Pharmaceutical composition for functional dyspepsia and preparation method and application thereof

Abstract

The invention provides a pharmaceutical composition for functional dyspepsia as well as a preparation method and application thereof, and belongs to the technical field of medicines. The pharmaceutical composition comprises radix aucklandiae, rhizoma atractylodis, mint, agastache rugosus, exocarpium citri grandis, uncaria rhynchophylla, tribulus terrestris, Guangdong medicated leaven, chrysanthemum, poria cocos, radix trichosanthis, semen coicis, magnolol, imperatorin, isoimperatorin, oxidized imperatorin, ferulic acid, vanillic acid, p-coumaric acid and puerarin. The pharmaceutical composition comprises traditional Chinese medicine components and compounds, all the components interact with one another, the effect of the pharmaceutical composition on improving functional dyspepsia can be improved, and meanwhile the pharmaceutical composition has excellent stability.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology and relates to a pharmaceutical composition for functional dyspepsia, and in particular to a pharmaceutical composition for functional dyspepsia and a preparation method and application thereof. Background Art

[0002] Functional dyspepsia (FD) is one of the most common functional gastrointestinal diseases in clinical practice. Its main symptoms are upper abdominal pain, upper abdominal distension, early satiety, belching, loss of appetite, nausea, vomiting, etc. It is a group of clinical syndromes after excluding organic diseases.

[0003] At present, the pathogenesis of functional dyspepsia is still not very clear. Studies have shown that factors such as impaired relaxation of the gastric fundus after eating, disordered coordination of gastric antrum and duodenal motility and visceral hypersensitivity, gastric acid stimulation, changes in gastrointestinal motility rhythm, psychological and mental adverse stress, bad eating habits, Helicobacter pylori infection, and genetics are related to the onset of FD. Therefore, the selection of therapeutic drugs and the combination of combined drugs should adhere to the principle of individualization. When combining drugs, the interaction between different drugs needs to be considered to avoid adverse reactions or weakening of efficacy.

[0004] The drugs currently used to treat FD are mainly divided into the following categories:

[0005] (1) Prokinetic drugs: Prokinetic drugs can help relieve meal-related upper abdominal symptoms such as upper abdominal distension and early satiety in patients with FD. They can be used as the first choice for empirical treatment of FD, especially postprandial distress syndrome (PDS). The most commonly used prokinetic drugs in China are mosapride and itopride.

[0006] (2) Acid suppressants: Acid suppressants are mainly divided into two categories, namely H2 receptor antagonists (H2RA) and proton pump inhibitors (PPIs). They can be used as empirical treatments for FD, especially epigastric pain syndrome (EPS), such as ranitidine, famotidine, omeprazole and rabeprazole.

[0007] (3) Digestive enzymes: Digestive enzymes can be used as an auxiliary medicine for the treatment of indigestion, improving symptoms such as abdominal distension and loss of appetite related to meals, such as compound digestive enzyme capsules.

[0008] (4) Drugs for eradication of Helicobacter pylori: For patients with FD infected with Helicobacter pylori, eradication of Helicobacter pylori can improve the symptoms of FD and reduce the risk of peptic ulcer, gastric cancer and gastric lymphoma, such as amoxicillin, clarithromycin and other drugs.

[0009] (5) Anti-anxiety and anti-depressant drugs: For patients with FD caused by adverse psychological and mental stress, anti-depressant and anxiolytic drugs play a certain role in the treatment of FD.

[0010] It can be seen that the best treatment for FD caused by different causes is not the same. Since FD is prone to relapse, the main population of the disease is young children, and it is difficult to cure, long-term use of Western medicine prescriptions is prone to drug resistance and has obvious side effects. Therefore, traditional Chinese medicine treatment has shown unique advantages and has gradually been applied to the treatment of FD, but it usually has problems such as slow efficacy, unclear effective ingredients, and large dosage.

[0011] The invention patent with publication number CN105232609A discloses a Chinese medicine composition for treating functional dyspepsia, which is prepared from the following raw materials in parts by weight: 15-25 parts of chicken gizzard lining, 15-25 parts of white atractylodes, 10-20 parts of codonopsis pilosula, 10-25 parts of luffa, 10-15 parts of magnolia bark, 10-15 parts of yanhusuo, 10-15 parts of citron, 10-15 parts of radish seeds, 1-30 parts of chrysanthemum, 5-10 parts of lobelia 10-25 parts of pulsatilla, 10-25 parts of whitehead, 10-30 parts of notoginseng, 10-20 parts of scutellaria, 10-30 parts of cinnamon bark, 10-30 parts of uncaria, 5-10 parts of polygala, 5-10 parts of lobelia, 5-10 parts of patrinia, 5-10 parts of ginger, 15-30 parts of sterculia lychnophora, 15-30 parts of toosendan, and 5-15 parts of gentiana. The Chinese medicine composition has the effects of strengthening the spleen and stomach, digesting food and eliminating stagnation, regulating qi and relieving pain, and replenishing qi, is used for treating functional dyspepsia, has no toxic side effects, and has good therapeutic effect, but the Chinese medicine composition is used for treating dyspepsia in adults and is not easy to preserve.

[0012] The invention patent with the publication number CN106540162A discloses a medicine for treating chronic dyspepsia, which comprises: Atractylodes macrocephala, Poria cocos, Atractylodes lancea, Magnolia officinalis, Tangerine peel, Cyperus rotundus, Ginseng, White Cardamom, Aucklandia lappa, Amomum villosum, Licorice, and Jujube. The preparation and administration method is: one dose per day, warm and taken, Ginseng can be decocted alone and taken together, and Cyperus rotundus is decocted later. The medicine solves the problems of existing drugs for treating chronic dyspepsia, such as large side effects, long taking time, high recurrence rate after discontinuation of the drug, and inability to cure the disease. The medicine is suitable for treating chronic dyspepsia, but the efficacy lasts for a long time, the effective time is more than 10 days, and it cannot be stored for a long time.

[0013] A journal article (Zhang Qunxiao, Observation on the efficacy of Baoji Pills in treating 60 cases of functional dyspepsia. 2005) disclosed a Baoji Pill composed of 16 Chinese herbal medicines, including Uncaria rhynchophylla, chrysanthemum, Magnolia officinalis, Atractylodes macrocephala, Patchouli grandiflora, Poria cocos, Citrus aurantium, Angelica dahurica, Coix seed, Malus domestica, Aucklandia lappa, Trichosanthes root, Guangdong Shenqu, Pueraria root, and Mentha. It was used to treat 73 cases of clinical manifestations of abdominal distension and belching after meals, 85 cases of anorexia, nausea, vomiting, and regurgitation, and 55 cases of heartburn and pain behind the sternum. After 10 courses of treatment, the total effective rate was 91.7%, the efficacy lasted for a long time, and the cause of the disease in FD patients was not distinguished.

[0014] Due to the above disadvantages, it is urgent to study a pharmaceutical composition with better efficacy and high stability that can be used for functional dyspepsia. Therefore, the present invention provides a pharmaceutical composition for functional dyspepsia. Summary of the invention

[0015] The present invention aims at the problems existing in the prior art and provides a pharmaceutical composition for functional dyspepsia and a preparation method and application thereof. The pharmaceutical composition comprises a Chinese medicine component and a compound, and the components interact with each other to improve the effect of the pharmaceutical composition on improving functional dyspepsia. At the same time, the pharmaceutical composition has excellent stability and the active ingredient has high stability.

[0016] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0017] In the first aspect, the present invention provides a pharmaceutical composition for functional dyspepsia, comprising: costus root, atractylodes, mint, patchouli, tangerine peel, Uncaria rhynchophylla, Tribulus terrestris, Guangdong Shenqu, chrysanthemum, Poria, Radix Trichosanthis, coix seed, magnolol, imperatorin, isoimperatorin, oxidized imperatorin, ferulic acid, vanillic acid, p-coumaric acid and puerarin.

[0018] Preferably, the pharmaceutical composition comprises the following components in parts by weight: 13.0-14.5 parts of costusroot, 13.0-14.5 parts of atractylodes, 5.5-9 parts of mint, 13.0-14.5 parts of patches, 6.0-7.8 parts of tangerine peel, 3.0-4.0 parts of Uncaria rhynchophylla, 3.0-4.0 parts of tribulus terrestris, 13.0-14.5 parts of Guangdong Shenqu, 6.0-7.5 parts of chrysanthemum, 2 5-30 parts, Radix Trichosanthis 9.5-11.0 parts, Semen Coicis 16-18 parts, Magnolol 0.25-0.40 parts, Imperatorin 0.2-1.1 parts, Isoperibolin 0.2-1.1 parts, Oxidized Imperatorin 0.2-1.1 parts, Ferulic acid 0.01-0.1 parts, Vanillic acid 0.01-0.1 parts, p-Coumaric acid 0.01-0.1 parts and Puerarin 0.1-1.5 parts.

[0019] More preferably, the pharmaceutical composition comprises the following components in parts by weight: 13.2-14.0 parts of costusroot, 13.2-14.0 parts of atractylodes, 6.0-7.5 parts of mint, 13.2-14.0 parts of patches, 6.0-7.0 parts of tangerine peel, 3.1-3.7 parts of Uncaria rhynchophylla, 3.1-3.7 parts of tribulus terrestris, 13.2-14.0 parts of Guangdong Shenqu, 6.5-7.0 parts of chrysanthemum, 26 -28 parts, Radix Trichosanthis 10.0-10.5 parts, Semen Coicis 17.0-17.5 parts, Magnolia officinalis 0.25-0.40 parts, Imperatorin 0.2-1.1 parts, Isoperibolin 0.2-1.1 parts, Oxidized Imperatorin 0.2-1.1 parts, Ferulic acid 0.01-0.1 parts, Vanillic acid 0.01-0.1 parts, p-coumaric acid 0.01-0.1 parts and Puerarin 0.1-1.5 parts.

[0020] Preferably, the mass ratio of imperatorin, isoimperatorin, oxidized imperatorin and puerarin in the pharmaceutical composition is 1-3:1-10:1-3:0.5-5, preferably 1-3:1-6:1-3:0.5-5, and more preferably 1-2:1-3:1-2:0.5-5.

[0021] Preferably, in the pharmaceutical composition, the mass ratio of magnolol, atractylodes, patches of tangerine peel and red orange is 1-2:30-80:30-80:15-50, preferably 1-2:30-60:30-60:15-30, and more preferably 1:30-60:30-60:15-30.

[0022] Preferably, in the pharmaceutical composition, Patchouli is Patchouli.

[0023] Preferably, the drug may also be used in combination with a pharmaceutically acceptable carrier.

[0024] In the present invention, the pharmaceutically acceptable carrier refers to all pharmaceutically acceptable carriers, including but not limited to diluents, binders, absorbents, disintegrants, dispersants, wetting agents, solubilizers, buffers, and surfactants.

[0025] In the present invention, the type and manufacturer of the pharmaceutically acceptable carrier have no significant impact on the technical effect of the drug.

[0026] In the present invention, the pharmaceutically acceptable carrier can be starch, dextrin, sucrose, milk powder, sweetener, mannitol, lactose, cellulose and its derivatives, calcium carbonate, cyclodextrin, β-cyclodextrin, phospholipid materials, magnesium stearate, talc, and flavors.

[0027] In one embodiment, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, and the pharmaceutically acceptable carrier is selected from sucrose and polysorbate.

[0028] In a second aspect, the present invention provides a method for preparing the pharmaceutical composition, comprising the following steps:

[0029] 1) distilling costusroot, atractylodes, mint, patchouli and red tangerine peel, collecting volatile oil and residual substances, decocting the residual substances in water, concentrating the decoction, adding ethanol, collecting and concentrating the filtrate 1, and obtaining an extract 1;

[0030] 2) decoct Uncaria rhynchophylla, Tribulus terrestris, Guangdong Shenqu and chrysanthemum in water, concentrate the decoction, add ethanol, collect and concentrate the filtrate 2 to obtain extract 2;

[0031] 3) boiling coix seeds in water, concentrating the decoction, adding ethanol, collecting and concentrating the filtrate 3 to obtain extract 3;

[0032] 4) decoct Poria cocos and Radix Trichosanthis in water, concentrate the decoction, add ethanol, collect and concentrate the filtrate 4 to obtain extract 4;

[0033] 5) Evenly mix extract 1, extract 2, extract 3, extract 4, magnolol, imperatorin, isoimperatorin, oxidized imperatorin, ferulic acid, vanillic acid, p-coumaric acid and puerarin, then add volatile oil, mix evenly, and obtain a pharmaceutical composition.

[0034] The step 1) is specifically as follows: distilling costusroot, atractylodes, mint, patches and red orange peel for 1-3 hours, preferably 2-3 hours; collecting volatile oil and residual substances, decocting the residual substances in water for 1-3 times, and the time of each decoction is not limited, preferably 1-3 hours; concentrating the decoction, adding ethanol, and standing for preferably 12-48 hours, and then collecting filtrate 1, the volume fraction of ethanol in filtrate 1 is 40-50%, preferably 45-50%; concentrating filtrate 1 to obtain extract 1.

[0035] The step 2) is specifically as follows: decoct Uncaria rhynchophylla, Tribulus terrestris, Guangdong Shenqu and chrysanthemum in water for 1-3 times, and the time of each decoction is not limited, preferably 1-3 hours; concentrate the decoction, add ethanol, let stand, the standing time is preferably 12-48 hours, and then collect filtrate 2, the volume fraction of ethanol in filtrate 2 is 40-60%; concentrate filtrate 2 to obtain extract 2.

[0036] The step 3) is specifically as follows: boiling coix seeds in water for 1-3 times, with no limitation on the time of each boiling, preferably 1-3 hours; concentrating the decoction, adding ethanol, and standing for preferably 12-48 hours, and then collecting filtrate 3, wherein the volume fraction of ethanol in filtrate 3 is 40-60%; concentrating filtrate 3 to obtain extract 3.

[0037] The step 4) is specifically as follows: decocting Poria cocos and Radix Trichosanthis in water for 1-3 times, with no limitation on the time of each decoction, preferably 1-3 hours; concentrating the decoction, adding ethanol, and standing for preferably 12-48 hours, and then collecting filtrate 4, wherein the volume fraction of ethanol in filtrate 4 is 40-60%; concentrating filtrate 4 to obtain extract 4.

[0038] The step 5) is specifically as follows: extract 1, extract 2, extract 3, extract 4, magnolol, imperatorin, isoimperatorin, oxidized imperatorin, ferulic acid, vanillic acid, p-coumaric acid and puerarin are mixed, stirred until the mixture is uniform, and then volatile oil is added dropwise while stirring, and the mixture is stirred uniformly to obtain a pharmaceutical composition. During the stirring process, the temperature of the system is preferably controlled within the range of 25-30° C. to avoid volatilization of the volatile oil due to temperature increase.

[0039] In a third aspect, the present invention also provides an application of the pharmaceutical composition described in the above technical solution or the pharmaceutical composition prepared by the preparation method in the preparation of a drug for treating functional elimination disorder.

[0040] Preferably, in the application, the administration of the drug includes oral, sublingual, oral mucosal, intravenous, intramuscular, intraperitoneal, subcutaneous, transdermal, nasal and rectal routes.

[0041] In the present invention, in the application, the dosage form of the drug can be solid, liquid or gas.

[0042] The pharmaceutical composition can be prepared in different dosage forms, including but not limited to powders, tablets, granules, pills, hard capsules, soft capsules, creams, ointments, plasters, gels, pastes, powders, patches, solutions, suspensions, injections, syrups, liniments, emulsions, tinctures, elixirs, aerosols or sprays.

[0043] Compared with the prior art, the present invention has the following beneficial effects:

[0044] Firstly, the present invention adopts a mixture of traditional Chinese medicine components and compounds, and the components interact with each other, which can improve the effect of the pharmaceutical composition in improving functional dyspepsia. At the same time, the pharmaceutical composition has excellent stability and the active ingredients have high stability.

[0045] Secondly, under the condition that the mass ratio of imperatorin, isoimperatorin, oxidized imperatorin and puerarin is 1-3:1-10:1-3:0.5-5, the three coumarin compounds interact with puerarin, and functional dyspepsia can be improved.

[0046] Thirdly, the magnolol in the present invention cooperates with atractylodes, patches of podophyllum and red orange peel in a mass ratio of 1-2:30-80:30-80:15-50 to improve the effect of treating functional dyspepsia. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] Figure 1 This is the animal experiment flow chart of the cisplatin-induced functional dyspepsia model in mice;

[0048] Figure 2 The weight of mice after five days of drug administration; compared with the normal group, ### P<0.001; compared with the model control group, * P<0.05, ** P<0.01, *** P<0.001; compared with the middle dose group (D6) in comparative example 6, + P<0.05, +++ P < 0.001;

[0049] Figure 3 The results of gastric emptying rate of mice after five days of administration; compared with the normal group, ### P<0.001; compared with the model control group, * P<0.05, ** P<0.01, *** P<0.001; compared with the middle dose group (D6) in comparative example 6, +++ P < 0.001;

[0050] Figure 4 The results of the intestinal propulsion rate of mice after five days of administration; compared with the normal group, ### P<0.001; compared with the model control group, ** P<0.01, *** P<0.001; compared with the middle dose group (D6) in comparative example 6, + P<0.05, ++ P < 0.01;

[0051] Figure 5 is the gastrin (GAS) level of mice after five days of administration; compared with the normal group, ### P<0.001; compared with the model control group, * P<0.05, ** P<0.01, *** P<0.001; compared with the middle dose group (D6) in comparative example 6, + P<0.05, ++ P<0.01, +++ P < 0.001;

[0052] Figure 6 is the level of motilin (MTL) in mice after five days of administration; compared with the normal group, ### P<0.001; compared with the model control group, * P<0.05, ** P<0.01, *** P<0.001; compared with the middle dose group (D6) in comparative example 6, + P<0.05, ++ P<0.01, +++ P < 0.001;

[0053] Figure 7 The interleukin 4 (IL-4) level of mice after five days of administration; compared with the normal group, ### P<0.001; compared with the model control group, * P<0.05, ** P<0.01, *** P<0.001; compared with the middle dose group (D6) in comparative example 6, + P<0.05, ++ P < 0.01;

[0054] Figure 8 The interleukin (IL-1β) level of mice after five days of administration; compared with the normal group, ### P<0.001; compared with the model control group, * P<0.05, ** P<0.01; compared with the middle dose group (D6) in comparative example 6, + P<0.05, ++ P < 0.01;

[0055] Fig. 9 The figure is a graph showing the loss rate of puerarin in the pharmaceutical composition over 48 months; wherein different letters between ac indicate significant differences, and the significance level α=0.05. DETAILED DESCRIPTION

[0056] It is worth noting that, unless otherwise specified, the raw materials used in the present invention are all common commercially available products, and their sources are not specifically limited.

[0057] Magnolia officinalis: purity ≥98% (HPLC), purchased from Maclean, product number M813634;

[0058] Imperatorin: purity ≥98% (HPLC), purchased from Chengdu Gelipu Biotechnology Co., Ltd., product number JOT-10460;

[0059] Isoimperatorin: purity 98%, purchased from FUORAIN / Fu Yu, product number NP01139;

[0060] Oxypeucedanum: purity ≥98%, purchased from Top Biotechnology, product number TOP0067;

[0061] Ferulic acid: purity 98%, purchased from source leaves, product number S30464;

[0062] Vanillic acid: purity 98%, purchased from source leaves, product number S31038;

[0063] p-Coumaric acid: purity 98%, purchased from Le Yan, product number 1033825;

[0064] Puerarin: Purity 98%, purchased from McLean, product number P816259.

[0065] Examples 1-8 and Comparative Examples 1-6

[0066] The pharmaceutical composition was prepared according to the formulation in Table 1.

[0067] Table 1 Pharmaceutical composition formula of Examples 1-8 and Comparative Examples 1-6

[0068]

[0069]

[0070] The preparation steps of the pharmaceutical composition of Examples 1-8 are as follows:

[0071] 1) steam distilling costusroot, atractylodes, mint, patchouli, and red orange peel for 2 hours, collecting volatile oil and residual substances, decocting the residual substances twice, each time for 2 hours, filtering and combining the two decoctions, and then concentrating the decoction to a relative density of 1.08-1.12 (60° C.), cooling, adding ethanol to make the alcohol content (volume fraction of ethanol) 45%, standing overnight, collecting the filtrate and concentrating it to obtain extract 1;

[0072] 2) decoct Uncaria rhynchophylla, Tribulus terrestris, Guangdong Shenqu and chrysanthemum twice in water, each time for 2 hours, filter the two decoctions and combine them, then concentrate the decoction to a relative density of 1.02-1.05 (60° C.), add ethanol to make the alcohol content 40%, collect and concentrate the filtrate to obtain extract 2;

[0073] 3) boiling coix seeds in water twice, each time for 1.5 hours, filtering the two decoctions and combining them, then concentrating the decoction to a relative density of 1.02-1.05 (60° C.), adding ethanol to make the alcohol content 50%, collecting and concentrating the filtrate to obtain extract 3;

[0074] 4) decoct Poria cocos and Radix Trichosanthis twice, each time for 2 hours, filter the two decoctions and combine them, then concentrate the decoction to a relative density of 1.02-1.05 (60° C.), cool, add ethanol to make the alcohol content 60%, collect and concentrate the filtrate to obtain extract 4;

[0075] 5) At room temperature, extract 1, extract 2, extract 3, extract 4, magnolol, imperatorin, isoimperatorin, oxidized imperatorin, ferulic acid, vanillic acid, p-coumaric acid and puerarin are mixed, and the mixture is stirred until the mixture is uniformly mixed. Then, volatile oil is added dropwise while stirring, and the mixture is mixed uniformly to obtain a pharmaceutical composition having a relative density of 1.3 (25° C.), and the obtained pharmaceutical composition is sealed and stored.

[0076] The difference between Comparative Example 1 and Example 1 is that "ferulic acid 0.04 g, vanillic acid 0.08 g, p-coumaric acid 0.04 g" is replaced by "ferulic acid 0.16 g", and the rest is the same as Example 1 to prepare a pharmaceutical composition.

[0077] The difference between Comparative Example 2 and Example 1 is that "ferulic acid 0.04 g, vanillic acid 0.08 g, p-coumaric acid 0.04 g" is replaced by "ferulic acid 0.12 g, p-coumaric acid 0.04 g", and the rest is the same as Example 1 to prepare a pharmaceutical composition.

[0078] The difference between Comparative Example 3 and Example 1 is that "0.3 g of imperatorin, 0.9 g of isoimperatorin and 0.3 g of oxidized imperatorin" are replaced by "1.1 g of imperatorin and 0.4 g of oxidized imperatorin", and the rest is the same as Example 1 to prepare a pharmaceutical composition.

[0079] The difference between Comparative Example 4 and Example 1 is that "0.3 g of imperatorin, 0.9 g of isoimperatorin, 0.3 g of oxidized imperatorin and 1.5 g of puerarin" are replaced by "1.2 g of imperatorin, 0.1 g of isoimperatorin, 0.1 g of oxidized imperatorin and 1.6 g of puerarin", and the rest is the same as Example 1, to prepare a pharmaceutical composition.

[0080] The difference between Comparative Example 5 and Example 1 is that "magnolia officinalis 0.3g, atractylodes 13.6g, patchouli 13.6g, and tangerine peel 6.8g" are replaced by "magnolia officinalis 2.3g, atractylodes 11g, patchouli 16g, and tangerine peel 5g", and the rest is the same as Example 1, to prepare a pharmaceutical composition.

[0081] The difference between Comparative Example 6 and Example 1 is that "magnolia bark 0.3g, imperatorin 0.3g, isoimperatorin 0.9g, oxidized imperatorin 0.3g, ferulic acid 0.04g, vanillic acid 0.08g, p-coumaric acid 0.04g and puerarin 1.5g" are replaced by "Magnolia bark 15g, Angelica dahurica 15g, rice sprout 10g, Pueraria root 15g"; the preparation steps of the pharmaceutical composition are:

[0082] 1) steam distilling costusroot, atractylodes, mint, patchouli, and red orange peel for 2 hours, collecting volatile oil and residual substances, decocting the residual substances twice, each time for 2 hours, filtering and combining the two decoctions, and then concentrating the decoction to a relative density of 1.08-1.12 (60° C.), cooling, adding ethanol to make the alcohol content 45%, standing overnight, collecting the filtrate and concentrating it to obtain extract 1;

[0083] 2) decoct Uncaria rhynchophylla, Tribulus terrestris, Guangdong Shenqu, chrysanthemum and Magnolia officinalis twice, each time for 2 hours, filter and combine the two decoctions, and then concentrate the decoction to a relative density of 1.02-1.05 (60° C.), add ethanol to make the alcohol content 40%, collect and concentrate the filtrate to obtain extract 2;

[0084] 3) boiling coix seeds and rice sprouts in water twice, each time for 1.5 hours, filtering and combining the two decoctions, and then concentrating the decoction to a relative density of 1.02-1.05 (60° C.), adding ethanol to make the alcohol content 50%, collecting and concentrating the filtrate to obtain extract 3;

[0085] 4) decoct Poria cocos, Radix Trichosanthis, Angelica dahurica and Radix Puerariae twice, each time for 2 hours, filter and combine the two decoctions, and then concentrate the decoction to a relative density of 1.02-1.05 (60° C.), cool, add ethanol to make the alcohol content 60%, collect and concentrate the filtrate to obtain extract 4;

[0086] 5) At room temperature, extract 1, extract 2, extract 3 and extract 4 are mixed and stirred thoroughly until the mixture is uniformly mixed. Then, volatile oil is added dropwise while stirring and mixed uniformly to obtain a pharmaceutical composition having a relative density of 1.3 (25° C.). The obtained pharmaceutical composition is sealed and stored.

[0087] Test Example 1

[0088] Experiment on cisplatin-induced functional dyspepsia in mice

[0089] A cisplatin-induced functional dyspepsia model in mice was established. The drug composition of different concentrations was administered by gavage, and the changes in mouse body weight were observed. The gastric emptying rate, small intestinal propulsion rate, and the expression levels of mouse serum and tissue biochemical indices were measured to investigate the effect of the drug composition on the functional dyspepsia model in young mice.

[0090] 1. Experimental Materials

[0091] 1.1 Experimental animals

[0092] 3-4 week old male ICR mice weighing 13-15 g were purchased (experimental animal license number: SCXK (Guangdong) 2022-0002). After purchase, the mice were fed freely and were adaptively raised for three days at a temperature of 25 ± 0.5 ° C, a relative humidity of 55 ± 5%, and alternating light conditions (12 h light-dark cycle). During this study, the experiments were conducted in strict accordance with the requirements of experimental animal protection and ethics. The animal experiment protocol was approved by the Experimental Animal Welfare Ethics Committee (No.: 20231226007).

[0093] 1.2 Experimental Reagents

[0094] The main experimental reagents for the pharmacological effects on the mouse functional dyspepsia model are shown in Table 2.

[0095] Table 2 Main experimental reagents for pharmacological effects on the mouse functional dyspepsia model

[0096]

[0097]

[0098] 1.3 Experimental instruments

[0099] The main experimental instruments for the pharmacological effects on the mouse functional dyspepsia model are shown in Table 3.

[0100] Table 3 Main experimental instruments for pharmacological effects on the mouse functional dyspepsia model

[0101]

[0102] 2. Experimental methods

[0103] 2.1 Preparation of drug solution

[0104] The dose of cisplatin was 2 mg / kg. 2 mg was accurately weighed and added to 1 mL of normal saline to prepare a 2 mg / mL stock solution. The solution was then diluted to 0.2 mg / mL with normal saline and administered intragastrically at a dose of 0.1 mL / 10 g.

[0105] The dosage of Mosapride Citrate Tablets is 20 mg / kg. Accurately weigh 20 mg of Mosapride, add 1 mL of normal saline to make a 20 mg / mL stock solution, then dilute it to 2 mg / mL with normal saline, and gavage once at a dose of 0.1 mL / 10 g.

[0106] The specification of the drug composition is that each 1mL is equivalent to 0.187g of the decoction piece, and the dosage is oral, 10mL at a time, 3 times a day. According to modern pharmacological research and routine clinical dosage, the clinical dosage of the drug composition is 0.187g / mL×10mL×3 times / 70kg=0.08g / kg. According to the body surface area conversion coefficient of humans and mice, that is, 0.08g / kg×9.1=0.728g / kg / d. In order to explore the optimal dose of the drug composition for the treatment of functional dyspepsia in mice and observe whether its pharmacological effect is dose-dependent, this experiment used the clinical equivalent dose of the drug composition as a reference to set up a low-dose group (0.365g / d) of the drug composition, a medium-dose group (0.73g / d) of the drug composition, and a high-dose group (1.46g / d) of the drug composition.

[0107] High-dose group of the drug composition: accurately measure 730 mg of the drug composition and add 5 mL of normal saline to make a 146 mg / mL solution. Medium-dose group of the drug composition: dilute the solution of the high-dose group of the drug composition in half and make a 73 mg / mL solution. Low-dose group of the drug composition: dilute the solution of the medium-dose group of the drug composition in half and make a 36.5 mg / mL solution. The above different doses of the drug solution were gavaged once at a dose of 0.1 mL / 10 g.

[0108] Semisolid paste (300 mL) was prepared with 10 g sodium carboxymethylcellulose (CMC-Na), 16 g milk powder, 8 g edible corn starch, 8 g white sugar, 3 g activated carbon, and 2 mL ink, and was administered intragastrically at a dose of 0.4 mL (g) per head.

[0109] The solvent for preparing the medicine solution is physiological saline, which should be prepared before use and stored temporarily at 4°C for future use.

[0110] 2.2 Animal grouping, medication and sampling

[0111] 2.2.1 Animal grouping and drug intervention

[0112] Figure 1 This is the animal experiment flow chart of the cisplatin-induced functional dyspepsia model in mice, specifically:

[0113] The mice were weighed and then separated into cages for three days of adaptive feeding. They were randomly divided into 19 groups, 8 mice in each group. The specific groups were as follows: normal control group (N), model control group (FD), positive control group (Mosapride citrate tablets, Mosa), low-dose group (S1-1) of Example 1, medium-dose group (S1-2) of Example 1, high-dose group (S1-3) of Example 1, medium-dose group (S2-S8) of Example 2-8, and medium-dose group (D1-D6) of Comparative Examples 1-6.

[0114] Except for the normal control group, the rest of the groups were intraperitoneally injected with cisplatin for 4 days (2 mg / kg / d). The normal group was intraperitoneally injected with an equal volume of saline. All mice were fed with standard feed and had free access to water.

[0115] After 4 days of modeling, starting from the 5th day, the drug-dosing groups were gavaged with different doses of drug solution: positive control group: 20 mg / kg / d of Mosapride Citrate Tablets; low-dose group in Example 1: 365 mg / kg / d; medium-dose group in Example 1: 730 mg / kg / d; high-dose group in Example 1: 1460 mg / kg / d; medium-dose group in Examples 2-8 and Comparative Examples 1-6: 730 mg / kg / d. The control group and the model group were gavaged with an equal volume of normal saline once a day for five consecutive days, and all mice were fed with standard feed and had free access to water. After the last gavage, the mice were fasted for 24 hours and had free access to water. The mice were weighed.

[0116] 2.3 Gastric emptying and small intestinal propulsion experiments

[0117] After fasting for 24 hours, mice were given 0.4 mL (g) of semisolid nutrient paste. After 20 minutes, the mice were euthanized and the cardia and pylorus were ligated. The total weight and net weight of the stomach were weighed, the total length of the small intestine and the distance from the front end of the solid paste to the pylorus were recorded, and the gastric emptying rate and small intestinal propulsion rate were calculated.

[0118] 2.4 Collection of serum and tissue samples

[0119] Eyeballs were removed to collect blood, and mouse blood was collected and centrifuged at room temperature for 1 hour (centrifuge parameters: 3000 rpm, 10 min), and the upper serum was separated and stored in a -80°C refrigerator for later use. Mouse stomach tissue was cut and placed in a cryopreservation tube, and frozen in a -80°C refrigerator for later use.

[0120] 2.5 Detection of biochemical index levels in mouse serum and tissues

[0121] The serum and tissue samples stored in "2.4 Collection of serum and tissue samples" were reconstituted using enzyme-linked immunosorbent assay, and the kit was taken out of the refrigerator in advance and allowed to equilibrate to room temperature. According to the instructions for use of the kit, the expression levels of gastrin (GAS) and motilin (MTL) in mouse serum and interleukin 4 (IL-4) and interleukin 1β (IL-1β) in mouse gastric tissue were detected.

[0122] 3. Experimental results:

[0123] 3.1 Effect of the drug composition on functional dyspepsia in young mice

[0124] 3.1.1 Effect of the drug combination on the body weight of young mice with dyspepsia

[0125] The weight of mice after five days of administration is shown in Figure 2The results are as follows:

[0126] (1) Compared with the normal group, the body weight of mice in the model control group (FD) was significantly reduced ( ### P<0.001).

[0127] The results showed that compared with the normal group, the weight gain of young mice after modeling was significantly slowed down due to indigestion.

[0128] (2) Compared with the model control group, the body weight of mice in the positive control group (Mosa), the low-dose group (S1-1) of Example 1, the medium-dose group (S1-2) of Example 1, the high-dose group (S1-3) of Example 1, the medium-dose groups (S2-S8) of Examples 2-8, and the medium-dose groups (D1-D6) of Comparative Examples 1-6 were significantly increased ( * P<0.05, ** P<0.01, *** P<0.001). Among them, the body weights of mice in the medium dose groups (D1-D6) of Comparative Examples 1-6 were all lower than those in the medium dose group (S1-2) of Example 1, the high dose group (S1-3) of Example 1, and the medium dose group (S2-S8) of Example 2-8.

[0129] The results show that the pharmaceutical compositions of Examples 1-8 and Comparative Examples 1-6 of the present invention can regulate the body weight of functional dyspepsia model mice and significantly increase the body weight of mice. Among them, the pharmaceutical composition of Example 1 has a better effect.

[0130] (3) Furthermore, the effects of the pharmaceutical compositions of Comparative Examples 1-6 on the body weight of mice were compared, and it was found that the pharmaceutical composition of Comparative Example 6 had a more excellent effect. Therefore, Comparative Example 6 was compared with the compositions of Examples 1-8.

[0131] Compared with the medium dose group (D6) in Comparative Example 6, the body weight of mice in the medium dose group (S1-2) in Example 1, the high dose group (S1-3) in Example 1, and the medium dose groups (S2-S8) in Examples 2-8 were significantly increased ( + P<0.05, +++ P<0.001).

[0132] The results showed that the body weight of mice in the middle dose groups of Examples 1-8 and the high dose group of Example 1 was significantly increased compared with the optimal group in the comparative example (i.e., Comparative Example 6). Therefore, compared with the middle dose groups (D1-D5) of Comparative Examples 1-5, which were slightly worse than the middle dose group (D6) of Comparative Example 6, the body weight of mice in the middle dose group (S1-2) of Example 1 was significantly increased.

[0133] The pharmaceutical composition of the dosage group (D1-D2) in Comparative Examples 1-2 uses one or two of ferulic acid, vanillic acid and p-coumaric acid. Compared with the dosage group (D1-D2) in Comparative Examples 1-2, the body weight of mice in the dosage group (S1-2) in Example 1 is significantly increased. This shows that the pharmaceutical composition of the example uses ferulic acid, vanillic acid, p-coumaric acid to interact with other components, which can significantly increase the body weight of mice.

[0134] The pharmaceutical composition of the dosage group (D3) in Comparative Example 3 uses two of imperatorin, isoimperatorin and oxidized imperatorin. Compared with the dosage group (D3) in Comparative Example 3, the body weight of mice in the dosage group (S1-2) in Example 1 is significantly increased. This shows that the pharmaceutical composition in the example uses imperatorin, isoimperatorin and oxidized imperatorin in combination with other components to significantly increase the body weight of mice.

[0135] Furthermore, compared with the dosage group (D4) in Comparative Example 4, the body weight of mice in the dosage group (S1-2) in Example 1 was significantly increased. This indicates that the mass ratio of imperatorin, isoimperatorin, oxidized imperatorin and puerarin in the pharmaceutical composition of the embodiment can more effectively increase the body weight of mice in the range of 1-3:1-10:1-3:0.5-5.

[0136] Compared with the dosage group (D5) in comparative example 5, the weight of mice in the dosage group (S1-2) in Example 1 was significantly increased. This indicates that the mass ratio of magnolol, atractylodes, patchouli and tangerine peel in the pharmaceutical composition of the example can more effectively increase the weight of mice in the range of 1-2:30-80:30-80:15-50.

[0137] In the pharmaceutical composition of the dosage group (D6) in Comparative Example 6, magnolol, imperatorin, isoimperatorin, oxidized imperatorin, ferulic acid, vanillic acid, p-coumaric acid and puerarin are replaced with Chinese medicinal components magnolia bark, angelica dahurica, rice sprout and pueraria root. Compared with the dosage group (D6) in Comparative Example 6, the body weight of mice in the dosage group (S1-2) in Example 1 is significantly increased. This shows that the components in the pharmaceutical composition of the embodiment interact with each other and can more effectively increase the body weight of mice.

[0138] The above results show that the components of the pharmaceutical composition of the embodiment interact with each other and can significantly alleviate the slowdown of weight gain caused by indigestion. Further, the mass ratio of imperatorin, isoimperatorin, oxidized imperatorin and puerarin in the pharmaceutical composition can be more effectively increased in the range of 1-3:1-10:1-3:0.5-5, and the mass ratio of magnolol, atractylodes, patchouli and tangerine peel in the pharmaceutical composition can be more effectively increased in the range of 1-2:30-80:30-80:15-50.

[0139] 3.1.2 Effect of the drug composition on gastric emptying rate in young mice with dyspepsia

[0140] The gastric emptying rate of mice after five days of administration is as follows Figure 3 The results are as follows:

[0141] (1) Compared with the normal group, the gastric emptying rate of mice in the model control group (FD) was significantly decreased ( ### P<0.001).

[0142] The results showed that compared with the normal group, the gastric emptying rate of young mice was significantly reduced after modeling.

[0143] (2) Compared with the model control group, the gastric emptying rates of mice in the positive control group (Mosa), the low-dose group (S1-1) of Example 1, the medium-dose group (S1-2) of Example 1, the high-dose group (S1-3) of Example 1, the medium-dose groups (S2-S8) of Examples 2-8, and the medium-dose groups (D1-D6) of Comparative Examples 1-6 were significantly increased ( * P<0.05, ** P<0.01, *** P<0.001). Among them, the gastric emptying rates of mice in the medium dose groups (D1-D6) of Comparative Examples 1-6 were lower than those in the low dose group (S1-1) of Example 1, the medium dose group (S1-2) of Example 1, the high dose group (S1-3) of Example 1, and the medium dose group (S2-S8) of Example 2-8.

[0144] The results showed that the pharmaceutical compositions of Examples 1-8 and Comparative Examples 1-6 of the present invention can alleviate the symptoms of delayed gastric emptying in the model group mice and significantly improve the gastric emptying rate of the mice. Among them, the pharmaceutical composition of Example 1 has a better effect.

[0145] (3) Further, the effects of the pharmaceutical compositions of Comparative Examples 1-6 on the emptying rate of mice were compared, and it was found that the pharmaceutical composition of Comparative Example 6 had a more excellent effect. Therefore, Comparative Example 6 was compared with the compositions of Examples 1-8.

[0146] Compared with the middle dose group (D6) of Comparative Example 6, the gastric emptying rates of mice in the low dose group (S1-1) of Example 1, the middle dose group (S1-2) of Example 1, the high dose group (S1-3) of Example 1, and the middle dose groups (S2-S8) of Examples 2-8 were significantly increased ( +++ P<0.001).

[0147] The results showed that the gastric emptying rate of mice in the medium dose groups of Examples 1-8, the low dose group of Example 1 and the high dose group of Example 1 was significantly improved compared with the optimal group in the comparative example (i.e., comparative example 6). Therefore, compared with the medium dose groups (D1-D5) of Comparative Examples 1-5, which were slightly worse than the medium dose group (D6) of Comparative Example 6, the gastric emptying rate of mice in the medium dose group (S1-2) of Example 1 was significantly improved.

[0148] Compared with the dose groups (D1-D2) in comparative examples 1-2, the gastric emptying rate of mice in the dose group (S1-2) in Example 1 was significantly improved. This shows that the pharmaceutical composition of the example uses ferulic acid, vanillic acid, p-coumaric acid and other components to significantly improve the gastric emptying rate of mice.

[0149] Compared with the dose group (D3) in comparative example 3, the gastric emptying rate of mice in the dose group (S1-2) in Example 1 was significantly improved. This shows that the pharmaceutical composition of the example uses imperatorin, isoimperatorin and oxidized imperatorin, which interact with other components to improve the gastric emptying rate of mice.

[0150] Compared with the dosage group (D4) in Comparative Example 4, the gastric emptying rate of mice in the dosage group (S1-2) in Example 1 was significantly improved, which indicates that the mass ratio of imperatorin, isoimperatorin, oxidized imperatorin and puerarin in the pharmaceutical composition of the example can more effectively improve the gastric emptying rate of mice in the range of 1-3:1-10:1-3:0.5-5.

[0151] Compared with the dosage group (D5) in comparative example 5, the gastric emptying rate of mice in the dosage group (S1-2) in Example 1 was significantly improved, which indicates that the mass ratio of magnolol, atractylodes, patchouli and tangerine peel in the pharmaceutical composition of the example can more effectively improve the gastric emptying rate of mice in the range of 1-2:30-80:30-80:15-50.

[0152] Compared with the dose group (D6) in comparative example 6, the gastric emptying rate of mice in the dose group (S1-2) in Example 1 was significantly improved. This shows that the components in the pharmaceutical composition of the example interact with each other, which can more effectively improve the gastric emptying rate of mice and alleviate the symptoms of delayed gastric emptying in mice.

[0153] The above results show that the components of the pharmaceutical composition of the embodiment interact with each other and can significantly alleviate the reduced gastric emptying rate caused by indigestion. Further, the mass ratio of imperatorin, isoimperatorin, oxidized imperatorin and puerarin in the pharmaceutical composition can more effectively improve the gastric emptying rate of mice in the range of 1-3:1-10:1-3:0.5-5, and the mass ratio of magnolol, atractylodes, patchouli and tangerine peel in the pharmaceutical composition can also more effectively improve the gastric emptying rate of mice in the range of 1-2:30-80:30-80:15-50.

[0154] 3.1.3 Effect of the drug combination on intestinal propulsion rate in young mice with dyspepsia

[0155] The intestinal propulsion rate of mice after five days of administration is as follows Figure 4 The results are as follows:

[0156] (1) Compared with the normal group, the intestinal propulsion rate of mice in the model control group (FD) was significantly reduced ( ### P<0.001).

[0157] The results showed that compared with the normal group, the intestinal propulsion rate of young mice was significantly reduced after modeling.

[0158] (2) Compared with the model control group, the intestinal propulsion rate of mice in the positive control group (Mosa), the low-dose group (S1-1) of Example 1, the medium-dose group (S1-2) of Example 1, the high-dose group (S1-3) of Example 1, the medium-dose group (S2-S8) of Examples 2-8, and the medium-dose group (D1-D6) of Comparative Examples 1-6 were significantly increased ( ** P<0.01, *** P<0.001). Among them, the intestinal propulsion rate of mice in the medium dose groups (D1-D6) of comparative examples 1-6 was lower than that in the low dose group (S1-1) of example 1, the medium dose group (S1-2) of example 1, the high dose group (S1-3) of example 1, and the medium dose group (S2-S8) of example 2-8.

[0159] The results show that the pharmaceutical compositions of Examples 1-8 and Comparative Examples 1-6 of the present invention can alleviate the problem of low intestinal propulsion rate in the model group mice and significantly improve the intestinal propulsion rate of the mice. Among them, the pharmaceutical composition of Example 1 has better effect.

[0160] (3) Further, the effects of the pharmaceutical compositions of Comparative Examples 1-6 on the intestinal propulsion rate of mice were compared, and it was found that the pharmaceutical composition of Comparative Example 6 had a more excellent effect. Therefore, the compositions of Comparative Example 6 and Examples 1-8 were compared.

[0161] It was found that compared with the medium dose group (D6) of Comparative Example 6, the gastrointestinal propulsion rate of mice in the low dose group (S1-1) of Example 1, the medium dose group (S1-2) of Example 1, the high dose group (S1-3) of Example 1, and the medium dose groups (S2-S8) of Examples 2-8 were significantly increased ( + P<0.05, ++ P<0.01).

[0162] The results showed that the intestinal propulsion rate of mice in the medium dose groups of Examples 1-8, the low dose group of Example 1 and the high dose group of Example 1 was significantly improved compared with the optimal group in the comparative example (i.e., comparative example 6). Therefore, compared with the medium dose groups (D1-D5) of Comparative Examples 1-5, which were slightly worse than the medium dose group (D6) of Comparative Example 6, the intestinal propulsion rate of mice in the medium dose group (S1-2) of Example 1 was significantly improved.

[0163] Compared with the dose groups (D1-D2) in comparative examples 1-2, the intestinal propulsion rate of mice in the dose group (S1-2) in Example 1 was significantly improved. This indicates that the pharmaceutical composition of the example uses ferulic acid, vanillic acid, p-coumaric acid and other components to interact with each other, which can significantly improve the intestinal propulsion rate of mice.

[0164] Compared with the dose group (D3) in comparative example 3, the intestinal propulsion rate of mice in the dose group (S1-2) in Example 1 was significantly improved. This shows that the pharmaceutical composition of the example uses imperatorin, isoimperatorin and oxidized imperatorin, which interact with other components to significantly improve the intestinal propulsion rate of mice.

[0165] Compared with the dosage group (D4) in comparative example 4, the intestinal propulsion rate of mice in the dosage group (S1-2) in example 1 was significantly improved, which indicates that the mass ratio of imperatorin, isoimperatorin, oxidized imperatorin and puerarin in the pharmaceutical composition of the example can more effectively improve the intestinal propulsion rate of mice in the range of 1-3:1-10:1-3:0.5-5.

[0166] Compared with the dosage group (D5) in comparative example 5, the intestinal propulsion rate of mice in the dosage group (S1-2) in Example 1 was significantly improved, which indicates that the mass ratio of magnolol, atractylodes, patchouli and tangerine peel in the pharmaceutical composition of the example can more effectively improve the intestinal propulsion rate of mice in the range of 1-2:30-80:30-80:15-50.

[0167] Compared with the dosage group (D6) in comparative example 6, the intestinal propulsion rate of mice in the dosage group (S1-2) in Example 1 was significantly improved, which indicates that the components in the pharmaceutical composition of the example interact with each other and can more effectively improve the intestinal propulsion rate of mice.

[0168] The above results show that the components in the pharmaceutical composition of the embodiment interact with each other and can significantly alleviate the reduced intestinal propulsion rate caused by indigestion. Further, the mass ratio of imperatorin, isoimperatorin, oxidized imperatorin and puerarin in the pharmaceutical composition can more effectively improve the intestinal propulsion rate of mice in the range of 1-3:1-10:1-3:0.5-5, and the mass ratio of magnolol, atractylodes, patchouli and tangerine peel in the pharmaceutical composition can also more effectively improve the intestinal propulsion rate of mice in the range of 1-2:30-80:30-80:15-50.

[0169] 3.2 Effect of the drug combination on the expression of biomarkers in serum and gastric tissue of mice with functional dyspepsia

[0170] 3.2.1 Gastrin (GAS)

[0171] After five days of administration, the gastrin (GAS) level of mice was Figure 5 The results are as follows:

[0172] (1) Compared with the normal group, the gastrin level of mice in the model control group (FD) was significantly decreased ( ### P<0.001).

[0173] The results showed that compared with the normal group, the gastrin level in young mice was significantly reduced after modeling.

[0174] (2) Compared with the model control group, the gastrin levels of mice in the positive control group (Mosa), the low-dose group (S1-1) of Example 1, the medium-dose group (S1-2) of Example 1, the high-dose group (S1-3) of Example 1, the medium-dose groups (S2-S8) of Examples 2-8, and the medium-dose groups (D1-D6) of Comparative Examples 1-6 were significantly increased ( * P<0.05, ** P<0.01, *** P<0.001). Among them, the gastrin levels of mice in the medium dose groups (D1-D6) of Comparative Examples 1-6 were lower than those in the low dose group (S1-1) of Example 1, the medium dose group (S1-2) of Example 1, the high dose group (S1-3) of Example 1, and the medium dose group (S2-S8) of Example 2-8.

[0175] The results show that the pharmaceutical compositions of Examples 1-8 and Comparative Examples 1-6 of the present invention can regulate and improve the gastrin secretion level of the model group mice, and significantly increase the gastrin secretion of the mice. Among them, the pharmaceutical composition of Example 1 has a better effect.

[0176] (3) Further, the effects of the pharmaceutical compositions of Comparative Examples 1-6 on gastrin secretion in mice were compared, and it was found that the pharmaceutical composition of Comparative Example 6 had a more excellent effect. Therefore, the compositions of Comparative Example 6 and Examples 1-8 were compared.

[0177] Compared with the middle dose group (D6) of comparative example 6, the gastrin levels of mice in the low dose group (S1-1) of example 1, the middle dose group (S1-2) of example 1, the high dose group (S1-3) of example 1, and the middle dose groups (S2-S8) of examples 2-8 were significantly increased ( + P<0.05, ++ P<0.01, +++ P<0.001).

[0178] The results showed that the gastrin levels of mice in the middle dose groups of Examples 1-8, the low dose group of Example 1 and the high dose group of Example 1 were significantly increased compared with the optimal group in the comparative example (i.e., comparative example 6). Therefore, compared with the middle dose groups (D1-D5) of Comparative Examples 1-5, which were slightly worse than the middle dose group (D6) of Comparative Example 6, the gastrin levels of mice in the middle dose group (S1-2) of Example 1 were significantly increased.

[0179] Compared with the dosage groups (D1-D2) in Comparative Examples 1-2, the gastrin level of mice in the dosage group (S1-2) in Example 1 was significantly increased, which indicates that the pharmaceutical composition of the example uses ferulic acid, vanillic acid, p-coumaric acid and other components to cooperate with each other, which can significantly promote gastrin secretion in mice.

[0180] Compared with the dosage group (D3) in comparative example 3, the gastrin level of mice in the dosage group (S1-2) in example 1 was significantly increased, which indicates that the pharmaceutical composition of the example uses imperatorin, isoimperatorin and oxidized imperatorin, and the three interact with other components to significantly increase the gastrin secretion level of mice.

[0181] Compared with the dosage group (D4) in Comparative Example 4, the gastrin level of mice in the dosage group (S1-2) in Example 1 was significantly increased, which indicates that the mass ratio of imperatorin, isoimperatorin, oxidized imperatorin and puerarin in the pharmaceutical composition of the example can more effectively promote gastrin secretion in mice in the range of 1-3:1-10:1-3:0.5-5.

[0182] Compared with the dosage group (D5) in comparative example 5, the gastrin level of mice in the dosage group (S1-2) in Example 1 was significantly increased, which indicates that the mass ratio of magnolol, atractylodes, patchouli and tangerine peel in the pharmaceutical composition of the example can more effectively promote gastrin secretion in mice in the range of 1-2:30-80:30-80:15-50.

[0183] Compared with the dosage group (D6) in comparative example 6, the gastrin level of mice in the dosage group (S1-2) in example 1 was significantly increased, which indicates that the components in the pharmaceutical composition of the example interact with each other and can more effectively increase the gastrin secretion level of mice.

[0184] The above results show that in the pharmaceutical composition of the embodiment, the components interact with each other and can significantly alleviate the reduced gastrin secretion caused by indigestion. Further, the mass ratio of imperatorin, isoimperatorin, oxidized imperatorin and puerarin in the pharmaceutical composition can more effectively improve the gastrin secretion level of mice in the range of 1-3:1-10:1-3:0.5-5, and the mass ratio of magnolol, atractylodes, patchouli and tangerine peel in the pharmaceutical composition can also more effectively improve the gastrin secretion level of mice in the range of 1-2:30-80:30-80:15-50.

[0185] 3.2.2 Motilin (MTL)

[0186] After five days of administration, the levels of motilin (MTL) in mice were Figure 6 The results are as follows:

[0187] (1) Compared with the normal group, the MTL level of mice in the model control group (FD) was significantly decreased ( ### P<0.001).

[0188] The results showed that compared with the normal group, the MTL level in young mice was significantly reduced after modeling.

[0189] (2) Compared with the model control group, the MTL levels of mice in the positive control group (Mosa), the low-dose group (S1-1) of Example 1, the medium-dose group (S1-2) of Example 1, the high-dose group (S1-3) of Example 1, the medium-dose groups (S2-S8) of Examples 2-8, and the medium-dose groups (D1-D6) of Comparative Examples 1-6 were significantly increased ( * P<0.05, ** P<0.01, *** P<0.001). Among them, the MTL levels of mice in the medium dose groups (D1-D6) of Comparative Examples 1-6 were lower than those in the low dose group (S1-1) of Example 1, the medium dose group (S1-2) of Example 1, the high dose group (S1-3) of Example 1, and the medium dose group (S2-S8) of Example 2-8.

[0190] The results show that the pharmaceutical compositions of Examples 1-8 and Comparative Examples 1-6 of the present invention can regulate and improve the MTL level of mice in the model group and significantly increase the MTL level of mice. Among them, the pharmaceutical composition of Example 1 has a better effect.

[0191] (3) Further, by comparing the effects of the pharmaceutical compositions of Comparative Examples 1-6 on the expression level of mouse MTL, it was found that the pharmaceutical composition of Comparative Example 6 had a more excellent effect.

[0192] Next, compared with the middle dose group (D6) in Comparative Example 6, the MTL levels of mice in the low dose group (S1-1) of Example 1, the middle dose group (S1-2) of Example 1, the high dose group (S1-3) of Example 1, and the middle dose groups (S2-S8) of Examples 2-8 were significantly increased ( + P<0.05, ++ P<0.01, +++ P<0.001).

[0193] The results showed that the MTL levels of mice in the middle dose groups of Examples 1-8, the low dose group of Example 1, and the high dose group of Example 1 were significantly increased compared with the optimal group in the comparative example (i.e., Comparative Example 6). Therefore, compared with the middle dose groups (D1-D5) of Comparative Examples 1-5, which were slightly worse than the middle dose group (D6) of Comparative Example 6, the MTL levels of mice in the middle dose group (S1-2) of Example 1 were significantly increased.

[0194] Compared with the dosage groups (D1-D2) in Comparative Examples 1-2, the MTL level of mice in the dosage group (S1-2) in Example 1 was significantly increased, indicating that the pharmaceutical composition of the example uses ferulic acid, vanillic acid, p-coumaric acid to interact with other components to significantly increase the MTL level of mice.

[0195] Compared with the dosage group (D3) in comparative example 3, the MTL level of mice in the dosage group (S1-2) in Example 1 was significantly increased, which indicates that the pharmaceutical composition of the example uses imperatorin, isoimperatorin and oxidized imperatorin, and the three interact with other components to significantly increase the MTL level of mice.

[0196] Compared with the dosage group (D4) in Comparative Example 4, the MTL level of mice in the dosage group (S1-2) in Example 1 was significantly increased, indicating that the mass ratio of imperatorin, isoimperatorin, oxidized imperatorin and puerarin in the pharmaceutical composition of the example can more effectively increase the MTL level of mice in the range of 1-3:1-10:1-3:0.5-5.

[0197] Compared with the dosage group (D5) in Comparative Example 5, the MTL level of mice in the dosage group (S1-2) in Example 1 was significantly increased, indicating that the mass ratio of magnolol, atractylodes, patchouli and tangerine peel in the pharmaceutical composition of the example can more effectively increase the MTL level of mice in the range of 1-2:30-80:30-80:15-50.

[0198] Compared with the dosage group (D6) in Comparative Example 6, the MTL level of mice in the dosage group (S1-2) in Example 1 was significantly increased, which indicates that the components in the pharmaceutical composition of the example interact with each other and can more effectively increase the MTL level of mice.

[0199] The above results show that the components of the pharmaceutical composition of the embodiment interact with each other and can significantly alleviate the reduction of MTL levels caused by indigestion. Further, the mass ratio of imperatorin, isoimperatorin, oxidized imperatorin and puerarin in the pharmaceutical composition can more effectively improve the MTL level of mice in the range of 1-3:1-10:1-3:0.5-5, and the mass ratio of magnolol, atractylodes, patchouli and tangerine peel in the pharmaceutical composition can also more effectively improve the MTL level of mice in the range of 1-2:30-80:30-80:15-50.

[0200] 3.2.3 Interleukin 4 (IL-4)

[0201] After five days of administration, the levels of interleukin 4 (IL-4) in mice were Figure 7 The results are as follows:

[0202] (1) Compared with the normal group, the IL-4 level of mice in the model control group (FD) was significantly decreased ( ### P<0.001).

[0203] The results showed that compared with the normal group, the IL-4 level in young mice was significantly decreased after modeling.

[0204] (2) Compared with the model control group, the IL-4 levels of mice in the positive control group (Mosa), the low-dose group (S1-1) of Example 1, the medium-dose group (S1-2) of Example 1, the high-dose group (S1-3) of Example 1, the medium-dose groups (S2-S8) of Examples 2-8, and the medium-dose groups (D1-D6) of Comparative Examples 1-4 were significantly increased ( * P<0.05, ** P<0.01, *** P<0.01). Among them, the IL-4 levels of mice in the medium dose groups (D1-D6) of Comparative Examples 1-6 were lower than those in the low dose group (S1-1) of Example 1, the medium dose group (S1-2) of Example 1, the high dose group (S1-3) of Example 1, and the medium dose group (S2-S8) of Example 2-8.

[0205] The results show that the pharmaceutical compositions of Examples 1-8 and Comparative Examples 1-6 of the present invention can regulate and improve the IL-4 expression level of the model group mice and significantly increase the IL-4 level of the mice. Among them, the pharmaceutical composition of Example 1 has a better effect.

[0206] (3) Further, by comparing the effects of the pharmaceutical compositions of Comparative Examples 1-6 on the expression level of IL-4 in mice, it was found that the pharmaceutical composition of Comparative Example 6 had a better effect.

[0207] Then, compared with the middle dose group (D6) of Comparative Example 6, the IL-4 levels of mice in the low dose group (S1-1) of Example 1, the middle dose group (S1-2) of Example 1, the high dose group (S1-3) of Example 1, and the middle dose groups (S2-S8) of Examples 2-8 were significantly increased ( + P<0.05, ++ P<0.01).

[0208] The results show that the pharmaceutical compositions of Examples 1-8 can significantly increase the expression level of mouse IL-4 compared with the optimal group in the comparative example (i.e., comparative example 6). Therefore, compared with the dosage groups (D1-D5) in comparative examples 1-5, which are slightly worse than the dosage group (D6) in comparative example 6, the mouse IL-4 level in the dosage group (S1-2) in Example 1 is significantly increased.

[0209] Compared with the dosage groups (D1-D2) in comparative examples 1-2, the IL-4 level of mice in the dosage group (S1-2) in Example 1 was significantly increased, indicating that the pharmaceutical composition of the example uses ferulic acid, vanillic acid, p-coumaric acid and other components to cooperate with each other, which can significantly increase the IL-4 level of mice.

[0210] Compared with the dosage group (D3) in comparative example 3, the IL-4 level of mice in the dosage group (S1-2) in Example 1 was significantly increased, which indicates that the pharmaceutical composition of the example uses imperatorin, isoimperatorin and oxidized imperatorin, and the three interact with other components to significantly increase the IL-4 level of mice.

[0211] Compared with the dosage group (D4) in Comparative Example 4, the IL-4 level of mice in the dosage group (S1-2) in Example 1 was significantly increased, indicating that the mass ratio of imperatorin, isoimperatorin, oxidized imperatorin and puerarin in the pharmaceutical composition of the example can more effectively increase the IL-4 level of mice in the range of 1-3:1-10:1-3:0.5-5.

[0212] Compared with the dosage group (D5) in Comparative Example 5, the IL-4 level of mice in the dosage group (S1-2) in Example 1 was significantly increased, indicating that the mass ratio of magnolol, atractylodes, patchouli and tangerine peel in the pharmaceutical composition of the example can more effectively increase the IL-4 level of mice in the range of 1-2:30-80:30-80:15-50.

[0213] Compared with the dosage group (D6) in comparative example 6, the IL-4 level of mice in the dosage group (S1-2) in Example 1 was significantly increased, which indicates that the components in the pharmaceutical composition of the example interact with each other and can more effectively increase the IL-4 level of mice.

[0214] The above results show that the components in the pharmaceutical composition of the embodiment interact with each other and can significantly alleviate the decrease in IL-4 levels caused by indigestion. Further, the mass ratio of imperatorin, isoimperatorin, oxidized imperatorin and puerarin in the pharmaceutical composition can more effectively improve the IL-4 level of mice in the range of 1-3:1-10:1-3:0.5-5, and the mass ratio of magnolol, atractylodes, patchouli and tangerine peel in the pharmaceutical composition can also more effectively improve the IL-4 level of mice in the range of 1-2:30-80:30-80:15-50.

[0215] 3.2.4 Interleukin (IL-1β) index

[0216] After five days of administration, the levels of interleukin (IL-1β) in mice were Figure 8 The results are as follows:

[0217] (1) Compared with the normal group, the IL-1β level of mice in the model control group (FD) was significantly increased ( ### P<0.001).

[0218] The results showed that compared with the normal group, the IL-1β level in young mice increased significantly after modeling.

[0219] (2) Compared with the model control group, the IL-1β levels of mice in the positive control group (Mosa), the low-dose group (S1-1) of Example 1, the medium-dose group (S1-2) of Example 1, the high-dose group (S1-3) of Example 1, the medium-dose groups (S2-S8) of Examples 2-8, and the medium-dose groups (D1-D6) of Comparative Examples 1-6 were significantly reduced ( * P<0.05, ** P<0.01). Among them, the IL-1β levels of mice in the medium dose groups (D1-D6) of Comparative Examples 1-6 were higher than those in the low dose group (S1-1) of Example 1, the medium dose group (S1-2) of Example 1, the high dose group (S1-3) of Example 1, and the medium dose group (S2-S8) of Example 2-8.

[0220] The results showed that the pharmaceutical compositions of Examples 1-8 and Comparative Examples 1-6 of the present invention can regulate the expression level of IL-1β in the model group mice and significantly reduce the secretion of IL-1β in the mice. Among them, the pharmaceutical composition of Example 1 has a better effect.

[0221] (3) Comparing the effects of the pharmaceutical compositions of Comparative Examples 1-6 on the expression level of mouse IL-1β, it was found that the pharmaceutical composition of Comparative Example 6 had the best effect. Then, Comparative Example 6 was compared with the pharmaceutical compositions of Examples 1-8.

[0222] It was found that compared with the medium dose group (D6) of Comparative Example 6, the IL-1β levels of mice in the low dose group (S1-1) of Example 1, the medium dose group (S1-2) of Example 1, the high dose group (S1-3) of Example 1, and the medium dose groups (S2-S8) of Examples 2-8 were significantly reduced ( + P<0.05, ++ P<0.01).

[0223] The results showed that the pharmaceutical compositions of Examples 1-8 can significantly reduce the IL-1β expression level of mice compared with the optimal group in the comparative example (i.e., comparative example 6). Therefore, compared with the dosage groups (D1-D5) in comparative examples 1-5, which are slightly worse than the dosage group (D6) in comparative example 6, the IL-1β expression level of mice in the dosage group (S1-2) in Example 1 is significantly reduced.

[0224] Compared with the dosage groups (D1-D2) in comparative examples 1-2, the IL-1β level of mice in the dosage group (S1-2) in Example 1 was significantly reduced, indicating that the pharmaceutical composition of the example uses ferulic acid, vanillic acid, p-coumaric acid and other components to cooperate with each other, which can significantly reduce the secretion of IL-1β in mice.

[0225] Compared with the dosage group (D3) in comparative example 3, the IL-1β level of mice in the dosage group (S1-2) in Example 1 was significantly reduced, which indicates that the pharmaceutical composition of the example uses imperatorin, isoimperatorin and oxidized imperatorin, and the three interact with other components to significantly reduce the IL-1β secretion of mice.

[0226] Compared with the dosage group (D4) in Comparative Example 4, the IL-1β level of mice in the dosage group (S1-2) in Example 1 was significantly reduced, indicating that the mass ratio of imperatorin, isoimperatorin, oxidized imperatorin and puerarin in the pharmaceutical composition of the example can more effectively reduce the IL-1β level of mice in the range of 1-3:1-10:1-3:0.5-5.

[0227] Compared with the dosage group (D5) in Comparative Example 5, the IL-1β level of mice in the dosage group (S1-2) in Example 1 was significantly reduced, indicating that the mass ratio of magnolol, atractylodes, patchouli and tangerine peel in the pharmaceutical composition of the example can more effectively reduce the IL-1β level of mice in the range of 1-2:30-80:30-80:15-50.

[0228] Compared with the dosage group (D6) in comparative example 6, the IL-1β level of mice in the dosage group (S1-2) in Example 1 was significantly reduced, which indicates that the components in the pharmaceutical composition of the example interact with each other and can more effectively reduce the IL-1β level of mice.

[0229] The above results show that the components of the pharmaceutical composition of the embodiment interact with each other and can significantly alleviate the increase in IL-1β levels caused by indigestion. Further, the mass ratio of imperatorin, isoimperatorin, oxidized imperatorin and puerarin in the pharmaceutical composition can more effectively reduce the IL-1β level of mice in the range of 1-3:1-10:1-3:0.5-5, and the mass ratio of magnolol, atractylodes, patchouli and tangerine peel in the pharmaceutical composition can also more effectively reduce the IL-1β level of mice in the range of 1-2:30-80:30-80:15-50.

[0230] In summary: In the pharmaceutical composition of the embodiment, the components interact with each other and can significantly alleviate the effects of indigestion. Further, the mass ratio of imperatorin, isoimperatorin, oxidized imperatorin and puerarin in the pharmaceutical composition in the range of 1-3:1-10:1-3:0.5-5 can more effectively alleviate indigestion in mice, and the mass ratio of magnolol, atractylodes, patchouli and tangerine peel in the pharmaceutical composition in the range of 1-2:30-80:30-80:15-50 can also more effectively alleviate indigestion in mice.

[0231] Test Example 2

[0232] Take the pharmaceutical compositions obtained in Example 1 and Comparative Examples 1-6 respectively, add an appropriate amount of water, stir evenly, add 90 g of sucrose, dissolve it, then add 50 g of sorbitol 80, add water to 1000 mL, mix well, package, sterilize by hot pressing at 121° C., and package to obtain an aqueous solution of the pharmaceutical composition.

[0233] The mixture was placed at 30±2°C and relative humidity of 65±5%, and samples were taken for observation and testing at 0, 3, 6, 12, 18, 24, 30, 36, 42, and 48 months, respectively. The content of puerarin in the aqueous solution of the pharmaceutical composition was detected by liquid chromatography with reference to the 2020 Chinese Pharmacopoeia. The results are shown in Tables 4 and Fig. 9 .

[0234] The conditions for the liquid chromatography detection of puerarin were as follows: chromatographic column Agilent ZORBAX SB-C18 (4.6 mm × 250 mm, 5 μm), mobile phase methanol-water (25:75), detection wavelength 250 nm, column temperature 40 °C, flow rate 1.0 mL / min.

[0235] Fig. 9 The figure is a graph of the loss rate of puerarin in the pharmaceutical composition over 48 months, wherein different letters between a and c indicate significant differences, and the significance level α=0.05.

[0236] Fig. 9The results in Table 4 show that the pharmaceutical compositions of the examples have excellent stability and can be stored for a long time. After 48 months of storage, the loss rate of puerarin in the pharmaceutical compositions of Comparative Examples 1-3 and Comparative Examples 5-6 was significantly increased compared with Example 1. There was no significant difference in the loss rate of puerarin in the pharmaceutical compositions of Example 1 and Comparative Example 4.

[0237] Compared with Example 1, the content of puerarin in the pharmaceutical compositions of Comparative Examples 1-3 is the same, but the components of the compositions are different, and the loss rate of puerarin is significantly increased, and the stability is significantly reduced. The results show that the components in Example 1 interact with each other, which is beneficial to improving the stability of puerarin.

[0238] Compared with Example 1, the content of puerarin in the pharmaceutical composition of Comparative Example 5 is the same, but the proportion of the components of the composition is different, and the loss rate of puerarin is significantly increased, and the stability is significantly reduced. The results show that the components in Example 1 interact with each other at a certain ratio, which is conducive to improving the stability of puerarin.

[0239] Table 4 Detection results of puerarin content in the pharmaceutical composition

[0240]

[0241]

[0242] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A pharmaceutical composition for functional dyspepsia, characterized in that: include: Costus root, Atractylodes lancea, Menthus alba, Patchouli, Citrus aurantium, Uncaria rhynchophylla, Tribulus terrestris, Guangdong Shenqu, Chrysanthemum, Poria, Radix Trichosanthis, Coix seed, Magnolia officinalis, Imperatorin, Isoproterosin, Oxyimperatorin, Ferulic acid, Vanillic acid, p-coumaric acid and puerarin.

2. The pharmaceutical composition according to claim 1, characterized in that The invention comprises the following components in parts by weight: 13.0-14.5 parts of costusroot, 13.0-14.5 parts of atractylodes, 5.5-9 parts of mint, 13.0-14.5 parts of patches, 6.0-7.8 parts of tangerine peel, 3.0-4.0 parts of Uncaria rhynchophylla, 3.0-4.0 parts of tribulus terrestris, 13.0-14.5 parts of Guangdong Shenqu, 6.0-7.5 parts of chrysanthemum, 25-30 parts of tuckahoe, 9.5-11.0 parts of Radix Trichosanthis, 16-18 parts of Semen Coicis, 0.25-0.40 parts of Magnolia officinalis, 0.2-1.1 parts of Imperatorin, 0.2-1.1 parts of Isoophorus imperatorin, 0.2-1.1 parts of Oxidized Imperatorin, 0.01-0.1 parts of Ferulic acid, 0.01-0.1 parts of Vanillic acid, 0.01-0.1 parts of p-Coumaric acid and 0.1-1.5 parts of Puerarin.

3. The pharmaceutical composition according to claim 2, characterized in that: The invention comprises the following components by weight: 13.2-14.0 parts of costusroot, 13.2-14.0 parts of atractylodes, 6.0-7.5 parts of mint, 13.2-14.0 parts of patchouli, 6.0-7.0 parts of tangerine peel, 3.1-3.7 parts of Uncaria rhynchophylla, 3.1-3.7 parts of tribulus terrestris, 13.2-14.0 parts of Guangdong Shenqu, 6.5-7.0 parts of chrysanthemum, 26-28 parts of tuckahoe, and 13.2-14.0 parts of chrysanthemum. 10.0-10.5 parts of powder, 17.0-17.5 parts of coix seed, 0.25-0.40 parts of magnolol, 0.2-1.1 parts of imperatorin, 0.2-1.1 parts of isoimperatorin, 0.2-1.1 parts of oxidized imperatorin, 0.01-0.1 parts of ferulic acid, 0.01-0.1 parts of vanillic acid, 0.01-0.1 parts of p-coumaric acid and 0.1-1.5 parts of puerarin.

4. The pharmaceutical composition according to claim 1, characterized in that The mass ratio of imperatorin, isoimperatorin, oxidized imperatorin and puerarin is 1-3:1-10:1-3:0.5-5.

5. The pharmaceutical composition according to claim 1, characterized in that: The mass ratio of magnolol, atractylodes, patches of podophyllum and red orange peel is 1-2:30-80:30-80:15-50.

6. The pharmaceutical composition according to claim 1, characterized in that: The patchouli is patchouli.

7. A method for preparing the pharmaceutical composition according to any one of claims 1 to 6, characterized in that: The following steps are involved: 1) distilling costusroot, atractylodes, mint, patchouli and red tangerine peel, collecting volatile oil and residual substances, decocting the residual substances in water, concentrating the decoction, adding ethanol, collecting and concentrating the filtrate 1, and obtaining an extract 1; 2) decoct Uncaria rhynchophylla, Tribulus terrestris, Guangdong Shenqu and chrysanthemum in water, concentrate the decoction, add ethanol, collect and concentrate the filtrate 2 to obtain extract 2; 3) boiling coix seeds in water, concentrating the decoction, adding ethanol, collecting and concentrating the filtrate 3 to obtain extract 3; 4) decoct Poria cocos and Radix Trichosanthis in water, concentrate the decoction, add ethanol, collect and concentrate the filtrate 4 to obtain extract 4; 5) Evenly mix extract 1, extract 2, extract 3, extract 4, magnolol, imperatorin, isoimperatorin, oxidized imperatorin, ferulic acid, vanillic acid, p-coumaric acid and puerarin, then add volatile oil, mix evenly, and obtain a pharmaceutical composition.

8. The preparation method according to claim 7, characterized in that: In the step 1), the distillation time is 1-3 hours, the number of water decoctions is 1-3 times, and the volume fraction of ethanol in the filtrate 1 is 40-50%.

9. The preparation method according to claim 7, characterized in that: In the filtrate 2-4, the volume fraction of ethanol is 40-60%.

10. Use of the pharmaceutical composition according to any one of claims 1 to 6 or the pharmaceutical composition prepared by the preparation method according to any one of claims 7 to 9 in the preparation of a medicament for treating functional dyspepsia.

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