Application of neohesperidin dihydrochalcone in prevention or treatment of acute stomach injury

Abstract

The invention discloses an application of neohesperidin dihydrochalcone in prevention or treatment of acute stomach injury, and comprises an application of neohesperidin dihydrochalcone in preparation of drugs for prevention or treatment of acute stomach injury, and the drugs comprise a pharmaceutical composition containing neohesperidin dihydrochalcone. The pharmaceutical composition is designed as an intragastric targeted delivery system; the intragastric targeted delivery system is in an oral solid dosage form and comprises an immediate release unit and a sustained release unit, the immediate release unit is used for quickly releasing a first part of neohesperidin dihydrochalcone in the stomach, and the sustained release unit is used for retaining and continuously releasing a second part of neohesperidin dihydrochalcone in the stomach. By designing a unique intragastric targeting delivery system, neohesperidin dihydrochalcone can continuously and efficiently play a multi-target gastric mucosa protection role at an injured part.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically relating to the application of neohesperidin dihydrochalcone in the prevention or treatment of acute gastric injury. Background Technology

[0002] Acute gastric injury refers to rapid and diffuse damage to the gastric mucosa caused by various pathogenic factors such as nonsteroidal anti-inflammatory drugs, ethanol, stress, and ischemia-reperfusion. Clinical manifestations include mucosal congestion, edema, erosion, bleeding, and even acute ulcer formation. This condition has a rapid onset, and if not controlled promptly, it can lead to severe upper gastrointestinal bleeding, affecting the patient's quality of life and increasing the medical burden.

[0003] Currently, drugs used clinically for the prevention and treatment of acute gastric injury mainly fall into three categories: drugs that inhibit gastric acid secretion (such as proton pump inhibitors and H2 receptor antagonists), antacids that neutralize gastric acid, and mucosal protectants that enhance mucosal defense function (such as bismuth preparations and sucralfate). However, existing treatment options still have certain limitations. For example, while acid-suppressing drugs can effectively reduce attacking factors, their ability to repair damaged mucosa is limited, and long-term use may lead to certain side effects. Traditional mucosal protectants often have relatively simple mechanisms of action, and their protective efficacy may be insufficient when dealing with complex gastric mucosal injuries involving multiple aspects such as oxidative stress and inflammatory responses. Therefore, developing novel gastric mucosal protectants with multi-target protective effects and high safety is an urgent clinical problem to be solved.

[0004] Regarding administration methods, most existing oral formulations have a short residence time in the stomach, making it difficult to maintain an effective drug concentration at the site of injury for an extended period, thus affecting therapeutic efficacy. Exploring formulation technologies that can prolong drug residence time in the stomach and achieve local targeted delivery is of great significance for improving the prevention and treatment efficiency of acute gastric injury.

[0005] Neohesperidin dihydrochalcone (NHDC) is a natural sweetener extracted from citrus plants, widely used in the food industry due to its high sweetness and low calorie content. Recent studies have shown that NHDC possesses multiple biological activities, including anti-inflammatory, antioxidant, and metabolic regulatory effects, suggesting its potential therapeutic value. However, its application in the prevention and treatment of acute gastric injury remains unexplored and lacks systematic research and clear reports. In particular, overcoming its physicochemical limitations and utilizing delivery systems to efficiently target it to the site of gastric mucosal injury, thereby fully realizing its multiple pharmacological potential, remains an unexplored technological area. Summary of the Invention

[0006] The purpose of this invention is to provide the application of neohesperidin dihydrochalcone in the prevention or treatment of acute gastric injury. By designing a unique intragastric targeted delivery system, neohesperidin dihydrochalcone can exert a sustained and efficient multi-target gastric mucosal protective effect at the site of injury, solving the problems of relatively simple drug action mechanism, short residence time in the stomach and insufficient local drug utilization of existing drugs.

[0007] To solve the above-mentioned technical problems, the present invention is achieved through the following technical solution: This invention relates to the application of neohesperidin dihydrochalcone in the prevention or treatment of acute gastric injury, comprising: The use of a neohesperidin dihydrochalcone in the preparation of a medicament for the prevention or treatment of acute gastric injury, characterized in that the medicament comprises a pharmaceutical composition containing neohesperidin dihydrochalcone, the pharmaceutical composition being designed as an intragastric targeted delivery system; The gastric targeted delivery system is an oral solid dosage form, comprising an immediate-release unit and a sustained-release unit, wherein the immediate-release unit is used to rapidly release a first portion of neohesperidin dihydrochalcone in the stomach, and the sustained-release unit is used to remain in the stomach and continuously release a second portion of neohesperidin dihydrochalcone. The oral solid dosage form is a bilayer tablet, which includes an immediate-release layer as an immediate-release unit and a sustained-release-retention layer as a sustained-release unit. The sustained-release-retention layer comprises a hydrophilic gel framework material, a foaming agent, and a low-density excipient, enabling the layer to absorb water and swell in gastric juice, generate gas, and reduce density, thereby achieving floating and retention in the stomach. The sustained-release-retention layer also contains a bioadhesive polymer to enhance the adhesion of the bilayer tablet to the gastric mucosa; The immediate-release layer contains a super-disintegrant to induce rapid disintegration of the layer and release of the drug in the gastric environment; The outer surface of the double-layer tablet is coated with a pH-sensitive coating layer that dissolves in the acidic environment of gastric juice to expose the tablet core.

[0008] A method for preparing a pharmaceutical composition for the prevention or treatment of acute gastric injury, said pharmaceutical composition being a bilayer tablet containing neohesperidin dihydrochalcone, the method comprising the following steps: A sustained-release-retention layer mixture and an immediate-release layer mixture were prepared separately, both containing neohesperidin dihydrochalcone. The sustained-release-retention layer mixture contained a hydrophilic gel skeleton material, a foaming agent, and a low-density excipient, while the immediate-release layer mixture contained a superdisintegrant. The sustained-release-retention layer mixture and the immediate-release layer mixture are sequentially filled into a tableting mold and double-layered tableting is performed to obtain a double-layered tablet core. A pH-sensitive coating layer is wrapped around the double-layer tablet core to form a coated tablet.

[0009] Furthermore, a bioadhesive polymer is added to the sustained-release-retention layer mixture; the neohesperidin dihydrochalcone is micronized before tableting.

[0010] The present invention has the following beneficial effects: 1. This invention overcomes the limitations of short duration of action and insufficient local concentration of active ingredients in the stomach by designing a bilayer tablet delivery system with gastric retention and pH-responsive release characteristics. This dosage form rapidly initiates action in the stomach, with its immediate-release portion quickly releasing the drug to provide initial protection for the gastric mucosa; the sustained-release portion prolongs the retention time in the stomach through floating and adhesion mechanisms and continuously releases the drug. This process allows the drug to concentrate in the lesion area of ​​the stomach for a longer period of time, which helps to improve local bioavailability and thus more comprehensively and coherently address the pathological process of acute gastric injury. At the same time, this targeted delivery method reduces the distribution of the drug in non-target sites to a certain extent, which provides the possibility of reducing potential systemic effects.

[0011] 2. This invention integrates preventative intervention and therapeutic effects into a single dosage form, optimizing the medication regimen. The synergistic design of the immediate-release and sustained-release layers ensures a smooth transition in the drug's action time, enabling rapid response to immediate threats or initial damage while providing continuous protection and repair support. This integrated design simplifies the medication process, avoiding the hassle of taking multiple doses of different functional drugs, and improving the convenience of medication and patient compliance. It provides a simple and effective drug approach for achieving complete coverage of acute gastric injury from early prevention to subsequent continuous treatment.

[0012] Of course, any product implementing this invention does not necessarily need to achieve all of the advantages described above at the same time. Attached Figure Description

[0013] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings used in the description of the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0014] Figure 1 This is a flowchart illustrating the application of the novel hesperidin dihydrochalcone of the present invention in the prevention or treatment of acute gastric injury. Figure 2 This is a schematic diagram of the chemical structure of the novel hesperidin dihydrochalcone of this invention; Figure 3 This is a comparative diagram showing the effect of the novel hesperidin dihydrochalcone of this invention on acute gastric injury induced by anhydrous ethanol in mice. Figure 4 This is a schematic diagram illustrating the effect of the novel hesperidin dihydrochalcone of the present invention on the pathological changes of gastric tissue in mice induced by anhydrous ethanol. Figure 5 This is a schematic diagram illustrating the effect of the novel hesperidin dihydrochalcone of the present invention on changes in oxidative stress indicators of gastric tissue in mice induced by anhydrous ethanol. Figure 6 This is a schematic diagram illustrating the effect of the novel hesperidin dihydrochalcone of the present invention on the cell viability of GES-1 cells induced by anhydrous ethanol. Figure 7 This is a schematic diagram illustrating the protective effect of the novel hesperidin dihydrochalcone of the present invention on GES-1 cells induced by anhydrous ethanol. Detailed Implementation

[0015] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0016] Please see Figure 1-2 As shown, this invention relates to the application of neohesperidin dihydrochalcone in the prevention or treatment of acute gastric injury. The specific steps of the application method are as follows: Step S1: Pretreatment and specification confirmation of active ingredients Step S11: Select high-purity (≥98%) neohesperidin dihydrochalcone raw material, whose physicochemical properties should meet pharmaceutical standards; Step S12: Micronize the active pharmaceutical ingredient using a fluid energy mill or ball mill, controlling the grinding parameters to ensure that more than 90% of the particles have a particle size (D90) between 5 micrometers and 20 micrometers. This step aims to increase the specific surface area of ​​the drug, which is beneficial for the dissolution and absorption of the subsequent formulation. More importantly, it ensures that the drug particles can be uniformly dispersed in the subsequent polymer matrix. Step S13: Store the micronized NHDC in a dry environment with humidity below 30%RH and temperature below 25℃, sealed for later use.

[0017] Step S2: Preparation of gastric retention type double-layer core The core of this invention lies in its unique dual-layer tablet design: one layer is a fast-acting, immediate-release layer, and the other layer is a sustained-release-retention layer that provides long-lasting protection and treatment; Step S21, Preparation of the sustained-release-retention layer (lower layer): Step S211, Formula Weighing: Accurately weigh the following by weight percentage: micronized NHDC (15%–30%), hydrophilic gel skeleton material (e.g., hydroxypropyl methylcellulose K4M-K100M, 40%–60%), foaming agent (e.g., sodium bicarbonate or calcium carbonate, 8%–15%), low-density excipient (e.g., glyceryl monostearate microspheres or powdered polypropylene, 5%–12%), and adhesive material (e.g., carbomer 974P or sodium alginate, 3%–8%); and add appropriate amounts of lubricant (magnesium stearate, 1%) and filler (microcrystalline cellulose, to bring the total to 100%). Step S212, Mixing: Place NHDC and all auxiliary materials except lubricant into a three-dimensional motion mixer and mix at 20-30 rpm for 20-30 minutes until the color and composition are uniform. Step S213: Add lubricant: Pass magnesium stearate through an 80-mesh sieve and add it to the above mixture, and continue mixing for 3 to 5 minutes; Step S214, Pre-compression treatment: The mixed granules or powder are directly used for tableting, or dry granulation is performed as needed to improve flowability; Step S22, Preparation of the immediate-release layer (upper layer): Step S221, Formula Weighing: Accurately weigh the following by weight percentage: micronized NHDC (20%–40%), superdisintegrant (such as crospovidone or crospovidone sodium carboxymethyl cellulose, 5%–10%), water-soluble filler (such as mannitol or lactose, 45%–70%), and flow aid (colloidal silica, 0.5%–1.5%). Step S222: Mixing: Place all ingredients into a mixer and mix at 15-25 rpm for 15-25 minutes until homogeneous; Step S223: Add lubricant: Add sieved magnesium stearate (1%) and mix for 2-3 minutes; Step S23, Double-layer tableting: Step S231: Using a specially designed double-layer tablet press, a fixed amount (e.g., 60% to 70% of the total tablet weight) of sustained-release-retention layer powder or granules is first loaded into the die cavity and lightly pre-compressed (e.g., 2-5 kN pressure) to form a flat lower layer. Step S232: Without removing the lower layer, load a fixed amount (30% to 40% of the total tablet weight) of immediate-release powder into the same die cavity; Step S233: Perform final tablet compression, with the pressure controlled in the range of 8 to 15 kN, to form a double-layer tablet core with a hardness of about 50 to 80 N and a clear interface; the tablet shape is preferably biconvex circular or elliptical to facilitate coating.

[0018] Step S3: Preparation of pH-responsive enteric coating layer This coating layer is not for enteric coating, but is designed to dissolve rapidly after the tablet reaches the stomach, exposing the underlying adhesive surface, while protecting the tablet from irritation in the mouth and esophagus; Step S31, Preparation of coating solution: Step S311: Dissolve the enteric material (such as acrylic resin II or hydroxypropyl methylcellulose phthalate, in an amount of 3% to 8% of the tablet core weight) in an appropriate proportion of ethanol-water mixed solvent (such as ethanol:water = 8:2), and stir until completely dissolved to form a clear solution; Step S312: Add plasticizer (such as triethyl citrate, the amount of which is 10% to 20% of the dry weight of the polymer), and continue to stir and homogenize; Step S313: Optional anti-sticking agent (such as talc powder, passed through a 200-mesh sieve, the amount of which is 30% to 50% of the dry weight of the polymer) is added and dispersed evenly under continuous high-speed shearing to obtain a uniform suspension coating liquid; Step S32, Coating process: Step S321: Place the double-layer film core obtained in the second step into a high-efficiency coating pan and preheat the film bed to 30-35℃; Step S322: Coating is performed under precise control of parameters such as tablet bed rotation speed, inlet air temperature, exhaust air temperature and spray rate; specific parameters are as follows: tablet bed rotation speed 8-15 rpm, inlet air temperature 40-50℃, exhaust air temperature 30-38℃, spray rate 5-15 ml / min, atomization pressure 0.8-1.5 bar; Step S323: Continue spraying liquid until the coating weight gain reaches the preset range (3% to 8%); place the coated tablets in an oven at 30 to 40°C for 2 to 4 hours to cure, so as to enhance the strength of the coating film.

[0019] Step S4: Packaging and storage of the final product Step S41: Inspect the coated tablets for appearance, weight variation, hardness, and disintegration time (the coating layer should dissolve within 5 minutes in a hydrochloric acid solution with a pH of 1.0–1.5); Step S42: Qualified products are packaged in aluminum-plastic blister packs, and each blister pack can be designed to include a combination of preventative and therapeutic dosages; Step S43: Store the finished product in a cool, dry place, at a temperature not exceeding 25°C and a relative humidity not exceeding 60%.

[0020] Step S5, Usage and Dosage Regimen Step S51, for the prevention of acute gastric injury: Take one tablet on an empty stomach with about 100-200 ml of warm water 30-60 minutes before an event that is expected to induce gastric injury (such as taking nonsteroidal anti-inflammatory drugs, before major surgery, or before high-intensity stress exposure); after the tablet enters the stomach, its enteric coating layer dissolves rapidly under the action of gastric acid. Step S52, the process of the tablet's action in the stomach: Step S521, Rapid action of the immediate-release layer: The exposed immediate-release layer rapidly disintegrates within 5 to 15 minutes under the action of gastric juice and superdisintegrant, releasing the first dose of NHDC; this part of the drug can be rapidly dispersed on the gastric mucosal surface, providing initial protection, neutralizing early-generated free radicals, and inhibiting initial inflammatory signals; Step S522, Activation and Function of the Sustained-Release-Retention Layer: After the immediate-release layer is released, the exposed lower layer begins to function; the foaming agent reacts with gastric acid to produce carbon dioxide gas, which is captured by the hydrophilic gel matrix, reducing the tablet density (<1g / cm³), thus allowing it to float in gastric juice; simultaneously, the hydrophilic gel material (HPMC) absorbs water and swells, forming a gel barrier, and works in conjunction with the adhesive material (carbomer) to adhere to gastric mucosal glycoproteins; low-density excipients help maintain buoyancy; this process allows the tablet to remain in the stomach (especially the antrum) for 4–6 hours or more; Step S523, Continuous Release and Treatment: During the retention period, NHDC is slowly and continuously released from the hydrophilic gel skeleton through diffusion and skeleton dissolution mechanisms, maintaining an effective drug concentration locally in the damaged or vulnerable gastric mucosa, and continuously exerting its multiple protective effects such as anti-inflammatory, antioxidant, and possible enhancement of mucosal barrier function, thereby achieving the prevention and continuous treatment of acute gastric injury. Step S53: For the treatment of acute gastric injury that has already occurred: Take one tablet as soon as possible after the injury occurs, 2 to 3 times a day, on an empty stomach between meals or before bedtime; the course of treatment lasts 3 to 7 days depending on the severity of the injury.

[0021] The specific application of this embodiment is as follows: Example 1: Pretreatment of neohesperidin dihydrochalcone (NHDC) raw material Weigh out high-purity (≥98%) neohesperidin dihydrochalcone raw material. Micronize it using a fluid energy mill, controlling the grinding parameters to ensure the particle size distribution of the resulting powder meets the D90 requirement of 5 to 20 micrometers. Store the micronized NHDC powder in a desiccator at a humidity below 30% RH and a temperature below 25°C, sealed, for later use.

[0022] Example 2: Preparation of intragastric targeted bilayer tablets Preparation of sustained-release-retention layer mixture: Weigh the following components by weight percentage: 20% micronized NHDC, 50% hydroxypropyl methylcellulose (K100M), 10% sodium bicarbonate, 8% glyceryl monostearate (microspheres), 5% carbomer 974P, and bring the total to 100% with microcrystalline cellulose. Place the NHDC, hydroxypropyl methylcellulose, sodium bicarbonate, glyceryl monostearate, carbomer, and most of the microcrystalline cellulose into a three-dimensional motion mixer and mix at 25 rpm for 25 minutes. After homogeneous mixing, add the prescribed amount of magnesium stearate (1%) and continue mixing for 3 minutes to obtain a sustained-release-retention layer mixture.

[0023] Preparation of the immediate-release layer mixture: Weigh the following components by weight percentage: micronized NHDC 30%, crospovidone (XL-10) 8%, mannitol 60%, and colloidal silica 1%. Place all components into a mixer and mix at 20 rpm for 20 minutes. After homogeneity, add the prescribed amount of magnesium stearate (1%) and continue mixing for 2 minutes to obtain the immediate-release layer mixture.

[0024] Pressing of double-layer cores: Tableting is performed using a double-layer tablet press. First, a measured amount (65% of the total weight of the target tablet core) of the sustained-release-retention layer mixture is filled into the die cavity and pre-compressed at 4 kN to form a flat lower layer. Then, without removing the lower layer, a measured amount (35% of the total weight of the target tablet core) of the immediate-release layer mixture is filled into the same die cavity. Finally, the main tableting is performed at a pressure controlled at 12 kN, yielding a biconvex, rounded, double-layer tablet core with a hardness of approximately 65 N.

[0025] pH-sensitive isolation coating: Weigh 5% of the tablet core weight of acrylic resin II and dissolve it in a mixed solvent of ethanol and water (volume ratio 8:2), stirring until clear. Add triethyl citrate equivalent to 15% of the dry weight of acrylic resin II as a plasticizer and stir until homogeneous. Place the bilayer tablet core obtained in Example 2.3 into a high-efficiency coating pan and preheat the tablet bed to 32°C. Spray the coating solution under the following parameters: tablet bed rotation speed 12 rpm, inlet air temperature 45°C, outlet air temperature 35°C, spray rate 10 ml / min, and atomization pressure 1.2 bar, until the coating weight gain reaches 5%. Place the coated tablets in a 35°C oven for curing for 3 hours to obtain the final intragastric targeted bilayer tablet (hereinafter referred to as NHDC bilayer tablet).

[0026] Example 3: Study on the preventive effect of NHDC double-layer tablets on ethanol-induced acute gastric injury Grouping and administration of experimental animals: Healthy male ICR mice were acclimatized and then randomly divided into 4 groups of 8 mice each: 1) Blank control group: The same volume of physiological saline was administered by gavage.

[0027] 2) Model group: Acute gastric injury was induced by gavage administration of anhydrous ethanol.

[0028] 3) NHDC prevention group: One hour before oral administration of anhydrous ethanol, NHDC bilayer tablet suspension (dispersed in 0.5% sodium carboxymethyl cellulose solution, dose of 100 mg / kg based on NHDC) was administered by oral administration.

[0029] 4) Positive drug control group: One hour before gavage administration of anhydrous ethanol, omeprazole suspension (dose of 40 mg / kg) was administered by gavage.

[0030] Establishment of an acute gastric injury model and sample collection: Mice in each group were administered drugs according to the above design. One hour after administration to the NHDC prevention group and the positive drug control group, except for the blank control group, all other groups of mice were given a single oral gavage of anhydrous ethanol (5 ml / kg) to establish an acute gastric injury model. One hour later, all mice were anesthetized and sacrificed, and the entire stomach was removed by laparotomy.

[0031] Assessment and analysis of gastric mucosal injury: The stomach body was cut open along the greater curvature and gently rinsed with ice-cold saline to flatten the gastric mucosa. The extent of gastric mucosal damage was observed, including congestion, edema, linear hemorrhages, and ulceration, and a damage index was calculated. Subsequently, a portion of the gastric antrum tissue was taken and fixed in paraformaldehyde for subsequent histopathological examination (H&E staining).

[0032] Result: As Figure 3 As shown, the gastric mucosa of rats in the model group exhibited widespread congestion, edema, and typical cord-like hemorrhages, with a damage index higher than that of the blank control group. Compared with the model group, the NHDC prevention group showed significantly reduced gross damage to the gastric mucosa, with fewer and smaller hemorrhages, and a lower damage index; its protective effect was comparable to that of the positive control group treated with omeprazole. Figure 4 As shown in the histopathological sections, the model group showed a large number of gastric mucosal epithelial cells sloughed off and missing, severe congestion and edema of the lamina propria, and inflammatory cell infiltration. In contrast, the NHDC prevention group maintained better gastric mucosal structural integrity, with reduced epithelial cell shedding, and reduced edema and inflammatory cell infiltration of the lamina propria.

[0033] Example 4: Study on the therapeutic effect of NHDC bilayer tablets on nonsteroidal anti-inflammatory drug-induced acute gastric injury Grouping and administration of experimental animals: Healthy male ICR mice were randomly divided into 3 groups, with 8 mice in each group: 1) Model group: Indomethacin (40 mg / kg) was administered by gavage to induce acute gastric injury.

[0034] 2) NHDC treatment group: Indomethacin (40 mg / kg) was administered by gavage, followed immediately by NHDC bilayer tablet suspension (100 mg / kg in NHDC form), and the same dose of NHDC bilayer tablet suspension was administered again 3 hours after the first administration.

[0035] 3) Positive drug control group: Ranitidine suspension (30 mg / kg) was administered immediately after gavage administration of indomethacin (40 mg / kg).

[0036] Sample collection and indicator detection: Six hours after administering indomethacin, all rats were sacrificed, and their stomachs were collected to prepare homogenates. Superoxide dismutase (SOD) activity, malondialdehyde (MDA) content, and glutathione (GSH) content were detected using commercially available kits.

[0037] Results: Multiple punctate and patchy hemorrhages and erosions appeared in the gastric mucosa of rats in the model group. The gastric mucosal damage index in the NHDC treatment group was lower than that in the model group. Biochemical analysis of gastric tissue homogenate was as follows: Figure 5 As shown, compared with the model group, the NHDC treatment group exhibited increased SOD activity, decreased MDA content, and increased GSH content in the gastric mucosa. This indicates that NHDC bilayer tablets not only alleviate morphological damage to the mucosa but also exert a therapeutic effect by enhancing antioxidant defense capabilities.

[0038] Example 5: In vitro protective effect of NHDC against gastric mucosal epithelial cell damage Cell culture and grouping: Human gastric mucosal epithelial cells (GES-1) were cultured using standard methods. The experiment was divided into 4 groups: 1) Blank control group: cultured in normal culture medium.

[0039] 2) Damage model group: Add culture medium containing anhydrous ethanol (final concentration 8%) and incubate together.

[0040] 3) NHDC pretreatment group: First, add culture medium containing NHDC (dissolved in DMSO, final concentration 100 μM) for 2 hours for pretreatment, then add anhydrous ethanol (final concentration 8%) for co-incubation.

[0041] 4) Solvent control group: Add an equal volume of DMSO for pretreatment for 2 hours, then add anhydrous ethanol (final concentration 8%) for co-incubation.

[0042] Cell viability assay: Cell viability was detected by CCK-8 assay 6 hours after treatment of each group of cells.

[0043] Result: As Figure 6 and Figure 7As shown, compared with the blank control group, the cell viability of the injury model group decreased. The cell viability of the NHDC pretreatment group was significantly higher than that of the injury model group. This indicates that NHDC itself can directly resist the toxic effects of ethanol on gastric mucosal epithelial cells and inhibit cell apoptosis, thus confirming its gastric mucosal protective potential at the cellular level.

[0044] In summary, the novel hesperidin dihydrochalcone gastric-targeting bilayer tablet provided by this invention achieves targeted and long-lasting drug delivery in the stomach through a unique design combining immediate release and sustained-release-retention. In vitro and in vivo experiments demonstrate that this formulation can effectively prevent and treat acute gastric injury induced by ethanol or nonsteroidal anti-inflammatory drugs (NSAIDs), and its mechanism may be related to enhancing mucosal antioxidant capacity, inhibiting inflammatory responses, and reducing epithelial cell apoptosis.

[0045] In the description of this specification, references to terms such as "an embodiment," "example," "specific example," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the invention. In this specification, illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples.

[0046] The preferred embodiments of the present invention disclosed above are merely illustrative of the invention. These preferred embodiments do not exhaustively describe all details, nor do they limit the invention to the specific implementations described. Clearly, many modifications and variations can be made based on the content of this specification. This specification selects and specifically describes these embodiments to better explain the principles and practical applications of the invention, thereby enabling those skilled in the art to better understand and utilize the invention. The invention is limited only by the claims and their full scope and equivalents.

Claims

1. Use of neohesperidin dihydrochalcone in the manufacture of a medicament for the prevention or treatment of acute gastric injury, characterized in that, The medicament comprises a pharmaceutical composition containing neohesperidin dihydrochalcone, which is designed as a gastric-targeted delivery system; The gastric-targeted delivery system is an oral solid dosage form, which comprises a fast-release unit for rapidly releasing a first portion of neohesperidin dihydrochalcone in the stomach and a sustained-release unit for retarding and continuously releasing a second portion of neohesperidin dihydrochalcone in the stomach; The oral solid dosage form is a bilayer tablet, which comprises a fast-release layer as the fast-release unit and a sustained-release-retention layer as the sustained-release unit; The sustained-release-retention layer comprises a hydrophilic gel matrix material, a foaming agent, and a low-density excipient, so that the layer can absorb water, produce gas and reduce density in gastric juice, thereby achieving gastric floating and retention; The sustained-release-retention layer further comprises a bioadhesive polymer to enhance the adhesion of the bilayer tablet to the gastric mucosa; The fast-release layer comprises a super-disintegrant for promoting the rapid disintegration of the layer and the release of the drug in the gastric environment; The outer surface of the bilayer tablet is coated with a pH-sensitive coating layer, which dissolves in the acidic environment of gastric juice to expose the tablet core.

2. A method for preparing a pharmaceutical composition for preventing or treating acute gastric injury, the pharmaceutical composition being a double-layer tablet comprising neohesperidin dihydrochalcone, characterized in that, The method comprises the following steps: Preparation of a sustained-release-retention layer mixture and a fast-release layer mixture, both containing neohesperidin dihydrochalcone, wherein the sustained-release-retention layer mixture comprises a hydrophilic gel matrix material, a foaming agent and a low-density excipient, and the fast-release layer mixture comprises a super-disintegrant; Sequentially filling the sustained-release-retention layer mixture and the fast-release layer mixture into a tablet press die and performing double-layer tablet pressing to obtain a double-layer tablet core; Coating the double-layer tablet core with a pH-sensitive coating layer to form a coated tablet.

3. The method of claim 2, wherein the pharmaceutical composition is prepared by mixing the active ingredient and the pharmaceutically acceptable carrier. In the sustained-release-retention layer mixture, a bioadhesive polymer is further added; the neohesperidin dihydrochalcone is micronized before tablet pressing.

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