CN116036123A - Compound montmorillonite particles for treating Helicobacter pylori infection and preparation method thereof - Google Patents

Abstract

The invention belongs to the technical field of medicines, and in particular relates to compound montmorillonite particles for treating helicobacter pylori infection and a preparation method thereof. The invention relates to compound montmorillonite particles for treating helicobacter pylori infection, which are prepared by the following steps: the composite material comprises a component A and a component B, wherein the component A is prepared from the following raw materials in parts by weight: 50-65 parts of montmorillonite; 5-15 parts of filler a; 0.1 to 1.5 parts of adhesive a; 2-7 parts of disintegrating agent; the component B is prepared from the following raw materials in parts by weight: 5-10 parts of amoxicillin; 0.2 to 0.5 part of rifabutin; 4-15 parts of filler b; 1-6 parts of adhesive b; 2-7 parts of disintegrating agent. The compound montmorillonite particles for treating helicobacter pylori infection provided by the invention have no drug resistance problem, and improve the compliance of dysphagia patients and children patients to drug administration; the invention also provides a preparation method of the preparation method, which is simple to operate and stable in process.

Description

Compound montmorillonite particles for treating Helicobacter pylori infection and preparation method thereof

technical field

The invention belongs to the technical field of medicine, and in particular relates to a compound montmorillonite particle for treating Helicobacter pylori infection and a preparation method thereof.

Background technique

Helicobacter pylori (Helicobacter pylori, HP) is a class of spiral Gram-negative bacilli with several flagella at one end and resides in the human gastric mucosa. In 1983, Marshall, B.J. and Warren, J.R. from Australia reported that this bacterium could be detected with high efficiency in gastric biopsy samples taken from patients with gastritis and gastric ulcer. Since then, many reports have continuously focused on this bacterium. For example, the results of epidemiological studies have reported that this bacterium causes gastritis, gastric ulcer and duodenal ulcer, and is associated with diseases such as gastric cancer.

Currently, eradication of H. pylori is considered essential for permanent healing of peptic ulcers. Combination therapy with antibiotics and inhibitors of gastric acid secretion has been widely used as eradication therapy for H. pylori. Because hydrochloric acid keeps the pH level in the stomach very low, many antibiotics are ineffective. Therefore, proton pump inhibitors, which potently inhibit gastric acid secretion, are used in combination with antibiotics to eradicate H. pylori. Combination therapy utilizing triple therapy such as amoxicillin, clarithromycin, and lansoprazole is currently the standard treatment for H. pylori eradication. However, long-term administration of antibiotics can cause serious problems, such as an increase in the number of resistant strains and side effects. For example, CN1875982A discloses a combined preparation for treating Helicobacter pylori, which includes omeprazole, clarithromycin and pharmaceutically acceptable auxiliary materials.

Helicobacter pylori has been classified as a class I carcinogen and remains the strongest known risk factor for gastric cancer and a major risk factor for peptic ulcer and gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Globally, H. pylori affects more than 50% of the population. Therefore, there is an urgent need in the market for a pharmaceutical composition or compound preparation that is safe and can effectively eradicate Helicobacter pylori.

Contents of the invention

The technical problem to be solved in the present invention is to overcome the above problems existing in the prior art, to provide a compound montmorillonite granule for treating Helicobacter pylori infection, which does not have the problem of drug resistance, and improves the sensitivity of patients with dysphagia and children to the drug. Drug compliance; the invention also provides a preparation method thereof, which is simple in operation and stable in process.

The compound montmorillonite granule used for treating Helicobacter pylori infection according to the present invention: includes A component and B component, wherein A component is made of the following raw materials in parts by weight:

Component B is made from the following raw materials in parts by weight:

It also includes 0.5-7 parts by weight of lubricant and 0.1-2 parts by weight of flavoring agent.

The flavoring agent is one or more of sucralose, aspartame, strawberry essence, and menthol, preferably aspartame and strawberry essence by weight, and the flavoring agent makes the product taste good without bitterness and Gritty.

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

Filler a is sucrose or starch, preferably 5-15 parts by weight; filler b is mannitol or sorbitol, preferably 4-15 parts by weight.

Binder a is hypromellose or povidone, preferably 0.1-1.5 parts by weight; binder b is pregelatinized starch or hypromellose, preferably 1-6 parts by weight.

The disintegrant is one of crospovidone, croscarmellose sodium and carboxymethyl starch sodium.

The lubricant is sodium stearyl fumarate or a mixture of talc and macrogol 4000. Sodium stearyl fumarate is preferred.

The preparation method of the compound montmorillonite particles for treating Helicobacter pylori infection: comprises the following steps:

① Preparation of montmorillonite particles of component A:

1) configuring the adhesive into an aqueous solution;

2) Mix montmorillonite, filler and disintegrant evenly;

3) adding the aqueous solution of step 1) to step 2) for wet granulation;

4) The material in step 3) is screened for granulation, dried, and the moisture content is controlled to be less than 5%, so as to obtain montmorillonite particles;

② Preparation of Amoxicillin and rifabutin mixed granules of component B:

5) configuring the adhesive into an aqueous solution;

6) Mix amoxicillin, rifabutin and filler evenly;

7) adding the aqueous solution of step 5) to step 6) for wet granulation;

8) Sieve the material in step 7), dry it, and control the water content to be less than 5%, to obtain mixed granules of amoxicillin and rifabutin;

③ Preparation of compound montmorillonite particles:

9) Sieve the obtained montmorillonite particles, amoxicillin and rifabutin mixed particles respectively;

10) mix the material, sweetener and corrective agent in step 9), and finally add lubricant and mix evenly;

11) Subpackage the mixed particles obtained in step 10) to obtain compound montmorillonite particles for treating Helicobacter pylori infection.

The particle size of the compound montmorillonite particles cannot pass through the No. 1 sieve and the sum of the No. 5 sieve does not exceed 15%.

The preparation method of the compound montmorillonite granules used for treating Helicobacter pylori infection of the present invention adopts A and B two-components to prepare compound granules of montmorillonite, amoxicillin and rifabutin, which can effectively overcome the It can prevent the drug resistance of mycin and metronidazole, and can improve the compliance of patients with dysphagia and children.

Montmorillonite (montmorillonite), also known as microcrystalline kaolinite, is the main component of bentonite ore and is a dioctahedral subgroup mineral. It was named after the study of clay near Montmorillon, France in 1847. Different cations carried in the structure can present yellow-green, yellow-white, off-white or light red colors. After washing and grinding, the montmorillonite particles are fine, and layered structure and scale-like crystals can be seen under the electron microscope; montmorillonite The microscopic morphology of the stone is a dioctahedral layered structure composed of silicon-oxygen tetrahedron and aluminum-oxygen octahedron, which is usually vividly compared to a "sandwich" structure, and its general structural formula is: (K, Na, Ca, Mg) _y (Al,Mg) ₂ (Si,Al) ₄ O ₁₀ (OH) ₂ xH ₂ O, where (K,Na,Ca,Mg) _y is the interlayer exchangeable cation, (Al,Mg) ₂ is the octahedron The cation in , (Si,Al) ₄ is the cation in the tetrahedron, and the random substitution of Si and Al by Al and Mg in the structure causes charge imbalance, which makes it have the characteristics of chargeability and ion exchange. The charging and ion exchange properties of montmorillonite make it have a strong immobilization and adsorption effect on viruses, germs and their toxins and gases in the digestive tract, making the latter lose their pathogenicity; With a huge specific surface area, it has a strong ability to cover and protect the digestive tract mucosa, and by combining with mucus glycoproteins, it repairs and improves the defense function of the mucosal barrier against attacking factors, and has the effect of balancing normal flora and local analgesia.

Amoxicillin, also known as amoxicillin, is a broad-spectrum β-lactam antibiotic commonly used clinically, and it is also an antibacterial drug commonly used in the treatment of Helicobacter pylori (HP). Streptococcus, non-penicillinase-producing Staphylococcus, Enterococcus faecalis and other aerobic Gram-positive cocci, Escherichia coli, Proteus mirabilis, Salmonella, Haemophilus influenzae, Neisseria gonorrhoeae and other aerobic Gram-negative bacteria Bacteria that do not produce β-lactamase and Helicobacter pylori have good antibacterial activity. Amoxicillin exerts a bactericidal effect by inhibiting the synthesis of bacterial cell walls, and can rapidly dissolve and rupture bacteria into spheroids. Compared with other commonly used antibiotics in the treatment of Helicobacter pylori, amoxicillin has a strong bactericidal effect, and the rate of primary and secondary drug resistance is very low. It is not only preferred in newly diagnosed patients, but also can be used repeatedly in salvage treatment. Amoxicillin is well absorbed orally, and can be secreted into gastric juice and mucous membrane, and its structure can remain stable in 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, and the combined application of amoxicillin with alkaline montmorillonite can significantly improve its bactericidal activity. On the one hand, this is because montmorillonite provides an alkaline gastric absorption environment for the absorption of amoxicillin, which significantly increases the concentration of amoxicillin in the stomach, exceeding the minimum inhibitory concentration (MIC) of Helicobacter pylori. ); On the other hand, the increase of gastric pH can reduce the minimum inhibitory concentration of amoxicillin.

Rifabutin is an antibiotic used for the treatment of tuberculosis and the prevention and treatment of Mycobacterium avium tuberculosis. It inhibits bacterial DNA-dependent RNA synthesis by inhibiting bacterial DNA-dependent RNA polymerase. Rifabutin has shown potential use in the treatment of H. pylori because it does not share resistance with clarithromycin. Resistance of Helicobacter pylori to amoxicillin or rifabutin is very rare. The mean rate of H. pylori resistance to rifabutin (calculated from 11 studies involving 2982 patients) was generally 1.3%, and for patients who had never received H. pylori eradication therapy, it was 0.6%. Combining with amoxicillin can effectively avoid the problem of bacterial resistance.

Currently, the main drugs for the treatment of Helicobacter pylori are: clarithromycin, amoxicillin, metronidazole, levofloxacin, furazolidone and tetracycline. With the widespread use of antibacterial drugs, the number of resistant strains of Helicobacter pylori is increasing, and the eradication rate of traditional standard regimens is also getting lower and lower. Studies have found that the primary drug resistance rates of Helicobacter pylori in my country are 20% to 50% for clarithromycin, 40% to 70% for metronidazole, and 20% to 50% for levofloxacin. More heavy drug resistance. The triple therapy of montmorillonite, amoxicillin and rifabutin can completely kill Helicobacter pylori through physical adsorption, inhibition of bacterial cell wall synthesis and ribonucleic acid (RNA) synthesis, etc.

Compared with prior art, the beneficial effect that the present invention has is:

(1) The compound montmorillonite granule used for the treatment of Helicobacter pylori infection prepared by the present invention overcomes the difficult problem of antibiotic resistance, improves the eradication rate of Helicobacter pylori, and provides a new method for clinical patients to radically cure the diseases caused by Helicobacter pylori A new option.

(2) The compound montmorillonite granules used for treating Helicobacter pylori infection prepared by the present invention improve the administration compliance of patients with dysphagia and children.

(3) the preparation method of the compound montmorillonite granule that is used for the treatment of Helicobacter pylori infection of the present invention, simple to operate, process is stable, is suitable for the preparation method of the compound granule of large-scale production, and required production equipment is conventional equipment, has saved cost and increase the feasibility of production.

Detailed ways

Embodiments of the present invention will be described in detail below in conjunction with examples, but those skilled in the art will understand that the following examples are only for illustrating the present invention, and should not be regarded as limiting the scope of the present invention. Those who do not indicate the specific conditions in the examples are carried out according to the conventional conditions or the conditions suggested by the manufacturer. The reagents or instruments used were not indicated by the manufacturer, and they were all conventional products that could be purchased from the market.

The parts by weight described in the examples of the present invention and the comparative examples are all on a mass basis.

Example 1-Example 6

The compound montmorillonite particles for the treatment of Helicobacter pylori infection: comprise A component and B component, the raw material composition and quality that wherein comprise, wherein the average particle diameter of montmorillonite used in the embodiment 1-6 (D[4,3]) is 20 μm; the average particle size of amoxicillin (D[4,3]) is 20 μm; the average particle size of rifabutin (D[4,3]) is 10 μm. As shown in Table 1.

Table 1 raw material components and formula

Example 7-Example 12

The compound montmorillonite particles for the treatment of Helicobacter pylori infection: comprise A component and B component, the raw material composition and quality that wherein comprise, the montmorillonite average particle diameter used in wherein embodiment 7-12 (D[4,3]) is 20 μm; the average particle size of amoxicillin (D[4,3]) is 20 μm; the average particle size of rifabutin (D[4,3]) is 10 μm. As shown in table 2.

Table 2 raw material components and formula

Example 13-20

With the formula of Example 6, according to the following particle size distribution, others are all the same as in Example 6, and the compound montmorillonite particles for the treatment of Helicobacter pylori infection are prepared respectively, as shown in Table 3,

Table 3 Particle Size Distribution

The raw materials described in the above Examples 1-20 are prepared according to the following preparation methods for the treatment of Helicobacter pylori infection compound montmorillonite particles:

① Preparation of montmorillonite particles of component A:

1) Dissolving the adhesive in an appropriate amount of purified water to prepare a 5% solution;

2) placing montmorillonite, filler and disintegrant in a high-shear wet granulator and mixing uniformly;

3) adding the aqueous solution of step 1) to step 2) for wet granulation;

4) passing the material in step 3) through a 20-mesh sieve for granulation, drying, and controlling the moisture content to be less than 5%, to obtain montmorillonite particles;

② Preparation of Amoxicillin and rifabutin mixed granules of component B:

5) Dispersing the adhesive in an appropriate amount of purified water to prepare a 10% suspension;

6) Amoxicillin, rifabutin and filler are placed in a high-shear wet granulator and mixed uniformly;

7) adding the aqueous solution of step 5) to step 6) for wet granulation;

8) Sieve the material in step 7), dry it, and control the water content to be less than 5%, to obtain mixed granules of amoxicillin and rifabutin;

③ Preparation of compound montmorillonite particles:

9) Pass the obtained montmorillonite particles, amoxicillin and rifabutin mixed particles through a 30-mesh sieve respectively;

10) mix the material, sweetener and corrective agent in step 9), and finally add lubricant and mix evenly;

11) Subpackage the mixed particles obtained in step 10) to obtain compound montmorillonite particles for treating Helicobacter pylori infection.

The compound montmorillonite granules used in the treatment of Helicobacter pylori infection in all the above examples were used for in vitro pharmaceutical evaluation according to the second part of the Chinese Pharmacopoeia 2020 edition (the standard basis for each item), and another sample of Example 6 was selected. Carry out clinical effectiveness test (give montmorillonite compound granule (montmorillonite 3g, amoxicillin 300mg and rifabutin 30mg) 2 times every day, take continuously for 2 weeks), count the effective rate of Helicobacter pylori in patients ( All patients were diagnosed by gastroscopy, and two biopsies were taken from gastric antrum and gastric body mucosa, respectively, for rapid urease test, tissue smear Gram staining and tissue fixation, dehydration, section staining and microscopic examination of HP; If 2 or more items are positive, it is diagnosed as HP positive).

The evaluation results are shown in Table 4 and Table 5 respectively.

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

Dissolution of amoxicillin (30min): using pH6.8, paddle method 50rpm, the dissolution of amoxicillin in 45min shall not be less than 85%.

Dissolution of rifabutin (30min): pH 6.8, paddle method 50rpm, dissolution of rifabutin in 45min shall not be less than 85%.

Judgment criteria for patient acceptability: above 95-very satisfied, 85-95-satisfied, 75-85-basically satisfied and below 75-dissatisfied.

Wherein, the experimental parameters in Table 5 are: daily administration of montmorillonite compound granules (montmorillonite 3g, amoxicillin 300mg and rifabutin 30mg) 2 times, breakfast and dinner after meals, continuous administration for 2 weeks . All patients were diagnosed by gastroscopy, and two biopsies were taken from gastric antrum and gastric body mucosa, respectively, for rapid urease test, tissue smear Gram staining and tissue fixation, dehydration, section staining and microscopic examination of HP; If 2 or more items are positive, it is diagnosed as HP positive, otherwise it is negative.

Table 4 In vitro pharmaceutical evaluation results of compound montmorillonite granules

Table 5 Compound Montmorillonite Granules Clinical Effectiveness Test Results

Of course, the above content is only a preferred embodiment of the present invention, and should not be considered as limiting the scope of the embodiments of the present invention. The present invention is not limited to the above-mentioned examples, and equal changes and improvements made by those skilled in the art within the essential scope of the present invention shall all belong to the scope covered by the patent of the present invention.

Claims (10)

1. A compound montmorillonite particle for the treatment of Helicobacter pylori infection, characterized in that: comprise A component and B component, wherein A component is made by the following raw materials in parts by weight:

Component B is made from the following raw materials in parts by weight:

2 . The compound montmorillonite granule for treating Helicobacter pylori infection according to claim 1 , further comprising 0.5-7 parts by weight of lubricant and 0.1-2 parts by weight of flavoring agent. 3. the compound montmorillonite granule that is used for the treatment of Helicobacter pylori infection according to claim 2, is characterized in that: corrective agent is a kind of in sucralose, aspartame, strawberry essence, menthol or Various. 4. The compound montmorillonite particle for treating Helicobacter pylori infection according to claim 1, characterized in that: the average particle diameter of montmorillonite is 10～100 μm; the average particle diameter of amoxicillin is 30～100 μm; The average particle size of forbutin is 10-30 μm. 5. The compound montmorillonite granule for treating Helicobacter pylori infection according to claim 1, characterized in that: filler a is sucrose or starch; filler b is mannitol or sorbitol. 6. the compound montmorillonite particle that is used for the treatment of Helicobacter pylori infection according to claim 1 is characterized in that: binder a is hydroxypropyl cellulose or povidone; binder b is pregelatinized starch or hypromellose. 7. the compound montmorillonite particle that is used for the treatment of Helicobacter pylori infection according to claim 1, is characterized in that: disintegrant is crospovidone, cross-linked sodium carboxymethyl cellulose, sodium starch glycolate One of. 8. The compound montmorillonite particle for treating Helicobacter pylori infection according to claim 2, characterized in that: the lubricant is a mixture of sodium stearyl fumarate or talcum powder and polyethylene glycol. 9. a preparation method for the compound montmorillonite granule for the treatment of helicobacter pylori infection described in any one of claim 1-8, it is characterized in that: comprise the following steps: ① Preparation of montmorillonite particles of component A: 1) configuring the adhesive into an aqueous solution; 2) Mix montmorillonite, filler and disintegrant evenly; 3) adding the aqueous solution of step 1) to step 2) for wet granulation; 4) The material in step 3) is screened for granulation, dried, and the moisture content is controlled to be less than 5%, so as to obtain montmorillonite particles; ② Preparation of Amoxicillin and rifabutin mixed granules of component B: 5) configuring the adhesive into an aqueous solution; 6) Mix amoxicillin, rifabutin and filler evenly; 7) adding the aqueous solution of step 5) to step 6) for wet granulation; 8) Sieve the material in step 7), dry it, and control the water content to be less than 5%, to obtain mixed granules of amoxicillin and rifabutin; ③ Preparation of compound montmorillonite particles: 9) Sieve the obtained montmorillonite particles, amoxicillin and rifabutin mixed particles respectively; 10) mix the material, sweetener and corrective agent in step 9), and finally add lubricant and mix evenly; 11) Subpackage the mixed particles obtained in step 10) to obtain compound montmorillonite particles for treating Helicobacter pylori infection. 10. the preparation method for the compound montmorillonite particle that is used for the treatment of Helicobacter pylori infection according to claim 9, is characterized in that: the particle diameter of compound montmorillonite particle cannot pass through No. 1 sieve and can pass through No. 5 sieve The sum does not exceed 15%.