3D printing combination tablet for treating helicobacter pylori infection and preparation method thereof

Abstract

The application discloses a 3D printing combination tablet for treating helicobacter pylori infection, which comprises three layers from top to bottom, wherein the first layer is a stomach floating delayed release layer, the second layer is a bismuth agent immediate release layer, and the third layer is an enteric layer; the stomach floating delayed release layer comprises a delayed release shell, an antibiotic inner core and an air chamber, the delayed release shell is wrapped outside the antibiotic inner core and the air chamber, and the air chamber is arranged above the antibiotic inner core; the enteric layer comprises an enteric shell and a proton pump inhibitor tablet core, and the enteric shell is wrapped outside the proton pump inhibitor tablet core; and a drug release channel is arranged at the bottom of the stomach floating delayed release layer. The 3D printing combination tablet can realize the immediate release of the bismuth agent, the delayed release of the antibiotic and the pH-dependent release of the proton pump inhibitor in the quadruple drug formula, and solves the problems of complex taking sequence, poor patient compliance and single drug dosage of the drug formula for treating helicobacter pylori infection on the market.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical preparations, and particularly relates to a 3D-printed combination tablet for treating Helicobacter pylori infection and a preparation method thereof. BACKGROUND

[0002] Helicobacter pylori parasitizes in gastric mucosa and can cause diseases such as gastritis and digestive tract ulcer. The best first-line drug regimen for treating Helicobacter pylori infection is a quadruple therapy, i.e., two kinds of antibiotics, bismuth agent and proton pump inhibitor (2016 Toronto Consensus). However, the quadruple therapy has a complex administration regimen, the proton pump inhibitor needs to be taken before meals, the bismuth agent should be taken before meals and then quickly dispersed to form a diffuse protective layer in the acidic environment of the stomach, and the antibiotic needs to be taken after meals to reduce the irritation to the stomach.

[0003] In order to improve the compliance of patients with Helicobacter pylori infection, there are currently combination drugs on the market, of which Pylera is a fixed-dose combination capsule for treating adult Helicobacter pylori, containing bismuth citrate potassium, metronidazole and tetracycline; and Lizhu Weisanlian is a combination package of bismuth citrate potassium tablets, metronidazole tablets and clarithromycin tablets. These two drugs on the market do not contain proton pump inhibitor components and need to be taken separately by patients. It can be seen that there is a lack of integrated quadruple drug preparations on the market, and the effective components are fixed, which cannot be adjusted according to the patient's age, antibiotic allergy history, etc.

[0004] Pylera capsule is taken after meals, which reduces the irritation of the antibiotic to the stomach, but the food in the stomach after meals greatly reduces the efficacy of bismuth citrate potassium. Lizhu Weisanlian is a combination package of bismuth agent and two kinds of antibiotics, in which bismuth citrate potassium tablets are taken twice a day before meals, two tablets each time, and metronidazole tablets and clarithromycin tablets are taken twice a day after meals, one tablet each time. The complex formula and taking time often bring inconvenience to patients, which may lead to patients not complying with the specific administration time and interval or forgetting to administer, or taking the wrong dose, thereby reducing the drug efficacy or producing greater toxic side effects, especially for the elderly and children, who have poorer compliance to the complex medication method and are more likely to have adverse reactions.

[0005] In summary, there is currently a lack of integrated quadruple drug preparations for treating Helicobacter pylori infection, and it is impossible to provide personalized customization according to patient needs. The administration regimen for treating Helicobacter pylori infection is complex, and the traditional administration method cannot meet the needs of clinical application, forcing the pharmaceutical industry to consider new drug production methods. SUMMARY

[0006] The purpose of the present application is to provide a 3D-printed combination tablet for treating Helicobacter pylori infection and a preparation method thereof.

[0007] In order to achieve the above object, the present application adopts the following technical solutions:

[0008] A combined tablet for treating Helicobacter pylori infection comprises three layers from top to bottom, wherein:

[0009] The first layer is a gastric floating delayed release layer, which comprises a delayed release shell, an antibiotic inner core and an air chamber, the delayed release shell is wrapped outside the antibiotic inner core and the air chamber, and the air chamber is arranged above the antibiotic inner core.

[0010] The second layer is a bismuth agent immediate release layer.

[0011] The third layer is an enteric layer, which comprises an enteric shell and a proton pump inhibitor tablet core, and the enteric shell is wrapped outside the proton pump inhibitor tablet core.

[0012] Further, the size of the combined tablet is: diameter 5-15 mm, height 4-20 mm.

[0013] The diameter of the delayed release shell is 5-15 mm, the height is 2-8 mm, the diameter of the antibiotic inner core is 3-14.6 mm, the height is 1-7 mm, the diameter of the air chamber is 4.6-14.6 mm, the height is 1-7 mm, the diameter of the bismuth agent immediate release layer is 5-15 mm, the height is 1-6 mm, the diameter of the enteric shell is 5-15 mm, the height is 1-6 mm, and the diameter of the proton pump inhibitor tablet core is 4.2-11.2 mm, the height is 0.2-5.4 mm.

[0014] Further, the bottom of the gastric floating delayed release layer is provided with an inwardly recessed drug release channel, the top of the bismuth agent immediate release layer is provided with a protrusion matched with the recess, and the recess is matched with the protrusion. In order to achieve the delayed release effect, a drug release channel is arranged at the bottom of the gastric floating delayed release layer, which can be a micropore or a thin layer arranged at the bottom of the delayed release layer. In one specific embodiment of the present application, the drug release channel is an inward recess, and a protrusion matched with the recess is arranged at the top of the bismuth agent immediate release layer, and the recess is matched with the protrusion.

[0015] The combined tablet structure adopted by the present application is divided into three layers: the first layer is a gastric floating delayed release tablet with high drug loading, the delayed release part has high drug loading and a release effect after 2-3 hours after taking, which is an antibiotic tablet and an air chamber inside a water-soluble erodible polymer material shell with delayed release function, which can realize instant floating and sustained floating capacity; the second layer is a bismuth agent immediate release layer, which comprises bismuth agent and filler / binder, and can realize the effect of rapid dispersion when meeting water; the third layer is an enteric polymer material shell, which wraps a proton pump inhibitor tablet, which can protect the activity of the proton pump inhibitor in an acidic environment and release the proton pump inhibitor when pH≥5.8.

[0016] The preparation method of the above combined tablet comprises the following steps:

[0017] Step 1, the proton pump inhibitor, drug carrier, plasticizer are mixed uniformly, and are put into a double screw extruder to be extruded into a printing wire material containing the proton pump inhibitor;

[0018] Step 2, the enteric auxiliary material, plasticizer are mixed uniformly, and are put into a double screw extruder to be extruded into a printing wire material of the enteric shell;

[0019] Step 3, the water-soluble erodible polymer material, plasticizer are mixed uniformly, and are put into a double screw extruder to be extruded into a printing wire material of the delayed-release shell;

[0020] Step 4, the bismuth agent is mixed with a filler or a binder, and a solvent is added to prepare a semi-solid as the printing material of the bismuth agent;

[0021] Step 5, the antibiotic is mixed with a filler or a binder, and a solvent is added to prepare a semi-solid as the printing material of the antibiotic;

[0022] Step 6, a computer-aided design software is used to design a model of the combination tablet, and the model is converted into an.STL format file and imported into software adapted to the printer to generate a G-code meeting the requirements by selecting a suitable slicing method;

[0023] Step 7, the printing wire material and the printing material are supplied to a multi-head 3D printer, and the generated G-code file is imported into the printer to print according to the program, thereby obtaining a multi-layer tablet semi-finished product;

[0024] Step 8, the multi-layer tablet semi-finished product is dried to obtain the 3D printed combination tablet.

[0025] Further, in Step 1, the mass ratio of the proton pump inhibitor, the drug carrier and the plasticizer is 5-25: 85-55: 10-20; the proton pump inhibitor is selected from omeprazole, lansoprazole and rabeprazole, the drug carrier is polyethylene oxide or The plasticizer is polyethylene glycol.

[0026] Further, in Step 2, the mass ratio of the enteric auxiliary material and the plasticizer is 80-99.9: 20-0.1; the enteric auxiliary material is selected from hydroxypropyl methyl cellulose acetate succinate, EUDRAGIT L100 or EUDRAGIT L100-50, and the plasticizer is polyethylene glycol or triethyl citrate.

[0027] Further, in Step 3, the mass ratio of the water-soluble erodible polymer material and the plasticizer is 80-90: 20-10; the water-soluble erodible polymer material is selected from hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, gelatin, chitosan, polyvinyl alcohol or polyacrylic acid; and the plasticizer is polyethylene glycol or triethyl citrate.

[0028] Further, in step 4, the mass ratio of the bismuth agent, the filler and the binder is 99.9-80:0.1-20:0.1-20; the bismuth agent is bismuth potassium citrate or colloidal pectin bismuth, the filler is selected from starch, pregelatinized starch, dextrin, sorbitol, mannitol, lactose, microcrystalline cellulose, calcium sulfate or calcium carbonate, and the binder is selected from povidone, gelatin, polyethylene glycol, polyvinyl alcohol, poloxamer, sodium alginate, glucose, maltitol, acrylic acid resin or sodium carboxymethyl cellulose.

[0029] Further, in step 5, the mass ratio of the antibiotic, the filler and the binder is 99.9-90:0.1-10:0.1-10; the antibiotic is selected from aminoglycoside antibiotic, cephalosporin antibiotic, tetracycline or macrolide antibiotic, the filler is selected from starch, pregelatinized starch, dextrin, sorbitol, mannitol, lactose, microcrystalline cellulose, calcium sulfate or calcium carbonate, and the binder is selected from povidone, gelatin, polyethylene glycol, polyvinyl alcohol, poloxamer, sodium alginate, glucose, maltitol, acrylic acid resin or sodium carboxymethyl cellulose.

[0030] The present application adopts the way of combining the fused deposition modeling technology and the semi-solid extrusion technology to prepare a multi-layer tablet by using the 3D printing technology, and concentrates the bismuth agent, the proton pump inhibitor and the two antibiotics in one 3D printing tablet with high drug loading capacity according to the prescription and model design. Based on the drug release scheme design of the combined tablet, the patient only needs to take one 3D printing tablet before meal (the traditional scheme needs to take the bismuth agent and the proton pump inhibitor before meal and the two antibiotics after meal), which greatly reduces the frequency of taking medicine by the patient, can effectively reduce the probability of missing or taking the medicine by mistake, and improves the compliance of the patient.

[0031] The combined tablet of the present application not only has high drug loading capacity, but also can realize the separation of three tablet layers in the stomach: the bismuth agent realizes the immediate release effect after entering the stomach, the antibiotic releases the drug after floating in the stomach for two hours, and the proton pump inhibitor realizes the release in the intestinal tract. The immediate release, delayed release and pH-dependent release are realized in one tablet, which overcomes the defects that the antibiotic is difficult to stay in the stomach for a long time and the current clinical four-drug combination preparation has many times of taking medicine and complex time periods, effectively reduces the frequency of taking medicine, and improves the compliance of the patient. BRIEF DESCRIPTION OF DRAWINGS

[0032] Figure 1 FIG. 1 is a structural schematic diagram of the combined tablet of the present application.

[0033] Figure 2 FIG. 2 is a finished product diagram of the combined tablet of the present application.

[0034] Figure 3 FIG. 3 is a dissolution appearance photograph of the combined tablet of Example 1 at 3 min, 100 min and 180 min.

[0035] Figure 4 Dissolution profile of the combination tablet of Example 1. DETAILED DESCRIPTION

[0036] The application will be further described in conjunction with the drawings and specific examples, but should not be construed as limiting the application. Modifications or replacements of the method, steps or conditions of the application, without departing from the spirit and essence of the application, all belong to the scope of the application. The experimental methods not specified in the examples and the reagents not specified in the formula are all according to the conventional conditions in the art.

[0037] Example 1

[0038] Preparation of 3D printed combination tablet for treating Helicobacter pylori infection

[0039] (a) Mix omeprazole 10 g, polyethylene oxide 70 g, polyethylene glycol-400 10 g uniformly, feed into a double screw extruder at a speed of 10 rpm, the extrusion temperature is 60℃, the extrudate is solid after cooling at the die, forming a linear material with a diameter of 2.5 mm, i.e. to obtain a printing wire containing omeprazole.

[0040] (b) Mix hydroxypropyl methylcellulose acetate succinate 80 g, polyethylene glycol-400 20 g uniformly, feed into a double screw extruder at a speed of 10 rpm, the extrusion temperature is 160℃, the extrudate is solid after cooling at the die, forming a linear material with a diameter of 2.5 mm, i.e. to obtain an enteric material printing wire.

[0041] (c) Mix hydroxypropyl methylcellulose 80 g, polyethylene glycol-1500 20 g powder uniformly, feed into a double screw extruder at a speed of 10 rpm, the extrusion temperature is 180℃, the extrudate is solid after cooling at the die, forming a linear material with a diameter of 2.5 mm, i.e. to obtain a water-erodible polymer material printing wire.

[0042] (d) Take bismuth potassium citrate 5.0 g, calcium carbonate 1.0 g, pass through a 100 mesh sieve, mix with 2.0 mL of distilled water uniformly, stir for 10 min to form a semi-solid with certain viscoelasticity, i.e. to obtain a semi-solid printing material containing bismuth agent.

[0043] (e) Mix tetracycline hydrochloride 2.5 g, metronidazole 2 g, polyvinylpyrrolidone-K30 0.2 g uniformly, pass through a 100 mesh sieve, add 2 mL of distilled water, stir for 10 min to form a semi-solid with certain viscoelasticity, to obtain a semi-solid printing material containing antibiotics.

[0044] (f) Designing a three-layer combination tablet model using computer-aided design software, wherein: the stomach floating shell has a diameter of 10 mm and a height of 5 mm, the air chamber part has a diameter of 9.2 mm and a height of 4.5 mm, the drug release channel has a diameter of 6 mm and a height of 0.2 mm; the antibiotic tablet has a height of 3 mm and a diameter of 9.2 mm; the bismuth citrate potassium layer has a diameter of 10 mm and a height of 2 mm; the enteric shell has a diameter of 10 mm and a height of 2 mm, and the omeprazole layer has a diameter of 8 mm and a height of 1.6 mm.

[0045] The designed model is converted into an STL format file and imported into a printer-adapted slicing software, with the printing layer height set to 0.2 mm, the printing speed set to 5 mm / s, the printing pressure set to 2 psi, the hot bed temperature set to 60℃, the wall thickness set to 0.4 mm, the hydroxypropyl methyl cellulose wire printing temperature set to 220℃, the hydroxypropyl methyl cellulose acetate succinate wire printing temperature set to 160℃, and the omeprazole wire printing temperature set to 80℃, to generate a G-code that meets the requirements.

[0046] (g) Feeding the above wires and semi-solid materials into a multi-head 3D printer and importing the generated G-code file into the printer, and printing according to the program to obtain a semi-finished product of a multi-layer tablet for resisting H. pylori.

[0047] (h) Placing the prepared combination tablet semi-finished product in an oven and setting the temperature to 35℃ for drying for 1 h to obtain the target preparation.

[0048] Example 2

[0049] Preparation of a 3D-printed combination tablet for treating H. pylori infection

[0050] (a) Mixing 20 g of rabeprazole, 75 g of polyethylene oxide, and 5 g of polyethylene glycol-400 uniformly, and feeding into a twin-screw extruder at a speed of 40 rpm, with the extrusion temperature set to 58℃, and the extrudate cooled to solid state at the die to form a wire-shaped material with a diameter of 2.5 mm, thereby obtaining a printing wire containing omeprazole.

[0051] (b) Mixing 70 g of EUDRAGIT L100 and 30 g of polyethylene glycol-400 uniformly, and feeding into a twin-screw extruder at a speed of 40 rpm, with the extrusion temperature set to 190℃, and the extrudate cooled to solid state at the die to form a wire-shaped material with a diameter of 2.5 mm, thereby obtaining an enteric material printing wire.

[0052] (c) Mixing 90 g of hydroxypropyl cellulose and 10 g of polyethylene glycol-400 powder uniformly, and feeding into a twin-screw extruder at a speed of 40 rpm, with the extrusion temperature set to 185℃, and the extrudate cooled to solid state at the die to form a wire-shaped material with a diameter of 2.5 mm, thereby obtaining a water-erodible polymer material printing wire.

[0053] (d) Weigh 8g of colloidal bismuth pectin and 2g of mannitol, mix them evenly with 2.0mL of distilled water, and stir for 20min to prepare a semi-solid with a certain viscoelasticity, thus obtaining a semi-solid printing material containing bismuth.

[0054] (e) Weigh 5g of ofloxacin, 4g of furazolidone, and 1g of maltitol, mix them evenly, add 4mL of distilled water, and stir for 10min to make a semi-solid with certain viscoelasticity, thus obtaining a semi-solid printing material containing antibiotics.

[0055] (f) A three-layer composite tablet model was designed using computer-aided design software, wherein: the gastric floating outer shell has a diameter of 12 mm and a height of 4 mm; the air chamber has a diameter of 11.2 mm and a height of 3.5 mm; the drug release channel has a diameter of 6 mm and a height of 0.2 mm; the antibiotic tablet has a height of 3 mm and a diameter of 11.2 mm; the bismuth potassium citrate layer has a diameter of 12 mm and a height of 1.5 mm; the enteric outer shell has a diameter of 12 mm and a height of 1.2 mm; and the omeprazole layer has a diameter of 10 mm and a height of 1 mm.

[0056] Convert the designed model into an .STL format file, import it into the printer-compatible slicing software, set the printing layer height of each part to 0.2mm, the printing speed to 5mm / s, the printing pressure to 2psi, the heated bed temperature to 60℃, the wall thickness to 0.4mm, the printing temperature of hydroxypropyl methylcellulose filament to 220℃, the printing temperature of hydroxypropyl methylcellulose acetate succinate filament to 160℃, and the printing temperature of omeprazole filament to 80℃, and generate a G-code that meets the requirements.

[0057] (g) The above filament and semi-solid are supplied to a multi-head 3D printer, and the generated G-code file is imported into the printer. Printing is performed according to the program to obtain a multi-layer semi-finished product of anti-Helicobacter pylori sheet.

[0058] (h) Place the prepared combination tablet semi-finished product in an oven and dry it at 30°C for 2 hours to obtain the target formulation.

[0059] Example 3

[0060] Preparation of 3D-printed composite sheets for the treatment of Helicobacter pylori infection in children

[0061] (a) Mix 25g of lansoprazole, 70g of polyethylene oxide and 5g of polyethylene glycol-400 evenly, put them into a twin-screw extruder, feed at 30rpm, and extrusion temperature is 55℃. After the extrudate cools at the die, it becomes solid and forms a linear material with a diameter of 2.5mm, which is the printing filament containing omeprazole.

[0062] (b) Mix 80g of hydroxypropyl methylcellulose succinate and 20g of polyethylene glycol-400 evenly, put them into a twin-screw extruder, feed at a speed of 30rpm, and extrusion temperature of 160℃. After the extrudate cools at the die, it becomes solid and forms a linear material with a diameter of 2.5mm, which is the enteric material printing filament.

[0063] (c) Mix 80g of polyethylene glycol-polyvinyl alcohol copolymer and 20g of triethyl citrate powder evenly, put them into a twin-screw extruder, feed at a speed of 30rpm, and extrusion temperature of 190℃. After the extrudate cools at the die, it becomes solid and forms a linear material with a diameter of 2.5mm, thus obtaining a water-soluble polymer printing filament.

[0064] (d) Weigh 9.5g of potassium bismuth citrate, 0.5g of microcrystalline cellulose and 4.0mL of distilled water, mix them evenly and stir for 10min to make a semi-solid with certain viscoelasticity, thus obtaining a semi-solid printing material containing bismuth.

[0065] (e) Weigh 0.5g of doxycycline hydrochloride, 2g of metronidazole, and 0.13g of other substances and mix them evenly. Add 1.5mL of distilled water and stir for 15min to make a semi-solid with certain viscoelasticity, thus obtaining a semi-solid printing material containing antibiotics.

[0066] (f) A three-layer composite tablet model was designed using computer-aided design software, wherein: the gastric floating outer shell has a diameter of 9mm and a height of 4mm; the air chamber has a diameter of 8.2mm and a height of 3.5mm; the drug release channel has a diameter of 6mm and a height of 0.2mm; the antibiotic tablet has a height of 3mm and a diameter of 8.2mm; the bismuth potassium citrate layer has a diameter of 9mm and a height of 1.5mm; the enteric-coated outer shell has a diameter of 9mm and a height of 1.5mm; and the omeprazole layer has a diameter of 8mm and a height of 1mm. The designed model was converted into an .STL format file and imported into the slicing software adapted to the printer. The printing layer height of each part was set to 0.2mm, the printing speed to 5mm / s, the printing pressure to 2psi, the heated bed temperature to 60℃, the wall thickness to 0.4mm, the printing temperature of hydroxypropyl methylcellulose filament to 220℃, the printing temperature of hydroxypropyl methylcellulose acetate succinate filament to 160℃, and the printing temperature of omeprazole filament to 80℃, generating a G-code that meets the requirements.

[0067] (g) The above filament and semi-solid are supplied to a multi-head 3D printer, and the generated G-code file is imported into the printer. Printing is performed according to the program to obtain a multi-layer semi-finished product of anti-Helicobacter pylori sheet.

[0068] (h) Place the prepared combination tablets in an oven and dry at 28°C for 2 hours to obtain the target formulation.

[0069] Example 4 Dissolution Study

[0070] The combined tablets prepared in Example 1 were subjected to dissolution testing according to Method II (paddle method) of the Dissolution and Release Determination Method in the 2020 edition of the Chinese Pharmacopoeia, in 500 mL of 0.01 M HCl dissolution medium at 37 °C and 100 rpm. After 120 min, 400 mL of 0.235 mol / L disodium hydrogen phosphate dodecahydrate solution preheated to 37 °C was added to bring the medium to pH 6.8, and the dissolution test was continued.

[0071] The dissolution phenomenon is shown in the appendix. Figure 3 The dissolution curve results are attached. Figure 4 .from Figure 3 As can be seen, at 3 minutes, bismuth potassium citrate dispersed significantly, metronidazole and doxycycline hydrochloride encapsulated in the hydroxypropyl methylcellulose shell floated in the dissolution medium, while omeprazole encapsulated in the enteric-coated shell sank to the bottom. At 100 minutes, the hydroxypropyl methylcellulose shell had broken and sank to the bottom, and the antibiotic tablets gradually dissolved. At 180 minutes, the enteric-coated shell had broken, and the omeprazole tablet core gradually dissolved. Figure 4 The results show that the drugs in the combination tablets were not released before 80 minutes. After 80 minutes, the delayed-release shell of hydroxypropyl methylcellulose broke, and metronidazole and doxycycline hydrochloride gradually dissolved. After adding an alkaline medium at 120 minutes, the enteric-coated shell gradually broke, and omeprazole gradually dissolved. This design achieved the effects of rapid dispersion of bismuth, delayed release of antibiotics, and enteric coating of proton pump inhibitors.

[0072] The foregoing description of specific exemplary embodiments of the invention is for illustrative and explanatory purposes. These descriptions are not intended to limit the invention to the precise forms disclosed, and it will be apparent that many changes and variations can be made in accordance with the foregoing teachings. The exemplary embodiments were chosen and described in order to explain the specific principles of the invention and its practical application, thereby enabling those skilled in the art to implement and utilize various different exemplary embodiments of the invention, as well as various different choices and variations. The scope of the invention is intended to be defined by the claims and their equivalents.

Claims

1. A combination tablet for treating Helicobacter pylori infection, characterized in that, The drug delivery system comprises three layers from top to bottom: the first layer is a gastric floating delayed-release layer, including a delayed-release outer shell, an antibiotic core, and an air chamber. The delayed-release outer shell surrounds the antibiotic core and the air chamber, with the air chamber positioned above the antibiotic core; the second layer is a bismuth immediate-release layer; and the third layer is an enteric layer, including an enteric-coated outer shell and a proton pump inhibitor core. The enteric-coated outer shell surrounds the proton pump inhibitor core. The bottom of the gastric floating delayed-release layer has an inwardly recessed drug release channel, and the top of the bismuth immediate-release layer has a protrusion that mates with the recess, with the recess and protrusion fitting together. The combined tablets are prepared using the following steps: Step 1: Mix the proton pump inhibitor, drug carrier, and plasticizer evenly, and put them into a twin-screw extruder for extrusion molding to obtain a printing wire containing the proton pump inhibitor. The mass ratio of proton pump inhibitor, drug carrier, and plasticizer is 5~25:85~55:10~20; the proton pump inhibitor is selected from omeprazole, lansoprazole, and rabeprazole, and the drug carrier is polyethylene oxide or Soluplus. ® The plasticizer is polyethylene glycol; Step 2: Mix the enteric coating excipients and plasticizer evenly, and feed them into a twin-screw extruder for extrusion molding to obtain the printed wire with the enteric coating shell; The mass ratio of enteric excipient to plasticizer is 80~99.9:20~0.1; the enteric excipient is selected from hydroxypropyl methylcellulose acetate succinate, EUDRAGIT L100 or EUDRAGIT L100-50, and the plasticizer is polyethylene glycol or triethyl citrate. Step 3: Mix the water-soluble polymer material and plasticizer evenly, and put them into a twin-screw extruder for extrusion molding to obtain the printing wire with delayed release shell; The mass ratio of water-soluble polymer material to plasticizer is 80-90:20-10; the water-soluble polymer material is selected from hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, gelatin, chitosan, polyvinyl alcohol, or polyacrylic acid; the plasticizer is polyethylene glycol or triethyl citrate. Step 4: Mix the bismuth agent with the filler or binder, add solvent to make a semi-solid, which is used as the printing material for the bismuth agent; The mass ratio of bismuth agent, filler, and binder is 99.9~80:0.1~20:0.1~20; the bismuth agent is bismuth potassium citrate or colloidal pectin bismuth, the filler is selected from starch, pregelatinized starch, dextrin, sorbitol, mannitol, lactose, microcrystalline cellulose, calcium sulfate or calcium carbonate, and the binder is selected from povidone, gelatin, polyethylene glycol, polyvinyl alcohol, poloxamer, sodium alginate, glucose, maltitol, acrylic resin or sodium carboxymethyl cellulose; Step 5: Mix the antibiotic with filler or binder, add solvent to make a semi-solid, which can be used as the printing material for the antibiotic; The mass ratio of antibiotics, fillers, and binders is 99.9~90:0.1~10:0.1~10; the antibiotics are selected from aminoglycoside antibiotics, cephalosporin antibiotics, tetracyclines, or macrolide antibiotics; the fillers are selected from starch, pregelatinized starch, dextrin, sorbitol, mannitol, lactose, microcrystalline cellulose, calcium sulfate, or calcium carbonate; and the binders are selected from povidone, gelatin, polyethylene glycol, polyvinyl alcohol, poloxamer, sodium alginate, glucose, maltitol, acrylic resin, or sodium carboxymethyl cellulose. Step 6: Use computer-aided design software to design the model of the composite piece, convert it into an .STL format file, import it into the printer-compatible software, select the appropriate slicing method to generate the required G-code; Step 7: Supply the above printing filament and printing material to the multi-head 3D printer, import the generated G-code file into the printer, and print according to the program to produce a multi-layer semi-finished product; Step 8: Dry the multi-layer semi-finished product to obtain the 3D printed composite sheet.

2. The combination tablet according to claim 1, characterized in that, The size of the combination tablets is: 5~15mm in diameter and 4~20mm in height; The delayed-release outer shell has a diameter of 5-15 mm and a height of 2-8 mm; the antibiotic inner core has a diameter of 3-14.6 mm and a height of 1-7 mm; the air chamber has a diameter of 4.6-14.6 mm and a height of 1-7 mm; the bismuth immediate-release layer has a diameter of 5-15 mm and a height of 1-6 mm; the enteric outer shell has a diameter of 5-15 mm and a height of 1-6 mm; and the proton pump inhibitor tablet core has a diameter of 4.2-11.2 mm and a height of 0.2-5.4 mm.

3. The method for preparing the combined tablets according to claim 1, characterized in that, Includes the following steps: Step 1: Mix the proton pump inhibitor, drug carrier, and plasticizer evenly, and put them into a twin-screw extruder for extrusion molding to obtain a printing wire containing the proton pump inhibitor. Step 2: Mix the enteric coating excipients and plasticizer evenly, and feed them into a twin-screw extruder for extrusion molding to obtain the printed wire with the enteric coating shell; Step 3: Mix the water-soluble polymer material and plasticizer evenly, and put them into a twin-screw extruder for extrusion molding to obtain the printing wire with delayed release shell; Step 4: Mix the bismuth agent with the filler or binder, add solvent to make a semi-solid, which is used as the printing material for the bismuth agent; Step 5: Mix the antibiotic with filler or binder, add solvent to make a semi-solid, which can be used as the printing material for the antibiotic; Step 6: Use computer-aided design software to design the model of the composite piece, convert it into an .STL format file, import it into the printer-compatible software, select the appropriate slicing method to generate the required G-code; Step 7: Supply the above printing filament and printing material to the multi-head 3D printer, import the generated G-code file into the printer, and print according to the program to produce a multi-layer semi-finished product; Step 8: Dry the multi-layer semi-finished product to obtain the 3D printed composite sheet.

4. The preparation method according to claim 3, characterized in that, In step 1, the mass ratio of the proton pump inhibitor, drug carrier, and plasticizer is 5~25:85~55:10~20; the proton pump inhibitor is selected from omeprazole, lansoprazole, and rabeprazole, and the drug carrier is polyethylene oxide or Soluplus. ® The plasticizer is polyethylene glycol.

5. The preparation method according to claim 3, characterized in that, In step 2, the mass ratio of enteric excipient to plasticizer is 80~99.9:20~0.1; the enteric excipient is selected from hydroxypropyl methylcellulose acetate succinate, EUDRAGIT L100 or EUDRAGIT L100-50, and the plasticizer is polyethylene glycol or triethyl citrate.

6. The preparation method according to claim 3, characterized in that, In step 3, the mass ratio of water-soluble polymer material to plasticizer is 80~90:20~10; the water-soluble polymer material is selected from hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, gelatin, chitosan, polyvinyl alcohol or polyacrylic acid; the plasticizer is polyethylene glycol or triethyl citrate.

7. The preparation method according to claim 3, characterized in that, In step 4, the mass ratio of bismuth agent, filler, and binder is 99.9~80:0.1~20:0.1~20; the bismuth agent is bismuth potassium citrate or colloidal pectin bismuth, the filler is selected from starch, pregelatinized starch, dextrin, sorbitol, mannitol, lactose, microcrystalline cellulose, calcium sulfate or calcium carbonate, and the binder is selected from povidone, gelatin, polyethylene glycol, polyvinyl alcohol, poloxamer, sodium alginate, glucose, maltitol, acrylic resin or sodium carboxymethyl cellulose.

8. The preparation method according to claim 3, characterized in that, In step 5, the mass ratio of antibiotic, filler, and binder is 99.9~90:0.1~10:0.1~10; the antibiotic is selected from aminoglycoside antibiotics, cephalosporin antibiotics, tetracycline or macrolide antibiotics; the filler is selected from starch, pregelatinized starch, dextrin, sorbitol, mannitol, lactose, microcrystalline cellulose, calcium sulfate or calcium carbonate; and the binder is selected from povidone, gelatin, polyethylene glycol, polyvinyl alcohol, poloxamer, sodium alginate, glucose, maltitol, acrylic resin or sodium carboxymethyl cellulose.

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