Oral dissolving film agent for treating helicobacter pylori infection and preparation method thereof

Abstract

The invention discloses an oral dissolving film agent for treating helicobacter pylori infection. The oral dissolving film agent comprises a medicine carrying layer, a first film covering layer and a second film covering layer, wherein the first film covering layer and the second film covering layer are attached to the two faces of the medicine carrying layer; wherein the medicine carrying layer comprises the following raw materials: a substance a, a first film forming substance, a first plasticizer, a first sweetening agent and a pH regulator; the first covering film layer and the second covering film are the same in raw material and comprise a second film forming substance, a second plasticizer, a second sweetening agent and a stabilizer; the structural formula of the substance a is shown as a formula (I). The invention further discloses a preparation method of the oral dissolving film agent for treating helicobacter pylori infection. The substance a has a good bactericidal effect on helicobacter pylori, is very high in safety and does not generate drug resistance; the substance a is prepared into the oral dissolving film agent which has good stability and drug effect.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and in particular to an orally dissolving film for treating Helicobacter pylori infection and a preparation method thereof. Background Art

[0002] Clinically, the onset of most patients with gastritis and gastric ulcer is caused by Helicobacter pylori infection. Seriously, it can also cause diseases such as chronic pharyngitis and oral ulcers. It infects people of different races and regions in the world, and the infection rate increases with age. It is about 80% in developing countries and about 40% in developed countries. The infection rate in men is slightly higher than that in women, and the infection rate in pets is higher than that in humans.

[0003] At present, the treatment regimens for Helicobacter pylori positive include two major categories. One is the regimen mainly based on antibiotics supplemented with acid suppressants (bismuth agents), and the second is the regimen based on proton pump inhibitors. In addition, there are two other antibiotics, and the most commonly used ones are amoxicillin, metronidazole, etc. The above-mentioned drugs have a long treatment cycle, a large number of drugs to be taken, and relatively large side effects on the human body.

[0004] Quaternary ammonium salt disinfectants belong to cationic surfactants and have bactericidal and detergency effects. They are generally used for the cleaning and disinfection of non-critical items in hospitals and can also be used for hand disinfection. Dissolving them in ethanol can enhance their bactericidal effect as skin disinfectants, and they are often used for item or in vitro disinfection. Since these compounds can change the permeability of the bacterial cell membrane, they are often compounded with other disinfectants to improve their bactericidal effect and speed. Although there are also literatures disclosing that quaternary ammonium salts with specific structures can be combined with other substances to inhibit Helicobacter pylori, generally they are used in vitro or for Helicobacter pylori in the oral cavity, and their treatment effect still needs to be improved.

[0005] Moreover, since Helicobacter pylori mainly exists in the stomach and also exists in the oral cavity and esophagus, comprehensive killing from the oral cavity to the stomach should be considered when killing Helicobacter pylori. However, the existing treatment methods are generally direct perfusion or swallowing, and the residence time in the oral cavity is very short, so comprehensive sterilization from the oral cavity to the stomach cannot be achieved. Summary of the Invention

[0006] Based on the technical problems existing in the background art, the present invention proposes an orally dissolving film for treating Helicobacter pylori infection and a preparation method thereof. Substance a of the present invention has a good bactericidal effect on Helicobacter pylori and can be used for treating and preventing Helicobacter pylori infection; Substance a can be rapidly degraded in vivo, and substance a and its common degradation products are all actually non-toxic and have high safety. Substance a will not be absorbed by the human body, has no side effects, and will not cause Helicobacter pylori to develop drug resistance. Preparing substance a into an orally dissolving film has good stability and drug efficacy, and can achieve comprehensive killing of Helicobacter pylori from the oral cavity to the esophagus to the stomach.

[0007] The present invention provides an orally dissolving film for treating Helicobacter pylori infection, which comprises: a drug-loading layer and a first coating layer and a second coating layer attached to both sides of the drug-loading layer;

[0008] Among them, the raw materials of the drug-loading layer include: substance a, a first film-forming substance, a first plasticizer, a first sweetening agent, and a pH regulator;

[0009] The raw materials of the first coating layer and the second coating layer are the same, including: a second film-forming substance, a second plasticizer, a second sweetening agent, and a stabilizer;

[0010] The structural formula of substance a is shown in formula (I):

[0011]

[0012] Among them, R1 and R2 are each independently selected from one of C6-C12 alkyl groups, and X is one of Cl, Br, I or NO3 - one of;

[0013] R3 is any one of the following structures:

[0014]

[0015] R4, R5, R6, and R7 are each independently selected from one of C1-C4 saturated alkyl groups.

[0016] Preferably, R1 and R2 are each independently selected from one of C6-C12 saturated straight-chain alkyl groups.

[0017] Preferably, R3 is

[0018] Preferably, R4, R5, R6, and R7 are all methyl groups.

[0019] Preferably, R1 and R2 are C8 saturated straight-chain alkyl groups.

[0020] Preferably, the structural formula of substance a is shown in one of formula (II)-(III):

[0021] It is named compound 10;

[0022] It is named compound 11.

[0023] The preparation method of the above-mentioned substance a can refer to the preparation method described in the patent with the application number 202210890033.2 and the invention name "A Degradable Gemini Quaternary Ammonium Salt and Its Preparation Method, Fungicide".

[0024] It is found through research that the cationic group in the molecule of substance a adsorbs negatively charged Helicobacter pylori through electrostatic force, hydrogen bond force, hydrophobic binding and other interactions, aggregates on the cell wall, produces a chamber resistance effect, resulting in the inhibition of the growth of Helicobacter pylori and its death; at the same time, there is an obvious interaction between the non-bonding orbital n of the sulfur atom in the structure and the π-π* orbital of P=O of the phospholipid molecule, resulting in a large deformation of the molecule of substance a in the cell membrane of Helicobacter pylori, changing the permeability of the cell membrane, destroying the cell structure, and causing the dissolution and death of Helicobacter pylori cells.

[0025] Moreover, due to its specific structure, substance a can achieve efficient sterilization in the body while being rapidly degraded, and the degradation products can be quickly excreted from the body without residue; the acute oral toxicity tests (in mice) of substance a and its common degradation products are both >5000 mg / kg, both are actually non-toxic, with high safety, and the application to the human body has a low safety risk; the degradation products of substance a are fatty acid-like / fatty acids and dicationic choline, substance a will not be absorbed by the human body, has no side effects, will not cause Helicobacter pylori to develop drug resistance, and the treatment cycle of substance a for Helicobacter pylori infection is very short with rapid curative effect.

[0026] The substance a described in the present invention has a good bactericidal effect on Helicobacter pylori and can be used to treat Helicobacter pylori infection; when using a very small dosage, substance a still has a good effect of killing Helicobacter pylori, and its bactericidal effect is much better than that of the existing quaternary ammonium salts.

[0027] Preferably, the first film-forming substance is polyvinyl alcohol.

[0028] Preferably, the viscosity of the polyvinyl alcohol is 6-10 mPa·s.

[0029] Preferably, the second film-forming substance is gelatin.

[0030] Preferably, the viscosity of the gelatin is 15-20 mPa·s.

[0031] Preferably, the first plasticizer and the second plasticizer are at least one of polyethylene glycol, ethylene glycol, and glycerol.

[0032] Preferably, the first plasticizer and the second plasticizer are both polyethylene glycol 400.

[0033] Preferably, the first sweetener and the second sweetener are at least one of aspartame, menthol, stevioside, glycyrrhizin, and sucrose.

[0034] Preferably, the stabilizer is magnesium stearate.

[0035] Preferably, the pH regulator is at least one of L(+)-tartaric acid and citric acid.

[0036] Preferably, when preparing the drug-loading layer solution, a pH regulator is used to adjust the pH of the drug-loading layer solution to 3-4.

[0037] Preferably, the weight ratio of substance a, the first film-forming substance, the first plasticizer, and the first sweetener is 0.8-1.2:10-15:1-1.5:0.4-0.6.

[0038] Preferably, the weight ratio of the second film-forming substance, the second plasticizer, the second sweetener, and the stabilizer is 10-15:1-1.5:0.4-0.6:1-1.5.

[0039] Preferably, the thickness of the drug-loading layer is 15-25 μm; the thicknesses of the first film-coating layer and the second film-coating layer are both 5-10 μm.

[0040] The present invention also provides a preparation method of the above-mentioned orally dissolving film for treating Helicobacter pylori infection, which includes the following steps: mixing the raw materials of the film-coating layer with hot water to obtain a film-coating layer solution; mixing the raw materials of the drug-loading layer with water to obtain a drug-loading layer solution; taking the film-coating layer solution to prepare the first film-coating layer, then using the drug-loading layer solution to prepare a drug-loading layer on the surface of the first film-coating layer, and then using the film-coating layer solution to prepare a second film-coating layer on the surface of the drug-loading layer to obtain an orally dissolving film for treating Helicobacter pylori infection.

[0041] Preferably, the temperature of the hot water is 60-70 °C.

[0042] The pH of the above-mentioned drug-loading layer solution is 3-4.

[0043] The above-mentioned drug-loading layer solution and film-coating layer solution are both degassed before film preparation.

[0044] The weight ratio of the above-mentioned first film-forming substance to water can be 1:3; the weight ratio of the second film-forming substance to hot water can be 1:4.

[0045] The above-mentioned water is all purified water.

[0046] Since substance a has the property of being easily degraded, when it is prepared into an orally dissolving film, there will be a problem of unstable preparation quality. And because oral saliva is alkaline and substance a will degrade under alkaline conditions, the inventor found through multiple experiments that by selecting a suitable pH regulator, when the orally dissolving film disintegrates in the mouth, substance a is still in an acidic environment, maintaining the stability of substance a in the mouth; and gelatin is also slightly acidic, which can further improve the stability of substance a; and through the cooperation of the pH regulator and the stabilizer, the quality stability of the orally dissolving film of substance a during long-term storage can be improved, and the shelf life can be extended.

[0047] Since gelatin has a relatively fast disintegration rate and good taste, but it is prone to water absorption, resulting in low preparation stability; while polyvinyl alcohol has a slow disintegration rate, its water absorption is lower than that of gelatin, and it can adhere in the oral cavity; the present invention selects polyvinyl alcohol as the first film-forming substance and gelatin as the second film-forming substance, and cooperates with polyethylene glycol 400, which can make substance a have a suitable disintegration rate, so that its disintegration time in water at 37 °C is less than 60 s, it can disintegrate and disperse in the oral cavity, release the drug, and increase the residence time of substance a in the oral cavity, improving the killing effect on the oral cavity and esophagus; and the stabilizer magnesium stearate can also improve the moisture-proof performance of the orally disintegrating film agent, further improving the preparation stability; selecting appropriate first and second sweeteners can well cover up the bitterness of substance a in the oral cavity and improve its palatability.

[0048] The present invention selects appropriate excipients and ratios to prepare substance a into an orally disintegrating film agent. On the one hand, it can make the orally disintegrating film agent of substance a have a uniform and smooth appearance, good mechanical properties and good taste. On the other hand, it can achieve the all-round killing of Helicobacter pylori from the oral cavity - esophagus - stomach; the orally disintegrating film agent of the present invention has good stability, palatability and pharmacodynamic effect. The orally disintegrating film agent of the present invention only needs to be used once on an empty stomach 2 hours before breakfast and continuously used for 2 - 3 days to completely eliminate Helicobacter pylori in the body. The use cycle is very short, the side effects on the human body are small, and the treatment effect is remarkable. Brief Description of the Drawings

[0049] Figure 1 For the experimental results of compound 10 in Experiment 1.

[0050] Figure 2 For the interaction diagrams of compound 11 and benzalkonium chloride with the phospholipid bilayer respectively, where (1) is benzalkonium chloride and (2) is compound 11.

[0051] Figure 3 For the acute oral toxicity experimental results of compound 10.

[0052] Figure 4 For the acute oral toxicity experimental results of compound 11.

[0053] Figure 5 For the acute oral toxicity experimental results of the degradation products of compound 10.

[0054] Figure 6 For the degradation rate results of compound 10, compound 13 and Ephemora, where C8 - S - Br is compound 10, C8 - S - Br - Me is compound 13, and Ephemora is Ephemora.

[0055] Figure 7 For the results of acute oral toxicity of Ephemora in mice. Detailed Description of the Invention

[0056] Next, the technical solutions of the present invention will be described in detail through specific embodiments.

[0057] Example 1

[0058] Compounds 1-9 were prepared according to Examples 1-9 in the invention patent with the application number 202210890033.2.

[0059] Example 2

[0060] Prepare Compounds 10 and 11

[0061] Add 0.02 mol of dimethylaminoethyl acrylate, 0.02 mol of 1-octanethiol, 0.01 mol of 1,3-dibromopropane, and 10 mL of ethanol to a single-necked flask, stir at 60 °C under normal pressure for 12 h, then distill off the solvent under reduced pressure, wash with acetone 2-3 times, and freeze-dry to obtain Compound 10.

[0062] Replace 1,3-dibromopropane with 1,3-dichloropropane, and prepare Compound 11 according to the method of Compound 10.

[0063] Example 3

[0064] Prepare Compound 12

[0065] Take an aqueous solution of Compound 10 with a mass fraction of 1 wt%, add silver nitrate and mix well (the molar ratio of Compound 10 to silver nitrate is 1:2), stir at room temperature in the dark for 2 h, centrifuge to take the supernatant, and freeze-dry to obtain Compound 12.

[0066] Comparative Example 1

[0067] Prepare Compound 13

[0068] Replace "dimethylaminoethyl acrylate" with "dimethylaminoethyl methacrylate", and prepare Compound 13 according to the method of Compound 10 for the rest.

[0069] Comparative Example 2

[0070] Prepare Compound 14

[0071] Add 0.1 mol of lauric acid to a four-necked flask equipped with a magnetic stir bar, insert a thermometer, set up a fractional distillation apparatus, set the oil bath to 70 °C, heat and stir until the lauric acid is completely melted, then add a certain amount of p-toluenesulfonic acid and hypophosphorous acid as catalysts, introduce nitrogen for protection, and slowly add 0.18 mol of N,N-dimethylethanolamine dropwise using a constant pressure funnel. Then raise the temperature to 160 °C and stir for the esterification reaction. During this period, measure the acid value every hour. When the change in acid value is not significant after 7 hours of reaction, stop the reaction; cool to room temperature, add a 50 wt% aqueous potassium hydroxide solution, stir at 75 °C for 30 min to remove impurities, then transfer to a pear-shaped separatory funnel, add CCl4 for extraction, let stand for 12 h, take the lower layer liquid, and rotary evaporate to remove CCl4 to obtain the intermediate;

[0072] Add the intermediate, 1,3-dichloropropane, and isopropanol to a three-necked flask equipped with a thermometer and a reflux device in sequence. After stirring at room temperature for 15 min, measure the initial amine value; raise the temperature of the system to 100 °C and reflux and stir for 6 h, measuring the amine value once every hour during this period; after the reaction is completed, distill off the isopropanol under reduced pressure to obtain the crude product; recrystallize with a mixed solvent of isopropanol and ethyl acetate to obtain Compound 14.

[0073] Comparative Example 3

[0074] Prepare Compounds 15 and 16

[0075] Replace "1-octanethiol" with "tetradecanethiol" and prepare Compound 15 according to the method of Compound 10.

[0076] Replace "1,3-dibromopropane" with "1,7-dibromoheptane" and prepare Compound 16 according to the method of Compound 10.

[0077] The structural formulas of the above Compounds 1-16 are shown in Table 1.

[0078] Table 1 Structural Formulas of Compounds 1-16

[0079]

[0080]

[0081] Comparative Example 4

[0082] Dodecyldimethylbenzylammonium chloride and dioctyldimethylammonium chloride are mixed in a weight ratio of 1:1 to obtain a fungicide.

[0083] Comparative Examples 5-9 are commercially available chitosan quaternary ammonium salts, benzalkonium chloride, didodecyldimethylammonium chloride, benzethonium chloride, and Evomor, respectively.

[0084] Experiment 1

[0085] The killing experiment of Helicobacter pylori in simulated gastric acid was carried out on compounds 1-12, and the results are shown in Table 2 and Figure 1 as follows.

[0086] The method for the killing experiment of Helicobacter pylori in simulated gastric acid was as follows: Each group of substances was taken and placed in simulated gastric acid at 37°C for 2 h, and its killing effect on Helicobacter pylori was investigated. The concentrations of each group of substances were the same, all 0.1% w / w.

[0087] Figure 1 They are the experimental results of compound 10 in Experiment 1.

[0088] Table 2 Detection results

[0089]

[0090]

[0091] It can be seen from Table 2 that compounds 1-12 have a good effect on killing Helicobacter pylori, and the bactericidal rate reaches 99.9999% after 2 h at a concentration of 0.1% w / w.

[0092] Experiment 2

[0093] The killing experiment of Helicobacter pylori in simulated gastric acid was carried out on compounds 1-12, and they were compared with the substances in compounds 13-16 and Comparative Examples 4-9. The results are shown in Table 3.

[0094] The method for the killing experiment of Helicobacter pylori in simulated gastric acid was as follows: Each group of substances was taken and placed in simulated gastric acid at 37°C for 2 h, and they were serially diluted from 0.1% w / w in a two-fold manner. The minimum bactericidal concentration of the compound was the minimum concentration to reach a bactericidal rate of 99.999%. The 2-h minimum bactericidal concentrations of compounds 1-12, compounds 13-16, and the substances in Comparative Examples 4-9 against Helicobacter pylori were compared.

[0095] Table 3 Detection results of minimum bactericidal concentration

[0096]

[0097] It can be seen from Table 3 that compounds 1-12 have a good effect on killing Helicobacter pylori, and their minimum bactericidal concentration is much lower than that of compounds 13-16 (Comparative Examples 1-3); it is also much lower than that of commercially available quaternary ammonium salts (Comparative Examples 4-9); it shows that the ability of compounds 1-12 to kill Helicobacter pylori is significantly higher than that of Comparative Examples 1-9;

[0098] Comparing Compounds 10 - 11 with Compounds 14 - 16 shows that: when sulfur is not present, even if the alkyl chain lengths of R1 and R2 in Compound 14 are the same as those in Compound 11, the effect of killing Helicobacter pylori will still be significantly reduced; when sulfur is present, the alkyl chain lengths of R1 and R2 in Compound 15 are too long, and the chain length of R3 in Compound 16 is too long, and the effect of killing Helicobacter pylori will be significantly reduced in both cases.

[0099] Experiment 3

[0100] To explore the mechanism of Substance a in killing Helicobacter pylori, since Compounds 1 - 12 have the same parent nucleus structure, the inventor selected Compound 11 from Compounds 1 - 12 as a representative, performed quantum mechanics calculations and simulations on the binding force between Compound 11 and the phospholipid bilayer of the cell membrane, and used benzalkonium chloride as a control group. The results are as Figure 2 shown.

[0101] Figure 2 Figure showing the interaction of Compound 11 and benzalkonium chloride with the phospholipid bilayer respectively, where (1) is benzalkonium chloride and (2) is Compound 11.

[0102] The research results show that: in addition to the charge (long - range) interaction between benzalkonium chloride and phospholipid molecules, there is no obvious orbital (short - range) interaction. The energy decrease value of this system due to the interaction is 18.6 kcal / mol;

[0103] In addition to the long - range charge interaction between Compound 11 and phospholipid molecules, there is an obvious interaction between the non - bonding orbital n of the sulfur atom and the π - π* orbital of P = O of the phospholipid molecule, resulting in a change in the head structure of the phospholipid molecule. The energy decrease value of this system due to the interaction is 19.1 kcal / mol, which is greater than that of benzalkonium chloride.

[0104] This shows that Compound 11 not only has a long - range interaction with the cell membrane structure, but can also change the electronic structure of phospholipid molecules through orbital interaction, making it easier to interact with the phospholipid molecules of microorganisms, resulting in deformation of the phospholipid molecules, destruction of the bacterial cell membrane, and ultimately inactivation of the bacteria.

[0105] In summary, the principle of Substance a in killing Helicobacter pylori is as follows: the cationic group in the Substance a molecule adsorbs the negatively charged Helicobacter pylori through electrostatic force, hydrogen bond force, and hydrophobic binding, etc., aggregates on the cell wall, produces a steric hindrance effect, resulting in the inhibition of the growth of Helicobacter pylori and its death; at the same time, there is an obvious interaction between the non - bonding orbital n of the sulfur atom in the structure and the π - π* orbital of P = O of the phospholipid molecule, resulting in a large deformation of the Substance a molecule in the cell membrane of Helicobacter pylori, changing the cell membrane permeability, destroying the cell structure, and causing the dissolution and death of Helicobacter pylori cells.

[0106] Experiment 4

[0107] Compound 10, Compound 11, and the degradation product of Compound 10 (the structural formula of the degradation product is ) were selected to investigate their toxicological properties. Entrusted to the Anhui Provincial Center for Disease Control and Prevention, the experiment was conducted using the Horn's method in accordance with the "Procedures and Methods for Toxicological Evaluation of Disinfectants Safety (GB / T 38496.6.1 - 2020)" and the SOP system of the center.

[0108] The experimental results were as follows: According to the acute toxicity evaluation criteria of the "Procedures and Methods for Toxicological Evaluation of Disinfectants Safety (GB / T 38496.6.1 - 2020)", the acute oral toxicity tests (mice) of Compound 10, Compound 11, and the degradation product of Compound 10 were all > 5000 mg / kg, and they were all actually non - toxic (the results are as Figures 3 - 5 shown), with high safety and low safety risks when applied to humans.

[0109] For the existing benzalkonium chloride, didodecyldimethylammonium chloride, and benzethonium chloride, the acute oral toxicity tests of their raw materials were all < 500 mg / kg, showing moderate toxicity. See Table 4 for details.

[0110] Table 4 Acute Oral Toxicity of Various Quaternary Ammonium Salts in Mice

[0111]

[0112] Note: a) Extremely toxic: LD 50 < 1 mg / kg, b) Highly toxic: LD 50 = 1 - 50 mg / kg, c) Moderately toxic: LD 50 = 51 - 500 mg / kg, d) Slightly toxic: LD 50 = 501 - 5000 mg / kg, e) Non - toxic: LD 50 > 5000 mg / kg.

[0113] Experiment 5

[0114] Compound 10, Compound 13, and Evmola were taken to investigate their degradation rates respectively. The specific investigation method was as follows: The above substances were respectively prepared into 1 wt% solutions with pond water, and samples were taken regularly to detect the ratio of the peak integration areas of the trimethyl hydrogen at the quaternary ammonium salt end (the retention times of the trimethyl hydrogen at the quaternary ammonium salt end before and after degradation were different) before and after degradation by nuclear magnetic resonance hydrogen spectrum, and the degradation rate was calculated. The results are as Figure 6 shown.

[0115] The structural formula of Evmola is as follows:

[0116]

[0117] Figure 6 Degradation rate results of Compound 10, Compound 13, and Ephemora, where C8-S-Br is Compound 10, C8-S-Br-Me is Compound 13, and Ephemora is Ephemora.

[0118] Refer to "Procedures and Methods for Toxicological Evaluation of the Safety of Disinfectants (GB / T 38496.6.1 - 2020)", acute oral toxicity test of Ephemora on mice was carried out, and the results are as Figure 7 shown.

[0119] Figure 7 Results of acute oral toxicity of Ephemora in mice.

[0120] It can be seen from Figures 6 - 7 that when there is a branched alkyl group beside the ester group, its degradation rate will be significantly reduced; while the acute oral toxicity of Ephemora in male mice LD 50 = 2710 mg / kg, belonging to low toxicity; female LD 50 = 1710 mg / kg, belonging to low toxicity; it can be known that the toxicity of Ephemora is higher than that of Compound 10 (practically non-toxic).

[0121] The inventors found through research that when there is a branched alkyl group (such as methyl) beside the ester group, it will reduce its degradation rate in the body, thereby increasing its toxicity;

[0122] The present invention discovers that Substance a has a specific structure, can achieve efficient sterilization in the body while being rapidly degraded, and enables the degradation products to be rapidly excreted from the body without residue in the body, and both Substance a and its degradation products are practically non-toxic, with high safety and low application safety risk to the human body.

[0123] Example 4

[0124] An orally disintegrating film for treating Helicobacter pylori infection, which comprises: a drug-loading layer and a first coating layer and a second coating layer attached to both sides of the drug-loading layer;

[0125] Among them, the raw materials of the drug-loading layer include: Compound 11, polyvinyl alcohol with a viscosity of 6 mPa·s, polyethylene glycol 400, aspartame, and citric acid, where the weight ratio of Compound 11, polyvinyl alcohol, polyethylene glycol 400, and aspartame is 1:10:1:0.4;

[0126] The raw materials of the first coating layer and the second coating layer are the same, including: gelatin with a viscosity of 20 mPa·s, polyethylene glycol 400, aspartame, and magnesium stearate, where the weight ratio of gelatin, polyethylene glycol 400, aspartame, and magnesium stearate is 10:1:0.4:1;

[0127] The thickness of the drug-loading layer is 15 μm; the thicknesses of the first film coating layer and the second film coating are both 5 μm.

[0128] The preparation method of the above-mentioned orally dissolving film agent for treating Helicobacter pylori infection comprises the following steps:

[0129] Add aspartame and magnesium stearate into hot water at 60 - 70 °C, stir and mix evenly, then add gelatin and polyethylene glycol 400, stir for 2 h to mix evenly, and degas to obtain the film coating layer solution;

[0130] Add Compound 11 into water and mix evenly, then add citric acid to adjust the pH to 3, then add polyvinyl alcohol, polyethylene glycol 400, and aspartame, stir for 2 h to mix evenly, and degas to obtain the drug-loading layer solution;

[0131] Coat the film coating layer solution on the surface of the substrate, dry it at 40 °C to obtain the first film coating layer, then coat the drug-loading layer solution on the surface of the first film coating layer, dry it at 40 °C to obtain the drug-loading layer, and then coat the film coating layer solution on the surface of the drug-loading layer, dry it at 40 °C to obtain the second film coating layer, thus obtaining the orally dissolving film agent for treating Helicobacter pylori infection.

[0132] Example 5

[0133] An orally dissolving film agent for treating Helicobacter pylori infection, which comprises: a drug-loading layer and a first film coating layer and a second film coating layer attached to both sides of the drug-loading layer;

[0134] Among them, the raw materials of the drug-loading layer include: Compound 10, polyvinyl alcohol with a viscosity of 10 mPa·s, polyethylene glycol 400, aspartame, and citric acid, wherein the weight ratio of Compound 10, polyvinyl alcohol, polyethylene glycol 400, and sucrose is 1:15:1.5:0.6;

[0135] The raw materials of the first film coating layer and the second film coating are the same, including: gelatin with a viscosity of 15 mPa·s, polyethylene glycol 400, aspartame, and magnesium stearate, wherein the weight ratio of gelatin, polyethylene glycol 400, sucrose, and magnesium stearate is 15:1.5:0.6:1.5;

[0136] The thickness of the drug-loading layer is 25 μm; the thicknesses of the first film coating layer and the second film coating are both 10 μm.

[0137] The preparation method of the above-mentioned orally dissolving film agent for treating Helicobacter pylori infection comprises the following steps:

[0138] Add sucrose and magnesium stearate into hot water at 60 - 70 °C, stir and mix evenly, then add gelatin and polyethylene glycol 400, stir for 2 h to mix evenly, and degas to obtain the film coating layer solution;

[0139] Add compound 10 to water and mix well. Then add citric acid to adjust the pH to 4. Next, add polyvinyl alcohol, polyethylene glycol 400, and sucrose, and stir for 2 h to mix well. After degassing, a drug-loading layer solution is obtained.

[0140] Coat the film-coating layer solution on the surface of the substrate and dry it at 40 °C to obtain the first film-coating layer. Then coat the drug-loading layer solution on the surface of the first film-coating layer and dry it at 40 °C to obtain the drug-loading layer. Next, coat the film-coating layer solution on the surface of the drug-loading layer and dry it at 40 °C to obtain the second film-coating layer, thus obtaining an orally dissolving film agent for treating Helicobacter pylori infection.

[0141] Example 6

[0142] An orally dissolving film agent for treating Helicobacter pylori infection, which comprises: a drug-loading layer and a first film-coating layer and a second film-coating layer attached to both sides of the drug-loading layer;

[0143] Among them, the raw materials of the drug-loading layer include: compound 11, polyvinyl alcohol with a viscosity of 8 mPa·s, polyethylene glycol 400, aspartame, and citric acid. Among them, the weight ratio of compound 11, polyvinyl alcohol, polyethylene glycol 400, and aspartame is 1:12:1.2:0.5;

[0144] The raw materials of the first film-coating layer and the second film-coating layer are the same, including: gelatin with a viscosity of 17 mPa·s, polyethylene glycol 400, aspartame, and magnesium stearate. Among them, the weight ratio of gelatin, polyethylene glycol 400, aspartame, and magnesium stearate is 12:1.2:0.5:1.5;

[0145] The thickness of the drug-loading layer is 20 μm; the thicknesses of the first film-coating layer and the second film-coating layer are both 8 μm.

[0146] The preparation method of the above-mentioned orally dissolving film agent for treating Helicobacter pylori infection includes the following steps:

[0147] Add aspartame and magnesium stearate to hot water at 60 - 70 °C and stir to mix well. Then add gelatin and polyethylene glycol 400, and stir for 2 h to mix well. After degassing, a film-coating layer solution is obtained;

[0148] Add compound 11 to water and mix well. Then add citric acid to adjust the pH to 3.5. Next, add polyvinyl alcohol, polyethylene glycol 400, and aspartame, and stir for 2 h to mix well. After degassing, a drug-loading layer solution is obtained;

[0149] Coat the film-coating layer solution on the surface of the substrate and dry it at 40 °C to obtain the first film-coating layer. Then coat the drug-loading layer solution on the surface of the first film-coating layer and dry it at 40 °C to obtain the drug-loading layer. Next, coat the film-coating layer solution on the surface of the drug-loading layer and dry it at 40 °C to obtain the second film-coating layer, thus obtaining an orally dissolving film agent for treating Helicobacter pylori infection.

[0150] Comparative Example 10

[0151] An orally dissolving film for treating Helicobacter pylori infection, comprising the following steps: preparing a drug-loading layer according to the method of Example 6 to obtain the orally dissolving film.

[0152] Comparative Example 11

[0153] An orally dissolving film for treating Helicobacter pylori infection, comprising the following steps: replacing polyvinyl alcohol in the drug-loading layer with gelatin having a viscosity of 17 mPa·s, preparing the drug-loading layer according to the method of Example 6 to obtain the orally dissolving film.

[0154] The orally dissolving films of Examples 4 - 6 and Comparative Examples 10 - 11 were tested, and the results are shown in Table 5.

[0155] Table 5 Test Results

[0156] Evaluation index Example 4 Example 5 Example 6 Comparative example 10 Comparative example 11 Film appearance Smooth and flat Smooth and flat Smooth and flat Smooth and flat Smooth and flat Film forming property Good Good Good Good Good Disintegration time limit 34s 36s 35s 65s 19s Taste Good Good Good Good Good Folding endurance >100 >100 >100 >100 >100 Dissolution rate %(15min) 99 98 99 93 99

[0157] It can be seen from Table 5 that: the orally dissolving film of the present invention has a good taste and can improve palatability; and has a good disintegration time limit and a good dissolution rate; while the disintegration time limit of Comparative Example 10 is too long and the dissolution rate is low; the disintegration time limit of Comparative Example 11 is too short.

[0158] Comparative Example 12

[0159] An orally dissolving film for treating Helicobacter pylori infection, comprising the following steps: without adding magnesium stearate, and the others are the same as in Example 6.

[0160] Comparative Example 13

[0161] An orally dissolving film for treating Helicobacter pylori infection, comprising the following steps: replacing magnesium stearate with talc powder, and the others are the same as in Example 6.

[0162] Comparative Example 14

[0163] An orally dissolving film for treating Helicobacter pylori infection, comprising the following steps: without adding citric acid, and the others are the same as in Example 6.

[0164] Comparative Example 15

[0165] An orally dissolving film for treating Helicobacter pylori infection, comprising the following steps: replacing citric acid with sodium bicarbonate and adjusting the pH to 7.6, and the others are the same as in Example 6.

[0166] The orally dissolving films of Example 6 and Comparative Examples 12 - 15 were taken to investigate their stability under accelerated conditions for 6 months (40°C / 75% RH), and the results are shown in Table 6.

[0167] Table 6 Results of the accelerated experiment

[0168]

[0169]

[0170] Note: The structural formula of the above degradation product is as follows:

[0171] As can be seen from Table 6, the orally disintegrating film of the formula of the present invention has good stability.

[0172] Select 10 patients without other diseases and with a positive Helicobacter pylori test, aged 30 - 50 years old. Detect the Helicobacter pylori of the patients by C13 breath test, and then use the drug of Example 6 above on an empty stomach 2 hours before breakfast once a day for 3 consecutive days. After stopping the drug for 3 days, conduct the C13 breath test again. The statistical cure rate is 100%.

[0173] The above is only the preferred specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art within the technical scope disclosed by the present invention, according to the technical solution and inventive concept of the present invention, makes equivalent substitutions or changes, and all should be covered within the protection scope of the present invention.

Claims

1. An orally disintegrating film for treating Helicobacter pylori infection, characterized in that, It includes: a drug-loading layer and a first film layer and a second film layer attached to both sides of the drug-loading layer; Among them, the raw materials of the drug-loading layer include: substance a, a first film-forming substance, a first plasticizer, a first sweetener, and a pH regulator; The raw materials of the first film layer and the second film layer are the same, including: a second film-forming substance, a second plasticizer, a second sweetener, and a stabilizer; The structural formula of substance a is shown in formula (I): Among them, R1 and R2 are each independently selected from one of C6-C12 alkyl groups, and X is one of Cl, Br, I or NO3 - ; R3 is any one of the following structures: R4, R5, R6, and R7 are independently selected from one of C1-C4 saturated alkyl groups.

2. The orally disintegrating film for treating Helicobacter pylori infection according to claim 1, wherein R3 is Preferably, R4, R5, R6, and R7 are all methyl; preferably, R1 and R2 are C8 saturated straight-chain alkyl groups.

3. The orally disintegrating film for treating Helicobacter pylori infection according to claim 1 or 2, characterized in that, The structural formula of substance a is shown in one of formula (II)-(III):

4. The orally disintegrating film for treating Helicobacter pylori infection according to any one of claims 1-3, wherein The first film-forming substance is polyvinyl alcohol; preferably, the viscosity of polyvinyl alcohol is 6-10 mPa·s; preferably, the second film-forming substance is gelatin; preferably, the viscosity of gelatin is 15-20 mPa·s.

5. The orally disintegrating film for treating Helicobacter pylori infection according to any one of claims 1-4, characterized in that, The first plasticizer and the second plasticizer are both at least one of polyethylene glycol, ethylene glycol, and glycerol; preferably, the first plasticizer and the second plasticizer are both polyethylene glycol 400; preferably, the first sweetener and the second sweetener are both at least one of aspartame, menthol, stevioside, glycyrrhizin, and sucrose; preferably, the stabilizer is magnesium stearate.

6. The orally disintegrating film for treating Helicobacter pylori infection according to any one of claims 1-5, characterized in that, The pH regulator is at least one of L(+)-tartaric acid and citric acid; preferably, when preparing the drug-loading layer solution, the pH of the drug-loading layer solution is adjusted to 3-4 with the pH regulator.

7. The orally disintegrating film for treating Helicobacter pylori infection according to any one of claims 1-6, characterized in that, The weight ratio of substance a, the first film-forming substance, the first plasticizer, and the first sweetener is 0.8-1.2:10-15:1-1.5:0.4-0.6; preferably, the weight ratio of the second film-forming substance, the second plasticizer, the second sweetener, and the stabilizer is 10-15:1-1.5:0.4-0.6:1-1.

5.

8. The orally disintegrating film for treating Helicobacter pylori infection according to any one of claims 1-7, characterized in that, The thickness of the drug-loading layer is 15-25 μm; the thicknesses of the first film layer and the second film layer are both 5-10 μm.

9. A preparation method of an orally dissolving film for treating Helicobacter pylori infection according to any one of claims 1-8, characterized in that, It includes the following steps: mixing the raw materials of the film layer with hot water to obtain a film layer solution; mixing the raw materials of the drug-loading layer with water to obtain a drug-loading layer solution; taking the film layer solution to prepare the first film layer, then using the drug-loading layer solution to prepare a drug-loading layer on the surface of the first film layer, and then using the film layer solution to prepare a second film layer on the surface of the drug-loading layer to obtain an orally dissolving film agent for treating Helicobacter pylori infection.

10. The preparation method of the orally disintegrating film for treating Helicobacter pylori infection according to claim 9, characterized in that, The temperature of the hot water is 60-70 °C.

Images