Composite solution for treating reflux esophagitis and preparation method and application thereof

Abstract

The invention discloses a composite solution for treating reflux esophagitis and a preparation method and application thereof, and relates to the technical field of pharmaceutical preparations, the composite solution is formed by physically mixing drug-loaded microspheres and a gastric buoyant raft matrix solution; wherein the drug-loaded microspheres are solid particles which take thiolated pectin as a carrier, are crosslinked and cured through divalent metal ions and are coated with a periplaneta americana extract; the gastric buoyant raft matrix solution comprises a hydrophilic colloid, a component capable of generating gas when encountering acid and a stabilizer. The magnesium mercapto pectin microspheres provide excellent mucous membrane adhesion, and the acting time of the medicine on the esophageal focus is prolonged; the gastric buoyant raft substrate forms a physical barrier in a gastric acid environment to inhibit regurgitation of gastric contents. Through cooperation of the two, a dual treatment mechanism of local repair and source control is realized. The preparation can remarkably prolong the in-vivo residence time and effectively promote esophageal mucosa healing, and the curative effect is better than that of a pure periplaneta americana extract preparation.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, specifically to a pharmaceutical formulation for treating reflux esophagitis (GERD), particularly a composite solution containing extracts of American cockroaches that has both mucosal adhesion and gastric buoyancy functions, as well as its preparation method and its use in pharmaceutical manufacturing. Background Technology

[0002] Gastroesophageal reflux disease (GERD) is a chronic inflammatory disease caused by the reflux of stomach and duodenal contents into the esophagus. Its characteristic pathological changes include inflammation, erosion, and even ulceration of the esophageal mucosa. Global epidemiological surveys show that its incidence is on the rise, making it a common digestive system disease affecting public health. While current first-line systemic treatments (such as proton pump inhibitors) can effectively suppress acid, they have drawbacks including the need for long-term medication, potential side effects, and the inability to resolve the physical irritation caused by reflux.

[0003] American cockroach extract (PAE) is a known natural drug with good anti-inflammatory and tissue-repairing activities, and its commercially available formulation, Kangfuxin Liquid, is often used clinically for mucosal repair. However, conventional liquid formulations have significant drawbacks: First, they have poor adhesion to the esophageal and gastric mucosa, are rapidly cleared after oral administration, and cannot form an effective drug concentration at the lesion site, resulting in low local bioavailability; second, they lack physical intervention against the core pathological link of GERD—gastric contents reflux, leading to limited therapeutic effects.

[0004] In the existing technology, there is research on bioadhesive materials (such as pectin and chitosan) for improving drug adhesion, as well as flotation formulations for gastric retention. However, simply improving adhesion cannot prevent the continued occurrence of reflux; and simple gastric flotation formulations lack specific therapeutic effects on damaged esophageal mucosa. Therefore, there is an urgent need in the field for an innovative formulation that can simultaneously achieve both long-acting local adhesive drug delivery and physical anti-reflux functions, so as to treat reflux esophagitis more efficiently and specifically through the synergistic treatment of "long-acting local drug delivery" and "immediate physical anti-reflux". Summary of the Invention

[0005] The primary objective of this invention is to overcome the shortcomings of existing PAE formulations, such as poor adhesion and lack of anti-reflux function, and to provide a novel composite solution formulation. This formulation aims to simultaneously achieve two major goals through innovative carrier and delivery system design: 1) significantly prolonging the retention and action time of PAE on the esophageal and upper gastric mucosa; 2) forming a physical barrier within the stomach to immediately inhibit the upward reflux of gastric contents, thereby achieving a dual synergistic therapeutic effect of "local repair" and "etiological control".

[0006] To achieve the above objectives, the present invention provides the following technical solution: In a first aspect, the present invention provides a composite solution for treating reflux esophagitis, which is formed by physically mixing drug-loaded microspheres and a gastric raft matrix solution.

[0007] The drug-loaded microspheres are solid particles containing American cockroach extract, which are cross-linked and solidified with divalent metal ions using thiolated pectin as a carrier.

[0008] The gastric raft matrix solution contains hydrophilic colloids, components that produce gas upon contact with acid, and stabilizers.

[0009] In the composite solution, the final concentration of the American cockroach extract is from 0.1% (w / v) to 10.0% (w / v), preferably from 0.5% (w / v) to 2.0% (w / v), and the final concentration of the thiolated pectin is from 0.1% (w / v) to 10.0% (w / v), preferably from 1.0% (w / v) to 5.0% (w / v).

[0010] The American cockroach extract was obtained by an alcohol extraction and water precipitation process.

[0011] Furthermore, the thiolated pectin is prepared by esterification reaction of low-ester pectin and mercaptoacetic acid. The preparation method is as follows: dissolve low-ester pectin (esterification degree <50%) in hot water, add mercaptoacetic acid and a catalytic amount of hydrochloric acid, and react at 70℃-85℃. The reaction product is then precipitated with an organic solvent, washed, and dried.

[0012] Furthermore, the divalent metal ions include magnesium ions, calcium ions, zinc ions, iron ions, copper ions, and manganese ions, preferably magnesium ions.

[0013] Furthermore, the hydrophilic colloid in the gastric raft matrix solution is capable of gelling in an acidic environment and is selected from one or more of sodium alginate, pectin, and xanthan gum, preferably a combination of sodium alginate and pectin, with a mass ratio of sodium alginate to pectin of 1:10 to 10:1, preferably 1:3 to 3:1. The component that generates gas upon contact with acid is selected from one or more of sodium bicarbonate, sodium carbonate, calcium carbonate, and magnesium carbonate, preferably sodium bicarbonate and / or calcium carbonate. The stabilizer is selected from one or more of glyceryl monooleate, polysorbate 80, xanthan gum, hydroxypropyl methylcellulose, magnesium stearate, and polyethylene glycol 4000, preferably a combination of glyceryl monooleate and xanthan gum.

[0014] In an embodiment of the present invention, the composite solution comprises the following components (by final solution volume percentage w / v): 0.1%-10.0% American cockroach extract, 0.1%-10.0% thiolated pectin, 0.1%-10.0% sodium alginate, 0.2%-15.0% pectin, 1.0%-20.0% sodium bicarbonate, 1.0%-20.0% calcium carbonate, 0%-5.0% xanthan gum, 1.0%-30.0% glyceryl monooleate, 1.0%-5.0% magnesium chloride, with the balance being water.

[0015] In a preferred embodiment of the present invention, the composite solution comprises the following components (by final solution volume percentage w / v): 0.5%-2.0% American cockroach extract, 1.0%-5.0% thiolated pectin, 0.1%-4.0% sodium alginate, 0.2%-8.0% pectin, 1.0%-10.0% sodium bicarbonate, 1.0%-10.0% calcium carbonate, 0%-2.0% xanthan gum, 1.0%-20.0% glyceryl monooleate, 1.0%-5.0% magnesium chloride, with the balance being water.

[0016] In a preferred embodiment, the composite solution comprises the following components (by final solution volume percentage w / v): 0.5% American cockroach extract, 1.0% thiolated pectin, 1.0% sodium alginate, 1.5% pectin, 2.0% sodium bicarbonate, 2.0% calcium carbonate, 10.0% glyceryl monooleate, and the balance being water.

[0017] In a second aspect, the present invention provides a method for preparing the composite solution described in the first aspect, comprising the following steps: (1) Preparation of thiolized pectin; (2) Preparation of thiol pectin-metal ion microspheres loaded with American cockroach extract: The thiol pectin obtained in step (1) is co-dissolved with American cockroach extract in water to obtain a drug-loaded solution; the drug-loaded solution is added dropwise to a divalent metal ion salt solution, cross-linked and cured, and then separated, washed and dried to obtain drug-loaded microspheres; (3) Preparation of gastric raft matrix solution: hydrophilic colloid and acid-producing gas components are dissolved or dispersed in water in sequence, then stabilizer is added and homogenized to obtain the solution; (4) Combining: The dried drug-loaded microspheres obtained in step (2) are added to the gastric raft matrix solution obtained in step (3) in proportion, and stirred at low speed to disperse them evenly, thus obtaining the final composite solution.

[0018] In step (2), the concentration of the divalent metal ion salt solution is 1%-10% (w / v).

[0019] In step (4), the mixture is intermittently stirred at a very low speed of 5 rpm to 20 rpm for 8 to 15 minutes to ensure that the microspheres are uniformly dispersed in the solution without compromising the homogeneity of the solution.

[0020] Thirdly, the present invention provides the use of the composite solution described in the first aspect in the preparation of a medicament for treating reflux esophagitis.

[0021] Compared with the prior art, the technical solution provided by the present invention has the following significant progress and beneficial effects: This invention creates a novel synergistic therapeutic mechanism: It is not a simple superposition of existing adhesion and flotation technologies, but rather a functional combination of "drug-loaded adhesive microspheres" and "gastric floating gel" to construct a spatiotemporally coordinated delivery system. After oral administration, the microspheres adhere tightly to the esophageal and cardia mucosa due to the adhesive properties of their thiol groups, achieving localized and long-lasting release of PAE and directly repairing damage. Simultaneously, the gastric raft matrix solution rapidly forms a gel-like floating raft under the action of gastric acid. This raft, located on top of the gastric contents, physically blocks gastric reflux, creating a non-irritating environment for esophageal mucosal repair. The two work synergistically from different levels and mechanisms, producing a therapeutic effect greater than the sum of its parts ("1+1>2").

[0022] The invention provides solid experimental evidence: its effectiveness has been verified through systematic in vivo and in vitro experiments.

[0023] In vivo retention experiment (see Example 10, Figure 1 In vivo imaging results showed that the composite solution of the present invention still exhibited strong fluorescence signals in the esophagus and stomach of rats 2 hours after administration, while the signal of the control ordinary Kangfuxin solution essentially disappeared after 30 minutes. This directly demonstrates the excellent mucosal adhesion and gastric retention capabilities of the formulation of the present invention.

[0024] Pharmacodynamic experiments (see Example 10) Figure 2 , Figure 3 After 7 days of treatment with the formulation of this invention, rats with reflux esophagitis showed a significant reduction in the esophageal mucosal damage index (P<0.01). Histopathological sections showed a significant improvement in inflammatory cell infiltration and erosion ulceration, with a repair effect significantly superior to that of Kangfuxin liquid alone, and comparable to or better than the positive control drug Gaviscon. This strongly confirms the synergistic therapeutic benefit brought about by the dual mechanism.

[0025] Physicochemical characterization (see Example 11): The gastric raft thickness formed by the formulation of the present invention can reach 3.5 cm, which is superior to the commercially available control, and it has suitable rheological properties (shear thinning behavior), ensuring good oral compliance and gastric raft formation performance. Attached Figure Description

[0026] Figure 1This is a comparison of real-time retention images of the fluorescently labeled preparations in the esophagus and stomach of rats in Example 10 of the present invention. Figure 2 These are representative pathological sections (H&E staining, ×100) of esophageal tissue from each group of rats after treatment in Example 10 of the present invention. Figure 3 This is a statistical analysis chart of the esophageal mucosal damage index of each group of rats based on the pathological scoring criteria in Example 10 of the present invention (*P<0.05, **P<0.01, ***P<0.001, ****P<0.0001, ns indicates no statistical difference). Detailed Implementation

[0027] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to specific embodiments and accompanying drawings. Unless otherwise specified, the experimental methods used in the following embodiments are conventional methods; the materials and reagents used, unless otherwise specified, are commercially available. The American cockroach extract described in this invention is obtained by referring to the preparation method described in patent application CN117018035A.

[0028] Example 1 Synthesis of thiol pectin: Weigh 16.02 g of low-ester pectin (esterification degree <30%) and disperse it in 200 mL of deionized water preheated to 70 °C. Stir until completely dissolved to obtain a clear pectin solution. Add 6.59 g of 92% (w / w) mercaptoacetic acid and 1.67 mL of 12 mol / L concentrated hydrochloric acid to the above pectin solution and stir to mix well. Place the reaction system in an 80 °C water bath and stir continuously for 150 minutes. After the reaction is complete, slowly pour the reaction solution into 500 mL of cold methanol and let it stand overnight to allow the white fibrous precipitate to completely precipitate. Collect the precipitate by suction filtration, wash it thoroughly three times with methanol, dry it at room temperature in a fume hood for 48 hours, grind it to obtain a white powdery mercapto-modified pectin, and seal it for later use.

[0029] Example 2 Synthesis of thiol pectin: Weigh 16.02 g of low-ester pectin (esterification degree <30%) and disperse it in 200 mL of deionized water preheated to 70 °C. Stir until completely dissolved to obtain a clear solution. Add 6.59 g of 92% (w / w) mercaptoacetic acid and 1.67 mL of 12 mol / L concentrated hydrochloric acid to the solution sequentially. Place the reaction system in a 75 °C water bath and stir continuously for 180 minutes. After the reaction is complete, slowly pour the reaction solution into 520 mL of cold methanol and let it stand overnight to allow a white fibrous precipitate to completely precipitate. Collect the precipitate by suction filtration, wash it thoroughly three times with methanol, dry it at room temperature in a fume hood for 48 hours, grind it to obtain a white powdery mercapto-treated pectin, and store it in a sealed container for later use.

[0030] Example 3 Synthesis of thiol pectin: Weigh 16.02 g of low-ester pectin (esterification degree <30%) and disperse it in 200 mL of deionized water preheated to 70 °C. Stir until completely dissolved to obtain a clear solution. Add 8.24 g of 92% (w / w) mercaptoacetic acid and 1.67 mL of 12 mol / L concentrated hydrochloric acid to the solution sequentially. Place the reaction system in an 80 °C water bath and stir continuously for 150 minutes. After the reaction is complete, slowly pour the reaction solution into 600 mL of cold methanol and let it stand overnight to allow a white fibrous precipitate to completely precipitate. Collect the precipitate by suction filtration, wash it thoroughly three times with 70% methanol aqueous solution, dry it at room temperature in a fume hood for 48 hours, grind it to obtain a white powdery mercapto-treated pectin, and store it in a sealed container for later use.

[0031] Example 4 Preparation of thiol pectin magnesium microspheres loaded with American cockroach extract (PAE-TP-Mg): Accurately weigh 0.1 g of the thiolized pectin powder prepared in Example 1 and dissolve it in 10 mL of deionized water. Add 0.05 g of freeze-dried American cockroach extract powder (mass of dried American cockroach extract extract), and stir magnetically for 2 hours to completely dissolve and mix evenly, obtaining a light brown drug-loaded gel. Using a 5 mL sterile syringe (equipped with a 22G needle), draw up the gel and drop it vertically at a constant rate (approximately 1 mL / min) into a beaker containing 50 mL of 3% (w / v) magnesium chloride solution. After the addition is complete, allow it to stand and solidify for 20 minutes. Collect the formed spherical microspheres through a sieve (200 mesh) and rinse three times with deionized water to remove excess magnesium ions and unloaded drug. After pre-freezing the wet microspheres at -80°C, freeze-dry them for 24 hours to obtain dried thiolized pectin magnesium microspheres loaded with 0.5% PAE, denoted as PAE-TP-Mg.

[0032] Example 5 Preparation of thiol pectin magnesium microspheres loaded with American cockroach extract (PAE-TP-Mg): Accurately weigh 0.15 g of the thiolized pectin powder prepared in Example 1 and dissolve it in 10 mL of deionized water. Add 0.08 g of freeze-dried American cockroach extract powder (mass of dried American cockroach extract extract), and stir magnetically for 2 hours to completely dissolve and mix evenly, obtaining a light brown drug-loaded gel. Using a 5 mL sterile syringe (equipped with a 22G needle), draw up the gel and drop it vertically at a constant rate (approximately 1 mL / min) into a beaker containing 50 mL of 3% (w / v) magnesium chloride solution. After the addition is complete, allow it to stand and solidify for 20 minutes. Collect the formed spherical microspheres through a sieve (200 mesh) and rinse three times with deionized water to remove excess magnesium ions and unloaded drug. After pre-freezing the wet microspheres at -80°C, freeze-dry them for 24 hours to obtain dried thiolized pectin magnesium microspheres loaded with 0.8% PAE, denoted as PAE-TP-Mg.

[0033] Example 6 Preparation of gastric raft matrix solution: Measure 10 mL of deionized water into a 50 mL beaker. Accurately add 0.15 g of pectin, 0.1 g of sodium alginate, and 0.2 g of sodium bicarbonate sequentially. Place the beaker in a 45°C constant temperature water bath and magnetically stir at a gentle speed of 20 rpm for 30 minutes until all solids are completely dissolved, resulting in a clear, viscous solution. Subsequently, add 0.2 g of calcium carbonate powder and 1.0 g of glyceryl monooleate sequentially to this solution. Maintain the same temperature and stirring speed, and continue stirring for 10 minutes to ensure thorough and uniform dispersion of all components. Remove from the water bath and allow to cool naturally to room temperature (25°C) to obtain the gastric raft matrix solution.

[0034] Example 7 Preparation of gastric raft matrix solution: Measure 10 mL of deionized water into a 50 mL beaker. Accurately add 0.20 g of pectin, 0.20 g of sodium alginate, and 0.25 g of sodium bicarbonate in sequence. Place the beaker in a 45°C constant temperature water bath and magnetically stir at a gentle speed of 20 rpm for 37 minutes until all solids are completely dissolved, resulting in a clear, viscous solution. Subsequently, add 0.15 g of calcium carbonate powder and 1.50 g of glyceryl monooleate to this solution in sequence. Maintain the same temperature and stirring speed, and continue stirring for 15 minutes to ensure thorough and uniform dispersion of all components. Remove from the water bath and allow to cool naturally to room temperature (25°C) to obtain the gastric raft matrix solution.

[0035] Example 8 Preparation of the composite solution (PAE-TP-Mg-RF): Accurately weigh 10.0 mg of the dried PAE-TP-Mg microspheres prepared in Example 4 and place them in a sterile vial. Measure 10.0 mL of the gastric raft matrix solution prepared in Example 6 and add it to the same vial. Fix the vial on a vortex mixer and stir intermittently at a very low speed (approximately 10 rpm) for 10 minutes to ensure that the microspheres are uniformly dispersed in the solution without compromising the homogeneity of the solution. This yields the final American cockroach thiol pectin magnesium microsphere-gastric raft composite solution, labeled as PAE-TP-Mg-RF.

[0036] Example 9 Preparation of the composite solution (PAE-TP-Mg-RF): Accurately weigh 10.0 mg of the dried PAE-TP-Mg microspheres prepared in Example 5 and place them in a sterile vial. Measure 10.0 mL of the gastric raft matrix solution prepared in Example 7 and add it to the same vial. Fix the vial on a vortex mixer and stir intermittently for 10 minutes at a very low speed (approximately 10 rpm) to ensure that the microspheres are uniformly dispersed in the solution without compromising the homogeneity of the solution. This yields the final American cockroach thiol pectin magnesium microsphere-gastric raft composite solution, labeled as PAE-TP-Mg-RF.

[0037] Example 10 Pharmacodynamic evaluation of compound solution for the treatment of reflux esophagitis: Animal model establishment: Healthy male SD rats (180 g-220 g) were selected, and a modified surgical method combining partial pyloric ligation and cardiac sphincter incision was used to establish an animal model of reflux esophagitis. The sham-operated group underwent only laparotomy and laparotomy.

[0038] Experimental grouping and administration: Twenty-five rats that successfully established the model were randomly divided into five groups (n=5): normal control group (sham surgery, administered saline), model control group (modeling, administered saline), Kangfuxin liquid positive control group (modeling, administered commercially available Kangfuxin liquid (KF-Liquid), manufacturer: Sichuan Good Doctor Panxi Pharmaceutical Co., Ltd.), Gaviscon positive control group (modeling, administered commercially available aluminum magnesium carbonate suspension (Gaviscon), manufacturer: Reckitt Benckiser Healthcare (UK) Limited), and the formulation of this invention group (modeling, administered PAE-TP-Mg-RF prepared in Example 8). All formulations were administered by gavage, 2 mL twice daily (8 hours apart), for 7 consecutive days.

[0039] In vivo fluorescence imaging was used to evaluate retention: All formulations were pre-labeled with the near-infrared fluorescent dye DiR at the time of administration. Following gavage, fluorescence intensity in the esophagus and stomach of rats was monitored at time points of 5 min, 15 min, 30 min, and 120 min using a small animal in vivo imaging system. Results are as follows: Figure 1 As shown, the PAE-TP-Mg-RF group of this invention still maintained a strong fluorescence signal in the esophagus and stomach at 120 min, which was significantly better than the Kangfuxin liquid group (the signal almost disappeared after 30 min), indicating that it has excellent mucosal adhesion and gastric retention ability.

[0040] Histopathological and Damage Index Evaluation: Animals were sacrificed 24 hours after the last administration. Tissue from the lower esophagus was collected, fixed in formalin, embedded in paraffin, sectioned, and stained with H&E. Two pathologists, unaware of the group assignments, observed and scored the tissue under a light microscope. Scoring criteria: 0 points, intact mucosa without damage; 1 point, inflammatory cell infiltration within the epithelial layer; 2 points, erosion limited to the muscularis mucosae; 3 points, ulceration extending to the submucosa or muscularis propria. Results are as follows: Figure 2 , Figure 3 As shown, the damage index of the model group was significantly increased; the damage index of the PAE-TP-Mg-RF group of this invention was the lowest, with no statistical difference from the normal control group, and was significantly better than the Kangfuxin liquid group, proving its excellent therapeutic effect.

[0041] Example 11 Physicochemical characterization of the composite solution: pH value: The pH value of the fresh PAE-TP-Mg-RF composite solution prepared in Example 8 was measured to be 8.55±0.06 (n=3) using a pH meter.

[0042] Intragastric raft formation performance: 10 mL of the composite solution was added to a 100 mL graduated cylinder containing 50 mL of 0.1 M HCl (simulating gastric acid), and timing was started immediately. The final thickness of the formed gel raft was observed and measured to be 3.5 ± 0.12 cm (n=3), and the raft remained intact and floated for more than 4 hours.

[0043] Rheological properties: The composite solution exhibits typical "shear-thinning" non-Newtonian fluid behavior, as measured by a rotational rheometer. Its zero-shear viscosity (η0) is 3.14 ± 0.04 Pa·s (n=3), indicating that its high viscosity at rest is conducive to adhesion, and its viscosity decreases during swallowing due to shear force, making it easy to take orally.

[0044] Comparative Example 1 Adhesive microsphere suspension without gastric rafts: Only the PAE-TP-Mg microspheres of Example 4 were prepared and uniformly dispersed in 10 mL of physiological saline to form a microsphere suspension. This comparative example only has adhesive function and lacks gastric rafting and anti-reflux ability. Animal experiments showed that its retention time in the stomach was shorter than that of PAE-TP-Mg-RF, and its overall improvement effect on esophageal mucosal damage was also inferior to that of the composite solution of this invention.

[0045] Comparative Example 2 Ordinary gastric raft solution without adhesive microspheres: Only the gastric raft matrix solution of Example 6 was prepared. This comparative example only has anti-reflux function, but lacks specific therapeutic components (PAE) for the esophageal mucosa. Animal experiments showed that although it could alleviate reflux irritation to some extent, its repair effect on existing esophageal inflammation and erosion was far inferior to the composite solution of the present invention.

[0046] The above examples and comparative examples collectively demonstrate that the technical solution of this invention, which combines drug-loaded adhesive microspheres with a gastric raft solution, produces a significant improvement in synergistic efficacy. Thiol-based magnesium pectin microspheres provide excellent mucosal adhesion, prolonging the drug's action time at the esophageal lesion; the gastric raft matrix forms a physical barrier in the acidic environment of the stomach, inhibiting the reflux of gastric contents. The two work synergistically to achieve a dual therapeutic mechanism of "local repair" and "source control." This formulation can significantly prolong the retention time in the body, effectively promoting esophageal mucosal healing, and its efficacy is superior to that of simple American cockroach extract formulations, providing an innovative and highly effective local treatment strategy for reflux esophagitis.

Claims

1. A compound solution for treating reflux esophagitis, characterized in that, It is formed by physically mixing drug-loaded microspheres and a gastric raft matrix solution; wherein, the drug-loaded microspheres are solid particles with thiolized pectin as a carrier, cross-linked and solidified by divalent metal ions, and loaded with American cockroach extract; the gastric raft matrix solution contains hydrophilic colloids, components that produce gas upon contact with acid, and stabilizers.

2. The compound solution for treating reflux esophagitis according to claim 1, characterized in that, The final concentration of the American cockroach extract in the compound solution was from 0.1% (w / v) to 10.0% (w / v).

3. The compound solution for treating reflux esophagitis according to claim 1, characterized in that, The thiolated pectin is prepared by esterification of low-ester pectin and thioglycolic acid.

4. The compound solution for treating reflux esophagitis according to claim 1, characterized in that, The divalent metal ions include magnesium ions, calcium ions, zinc ions, iron ions, copper ions, and manganese ions.

5. The compound solution for treating reflux esophagitis according to claim 1, characterized in that, The hydrophilic colloid is capable of gelling in an acidic environment and is selected from one or more of sodium alginate, pectin, and xanthan gum; the component that produces gas upon contact with acid is selected from one or more of sodium bicarbonate, sodium carbonate, calcium carbonate, and magnesium carbonate; the stabilizer is selected from one or more of glyceryl monooleate, polysorbate 80, xanthan gum, hydroxypropyl methylcellulose, magnesium stearate, and polyethylene glycol 4000.

6. The compound solution for treating reflux esophagitis according to claim 5, characterized in that, The hydrophilic colloid is a combination of sodium alginate and pectin, and the mass ratio of sodium alginate to pectin is 1:10 to 10:1; the component that produces gas upon contact with acid is sodium bicarbonate and / or calcium carbonate; the stabilizer is a combination of glyceryl monooleate and xanthan gum.

7. The compound solution for treating reflux esophagitis according to any one of claims 1-6, characterized in that, The composite solution is composed of the following components, by final solution volume percentage (w / v): American cockroach extract 0.1%-10.0%, thiolated pectin 0.1%-10.0%, sodium alginate 0.1%-10.0%, pectin 0.2%-15.0%, sodium bicarbonate 1.0%-20.0%, calcium carbonate 1.0%-20.0%, xanthan gum 0%-5.0%, glyceryl monooleate 1.0%-30.0%, magnesium chloride 1.0%-5.0%, with the balance being water.

8. A method for preparing a composite solution for treating reflux esophagitis according to any one of claims 1-7, characterized in that, Includes the following steps: Preparation of thiolized pectin; The prepared thiolized pectin was co-dissolved in water with American cockroach extract to obtain a drug-loaded gel solution; the drug-loaded gel solution was added dropwise to a divalent metal ion salt solution, and after cross-linking and solidification, it was separated, washed and dried to obtain drug-loaded microspheres; The hydrophilic colloid and the component that produces gas upon contact with acid are dissolved or dispersed sequentially in water, then a stabilizer is added, and the mixture is homogenized to obtain a gastric raft matrix solution. The prepared drug-loaded microspheres were added to the prepared gastric raft matrix solution in a certain proportion and stirred at low speed to disperse them evenly, thus obtaining the composite solution.

9. The method for preparing the composite solution for treating reflux esophagitis according to claim 8, characterized in that, The concentration of the divalent metal ion salt solution is 1%-10% (w / v); stir intermittently for 8-15 minutes at a very low speed of 5 rpm-20 rpm.

10. The use of the compound solution for treating reflux esophagitis according to any one of claims 1-7 in the preparation of a medicament for treating reflux esophagitis.

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