soft.
  • the liver of the model group is larger than the normal group, the color is yellow, the edges are dull, the texture is brittle, and the cut surface is greasy.
  • the liver color and texture of the rats in each dose group were significantly improved compared with the model control group.
  • the liver pathological sections were observed under the microscope.
  • the liver lobules of the normal group were clear in structure, the cells were arranged neatly, the size was uniform, the boundary was clear, the nucleus was located in the center of the cell, round and clear, no fat vacuoles were found in the cytoplasm, and no fat degeneration or necrosis occurred.
  • Model group Hepatocytes showed varying degrees of steatosis, the cell volume became significantly larger, the nucleus was squeezed at the edge, and there were a lot of fat vacuoles in the cytoplasm, similar in morphology to fat cells.
  • the liver cells of the mice in each dose group were mildly disordered, and the hepatic steatosis and cytoplasmic lipid droplet deposition were improved to some extent, and the improvement was most obvious in the high dose group.
  • 3T3-L1 preadipocytes differentiate into adipocytes and are divided into normal group, model group (IR), positive drug group (rosiglitazone, Ros 20 ⁇ /mL), combined with low, medium and high concentrations (50, 100)
  • IR model group
  • rosiglitazone Ros 20 ⁇ /mL
  • 50, 100 low, medium and high concentrations
  • the 20 ( ⁇ g/mL) group insulin was added at a concentration of 1.7 ⁇ /L.
  • the other groups were additionally added with dexamethasone of ⁇ . ⁇ ⁇ /L. After 48 hours of incubation, the cells were aspirated. In the supernatant, glucose was oxidized to detect residual glucose in the supernatant, and glucose consumed by the cells was calculated. The results are shown in Fig.
  • 3T3-L1 preadipocytes differentiate into adipocytes and are divided into normal group, model group (IR), positive drug group (rosiglitazone, Ros 20 ⁇ /mL), combined with low, medium and high concentrations (50, 100)
  • IR model group
  • rosiglitazone Ros 20 ⁇ /mL
  • low, medium and high concentrations 50, 100
  • the residual glucose was detected after 48 hours of direct dosing, and the consumed glucose was calculated.
  • Figure 9 The absorption of glucose by the fat cells in the combination of high concentration and high concentration Compared with the model group, there was a significant increase in metabolism, indicating that the combination can enhance the function of glucose uptake by cells to some extent.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Molecular Biology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un médicament pour traiter le syndrome métabolique, les ingrédients médicinaux de ceux-ci comprenant en pourcentage en masse : 60 % à 90 % de saponine d'akebia D, et 10 % à 30 % de la curcumine. Le médicament peut être réalisé sous la forme de comprimés, capsules ou injections, et peut prévenir ou traiter un syndrome métabolique par régulation des réactions métaboliques de protéines, de lipides et de glucides chez des patients.
PCT/CN2014/083363 2014-06-10 2014-07-31 Médicament pour le traitement du syndrome métabolique Ceased WO2015188428A1 (fr)

Applications Claiming Priority (2)

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CN201410256108.7 2014-06-10
CN201410256108.7A CN103977014B (zh) 2014-06-10 2014-06-10 一种应用于治疗代谢综合征的药物

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Cited By (1)

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CN118892490A (zh) * 2024-07-18 2024-11-05 中日友好医院(中日友好临床医学研究所) Asd在制备缓解/治疗高血压及并发症药物中的应用

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CN109628358B (zh) 2019-02-20 2021-03-19 无限极（中国）有限公司 一种复合益生菌及其应用
CN109666615B (zh) 2019-02-20 2021-03-19 无限极（中国）有限公司 一种益生菌组合物及其应用
CN111217885B (zh) * 2020-02-27 2021-05-18 首都医科大学附属北京朝阳医院 木通皂苷d-有机酸的药物共晶体及其用途

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CN102462688A (zh) * 2010-11-04 2012-05-23 中国人民解放军第二炮兵总医院 木通皂苷d在制备治疗与预防脂肪肝及其相关疾病的药物中的应用

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CN102462688A (zh) * 2010-11-04 2012-05-23 中国人民解放军第二炮兵总医院 木通皂苷d在制备治疗与预防脂肪肝及其相关疾病的药物中的应用

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ZHAO, HUIJUAN ET AL.: "Effects of Curcumin on TNF-a Level in Plasm and sICAM-1 Level in Serum of Metabolic Syndrome Rats", CHINESE JOURNAL OF REHABILITATION MEDICINE, vol. 21, no. 7, 31 July 2006 (2006-07-31), pages 599 - 601, XP009083918 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN118892490A (zh) * 2024-07-18 2024-11-05 中日友好医院(中日友好临床医学研究所) Asd在制备缓解/治疗高血压及并发症药物中的应用

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