Esomeprazole enteric preparation

Abstract

To provide an esomeprazole-containing particulate composition used for producing an esomeprazole enteric tablet having excellent content uniformity, acid resistance and stability of medicine.SOLUTION: Provided is an esomeprazole-containing particulate composition in which particulate low-solubility saccharide is carried on a surface of esomeprazole enteric particles including (a) an esomeprazole-containing pharmacophore, (b) a middle layer and (c) an enteric layer.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a novel enteric-coated esomeprazole-containing particulate composition, tablets containing the composition, and methods for producing them.

Background Art

[0002] Esomeprazole is the S-isomer of omeprazole, which is a racemate, and has a proton pump inhibitory action. It is commercially available as esomeprazole magnesium hydrate in the form of hard capsules or suspension granules as a therapeutic agent for gastric ulcers and duodenal ulcers (Non-Patent Document 1). Since esomeprazole is unstable in acid, measures such as making it an alkaline salt and making it an enteric preparation have been taken. Hard capsules and suspension granules are difficult to take orally. In particular, hard capsules have a feeling of adhesion to the throat, are easy to roll, and the formulation size becomes large, so a tablet form is required as an easy-to-take form.

[0003] In enteric-coated tablets, it is necessary to sufficiently form an enteric layer. However, since tableting is performed at a pressure of 0.3 to 5 kN during tablet production, it is necessary to form an enteric film with sufficient strength that does not cause breakage. So far, as esomeprazole enteric-coated tablets, for example, tablets containing enteric granules in which esomeprazole is supported on a spherical nucleus of sugar, a separating layer of hydroxypropyl cellulose is provided, and an enteric layer is provided with a methacrylic acid copolymer (Patent Document 1), enteric-coated granules coated with an enteric film containing an enteric polymer and an ethyl acrylate / methyl methacrylate copolymer (Patent Document 2), tablets obtained by tableting enteric granules having an enteric layer containing an enteric polymer and macrogol (Patent Document 3), orally disintegrating tablets containing enteric granules having a first shielding layer, a second shielding layer, a first enteric layer, an intermediate layer, a second enteric layer, and an outermost layer containing 4% by mass or more of mannitol (Patent Document 4) are known.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

[0005] [Non-Patent Document 1] Drug Interview Form for "Nexium (registered trademark) Capsules 10 mg, 20 mg", Revised in June 2024 (16th Revision) [Summary of the Invention] [Problems to be Solved by the Invention]

[0006] The present invention relates to an esomeprazole-containing particulate composition suitable for the production of esomeprazole enteric-coated tablets excellent in drug content uniformity, acid resistance, and stability. [Means for Solving the Problems]

[0007] The present inventors have found that a particulate composition in which particulate poorly soluble saccharides are supported on the surface of enteric particles having a drug core containing esomeprazole, an intermediate layer, and an enteric layer is useful for the production of esomeprazole enteric-coated tablets in which content uniformity, acid resistance, and stability are ensured.

[0008] That is, the present invention relates to the following (1) to (15). (1) An esomeprazole-containing particulate composition obtained by supporting particulate poorly soluble saccharides on the surface of esomeprazole enteric particles containing (a) an esomeprazole-containing drug core, (b) an intermediate layer, and (c) an enteric layer. (2) The composition according to (1), wherein the average particle diameter of the poorly soluble saccharides is 20 to 300 μm. (3) The composition according to (1), which contains 50 to 500 parts by mass of poorly soluble saccharides with respect to 100 parts by mass of esomeprazole enteric particles. 4) The composition of 1), wherein the poorly soluble saccharide is at least one selected from D-mannitol, erythritol, and lactose. 5) The composition of 1), wherein the poorly soluble saccharide is D-mannitol. 6) The composition of 5), wherein the crystalline content of D-mannitol is 5 to 40% by mass of β-type crystals and 5 to 40% by mass of α-type crystals with respect to the whole D-mannitol. 7) The composition of 1), wherein the average particle diameter of the particulate composition is 400 to 2000 μm. 8) The composition of 1), wherein the enteric coating layer contains at least one selected from copolymers of methacrylic acid LD, macrogol, glycerol monostearate, polysorbate 80, and triethyl citrate. 9) The composition of 1), wherein the intermediate layer contains at least one selected from hydroxypropyl cellulose, hypromellose, talc, titanium oxide, and magnesium stearate. 10) An esomeprazole enteric-coated tablet containing the composition, disintegrant, and lubricant according to 1) to 9). 11) The composition of 10), wherein the disintegrant is at least one selected from crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium, and sodium carboxymethyl starch. 12) The composition of 10), wherein the lubricant is at least one selected from magnesium stearate, calcium stearate, and talc. 13) A method for producing the esomeprazole-containing particulate composition of 1), comprising a step of spraying a binder-containing solution onto a mixture of the esomeprazole enteric-coated particles and the poorly soluble saccharide, and a step of removing the solvent. 14) A method for producing an esomeprazole enteric-coated tablet, comprising a step of mixing a disintegrant and a lubricant with the esomeprazole-containing particulate composition of 1), and a step of compression molding. 15) The method according to 14), wherein the compression molding is performed at 35 to 50 °C.

Advantages of the Invention

[0009] According to the present invention, an esomeprazole enteric-coated tablet with ensured content uniformity, acid resistance, and stability of esomeprazole can be produced.

Brief Description of the Drawings

[0010]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Mode for Carrying Out the Invention

[0011] The esomeprazole-containing particulate composition of the present invention has a structure in which particulate poorly water-soluble saccharides are supported on the surface of enteric-coated esomeprazole particles. The average particle diameter of the particulate composition is, for example, 400 to 2000 μm, preferably 500 to 1400 μm, more preferably 600 to 1100 μm. In the present invention, the average particle diameter is the median diameter (D50) based on volume unless otherwise specified, and can be measured using a dry laser diffraction / scattering particle size distribution measuring device. The SEM photograph thereof is shown in Fig. 1, and the schematic diagram thereof is shown in Fig. 5. Such a structure is different from granules having an outermost layer of poorly water-soluble saccharide particles formed by spraying a solution of poorly water-soluble saccharides onto enteric-coated particles.

[0012] The esomeprazole-containing particulate composition of the present invention is a composition useful for producing an enteric-coated solid pharmaceutical preparation containing esomeprazole, particularly an enteric-coated tablet. When the esomeprazole-containing particulate composition is tabletted, in addition to preventing damage to the enteric layer and the intermediate layer in the particulate composition, it has the function of maintaining the content uniformity of esomeprazole tablets. The prevention of damage to the enteric layer and the intermediate layer during tabletting is due to the low-solubility saccharide particles supported on the enteric esomeprazole particles. When stress is applied to the particulate composition by compression during tabletting, the low-solubility saccharide particles are broken and peeled off to fill the voids, thereby dispersing the stress. In addition, the improvement in content uniformity when manufacturing tablets is because the components mixed during mixing and tabletting are uniformly mixed and do not segregate. This is considered to be because the particles of the esomeprazole-containing particulate composition are particularly large, and additives such as binders, lubricants, and fluidizing agents are relatively small.

[0013] <Enteric esomeprazole particles> The enteric esomeprazole particles of the present invention are composed of (a) a drug core containing esomeprazole, (b) an intermediate layer, and (c) an enteric layer. It has an intermediate layer (b) as a continuous layer outside the drug core (a) containing esomeprazole, and further has an enteric layer (c) as a continuous layer outside that. The average particle diameter of the enteric esomeprazole particles is 0.3 to 1.5 mm, preferably 0.4 to 1 mm, and more preferably 0.5 to 0.8 mm.

[0014] (a) Drug core containing esomeprazole In the present invention, the drug core containing esomeprazole means a drug core containing esomeprazole as an active ingredient. Specifically, drug cores containing esomeprazole or its salts, or their hydrates can be mentioned. Preferably, drug cores containing esomeprazole magnesium hydrate, more preferably drug cores containing esomeprazole magnesium trihydrate can be mentioned. Esomeprazole or its salts, or their hydrates can be produced, for example, by the production methods described in Japanese Patent No. 3549111, Japanese Patent No. 3635432, and Japanese Patent No. 4002303. For example, esomeprazole magnesium hydrate with a volume average particle size (D90) of 0.1 μm or more and 50 μm or less, preferably 0.5 μm or more and 30 μm or less, more preferably 1 μm or more and 10 μm or less can be used. The volume average particle size (D90) can be measured by a laser diffraction particle size distribution measurement method using a laser diffraction / scattering particle size distribution analyzer (SALD-2300 type, manufactured by Shimadzu Corporation) or the like.

[0015] The drug core containing esomeprazole includes a granulated product provided with a layer containing esomeprazole or a salt thereof, which is an active ingredient, or a hydrate thereof on the outer periphery of the core particles, or a core granulated product formed from esomeprazole or a salt thereof, or a hydrate thereof and an additive that can be used. Among these, a granulated product provided with a layer containing esomeprazole magnesium hydrate, which is an active ingredient, on the outer periphery of the core particles is preferred. The average particle size of these drug cores is 100 to 1000 μm, preferably 200 to 800 μm, more preferably 200 to 600 μm. The content of esomeprazole in the drug core is 20 to 90% by mass, preferably 30 to 80% by mass, more preferably 35 to 75% by mass, still more preferably 50 to 70% by mass based on the total mass of the drug core.

[0016] The core particles used in the drug layer are not particularly limited as long as they do not interact with esomeprazole and other additives. For example, sucrose·starch spherical granules, refined sucrose granules, lactose·crystalline cellulose spherical granules (Shugrets (product name): manufactured by Karakon Co., Ltd., Nonpareil (registered trademark): manufactured by Freund Industry Co., Ltd.), crystalline cellulose (Celluia (registered trademark): manufactured by Asahi Kasei Corporation), and inert carriers such as spherical D-mannitol can be mentioned. The average particle size of the core particles can be selected in the range of 100 to 1000 μm, preferably 150 to 700 μm, more preferably 200 to 500 μm.

[0017] To obtain a drug core with a layer containing esomeprazole on the nuclear particles, for example, esomeprazole or its salt, or their hydrates are dissolved or dispersed in a solution of water, methanol, ethanol, propanol, butanol, acetone, hexane and their mixtures containing binders described below, and this is sprayed onto the core of the inert carrier and then dried to coat it. The solvent to be used is preferably water or ethanol. The manufacturing apparatus is not particularly limited, and for example, a fluidized bed granulator, a centrifugal rolling granulator, a rolling granulator, etc. can be used. The layer thickness of the formed coating layer is 20 - 200 μm, preferably 50 - 140 μm, more preferably 70 - 120 μm.

[0018] When not using nuclear particles, granulated products granulated with a stirring granulator, a wet extrusion granulator, a fluidized bed granulator, a centrifugal rolling granulator, a rolling granulator, a spray dryer, etc. using esomeprazole or its salt, or their hydrates, and excipients, binders, etc. described below are used as the drug core. The obtained granulated products can select particles of a desired size by a sieving operation. The drug core may be prepared by dry granulation using a roller compactor or the like.

[0019] In addition to nuclear particles, binders and excipients, surfactants can be added to improve the elution property of esomeprazole, and basic inorganic salts can be added for the stability of esomeprazole to the drug core. As the binders, excipients and surfactants, those described below can be used. The basic inorganic salts are salts of alkali metals, alkaline earth metals and ammonia, for example, magnesium aluminometasilicate, magnesium aluminosilicate, magnesium carbonate, magnesium hydroxide, magnesium oxide, calcium silicate, talc, sodium phosphate and sodium hydrogen phosphate, and preferably magnesium aluminometasilicate, magnesium aluminosilicate and magnesium oxide.

[0020] (b) Intermediate layer The intermediate layer is provided to separate the drug core and the enteric layer so that they do not come into direct contact. The enteric coating base of the present invention is acidic at about pH 2 to 4 and is likely to produce decomposition products when in contact with esomeprazole. In the intermediate layer, pharmaceutical additives such as binders, disintegrants, excipients, plasticizers, lubricants, fluidizing agents, light-shielding agents, coloring agents, coating agents, etc., which will be described later, can be used in appropriate combinations, but usually, it is preferable to use a binder, a lubricant, and a fluidizing agent. As the binder, it is preferable to use hydroxypropyl cellulose or hypromellose, and as the lubricant, it is preferable to use talc or magnesium stearate as the lubricant. The intermediate layer can have a two-layer structure including an intermediate layer containing at least a binder and a light-shielding layer containing at least a coloring agent.

[0021] The intermediate layer can be formed in the range of 50 to 400 parts by mass, preferably 50 to 200 parts by mass, and more preferably 100 to 150 parts by mass with respect to 100 parts by mass of esomeprazole. The amount of the coating agent used in the intermediate layer can be used in the range of 1 to 99% by mass with respect to the total amount of the intermediate layer, and the amount of the binder used in the intermediate layer can be used in the range of 5 to 30% by mass with respect to the total amount of the intermediate layer. For other additives, they can be appropriately adjusted and used within the range that does not impair the effects of the present invention.

[0022] The method for forming the intermediate layer may be the same as the drug coating of the core particles in the drug core of (a). Specifically, a solution or dispersion obtained by dissolving or dispersing the above-mentioned pharmaceutical additives for the intermediate layer in an appropriate solvent such as the above-mentioned water or lower alcohol is sprayed onto the drug core and dried to form the desired intermediate layer. There is no particular limitation on the layer thickness of the intermediate layer, but if it is too thin, the expected effect cannot be fully exerted, and if the thickness is more than necessary, the particle size of the particles will increase, and there are concerns such as a decrease in tablet hardness. Therefore, it is 2 to 30 μm, preferably 5 to 15 μm, and more preferably 7 to 13 μm.

[0023] (c) Enteric layer Examples of enteric coating bases for forming an enteric layer include: 1) enteric methacrylic acid copolymers such as methacrylic acid copolymer LD, methacrylic acid copolymer L, methacrylic acid copolymer S, and methyl acrylate-methyl methacrylate-methacrylic acid copolymer; 2) enteric cellulose-based polymers such as hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, and carboxymethyl ethylcellulose; and 3) enteric vinyl alcohol-based polymers such as polyvinyl alcohol acetate phthalate. Among these, methacrylic acid copolymers are preferably used, more preferably methacrylic acid copolymer LD, methacrylic acid copolymer L, and methacrylic acid copolymer S, and even more preferably methacrylic acid copolymer LD. These enteric coating bases can be used by blending one type or two or more types. The use of these enteric polymers may be one type or a blend of two or more types, but preferably one type.

[0024] Pharmaceutical additives described below, such as plasticizers, lubricants, fluidizing agents, surfactants, coloring agents, light-shielding agents, excipients, pH adjusters, and coating agents, can be incorporated into the enteric layer. Examples of plasticizers that can be used include polyethylene glycol, triacetin, triethyl citrate, and glycerin monostearate. Triethyl citrate and polyethylene glycol are preferred.

[0025] The enteric layer can be formed in the range of 100 to 400 parts by mass, preferably 100 to 300 parts by mass, and more preferably 120 to 200 parts by mass with respect to 100 parts by mass of esomeprazole. The amount of the enteric coating base used in the enteric layer can be in the range of 50 to 99% by mass based on the total amount of the enteric layer, and the amount of the binder used in the enteric layer can be in the range of 70 to 90% by mass based on the total amount of the enteric layer. For other additives, appropriate adjustment and use can be made within a range that does not impair the effects of the present invention.

[0026] Regarding the method for forming the enteric layer, it may be the same as the drug coating of the core particles in the above drug core. Specifically, an enteric coating base and pharmaceutical additives such as the above plasticizer are dissolved or dispersed in a suitable solvent such as the above water or lower alcohol to obtain a solution or dispersion, which is then sprayed onto the drug core provided with an intermediate layer and dried to form the desired enteric layer. The layer thickness of the formed enteric layer is 20 to 150 μm, preferably 50 to 120 μm, more preferably 70 to 100 μm.

[0027] <Esomeprazole-containing particulate composition> The esomeprazole-containing particulate composition of the present invention is formed by supporting particulate poorly soluble saccharides on the surface of the above esomeprazole enteric particles. Examples of the poorly soluble saccharides used here include saccharides having a solubility in water of 30 g or less, such as D-mannitol, lactose, and erythritol, and preferably D-mannitol. Any crystalline form of the poorly soluble saccharide may be used, but those having multiple crystalline forms or amorphous forms are preferred, and crystalline or granulated products of the poorly soluble saccharide can be used. For example, for lactose, it is lactose containing amorphous, and for D-mannitol, it is D-mannitol containing any one or more of β-type crystals, α-type crystal amorphous, and amorphous. More preferably, it is D-mannitol containing α-type crystals, β-type crystals, and amorphous. With respect to the total amount of D-mannitol, the β-type crystals are 5 to 40% by mass, preferably 10 to 25% by mass, the α-type crystals are 5 to 40% by mass, preferably 10 to 30% by mass, and the amorphous is 40 to 80% by mass, preferably 50 to 70% by mass. The ratios of the α-type crystals, β-type crystals, and amorphous of D-mannitol can be determined from the characteristic peaks using α-type crystals and β-type crystals as standards by X-RD, for example, the intensity of the

[0120] plane. In addition, for the poorly soluble saccharides, those having an average particle diameter of the particles of, for example, 20 to 300 μm, preferably 50 to 250 μm, more preferably 100 to 200 μm are preferably used.

[0028] In the esomeprazole-containing particulate composition of the present invention, the content of the poorly water-soluble saccharide particles is preferably 50 to 500 parts by mass, more preferably 60 to 300 parts by mass, and even more preferably 100 to 200 parts by mass with respect to 100 parts by mass of the esomeprazole enteric-coated particles, from the viewpoints of ensuring the effect of preventing the breakage of the enteric layer during tableting and preventing the enlargement of the formulation size.

[0029] The esomeprazole-containing particulate composition can be produced by putting esomeprazole enteric-coated particles and particulate poorly water-soluble saccharides into a granulator such as a fluidized bed granulator, spraying a solution containing a binder, and further, if necessary, a light-shielding agent, a coloring agent, etc. for granulation, classifying after drying. In addition, in the binder solution, in order to improve the adhesion of the particulate poorly water-soluble saccharides to the surface of the esomeprazole enteric-coated particles by granulation, a poorly water-soluble saccharide having the same components as the particulate poorly water-soluble saccharides used for granulation can also be added. In addition to the fluidized bed granulation method such as rolling fluidized bed granulation and fluidized granulation, granulation can employ a rolling granulation method such as a centrifugal rolling granulation method, a stirring granulation method, etc., but preferably fluidized bed granulation. Also, the spraying of the binder solution can be carried out with the same apparatus and conditions as the film formation of the enteric-coated particles. In order to improve the adhesion of the poorly water-soluble saccharide particles, a method of shortening the distance from the solution nozzle to the particles or a method of dispersing the particles during the solution spraying is preferable. For example, in the fluidized bed granulation method, it can be produced by side spraying or a Wurster-type apparatus.

[0030] The esomeprazole-containing particulate composition of the present invention is appropriately formulated into solid preparations such as tablets, orally disintegrating tablets, granules, fine granules, chewable tablets, and capsules, but preferably tablets. These solid preparations can be produced by generally known methods.

[0031] When producing a tablet (enteric-coated tablet) using the esomeprazole-containing particulate composition of the present invention, it can be produced by mixing the esomeprazole-containing granular composition with pharmaceutical additives such as an excipient, a lubricant, a plasticizer, a binder, a disintegrant, a fluidizing agent, a surfactant, a light-shielding agent, a pH adjuster, a coloring agent, an antistatic agent, etc. and compression molding with a tableting machine.

[0032] Here, mixing can be carried out by generally used mixing methods, such as mixing, kneading, granulation, etc. Mixing can be carried out using, for example, a high-speed stirring mixer, a universal kneader, a fluidized bed granulator, a V-type mixer, a tumbler mixer, a double cone mixer, a ribbon-type mixer, a rotary screw-type mixer, manual mixing in a bag, etc.

[0033] Compression molding can be carried out using a rotary tablet press or the like commonly used for pharmaceuticals. The molding pressure during tablet pressing varies depending on the size of the tablet. For example, for a φ10 mm tablet, it is 2 - 10 kN, preferably 3 - 9 kN, and for a φ8.5 mm tablet, it is 2 - 6 kN, preferably 3 - 5 kN. At this time, the set hardness is 30 - 100 N, preferably 40 - 90 N, more preferably 40 - 80 N.

[0034] By heating the tablet powder to a specific temperature during compression molding, the plasticity of the enteric coating layer can be improved, and breakage due to the stress of compression molding can be prevented. The temperature of the tablet powder is 30 - 65°C, preferably 35 - 49°C, more preferably 40 - 48°C. As the manufacturing apparatus, it may be heated so that the temperature of the tablet powder on the turntable is within the above-mentioned range, and the heating method such as heating the turntable itself, heating in the hopper, or heating the entire tablet press may be appropriately selected.

[0035] Pharmaceutical additives (for example, excipients, lubricants, plasticizers, binders, disintegrants, fluidizing agents, surfactants, light-shielding agents, pH adjusters, colorants, antistatic agents) used in the production of the esomeprazole-containing particulate composition of the present invention or solid preparations produced using the same are specifically as follows. Lubricants: For example, talc, glycerin monostearate, macrogol, magnesium stearate, calcium stearate, or sodium stearyl fumarate, preferably talc, glycerin monostearate, magnesium stearate, calcium stearate, or sodium stearyl fumarate, and most preferably magnesium stearate.

[0036] Plasticizer: For example, polyethylene glycol (e.g., polyethylene glycol 400, polyethylene glycol 4000, polyethylene glycol 6000, etc.), triethyl citrate, glycerin, castor oil, polyoxyethylene hydrogenated castor oil, polysorbate 80, macrogol, lauromacrogol, triacetin, etc. are mentioned, and triethyl citrate is preferred.

[0037] Binder: For example, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, polyvinyl alcohol, macrogol, pluronic (registered trademark) F68, gum arabic, gelatin, starch, etc. are mentioned. Preferably, hydroxypropyl methylcellulose, hydroxypropyl cellulose, and methylcellulose are mentioned, and more preferably, hydroxypropyl methylcellulose and hydroxypropyl cellulose are mentioned.

[0038] Disintegrant: For example, starches such as corn starch and potato starch, partially α - gelatinized starch, sodium carboxymethyl starch, carmellose, carmellose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropylpropyl cellulose, crystalline cellulose, hydroxypropyl starch, etc. are mentioned.

[0039] Glidant: For example, talc, hydrated silicon dioxide, light anhydrous silicic acid, magnesium aluminometasilicate, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium aluminum hydroxide, stearic acid, calcium stearate, and magnesium stearate, etc. are mentioned.

[0040] Surfactants: For example, polyoxyethylene sorbitan fatty acid esters (polysorbates) such as polysorbate 80; polyoxyethylene polyoxypropylene glycols such as poloxamer; macrogols such as polyethylene glycol with a weight average molecular weight of 300 to 6000; polyoxyethylene hydrogenated oils such as pluronic (registered trademark), polyoxyethylene hydrogenated castor oil; glycerin fatty acid esters such as glycerin monostearate; sorbitan fatty acid esters such as sorbitan monostearate, sorbitan monolaurate; sucrose fatty acid esters such as sucrose laurate; fatty acid metal salts such as sodium lauryl sulfate, etc. Preferably, it is a polyoxyethylene sorbitan fatty acid ester such as polysorbate 80.

[0041] Sunblock agents: For example, titanium oxide, zinc oxide, talc, yellow ferric oxide, ferric oxide, black ferric oxide, etc., food yellow No. 5, food red No. 102, etc. Preferably, titanium oxide is mentioned.

[0042] pH adjusters: For example, acids such as succinic acid, maleic acid, tartaric acid, citric acid, aspartic acid, etc., alkalis such as sodium hydroxide, ammonia, magnesium oxide, silicon dioxide, sodium hydrogen carbonate, etc.

[0043] Colorants: For example, food blue No. 1, food blue No. 2, food yellow No. 4, food red No. 2, food red No. 3, food blue No. 1 aluminum lake, food blue No. 2 aluminum lake, food red No. 2 aluminum lake, ferric oxide (red), titanium oxide, yellow ferric oxide, caramel, talc, etc.

[0044] Antistatic agents: For example, silicon dioxide (including hydrated silicon dioxide), anhydrous silicon, talc, titanium oxide, stearic acid, magnesium stearate, calcium stearate.

[0045] Coating agents: For example, talc, magnesium oxide, polysorbate 80, magnesium stearate, etc.

[0046] The following shows an example of the process for manufacturing the esomeprazole-containing particulate composition of the present invention and the process for manufacturing esomeprazole enteric-coated tablets from the particulate composition. In each process, drying can be carried out as necessary, and it can be carried out by any method used for general pharmaceutical drying, such as fluidized bed drying, shelf drying, vacuum drying, etc. (Step 1: Formation of drug core) Nuclear particles such as sucrose-starch spherical granules are put into a granulator such as a fluidized bed granulator, and a drug layer spray solution of esomeprazole magnesium hydrate (esomeprazole magnesium hydrate, purified water, binder such as hypromellose, etc.) is sprayed for layering and dried to obtain a drug core. Subsequently, after additional drying is carried out as desired, classification is carried out by passing through a sieve. (Step 2: Formation of intermediate layer) The drug layer produced in the first step is put into a granulator such as a fluidized bed granulator, and an intermediate layer spray solution (purified water, binder such as hypromellose, coating agent such as talc, etc.) is sprayed and dried to form an intermediate layer. Subsequently, after additional drying is carried out as desired, classification is carried out by passing through a sieve. (Step 3: Formation of enteric layer) The granular material produced in the second step is put into a granulator such as a fluidized bed granulator, and an enteric layer spray solution (methacrylic acid copolymer LD, purified water, plasticizer such as glycerol monostearate, surfactant, etc.) is sprayed and dried to form an enteric layer. Subsequently, after additional drying is carried out as desired, classification is carried out by passing through a sieve. (Step 4: Manufacture of particulate composition) The esomeprazole enteric-coated particles produced in the third step and particulate poorly water-soluble saccharides such as D-mannitol are put into a granulator such as a fluidized bed granulator, and a spray solution (containing excipient, purified water, binder, etc.) is sprayed and granulated laterally. Subsequently, after drying, classification is carried out by passing through a sieve to obtain a particulate composition in which particulate poorly water-soluble saccharides are supported on the surface of the esomeprazole enteric-coated particles. (Step 5: Tableting) The particulate composition produced in the fourth step, disintegrant, lubricant, etc. are put into a V-type mixer and mixed, and tablets are obtained by heating and tableting with a tableting machine such as a rotary tableting machine.

Example

[0047] An example of the production method of the granulated particles of esomeprazole and esomeprazole tablets according to the present invention is shown below, but this description is only an example and is not limited thereto.

[0048] (Reference Example) The D-mannitol and β-form crystalline D-mannitol used in the examples were measured by XRD. The results are shown in C and D of FIG. 4. The ratios of the β-form crystal, α-form crystal, and amorphous of D-mannitol used in the examples were 15%, 22%, and 63%, respectively.

[0049] Example 1 (Production of Esomeprazole-Containing Particulate Composition) 24 parts by mass of sucrose-starch spherical granules were placed in a fluidized bed granulator, and a drug dispersion solution of 22.27 parts by mass of esomeprazole magnesium trihydrate, 5 parts by mass of hypromellose, and 0.8 part by mass of polysorbate 80 was sprayed and dried at an exhaust temperature of about 40°C to produce drug core particles. 26.04 parts by mass of the drug core particles were placed in a fluidized bed granulator, and an intermediate layer dispersion solution of 5 parts by mass of hydroxypropylcellulose, 10 parts by mass of talc, 1 part by mass of magnesium stearate, and 2 parts by mass of titanium oxide was sprayed and dried at an exhaust temperature of about 40°C to produce intermediate layer particles. 26.42 parts by mass of the intermediate layer particles were placed in a fluidized bed granulator, and an enteric-coated layer dispersion solution of 40 parts by mass of methacrylic acid copolymer LD, 1.28 parts by mass of glyceryl monostearate, 0.096 part by mass of polysorbate 80, and 21 parts by mass of purified water was sprayed and dried at an exhaust temperature of about 40°C to produce enteric-coated particles. 18.68 parts by mass of the enteric-coated particles and 18.68 parts by mass of D-mannitol were placed in a fluidized bed granulator, and a granulation dispersion solution of 2 parts by mass of hydroxypropylcellulose and 0.028 part by mass of ferric sesquioxide was spray-dried laterally at an exhaust temperature of about 40°C to produce granulated particles (particulate composition) with a particle diameter of about 600 μm. The XRD pattern of the enteric-coated particles is shown in B of FIG. 3, and the XRD pattern of the particulate composition is shown in A of FIG. 3. It was confirmed that the D-mannitol in the particulate composition contained α-form, β-form, and amorphous forms.

[0050] Example 2 (Manufacture of Esomeprazole Enteric-coated Tablets) 68.5 parts by mass of the particulate composition produced in Example 1, 0.6 part by mass of crospovidone, 0.3 part by mass of light anhydrous silicic acid, and 0.6 part by mass of magnesium stearate were mixed to obtain a mixed powder. Using a rotary tablet press, the mixed powder was heated to about 42°C and tableted under the conditions of a rotation speed of 30 rpm, a pestle shape of 9.5 mm φ-R13.5, and a set hardness of 20 N to produce 300 mg esomeprazole enteric-coated tablets.

[0051] Example 3 (Manufacture of Esomeprazole-containing Particulate Composition) 18 parts by mass of sucrose-starch spherical granules were placed in a fluidized bed granulator, and a drug dispersion solution of 22.27 parts by mass of esomeprazole magnesium trihydrate, 4.2 parts by mass of hypromellose, 0.4 part by mass of polysorbate 80, and 0.28 part by mass of magnesium oxide was spray-dried at an exhaust temperature of about 40°C to produce drug core particles. 45.15 parts by mass of the drug core particles were placed in a fluidized bed granulator, and an intermediate layer dispersion solution of 6 parts by mass of hydroxypropylcellulose, 16 parts by mass of talc, 1.2 parts by mass of magnesium stearate, and 4 parts by mass of titanium oxide was spray-dried at an exhaust temperature of about 40°C to produce intermediate layer particles. 74.15 parts by mass of the intermediate layer particles were placed in a fluidized bed granulator, and an enteric layer dispersion solution of 32 parts by mass of methacrylic acid copolymer LD, 3 parts by mass of macrogol 6000, 3.2 parts by mass of glyceryl monostearate, and 0.32 part by mass of polysorbate 80 was spray-dried at an exhaust temperature of about 40°C to produce enteric particles. 110.87 parts by mass of the enteric particles and 166.33 parts by mass of D-mannitol were placed in a fluidized bed granulator, and a granulation dispersion solution of 16 parts by mass of hydroxypropylcellulose and 0.28 part by mass of ferric sesquioxide was spray-dried from the side at an exhaust temperature of about 40°C to produce granulated particles (particulate composition) with a particle diameter of about 600 μm.

[0052] Example 4 (Manufacture of Esomeprazole Enteric-coated Tablets) 295.28 parts by mass of the particulate composition produced in Example 3, 2 parts by mass of crospovidone, 1 part by mass of light anhydrous silicic acid, and 2 parts by mass of magnesium stearate were mixed to obtain a mixed powder. Using a rotary tableting machine, the mixed powder was heated to about 42°C and tableted under the conditions of a rotation speed of 30 rpm, a pestle shape of 9.5 mm φ - R13.5, and a set hardness of 20 N to produce 300 mg of esomeprazole enteric-coated tablets.

[0053] Comparative Example 1 217.74 parts by mass of the enteric-coated particles of Example 1, 155.85 parts by mass of mannitol, 4 parts by mass of crospovidone, 2 parts by mass of light anhydrous silicic acid, and 4 parts by mass of magnesium stearate were mixed, and using a rotary tableting machine, tableting was carried out under the conditions of a rotation speed of 30 rpm, a pestle shape of 9.5 mm φ - R13.5, and a set hardness of 20 N to produce esomeprazole enteric-coated tablets.

[0054] Comparative Example 2 108.87 parts by mass of the enteric-coated particles of Example 3 were put into a fluidized bed granulator, and at an exhaust temperature of about 40°C, the outermost layer solution of 9.47 parts by mass of D-mannitol was sprayed and dried to produce mannitol-coated particles. 236.68 parts by mass of these mannitol-coated particles, 353.3 parts by mass of mannitol, 4 parts by mass of crospovidone, 2 parts by mass of light anhydrous silicic acid, and 4 parts by mass of magnesium stearate were mixed, and using a rotary tableting machine, tableting was carried out under the conditions of a rotation speed of 30 rpm, a pestle shape of 9 mm φ - R13.5, and a set hardness of 20 N to produce 600 mg of esomeprazole enteric-coated tablets.

[0055] (Content Uniformity Test) It was measured according to the content uniformity test method of the Japanese Pharmacopoeia.

[0056] (Acid Resistance Test) According to the method of Dissolution Test 1 solution of the Japanese Pharmacopoeia, using the paddle method, under the condition of a rotation speed of 50 rpm, the dissolution rate of the drug after 2 hours was measured.

[0057] [Table 1]

[0058] (Stability Test) The tablets were kept under sealed conditions at 50 °C and 75% RH, and the content and related substances were measured. Since the tablets of Comparative Example 1 and Comparative Example 2 had insufficient content uniformity, the stability test was not carried out.

[0059]

Table 2

[0060] The esomeprazole enteric-coated tablets of Example 2 and Example 4 with granulation were superior in content uniformity and acid resistance compared to the esomeprazole enteric-coated tablets of Comparative Example 1 and Comparative Example 2 without granulation. In addition, the esomeprazole enteric-coated tablets of Example 2 and Example 4 had no increase in related substances and no decomposition due to the contact between the drug and the enteric solvent, and were excellent in stability.

[0061] From the results of content uniformity, it can be seen that the enteric granules and other pharmaceutical additives were uniformly mixed and tabletted by granulation with D-mannitol in Example 2 and Example 4. On the other hand, in Comparative Example 1 and Comparative Example 2, since the particle sizes of the enteric granules, D-mannitol and other pharmaceutical additives, especially D-mannitol, were different and they were not uniformly mixed, there was a problem with content uniformity. The acid resistance test is a test to confirm that the enteric layer is not damaged by the load such as tabletting. Example 1 and Example 2 had sufficiently low values, indicating that the enteric layer was not damaged. On the other hand, Comparative Example 1 and Comparative Example 2 showed higher values, indicating that the enteric layer was damaged. The stability test is a test to confirm that the intermediate layer is not damaged by the load such as tabletting. Esomeprazole generates related substances when it comes into contact with the acidic methacrylic acid copolymer LD in the enteric layer. Since the intermediate layer of Example 2 and Example 4 was not damaged, there was almost no increase in related substances. On the other hand, Comparative Example 1 and Comparative Example 2 showed higher values, indicating that the enteric layer was damaged.

[0062] Formulation Example 1 A particulate composition of esomeprazole is produced in the same manner as in Example 1 except that D-mannitol is changed to granulated lactose. Then, an enteric-coated tablet of esomeprazole is produced in the same manner as in Example 2 except that this particulate composition is used.

Claims

1. An esomeprazole-containing particulate composition comprising an esomeprazole enteric particle comprising (a) an esomeprazole-containing drug core, (b) an intermediate layer, and (c) an enteric layer, and a particulate low-solubility saccharide is supported on the surface of the esomeprazole enteric particle.

2. 2. The composition according to claim 1, wherein the low-solubility saccharide has an average particle size of 20 to 300 μm.

3. The composition according to claim 1, comprising 50 to 500 parts by mass of a low-solubility saccharide per 100 parts by mass of the esomeprazole enteric particles.

4. 2. The composition according to claim 1, wherein the low-solubility saccharide is one or more selected from the group consisting of D-mannitol, erythritol and lactose.

5. 2. The composition according to claim 1, wherein the low-solubility saccharide is D-mannitol.

6. The composition according to claim 5, wherein the crystalline content of D-mannitol is 5 to 40% by mass of β-type crystals and 5 to 40% by mass of α-type crystals based on the total amount of D-mannitol.

7. The composition according to claim 1, wherein the particulate composition has an average particle size of 400 to 2000 μm.

8. 2. The composition of claim 1, wherein the enteric layer comprises one or more selected from methacrylic acid copolymer LD, macrogol, glyceryl monostearate, polysorbate 80, and triethyl citrate.

9. 2. The composition of claim 1, wherein the intermediate layer comprises one or more selected from the group consisting of hydroxypropyl cellulose, hypromellose, talc, titanium oxide, and magnesium stearate.

10. An enteric coated tablet of esomeprazole comprising the composition according to claims 1 to 9, a disintegrant and a lubricant.

11. The composition of claim 10, wherein the disintegrant is one or more selected from the group consisting of crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium and sodium carboxymethyl starch.

12. The composition of claim 10, wherein the lubricant is one or more selected from magnesium stearate, calcium stearate and talc.

13. The method for producing the esomeprazole-containing particle composition according to claim 1 , comprising the steps of spraying a binder-containing solution onto the mixture of the esomeprazole enteric-coated particles and the low-solubility saccharide, and removing the solvent.

14. A method for producing an esomeprazole enteric coated tablet, comprising the steps of mixing the esomeprazole-containing granular composition according to claim 1 with a disintegrant and a lubricant, and compressing the mixture.

15. The method according to claim 14, wherein the compression molding is carried out at 35 to 50°C.

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