CN111346193A

CN111346193A - Pharmaceutical composition for preventing and/or treating diarrhea-predominant irritable bowel syndrome, and preparation method and application thereof

Info

Publication number: CN111346193A
Application number: CN201910741714.0A
Authority: CN
Inventors: 张声生; 汪正芳; 赵鲁卿; 陶琳; 吴兵
Original assignee: Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital University of Medicine Sciences
Current assignee: Jiangsu Kanion Pharmaceutical Co Ltd
Priority date: 2019-08-12
Filing date: 2019-08-12
Publication date: 2020-06-30
Anticipated expiration: 2039-08-12
Also published as: CN111346193B

Abstract

The invention relates to a pharmaceutical composition for preventing and/or treating Diarrhea-Predominant Irritable Bowel Syndrome (IBS-D), and a preparation method and application thereof. The pharmaceutical composition of the invention has the following effects: 1. significantly improve the clinical symptoms of patients; 2. the abdominal pain degree of the patient is effectively relieved, and the stool character of the patient is improved; 3. the life quality of the patient is obviously improved; 4. significantly reduces the serum 5-HT level of the patient; 5. the recurrence rate is low.

Description

Pharmaceutical composition for preventing and/or treating diarrhea-predominant irritable bowel syndrome, and preparation method and application thereof

Technical Field

The invention belongs to the field of traditional Chinese medicines, and particularly relates to a pharmaceutical composition for preventing and/or treating diarrhea-predominant irritable bowel syndrome, and a preparation method and application thereof.

Background

Irritable Bowel Syndrome (IBS) is a clinically common functional Bowel disease, and is a group of symptoms including abdominal pain, abdominal distension with altered Bowel habits, abnormal stool characteristics and other clinical manifestations, with persistent or intermittent attacks, and clinically most common Diarrhea type (IBS-D). IBS has a female morbidity rate of 14-24% and a male morbidity rate of 5-19%, and has become a global functional bowel disease. The etiology and pathogenesis of IBS are not clear, and at present, the IBS are generally considered to be related to psychology, diet, infection, immunity, heredity and other factors, and the IBS is caused by influencing abnormal brain-intestine interaction, finally influencing abnormal intestinal dynamics and improving visceral sensitivity.

For IBS, a satisfactory treatment method is not available in Western medicine at present, mainly symptomatic treatment is taken as the main treatment, gastrointestinal tract power drugs, calcium channel antagonists and agents for regulating the functions of vegetative nerves are mostly used, and relapse is easy to occur after the drugs are stopped.

Disclosure of Invention

The invention provides a pharmaceutical composition for preventing and/or treating diarrhea-predominant irritable bowel syndrome, and a preparation method and application thereof. The invention adopts the prescription for regulating liver and spleen to treat diarrhea-predominant irritable bowel syndrome, can effectively relieve abdominal discomfort symptoms such as diarrhea and abdominal pain of patients, improve the stool characteristics of the patients, improve the life quality of the patients and obviously reduce the 5-HT content in the serum of the patients.

The inventor finds that the pathological mechanism of diarrhea-predominant irritable bowel syndrome is primarily liver and spleen disorder. The spleen governs transportation and transformation, and transport and transform food essence, and transport and transform water, so when the spleen and stomach are weak, the transportation and transformation fails, the clear and turbid are not separated, and food flows through the large intestine to purge. Meanwhile, the function of the spleen is closely related to the function of the liver governing smoothing flow of qi, so called "the liver disease indicates the transmission of the liver to the spleen". The pathogenesis and induction of this disease are closely related to emotional factors, and disorder of seven emotions can cause visceral dysfunction, especially have great influence on the liver, which is the general organ and is not obstructed, and is mainly responsible for regulating qi flow, thus it is easily damaged by emotions. Stagnation of liver qi, transverse invasion of spleen, dysfunction of large intestine, dysfunction of qi in descending and circulation of qi, and coexistence of liver depression and spleen deficiency can lead to the occurrence of the disease. Therefore, the key to the treatment of diarrhea-predominant irritable bowel syndrome is regulating the liver and regulating the spleen, strengthening the spleen and replenishing qi to eliminate dampness, soothing the liver and promoting the circulation of qi to relieve pain, and recovering the ascending and descending of qi and the transportation and transformation functions of the spleen and the stomach.

Through a large number of researches, the inventor provides the formula for regulating liver and regulating spleen, which comprises the following steps: radix astragali Preparata, parched Atractylodis rhizoma, radix Paeoniae alba, rhizoma corydalis, fructus Alpinae Oxyphyllae, parched semen euryales, fructus Citri Sarcodactylis, parched cortex Ailanthi, and semen Myristicae. The method is: on the basis of invigorating spleen and regulating liver, aiming at the pathogenesis of the irritable bowel syndrome, the traditional Chinese medicine composition has the functions of promoting qi circulation, relieving pain, eliminating dampness and stopping diarrhea, and can promote the recovery of the functions of spleen and stomach through the liver and spleen concoction so as to achieve the effect of treating diarrhea-type irritable bowel syndrome.

According to one aspect of the present invention, the present invention provides a pharmaceutical composition for preventing and/or treating diarrhea-predominant irritable bowel syndrome, comprising radix astragali Preparata, parched rhizoma Atractylodis Macrocephalae, radix Paeoniae alba, rhizoma corydalis, fructus Alpinae Oxyphyllae, parched semen euryales, fructus Citri Sarcodactylis, parched cortex Ailanthi and semen Myristicae; preferably, the pharmaceutical composition consists of radix astragali Preparata, parched Atractylodis rhizoma, radix Paeoniae alba, rhizoma corydalis, fructus Alpinae Oxyphyllae, parched semen euryales, fructus Citri Sarcodactylis, parched cortex Ailanthi and semen Myristicae.

According to the invention, the pharmaceutical composition comprises the following components in parts by weight: 20-30 parts of roasted astragalus membranaceus, 10-15 parts of fried bighead atractylodes rhizome, 10-20 parts of white peony root, 5-15 parts of rhizoma corydalis, 5-15 parts of fructus alpiniae oxyphyllae, 5-15 parts of fried gordon euryale seed, 5-15 parts of fingered citron, 5-15 parts of fried ailanthus bark and 5-15 parts of nutmeg; preferably, 25 parts of radix astragali Preparata, 12 parts of parched Atractylodis rhizoma, 15 parts of radix Paeoniae alba, 10 parts of rhizoma corydalis, 10 parts of fructus Alpinae Oxyphyllae, 10 parts of parched semen euryales, 10 parts of fructus Citri Sarcodactylis, 9 parts of parched cortex Ailanthi and 10 parts of semen Myristicae.

The components of the pharmaceutical composition of the invention are processed according to the conventional method in the field, or can be directly obtained commercially.

In the formula of the invention, the radix astragali preparata is selected firstly, the spleen and the qi are mainly strengthened and supplemented, the spleen and the stomach are the sources of qi and blood generation, the food and drink enter the stomach, the food and drink depends on the receiving and decomposing function of the stomach, the spleen qi is healthy and transformed to generate clear qi, the spleen ascending clear qi is up-coming to the lung, the body is distributed, the stomach descending turbid is descended to the small intestine, the body is discharged, and the spleen ascending stomach is descended to the stomach, so the transportation and transformation of the whole body are controlled. Parched Atractylodis rhizoma helps radix astragali Preparata invigorate spleen and invigorate qi. Radix Paeoniae alba can soften liver, relieve pain, and suppress liver yang. Rhizoma corydalis is used for promoting blood circulation, removing blood stasis, promoting qi circulation and relieving pain. Yi Zhi ren warms spleen to check diarrhea, controls saliva, warms kidney to reduce urination and emission. Parched semen euryales can be used for invigorating kidney, stopping nocturnal emission, invigorating spleen, relieving diarrhea, eliminating dampness, and stopping leukorrhagia. Fingered citron can soothe the liver and regulate qi, and can relieve pain. The fried Ailanthus altissima bark is used for clearing heat and drying dampness, astringing and stopping diarrhea and stopping bleeding. Nutmeg is used for warming middle energizer, astringing intestine, promoting qi circulation and promoting digestion.

Those skilled in the art can understand that the pharmaceutical composition of the present invention can be further prepared into decoction. Therefore, according to another aspect of the present invention, the present invention provides a decoction for preventing and/or treating diarrhea-predominant irritable bowel syndrome, which is prepared by decocting the above pharmaceutical composition.

The invention further provides a preparation method of the decoction, the medicine composition is soaked in water for more than 10 minutes, preferably 20 minutes to 1 hour, further preferably 20 to 30 minutes, the weight ratio of the medicine composition to the water is 1 (2-10), preferably 1 (4-7), further preferably about 1:5.5, the medicine composition is heated to boiling and then is continuously heated for more than 10 minutes, preferably 20 minutes to 1 hour, further preferably 20 to 30 minutes, so that the volume of the residual medicine liquid is 150 plus 300ml, preferably about 200ml, calculated by every 100 plus 300g of the total weight of the medicine composition, and the medicine residue is filtered out to obtain the medicine. Preferably, the above process is repeated and the second resulting solution is combined with the first resulting solution.

It will be appreciated by those skilled in the art that the pharmaceutical composition of the present invention may be further formulated into granules. Therefore, according to another aspect of the present invention, there is provided a granule for preventing and/or treating diarrhea-predominant irritable bowel syndrome, prepared from the above pharmaceutical composition. Preferably, the granules of the present invention further comprise pharmaceutically acceptable excipients.

It will be appreciated by those skilled in the art that the granules of the present invention can be prepared by various conventional methods in the art.

According to an aspect of the present invention, the granules of the present invention may be prepared by pulverizing the above-mentioned pharmaceutical composition. Preferably, the above pharmaceutical composition is pulverized to a particle size of 60-100 mesh, more preferably 65-80 mesh.

According to another aspect of the present invention, the granule of the present invention may be prepared by concentrating an aqueous extract of the above-mentioned pharmaceutical composition and drying. The aqueous extract of the pharmaceutical composition of the present invention can be prepared by various conventional methods in the art, such as decoction, maceration, percolation, reflux extraction, steam distillation, etc., and the decoction method, such as the decoction method described above, is preferred. Various conventional drying methods in the art may be used in the present invention, such as freeze drying, vacuum drying, spray drying, and the like.

According to another aspect of the present invention, the granules or powder prepared by pulverizing the above pharmaceutical composition or by concentrating and drying the aqueous extract of the above pharmaceutical composition are further made into granules with pharmaceutically acceptable excipients.

It will be understood by those skilled in the art that the pharmaceutical composition of the present invention can be further formulated into various other conventional preparations in the art, such as tablets (including dispersible tablets, orally disintegrating tablets, etc.), soft or hard capsules, dripping pills, granules, powders, oral liquid preparations (including oral liquids, syrups, suspensions, etc.), etc. Therefore, according to another aspect of the present invention, the present invention provides a Chinese medicine preparation, which is prepared from the above-mentioned pharmaceutical composition and pharmaceutically acceptable excipients. Preferably, the Chinese medicinal preparation is an oral dosage form. Further preferably, the oral dosage form is a tablet (including dispersible tablet, orally disintegrating tablet, etc.), soft or hard capsule, dripping pill, granule, powder, oral liquid preparation (including oral liquid, syrup, suspension, etc.), etc.

Those skilled in the art will appreciate that various pharmaceutically acceptable excipients commonly used in the art may be used in the present invention, including, but not limited to, diluents, disintegrants, lubricants, binders, colorants, flavoring agents, wetting agents, and the like, and that tablets may be coated if necessary. Adjuvants useful in the present invention include, but are not limited to: lactose, mannose, starch, polyvinylpyrrolidone, magnesium stearate, sodium lauryl sulfate, sorbitol, methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, lecithin, gelatin, p-hydroxy-benzyl ester, tween 80, polyethylene glycol, cyclodextrin, and the like.

According to another aspect of the invention, the invention provides application of the pharmaceutical composition, decoction, granules or traditional Chinese medicine preparation in preparation of medicines for preventing and/or treating diarrhea-predominant irritable bowel syndrome.

According to another aspect of the present invention, there is provided a method for preventing and/or treating irritable bowel syndrome with diarrhea, comprising administering to an individual in need thereof a therapeutically effective amount of the pharmaceutical composition, decoction, granule or Chinese medicinal preparation of the present invention. As will be understood by those skilled in the art, the dosage of the pharmaceutical composition, decoction, granule or Chinese medicinal preparation of the present invention can be determined by the clinician according to the specific condition of the patient, the severity of the disease, etc. For the pharmaceutical composition, the preferable dosage is 70-155g per day, such as 20-30g of radix astragali preparata, 10-15g of fried rhizoma atractylodis macrocephalae, 10-20g of radix paeoniae alba, 5-15g of rhizoma corydalis, 5-15g of fructus alpiniae oxyphyllae, 5-15g of fried semen euryales, 5-15g of fingered citron, 5-15g of fried cortex ailanthi and 5-15g of nutmeg; preferably, 25g of radix astragali Preparata, 12g of parched white atractylodes rhizome, 15g of white peony root, 10g of rhizoma corydalis, 10g of fructus alpiniae oxyphyllae, 10g of parched gordon euryale seed, 10g of fingered citron, 9g of parched cortex ailanthi and 10g of nutmeg. The pharmaceutical composition, decoction, granules or traditional Chinese medicine preparation can be taken 2 times or 3 times daily, preferably before meals.

The invention adopts random double-blind double-simulation contrast research, and objectively evaluates the curative effect of the pharmaceutical composition on diarrhea-predominant irritable bowel syndrome by observing and contrasting main clinical symptoms, traditional Chinese medicine symptoms, abdominal pain degree, stool characteristics, life quality and serum 5-HT content of a patient. Clinical tests show that the pharmaceutical composition has the following effects:

1. remarkably improves the clinical symptoms of patients.

2. Effectively reduce the abdominal pain degree of the patient and improve the stool character of the patient.

3. Obviously improve the life quality of the patients.

4. Obviously reduces the level of 5-HT in the serum of patients.

5. The recurrence rate is low.

Detailed Description

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Furthermore, it should be understood that various changes or modifications can be made by those skilled in the art after reading the description of the present invention, and such equivalents also fall within the scope of the invention.

Example 1

Weighing 20g of radix astragali Preparata, 5g of parched white atractylodes rhizome, 10g of white peony root, 5g of rhizoma corydalis, 5g of fructus alpiniae oxyphyllae, 5g of parched gordon euryale seed, 5g of fingered citron, 5g of parched cortex ailanthi and 5g of nutmeg (all commercially available from Beijing kang Kernel Tang pharmaceutical industry Co., Ltd.), mixing, adding 357.5g of water, soaking for 30 minutes, boiling with strong fire, continuously heating with slow fire for about 20 minutes until the residual liquid medicine is about 200ml, repeating the above decocting process, and mixing the liquid medicines obtained in the two times.

Example 2

Weighing 25g of radix astragali Preparata, 10g of parched rhizoma Atractylodis Macrocephalae, 15g of radix Paeoniae alba, 10g of rhizoma corydalis, 10g of fructus Alpinae Oxyphyllae, 10g of parched semen euryales, 10g of fructus Citri Sarcodactylis, 10g of parched cortex Ailanthi and 10g of semen Myristicae (all commercially available from Beijing KANGRENTANG pharmaceutical Co., Ltd.), mixing, adding 605g of water, soaking for 30 minutes, boiling with strong fire, heating with slow fire for about 20 minutes until the residual liquid medicine is about 200ml, repeating the above decocting process, and mixing the liquid medicines obtained in two times.

Example 3

Weighing 30g of radix astragali Preparata, 15g of parched white atractylodes rhizome, 20g of white peony root, 15g of rhizoma corydalis, 15g of fructus alpiniae oxyphyllae, 15g of parched gordon euryale seed, 15g of fingered citron, 15g of parched cortex ailanthi and 15g of nutmeg (all commercially available from Beijing kang Kernel Tang pharmaceutical Co., Ltd.), mixing, adding 852.5g of water, soaking for 30 minutes, boiling with strong fire, continuously heating with slow fire for about 20 minutes until the residual liquid medicine is about 200ml, repeating the above decocting process, and mixing the liquid medicines obtained in the two times.

Example 4

Weighing 25g of radix astragali Preparata, 12g of parched rhizoma Atractylodis Macrocephalae, 15g of radix Paeoniae alba, 10g of rhizoma corydalis, 10g of fructus Alpinae Oxyphyllae, 10g of parched semen euryales, 10g of fructus Citri Sarcodactylis, 9g of parched cortex Ailanthi and 10g of semen Myristicae (all commercially available from Beijing Kangrentang pharmaceutical Co., Ltd.), mixing, and pulverizing to particle size of 65-80 mesh to obtain granule.

EXAMPLE 5 evaluation of drug efficacy

The invention adopts random double-blind double-simulation contrast research, and objectively and systematically evaluates the curative effect of the pharmaceutical composition on the diarrhea-predominant irritable bowel syndrome by comparing the main clinical symptoms, the traditional Chinese medicine symptoms, the abdominal pain degree, the stool characteristics, the life quality and the serum 5-HT content of a patient.

First, case selection

1. Sample size

According to the design of non-inferior effect tests and the 1:1 comparison principle, the sample amount required by the test group and the comparison group is calculated to be 113 cases respectively, the falling rate of the research is designed to be 15%, the sample amount required by the test group and the comparison group is calculated to be 130 cases respectively, and the total sample amount is 260 cases.

2. Diagnostic criteria for diarrhea-predominant irritable bowel syndrome

The Roman III standard of the irritable bowel syndrome is used for diagnosing the irritable bowel syndrome, wherein the Roman III standard of the irritable bowel syndrome is that repeatedly-occurring abdominal pain or discomfort is accompanied by 2 or more than 2 items of ① symptoms improved after defecation, ② symptoms changed with defecation frequency at the onset, ③ symptoms changed with stool characters at the onset, the first symptom onset time must exceed 6 months, and the symptom duration time of the last 3 months is more than or equal to 3 days/month, and when the irritable bowel syndrome patient has no discharge of the form (pasty stools) or watery stools more than or equal to 25 percent and the proportion of the hard or blocky stools is less than or equal to 25 percent, the irritable bowel syndrome is diagnosed as the diarrhea type irritable bowel syndrome.

In diagnosing diarrhea-predominant irritable bowel syndrome, the following points should be noted:

(1) the diagnosis should be based on the elimination of organic diseases, and the identified diseases mainly include ulcerative colitis, Crohn's disease, intestinal tumor, malabsorption syndrome, lactase deficiency, hyperthyroidism, intestinal pseudo-obstruction, Hirschsprung's disease, ischemic bowel disease, etc.

(2) Intestinal symptoms of irritable bowel syndrome have certain characteristics, such as abdominal pain or relationship between abdominal discomfort and defecation, and are different from other functional intestinal diseases (such as functional constipation, functional diarrhea and functional abdominal pain);

(3) irritable bowel syndrome often coexists with other functional gastrointestinal disorders.

3. Inclusion criteria

(1) Meets the diagnosis standard of diarrhea-predominant irritable bowel syndrome Roman III;

(2) the age is 18-65 years old, and the nature is not limited;

(3) and (4) carrying out informed consent, volunteering to be tested, and signing an informed consent form, wherein the informed consent process conforms to the specification of GCP.

4. Exclusion criteria

(1) Infectious diarrhea;

(2) diarrhea due to systemic diseases, poisoning, and malignant tumor;

(3) serious primary diseases of heart, cerebral vessels, liver and kidney, endocrine and hematopoietic systems are combined;

(4) pregnant or lactating women;

(5) allergic constitution;

(6) mental disorders, suspected or confirmed history of alcohol, drug abuse.

(7) According to the judgment of researchers, other pathological changes which reduce the possibility of group entry or complicate the group entry are caused, such as the condition that the working environment is frequently changed and the like, which easily causes missed visits.

(8) Patients who are participating in clinical trials with other drugs.

5. Rejection criteria

Cases that have entered the group but meet one of the following should be rejected:

(1) misdiagnosis and mistaking;

(2) those who have not been administered;

(3) no detection record;

(4) the therapeutic effect cannot be evaluated due to the use of drugs that are prohibited.

The reason should be explained for the removed cases, and the "report of cases" should be kept for future reference. The patients who do not do the statistical analysis of the curative effect but receive at least one treatment and have records can participate in the analysis of adverse reactions.

Second, test method

1. The design method comprises the following steps:

random double-blind double-simulation and parallel control test are adopted.

2. The grouping method comprises the following steps:

the random grouping was performed according to the block random method, and a random arrangement of 260 subjects receiving treatment was generated by means of the SAS statistical analysis system, i.e., treatment assignments corresponding to the flow numbers 001-260 were listed. Each center is assigned 52 consecutive codes that are concatenated to each other. The subject responsible unit and the cooperation unit cooperate to complete the cost test.

3. The treatment method comprises the following steps:

(1) test groups:

the granules prepared in the example 4 are divided into 2 bags, 1 bag is taken every time, 200ml of boiled water is taken with water, and the granules are taken orally before meals and once in the morning and at night; and

the pinaverium bromide tablet simulation tablet only contains auxiliary materials (starch, lactose, pregelatinized starch, microcrystalline cellulose, magnesium stearate and water) and does not contain active ingredients, is uniformly prepared by Huarun Sanjiu medicine Co., Ltd, and is orally taken 1 tablet at a time for 1 day and 3 times.

(2) Control group:

the granular simulator is uniformly prepared by Huarun Sanjiu medicine Co Ltd, only contains one fourth of the medicine of the granular formulation in the embodiment 4, the rest is dextrin, 1 bag of the medicine is taken with 200ml of boiled water each time, and the medicine is taken orally before a meal and is taken once in the morning and at night; and

pinaverium bromide tablet (Desu, containing 50 mg/tablet of pinaverium bromide, produced by French Suwei pharmaceutical factory, batch number: H20040759) is orally administered 1 tablet at a time for 3 times in 1 day.

(3) The course of treatment is as follows: both groups were administered for 4 weeks. All the medicines for treating diarrhea-predominant irritable bowel syndrome are stopped 2 weeks before the patients enter the group, and the patients enter the elution stage.

4. Combined use of medicine

(1) The name (or other treatment), the application, the amount and the time of the drug or other treatment which is necessary to be continuously used for the combined disease or symptom (except the symptom) which is not related to the disease and is already existed before the study is started should be recorded in detail so as to be analyzed and reported at the time of summarization.

(2) Any co-morbidities or symptoms that occur after the study has begun require intervention by the processor, and their intervention should be recorded in detail on the "co-medication" table in "study history" and "case report table". When the abdominal pain, defecation frequency and defecation quality are all aggravated progressively, corresponding measures should be taken to intervene.

(3) Except for the prescribed medication, all other Chinese and western medicines or therapies which have the same effect as the study medicines and have influence on the endocrine function of the digestive system, such as antibiotics, are forbidden to be used in the study period: compound sulfamethoxazole, norfloxacin and the like, spasmolytic: otilonium bromide, trimebutine maleate, anisodamine and the like, and prokinetic agents: cisapride, mosapride, etc., antidiarrheal agents: loperamide, symmetrel, etc., antidepressants: celebrate, worship, etc., gastrointestinal microecologics: siliankang, pefeikang, Lizhu Changle and the like, and traditional Chinese medicine, acupuncture massage, decoction medicated bath and other therapies for strengthening spleen and stopping diarrhea in traditional Chinese medicine.

5. The statistical method comprises the following steps:

data processing application software SPSS 22.0 statistics. The measurement data is statistically described by means of the mean plus or minus standard deviation, and the comparison of the measurement data before and after the treatment in the group is carried out by adopting a paired sample t test; the comparison of the measurement data among the groups adopts independent sample t test; the counting data is tested by adopting X2;

p >0.05 means that the difference is not statistically significant, P <0.05 means that the difference is statistically significant, and P <0.01 means that the difference is statistically significant.

Third, observe the index

3.1 Main Observation indicators

Irritable bowel syndrome disease change score table (BSS) scoring system: the abdominal pain and abdominal pain training system comprises 5 projects of abdominal pain, abdominal pain days, abdominal distension conditions, defecation satisfaction and life interference, wherein each project is divided into no (0 point), not very serious (25 points), serious (50 points), serious (75 points) and very serious grade 5 (100 points), and the total score of each project is 500 points at most. Is mainly used for evaluating the overall curative effect of the medicine and the influence on the main symptoms.

3.2 secondary Observation indicators

3.2.1 the Chinese medicine symptom curative effect indexes are as follows:

referring to the guiding principles of clinical research on new traditional Chinese medicines, the digestive system of practical traditional Chinese medicine, the gastrointestinal system of traditional Chinese medicine and the diagnosis and treatment guidelines of digestive system of traditional Chinese medicine, the method of the syndrome score table shown in the following table 1 is adopted in combination with the traditional Chinese medicine syndrome characteristics of the diarrhea-type irritable bowel syndrome, so that the symptoms are divided into three grades of light, medium and severe, which are respectively counted for 1, 2 and 3, and no symptom is counted for 0. The curative effect index is calculated by adopting a nimodipine method:

the curative effect index is × 100% before treatment score-after treatment score/before treatment score, the symptom and the physical sign disappear or basically disappear after clinical recovery, and the curative effect index is more than or equal to 95%;

the effect is shown: the symptoms and physical signs are obviously improved, and the curative effect index is more than or equal to 70 percent and less than 95 percent;

the method has the following advantages: the symptoms and physical signs are improved, and the curative effect index is more than or equal to 30 percent and less than 70 percent;

and (4) invalidation: symptoms and physical signs are not obviously improved or even aggravated, and the curative effect index is less than 30 percent.

TABLE 1 syndrome integrating chart

Wherein one term of the tongue does not participate in the score.

3.2.2 degree of abdominal pain 11 points (0-10) pain rating scale, i.e. one line, divided into 10 equal parts, faithfully evaluated by the subjects according to the degree of the most severe abdominal pain per day, and the corresponding numbers are plotted as "○".

3.2.3 stool traits questionnaire (DSQ): including the maximum number of bowel movements per day (times/day), stool characteristics (scored according to the Bristol stool characteristics scale of table 2 below).

TABLE 2Bristol stool Property Scale

3.2.4 Irritable bowel syndrome patient quality of Life Scale (Irritable bowel syndrome-quality of life quehonnaire IBS-QOL): the following table 3IBS-QOL special scale is adopted and consists of 34 items reflecting 8 dimensions of anxiety, behavior disorder, somatic ideation, food choosing, health anxiety, social function, sexual behavior and interpersonal relationship, scores of each dimension are converted to be in the range of 0-100, and the higher the score is, the higher the life quality is.

TABLE 3 quality of Life Scale for irritable bowel syndrome patients

Please draw a square root under the corresponding selection "

Grading standard: no at 0, one at 1, more at 2, considerably more at 3, and completely so at 4

3.2.5 determination of serum 5-HT concentration

① the main reagent 5-HT is Sigma.

② Main equipment comprises LC-6A liquid chromatograph and L-ECD-6A electrochemical detector, and fluorescence measurement adopts Shimadzu 3000 fluorescence spectrophotometer.

③ detection method:

[ serum sample treatment ]: after the patient fasting for 12h, 3ml of venous blood is extracted in the next morning, placed in a refrigerator at 4 ℃ for 40min and then centrifuged for 3min, and the supernatant is taken and placed in a refrigerator at-80 ℃ for storage to be tested.

[ serum 5-HT assay ]: fluorescence was measured at room temperature with 10nm slits for excitation and emission. Measured in a 4ml quartz cup. Excitation light is 360nm and emission light is 470 nm; the blank tube is used for zero adjustment, and the measured value is processed by an automatic value processing system.

3.3 follow-up recurrence index

Follow-up is respectively carried out for 1 month and 3 months after the medicine is stopped, and the change integral of the disease condition of the irritable bowel syndrome, the integral of the traditional Chinese medicine syndrome, the abdominal pain (degree), the stool character questionnaire and the life quality scale of the irritable bowel syndrome patient are obtained.

3.4 safety indices

Normal blood, liver and kidney function, electrocardiogram

3.5 observation time point

The medication of all observation cases is 4 weeks, the disease condition change is recorded once in the 2 nd week and the 4 th week respectively, and safety index and 5-HT index detection are carried out before and after treatment. The follow-up is carried out 1 month and 3 months after the withdrawal of the medicine, and the change of symptoms and the relapse condition of the disease are recorded in detail.

Fourth, abort and drop criteria

4.1 abort criterion

(1) Serious safety problems occur in the test process, and the test should be stopped in time;

(2) in the test process, the clinical test scheme has major errors, and the drug effect is difficult to evaluate; or a better designed scheme, which has serious deviation in implementation, continues again, and is difficult to evaluate the drug effect.

4.2 shedding criterion

(1) Intolerance to subjects after onset of observation;

(2) severe side effects after the start of observation;

(3) the observation period is less than 2 weeks.

Fifthly, exit and accident handling of the observed object

For the cases of abscission, the number and the cause of abscission cases were clearly recorded, and sensitivity analysis was performed.

Sixthly, a method for recording and reporting adverse reactions comprises the following steps:

the investigator will prescribe the patient to faithfully reflect the changes in the condition after administration. The doctor needs to avoid inducing questions, closely pay attention to observing adverse reactions or unexpected toxic and side effects while observing curative effects, analyzing reasons, making judgment, tracking, observing and recording, and counting the incidence rate of the adverse reactions.

When an adverse reaction is found, the physician needs to judge the causal relationship between the adverse reaction and the drug. Whether the test is stopped or not can be determined according to the state of illness, the case of drug withdrawal due to adverse reaction is tracked and investigated, and the result is recorded in detail.

Seven, case data and statistical analysis

The clinical research data cases come from Beijing medical science hospital affiliated to capital medical university, Beijing Chaoyang hospital affiliated to capital medical university, first affiliated hospital of Tianjin traditional Chinese medicine university, second affiliated hospital of Tianjin traditional Chinese medicine university, first affiliated hospital of Henan traditional Chinese medicine university, outpatients from 07 to 2016 and 11 months in 2015, 260 cases are entered into the group together according to inclusion and exclusion standards, wherein 130 cases are in the test group, and 130 cases are in the control group. At the end of the trial, there were 31 cases of droppings, of which 18 cases in the trial group, 13 cases in the control group, and 229 cases of final case data, of which 49 cases were from the beijing chinese medical hospital affiliated to the capital medical university, 43 cases were from the beijing chaoyang hospital affiliated to the capital medical university, 45 cases were from the first affiliated hospital affiliated to the tianjin chinese medical university, 44 cases were from the second affiliated hospital to the tianjin chinese medical university, and 48 cases were from the first affiliated hospital affiliated to the henan chinese medical university.

(I) case data

1. General conditions (sex composition, age, course of disease) in two groups of patients:

(1) sex: test groups 48 men and 64 women; the sex constitution difference of the two groups of the control group of 56 men and 61 women has no statistical significance (P is more than 0.05) and is comparable.

(2) Age: the mean age of the test group was 48.46 + -11.57 years, the mean age of the control group was 50.73 + -10.52 years, and the difference in age between the patients in both groups was not statistically significant (P >0.05) and was comparable.

(3) The course of the disease is as follows: the mean disease course of the test group is 5.53 +/-5.41 years, the mean disease course of the control group is 5.02 +/-5.02 years, and the difference of the disease courses of the two groups of patients has no statistical significance (P is more than 0.05) and is comparable.

(II) statistical results

1. Scoring condition of disease condition change score table of two groups of patients

The test group and the control group have no statistical significance in the difference of scores before treatment (P is more than 0.05). In-group comparison, the test group had a lower score than before treatment for 2 weeks of treatment, 4 weeks of treatment, 1 month of discontinuation, and 3 months of discontinuation, with improved symptoms (P0.000 < 0.01); the control group had a lower score than before treatment for 2 weeks, 4 weeks, 1 month and 3 months of withdrawal, and improved symptoms (P < 0.01). Comparison between the two groups, after 2 weeks of treatment, the control group scored less than the test group but not statistically significant (P > 0.05); the treatment period is 4 weeks, the medicine is stopped for 1 month and the medicine is stopped for 3 months, the score of the test group is lower than that of the control group, and the test group has statistical significance (P < 0.05). The specific scores are given in table 4 below:

TABLE 4 comparison of disease Change integral (+ -SD) before and after treatment

^＊Comparison with Pre-treatment P<0.01，^△Comparison with Pre-treatment P<0.01

2. Improvement of Chinese medicine symptoms of two groups of patients

The difference in the pre-treatment integrals between the test group and the control group is not statistically significant (P > 0.05). Compared with the group, the symptoms of the test group are improved (P is less than 0.01) compared with the symptoms before treatment in 2 weeks of treatment, 4 weeks of treatment, 1 month of withdrawal of the medicine and 3 months of withdrawal of the medicine; the control group had improved symptoms (P <0.01) compared to the control group before treatment in 2 weeks, 4 weeks, 1 month and 3 months. Comparison between the two groups, after 2 weeks of treatment, the test group score was lower than the control group, but not statistically significant (P > 0.05); the treatment period is 4 weeks, the medicine is stopped for 1 month and the medicine is stopped for 3 months, the score of the test group is lower than that of the control group, and the statistical significance is achieved (P < 0.05). Specific integrals are shown in table 5 below:

TABLE 5 comparison of syndrome integral before and after treatment (+ -SD)

3. The traditional Chinese medicine symptoms of two groups of patients improve the effective rate

The difference of the total effective rate of the traditional Chinese medicine symptom improvement of the test group and the control group has no statistical significance. See in particular table 6 below:

table 6 effective rate for improving symptoms of chinese medicine

Chi-square test P >0.05

4. Comparison of Abdominal pain (degree) in two groups

The test group and the control group have no statistical significance in the difference of scores before treatment (P is more than 0.05). Compared with the group, the symptoms of the test group are improved (P is less than 0.01) compared with the symptoms before treatment in 2 weeks of treatment, 4 weeks of treatment, 1 month of withdrawal of the medicine and 3 months of withdrawal of the medicine; the control group had improved symptoms (P <0.01) compared to the control group before treatment in 2 weeks, 4 weeks, 1 month and 3 months. Comparison between the two groups, after 2 weeks of treatment, the control group scored less than the test group but not statistically significant (P > 0.05); the treatment period is 4 weeks, the medicine is stopped for 1 month and the medicine is stopped for 3 months, the score of the test group is lower than that of the control group, and the test group has statistical significance (P < 0.05). The specific scores are given in table 7 below:

TABLE 7 comparison of Abdominal pain levels before and after treatment (+/-SD)

5. Stool character score comparison of two groups of patients

(1) Comparison of diarrhea frequency between two groups of patients

The difference of the times of diarrhea before treatment between the test group and the control group has no statistical significance (P is more than 0.05). Compared with the group, the symptoms of the test group are improved (P is less than 0.01) compared with the symptoms before treatment in 2 weeks of treatment, 4 weeks of treatment, 1 month of withdrawal of the medicine and 3 months of withdrawal of the medicine; the control group had improved symptoms (P <0.01) compared to the control group before treatment in 2 weeks, 4 weeks, 1 month and 3 months. Compared between the two groups, the curative effect of the test group is better than that of the control group in the treatment and follow-up period, and the statistical significance is achieved (P is less than 0.05). See in particular table 8 below:

TABLE 8 comparison of diarrhea frequency before and after treatment (+ -SD)

(2) Stool character comparison of two groups of patients

The test group and the control group have no statistical significance in the difference of scores before treatment (P is more than 0.05). Compared with the group, the symptoms of the test group are improved (P is less than 0.01) compared with the symptoms before treatment in 2 weeks of treatment, 4 weeks of treatment, 1 month of withdrawal of the medicine and 3 months of withdrawal of the medicine; the control group had improved symptoms (P <0.05) compared to the control group before treatment in 2 weeks, 4 weeks, 1 month and 3 months. Compared between the two groups, the curative effect of the test group is better than that of the control group in the treatment and follow-up period, and the statistical significance is achieved (P is less than 0.05). See in particular table 9 below:

TABLE 9 stool trait comparison before and after treatment (+ -SD)

^＊Comparison with Pre-treatment P<0.01，^△Comparison with Pre-treatment P<0.05

6. Comparison of quality of Life Scale scores for two groups of patients

Before treatment, the IBS-QOL scale has 8 dimensionalities, has no statistical significance (P is more than 0.05) in the balance test among groups, and has comparability. In comparison, the test group treated for 4 weeks, stopped for 1 month and stopped for 3 months, all 8 dimensions were significantly improved compared to those before treatment (P < 0.01). Compared with the 2 groups, the differences of the 2 groups treated for 4 weeks IN DY, IN, HW, SR, RL, FA and SX 7 dimensions have no statistical significance (P >0.05), and the improvement of the test group is better than that of the control group (P <0.05) only IN BI dimension, namely somatic idea dimension; stopping taking the medicine for 1 month, and improving 6 dimensionalities of DY, IN, BI, HW, SR and RL by the test group better than that of a control group (P < 0.01); the drug withdrawal was 3 months, and the experimental group improved better than the control group in all 8 dimensions (P < 0.01). See in particular table 10 below:

TABLE 10 comparison of quality of life improvements (± s) before and after treatment

Note that P <0.05 and P <0.01 compared to pre-treatment, and △ P <0.05 and △△ P <0.01 compared to control.

7. Comparison of serum 5-HT concentrations in two groups of patients

The difference in serum 5-HT concentration between the test group and the control group before treatment was not statistically significant (P > 0.05). In-group comparison, the test group showed a significant decrease in serum 5-HT concentration after 4 weeks of treatment (P <0.01) compared to pre-treatment; the control group had a significant decrease in serum 5-HT concentration 4 weeks after treatment (P <0.01) compared to pre-treatment. The difference between the two groups was not statistically significant (P > 0.05). See in particular table 11 below:

TABLE 11 comparison of serum 5-HT before and after treatment (+ -SD)

8. Safety observations of test and control groups

The blood routine, liver and kidney function and electrocardiogram examination carried out at the 4 th week of treatment of the test group and the control group have no obvious abnormality.

The clinical tests show that the medicament prepared by the pharmaceutical composition can effectively and safely treat diarrhea-predominant irritable bowel syndrome.

The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A pharmaceutical composition for preventing and/or treating diarrhea-predominant irritable bowel syndrome, which comprises radix astragali Preparata, parched Atractylodis rhizoma, radix Paeoniae alba, rhizoma corydalis, fructus Alpinae Oxyphyllae, parched semen euryales, fructus Citri Sarcodactylis, parched cortex Ailanthi and semen Myristicae.

Preferably, the pharmaceutical composition consists of radix astragali Preparata, parched Atractylodis rhizoma, radix Paeoniae alba, rhizoma corydalis, fructus Alpinae Oxyphyllae, parched semen euryales, fructus Citri Sarcodactylis, parched cortex Ailanthi and semen Myristicae.

2. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises the following components in parts by weight: 20-30 parts of roasted astragalus membranaceus, 10-15 parts of fried bighead atractylodes rhizome, 10-20 parts of white peony root, 5-15 parts of rhizoma corydalis, 5-15 parts of fructus alpiniae oxyphyllae, 5-15 parts of fried gordon euryale seed, 5-15 parts of fingered citron, 5-15 parts of fried ailanthus bark and 5-15 parts of nutmeg.

Preferably, 25 parts of radix astragali Preparata, 12 parts of parched Atractylodis rhizoma, 15 parts of radix Paeoniae alba, 10 parts of rhizoma corydalis, 10 parts of fructus Alpinae Oxyphyllae, 10 parts of parched semen euryales, 10 parts of fructus Citri Sarcodactylis, 9 parts of parched cortex Ailanthi and 10 parts of semen Myristicae.

3. A granule for preventing and/or treating diarrhea-predominant irritable bowel syndrome, which is prepared from the pharmaceutical composition according to claim 1 or 2.

4. A decoction for preventing and/or treating diarrhea-predominant irritable bowel syndrome, which is prepared by decocting the pharmaceutical composition according to claim 1 or 2.

5. A method of preparing a decoction as claimed in claim 4, wherein the decoction is prepared by

Soaking the medicine composition in water for more than 10 minutes, preferably 20 minutes to 1 hour, further preferably 20 to 30 minutes, wherein the weight ratio of the medicine composition to the water is 1 (2-10), preferably 1 (4-7), further preferably about 1:5.5, heating to boiling, continuing to heat for more than 10 minutes, preferably 20 minutes to 1 hour, further preferably 20 to 30 minutes, so that the volume of the residual medicine liquid is 300ml, preferably about 200ml, calculated by the total weight of the medicine composition per 100 grams, and filtering the medicine residue to obtain the medicine.

6. A Chinese medicinal preparation for preventing and/or treating diarrhea-predominant irritable bowel syndrome, which is prepared from the pharmaceutical composition of claim 1 or 2 and pharmaceutically acceptable adjuvants.

Preferably, the Chinese medicinal preparation is an oral dosage form.

Preferably, the oral dosage form is a tablet (including dispersible tablets and orally disintegrating tablets), a soft or hard capsule, a dripping pill, a medicinal granule, powder or an oral liquid preparation (including oral liquid, syrup and suspension).

7. Use of the pharmaceutical composition, the granule, the decoction and the Chinese medicinal preparation according to any one of claims 1 to 4 and 6 in the preparation of medicaments for preventing and/or treating diarrhea-predominant irritable bowel syndrome.