CN108815384B

CN108815384B - Composition for treating ulcerative colitis

Info

Publication number: CN108815384B
Application number: CN201811068290.8A
Authority: CN
Inventors: 宫彤林; 沈洪; 赵守田; 欧阳汉霖; 李晓亮
Original assignee: Anhui Joyfar Pharmaceutical Co ltd
Current assignee: Anhui Joyfar Pharmaceutical Co ltd
Priority date: 2018-09-13
Filing date: 2018-09-13
Publication date: 2024-03-19
Anticipated expiration: 2038-09-13
Also published as: CN108815384A

Abstract

The present invention provides compositions for treating ulcerative colitis comprising an aminosalicylic acid-based drug and an enteric tiger-ground formulation. Clinical experiments prove that the two drugs are combined to be used, do not respectively act, and also act synergistically. The curative effect of the combined medicine is better than that of each single medicine, and the combined medicine can improve the healing condition of the diseases.

Description

Composition for treating ulcerative colitis

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a composition for treating ulcerative colitis.

Background

Chronic nonspecific ulcerative colitis (abbreviated as ulcerative colitis (ulcerative colitis, UC)) is a chronic nonspecific inflammation mainly affecting the mucous membrane and submucosa of rectum, colon, and is mainly clinically manifested by abdominal pain, diarrhea, mucous bloody stool, tenesmus, and the duration of disease can be as long as decades or even decades, and the possibility of canceration is also present. The disease belongs to the categories of 'intestinal rarely', 'diarrhea', 'dysentery' in traditional Chinese medicine. The traditional Chinese medicine composition has the advantages of complex etiology, long course of disease and difficult cure, the current chemical medicine has limited curative effect, the commonly used medicine is aminosalicylic acid, hormone or immunosuppressant is sometimes needed to be used, the side effect of the medicine is large, the medicine taking compliance of patients is poor, the illness state is prolonged, and the life quality of the patients is seriously influenced. In recent years, the incidence rate and the incidence number of ulcerative colitis are obviously improved due to the combination of various reasons, but the traditional Chinese medicine for treating ulcerative colitis has limited variety and inaccurate curative effect, and partial patients need to be treated by medicines such as hormone, immunosuppressant and the like, and have long administration period, high treatment cost and poor patient treatment compliance, so that the clinical prognosis of the ulcerative colitis patients is seriously influenced.

UC can occur at any age, and the young are more common, so that the sex difference of men and women is not great, and the peak age of onset is 20-49 years. Clinically, diarrhea with continuous or repeated attacks, mucopurulent bloody stool with abdominal pain and tenesmus are the main manifestations, and the course of the disease is more than 4-6 weeks. Can be accompanied by external manifestations of skin mucosa, joints, eyes, liver and gall. Wherein the skin mucosa exhibits such as canker sore, erythema nodosum and pyoderma gangrenosum; joint damage such as peripheral arthritis, spinal arthritis, etc.; ocular lesions such as iritis, scleritis, uveitis, etc.; liver and gall diseases such as fatty liver, primary sclerosing cholangitis, cholelithiasis, etc. Mucopurulent blood is the most common symptom of UC.

The prevalence rate of ulcerative colitis (ulcerative colitis, UC) in China is estimated to be 11.6/10 ten thousand, epidemiological data of large sample populations are not available at present, UC patients account for 1.37% of the total population of colonoscopy according to the statistics of Nanchang, and UC patients account for 3.27% of the total population of hospitalization in the digestive tract in 2014 of Ningxia autonomous region statistics. The traditional Chinese medicine has better curative effect for treating the disease.

According to the clinical manifestation of UC mucus purulent blood stool and the characteristics of repeated attacks and persistent difficult recovery, the Chinese medicine belongs to the category of 'chronic dysentery'. The pathogenic factors, such as deficiency of spleen-qi, are the basis of the pathogenesis, and feeling of exogenous evil, improper diet (clean) and emotional disorder are the main causes of the pathogenesis. The disease is in large intestine and is related to dysfunction of spleen, liver, kidney and lung. Its pathogenesis is the principal deficiency with the secondary excess. The pathological factors are mainly as follows: (1) damp evil (heat); (2) stagnant heat; (3) toxic heat; (4) turbid phlegm; (5) stagnation of qi; (6) blood stasis, etc. Pathological characteristics are represented: the active period is mainly due to excessive syndrome, the pathogenesis is that damp-heat is accumulated in the intestines, qi and blood are not regulated, and the serious condition is mainly due to heat toxin and stagnant heat, so that the factors of turbid phlegm and blood stasis should be considered for the repeated difficult recovery. In the remission stage, deficiency and excess are mixed, and the pathogenesis is spleen deficiency and damp loving and transportation and transformation failing to strengthen. Some patients may have clinical symptoms of liver depression, kidney deficiency, lung deficiency, blood deficiency, yin deficiency and yang deficiency. Clinically, the main pathogenesis of purulent stool is the accumulation of damp-heat in the intestines and the injury of blood collaterals of lipid membranes. Diarrhea excess syndrome refers to damp-heat accumulating in the intestines and dysfunction of large intestine conduction; the deficiency syndrome refers to spleen deficiency with excessive dampness, failing to transport and transform. The pattern of hematochezia is damp-heat accumulated in the intestines, damaging the collaterals of the intestines and causing collateral damage and blood overflow; the deficiency syndrome is the impairment of yin by damp-heat, internal flaming of deficiency fire, burning of the intestinal collaterals or spleen qi deficiency, failing to control blood and overflowing the pulse. The symptoms of abdominal pain and excessive syndrome are that damp-heat is accumulated in the intestines, qi and blood are not regulated, the intestinal collaterals are blocked, and pain is caused by obstruction; the deficiency syndrome refers to the hyperactivity of wood due to the deficiency of earth, imbalance of liver and spleen, disturbance of the interior due to the deficiency of wind, and disharmony of intestinal collaterals. The key of the pathogenesis of refractory UC is mainly spleen-kidney deficiency, retention of turbid dampness, concurrent diseases of qi and blood, cold and heat, and deficiency-excess.

Western medicine treatment: the therapeutic goal of UC is to induce and maintain clinical relief, promote mucosal healing, prevent complications, and improve patient quality of life; treatment is formulated according to the classification, stage and segment. The active stage mild UC is prepared from an aminosalicylic acid preparation (SASP or 5-ASA); the moderate UC uses the poor effect of aminosalicylic acid preparation, changes the oral corticosteroid hormone, the hormone resistance or the occurrence of dependence on available immunosuppressant, and the ineffectiveness is that the anti-TNF-alpha can be recommended; infusion for severe UC hospitalization and intravenous hormone treatment. The remission period should be maintained for at least 1 year or long, and hormone cannot be used as a medicine for maintenance treatment. The aminosalicylic acid preparation, azathioprine medicine, biological preparation medicine and intestinal probiotics can be used for maintenance treatment.

The traditional Chinese medicine treatment comprises the following steps: dialectical treatment is that the syndrome of damp-heat in large intestine should clear heat and remove dampness, regulate qi and blood; the syndrome of excessive heat toxin needs to clear heat and remove dampness, cool blood and detoxify; the pattern of spleen deficiency and dampness accumulation requires replenishing qi to invigorate the spleen, resolving dampness and harmonizing the middle warmer; the syndrome of cold and heat complicated with deficiency is required to warm the middle energizer and tonify deficiency, clear heat and resolve dampness; liver depression and spleen deficiency syndrome requires soothing liver and regulating qi, strengthening spleen and eliminating dampness; spleen and kidney yang deficiency syndrome requires strengthening spleen and tonifying kidney, warming yang and resolving dampness.

The tiger-ground enteric capsule is prepared from seven 525g of cinnabar, 525g of giant knotweed, 1050g of oldenlandia diffusa, 1050g of herba patriniae, 1050g of limonium bicolor, 1050g of garden burnet (charcoal), 420g of bletilla striata and 350g of liquorice by decocting, concentrating, and making into 1000 capsules, wherein each capsule is equivalent to 6.02g of crude drug. The application of the traditional Chinese medicine composition is patented. The product has effects of clearing heat, promoting diuresis, and cooling blood. Approval by the national drug administration (national drug standard is Z20020035) was obtained in 2002, and the approval was used for treating nonspecific ulcerative colitis, chronic bacillary dysentery with damp-heat accumulation, abdominal pain, diarrhea, purulent blood, tenesmus; the dosage is 4 granules for oral administration, 3 times a day.

The mesalazine slow release granule is granule, and is antiulcer. It acts on intestinal inflammatory mucosa to inhibit prostaglandin synthesis and formation of inflammatory mediator leukotriene, thereby having remarkable anti-inflammatory effect on intestinal wall, and has good effect on inflamed intestinal wall connective tissue. Can be used for treating ulcerative colitis and Crohn's disease (segmental enteritis) also known as regional enteritis.

Mesalamine Qin Koufu is converted to aspirin after colonic release, and part of the salicylic acid acetate is decomposed by bacteria in the intestinal tract and is discharged from the feces. The other part is absorbed by intestinal mucosa, about 40% is combined with plasma protein, and is metabolized in vivo to generate acetyl substance, about 80% of the acetyl substance is combined with plasma protein, and is discharged from urine, has half-life of 5-10 h, and rarely penetrates placenta and enters milk. The mesalazine sustained release tablet consists of mesalazine microparticles (with the diameter of 0.7-1 mm) coated by ethyl cellulose. The medicine starts to disintegrate in the stomach, the microparticles enter the small intestine through the pylorus, gastric emptying is not needed, the medicine is not released in a large amount, the peak concentration of the medicine does not exist, the residual time in the stomach is short, and mesalazine can be detected in blood within 20 minutes after taking the medicine. Mesalazine is released continuously and uniformly in the intestinal tract (from the duodenum to the colon) at a constant rate. The decrease in intestinal transit time has little effect on the release of mesalazine and absorption is relatively unchanged, unaffected by intestinal flora. Oral mesalazine is released about 50% in the small intestine and 50% in the large intestine. The sustained release tablet can also prevent mesalamine from being absorbed prematurely in the proximal small intestine, thereby ensuring that the mesalamine has higher bioavailability in the distal small intestine. Because mesalazine is uniformly released in the whole intestinal tract, the chronic inflammatory diseases of the intestinal tract can be safely and effectively treated. The mesalazine suppository consists of slow release microcapsules, can directly reach an action part, is slowly released, has high local concentration, is matched with a physiological structure, and can effectively treat ulcerative colitis.

Disclosure of Invention

In order to solve the above problems, the present invention provides a composition for treating ulcerative colitis, which comprises an aminosalicylic acid-based drug and an enteric preparation of tiger land.

In one embodiment, the aminosalicylic acid-based drug is one or more of mesalamine, sulfasalazine, 5-aminosalicylic acid, olsalazine He Baliu nitrogen.

In one embodiment, the aminosalicylic acid drug is mesalamine.

In one embodiment, the tiger enteric formulation is a tiger enteric capsule formulation, a pill, a tablet, a paste or a suppository.

In the invention, western medicines for treating ulcerative colitis are used in combination, and clinical experiments prove that the two medicines are used in combination, do not respectively play roles, and play a synergistic effect. The curative effect of the combined medicine is better than that of each single medicine, and the combined medicine can improve the healing condition of the diseases.

Detailed Description

In order that those skilled in the art will better understand the technical solutions of the present application, the present invention will be further described with reference to the following examples, and it is apparent that the described examples are only some of the examples of the present application, not all the examples. All other embodiments, which can be made by one of ordinary skill in the art based on the embodiments herein without making any inventive effort, shall fall within the scope of the present application. The invention is further described below with reference to examples.

Purpose of experiment

The mesalazine enteric-coated tablet is used as a control to objectively evaluate the clinical application effectiveness and safety of the tiger-land enteric-coated capsule and the combined use of the tiger-land enteric-coated capsule and the mesalazine enteric-coated tablet for treating the ulcerative colitis (damp-heat accumulation syndrome) in the active period.

Design of experiment group

Test group: tiger-shaped enteric capsule

Positive control group: mesalazine enteric-coated tablet.

Combination group: tiger-ground enteric capsule and mesalazine enteric tablet

The selection basis is as follows: the positive control medicine adopts the principle of comparability, admittance and effectiveness and preference of the same kind, and selects an amino salicylic acid preparation-mesalazine enteric-coated tablet which is recommended by the current guideline for treating ulcerative colitis; meanwhile, a combined medicine group is additionally arranged for exploring and evaluating the characteristics of the combined treatment of Chinese and western medicines.

Third treatment scheme

1. Test drug name and specification

(1) Tiger land enteric coated capsule (produced by Anhui Jiufang pharmaceutical Co., ltd., 0.4 g/grain, approval mark: national drug standard Z20020035);

(2) Mesalazine enteric coated tablet (produced by Heilongjiang Tianma pharmaceutical industry Co., ltd., 0.25 g/tablet, 3 g/day, approval mark: national drug standard character H20103359);

(3) Both the tiger enteric capsule simulant and the mesalazine enteric tablet simulant are provided by Anhui Jiufang pharmaceutical Co.

2. Medicine taking method

(1) Test group: the medicine is taken 1h before breakfast, middleman and supper respectively: tiger land enteric capsule, 4 granules at a time, 3 times daily; the mesalazine enteric-coated tablet mimics are 4 tablets at a time and 3 times a day.

(2) Positive control group: the medicine is taken 1h before breakfast, middleman and supper respectively: the tiger enteric capsule simulant is prepared by 4 granules at a time and 3 times a day; mesalazine enteric-coated tablet, 4 tablets at a time, 3 times a day.

(3) Combination group: the medicine is taken 1h before breakfast, middleman and supper respectively: the tiger field enteric capsule has 4 granules at a time and 3 times a day; the mesalazine enteric-coated tablet is orally taken, 4 tablets at a time and 3 times a day.

Fourth, evaluation criteria

(1) Clinically effective

The total Mayo score decreased from baseline levels by no less than 30% or no less than 3 points, while the absolute score associated with a hematocrit sub-score decrease of no less than 1 point or a hematocrit sub-score was 0 or 1 point.

(2) Clinical remission

The total Mayo score is less than or equal to 2 points and no single term score is greater than 1 point.

(3) Endoscope response

Mayo score the endoscopic sub-score decreased by at least 1 score relative to baseline.

(4) Mucous membrane healing

The absolute score of the Mayo score endoscope sub-score was either 0 or 1.

Fifth, statistics and analysis of curative effect data

Table 1 analysis of the Main efficacy index Mayo score clinical efficacy of three groups of patients (enteroscopy patients after treatment) (FAS)

Table 2 analysis of the Main efficacy index Mayo score clinical efficacy of three groups of patients (enteroscopy patients after treatment) (PPS)

TABLE 3 analysis of the Main efficacy index Mayo scoring clinical efficacy for three groups of patients (all groups did not consider enteroscopy) (FAS)

Table 4 analysis of the Main efficacy index Mayo scoring clinical efficacy of three groups of patients (all groups did not consider enteroscopy) (PPS)

Efficacy analysis

The crowd is divided into two layers according to whether the crowd performs enteroscopy or not: the group of people who had undergone enteroscopy after treatment and all groups (the Mayo score was calculated without enteroscopy).

1. Crowd who have undergone enteroscopy after treatment

After treatment, 51 cases were tested, 56 cases were tested for positive drug control, and 58 cases were tested for combined drug. At the base line, the average test group FAS (PPS) is divided into 6.12+/-1.73 (6.08+/-1.72), the positive drug control group is divided into 5.75+/-1.68 (5.80+/-1.67), and the combined drug group is divided into 6.05+/-1.69 (6.09+/-1.68).

After 6 weeks of administration, the Mayo score was statistically significant (P < 0.05) for the differences between the three groups in FAS and PPS, and the differences between the two-by-two comparison test groups and the combination, positive drug control group and the combination were statistically significant (P < 0.0167). The FAS (PPS) average test group was 3.71+ -2.10 (3.70+ -2.12) min, the positive drug control group was 3.43+ -2.11 (3.47+ -2.17) min, and the combination group was 2.45+ -2.03 (2.49+ -2.02) min.

The Mayo score differences (baseline-6 weeks post-dose) were statistically significant for the differences between three groups in FAS and PPS (P < 0.05), and for the differences between the pairwise comparison test group and the combination, positive control group and the combination (P < 0.0167). The mean value FAS (PPS) test group of the three groups is 2.41+/-2.35 (2.38+/-2.36) for the positive medicine control group is 2.32+/-2.17 (2.33+/-2.22) for the combined medicine group is 3.60+/-2.07 (3.60+/-2.09) for the combined medicine group. Paired non-zero test within the three groups was statistically significant (P < 0.05).

After 6 weeks of administration, the clinical effectiveness of the Mayo score was statistically significant for the differences between the three groups in FAS and PPS (P < 0.05), and for the comparison between the groups in the pairwise comparison test group and the combination, positive control group and the combination (P < 0.0167). Three groups were tested for effective FAS (PPS) 58.82% (58%), positive control 60.71% (58.82%), and combination 82.76% (82.46%).

After 6 weeks of administration, the Mayo scoring clinical remission rate was statistically significant (P < 0.05) for the differences between the three groups in FAS and PPS, where the group comparison positive drug control group and the combination drug group were statistically significant (P < 0.0167). The three groups had 31.37% (32.00%), the positive control group 30.36% (29.41%) and the combination group 53.45% (52.63%) for the remission rate FAS (PPS) test group.

2. All people (calculating Mayo score without enteroscopy)

After 6 weeks of administration, the partial Mayo score had a statistical significance for the comparison differences between the three groups in FAS (P < 0.05), no statistical significance for the comparison differences between the groups (P > 0.05), and no statistical significance for the comparison differences between the three groups in PPS (P > 0.05).

The difference in partial Mayo scores (baseline-6 weeks post-dose) was statistically significant for comparison differences between three groups in FAS and PPS (P < 0.05), for comparison differences between the positive drug control group and the combination group pairwise (P < 0.0167), for pairing non-zero test within three groups (P < 0.05).

After 6 weeks of administration, the clinical efficacy of the partial Mayo score was not statistically significant (P > 0.05) for the comparison differences between the three groups in FAS and PPS.

After 6 weeks of administration, the partial Mayo score clinical remission rate was statistically significant (P > 0.05) for the comparison differences between the three groups in FAS and PPS.

Sixth test results

Because of poor compliance of the two enteroscopies in a short time, 51 cases of the final result of the enteroscopy before and after treatment are included in the test group, 56 cases of the positive drug control group and 58 cases of the combined drug group. The main curative effect index Mayo score shows that the curative effect of the modified value tiger-ground enteric capsule is equivalent to that of mesalazine enteric tablet after 6 weeks of administration, and the combined administration curative effect is better than that of two groups of independent administration. The partial Mayo score excluding enteroscopy showed that the change after 6 weeks of administration was only different for mesalazine enteric-coated tablet and combination, and not for tiger-land enteric-coated capsule. Because the two types of analysis sample sizes are different, different results cannot be further analyzed, but the final results show that the healing condition of the diseases can be improved by the combined use of the two types of analysis sample sizes.

It is to be understood that this invention is not limited to the particular methodology, protocols, and materials described, as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims.

Those skilled in the art will also recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are also encompassed by the appended claims.

Claims

1. The application of mesalazine enteric-coated tablet and tiger-land enteric-coated capsule in combination in preparing medicines for treating ulcerative colitis;

the tiger field enteric capsule is produced by Anhui Jiufang pharmaceutical Co Ltd, 0.4 g/granule, approval character Z20020035, which is composed of seven 525g cinnabar, 525g giant knotweed, 1050g oldenlandia diffusa, 1050g patrinia, 1050g bicolor limonium, 1050g garden burnet root charcoal, 420g bletilla striata and 350g liquorice;

the mesalazine enteric-coated tablet is produced by Heilongjiang Tianma pharmaceutical industry Co., ltd, 0.25 g/tablet, 3 g/day, and approved culture mark is national medicine standard H20103359;

the mesalamine enteric tablet and the tiger-land enteric capsule are taken in the following modes: the medicine is taken 1h before breakfast, middleman and supper respectively: tiger land enteric capsule, 4 granules at a time, 3 times daily; mesalazine enteric-coated tablet, 4 tablets at a time, 3 times a day, is administered for six weeks.