WO2010133016A1 - Composition pharmaceutique destinée à traiter la dépression et procédé de préparation et utilisation de celle-ci - Google Patents

Composition pharmaceutique destinée à traiter la dépression et procédé de préparation et utilisation de celle-ci Download PDF

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Publication number
WO2010133016A1
WO2010133016A1 PCT/CN2009/001491 CN2009001491W WO2010133016A1 WO 2010133016 A1 WO2010133016 A1 WO 2010133016A1 CN 2009001491 W CN2009001491 W CN 2009001491W WO 2010133016 A1 WO2010133016 A1 WO 2010133016A1
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Prior art keywords
pharmaceutical composition
weight
parts
ginsenoside
depression
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PCT/CN2009/001491
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English (en)
Chinese (zh)
Inventor
张作光
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Zhang Zuoguang
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Publication of WO2010133016A1 publication Critical patent/WO2010133016A1/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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/25—Araliaceae (Ginseng family), e.g. ivy, aralia, schefflera or tetrapanax
    • A61K36/258—Panax (ginseng)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A61K36/484—Glycyrrhiza (licorice)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants

Definitions

  • composition for treating depression preparation method and use thereof
  • the present invention relates to a pharmaceutical composition for treating depression comprising ginsenoside Rgl, ginsenoside Rbl and glycyrrhizic acid (or glycyrrhetinic acid), which can be used as a pharmaceutical preparation, a nutrient and a health care product.
  • the invention also relates to a process for the preparation of the above pharmaceutical compositions and to their use. Background technique
  • Depression is a common disease. According to statistics, about 25% of women in the general population have experienced depression in their lifetime, and about 10% of men have experienced depression (Zhang Chunxing: Modern Psychology) . Data from the World Health Organization (WHO): The incidence of depression in the world is about 11%. There are currently about 340 million people with depression in the world, and this number is still on the rise. The survey found that in the next 20 years, depression It will rise to the second most common disease in the world.
  • WHO World Health Organization
  • the antidepressant drugs are mainly based on Prozac, Xelote, Zoloft, etc. (SS-, SNRI, NDRI, etc. 5-HT, NE, DA reuptake inhibitors), and the mechanism of action is Regulate the content of monoamine neurotransmitters (5-HT, NE, etc.) in the human body to alleviate depressive symptoms.
  • the anti-depressant drugs that have been asked have different degrees of side effects, such as: increased suicide rate, headache, dizziness, dizziness, insomnia, lethargy, tinnitus, dry mouth, anorexia, increased appetite, weight gain, blood pressure rise, gastrointestinal Discomfort, nausea, nausea, vomiting, indigestion, diarrhea, constipation, lower limb pain, skin rash, trembling, cramps, sweating, edema, loss of libido, sexual incompetence, etc.
  • anti-depressant drugs such as Prozac have become a serious concern in the society.
  • the US Food and Drug Administration (FDA) in 2004 asked the pharmaceutical companies to relabel the main 32 antidepressants on the market.
  • FDA US Food and Drug Administration
  • roller Pula is
  • PDE4 phosphodiesterase 4
  • ginsenoside Rgl, Rbl, glycyrrhizic acid (or glycyrrhetinic acid) which can be used to treat or alleviate depression, and can be used for treatment or relief.
  • a drug for depression and its associated diseases, disorders or conditions such as anxiety, sleep disorders and post-traumatic stress disorder.
  • Another object of the present invention is to provide a process for the preparation of the above pharmaceutical composition for treating depression.
  • Another object of the present invention is to provide a use of the above pharmaceutical composition, comprising preparing a medicament, a health care product or a nutrient for treating or ameliorating depression, and for treating or alleviating depression and a disease, disorder or condition complicated therewith.
  • the present invention provides the following technical solutions:
  • the invention provides a pharmaceutical composition for treating depression, the pharmaceutical composition comprising at least two active ingredients selected from the group consisting of:
  • the pharmaceutical composition is a pharmaceutical preparation, a health care preparation or a nutritional preparation; preferably, the ginsenoside Rgl contained in the pharmaceutical composition is 20 to 100 parts by weight, and the ginsenoside Rbl is 5 to 100 weight. And the glycyrrhizic acid or glycyrrhetinic acid is 5 to 100 parts by weight; More preferably, the ginsenoside Rgl contained in the pharmaceutical composition is 60 parts by weight, the ginsenoside Rbl is 30 to 60 parts by weight, and the glycyrrhizic acid or glycyrrhetic acid is 30 to 60 parts by weight.
  • the pharmaceutical composition as described above comprises: ginsenoside Rgl, ginsenoside Rbl and glycyrrhizic acid or glycyrrhetinic acid; more preferably, the pharmaceutical composition does not contain other active ingredients;
  • the ginsenoside Rgl in the pharmaceutical composition is 20 to 100 parts by weight, the ginsenoside Rbl is 5 to 100 parts by weight, and the glycyrrhizic acid or glycyrrhetinic acid is 5 to 100 parts by weight;
  • the ginsenoside Rgl in the pharmaceutical composition is 60 parts by weight, the ginsenoside Rbl is 30 to 60 parts by weight, and the glycyrrhizic acid or glycyrrhetinic acid is 30 to 60 parts by weight.
  • the pharmaceutical composition as described above comprises: two active ingredients: ginsenoside Rgl and ginsenoside Rbl; preferably, the pharmaceutical composition does not comprise other active ingredients;
  • the ginsenoside Rgl in the pharmaceutical composition is 20 to 100 parts by weight, and the ginsenoside Rbl is 5 to 100 parts by weight;
  • the ginsenoside Rgl in the pharmaceutical composition is 60 parts by weight, and the ginsenoside Rbl is 30 to 60 parts by weight.
  • the pharmaceutical composition as described above comprises: ginsenoside Rgl and glycyrrhizic acid or glycyrrhetinic acid; preferably, the pharmaceutical composition does not comprise other active ingredients;
  • the ginsenoside Rgl in the pharmaceutical composition is 20 to 100 parts by weight, and the glycyrrhizic acid or glycyrrhetinic acid is 5 to 100 parts by weight;
  • the ginsenoside Rgl in the pharmaceutical composition is 60 parts by weight, and the glycyrrhizic acid or glycyrrhetinic acid is 30 to 60 parts by weight.
  • the pharmaceutical composition as described above comprises: ginsenoside Rbl, and glycyrrhizic acid or glycyrrhetinic acid; preferably, the pharmaceutical composition does not comprise other active ingredients;
  • the ginsenoside Rbl in the pharmaceutical composition is 5 to 100 parts by weight, and the glycyrrhizic acid or glycyrrhetinic acid is 5 to 100 parts by weight;
  • the ginsenoside Rbl in the pharmaceutical composition is 30 to 60 parts by weight, and the glycyrrhizic acid or glycyrrhetinic acid is 30 to 60 parts by weight.
  • the purity of ginsenoside Rgl is 50 to 98%, The purity of Rbl is 50 to 98% and the purity of glycyrrhizic acid or glycyrrhetinic acid is 50 to 98%; more preferably, the purity of ginsenoside Rgl in the pharmaceutical composition is 90% to 98%, and the purity of Rbl is The purity of 90% ⁇ 98% and glycyrrhizic acid or glycyrrhetinic acid is 90% ⁇ 98%.
  • the pharmaceutical composition as described above further comprises: one or more pharmaceutically acceptable carriers or additives;
  • the pharmaceutical composition is selected from the group consisting of: oral preparations, parenteral preparations, topical and inhaled preparations, and transdermal preparations.
  • the dosage form is an oral preparation selected from the group consisting of a tablet, a capsule, a powder, a tablet, a powder, a solution, a micro-stringing agent, a suspension, an emulsion, a granule, a pill, and a pill;
  • the pharmaceutically acceptable carrier or additive is selected from the group consisting of: a disintegrant, a lubricant, a binder, a filler, a solvent, a fragrance, a sweetener, an antioxidant, a surfactant, a preservative, a correction Flavors and pigments.
  • the invention provides a method of preparing a pharmaceutical composition as described above, which comprises
  • ginsenoside Rgl 20-100 parts by weight of ginsenoside Rgl, 5 to 100 parts by weight of ginsenoside Rbl and 5 to 100 parts by weight of glycyrrhizic acid or glycyrrhetinic acid mixed pulverization step;
  • the method further comprises mixing 20 to 100 parts by weight of ginsenoside Rgl, 5-100 parts by weight of ginsenoside Rbl, 5-100 parts by weight of glycyrrhizic acid or glycyrrhetinic acid together with a pharmaceutically acceptable carrier or additive.
  • a pharmaceutically acceptable carrier or additive e.g., a pharmaceutically acceptable carrier or additive.
  • the present invention provides the use of the pharmaceutical composition for the preparation of a pharmaceutical preparation, a health supplement or a nutraceutical for treating or ameliorating depression.
  • the present invention provides the use of the pharmaceutical composition in the preparation of a pharmaceutical preparation, a health supplement or a nutraceutical for simultaneously treating or ameliorating depression and a disease, disorder or condition complicated by depression;
  • the concurrent disease, disorder or condition is selected from the group consisting of anxiety, sleep disorders and post-traumatic stress disorder.
  • the invention provides a method of treating or ameliorating depression, the method comprising administering to a subject in need thereof a therapeutically effective amount of any of the above pharmaceutical compositions.
  • the therapeutically effective amount is 0.5 to 5 mg/kg/d, preferably 1 to 4 mg/kg/d, and more preferably 2 to 3 mg/kg/d.
  • the present invention provides a method of treating or ameliorating depression or for simultaneously treating or ameliorating depression and a disease, disorder or condition associated with depression, the method comprising administering to a subject in need thereof An effective amount of any of the above pharmaceutical compositions;
  • the concurrent disease, disorder or condition is selected from the group consisting of anxiety, sleep disorders and post-traumatic stress disorder.
  • the therapeutically effective amount is 0.5 to 5 mg/kg/d, preferably 1 to 4 mg/kg/d, and more preferably 2 to 3 mg/kg/d.
  • the invention can also be implemented by the following technical solutions.
  • the present invention provides a group of pharmaceutical compositions for the treatment of depression, which are prepared from ginsenosides Rgl, Rbl, glycyrrhizic acid (or glycyrrhetinic acid).
  • the pharmaceutical composition of the present invention is prepared from a raw material comprising 1 to 100 parts by weight of ginsenoside Rgl, 0.5 to 100 parts by weight of ginsenoside Rbl, and 0.5 to 100 parts by weight of glycyrrhizic acid (or glycyrrhetinic acid).
  • the pharmaceutical composition of the present invention is prepared from a raw material comprising 10 parts by weight of ginsenoside Rgl, 5-10 parts by weight of ginsenoside Rbl, and 5-10 parts by weight of glycyrrhizic acid (or glycyrrhetinic acid).
  • the purity of ginsenoside Rgl is 50 to 98%, and ginsenoside
  • the purity of Rbl is 50 to 98%, and the purity of glycyrrhizic acid (or glycyrrhetinic acid) is 50 to 98%.
  • the preferred purity of ginsenoside Rgl is 90%
  • the preferred purity of ginsenoside Rbl is 90%
  • the preferred purity of glycyrrhizic acid (or glycyrrhetinic acid) is 90%.
  • the invention also provides a method for preparing a pharmaceutical composition for treating depression:
  • ginsenoside Rgl 1 to 100 parts by weight of ginsenoside Rgl, 0.5-100 parts by weight of ginsenoside Rbl, 0.5-100 parts by weight of glycyrrhizic acid (or glycyrrhetinic acid) and starch, lactose, micronized silica gel and other auxiliary materials are mixed and pulverized A pharmaceutical composition of the invention.
  • the preferred ratio of the three raw materials in the above preparation method is composed of 10 parts by weight of ginsenosides.
  • Rgl is prepared from 5 to 10 parts by weight of ginsenoside Rbl and 5 to 10 parts by weight of glycyrrhizic acid (or glycyrrhetinic acid).
  • the pharmaceutical composition of the present invention can be processed into a dosage form selected from the group consisting of a tablet, a capsule, a powder, a tablet, a powder, a solution, a microclay, a suspension, an emulsion, a granule, and a drop.
  • a dosage form selected from the group consisting of a tablet, a capsule, a powder, a tablet, a powder, a solution, a microclay, a suspension, an emulsion, a granule, and a drop.
  • the pharmaceutical compositions of the invention may comprise a pharmaceutically acceptable carrier or additive.
  • the pharmaceutical compositions of the invention are also useful in the manufacture of nutraceuticals and nutrients.
  • Ginsenoside Rgl, Ginsenoside Rbl, Glycyrrhizin (or glycyrrhetinic acid) are cAMP phosphodiesterase inhibitors, which are compatible with each other and synergistically act through the blood-brain barrier to rapidly activate cAMP in the hippocampus.
  • the PKA pathway enhances the expression of CREB and BDNF, so it has significant antidepressant function.
  • ginsenoside Rgl ginsenoside Rbl, glycyrrhizin (or glycyrrhetinic acid) each have a certain degree of antidepressant effect
  • the results of orthogonal experiment of mouse tail suspension show that the preferred ratio of the three
  • the antidepressant effect of the composition i.e., the preferred pharmaceutical composition of the invention is significantly stronger than any of the monomers.
  • the present invention includes a pharmaceutical composition of ginsenoside Rgl, ginsenoside Rbl, and glycyrrhizic acid (or glycyrrhetinic acid) having a significant improvement in antidepressant effect relative to ginsenoside Rgl, ginsenoside Rbl, glycyrrhizic acid (or glycyrrhetinic acid) Effect.
  • Ginsenoside Rgl, ginsenoside Rbl, glycyrrhizic acid (or glycyrrhetinic acid), a combination of drugs or health supplements, with the same side effects, can be taken for a long time, for the treatment of conditioning.
  • the post-receptor antidepressant pharmaceutical composition provided by the present invention is characterized in that the three raw materials of the prescription, ginsenoside Rgl, ginsenoside Rbl and glycyrrhizic acid (or glycyrrhetinic acid) are high.
  • the monomer extract of purity 50 ⁇ 98%) has clear functional ingredients, clear mechanism of action, and can be quantified. Therefore, the quality of the drug prepared by the drug is controllable, stable, effective, safe, easy to take, and It works quickly.
  • the pharmaceutical composition provided by the present invention is a core formulation for achieving the object of the present invention.
  • those skilled in the art can routinely add or subtract the above pharmaceutical composition according to the theory of traditional Chinese medicine or related modern pharmacological theory. Reduction. Such conventional addition and subtraction is a general technical activity of those skilled in the art, and any general technical addition or subtraction performed on the basis of the formulation of the pharmaceutical composition of the present invention is within the scope of the present invention.
  • Figure 1 is a flow chart showing the preparation method of the pharmaceutical composition in Example 1 and Example 3 of the present invention.
  • Figure 2 is a flow chart showing the preparation method of the pharmaceutical composition in Example 1 of the present invention.
  • Fig. 3 is a graph showing the results of a mouse forced swimming test performed in Example 6 of the present invention.
  • Fig. 4 is a graph showing the results of cAMP content in rat hippocampal tissue measured in Example 7 of the present invention.
  • 5A is a gel electrophoresis diagram of an experiment for cAMP-dependent PKA activity in rat hippocampus tissue measured in Example 7 of the present invention, wherein the lanes are from left to right 1-4 saline group (group A); 5-8 paroxetine Group (Group B); 9-11 The pharmaceutical composition group of the present invention (Group C); 12 positive control samples; 13 negative control samples).
  • Fig. 5B is a graph showing the results of differences in cAMP-dependent PKA activity in rat hippocampus tissues measured in Example 7 of the present invention.
  • Fig. 6 is a graph showing the results of changes in p-CREB content in rat hippocampus tissues measured in Example 7 of the present invention.
  • Fig. 7 is a graph showing the results of PDE activity in rat hippocampus tissues measured in Example 7 of the present invention. The best way to implement the invention
  • Example 1 Preparation of the pharmaceutical composition of the present invention
  • This embodiment provides a preferred preparation method of the pharmaceutical composition of the present invention, and the specific scheme is shown in FIG. As shown in the method flow chart of Figure 1, 100 g of ginsenoside Rgl, which has been prepared to a purity of 95%, is directly prepared.
  • Example 2 Preparation of the pharmaceutical composition of the present invention
  • This embodiment provides another preferred preparation method of the pharmaceutical composition of the present invention. figure 2.
  • This embodiment provides a preferred preparation method of the pharmaceutical composition of the present invention, and the specific scheme is the same as that of the embodiment 1. See FIG.
  • This example provides the effect of the pharmaceutical composition of the present invention and the components thereof on the tail suspension test of mice, that is, the ginsenoside Rgl (90% purity), ginsenoside Rbl (90% purity), glycyrrhizic acid were carried out in this example. (90% purity) Screening studies on antidepressant effects of various combinations to screen out the optimal combination of anti-depression of ginsenoside Rgl, ginsenoside Rbl and glycyrrhizic acid. The specific experiment is detailed below.
  • mice ICR mice, male, weighing 20 ⁇ lg, purchased from the Vitallihua Animal Experimental Center.
  • Test drug ginsenoside Rgl (90% purity, purchased from Shanghai Eternal Biotechnology Co., Ltd.), ginsenoside Rbl (90% pure, purchased from Shanghai Eternal Biotechnology Co., Ltd.), glycyrrhizic acid (90% purity, purchased from Xi'an) Fujie Pharmaceutical Co., Ltd.);
  • Positive drugs Fluoxetine hydrochloride capsule (Baiyoujie), Lilly Suzhou Pharmaceutical Co., Ltd. product, batch number: A333341-070608, Chinese medicine Zhunji J20030017, daily dosage, 20mg/ ⁇ .
  • JZ type 300g tension transducer (Gaobeidian Xinhang Accumulation Equipment Co., Ltd.), Medlab biological signal acquisition and processing system (Nanjing Meiyi Technology Co., Ltd.)
  • ginsenoside Rgl A drug
  • ginsenoside Rbl B drug
  • glycyrrhizic acid C drug
  • the factor level table is shown in Table 1, and the orthogonal test table is shown in Table 2.
  • mice normal mice were randomly divided into 11 groups according to their body weight. Each group was 20 blank control group (administration group 0), 1-9 group, positive drug fluoxetine hydrochloride capsule (to ⁇ 10 group) . Each group was administered at 0.2 ml/10 g body weight for 2 consecutive days, once a day.
  • Each of the above groups was administered continuously for 2 days, and the experiment was carried out 1 hour after the administration on the second day.
  • the tail end of the mouse (2 cm from the tip of the tail) was fixed with a tape on the line of the 100 g tension transducer, and the head was placed in an upside down state.
  • the head was about 15 cm away from the test bench, and two animals were tested at the same time. Separated by cardboard.
  • the transducer is connected to the Medlab biosignal acquisition and processing system. After 2 minutes of adaptation, the results within 4 minutes are recorded and the immobile state is converted to time (seconds, s).
  • Example 4 Based on the results obtained in Example 4, the anti-depressant effects of various combinations of ginsenoside Rgl, ginsenoside Rbl and glycyrrhizic acid in the pharmaceutical composition were further selected by the mouse tail suspension experiment. And determine, the specific experiment is detailed below.
  • mice ICR mice, male, weighing 20 ⁇ lg, purchased from the Vitallihua Animal Experimental Center.
  • Test drug ginsenoside Rgl (90% purity, purchased from Shanghai Eternal Biotechnology Co., Ltd.), ginsenoside Rbl (90% pure, purchased from Shanghai Eternal Biotechnology Co., Ltd.), glycyrrhizic acid (90% purity, purchased from Xi'an) Fujie Pharmaceutical Co., Ltd.);
  • JZ type 300g tension transducer (Gaobeidian Xinhang Accumulation Equipment Co., Ltd.), Medlab biological signal acquisition and processing system (Nanjing Meiyi Technology Co., Ltd.)
  • mice Normal mice were randomly divided into 3 groups according to body weight, 20 rats in each group, namely, blank control group and 1-6 groups (for ginsenoside Rgl (A drug), ginsenoside Rbl (B drug), glycyrrhizic acid (C) The different combinations of drugs, as shown in Table 6), the positive drug fluoxetine hydrochloride (3.5mg/kg/d). Each group was administered at 0.2 ml/10 g body weight for 2 consecutive days.
  • Each of the above groups was administered continuously for 2 days, and the experiment was carried out 1 hour after the administration on the second day.
  • the tail end of the mouse (2 cm from the tip of the tail) was fixed with a tape on the line of the 100 g tension transducer, and the head was placed in an upside down state.
  • the head was about 15 cm away from the test bench, and two animals were tested at the same time. Separated by cardboard.
  • the transducer is connected to the Medlab biosignal acquisition and processing system. After 2 minutes of adaptation, the results within 4 minutes are recorded and the immobile state is converted to time (seconds, s).
  • This example provides the effect of the pharmaceutical composition of the present invention on the immobility time of chronic stress-suppressed mice in a forced swimming test in mice.
  • the specific experimental process is detailed below.
  • mice 12 KM mice, male (20 ⁇ 2g), purchased from Institute of Experimental Animals, Chinese Academy of Medical Sciences (certificate No. SCXK (Beijing) 2004-0001), animals were kept in light and dark (12 h: 12 h) In the clean animal room, eat freely. Animals were acclimated to the environment in the animal room and experiments were started 3 days later.
  • Test drug The pharmaceutical composition prepared in Example 3 of the present invention is divided into a low dose group
  • mice were placed in a glass jar with a water depth of 10 cm and a diameter of 14 cm at a water temperature of 25 ° C for 5 minutes. The cumulative time of the rat in the water. Each group of animals was tested in parallel.
  • This example provides the effect of the pharmaceutical composition of the present invention on the cAMP-PKA-CREB (p-CREB) pathway in the hippocampus of normal rats, through cAMP, cAMP-dependent protein kinase (PKA), cAMP response element Detection of changes in the binding protein (CREB or p-CREB) and phosphodiesterase (PDE) levels.
  • p-CREB cAMP-PKA-CREB
  • PDA cAMP-dependent protein kinase
  • PDE phosphodiesterase
  • mice Healthy male SD rats weighing 180-200 g, 70, purchased from Beijing Vittoni China Animal Testing Center.
  • Real horse reagent Parameter CAMP Assay Kit, KGE002 (American R&D Systems, Inc.); DuoSet IC Human/Mouse/Rat Phospho-CREB (S 133) ELISA Kit,
  • DYC2510-2 (American R&D Systems, Inc.); PepTag Assay for Non-Radioactive Detection of cAMP-Dependent Protein Kinase Kit, V5340 (Promega Corporation, USA); PDE-Glo Phosphodiesterase Assay Kit, V1361 (Promega Corporation, USA); Pierce BCA Protein Assay Kit, 23227, (Thermo, USA); Paroxetine Hydrochloride (Batch No.: 08030078, purchased from Sino-US Tianjin Shike Pharmaceutical Co., Ltd.); Controls such as adenosine monophosphate and adenosine were purchased from China Pharmaceutical and Biological Products Co., Ltd.
  • Tris Base, Tris-HCl and other reagents are all cell culture grade biochemical reagents, purchased from Sigma, USA; E-64, APROTININ, LEUPEPTIN, Pepstatin A, PMSF, NaF, EDTA, EGTA, DTT, NaV04, Sodium pyrophosphate, agarose, glycerol and other reagents are all pure grade, purchased from BioBasic, Canada; acetonitrile, sterol (chromatographically pure, German MERCK) Company); Ultrapure water (MilliQ pure water, homemade).
  • Test drug The pharmaceutical composition prepared in Example 1 of the present invention.
  • Positive drugs paroxetine hydrochloride tablets, Lilly Suzhou Pharmaceutical Co., Ltd. products, daily dose, 20mg / day.
  • group A blank control saline group
  • group B positive drug paroxetine group
  • group C prepared by test drug example 1).
  • Pharmaceutical composition group
  • the paroxetine hydrochloride tablets were crushed and mixed with ultrapure water to a certain concentration.
  • the rats were intragastrically administered at a dose of 5 mg/kg.
  • the pharmaceutical composition prepared in Example 1 was formulated with water to a certain concentration.
  • the solution was administered to rats at a dose of 30 mg/kg; the blank control saline group was given an equal volume of 0.9% saline; all rats were weighed and labeled with picric acid before administration, all at 37 °C.
  • the drug was administered after 30 minutes of preheating.
  • the rats Eight hours after administration of the three groups of A, B and C, the rats were anesthetized with ether, the femoral artery was exsanguinated, and the brain was decapitated on ice.
  • the hippocampus tissue was divided and finely cut into three parts, which were placed in the pre-numbered 1.5.
  • the mL color cap screw is stored in the frozen tube, accurately weighed and quickly put into liquid nitrogen for quick freezing for 15 minutes, and then stored in a -80 °C refrigerator for later use.
  • the hippocampal tissue samples were thawed, rinsed with a small amount of saline, and then added to the PKA extraction buffer in a ratio of 1:10 (g: mL) (according to the formula in the kit;), homogenized by an ultrasonic homogenizer for 30 seconds, 4° Centrifuge at 100 rpm for 5 minutes at C. The supernatant was placed in a pre-coded 1.5 mL color Eppendorf centrifuge tube and placed in an ice box for testing. Detection and analysis were performed using Prop PepTag Assay for Non-Radioactive Detection of cAMP-Dependent Protein Kinase kit.
  • Premixed reagents were added to the pre-coded 200 ⁇ PCR occlusion tube according to the kit instructions. 9 L of each sample was added to each tube, vortexed, centrifuged, reacted at room temperature for 30 minutes, and placed in a PCR machine. The enzyme was inactivated at 98 ° C for 5 minutes. In the experiment, positive control and negative control tubes were set according to the requirements of the manual, and the experiment was carried out.
  • a 0.8% agarose gel was prepared, and 10 ⁇ L of each sample after the enzyme reaction was added to the comb hole of the gel, and electrophoresis was carried out for 30 minutes at 100 V, 130 mA, and the electrophoresis solution was 50 mM Tris-HCl (pH 8.0) buffer. After electrophoresis, the agarose gel was taken out, photographed by a gel imager, and then placed on an ultraviolet analyzer. The phosphorylated PipTag A1 peptide spots were cut out and placed in a pre-numbered 1.5 mL cap screw. In the tube.
  • the total protein content of the sample needs to be determined.
  • the supernatant after centrifugation of the tissue homogenate in the p-CREB assay was diluted 25 times with PBS, and then used as a test sample, and the OD value was measured at 562 nm using a perforated plate analyzer according to the Pierce BCA Protein Assay Kit reagent specification.
  • BSA bovine serum albumin
  • Samples were tested using the American R&D Systems DuoSet IC Human/Mouse/Rat Phospho-CREB (S 133) ELISA kit.
  • the hippocampal tissue samples were thawed, rinsed with a small amount of physiological saline, and added to the tissue extract slurry at a ratio of 1:20 (g: mL) (according to the IC DELUENT 6# formula in the kit;), electronic ultrasonic homogenizer homogenate 30
  • the cells were centrifuged at 1000 °C for 5 minutes at 4 ° C. The supernatant was placed in a pre-coded 1.5 mL color Eppendorf centrifuge tube and placed in an ice box for testing.
  • the sample was returned to room temperature during the assay, and the p-CREB content in the sample was determined by double-anti-sandwich ELISA according to the kit instructions.
  • the OD value was measured at 450 nm using a multiwell plate analyzer, and the p-CREB content in the sample was calculated from the standard curve.
  • the Phosphodiesterase Assay kit measures the effect of the test drug on PDE activity in rat hippocampus.
  • test drug ie, the pharmaceutical composition prepared in Example 1, Group C
  • the test drug was prepared into a content.
  • Group C low dose (0.02mg/mL), group C medium dose (0.05mg/mL) and group C high dose (1.0mg/mL) three dose groups.
  • PDE-Glo Reaction Buffer Tris-HCl 40mM, MgC12 lOmM, BSA O. lmg/ml, in a ratio of 1: 10 (g: mL).
  • the enzyme reaction solution is partially added with a solution of 1.5 ⁇ M enzyme solution for 2.5 ⁇ M; a substrate solution containing 2 ⁇ 1 cAMP is added at 2.5 ⁇ M, mixed, and reacted at 37 ° C for 30 minutes. Then, add 2.5 ⁇ of the reaction termination solution containing the strong inhibitor of PDE, IBMX, and mix; add 2.5 L of the test solution, mix and react at room temperature for 20 minutes; finally add the luminescent reagent lO L, react at room temperature for 10 minutes and then in the multifunctional microporous Test on the board analyzer.
  • cAMP concentration in the rat hippocampal tissue homogenate determined by ELISA was divided by the weight of the weighed tissue sample to obtain the cAMP content in the hippocampus, expressed as "pmol/g tissue", and the results are shown in Fig. 4.
  • the content of cAMP in the hippocampus of rats was changed after 8 hours of administration, the group C (the pharmaceutical composition group prepared by the test drug example 1) and the eight groups (the blank control saline group), 8 groups.
  • FIG. 5A A typical gel electrophoresis pattern in the cAMP-dependent PKA activity experiment is shown in Figure 5A, for which a rough analysis is performed.
  • the phosphorylated PepTag-Al peptide has a negative charge and moves toward the positive electrode; the unphosphorylated PepTag-Al peptide has a positive charge and moves toward the negative electrode to separate the two.
  • the brightness of the positive direction direction of the group C (test drug) sample was higher than that of the group A (saline) and the group B (paroxetine).
  • cAMP-dependent PKA activity in the hippocampus of rats was measured by fluorescence.
  • the experimental results expressed by fluorescence intensity are shown in Fig. 5B.
  • group C the pharmaceutical composition group prepared by the test drug example 1
  • eight groups blank control
  • the concentration of total protein in the rat hippocampal tissue homogenate was determined by BCA method to calibrate the amount of P-CREB per total protein. The results are shown in Table 6. Table 6 Total protein concentration of rat hippocampal tissue homogenate (g/mL)
  • Group A blank control
  • Group B praroxetine
  • Group C test drug
  • the activity of PDE in hippocampus and the inhibition of PDE activity in vitro were determined by bioluminescence.
  • the PDE activity was expressed by the luminescence intensity.
  • the luminescence intensity was higher, indicating that the PDE activity was higher; the luminescence intensity was lower, indicating that the PDE activity was inhibited as shown in Fig. 7.
  • the medium dose group 0.05 mg/mL
  • the middle dose group of the pharmaceutical composition of the present invention can significantly inhibit the activity of phosphodiesterase in rat hippocampus, since the phosphodiesterase is an inactivated enzyme of cAMP, which can inhibit the rat hippocampus after being inhibited.
  • the cAMP content in the tissue is elevated.
  • the pharmaceutical composition prepared in Example 1 of the present invention was compared with the saline group and the paroxetine group, and the hippocampus tissue of the brain was compared.
  • the cAMP content increased significantly; cAMP-dependent PKA activity was significantly enhanced; p-CREB content was also mentioned! 3 ⁇ 4.
  • the pharmaceutical composition provided by the present invention can exert pharmacological action through the second messenger cAMP cell signal transduction pathway, and can rapidly activate cAMP-PKA-CREB (p-CREB) after administration for 8 hours.
  • Pathway significantly different from the blank control saline group and the positive drug paroxetine group, *P ⁇ 0.05
  • the same control drug, paroxetine failed to activate cAMP-PKA-CREB (p-CREB)

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Abstract

La présente invention concerne une composition pharmaceutique destinée à traiter la dépression et un procédé de préparation et une utilisation de celle-ci. La composition pharmaceutique comprend le ginsenoside Rg1, le ginsenoside Rb1 et l'acide glycyrrhizique ou l'énoxolone, et a le rapport préféré en composants, selon les résultats du criblage. La composition pharmaceutique selon la présente invention peut prévenir et traiter la dépression et ses complications, ce qui a été prouvé par des tests.
PCT/CN2009/001491 2009-05-21 2009-12-17 Composition pharmaceutique destinée à traiter la dépression et procédé de préparation et utilisation de celle-ci WO2010133016A1 (fr)

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Cited By (2)

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CN102204676A (zh) * 2011-05-16 2011-10-05 李晓莉 一种抗睡眠剥夺应激损伤的食品
RU2625765C2 (ru) * 2012-08-15 2017-07-18 ЧИЮйФэнь Фармацевтическая композиция для повышения содержания и доступности циклического аденозинмонофосфата в организме и ее получение

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102125573A (zh) * 2011-01-20 2011-07-20 中山大学 人参皂苷Rg1在制备抗抑郁症药物中的应用
CN109568329A (zh) * 2018-12-07 2019-04-05 中国人民解放军第二军医大学 甘草酸及其药学上可接受的盐在制备抗抑郁药物中的应用
CN112022858B (zh) * 2020-09-25 2023-05-23 山东中医药大学 中药单体化合物组合在改善认知功能中的应用

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CN1611232A (zh) * 2003-10-30 2005-05-04 北京欧纳尔生物工程技术有限公司 一种以抗疲劳、抗辐射、抗忧郁为主功效的药物组合物及其制法
CN1615956A (zh) * 2004-09-20 2005-05-18 四川乐山三民药物科技开发有限公司 人参四逆注射剂及制备方法
CN101015548A (zh) * 2007-02-15 2007-08-15 黄成安 一种含有磷脂分散物的复方紫杉醇制剂及其制备方法
CN101450103A (zh) * 2007-11-30 2009-06-10 戚郁芬 用于治疗忧郁症及焦虑症的药物组合物

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CN1611232A (zh) * 2003-10-30 2005-05-04 北京欧纳尔生物工程技术有限公司 一种以抗疲劳、抗辐射、抗忧郁为主功效的药物组合物及其制法
CN1615956A (zh) * 2004-09-20 2005-05-18 四川乐山三民药物科技开发有限公司 人参四逆注射剂及制备方法
CN101015548A (zh) * 2007-02-15 2007-08-15 黄成安 一种含有磷脂分散物的复方紫杉醇制剂及其制备方法
CN101450103A (zh) * 2007-11-30 2009-06-10 戚郁芬 用于治疗忧郁症及焦虑症的药物组合物

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102204676A (zh) * 2011-05-16 2011-10-05 李晓莉 一种抗睡眠剥夺应激损伤的食品
RU2625765C2 (ru) * 2012-08-15 2017-07-18 ЧИЮйФэнь Фармацевтическая композиция для повышения содержания и доступности циклического аденозинмонофосфата в организме и ее получение

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