Dry suspension granules for a dry suspension agent, a method for producing the same, and uses thereof

Abstract

The present invention relates to a dry suspension granule for a dry suspension, a dry suspension containing the dry suspension granule, and a manufacturing method and use thereof. The dry suspension granule contains an anionic gelling agent and a cationic polymer, and the weight ratio of the anionic gelling agent to the cationic polymer is (0.5-50:1).

Description

Detailed Description of the Invention

[0001] [Priority and Related Applications] This application claims the priority of a patent for invention filed with the China National Intellectual Property Administration on August 26, 2021, with application number 202110990993.1 and invention title "Dry Suspension Granules for Dry Suspending Agents, Their Manufacturing Method and Use". The full text of the prior application is incorporated herein by reference.

[0002] [Technical Field] The present invention relates to dry suspension granules for dry suspending agents, dry suspending agents containing the above dry suspension granules, and their manufacturing method and use.

[0003] [Background Art] Proton Pump Inhibitors (PPIs) are drugs that can selectively inhibit H + / K + -ATPase (also called proton pump or acid pump) on the secretory canalicular membrane of human gastric mucosal cells. The H + / K + -ATPase is the final pathway for inhibiting gastric acid secretion, and by inhibiting it, gastric acid secretion can be significantly reduced. Therefore, proton pump inhibitors are generally used in the treatment of gastrointestinal diseases (i.e., acid-related diseases) induced or caused by gastric acid action, including gastric and duodenal ulcers, gastroesophageal reflux disease, surgical anastomotic ulcers, and Zollinger-Ellison syndrome. Based on 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 quickly pass through the parietal cell membrane and accumulate in the strongly acidic secretory canaliculus, then are protonated and converted into sulfenamide compounds, and the latter can form a disulfide bond covalently bonded to the sulfhydryl group on the cysteine residue in the α subunit of H + / K + -ATPase, thereby forming a disulfide bond covalently bonded to the sulfhydryl group on the cysteine residue in the α subunit of H + / K +-Irreversibly inactivate -ATPase and inhibit its acid secretion activity (Zhang Xuan, "Overview of Patent Technologies of Proton Pump Inhibitors - Lazo Drugs", "Patent Literature Research 2018 - Pharmaceutical Manufacturing", Intellectual Property Publishing House, Beijing, September 2019: pp554 - 567). Currently, such drugs that have already been commercially available worldwide include Omeprazole, Lansoprazole, Pantoprozole, Rabeprazole, Esomeprazole, Ilaprazole, Delansoprazole, etc.

[0004] Similar to other lazo drugs, Ilaprazole also belongs to acid - labile compounds. However, Ilaprazole has relatively lower stability compared to other conventional lazo drugs. Acid - labile compounds are substances that are unstable in acidic media but have relatively good stability in neutral and basic media. These compounds are common in that they can be rapidly decomposed / transformed into biologically active compounds in acidic media. Acid - labile proton pump inhibitors are sensitive to decomposition / transformation in acidic and neutral media. Therefore, when used for oral administration, it is necessary to avoid contact with gastric acid and affect their stability. One way to solve this problem is to coat oral dosage forms of such drugs with enteric - soluble materials to produce enteric - coated micropellet formulations.

[0005] Enteric-coated micropellets are usually not administered by direct administration, but are formulated into other dosage forms, such as tablets, capsules, or dry suspensions, etc., to facilitate administration. A dry suspension is a powder or granule produced from a poorly soluble solid drug and a suitable adjuvant, and can be dispersed as a suspension by adding water and shaking before use. Other liquid dispersion media and additives suitable for oral administration can be added to the dry suspension to improve properties such as texture. Suspension is a process of mechanically dispersing insoluble solid microparticles almost uniformly in a suitable liquid dispersion medium. The solid microparticles in the formed suspension have a relatively high surface free energy due to their large degree of dispersion, are prone to aggregation, belong to a thermodynamically unstable system, and the solid particles in the suspension are larger than colloidal particles and are prone to sedimentation by gravity, so they also belong to a kinetically unstable system.

[0006] Therefore, when preparing a suspension by adding a dispersion medium, especially water, how to improve the thermodynamic and kinetic properties of the dry suspension, especially the dry suspension containing micropellets, such as the time to reach a stable viscosity level and the time for solid particles such as micropellets to be stably suspended, is a problem faced in this technical field.

[0007] 〔Summary of the Invention〕 Surprisingly, the inventors have found that by using an anionic gelling agent in combination with a cationic polymer such as chitosan and its derivatives in dry suspension granules, the suspension thus obtained can quickly reach a stable viscosity level, and the prepared suspension gel can stably suspend micropellets for a longer time.

[0008] The object of the present invention is solved by the dry suspension granules according to the present invention containing an anionic gelling agent and a cationic polymer. In particular, the composition of the above dry suspension granules can stably suspend micropellets in the suspension gel after the formation of the suspension / suspension gel. Therefore, according to the dry suspension granules according to the present invention, a dry suspending agent that can form a stable suspension gel more quickly can be provided, and the micropellets in the suspension gel formed by the dry suspending agent can be stably suspended for a longer time.

[0009] Therefore, in one aspect, the present invention provides dry suspension granules for a dry suspending agent containing an anionic gelling agent and a cationic polymer, wherein the weight ratio of the anionic gelling agent to the cationic polymer is (0.5 to 50):1.

[0010] According to one embodiment of the present invention, the weight ratio of the anionic gelling agent to the cationic polymer is preferably (0.8 to 20):1, more preferably (0.9 to 10):1, and most preferably (1 to 3):1.

[0011] According to one embodiment of the present invention, the anionic gelling agent is one, two or more selected from gum arabic, gelatin, alginates such as sodium alginate, pectin, xanthan gum, gellan gum, locust bean gum, guar gum, agar, carrageenan, tamarind gum, konjac gum, cassia seed gum, tragacanth gum, karaya gum.

[0012] According to one embodiment of the present invention, the cationic polymer is selected from chitosan or its derivatives.

[0013] According to one embodiment of the present invention, the weight percentage of the cationic polymer in the dry suspension granules is 0.5 to 5%, preferably 0.6 to 4%, more preferably 0.8 to 3.5%, and most preferably 0.9 to 3.0%.

[0014] According to an embodiment of the present invention, the dry suspension granules according to the present invention further contain one, two or more selected from an adhesive, a disintegrant, a diluent and a pH regulator.

[0015] According to an embodiment of the present invention, the above-mentioned adhesive is one, two or more selected from polyvinylpyrrolidone, hypromellose, hydroxypropylcellulose, methylcellulose, polyvinyl alcohol, starch.

[0016] According to an embodiment of the present invention, the above-mentioned disintegrant is one, two or more selected from sodium carboxymethylcellulose, calcium carboxymethylcellulose, cross-linked sodium carboxymethylcellulose, cross-linked sodium carboxymethyldextrin, low-substituted hydroxypropylcellulose, cross-linked polyvinylpyrrolidone, microcrystalline cellulose, pregelatinized starch.

[0017] According to an embodiment of the present invention, the above-mentioned diluent is one, two or more selected from xylitol, mannitol, sucrose, glucose, sorbitol, maltitol, fructose.

[0018] According to an embodiment of the present invention, the above-mentioned pH regulator is an organic acid or an inorganic acid, preferably one, two or more selected from tartaric acid, citric acid, oxalic acid, succinic acid, fumaric acid, ascorbic acid, malic acid, glutamic acid, caffeic acid.

[0019] According to an embodiment of the present invention, the pH value of the suspension gel formed by the above-mentioned dry suspension granules in an aqueous medium is in the range of 2.5 to 7.0, preferably in the range of 3.0 to 5.0.

[0020] According to an embodiment of the present invention, when producing the suspension gel, the amount of the 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.

[0021] In a further aspect, the present invention provides a method for producing the dry suspension granules according to the present invention. (1) Mixing an anionic gelling agent and a cationic polymer with optional other auxiliary agents; (2) Separately manufacturing an adhesive solution; (3) Adding the adhesive solution obtained in step (2) to the mixture obtained in step (1) to produce a wet mixture; (4) Granulating the wet mixture obtained in step (3) to obtain the dry suspension granules according to the present invention.

[0022] Preferably, the other auxiliary agents include a diluent, a pH adjuster, a disintegrant, etc.

[0023] Preferably, water and / or ethanol is used as a solvent in step (2).

[0024] In a further aspect, the present invention provides a method for manufacturing the dry suspension granules according to the present invention (1) Mixing an anionic gelling agent and a cationic polymer with optional other auxiliary agents; (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 produce a wet mixture; (4) Granulating the wet mixture obtained in step (3) to obtain the dry suspension granules according to the present invention.

[0025] Preferably, the other auxiliary agents include a diluent, a pH adjuster, a disintegrant and / or an adhesive, etc.

[0026] In the method for manufacturing the dry suspension granules according to the present invention, preferably, after step (4), step (5) of drying the dry suspension granules according to the present invention is further included.

[0027] In the method for manufacturing the dry suspension granules according to the present invention, preferably, after step (5), step (6) of sizing the dry suspension granules according to the present invention in granular form is further included.

[0028] In another aspect, the present invention further provides a pharmaceutical composition comprising the dry suspension granules according to the present invention, particularly a dry suspension agent.

[0029] According to one embodiment of the present invention, the present invention further provides a pharmaceutical composition, particularly a dry suspension agent, comprising the dry suspension granules according to the present invention and enteric-coated micro pellets, particularly enteric-coated micro pellets containing ilaprazole.

[0030] According to one embodiment of the present invention, in the pharmaceutical composition according to the present invention, the mass ratio of the dosage of ilaprazole in the enteric-coated micro pellets to the dosage of the dry suspension granules is 1:200 to 1000.

[0031] According to one embodiment of the present invention, after adding a dispersion medium to the pharmaceutical composition according to the present invention, preferably a dry suspension agent, the elapsed time until the obtained suspension gel reaches 75% of the maximum viscosity is less than 8 min, preferably 7 min.

[0032] According to one embodiment of the present invention, after adding a dispersion medium to the pharmaceutical composition according to the present invention, preferably a dry suspension agent, the elapsed time until the obtained suspension gel reaches 90% of the maximum viscosity is less than 12 min, preferably less than 11 min.

[0033] According to one embodiment of the present invention, after adding an aqueous medium to the pharmaceutical composition according to the present invention, preferably a dry suspension agent, the time to form a suspension gel is less than 120 s, preferably less than 90 s, more preferably less than 70 s, and most preferably less than 50 s.

[0034] According to one embodiment of the present invention, after adding the pharmaceutical composition according to the present invention, preferably a dry suspension agent, to a dispersion medium to form a solution with a pH of 1.2, the release rate of ilaprazole within 1 h is 10% or less.

[0035] According to one embodiment of the present invention, after adding the pharmaceutical composition according to the present invention, preferably a dry suspension, to a dispersion medium to form a solution with a pH of 6.8, the release rate of ilaprazole within 45 minutes is 70% or more.

[0036] In the research of animal experiments that have already been conducted, the inventor has found that a formulation containing enteric-coated micropellets according to the present invention, particularly a dry suspension, exhibits beneficial effects in the treatment and / or prevention of gastrointestinal diseases. The above-mentioned gastrointestinal diseases 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, gastric paresis, Zollinger-Ellison syndrome, gastroesophageal reflux disease (GERD), Helicobacter pylori-related diseases or eradication of Helicobacter pylori, esophagitis of any grade, short bowel syndrome, or any combination of the above diseases.

[0037] Therefore, according to one aspect of the present invention, the present invention provides a method for treating and / or preventing gastrointestinal diseases. The method includes the step of administering a therapeutically and / or prophylactically effective amount of the 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 by using the method include, but are not limited to, 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, gastric paresis, Zollinger-Ellison syndrome, gastroesophageal reflux disease (GERD), Helicobacter pylori-related diseases or eradication of Helicobacter pylori, esophagitis of any grade, short bowel syndrome, or any combination of the above diseases.

[0038] Accordingly, according to another aspect of the present invention, the present invention provides the use of the dry suspension agent according to the present invention in the manufacture of a drug for treating and / or preventing gastrointestinal diseases, wherein the gastrointestinal diseases 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, gastric hypomotility, Zollinger-Ellison syndrome, gastroesophageal reflux disease (GERD), Helicobacter pylori-related diseases or eradication of Helicobacter pylori, erosive esophagitis of any grade, short bowel syndrome, or any combination of the above diseases, but not limited thereto.

[0039] Furthermore, when the dry suspension agent according to the present invention is used in the manufacture of 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), Helicobacter pylori-related diseases, or the drug can be used for the eradication of Helicobacter pylori, and can also prevent peptic ulcer diseases caused by non-steroidal anti-inflammatory drugs, gastrointestinal bleeding and related ulcers caused by antiplatelet aggregation drugs (including but not limited to clopidogrel, prasugrel, ticagrelor).

[0040] 〔Brief Description of the Drawings〕 〔Figure 1〕Shows the time taken for the dry suspension granules I to III according to the present invention, the dry suspension granules IV of the prior art, and the dry suspension granules V of the comparative example to reach the maximum percentage viscosity after adding water as the dispersion medium.

[0041] 〔Figure 2〕Shows the micro-pellet suspension-sedimentation time within a volume of 0 - 5 mL measured in a 15 mL graduated cylinder for the dry suspension agents prepared by adding different micro-pellets to the dry suspension granules I to III according to the present invention and the dry suspension granules IV of the prior art.

[0042] [Figure 3] Dry suspension agents prepared by adding different micro - pellets to dry suspension granules I - III according to the present invention and dry suspension granules IV of the prior art show the micro - pellet suspension - sedimentation time within a volume of 5 - 10 mL, measured in a 15 mL graduated cylinder.

[0043] [Figure 4] Dry suspension agents prepared by adding different micro - pellets to dry suspension granules I - III according to the present invention and dry suspension granules IV of the prior art show the micro - pellet suspension - sedimentation time within a volume of 10 - 15 mL, measured in a 15 mL graduated cylinder.

[0044] [Advantageous Effects of the Present Invention] Compared with the prior art, the dry suspension granules and the dry suspension agent containing the same according to the present invention can be rapidly dispersed in an aqueous medium to form a stable suspension gel. And when micro - pellets are present simultaneously, a uniform and stable dispersion system containing suspended micro - pellets can be obtained. The solution / gel thus obtained can reach a stable viscosity within a shorter time than the dry suspension granules and dry suspension agents of the prior art, and can maintain a stable suspended state of the micro - pellets for a longer time.

[0045] In the case of acid - labile proton pump inhibitors, especially ilaprazole, the suspension obtained by the dry suspension agent according to the present invention can further improve its elution property.

[0046] [Modes for Carrying Out the Invention] In a preferred embodiment according to the present invention, the dry suspension preparation according to the present invention contains enteric - coated micro - pellets, preferably enteric - coated ilaprazole micro - pellets and the dry suspension granules according to the present invention. The dry suspension agent according to the present invention may contain, but is not limited to, the following components by weight parts.

[0047] Enteric - coated micro - pellets 1 - 30, Gelling agent 0.1 - 15, Adhesive 0.1 - 20, Disintegrant 0.1 - 15, Diluent 1 - 90, pH adjuster 0.02 - 6, Cationic polymer 0.1 - 15.

[0048] In the case of enteric - coated micro - pellets, in each aspect according to the present invention, conventional micro - pellets may be used, and preferably, enteric - coated micro - pellets of the following embodiments may be used.

[0049] According to the present invention, in the first embodiment of the enteric - coated micro - pellets, the enteric - coated micro - pellets include, in order from the inside to the outside, a pellet core, a first isolation layer, a second isolation layer, and an enteric layer. Among them, the pellet core includes ilaprazole and / or a pharmaceutically acceptable salt of ilaprazole and a first adjuvant. The enteric - coated micro - pellets contain a water - insoluble basic compound in the first isolation layer, and the weight ratio of the first adjuvant to ilaprazole and / or a pharmaceutically acceptable salt of ilaprazole is 0.2 - 5:1.

[0050] According to the present invention, in the second embodiment of the enteric - coated micro - pellets, the enteric - coated micro - pellets include, in order from the inside to the outside, a pellet core, a first isolation layer, a second isolation layer, and an enteric layer. Among them, the pellet core includes ilaprazole and / or a pharmaceutically acceptable salt of ilaprazole and a first adjuvant. The enteric - coated micro - pellets contain a water - insoluble basic compound in the first isolation layer, the first adjuvant is a water - insoluble basic compound, and the water - insoluble basic compound contained in the first isolation layer and the water - insoluble basic compound of the first adjuvant may be the same or different.

[0051] According to the present invention, in a third embodiment of the enteric-coated micropellets, the enteric-coated micropellets include, in order from the inside to the outside, a pellet core, a first isolation layer, a second isolation layer, and an enteric layer. Among them, the pellet core includes ilaprazole and / or a pharmaceutically acceptable salt of ilaprazole and a first adjuvant. The enteric-coated micropellets 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 a basic substance.

[0052] Preferably, for the enteric-coated micropellets according to the present invention, a protective layer is further provided outside the enteric layer.

[0053] Preferably, in the enteric-coated micropellets according to the present invention, there is no other layer between the pellet core and the first isolation layer.

[0054] Preferably, in the enteric-coated micropellets according to the present invention, there is no other layer between the second isolation layer and the enteric layer.

[0055] Preferably, in the enteric-coated micropellets according to the present invention, there is no other layer between the first isolation layer and the second isolation layer.

[0056] Preferably, the first adjuvant in the enteric-coated micropellets according to the present invention is a basic compound, preferably a water-insoluble basic compound, more preferably selected from magnesium hydroxide, aluminum hydroxide, magnesium oxide, magnesium carbonate, calcium carbonate, and calcium hydroxide.

[0057] Preferably, the pharmaceutically acceptable salt of ilaprazole may be, for example, sodium ilaprazole, magnesium ilaprazole, zinc ilaprazole, potassium ilaprazole, lithium ilaprazole, or calcium ilaprazole. Here, those skilled in the art can select an appropriate salt as needed.

[0058] Preferably, the pellet core of the enteric-coated micropellets according to the present invention further contains a surfactant. Preferably, the surfactant is Tween 80 or sodium dodecyl sulfate.

[0059] Preferably, the weight ratio of the water-insoluble basic compound in the first isolation layer 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.

[0060] Preferably, the second isolation layer contains a water-insoluble inert substance that can prevent the adhesion of the micropellets, and the dosage ratio of the water-insoluble inert substance to the adhesive is within the range of 1 to 8:1.5 to 10, or 1 to 10:1 to 20, or 4 to 26:7 to 44 in terms of weight ratio.

[0061] Preferably, the D90 particle size of ilaprazole and / or its pharmaceutically acceptable salt is within a range selected from between any two endpoints of 0 μm (when constituting the range, the endpoint values are not included), 10 μm, 20 μm, 30 μm, 40 μm, 50 μm, 60 μm, 70 μm, 80 μm, 90 μm, 100 μm.

[0062] Regarding the pellet core of the enteric-coated micropellets The pellet core of the enteric-coated micropellets according to the present invention (also referred to as a drug-containing pellet) may be a completely active pellet core or a blank micropellet core coated with a drug-carrying layer. As used herein, the term "completely active pellet core" refers to a pellet core containing ilaprazole and / or a pharmaceutically acceptable salt of ilaprazole, a first auxiliary agent, and one or more other pharmaceutically acceptable excipients, wherein the ilaprazole and / or the pharmaceutically acceptable salt of ilaprazole as the active ingredient does not form other layers alone or together with any other component, but is dispersed in other components (such as the first auxiliary agent and one or more other pharmaceutically acceptable excipients), and in the blank micropellet core coated with the drug-carrying layer, the drug-carrying layer contains ilaprazole and / or a pharmaceutically acceptable salt of ilaprazole, a first auxiliary agent, and an optional excipient.

[0063] When the ilaprazole and / or its pharmaceutically acceptable salt in the pellet core cannot achieve sufficient storage stability only by the action of the water-insoluble basic compound contained in the first isolation layer, the first auxiliary agent added to the pellet core can improve its storage stability.

[0064] The first auxiliary agent in the pellet core may be a conventional auxiliary agent used in the prior art to improve the stability of acid-labile compounds. Preferably, the first auxiliary agent is a basic compound containing a water-insoluble basic compound and a water-soluble basic compound. According to the present invention, preferably, a water-insoluble basic compound is used as the first auxiliary agent in the pellet core, and more preferably, by making the water-insoluble basic compound contained in the pellet core the same as the water-insoluble basic compound contained in the isolation layer, the pH buffering effect of the isolation layer can be further enhanced. In an embodiment according to the present invention, the water-insoluble basic compound may be one or more selected from magnesium hydroxide, aluminum hydroxide, magnesium oxide, magnesium carbonate, calcium carbonate, calcium hydroxide, but is not limited thereto. Preferably, the weight ratio of the basic 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, most preferably 0.8 to 1.2:1, for example 1:1.

[0065] According to the present invention, the pellet core may further contain a surfactant. From the results of the examples according to the present invention, it has been demonstrated that the surfactant can effectively improve their bioavailability by improving the elution properties of ilaprazole and / or its pharmaceutically acceptable salt in enteric-coated micropellets and their formulations. In the examples according to the present invention, the surfactant contained in the pellet core may be selected from nonionic surfactants, anionic surfactants, and zwitterionic surfactants. Preferably, the nonionic surfactant may be selected from polyethylene glycol-based, polyol-based (e.g., Tween 80), etc., the anionic surfactant may be selected from higher fatty acid salts such as sodium dodecyl sulfate, sulfate esters, sulfonates, etc., and the zwitterionic surfactant may be selected from phosphate ester-based.

[0066] According to the present invention, the particle size of ilaprazole and / or its pharmaceutically acceptable salt can affect the elution property and / or drug loading amount 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 may be such that the particle size D90 ≦ 100 μm. In this case, the enteric-coated micropellets have good elution properties, and furthermore, the bioavailability of the enteric-coated micropellet preparation produced by the enteric-coated micropellets can be enhanced. More preferably, the particle size D90 of ilaprazole and / or its pharmaceutically acceptable salt may be in a range selected from between any two endpoints of 10 μm, 20 μm, 30 μm, 40 μm, 50 μm, 60 μm, 70 μm, 80 μm, 90 μm, 100 μm, and in particular D90 ≦ 50 μm, whereby the drug loading amount can be improved.

[0067] According to an embodiment of the present invention, the blank micropellet core is a blank micropellet core commonly used in the prior art. In an embodiment according to the present invention, the blank micropellet core may be selected from a microcrystalline cellulose pellet core, a sucrose pellet core, or a mannitol pellet core, but is not limited thereto, and its particle size may be 50 to 500 μm, preferably 100 to 400 μm, more preferably 250 to 350 μm, and most preferably about 300 μm.

[0068] According to an embodiment of the present invention, the above drug-carrying layer may further contain an adhesive. The adhesive may be one or more selected from hydroxypropyl cellulose, hypromellose, hydroxymethyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, methyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol, syrup, and starch, but is not limited thereto. In the embodiment according to the present invention, the adhesive may be one or more selected from hydroxypropyl cellulose-SSL (for example, a commercially available series from Nisso), hypromellose E5, polyvinyl pyrrolidone K30, polyvinyl alcohol, methyl cellulose, and polyethylene glycol. Regarding the isolation layer of enteric-coated micro pellets, The basic function of the isolation layer of enteric-coated micro pellets is to isolate the pellet core in a basic environment from the enteric layer containing free carboxy groups in order to prevent the decomposition or discoloration of ilaprazole and / or its pharmaceutically acceptable salts during the coating process or storage process. The inventor has found that in the research on ilaprazole enteric-coated micro pellets and their formulations, water-insoluble inert substances (such as talc powder, silica, titanium dioxide, magnesium stearate, etc.) and / or water-soluble basic compounds that can generally prevent the adhesion of micro pellets, which are commonly used in the conventional manufacturing methods in the prior art (for example, when manufacturing the isolation layer closely adjacent to the pellet core), and basic compounds commonly used when manufacturing the isolation layer closely adjacent to the enteric layer reduce the stability and / or acid resistance of enteric-coated micro pellets and their formulations. In particular, in the case of acid-labile compounds with relatively low stability such as ilaprazole, it is impossible to simultaneously meet the requirements for both the stability and acid resistance of the enteric-coated micro pellets and their formulations. As used herein, the term "closely adjacent" means that there is no other layer between the pellet core of the enteric-coated micro pellet and its coating or coating layer, or between the two layers.

[0069] As one of the causes of this technical problem, the inventor has found that the compatibility between the water-insoluble inert substance contained in the isolation layer (corresponding to the first isolation layer according to the present invention) that is closely adjacent to the pellet core and can prevent the adhesion of micro pellets, and the acid-labile compound contained in the pellet core varies in stability depending on the acid-labile compound. That is, in enteric-coated micro pellets and their formulations manufactured by the prior art, when the stability of the acid-labile compound (such as ilaprazole) contained in the pellet core is low, the compatibility between the water-insoluble inert substance (such as talc powder) that can prevent the adhesion of micro pellets and contained in the isolation layer closely adjacent to the pellet core and the acid-labile compound also decreases, as demonstrated by tests and is considered to be the case (not limited to this). Therefore, even in the protection of the basic compound used as a stabilizer contained in the pellet core and / or the isolation layer, the related substances (i.e., impurities) in the accelerated test results still clearly increase, thereby reducing the stability of the enteric-coated micro pellet formulation. This somewhat limits the range of acid-labile compounds applicable to enteric-coated micro pellets and their formulations manufactured by the prior art. That is, the formulation method or composition of enteric-coated micro pellets and their formulations manufactured by the prior art cannot be well applied to ilaprazole with relatively low stability and / or its pharmaceutically acceptable salts. Also, when the isolation layer (corresponding to the first isolation layer according to the present invention) that is closely adjacent to the pellet core contains a water-soluble basic compound, under long-term high-temperature and high-humidity conditions, the isolation layer of the enteric-coated micro pellet absorbs free water and dissolves the water-soluble basic compound, increasing the basicity of the isolation layer closely adjacent to the enteric layer and causing the basicity to appear. When water penetrates into the enteric layer in an acidic medium, the enteric layer is dissolved in advance, reducing the acid resistance of the enteric-coated micro pellet and its formulation. Since the basicity appears in the isolation layer closely adjacent to the enteric layer, the principle of dissolving the enteric layer in advance also applies when the isolation layer (corresponding to the second isolation layer according to the present invention) that is closely adjacent to the enteric layer contains a basic compound.

[0070] Accordingly, according to the present invention, the enteric-coated micropellets comprise at least two isolation layers containing inert substances, i.e., a first isolation layer that is closely adjacent to the pellet core, at least close to the pellet core, and a second isolation layer that is farther from the pellet core than the first isolation layer or is closely adjacent to the enteric layer. Among them, the first isolation layer contains a water-insoluble basic compound and does not contain a water-soluble basic compound and a water-insoluble inert substance that can prevent the adhesion of the micropellets, and the second isolation layer does not contain a basic compound. When the enteric-coated micropellets contain three or more isolation layers, the other isolation layers located between the first isolation layer and the second isolation layer may be isolation layers that conform to the definition of the first isolation layer or the second isolation layer according to the present invention, or may be isolation layers generally used in the prior art.

[0071] According to the present invention, the water-insoluble basic compound may be a water-insoluble basic compound generally used in the prior art in order to improve the stability of the acid-labile compound. In an embodiment according to the present invention, the water-insoluble basic compound may be one or more selected from magnesium hydroxide, aluminum hydroxide, magnesium oxide, magnesium carbonate, calcium carbonate, calcium hydroxide, but is not limited thereto.

[0072] According to the present invention, the water-insoluble inert substance capable of preventing the adhesion of micro pellets may be one or more selected from one or more lubricants, fluidizing agents, and anti-adhesive agents (i.e., anti-adhesion agents, the same hereinafter) commonly used in pharmacy. In an embodiment according to the present invention, the water-insoluble inert substance capable of preventing the adhesion of micro pellets may be selected from silica, calcium silicate, colloidal silica, aluminum silicate, calcium aluminum silicate, magnesium silicate, sodium stearate, zinc stearate, magnesium stearate, talc powder, titanium dioxide, etc., but is not limited thereto. In an embodiment of the ilaprazole enteric-coated micro pellets according to the present invention, the first isolation layer of the enteric-coated micro pellets does not contain one or more water-insoluble inert substances capable of preventing the adhesion of micro pellets, such as talc powder, silica, titanium dioxide, and magnesium stearate.

[0073] In a preferred embodiment according to the present invention, the first isolation layer is mainly composed of a water-insoluble basic compound and an adhesive, and the second isolation layer is mainly composed of a water-insoluble inert substance capable of preventing the adhesion of micro pellets and an adhesive. According to the present invention, by adjusting the dosage of the water-insoluble basic compound and the adhesive contained in the first isolation layer or the dosage of the water-insoluble inert substance capable of preventing the adhesion of micro pellets and the adhesive contained in the second isolation layer, the elution property of the enteric-coated micro pellet preparation can be affected, and further its bioavailability can be affected. For example, in a preferred embodiment of the ilaprazole enteric-coated micro pellets according to the present invention, the blending ratio of each component may be as follows. When the dosage of ilaprazole is 5 to 15 parts by weight, the first isolation layer contains 5 to 36 parts by weight of an adhesive and 5 to 36 parts by weight of a water-insoluble basic compound, and the second isolation layer contains 4 to 26 parts by weight of an adhesive and 7 to 44 parts by weight of a water-insoluble inert substance capable of preventing the adhesion of micro pellets.

[0074] The above-mentioned adhesive is an adhesive generally used in the barrier layer according to the prior art. According to the present invention, the adhesive may be one or more selected from pharmaceutically approved water-soluble inert compounds such as hydroxypropyl cellulose, hypromellose, hydroxymethyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, methyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol, syrup and starch, or polymers used as coating films.

[0075] Regarding the enteric layer of enteric-coated micro pellets, The enteric layer generally used in prior art enteric-coated micro pellet formulations is also applicable to the present invention. For example, CN87103285A (Chinese counterpart of US4786505) describes a detailed explanation related to the enteric layer. The inventor incorporated the content related to the enteric layer in the above-mentioned document and the related content of all the documents cited therein into the present application with reference thereto.

[0076] According to the present invention, the enteric layer may contain one or more substances selected from the group consisting of acrylic resin-based, cellulose-based such as carboxymethyl ethyl cellulose, enteric coating materials such as Opadry, and optional one or more additives selected from plasticizers, anti-adhesives, and lubricants. In an embodiment according to the present invention, the enteric layer may contain an acrylic resin-based enteric coating material, a plasticizer (such as polyethylene glycol, glyceryl triacetate, triethyl citrate, phthalic acid ester), and an anti-adhesive (such as talc powder, glyceryl monostearate). Among them, the acrylic resin-based enteric coating material is one or more selected from cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, solution or dispersion L30D55 of methacrylic acid copolymer, hydroxypropyl methylcellulose acetate succinate, polyethyl acetate phthalate, and shellac. In a preferred embodiment of the ilaprazole enteric-coated 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 ilaprazole and / or its pharmaceutically acceptable salt is 0.6 to 6:1, preferably 0.8 to 4:1, and more preferably 1 to 2:1.

[0077] Regarding the protective layer of the enteric-coated micropellets, According to the present invention, a protective layer may be further provided outside the enteric layer of the enteric-coated micropellets, and preferably the protective layer is closely adjacent to the enteric layer. The above protective layer can prevent adhesion that may occur between each semi-finished product / product during the standing process before the preparation is manufactured, or during the manufacturing process of the preparation, or during the standing process after the preparation is manufactured. In addition, by providing the protective layer, the elution property of the enteric-coated micropellets can be efficiently improved, and the bioavailability of the manufactured enteric-coated micropellet preparation can also be improved.

[0078] In an embodiment according to the present invention, the protective layer may include an adhesive and an anti-adhesive agent. The adhesive may be one or more selected from hypromellose, hydroxypropyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, methyl cellulose, and polyethylene glycol. The anti-adhesive agent may be one or more selected from talc powder, magnesium stearate, titanium dioxide, and silica.

[0079] According to the present invention, by increasing the dosage of the anti-adhesive agent in the protective layer, the acid resistance of the enteric-coated micropellets can be improved. In a preferred embodiment of the ilaprazole enteric-coated micropellets according to the present invention, when ilaprazole and / or its pharmaceutically acceptable salt is 5 to 15 parts by weight, the dosage of the anti-adhesive agent is 0.5 to 5 parts by weight.

[0080] According to a fourth aspect of the present invention, the present invention provides a method for manufacturing enteric-coated micropellets, including at least 1) a step of manufacturing a pellet core including ilaprazole and / or a pharmaceutically acceptable salt of ilaprazole and a first adjuvant, 2) a step of coating a second isolation layer after coating a first isolation layer, and 3) a step of coating an enteric layer.

[0081] Preferably, step 2) includes manufacturing a first suspension including a water-insoluble basic compound and not including a water-soluble basic compound and a water-insoluble inert substance capable of preventing the adhesion of micropellets, and coating the pellet obtained in step 1) with the first suspension, and manufacturing a second suspension not including a basic compound, and coating a second isolation layer, preferably a second isolation layer closely adjacent to the enteric layer, with the second suspension.

[0082] Preferably, in step 1), the first adjuvant and the water-insoluble basic compound included in the first isolation layer act together to achieve the storage stability of ilaprazole and / or a pharmaceutically acceptable salt of ilaprazole.

[0083] Preferably, the method for manufacturing enteric-coated micro pellets further includes the step of coating a protective layer.

[0084] In an embodiment according to the present invention, the method for manufacturing enteric-coated micro pellets may include one or more of the following steps.

[0085] 1) For example, by a fluidized bed method, a blank micro pellet core is coated with a drug-carrying layer to produce a pellet core. The drug-carrying layer includes ilaprazole and / or a pharmaceutically acceptable salt of ilaprazole, a basic compound as a first auxiliary agent, and an adhesive.

[0086] 2) For example, by a fluidized bed method, from the inside to the outside, the pellet core obtained in step 1) is coated with at least a first suspension and a second suspension respectively to produce an isolated pellet. Among them, the first suspension contains a water-insoluble basic compound, but does not contain a water-soluble basic compound and a water-insoluble inert substance that can prevent the adhesion of micro pellets, forming a first isolation layer. The second suspension does not contain a basic compound, forming a second isolation layer.

[0087] 3) An enteric coating material and one or more selected from a plasticizer, an anti-adhesive, a lubricant, and an emulsifier are prepared into an enteric layer suspension. For example, by a fluidized bed method, the isolated pellet obtained in step 2) is coated with the enteric layer suspension to produce enteric-coated micro pellets.

[0088] Preferably, the method for manufacturing the enteric-coated micro pellets may further include the step of adding one or more adhesives selected from hydroxypropyl cellulose, hypromellose, methyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, carboxymethyl cellulose, and polyethylene glycol to purified water to produce a protective layer coating solution. For example, by a fluidized bed method, the enteric-coated micro pellets obtained in step 3) are coated with the protective layer coating solution to produce enteric-coated micro pellets having a protective layer.

[0089] Hereinafter, taking the dry suspension agent as an example, the enteric-coated micro pellets according to the present invention, the manufacturing method of the dry suspension agent containing them, and the experiment of property test will be described.

[0090] Example Example 1: Manufacture of Micro Pellets First, in this example, taking ilaprazole and / or its pharmaceutically acceptable salt as an example, the enteric-coated micro pellets A, D, and E according to the present invention are manufactured.

[0091] (I) Manufacturing Formulation of Each Composition Layer of Micro Pellets: 1.1 Manufacture of Drug-Containing Pellets (i.e., Pellet Core W) and Its Drug Application Rate (1) Weigh 150 g of hydroxypropyl cellulose-SSL and 4 g of polysorbate 80, dissolve them in 3000 g of purified water to obtain a hydroxypropyl cellulose adhesive solution. Next, add 100 g of magnesium hydroxide to the adhesive solution, disperse it at 10000 rpm for 5 min by high-shear dispersion. Then, disperse 100 g of ilaprazole with a D90 particle size of 46.8 μm in the adhesive solution containing magnesium hydroxide, and uniformly disperse it by high-shear at 10000 rpm. Spray the ilaprazole suspension on 100 g of sucrose pellet cores using a GLATT GPCG-1 fluidized bed to manufacture drug-containing pellets W1.

[0092] The process parameters of the fluidized bed were as follows.

[0093] [Table 1]

[0094] Among them, the drug application rate of the drug-containing pellets W1 = (actual content of the drug-containing pellets) / (theoretical content of the drug-containing pellets) × 100% = 95.6% (2) Weighed 180 g of polyvinylpyrrolidone K30 and 6 g of polysorbate 80, dissolved them in 3000 g of purified water, added 50 g of magnesium oxide thereto, and uniformly dispersed it by high shear at 10,000 rpm to obtain an adhesive containing magnesium oxide. Next, 150 g of ilaprazole was dispersed in the adhesive containing magnesium oxide and uniformly dispersed by high shear at 10,000 rpm. The ilaprazole suspension was sprayed onto 100 g of mannitol pellet cores by a GLATT GPCG-1 fluidized bed to produce drug-containing pellets W4.

[0095] Among them, the process parameters of the fluidized bed were as follows.

[0096]

Table 2

[0097] Among them, the drug application rate of the drug-containing pellets W4 = (actual content of the drug-containing pellets) / (theoretical content of the drug-containing pellets) × 100% = 93.3% (3) Weighed 80 g of hypromellose E5 and 6 g of polysorbate 80, dissolved them in 1600 g of purified water, added 50 g of magnesium hydroxide thereto, and uniformly dispersed it by high shear at 10,000 rpm to obtain an adhesive containing magnesium hydroxide. Next, 150 g of ilaprazole was dispersed in the adhesive containing magnesium hydroxide and uniformly dispersed by high shear at 10,000 rpm. The ilaprazole drug suspension was sprayed onto 150 g of sucrose pellet cores by a GLATT GPCG-1 fluidized bed to produce drug-containing pellets W5.

[0098] Among them, the process parameters of the fluidized bed were as follows.

[0099]

Table 3

[0100] Among them, the drug application rate of the drug-containing pellet W5 = (actual content of the drug-containing pellet) / (theoretical content of the drug-containing pellet) × 100% = 94.1% 1.2 Manufacture of the isolation layer (G) Weighed 23 g of hydroxypropylcellulose-SSL, dissolved it in 460 g of purified water, then added 23 g of magnesium carbonate, and dispersed it uniformly by high shear at 10,000 rpm to produce the formulation of the first-layer isolation layer. Weighed 17.2 g of hydroxypropylcellulose-SSL, dissolved it in 344 g of purified water, added 28.8 g of talc powder, and dispersed it uniformly by high shear at 10,000 rpm to produce the formulation of the second-layer isolation layer. Using the GLATT GPCG-1 fluidized bed, the two-layer isolation suspension was sequentially sprayed onto 90 g of the corresponding pellet cores.

[0101] Among them, the process parameters of the fluidized bed were as follows.

[0102]

Table 4

[0103] 1.3 Manufacture of the enteric layer (C) Enteric layer formulation C (unit: g)

[0104]

Table 5

[0105] Manufacturing process: Weighed 20.1 g of triethyl citrate, dissolved it in 447.6 g of purified water, added 3.4 g of talc powder, and dispersed it uniformly by high shear at 10,000 rpm. Then, stirred it with 223.8 g of Eudragit L30D-55 for 45 min for use. Using the GLATT GPCG-1 fluidized bed, the enteric coating solution was sprayed onto the isolated micropellets.

[0106] The specific process parameters were as follows.

[0107]

Table 6

[0108] 1.4 Manufacture of protective layer (B) 1) Protective layer formulation B1 (unit: g)

[0109]

Table 7

[0110] Manufacturing process: Weighed 2.5 g of hypromellose E5, dissolved it in 50 g of purified water, then added 1.2 g of magnesium stearate, and dispersed it uniformly by high shear at 5000 rpm to produce a protective layer coating solution. The protective layer coating solution was sprayed onto enteric-coated micropellets using a GLATT GPCG-1 fluidized bed.

[0111] The specific process parameters were as follows.

[0112]

Table 8

[0113] 2) Protective layer formulation B4 (unit: g)

[0114]

Table 9

[0115] Manufacturing process: Weighed 2.5 g of hydroxypropyl cellulose-SSL, dissolved it in 50 g of purified water, then added 1.2 g of talc powder, and dispersed it uniformly by high shear at 5000 rpm to produce a protective layer coating solution. The protective layer coating solution was sprayed onto enteric-coated micropellets using a GLATT GPCG-1 fluidized bed.

[0116] Specific process parameters were referred to the above protective layer formulation B1.

[0117] 3) Protective layer formulation B5 (unit: g)

[0118]

Table 10

[0119] Manufacturing process: Weighed 2.5 g of hydroxypropyl cellulose - SSL, dissolved it in 50 g of purified water, then added 1.2 g of titanium dioxide, and dispersed it uniformly by high shear at 5000 rpm to produce a protective layer coating solution. The protective layer coating solution was sprayed onto enteric - coated micropellets by a GLATT GPCG - 1 fluidized bed.

[0120] Specific process parameters were referred to the above protective layer formulation B1.

[0121] (II) Manufacture of enteric - coated micropellets: According to the formulations of each composition layer of the enteric - coated micropellets listed in Section (I) of this example, enteric - coated micropellets A, D, and E according to the present invention shown in Table 1 below were manufactured.

[0122]

Table 11

[0123] Among them, W x Drug application rate of drug - containing pellets=(Actual content of drug - containing pellets) / (Theoretical content of drug - containing pellets)×100% Example 2 Manufacture of micropellet dry suspension In this example, first, dry suspension granules were manufactured, and then different micropellets were added to manufacture a dry suspension containing micropellets.

[0124] 2.1 Manufacture of Dry Suspending Agent A-I 1) Manufacture of Dry Suspending Granules

[0125] [Table 12]

[0126] Manufacturing method: Weigh 10 g of hydroxypropyl cellulose LF, dissolve it in 190 g of purified water, weigh the prescription amounts of carrageenan, crospovidone, chitosan, mannitol, glucose, and malic acid, put them into the HLSH2-6 wet mixing granulator, mix while stirring at 400 rpm for 4 min, then add hydroxypropyl cellulose LF to the mixer, continue stirring for 3 min, start shearing at 800 rpm, discharge after 1 min to produce wet granules, dry the wet granules, and then screen them through a 1.2 mm sieve for sizing. Dry suspending granules I were obtained.

[0127] 2) Manufacture of Dry Suspending Agent Mix 94.5 mg of ilaprazole enteric-coated micropellets A and 1.5 g of the above dry suspending granules to obtain dry suspending agent A-I.

[0128] 2.2 Manufacture of Dry Suspending Agent D-II 1) Manufacture of Dry Suspending Granules

[0129] [Table 13]

[0130] Manufacturing method: Weigh the prescription amounts of gum arabic, sodium alginate, hypromellose E5, cross-linked sodium carboxymethyl cellulose, mannitol, sucrose, citric acid, and chitosan, put them into the HLSH2-6 wet mixing granulator, mix while stirring at 400 rpm for 5 min, then gradually add purified water while stirring, continue stirring for 5 min, start shearing at 700 rpm for 1 min to produce wet granules, discharge, dry, and screen them through a 1.0 mm sieve for sizing. Dry suspending granules II were obtained.

[0131] 2) Preparation of Dry Suspension Agent 67.4 mg of ilaprazole enteric-coated micropellets D and 2.5 g of the above dry suspension granules were mixed and bottled to obtain ilaprazole enteric-coated dry suspension agent D-II with a specification of 5 mg.

[0132] 2.3 Preparation of Dry Suspension Agent E-III 1) Preparation of Dry Suspension Granules III

[0133]

Table 14

[0134] Manufacturing method: Weigh 10 g of polyvinylpyrrolidone K30, dissolve it in 190 g of purified water, weigh the prescription amounts of pectin, sodium alginate, crospovidone, maltose, xylitol, ascorbic acid, and chitosan and put them into the HLSH2-6 wet mixing granulator, mix while stirring at 400 rpm for 4 min, then add the polyvinylpyrrolidone solution to the mixer, continue stirring for 4 min, start shearing at 800 rpm, discharge after 1 min to produce wet granules, dry the wet granules, and then screen them through a 1.2 mm sieve for sizing. Dry suspension granules III were obtained.

[0135] 2) Preparation of Dry Suspension Agent 60.5 mg of ilaprazole enteric-coated micropellets E and 2.0 g of the above dry suspension granules were mixed and bottled to obtain ilaprazole enteric-coated dry suspension agent E-III with a specification of 5 mg.

[0136] 2.4 Preparation of Dry Suspension Agent A-VI 1) Preparation of Dry Suspension Granules VI

[0137]

Table 15

[0138] Manufacturing method: Weigh 8 g of hydroxypropyl methylcellulose E5, dissolve it in 220 g of purified water, weigh the prescription amounts of xanthan gum, cross-linked sodium carboxymethylcellulose, chitosan, mannitol, sucrose, and citric acid, put them into the HLSH2-6 wet mixing granulator, mix while stirring at 400 rpm for 4 min, then add the hydroxypropyl methylcellulose E5 solution to the mixer, continue stirring for 3 min, start shearing at 1000 rpm, discharge after 1 min, manufacture wet granules, dry the wet granules, and then screen them through a 1.2 mm sieve for sizing. Obtain dry suspension granules VI.

[0139] 2) Manufacturing of dry suspension agent Mix 94.5 mg of ilaprazole enteric-coated pellet micropellet A and 1.6 g of the above dry suspension granules, bottle them, and obtain ilaprazole enteric-coated dry suspension agent A-VI with a specification of 5 mg.

[0140] 2.5 Manufacturing of dry suspension agent A-VII 1) Manufacturing of dry suspension granules VII

[0141]

Table 16

[0142] Manufacturing method: Weigh 18 g of hydroxypropyl methylcellulose VLV, dissolve it in 280 g of purified water, weigh the prescription amounts of xanthan gum, cross-linked sodium carboxymethylcellulose, chitosan, mannitol, sucrose, and citric acid, put them into the HLSH2-6 wet mixing granulator, mix while stirring at 400 rpm for 4 min, then add the hydroxypropyl methylcellulose VLV solution to the mixer, continue stirring for 3 min, start shearing at 800 rpm, discharge after 1 min, manufacture wet granules, dry the wet granules, and then screen them through a 1.2 mm sieve for sizing. Obtain dry suspension granules VII.

[0143] 2) Manufacturing of dry suspension agent 94.5 mg of ilaprazole enteric-coated pellet micropellet A and 2.0 g of the above dry suspension granules were mixed, bottled, and ilaprazole enteric-coated dry suspension A-VII with a specification of 5 mg was obtained.

[0144] 2.6 Manufacture of dry suspension A-VIII 1) Manufacture of dry suspension granules VIII

[0145]

Table 17

[0146] Manufacturing method: Weigh 18 g of hydroxypropyl methylcellulose VLV, dissolve it in 280 g of purified water, weigh the prescription amounts of xanthan gum, crosslinked sodium carboxymethylcellulose, chitosan, mannitol, sucrose, and citric acid and put them into the HLSH2-6 wet mixing granulator, mix while stirring at 400 rpm for 4 min, then add the hydroxypropyl methylcellulose VLV solution to the mixer, continue stirring for 3 min, start shearing at 800 rpm, discharge after 1 min, manufacture wet granules, dry the wet granules, and then screen them through a 1.2 mm sieve for sizing. Dry suspension granules VIII were obtained.

[0147] 2) Manufacture of dry suspension 94.5 mg of ilaprazole enteric-coated pellet micropellet A and 1.8 g of the above dry suspension granules were mixed, bottled, and ilaprazole enteric-coated dry suspension A-VIII with a specification of 5 mg was obtained.

[0148] 2.7 Manufacture of dry suspension A-IX 1) Manufacture of dry suspension granules IX

[0149]

Table 18

[0150] Manufacturing method: Weigh 20 g of hydroxypropyl methylcellulose VLV, dissolve it in 300 g of purified water, weigh the prescribed amounts of xanthan gum, crosslinked carboxymethylcellulose sodium, chitosan, mannitol, sucrose, and citric acid, put them into the HLSH2-6 wet mixing granulator, mix while stirring at 400 rpm for 4 min, then add the hydroxypropyl methylcellulose VLV solution to the mixer, continue stirring for 3 min, start shearing at 800 rpm, discharge after 1 min, manufacture wet granules, dry the wet granules, and then screen them through a 1.2 mm sieve for sizing. Dry suspension granules IX were obtained.

[0151] 2) Manufacturing of dry suspension agent Mix 94.5 mg of ilaprazole enteric-coated pellet micropellet A and 1.8 g of the above dry suspension granules, bottle them, and obtain ilaprazole enteric-coated dry suspension agent A-IX with a specification of 5 mg.

[0152] 2.8 Manufacturing of dry suspension agent for comparative example 1) Formulation of dry suspension granules V for comparison (unit: g)

[0153]

Table 19

[0154] Manufacturing method: After uniformly mixing xanthan gum, chitosan, CCNA, and aspartame, put them into a dry granulator for granulation. The process parameters were a pinch roll gap of 0.2 mm, a feed rate of 30 rpm, a pinch roll rotation speed of 5 rpm, and a sizing rotation speed of 10 rpm. After granulation, screen them to control the particle size between 0.5 and 0.7 mm for sizing. Dry suspension granules V were obtained.

[0155] 2) Manufacturing of dry suspension agent Mix 60.5 mg of ilaprazole enteric-coated micropellet E and 2.0 g of the above dry suspension granules V, bottle them, and obtain ilaprazole enteric-coated dry suspension agent E-V with a specification of 5 mg.

[0156] Example 3 Measurement of the Performance of Dry Suspension Granules 3.1 Measurement of the Viscosity of Dry Suspension Granules 3.1.1 Dry Suspension Granule I according to the Present Invention 1.5 g was added to 15 mL of water, stirred for 60 s, measured to have a pH of 3.9 using a calibrated pH meter, and then the viscosity of the suspension gel was continuously measured.

[0157] 3.1.2 Dry Suspension Granule II according to the Present Invention 2.5 g was added to 25 mL of water, stirred for 60 s, measured to have a pH of 3.8 using a calibrated pH meter, and then the viscosity of the suspension gel was continuously measured.

[0158] 3.1.3 Dry Suspension Granule III according to the Present Invention 2.0 g was added to 20 mL of water, stirred for 60 s, measured to have a pH of 4.0 using a calibrated pH meter, and then the viscosity of the suspension gel was continuously measured.

[0159] 3.1.4 Dry Suspension Granule VI according to the Present Invention 2.0 g was added to 20 mL of water, stirred for 60 s, measured to have a pH of 4.0 using a calibrated pH meter, and then the viscosity of the suspension gel was continuously measured.

[0160] 3.1.5 Dry Suspension Granule VII according to the Present Invention 2.0 g was added to 20 mL of water, stirred for 60 s, measured to have a pH of 3.9 using a calibrated pH meter, and then the viscosity of the suspension gel was continuously measured.

[0161] 3.1.6 Dry Suspension Granule VIII according to the Present Invention 2.0 g was added to 20 mL of water, stirred for 60 s, measured to have a pH of 3.9 using a calibrated pH meter, and then the viscosity of the suspension gel was continuously measured.

[0162] 3.1.7 Dry Suspension Granule IX according to the Present Invention 2.0 g was added to 20 mL of water and stirred for 60 s. It was measured that the pH was 4.0 using a calibrated pH meter, and then the viscosity of the suspension gel was continuously measured.

[0163] 3.1.8 Dry Suspension Granules IV of Comparative Example It is a sample of the prior art. NEXIUM (registered trademark) (ORAL SUSPENSION, specification 40 mg) from AstraZeneca was used. The enteric-coated micro pellets containing esomeprazole magnesium were removed from the granules of the product. 15 mL of purified water was added to the remaining powder and stirred for 6 s. Then, the viscosity of the suspension gel was continuously measured.

[0164] 3.1.9 Dry Suspension Granules V of Comparative Example 2.0 g was added to 20 mL of water and stirred for 60 s. It was measured that the pH was 8.0 using a calibrated pH meter, and then the viscosity of the suspension gel was continuously measured.

[0165] Equipment: BROOKFIELD DV2T viscometer, small sample adapter SSA, MV1Y flag impeller blade rotor.

[0166] The results of the viscosity measurement of the above dry suspension granules are shown in Table 2 and Figure 1 below.

[0167]

Table 20

[0168] As can be seen from Table 2 and Figure 1, compared with the dry suspension granules IV of the prior art, the dry suspension granules I - III and VI - VIII according to the present invention can reach the maximum viscosity more rapidly. On the other hand, for the comparative dry suspension granules V, due to the large dosage of chitosan, after adding the dry suspension granules to water, the time to reach the maximum viscosity is significantly longer. Moreover, after adding the comparative dry suspension granules V to water, since it shows basicity, the enteric coating of the ilaprazole enteric pellets was dissolved.

[0169] 3.2 Test on the time required for ilaprazole micropellets to maintain a suspended state in a dry suspension agent (1) Add 15 mL of water to the dry suspension agent A-I of Example 2.1, stir at a constant speed, start timing after 30 s, and observe the time required for the enteric-coated micropellets to be completely suspended. (2) Add 25 mL of water to the dry suspension agent D-II of Example 2.2, stir at a constant speed, start timing after 30 s, and observe the time required for the enteric-coated micropellets to be completely suspended. (3) Add 20 mL of water to the dry suspension agent E-III of Example 2.3, stir at a constant speed, start timing after 30 s, and observe the time required for the enteric-coated micropellets to be completely suspended. (4) Add 15 mL of purified water to AstraZeneca's NEXIUM (registered trademark) (ORAL SUSPENSION, specification 40 mg), stir at a constant speed, start timing after 30 s, and observe the time required for the enteric-coated micropellets to be completely suspended. (5) Add 20 mL of water to the comparative dry suspension agent E-V of Example 2.4, stir at a constant speed, start timing after 30 s, and observe the time required for the enteric-coated micropellets to be completely suspended.

[0170] The above test results are shown in Table 3 below.

[0171]

Table 21

[0172] As can be seen from Table 3, all of the dry suspension agents A-I, D-II, and E-III according to the present invention can form a suspension gel within a shorter time than the prior art. The time required for the micropellets of the dry suspension granules to maintain a suspended state in the comparative dry suspension agent E-V reached 735 s, and the gel strength was too strong, which affected the suspension rate.

[0173] 3.3 Suspension-sedimentation time of micropellets in the suspension gel (1) Add 100 enteric-coated micro pellets A of ilaprazole to 1.5 g of the dry suspension granules I according to the present invention, add 15 mL of water, stir for 150 s until the enteric-coated micro pellets are completely suspended, then inject into a 15 mL graduated cylinder, and count the number of enteric-coated micro pellets within the measurement ranges of 0 - 5 mL, 5 - 10 mL, and 10 - 15 mL, and calculate continuously 12 h at 1 h intervals. At the same time, conduct 10 sets of tests. Calculate the average ratio of the micro pellets within the measurement ranges of 0 - 5 mL, 5 - 10 mL, and 10 - 15 mL (refer to the curves of the dry suspension granules I in FIGS. 2 - 4).

[0174] (2) Add 100 enteric-coated micro pellets D of ilaprazole to 1.5 g of the dry suspension granules II according to the present invention, add 15 mL of water, stir for 150 s until the micro pellets are completely suspended, then inject into a 15 mL graduated cylinder, and count the number of enteric-coated micro pellets within the measurement ranges of 0 - 5 mL, 5 - 10 mL, and 10 - 15 mL, and calculate continuously 12 h at 1 h intervals. At the same time, conduct 10 sets of tests. Calculate the average ratio of the micro pellets within the measurement ranges of 0 - 5 mL, 5 - 10 mL, and 10 - 15 mL (refer to the curves of the dry suspension granules II in FIGS. 2 - 4).

[0175] (3) Add 100 enteric-coated micro pellets E of ilaprazole to 1.5 g of the dry suspension granules III according to the present invention, add 15 mL of water, stir for 150 s until the micro pellets are completely suspended, then inject into a 15 mL graduated cylinder, and count the number of enteric-coated micro pellets within the measurement ranges of 0 - 5 mL, 5 - 10 mL, and 10 - 15 mL, and calculate continuously 12 h at 1 h intervals. At the same time, conduct 10 sets of tests. Calculate the average ratio of the micro pellets within the measurement ranges of 0 - 5 mL, 5 - 10 mL, and 10 - 15 mL (refer to the curves of the dry suspension granules III in FIGS. 2 - 4).

[0176] (4) Using a prior art product as dry suspension granules IV, i.e., NEXIUM® (ORAL SUSPENSION, specification 40 mg) from AstraZeneca, all enteric-coated micro pellets containing esomeprazole magnesium were removed from the dry suspension granules of the product. Then, 100 enteric-coated micro pellets of esomeprazole magnesium were added to the granules, 15 mL of water was added, and the mixture was stirred for 150 s until the micro pellets were completely suspended. Next, it was injected into a 15 mL graduated cylinder, and the number of enteric-coated micro pellets within the measurement ranges of 0 - 5 mL, 5 - 10 mL, and 10 - 15 mL was counted, and calculated continuously for 12 h once every 1 h. At the same time, 10 sets of tests were conducted. The ratio of micro pellets within the measurement ranges of 0 - 5 mL, 5 - 10 mL, and 10 - 15 mL was calculated (refer to the curves of the prior art NEXIUM dry suspension granules IV in Figures 2 - 4).

[0177] (5) To 1.5 g of the dry suspension granules I according to the present invention, 100 enteric-coated micro pellets of esomeprazole magnesium in NEXIUM® (ORAL SUSPENSION) from AstraZeneca were added, 15 mL of water was added, and the mixture was stirred for 150 s until the enteric-coated micro pellets were completely suspended. Next, it was injected into a 15 mL graduated cylinder, and the number of enteric-coated micro pellets within the measurement ranges of 0 - 5 mL, 5 - 10 mL, and 10 - 15 mL was counted, and calculated continuously for 12 h once every 1 h. At the same time, 10 sets of tests were conducted. The average ratio of micro pellets within the measurement ranges of 0 - 5 mL, 5 - 10 mL, and 10 - 15 mL was calculated (refer to the curves of the dry suspension granules Ia in Figures 2 - 4).

[0178] (6) Add 100 microcrystalline cellulose blank pellets (particle size range of 500 μm to 700 μm) from Asahi Kasei Celphere CP-507 to 1.5 g of the dry suspension granules II according to the present invention, add 15 mL of water, stir for 150 s until the enteric-coated micro pellets are completely suspended, then inject into a 15 mL graduated cylinder, and count the number of enteric-coated micro pellets within the measurement ranges of 0 - 5 mL, 5 - 10 mL, and 10 - 15 mL, and calculate continuously for 12 h, once every 1 h. At the same time, 10 sets of tests were conducted. Calculate the average ratio of the micro pellets within the measurement ranges of 0 - 5 mL, 5 - 10 mL, and 10 - 15 mL (refer to the curves of dry suspension granules IIa in Figures 2 - 4).

[0179] The results of the above tests are shown in Figures 2 - 4. From the results, within the measurement range of 0 - 5 mL, the ratio of enteric-coated micro pellets in the suspending agent formed by the dry suspension granules IV of the prior art is greater than the ratio of enteric-coated micro pellets in the suspending agent formed by the dry suspension granules I or II or III according to the present invention, and with the passage of time, it is shown that the increase in the ratio of enteric-coated micro pellets in the suspending agent formed by dry suspension granules IV is relatively obvious. In contrast, within the measurement range of 10 - 15 mL, the ratio of enteric-coated micro pellets in the suspending agent formed by dry suspension granules IV is smaller than the ratio of enteric-coated micro pellets in the dry suspension granules I or II or III suspending agent, and with the passage of time, the ratio of enteric-coated micro pellets in the suspending agent formed by dry suspension granules IV becomes smaller and smaller. These facts indicate that the suspending agent / suspending gel produced by the dry suspension granules according to the present invention can suspend the enteric-coated micro pellets for a longer time without sedimentation.

[0180] 3.4 Measurement of acid resistance of ilaprazole enteric-coated micro pellets in different dry suspending agents Referring to the following measurement method, measure the acid resistance of ilaprazole enteric-coated micro pellets in the dry suspending agent according to the present invention and the dry suspending agent of the comparative example, and the results are shown in Table 4 below.

[0181] Measurement method: Take a dry suspension containing enteric-coated micro pellets, use a 0.1 mol / L hydrochloric acid solution (9.0 mL of concentrated hydrochloric acid with water added to make 1000 mL) as the elution medium, rotate at 100 revolutions per minute, take out the elution cup after 120 minutes, filter the solution using a suction filtration device, collect the remaining micro pellets in a 50 mL volumetric flask, add 20 mL of 0.05 mol / L sodium hydroxide solution, shake in a shaker (250 revolutions / minute) for 20 minutes, add 30 mL of methanol and perform ultrasonic treatment for 10 minutes, dilute to the scale with water, shake evenly, centrifuge, and take the supernatant. Measure the remaining drug content in the micro pellets, that is, the acid resistance of the sample.

[0182]

Table 22

[0183] 3.5 Measurement of the dissolution of ilaprazole enteric-coated micro pellets in different dry suspensions Refer to the measurement methods of dissolution and release rate (for the general method, refer to Method 1 of General Rule 0931 in the Fourth Part of the Chinese Pharmacopoeia 2015 Edition), measure the dissolution of ilaprazole enteric-coated micro pellets in the dry suspensions according to the present invention and the dry suspensions of the comparative examples, and the results are shown in Table 5 below.

[0184] Measurement method: Take the sample waiting for measurement, use 300 mL of a 0.1 mol / L hydrochloric acid solution (9.0 mL of hydrochloric acid with water added to make 1000 mL) as the elution medium, rotate at 100 revolutions per minute, according to the conventional method, add 700 mL of a 0.086 mol / L disodium hydrogen phosphate solution (30.8 g of disodium hydrogen phosphate and 7 g of Tween 80 with water added to make 1000 mL) preheated to 37 ± 0.5 °C to each elution cup after 120 minutes, mix evenly, operate according to the Chinese Pharmacopoeia without changing the rotation speed, and sample after 45 minutes.

[0185] Test sample solution: Weigh an appropriate amount of eluent, filter it, precisely measure 5 mL of the additional filtrate, immediately and precisely add 1 mL of 0.15 mol / L sodium hydroxide solution, shake it uniformly, filter it, and use the additional filtrate as the test sample solution.

[0186] Reference standard solution: Precisely weigh about 10 mg of ilaprazole reference standard, put it into a 20 mL volumetric flask, add an appropriate amount of acetonitrile to dissolve it, dilute it to the mark with acetonitrile, shake it uniformly, precisely measure 1 mL and put it into a 100 mL volumetric flask, dilute it to the mark with phosphate buffer (pH 6.8) (obtained by uniformly mixing 700 mL of 0.086 mol / L disodium hydrogen phosphate solution and 300 mL of 0.1 mol / L hydrochloric acid solution), shake it uniformly, precisely measure 5 mL, immediately and precisely add 1 mL of 0.05 mol / L sodium hydroxide solution, shake it uniformly, filter it, and use the additional filtrate as the reference standard solution.

[0187]

Table 23

[0188] As described above, the dry suspending agent E-V uses the formulation of the comparative example. The acid resistance of the prepared suspension formulation is equivalent to that of the suspension formulation of the present invention, but the dissolution rate is significantly slower. Due to the high dosage of chitosan, the gel strength is too high, which affects the dissolution of the micropellets.

[0189] As can be seen from the above, in the ilaprazole dry suspension according to the present invention, by combining an anionic gelling agent and a cationic polymer (especially chitosan and its derivatives), the suspension can quickly reach a stable viscosity level, and the prepared suspension gel can suspend enteric-coated micropellets more stably for a longer time. Furthermore, for acid-labile proton pump inhibitors, especially in the case of ilaprazole, its dissolution rate can be improved.

Brief Description of the Drawings

[0190]

Figure 1

Figure 2

Figure 3

Figure 4

Claims

**Claim 1**: A pharmaceutical composition which is a dry suspension agent, comprising: dry suspension granules and enteric-coated micropellets containing ilaprazole and / or a pharmaceutically acceptable salt thereof; wherein the dry suspension granules contain an anionic gelling agent and a cationic polymer; the weight ratio of the anionic gelling agent to the cationic polymer is (1 to 10):1; the anionic gelling agent is one, two or more selected from gum arabic, alginate, pectin, xanthan gum, carrageenan; the cationic polymer is selected from chitosan; the weight percentage of the cationic polymer in the dry suspension granules is 0.5 to 5%; the pH value of the suspension gel formed by the dry suspension granules in an aqueous dispersion medium is in the range of 2.5 to 7.0; a pharmaceutical composition characterized by the above. **Claim 2**: The alginate is sodium alginate; a pharmaceutical composition according to Claim 1, characterized by the above. **Claim 3**: The weight percentage of the cationic polymer in the dry suspension granules is 0.6 to 4%; a pharmaceutical composition according to Claim 1 or 2, characterized by the above. **Claim 4**: The dry suspension granules further contain one, two or more selected from adhesives, disintegrants, diluents and pH regulators; a pharmaceutical composition according to Claim 1 or 2, characterized by the above. **Claim 5**: The adhesive is one, two or more selected from polyvinylpyrrolidone, hypromellose, hydroxypropylcellulose, methylcellulose, polyvinyl alcohol, starch; the disintegrant is one, two or more selected from sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, croscarmellose sodium starch, low-substituted hydroxypropylcellulose, crospovidone, microcrystalline cellulose, pregelatinized starch; the diluent is one, two or more selected from xylitol, mannitol, sucrose, glucose, sorbitol, maltitol, fructose; the pH regulator is one, two or more selected from tartaric acid, citric acid, oxalic acid, succinic acid, fumaric acid, ascorbic acid, malic acid, glutamic acid, caffeic acid; a pharmaceutical composition according to Claim 4, characterized by the above. **Claim 6**: The pH value of the suspension gel formed by the dry suspension granules in an aqueous medium is within the range of 3.0 to 5.0, and / or when producing the suspension gel, the amount of the aqueous dispersion medium added to the dry suspension granules is 2 to 50 times the weight of the dry suspension granules. The pharmaceutical composition according to claim 1 or 2, characterized in that.

7. The mass ratio of the dosage of ilaprazole in the enteric-coated micropellets to the dosage of the dry suspension granules is 1:200 to 1000. The pharmaceutical composition according to claim 1 or 2, characterized in that.

8. The pharmaceutically acceptable salt of ilaprazole is sodium ilaprazole, magnesium ilaprazole, zinc ilaprazole, potassium ilaprazole, lithium ilaprazole or calcium ilaprazole. The pharmaceutical composition according to claim 1 or 2, characterized in that.

9. A method for producing the pharmaceutical composition according to claim 1 or 2, comprising: (1) mixing an anionic gelling agent and a cationic polymer with any optional other adjuvants; (2) separately producing an adhesive solution; (3) adding the adhesive solution obtained in step (2) to the mixture obtained in step (1) to produce a wet mixture; (4) granulating the wet mixture obtained in step (3) to obtain dry suspension granules; (5) mixing the dry suspension granules with enteric-coated micropellets containing ilaprazole and / or its pharmaceutically acceptable salt.

10. A method for producing the pharmaceutical composition according to claim 1 or 2, comprising: (1) mixing an anionic gelling agent and a cationic polymer with any optional other adjuvants; (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 produce a wet mixture; (4) granulating the wet mixture obtained in step (3) to obtain dry suspension granules; (5) mixing the dry suspension granules with enteric-coated micropellets containing ilaprazole and / or its pharmaceutically acceptable salt.

11. The pharmaceutical composition is used for treating and / or preventing gastrointestinal diseases. The gastrointestinal diseases 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, gastric hypomotility, Zollinger-Ellison syndrome, gastroesophageal reflux disease (GERD), Helicobacter pylori-related diseases or eradication of Helicobacter pylori, any grade of erosive esophagitis, short bowel syndrome, or any combination of the above diseases, the pharmaceutical composition according to claim 1 or 2. The pharmaceutical composition according to claim 1 or 2, which includes diseases related to Helicobacter pylori or eradication of Helicobacter pylori, any grade of erosive esophagitis, short bowel syndrome, or any combination of the above diseases.

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