RU2452505C2 - Pharmaceutical compositions with multipurpose receptor reaction mechanism for treating depression - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a pharmaceutical composition, particularly to a composition (versions) for treating depression. A pharmaceutical composition with a multipurpose post-receptor mechanism for treating depression containing ginsenosides Rg1 and Rb1; and a glycyrrhizic acid derivative being specified in a group consisting of glycyrrhizic acid, glycyrrhetinic acid and their combination taken in specific proportions. The multipurpose post-receptor pharmaceutical composition for treating depression containing ginsenosides Rg1 and Rb1; and the glycyrrhizic acid derivative being specified in the group consisting of glycyrrhizic acid, glycyrrhetinic acid and their combination; and a cyclic adenosine monophosphate jojoba (cAMP jojoba) taken in specific proportions.

EFFECT: pharmaceutical compositions shows substantial antidepressant efficacy.

13 cl, 17 tbl, 6 dwg, 8 ex

Description

FIELD OF THE INVENTION

[0001] The present invention relates to a multi-purpose, post-receptor-based pharmaceutical composition made from the raw materials ginsenoside Rg1 and Rb1, glycyrrhizic acid and cyclic jujuba adenosine monophosphate (jujuba cAMP) for the treatment of depression. In particular, this invention relates to a pharmaceutical preparation for oral administration or nutritional therapy for the treatment of depression, which have certain functions and components, obvious therapeutic effects and high safety for prolonged use and which are free from side effects, such as severe vomiting.

BACKGROUND OF THE INVENTION

[0002] Depression is a common disease. According to statistics, about 25% of women in the world experienced depression in their lives and about 10% of men experienced depression (link to Modern Psychology, written by Ch'un-Hsing Chang). The World Health Organization (WHO) published "The incidence of depression in the world is approximately 11%. Currently, there are approximately 340 million patients with psychological depression in the world, and the number is increasing. The study found that depression will increase to become the second most common disease in the world from now on for the next 20 years. "

[0003] Currently, the main antidepressant drugs are Prozac, Paxil, Zoloft, etc., which relate to selective serotonin reuptake inhibitors (SSRI), serotonin reuptake inhibitors, norepinephrine (SNRI) and norepinephrine reuptake inhibitors and dopamine (NDRI), an inhibitory uptake of neurotransmitters such as 5-hydroxytryptamine (5-HT), norepinephrine (NE) and dopamine (DA). The mechanism by which these antidepressant drugs function is to increase the level of human 5-HT neurotransmitters to reduce and alleviate the symptoms of depression.

[0004] However, marketed antidepressant drugs have various side effects with varying severity, such as increased suicide, headache, dizziness, vertigo, insomnia, hypersomnia, tinnitus, thirst, aversion to food, orexia, increased body weight, high blood pressure, indigestion, regurgitation with nausea, vomiting, dyspepsia, diarrhea, constipation, leg pain, skin rash, chills, cramps, hyperhidrosis, edema, sex drive and impotence, etc. In recent years, drugs for depression, such as Prozac, etc., have become a serious social problem. In 2004, the U.S. Food and Drug Administration (FDA) further requested pharmaceutical companies to revise medical use instructions to clearly indicate side effects and warnings on 32 of the most important antidepressant drugs on the market and focused the attention of doctors and nurses on that these drugs can increase suicide in children and adolescents. In 1996, it was even discovered that among 32 antidepressants, Paxil is dangerous and has been repeatedly withdrawn from the market since 2001. In June 2004, the New York State Attorney General accused GlaxoSmithKline, UK of fraudulently hiding a report on a study of the link between paxil and "increased risk of suicidal behavior and adolescent tendencies." In the light of the current situation, the search for a new generation of drugs with fewer side effects and more pronounced / strong antidepressant qualities has become the focus of attention of the entire pharmaceutical world.

[0005] In recent years, scientists in pharmacology have made a new breakthrough in studying the mechanism of the pathogenesis of depression, they found that in addition to inhibiting the reuptake of neurotransmitters such as 5-HT, NE and DA, as strategies for treating depression, regulation of the post-receptor mechanism is also could be adapted to treat depression. In addition, since the advent of the drug that regulates the post-receptor mechanism, Rolipram, the post-receptor mechanism has become a hot spot in the study of the treatment of depression in pharmacology. Rolipram is an inhibitor of phosphodiesterase 4 (PDE4, trans., PDE-4) and in clinical trials it was shown that it has a noticeable antidepressant function; however, since rolipram causes severe vomiting, further study of rolipram has been completely stopped. Despite this setback, rolipram opened up a whole new way of thinking about the “post-receptor mechanism for antidepressant drugs.”

[0006] Therefore, an attempt was made by the authors of the application to consider the above situation, found in the prior art.

SUMMARY OF THE INVENTION

[0007] To overcome the insufficiency of this technology, the aim of the present invention is to provide a multi-purpose pharmaceutical preparation for oral administration or nutrition based on a post-receptor mechanism of action in the form of ginsenoside Rg1 and Rb1, glycyrrhizic acid and jujuba cAMP made from the starting materials for the treatment of depression. In particular, they provide new technological schemes leading to certain functions and components, an obvious therapeutic effect and high safety during prolonged use without side effects, such as severe vomiting, etc.

[0008] The approval scheme of a pharmaceutical preparation of the present invention is a result undertaken by the applicant in accordance with the pathological and pharmacological theories of modern medicine for the treatment of depression. In particular, this invention combines the progress of the latest research on antidepressant drugs and post-receptor mechanisms by applying the stimulating effect of ginsenoside on adenylate cyclase (AC) and the potent inhibitory effect of glycyrrhizic acid (and glycyrrhetinic acid) on cAMP phosphodiesterase (CAPD). The antidepressant function of the present invention has been confirmed in many animal experiments. Ginsenoside and glycyrrhizic acid (and glycyrrhetinic acid) (trans., Glycyrrhetic acid) act synergistically when combined to further increase the use and activity of cAMP. The resulting concentration and activity of cAMP can (1) increase the synthesis and release of a neurotransmitter (trans., Neurotransmitter), such as norepinephrine, etc., (2) increase the expression of brain neurotrophic factor (BDNF) and (3) inhibit hypothalamic hyperactivity pituitary-adrenal axis (NRA) and glucocorticoid secretion to achieve significant antidepressant function. In addition, jujuba cAMP can also increase cAMP levels in humans to induce antidepressant function. A trace amount of jujuba cAMP (approximately one ten thousandth) of jujuba is extracted and purified as a jujuba extract having 1% jujuba cAMP to perform the antiexperimental function of depression in animal experiments. The result shows that jujuba extract containing 1% jujuba cAMP has a significant antiexperimental function of depression. However, the usual jujuba extract (for example, jujuba extracted in water when heated, but the concentration of jujuba cAMP in it does not increase further), although containing a trace of jujuba cAMP does not have a noticeable antiexperimental function of depression. In order to further increase the antidepressant effect of the present invention, in which jujuba cAMP, ginsenoside and glycyrrhizic acid are additionally combined for joint action. Ginseng, licorice and jujuba are commonly used raw materials for the pharmaceutical industry and food products in Chinese medicine and have been used in dietetic nutritional therapeutic nutrition for several thousand years. In this thousand-year clinical and nutritional history, the safety and effectiveness of the integrated use of ginseng, licorice and jujuba have been fully proven. A study of the inventor and experimental results show that if these three types of pharmaceutical raw materials are only standardly infused and extracted separately to obtain an extract, the extract does not have a significant antidepressant effect compared to the extract of a modern antidepressant drug for the treatment of depression. The reason is that in this invention, the concentrations of effective components (such as ginsenoside Rg1 and Rb1 and jujuba cAMP, etc.) of the extract are further increased by purification (such as chromatography), and starting materials (such as glycyrrhizic acid and glycyrrhetinic acid, etc.) etc.) are added to the extract to produce a medicament for treating depression. Animal experiments demonstrate that a drug produced in this way has a significantly superior antidepressant function compared to previous antidepressant drugs. Debris (residues) of these three types of pharmaceutical raw materials after extraction, chromatography and purification are also collected and analyzed by high performance liquid chromatography (HPLC) (HPLC). Although debris contains trace amounts of ginsenoside Rg1 and Rb1, glycyrrhizic acid, and jujuba cAMP, this debris does not have significant antidepressant function in animal experiments. It is important that the administration of ginseng, licorice and jujuba does not produce side effects, such as severe vomiting, etc. Thus, the inventor presents a pharmaceutical preparation for oral administration or medical nutrition made from starting materials, including ginsenoside Rg1 and Rb1, glycyrrhizic acid and jujuba cAMP, with a multipurpose and post-receptor mechanism for treating depression. In particular, in addition to extraction by heating in a solvent (such as water and ethanol, etc.), the extract is further purified to increase the concentrations of the starting materials (ginsenoside Rg1 and Rb1 and jujuba cAMP) and glycyrrhizic acid and glycyrrhetinic acid are added to them. A new technological scheme is created to obtain certain functions and components, obvious therapeutic effect, high safety with prolonged use and without stimulating side effects, such as severe vomiting, etc., to overcome the insufficiency of currently available antidepressants.

[0009] Comparisons of the antidepressant drug target and mechanism of action of the pharmaceutical composition of the present invention and rolipram are provided as follows.

Drug name Rolypram The pharmaceutical composition of the present invention Type of drug Antidepressant drug that regulates the post-receptor mechanism (chemical pharmaceutical product) Antidepressant drug that regulates the post-receptor mechanism (pharmaceutical composition) Drug Target Single Target (CAPD) Multipurpose (CAPD, CA and APR, etc.) Mechanism 1. Launch (trigger) cAMP-dependent tyrosine hydroxylase to enhance the synthesis of norepinephrine;
2. Phosphorylation of synapsin and increased release of norepinephrine; and
3. Inhibition of phosphodiesterase, reduced cAMP degradation, and increased use of cAMP to generate a downstream function. 1. Launch (trigger) cAMP-dependent tyrosine hydroxylase to enhance the synthesis of norepinephrine;
2. Phosphorylation of synapsin and increased release of norepinephrine;
3. Inhibition of phosphodiesterase, reduced cAMP degradation, and increased use of cAMP to detect function;
4. Starting AS, increasing the concentration and activity of cAMP;
5. Increased ATP to activate the synthesis of cAMP;
6. Activation of benzenepropionic acid by the blood-brain barrier, activation of the synthesis of NE and DA, and down-regulation of the hypothalamic-pituitary-adrenal system (NRA axis); and
7. up-regulation of the expression of BDNF (trans., Neurotrophic factor of the brain) and neurotrophin (NT-3) directly in the cells of the brain during an anti-stress reaction. Dose response Induction of side effects such as severe vomiting, etc. High safety and few side effects with prolonged use, and the prevention and improvement of degenerative nervous disorders, and the prevention of aging.

[0010] The differences between the pharmaceutical composition of the present invention and the antidepressant drug with a postreceptor mechanism (rolipram) are that the antidepressant reaction is achieved by the multipurpose and postreceptor mechanism and the side effect induced by rolipram (such as severe vomiting) is avoided.

[0011] The conversion rate of glycyrrhizic acid to glycyrrhetinic acid in the human body is almost 100%, and glycyrrhetinic acid, due to its higher lipid solubility than glycyrrhizic acid, can penetrate the brain through the blood-brain barrier. Thus, the inhibition of CAPD (per., CAMP phosphodiesterase) by glycyrrhizic acid occurs by the transformation of glycyrrhizic acid into glycyrrhetinic acid in the body. Thus, glycyrrhizic acid or glycyrrhetinic acid may be the starting material for the manufacture of the pharmaceutical composition of the present invention.

[0012] In accordance with one aspect of the present invention, there is provided a pharmaceutical composition with a multipurpose post-receptor mechanism for treating depression. The pharmaceutical composition includes: ginsenoside Rg1 and Rb1, a derivative of glycyrrhizic acid, being selected from the group consisting of glycyrrhizic acid, glycyrrhetinic acid and a combination thereof and jujuba cAMP.

[0013] Preferably, the pharmaceutical composition includes 2 ~ 26 wt. parts of ginsenoside, 3 ~ 48 wt. derivative of glycyrrhizic acid and 0.002 ~ 0.5 wt. parts of cAMP jujuba.

[0014] Preferably, the pharmaceutical composition includes 4 ~ 13 wt. parts of ginsenoside, 5 ~ 16 wt. parts of a derivative of glycyrrhizic acid and 0.01 ~ 0.1 parts by weight of jujuba cAMP.

[0015] Preferably, ginsenoside is extracted from ginseng, a glycyrrhizic acid derivative is extracted from licorice, and jujuba cAMP is extracted from jujuba.

[0016] Preferably, jujuba is extracted to obtain a primary extract having a primary concentration of jujuba cAMP, the primary extract is further extracted to obtain a secondary extract having a secondary concentration of jujuba cAMP, the secondary concentration of jujuba cAMP is higher than the primary concentration of jujuba cAMP, and the secondary extract is starting material in a pharmaceutical composition.

[0017] In accordance with another aspect of the present invention, a multi-purpose post-receptor pharmaceutical composition for treating depression is provided. The pharmaceutical composition includes ginsenoside and a glycyrrhizic acid derivative, being selected from the group consisting of glycyrrhizic acid, glycyrrhetinic acid, and a combination thereof.

[0018] Preferably, ginsenoside includes Rg1 and Rb1.

[0019] Preferably, the pharmaceutical composition includes 2 ~ 26 wt. parts of ginsenoside and 3 ~ 48 wt. parts of a derivative of glycyrrhizic acid.

[0020] Preferably, the pharmaceutical composition includes 4 ~ 13 wt. parts of ginsenoside and 5 ~ 16 wt. parts of a derivative of glycyrrhizic acid.

[0021] Preferably, ginsenoside is purified from ginseng and the glycyrrhizic acid derivative is purified from licorice.

[0022] Preferably, the pharmaceutical composition includes at least one pharmacologically acceptable carrier and additive.

[0023] Preferably, the pharmaceutical composition has a dosage form, being one selected from the group consisting of a tablet, capsule, powder, dragee, powder, solution, microcapsule, suspension, emulsion, particle, droplet and a bead.

[0024] Preferably, the pharmaceutical composition is in the form of one of a nutritional supplement and a nutritional supplement.

[0025] In accordance with another aspect of the present invention, a method for producing a pharmaceutical composition with a multi-purpose post-receptor mechanism for treating depression is provided. The pharmaceutical composition includes jujuba cAMP as a starting material. The method of obtaining includes the steps of: (a) extracting jujuba to obtain a primary extract having a primary concentration of jujuba cAMP; and (b) purifying the primary extract to obtain a secondary extract having a secondary concentration of jujuba cAMP, where the secondary concentration of jujuba cAMP is higher than the primary concentration of jujuba cAMP.

[0026] Preferably, step (b) is carried out by chromatography of the primary extract using a macroporous resin bound to an aldehyde group (bound aldehyde group).

[0027] Preferably, the macroporous resin is OU-2.

[0028] Preferably, the primary extract is further chromatographed on macroporous resin ME-2 bound to the aldehyde group.

[0029] An oral pharmaceutical preparation for the treatment of depression described in the description and claims of this invention is the main content of the purpose of this invention. After the publication of this invention, any specialist in this field will be able to continue the normal increase / decrease or replace with other effective components of herbal medicine (such as onjisaponin, saicosaponin and licorice coumarin, etc.) having effects / functions identical to the above medicinal means in accordance with the theory of Chinese medicine or a related theory of modern pharmacology. Substitution of the indicated normal increase / decrease of medicine based on medicinal herbs having a similar mechanism with another identical CAPD inhibitor, AC activator, or corresponding effective components refers to the normal activities of an ordinary specialist in this field. Thus, substitutions are within the scope of the invention.

[0030] The above objectives and advantages of the present invention will become fully apparent to one of ordinary skill in the art after reviewing the following detailed descriptions and figures.

BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 is a flowchart showing a method for preparing a pharmaceutical composition in accordance with a first preferred embodiment of the present invention;

[0032] Figure 2 is a flowchart showing a method for preparing a pharmaceutical composition in accordance with a second preferred embodiment of the present invention;

[0033] Figure 3 is a flowchart showing a method for preparing a pharmaceutical composition in accordance with a third preferred embodiment of the present invention;

[0034] Figure 4 is a flowchart showing a method for preparing a pharmaceutical composition in accordance with a fourth preferred embodiment of the present invention;

[0035] Figure 5 is a flowchart showing a method for preparing a pharmaceutical composition in accordance with a fifth preferred embodiment of the present invention; and

[0036] Figure 6 is a flowchart showing a method for preparing a pharmaceutical composition in accordance with a sixth preferred embodiment of the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

[0037] The present invention will now be described more specifically with reference to the following options. It should be noted that the following descriptions of the preferred variants of the present invention are presented here only for purposes of illustration and description; they are not intended to be exhaustive or limited to the exact form disclosed.

[0038] In order to accomplish the purpose of the present invention, the process diagrams of the present invention are specifically provided as set forth below.

[0039] The present invention discloses a pharmaceutical composition with a multi-purpose and post-receptor mechanism for treating depression, and a pharmaceutical composition is prepared, inter alia, using raw materials of ginsenoside Rg1 and Rb1 and glycyrrhizic acid (or glycyrrhetinic acid).

Example 1:

[0040] A pharmaceutical composition of the present invention with a multi-purpose and post-receptor mechanism for treating depression is prepared, including from the raw materials of ginsenoside Rg1 and Rb1 and glycyrrhizic acid (or glycyrrhetinic acid).

Example 2:

[0041] The pharmaceutical composition of this invention is made from starting materials having only 2 ~ 26 wt. parts of ginsenoside Rg1 and Rb1 and 3 ~ 48 wt. parts of glycyrrhizic acid (or glycyrrhetinic acid).

Example 3:

[0042] The pharmaceutical composition of the present invention is also made from starting materials having only 4 ~ 13 wt. parts of ginsenoside Rg1 and Rb1 and 5 ~ 16 wt. parts of glycyrrhizic acid (or glycyrrhetinic acid).

Example 4:

[0043] The pharmaceutical composition of the present invention with a multi-purpose and post-receptor mechanism for treating depression is prepared, inter alia, from the raw materials ginsenoside Rg1 and Rb1, glycyrrhizic acid (or glycyrrhetinic acid) and jujuba cAMP.

Example 5:

[0044] The pharmaceutical composition of the present invention is made including from starting materials having only 2 ~ 26 wt. parts of ginsenosides Rg1 and Rb1, 3 ~ 48 wt. parts of glycyrrhizic acid (or glycyrrhetinic acid) and 0.002 ~ 0.5 wt. parts of cAMP jujuba.

Example 6:

[0045] The pharmaceutical composition of the present invention is prepared including from starting materials having only 4 ~ 13 parts by weight of ginsenoside Rg1 and Rb1, 5 ~ 16 wt. parts of glycyrrhizic acid (or glycyrrhetinic acid) and 0.01 ~ 0.1 wt. parts of cAMP jujuba.

Example 7

[0046] The pharmaceutical composition of the present invention may include pharmacologically acceptable carriers or additives. The pharmaceutical composition can be made in the form of a dosage form, and the dosage form is selected from one of the forms of a tablet, capsule, powder, dragee, powder, solution, microcapsule, suspension, emulsion, particle, drip, bead, and a pharmaceutical pharmaceutical dosage form for oral administration .

Example 8:

[0047] The pharmaceutical composition of the present invention can be formulated as drugs, nutritional supplements, and nutritional supplements for the treatment of depression.

[0048] In order to achieve the objective of the present invention, methods for preparing a pharmaceutical composition are described as follows.

Method 1:

[0049] The pharmaceutical composition of the present invention with a multi-purpose and post-receptor mechanism for treating depression is made from one extract having ginsenoside Rg1 and Rb1 extracted from ginseng and another extract having glycyrrhizic acid extracted from licorice as starting materials. In addition, the above pharmaceutical composition is prepared by direct use of prepared starting materials having ginsenoside Rg1 and Rb1 and glycyrrhizic acid (or glycyrrhetinic acid).

Method 2:

[0050] The pharmaceutical composition of this invention is made from starting materials having a total of 2 ~ 26 wt. parts of ginsenoside Rg1 and Rb1 and 3 ~ 48 wt. parts of glycyrrhizic acid (or glycyrrhetinic acid).

Method 3:

[0051] The pharmaceutical composition of the present invention is also made from starting materials having only 4 ~ 13 wt. parts of ginsenoside Rg1 and Rb1 and 5 ~ 16 wt. parts of glycyrrhizic acid (or glycyrrhetinic acid).

Method 4:

[0052] A pharmaceutical composition of the present invention with a multi-purpose and post-receptor mechanism for treating depression is made from one extract having ginsenoside Rg1 and Rb1 extracted from ginseng, another extract having glycyrrhizic acid extracted from licorice, and another extract having cAMP jujube extracted from jujub, in the form of starting materials. In addition, the above pharmaceutical composition is prepared by direct use of prepared starting materials having ginsenoside Rg1 and Rb1, glycyrrhizic acid (or glycyrrhetinic acid) and jujuba cAMP.

Method 5:

[0053] The pharmaceutical composition of this invention is made from starting materials having only 2 ~ 26 wt. parts of ginsenoside Rg1 and Rb1, 3 ~ 48 wt. parts of glycyrrhizic acid (or glycyrrhetinic acid) and 0.002 ~ 0.5 wt. parts of cAMP jujuba.

Method 6:

[0054] The pharmaceutical composition of this invention is made from starting materials having only 4 ~ 13 wt. parts of ginsenoside Rg1 and Rb1, 5 ~ 16 glycyrrhizic acid (or glycyrrhetinic acid) and 0.01 ~ 0.1 wt. parts of cAMP jujuba.

Method 7:

[0055] The pharmaceutical composition of the present invention may include pharmacologically acceptable carriers or additives. The pharmaceutical composition can be made in the form of a dosage form, and the dosage form is selected from one of the forms of a tablet, capsule, powder, dragee, powder, solution, microcapsule, suspension, emulsion, particle, drip, bead, and a pharmaceutical pharmaceutical dosage form for oral administration .

Method 8:

[0056] The pharmaceutical composition of the present invention can be made from the starting materials described in this invention in accordance with the pharmaceutical standards of Good Manufacturing Practices (GMP) for clinical nutrition.

PREFERRED EMBODIMENT

[0057] The invention is further illustrated, as set forth below, by a combination of figures and preferred embodiments of the invention.

Option 1:

[0058] Please refer to FIG. 1, which is a flowchart showing a method for preparing a pharmaceutical composition in accordance with a first preferred embodiment of the present invention. In figure 1, after grinding 20 kg of ginseng (stage 101), the destroyed ginseng is heated for extraction with a solution of ethanol of 70% concentration. The extracted ginseng is separated and purified by column chromatography and dried to obtain 0.8 kg of ginseng extract having 120 g of ginsenoside Rg1 and Rb1 (step 102). Then, after grinding 10 kg of licorice (step 103), the crushed licorice is soaked at room temperature for 12 hours.

The soaked licorice is extracted by digestion and precipitation with alcohol, concentrated and dried to give 2 kg of licorice extract having 200 g of glycyrrhizic acid (step 104). After that, 150 g of the obtained ginseng extract and 200 g of the obtained licorice extract are pulverized and mixed to obtain 350 g of the pharmaceutical composition (containing 22.5 g of ginsenoside Rg1 and Rb1 and 20 g of glycyrrhizic acid) of option 1 of the present invention (step 105).

Option 2:

[0059] Please refer to FIG. 2, which is a flowchart showing a method for preparing a pharmaceutical composition in accordance with a second preferred embodiment of the present invention. In figure 2, after grinding into a powder and mixing 3.96 g of the obtained glycyrrhetinic acid having 96% purity (step 202) and 200 g of ginseng extract obtained in embodiment 1 (step 201), 203.96 g of the pharmaceutical composition are obtained (containing 30 g of ginsenoside Rg1 and Rb1 and 3.8 g of glycyrrhetinic acid) option 2 of the present invention (stage 203).

Option 3:

[0060] Please refer to FIG. 3, which is a flowchart showing a method for preparing a pharmaceutical composition in accordance with a third preferred embodiment of the present invention. Figure 3, after grinding into powder and mixing 3.4 g of the obtained ginsenoside Rg1 having 90% purity (step 301), 7.8 g of the obtained ginsenoside Rg1 having 90% purity (step 302), and 36.8 g glycyrrhizic acid having 90% purity (step 303), 48 g of a pharmaceutical composition (containing 10 g of ginsenoside Rg1 and Rb1 and 35 g of glycyrrhizic acid) of variant 3 of the present invention are obtained (step 304).

Option 4:

[0061] Please refer to FIG. 4, which is a flowchart showing a method for preparing a pharmaceutical composition in accordance with a fourth preferred embodiment of the present invention. In figure 4, 10 kg of jujuba (stage 401) is crushed and soaked in water at room temperature. Then, the soaked jujuba was extracted by digestion and precipitation in alcohol to obtain a jujuba extract, which was further absorbed and separated sequentially on OU-2 and ME-2 macroporous resins and dried. Obtain thirty (30) g of jujuba extract containing 0.3 g of jujuba cAMP, which are the raw material for the pharmaceutical composition of the present invention (step 402).

[0062] Then, after grinding into a powder 150 g of ginseng extract and 200 g of licorice extract obtained in embodiment 1, and mixing with 3 g of the above jujuba extract, 353 g of a pharmaceutical composition (containing 22.5 g of ginsenoside Rg1 and Rb1, 20 g of glycyrrhizic acid and 0.03 g of jujuba cAMP) option 4 of the present invention (stage 403).

Option 5:

[0063] Please refer to FIG. 5, which is a flowchart showing a method for preparing a pharmaceutical composition in accordance with a fifth preferred embodiment of the present invention. In Fig. 5, after grinding into a powder 150 g of ginseng extract (stage 501) and 200 g of licorice extract (stage 502) obtained in option 1, respectively, and mixing with 0.5 g of jujuba extract obtained in option 4 (stage 503) ), 350.5 g of a pharmaceutical composition are obtained (containing 22.5 g of ginsenoside Rg1 and Rb1, 20 g of glycyrrhizic acid and 0.005 g of jujuba cAMP) of Embodiment 5 of the present invention (step 504).

Option 6:

[0064] Please refer to FIG. 6, which is a flowchart showing a method for preparing a pharmaceutical composition in accordance with a sixth preferred embodiment of the present invention. 6, after grinding into a powder and mixing 6.8 g of the obtained ginsenoside Rg1 having 90% purity (step 601), 15.6 g of the obtained ginsenoside Rb1 having 90% purity (step 602), 26 g of glycyrrhetinic acid, having 96% purity (step 603), and 10 g of jujuba extract obtained in embodiment 4 (step 604), 58.4 g of a pharmaceutical composition (containing 20 g of ginsenoside Rg1 and Rb1, 25 g of glycyrrhetinic acid and 0.1 g of cAMP are obtained jujuba) option 6 of the present invention (stage 605).

Experiment 1: Effect of Option 1 in a Tail Suspension Experiment

[0065] 1.1 Experimental animals: ICR mice, males, body weight 22.0 ± 2 g, secondary, provided by the Department of Experimental Animals of the Capital Medical University, Beijing.

[0066] 1.2 Experimental Medicines: Option 1 drug provided by Beijing Wonner Biotech. Ltd. Co., and paroxetine (paxil) is a product of Zhong Mei Tianjin Smith Kline pharmaceuticals Co. Ltd.

[0067] 1.3 Experimental equipment: stopwatch.

[0068] 1.4 Dose designs: 1. High dose of option 1 (80 mg / kg / day); 2. The average dose of option 1 (40 mg / kg / day); and 3. Low dose of option 1 (20 mg / kg / day).

[0069] 1.5 Experimental method and result:

[0070] 1.5.1 Grouping and drug administration: Mice are randomly divided into groups and 10 mice are in each group. 1. A high dose of option 1 (80 mg / kg, orally (P.O.), was administered for 7 days); 2. The average dose of option 1 (40 mg / kg, P.O., was administered over 7 days); 3. The low dose of option 1 (20 mg / kg, P.O., was administered over 7 days); 4. Paroxetine (3 mg / kg, P.O., was administered over 7 days); and 5. Saline solution (P.O.). 1 hour after the last administration of the drug, an experiment was performed by hanging the mouse by the tail.

[0071] 1.5.2 Experimental method: The tail of the mouse (1 cm to the tip of the tail) is glued with adhesive tape to a wooden plank 5 cm higher than the platform and suspended for 6 minutes. Record the time of immobility of the mouse for at least 5 minutes.

и результат эксперимента вычисляют в виде дисперсионного анализа (ANOVA) с помощью пакета программ обработки статистических данных SPSS 11.5.[0072] 1.5.3 Statistical calculation: Experimental data are presented as

and the result of the experiment is calculated as analysis of variance (ANOVA) using the SPSS 11.5 statistical software package.

[0073] 1.5.4 Experiment result: see table 1.

Table 1 The effect of option 1 on the time of immobility of the mouse Group Number of animals Immobility time (seconds) Saline solution (control) 10 113.22 ± 21.18 Paroxetine 10 75.33 ± 22.91 * High Dose Option 1 10 54.67 ± 26.38 ** The average dose of option 1 10 72.68 ± 27.06 * Low Dose Option 1 10 95.26 ± 49.91 Compared with the control group: * P <0.05 and ** P <0.01.

[0074] Conclusion: According to the above experiment, it can be found that all high and medium doses of Embodiment 1 of the present invention and paroxetine all reduce the immobility time after hanging by the tail of the mouse, which is significantly different compared to the physiological saline group (control). Thus, embodiment 1 of the present invention, as having the antiexperimental function of depression, can be extrapolated.

Experiment 2: The effect of option 1 in the experiment Resetpine-induced decrease in body temperature of mice

[0075] 2.1 Experimental animals: ICR mice, males, body weight 22.0 ± 2 g, secondary, provided by the Department of Experimental Animal Science of Capital Medical University, Beijing.

[0076] 2.2 Experimental Medicines: Option 1 drug provided by Beijing Wonner Biotech. Ltd. Co., paroxetine (paxil) is a product of Zhong Mei Tianjin Smith Kline pharmaceuticals Co. Ltd., and Resetpine is a product of Guangdong BangMin Pharmaceutical Co., Ltd.

[0077] 2.3 Experimental equipment: Electronic thermometer (model: GM222) and a stopwatch.

[0078] 2.4 Dose structures: 1. High dose of option 1 (80 mg / kg / day); 2. The average dose of option 1 (40 mg / kg / day); and 3. Low dose of option 1 (20 mg / kg / day).

[0079] 2.5 Experimental method and result:

[0080] 2.5.1 Grouping and drug administration: Mice are randomly divided into groups, and each group contains 10 mice. 1. A high dose of option 1 (80 mg / kg, P.O., was administered over 7 days); 2. The average dose of option 1 (40 mg / kg, P.O., was administered over 7 days); 3. The low dose of option 1 (20 mg / kg, P.O., was administered over 7 days); 4. Paroxetine (3 mg / kg, P.O., was administered over 7 days); and 5. Saline solution (P.O.).

[0081] 2.5.2 Experimental method: 1 hour after the last drug administration, the anal temperature in mice was determined on the eighth day. Then, 2 mg of Resetpine per kilogram of body weight is given by intraperitoneal injection. 4 hours after injection of Resetpine, the anal temperature in mice was determined again. The depth and time of insertion of the thermometer into the anus of mice are identical at each temperature measurement.

и результат эксперимента вычисляют в виде ANOVA с помощью пакета программ обработки статистических данных SPSS 11.5.[0082] 2.5.3 Statistical calculation: Experimental data are presented as

and the result of the experiment is calculated as ANOVA using the SPSS 11.5 statistical processing software package.

[0083] 2.5.4 Experiment result: see table 2.

table 2 The effect of option 1 on Resetpine-induced decrease in mouse body temperature Group Number of animals Temperature reduction (° C) Saline solution (control) 10 3.65 ± 0.77 Paroxetine 10 2.38 ± 0.69 ** High Dose Option 1 10 1.85 ± 1.01 ** The average dose of option 1 10 2.05 ± 1.03 ** Low Dose Option 1 10 2.35 ± 0.69 ** Compared with the control group: * P <0.05 and ** P <0.01.

[0084] Conclusion: According to the above experiment, it can be found that high, medium and low doses of Embodiment 1 of the present invention and paroxetine all reduce the reduced body temperature induced by Resetpine, which means that those anti-experimental depression functions of these pharmaceuticals could be related with their effects on the content of monoamine neurotransmitter. Thus, embodiment 1 of the present invention, as having the antiexperimental function of depression, can be extrapolated.

Experiment 3: Effect of Option 2 in a Tail Suspension Experiment

[0085] 3.1 Experimental animals: ICR mice, males, body weight 22.0 ± 2 g, secondary, provided by the Department of Experimental Animals of the Capital Medical University, Beijing.

[0086] 3.2 Experimental drugs: Option 2 drug provided by Beijing Wonner Biotech. Ltd. Co., and paroxetine (paxil) is a product of Zhong Mei Tianjin Smith Kline pharmaceuticals Co. Ltd.

[0087] 3.3 Experimental equipment: stopwatch.

[0088] 3.4 Dose designs: 1. High dose of option 2 (80 mg / kg / day); 2. The average dose of option 2 (40 mg / kg / day); and 3. Low dose of option 2 (20 mg / kg / day).

[0089] 3.5 Experimental method and result:

[0090] 3.5.1 Grouping and drug administration: Mice are randomly divided into groups, and each group contains 10 mice. 1. A high dose of option 2 (80 mg / kg, orally (P.O.), was administered for 7 days); 2. The average dose of option 2 (40 mg / kg, P.O., was administered over 7 days); 3. A low dose of option 2 (20 mg / kg, P.O., was administered over 7 days); 4. Paroxetine (3 mg / kg, P.O., was administered over 7 days); and 5. Saline solution (P.O.). 1 hour after the last administration of the drug, an experiment was performed by hanging the mouse by the tail.

[0091] 3.5.2 Experimental method: The mouse tail (1 cm to the tip of the tail) is glued with adhesive tape to a wooden plank 5 cm higher than the platform and suspended for 6 minutes. Record the time of immobility of the mouse for at least 5 minutes.

и результат эксперимента вычисляют в виде ANOVA с помощью пакета программ обработки статистических данных SPSS 11.5.[0092] 3.5.3 Statistical calculation: Experimental data are presented as

and the result of the experiment is calculated as ANOVA using the SPSS 11.5 statistical processing software package.

[0093] 3.5.4 Experiment result: see table 3.

Table 3 The effect of option 2 on the time of immobility of the mouse Group Number of animals Immobility time (seconds) Saline solution (control) 10 113.22 ± 21.18 Paroxetine 10 75.33 ± 22.91 * High Dose Option 1 10 93.27 ± 36.42 The average dose of option 1 10 76.21 ± 28.36 * Low Dose Option 1 10 107.79 ± 32.56 Compared with the control group: * P <0.05 and ** P <0.01.

[0094] Conclusion: In accordance with the above experiment, it can be found that the average dose of option 2 of the present invention and paroxetine all reduce the immobility time after hanging by the tail of the mouse, which is significantly different compared to the physiological saline group (control). Thus, embodiment 2 of the present invention, as having the antiexperimental function of depression, can be extrapolated.

Experiment 4: The effect of option 2 in the experiment Resetpine-induced decrease in body temperature of mice

[0095] 4.1 Experimental animals: ICR mice, males, body weight 22.0 ± 2 g, secondary, provided by the Department of Experimental Animal Science of Capital Medical University, Beijing.

[0096] 4.2 Experimental Medicines: Option 2 drug provided by Beijing Wonner Biotech. Ltd. Co., paroxetine (paxil) is a product of Zhong Mei Tianjin Smith Kline pharmaceuticals Co. Ltd. and Resetpine is a product of Guangdong BangMin Pharmaceutical Co., Ltd.

[0097] 4.3 Experimental equipment: Electronic thermometer (model: GM222) and a stopwatch.

[0098] 4.4 Dose designs: 1. High dose of option 2 (80 mg / kg / day); 2. The average dose of option 2 (40 mg / kg / day); and 3. Low dose of option 2 (20 mg / kg / day).

[0099] 4.5 Experimental method and result:

[00100] 4.5.1 Grouping and drug administration: Mice are randomly divided into groups, and each group contains 10 mice. 1. A high dose of option 2 (80 mg / kg, P.O., was administered over 7 days); 2. The average dose of option 2 (40 mg / kg, P.O., was administered over 7 days); 3. A low dose of option 2 (20 mg / kg, P.O., was administered over 7 days); 4. Paroxetine (3 mg / kg, P.O., was administered over 7 days); and 5. Saline solution (P.O.).

[00101] 4.5.2 Experimental method: 1 hour after the last drug administration, the anal temperature in mice was determined on the eighth day. Then, 2 mg of Resetpine per kilogram of body weight is given by intraperitoneal injection. 4 hours after injection of Resetpine, the anal temperature in mice was determined again. The depth and time of insertion of the thermometer into the anus of mice are identical at each temperature measurement.

и результат эксперимента вычисляют в виде ANOVA с помощью пакета программ обработки статистических данных SPSS 11.5.[00102] 4.5.3 Statistical calculation: Experimental data are presented as

and the result of the experiment is calculated as ANOVA using the SPSS 11.5 statistical processing software package.

[00103] 4.5.4 Experiment result: see table 4.

Table 4 The effect of option 2 on the reduced mouse body temperature induced by Resetpine Group Number of animals Temperature reduction (° C) Saline solution (control) 10 3.65 ± 0.77 Paroxetine 10 2.38 ± 0.69 ** High Dose Option 2 10 2.93 ± 0.74 * The average dose of option 2 10 2.31 ± 0.82 ** Low Dose Option 2 10 3.21 ± 0.71 Compared with the control group: * P <0.05 and ** P <0.01

[00104] Conclusion: According to the above experiment, it can be found that the average dose of option 2 of the present invention and parksetin all reduce the reduced body temperature induced by Resetpine, which means that the antiexperimental functions of the depression of pharmaceuticals could be related to their effects on the amount of monoamine neurotransmitter. Thus, embodiment 2 of the present invention, as having the antiexperimental function of depression, can be extrapolated.

Experiment 5: Effect of Option 3 in a Tail Suspension Experiment

[00105] 5.1 Experimental animals: ICR mice, males, body weight 22.0 ± 2 g, secondary, provided by the Department of Experimental Animal Science of Capital Medical University, Beijing.

[00106] 5.2 Experimental Medicines: Option 3 drug provided by Beijing Wonner Biotech. Ltd. Co., and paroxetine (paxil) is a product of Zhong Mei Tianjin Smith Kline pharmaceuticals Co. Ltd.

[00107] 5.3 Experimental equipment: stopwatch.

[00108] 5.4 Dose designs: 1. High dose of option 3 (80 mg / kg / day); 2. The average dose of option 3 (40 mg / kg / day); and 3. Low dose option 3 (20 mg / kg / day).

[00109] 5.5 Experimental method and result:

[00110] 5.5.1 Grouping and drug administration: Mice are randomly divided into groups, and each group contains 10 mice. 1. A high dose of option 3 (80 mg / kg, P.O., was administered over 7 days); 2. The average dose of option 3 (40 mg / kg, P.O., was administered over 7 days); 3. Low dose of option 3 (20 mg / kg, P.O., administered over 7 days); 4. Paroxetine (3 mg / kg, P.O., was administered over 7 days); and 5. Saline solution (P.O.). 1 hour after the last administration of the drug, an experiment was performed by hanging the mouse by the tail.

[00111] 5.5.2 Experimental method: The tail of the mouse (1 cm to the tip of the tail) is glued with adhesive tape to a wooden plank 5 cm higher than the platform and suspended for 6 minutes. Record the time of immobility of the mouse for at least 5 minutes.

и результат эксперимента вычисляют в виде ANOVA с помощью пакета программ обработки статистических данных SPSS 11.5.[00112] 5.5.3 Statistical calculation: Experimental data are presented as

and the result of the experiment is calculated as ANOVA using the SPSS 11.5 statistical processing software package.

[00113] 5.5.4 Experiment result: see table 5.

Table 5 The effect of option 3 on the time of immobility of the mouse Group Number of animals Immobility time (seconds) Saline solution (control) 10 113.22 ± 21.18 Paroxetine 10 75.33 ± 22.91 * High Dose Option 3 10 70.37 ± 28.14 * The average dose of option 3 10 76.26 ± 23.81 * Low Dose Option 3 10 90.40 ± 31.32 Compared with the control group: * P <0.05 and ** P <0.01.

[00114] Conclusion: According to the above experiment, it can be found that high and medium doses of Embodiment 3 of the present invention and paroxetine can all reduce the immobility time after hanging by the tail of a mouse, significantly different from the physiological saline group (control). Thus, embodiment 3 of the present invention, as having the antiexperimental function of depression, can be extrapolated.

Experiment 6: Effect of Option 3 in an Experiment of Resetpine-Induced Decrease in Mouse Body Temperature

[00115] 6.1 Experimental animals: ICR mice, males, body weight 22.0 ± 2 g, secondary, provided by the Department of Experimental Animal Science of Capital Medical University, Beijing.

[00116] 6.2 Experimental Medicines: Option 3 drug provided by Beijing Wonner Biotech. Ltd. Co., paroxetine (paxil) is a product of Zhong Mei Tianjin Smith Kline pharmaceuticals Co. Ltd., and Resetpine is a product of Guangdong BangMin Pharmaceutical Co., Ltd.

[00117] 6.3 Experimental equipment: Electronic thermometer (model: GM222) and a stopwatch.

[00118] 6.4 Dose designs: 1. High dose of option 3 (80 mg / kg / day); 2. The average dose of option 3 (40 mg / kg / day); and 3. Low dose option 3 (20 mg / kg / day).

[00119] 6.5. Experimental method and result:

[00120] 6.5.1 Grouping and drug administration: Mice are randomly divided into groups, and each group contains 10 mice. 1. A high dose of option 3 (80 mg / kg, P.O., was administered over 7 days); 2. The average dose of option 3 (40 mg / kg, P.O., was administered over 7 days); 3. Low dose of option 3 (20 mg / kg, P.O., administered over 7 days); 4. Paroxetine (3 mg / kg, P.O., was administered over 7 days); and 5. Saline solution (P.O.).

[00121] 6.5.2 Experimental method: 1 hour after the last administration of the drug on the eighth day, the anal temperature in mice was determined. Then, 2 mg of Resetpine per kilogram of body weight is given by intraperitoneal injection. 4 hours after injection of Resetpine, the anal temperature in mice was determined again. The depth and time of insertion of the thermometer into the anus of mice are identical at each temperature measurement.

и результат эксперимента вычисляют в виде ANOVA с помощью пакета программ обработки статистических данных SPSS 11.5.[00122] 6.5.3 Statistical calculation: Experimental data are presented as

and the result of the experiment is calculated as ANOVA using the SPSS 11.5 statistical processing software package.

[00123] 6.5.4 Experiment result: see table 6.

Table 6 Effect of Option 3 on Resetpine-Induced Mouse Body Temperature Group Number of animals Temperature reduction (° C) Saline solution (control) 10 3.65 ± 0.77 Paroxetine 10 2.38 ± 0.69 ** High Dose Option 3 10 2.18 ± 0.92 ** The average dose of option 3 10 2.36 ± 0.83 ** Low Dose Option 3 10 2.97 ± 0.67 * Compared with the control group: * P <0.05 and ** P <0.01

[00124] Conclusion: According to the above experiment, it can be found that high, medium and low doses of Embodiment 3 of the present invention and paroxetine can all reduce the reduced body temperature induced by Resetpine, and this means that the antiexperimental functions of the depression of pharmaceuticals could be related with their effects on the amount of monoamine neurotransmitter. Thus, embodiment 3 of the present invention, as having the antiexperimental function of depression, can be extrapolated.

Experiment 7: The effect of option 4 in the experiment on the defeat of the olfactory bulbs in mice

[00125] 7.1 Experimental animals:

[00126] Olfactory bulb lesion model: healthy male Wistar rats, secondary, body weight 330 ± 20 g, purchased from Beijing Vital River Experimental Animal Technology Ltd. Co. (quality certificate number: SCXK (JING) 2002-2003).

[00127] 7.2 Reagents and Medicines: The Option 4 drug is provided by Beijing Wonner Biotech Ltd. Co. (Lot: 060313), and paroxetine is a product of Zhong Mei Tianjin Smith Kline pharmaceuticals Co. Ltd. (Lot: 04050011). The above medications are prepared in 0.5% sodium carboxymethyl cellulose (CMC-Na) for administration to the stomach. Benzylpenicillin Sodium for Injection is a product of North China Pharmaceutical Huasheng Co. Ltd. (Lot: S0511204), and the norepinephrine (NE) and 5-hydrotryptamine (5-HT) standards are Sigma Co products. Other reagents are supplied.

[00128] 7.3 Equipment: A home-made camera for studying behavior in an open field, a step through the camera, a stereotactic instrument for rats, high performance liquid chromatography (HPLC) and a 10-channel noise-resistant counter for radiation (type: DFM-96).

[00129] 7.4 Experimental methods:

[00130] 7.4.1 Grouping and drug administration: Rats are randomly divided into 6 groups. 1. False therapeutic group; 2. Model group (control); 3. A high dose of option 4 (60 mg / kg / day); 4. The average dose of option 4 (30 mg / kg / day); 5. Low dose of option 4 (15 mg / kg / day); and 6. Paroxetine (2 mg / kg / day). The test drugs and the positive drug are prepared with 0.5% CMC-Na for administration to the stomach once a day.

[00131] 7.4.2 Method of Model Preparation: Rats are anesthetized with chloral hydrate. After anesthesia, a midline incision is made in the rat fontanel from 1 cm to the frontal fontanel to 1 cm behind the frontal fontanel and the bones of the skull are exposed. Open the windows on the skull, having a diameter of 2 mm, from 8 mm in front of the frontal fontanel and 2 mm on both sides of the midline. A specially made electric soldering iron is inserted perpendicularly into the skull for 2 seconds and the olfactory bulb is destroyed. A hemostatic sponge is immersed in the windows of the skull and the skin is sutured. After treatment, 40,000 units of benzylpenicillin sodium per kilogram of body weight, performed by intraperitoneal injection for every four days, give the test drug continuously for 24 days.

[00132] 7.5 Indicators of visual observation:

[00133] 7.5.1 Open-field camera experiment: An open-field camera (1 m × 1 m × 0.4 m) is constructed using light blue plywood and an aluminum alloy frame. The bottom of the camera is divided into 25 squares (20 cm × 20 cm for each square), the perimeter is peripheral squares (16 squares), and the rest are central squares (9 squares). The rat is placed in the center of the central squares and the number of rats crossed by the rat (the number of intersections of the adjacent square by more than three claws) and the number of standing rats (two forelimbs leaving a bottom of more than 1 cm) are counted / obtained by observation for 3 minutes.

[00134] 7.5.2 Passive avoidance experiment (stepping test): A septum through the chamber is formed between the light chamber and the dark chamber, and a passage connects the light chamber and the dark chamber to exit and enter the mouse. The lattice of the dark chamber is connected to the equipment for electric shock and there in the gap a mobile plate is installed. If the rat enters a dark chamber, the rat will be exposed to electric shock. During training, the rat is placed in a bright chamber and then back into the hole for adaptation within 5 minutes. Then the plate is removed and the rat is observed for the next 5 minutes. Record the time when the rat enters for the first time (electroshock latent period), and this time is the result of the study. After 24 hours, the test is repeated. The plate is removed and the dark chamber is exposed to electric shock for 5 minutes to set the time when the rat enters the dark chamber for the first time. This time is a memory record.

и результат эксперимента вычисляют в виде ANOVA с помощью пакета программ обработки статистических данных SPSS 11.5.[00135] 7.6 Statistical calculation: Experimental data are presented as

and the result of the experiment is calculated as ANOVA using the SPSS 11.5 statistical processing software package.

[00136] 7.7 Experimental results:

[00137] 7.7.1 The result of an experiment of behavior in a chamber is an open field: see table 7.

Table 7 The result of the model of lesion of the olfactory bulbs of rats in an experiment in open-field chamber behavior Group Number of animals Horizontal movement (number of crossed squares) Vertical movement (number of vertical posts) High Dose Option 4 eleven 49.18 ± 27.68 ** 10.91 ± 6.91 ** The average dose of option 4 eleven 54.55 ± 23.01 13.45 ± 5.72 * Low Dose Option 4 eleven 61.82 ± 21.43 15.18 ± 4.47 Paroxetine eleven 55.36 ± 25.96 * 14.36 ± 5.55 Model group (control) eleven 79.55 ± 24.33 19.09 ± 8.53 False Therapeutic Group eleven 45.36 ± 26.84 ** 10.45 ± 6.19 ** Compared with the control group: * P <0.05 and ** P <0.01.

[00138] 7.7.2 Step test result: see, table 8.

Table 8 The result of the rat olfactory bulb lesion model in the step test Group Number of animals Latency of the first day (seconds) Latency of the second day (seconds) High Dose Option 4 eleven 187.00 ± 87.59 * 289.82 ± 28.59 * The average dose of option 4 eleven 191.71 ± 72.95 * 288.82 ± 37.09 * Low Dose Option 4 eleven 152.44 ± 76.81 271.18 ± 38.61 Paroxetine eleven 181.87 ± 90.54 * 265.00 ± 65.39 Model group (control) eleven 111.21 ± 82.93 236.88 ± 74.17 False Therapeutic Group eleven 211.46 ± 82.10 ** 292.82 ± 14.37 * Compared with the control group: * P <0.05 and ** P <0.01.

[00139] Conclusion: The result of experiment 7 demonstrates that a high dose of option 4 can markedly reduce the growth of horizontal and vertical movements of rats caused by damage to the olfactory bulbs, and the average dose of option 4 also has a noticeably improved effect on the growth of vertical movement in the olfactory bulb lesion model in rats. In addition, the high and medium doses of option 4 have markedly improved effects on decreased learning and memory functions in rats caused by damage to the olfactory bulbs.

Experiment 8: The effect of option 4 in an experiment of unpredictable long-term stimuli in rats

[00140] 8.1 Experimental animals:

[00141] Model of unpredictable long-term stimuli: male Health Wistar rats, secondary, 240 ~ 270 g body weight, purchased from Beijing Vital River Experimental Animal Technology Ltd. Co. (Quality Certificate Number: SCXK (JING) 2002-2003).

[00142] 8.2 Reagents and Pharmaceutical Preparations: Option 4 pharmaceutical preparation provided by Beijing Wonner Biotech Ltd. Co. (Lot: 060313) and paroxetine is a product of Zhong Mei Tianjin Smith Kline pharmaceuticals Co. Ltd. (Lot: 04050011). The above medications are prepared in 0.5% sodium carboxymethyl cellulose (CMC-Na) for administration to the stomach. Benzylpenicillin Sodium for Injection is a product of North China Pharmaceutical Huasheng Co. Ltd. (Lot: S0511204), and the norepinephrine (NE) and 5-hydrotryptamine (5-HT) standards are products of Sigma Co. Other reagents are supplied.

[00143] 8.3 Equipment: A home-made camera for studying behavior in an open field, a step through the camera, a stereotactic instrument for rats, high performance liquid chromatography (HPLC) and a 10-channel noise-resistant counter for radiation (type: DFM-96).

[00144] 8.4 Experiment Methods:

[00145] 8.4.1 Grouping and drug administration: Rats are randomly divided into 6 groups. 1. False therapeutic group; 2. Model group (control); 3. A high dose of option 4 (60 mg / kg / day); 4. The average dose of option 4 (30 mg / kg / day); 5. Low dose of option 4 (15 mg / kg / day); and 6. Paroxetine (2 mg / kg / day). The test drugs and the positive drug are prepared with 0.5% CMC-Na for administration to the stomach once a day.

[00146] 8.4.2 The method of obtaining the model:

[00147] Model of unpredictable long-term stimuli: Rats in the control group eat and drink normally, and there are no fulfilled stimuli. In the other 5 groups, one rat is fed in each cage and the rat is exposed to 24-day unpredictable stress / stimulus, including 24-hour absorption 3 times, 24-hours without drinking 3 times, 24-hour wet bed 3 times (200 ml of water poured into the rat’s cage), lighting all night 3 times, swimming at 4 ° C for 5 minutes 3 times, heating at 45 ° C in the oven for 5 minutes 3 times, applying clamps to the tail of the rat for 1 minute 3 times and 30 minutes high speed horizontal shaking 3 times. One stimulus is performed arbitrarily every day and only 24 days. Each stimulus cannot be performed continuously. The pharmaceutical preparation is fed into the stomach of the rat once a day and only 24 days.

[00148] 8.5 Indicators of visual observation:

[00149] 8.5.1 Open Field Behavior Experiment: Same as above.

[00150] 8.5.2 Passive avoidance experiment: Same as above.

[00151] 8.5.3 Swimming of rats in a forced swimming test: This experiment is continued for two days after the last administration of the drug. On the first day, the experiment is performed preliminarily for 15 minutes. The water temperature in the glass tank is 25 ° C and the water depth is 25 cm. After 24 hours, the formal experiment is continued. 1 hour after drug administration, the rat is placed in the reservoir and the rat immobility time is recorded for the last 5 minutes.

[00152] 8.5.4 Measurement of body weight: Compare increasing values before and after each experiment with animals.

[00153] 8.5.5 Volumetric test for drinking sucrose: Compare the volumes of sucrose absorbed in rats. Rats in each group drink 1% sucrose for 1 hour. Drinking volumes are determined before the stimulus and after 3 weeks of the stimulus. After the rat is absent and in water for 14 hours, 1% sucrose is placed in the cage and replaced with ordinary drinking water. Measure and record the difference in weight of the bottle before and after drinking the sucrose with the rat for 1 hour and calculate the amount of sucrose consumed for each point in time. Compare the amount of sucrose absorbed for each point in time.

[00154] 8.5.6 HPLC electrochemical test: The amounts of norepinephrine and 5-hydrotriptamine in the rat cerebral cortex are measured.

и результат эксперимента вычисляют в виде ANOVA с помощью пакета программ обработки статистических данных SPSS 11.5.[00155] 8.6 Statistical calculation: Experimental data are presented as

and the result of the experiment is calculated as ANOVA using the SPSS 11.5 statistical processing software package.

[00156] 8.7 The results of the experiment:

[00157] 8.7.1 Volumetric test for drinking sucrose: see table 9.

Table 9 Rat sucrose uptake in an unpredictable long-term stimulus model Group Number of animals The amount of absorbed sucrose (g) High Dose Option 4 13 22.55 ± 5.03 The average dose of option 4 13 26.53 ± 4.99 ** Low Dose Option 4 13 26.97 ± 6.93 ** Paroxetine 13 26.29 ± 4.87 ** Model group (control) 13 19.42 ± 4.25 False Therapeutic Group 13 29.41 ± 3.83 ** Compared with the control group: * P <0.05 and ** P <0.01.

[00158] 8.7.2 The result of an increase in rat body weight: see table 10.

Table 10 Rat weight gain in an unpredictable long-term stimulus model Group Number of animals Weight gain (g) High Dose Option 4 13 86.08 ± 10.84 The average dose of option 4 13 96.00 ± 11.05 ** Low Dose Option 4 13 95.15 ± 15.46 ** Paroxetine 13 96.85 ± 9.30 ** Model group (control) 13 84.92 ± 12.61 False Therapeutic Group 13 120.54 ± 10.60 ** Compared with the control group: * P <0.05 and ** P <0.01.

[00159] 8.7.3 The time of immobility of the rat during forced swimming: see table 11.

Table 11 The immobility time in the model of unpredictable long-term stimuli in the rat forced swimming test Group Number of animals Immobility time (seconds) High Dose Option 4 13 23.28 ± 18.05 ** The average dose of option 4 13 18.95 ± 12.55 ** Low Dose Option 4 13 25.20 ± 13.60 * Paroxetine 13 31.38 ± 19.59 Model group (control) 13 39.95 ± 17.46 False Therapeutic Group 13 26.96 ± 12.76 * Compared with the control group: * P <0.05 and ** P <0.01.

[00160] 8.7.4 Result of an open field behavior experiment: see table 12.

Table 12 The result of an unpredictable long-term stimulus model in an open field behavior experiment Group Number of animals Horizontal movement (number of crossed squares) Vertical movement (number of vertical posts) High Dose Option 4 fourteen 58.31 ± 15.35 * 16.54 ± 4.24 ** The average dose of option 4 fourteen 49.15 ± 14.26 13.54 ± 4.48 Low Dose Option 4 fourteen 52.62 ± 21.83 16.15 ± 7.32 * Paroxetine fourteen 61.85 ± 21.68 ** 14.69 ± 4.2 Model group (control) fourteen 39.54 ± 16.31 11.46 ± 3.26 False Therapeutic Group fourteen 64.00 ± 11.97 ** 16.85 ± 3.18 ** Compared with the control group: * P <0.05 and ** P <0.01.

[00161] 8.7.5 Step test result: see table 13.

Table 13 Step test result in unpredictable long-term incentive model Group Number of animals Latency of the first day (seconds) Latency of the second day (seconds) High Dose Option 4 13 65.43 ± 31.44 259.22 ± 56.51 The average dose of option 4 13 58.18 ± 18.0 212.76 ± 77.27 Low Dose Option 4 13 75.98 ± 32.22 * 204.85 ± 94.99 Paroxetine 13 75.75 ± 46.52 * 257.46 ± 66.92 Model group (control) 13 50.01 ± 15.7 189.25 ± 111.99 False Therapeutic Group 13 80.00 ± 39.17 * 263.38 ± 59.68 Compared with the control group: * P <0.05 and ** P <0.01.

[00162] 8.7.6 The result of the content of NE and 5-HT in the rat cerebral cortex: see table 14.

Table 14 The result of the content of NE and 5-HT in the rat cerebral cortex in a model of unpredictable long-term stimuli Group Number of animals 5-HT (nmol / L brain tissue extract) NE (nmol / L brain tissue extract) High Dose Option 4 12 230.4157 ± 47.78554 * 269.5409 ± 58.86389 ** The average dose of option 4 12 303.4418 ± 70.31711 ** 227.2976 ± 28.95101 * Low Dose Option 4 12 332.7343 ± 76.25168 ** 201.8688 ± 29.80775 ** Paroxetine 12 227.0637 ± 46.53838 * 220.5419 ± 38.31681 ** Model group (control) 12 179.3866 ± 20.49374 57.6671 ± 77.66958 False Therapeutic Group 12 228.1478 ± 28.40397 * 132.8598 ± 20.84756 ** Compared with the control group: * P <0.05 and ** P <0.01.

[00163] Conclusion: The results of experiment 8 are shown as follows. Medium and low doses of option 4 can significantly increase the reduced volume of drinking sucrose and reduce body weight in response to unpredictable long-term stress / stimuli. High, medium and low doses of option 4 can significantly increase the immobility time during forced swimming of rats. The high dose of option 4 can significantly improve the reduced horizontal and vertical rat motions caused by unpredictable long-term stress / stimuli. The low dose of option 4 also has a notable function of improving the reduced vertical movement of rats caused by unpredictable long-term stress / stimuli. The low dose of option 4 has the function of improving the reduced learning ability of rats caused by unpredictable long-term stress / stimuli. High, medium and low doses of option 4 can all significantly increase the content of NE and 5-HT in the rat cerebral cortex.

Experiment 9: Effect of Option 5 in a Tail Suspension Experiment

[00164] 9.1 Experimental drugs: option 5 pharmaceutical preparation provided by Beijing Wonner Biotech. Ltd. Co. (an experimental storage product) and paroxetine is a product of Zhong Mei Tianjin Smith Kline pharmaceuticals Co. Ltd (Lot: 05070384). The above pharmaceutical preparations are prepared with saline for delivery to the stomach.

[00165] 9.2 Experimental animals: ICR mice, males, body weight 20.0 ± 1 g, secondary, provided by the Department of Experimental Animal Science of Capital Medical University, Beijing. The mouse quality certificate number is SCXK (JING) 2006-2008.

[00166] 9.3 Experimental Equipment: Stopwatch.

[00167] 9.4 Method: Seventy (70) mice are randomly divided into 5 groups: physiological saline (NS) group, paroxetine (3 mg / kg / day), high dose variant 5 (80 mg / kg / day), average dose option 5 (40 mg / kg / day) and a low dose of option 5 (20 mg / kg / day). Drugs are injected into the mouse’s stomach once a day. 1 hour after the last injection of the drug on the eighth day, the mouse tail (1 cm to the tip of the tail) is glued with adhesive tape to a horizontal support in an open chamber, and the mouse is in an inverted hanging position. The mouse head is approximately 10 cm below the bottom of the open chamber, and the mouse is suspended for 6 minutes. The immobility of the mouse is recorded over the last 5 minutes.

и результат эксперимента вычисляют в виде однонаправленного ANOVA с помощью пакета программ обработки статистических данных SPSS 11.5.[00168] 9.5 Statistical calculation: Experimental data are presented as

and the result of the experiment is calculated as a unidirectional ANOVA using the SPSS 11.5 statistical processing software package.

[00169] 9.6 Experiment result: The result of the immobility time in the experiment by hanging the mouse by the tail: see table 15.

Table 15 The effect of option 5 on the total time of immobility of the mouse in the experiment of hanging the mouse by the tail Group Number of animals Dose (mg / kg / day) Immobility time (seconds) High Dose Option 5 fourteen 80 64.75 ± 42.22 ** The average dose of option 5 fourteen 40 55.41 ± 33.83 ** Low Dose Option 5 fourteen twenty 62.75 ± 26.61 ** Paroxetine fourteen 3 53.27 ± 20.02 ** Saline Group (NS) fourteen 113.59 ± 36.11 Compared to the NS group: * P <0.05 and ** P <0.01.

[00170] Conclusion: The result of the study demonstrates that high, medium, and low doses of option 5 and a clinically effective antidepressant drug, paroxetine, all can significantly reduce the total immobility time in the mouse suspension experiment. The result shows that option 5 of the present invention has a specific antiexperimental depressive function.

Experiment 10: The effect of option 5 in the experiment forced swimming mice.

[00171] 10.1 Experimental Medicines: Option 5 pharmaceutical preparation provided by Beijing Wonner Biotech. Ltd. Co. (a pilot accumulation product), and paroxetine is a product of Zhong Mei Tianjin Smith Kline phannaceuticals Co. Ltd (Lot: 05070384). The above pharmaceutical preparations are prepared with saline for delivery to the stomach.

[00172] 10.2 Experimental animals: ICR mice, males, body weight 20.0 ± 1 g, secondary, provided by the Department of Experimental Animals of the Capital Medical University, Beijing. The mouse quality certificate number is SCXK (JING) 2006-2008.

[00173] 10.3 Experimental Equipment: Stopwatch.

[00174] 10.4 Experimental method: The mouse groups and drug administration are the same as in the experiment by hanging the mouse by the tail. In each group of test mice, the experiment is continued 1 hour after drug administration. Mice are taught swimming for 15 minutes before the experiment and on the eighth day. The experiment is performed in 24 hours. Mice are placed in a glass tank having a water depth of 10 cm, a diameter of 14 cm at a water temperature of 25 ° C. The total immobility time for the last 5 minutes is recorded.

и результат эксперимента вычисляют в виде однонаправленного ANOVA[00175] 10.5 Statistical calculation: Experimental data are presented as

and the result of the experiment is calculated as a unidirectional ANOVA

using the statistical processing software package SPSS 11.5.

[00176] 10.6 Experimental result: Forced swimming of mice: see table 16.

Table 16 The effect of option 5 in the experiment of forced swimming mice Group Number of animals Dose (mg / kg / day) Immobility time (seconds) High Dose Option 5 fourteen 80 88.35 ± 51.64 * The average dose of option 5 fourteen 40 65.87 ± 38.96 ** Low Dose Option 5 fourteen twenty 88.12 ± 38.57 * Paroxetine fourteen 3 57.80 ± 38.07 ** Saline Group (NS) fourteen 132.47 ± 40.64 Compared to the NS group: * P <0.05 and ** P <0.01.

[00177] Conclusion: The experimental result shows that the high, medium, and low doses of option 5 and the clinically effective antidepressant drug paroxetine can all significantly reduce the total immobility time of mice in the forced swimming test. The result shows that option 5 of the present invention has a specific antiexperimental depressive function.

Experiment 11:

[00178] Nine (9) kg of remaining ginseng debris, 7 kg of remaining licorice debris and 0.9 kg of jujuba debris from the extraction procedures of options 1 and 4 are collected, dried, pulverized and mixed well to obtain a debris mixture containing trace amounts of ginsenoside Rg1 and Rb1, glycyrrhizic acid and jujuba cAMP. Conduct a control experiment of the effect of debris in the experiment of hanging the mouse by the tail.

[00179] 11.1 Experimental animals: ICR mice, males, body weight 22.0 ± 2 g, secondary, provided by the Department of Experimental Animal Science of Capital Medical University, Beijing.

[00180] 11.2 Experimental Medicines: A mixture of debris was provided by Beijing Wonner Biotech. Ltd. Co., And paroxetine (paxil) is a product of Zhong Mei Tianjin Smith Kline pharmaceuticals Co. Ltd.

[00181] 11.3 Experimental Equipment: Stopwatch.

[00182] 11.4 Dose designs: 1. High dose debris mixture (160 mg / kg / day); 2. The average dose of a mixture of debris (80 mg / kg / day) and 3. The low dose of a mixture of debris (40 mg / kg / day).

[00183] 11.5 Experimental method and result:

[00184] 11.5.1 Dividing into groups and drug administration: Mice are randomly distributed, 10 mice are in each group. 1. A high dose of a mixture of debris (160 mg / kg, P.O., administered within 7 days); 2. The average dose of a mixture of debris (80 mg / kg, P.O., administered within 7 days); 3. A low dose of a mixture of debris (40 mg / kg, P.O., administered within 7 days); 4. Paroxetine (3 mg / kg, P.O., administered over a period of 7 days); and 5. Saline (P.O.). 1 hour after the last injection of the drug, an experiment is performed by hanging the mouse by the tail.

[00185] 11.5.2 Experimental method: The tail of the mouse (1 cm to the tip of the tail) is glued with adhesive tape to a wooden plank 5 cm higher than the platform and suspended for 6 minutes. Record the time of immobility of the mouse in the last 5 minutes.

[00186] 11.5.3 Statistical Calculation: Experimental Data

и результат эксперимента вычисляют в виде ANOVA с помощью пакета программ обработки статистических данных SPSS 11.5.present as

and the result of the experiment is calculated as ANOVA using the SPSS 11.5 statistical processing software package.

[00187] 11.5.4 Experiment result: see table 17.

Table 17 The effect of a mixture of debris on the immobility time of mice Group Number of animals Immobility time (seconds) Saline solution (control) 10 82.03 ± 43.01 Paroxetine 10 38.37 ± 20.76 * High dose debris mix 10 76.91 ± 31.09 The average dose of a mixture of debris 10 78.89 ± 48.18 Low dose debris mix 10 81.31 ± 58.68 Compared with the control group: * P <0.05 and ** P <0.01.

[00188] Conclusion: In accordance with the above experiment, it can be found that although high, medium and low doses of debris mixtures can reduce the time of immobility of the mouse suspended by the tail, these differences are not statistically significant compared with the saline group (control). Thus, the conclusion is that a mixture of debris can be extrapolated as deprived of the antiexperimental function of depression.

[00189] The scope of the pharmaceutical composition for oral administration of the present invention for the treatment of depression is that:

[00190] 1. The described pharmaceutical preparation for oral administration of the present invention for the treatment of depression may include pharmacologically acceptable additives;

[00191] 2. The described pharmaceutical preparation for oral administration of the present invention for the treatment of depression can be made in the form of known dosage forms such as a powder, capsule, tablet, etc .; and

[00192] 3. The described pharmaceutical preparation for oral administration of the present invention for the treatment of depression can be formulated as a nutritional medicine for the treatment of depression.

[00193] While the invention has been described in the context of what is currently believed to be the most practical and preferred embodiments of the invention, it should be understood that the invention should not be limited by the disclosed embodiments. On the contrary, the invention is intended to cover various modifications and similar compositions included within the spirit and scope of the appended claims, which should be consistent with the broadest interpretation so as to encompass all such modifications and similar structures.

Claims (13)

1. A pharmaceutical composition with a multi-purpose post-receptor mechanism for the treatment of depression, comprising:
2 ~ 26 parts by weight ginsenosides Rg1 and Rb1; and
3 ~ 48 parts by weight a derivative of glycyrrhizic acid, being one selected from the group consisting of glycyrrhizic acid, glycyrrhetinic acid, and a combination thereof. 2. The pharmaceutical composition according to claim 1, containing 4 ~ 13 parts by weight ginsenosides Rg1 and Rb1 and 5 ~ 16 parts by weight glycyrrhizic acid derivative. 3. The pharmaceutical composition according to claim 1, ginsenosides Rg1 and Rb1 are extracted from ginseng. 4. The pharmaceutical composition according to claim 1, containing at least one of pharmacologically acceptable carriers and an additive. 5. The pharmaceutical composition according to claim 1, having a dosage form selected from the group consisting of tablets, capsules, powder, dragees, powders, solutions, microcapsules, suspensions, emulsions, particles, droplets and a ball. 6. The pharmaceutical composition according to claim 1, produced in the form of one of the therapeutic nutrition and nutritional supplements. 7. A multi-purpose post-receptor pharmaceutical composition for the treatment of depression, comprising:
2 ~ 26 parts by weight ginsenosides Rg1 and Rb1; and
3 ~ 48 parts by weight a glycyrrhizic acid derivative, being one selected from the group consisting of glycyrrhizic acid, glycyrrhetinic acid, and a combination thereof; and
0.002 ~ 0.5 parts by weight cyclic jujuba adenosine monophosphate (jujuba cAMP). 8. The pharmaceutical composition according to claim 7, containing 4 ~ 13 parts by weight ginsenosides Rg1 and Rb1, 5 ~ 16 parts by weight glycyrrhizic acid derivative and 0.01 ~ 0.1 parts by weight cAMP jujuba. 9. The pharmaceutical composition according to claim 7, where the ginsenosides Rg1 and Rb1 are extracted from ginseng, the glycerrhizic acid derivative is a licorice extract containing glycyrrhizic acid, and jujuba cAMP is extracted from jujuba. 10. The pharmaceutical composition according to claim 7, wherein the jujuba cAMP is extracted from jujub to obtain a primary extract having a primary jujuba cAMP concentration, the primary extract is further extracted to obtain a secondary extract having a jujuba cAMP secondary concentration, wherein the secondary jujuba cAMP concentration is higher than the primary the concentration of jujuba cAMP, and the secondary extract is a raw material for the pharmaceutical composition. 11. The pharmaceutical composition according to claim 7, containing at least one of pharmacologically acceptable carriers and an additive. 12. The pharmaceutical composition according to claim 7, having a dosage form selected from the group consisting of tablets, capsules, powder, dragees, powders, solutions, microcapsules, suspensions, emulsions, particles, droplets and a ball. 13. The pharmaceutical composition according to claim 7, produced in the form of one of the therapeutic nutrition and nutritional supplements.

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