阅读说明：本技术 一种治疗幽门螺旋杆菌感染的药物组合物 (Pharmaceutical composition for treating helicobacter pylori infection ) 是由 李勇 段生宝 于海利 王红梅 陈晔洲 丁少华 田晶晶 王玉珏 刘杰 王泽龙 王晴 于 2021-10-26 设计创作，主要内容包括：本发明公开了一种幽门螺旋杆菌感染的药物组合物,属于医药技术领域。具体而言,本发明提供了苦楝皮单独作为活性成分在制备治疗幽门螺旋杆菌感染的药物中的应用。此外,本发明还提供了苦楝皮作为活性成分与其他药物联合在制备治疗幽门螺旋杆菌感染的药物中的应用以及一种药物组合物。苦楝皮水提取物对于幽门螺旋柑橘具有显著的抑制作用。将苦楝皮水提取物与其他治疗幽门螺旋杆菌感染的药物联用,能够有效的根除幽门螺旋杆菌。本发明为幽门螺旋杆菌的治疗和预防提供了新的思路。(The invention discloses a pharmaceutical composition for helicobacter pylori infection, and belongs to the technical field of medicines. Specifically, the invention provides an application of cortex meliae as an active ingredient in preparation of a medicament for treating helicobacter pylori infection. In addition, the invention also provides application of the cortex meliae as an active ingredient in the preparation of a medicament for treating helicobacter pylori infection by combining with other medicaments and a pharmaceutical composition. The melia azedarach water extract has obvious inhibiting effect on the helicobacter pylori. The melia azedarach water extract is combined with other medicines for treating helicobacter pylori infection, so that the helicobacter pylori can be effectively eradicated. The invention provides a new idea for treating and preventing helicobacter pylori.)

1. The application of cortex Meliae as active ingredient in preparing medicine for treating helicobacter pylori infection is provided.

2. The use as claimed in claim 1, wherein the cortex Meliae comprises an extract thereof.

3. The use as claimed in claim 2, wherein the cortex Meliae comprises an aqueous extract thereof.

4. The use as claimed in claim 3, wherein said aqueous extract is included with β -cyclodextrin.

5. The cortex Meliae is used as active ingredient and combined with other medicines for preparing medicine for treating helicobacter pylori infection.

6. Use according to claim 5, wherein the other drugs comprise proton pump inhibitors, antibiotics and bismuth agents.

7. The use of claim 6, wherein the proton pump inhibitor comprises one of omeprazole, lansoprazole, esomeprazole, pantoprazole, or rabeprazole.

8. The use of claim 6, wherein the antibiotic comprises one of amoxicillin, clarithromycin, levofloxacin, metronidazole, furazolidone, tetracycline, or minocycline.

9. The use of claim 6, wherein the bismuth agent comprises one of bismuth potassium citrate, colloidal bismuth subcitrate, or colloidal bismuth pectin.

10. A pharmaceutical composition for the treatment of helicobacter pylori infection, wherein the pharmaceutical composition comprises the following components:

proton pump inhibitors: 10-20 parts by weight;

antibiotics: 300-500 parts by weight;

a bismuth agent: 200-300 parts by weight; and

400 parts of cortex meliae water extract inclusion compound; wherein the content of the first and second substances,

clathrating cortex Meliae water extract with beta-cyclodextrin to obtain cortex Meliae water extract clathrate; the mass fraction of the cortex meliae water extract in the cortex meliae water extract clathrate is 10% -30%; wherein:

the proton pump inhibitor comprises one of omeprazole, lansoprazole, esomeprazole, pantoprazole or rabeprazole;

the antibiotic comprises one of amoxicillin, clarithromycin, levofloxacin, metronidazole, furazolidone, tetracycline or minocycline;

the bismuth agent comprises one of bismuth potassium citrate, colloidal bismuth subcitrate or colloidal bismuth pectin.

Technical Field

The invention belongs to the technical field of medicines. In particular to a pharmaceutical composition for treating helicobacter pylori infection.

Background

Helicobacter pylori (h. pylori) is a spiral, microaerophilic, gram-negative bacterium with very stringent growth conditions, and is currently the only species of microorganism known to be able to survive in the human stomach. In 1982, the australian scholars Marshall and Warren discovered h.pyri and elucidated the role of h.pyri in gastritis and peptic ulcer disease. H. pyriori was formally identified as a class i (i.e., positive) carcinogen by the world health organization in 1994. The discovery of pylori revolutionarily changes the cognition, treatment concept and treatment method of the stomach diseases of the old people, so that the stomach-duodenum diseases, especially peptic ulcer diseases are not diseases with long-term and frequent relapse any more, but the stomach-duodenum diseases can be cured only by short-range antibiotic and acid inhibitor. Eradication therapy of pylori and a decrease in the rate of h.pylori infection due to changes in concept also significantly reduces the incidence of gastric cancer and gastric mucosa-associated lymphoid tissue (MALT) lymphoma, thus benefiting hundreds of millions of gastro-duodenal disease patients worldwide, an important milestone in the history of gastroenterology development, and Marshall and Warren thus also receive a 2005 norbell physiological or medical prize.

Epidemiological studies show that the infection rate of helicobacter pylori is about 50% worldwide, about 80% in developing countries, about 40% in developed countries, 30-60% in China, about 20 years earlier than developed countries, 41.98% in 20-29 years old and 78.9% above 70 years old. Helicobacter pylori is an important pathogenic factor of digestive tract diseases such as chronic gastritis, peptic ulcer, gastric cancer and the like. In addition, more and more researches show that helicobacter pylori is a chronic persistent infection, can cause systemic immune response and chronic inflammatory response, induces release of a large amount of inflammatory mediators, cytokines and acute reactants, and causes in-situ and distant injuries, thereby causing the occurrence of diseases outside the gastrointestinal tract, such as iron deficiency anemia with unknown reasons, idiopathic thrombocytopenic purpura, coronary heart disease, chronic urticaria and the like, and related evidence shows that the infection is associated with the helicobacter pylori.

The current standard treatment regimens for eradication of helicobacter pylori are primarily triple therapy and quadruple therapy, i.e. with a Proton Pump Inhibitor (PPI) plus two antibiotics or a bismuth agent. Both PPI and bismuth agents can overcome the primary resistance of h. At present, the main antibiotics mainly comprise amoxicillin, clarithromycin, metronidazole, tetracycline, furazolidone, quinolone drugs and the like. However, the more antibiotics that are used in combination, the higher the incidence of adverse reactions and the higher the drug resistance rate. However, as the problem of antibiotic resistance of H.pyri becomes more serious, the eradication difficulty is increased, the initial eradication rate is more than 90%, and the eradication rate reported recently is even as low as 60-70%. The failure of eradication of h.pylori is due to many factors, including the strain itself, host factors, environmental factors, various clinical conditions and the method of treatment, among which the most important is the drug resistance of h.pylori. The drug resistance of the helicobacter pylori is increasingly serious due to factors such as abuse of antibiotics, non-standard treatment scheme, poor control of eradication indications and the like, and the eradication rate is reduced.

Disclosure of Invention

The invention aims to provide a medicament and a medicinal composition for treating helicobacter pylori infection, which improve the eradication rate and the effective rate of helicobacter pylori and reduce the drug resistance rate and the incidence rate of adverse reactions.

The inventor of the invention finds that the cortex meliae has a remarkable inhibiting effect on helicobacter pylori in research. Therefore, based on the above findings, the present invention provides the following technical solutions:

the application of cortex Meliae as active ingredient in preparing medicine for treating helicobacter pylori infection is provided.

The cortex Meliae is dried bark and root bark of Melia toosendan Sieb. et Zucc. or Melia azedarach L. belonging to Meliaceae. Peeling in spring and autumn, and sun drying, or removing coarse skin and sun drying.

According to a specific embodiment of the present invention, the cortex meliae includes an extract thereof.

According to a specific embodiment of the present invention, the cortex meliae includes an aqueous extract thereof.

According to a particular embodiment of the invention, in the present invention, said aqueous extract is included with β -cyclodextrin.

The invention also provides the application of the cortex meliae as an active ingredient in the preparation of the medicament for treating helicobacter pylori infection by combining with other medicaments.

According to a specific embodiment of the present invention, the other drugs in the present invention include proton pump inhibitors, antibiotics, and bismuth agents.

According to a specific embodiment of the present invention, the proton pump inhibitor comprises one of omeprazole, lansoprazole, esomeprazole, pantoprazole or rabeprazole.

According to a specific embodiment of the present invention, the antibiotic comprises one of amoxicillin, clarithromycin, levofloxacin, metronidazole, furazolidone, tetracycline or minocycline.

According to an embodiment of the present invention, the bismuth agent comprises one of bismuth potassium citrate, colloidal bismuth subcitrate or colloidal bismuth pectin.

In addition, the invention also provides a pharmaceutical composition for treating helicobacter pylori infection, wherein the pharmaceutical composition comprises the following components:

proton pump inhibitors: 10-20 parts by weight;

antibiotics: 300-500 parts by weight;

a bismuth agent: 200-300 parts by weight; and

400 parts of cortex meliae water extract inclusion compound; wherein the content of the first and second substances,

clathrating cortex Meliae water extract with beta-cyclodextrin to obtain cortex Meliae water extract clathrate; the mass fraction of the cortex meliae water extract in the cortex meliae water extract clathrate is 10% -30%; wherein:

the proton pump inhibitor comprises one of omeprazole, lansoprazole, esomeprazole, pantoprazole or rabeprazole;

the antibiotic comprises one of amoxicillin, clarithromycin, levofloxacin, metronidazole, furazolidone, tetracycline or minocycline;

the bismuth agent comprises one of bismuth potassium citrate, colloidal bismuth subcitrate or colloidal bismuth pectin.

In conclusion, the invention provides a new application of cortex meliae. The cortex meliae is applied to the treatment of helicobacter pylori infection, so that the use of antibiotics can be reduced, and the problem of drug resistance caused by the overuse of antibiotics can be avoided. In addition, the cortex meliae belongs to natural medicines, and has higher safety compared with antibiotics. The experimental result shows that the melia azedarach water extract has obvious inhibiting effect on the helicobacter pylori citrus. The melia azedarach water extract is combined with other medicines for treating helicobacter pylori infection, so that the helicobacter pylori can be effectively eradicated. The invention provides a new idea for treating and preventing helicobacter pylori.

Detailed Description

The technical solutions of the present invention will be described in detail below in order to clearly understand the technical features, objects, and advantages of the present invention, but the present invention is not limited to the practical scope of the present invention.

Example 1 inhibition of helicobacter pylori by aqueous extract of Melia azedarach

1.1 preparation of aqueous extract of Melia azedarach

Taking 60g of cortex meliae, adding 800mL of ddH₂O, soaking for 30min, decocting with strong fire for 15min, decocting with slow fire for 20min, collecting the liquid medicine, centrifuging to obtain supernatant, and filtering with 0.22 μm filter membrane for sterilization to obtain cortex Meliae water extract.

1.2 preparation of brain-heart infusion liquid culture medium: weighing 3.7g of brain-heart infusion broth culture medium powder, dissolving in 100mL of deionized water, mixing well with a magnetic stirrer, subpackaging in 100mL conical bottles with 27mL each, sealing with two layers of breathable sealing films and four layers of newspaper, and sterilizing with high-pressure steam at 121 deg.C for 30 min. And (3) after the sterilization is finished and the temperature is reduced to the room temperature, adding 3mL of serum into each bottle in a super clean bench, uniformly mixing, sealing by using a breathable sealing film and newspaper, and placing in a refrigerator at 4 ℃ for later use.

1.3 preparation of Columbia blood plate solid culture medium: dissolving 21.5g of Columbia blood agar base of Beijing Solebao scientific and technological Limited in 500mL of deionized water, mixing uniformly by a magnetic stirrer, sterilizing for 30min by high-pressure steam at 121 ℃, adding 25mL of defibered sheep blood when the temperature is reduced to 50 ℃ after the sterilization, mixing uniformly, sucking 20mL of agar in each plate, cooling the agar, inverting the culture dish, and refrigerating at 4 ℃.

1.4 preparation of inhibitor:

an experimental group (sample No. 1-3) and a blank control group are set. Specifically, the total volume of the experimental group (sample No. 1-3) and the blank control group is consistent: sample No. 1 is a mixture of the aqueous extract of cortex Meliae prepared in example 1 and the prepared brain-heart infusion liquid medium, and the volume ratio of the aqueous extract of cortex Meliae to the brain-heart infusion liquid medium is 1: 4; sample No. 2 is a mixture of the aqueous extract of cortex Meliae prepared in example 1 and the prepared brain-heart infusion liquid medium, and the volume ratio of the aqueous extract of cortex Meliae to the brain-heart infusion liquid medium is 1: 16; sample No. 3 is a mixture of the aqueous extract of cortex Meliae prepared in example 1 and the prepared brain-heart infusion liquid medium, and the volume ratio of the aqueous extract of cortex Meliae to the brain-heart infusion liquid medium is 1: 32, a first step of removing the first layer; the placebo group contained only brain heart infusion medium.

1.5 inhibition assay:

taking out the frozen helicobacter pylori from a refrigerator at-80 deg.C, and thawing at room temperature. Lightly blowing and beating uniformly in the biological safety cabinet, respectively sucking 300 μ L, adding into a prepared experimental group (No. 1-3 sample) and a blank control, setting three parallel controls for the experimental group and the blank control, and placing in a three-gas culture box under the condition of microaerophilic (5% O)₂、10％CO₂、85％N₂) Culturing at 37 deg.C for 3 d;

after 3d, 100. mu.L of the suspension was taken from each flask and diluted in a gradient (10)^-5、10^-6、10^-7Dilutions), 100. mu.L of the bacterial solution was dropped into the center of Columbia blood agar medium for each dilution, and the coating rod was spread evenly over the entire plate. Placing in a three-gas culture box under the condition of microaerophilic (5% O)₂、10％CO₂、85％N₂) Culturing at 37 deg.C for 3d, taking 10 after 3d^-7Under the dilution, the colony count is carried out on a plate with a single colony between 30 and 300, and the statistical result is shown in the following table 1.

TABLE 1 growth of helicobacter pylori after sample treatment

The results in the table 1 show that the melia azedarach water extract provided by the invention can inhibit the activity of helicobacter pylori, the inhibition effect is enhanced along with the increase of the content of the melia azedarach water extract, and the inhibition effect on the helicobacter pylori reaches 100%.

Example 2 preparation of Water extract clathrate of cortex Meliae

20g of the aqueous extract of cortex Meliae prepared in example 1 was taken, and 160g of beta-cyclodextrin was added to obtain an inclusion compound in which the content of the aqueous extract of cortex Meliae was 11.1 wt%.

EXAMPLE 3 preparation of pharmaceutical composition

And sequentially coating a drug layer, an isolating layer, an enteric coating layer (the enteric coating material is methacrylic acid copolymer) and an outer coating layer on the blank sugar core to obtain the enteric-coated pellet with the rabeprazole drug content of 18.36 wt%.

108g of prepared enteric-coated pellets, 400g of amoxicillin, 220g of bismuth potassium citrate and 2727g of the melia azedarach water extract inclusion compound prepared in the embodiment 2 are taken, and proper amount of lactose, polyvinylpyrrolidone and microcrystalline cellulose are added to prepare granules.

Example 4

Clinical experiments prove that the pharmaceutical composition has the treatment effect on helicobacter pylori infection, and the test method and the results are as follows:

4.1 diagnostic criteria

Refer to the diagnostic criteria in "consensus opinion on fourth national helicobacter pylori infection treatment", 2012.

4.2 clinical data

100 patients who met the above diagnostic criteria were included for clinical observation and randomized into treatment and control groups. Treatment groups 50, of which 25 men, 25 women, the minimum age 23 years, the maximum age 87 years, and the mean age 48 years. Control group 50, of which 30 men, 20 women, the minimum age 24 years, the maximum age 66 years, and the mean age 43.5 years.

4.3 methods of treatment

Treatment groups: the granules of example 3 were administered 1000g each time 2 times a day.

Control group: administration was according to the existing four-combination therapy.

The treatment course is 2 weeks. The treatment is repeated for 4-8 weeks¹³C, urea breath test.

4.4 therapeutic criteria

And (3) curing:¹³c Urea breath testThe result of (5) is negative;

the method has the following advantages:¹³the result of the urea breath test is positive, but the DOB value is reduced by more than 1/2 compared with that before treatment;

and (4) invalidation:¹³the results of the urea breath test were positive and the DOB values were elevated, unchanged or decreased less than 1/2 compared to before treatment.

4.5 therapeutic results

Treatment groups: 35 cases are cured, 10 cases are effective, 5 cases are ineffective, the cure rate is 70%, the total effective rate reaches 90%, and no adverse reaction occurs.

Control group: 50 cases are cured, and 1 case has mild adverse reaction.

The pharmaceutical composition for treating helicobacter pylori infection provided by the invention has a curative effect equivalent to that of the currently common quadruple therapy, does not have adverse reaction and has high safety.

The preferred embodiments of the present invention have been described above in detail, but the present invention is not limited thereto. Various alternatives, modifications and combinations of the features of the invention can be made without departing from the spirit and nature of the invention as claimed, and such simple variations and combinations should also be considered as disclosed in the present application, all falling within the scope of the invention.