Gastrointestinal tract adhesion type retention tablet and preparation method thereof

Abstract

The invention provides a gastrointestinal tract adhesion type retention tablet and a preparation method thereof. The retention tablet is prepared from the following components in parts by mass: 0.01-1 part of a nano-drug compound, 2-3.5 parts of a filler, 1.5-2.5 parts of a disintegrating agent, 0.7-1.5 parts of an adhesive mixture and 0.3-0.9 part of carbonate coated Fe3O4 microspheres. Wherein the nano-drug compound is a compound of a gastroenteritis treatment drug wrapped by PLGA and DHA; the adhesive mixture is prepared by mixing an adhesive and polydopamine according to the ratio of 1: 1; the carbonate coated Fe3O4 microspheres have the characteristics of magnetic targeting and sonokinetic response through a Fe3O4 coated sonokinetic response agent. The preparation method comprises a direct tabletting method or an indirect tabletting method, and the indirect tabletting method comprises wet granulation and fluidized bed granulation and is realized by controlling pressure and process parameters. The retention tablet has the characteristics of intragastric adhesion, magnetic targeting and sonokinetic response, so that a medicinal preparation is firmly attached to the surface of gastrointestinal mucosa, and the gastrointestinal tract retention time of the medicine is prolonged.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and particularly relates to a gastrointestinal mucosal adhesion type retention tablet and a preparation method thereof. BACKGROUND

[0002] Gastric retention tablets refer to tablets that can maintain their own density less than that of gastric contents after oral administration, and float in gastric juice. Gastric floating preparations are long retained in the stomach and are suitable for gastric treatment drugs or gastric acid secretion inhibitors.

[0003] Gastrointestinal retention tablets, as an advanced drug delivery system, have received extensive attention in the field of pharmaceutical preparations in recent years. The core advantage lies in the ability to stay in the stomach for a long time, thus achieving drug sustained release and controlled release, prolonging drug action time, improving drug bioavailability, and reducing drug administration frequency. This preparation form is particularly suitable for drugs that need to act locally in the stomach, such as drugs for treating gastric ulcers, gastroesophageal reflux disease and other gastric diseases, and drugs that need to be slowly released in the stomach to reduce gastrointestinal irritation.

[0004] Compared with floating and swelling gastric retention tablets, gastrointestinal mucosal adhesion type retention tablets have many advantages, especially the gastrointestinal retention time is not affected by the body position. The adhesion of gastrointestinal mucosal adhesion type retention tablets mainly depends on biological adhesion or mucosal adhesion materials. These materials can make the drug preparation firmly adhere to the gastrointestinal mucosa, thereby prolonging the gastrointestinal retention time of the drug.

[0005] There are still some problems to be solved in the traditional gastrointestinal mucosal adhesion type retention tablets, one of the most prominent problems is that the gastrointestinal mucosal adhesion type retention tablets are not firmly attached to the stomach wall. One of the main reasons is that the barrier effect of biological tissues, the wet gastric mucosa and other surface limitations limit the penetration and adhesion of biological adhesion agents, which is difficult to overcome for biological adhesion agents based on physical interaction. Biological adhesion agents that can adapt to the complex environment of the human body have always been an important direction of scientific research. Although some chemical strategies have achieved high adhesion, the reagents contained in the adhesion agent and the chemical reactions with biological tissues may derive new problems, such as interference with the drug delivery process, residues generated after degradation, and inflammatory reactions caused by reaction byproducts. In addition, invasive strategies such as suture anchoring and inflatable microneedles have very limited practical application scenarios because they can cause damage to the body's biological tissues.

[0006] The prior art CN101721417B discloses a gastric retention floating sustained-release tablet for treating gastrointestinal malignant tumors, which mainly relies on physical floating and does not involve biological adhesion. SUMMARY

[0007] In view of the problem that the gastrointestinal tract adhesion type retention tablets are not firmly attached to the stomach wall, the present application provides a gastrointestinal tract adhesion type retention tablet and a preparation method thereof, through the synergistic design of adhesion retention+magnetic targeting+sono-kinetics response+nanometer drug loading, the problems of short retention time, poor targeting, easy drug degradation and the like of the traditional gastric drug delivery system are solved, the treatment effect of the gastrointestinal inflammation drug is significantly improved, the drug preparation is firmly attached to the gastric mucosa surface, thereby prolonging the gastric residence time of the drug, and the gastrointestinal tract adhesion type retention tablet has a wide clinical application prospect.

[0008] In one aspect, the present application provides a gastrointestinal tract adhesion type retention tablet, wherein the retention tablet is prepared from the following components in a mass ratio: 0.01-1 parts of a nanometer drug compound, 2-3.5 parts of a filler, 1.5-2.5 parts of a disintegrant, 0.7-1.5 parts of an adhesion agent mixture and 0.3-0.9 parts of a carbonate@Fe3O4 microsphere.

[0009] Preferably, the nanometer drug compound is a PLGA-wrapped gastrointestinal inflammation treatment drug and DHA, wherein the gastrointestinal inflammation treatment drug is one or more of a proton pump inhibitor, an antibiotic or a gastric mucosa protective agent, the proton pump inhibitor is one or more of omeprazole and rabeprazole, the antibiotic is one or more of clarithromycin, amoxicillin and azithromycin, and the gastric mucosa protective agent is sucralfate, and the gastrointestinal inflammation treatment drug and DHA are mixed in a mass ratio of 9:1.

[0010] Preferably, the filler is one or more of microcrystalline cellulose, lactose, mannitol and pregelatinized starch.

[0011] Preferably, the disintegrant is one or more of cross-linked sodium carboxymethyl cellulose, cross-linked povidone, low-substituted hydroxypropyl cellulose and sodium carboxymethyl starch.

[0012] Preferably, the adhesion agent mixture is obtained by mixing an adhesion agent and polydopamine in a mass ratio of 1:1, wherein the adhesion agent is one or more of chitosan, carrageenan, sodium alginate, carbomer, hypromellose and polyacrylic acid.

[0013] Preferably, the carbonate@Fe3O4 microsphere is a magnetic nanoparticle Fe3O4-wrapped sono-kinetics response agent, wherein the sono-kinetics response agent is one or more of calcium carbonate, sodium carbonate and sodium bicarbonate.

[0014] In another aspect, the present application provides a preparation method of the gastrointestinal tract adhesion type retention tablet, wherein the preparation method comprises a direct compression method and an indirect compression method.

[0015] Preferably, the compression method comprises the following steps: A. Direct compression method: (1) raw material pretreatment: the filler, disintegrant, respectively after crushing through 60-100 mesh screen; (2) mixing: the above pretreated components and nano drug compound, adhesion agent mixture, carbonate@Fe3O4 microspheres are mixed according to the mass ratio of claim 1; (3) direct compression method: the mixed powder is directly compressed into tablets, and the pressure is controlled at 4-7.5 kg / cm².

[0016] B. indirect compression method: (1) raw material pretreatment: the filler, disintegrant, respectively after crushing through 60-100 mesh screen; (2) mixing: the above pretreated components and nano drug compound, adhesion agent mixture, carbonate@Fe3O4 microspheres are mixed according to the mass ratio of claim 1; (3) indirect compression method: the mixed powder is granulated by wet granulation process or fluidized bed one-step granulation process, dried and tableted, and the pressure is controlled at 3-6.5 kg / cm².

[0017] Preferably, the preparation method of the nano drug compound is: (1) the gastrointestinal inflammation treating drug and DHA are dissolved and mixed according to the mass ratio of 9:1, ground and passed through 100-200 mesh screen to obtain a drug-DHA compound; (2) the drug-DHA compound and PLGA are dissolved in DCM according to the mass ratio of 3:1, magnetically stirred at 20-26°C for 24 h at a speed of 100-200 rpm, and DCM is volatilized to obtain a nano drug compound; Preferably, the preparation method of the adhesion agent mixture is: The adhesion agent and polydopamine are dissolved and mixed according to the mass ratio of 1:1, rotary evaporated, and the parameters are set as temperature 40-50°C and vacuum degree-0.08 MPa to remove the solvent to obtain an adhesion agent mixture; Preferably, the preparation method of the carbonate@Fe3O4 microspheres is: (1) sonodynamic response agent dissolution: the sonodynamic response agent and Fe3O4 are weighed according to the mass ratio of 5:1, 5 g of the sonodynamic response agent is dispersed in 100 mL of deionized water, and ultrasonic treatment is performed for 20 min to form a uniform suspension; (2) carbonate solution: 0.5-1 g of dispersant PVP is added and stirred for 30 min to adsorb the dispersant on the surface of the carbonate, which is helpful for the coating of the magnetic layer in the next step to obtain a carbonate solution; (3) iron salt solution: 1 g of Fe3O4 is dissolved in 50 mL of deionized water, and stirred until completely dissolved to obtain an iron salt solution; (4) Coating: slowly drop the iron salt solution into the carbonate suspension while stirring vigorously under nitrogen protection, maintain the temperature at 50-60 DEG C, adjust the pH to 9-10 by dropping ammonia water, initiate the coprecipitation reaction, black Fe3O4 particles are generated in the solution and coated on the surface of the carbonate core, continue stirring for 1-2 h to ensure complete coating; (5) Magnetic separation and washing: after the reaction of the above step is completed, magnetic separation is performed by using a magnet, the precipitate is collected, and the precipitate is washed with deionized water and ethanol alternately for 3-5 times to remove residual salt ions and dispersants; (6) Drying: the washed microspheres are placed in an oven at 60-80 DEG C for 12 h to obtain carbonate@Fe3O4 microspheres.

[0018] The embodiment of the present application has the following beneficial effects: (1) Rapid disintegration in the stomach and fast effect: the ratio of the disintegrating agent of the gastrointestinal adhesion type retention tablet is high in the in-vitro sonodynamic response, so the disintegration time of the gastrointestinal adhesion type retention tablet is short, the disintegration in the gastrointestinal tract is rapid, and the effect is fast.

[0019] (2) The PLGA wrapped drug can protect the easily degradable drug from being destroyed by gastric acid and achieve slow release, prolong the drug effect time, and the combination of DHA and gastrointestinal inflammation drugs has a synergistic effect, which enhances the antibacterial or anti-inflammatory effect.

[0020] (3) The adhesion agent mixture can be closely adhered to the gastric mucosa, reduce the influence of gastric emptying, make the drug stay in the gastrointestinal tract for a long time, improve the local drug concentration, and enhance the treatment effect.

[0021] (4) The adhesion between the preparation and the stomach wall is firm: the sonodynamic response agent promotes the disintegration of the gastrointestinal retention tablet to form a colloidal suspension containing a large number of bubbles, which is quickly attached to the stomach wall, and the sonoporation effect generated by the sonodynamic effect not only helps to overcome the mucosal barrier, but also enhances the adhesion effect of the adhesion agent to the stomach wall, avoids the problem of short gastrointestinal retention time caused by insufficient adhesion, and ensures the effective release of the drug in the gastrointestinal tract.

[0022] (5) The carbonate@Fe3O4 microspheres have magnetic response characteristics, can be precisely positioned to the gastric lesion area under the guidance of an external magnetic field, improve the targeting, and the carbonate in the microspheres can be decomposed under the sonodynamic response and gastric acid environment to trigger drug release.

[0023] (6) Enhance the treatment effect of gastric diseases: the gastrointestinal retention tablet can form a larger surface area in the gastrointestinal tract, thereby more effectively contacting the gastric mucosa, improving the local concentration of the drug, and enhancing the therapeutic effect of the drug. This has important clinical significance for the treatment of gastrointestinal inflammation. BRIEF DESCRIPTION OF DRAWINGS

[0024] Figure 1 Preparation flowchart of the nanometer barium sulfate complex of Preparation Example 1 of the present application.

[0025] Figure 2 Preparation flowchart of the hydroxypropyl methyl cellulose mixture of Preparation Example 2 of the present application.

[0026] Figure 3 Data diagram of the gastric distribution of Test Example 1 of the present application.

[0027] Figure 4 Data diagram of the gastric retention time of Test Example 1 of the present application.

[0028] Figure 5 HE pathological staining diagram of the stomach of Group C of Test Example 2 of the present application.

[0029] Figure 6 HE pathological staining diagram of the intestine of Group C of Test Example 2 of the present application. DETAILED DESCRIPTION

[0030] The technical solutions of the present application will be described below in conjunction with the embodiments, obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all the other embodiments obtained by those skilled in the art without creative labor fall within the scope of protection of the present application.

[0031] The reagents and equipment used in the embodiments of the present disclosure are all conventional and commercially available.

[0032] Preparation Example 1 The preparation flowchart of the nanometer barium sulfate complex is as shown in Figure 1 (1) Barium sulfate-DHA complex: 9 g of barium sulfate as a model drug is dissolved in 1 g of DHA in 100 mL of DMC, the ultrasonic frequency is set to 40-60 kHz, the ultrasonic power is 100-200 W, and the ultrasonic time is 30 min to completely dissolve; (2) Drying: the rotary evaporation temperature is set to 40°C, the rotor speed of the rotary evaporator is set to 100 rpm, a uniform film is formed on the inner wall of the evaporation flask, the solvent evaporation area is increased, the vacuum degree is controlled to 0.06-0.09 MPa, the solvent boiling point is reduced, the evaporation speed is accelerated, and at the same time, excessive negative pressure is avoided to cause the material to boil and splash, the time is 1 h, and through observation, no obvious solvent droplets are left in the flask, and the material is in the form of loose solid, indicating that the solvent is completely volatilized; (3) Grinding and sieving: the solid dispersion obtained by volatilizing the solvent is placed in a mortar and ground, and then sieved through a 100-mesh sieve to obtain a barium sulfate-DHA complex; ​(4) Nanometer barium sulfate complex: 3g of barium sulfate-DHA complex and 1g of PLGA were dissolved in 40mL of DMC, 200mL of water phase containing 2% PVA was prepared, ultrasonic degassing was performed, the oil phase was slowly dropped into the water phase under the stirring of a magnetic force with a rotating speed of 150rpm, an emulsion was formed, the stirring was continuously performed at 25°C for 24h, DCM was volatilized, centrifugation was performed at 10000rpm for 15min, nanometer particles were collected, the nanometer particles were washed twice with ultrapure water, and freeze-drying was performed to obtain the finished nanometer barium sulfate complex.

[0033] Preparation Example 2 Preparation of adhesive mixture A: Preparation of polyacrylic acid mixture: (1) Preparation of polydopamine solution: 1g of polydopamine powder was added into 100mL of Tris-HCl (pH 8.5) buffer, the solution was stirred by a magnetic force in the dark, the rotating speed was set to 300rpm, and the solution was reacted at room temperature for 12h until the solution was brown-black, and the polydopamine solution was obtained; (2) Preparation of polyacrylic acid solution: 1g of polyacrylic acid powder was added into 100mL of deionized water, the solution was stirred by a magnetic force at a rotating speed of 200rpm for 12h until the powder was completely dissolved, and the polyacrylic acid solution was obtained; (3) Preparation of mixed solution: the above solutions were mixed at a ratio of 1:1, the mixed solution was stirred by a magnetic force at a constant temperature of 40°C for 3h to make the molecules fully contact, and the mixed solution was obtained; (4) Drying: the mixed solution was subjected to rotary evaporation, the parameters were set to a temperature of 45°C and a vacuum degree of-0.08MPa to remove the solvent, and the polyacrylic acid mixture was obtained.

[0034] B: Preparation of chitosan mixture: (1) Preparation of polydopamine solution: 1g of polydopamine powder was added into 100mL of Tris-HCl (pH 8.5) buffer, the solution was stirred by a magnetic force in the dark, the rotating speed was set to 300rpm, and the solution was reacted at room temperature for 12h until the solution was brown-black, and the polydopamine solution was obtained; (2) Preparation of chitosan solution: 1g of chitosan was added into 100mL of 1% acetic acid solution, the solution was stirred by a magnetic force at room temperature (300rpm) for 4h until the chitosan was completely dissolved to form a clear and transparent solution, and the pH was adjusted to 5-6; (3) Preparation of mixed solution: the above solutions were mixed at a ratio of 1:1, the mixed solution was stirred by a magnetic force at a constant temperature of 40°C for 3h to make the molecules fully contact, and the mixed solution was obtained; (4) Drying: the mixed solution was subjected to rotary evaporation, the parameters were set to a temperature of 45°C and a vacuum degree of-0.08MPa to remove the solvent, and the chitosan mixture was obtained.

[0035] C: Preparation of carrageenan mixture: (1) Preparation of polydopamine solution: 1 g of dopamine powder was added to 100 mL of Tris-HCl (pH 8.5) buffer, and magnetic stirring was performed in the dark, with a rotation speed of 300 rpm, at room temperature for 12 h, until the solution was brown-black, to obtain a polydopamine solution; (2) Preparation of carrageenan solution: 1 g of carrageenan was added to 100 mL of deionized water, heated to 80°C, and magnetic stirring (300 rpm) was performed for 2 h until complete dissolution, to form a clear solution; (3) Preparation of mixed solution: the above solutions were mixed at a ratio of 1:1, and magnetic stirring was performed at 40°C for 3 h to allow the molecules to fully contact, to obtain a mixed solution; (4) Drying: the mixed solution was subjected to rotary evaporation, with the parameters set to a temperature of 45°C and a vacuum degree of -0.08 MPa to remove the solvent, to obtain a carrageenan mixture.

[0036] D: Preparation of sodium alginate mixture: (1) Preparation of polydopamine solution: 1 g of dopamine powder was added to 100 mL of Tris-HCl (pH 8.5) buffer, and magnetic stirring was performed in the dark, with a rotation speed of 300 rpm, at room temperature for 12 h, until the solution was brown-black, to obtain a polydopamine solution; (2) Preparation of sodium alginate solution: 1 g of sodium alginate was slowly added to 100 mL of deionized water, and magnetic stirring (300 rpm) was performed for 2 h until complete dissolution, to form a clear solution; the pH was adjusted to 6.5-7.0; (3) Preparation of mixed solution: the above solutions were mixed at a ratio of 1:1, and magnetic stirring was performed at 40°C for 3 h to allow the molecules to fully contact, to obtain a mixed solution; (4) Drying: the mixed solution was subjected to rotary evaporation, with the parameters set to a temperature of 45°C and a vacuum degree of -0.08 MPa to remove the solvent, to obtain a sodium alginate mixture.

[0037] E: Preparation process of carbomer mixture: (1) Preparation of polydopamine solution: 1 g of dopamine powder was added to 100 mL of Tris-HCl (pH 8.5) buffer, and magnetic stirring was performed in the dark, with a rotation speed of 300 rpm, at room temperature for 12 h, until the solution was brown-black, to obtain a polydopamine solution; (2) Preparation of carbomer solution: 1 g of carbomer was slowly added to 100 mL of deionized water, and magnetic stirring (300 rpm) was performed for 2 h until complete dissolution, to form a clear solution; the pH was adjusted to 6.5-7.0; (3) Preparation of mixed solution: the above solutions were mixed at a ratio of 1:1, and magnetic stirring was performed at 40°C for 3 h to allow the molecules to fully contact, to obtain a mixed solution; (4) Drying: The mixed solution was subjected to rotary evaporation, and the parameters were set as temperature 45°C and vacuum degree -0.08 MPa to remove the solvent, to obtain the carbomer mixture.

[0038] F: The preparation process of the hydroxypropyl methyl cellulose mixture is shown in Figure 2 (1) Preparation of polydopamine solution: 1 g of polydopamine powder was added to 100 mL of Tris-HCl (pH 8.5) buffer, and the solution was stirred at 300 rpm in the dark, and reacted at room temperature for 12 h until the solution was brown-black, to obtain the polydopamine solution; (2) Preparation of hydroxypropyl methyl cellulose solution: 1 g of hydroxypropyl methyl cellulose was slowly added to 100 mL of deionized water (magnetic stirring at 50 rpm) at 2-8°C, and was allowed to swell for 2 h. After swelling, the temperature was increased to 45°C, and the solution was stirred until it became completely transparent; (3) Preparation of mixed solution: The above solutions were mixed at a ratio of 1:1, and were subjected to magnetic stirring at 40°C for 3 h to allow the molecules to fully contact, to obtain the mixed solution; (4) Drying: The mixed solution was subjected to rotary evaporation, and the parameters were set as temperature 45°C and vacuum degree -0.08 MPa to remove the solvent, to obtain the hydroxypropyl methyl cellulose mixture.

[0039] Preparation Example 3 Preparation of carbonate@Fe3O4 microspheres A: Preparation of calcium carbonate@Fe3O4 microspheres (1) Dissolution of calcium carbonate: Calcium carbonate and Fe3O4 were weighed according to a mass ratio of 5:1. 5 g of calcium carbonate was dispersed in 100 mL of deionized water, and was subjected to ultrasonic treatment for 20 min to form a uniform suspension; (2) Calcium carbonate solution: 0.5 g of dispersant PVP was added, and was stirred for 30 min to allow the dispersant to be adsorbed on the surface of the calcium carbonate, which was helpful for the coating of the magnetic layer in the next step, to obtain the calcium carbonate solution; (3) Iron salt solution: 1 g of Fe3O4 was dissolved in 50 mL of deionized water, and was stirred until it was completely dissolved to obtain the iron salt solution; (4) Coating: The iron salt solution was slowly added dropwise into the calcium carbonate suspension, and was stirred at 600 rpm under nitrogen protection, while the temperature was maintained at 55°C. Ammonia water was added dropwise to adjust the pH to 9-10, to initiate the coprecipitation reaction. Black Fe3O4 particles were generated in the solution and were coated on the surface of the calcium carbonate core. The stirring was continued for 2 h to ensure complete coating; (5) Magnetic separation and washing: After the reaction in the above step was completed, the magnetic separation was performed using a magnet, and the precipitate was collected. The precipitate was washed with deionized water and ethanol alternately for 3 times to remove the residual salt ions and dispersant; ​(6) Drying: The washed microspheres were placed in a 70°C oven for drying for 12 h to obtain the calcium carbonate@Fe3O4 microspheres.

[0040] B: Preparation of sodium carbonate@Fe3O4 microspheres (1) Dissolution of sodium carbonate: Sodium carbonate and Fe3O4 were weighed according to a mass ratio of 5:1, 5 g of sodium carbonate was dispersed in 100 mL of deionized water, and ultrasonic treatment was performed for 20 min to form a uniform suspension; (2) Sodium carbonate solution: 0.5 g of dispersant PVP was added, and stirring was performed for 30 min to enable the sodium carbonate surface to adsorb the dispersant, which is conducive to the coating of the magnetic layer in the next step, thereby obtaining a sodium carbonate solution; (3) Iron salt solution: 1 g of Fe3O4 was dissolved in 50 mL of deionized water, and stirring was performed until complete dissolution to obtain an iron salt solution; (4) Coating: The iron salt solution was slowly added dropwise into the sodium carbonate suspension, stirring was performed at 600 rpm under nitrogen protection, the temperature was maintained at 55°C, ammonia water was added dropwise to adjust the pH to 9-10, a coprecipitation reaction was initiated, black Fe3O4 particles were generated in the solution and coated on the surface of the sodium carbonate core, and stirring was continuously performed for 2 h to ensure complete coating; (5) Magnetic separation and washing: After the reaction in the above step was completed, magnetic separation was performed using a magnet, the precipitate was collected, and the precipitate was washed with deionized water and ethanol alternately for 3 times to remove residual salt ions and dispersants; (6) Drying: The washed microspheres were placed in a 70°C oven for drying for 12 h to obtain the calcium carbonate@Fe3O4 microspheres.

[0041] C: Preparation of sodium bicarbonate@Fe3O4 microspheres (1) Dissolution of sodium bicarbonate: Sodium bicarbonate and Fe3O4 were weighed according to a mass ratio of 5:1, 5 g of sodium bicarbonate was dispersed in 100 mL of deionized water, and ultrasonic treatment was performed for 20 min to form a uniform suspension; (2) Sodium bicarbonate solution: 0.5 g of dispersant PVP was added, and stirring was performed for 30 min to enable the sodium bicarbonate surface to adsorb the dispersant, which is conducive to the coating of the magnetic layer in the next step, thereby obtaining a sodium bicarbonate solution; (3) Iron salt solution: 1 g of Fe3O4 was dissolved in 50 mL of deionized water, and stirring was performed until complete dissolution to obtain an iron salt solution; (4) Coating: The iron salt solution was slowly added dropwise into the sodium bicarbonate suspension, stirring was performed at 600 rpm under nitrogen protection, the temperature was maintained at 55°C, ammonia water was added dropwise to adjust the pH to 9-10, a coprecipitation reaction was initiated, black Fe3O4 particles were generated in the solution and coated on the surface of the sodium bicarbonate core, and stirring was continuously performed for 2 h to ensure complete coating; (5) Magnetic separation and washing: after the reaction of the above step is completed, magnetic separation is performed using a magnet, and the precipitate is collected and washed with deionized water and ethanol alternately 3 times to remove residual salt ions and dispersants; (6) Drying: the washed microspheres are placed in a 70°C oven for drying for 12 h to obtain sodium bicarbonate@Fe3O4 microspheres.

[0042] Example 1 280 mg retention tablets are prepared using barium sulfate as a model drug (1) Raw material preparation: the filler and disintegrant are respectively pulverized and passed through a 100 mesh sieve, the relative temperature of the environment is ≤40% (to prevent moisture absorption of the raw materials), the nanobarium sulfate complex is prepared as in Preparation Example 1, the adhesion agent mixture is prepared as in Preparation Example 2, and the carbonate@Fe3O4 microspheres are prepared as in Preparation Example 3; (2) Calculation of the addition amount: the preparation is performed according to the mass ratio of each component: nanobarium sulfate complex 0.9 parts, filler 2.5 parts, disintegrant 2 parts, adhesion agent mixture 1 part, and carbonate@Fe3O4 microspheres 0.6 parts, and the calculation formula is: , and the specific addition amount data are shown in Table 1: Table 1: Addition amount of each component in Example 1

[0043] (3) Mixing: stepwise mixing is performed using a three-dimensional mixer: 1) Initial mixing: nanobarium sulfate complex + microcrystalline cellulose (50 mg) are mixed using the equal increment method for 5 min at a rotation speed of 25 rpm; 2) Addition of crosslinked povidone: the remaining microcrystalline cellulose + crosslinked povidone are mixed for 10 min at a rotation speed of 25 rpm; 3) Addition of polyacrylic acid mixture and calcium carbonate@Fe3O4 microspheres: finally added, mixed for 15 min at a rotation speed of 15 rpm to prevent electrostatic adsorption, to obtain the final mixed powder; (4) Direct compression method: a single punch tablet machine is used, the pressure is set to 4 kg / cm², a concave punch die with a diameter of 8 mm is used to reduce the risk of edge breakage, and the environmental control is: relative humidity ≤45%, temperature 25±2°C.

[0044] Example 2 280 mg retention tablets are prepared using barium sulfate as a model drug (1) Raw material preparation: same as Example 1; (2) Calculation of the addition amount: same as Example 1, and the specific addition amount data are shown in Table 2: Table 2: Addition amount of each component in Example 2

[0045] (3) Mixing: stepwise mixing was performed using a three-dimensional mixer: 1) Initial mixing: nano-barium sulfate complex + lactose (50 mg) were mixed using the equal increment method for 5 min at a rotation speed of 25 rpm; 2) Adding sodium carboxymethyl starch: the remaining lactose + sodium carboxymethyl starch were mixed for 10 min at a rotation speed of 25 rpm; 3) Adding chitosan mixture and sodium carbonate@Fe3O4 microspheres: finally added, mixed for 15 min at a rotation speed of 15 rpm to prevent electrostatic adsorption, to obtain the final mixed powder; (4) Wet granulation method for tabletting: 15% of 2% PVP K30 ethanol solution by weight of the powder was added to the above prepared mixed powder for binding, which was added gradually by spraying for 5 min to a moderate wet mass (held into a mass, and scattered by light pressure), the wet mass was granulated by passing through a 16-20 mesh screen, dried in an oven at 50°C for 2 h to dryness, and then tabletted using a single punch tablet machine, with a pressure of 6.5 kg / cm2, using a concave punch die with a diameter of 8 mm to reduce the risk of edge breakage, and environmental control: relative humidity ≤45%, temperature 25±2°C.

[0046] Example 3 Preparation of 280 mg retention tablets using barium sulfate as a model drug (1) Raw material preparation: same as Example 1; (2) Calculation of addition amount: same as Example 1, with specific addition amount data shown in Table 3: Table 3: Addition amount of each component in Example 3

[0047] (3) Mixing: stepwise mixing was performed using a three-dimensional mixer: 1) Initial mixing: nano-barium sulfate complex + pre-gelatinized starch (50 mg) were mixed using the equal increment method for 5 min at a rotation speed of 25 rpm; 2) Adding cross-linked povidone: the remaining pre-gelatinized starch + cross-linked povidone were mixed for 10 min at a rotation speed of 25 rpm; 3) Adding carrageenan mixture and sodium bicarbonate@Fe3O4 microspheres: finally added, mixed for 15 min at a rotation speed of 15 rpm to prevent electrostatic adsorption, to obtain the final mixed powder; (4) Fluidized bed one-step granulation method for tabletting: 15% of 5% PVP K30 ethanol solution by weight of the powder was added to the above prepared mixed powder for binding, with the fluidized bed granulation parameters set as: inlet air temperature 55°C, atomization pressure 1.5 bar, liquid spraying rate 3-5 mL / min, fluidized air volume 30 m3 / h, material temperature 30-35°C, the premixed powder is added to the fluidized bed hopper, initial fluidization (air volume 30 m3 / h) for 5 min preheating, the spray is turned on, uniform spraying with a concentric spray gun, spray distance 15-20 cm, first low rate (3 mL / min) to wet the surface, then adjust to 5 mL / min to the end point, after spraying stops, keep fluidized drying for 15 min, wait for the granules to cool to 25°C, pass through an 18-mesh sieve to size the particles; tabletting is performed using a single-punch tablet press, set the pressure to 5 kg / cm2, use a concave punch die with a diameter of 8 mm to reduce the risk of edge breakage, environmental control: relative humidity ≤45%, temperature 25±2°C.

[0048] Example 4 Preparation of 280 mg retention tablets of barium sulfate as a model drug (1) Raw material preparation: same as Example 1; (2) Calculation of addition amount: same as Example 1, the specific addition amount data is shown in Table 4: Table 4: Addition amount of each component in Example 4

[0049] (3) Mixing: step-by-step mixing is performed using a three-dimensional mixer: 1) Initial mixing: nano-barium sulfate complex + lactose (50 mg) is mixed for 5 min using the equal increment method, set the rotation speed to 25 rpm; 2) Add sodium carboxymethyl starch: mix the remaining lactose + sodium carboxymethyl starch for 10 min, set the rotation speed to 25 rpm; 3) Add sodium alginate mixture and sodium bicarbonate@Fe3O4 microspheres: finally add, mix for 15 min, set the rotation speed to 15 rpm to prevent electrostatic adsorption, to obtain the final mixed powder; (4) Direct tabletting method: use a single-punch tablet press, set the pressure to 6 kg / cm2, use a concave punch die with a diameter of 8 mm to reduce the risk of edge breakage, environmental control: relative humidity ≤45%, temperature 25±2°C.

[0050] Example 5 Preparation of 280 mg retention tablets of barium sulfate as a model drug (1) Raw material preparation: same as Example 1; (2) Calculation of addition amount: same as Example 1, the specific addition amount data is shown in Table 5: Table 5: Addition amount of each component in Example 5

[0051] (3) Mixing: step-by-step mixing is performed using a three-dimensional mixer: 1) Initial mixing: nano-barium sulfate complex + pregelatinized starch (50 mg) mixed for 5 min using the equal increment method, with a rotation speed of 25 rpm; 2) Adding cross-linked povidone: the remaining pregelatinized starch + cross-linked povidone were mixed for 10 min, with a rotation speed of 25 rpm; 3) Adding carbomer mixture and calcium carbonate@Fe3O4 microspheres: finally added, mixed for 15 min, with a rotation speed of 15 rpm to prevent electrostatic adsorption, to obtain the final mixed powder; (4) Wet granulation method for tabletting: 15% of 2% PVP K30 ethanol solution by weight of the powder was added to the above prepared mixed powder for binding, added gradually in a spray manner, for 5 min to a moderate wet mass (held into a mass, and scattered by light pressure), the wet mass was granulated through a 16-20 mesh screen, dried in an oven at 50°C for 2 h, tabletted, using a single punch tablet machine, with a pressure of 4 kg / cm2, using a concave punch die with a diameter of 8 mm to reduce the risk of edge breakage, with environmental control: relative humidity ≤45%, temperature 25±2°C.

[0052] Example 6 Preparation of 280 mg retention tablets using barium sulfate as a model drug (1) Raw material preparation: same as Example 1; (2) Calculation of addition amount: same as Example 1, with specific addition amount data shown in Table 6: Table 6: Addition amount of each component in Example 6

[0053] (3) Mixing: stepwise mixing was performed using a three-dimensional mixer: 1) Initial mixing: nano-barium sulfate complex + microcrystalline cellulose (50 mg) mixed for 5 min using the equal increment method, with a rotation speed of 25 rpm; 2) Adding sodium carboxymethyl starch: the remaining microcrystalline cellulose + sodium carboxymethyl starch were mixed for 10 min, with a rotation speed of 25 rpm; 3) Adding hydroxypropyl methylcellulose mixture and sodium carbonate@Fe3O4 microspheres: finally added, mixed for 15 min, with a rotation speed of 15 rpm to prevent electrostatic adsorption, to obtain the final mixed powder; (4) Fluidized bed one-step granulation method for tabletting: 15% of 5% PVP K30 ethanol solution by weight of the powder was added to the above prepared mixed powder for binding, with fluidized bed granulation parameters set as: inlet air temperature 55°C, atomization pressure 1.5 bar, liquid spraying rate 3-5 mL / min, fluidized air volume 30 m 3 / h, material temperature 30-35°C, the premixed powder is added to the fluidized bed hopper, initial fluidization (air volume 30 m3 / h) for 5 min preheating, spray is started, uniform spraying with the concentric spray gun, spray distance 15-20 cm, first low rate (3 mL / min) to wet the surface, then adjusted to 5 mL / min to the end point, after spraying stops, keep fluidized drying for 15 min, when the particles are cooled to 25°C, pass through 18 mesh sieve to size; tabletting is performed, using a single punch tablet machine, set the pressure to 3 kg / cm2, using a concave punch die with a diameter of 8 mm to reduce the risk of edge breakage, environmental control: relative humidity < 45%, temperature 25 ± 2°C.

[0054] Example 3 differs from the components of Example 1 in that the filler, the mixture of adhesives, the carbonate@Fe3O4 microspheres are different, and the disintegrant is the same; Example 5 differs from the components of Example 1 in that the filler, the mixture of adhesives are different, and the disintegrant, the carbonate@Fe3O4 microspheres are the same; Example 6 differs from the components of Example 1 in that the disintegrant, the carbonate@Fe3O4 microspheres, the mixture of adhesives are different, and the filler is the same; Example 4 differs from the components of Example 2 in that the mixture of adhesives, the carbonate@Fe3O4 microspheres are different, and the filler, the disintegrant are the same; Example 6 differs from the components of Example 2 in that the mixture of adhesives, the filler are different, and the disintegrant, the carbonate@Fe3O4 microspheres are the same; Example 4 differs from the components of Example 3 in that the mixture of adhesives, the filler, the disintegrant are different, and the carbonate@Fe3O4 microspheres are the same; Example 5 differs from the components of Example 3 in that the mixture of adhesives, the carbonate@Fe3O4 microspheres are different, and the filler, the disintegrant are the same; Example 6 differs from the components of Example 4 in that the filler, the mixture of adhesives, the carbonate@Fe3O4 microspheres are different, and the disintegrant is the same.

[0055] Comparative Examples 1-4: Barium sulfate as a model drug to prepare 280 mg retention tablets The components of the comparative examples are shown in Table 7, and the tablet preparation method parameters and component addition amounts are the same as those of Example 3: Table 7 Components of Comparative Examples 1-4

[0056] Preparation method of Comparative Example 1: Mix nano-barium sulfate complex, pregelatinized starch, cross-linked povidone, carrageenan, sodium bicarbonate@Fe3O4 microspheres through a 100 mesh sieve, and tablet the same as Example 3. Preparation method of Comparative Example 3: the nano-barium sulfate complex, pregelatinized starch, crosslinked povidone, carrageenan, and sodium bicarbonate were mixed through a 100-mesh sieve, and the tablet was pressed according to the method of Example 3. Preparation method of Comparative Example 3: the nano-barium sulfate complex, pregelatinized starch, crosslinked povidone, carrageenan, and sodium bicarbonate were mixed through a 100-mesh sieve, and the tablet was pressed according to the method of Example 3. Preparation method of Comparative Example 3: the nano-barium sulfate complex, pregelatinized starch, crosslinked povidone, carrageenan, and sodium bicarbonate were mixed through a 100-mesh sieve, and the tablet was pressed according to the method of Example 3. The difference between Comparative Example 1 and Example 3 is that the adhesion agent mixture is pure carrageenan; the difference between Comparative Example 2 and Example 3 is that the carbonated salt@Fe3O4 microspheres are pure sodium bicarbonate; the difference between Comparative Example 3 and Example 3 is that the adhesion agent mixture is pure carrageenan and the carbonated salt@Fe3O4 microspheres are pure sodium bicarbonate; the difference between Comparative Example 4 and Example 3 is that the simulated drug is pure barium sulfate, the adhesion agent mixture is pure carrageenan, and the carbonated salt@Fe3O4 microspheres are pure sodium bicarbonate.

[0057] Comparative Example 5: the parameters are the same as those of Example 3, but the mass ratio of each component in the preparation is: nano-barium sulfate complex 0.9 parts, filler 2.5 parts, disintegrant 2 parts, adhesion agent mixture 2.5 parts, and carbonated salt@Fe3O4 microspheres 0.6 parts.

[0058] Comparative Example 6: the parameters are the same as those of Example 3, but the mass ratio of each component in the preparation is: nano-barium sulfate complex 0.9 parts, filler 2.5 parts, disintegrant 2 parts, adhesion agent mixture 1 part, and carbonated salt@Fe3O4 microspheres 0.1 part.

[0059] Test Example 1 Application effect of retention tablets (1) Experimental materials: the preparations of the examples and comparative examples of the application, and test animals and grouping: healthy adult beagle dogs, weighing 10-15 kg, 4 dogs in each group, a total of 12 groups, provided by Slick Jingda (Shanghai) Experimental Animal Co., Ltd.; (2) Test scheme: 12 h fasting before administration to reduce the influence of food on drug absorption and gastric emptying, the preparations of the example group and the comparative example group were orally administered, and normal water was drunk, and a neodymium-iron-boron magnet was fixed on the stomach to accurately position the carbonated salt@Fe3O4 microspheres, and the comparative examples 2-4 did not need to add a magnet, and the stomach was ultrasonically treated after 10 min (ultrasonic frequency 3 MHz, ultrasonic time 5 min); (3) Gastric retention evaluation: After ultrasound, the gastric distribution effect of the preparations in the example group and the comparative example group was recorded at 0.5 h after administration, and the gastric retention time of the preparations in the example group and the comparative example group was observed and recorded every 0.5 h after administration (each was divided into 10 grades, and the higher the grade, the more uniform the gastric distribution and the longer the retention time), and the gastric distribution data of each group were compared as shown in Figure 3 , the gastric retention time data were compared as shown in Figure 4 , and the results were shown in Table 8, and the content represented by each grade was shown in Table 9. Table 8 Distribution and retention time of the preparation in the stomach

[0060] It should be noted that the grades of the gastric distribution effect and the gastric retention time in Table 8 are the average values of each group.

[0061] Table 9 Content represented by the distribution and retention time in the stomach of each grade

[0062] Experimental results: As can be seen from the results in Table 8, the gastric distribution effect and the retention time of the gastric adhesion type retention tablets in the example group of the present application were obviously higher than those in the comparative example group, the effects of example 3 and example 4 were the best, and the example 3 group was better than the example 4 group. The distribution and retention time of the retention tablets in the intestinal tract were tested by the same method, and the example 3 group was better than the other groups.

[0063] Test example 2 Synergistic effect of DHA and gastrointestinal inflammation drugs (1) Experimental materials: physiological saline, omeprazole, azithromycin, DHA; experimental animals: half of the gastrointestinal inflammation model SD rats were male and half were female, with a body weight of 200-250 g, 8 weeks old, 10 in each group, half male and half female, provided by Slick Jingda (Shanghai) Experimental Animal Co., Ltd.; (2) Test scheme: Before the experiment, the rats were raised in a standard animal room, with a temperature controlled at 22±3℃, a humidity of 40%-60%, 12h light / dark alternation, free drinking and eating, and adapting to the environment for 3-5d. The rats were fasted for 12h before the experiment, and the experimental groups were as shown in Table 10: Table 10 Experimental grouping and administration information

[0064] The rats were administered by gavage at 9 am every day for 7 consecutive days, and the rats were sacrificed on the 8th day for HE staining observation of the gastrointestinal tract. The C group had no obvious lesions, and the stomach was as shown in Figure 5 , and the intestinal tract was as shown in Figure 6 , the drug effect was better than that of the B group, indicating that DHA and gastrointestinal inflammation drugs had a synergistic effect.

[0065] Test Example 3 In vitro performance verification (1) In vitro drug release test (USP dissolution method) 1) Test method: instrument: USP type II dissolution tester (paddle method) medium: simulated gastric juice (pH 1.2): 0.1M HCl + 0.2% NaCl, simulated intestinal juice (pH 6.8): phosphate buffer, detection method: HPLC (omeprazole detection wavelength 302nm); 2) Operation steps Take 6 pieces of the retention tablets (containing nano-drug compound) prepared by the method of Example 3 of the present application and control samples (ordinary tablets, PLGA blank carrier) respectively, and place them in 900mL medium at 37±0.5℃, 50rpm, and take 5mL (make up with fresh medium) samples at 0.5, 1, 2, 4, 6, 8, 12h, filter them through a 0.22μm filter membrane, and then detect the drug concentration by HPLC; 3) The test data are shown in Table 11: Table 11 In vitro drug release test data

[0066] 4) Test conclusion: the retention tablets of the present application release 82% in 12 hours, have significant sustained-release effect (ordinary tablets release 85% in 2 hours), and the PLGA wrapping effectively protects the drug.

[0067] (2) In vitro adhesion test (ex vivo mucosal adhesion experiment) 1) Test method: materials: fresh ex vivo pig gastric mucosa (thickness 2mm), adhesion tablets (diameter 6mm) instrument: texture analyzer (TA.XT Plus) equipped with adhesion force probe, environment: 37℃ simulated gastric juice (pH 1.2) wet conditions; 2) Operation steps: fix the mucosa on a glass slide, cover with simulated gastric juice, pre-press the adhesion tablet at 0.5N for 10 seconds, vertically peel off with the probe at a speed of 0.1mm / s, and record the maximum peeling force (N) and adhesion work (N·mm); 3) The test data are shown in Table 12: Table 12 In vitro adhesion test data

[0068] 4) Test conclusion: the adhesion force of the adhesion agent mixture of the present application reaches 0.52N / cm², which is increased by 68% compared with the commercially available product.

[0069] (3) Magnetic targeting efficiency test (in vitro magnetic field guidance experiment) 1) Test method: device: transparent plastic tube (inner diameter 3 cm) + neodymium-iron-boron magnet (0.5T) medium: simulated gastric juice (pH 1.2, flow rate 10 mL / min), marker: fluorescently labeled Fe3O4 microspheres; 2) Operation steps: inject the retentive tablet disintegration suspension into the pipeline, turn on the magnetic field, and observe the microsphere aggregation after 30 min, and quantitatively analyze the enrichment rate by fluorescence microscope / ICP-OES; 3) The test data are shown in Table 13: Table 13 In vitro adhesion force test data:

[0070] 4) Test conclusion: the targeting efficiency of the microspheres of the application is 92%, which is significantly higher than that of ordinary microspheres (p<0.01) 68%.

[0071] (4) Acousticokinetic response test (ultrasound triggered release) 1) Test method: instrument: ultrasonic generator (1 MHz, 1 W / cm²) dissolution condition: same as the drug release test, detection: CO2 bubble generation amount (drainage method) + HPLC release rate; 2) Operation steps: place the retentive tablet in simulated gastric juice, and monitor the bubble amount and drug release rate under ultrasonic treatment (5 min, interval 30 min); 3) The test data are shown in Table 14: Table 14 In vitro adhesion force test data:

[0072] 4) Test results: ultrasound increases the drug release rate of the application by 53%, and Fe3O4 coating enhances the acousticokinetic response.

[0073] In summary: PLGA coated drugs avoid gastric acid destruction, achieve long-acting sustained release, DHA and gastrointestinal inflammation drugs play a synergistic effect; the adhesion agent mixture and the acousticokinetic response agent jointly act to form a bubble-containing colloidal suspension, which closely adheres to the gastric mucosa, overcomes the mucosal barrier, significantly prolongs the gastrointestinal retention time, and the carbonated Fe3O4 microspheres are guided by the magnetic field and synergize with ultrasound, so that the distribution of the retentive agent in the stomach is more uniform and the retention time is prolonged.

[0074] Although the embodiments of the application have been shown and described, it can be understood by those of ordinary skill in the art that various changes, modifications, replacements and variations can be made to these embodiments without departing from the principles and spirits of the application, and any equivalent changes and improvements made within the scope of the application should still fall within the scope of the patent coverage of the application.

Claims

1. A gastrointestinal adhesion-type retention tablet, characterized in that, The retention tablet is made of the following components in the indicated mass ratios: 0.01-1 parts of nano-drug complex, 2-3.5 parts of filler, 1.5-2.5 parts of disintegrant, 0.7-1.5 parts of binder mixture and 0.3-0.9 parts of carbonate@Fe3O4 microspheres.

2. The gastrointestinal adhesion-type retention tablet according to claim 1, characterized in that, The nanomedicine complex consists of PLGA encapsulating a gastroenteritis treatment drug and DHA. The gastroenteritis treatment drug is one or more of a proton pump inhibitor, an antibiotic, or a gastric mucosal protectant. The proton pump inhibitor is one or more of omeprazole and rabeprazole. The antibiotic is one or more of clarithromycin, amoxicillin, and azithromycin. The gastric mucosal protectant is sucralfate. The gastroenteritis treatment drug and DHA are mixed at a mass ratio of 9:

1.

3. The gastrointestinal adhesion-type retention tablet according to claim 1, characterized in that, The filler is one or more of microcrystalline cellulose, lactose, mannitol, and pregelatinized starch.

4. The gastrointestinal adhesion-type retention tablet according to claim 1, characterized in that, The disintegrant is one or more of croscarmellose sodium, croscarmellose, low-substituted hydroxypropyl cellulose, or sodium carboxymethyl starch.

5. The gastrointestinal adhesion-type retention tablet according to claim 1, characterized in that, The adhesive mixture is obtained by mixing an adhesive and polydopamine at a mass ratio of 1:1, wherein the adhesive is one or more of chitosan, carrageenan, sodium alginate, carbomer, hydroxypropyl methylcellulose, and polyacrylic acid.

6. The gastrointestinal adhesion-type retention tablet according to claim 1, characterized in that, The carbonate@Fe3O4 microspheres are magnetic nanoparticles Fe3O4 encapsulating an acoustic response agent, wherein the acoustic response agent is one or more of calcium carbonate, sodium carbonate, or sodium bicarbonate.

7. A method for preparing a gastrointestinal adhesion-type retention tablet, characterized in that, The preparation methods include direct compression and indirect compression.

8. The method for preparing a gastrointestinal adhesion-type retention tablet according to claim 7, characterized in that, The tableting method includes the following steps: (1) Raw material pretreatment: The filler and disintegrant are crushed separately and then passed through a 60-100 mesh sieve; (2) Mixing: The pretreated components, nanomedicine complex, adhesive mixture, and carbonate@Fe3O4 microspheres are mixed in the mass ratio described in claim 1. (3) Direct compression method: The mixed powder is directly compressed into tablets, and the pressure is controlled at 4 to 7.5 kg / cm². (1) Raw material pretreatment: The filler and disintegrant are crushed separately and then passed through a 60-100 mesh sieve; (2) Mixing: The pretreated components, nanomedicine complex, adhesive mixture, and carbonate@Fe3O4 microspheres are mixed in the mass ratio described in claim 1. (3) Indirect tableting method: The mixed powder is made into granules by wet granulation or fluidized bed one-step granulation process, dried and granulated, and then tableted. The pressure is controlled at 3 to 6.5 kg / cm².

9. The method for preparing a gastrointestinal adhesion-type retention tablet according to claim 8, characterized in that, The preparation method of the nanomedicine complex is as follows: The gastroenteritis treatment drug and DHA were dissolved and mixed at a mass ratio of 9:1, ground, and passed through a 100-200 mesh sieve to obtain the drug-DHA complex. The drug-DHA complex and PLGA were dissolved in DCM at a mass ratio of 3:

1. The mixture was magnetically stirred at 20-26°C for 24 hours at a speed of 100-200 rpm to volatilize the DCM and obtain the nano-drug complex. The method for preparing the adhesive mixture is as follows: The adhesive and polydopamine were dissolved and mixed in a mass ratio of 1:1, and then removed by rotary evaporation with parameters set at a temperature of 40-50°C and a vacuum of -0.08 MPa to obtain an adhesive mixture.

10. The method for preparing a gastrointestinal adhesion-type retention tablet according to claim 8, characterized in that, The method for preparing the carbonate@Fe3O4 microspheres is as follows: (1) Dissolution of acoustic response agent: Weigh the acoustic response agent and Fe3O4 at a mass ratio of 5:1, weigh 5g of acoustic response agent and disperse it in 100mL of deionized water, and sonicate for 20min to form a uniform suspension; (2) Carbonate solution: Add 0.5-1g of dispersant PVP and stir for 30 minutes to allow the dispersant to be adsorbed on the carbonate surface, which helps the magnetic layer coating in the next step to obtain the carbonate solution. (3) Iron salt solution: Dissolve 1g Fe3O4 in 50mL of deionized water and stir until completely dissolved to obtain iron salt solution; (4) Coating: Slowly drop the iron salt solution into the carbonate suspension while stirring vigorously under nitrogen protection, maintaining the temperature at 50-60°C, and add ammonia to adjust the pH to 9-10 to initiate a co-precipitation reaction. Black Fe3O4 particles are generated in the solution and coated on the carbonate core surface. Continue stirring for 1-2 hours to ensure complete coating. (5) Magnetic separation and washing: After the above steps are completed, magnetic separation is performed using a magnet, the precipitate is collected, and the precipitate is washed 3 to 5 times with deionized water and ethanol alternately to remove residual salt ions and dispersant. (6) Drying: The washed microspheres were placed in an oven at 60-80℃ and dried for 12 hours to obtain carbonate@Fe3O4 microspheres.

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