Dry suspension granules for dry suspension and preparation method and use thereof

Abstract

The present invention relates to dry suspension particles for dry suspension, dry suspension containing the dry suspension particles, and preparation method and use thereof. The dry suspension particles contain anionic gelling agent and cationic polymer, wherein the weight ratio of the anionic gelling agent to the cationic polymer is (0.5-50):1.

Description

Technical Field

[0001] The invention relates to dry suspension particles for dry suspension, a dry suspension comprising the dry suspension particles, and a preparation method and application thereof. Background Art

[0002] Proton Pump Inhibitors (PPIs) are drugs that selectively inhibit the secretion of H + / K + -ATPase (also known as proton pump or acid pump). + / K + -ATPase is the final pathway for inhibiting gastric acid secretion. Inhibition of it can significantly reduce gastric acid secretion. Therefore, proton pump inhibitors are usually used to treat diseases of the digestive tract induced or caused by gastric acid (i.e., acid-related diseases), including gastric and duodenal ulcers, gastroesophageal reflux disease, surgical anastomotic ulcers, and Zollinger-Ellison syndrome. According to the mechanism of action, known PPIs can be divided into irreversible PPIs and reversible PPIs (RPPIs). Among them, irreversible PPIs are mainly benzimidazole derivatives, which can quickly pass through the parietal cell membrane and accumulate in the highly acidic secretory tubules, and then be protonated and converted into sulfonamide compounds, which can react with H + / K + -ATPase α subunit cysteine ​​residues on the sulfhydryl group to form a covalent disulfide bond, thereby H + / K + -ATPase is irreversibly inactivated and its acid secretion activity is inhibited (Zhang Xuan, "Proton Pump Inhibitor-Protazole Drug Patent Technology Review", "Patent Literature Research 2018-Pharmaceuticals", Intellectual Property Publishing House, Beijing, 2019.9: p554-567). Currently, such drugs that have been marketed worldwide include: Omeprazole, Lansoprazole, Pantoprazole, Rabeprazole, Esomeprazole, Ilaprazole, Delansoprazole, etc.

[0003] Similar to other prazole drugs, ilaprazole is also an acid-labile compound. However, compared with other existing prazole drugs, ilaprazole has lower stability. Acid-labile compounds are substances that are unstable in acidic media but have good stability in neutral and alkaline media. The common feature of these compounds is that they can become biologically effective compounds after rapid degradation / transformation in acidic media. Acid-labile proton pump inhibitors are sensitive to degradation / transformation in acidic and neutral media. When used orally, they should be avoided from contact with gastric acid to affect their stability. One way to solve this problem is to coat the oral preparations of this type of drug with enteric materials to prepare enteric-coated micropellet preparations.

[0004] Enteric-coated pellets are usually not administered directly, but are further made into other dosage forms for easy administration, such as tablets, capsules or dry suspensions. Dry suspensions are powders or granules made of poorly soluble solid drugs and suitable excipients, which can be dispersed into suspensions by adding water and shaking before use. Other liquid dispersion media and additives suitable for oral administration other than water can be added to dry suspensions to improve properties such as taste. Suspension is the process of dispersing insoluble solid particles in a suitable liquid dispersion medium almost uniformly by mechanical means. The solid particles in the formed suspension have a high surface free energy due to their large dispersion degree, are easy to aggregate, and belong to a thermodynamically unstable system; and because the solid particles in the suspension are larger than the colloid particles, they are easily affected by gravity and settle, so they also belong to a kinetically unstable system.

[0005] Therefore, how to improve the thermodynamic and kinetic properties of dry suspensions, especially dry suspensions containing pellets, when adding a dispersion medium, especially water to form a suspension, such as the time to reach a stable viscosity level and the time for solid particles such as pellets to be stably suspended, has become a problem faced in the art. Summary of the invention

[0006] Surprisingly, the inventors found that by combining anionic gelling agents with cationic polymers, such as chitosan and its derivatives, in dry suspension particles, the suspension obtained thereby can quickly reach a stable viscosity level, and the prepared suspension gel can keep the pellets stably suspended for a long time.

[0007] The object of the present invention is solved by the dry suspension granules according to the present invention comprising anionic gelling agents and cationic polymers, in particular, the composition of the dry suspension granules can stably suspend the pellets in the suspension gel after forming the suspension liquid / suspension gel. Therefore, the dry suspension granules according to the present invention can provide a dry suspension that forms a stable suspension gel more quickly, and can stably suspend the pellets in the suspension gel formed by the dry suspension for a longer time.

[0008] Therefore, in one aspect, the present invention provides a dry suspension granule for a dry suspension, comprising an anionic gelling agent and a cationic polymer, wherein the weight ratio of the anionic gelling agent to the cationic polymer is (0.5-50):1.

[0009] According to one embodiment of the present invention, the weight ratio of the anionic gelling agent to the cationic polymer is preferably (0.8-20):1, more preferably (0.9-10):1, and most preferably (1-3):1.

[0010] According to one embodiment of the present invention, the anionic gelling agent is selected from one, two or more of gum arabic, gelatin, alginate such as sodium alginate, pectin, xanthan gum, gellan gum, locust bean gum, guar gum, agar, carrageenan, tamarind gum, konjac gum, cassia gum, tragacanth gum, and karaya gum.

[0011] According to one embodiment of the present invention, the cationic polymer is selected from chitosan or its derivatives.

[0012] According to one embodiment of the present invention, the weight percentage of the cationic polymer in the dry suspension particles is 0.5-5%, preferably 0.6-4%, more preferably 0.8-3.5%, and most preferably 0.9-3.0%.

[0013] According to one embodiment of the present invention, the dry suspension granules according to the present invention further comprise one, two or more of a binder, a disintegrant, a diluent and a pH adjuster.

[0014] According to one embodiment of the present invention, the binder is one, two or more selected from polyvinyl pyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose, polyvinyl alcohol and starch.

[0015] According to one embodiment of the present invention, the disintegrant is selected from one, two or more of sodium carboxymethylcellulose, calcium carboxymethylcellulose, cross-linked sodium carboxymethylcellulose, cross-linked sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone, microcrystalline cellulose and pregelatinized starch.

[0016] According to one embodiment of the present invention, the diluent is selected from one, two or more of xylitol, mannitol, sucrose, glucose, sorbitol, maltitol and fructose.

[0017] According to one embodiment of the present invention, the pH adjuster is selected from organic acids or inorganic acids, preferably one, two or more of tartaric acid, citric acid, oxalic acid, succinic acid, fumaric acid, ascorbic acid, malic acid, glutamic acid and caffeic acid.

[0018] According to one embodiment of the present invention, the pH value of the suspension gel formed by the dry suspension particles in the aqueous medium is in the range of 2.5-7.0; preferably in the range of 3.0-5.0.

[0019] According to one embodiment of the present invention, when preparing the suspension gel, the amount of aqueous dispersion medium added to the dry suspension granules according to the present invention is 2 to 50 times the weight of the dry suspension granules.

[0020] In yet another aspect, the present invention provides a method for preparing the dry suspension particles according to the present invention, comprising the steps of:

[0021] (1) mixing anionic gelling agent, cationic polymer and other optional auxiliary materials;

[0022] (2) preparing a binder solution separately;

[0023] (3) adding the binder solution obtained in step (2) to the mixture obtained in step (1) to prepare a wet mixture;

[0024] (4) Granulating the wet mixture obtained in step (3) to obtain the dry suspension granules according to the present invention.

[0025] Preferably, the other excipients include diluents, pH adjusters, disintegrants and the like.

[0026] Preferably, water and / or ethanol are used as solvent in step (2).

[0027] In yet another aspect, the present invention provides a method for preparing the dry suspension particles according to the present invention, comprising the steps of:

[0028] (1) mixing anionic gelling agent, cationic polymer and other optional auxiliary materials;

[0029] (2) providing water and / or ethanol as a wetting agent;

[0030] (3) adding the wetting agent provided in step (2) to the mixture obtained in step (1) to prepare a wetted mixture;

[0031] (4) Granulating the wet mixture obtained in step (3) to obtain the dry suspension granules according to the present invention.

[0032] Preferably, the other auxiliary materials include diluents, pH regulators, disintegrants and / or binders.

[0033] In the method for preparing the dry suspension granules according to the present invention, preferably, after step (4), the method further comprises step (5): drying the dry suspension granules according to the present invention.

[0034] In the method for preparing the dry suspension granules according to the present invention, preferably, after step (5), the method further comprises step (6): granulating the dry suspension granules according to the present invention in the form of granules.

[0035] In another aspect, the present invention also provides a pharmaceutical composition, in particular a dry suspension, comprising the dry suspension granules according to the present invention.

[0036] According to one embodiment of the present invention, the present invention also provides a pharmaceutical composition, especially a dry suspension, which comprises the dry suspension granules according to the present invention and enteric-coated pellets, especially enteric-coated pellets containing ilaprazole.

[0037] According to one embodiment of the present invention, in the pharmaceutical composition according to the present invention, the mass ratio between the amount of ilaprazole in the enteric-coated micropellets and the amount of the dry suspension granules is 1:200-1000.

[0038] According to one embodiment of the present invention, after adding the dispersion medium to the pharmaceutical composition according to the present invention, preferably the dry suspension, the time it takes for the obtained suspension gel to reach 75% of the maximum viscosity is less than 8 min, preferably 7 min.

[0039] According to one embodiment of the present invention, after adding the dispersion medium to the pharmaceutical composition according to the present invention, preferably the dry suspension, the time for the obtained suspension gel to reach 90% of the maximum viscosity is less than 12 min, preferably less than 11 min.

[0040] According to one embodiment of the present invention, the time for forming a suspension gel after adding an aqueous medium to the pharmaceutical composition according to the present invention, preferably a dry suspension, is less than 120 s, preferably less than 90 s, more preferably less than 70 s, most preferably less than 50 s.

[0041] According to one embodiment of the present invention, after the dry suspension is added to the dispersion medium to form a solution with a pH of 1.2, the release rate of ilaprazole within 1 hour is preferably no more than 10%.

[0042] According to one embodiment of the present invention, the pharmaceutical composition of the present invention preferably has an ilaprazole release rate of not less than 70% within 45 minutes after the dry suspension is added to the dispersion medium to form a solution of pH 6.8.

[0043] In the ongoing animal experimental studies, the inventors found that the preparations containing the enteric-coated micropellets according to the present invention, especially the dry suspension, showed beneficial effects in the treatment and / or prevention of gastrointestinal diseases, which mainly include heartburn, inflammatory bowel disease, Crohn's disease, irritable bowel syndrome, ulcerative colitis, peptic ulcer, stress ulcer, hemorrhagic peptic ulcer, duodenal ulcer and duodenal ulcer recurrence, NSAID-related gastric ulcer, active benign gastric ulcer in adults, infectious enteritis, colitis, hyperacidity, dyspepsia, gastroparesis, Zollinger-Ellison syndrome, gastroesophageal reflux disease (GERD), Helicobacter pylori-related diseases or eradication of Helicobacter pylori, all grades of erosive esophagitis, short bowel syndrome, or any combination of the above diseases.

[0044] Therefore, according to one aspect of the present invention, the present invention provides a method for treating and / or preventing gastrointestinal diseases. The method comprises the step of administering a therapeutic and / or preventive effective amount of a dry suspension according to the present invention to a patient in need of such treatment and / or prevention. Among them, the gastrointestinal diseases that can be treated and / or prevented using this method include, but are not limited to, heartburn, inflammatory bowel disease, Crohn's disease, irritable bowel syndrome, ulcerative colitis, peptic ulcer, stress ulcer, bleeding peptic ulcer, duodenal ulcer and duodenal ulcer recurrence, gastric ulcer associated with NSAID, active benign gastric ulcer in adults, infectious enteritis, colitis, hyperacidity, dyspepsia, gastroparesis, Zollinger-Ellison syndrome, gastroesophageal reflux disease (GERD), Helicobacter pylori-related diseases or eradication of Helicobacter pylori, all grades of erosive esophagitis, short bowel syndrome, or any combination of the above diseases.

[0045] Accordingly, according to another aspect of the present invention, the present invention provides use of the dry suspension according to the present invention in the preparation of a medicament for treating and / or preventing gastrointestinal diseases, including, but not limited to, heartburn, inflammatory bowel disease, Crohn's disease, irritable bowel syndrome, ulcerative colitis, peptic ulcer, stress ulcer, bleeding peptic ulcer, duodenal ulcer and duodenal ulcer recurrence, NSAID-related gastric ulcer, active benign gastric ulcer in adults, infectious enteritis, colitis, hyperacidity, dyspepsia, gastroparesis, Zollinger-Ellison syndrome, gastroesophageal reflux disease (GERD), Helicobacter pylori-related diseases or eradication of Helicobacter pylori, all grades of erosive esophagitis, short bowel syndrome, or any combination of the above diseases.

[0046] Furthermore, when the dry suspension according to the present invention is used to prepare a drug for treating and / or preventing gastrointestinal diseases, the gastrointestinal diseases include, but are not limited to, duodenal ulcer and ulcer recurrence, gastric ulcer, gastroesophageal reflux disease (GERD), and Helicobacter pylori-related diseases; or the drug can be used to eradicate Helicobacter pylori, and can also prevent peptic ulcer diseases caused by non-steroidal anti-inflammatory drugs, and prevent gastrointestinal bleeding and related ulcers caused by antiplatelet aggregation drugs (including, but not limited to clopidogrel, prasugrel, ticagrelor) and the like. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] Figure 1 The time to reach the maximum percent viscosity after adding water as a dispersion medium is shown for the dry suspension granules I-III according to the present invention, the dry suspension granules IV of the prior art, and the comparative dry suspension granules V.

[0048] Figure 2 The dry suspension prepared by adding different pellets to the dry suspension granules I-III according to the present invention and the dry suspension granules IV of the prior art is shown, and the pellet suspension-sedimentation time in a volume of 0-5 mL measured in a 15 mL measuring cylinder is shown.

[0049] Figure 3 The dry suspension prepared by adding different pellets to the dry suspension granules I-III according to the present invention and the dry suspension granules IV of the prior art is shown, and the pellet suspension-sedimentation time in a volume of 5-10 mL measured in a 15 mL measuring cylinder is shown.

[0050] Figure 4 The dry suspension prepared by adding different pellets to the dry suspension granules I-III according to the present invention and the dry suspension granules IV of the prior art is shown, and the pellet suspension-sedimentation time in a volume of 10-15 mL measured in a 15 mL measuring cylinder is shown.

[0051] Beneficial effects of the present invention

[0052] Compared with the prior art, the dry suspension particles and the dry suspension containing the same according to the present invention can be quickly dispersed in an aqueous medium to form a stable suspension gel, and a uniform and stable dispersion system containing suspended pellets can be obtained in the presence of pellets; the solution / gel obtained thereby can reach a stable viscosity in a shorter time than the dry suspension particles and dry suspension in the prior art, and can maintain the stable suspension state of the pellets for a longer time.

[0053] For acid-labile proton pump inhibitors, in particular ilaprazole, the suspensions obtained by means of the dry suspensions according to the invention can additionally improve their dissolution. DETAILED DESCRIPTION

[0054] In a preferred embodiment according to the present invention, the dry suspension preparation according to the present invention comprises enteric-coated pellets, preferably ilaprazole enteric-coated pellets and the dry suspension granules according to the present invention. The dry suspension according to the present invention may be, but is not limited to, comprising the following components by weight:

[0055]

[0056] As for the enteric-coated micropellets, according to various aspects of the present invention, either micropellets in the prior art or enteric-coated micropellets according to the following embodiments may be preferably used.

[0057] According to the present invention, in a first embodiment of the enteric-coated microcapsules, the enteric-coated microcapsules include, from the inside to the outside, a pill core, a first isolation layer, a second isolation layer and an enteric layer, wherein the pill core contains ilaprazole and / or a pharmaceutically acceptable salt of ilaprazole and a first excipient, and the enteric-coated microcapsules are characterized in that the first isolation layer contains a water-insoluble alkaline compound, and the weight ratio between the first excipient and ilaprazole and / or a pharmaceutically acceptable salt of ilaprazole is 0.2 to 5:1.

[0058] According to the present invention, in a second embodiment of the enteric-coated microcapsules, the enteric-coated microcapsules include, from the inside to the outside, a pill core, a first isolation layer, a second isolation layer and an enteric layer, wherein the pill core contains ilaprazole and / or a pharmaceutically acceptable salt of ilaprazole and a first excipient, and the enteric-coated microcapsules are characterized in that the first isolation layer contains a water-insoluble alkaline compound and the first excipient is a water-insoluble alkaline compound, wherein the water-insoluble alkaline compound contained in the first isolation layer and the water-insoluble alkaline compound of the first excipient may be the same or different.

[0059] According to the present invention, in a third embodiment of the enteric-coated microcapsules, the enteric-coated microcapsules include, from the inside to the outside, a pill core, a first isolation layer, a second isolation layer and an enteric layer, wherein the pill core contains ilaprazole and / or a pharmaceutically acceptable salt of ilaprazole and a first excipient, and the enteric-coated microcapsules are characterized in that the particle size D90 of ilaprazole and / or a pharmaceutically acceptable salt of ilaprazole is ≤100 μm, and the second isolation layer does not contain alkaline substances.

[0060] Preferably, the enteric-coated micropellets according to the present invention are further provided with a protective layer outside the enteric layer.

[0061] Preferably, in the enteric pellets according to the present invention, no other layers exist between the pellet core and the first isolation layer.

[0062] Preferably, in the enteric pellets according to the present invention, no other layer exists between the second isolation layer and the enteric layer.

[0063] Preferably, in the enteric pellets according to the present invention, no other layer exists between the first isolation layer and the second isolation layer.

[0064] Preferably, the first excipient in the enteric-coated pellets according to the present invention is an alkaline compound, preferably a water-insoluble alkaline compound, more preferably selected from magnesium hydroxide, aluminum hydroxide, magnesium oxide, magnesium carbonate, calcium carbonate, and calcium hydroxide.

[0065] Preferably, the pharmaceutically acceptable salt of ilaprazole may be, for example, ilaprazole sodium, ilaprazole magnesium, ilaprazole zinc, ilaprazole potassium, ilaprazole lithium or ilaprazole calcium, etc. Here, those skilled in the art can select a suitable salt as needed.

[0066] Preferably, the pellet core of the enteric-coated micropellets according to the present invention further comprises a surfactant, preferably, the surfactant is Tween 80 or sodium dodecyl sulfate.

[0067] Preferably, the weight ratio of the water-insoluble alkaline compound in the first isolation layer to ilaprazole and / or its pharmaceutically acceptable salt is 0.2-5:1, preferably 0.25-4:1, more preferably 0.3-3:1, particularly preferably 0.5-2:1, most preferably 0.8-1.2:1, for example 1:1.

[0068] Preferably, the second isolation layer contains a water-insoluble inert substance capable of preventing the pellets from sticking together, and the weight ratio of the water-insoluble inert substance to the binder is in the range of 1-8:1.5-10, or 1-10:1-20, or 4-26:7-44.

[0069] Preferably, the particle size D90 of ilaprazole and / or a pharmaceutically acceptable salt of ilaprazole can be a range selected between any two of the following endpoints: 0 μm (excluding this point value when forming the range), 10 μm, 20 μm, 30 μm, 40 μm, 50 μm, 60 μm, 70 μm, 80 μm, 90 μm, 100 μm.

[0070] About the Pill Core of Enteric Coated Pellets :

[0071] The pellet core (or pill containing pill) of the enteric-coated pellets according to the present invention can be a fully active pellet core or a blank pellet core coated with a drug-carrying layer. In this article, the term "fully active pellet core" refers to a pellet core containing ilaprazole and / or a pharmaceutically acceptable salt of ilaprazole and a first excipient, as well as one or more other pharmaceutically acceptable excipients, wherein ilaprazole and / or a pharmaceutically acceptable salt of ilaprazole as an active ingredient is dispersed in other ingredients (the first excipient and one or more other pharmaceutically acceptable excipients, etc.), and does not form another layer independently or together with any other ingredients; in the blank pellet core coated with a drug-carrying layer, the drug-carrying layer contains ilaprazole and / or a pharmaceutically acceptable salt of ilaprazole and a first excipient and optional excipients.

[0072] When the ilaprazole and / or its pharmaceutically acceptable salt in the pill core cannot achieve sufficient storage stability under the action of the water-insoluble alkaline compound contained in the first isolation layer alone, the first excipient added to the pill core can improve its storage stability.

[0073] The first excipient in the pill core can be a conventional excipient used in the prior art to improve the stability of acid-labile compounds. Preferably, the first excipient is an alkaline compound, including a water-insoluble alkaline compound and a water-soluble alkaline compound. According to the present invention, preferably, a water-insoluble alkaline compound is used as the first excipient in the pill core; more preferably, the water-insoluble alkaline compound contained in the pill core is the same as the water-insoluble alkaline compound contained in the first isolation layer, thereby further enhancing the pH buffering effect of the isolation layer. In an embodiment according to the present invention, the water-insoluble alkaline compound can be selected from, but not limited to, one or more of magnesium hydroxide, aluminum hydroxide, magnesium oxide, magnesium carbonate, calcium carbonate, and calcium hydroxide. Preferably, the weight ratio of the alkaline compound to ilaprazole and / or its pharmaceutically acceptable salt is 0.2 to 5:1, preferably 0.25 to 4:1, more preferably 0.3 to 3:1, particularly preferably 0.5 to 2:1, and most preferably 0.8 to 1.2:1, for example 1:1.

[0074] According to the present invention, a surfactant may also be included in the pill core. The results of the embodiments of the present invention show that surfactants can improve the solubility of ilaprazole and / or its pharmaceutically acceptable salts in enteric-coated pellets and their preparations, thereby effectively improving their bioavailability. In the embodiments of the present invention, the surfactant included in the pill core may be selected from nonionic surfactants, anionic surfactants and zwitterionic surfactants. Preferably, the nonionic surfactant may be selected from polyethylene glycol type, polyol type (such as Tween 80), etc.; the anionic surfactant may be selected from higher fatty acid salts, sulfate ester salts, sulfonates, etc., such as sodium lauryl sulfate; the zwitterionic surfactant may be selected from phospholipids.

[0075] According to the present invention, the particle size of ilaprazole and / or its pharmaceutically acceptable salt can affect the dissolution and / or drug loading of the enteric-coated micropellets. In a preferred embodiment according to the present invention, the particle size of ilaprazole and / or its pharmaceutically acceptable salt can be a particle size D90≤100 μm; in this case, the enteric-coated micropellets have good dissolution, and the bioavailability of the enteric-coated micropellets preparation prepared from the enteric-coated micropellets can be improved. More preferably, the particle size D90 of ilaprazole and / or its pharmaceutically acceptable salt can be a range selected between any two of the following endpoints: 10 μm, 20 μm, 30 μm, 40 μm, 50 μm, 60 μm, 70 μm, 80 μm, 90 μm, 100 μm, especially D90≤50 μm, thereby achieving an increased drug loading.

[0076] According to one embodiment of the present invention, the blank micropellet core is a blank micropellet core conventionally used in the prior art. In an embodiment according to the present invention, the blank micropellet core can be selected from, but not limited to, microcrystalline cellulose pellet core, sucrose pellet core or mannitol pellet core, and its particle size can be 50-500 μm, preferably 100-400 μm, more preferably 250-350 μm, and most preferably about 300 μm.

[0077] According to one embodiment of the present invention, the drug-carrying layer as described above may further comprise a binder. The binder may be selected from, but not limited to, one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, methyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol, syrup and starch. In an embodiment according to the present invention, the binder may be selected from one or more of hydroxypropyl cellulose-SSL (e.g., a commercially available series from Nisso), hydroxypropyl methylcellulose E5, polyvinyl pyrrolidone K30, polyvinyl alcohol, methyl cellulose and polyethylene glycol.

[0078] About the isolation layer of enteric coated pellets :

[0079] The basic function of the isolation layer of the enteric-coated micro-pellets is to isolate the pill core in an alkaline environment from the enteric layer containing free carboxyl groups, so as to prevent degradation or discoloration of ilaprazole and / or its pharmaceutically acceptable salt during the coating process or during storage. In the study of ilaprazole enteric-coated micro-pellets and their preparations, the inventors found that the water-insoluble inert substances (such as talc, silicon dioxide, titanium dioxide, magnesium stearate, etc.) and / or water-soluble alkaline compounds that can prevent the micro-pellets from sticking together, which are commonly used in the conventional preparation method in the prior art (for example, when preparing the isolation layer closely adjacent to the pill core) and the alkaline compounds commonly used when preparing the isolation layer closely adjacent to the enteric layer, will reduce the stability and / or acid resistance of the enteric-coated micro-pellets and their preparations, especially for acid-unstable compounds with relatively low stability such as ilaprazole, which results in the enteric-coated micro-pellets and their preparations being unable to simultaneously meet the requirements of stability and acid resistance. In this context, the term "immediately adjacent to" means that there is no additional layer between the pellet core of the enteric coated pellets and its coating or coating layer, or between the two layers.

[0080] One of the reasons leading to the technical problem is that the inventors have proved through experiments and believe (but not limited to this) that the compatibility between the water-insoluble inert substance that can prevent the micro-pills from sticking and contained in the isolation layer (corresponding to the first isolation layer according to the present invention) closely adjacent to the pill core and the acid-unstable compound contained in the pill core is different due to the different stabilities of the acid-unstable compounds, that is, in the enteric-coated micro-pills and their preparations prepared according to the prior art, when the stability of the acid-unstable compound (such as ilaprazole) contained in the pill core is low, the compatibility between the water-insoluble inert substance that can prevent the micro-pills from sticking and contained in the isolation layer closely adjacent to the pill core (such as talc) and the acid-unstable compound will also decrease. Therefore, even under the protection of the alkaline compound as a stabilizer contained in the pill core and / or the isolation layer, the related substances (i.e., impurities) in the accelerated test results will still increase significantly, thereby reducing the stability of the enteric-coated micro-pill preparation. This limits to a certain extent the scope of acid-unstable compounds that can be applied to enteric-coated micropills and their preparations prepared according to the prior art, that is, the formula or composition of the enteric-coated micropills and their preparations prepared according to the prior art cannot be well applied to ilaprazole and / or its pharmaceutically acceptable salts with relatively low stability. In addition, when the isolation layer (corresponding to the first isolation layer according to the present invention) closely adjacent to the pill core contains a water-soluble alkaline compound, under long-term high temperature and high humidity conditions, the isolation layer of the enteric-coated micropill will absorb free water and cause the water-soluble alkaline compound to dissolve, thereby increasing the alkalinity of the isolation layer closely adjacent to the enteric layer and showing alkalinity. When water penetrates into the enteric layer under an acidic medium, the enteric layer dissolves prematurely, resulting in a decrease in the acid resistance of the enteric-coated micropills and their preparations. The principle that the enteric layer dissolves prematurely due to the alkalinity of the isolation layer closely adjacent to the enteric layer is also applicable to the case where the isolation layer (corresponding to the second isolation layer according to the present invention) closely adjacent to the enteric layer contains an alkaline compound.

[0081] Therefore, according to the present invention, the enteric-coated pellets include at least two isolation layers containing inert substances, that is, at least a first isolation layer close to the pill core and closely adjacent to the pill core and a second isolation layer farther from the pill core or closely adjacent to the enteric layer than the first isolation layer, wherein the first isolation layer contains a water-insoluble alkaline compound, but does not contain a water-soluble alkaline compound and a water-insoluble inert substance capable of preventing the pellets from sticking, and the second isolation layer does not contain an alkaline compound. When the enteric-coated pellets include three or more isolation layers, the other isolation layers between the first isolation layer and the second isolation layer may be isolation layers that meet the definition of the first isolation layer or the second isolation layer according to the present invention, or may be isolation layers commonly used in the prior art.

[0082] According to the present invention, the water-insoluble alkaline compound can be a water-insoluble alkaline compound commonly used in the prior art for improving the stability of acid-instability compounds. In an embodiment according to the present invention, the water-insoluble alkaline compound can be selected from, but not limited to, one or more of magnesium hydroxide, aluminum hydroxide, magnesium oxide, magnesium carbonate, calcium carbonate, and calcium hydroxide.

[0083] According to the present invention, the water-insoluble inert substance that can prevent the micro-pellets from sticking can be selected from one or more lubricants, glidants and anti-adhesives (i.e., anti-adhesives, the same below) conventionally used in pharmacy. In an embodiment of the present invention, the water-insoluble inert substance that can prevent the micro-pellets from sticking can be selected from, but not limited to, silicon dioxide, calcium silicate, colloidal silicon dioxide, aluminum silicate, calcium aluminum silicate, magnesium silicate, sodium stearate, zinc stearate, magnesium stearate, talc and titanium dioxide. In one embodiment of the enteric-coated micro-pellets of ilaprazole according to the present invention, the first isolation layer of the enteric-coated micro-pellets does not contain the following water-insoluble inert substances that can prevent the micro-pellets from sticking: one or more of talc, silicon dioxide, titanium dioxide and magnesium stearate.

[0084] In a preferred embodiment according to the present invention, the first isolation layer is mainly composed of a water-insoluble alkaline compound and a binder, and the second isolation layer is mainly composed of a water-insoluble inert substance capable of preventing the micropills from sticking together and a binder. According to the present invention, by adjusting the amount of the water-insoluble alkaline compound and the binder contained in the first isolation layer or the amount of the water-insoluble inert substance capable of preventing the micropills from sticking together and the binder contained in the second isolation layer, the dissolution of the enteric-coated micropill preparation can be affected, thereby affecting its bioavailability. For example, in a preferred embodiment of the enteric-coated micropill tablets of ilaprazole according to the present invention, the ratio of each component can be as follows: when the amount of ilaprazole is 5 to 15 parts by weight, the first isolation layer contains 5 to 36 parts by weight of the binder and 5 to 36 parts by weight of the water-insoluble alkaline compound; the second isolation layer contains 4 to 26 parts by weight of the binder and 7 to 44 parts by weight of the water-insoluble inert substance capable of preventing the micropills from sticking together.

[0085] The above-mentioned adhesive is to use adhesive usually in the isolation layer according to the prior art. According to the present invention, the adhesive can be selected from a pharmaceutically qualified water-soluble inert compound or a polymer used as a coating film, such as one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, methylcellulose, polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol, syrup and the starch.

[0086] About the enteric layer of enteric-coated pellets :

[0087] The enteric layer commonly used in the enteric micropellet preparations in the prior art is also applicable to the present invention. For example, a detailed description of the enteric layer is recorded in CN87103285A (the Chinese equivalent of US4786505); the inventor takes it as a reference and introduces the contents related to the enteric layer in the document and the relevant contents of all documents cited therein into the present application.

[0088] According to the present invention, the enteric layer may contain one or more substances selected from the following group: acrylic resins, celluloses such as carboxymethyl ethyl cellulose, enteric coating materials such as Opadry, and optionally one or more additives selected from plasticizers, anti-adherents, and lubricants. In an embodiment according to the present invention, the enteric layer may contain acrylic resin enteric coating materials, plasticizers (such as polyethylene glycol, triacetin, triethyl citrate, phthalates, etc.), anti-adherents (such as talc, glyceryl monostearate, etc.). Among them, the acrylic resin enteric coating material is selected from one or more of cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer solution or dispersion L30D55, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, and shellac. In a preferred embodiment of the ilaprazole enteric micropellets according to the present invention, the weight ratio of the enteric coating material contained in the enteric layer to ilaprazole and / or its pharmaceutically acceptable salt is 2 to 20:1. In a preferred embodiment of the ilaprazole enteric-coated micropellets according to the present invention, the weight ratio of the plasticizer to the ilaprazole and / or its pharmaceutically acceptable salt is 0.6-6:1, preferably 0.8-4:1, and more preferably 1-2:1.

[0089] About the protective layer of enteric-coated micropellets :

[0090] According to the present invention, the enteric-coated micropellets may also be provided with a protective layer on the outside of the enteric layer, preferably the protective layer is closely adjacent to the enteric layer. The protective layer can prevent adhesion that may occur between various semi-finished products / products during the placement process before being prepared into a preparation, or during the preparation process of the preparation, or during the placement process after being prepared into a preparation. In addition, the provision of a protective layer can also effectively improve the dissolution of the enteric-coated micropellets, thereby improving the bioavailability of the enteric-coated micropellet preparation prepared therefrom.

[0091] In an embodiment according to the present invention, the protective layer may include a binder and an anti-adherent. The binder may be selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, methylcellulose and polyethylene glycol. The anti-adherent may be selected from one or more of talc, magnesium stearate, titanium dioxide and silicon dioxide.

[0092] According to the present invention, increasing the amount of the anti-adhesive agent in the protective layer can improve the acid resistance of the enteric-coated pellets. In a preferred embodiment of the ilaprazole enteric-coated pellets according to the present invention, when the amount of ilaprazole and / or a pharmaceutically acceptable salt thereof is 5 to 15 parts by weight, the amount of the anti-adhesive agent is 0.5 to 5 parts by weight.

[0093] According to the fourth aspect of the present invention, the present invention provides a method for preparing enteric-coated microcapsules, which method comprises at least the following steps: 1) preparing a pill core comprising ilaprazole and / or a pharmaceutically acceptable salt of ilaprazole and a first excipient; 2) coating a first isolation layer and then coating a second isolation layer; and 3) coating an enteric layer.

[0094] Preferably, step 2) comprises: preparing a first suspension containing a water-insoluble alkaline compound and not containing a water-soluble alkaline compound and a water-insoluble inert substance capable of preventing the pellets from sticking together, and coating the first suspension on the pellet cores obtained in step 1); preparing a second suspension not containing an alkaline compound, and coating the second suspension as a second isolation layer, preferably as a second isolation layer closely adjacent to the enteric layer;

[0095] Preferably, in step 1), the first excipient and the water-insoluble alkaline compound contained in the first isolation layer work together to achieve storage stability of ilaprazole and / or a pharmaceutically acceptable salt of ilaprazole.

[0096] Preferably, the method for preparing enteric-coated micropellets further comprises step 4): coating with a protective layer.

[0097] In an embodiment of the present invention, the method for preparing enteric-coated pellets may include one or more of the following steps:

[0098] 1) coating a drug-loading layer on a blank micro-pellet core by, for example, a fluidized bed method to prepare a pellet core, wherein the drug-loading layer comprises ilaprazole and / or a pharmaceutically acceptable salt of ilaprazole, an alkaline compound as a first excipient, and a binder;

[0099] 2) coating at least the first suspension and the second suspension on the pellet core obtained in step 1) from the inside out by, for example, a fluidized bed method, wherein the first suspension contains a water-insoluble alkaline compound but does not contain a water-soluble alkaline compound and a water-insoluble inert substance capable of preventing the pellets from sticking together, thereby forming a first isolation layer; and the second suspension does not contain an alkaline compound, thereby forming a second isolation layer; thereby preparing isolated pellets;

[0100] 3) preparing an enteric layer suspension by mixing an enteric coating material and one or more selected from a plasticizer, an anti-adherent agent, a lubricant and an emulsifier; coating the enteric layer suspension on the isolated pellets obtained in step 2) by, for example, a fluidized bed method, to prepare enteric micropellets.

[0101] Preferably, the method for preparing the enteric-coated microcapsules may further comprise step 4): adding one or more binders selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, methyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, carboxymethyl cellulose and polyethylene glycol to purified water to prepare a protective layer coating solution, and coating the protective layer coating solution on the enteric-coated microcapsules obtained in step 3) by, for example, a fluidized bed method, to prepare enteric-coated microcapsules with a protective layer.

[0102] Taking the dry suspension as an example, the preparation method and property testing experiment of the enteric-coated micropellets and the dry suspension containing the enteric micropellets according to the present invention are described below.

[0103] Example

[0104] Example 1: Preparation of micropellets

[0105] First, in this example, ilaprazole and / or a pharmaceutically acceptable salt thereof is used as an example to prepare enteric-coated pellets A, D and E according to the present invention.

[0106] (I) Preparation formula of each component layer of micropellets:

[0107] 1.1 Preparation of pills containing medicine (i.e., pill core W) and its drug loading rate

[0108] (1) Weigh 150 g of hydroxypropyl cellulose-SSL and 4 g of polysorbate 80 and dissolve them in 3000 g of purified water to obtain a hydroxypropyl cellulose binder solution, then add 100 g of magnesium hydroxide to the binder solution, and disperse it at 10,000 rpm for 5 min by high shear dispersion, then disperse 100 g of ilaprazole with a D90 particle size of 46.8 μm into the binder solution containing magnesium hydroxide, and disperse it evenly at 10,000 rpm by high shear dispersion; spray the ilaprazole suspension onto 100 g of sucrose pellet cores by GLATT GPCG-1 fluidized bed to prepare pills W1.

[0109] The fluidized bed process parameters are as follows:

[0110]

[0111] Among them, the drug content of W1 containing pills = (actual content of pills containing pills) / (theoretical content of pills containing pills) × 100% = 95.6%

[0112] (2) 180 g of polyvinyl pyrrolidone K30 and 6 g of polysorbate 80 were weighed and dissolved in 3000 g of purified water, 50 g of magnesium oxide was added thereto, and the mixture was dispersed uniformly at 10,000 rpm to obtain a binder containing magnesium oxide. Then 150 g of ilaprazole was dispersed in the binder containing magnesium oxide, and the mixture was dispersed uniformly at 10,000 rpm. The ilaprazole suspension was sprayed onto 100 g of mannitol pellets through a GLATT GPCG-1 fluidized bed to obtain pills containing W4.

[0113] The fluidized bed process parameters are as follows:

[0114]

[0115] Among them, the drug content of W4 containing pills = (actual content of pills containing pills) / (theoretical content of pills containing pills) × 100% = 93.3%

[0116] (3) 80 g of Hydroxypropyl methylcellulose E5 and 6 g of polysorbate 80 were weighed and dissolved in 1600 g of purified water, and 50 g of magnesium hydroxide was added and dispersed uniformly at 10,000 rpm to obtain a binder containing magnesium hydroxide. Then 150 g of ilaprazole was dispersed in the binder containing magnesium hydroxide and dispersed uniformly at 10,000 rpm. The ilaprazole drug suspension was sprayed onto 150 g of sucrose pellet cores through a GLATT GPCG-1 fluidized bed to obtain pills containing W5.

[0117] The fluidized bed process parameters are as follows:

[0118]

[0119]

[0120] Among them, the drug content of W5 containing pills = (actual content of pills containing pills) / (theoretical content of pills containing pills) × 100% = 94.1%

[0121] 1.2 Preparation of isolation layer (G)

[0122] Weigh 23g of hydroxypropyl cellulose-SSL and dissolve it in 460g of purified water, then add 23g of magnesium carbonate, and disperse it evenly at 10000rpm high shear to prepare the first isolation layer prescription. Weigh 17.2g of hydroxypropyl cellulose-SSL and dissolve it in 344g of purified water, add 28.8g of talcum powder, and disperse it evenly at 10000rpm high shear to prepare the second isolation layer prescription. Spray the two layers of isolation suspension onto 90g of the corresponding pill cores through the GLATT GPCG-1 fluidized bed.

[0123] The fluidized bed process parameters are as follows:

[0124]

[0125] 1.3 Preparation of enteric layer (C)

[0126] Enteric layer formulation C (unit: g)

[0127] Ilaprazole Isolate Pills 92 Utech L30D-55 223.8 talcum powder 3.4 Triethyl citrate 20.1 Purified water 447.6

[0128] Preparation process:

[0129] Weigh 20.1g of triethyl citrate and dissolve it in 447.6g of purified water, add 3.4g of talc, disperse it evenly at 10000rpm high shear, then stir it with 223.8g of Eudragit L30D-55 for 45min for use, and spray the enteric coating liquid onto the isolated micropellets through the GLATT GPCG-1 fluidized bed.

[0130] The specific process parameters are as follows:

[0131]

[0132] 1.4 Preparation of protective layer (B)

[0133] 1) Protective layer prescription B1 (unit: g)

[0134] Ilaprazole Enteric-coated Pellets 100 Hydroxypropyl methylcellulose E5 2.5 Magnesium Stearate 1.2 Purified water 50

[0135] Preparation process:

[0136] Weigh 2.5 g of Hydroxypropyl Methylcellulose E5 in the prescription amount and dissolve it in 50 g of purified water, then add 1.2 g of magnesium stearate, and disperse it evenly at 5000 rpm to prepare a protective coating liquid. Spray the protective coating liquid onto the enteric pellets through a GLATT GPCG-1 fluidized bed.

[0137] The specific process parameters are as follows:

[0138]

[0139] 2) Protective layer prescription B4 (unit: g)

[0140]

[0141]

[0142] Preparation process:

[0143] Weigh 2.5g of hydroxypropyl cellulose-SSL in the prescription amount and dissolve it in 50g of purified water, then add 1.2g of talcum powder, and disperse it evenly at 5000rpm high shear to prepare a protective layer coating liquid. Spray the protective layer coating liquid onto the enteric-coated pellets through a GLATT GPCG-1 fluidized bed.

[0144] For specific process parameters, please refer to the above-mentioned protective layer prescription B1.

[0145] 3) Protective layer prescription B5 (unit: g)

[0146] Ilaprazole Enteric-coated Pellets 100 Hydroxypropyl Cellulose-SSL 2.5 Titanium Dioxide 1.2 Purified water 50

[0147] Preparation process:

[0148] Weigh 2.5g of hydroxypropyl cellulose-SSL in the prescription amount and dissolve it in 50g of purified water, then add 1.2g of titanium dioxide, and disperse it evenly at 5000rpm high shear to prepare a protective layer coating liquid. Spray the protective layer coating liquid onto the enteric-coated pellets through a GLATT GPCG-1 fluidized bed.

[0149] For specific process parameters, please refer to the above-mentioned protective layer prescription B1.

[0150] (II) Preparation of enteric-coated pellets:

[0151] According to the formulations of the various constituent layers of the enteric-coated micropellets listed in Section (I) of this Example, enteric-coated micropellets A, D and E according to the present invention were prepared as shown in Table 1 below.

[0152] Table 1: Composition of enteric-coated pellets according to the present invention

[0153] Pellets A Pellets D Pellets E Containing pills W1 W4 W5 Isolation layer G2 G2 G2 Enteric layer C1 C1 C1 Protective layer B1 B4 B5 Drug content of pills (%) 95.6 93.3 94.1

[0154] Among them, W x Drug loading rate of pills = (actual content of pills) / (theoretical content of pills) × 100% Example 2 Preparation of micropill dry suspension

[0155] In this example, dry suspension granules were first prepared, and then a dry suspension containing pellets was prepared by adding different pellets.

[0156] 2.1 Preparation of dry suspension AI

[0157] 1) Preparation of dry suspension granules

[0158] prescription Dosage Carrageenan 25g Hydroxypropyl Cellulose LF 10g Crospovidone 25g Mannitol 700g glucose 250g Malic Acid 4g Chitosan 25g Purified water 190g

[0159] Preparation method: Weigh 10g of hydroxypropyl cellulose LF and dissolve it in 190g of purified water, weigh the prescribed amount of carrageenan, cross-linked polyvinylpyrrolidone, chitosan, mannitol, glucose, and malic acid and put them into a HLSH2-6 wet mixing granulator, stir and mix at 400rpm for 4min, then dissolve the hydroxypropyl cellulose LF and add it into the mixer, continue stirring for 3min, start shearing at 800rpm, and discharge the material after 1min to obtain wet granules; dry the wet granules, and then pass through a 1.2mm sieve to granulate. Dry suspension granules I are obtained.

[0160] 2) Preparation of dry suspension

[0161] 94.5 mg of ilaprazole enteric-coated pellets A and 1.5 g of the above dry suspension granules were mixed to obtain dry suspension AI.

[0162] 2.2 Preparation of dry suspension D-II

[0163] 1) Preparation of dry suspension granules

[0164]

[0165]

[0166] Preparation method: Weigh the prescribed amount of gum arabic, sodium alginate, hydroxypropyl methylcellulose E5, cross-linked sodium carboxymethylcellulose, mannitol, sucrose, citric acid, and chitosan and place them in a HLSH2-6 wet mixing granulator, stir and mix at 400 rpm for 5 minutes, then slowly add purified water while stirring, continue stirring for 5 minutes, start shearing at 700 rpm for 1 minute to obtain wet granules, discharge, dry, and pass through a 1.0 mm sieve to obtain dry suspension granules II.

[0167] 2) Preparation of dry suspension

[0168] 67.4 mg of ilaprazole enteric-coated pellets D and 2.5 g of the above dry suspension granules were mixed and bottled to obtain 5 mg ilaprazole enteric-coated dry suspension D-II.

[0169] 2.3 Preparation of dry suspension E-III

[0170] 1) Preparation of dry suspension granules III

[0171] prescription Dosage Pectin 30g Sodium alginate 5g Polyvinylpyrrolidone K30 10g Crospovidone 35g maltose 200g Xylitol 900g ascorbic acid 9g Chitosan 35g Purified water 190g

[0172] Preparation method: Weigh 10g of polyvinyl pyrrolidone K30 and dissolve it in 190g of purified water, weigh the prescribed amount of pectin, sodium alginate, cross-linked polyvinylpyrrolidone, maltose, xylitol, ascorbic acid, and chitosan, and put them into a HLSH2-6 wet mixing granulator, stir and mix at 400rpm for 4min, then add the polyvinyl pyrrolidone solution into the mixer, continue stirring for 4min, start shear at 800rpm, and discharge after 1min to obtain wet granules; dry the wet granules, and then pass through a 1.2mm sieve to obtain dry suspension granules III.

[0173] 2) Preparation of dry suspension

[0174] 60.5 mg of ilaprazole enteric-coated pellets E and 2.0 g of the above-mentioned dry suspension granules are mixed and bottled to obtain 5 mg ilaprazole enteric-coated dry suspension E-III.

[0175] 2.4 Preparation of dry suspension A-VI

[0176] 1) Preparation of dry suspension granules VI

[0177] prescription Dosage Xanthan gum 25g Hydroxypropyl methylcellulose E5 8g Croscarmellose Sodium 20g Mannitol 600g sucrose 250g Citric Acid 4g Chitosan 5g Purified water 220g

[0178] Preparation method: Weigh 8g of hydroxypropyl methylcellulose E5 and dissolve it in 220g of purified water, weigh the prescribed amount of xanthan gum, cross-linked sodium carboxymethylcellulose, chitosan, mannitol, sucrose, and citric acid, and place them in a HLSH2-6 wet mixing granulator, stir and mix at 400rpm for 4min, then add the hydroxypropyl methylcellulose E5 solution into the mixer, continue stirring for 3min, start shear at 1000rpm, and discharge after 1min to obtain wet granules; dry the wet granules, and then pass through a 1.2mm sieve to obtain dry suspension granules VI.

[0179] 2) Preparation of dry suspension

[0180] 94.5 mg of ilaprazole enteric-coated pellets A and 1.6 g of the above-mentioned dry suspension granules are mixed and bottled to obtain 5 mg ilaprazole enteric-coated dry suspension A-VI.

[0181] 2.5 Preparation of dry suspension A-VII

[0182] 1) Preparation of dry suspension granules VII

[0183]

[0184]

[0185] Preparation method: Weigh 18g of hydroxypropyl methylcellulose VLV and dissolve it in 280g of purified water, weigh the prescribed amount of xanthan gum, cross-linked sodium carboxymethylcellulose, chitosan, mannitol, sucrose, and citric acid, and place them in a HLSH2-6 wet mixing granulator, stir and mix at 400rpm for 4min, then add the hydroxypropyl methylcellulose VLV solution into the mixer, continue stirring for 3min, start shear at 800rpm, and discharge after 1min to obtain wet granules; dry the wet granules, and then pass through a 1.2mm sieve to obtain dry suspension granules VII.

[0186] 2) Preparation of dry suspension

[0187] 94.5 mg of ilaprazole enteric-coated pellets A and 2.0 g of the above-mentioned dry suspension granules are mixed and bottled to obtain 5 mg ilaprazole enteric-coated dry suspension A-VII.

[0188] 2.6 Preparation of dry suspension A-VIII

[0189] 1) Preparation of dry suspension granules VIII

[0190] prescription Dosage Xanthan gum 20g Hydroxypropyl Methylcellulose VLV 18g Croscarmellose Sodium 30g Mannitol 600g sucrose 260g Citric Acid 6g Chitosan 40g Purified water 280g

[0191] Preparation method: Weigh 18g of hydroxypropyl methylcellulose VLV and dissolve it in 280g of purified water, weigh the prescribed amount of xanthan gum, cross-linked sodium carboxymethyl cellulose, chitosan, mannitol, sucrose, and citric acid, and place them in a HLSH2-6 wet mixing granulator, stir and mix at 400rpm for 4min, then add the hydroxypropyl methylcellulose VLV solution into the mixer, continue stirring for 3min, start shear at 800rpm, and discharge after 1min to obtain wet granules; dry the wet granules, and then pass through a 1.2mm sieve to obtain dry suspension granules VIII.

[0192] 2) Preparation of dry suspension

[0193] 94.5 mg of ilaprazole enteric-coated pellets A and 1.8 g of the above-mentioned dry suspension granules are mixed and bottled to obtain 5 mg ilaprazole enteric-coated dry suspension A-VIII.

[0194] 2.7 Preparation of dry suspension A-IX

[0195] 1) Preparation of dry suspension granules IX

[0196] prescription Dosage Xanthan gum 20g Hydroxypropyl Methylcellulose VLV 20g Croscarmellose Sodium 30g Mannitol 660g sucrose 260g Citric Acid 8g Chitosan 60g Purified water 300g

[0197] Preparation method: Weigh 20g of hydroxypropyl methylcellulose VLV and dissolve it in 300g of purified water, weigh the prescribed amount of xanthan gum, cross-linked sodium carboxymethyl cellulose, chitosan, mannitol, sucrose, and citric acid, and place them in a HLSH2-6 wet mixing granulator, stir and mix at 400rpm for 4min, then add the hydroxypropyl methylcellulose VLV solution into the mixer, continue stirring for 3min, start shear at 800rpm, and discharge after 1min to obtain wet granules; dry the wet granules, and then pass through a 1.2mm sieve to obtain dry suspension granules IX.

[0198] 2) Preparation of dry suspension

[0199] 94.5 mg of ilaprazole enteric-coated pellets A and 1.8 g of the above-mentioned dry suspension granules are mixed and bottled to obtain 5 mg ilaprazole enteric-coated dry suspension A-IX.

[0200] 2.8 Preparation of Comparative Example Dry Suspension

[0201] 1) Comparison of dry suspension granules V prescription (unit: g)

[0202]

[0203]

[0204] Preparation method: After xanthan gum, chitosan, CCNA and aspartame are mixed evenly, they are added into a dry granulator for granulation. The process parameters are: wheel spacing 0.2 mm, feeding speed: 30 rpm, wheel speed 5 rpm, granulation speed 10 rpm. After granulation, the particles are sieved for granulation, and the particle size is controlled between 0.5-0.7 mm. Dry suspension particles V are obtained.

[0205] 2) Preparation of dry suspension

[0206] 60.5 mg of ilaprazole enteric-coated micropellets E and 2.0 g of the above-mentioned dry suspension granules V are mixed and bottled to obtain 5 mg ilaprazole enteric-coated dry suspension EV.

[0207] Example 3 Performance Determination of Dry Suspension Granules

[0208] 3.1 Dry suspension granules Viscosity measurement

[0209] 3.1.1 Dry suspension granules I of the present invention

[0210] 1.5 g was added to 15 mL of water and stirred for 60 s. The pH was measured at 3.9 using a calibrated pH meter and the viscosity of the suspension gel was continuously measured.

[0211] 3.1.2 Dry suspension granules II of the present invention

[0212] 2.5 g was added to 25 mL of water and stirred for 60 s. The pH was measured at 3.8 using a calibrated pH meter and the viscosity of the suspended gel was continuously measured.

[0213] 3.1.3 Dry suspension granules III of the present invention

[0214] 2.0 g was added to 20 mL of water and stirred for 60 s. The pH was measured to be 4.0 using a calibrated pH meter and the viscosity of the suspension gel was then continuously measured.

[0215] 3.1.4 Dry suspension granules VI of the present invention

[0216] 2.0 g was added to 20 mL of water and stirred for 60 s. The pH was measured to be 4.0 using a calibrated pH meter and the viscosity of the suspension gel was then continuously measured.

[0217] 3.1.5 Dry suspension granules VII of the present invention

[0218] 2.0 g was added to 20 mL of water and stirred for 60 s. The pH was measured at 3.9 using a calibrated pH meter and the viscosity of the suspension gel was then continuously measured.

[0219] 3.1.6 Dry suspension granules of the present invention VIII

[0220] 2.0 g was added to 20 mL of water and stirred for 60 s. The pH was measured at 3.9 using a calibrated pH meter and the viscosity of the suspended gel was then continuously measured.

[0221] 3.1.7 Dry suspension granules IX of the present invention

[0222] 2.0 g was added to 20 mL of water and stirred for 60 s. The pH was measured to be 4.0 using a calibrated pH meter and the viscosity of the suspension gel was then continuously measured.

[0223] 3.1.8 Comparative Example Dry Suspension Granules IV

[0224] As a prior art sample, a (ORAL SUSPENSION, specification 40 mg), the enteric-coated pellets containing esomeprazole magnesium were removed from the granules of the product, 15 mL of purified water was added to the remaining powder, stirred for 60 s, and then the viscosity of the suspension gel was continuously measured.

[0225] 3.1.9 Comparative Example Dry Suspension Granules V

[0226] 2.0 g was added to 20 mL of water and stirred for 60 s. The pH was measured to be 8.0 using a calibrated pH meter and the viscosity of the suspension gel was then continuously measured.

[0227] Equipment: BROOKFIELD DV2T viscometer, small sample adapter SSA, MV1Y flag impeller blade rotor.

[0228] The results of the viscosity measurement of the above dry suspension particles are shown in Tables 2 and Figure 1 :

[0229] Table 2: Viscosity test results of dry suspension granules.

[0230]

[0231]

[0232] From Table 2 and Figure 1 It can be seen that compared with the dry suspension granules IV of the prior art, the dry suspension granules I-III and VI-VIII of the present invention can reach the maximum viscosity faster; while for the comparative dry suspension granules V, due to the large amount of chitosan used, the time for the dry suspension granules to reach the maximum viscosity after adding water is significantly prolonged; and after the comparative dry suspension granules V are added to water, the enteric coating of the ilaprazole enteric-coated pills will be dissolved due to its alkalinity.

[0233] 3.2 Testing of the time required for ilaprazole pellets to remain suspended in the dry suspension

[0234] ① Add 15 mL of water to the dry suspension AI in Example 8.1 and stir at a constant speed. After 30 seconds, start timing and observe the time taken for the enteric-coated pellets to be completely suspended.

[0235] ② Add 25 mL of water to the dry suspension D-II in Example 8.2, stir at a constant speed, and start timing after 30 seconds to observe the time taken for the enteric-coated pellets to be completely suspended.

[0236] ③ Add 20 mL of water to the dry suspension E-III in Example 8.3 and stir at a constant speed. After 30 seconds, start timing and observe the time taken for the enteric-coated pellets to be completely suspended.

[0237] ④AstraZeneca (ORAL SUSPENSION, specification 40 mg), add 15 mL of purified water, stir at a constant speed, start timing after 30 seconds, and observe the time taken for the enteric-coated microcapsules to be completely suspended.

[0238] ⑤ Add 20 mL of water to the comparative dry suspension EV in Example 8.4, stir at a constant speed, start timing after 30 seconds, and observe the time taken for the enteric-coated pellets to be completely suspended.

[0239] The above test results are shown in Table 20 below:

[0240] Table 3: Test results on the time required for ilaprazole pellets to remain suspended in the dry suspension

[0241]

[0242] As can be seen from Table 3, the dry suspensions AI, D-II and E-III of the present invention can form suspension gels in a shorter time than the prior art; the dry suspension pellets in the comparative dry suspension EV need to remain suspended for 735 seconds, and the gel strength is too strong, which affects the suspension speed.

[0243] 3.3 Suspension-sedimentation time of pellets in suspension gel

[0244] (1) Add 100 ilaprazole enteric-coated pellets A to 1.5 g of the dry suspension granules I of the present invention, add 15 mL of water, stir for 150 s until the enteric-coated pellets are completely suspended, and then pour into a 15 mL graduated cylinder. Count the number of enteric-coated pellets within the range of 0-5 mL, 5-10 mL, and 10-15 mL, and count every 1 h for 12 h. Perform 10 groups of tests at the same time. Calculate the average proportion of pellets within the range of 0-5 mL, 5-10 mL, and 10-15 mL (see Figures 2 to 4 Curve of dry suspension particles I in ).

[0245] (2) Add 100 ilaprazole enteric-coated pellets D to 1.5 g of the dry suspension granules II of the present invention, add 15 mL of water, stir for 150 s until the pellets are completely suspended, and then pour into a 15 mL graduated cylinder. Count the number of enteric-coated pellets within the range of 0-5 mL, 5-10 mL, and 10-15 mL, and count every 1 h for 12 h. Perform 10 groups of tests at the same time. Calculate the average proportion of pellets within the range of 0-5 mL, 5-10 mL, and 10-15 mL (see Figures 2 to 4 curve of dry suspension particles II in FIG.

[0246] (3) Add 100 ilaprazole enteric-coated pellets E to 1.5 g of the dry suspension granules III of the present invention, add 15 mL of water, stir for 150 s until the pellets are completely suspended, and then pour into a 15 mL graduated cylinder. Count the number of enteric-coated pellets within the range of 0-5 mL, 5-10 mL, and 10-15 mL, and count every 1 h for 12 h. Perform 10 groups of tests at the same time. Calculate the average proportion of pellets within the range of 0-5 mL, 5-10 mL, and 10-15 mL (see Figures 2 to 4 curve of dry suspension particles III in FIG.

[0247] (4) The dry suspension granules IV are prior art products, i.e., using AstraZeneca (ORAL SUSPENSION, specification 40mg), remove all enteric-coated pellets containing esomeprazole magnesium from the dry suspension granules of the product, then add 100 esomeprazole magnesium enteric-coated pellets to the granules, add 15mL of water, stir for 150s until the pellets are completely suspended, then pour into a 15mL measuring cylinder, count the number of enteric-coated pellets within the range of 0-5mL, 5-10mL, and 10-15mL, and calculate every 1h for 12h. Carry out 10 groups of tests at the same time. Calculate the proportion of pellets within the range of 0-5mL, 5-10mL, and 10-15mL (see Figures 2 to 4 The IV curve of the prior art NEXIUM dry suspension granules in FIG.

[0248] (5) Add 100 tablets of AstraZeneca to 1.5 g of the dry suspension granules I of the present invention. Add 15 ml of water to the enteric-coated pellets of esomeprazole magnesium in (ORAL SUSPENSION) and stir for 150 seconds until the enteric-coated pellets are completely suspended. Then pour into a 15 ml graduated cylinder and count the number of enteric-coated pellets within the range of 0-5 ml, 5-10 ml, and 10-15 ml. Count every 1 hour for 12 hours. Perform 10 groups of tests at the same time. Calculate the average proportion of pellets within the range of 0-5 ml, 5-10 ml, and 10-15 ml (see Figures 2 to 4curve of the dry suspension particles Ia in FIG.

[0249] (6) Add 100 blank pellets of Celphere CP-507 microcrystalline cellulose (particle size range 500 μm to 700 μm) from Asahi Kasei of Japan to 1.5 g of the dry suspension granules II of the present invention, add 15 ml of water, stir for 150 s until the enteric-coated pellets are completely suspended, and then pour into a 15 ml graduated cylinder, count the number of enteric-coated pellets within the range of 0-5 ml, 5-10 ml, and 10-15 ml, and count every 1 hour for 12 hours. Perform 10 groups of tests at the same time. Calculate the average proportion of pellets within the range of 0-5 ml, 5-10 ml, and 10-15 ml (see Figures 2 to 4 curve of dry suspension particles IIa in ).

[0250] The results of the above tests are as follows Figure 2 to Figure 4 Shown, the result shows: in 0-5ml range, the ratio of enteric-coated micropills in the suspension formed by the dry suspended granules IV of the prior art is greater than the ratio of enteric-coated micropills in the suspension formed by the dry suspended granules I or II or III according to the present invention, and as time goes by, the ratio of enteric-coated micropills in the suspension formed by the dry suspended granules IV increases more obviously. On the contrary, in 10-15ml range, the ratio of enteric-coated micropills in the suspension formed by the dry suspended granules IV is less than the ratio of enteric-coated micropills in the suspension formed by the dry suspended granules I or II or III, and as time goes by, the ratio of enteric-coated micropills in the suspension formed by the dry suspended granules IV is getting smaller and smaller. These factual explanations make the enteric-coated micropills suspension time longer and difficult for sedimentation according to the suspension prepared by the dry suspended granules of the present invention / suspension gel.

[0251] 3.4 Determination of acid resistance of ilaprazole enteric-coated pellets in different dry suspensions

[0252] The acid resistance of the ilaprazole enteric-coated micropellets in the dry suspension of the present invention and the comparative dry suspension was determined by referring to the following determination method. The results are shown in Table 4 below:

[0253] Determination method: Take the dry suspension containing enteric-coated pellets, use 0.1mol / L hydrochloric acid solution (take 9.0mL of concentrated hydrochloric acid, add water to 1000mL) as the dissolution medium, the speed is 100 revolutions per minute, after 120 minutes, take out the dissolution cup, filter the solution with a suction filtration device, collect the remaining pellets in a 50mL volumetric flask, add 20mL of 0.05mol / L sodium hydroxide solution, shake in an oscillator (250 revolutions per minute) for 20 minutes, add 30mL of methanol and ultrasonicate for 10 minutes, dilute with water to the scale, shake well, centrifuge, and take the supernatant. Determine the remaining drug content in the pellets, that is, the acid resistance of the sample.

[0254] Table 4: Acid resistance test results of ilaprazole enteric-coated pellets in different dry suspensions.

[0255] time Dry suspension AI Dry suspension D-II Dry suspension E-III Dry suspension EV Day 0 97.5％ 95.5％ 96.4％ 95.6％ 1 month 95.6％ 96.1％ 95.8％ 96.8％ 3 months 96.4％ 95.7％ 96.5％ 95.4％ 6 months 94.5％ 96.0％ 97.5％ 94.8％

[0256] 3.5 Dissolution Determination of Ilaprazole Enteric-coated Pellets in Different Dry Suspensions

[0257] Referring to the dissolution and release determination method (for general methods, see Method 1 of the second method of Part 4 of the 2015 edition of the Chinese Pharmacopoeia, 0931), the dissolution of ilaprazole enteric-coated pellets in the dry suspension of the present invention and the comparative dry suspension was determined. The results are shown in Table 5:

[0258] Determination method:

[0259] Take the sample to be tested, use 300mL of 0.1mol / L hydrochloric acid solution (take 9.0mL of hydrochloric acid, add water to 1000mL) as the dissolution medium, rotate at 100 revolutions per minute, operate according to the law, after 120 minutes, then add 700mL of 0.086mol / L disodium hydrogen phosphate solution (take 30.8g disodium hydrogen phosphate and 7g Tween 80, add water to 1000mL) preheated to 37±0.5℃ into each dissolution cup, mix well, keep the speed unchanged, continue to operate according to the law, and take samples after 45 minutes.

[0260] Test solution: Take an appropriate amount of the dissolution solution, filter, accurately measure 5 mL of the filtrate, immediately add 1 mL of 0.15 mol / L sodium hydroxide solution, shake well, filter, and take the filtrate as the test solution.

[0261] Reference solution: accurately weigh about 10 mg of ilaprazole reference substance and place it in a 20 mL volumetric flask. Add an appropriate amount of acetonitrile to dissolve it. Dilute it to the mark with acetonitrile, shake well, accurately measure 1 mL and place it in a 100 mL volumetric flask. Dilute it to the mark with phosphate buffer (pH 6.8) (mix 700 mL of 0.086 mol / L disodium hydrogen phosphate solution and 300 mL of 0.1 mol / L hydrochloric acid solution to obtain the solution). Shake well, accurately measure 5 mL, immediately add 1 mL of 0.05 mol / L sodium hydroxide solution, shake well, filter, and take the filtrate as the reference solution.

[0262] Table 5: Dissolution test results of ilaprazole enteric-coated pellets in different dry suspensions.

[0263] T / min Dry suspension AI Dry suspension D-Ⅱ Dry suspension E-Ⅲ Dry suspension E-V 0 0％ 0％ 0％ 0％ 10 35.5％ 38.7％ 34.5％ 15.6％ 15 58.4％ 59.6％ 46.8％ 20.5％ 20 79.5％ 83.5％ 59.4％ 29.5％ 30 86.5％ 96.5％ 78.5％ 36.4％ 45 92.5％ 95.4％ 91.2％ 45.9％ 60 93.2％ 94.6％ 92.5％ 60.5％

[0264] In summary, the dry suspension EV adopts the prescription in the comparative example to prepare a suspension preparation. Although the acid resistance is comparable to that of the suspension preparation of the present invention, the dissolution rate is significantly slowed down because the high dosage of chitosan results in too high gel strength, which affects the dissolution rate of the microcapsules.

[0265] As can be seen from the above, in the ilaprazole dry suspension according to the present invention, the combination of anionic gelling agents and cationic polymers (especially chitosan and its derivatives) can make the suspension quickly reach a stable viscosity level, and the prepared suspension gel can allow the enteric-coated pellets to be stably suspended for a long time. Furthermore, for acid-labile proton pump inhibitors, especially ilaprazole, its solubility can be improved.

Claims

1. A pharmaceutical composition, characterized in that The pharmaceutical composition is a dry suspension, which comprises dry suspension granules and enteric-coated pellets containing ilaprazole and / or a pharmaceutically acceptable salt thereof, wherein the dry suspension granules comprise anionic gelling agents and cationic polymers, and the weight ratio of the anionic gelling agents to the cationic polymers is (1-10):1, The anionic gelling agent is selected from one, two or more of gum arabic, alginate, pectin, xanthan gum and carrageenan, wherein the cationic polymer is selected from chitosan, The weight percentage of the cationic polymer in the dry suspension particles is 0.5-5%. The pH value of the suspension gel formed by the dry suspension particles in the aqueous dispersion medium is in the range of 2.5-7.

0.

2. The pharmaceutical composition according to claim 1, characterized in that The weight ratio of the anionic gelling agent to the cationic polymer is (1-3):

1.

3. The pharmaceutical composition according to claim 1, characterized in that The alginate is sodium alginate.

4. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that The weight percentage of the cationic polymer in the dry suspension particles is 0.6-4%.

5. The pharmaceutical composition according to claim 4, characterized in that The weight percentage of the cationic polymer in the dry suspension particles is 0.8-3.5%.

6. The pharmaceutical composition according to claim 4, characterized in that The weight percentage of the cationic polymer in the dry suspension particles is 0.9-3.0%.

7. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that The dry suspension granules further include one, two or more of a binder, a disintegrant, a diluent and a pH adjuster.

8. The pharmaceutical composition according to claim 7, characterized in that The binder is selected from one, two or more of polyvinyl pyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose, polyvinyl alcohol and starch.

9. The pharmaceutical composition according to claim 7, characterized in that The disintegrant is selected from one, two or more of sodium carboxymethylcellulose, calcium carboxymethylcellulose, cross-linked sodium carboxymethylcellulose, cross-linked sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone, microcrystalline cellulose and pregelatinized starch.

10. The pharmaceutical composition according to claim 7, characterized in that The diluent is selected from one, two or more of xylitol, mannitol, sucrose, glucose, sorbitol, maltitol and fructose.

11. The pharmaceutical composition according to claim 7, characterized in that The pH adjuster is selected from organic acids or inorganic acids.

12. The pharmaceutical composition according to claim 11, characterized in that The pH adjuster is selected from one, two or more of tartaric acid, citric acid, oxalic acid, succinic acid, fumaric acid, ascorbic acid, malic acid, glutamic acid and caffeic acid.

13. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that The pH value of the suspension gel formed by the dry suspension particles in the aqueous dispersion medium is in the range of 3.0-5.0; and / or when preparing the suspension gel, the amount of the aqueous dispersion medium added to the dry suspension particles is 2 to 50 times the weight of the dry suspension particles.

14. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that The pharmaceutically acceptable salt of ilaprazole is ilaprazole sodium, ilaprazole magnesium, ilaprazole zinc, ilaprazole potassium, ilaprazole lithium or ilaprazole calcium.

15. The pharmaceutical composition according to claim 14, characterized in that The pharmaceutically acceptable salt of ilaprazole is ilaprazole magnesium.

16. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that The mass ratio of the amount of ilaprazole in the enteric-coated micropellets to the amount of the dry suspension granules is 1:200-1000.

17. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that After adding the aqueous dispersion medium to the pharmaceutical composition, the time elapsed for the obtained suspension gel to reach 75% of the maximum viscosity is less than 8 minutes.

18. The pharmaceutical composition according to claim 17, characterized in that After adding the aqueous dispersion medium to the pharmaceutical composition, the time elapsed for the obtained suspension gel to reach 75% of the maximum viscosity is less than 7 minutes.

19. The pharmaceutical composition according to claim 17, characterized in that After adding the aqueous dispersion medium to the pharmaceutical composition, the time elapsed for the obtained suspension gel to reach 90% of the maximum viscosity is less than 12 minutes.

20. The pharmaceutical composition according to claim 17, characterized in that After adding the aqueous dispersion medium to the pharmaceutical composition, the time elapsed for the obtained suspension gel to reach 90% of the maximum viscosity is less than 11 minutes.

21. The pharmaceutical composition according to claim 17, characterized in that The time to form a suspension gel after adding the aqueous dispersion medium to the pharmaceutical composition is less than 120 seconds.

22. The pharmaceutical composition according to claim 17, characterized in that The time to form a suspension gel after adding the aqueous dispersion medium to the pharmaceutical composition is less than 90 seconds.

23. The pharmaceutical composition according to claim 21, characterized in that The time to form a suspension gel after adding the aqueous dispersion medium to the pharmaceutical composition is less than 70 seconds.

24. The pharmaceutical composition according to claim 17, characterized in that The time to form a suspension gel after adding the aqueous dispersion medium to the pharmaceutical composition is less than 50 seconds.

25. The pharmaceutical composition according to claim 17, characterized in that After the pharmaceutical composition is added to an aqueous dispersion medium to form a solution at pH 1.2, the release rate of ilaprazole does not exceed 10% within 1 hour and / or after forming a solution at pH 6.8, the release rate of ilaprazole is not less than 70% within 45 minutes.

26. A method for preparing a pharmaceutical composition according to any one of claims 1 to 25, comprising the steps of: (1) mixing anionic gelling agent, cationic polymer and other optional auxiliary materials; (2) preparing a binder solution separately; (3) adding the binder solution obtained in step (2) to the mixture obtained in step (1) to prepare a wet mixture; (4) granulating the wet mixture obtained in step (3) to obtain dry suspension granules; and (5) Mixing the dry suspension granules and the enteric-coated pellets containing ilaprazole and / or a pharmaceutically acceptable salt thereof.

27. The method according to claim 26, wherein the other excipients include diluents, pH adjusters and / or disintegrants.

28. The method according to claim 26, wherein water and / or ethanol are used as solvent in step (2).

29. A method for preparing a pharmaceutical composition according to any one of claims 1 to 25, comprising the steps of: (1) mixing anionic gelling agent, cationic polymer and other optional auxiliary materials; (2) providing water and / or ethanol as a wetting agent; (3) adding the wetting agent provided in step (2) to the mixture obtained in step (1) to prepare a wetted mixture; (4) granulating the wet mixture obtained in step (3) to obtain dry suspension granules, and (5) Mixing the dry suspension granules and the enteric-coated pellets containing ilaprazole and / or a pharmaceutically acceptable salt thereof.

30. The method according to claim 29, wherein the other excipients include diluents, pH adjusters, disintegrants and / or binders.

31. The method according to claim 29, further comprising a step (4') after step (4): drying the dry suspension particles.

32. The method according to claim 31, further comprising a step (4") after step (4'): granulating the dry suspension particles in the form of granules.

33. Use of the pharmaceutical composition according to any one of claims 1 to 25 in the preparation of a medicament for treating and / or preventing gastrointestinal diseases, wherein the gastrointestinal diseases include heartburn, inflammatory bowel disease, irritable bowel syndrome, peptic ulcer, stress ulcer, hyperacidity, dyspepsia, gastroparesis, Zollinger-Ellison syndrome, gastroesophageal reflux disease (GERD), all grades of erosive esophagitis, short bowel syndrome, or a combination of any of the above diseases.

34. The use according to claim 33, wherein the inflammatory bowel disease is Crohn's disease, ulcerative colitis and / or infectious enteritis.

35. The use according to claim 33, wherein the inflammatory bowel disease is colitis.

36. The use according to claim 33, wherein the peptic ulcer is a bleeding peptic ulcer, a duodenal ulcer and a recurring duodenal ulcer, a gastric ulcer associated with NSAIDs and / or an active benign gastric ulcer in adults.

37. Use of the pharmaceutical composition according to any one of claims 1 to 25 in the preparation of a medicament for eradicating Helicobacter pylori.

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