Compound montmorillonite granules for treating helicobacter pylori infection and preparation method thereof

Abstract

The application belongs to the technical field of medicine, and particularly relates to a compound montmorillonite particle for treating Helicobacter pylori infection and a preparation method thereof. The compound montmorillonite particle for treating Helicobacter pylori infection comprises A component and B component, wherein the A component is prepared from the following raw materials according to weight fractions: montmorillonite 50-65 parts; filler a 5-15 parts; binder a 0.1-1.5 parts; disintegrant 2-7 parts; the B component is prepared from the following raw materials according to weight fractions: amoxicillin 5-10 parts; rifabutin 0.2-0.5 parts; filler b 4-15 parts; binder b 1-6 parts; disintegrant 2-7 parts. The compound montmorillonite particle for treating Helicobacter pylori infection provided by the application has no drug resistance problem, and improves the compliance of patients with dysphagia and children to drug administration; and the application further provides a preparation method thereof, which is simple to operate and stable in process.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and particularly relates to a compound montmorillonite particle for treating Helicobacter pylori infection and a preparation method thereof. BACKGROUND

[0002] Helicobacter pylori (HP) is a kind of spiral-shaped gram-negative bacillus with several flagella at one end and inhabiting in human gastric mucosa. In 1983, Marshall, B.J. and Warren, J.R. from Australia reported that a gastric biopsy sample taken from a patient with gastritis and gastric ulcer can be efficiently detected with this bacterium. Since then, many reports have successively focused on this bacterium. For example, epidemiological research results report that this bacterium causes gastritis, gastric ulcer and duodenal ulcer, and is related to diseases such as gastric cancer.

[0003] At present, it is considered that the eradication of Helicobacter pylori is necessary for the permanent cure of peptic ulcer. The combination treatment of antibiotics and gastric acid secretion inhibitors has been widely used as the Helicobacter pylori eradication treatment. Since hydrochloric acid keeps the pH level in the stomach very low, many antibiotics are ineffective. Therefore, the proton pump inhibitor that strongly inhibits gastric acid secretion is used in combination with antibiotics to eradicate Helicobacter pylori. At present, the combination treatment of triple therapy such as amoxicillin, clarithromycin and lansoprazole is the standard treatment for eradicating Helicobacter pylori. However, long-term administration of antibiotics can cause very serious problems such as an increase in the number of drug-resistant strains and side effects. For example, CN1875982A discloses a combination preparation for treating Helicobacter pylori, which comprises omeprazole and clarithromycin and a pharmaceutically acceptable excipient.

[0004] Helicobacter pylori has been listed as a class I carcinogen, and is still the strongest known risk factor for gastric cancer, and is also the main risk factor for peptic ulcer and gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Globally, Helicobacter pylori affects more than 50% of the population. Therefore, there is an urgent market demand for a pharmaceutical composition or compound preparation that is both safe and can effectively eradicate Helicobacter pylori. SUMMARY

[0005] The technical problem to be solved by the present application is to overcome the above problems existing in the prior art, and to provide a compound montmorillonite particle for treating Helicobacter pylori infection, which has no drug resistance problem and improves the compliance of patients with dysphagia and children to drug administration. The present application also provides a preparation method thereof, which is simple to operate and stable in process.

[0006] The compound montmorillonite particle for treating Helicobacter pylori infection comprises A component and B component, wherein the A component is prepared from the following raw materials according to weight fractions:

[0007]

[0008]

[0009] The B component is prepared from the following raw materials in parts by weight:

[0010]

[0011] Also included are 0.5-7 parts by weight of a lubricant and 0.1-2 parts by weight of a flavoring agent.

[0012] The flavoring agent is one or more of sucralose, aspartame, strawberry flavor, menthol, preferably aspartame and strawberry flavor in parts by weight, and the flavoring agent makes the product taste good, without bitterness and grit.

[0013] The average particle size (D [4,3] ) of the montmorillonite is 10-100 μm, preferably 10-30 μm; the average particle size (D [4,3] ) of the amoxicillin is 30-100 μm, preferably 20-30 μm; and the average particle size (D [4,3] ) of the rifabutin is 10-30 μm, preferably 10-20 μm.

[0014] The filler a is sucrose or starch, and the preferred parts by weight are 5-15; the filler b is mannitol or sorbitol, and the preferred parts by weight are 4-15.

[0015] The binder a is hydroxypropyl cellulose or povidone, and the preferred parts by weight are 0.1-1.5; the binder b is pregelatinized starch or hydroxypropyl methyl cellulose, and the preferred parts by weight are 1-6.

[0016] The disintegrant is one of cross-linked povidone, cross-linked sodium carboxymethyl cellulose, and sodium carboxymethyl starch.

[0017] The lubricant is sodium stearyl fumarate or a mixture of talc and polyethylene glycol 4000, and the preferred lubricant is sodium stearyl fumarate.

[0018] The preparation method of the compound montmorillonite granules for treating H. pylori infection comprises the following steps:

[0019] ①Preparation of the A component montmorillonite granules:

[0020] 1) The binder is configured into an aqueous solution;

[0021] 2) The montmorillonite, filler, and disintegrant are mixed uniformly;

[0022] 3) The aqueous solution of step 1) is added to step 2) to perform wet granulation;

[0023] 4) Screen the material of step 3) to make granules, dry, and control the moisture content to be less than 5%, to obtain the montmorillonite granules;

[0024] ②Prepare the amoxicillin and rifabutin mixed granules of B component:

[0025] 5) Prepare the binder into an aqueous solution;

[0026] 6) Mix the amoxicillin, rifabutin and the filler evenly;

[0027] 7) Add the aqueous solution of step 5) into step 6) to perform wet granulation;

[0028] 8) Screen the material of step 7) to make granules, dry, and control the moisture content to be less than 5%, to obtain the amoxicillin and rifabutin mixed granules;

[0029] ③Prepare the compound montmorillonite granules:

[0030] 9) Screen the obtained montmorillonite granules and the amoxicillin and rifabutin mixed granules respectively to make granules;

[0031] 10) Mix the material of step 9), the sweetening agent and the flavoring agent evenly, and then add the lubricant and mix evenly;

[0032] 11) Package the mixed granules obtained in step 10), to obtain the compound montmorillonite granules for treating Helicobacter pylori infection.

[0033] The particle size of the compound montmorillonite granules cannot pass through the sum of No. 1 sieve and No. 5 sieve, which is not more than 15%.

[0034] The preparation method of the compound montmorillonite granules for treating Helicobacter pylori infection of the present application uses A and B components to prepare the compound granules of montmorillonite, amoxicillin and rifabutin, which can effectively overcome the drug resistance problem of clarithromycin and metronidazole, and can improve the compliance of patients with dysphagia and children to the drug administration.

[0035] Montmorillonite is also known as microcrystalline kaolinite, which is the main component of bentonite mine, and is a double-octahedral subfamily mineral. It is named after the clay near Montmorillon in France in 1847. It can present yellow-green, yellow-white, gray-white or light red color due to different cations carried in the structure. The montmorillonite granules are small after water washing and fine grinding, and the layered structure and scale-like crystals can be seen under an electron microscope. The micro-morphology of montmorillonite is a double-octahedral layered structure composed of silicon-oxygen tetrahedron and aluminum-oxygen octahedron, which is often metaphorically referred to as a "sandwich" structure, and its general structure is: (K, Na, Ca, Mg) y (Al, Mg)2 (Si, Al)4O10 (OH)2·xH2O, wherein (K, Na, Ca, Mg) y As the interlayer exchangeable cation, (Al, Mg)2 as the cation in the octahedron, (Si, Al)4 as the cation in the tetrahedron, the random substitution of Al and Mg to Si and Al in the structure causes charge imbalance, which has the characteristics of electrification and ion exchange. The electrification and ion exchange characteristics of montmorillonite make it have extremely strong fixation and adsorption effect on viruses, bacteria and toxins, gases and the like generated by them in the digestive tract, so that the latter loses the pathogenic effect; and due to the flaky structure, it obtains a large specific surface area, has a very strong covering protection ability to the mucosa of the digestive tract, and through mutual combination with mucin glycoprotein, repairs and improves the defense function of the mucosal barrier to attack factors, has the effects of balancing normal flora and local analgesia.

[0036] Amoxicillin, also known as hydroxyl ampicillin, is a commonly used broad-spectrum β-lactam antibiotic in clinical practice, and is also a commonly used antibacterial drug in the treatment of Helicobacter pylori (HP). It has good antibacterial activity against Streptococcus pneumoniae, hemolytic streptococcus, Streptococcus, non-penicillinase-producing Staphylococcus, Enterococcus faecalis, aerobic gram-positive cocci, Escherichia coli, Proteus mirabilis, Salmonella, Haemophilus influenzae, Neisseria gonorrhoeae and Helicobacter pylori. Amoxicillin exerts bactericidal effect by inhibiting bacterial cell wall synthesis, which can make bacteria become spherical and dissolve and rupture rapidly. Compared with other commonly used antibiotics in the treatment of Helicobacter pylori, amoxicillin has strong bactericidal effect, and the primary and secondary drug resistance rates are very low. It is not only preferred in the initial treatment of patients, but also can be repeatedly used in rescue treatment. Amoxicillin is well absorbed orally and can be secreted into gastric juice and mucosa. Its structure can remain stable in the gastric acid environment. However, the eradication rate of Helicobacter pylori is less than 20% when amoxicillin is used alone. The bactericidal effect of amoxicillin on Helicobacter pylori is greatly affected by the pH value in the stomach. The combination of amoxicillin and the alkaline montmorillonite can significantly improve the bactericidal activity. On the one hand, the alkaline gastric absorption environment provided by montmorillonite for amoxicillin can significantly increase the concentration of amoxicillin in the stomach, which exceeds the minimum inhibitory concentration (MIC) of Helicobacter pylori; on the other hand, the increase of the pH value in the stomach can reduce the minimum inhibitory concentration of amoxicillin.

[0037] Rifabutin, an antibiotic, is used in the treatment of tuberculosis, and in the prophylaxis and treatment of Mycobacterium avium complex, by inhibiting the bacterial DNA-dependent RNA polymerase, which inhibits the bacterial DNA-dependent RNA synthesis. Rifabutin has shown potential use in the treatment of H. pylori, as it does not share resistance with clarithromycin. Resistance to amoxicillin or rifabutin is very rare in H. pylori. The average resistance rate to rifabutin (calculated from 11 studies comprising 2982 patients) is generally 1.3% and for patients who have never received H. pylori eradication therapy, it is 0.6%. The use of amoxicillin in combination can effectively avoid the problem of bacterial resistance.

[0038] At present, the main drugs for treating H. pylori are clarithromycin, amoxicillin, metronidazole, levofloxacin, furazolidone and tetracycline. With the widespread use of antibacterial drugs, drug-resistant strains of H. pylori are increasing, and the eradication rate of traditional standard regimens is also decreasing. Studies have found that the primary drug resistance rates of H. pylori in China are 20% to 50% for clarithromycin, 40% to 70% for metronidazole, and 20% to 50% for levofloxacin. H. pylori can develop double, triple or more resistance to these drugs. The triple therapy of montmorillonite, amoxicillin and rifabutin can completely kill H. pylori through physical adsorption, inhibition of bacterial cell wall synthesis and ribonucleic acid (RNA) synthesis.

[0039] Compared with the prior art, the present application has the beneficial effects that:

[0040] (1) The compound montmorillonite granules for treating H. pylori infection prepared by the present application overcome the problem of antibiotic resistance and improve the eradication rate of H. pylori, providing a new choice for clinical patients to eradicate diseases caused by H. pylori.

[0041] (2) The compound montmorillonite granules for treating H. pylori infection prepared by the present application improve the compliance of patients with dysphagia and children patients.

[0042] (3) The preparation method of the compound montmorillonite granules for treating H. pylori infection of the present application is simple to operate, stable in process, suitable for the preparation of compound granules in large-scale production, and the required production equipment is conventional equipment, saving cost and improving the feasibility of production. DETAILED DESCRIPTION

[0043] The embodiments of the present application will be described in detail by way of examples as follows, but those skilled in the art will understand that the following examples are for illustration only and should not be taken in a limiting sense. The specific conditions not mentioned in the examples are carried out according to the conventional conditions or the conditions recommended by the manufacturer. The reagents or instruments used are not specified by the manufacturer, which are all conventional products that can be purchased on the market.

[0044] The weight parts described in the examples and comparative examples of the present application are all measured by mass.

[0045] Examples 1-6

[0046] The compound montmorillonite granules for treating H. pylori infection: including A component and B component, wherein the raw material components and the mass are included, wherein the average particle size (D[4,3]) of the montmorillonite used in examples 1-6 is 20 μm; the average particle size (D[4,3]) of amoxicillin is 20 μm; the average particle size (D[4,3]) of rifabutin is 10 μm. As shown in Table 1.

[0047] Table 1 Raw material components and formulations

[0048]

[0049] Examples 7-12

[0050] The compound montmorillonite granules for treating H. pylori infection: including A component and B component, wherein the raw material components and the mass are included, wherein the average particle size (D[4,3]) of the montmorillonite used in examples 7-12 is 20 μm; the average particle size (D[4,3]) of amoxicillin is 20 μm; the average particle size (D[4,3]) of rifabutin is 10 μm. As shown in Table 2.

[0051] Table 2 Raw material components and formulations

[0052]

[0053] Examples 13-20

[0054] The formulation of example 6 is prepared according to the following particle size distribution, and the others are the same as example 6, to prepare compound montmorillonite granules for treating H. pylori infection, as shown in Table 3,

[0055] Table 3 Particle size distribution

[0056]

[0057] The raw materials described in the above examples 1-20 are prepared according to the following preparation method to prepare compound montmorillonite granules for treating H. pylori infection:

[0058] 1) Dissolve the binder in purified water to make a 5% solution;

[0059] 1) Dissolve the binder in purified water to make a 5% solution;

[0060] 2) Mix the montmorillonite, filler and disintegrant in a high shear wet granulator;

[0061] 3) Add the water solution of step 1) to step 2) and wet granulate;

[0062] 4) Screen the material of step 3) through a 20 mesh screen, dry and control the moisture to less than 5% to obtain the montmorillonite granules;

[0063] 2) Mix the amoxicillin, rifabutin and filler in a high shear wet granulator;

[0064] 5) Disperse the binder in purified water to make a 10% suspension;

[0065] 6) Mix the amoxicillin, rifabutin and filler in a high shear wet granulator;

[0066] 7) Add the water solution of step 5) to step 6) and wet granulate;

[0067] 8) Screen the material of step 7) and dry to control the moisture to less than 5% to obtain the amoxicillin and rifabutin mixed granules;

[0068] 3) Mix the montmorillonite granules, amoxicillin and rifabutin mixed granules separately through a 30 mesh screen;

[0069] 10) Mix the material of step 9), sweetener and flavoring agent and finally add the lubricant and mix well;

[0070] 11) Package the mixed granules of step 10) to obtain the compound montmorillonite granules for the treatment of H. pylori infection.

[0071] 11) Package the mixed granules of step 10) to obtain the compound montmorillonite granules for the treatment of H. pylori infection.

[0072] The compound montmorillonite granules for treating H. pylori infection made in all the above examples were subjected to in vitro pharmaceutical evaluation according to the standards in Chinese Pharmacopoeia 2020 edition (the standard of each item is based on), and the sample in Example 6 was selected for clinical effectiveness test (montmorillonite compound granules (montmorillonite 3 g, amoxicillin 300 mg and rifabutin 30 mg) were given twice a day, and continuously taken for 2 weeks), and the effective rate of H. pylori in patients was statistically analyzed (all patients were diagnosed by gastroscope, and 2 pieces of antral and gastric mucosa were taken for biopsy, and rapid urease test, tissue smear gram staining and tissue fixation, dehydration, section staining and microscopic examination of HP were performed; if 2 or more of the 3 methods were positive, the patient was diagnosed as HP positive).

[0073] The evaluation results are shown in Tables 4 and 5, respectively.

[0074] In Table 4, the adsorption force is the amount (mmol) of trichlorohexammine cobalt (III) {[Co(NH3)6]Cl3} adsorbed per 100 g of montmorillonite.

[0075] Amoxicillin dissolution (30 min): pH 6.8, paddle method 50 rpm, and the dissolution of amoxicillin at 45 min should not be less than 85%.

[0076] Rifabutin dissolution (30 min): pH 6.8, paddle method 50 rpm, and the dissolution of rifabutin at 45 min should not be less than 85%.

[0077] Patient acceptability judgment criteria: very satisfied (95 or above), satisfied (85-95), basically satisfied (75-85) and unsatisfied (75 or below).

[0078] In Table 5, the experimental parameters are: montmorillonite compound granules (montmorillonite 3 g, amoxicillin 300 mg and rifabutin 30 mg) were given twice a day, taken after breakfast and dinner, and continuously given for 2 weeks. All patients were diagnosed by gastroscope, and 2 pieces of antral and gastric mucosa were taken for biopsy, and rapid urease test, tissue smear gram staining and tissue fixation, dehydration, section staining and microscopic examination of HP were performed; if 2 or more of the 3 methods were positive, the patient was diagnosed as HP positive, otherwise, the patient was negative.

[0079] Table 4: In vitro pharmaceutical evaluation results of compound montmorillonite granules

[0080]

[0081] Table 5: Clinical effectiveness test results of compound montmorillonite granules

[0082]

[0083]

[0084] Of course, the above-described embodiments are merely the best modes of the application and cannot be considered to limit the scope of the embodiments of the application. The application is also not limited to the above-described examples, and equivalent changes and improvements made by those skilled in the art within the spirit of the application should be considered to fall within the scope of the patent coverage of the application.

Claims

1. A compound montmorillonite granule for treating Helicobacter pylori infection, characterized in that: It includes component A and component B, wherein component A is made from the following raw materials in parts by weight: 50-65 parts of montmorillonite; Filler a: 5-15 parts; Adhesive a: 0.1 to 1.5 parts; 2-7 parts disintegrant; Component B is made from the following raw materials in parts by weight: Amoxicillin 5-10 doses; Rifabutin 0.2–0.5 parts; Filler b4-15 parts; Adhesive b1 to 6 parts; 2-7 parts disintegrant; The average particle size of montmorillonite is 10–100 μm, that of amoxicillin is 30–100 μm, and that of rifabutin is 10–30 μm. The preparation method of the compound montmorillonite granules for treating Helicobacter pylori infection includes the following steps: ① Preparation of montmorillonite particles of component A: 1) Prepare adhesive a into an aqueous solution; 2) Mix montmorillonite, filler a, and disintegrant thoroughly; 3) Add the aqueous solution from step 1) to step 2) and perform wet granulation; 4) The material from step 3) is granulated by sieving and dried, with the moisture content controlled to be less than 5%, to obtain montmorillonite granules; ②Preparation of component B, amoxicillin and rifabutin mixed granules: 5) Prepare adhesive b into an aqueous solution; 6) Mix amoxicillin, rifabutin and filler b thoroughly; 7) Add the aqueous solution from step 5) to step 6) and perform wet granulation; 8) The material from step 7) is granulated by sieving and dried, with the moisture content controlled to be less than 5%, to obtain mixed granules of amoxicillin and rifabutin; ③ Preparation of compound montmorillonite granules: 9) The obtained montmorillonite granules, amoxicillin and rifabutin mixed granules are sieved and granulated separately; 10) Mix the materials, sweetener, and flavoring agent from step 9) thoroughly, and finally add the lubricant and mix thoroughly. 11) The mixed granules obtained in step 10) are packaged to obtain compound montmorillonite granules for the treatment of Helicobacter pylori infection.

2. The compound montmorillonite granules for treating Helicobacter pylori infection according to claim 1, characterized in that: The lubricant is 0.5 to 7 parts by weight and the flavoring agent is 0.1 to 2 parts by weight.

3. The compound montmorillonite granules for treating Helicobacter pylori infection according to claim 2, characterized in that: The flavoring agent is one or more of sucralose, aspartame, strawberry flavoring, and menthol.

4. The compound montmorillonite granules for treating Helicobacter pylori infection according to claim 1, characterized in that: Filler a is sucrose or starch; filler b is mannitol or sorbitol.

5. The compound montmorillonite granules for treating Helicobacter pylori infection according to claim 1, characterized in that: Adhesive a is hydroxypropyl cellulose or polyvinyl ketone; adhesive b is pregelatinized starch or hydroxypropyl methylcellulose.

6. The compound montmorillonite granules for treating Helicobacter pylori infection according to claim 1, characterized in that: The disintegrant is one of crospovidone, crospovidone sodium carboxymethyl cellulose, or sodium carboxymethyl starch.

7. The compound montmorillonite granules for treating Helicobacter pylori infection according to claim 2, characterized in that: The lubricant is sodium stearate fumarate or a mixture of talc and polyethylene glycol.

8. The compound montmorillonite granules for treating Helicobacter pylori infection according to claim 1, characterized in that: The total particle size of compound montmorillonite granules that cannot pass through sieve No. 1 and that can pass through sieve No. 5 does not exceed 15%.

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