A pharmaceutical composition

Abstract

The invention provides a pharmaceutical composition, which is prepared from paeoniflorin: paeoniflorin lactone glycosides: 1,2,3,4,6-O-pentagalloyl glucose, and the weight ratio thereof is 1:3-0.3:1-0.1; the composition can further improve the biological absorption of paeoniflorin and paeoniflorin lactone glycosides, further improve the drug efficacy, solve the problem that the existing peony extract components have low absorption rate and cannot be stably absorbed in the body, and further provides the use of the pharmaceutical composition in preparing a drug for treating depression.

Description

Technical Field

[0001] The invention provides a peony composition and a preparation method thereof, as well as application of the composition in treating diseases such as depression, and belongs to the field of traditional Chinese medicine. Background Art

[0002] Depression has become a global disease that threatens humanity. According to statistics from the World Health Organization (WHO), there are about 350 million people with depression worldwide, with a prevalence rate of 4.4%. Long-term depression not only affects people's work and life, but may also endanger their lives.

[0003] Drug therapy is currently the main means of treating depression. Because the pathogenesis of depression is very complex, a large number of factors are involved in the occurrence and development of depression. Although a variety of antidepressant drugs targeting different pathogenic factors have been developed, such as monoamine neurotransmitter modulators, glutamate system modulators, hypothalamus-pituitary-adrenal axis (HPA) axis modulators, opioid receptor modulators, neuroinflammatory modulators, γ-aminobutyric acid (GABA) receptor modulators and neurotrophic factor modulators, long-term use of these drugs is prone to drug resistance, and adverse drug reactions are also obvious.

[0004] Based on the country's rich Chinese herbal medicine resources, the applicant strives to find an alternative drug that can quickly and effectively treat depression. According to literature reports, the applicant has discovered that peony is a Chinese herbal medicine that has a clear anti-depression effect. However, due to the large number of ingredients in peony, it is not conducive to the development of drugs with stable quality and clear mechanisms of action. Therefore, the applicant needs to seek more accurate active substances for the treatment of depression.

[0005] According to patent search and preliminary experiments, the applicant screened that paeoniflorin and paeoniflorin may have significant antidepressant effects. Paeoniflorin and paeoniflorin are the main chemical components of Paeonia lactiflora Pall. or Paeonia veitchii Lynch, Ranunculaceae, and are also the main active ingredients. Studies have found that paeoniflorin and paeoniflorin exhibit significant antidepressant effects in both cell and animal models. Preliminary experiments have found that paeoniflorin and paeoniflorin may have a synergistic effect, but related technical problems have also been found. The preliminary experiments used a rat small intestine unidirectional perfusion model to investigate the changes in the absorption characteristics of paeoniflorin and paeoniflorin in the rat intestine. It was found that paeoniflorin was less absorbed and was a poorly absorbed compound, while paeoniflorin was a medium-absorbed compound. This problem directly became a key problem that prevented the effective application of the pharmaceutical composition. Summary of the invention

[0006] In order to solve the above technical problems, the applicant proposed a pharmaceutical composition, which consists of paeoniflorin, paeoniflorin and 1,2,3,4,6-O-pentagalloylglucose, and the weight ratio thereof is 1:0.3-3:0.1-1.

[0007] The invention provides a peony composition, which is mainly composed of paeoniflorin, paeoniflorin and 1,2,3,4,6-O-pentagalloylglucose, has a significant effect in treating depression, has little side effect, and is safe and reliable.

[0008] The present invention creatively provides a new pharmaceutical composition, which contains a third ingredient, 1,2,3,4,6-O-pentagalloyl glucose. The third ingredient also comes from peony, but it has not been reported to have a technical effect in treating depression. However, the new pharmaceutical composition improves the in vivo absorption and efficacy of the first two drugs, which is also a previously unpredictable result. At the same time, the third ingredient comes from peony, which avoids the intervention of exogenous ingredients and further increases the safety of related products.

[0009] Furthermore, in the above-mentioned pharmaceutical composition, the weight ratio of paeoniflorin to paeoniflorin is 1:1-2. According to experimental data, the effective range of paeoniflorin and paeoniflorin is preferably 1:1-2, preferably 1:1.4-1.7.

[0010] Furthermore, in the above-mentioned pharmaceutical composition, the weight ratio of paeoniflorin: paeoniflorin: 1,2,3,4,6-O-pentagalloylglucose is 1:1-2:0.3-0.8.

[0011] Furthermore, in the above-mentioned pharmaceutical composition, the weight ratio of paeoniflorin to paeoniflorin lactone glycosides is 1:1.5.

[0012] Furthermore, in the above-mentioned pharmaceutical composition, the weight ratio of paeoniflorin: paeoniflorin: 1,2,3,4,6-O-pentagalloylglucose is 1:1.5:0.5.

[0013] The present invention further provides a preparation containing the above-mentioned pharmaceutical composition, wherein the preparation also includes pharmaceutically acceptable pharmaceutical excipients, and the dosage form of the preparation is granules, tablets, hard capsules, soft capsules, pills, oral liquids, dripping pills or syrups.

[0014] The present invention further provides a preparation method of the above-mentioned pharmaceutical composition, which comprises the following steps: paeoniflorin, paeoniflorin and 1,2,3,4,6-O-pentagalloyl glucose are extracted respectively by the following methods: reflux extraction or cold soaking extraction is used to extract peony medicinal materials, and the extraction solution is 40-70% ethanol solution; the extract is sequentially separated by macroporous resin, and the concentration of the macroporous resin elution ethanol solution is 40-80%; and then the extract is subjected to a high performance liquid chromatography preparation system, and the mobile phase is 20-80% methanol-water solution; a fraction containing paeoniflorin, paeoniflorin and 1,2,3,4,6-O-pentagalloyl glucose is obtained, the solvent is evaporated, and recrystallization is performed to obtain paeoniflorin, paeoniflorin and 1,2,3,4,6-O-pentagalloyl glucose monomers; the above three compounds are proportioned to obtain the pharmaceutical composition.

[0015] The specific preparation method is as follows:

[0016] Paeoniflorin, paeoniflorin and 1,2,3,4,6-O-pentagalloylglucose are extracted by the following methods: reflux extraction or cold soaking extraction is used to extract peony medicinal materials, and the extraction solution is 40-70% ethanol solution; the extract is sequentially separated by macroporous resin, and the concentration of the macroporous resin elution ethanol solution is 40-80%; and then the extract is subjected to high performance liquid chromatography preparation system, the mobile phase is 20-80% methanol-water solution, and the flow rate is 50-100mL / min; the extract containing paeoniflorin, paeoniflorin and 1,2,3,4,6-O-pentagalloylglucose is obtained. The eluate of 2,3,4,6-O-pentagalloyl glucose is evaporated to dryness, and recrystallized at low temperature or room temperature, wherein the temperature is 0°C-25°C. The solvent used for recrystallization includes but is not limited to water, methanol, acetone, ethanol, acetonitrile, ethyl acetate, dichloromethane, pyridine, chloroform, petroleum ether, ether and other conventional solvents or a mixed solvent of the above conventional solvents to obtain paeoniflorin, paeoniflorin lactone glycosides and 1,2,3,4,6-O-pentagalloyl glucose monomers. The above three compounds are proportioned to obtain the pharmaceutical composition.

[0017] The invention provides a peony composition, which is mainly composed of paeoniflorin, paeoniflorin and 1,2,3,4,6-O-pentagalloylglucose, has a significant effect in treating depression, has little side effect, and is safe and reliable.

[0018] The beneficial effects of the present invention are as follows:

[0019] Paeoniflorin, paeoniflorin and 1,2,3,4,6-O-pentagalloyl glucose are the main chemical components of Paeonia lactiflora Pall. or Paeonia veitchii Lynch of the Ranunculaceae family. The present invention preferably uses Paeonia lactiflora Pall., Paeonia veitchii Lynch, Paeonia veitchii Lynch, Paeonia veitchii Lynch and other Paeonia species as extraction raw materials, and the medicinal parts are preferably roots and flowers.

[0020] The object of the present invention is to provide a composition for treating depression, which is mainly composed of paeoniflorin, paeoniflorin and 1,2,3,4,6-O-pentagalloyl glucose, and has significant therapeutic effect, small side effects, and is safe and reliable. The composition mainly contains paeoniflorin: paeoniflorin: 1,2,3,4,6-O-pentagalloyl glucose, and the weight ratio is 1:3-0.3:1-0.1.

[0021] The inventors found in previous studies that when paeoniflorin, paeoniflorin and 1,2,3,4,6-O-pentagalloylglucose were used alone or in combination, they had some improvement on depression. In order to obtain a clinically efficient Chinese medicine composite composition, the internationally recognized chemical fluoxetine was selected as a positive control, and a large number of pharmacological and pharmacodynamic screenings were conducted. The study found that a specific ratio of the three Chinese medicine monomer compounds had a very significant therapeutic effect on behavioral despair model mice and chronic unpredictable depression model rats, which was better than fluoxetine. This breakthrough research result meets the clinical demand for innovative Chinese medicine compositions and has milestone significance in the field of drugs for the treatment of depression.

[0022] Preferably, the monomer components of the composition are composed of: 1 part by weight of paeoniflorin, 3-0.3 parts by weight of paeoniflorin, and 1-0.1 parts by weight of 1,2,3,4,6-O-pentagalloyl glucose. At this weight ratio, the therapeutic efficacy is further improved. It was further found that when the weight ratio of paeoniflorin, paeoniflorin and 1,2,3,4,6-O-pentagalloyl glucose in the composition is 1:1.5:0.5, the therapeutic effect tends to be stable, and the drug effect is further improved.

[0023] By adding 1,2,3,4,6-O-pentagalloyl glucose, the absorption of paeoniflorin increased by 3.7 times, the absorption of paeoniflorin increased by 2.5 times, and the efficacy of the combination was significantly better than that of the positive drug fluoxetine.

[0024] Both paeoniflorin and paeoniflorin have antidepressant effects, but their absorption is poor. The antidepressant effect of the compound 1,2,3,4,6-O-pentagalloylglucose has not been reported, so 1,2,3,4,6-O-pentagalloylglucose itself does not have antidepressant function.

[0025] However, the inventors were surprised to find that when 1,2,3,4,6-O-pentagalloyl glucose was used in combination with paeoniflorin and paeoniflorin, it had a better antidepressant effect, and its antidepressant effect was significantly better than the use of paeoniflorin, paeoniflorin and 1,2,3,4,6-O-pentagalloyl glucose alone, and was also significantly better than the combination of any two of these three monomer compounds; this discovery further shows that 1,2,3,4,6-O-pentagalloyl glucose plays a certain unknown role in pharmacodynamics. The inventors were also surprised to find that when 1,2,3,4,6-O-pentagalloyl glucose was added, the absorption of paeoniflorin and paeoniflorin could be significantly promoted. This is also the first technical effect discovered, and it also provides a new idea for us to develop new drugs. The pharmaceutical composition of the present invention has a surprising therapeutic effect on rats with chronic unpredictable depression model, and the effect is significantly better than the Western medicine fluoxetine.

[0026] According to the needs of clinical use, the Chinese medicine formula will be further prepared into Chinese medicine preparations, which are not only easy to take and carry, but also ensure the stability of the quality of the medicine taken, and meet the needs of different clinical symptoms. According to the current status and development trend of pharmaceutical preparation technology, the composition can be made into granules, tablets, hard capsules, soft capsules, pills, oral liquids, dripping pills or syrups. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 is the UPLC chromatogram of paeoniflorin (230 nm);

[0028] Figure 2 is the UPLC chromatogram of paeoniflorin (230 nm);

[0029] Figure 3 UPLC chromatogram (280 nm) of 1,2,3,4,6-O-pentagalloylglucose. DETAILED DESCRIPTION

[0030] The following experimental examples are used to further illustrate the present invention but are not limited to the present invention. All technologies realized based on the above content of the present invention belong to the scope of the present invention. The following rats and mice were provided by Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.

[0031] The beneficial effects of the Chinese medicine composition of the present invention are further illustrated by the following experiments.

[0032] Example 1

[0033] Take 2500g of dried root of peony, slice it, add 15L ethanol-water (60:40) solution, reflux extract 2 times, filter and remove the residues for 1h each time, and the extract obtained is concentrated to 620g of fluid extract by reduced pressure, and the total glycosides of peony in the extract are about 40% by HPLC detection. Take 600g of fluid extract, dissolve it with about 2.5L 30% ethanol-water, separate it by 20L macroporous resin column chromatography, first elute 3 column volumes with 40% ethanol, then elute 5 times column volumes (5BV) with 60% ethanol, collect 60% ethanol eluent, and concentrate under reduced pressure to obtain 175g components containing paeoniflorin and paeoniflorin lactone glycosides. Take 170g of components containing paeoniflorin and paeoniflorin lactone glycosides, dissolve it with 35% methanol and prepare a solution with a content of 0.01g / mL, use a high performance liquid chromatography preparation system, and separate and purify it under methanol-water conditions. The preparation conditions used are: C18 reverse phase filler 10μm, preparation column inner diameter 300mm, dynamic axial compression chromatography or simulated moving bed chromatography, elution with 40% methanol aqueous solution, flow rate 80mL / min. After the sample was concentrated, 20.6g of crude paeoniflorin and 14.5g of crude paeoniflorin lactone glycosides were obtained; 20g of the crude paeoniflorin and 14g of the crude paeoniflorin lactone glycosides were taken and placed in a cold storage (4°C) and crystallized with methanol to obtain 15.6g of paeoniflorin and 9.8g of paeoniflorin lactone glycosides. The purity of the two compounds was tested as shown in Figure 1-Figure 2 .

[0034] Take 1500g of dried peony root, slice it, add 30L ethanol-water (50:50) solution, cold-immerse and extract 3 times, each time for 7 days, filter and remove the residue, and the obtained extract is concentrated under reduced pressure to 205g of fluid extract. Take 200g of the fluid extract, dissolve it in about 1.5L 30% ethanol-water, and separate it by 20L macroporous resin column chromatography, first elute with 50% ethanol for 3 column volumes, then elute with 60% ethanol and 70% ethanol for 5 times column volume (5BV), collect 70% ethanol eluate, and concentrate under reduced pressure to obtain 23g of 1,2,3,4,6-O-pentagalloyl glucose component. Take 20g of the component containing 1,2,3,4,6-O-pentagalloylglucose, dissolve it in 50% methanol and prepare a solution with a content of 0.1g / mL, purify it by Sephadex LH-20 column chromatography, elute with 50% methanol for 8 column volumes, collect 6-8 column volumes of eluate and concentrate under reduced pressure to obtain 1,2,3,4,6-O-pentagalloylglucose crude product (8g), dissolve it in 35% methanol and prepare a solution with a content of 0.01g / mL, and purify it under methanol-water conditions using dynamic axial compression chromatography or simulated moving bed chromatography. The preparation conditions used are: C18 reverse phase filler 10μm, preparation column inner diameter 300mm, mobile phase 48% methanol aqueous solution, flow rate 80mL / min. After the sample is concentrated, it is placed in a cold storage (10°C) and crystallized with acetone to obtain 3.2g of 1,2,3,4,6-O-pentagalloylglucose. The purity test of the compound is shown in Figure 3 The paeoniflorin, paeoniflorin and 1,2,3,4,6-O-pentagalloylglucose are mixed according to a certain proportion to obtain the pharmaceutical composition.

[0035] Example 2

[0036] The difference from Example 1 is that in the preparation method of paeoniflorin and paeoniflorin, an ethanol-water (70:30) solution is used for extraction to obtain 12.8 g of paeoniflorin and 10.2 g of paeoniflorin.

[0037] The difference from Example 1 is that in the preparation method of 1,2,3,4,6-O-pentagalloyl glucose, the ethanol-water (40:60) solution used for extraction obtains 3.9 g of 1,2,3,4,6-O-pentagalloyl glucose.

[0038] Example 3

[0039] The difference from Example 1 is that in the preparation method of paeoniflorin and paeoniflorin, an ethanol-water (40:60) solution was used for extraction to obtain 11.4 g of paeoniflorin and 11.2 g of paeoniflorin.

[0040] The difference from Example 1 is that in the preparation method of 1,2,3,4,6-O-pentagalloyl glucose, the ethanol-water (70:30) solution used for extraction obtains 2.6 g of 1,2,3,4,6-O-pentagalloyl glucose.

[0041] Example 4

[0042] The difference from Example 1 is that in the preparation method of paeoniflorin and paeoniflorin lactone glycosides, the solvent used for recrystallization is ethanol, and 14.9 g of paeoniflorin and 10 g of paeoniflorin lactone glycosides are obtained.

[0043] The difference from Example 1 is that in the preparation method of 1,2,3,4,6-O-pentagalloyl glucose, the solvent used for recrystallization is methanol, and 3.3 g of 1,2,3,4,6-O-pentagalloyl glucose is obtained.

[0044] Example 5

[0045] The difference from Example 1 is that in the preparation method of paeoniflorin and paeoniflorin lactone glycosides, the solvent used for recrystallization is ethyl acetate, and 12.4 g of paeoniflorin and 8.9 g of paeoniflorin lactone glycosides are obtained.

[0046] The difference from Example 1 is that in the preparation method of 1,2,3,4,6-O-pentagalloyl glucose, the solvent used for recrystallization is ethyl acetate, and 2.9 g of 1,2,3,4,6-O-pentagalloyl glucose is obtained.

[0047] Example 6

[0048] The difference from Example 1 is that in the preparation method of paeoniflorin and paeoniflorin lactone glycosides, the solvent used for recrystallization is dichloromethane, and 11.5 g of paeoniflorin and 7.9 g of paeoniflorin lactone glycosides are obtained.

[0049] The difference from Example 1 is that in the preparation method of 1,2,3,4,6-O-pentagalloyl glucose, the solvent used for recrystallization is pyridine, and 2.4 g of 1,2,3,4,6-O-pentagalloyl glucose is obtained.

[0050] Example 7

[0051] The difference from Example 1 is that in the preparation method of paeoniflorin and paeoniflorin lactone glycosides, the extract is peony flower, and 30.2 g of paeoniflorin and 22.5 g of paeoniflorin lactone glycosides are obtained.

[0052] The difference from Example 1 is that in the preparation method of 1,2,3,4,6-O-pentagalloyl glucose, the extract is peony flower, and 6.7 g of 1,2,3,4,6-O-pentagalloyl glucose is obtained.

[0053] Example 8

[0054] The difference from Example 1 is that in the preparation method of paeoniflorin and paeoniflorin, dynamic axial compression chromatography or simulated moving bed chromatography is used, eluted with 80% methanol aqueous solution, and the flow rate is 80 mL / min to obtain 5.4 g of paeoniflorin and 1.5 g of paeoniflorin.

[0055] The difference from Example 1 is that in the preparation method of 1,2,3,4,6-O-pentagalloyl glucose, dynamic axial compression chromatography or simulated moving bed chromatography is used, eluted with 80% methanol aqueous solution, and the flow rate is 80 mL / min to obtain 1.1 g of 1,2,3,4,6-O-pentagalloyl glucose.

[0056] Example 9

[0057] The difference from Example 1 is that in the preparation method of paeoniflorin and paeoniflorin, dynamic axial compression chromatography or simulated moving bed chromatography is used, eluted with 20% methanol aqueous solution, and the flow rate is 80 mL / min to obtain 10.8 g of paeoniflorin and 2.5 g of paeoniflorin.

[0058] The difference from Example 1 is that in the preparation method of 1,2,3,4,6-O-pentagalloyl glucose, dynamic axial compression chromatography or simulated moving bed chromatography is used, eluted with 20% methanol aqueous solution, and the flow rate is 80 mL / min to obtain 0.7 g of 1,2,3,4,6-O-pentagalloyl glucose.

[0059] Example 10

[0060] Experimental animals: Male ICR mice, weighing 20-22 g, were purchased from Weitonglihua Experimental Animal Co., Ltd., animal production license number: SCXK (Beijing) 2017-0020.

[0061] Animal Model: Mouse Behavioral Despair Model

[0062] (1) Animal grouping and drug administration: Mice were allowed to eat and drink freely, and the room temperature was 23-25℃, the humidity was 50±10%, and the light was on from 7:00 to 19:00. The experiment began after the animals were adapted to the new environment for 7 days. The mice were randomly divided into 11 groups, with 10 mice in each cage. They were set as the control group (distilled water, ig), the fluoxetine group (10 mg / kg, ig, Fluoxetine), and the combination group of paeoniflorin and paeoniflorin in different proportions (10 mg / kg, ig. According to literature records, the dosage of these two drugs is 7-14 mg / kg.ig, which is a safe concentration). Before modeling, except for the control group, all mice were given oral administration for 7 consecutive days, once a day, and the experiment was carried out 1 hour after the last administration.

[0063] (2) Mouse tail suspension test: A small clip is set at the top center of the tail suspension box. A piece of adhesive tape is attached to the mouse tail 2 cm away. The adhesive tape is clamped with the clip to make the mouse hang upside down with its head about 10 cm from the bottom of the box. The mouse is observed for 6 minutes and the cumulative immobility time in the last 4 minutes is recorded. The judgment criteria are that the animal is still and does not struggle.

[0064] (3) Mouse forced swimming test: The mouse was placed in a round glass container with a height of 20 cm, a diameter of 12 cm, and a water depth of 10 cm. The water temperature was 25°C. The mouse was observed for 6 minutes and the cumulative immobility time in the last 4 minutes was recorded. The judgment standard was that the animal stopped struggling in the water, was floating, and could make small limb movements to keep its head above the water.

[0065] (4) Mathematical statistics: The experimental results were expressed as (mean ± standard deviation), and one-way analysis of variance was used. Dunnett's test was used to compare the significance of the means between the two groups. The results are shown in Table 1.

[0066] The absorption experiment of the composition of paeoniflorin (A) and paeoniflorin (B) is as follows:

[0067] Drug preparation concentration: The concentration of paeoniflorin, paeoniflorin and the combination of paeoniflorin and paeoniflorin were all 20 μg / mL (set after screening based on rat intestinal characteristics).

[0068] Experimental animals: Male Wistar rats, weighing 180-200 g, were purchased from Weitonglihua Experimental Animal Co., Ltd., animal production license number: SCXK (Beijing) 2017-0020.

[0069] Animal model: rat small intestine unidirectional perfusion model. Take rats that have been fasted for 24 hours, anesthetize them, and fix them. Open the abdominal cavity, separate the intestinal segment to be examined (from the duodenum to the ileum), and rinse the intestine with 37°C saline. After the intestine is rinsed clean, the intubation (the insertion depth of the inlet and outlet is about 2 cm) is tied, and then perfused with 37°C KR solution. Cover the wound with absorbent cotton soaked in saline to keep it moist and keep it warm under the light. At the inlet, a vial with a known mass of test solution is used for perfusion at a flow rate of 0.2mL / min. At the outlet, another vial with a known mass is used to collect the perfusion fluid. The next test solution vial and collection solution vial are quickly replaced every 15 minutes, and the mass of the test solution vial and collection solution vial are weighed. The perfusion time lasts for 120 minutes. After the experiment, the rats are killed, the intestinal segment to be examined is cut off, and the length and inner diameter of the intestine are measured.

[0070] Data processing: In this experiment, the volume of the inflow and outflow of the perfusate was corrected by gravimetric analysis to eliminate the influence of volume change. The effective permeability coefficient of the drug (P eff ):

[0071]

[0072] Where: C out and C in are the mass concentrations of the inlet and outlet perfusates of the intestine (mg / L); Q in and Q out are the flow rates of the inlet and outlet perfusion fluids of the intestine (mL / min), Q is the perfusion rate (0.2 mL / min), and V is the volume of the perfused intestinal segment (cm 3 ); l and r are the length and inner diameter of the perfused intestinal segment (cm); P eff <3×10 -6 cm·min-1, indicating poor absorption; P eff >20×10 -6 cm·min-1, complete absorption; those between the two are moderate absorption. Table 1.

[0073] Table 1 Effects of compound A, B and their combination on tail suspension and swimming immobility time of stressed mice and their effective permeability coefficient in the intestine (*P<0.05; **P<0.01; ***P<0.001 compared with the normal control group)

[0074]

[0075] As can be seen from the above table, when the same dosage is set, when the ratio of compound A to B is fixed at 1:1 and 1:0.3, it has a good antidepressant effect, especially when the ratio of compound A to B is 1:1, the effect is significantly better than using A or B alone; the effective permeability coefficient (P eff ) was improved, but the intestinal absorption of the composition was still poor (P eff <20), which is a difficult to absorb compound.

[0076] Embodiment 11

[0077] In order to solve the above technical problems, the inventors screened other drug ingredients in order to find drugs that can further improve the efficacy of the drug, and found 1,2,3,4,6-O-pentagalloyl glucose. It is worth noting that 1,2,3,4,6-O-pentagalloyl glucose has not been found to have an antidepressant effect. At the same time, there is no report that 1,2,3,4,6-O-pentagalloyl glucose promotes the absorption of other related drugs.

[0078] Referring to the animal experimental method in Example 10, this example mainly examines the efficacy of adding 1,2,3,4,6-O-pentagalloylglucose (C) to the composition of paeoniflorin (A) and paeoniflorin (B) and its effect on the absorption of compounds A and B.

[0079] Table 2 Effects of the combination of compounds A, B and C on tail suspension and swimming immobility time of stressed mice and their effective permeability coefficient in the intestine (*P<0.05; **P<0.01; ***P<0.001 compared with the normal control group)

[0080]

[0081]

[0082] As can be seen from the table above, when the same dosage was set and the ratio of compound A to compound B was fixed at 1:1, the addition of 1,2,3,4,6-O-pentagalloylglucose (C) significantly improved the efficacy. At the same time, the effective permeability coefficients (P eff ) were higher than either a single component or the combination of the two, indicating that the addition of 1,2,3,4,6-O-pentagalloylglucose could promote the absorption of paeoniflorin and paeoniflorin and improve their bioavailability.

[0083] Example 12

[0084] Referring to the animal experimental method in Example 10, this example mainly examines the efficacy of different proportions of the composition of paeoniflorin (A), paeoniflorin (B), and 1,2,3,4,6-O-pentagalloylglucose (C), and first examines the optimal ratio of compounds A and B.

[0085] Table 3 Effects of the combination of compound A and compound B on tail suspension and swimming immobility time of stressed mice (*P<0.05; **P<0.01; ***P<0.001 compared with the normal control group)

[0086]

[0087] Table 4 Effects of the combination of compound A and compound B on tail suspension and swimming immobility time of stressed mice (*P<0.05; **P<0.01; ***P<0.001 compared with the normal control group)

[0088]

[0089] Table 5 Effects of the combination of compound A and compound B on tail suspension and swimming immobility time of stressed mice (*P<0.05; **P<0.01; ***P<0.001 compared with the normal control group)

[0090]

[0091] It can be seen from Tables 3-5 that when the same dosage is set, the combination ratio of compounds A and B is 1:1.4, 1:1.5, 1:1.6, 1:1.7, etc., which can significantly improve the tail suspension and swimming immobility time of mice, among which the efficacy is more significant when the combination ratio of A and B is 1:1.5 (P<0.01).

[0092] Example 13

[0093] Referring to the animal experimental method in Example 3, this example mainly examines the efficacy and absorption of different ratios of 1,2,3,4,6-O-pentagalloylglucose (C) when the combination ratio of A and B is 1:1.5, so as to determine the optimal ratio of compounds A, B, and C.

[0094] Table 6 Effects of the combination of compounds A, B, and C on tail suspension and swimming immobility time of stressed mice and their effective permeability coefficient in the intestine (*P<0.05; **P<0.01; ***P<0.001 compared with the normal control group)

[0095]

[0096]

[0097] As can be seen from Table 3-5, when the ratio of A and B is fixed at 1:1.5, the addition of different ratios of 1,2,3,4,6-O-pentagalloylglucose (C) has a more significant efficacy (P<0.001), and can promote the absorption of compounds A and B. In particular, when the ratio of compounds A, B and C is 1:1.5:0.5, the efficacy is significantly stronger than that of the positive drug fluoxetine (the shortening rate of the tail suspension and swimming tests is greater than 60%) than that of the combination of A and B (ratio 1:1.5), and the absorption of compound A is increased by 3.7 times, and the absorption of compound B is increased by 2.5 times. Therefore, the optimal ratio of the composition A, B, and C is 1:1.5:0.5.

[0098] Embodiment 14

[0099] A composition of paeoniflorin, paeoniflorin lactone glycosides and 1,2,3,4,6-O-pentagalloylglucose in a weight ratio of 1:1.5:0.5 is mixed evenly, 5 times the amount of dextrin is added, mixed evenly, 95% ethanol solution is added as a wetting agent, granulated, dried, and granulated to obtain granules.

[0100] Embodiment 15

[0101] A composition of paeoniflorin, paeoniflorin and 1,2,3,4,6-O-pentagalloylglucose in a weight ratio of 1:1.5:0.5 is uniformly mixed, microcrystalline cellulose and micropowder silica gel (in a ratio of 1:1) are added, mixed evenly, granulated with 90% ethanol, dried, and filled into hard hollow capsules to prepare a hard capsule preparation of the composition.

[0102] Example 16

[0103] The composition of paeoniflorin, paeoniflorin lactone glycosides and 1,2,3,4,6-O-pentagalloylglucose in a weight ratio of 1:1.5:0.5 is uniformly mixed, 27% citric acid and 20% dextrin are added, 2% anhydrous ethanol is used as a binder, and granulation is performed to obtain an acid source; the alkali source is obtained by mixing 17% sodium carbonate and 20% dextrin, and 2% anhydrous ethanol is used as a binder, and granulation is performed. After constant temperature drying at 40°C, the acid and alkali preparations are mixed, 0.5% PEG-4000 is added, the mixture is fully mixed, and the effervescent tablets are obtained by tableting.

[0104] Embodiment 17

[0105] A composition of paeoniflorin, paeoniflorin and 1,2,3,4,6-O-pentagalloylglucose in a weight ratio of 1:1.5:0.5 is uniformly mixed, 8 g of cross-linked polyvinyl pyrrolidone, 6 g of sodium carboxymethyl cellulose complex and 31 g of microcrystalline cellulose are added, granulated with 50% ethanol, dried and tableted to obtain dispersible tablets.

[0106] Embodiment 18

[0107] A composition of paeoniflorin, paeoniflorin and 1,2,3,4,6-O-pentagalloylglucose in a weight ratio of 1:1.5:0.5 was uniformly mixed, 3 times the amount of PEG4000 was added, heated in a water bath with stirring until melted, and the drug solution was added into a dropping tank to prepare dropping pills.

[0108] Embodiment 19

[0109] Mix a composition of paeoniflorin, paeoniflorin and 1,2,3,4,6-O-pentagalloyl glucose in a weight ratio of 1:1.5:0.5, add 10% ethanol, 0.1% sodium benzoate, 1% Tween-80, 0.05% citric acid and 3.0% white sugar, stir and mix evenly, add water to make up to volume, and package to obtain an oral solution.

[0110] Embodiment 20

[0111] A composition of paeoniflorin, paeoniflorin and 1,2,3,4,6-O-pentagalloyl glucose in a weight ratio of 1:1.5:0.5 is uniformly mixed with soybean oil and propylene glycol in a weight ratio of 2:1:1 to prepare a suspension, and then the suspension is placed on a soft capsule machine to prepare soft capsules.

Claims

1. A pharmaceutical composition for use in preparing a drug for treating depression, characterized in that: The pharmaceutical composition comprises paeoniflorin, paeoniflorin lactone glycosides and 1,2,3,4,6- O -pentagalloyl glucose, with a weight ratio of 1:1-2:0.1-1.

2. The use according to claim 1, characterized in that: The weight ratio of the paeoniflorin to the paeoniflorin lactone glycosides is 1:1.4-1.

7.

3. The use according to claim 2, characterized in that: The paeoniflorin: paeoniflorin lactone glycosides: 1,2,3,4,6- O -The weight ratio of pentagalloylglucose is 1:1.4-1.7:0.3-0.

8.

4. The use according to claim 3, characterized in that: The weight ratio of the paeoniflorin to the paeoniflorin lactone glycosides is 1:1.

5.

5. The use according to claim 4, characterized in that: Paeoniflorin: paeoniflorin lactone glycosides: 1,2,3,4,6- O -The weight ratio of pentagalloylglucose is 1:1.5:0.

5.

6. The use according to claim 1, characterized in that: The medicine also includes pharmaceutically acceptable excipients, and the dosage form of the medicine is granules, tablets, hard capsules, soft capsules, pills or oral liquids.

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