CN112438981A - Application of madecassic acid in preparation of medicine for preventing or treating ulcerative colitis - Google Patents

Application of madecassic acid in preparation of medicine for preventing or treating ulcerative colitis Download PDF

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CN112438981A
CN112438981A CN202010887181.XA CN202010887181A CN112438981A CN 112438981 A CN112438981 A CN 112438981A CN 202010887181 A CN202010887181 A CN 202010887181A CN 112438981 A CN112438981 A CN 112438981A
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madecassic acid
ulcerative colitis
acid
preparation
madecassic
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张贵民
齐长鹏
宁停波
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Lunan Pharmaceutical Group Corp
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

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Abstract

The invention relates to application of madecassic acid, or a salt or a complex thereof in preparation of a medicine for preventing or treating ulcerative colitis, and belongs to the field of medicines. Animal experiments show that the traditional Chinese medicine composition has a remarkable prevention and treatment effect on ulcerative colitis. The madecassic acid has definite curative effect on ulcerative colitis, low side effect and wide medical application prospect.

Description

Application of madecassic acid in preparation of medicine for preventing or treating ulcerative colitis
Technical Field
The invention belongs to the field of medicines, relates to a medical application of madecassic acid, and particularly relates to a medical application of madecassic acid in preparation of a medicine for preventing or treating ulcerative colitis.
Background
Centella asiatica (L.) Urban is a plant of centella asiatica of Umbelliferae. Centella has a long history of application in the traditional medicine field of many countries and regions, and the traditional Chinese medicine of China has two thousand years of history of internal and external application of centella, and is originally collected in one book of Shen nong Ben Cao Jing. The chemical components of centella asiatica mainly comprise triterpenes, flavonoids, polyacetylenes, volatile oils and the like. Triterpenes mainly include triterpenoid saponins such as asiaticoside and madecassoside, and triterpenoid acids such as asiatic acid and madecassic acid. The chemical structural formula of madecassic acid is as follows:
Figure BDA0002655916310000011
recent studies have shown that asiatic acid and madecassic acid have certain effects in resisting oxidation and cancer. Chinese patent CN201110040181.7 discloses that madecassic acid has obvious inhibitory effect on mammary gland hyperplasia of experimental rats. Chinese patent CN200910067429.1 discloses the use of asiatic acid and madecassic acid in the preparation of drugs for alpha-glucosidase inhibitors.
The content of aglycone such as madecassic acid in centella asiatica is much lower than that of madecassic acid glycoside, the content of saponin in centella asiatica is generally 1.8-5%, and the content ratio of sapogenin to saponin is generally 1: 2.5. chinese patent CN201610728601.3 discloses a method for preparing madecassic acid by hydrolyzing madecassoside, which can rapidly break glycosidic bonds at normal temperature and pressure, and has mild hydrolysis process, complete hydrolysis and no generation of configuration change of madecassic acid.
Ulcerative Colitis (UC), also known as chronic nonspecific ulcerative colitis, is a disease mainly caused by superficial and nonspecific inflammatory diseases of the rectum and colon with damage to multiple organs outside the intestine. The first is diffuse inflammatory changes in the superficial mucosa. The subsequent congestion, edema, hypertrophy and brittleness increase, small ulcer is generated, and then large ulcer is developed, and in the later stage, the colon tissue hyperplasia causes thickening and narrowing of the intestinal wall and shortening of the intestinal canal. The disease course is long, the health and the life quality of patients are seriously influenced, and the probability of colorectal cancer is increased along with the prolongation of the disease course, so the disease course is listed as one of the modern refractory diseases by the world health organization. The disease is less common in our country than Europe and America, and the course of the disease is generally mild, but in recent years, the prevalence rate is gradually increased, and severe cases are often reported.
The scheme for treating ulcerative colitis at home and abroad is basically consistent, and the sulfasalazine salicylic acid preparation, prednisone or dexamethasone and other hormone preparations, an immunosuppressant azathioprine and the like are mainly used for clinical treatment, but the curative effect is poor and the great adverse reaction is caused. Therefore, people pay attention to research and develop the medicine for treating the ulcerative colitis for a long time, and the medicine has very important significance for relieving the pain of patients and improving the life quality of the patients.
To date, no studies have been made on the biological activity or the application of madecassic acid against ulcerative colitis.
Disclosure of Invention
The invention provides a novel medicine for preventing or treating ulcerative colitis, which takes madecassic acid as a medicine active ingredient. The invention discloses madecassic acid which is a traditional Chinese medicine monomer prepared from traditional Chinese medicine centella asiatica, and relates to a new medical application of madecassic acid, namely an application of madecassic acid, or a salt or a complex thereof in preparing a medicine for preventing or treating ulcerative colitis. Specifically, the madecassic acid salt is a salt formed by madecassic acid and an organic base, and the madecassic acid complex is a complex formed by madecassic acid cyclodextrin and a rare earth metal.
In the medical application, the madecassic acid and pharmaceutically acceptable auxiliary materials can be prepared into a proper pharmaceutical dosage form for oral administration or injection administration, and the applicable object can be a human or other constant-temperature animals. When the subject to be applied is a human, the amount of madecassic acid used is 0.001 mg/kg-d to 50 mg/kg-d, preferably 0.01 mg/kg-d to 10 mg/kg-d, more preferably 0.5 mg/kg-d to 1 mg/kg-d, still more preferably 0.5 mg/kg-d or 1 mg/kg-d. The time and frequency of administration of the medicament for the prevention or treatment of ulcerative colitis according to the present invention are determined according to the specific diagnosis of the disease and are within the skill of those skilled in the art. For example, it will be apparent to those skilled in the art that a therapeutic regimen for preventing or treating ulcerative colitis in a rat or mouse can be applied to a human using a drug whose effective dose to the human can be converted to an effective dose of the drug to the rat or mouse.
In the medical application, the madecassic acid can be prepared into a proper pharmaceutical preparation according to the condition of animals and the application part so as to be convenient for administration, for example, the madecassic acid can be developed into an oral preparation, a sublingual buccal preparation or an injection preparation so as to be convenient for patients to use, wherein the oral preparation can be a tablet, a capsule or a microemulsion preparation, and is preferably a tablet; the sublingual buccal preparation is a pharmaceutical preparation containing madecassic acid and suitable for sublingual administration, and is preferably a sublingual tablet thereof; the injection preparation can be injection, injection microemulsion and the like, and is preferably injection. When madecassic acid is prepared into injection, the pharmaceutically acceptable carrier can be water for injection, sodium chloride, sodium citrate, citric acid, glycerol, ethanol, propylene glycol, etc. The above-mentioned madecassic acid injection can also be added with appropriate additives according to the nature of the medicine, such as osmotic pressure regulator, pH regulator, solubilizer, bacteriostatic agent, emulsifier, suspending agent, etc., wherein the solubilizer is any one or two of polyethylene glycol 400 and tween-80.
The preparation method of the pharmaceutical preparation can be prepared by adopting the conventional preparation method for preparing the dosage form by the technical personnel in the field. In the pharmaceutical preparation, each preparation unit contains 0.001 mg-50 mg of madecassic acid.
Compared with the prior art, the invention has the advantages that:
1. the madecassic acid has a remarkable effect of preventing or treating ulcerative colitis. The embodiment of the invention shows that the madecassic acid has obvious therapeutic action on rats with ulcerative colitis, improves the general conditions of the rats, reduces the decline of physical quality, improves the stool property, increases the activity, reduces the DAI score, increases the colon length and reduces the gross score, and the effect of the madecassic acid on improving the indexes is obviously better than that of madecassic acid glycoside.
2. The madecassic acid is a natural traditional Chinese medicine monomer prepared from traditional Chinese medicine centella, has low toxic and side effects on human bodies, can remarkably improve the medication safety and medication compliance of patients, and further greatly improves the treatment effect and life quality of patients with ulcerative colitis.
Detailed Description
The present invention is further illustrated below by specific examples in order to provide those skilled in the art with a full understanding of the present invention, but it should be understood by those skilled in the art that the examples of the present invention are not to be construed as limiting the present invention in any way. Tests prove that the madecassic acid salt and the madecassic acid complex can achieve similar technical effects.
Example Effect of Hydroxyasiatic acid on the therapeutic Effect of rats with ulcerative colitis
1. Animal grouping and administration
52 SPF SD rats with half male and half female and 150-170 g body weight.
A rat ulcerative colitis model (J) is established by a compound method according to Jianghangchuang and the like (Jianghangchuang, rightful Zhengzhen, Wangdong and the like)]The Qinghai medical college of academic, 1999,20(4):1-3) method to establish Ulcerative Colitis (UC) model, rats were adaptively fed for 1 week, fasted for 24h, and injected with 3% sodium pentobarbital (10 mL. kg.) intraperitoneally-1) Anaesthetizing by inserting polypropylene tube into the upper part of anus for about 8cm, and injecting 0.04 mmol.L-10.25mL of DNCB ethanol (50%) solution is continuously added for 2 days, 2mL of 8% acetic acid is injected on the 3 rd day, and the mixture is washed by 5mL of physiological saline to complete the molding of the UC.
Successfully modelled rats were randomly divided into 5 groups, namely a model control group, a normal control group, a madecassic acid low-dose group, a madecassic acid high-dose group and a madecassic acid glycoside group. The model controls 12, and the remaining groups each contain 10.
The following drugs were administered to each group:
normal control group: equal volume of sodium carboxymethylcellulose for intragastric administration
Model control group: equal volume of sodium carboxymethylcellulose for intragastric administration
Madecassic acid low dose group: 3mg/kg of madecassic acid, for intragastric administration
High dose group of madecassic acid: 6mg/kg madecassic acid, for intragastric administration
Madecassoside group: 6mg/kg of madecassoside for intragastric administration
Madecassic acid and madecassoside are suspended in 0.5% sodium carboxymethylcellulose, and are administered continuously, and equal volume of 0.5% sodium carboxymethylcellulose is administered to normal group and model group 2 times per day for 7 days.
2. Experimental methods and data processing
2.1 general case and DAI scores
Before the rats are sacrificed, the general conditions of mental state, activity, hair color, luster, diarrhea, feces, body quality and the like are observed; disease Activity Index (DAI) was scored with reference to table 1, and the formula was calculated: DAI ═ 3 (body mass loss score + stool trait score + hematochezia score).
TABLE 1 DAI scoring Table
Figure BDA0002655916310000041
2.2 Colon Length and gross morphology scores
The rats were sacrificed and the entire colon from 1cm from the rectum to 1cm from the cecum of the rats was removed and the length was measured. The intestinal lumen was cut along the longitudinal axis of the mesentery, the intestinal contents were flushed out with ice saline, spread flat on filter paper, and the colon tissue was visually observed for changes and gross morphology scoring was performed with reference to the following criteria. Grading standard: mucosa is not damaged, 0 point; congestion, edema, moderate erosion of mucous membrane, single ulcer, 1 point; congestion, edema and no ulcer of mucous membrane, 2 points; congestion, edema, mild erosion of mucous membrane, no ulcer, 3 points; congestion, edema, high erosion of mucous membrane, many ulcers, 4 points; mucous membrane congestion, edema, severe erosion, ulcer >1cm, score 5.
2.3 data statistics and analysis
Data to
Figure BDA0002655916310000042
Shown, analysis of variance was performed using SPSS17.0 software.
3. Results and discussion
3.1 Effect of Hydroxyasiatic acid on the general behavior of UC rats and the DAI score
After the treatment period is over, compared with the model group, the normal group rats have good general conditions, sensitive response, lively and vivid action, glossy hair and normal excrement conditions. The rat in the model group has reduced activity, dark and gloomy hair, feces are mucus stool, occult blood and even stool blood, and the physique is reduced. The high-dose group of madecassic acid and the low-dose group of madecassic acid are generally better than the model group, the decrease of the physical quality is not obvious, the stool property is improved, the activity is increased, and the DAI score is obviously reduced (P is less than 0.01) compared with the model group.
Compared with the madecassoside group, the madecassoside high-dose group and the madecassoside low-dose group have significant differences in body quality, stool characteristics, occult blood condition and activity index (P is less than 0.01).
The results of the DAI scores for the rats in each group are shown in table 2.
TABLE 2 Effect of Hydroxyasiatic acid on the DAI score of rats with ulcerative colitis
Figure BDA0002655916310000051
Compared with the normal control group, the composition has the advantages that,￥P<0.05，￥￥P<0.01；
compared with the model control group,#P<0.05，##P<0.01；
compared with the madecassoside group,&P<0.05，&&P<0.01。
3.2 Effect of Hydroxyasiatic acid on Colon Length and gross morphology scores in UC rats
Compared with the normal group, the colon mucosa of the model group is obvious in congestion and edema, part of the colon is adhered to surrounding tissues, the length of the colon is obviously shortened, and the gross score is obviously higher than that of the normal group (P < 0.01); the lesion of the colon mucous membrane of the high-dose madecassic acid group and the low-dose madecassic acid group is obviously improved, the colon is longer, and the general score is obviously lower than that of the model group (P < 0.01).
Compared with the madecassoside group, the rats with the madecassic acid high dose group and the madecassic acid low dose group have significant differences in colon length and gross morphology score (P < 0.01). See table 3.
TABLE 3 Effect of Hydroxyasiatic acid on Colon Length, gross morphology scores in rats with ulcerative colitis
Figure BDA0002655916310000061
Compared with the normal control group, the composition has the advantages that,￥P<0.05，￥￥P<0.01；
compared with the model control group,#P<0.05，##P<0.01；
compared with the madecassoside group,&P<0.05，&&P<0.01。
in conclusion, madecassic acid has the efficacy of preventing and/or treating ulcerative colitis diseases.

Claims (10)

1. Use of madecassic acid, or a salt or complex thereof, in the preparation of a medicament for the prevention or treatment of ulcerative colitis.
2. Use according to claim 1, characterized in that the madecassic acid salt is a salt of madecassic acid with an organic base; or a complex formed with madecassic acid cyclodextrin and rare earth metal.
3. Use according to claim 1, characterized in that the madecassic acid is used in an amount ranging from 0.001 mg/kg-d to 50 mg/kg-d.
4. Use according to claim 3, characterized in that the madecassic acid is used in an amount ranging from 0.01 mg/kg-d to 10 mg/kg-d.
5. Use according to claim 4, characterized in that the madecassic acid is used in an amount ranging from 0.5 mg/kg-d to 1 mg/kg-d.
6. Use according to claim 3, characterized in that the madecassic acid is used in an amount of 0.5 mg/kg-d, 1 mg/kg-d.
7. Use according to claim 1, characterized in that said madecassic acid can be formulated with pharmaceutically acceptable adjuvants into oral, sublingual or injectable preparations.
8. Use according to claim 5, characterized in that the oral formulation is a tablet, capsule or microemulsion formulation thereof.
9. Use according to claim 5, characterized in that the injectable preparation is an injectable solution or an injectable microemulsion thereof.
10. Use according to claim 5, characterized in that the madecassic acid is contained in an amount of 0.001mg to 50mg per unit of preparation.
CN202010887181.XA 2019-09-03 2020-08-28 Application of madecassic acid in preparation of medicine for preventing or treating ulcerative colitis Pending CN112438981A (en)

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CN201910826903 2019-09-03

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