CN112641889A

CN112641889A - Application of intestine-regulating decoction in preparation of medicament for treating Crohn's disease

Info

Publication number: CN112641889A
Application number: CN202110027759.9A
Authority: CN
Inventors: 黄彬; 黄明河; 许艺飞; 郭绍举; 林保福; 罗爽
Original assignee: Shenzhen Traditional Chinese Medicine Hospital
Current assignee: Shenzhen Traditional Chinese Medicine Hospital
Priority date: 2021-01-11
Filing date: 2021-01-11
Publication date: 2021-04-13
Anticipated expiration: 2041-01-11
Also published as: CN112641889B

Abstract

The invention relates to the field of biomedicine, in particular to application of intestine regulating decoction in preparation of a medicament for treating Crohn's disease. The technical scheme provided by the invention obviously improves occult blood, hematochezia, physical quality decline, DAI integral, pathological changes and other diseases caused by Crohn's Disease (CD), and opens up a new application for intestine-regulating soup.

Description

Application of intestine-regulating decoction in preparation of medicament for treating Crohn's disease

Technical Field

The invention relates to the field of biomedicine, in particular to application of intestine regulating decoction in preparation of a medicament for treating Crohn's disease.

Background

Crohn's disease is a chronic, recurrent inflammatory disease caused by multiple factors, and its onset is often related to genetic susceptibility, immune system damage, intestinal flora imbalance, environmental changes, large mental fluctuation and other factors. The clinical manifestations of crohn's disease are abdominal pain, diarrhea, abdominal mass, fistula formation and perianal lesions, which may be accompanied by bloody stool. The exact etiology and pathogenesis of the Crohn's disease are not clear, and the Crohn's disease has the characteristics of repeated attack, long course of disease and difficult recovery, is one of the common refractory diseases of the digestive system, has high cancer rate and is listed as a world refractory disease by WHO.

In the prior art, drugs for treating Crohn's disease mainly comprise 5-aminosalicylic acid, hormone, immunosuppressant, biological agents and the like, wherein glucocorticoid drugs and immunosuppressant drugs are the main treatment drugs for the active period of the current Crohn's disease. Although the medicament for treating the Crohn's disease can take effect quickly, the medicament has the defects of easy relapse, excessive adverse reaction and high tolerance rate.

Disclosure of Invention

In order to solve the problems, the invention provides application of intestine-regulating decoction in preparing a medicament for treating Crohn's disease. The technical scheme provided by the invention can effectively achieve the technical effect of treating the Crohn's disease, and has the advantages of few adverse reactions and radical treatment of the Crohn's disease.

In order to achieve the purpose, the invention provides the following technical scheme:

the invention provides application of intestine-regulating decoction in preparation of a medicament for treating Crohn's disease.

Preferably, the dosage form of the medicament for treating the Crohn's disease comprises decoction, honeyed pills, granules or oral liquid.

Preferably, the medicament for treating the Crohn's disease comprises a intestine regulating soup base material and auxiliary materials.

Preferably, the base material of the intestine regulating soup is prepared from raw materials for preparing the intestine regulating soup.

Preferably, when the dosage forms are decoction, honeyed pills, granules and oral liquid, the content of the intestine-regulating decoction raw material of the medicine for treating Crohn's disease is 0.2-5 g/g.

Preferably, when the dosage form is a pill, the auxiliary material is honey; when the dosage form is granules, the auxiliary materials are sucrose and dextrin; when the preparation is oral liquid, the auxiliary materials are arginine, citric acid, sodium tartrate and trehalose.

Preferably, the effective acting dosage of the medicament for treating the Crohn's disease is 2-5 g/kg/d.

The invention provides an application of intestine regulating soup in preparation of a medicament for treating Crohn's disease, wherein the intestine regulating soup comprises 15-40 parts of codonopsis pilosula, 5-25 parts of fried bighead atractylodes rhizome, 5-40 parts of ailanthus altissima root bark, 15-40 parts of coix seed, 10-40 parts of paniculate swallowwort root, 5-25 parts of myrobalan, 10-40 parts of red halloysite, 5-15 parts of pseudo-ginseng, 5-25 parts of raw pollen typhae, 5-25 parts of bletilla striata, 5-25 parts of sophora flower and 5-15 parts of liquorice. Radix Codonopsis and parched Atractylodis rhizoma have effects of invigorating qi and invigorating spleen; the cortex toonae sinensis, the semen coicis and the paniculate swallowwort root have the effects of clearing heat, eliminating dampness, detoxifying and reducing swelling; fructus Chebulae and Halloysitum rubrum for relieving diarrhea with astringents; notoginseng radix, pollen Typhae, rhizoma Bletillae, and flos Sophorae Immaturus with effects of promoting blood circulation, removing blood stasis, stopping bleeding, and promoting granulation; licorice root, radix Glycyrrhizae coordinates the effects of the other drugs in the recipe. The whole formula has the effects of invigorating spleen and replenishing qi, clearing heat and eliminating dampness, and promoting blood circulation and tissue regeneration. Can be used for treating Crohn's disease clinically.

The examples show that the intestine regulating decoction can obviously improve inflammatory lesions of colon of rats with the Crohn's disease induced by trinitrobenzene sulfonic acid (TNBS), and the rats taking the intestine regulating decoction are obviously improved in aspects of occult blood, hematochezia, physical quality reduction, DAI integral, pathological changes and the like. The intestine-clearing decoction preparation has the function of treating the Crohn disease and can be used for preparing the medicine for treating the Crohn disease.

Drawings

FIG. 1 shows the body weight statistics of rats in each group;

FIG. 2 shows the statistics of Disease activity index (Disease activity index DAI) of rats in each group;

FIG. 3 shows the pathological section results of colon mucosa of rats in each group;

FIG. 4 shows the results of H & E staining (100X) of colon tissues of rats in each group;

FIG. 5 shows the results of the levels of C-reactive protein in the serum of rats in each group;

FIG. 6 shows the results of the serum TNF-. alpha.levels in rats of each group.

Detailed Description

The invention provides application of intestine-regulating decoction in preparation of a medicament for treating Crohn's disease. Crohn's disease is a chronic nonspecific transmural inflammation that can affect any part of the gastrointestinal tract, and is clinically manifested by abdominal pain, persistent diarrhea, abdominal mass, fistula formation, perianal lesions, and sometimes bloody stool. Compared with other types of enteritis, the Crohn's disease has the characteristics of indefinite disease part and persistent diarrhea. Compared with other types of enteritis, the Crohn's disease has the characteristics of indefinite disease part and persistent diarrhea, the focus is not easy to master during the treatment period, which brings difficulty for determining diseases, and the Crohn's disease has inexhaustible disease condition, which brings great pressure to the body of a patient.

The dosage form of the medicament for treating the Crohn disease provided by the invention preferably comprises decoction, honeyed pills, granules or oral liquid; the medicine preferably comprises a bowel-regulating soup base material and auxiliary materials; in the invention, the intestine regulating soup base material is preferably prepared from raw materials for preparing intestine regulating soup; in the invention, the intestine rectifying soup is prepared from the following raw materials, preferably 15-40 parts of codonopsis pilosula, 5-25 parts of fried bighead atractylodes rhizome, 5-40 parts of ailanthus altissima bark, 15-40 parts of coix seed, 10-40 parts of cynanchum paniculatum, 5-25 parts of myrobalan, 10-40 parts of red halloysite, 5-15 parts of pseudo-ginseng, 5-25 parts of raw pollen typhae, 5-25 parts of bletilla striata, 5-25 parts of sophora flower and 5-15 parts of liquorice.

In the invention, when the dosage form of the medicament for treating the Crohn's disease is decoction, the decoction is directly prepared from the intestine-regulating decoction base material, and the preparation method is preferably as follows: decocting intestine-regulating decoction to obtain filtrate, i.e. decoction. The decoction preferably comprises soaking, first decoction and second decoction in sequence. The soaking time is preferably 20-40 min, and more preferably 30 min; the first decoction preferably comprises boiling with strong fire and decocting with slow fire; the time for the first decoction is preferably 30-40 min, and the mass ratio of the intestine regulating soup raw materials to water is preferably 1: 2-10; the second decoction method is the same as the first decoction method; the filtrate obtained by twice decoction is used as decoction. In the present invention, the red halloysite and raw pollen typhae in the raw materials are preferably pan-fried; the concentration of the decoction is preferably 0.4-1.2 g/mL, more preferably 0.8-1 g/mL, more preferably 1g/mL, and the dosage of the decoction is preferably 200-600 mL/d, more preferably 400 mL.

When the dosage form of the medicament for treating the Crohn's disease is honeyed pills, the auxiliary materials are preferably honey. The preparation method of the honeyed pill type medicament for treating the Crohn's disease is preferably as follows: crushing the raw materials of the intestine regulating soup to obtain raw material powder; refining the honey after impurity removal to obtain refined honey; processing the refined honey and the raw material powder according to the weight ratio of 1.2-1.4: 1 to prepare 0.5-10 g of honeyed pills. In the invention, the particle size of the raw material powder is preferably 80-100 meshes, and more preferably 100 meshes; the refining temperature is preferably 116-118 ℃, the water content of the refined honey is preferably 14-16%, and the specific gravity of the refined honey is preferably 1.36-1.38. The traditional Chinese medicine composition in the form of pills has lasting drug effect, is more suitable for the Crohn's disease with persistent diarrhea, and has more advantages of maintaining remission and preventing relapse of patients in a remission stage.

When the intestine-regulating soup base material is used for preparing granules, the auxiliary materials are preferably sucrose powder and dextrin. The preparation method of the medicine for treating the Crohn disease in the particle dosage form is preferably as follows: decocting intestine-regulating decoction to obtain filtrate, refining the filtrate to obtain fluid extract, mixing the fluid extract and adjuvants, granulating and drying to obtain granule. In the present invention, the decoction is preferably performed twice, and the time for each decoction is preferably 2 hours. The refining preferably comprises in sequence: concentrating the filtrate, extracting supernatant, and concentrating the supernatant to obtain fluid extract. In the concentration, the relative density of the filtrate is preferably concentrated to 1.25 to 1.30(80 ℃). The extraction supernatant is particularly preferably: adding 1500ml ethanol into the concentrated filtrate after standing and cooling, stirring uniformly, and standing for 24 hours to obtain a supernatant. In the invention, the supernatant is preferably concentrated to a relative density of 1.25-1.30 (80 ℃). In the present invention, the red halloysite and raw pollen typhae in the raw materials are preferably pan-fried. The drying temperature is preferably 65-75 ℃.

When the dosage form is decoction, honeyed pills, granules and oral liquid, the content of the intestine-regulating decoction raw material of the medicine for treating Crohn's disease is preferably 0.2-5 g/g, more preferably 0.2-1.3 g/g, and more preferably 1g/g, and the dosage of the honeyed pills or granules is preferably 10-30 g/d, and more preferably 20 g/d.

When the intestine regulating soup base stock is used for preparing the oral liquid, the preparation method is preferably as follows: preparing decoction according to the preparation scheme of the decoction; adding arginine, citric acid, sodium tartrate and natural trehalose into the decoction. In the invention, the solubilizer and the stabilizer are preferably arginine, and the stabilizer and the chelating agent are preferably citric acid and sodium tartrate which work together. The decoction is adopted, so that the drug effect is quickly absorbed, the drug effect can be quickly exerted in vivo, the drugs can be added or reduced conveniently according to the disease condition, and the curative effects of controlling inflammation and relieving symptoms of patients with acute Crohn's disease are relatively more advantageous.

In the invention, the effective dose of the medicament for treating the Crohn's disease is preferably 2-5 g/kg/d, and more preferably 3.5 g/kg/d. In rat treatment, the effective dose of the medicament for treating the Crohn's disease is preferably 11-44 g/kg/d, and more preferably 22 g/kg/d.

Experiments prove that the technical scheme of the application of the intestine-regulating decoction in preparing the medicament for treating the Crohn disease does not have adverse reaction and effectively treats the disease of a rat with the Crohn disease induced by trinitrobenzene sulfonic acid; the problems of indefinite disease parts of the Crohn's disease, persistent diarrhea and difficult cure are successfully solved, effective maintenance and relief can be achieved, the active period can be induced to relieve and improve symptoms, the life quality can be improved, and the pressure on the body of a patient caused by inexhaustible disease conditions of the Crohn's disease is relieved.

For further illustration of the present invention, the following detailed description of the application of the intestine-regulating decoction provided by the present invention in preparing drugs for treating Crohn's disease is provided in connection with the drawings and examples, but they should not be construed as antecedent for the scope of the present invention.

Example 1

30g of codonopsis pilosula, 15g of fried bighead atractylodes rhizome, 15g of myrobalan, 30g of red halloysite (bag decoction), 15g of sophora flower, 15g of raw cattail pollen (bag decoction), 15g of bletilla striata, 30g of ailanthus altissima root bark, 30g of coix seed, 10g of pseudo-ginseng slices, 30g of paniculate swallowwort root and 10g of liquorice slices.

Soaking the raw materials in 1225mL of distilled water for 30min, decocting with strong fire until boiling, decocting with slow fire for 30-40 min, and filtering to obtain filtrate; adding 700mL of water into the residue, decocting again, and filtering. Mixing the two filtrates, heating and stirring to mix well. The intestine regulating soup 84mL is transferred into a 10mL centrifuge tube, centrifuged at 12000rpm/min at 4 ℃ for 10min, and then the solution is concentrated to 0.55g/mL, 1.1g/mL and 2.2g/mL respectively by using a rotary evaporator.

Application example 1

SD male rats (6-8 weeks old) are selected, adaptively fed for 1 week and fasted for 48 hours. Randomly divided into 5 groups, i.e.: control group (Control), Model group (Model), intestine regulating soup low dose group (LCTL, 5.5g/kg), intestine regulating soup medium dose group (LCTM, 11g/kg), and intestine regulating soup high dose group (LCTH, 22 g/kg). After 2% pentobarbital sodium is injected into abdominal cavity according to the dose of 0.3mL/100g for anesthesia, normal saline is added into the control group by enema, TNBS/ethanol (90mg/kg) is added into the other groups by enema, the tail of the rat is lifted up and inverted for 1min, and the rat cage is put into the rat cage for normal feeding. The drug administration is started on the day of model building, distilled water is given to the control group and the model group, intestine regulating decoction with different concentrations is given to the other groups respectively, the stomach is infused according to 1mL/100g, the drug administration is carried out 1 time per day, the materials are obtained for 7 days continuously, and the materials are obtained on the 8 th day.

Application example 2

During the experiment of application example 1, the general conditions of the rats in each group, including mental status, activity, fecal characteristics and hematochezia, were observed and recorded daily, and changes in colonic lesions before and after treatment were analyzed and scored according to DAI scoring criteria. The percent change in rat body weight (Bodyweight) is shown in FIG. 1Table 1 shows the changes in DAI scores in rats as shown in fig. 2 and table 2. In FIGS. 1 and 2

n is 6, Control is a Control group; model is a Model group; LCD is intestine regulating decoction. Compared with Control group, # # # P<0.001; in contrast to the Model group,^*P<0.05；^**P<0.01；^***P<0.001。

TABLE 1 rat body weight (g)

TABLE 2 rat Disease Activity Index (DAI)

As can be seen from fig. 1 and table 1, the body weight of the rats in the model group was significantly reduced and the administration of the intestine regulating decoction had an improvement effect, particularly 22g/kg of intestine regulating decoction. The disease activity index is a comprehensive score combining the weight loss percentage, the stool consistency and the stool bleeding, and directly reflects the disease state of the rat.

As can be seen from fig. 2 and table 2, the TNBS/ethanol-induced CD rats had a significantly increased disease activity index starting at day 2, reaching a maximum at day 3, and then slowly decreased, compared to the control group. Compared with the model group, the disease activity index of each group of intestine-regulating decoction is reduced, which indicates that the intestine-regulating decoction is helpful for improving the disease state of the rat with the Crohn disease.

Application example 3

7 days after the experiment in application example 1, pathological sections were taken of colon tissues of the mice, and the results are shown in FIGS. 3 and 4.

As can be seen from FIGS. 3 and 4, compared with the control group, the rats in the model group have congestion, swelling and intestinal stenosis of the colon, and even the intestinal tube is wrapped by the mesenteric adipose tissue, and the adhesion of the colon tissue and the surrounding tissue occurs, most of the colon length changes insignificantly, but the colon length is obviously shortened in the serious case. Intestine regulating decoction has certain relieving effect on colon adhesion, but has no obvious effect on colon length change.

The colon is longitudinally cut open, as shown in figure 3, compared with the control group, the large amount of intestinal contents of the colon of the rat in the model group are adhered to the mucous membrane, the intestinal canal is thickened and is congested with blood; intestine regulating decoction has reduced adhesion of colon mucosa intestinal content, normal intestinal canal thickness, and less congestion.

The results of H & E staining of colon tissues are shown in FIG. 4, and the control group had intact colon tissue structure, well-arranged intestinal glands and no ulcer. The colon epithelium of the model group is exfoliated, and the surface mucous membrane has fissure ulcer and even erosion; the intestinal glands and the crypts are not regularly arranged, irregular in shape and even absent; a large amount of lymphocyte infiltration and granuloma appear in the lamina propria and submucosa; fibrosis and thickening of fat connective tissue occur. The intestine regulating decoction group has reduced lymphocyte infiltration of colon tissue, reduced granuloma, and recovery of crypt and intestinal gland.

Application example 4

After 7 days from the experiment in application example 1, the serum of the rat was analyzed for inflammatory factors, and the results are shown in fig. 5, table 3, and fig. 6. FIG. 5 shows the results of C-reactive protein (CRP) level, which is a non-specific inflammatory marker, and FIG. 6 shows the results of TNF-. alpha.level in serum. In FIGS. 5 and 6

n is 6, compared to the Control group,^##P<0.01，^###P<0.001; in contrast to the Model group,^**P<0.01；^***P<0.001。

TABLE 3 rat serum cytokines

As shown in fig. 5 and table 3, the serum CRP level of the model rat was significantly increased and the intestine-regulating soup was decreased compared to the control group.

As can be seen from FIG. 6 and Table 3, the serum TNF-. alpha.levels in CD rats were significantly increased as compared with the control group, and the TNF-. alpha.levels were restored to normal after administration of intestine-regulating decoction. Therefore, the intestine regulating decoction has an obvious relieving effect on the inflammation of the CD rat.

The above examples and application examples show that the intestine-regulating decoction can obviously improve symptoms such as occult blood, hematochezia, physical quality reduction, DAI integral, pathological changes and the like caused by the Crohn's disease, and can effectively treat the Crohn's disease. Particularly, the specific dosage form medicament provided by the invention can obviously improve trinitrobenzene sulfonic acid (TNBS) -induced colon inflammatory lesions of mice with Crohn's disease, and rats taking intestine regulating decoction groups are obviously improved in aspects of occult blood, hematochezia, physical quality reduction, DAI integral, pathological changes and the like; can treat Crohn's disease with completely different pathogenesis and disease part from traditional ulcerative colitis.

Although the present invention has been described with reference to the preferred embodiments, it should be understood that various changes and modifications can be made therein by those skilled in the art without departing from the spirit and scope of the invention as defined in the appended claims.

Claims

1. Application of intestine-regulating decoction in preparing medicine for treating Crohn's disease is provided.

2. The use according to claim 1, wherein the medicament for treating crohn's disease is in the form of decoction, honeyed pill, granule or oral liquid.

3. The use of claim 1, wherein the medicament for treating crohn's disease comprises a intestine-regulating soup base and an adjuvant.

4. The use of claim 3, wherein the base material of the soup for regulating intestines is prepared from raw materials for preparing the soup for regulating intestines.

5. The use of claim 1, wherein when the dosage form is decoction, honeyed pill, granule or oral liquid, the content of the intestine-regulating decoction for treating Crohn's disease is 0.2-5 g/g.

6. The use of claim 3, wherein when the dosage form is a pill, the excipient is honey; when the dosage form is granules, the auxiliary materials are sucrose and dextrin; when the preparation is oral liquid, the auxiliary materials are arginine, citric acid, sodium tartrate and trehalose.

7. The use according to any one of claims 1 to 6, wherein the effective amount of the medicament for the treatment of Crohn's disease is 2 to 5 g/kg/d.