JP2022024336A - Functional pharmaceutically effective particles and method for producing the same, and orally disintegrating tablet - Google Patents

Abstract

To provide pharmaceutically effective particles in which occurrence of a crack in a tablet itself can be suppressed even if tableting is performed in order to prepare an orally disintegrating tablet.SOLUTION: Pharmaceutically effective particles that are formed of: a spherical core part including a pharmaceutically effective component; and a coating part which coats the spherical core part, and includes a release control layer and an outermost layer including mannitol, in which a ratio of mannitol included in the outermost layer is adjusted to 4 mass% or more in the pharmaceutically effective particles. As the coating part, a first shielding layer, a second shielding layer, a first enteric layer, a middle layer, a second enteric layer and the outermost layer may be sequentially laminated on the spherical core part. The pharmaceutically effective particles and rapidly disintegrating particles may be combined to prepare an orally disintegrating tablet. The rapidly disintegrating particles include sugar alcohol and carmellose, and a ratio of crystalline cellulose may be less than 1 mass% in the particles.SELECTED DRAWING: None

Description

The present invention relates to functional medicinal particles for preparing an orally disintegrating tablet, a method for producing the same, and an orally disintegrating tablet containing the particles.

Orally disintegrating tablets (OD tablets) are designed to release medicinal properties in the gastrointestinal tract and are designed to be taken by patients, the elderly, and children who have difficulty swallowing. A tablet designed to disintegrate. This OD tablet is usually prepared by a method in which the medicinal effect component is coated with a functional coating layer, and the medicinal effect-containing particles are mixed with other components including an excipient or the like and compressed and tableted. However, since OD tablets are required to be disintegrating in the oral cavity, it is difficult to maintain the mechanical properties of the tablets, and damage due to tableting is likely to occur. In particular, when the functional coating layer is an enteric layer (enteric coating layer), the number of layers increases, so that the functional coating layer becomes hard and tableting failure is likely to occur. The following solid preparations and the like are known as solid preparations in which the tableting disorder is suppressed.

Japanese Patent Application Laid-Open No. 3-240723 (Patent Document 1) describes capping in which the surface of the upper die side of the tablet is peeled off at the time of tableting, and tableting disorders such as hitting and squeaking where the raw material pharmaceutical powder adheres to the punch and the mortar. As a tablet in which the amount of the drug is suppressed, a tablet containing granules for tableting in which fine granules containing a drug are liquid-coated with an aqueous lactose suspension is disclosed. Mannitol is exemplified in this document as a drug having a tableting disorder.

According to Japanese Patent No. 5366558 (Patent Document 2), a pharmaceutical product in which a part of the fine-grained coating film contained in the pharmaceutical product is destroyed at the time of tableting to suppress the masking effect of bitterness and the decrease in acid resistance. The outermost layer of the fine granules is coated with a coating layer containing hydroxypropylmethylcellulose and low-substituted hydroxypropylcellulose, and the orally disintegrating solid preparation containing the fine granules A in which the release of the pharmaceutically active ingredient is controlled is obtained. It has been disclosed. This document also discloses an orally disintegrating solidity in which the fine granules A and the fine granules B having a release rate of a pharmaceutically active ingredient different from the fine granules A are combined. , It is described that mannitol may be overcoated for the purpose of improving the strength of the orally disintegrating tablet. In the example, as the fine granules B, 260 mg of enteric fine granules containing 7.63 g of the methacrylic acid copolymer LD are overcoated with 10 mg of mannitol.

According to Japanese Patent No. 6440313 (Patent Document 3), it is effective as a laminated tablet in which tableting disorders such as binding that causes scratches on the side surface of the tablet and picking in which at least one convex portion of the tablet is peeled off from the hat tablet are suppressed. The layer containing the components contains an acid suppressant and one or more disintegrants selected from lactose, mannitol and sorbitol, and one or more disintegrants selected from low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose and sodium croscarmellose. Laminated tablets coated with a containing layer are disclosed.

Japanese Unexamined Patent Publication No. 3-240723 Japanese Patent No. 5366558 Japanese Patent No. 6440313

The present inventors have obtained it when preparing an orally disintegrating tablet by mixing and tableting functional medicinal particles coated with an enteric layer and fast-disintegrating particles containing no medicinal component. It was noticed that cracks were generated on the side surface of the orally disintegrating tablet itself along a direction substantially perpendicular to the thickness direction. Although the cause of such cracks is not clearly known, the functional medicinal particles coated with the enteric layer are hard and difficult to plastically deform, so that voids are likely to occur around the functional medicinal particles. It can be estimated that cracks will occur. However, neither of Patent Documents 1 to 3 describes the suppression of cracks in the tablet itself. Further, Patent Documents 1 and 3 do not describe orally disintegrating tablets.

Therefore, an object of the present invention is to provide functional medicinal particles capable of suppressing the occurrence of cracks in the tablet itself, a method for producing the same, and an orally disintegrating tablet even when the tablet is beaten to prepare an orally disintegrating tablet. be.

As a result of diligent studies to achieve the above-mentioned problems, the present inventors have formed a globose nucleus containing a medicinal ingredient and a coated portion covering the globose nucleus and including a release control layer and an outermost layer containing mannitol. In the formed medicinal particles (functional medicinal particles), the proportion of mannitol contained in the outermost layer is adjusted to 4% by mass or more in the medicinal particles to prepare an orally disintegrating tablet. However, they have found that the generation of cracks in the tablet itself can be suppressed, and have completed the present invention.

That is, the medicinal particle (functional medicinal particle) of the present invention is formed by a globose nucleus portion containing a medicinal effect component and a coat portion covering the globose nucleus portion and including a release control layer and an outermost layer containing mannitol. The proportion of mannitol contained in the outermost layer of the medicinal particles is 4% by mass or more in the medicinal particles. The release control layer may be an enteric layer. The coated portion may further include a shielding layer interposed between the enteric layer and the globose nucleus portion. As the coated portion, a first shielding layer, a second shielding layer, a first enteric layer, an intermediate layer, a second enteric layer and an outermost layer are sequentially laminated on the globose nucleus portion. May be good. The particle hardness of the medicinal particles may be 400 gf or more. The outermost layer may not contain a disintegrant. The medicinal ingredient may be esomeprazole or a salt thereof and / or a solvate. The central particle size of the medicinal particles may be 460 to 550 μm.

The present invention also includes a method for producing the medicinal particles by coating the globose nucleus with a coated portion to obtain medicinal particles.

The present invention also includes an orally disintegrating tablet containing the medicinal particles. The orally disintegrating tablet may further contain rapidly disintegrating particles. The fast-disintegrating particles contain sugar alcohol and carmellose, and the proportion of crystalline cellulose may be less than 1% by mass in the particles. The fast-disintegrating particles do not have to contain a medicinal ingredient.

In the present invention, in the medicinal particles formed by a globose nucleus portion containing a medicinal component and a coat portion covering the globose nucleus portion and including a release control layer and an outermost layer containing mannitol, the outermost layer thereof is formed. A method of suppressing the occurrence of cracks in tableting for preparing an orally disintegrating tablet containing the medicinal particles by adjusting the proportion of mannitol contained in the medicinal particles to 4% by mass or more is also included.

In the present invention, in the medicinal particles formed by the globose nucleus portion containing the medicinal component and the coat portion covering the globose nucleus portion and including the release control layer and the outermost layer containing mannitol, the medicinal particles are contained in the outermost layer. Since the proportion of mannitol is adjusted to 4% by mass or more in the medicinal particles, even if the tablet is beaten to prepare an orally disintegrating tablet, the generation of cracks in the tablet itself can be suppressed. In particular, when an orally disintegrating tablet is prepared in combination with specific rapidly disintegrating particles, it is possible to suppress the occurrence of cracks to a high degree while ensuring the pharmaceutical design, and it is also possible to improve the orally disintegrating property and the feeling of taking.

[Globose nucleus]
The medicinal particle (functional medicinal particle) of the present invention contains a globose nucleus in the center, and the globose nucleus contains a medicinal ingredient (active ingredient or active ingredient).

As medicinal ingredients, either conventional or novel medicinal ingredients can be used, for example, nourishing tonic health drugs, antihypertensive antihypertensive drugs, antidepressants, anxiolytics, antidepressants, hypnotic sedatives, antispasmodics, gastrointestinal drugs. , Antacids, antitussives and sputum, dental and oral medicines, antihistamines, cardiotonics, arrhythmias, diuretics, antihypertensives, vasoconstrictors, coronary dilators, peripheral vasodilators, biliary agents, antibiotics, Examples include chemotherapeutic agents, diabetic agents, osteoporosis agents, skeletal muscle relaxing agents, and the like. Of these, medicinal components that are easily decomposed by gastric juice (gastric acid) and require an enteric layer (for example, an anti-ulcer agent such as esomeprazole or a salt thereof and / or a solvate) are preferable.

The globose nucleus contains such a medicinal ingredient and is not particularly limited as long as it is substantially spherical, but usually includes a globose nucleus formed by the medicinal ingredient alone or other components such as a medicinal ingredient and an excipient. It is a globose nucleus formed by the complex of.

The ratio of the medicinal ingredient may be 10% by mass or more in the globose nucleus, preferably 20% by mass or more, preferably 30% by mass or more, and more preferably 40% by mass or more, depending on the type of the medicinal ingredient. Most preferably, it is 50% by mass or more. When the globose nucleus is formed of the complex, the proportion of the medicinal component may be 10 to 90% by mass, for example, 20 to 80% by mass, preferably 30 to 70% by mass in the globose nucleus. More preferably, it is 40 to 60% by mass. If the ratio of the medicinal component is too small, the particle size of the medicinal particles becomes large, which may deteriorate the pharmaceutical design.

Examples of the globose nucleus formed by the medicinal ingredient alone include globose crystals of the medicinal ingredient.

Examples of the globose nucleus formed by the complex include a complex in which the surface of a globose excipient is coated with a composition containing a medicinal ingredient.

As the spherical excipient, conventional spherical nuclei particles for pharmaceuticals can be used. Examples of the excipient constituting the spherical excipient include sugars such as lactose, glucose, fructose, malt sugar, sucrose, sucrose, powdered reduced maltose water candy; Sugar alcohols such as starch saccharified product, xylitol, reduced palatinose, and 4-carbon sugar fermented with glucose (for example, erythritol); celluloses such as microcrystalline cellulose, crystalline cellulose, and powdered cellulose; methylcellulose (MC), ethylcellulose (EC). ) And the like, such as alkyl cellulose. These excipients can be used alone or in combination of two or more. Of these, saccharides such as lactose and sucrose, sugar alcohols such as mannitol, and celluloses such as crystalline cellulose are preferable, and a combination of saccharides such as lactose and cellulose such as crystalline cellulose is particularly preferable.

The ratio of the spherical excipient is, for example, 1 to 50 parts by mass, preferably 5 to 40 parts by mass, more preferably 10 to 30 parts by mass, and most preferably 15 to 25 parts by mass with respect to 100 parts by mass of the medicinal ingredient. be.

The composition coating the spherical excipient may further contain a binder in addition to the medicinal ingredient.

Examples of the binder include polyvinylpyrrolidones (povidone, vinyl acetate-vinylpyrrolidone copolymer, etc.), polyvinyl alcohol, carboxyvinyl polymer, polyacrylic acid-based polymer (sodium polyacrylate, acrylic acid copolymer, etc.), and the like. Synthetic polymers such as polylactic acid, polyethylene glycol, polyvinyl acetate; carboxymethyl cellulose (carmellose or CMC), carboxymethyl ethyl cellulose (CMEC), hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (hypromellose or HPMC), etc. Cellulose ethers; examples include cellulose esters such as cellulose acetate.

These binders can be used alone or in combination of two or more. Of these, hydroxy C _2-4 alkyl C _1-2 alkyl cellulose such as hypromellose is preferable.

The ratio of the binder is, for example, 5 to 100 parts by mass, preferably 10 to 80 parts by mass, more preferably 30 to 70 parts by mass, and most preferably 40 to 60 parts by mass with respect to 100 parts by mass of the medicinal ingredient. If the proportion of the binder is too small, it may be difficult to attach the medicinal component to the surface of each spherical portion, and conversely, if it is too large, the particle size of the medicinal particles may increase.

The composition may further contain excipients in addition to the medicinal properties. Examples of the excipient include the excipients exemplified in the section of the spherical excipient. The excipient can be used alone or in combination of two or more. Among the excipients, sugar alcohols such as mannitol are preferable, and D-mannitol is particularly preferable.

The ratio of the excipient is, for example, 1 to 30 parts by mass, preferably 2 to 20 parts by mass, more preferably 3 to 15 parts by mass, and most preferably 5 to 10 parts by mass with respect to 100 parts by mass of the medicinal ingredient. .. If the proportion of the excipient is too small, the side crack prevention property of the medicinal particles may decrease, and conversely, if the proportion is too large, the particle size of the medicinal particles may increase.

The composition may further contain a conventional additive in addition to the medicinal ingredient.

Conventional additives include, for example, disintegrants, lubricants, plasticizers, surfactants, pH regulators, colorants, sweeteners or flavoring agents (aspartame, acesulfam potassium, sucralose, ascorbic acid, stevia, crude citrus). Extracts, simple syrups, etc.), flavoring agents or refreshing agents (yogurt micron, peppermint micron, menthol, ginger oil, etc.), antioxidants [dibutylhydroxytoluene (BHT), propyl citrate, butylhydroxyanisole (BHA), Tocopherol, citric acid, etc.], preservatives or preservatives (sodium benzoate, paraoxybenzoic acid esters, etc.), wetting agents, antistatic agents, disintegration aids, etc.

Examples of the disintegrant include cross-povidone (cross-linked polyvinylpyrrolidone), cross-povidone copolymer and other cross-linked polyvinylpyrrolidones; carmellose sodium, carmellose calcium, cross-carmellose sodium, low-substituted hydroxypropyl cellulose (L-HPC) and the like. Cellulose ethers; polysaccharides such as agar, carrageenan, arabic gum, alginic acid, sodium alginate, propylene glycol alginate, guar gum, locust bin gum, arabic gum, tragant gum, purulan, xanthan gum, hyaluronic acid, pectin, sodium chondroitin sulfate; gelatin , Casein, proteins such as soybean protein; silicic acid such as talc, light anhydrous silicic acid, calcium silicate, magnesium silicate, synthetic aluminum silicate, magnesium aluminometasilicate; silicic acid; bentonite, synthetic hydrotal Examples include sites and minerals such as silicic acid.

Examples of the lubricant include fatty acids or metal salts thereof (stearic acid, magnesium stearate, calcium stearate, stearyl sodium fumarate, sodium coconut oil fatty acids or other fatty acids or salts thereof; hydrous silicon dioxide (hydrous anhydrous silicic acid), etc. Silicon oxide such as silicon dioxide; polyorganosiloxane such as dimethylpolysiloxane; oils and fats such as hardened oil and cacao butter; waxes such as honeydew, sardine honeydew, carnauba wax, lanolin, paraffin, and vaseline.

Examples of the plasticizer include hydrophilic plasticizers such as ethylene glycol, propylene glycol and glycerin; and fat-soluble plasticizers such as triacetin, triethyl citrate, diethyl phthalate, dioctyl adipate, lauric acid, stearyl alcohol and cetanol. Can be mentioned.

Examples of the surfactant include macrogols such as polyethylene glycol having a weight average molecular weight of 300 to 6000; polyoxyethylene polyoxypropylene glycol such as Pluronic (registered trademark) and porox summer; and polyoxyethylene sorbitan fatty acid ester such as polysorbate 80. (Polysorbates); Polyoxyethylene hydrogenated oil such as polyoxyethylene hydrogenated castor oil; Glycerin fatty acid ester such as glycerin monostearate; Sorbitane fatty acid ester such as sorbitan monostearate and sorbitan monolaurate; Examples include sucrose fatty acid esters; fatty acid metal salts such as sodium lauryl sulfate.

Examples of the pH adjuster include inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid; organic acids such as acetic acid and citric acid; inorganic bases such as sodium hydroxide and sodium hydrogencarbonate; and organic bases such as amines. ..

Examples of the colorant include yellow sesquioxide, iron sesquioxide, edible blue No. 1, edible blue No. 2, edible yellow No. 4, edible yellow No. 5, edible green No. 3, edible red No. 2, and edible red No. 3. , Edible Red No. 102, Edible Red No. 104, Edible Red No. 105, Edible Red No. 106, Edible Lake Pigment, Bengala, Ukon Extract, Riboflavin, Riboflavin Phosphate Sodium, Carotene Liquid, Tar Pigment, Caramel, etc. ..

These conventional additives can be used alone or in combination of two or more. The ratio of the conventional additive may be 50 parts by mass or less (for example, 0.1 to 50 parts by mass) with respect to 100 parts by mass of the medicinal ingredient, for example, 30 parts by mass or less, preferably 20 parts by mass or less, and further. It may be preferably 10 parts by mass or less.

The shape of the globose nucleus is not particularly limited as long as it is spherical, and the sphericity (sphericity) may be 0.6 or more (for example, about 0.6 to 0.99), for example 0.7. The above (for example, 0.7 to 0.98), preferably 0.8 or more, more preferably 0.9 or more, and most preferably 0.95 or more. If the sphericity is too small, it may be difficult to form a uniform coated portion.

The central particle size (D ₅₀ ) of the globose nucleus may be 250 μm or less (for example, 10 to 250 μm), for example, 50 to 210 μm, preferably 100 to 200 μm, more preferably 130 to 180 μm, and most preferably 140 to 140. It is 160 μm. If the central particle size of the globose nucleus is too small, the medicinal effect may be deteriorated, and conversely, if it is too large, the pharmaceutical design may be deteriorated and the feeling of taking the drug may be deteriorated depending on the application.

In the present specification and claims, the particle size such as the central particle size (D ₅₀ ) can be measured on a volume basis using a laser diffraction type particle size distribution meter. D ₅₀ means the particle size of the particles having a cumulative total of 50% by volume from the small particle side of the particle size distribution.

[Release control layer]
The medicinal particles of the present invention further include a coated portion that covers the globose nucleus portion, and this coated portion includes a release control layer.

The release control layer may be a layer capable of controlling the release of esomeprazole, which is an active ingredient, and may be a sustained release layer for controlling the release rate, a movement control layer for controlling the movement, or the like. , An enteric layer (enteric coating layer) that does not dissolve in gastric juice and dissolves in intestinal juice is preferable.

The enteric layer contains an enteric polymer. As the enteric polymer, a conventional enteric polymer can be used. Conventional enteric polymers include, for example, cellulose derivatives such as cellulose phthalate, cellulose acetate phthalate, hydroxypropyl cellulose phthalate, hydroxypropylmethyl cellulose phthalate (HPMCF), hydroxypropylmethyl cellulose acetate succinate; ethyl methacrylate-ethyl acrylate copolymer. (Meta) acrylic polymers such as (methacrylic acid copolymer LD), methacrylic acid-n-butyl acrylate copolymer, methacrylic acid-methyl methacrylate copolymer (methacrylic acid copolymers L, S); polyvinyl acetate phthalate and the like. Can be mentioned. These enteric polymers can be used alone or in combination of two or more. Of these, (meth) acrylic copolymers such as methacrylic acid copolymer LD and ethyl acrylate-methyl methacrylate copolymer are preferable.

The proportion of the enteric polymer may be 10% by mass or more in the enteric layer, for example, 30 to 95% by mass, preferably 50 to 90% by mass, more preferably 60 to 85% by mass, and most preferably 70 to 70 to%. It is 80% by mass. If the proportion of enteric polymer is too low, enteric solubility and bioavailability may decrease.

The enteric layer may further contain a plasticizer in addition to the enteric polymer. Examples of the plasticizer include the plasticizer exemplified in the section of the globose nucleus. The plasticizer can be used alone or in combination of two or more. Among the plasticizers, a fat-soluble plasticizer such as triethyl citrate is preferable.

The proportion of the plasticizer is, for example, 5 to 80 parts by mass, preferably 10 to 50 parts by mass, more preferably 20 to 40 parts by mass, and most preferably 30 to 35 parts by mass with respect to 100 parts by mass of the enteric polymer. .. If the proportion of the plasticizer is too small, it may be difficult to form a uniform enteric layer, and conversely, if it is too large, the enteric solubility may decrease.

The enteric layer may further contain a surfactant in addition to the enteric polymer. Examples of the surfactant include the surfactant exemplified in the section of the globose nucleus. The surfactant can be used alone or in combination of two or more. Among the surfactants, glycerin fatty acid esters and polysorbates are preferable, and glycerin _{monoC 8-24} fatty acid esters such as glycerin monostearate are particularly preferable.

The ratio of the surfactant is, for example, 1 to 30 parts by mass, preferably 2 to 20 parts by mass, more preferably 3 to 10 parts by mass, and most preferably 4 to 8 parts by mass with respect to 100 parts by mass of the enteric polymer. be. If the proportion of the surfactant is too small, it may be difficult to form a uniform enteric layer, and conversely, if it is too large, the enteric solubility may decrease.

The enteric layer may further contain a lubricant in addition to the enteric polymer. Examples of the lubricant include the lubricant exemplified in the section of the globose nucleus. The lubricant can be used alone or in combination of two or more. Of the lubricants, silicon oxide such as hydrous silicon dioxide is preferable.

The ratio of the lubricant is, for example, 0.01 to 3 parts by mass, preferably 0.05 to 1 part by mass, and more preferably 0.1 to 0.5 part by mass with respect to 100 parts by mass of the enteric polymer. ..

The enteric layer may further contain other additives in addition to the enteric polymer. Other additives include, for example, excipients, binders, disintegrants, pH regulators, colorants, sweetening or flavoring agents, flavoring agents or fragrances, refreshing, exemplified in the section on spherical nuclei. Agents, antioxidants, preservatives or preservatives, wetting agents, antistatic agents, disintegration aids and the like. These additives can be used alone or in combination of two or more. The total ratio of these additives is, for example, 10 parts by mass or less (for example, 0.1 to 10 parts by mass), preferably 5 parts by mass or less, based on 100 parts by mass of the enteric polymer.

The release control layer (particularly, the enteric layer) may be a single layer or a combination of a plurality of layers. The combination of the plurality of layers may be two or more layers, for example, 2 to 4 layers. In the case of a combination of a plurality of layers, an intermediate layer described later may be interposed between the enteric layers (for example, in the case of two layers, between the first enteric layer and the second enteric layer). .. Of these, a combination of a plurality of layers is preferable, a combination of two or three layers is more preferable, and a combination of two layers is most preferable, from the viewpoint that cracks are likely to occur in the orally disintegrating tablet and the effect of the present invention is easily exhibited. ..

The ratio of the release control layer (particularly the enteric layer) (in the case of a combination of a plurality of layers, the ratio of each layer) is, for example, 30 to 200 parts by mass, preferably 50 to 150 parts by mass with respect to 100 parts by mass of the globose nucleus. It is more preferably 80 to 100 parts by mass, and most preferably 90 to 95 parts by mass. If the proportion of the release control layer is too small, the release controllability may be deteriorated, and conversely, if the ratio is too large, the formulation designability may be deteriorated.

The average thickness of the release control layer (particularly the enteric layer) (in the case of a combination of a plurality of layers, the average thickness of each layer) is, for example, 10 to 40 μm, preferably 15 to 35 μm, and more preferably 20 to 30 μm.

[Middle layer]
The intermediate layer interposed between the plurality of emission control layers may contain a binder. Examples of the binder include the binder exemplified in the section of the globose nucleus. The binder can be used alone or in combination of two or more. Among the binders, hydroxy C _2-4 alkyl C _1-2 alkyl cellulose such as hypromellose is preferable. By interposing an intermediate layer between a plurality of release control layers (particularly, an enteric layer), the control function of the release control layer can be adjusted.

The intermediate layer may further contain excipients in addition to the binder. Examples of the excipient include, in addition to the excipients exemplified in the section of the spherical nucleus, anhydrous silicic acid such as talc and light anhydrous silicic acid, hydrous silicon dioxide (hydrous anhydrous silicic acid), calcium silicate, and the like. Silicic acids such as magnesium silicate, synthetic aluminum silicate, magnesium aluminometasilicate; metal oxides such as magnesium oxide and titanium oxide; carbonates such as precipitated calcium carbonate and magnesium carbonate; lactates such as calcium lactate; anhydrous Phosphates such as calcium hydrogen phosphate, calcium monohydrogen phosphate; minerals such as bentonite, synthetic hydrotalcite, and silicate can also be used as excipients. These excipients can be used alone or in combination of two or more. Of these, silicates such as talc are preferred.

The ratio of the excipient is, for example, 30 to 200 parts by mass, preferably 50 to 150 parts by mass, and more preferably 90 to 100 parts by mass with respect to 100 parts by mass of the binder. If the proportion of the excipient is too small, the mechanical properties of the intermediate layer may be deteriorated, and if it is too large, the interlayer adhesion may be deteriorated.

The intermediate layer may further contain a lubricant in addition to the binder. Examples of the lubricant include lubricants (excluding talc and hydrous silicon dioxide) exemplified in the section on the globose nucleus. The lubricant can be used alone or in combination of two or more. Of the lubricants, silicon oxide such as hydrous silicon dioxide is preferable.

The ratio of the lubricant is, for example, 0.1 to 10 parts by mass, preferably 0.5 to 5 parts by mass, and more preferably 1 to 3 parts by mass with respect to 100 parts by mass of the binder.

The intermediate layer may further contain other additives in addition to the binder. Other additives include, for example, disintegrants, plasticizers, surfactants, pH regulators, colorants, sweeteners or flavoring agents, flavoring agents or fragrances, refreshing, exemplified in the section on spherical nuclei. Agents, antioxidants, preservatives or preservatives, wetting agents, antistatic agents, disintegration aids and the like. These additives can be used alone or in combination of two or more. The total ratio of these additives is, for example, 10 parts by mass or less (for example, 0.1 to 10 parts by mass), preferably 5 parts by mass or less, with respect to 100 parts by mass of the binder.

The ratio of the intermediate layer (in the case of a combination of a plurality of layers, the ratio of each layer) is, for example, 1 to 100 parts by mass, preferably 3 to 80 parts by mass, and more preferably 5 to 50 parts by mass with respect to 100 parts by mass of the globose nucleus. Parts, most preferably 10 to 30 parts by mass. If the proportion of the intermediate layer is too small, the mechanical properties of the enteric layer may be deteriorated, and conversely, if the ratio is too large, the pharmaceutical design may be deteriorated.

The average thickness of the intermediate layer (in the case of a combination of a plurality of layers, the average thickness of each layer) is, for example, 1 to 15 μm, preferably 2 to 10 μm, and more preferably 3 to 8 μm. If the thickness of the intermediate layer is too thin, the mechanical properties of the enteric layer may be deteriorated, and conversely, if the thickness is too thick, the pharmaceutical design may be deteriorated.

[Shielding layer]
In addition to the release control layer, the coat portion may further include a shielding layer interposed between the globose nucleus portion and the release control layer. Since the constituent components of the release control layer (particularly, the enteric polymer of the enteric layer) have a functional group such as a carboxyl group, a shielding layer should be interposed between the release control layer and the globose nucleus. Therefore, it is possible to suppress the medicinal effect of the globose nucleus from being lowered by the functional group. The shielding layer may be the first shielding layer, as will be described later.

(First shielding layer)
The shielding layer (first shielding layer) contains an excipient (first excipient). Examples of the excipient include the excipients exemplified in the section of the intermediate layer. Of these, silicates such as talc and metal oxides such as titanium oxide are preferred, and combinations of silicates and metal oxides are particularly preferred.

The proportion of the excipient may be 10% by mass or more in the shielding layer, for example, 30 to 95% by mass, preferably 50 to 93% by mass, more preferably 70 to 90% by mass, and most preferably 75 to 85%. It is about mass%. If the proportion of excipients is too low, the efficacy may be reduced.

The shielding layer (first shielding layer) may further contain a binder in addition to the excipient. Examples of the binder include the binder exemplified in the section of the globose nucleus. The binder can be used alone or in combination of two or more. Among the binders, hydroxy C _2-4 alkyl cellulose such as hydroxypropyl cellulose is preferable.

The ratio of the binder is, for example, 3 to 100 parts by mass, preferably 5 to 50 parts by mass, more preferably 10 to 30 parts by mass, and most preferably 15 to 25 parts by mass with respect to 100 parts by mass of the excipient. .. If the proportion of the binder is too small, the mechanical properties of the shielding layer may be deteriorated, and if it is too large, the medicinal effect may be deteriorated.

The shielding layer (first shielding layer) may further contain a lubricant in addition to the excipient. Examples of the lubricant include lubricants (excluding talc and hydrous silicon dioxide) exemplified in the section on the globose nucleus. The lubricant can be used alone or in combination of two or more. Among the lubricants, fatty acid metal salts such as magnesium stearate and silicon oxide such as hydrous silicon dioxide are preferable, and a combination of _C8-24 fatty acid metal salt and silicon oxide is particularly preferable.

The ratio of the lubricant is, for example, 1 to 20 parts by mass, preferably 2 to 10 parts by mass, and more preferably 3 to 8 parts by mass with respect to 100 parts by mass of the excipient.

The shielding layer (first shielding layer) may further contain other additives in addition to the excipient. Other additives include, for example, disintegrants, plasticizers, surfactants, pH regulators, colorants, sweeteners or flavoring agents, flavoring agents or fragrances, refreshing, exemplified in the section on spherical nuclei. Agents, antioxidants, preservatives or preservatives, wetting agents, antistatic agents, disintegration aids and the like. These additives can be used alone or in combination of two or more. The total ratio of these additives is, for example, 10 parts by mass or less (for example, 0.1 to 10 parts by mass), preferably 5 parts by mass or less, based on 100 parts by mass of the excipient.

The ratio of the shielding layer (first shielding layer) is, for example, 30 to 150 parts by mass, preferably 50 to 120 parts by mass, more preferably 70 to 100 parts by mass, and most preferably 70 to 100 parts by mass with respect to 100 parts by mass of the globose nucleus. It is 80 to 90 parts by mass. If the proportion of the shielding layer is too small, the medicinal effect may be deteriorated, and conversely, if it is too large, the pharmaceutical design may be deteriorated.

The average thickness of the shielding layer (first shielding layer) is, for example, 10 to 40 μm, preferably 15 to 35 μm, and more preferably 20 to 30 μm. If the thickness of the shielding layer is too thin, the medicinal effect may be deteriorated, and conversely, if it is too thick, the pharmaceutical design may be deteriorated.

The shielding layer may be such a layer of the shielding layer alone, but the strength of the shielding layer is improved, cracks of the orally disintegrating lock are likely to occur, and the effect of the present invention is likely to be exhibited. A combination of a plurality of shielding layers is preferable, and a first shielding layer formed by the shielding layer and a second shielding layer formed on the enteric layer side (a second shield layer laminated on the first shielding layer) are preferable. The combination with the shielding layer) is particularly preferable.

(Second shielding layer)
The second shielding layer contains an excipient (second excipient). Examples of the second excipient include the excipients exemplified in the section of the intermediate layer. Of the excipients, silicates such as talc are preferred.

The proportion of the second excipient may be 10% by mass or more in the second shielding layer, for example, 10 to 90% by mass, preferably 30 to 85% by mass, and more preferably 50 to 80% by mass. Most preferably, it is about 60 to 70% by mass. If the proportion of the second excipient is too small, the efficacy may be reduced.

The second shielding layer may further contain a binder in addition to the second excipient. Examples of the binder include the binder exemplified in the section of the globose nucleus. The binder can be used alone or in combination of two or more. Among the binders, hydroxy C _2-4 alkyl cellulose such as hydroxypropyl cellulose is preferable.

The ratio of the binder is, for example, 5 to 100 parts by mass, preferably 10 to 80 parts by mass, more preferably 20 to 70 parts by mass, and most preferably 30 to 50 parts by mass with respect to 100 parts by mass of the second excipient. It is a department. If the proportion of the binder is too small, the mechanical properties of the second shielding layer may be deteriorated, and conversely, if the proportion is too large, the medicinal efficacy may be deteriorated.

The second shielding layer may further contain a lubricant in addition to the second excipient. Examples of the lubricant include lubricants (excluding talc and hydrous silicon dioxide) exemplified in the section on the globose nucleus. The lubricant can be used alone or in combination of two or more. Among the lubricants, fatty acid metal salts such as magnesium stearate and silicon oxide such as hydrous silicon dioxide are preferable, and a combination of _C8-24 fatty acid metal salt and silicon oxide is particularly preferable.

The ratio of the lubricant is, for example, 1 to 20 parts by mass, preferably 3 to 15 parts by mass, and more preferably 5 to 10 parts by mass with respect to 100 parts by mass of the second excipient.

The second shielding layer may further contain other additives in addition to the second excipient. Other additives include, for example, disintegrants, plasticizers, surfactants, pH regulators, colorants, sweeteners or flavoring agents, flavoring agents or fragrances, refreshing, exemplified in the section on spherical nuclei. Agents, antioxidants, preservatives or preservatives, wetting agents, antistatic agents, disintegration aids and the like. These additives can be used alone or in combination of two or more. The total ratio of these additives is, for example, 10 parts by mass or less (for example, 0.1 to 10 parts by mass), preferably 5 parts by mass or less, with respect to 100 parts by mass of the second excipient.

The ratio of the second shielding layer is, for example, 3 to 80 parts by mass, preferably 5 to 50 parts by mass, more preferably 10 to 30 parts by mass, and most preferably 20 to 25 parts by mass with respect to 100 parts by mass of the globose nucleus. It is a department. If the proportion of the second shielding layer is too small, the effect of reinforcing the first shielding layer may be reduced, and conversely, if the ratio is too large, the pharmaceutical design may be deteriorated.

The average thickness of the second shielding layer is, for example, 1 to 15 μm, preferably 2 to 10 μm, and more preferably 3 to 8 μm. If the thickness of the second shielding layer is too thin, the effect of reinforcing the first shielding layer may be reduced, and conversely, if the thickness is too thick, the pharmaceutical design may be deteriorated.

[Outermost layer]
The outermost layer of the coated portion contains mannitol in an amount of 4% by mass or more in the medicinal particles, and in the present invention, the surface of the medicinal particles contains mannitol in a specific ratio in order to prepare an orally disintegrating tablet. Even when the tablet is beaten, the occurrence of cracks in the tablet itself can be suppressed. Although it is not clear why the outermost layer suppresses the generation of cracks, the outermost layer containing mannitol in a specific ratio absorbs stress, so that even if the hardness of the medicinal particles is high, they are plastically deformed and the medicinal particles are deformed. It can be presumed that the generation of voids in the periphery is suppressed.

As the mannitol, D-mannitol is preferable. The angle of repose of mannitol is, for example, 30 to 70 °, preferably 40 to 65 °, more preferably 45 to 60 °, and most preferably 50 to 55 °. If the angle of repose is too small, the mechanical properties of the fast-disintegrating particles may deteriorate, and if it is too large, the intraoral disintegration property may decrease.

In the present specification and claims, the angle of repose can be measured in accordance with JIS R9301-2-2.

The ratio of mannitol contained in the outermost layer may be 4% by mass or more (for example, about 4 to 30% by mass) in the medicinal particles, but it is preferably 5 from the viewpoint of suppressing cracking of tablets and high productivity. It is -25% by mass, more preferably 7 to 20% by mass, more preferably 8 to 15% by mass, and most preferably 9 to 12% by mass.

The proportion of mannitol may be 50% by mass or more in the outermost layer, for example, 80% by mass or more (80 to 100% by mass), preferably 90 to 99.99% by mass, and more preferably 95 to 99.9% by mass. %, Most preferably 98-99.5% by mass. If the proportion of mannitol is too small, the pharmaceutical design may be deteriorated.

The outermost layer may further contain, in addition to mannitol, the colorant exemplified in the globose nucleus section. The colorants can be used alone or in combination of two or more. Of the colorants, yellow iron sesquioxide and iron sesquioxide are preferable.

The ratio of the colorant is, for example, 0.01 to 5 parts by mass, preferably 0.05 to 3 parts by mass, more preferably 0.1 to 2 parts by mass, and most preferably 0.5, with respect to 100 parts by mass of mannitol. ~ 1.5 parts by mass.

The outermost layer may further contain other sugar alcohols in addition to mannitol. Examples of other sugar alcohols include sorbitol, mannitol, reduced maltose starch syrup (maltitol), reduced starch syrup, xylitol, reduced palatinose, and 4-carbon sugar obtained by fermenting glucose (for example, erythritol). The ratio of the other sugar alcohol is, for example, 50 parts by mass or less (for example, 0.1 to 50 parts by mass), preferably 30 parts by mass or less, and more preferably 10 parts by mass or less with respect to 100 parts by mass of mannitol.

The outermost layer may further contain other additives in addition to mannitol. Other additives include, for example, excipients, binders, plasticizers, surfactants, pH regulators, sweetening or flavoring agents, flavoring agents or fragrances, refreshing, exemplified in the section on spherical nuclei. Examples include agents, antioxidants, preservatives or preservatives, wetting agents, antistatic agents, disintegration aids and the like. These additives can be used alone or in combination of two or more. The total ratio of these additives is, for example, 10 parts by mass or less (for example, 0.1 to 10 parts by mass), preferably 5 parts by mass or less, with respect to 100 parts by mass of mannitol.

The outermost layer is preferably substantially free of disintegrants, and particularly preferably free of disintegrants. Examples of the disintegrant include the disintegrant exemplified in the section of the globose nucleus, and it is preferable that the disintegrant does not contain low-degree-of-substitution hydroxypropyl cellulose, sodium carboxymethyl cellulose and sodium croscarmellose.

The ratio of the outermost layer is, for example, 15 to 100 parts by mass, preferably 20 to 80 parts by mass, more preferably 30 to 60 parts by mass, and most preferably 40 to 50 parts by mass with respect to 100 parts by mass of the globose nucleus. .. If the ratio of the outermost layer is too small, cracks may occur, and conversely, if the ratio is too large, the pharmaceutical design may be deteriorated.

The average thickness of the outermost layer is, for example, 1 to 15 μm, preferably 2 to 10 μm, and more preferably 3 to 8 μm. If the thickness of the outermost layer is too thin, cracks may occur, and if it is too thick, the pharmaceutical design may be deteriorated.

[Characteristics of medicinal particles and manufacturing method]
The medicinal particles of the present invention may have high particle hardness. In the present invention, even if the hardness of the medicinal particles is high, even if the orally disintegrating tablet containing the functional particles is tableted and manufactured, it is possible to suppress the occurrence of cracks in the tablet.

The particle hardness of the medicinal particles of the present invention may be 350 gf or more (particularly 400 gf or more), for example, 400 to 600 gf, preferably 450 to 550 gf, more preferably 470 to 530 gf, and most preferably 480 to 520 gf. If the particle hardness is too low, the generation of cracks is suppressed, so that the effect of the present invention may not be sufficiently exhibited.

In addition, in the present specification and claims, the particle hardness can be measured by using a conventional texture analyzer, and in detail, can be measured by the method described in Examples.

The central particle size ( _D50 ) of the medicinal particles of the present invention is, for example, 460 to 550 μm, preferably 470 to 530 μm, more preferably 490 to 520 μm, and most preferably 495 to 510 μm. If the particle size is too small, the effect of the present invention may not be sufficiently exhibited, and conversely, if the particle size is too large, the pharmaceutical design may be deteriorated.

The medicinal particles of the present invention can be produced by coating the globose nucleus portion with a coated portion.

The method for preparing the globose nucleus can be appropriately selected depending on the type of the globose nucleus, and may be a conventional method. When the globose nucleus is a complex (a complex in which the surface of a spherical excipient is coated with a composition containing a medicinal ingredient), the composition containing the medicinal ingredient is coated on the globose nucleus by a conventional coating method. It may be coated. Conventional coating methods include, for example, coating, spraying, impregnation / immersion, pan coating, fluidized bed coating, rolling coating, rolling fluidized coating and the like. Of these, fluidized bed coatings and rolling fluidized coatings are preferred, and rolling fluidized coatings are particularly preferred.

As the coating method of the coated portion, the above-mentioned conventional method can be used, and a fluidized bed coating and a rolling fluidized coating are preferable, and a rolling fluidized coating is particularly preferable. The coated portion may be coated by a different coating method for each layer, or all the layers may be coated by the same method. From the viewpoint of productivity and the like, it is preferable to coat all the layers by the same coating method, and it is particularly preferable to coat all the layers by rolling flow coating.

[Orally disintegrating tablet]
The orally disintegrating tablet (OD tablet) of the present invention may contain the medicinal effect particles, but in order to improve the orally disintegrating property, the composition for OD tablets containing the medicinal effect particles and the rapidly disintegrating particles. The OD tablet obtained by tableting is preferable.

(Fast disintegrating particles)
The fast-disintegrating particles contained in the OD tablet may be formed of a composition containing a disintegrant, and may be fast-disintegrating particles used as the fast-disintegrating particles of the OD tablet. The fast-disintegrating particles may contain medicinal properties, but particles that do not contain medicinal properties are preferable from the viewpoint of pharmaceutical design, and cracks can be suppressed, and oral disintegration and a feeling of ingestion are also obtained. From the viewpoint of improvement, fast-disintegrating particles containing sugar alcohol and carmellose and having a crystalline cellulose content of less than 1% by mass in the particles are particularly preferable.

Sugar alcohols are formulated as excipients. Examples of sugar alcohols include sorbitol, mannitol, reduced maltose starch syrup (maltitol), reduced starch syrup, xylitol, reduced palatinose, and 4-carbon sugar obtained by fermenting glucose (for example, erythritol). These sugar alcohols can be used alone or in combination of two or more. Of these, mannitol, sorbitol, erythritol, xylitol and the like are widely used, mannitol is preferable, and D-mannitol is particularly preferable.

The shape of the sugar alcohol (raw sugar alcohol) is not particularly limited, and may be an indefinite shape, a fibrous shape, an ellipsoidal shape, a spherical shape, a flat plate shape, a powder granule, or the like, and is usually an indefinite shape, a powder granule, or the like. Is.

The average particle size (D ₅₀ ) of the sugar alcohol (raw sugar alcohol) is, for example, 1 to 350 μm, preferably 5 to 250 μm, and more preferably 20 to 150 μm. If the particle size of the sugar alcohol is too small, the mechanical properties of the fast-disintegrating particles may be deteriorated, and conversely, if the particle size is too large, the feeling of taking may be deteriorated.

The proportion of sugar alcohol (particularly mannitol) may be 30% by mass or more in the rapidly disintegrating particles, for example, 30 to 95% by mass, preferably 50 to 90% by mass, and more preferably 60 to 85% by mass. It is more preferably 65 to 80% by mass, and most preferably 70 to 75% by mass. If the proportion of sugar alcohol is too small, the feeling of taking the drug may be deteriorated, and if it is too large, the disintegration property in the oral cavity may be deteriorated.

The fast-disintegrating particles further contain carmellose as a disintegrant in addition to the sugar alcohol. In the fast-disintegrating particles, by combining the sugar alcohol and carmellose without substantially containing crystalline cellulose, not only the oral disintegration property but also the feeling of taking can be improved. In particular, in addition to sugar alcohols, by combining with ethyl cellulose, silicic acids and crospovidone, which will be described later, the water conductivity of carmellose has a synergistic effect with other components, and the oral disintegration property and the feeling of ingestion are greatly improved. At the same time, the mechanical properties required for orally disintegrating tablets can be guaranteed.

In the present specification and claims, the acid type conversion means the ratio of the number of moles of free carboxyl group to the total number of moles of free carboxyl group and the carboxyl group forming the salt. It can be measured using conventional methods such as acid or alkali titration and nuclear magnetic resonance spectra.

In carmellose, the average degree of substitution (or average degree of etherification) of the carboxymethyl group is, for example, 0.1 to 1, preferably 0.2 to 0.8, more preferably 0.3 to 0.7, and most preferably. Is 0.4 to 0.6. If the average degree of substitution is too low, the oral disintegration may decrease. The average degree of substitution is the average value of the degree of substitution (substitution ratio) with respect to the hydroxyl group at the 6-position of the glucose unit constituting cellulose, and the maximum value is 1.

The shape of carmellose (raw material carmellose) is not particularly limited, and may be indefinite shape, fibrous, ellipsoidal, spherical, flat plate, powdery granules, etc., and is usually indefinite shape, powdery granules, or the like. ..

The average particle size (D ₅₀ ) of carmellose (raw material carmellose) is, for example, 1 to 70 μm, preferably 3 to 50 μm, and more preferably 5 to 30 μm. If the particle size of carmellose is too small, the disintegration property in the oral cavity may decrease, and if it is too large, the feeling of taking the drug may decrease.

The bulk specific density of carmellose is, for example, 100 to 800 g / liter, preferably 200 to 500 g / liter, and more preferably 300 to 400 g / liter.

The ratio of carmellose can be selected from the range of about 1 to 100 parts by mass with respect to 100 parts by mass of sugar alcohol, for example, 3 to 50 parts by mass, preferably 5 to 45 parts by mass, and more preferably 10 to 40 parts by mass. It is preferably 20 to 35 parts by mass, and most preferably 25 to 30 parts by mass. The proportion of carmellose may be 3 to 50% by mass, preferably 5 to 40% by mass, more preferably 10 to 30% by mass, and most preferably 15 to 25% by mass in the particles. If the proportion of carmellose is too small, the disintegration property in the oral cavity may decrease, and if it is too large, the feeling of taking the drug may decrease.

The fast-disintegrating particles may further contain ethyl cellulose as a binder in addition to the sugar alcohol and carmellose.

The shape of ethyl cellulose is not particularly limited, and may be an irregular shape, a fibrous shape, an ellipsoidal shape, a spherical shape, a flat plate shape, a powder granular shape, or the like, and is usually an irregular shape, a powder granular shape, or the like.

The average particle size (D ₅₀ ) of ethyl cellulose is, for example, 1 to 60 μm, preferably 3 to 45 μm, and more preferably 5 to 15 μm. If the particle size of ethyl cellulose is too small, the mechanical properties of the fast-disintegrating particles may be deteriorated, and if it is too large, the feeling of taking may be deteriorated.

The ratio of ethyl cellulose is, for example, 0.1 to 10 parts by mass, preferably 1 to 5 parts by mass, more preferably 1.5 to 4 parts by mass, and most preferably 2 to 3.5 parts by mass with respect to 100 parts by mass of the sugar alcohol. It is a mass part. The proportion of ethyl cellulose may be 0.1 to 10% by mass, more preferably 0.5 to 5% by mass, still more preferably 1 to 3% by mass, and most preferably 1.5 to 2% in the rapidly disintegrating particles. It is 5.5% by mass. If the proportion of ethyl cellulose is too low, the mechanical properties of the particles may deteriorate, and if it is too high, the disintegration property in the oral cavity may deteriorate.

In addition to sugar alcohols and carmellose, the fast disintegrating particles may further contain silicic acids as binders and / or disintegrants. Silicic acids are generally used as excipients, but in the present invention, in addition to improving hardness, they also contribute to oral disintegration and a feeling of ingestion by combining with sugar alcohol and carmellose. However, by selecting silicic anhydride, it is possible to highly improve the disintegration property in the oral cavity and the feeling of ingestion, probably because the water conductivity is improved.

Examples of the silicic acid include the silicic acid exemplified as the excipient in the section of the intermediate layer. The silicic acids can be used alone or in combination of two or more. Of these, anhydrous silicic acid is preferable, and light anhydrous silicic acid is particularly preferable.

The shape of the silicic acid (raw material silicic acid) is not particularly limited, and may be an irregular shape, a fibrous shape, an ellipsoidal shape, a spherical shape, a flat plate shape, a powder granular shape, or the like, and is usually an irregular shape, a powder granular shape, or the like. Is.

The average particle size (D ₅₀ ) of silicic acids (particularly, anhydrous silicic acid) is, for example, 0.1 to 30 μm, preferably 0.5 to 10 μm, more preferably 1 to 5 μm, and most preferably 2 to 4 μm. If the particle size of the silicic acid is too small, the disintegration property in the oral cavity may be lowered, and if it is too large, the feeling of taking the medicine may be lowered.

The BET specific surface area of silicic acids (raw material silicic acids) is, for example, 50 to 1000 m ² / g, preferably 100 to 500 m ² / g, more preferably 150 to 450 m ² / g, and most preferably 200 to 400 m ² / g. be. If the specific surface area is too small, the hardness may decrease, and if it is too large, the oral disintegration property may decrease.

The ratio of silicic acids is, for example, 0.1 to 10 parts by mass, preferably 0.3 to 5 parts by mass, more preferably 0.5 to 3 parts by mass, and most preferably 1 to 1 to 100 parts by mass with respect to 100 parts by mass of the sugar alcohol. 2 parts by mass. The proportion of silicic acid may be 0.1 to 5% by mass in the particles, preferably 0.3 to 3% by mass, more preferably 0.5 to 2% by mass, and most preferably 0.5 to 1%. It is 5.5% by mass. If the proportion of silicic acid is too small, the effect of improving hardness and the disintegration property in the oral cavity may be lowered, and if it is too high, the feeling of taking may be deteriorated.

The fast-disintegrating particles may further contain crospovidone as a disintegrant in addition to the sugar alcohol and carmellose.

The shape of crospovidone (raw material crospovidone) is not particularly limited, and may be indefinite shape, fibrous, ellipsoidal, spherical, flat plate, powder granules, etc., and is usually indefinite shape, powder granules, etc. Is.

The average particle size (D ₅₀ ) of crospovidone is, for example, 0.5 to 50 μm, preferably 1 to 30 μm, more preferably 3 to 20 μm, and most preferably 5 to 10 μm. If the particle size of crospovidone is too small, the disintegration property in the oral cavity may be lowered, and if it is too large, the feeling of taking the drug may be lowered.

The ratio of crospovidone is, for example, 3 to 20 parts by mass, preferably 5 to 15 parts by mass, more preferably 6 to 10 parts by mass, and most preferably 7 to 9 parts by mass with respect to 100 parts by mass of sugar alcohol. The proportion of crospovidone may be 3 to 15% by mass, preferably 5 to 10% by mass, more preferably 5 to 8% by mass, and most preferably 6 to 7% by mass in the particles. If the proportion of crospovidone is too small, the disintegration property in the oral cavity may be deteriorated, and conversely, if the proportion is too large, the mechanical properties of the particles may be deteriorated.

The fast-disintegrating particles may further contain conventional additives to be added to the oral preparation. Conventional additives include, for example, disintegrants (excluding crospovidone), excipients (excluding sugar alcohols and ethyl cellulose), binders (excluding carmellose), and lubricants exemplified in the section on spherical nuclei. Agents, plasticizers, surfactants, pH regulators, colorants, sweeteners or flavoring agents, flavoring or cooling agents, antioxidants, preservatives or preservatives, wetting agents, antistatic agents, disintegration aids And so on.

These additives can be used alone or in combination of two or more. These additives may be 50% by mass or less (for example, 0.01 to 50% by mass) in the fast-disintegrating particles, for example, 30% by mass or less, preferably 20% by mass or less, and more preferably 10% by mass. Hereinafter, it is most preferably 5% by mass or less (for example, 0.1 to 5% by mass).

It is preferable that the fast-disintegrating particles do not substantially contain microcrystalline cellulose or crystalline cellulose from the viewpoint of achieving both oral disintegration property and a feeling of ingestion. Therefore, in the fast-disintegrating particles, the proportion of crystalline cellulose is less than 1% by mass, preferably 0.5% by mass or less, more preferably 0.1% by mass or less, and more preferably 0 in the fast-disintegrating particles. It is 0.01% by mass or less, and most preferably it does not contain crystalline cellulose. When crystalline cellulose is contained in the rapidly disintegrating particles, both the oral disintegration property and the feeling of ingestion are lowered.

From the viewpoint of achieving both oral disintegration and a feeling of ingestion, the fast-disintegrating particles are preferably substantially free of starch, and particularly preferably free of starch.

Examples of starches include starches such as corn starch and potato starch; starch derivatives such as pregelatinized starch, partially pregelatinized starch, oxidized starch, dextrin, cyclodextrin, hydroxypropyl starch, carboxymethyl starch and sodium carboxymethyl starch. Be done.

In the fast-disintegrating particles, the proportion of starches (particularly starch such as corn starch) is less than 1% by mass, preferably 0.5% by mass or less, and more preferably 0.1% by mass in the fast-disintegrating particles. % Or less, more preferably 0.01% by mass or less, and most preferably no starch. When starches (particularly starch) are contained in the rapidly disintegrating particles, both the oral disintegration property and the feeling of ingestion are lowered.

The shape of the fast-disintegrating particles is not particularly limited, and may be an amorphous shape, a fibrous shape, an ellipsoidal shape, a spherical shape, a flat plate shape, a powder granular shape, or the like, and an amorphous shape, a powder granular shape, or a spherical shape is preferable. An isotropic shape such as a spherical shape is particularly preferable.

The average particle size (D ₅₀ ) of the fast-disintegrating particles is, for example, 10 to 200 μm, preferably 30 to 150 μm, more preferably 50 to 100 μm, and most preferably 70 to 80 μm. If the particle size of the fast-disintegrating particles is too small, the oral disintegration property may decrease, and conversely, if the particle size is too large, the feeling of taking the drug may decrease.

The 10% by volume particle size (D ₁₀ ) of the fast-disintegrating particles is, for example, 1 μm or more (for example, 1 to 75 μm), preferably 5 μm or more (for example, 5 to 50 μm), and more preferably 10 μm or more (for example, 10 to 40 μm). It is more preferably 20 μm or more (for example, 20 to 35 μm), and most preferably 25 μm or more (for example, 25 to 30 μm). If D ₁₀ is too small, the oral disintegration property may decrease.

The 90% by volume particle size (D ₉₀ ) of the fast-disintegrating particles is, for example, 300 μm or less (for example, 80 to 300 μm), preferably 250 μm or less (for example, 100 to 250 μm), and more preferably 200 μm or less (for example, 130 to 200 μm). Most preferably, it is 180 μm or less (for example, 150 to 180 μm). If D ₉₀ is too large, the feeling of taking the drug may deteriorate.

In the composition for OD tablets, the ratio of the rapidly disintegrating particles is, for example, 10 to 1000 parts by mass, preferably 30 to 500 parts by mass, and more preferably 50 to 300 parts by mass with respect to 100 parts by mass of the medicinal particles. It is preferably 80 to 200 parts by mass, and most preferably 100 to 150 parts by mass. If the proportion of the rapidly disintegrating particles is too small, the oral disintegration property and the feeling of ingestion may be deteriorated, and conversely, if the proportion is too large, the pharmaceutical design may be deteriorated.

(Manufacturing method of fast-disintegrating particles)
The fast-disintegrating particles can be obtained by a conventional granulation method, for example, a rolling granulation method, a fluidized layer granulation method, a mixing / stirring granulation method, a spray-drying granulation method, a vibration granulation method, or the like. Obtained by granulating. Of these, the fluidized bed granulation method is preferable from the viewpoint of productivity and the like.

As the fluidized bed granulation method, a conventional method can be used, but when the fast-disintegrating particles contain sugar alcohol, carmellose, ethyl cellulose, silicic acid and crospovidone, components other than crospovidone are previously added to the fluidized bed granulator. A method of mixing and spraying an aqueous dispersion (granulation liquid) containing crospovidone for granulation is preferable. By mixing the solid sugar alcohol and the solid carmellose, it becomes easy to prepare fast-disintegrating particles capable of achieving both oral disintegration and a feeling of ingestion.

The solvent contained in the granulation solution is not particularly limited, but is limited to water, lower alcohols (eg, C _1-4 alcohols such as ethanol and isopropanol), aliphatic ketones (eg, acetone), or a mixed solvent thereof. Is widely used, and from the viewpoint of safety, water and / or ethanol is preferable, and water is particularly preferable. The ratio of the solvent is, for example, 1000 to 2000 parts by mass, preferably 1200 to 1800 parts by mass, and more preferably 1400 to 1600 parts by mass with respect to 100 parts by mass of crospovidone.

(Other ingredients)
In addition to the medicinal particles and the fast-disintegrating particles, the composition for OD tablets further contains an excipient, a disintegrant, a fluidizing agent, a lubricant, a sweetening agent or a flavoring agent, a flavoring agent or a refreshing agent. You may be.

The excipient may further include the excipient exemplified in the section of the globose nucleus. The excipient can be used alone or in combination of two or more. Among the excipients, celluloses such as crystalline cellulose and alkyl cellulose such as ethyl cellulose are preferable, and alkyl cellulose is particularly preferable. The ratio of the excipient is, for example, 1 to 100 parts by mass, preferably 3 to 50 parts by mass, more preferably 5 to 40 parts by mass, and most preferably 10 to 30 parts by mass with respect to 100 parts by mass of the medicinal particles. ..

The disintegrant may further include the disintegrant exemplified in the section on the globose nucleus. The disintegrant can be used alone or in combination of two or more. Among the disintegrants, crosslinked polyvinylpyrrolidones such as crospovidone are preferable. The ratio of the disintegrant is, for example, 1 to 50 parts by mass, preferably 2 to 30 parts by mass, more preferably 3 to 20 parts by mass, and most preferably 5 to 15 parts by mass with respect to 100 parts by mass of the medicinal particles.

Examples of the fluidizing agent include anhydrous silicic acid such as talc and light anhydrous silicic acid, and silicic acids such as calcium silicate, magnesium silicate, synthetic aluminum silicate, and magnesium aluminometasilicate. Among the fluidizing agents, anhydrous silicic acid such as light anhydrous silicic acid is preferable. The ratio of the fluidizing agent is, for example, 0.05 to 5 parts by mass, preferably 0.1 to 3 parts by mass, and more preferably 0.3 to 1 part by mass with respect to 100 parts by mass of the medicinal particles.

Examples of the lubricant include the lubricant exemplified in the section of the globose nucleus. The lubricant can be used alone or in combination of two or more. Among the lubricants, fatty acid metal salts such as magnesium stearate are preferable. The ratio of the lubricant is, for example, 0.05 to 5 parts by mass, preferably 0.1 to 3 parts by mass, and more preferably 0.3 to 1 part by mass with respect to 100 parts by mass of the medicinal particles.

Examples of the sweetening agent or flavoring agent include the sweetening agent or flavoring agent exemplified in the section of the globose nucleus. The ratio of the sweetening agent or the flavoring agent is, for example, 0.1 to 5 parts by mass, preferably 0.5 to 3 parts by mass, and more preferably 1 to 2 parts by mass with respect to 100 parts by mass of the medicinal particles.

Examples of the flavoring agent or the cooling agent include the flavoring agent or the cooling agent exemplified in the section of the globose nucleus. The ratio of the flavoring agent or the cooling agent is, for example, 0.01 to 3 parts by mass, preferably 0.05 to 1 part by mass, and more preferably 0.1 to 0.5 parts by mass with respect to 100 parts by mass of the medicinal particles. It is a department.

The tablet diameter of the OD tablet of the present invention is, for example, 3 to 20 mm, preferably 5 to 15 mm, more preferably 7 to 12 mm, and most preferably 8 to 11 mm.

The method for producing the OD tablet of the present invention may be any method as long as it is a method of locking using such an OD tablet composition, and a conventional method can be used.

Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited to these examples. The raw materials used and the evaluated methods in the following examples are shown below. Moreover, the weight of the raw materials used is all the weight of solid content.

[Evaluation methods]
(Particle size distribution)
The particle size distribution (D ₅₀ ) was measured on a volume basis using a laser diffraction type particle size distribution measuring device (manufactured by Malvern, trade name “Master Sizar 3000”).

(Particle hardness)
For the particle hardness, the granules were compressed under the following conditions using a texture analyzer (manufactured by SMS, trade name "Texture Analyzer TA.XT Plus") and a flat probe with a diameter of 3 mm as a jig, and the granules were damaged. The maximum pressure at which the pressure decreased was measured as the granule strength.

Load cell: 5 kg
Probe speed: 0.1 mm / sec
Trigger weight: Compressed from 1g to 2000g.

(Tablet hardness)
The tablet hardness was measured by a method of loading a tablet with an indenter by an electric weight load using an ERWEKA type tablet hardness tester (manufactured by ERWEKA, trade name "tablet hardness tester TBH425TD".

(Presence / absence of cracks)
The side surface of the obtained orally disintegrating tablet was visually observed and evaluated.

Comparative Examples 1 to 6
[Preparation of medicinal particles]
Medicinal particles were prepared by the following procedure. The mass of the raw material used per tablet is shown in Table 1. The mass of the raw material used for the outermost layer per tablet is shown in Table 2.

(Preparation of globose nucleus)
1) Lactose / crystalline cellulose spherical granules (manufactured by Freund Sangyo Co., Ltd., trade name "Nonparel-105 (grade 150)") were put into a rolling fluidized bed granulator / dryer.

2) Mix purified water and ethanol (manufactured by Japan Alcohol Corporation, standard content 99.5% by volume), and add esomeprazole magnesium hydrate (manufactured by Aurora) and hypromerose (manufactured by Shin-Etsu Chemical Co., Ltd.) to the mixing solution. The product name "TC-5R") was dissolved and dispersed, and the entire amount of this liquid was sprayed and coated, and then dried.

3) The dried product and talc (manufactured by Nippon Talc Co., Ltd., trade name "MICRO ACE P-3") are mixed, the mixed powder is classified by a 30M sieve and a 100M sieve, passed through a 30M sieve, and the particles remaining in the 100M sieve. Was designated as a globose nucleus.

(Covering step of the first shielding layer)
1) The globose nucleus was put into a rolling fluidized bed granulator / dryer.

2) After mixing purified water and ethanol and dissolving hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd., trade name "HPC-SL") in the mixing solution, talc (MICRO ACE P-3) and magnesium stearate (MICRO ACE P-3) A dispersion liquid A was prepared by dispersing grade "vegetable (Taipei)" manufactured by Taihei Kagaku Sangyo Co., Ltd.

3) Separately, titanium oxide (manufactured by Freund Sangyo Co., Ltd., trade name "titanium oxide FG") was dispersed in purified water and filtered through a 100 M sieve to prepare a filtrate B.

4) The dispersion liquid A and the filtrate liquid B were mixed, and the entire amount of this liquid was sprayed and coated, and then dried.

5) The dried product and hydrous silicon dioxide (manufactured by Fuji Silysia Chemical Ltd., trade name "Adsolider-102") are mixed, and the mixed powder is classified by a 30M sieve and a 100M sieve, passed through a 30M sieve, and remains in the 100M sieve. The particles were prepared as the first shielding layer coating particles.

(Coating step of the second shielding layer)
1) The first shielding layer coating particles were put into a rolling fluidized bed granulation dryer.

2) Mix purified water and ethanol, dissolve hydroxypropyl cellulose (HPC-SL) in the mixing solution, and then talc (MICRO ACE P-3) and magnesium stearate (manufactured by Taihei Kagaku Sangyo Co., Ltd., grade "plant". The sex (Taipei) ") was dispersed, and the whole amount of this solution was sprayed and coated, and then dried.

3) The dried product and hydrous silicon dioxide (addorider-102) are mixed, the mixed powder is classified by a 30M sieve and a 100M sieve, passed through the 30M sieve, and the particles remaining on the 100M sieve are the particles coated on the second shielding layer. Prepared as.

(Covering step of the first enteric layer)
1) The second shielding layer coating particles were placed in a rolling fluidized bed granulator / dryer.

2) Glyceric acid copolymer LD (manufactured by Evonik, trade name "Eudragit L30D-55"), polysolvate 80 (manufactured by Sanyo Kasei Kogyo Co., Ltd., trade name "polysolvate 80"), triethyl citrate (manufactured by Morimura Shoji Co., Ltd., trade name " Citroflex 2 (SC-60) ”) and glycerin monostearate (manufactured by RIKEN Vitamin Co., Ltd., trade name“ glycerin monostearate P-100 10K ”) are mixed with a dispersion in purified water and sieved through a 100M sieve. The whole amount of the filtered liquid was sprayed and coated, and then dried.

3) The dried product and hydrous silicon dioxide (addorider-102) are mixed, the mixed powder is classified by a 30M sieve and a 100M sieve, passed through the 30M sieve, and the particles remaining on the 100M sieve are coated with the first enteric layer. Prepared as particles.

(Intermediate layer coating process)
1) The first enteric layer-coated particles were put into a rolling fluidized bed granulator / dryer.

2) Hypromellose (TC-5R) and talc (MICRO ACE P-3) were dissolved and dispersed in purified water, and the entire amount of this solution was sprayed and coated, and then dried.

3) The dried product and hydrous silicon dioxide (addorider-102) were mixed, the mixed powder was classified by a 30M sieve and a 100M sieve, passed through a 30M sieve, and the particles remaining on the 100M sieve were prepared as intermediate layer coating particles. ..

(Coating step of the second enteric layer)
1) The intermediate layer coated particles were placed in a rolling fluidized bed granulator / dryer.

2) Dispersion of methacrylic acid copolymer LD (Eudragit L30D-55), polysolvate 80 (manufactured by Sanyo Kasei Kogyo Co., Ltd.), triethyl citrate (SC-60) and glycerin monostearate (P-100 10K) in purified water. The liquids were mixed, and the whole amount of the liquid filtered through a 100 M sieve was sprayed and coated, and then dried.

3) The dried product and hydrous silicon dioxide (addorider-102) are mixed, the mixed powder is classified by a 22M sieve and a 100M sieve, passed through the 22M sieve, and the particles remaining on the 100M sieve are coated with the second enteric layer. It was made into particles.

(Coating process of outermost layer)
1) The second enteric layer-coated particles were put into a rolling fluidized bed granulator / dryer.

2) D-mannitol (manufactured by ROQUETTE, trade name "PEARLITOR 50C") is dissolved in purified water, followed by dispersion of yellow iron sesquioxide (manufactured by Romi Kasei) and iron sesquioxide (manufactured by Romi Kasei). The entire amount of the filtrate filtered through a 200 M sieve was sprayed and coated, and then dried.

3) The dried product was classified with a 22M sieve and a 100M sieve, passed through the 22M sieve, and the particles remaining on the 100M sieve were used as medicinal particles. The central particle size (D ₅₀ ) of the obtained medicinal particles was 494 μm, and the particle hardness was 484.5 gf.

[Preparation of fast-disintegrating particles]
The fast-disintegrating particles were prepared by the following procedure. The mass of the raw material used per tablet is shown in Table 2.

1) D-mannitol, ethyl cellulose, light anhydrous silicic acid and carmellose are put into a fluidized bed granulation dryer, granulated with a granulating solution in which crospovidone is dispersed in purified water, and then dried and rapidly disintegrated. Particles were prepared.

[Preparation of OD tablets]
OD tablets were prepared by the following procedure. The mass of the raw material used per tablet is shown in Table 2.

1) Medicinal particles, fast-disintegrating particles, crystalline cellulose (manufactured by Asahi Kasei Corporation, trade name "Theoras KG-802"), crosspovidone (manufactured by BASF Japan, trade name "Corridon CL-F", type A), ethyl cellulose ( THE DOW CHEMICAL, trade name "Etocell Standard 7FP Premium"), Aspartame (Ajinomoto), fragrance mixed, and magnesium stearate (Taipei Chemical Industry, grade "Vegetable (Taipei)") It was put in and mixed to obtain a tableted powder.

2) The obtained tableting powder was tableted using a rotary tableting machine to prepare an OD tablet having a tablet diameter of 9 mm, a thickness of 5.4 mm and a hardness of 60 N.

The evaluation results of the obtained OD tablets are shown in Table 2.

As is clear from the results in Table 2, in Comparative Examples 1 to 6, cracks were generated at a small agent diameter.

Examples 1 to 6
OD tablets were prepared in the same manner as in Comparative Examples 1 to 6 except that the amount of D-mannitol in the outermost layer of the medicinal particles was changed to the ratio shown in Table 3 and the composition of the rapidly disintegrating particles was also changed to the ratio shown in Table 3. Prepared. The evaluation results of the obtained OD tablets are shown in Table 3.

As is clear from the results in Table 3, in Examples 1 to 6, the generation of cracks could be suppressed in a wide range of agent diameters.

Examples 7 to 13
OD tablets were prepared in the same manner as in Comparative Examples 1 to 6 except that the amount of D-mannitol in the outermost layer of the medicinal particles was changed to the ratio shown in Table 4 and the composition of the rapidly disintegrating particles was also changed to the ratio shown in Table 4. Prepared. The evaluation results of the obtained OD tablets are shown in Table 4.

As is clear from the results in Table 4, in Examples 7 to 13, the occurrence of cracks could be suppressed with a wide range of agent diameters.

Examples 14-18
OD tablets were prepared in the same manner as in Comparative Examples 1 to 6 except that the amount of D-mannitol in the outermost layer of the medicinal particles was changed to the ratio shown in Table 5 and the composition of the rapidly disintegrating particles was also changed to the ratio shown in Table 5. Prepared. The evaluation results of the obtained OD tablets are shown in Table 5.

As is clear from the results in Table 5, in Examples 14 to 18, the generation of cracks could be suppressed in a wide range of agent diameters.

Examples 19 and 20
OD tablets having the compositions shown in Tables 6 and 7 were prepared in the same manner as in the examples.

The medicinal particles of the present invention can be used as functional medicinal particles for preparing an orally disintegrating tablet containing various medicinal ingredients, and in particular, contain medicinal ingredients that are easily decomposed by gastric juice (gastric acid) and require an enteric layer. It is suitable as a functional medicinal particle for preparing an orally disintegrating tablet.

Claims (14)

A medicinal particle formed by a globose nucleus containing a medicinal component and a coat portion covering the globose nucleus and including a release control layer and an outermost layer containing mannitol, which is mannitol contained in the outermost layer. The ratio of the medicinal particles is 4% by mass or more in the medicinal particles. The medicinal particle according to claim 1, wherein the release control layer is an enteric layer. The medicinal particle according to claim 2, wherein the coated portion further includes a shielding layer interposed between the enteric layer and the globose nucleus. As the coated portion, a first shielding layer, a second shielding layer, a first enteric layer, an intermediate layer, a second enteric layer, and an outermost layer are sequentially laminated on the globose nucleus portion. The medicinal particle according to any one of claims 1 to 3. The medicinal particle according to any one of claims 1 to 4, wherein the particle hardness is 400 gf or more. The medicinal particle according to any one of claims 1 to 5, wherein the outermost layer does not contain a disintegrant. The medicinal particle according to any one of claims 1 to 6, wherein the medicinal ingredient is esomeprazole or a salt thereof and / or a solvate. The medicinal particle according to any one of claims 1 to 7, wherein the central particle size is 460 to 550 μm. The method for producing medicinal particles according to any one of claims 1 to 8, wherein the globose nucleus is coated with a coated portion to obtain medicinal particles. An orally disintegrating tablet containing the medicinal particles according to any one of claims 1 to 8. The orally disintegrating tablet according to claim 10, further comprising fast-disintegrating particles. The orally disintegrating tablet according to claim 11, wherein the rapidly disintegrating particles contain sugar alcohol and carmellose, and the proportion of crystalline cellulose in the particles is less than 1% by mass. The orally disintegrating tablet according to claim 11 or 12, wherein the rapidly disintegrating particles do not contain a medicinal ingredient. The ratio of mannitol contained in the outermost layer in the medicinal particles formed by the globose nucleus containing the medicinal component and the coat portion covering the globose nucleus and including the release control layer and the outermost layer containing mannitol. A method for suppressing the occurrence of cracks in tableting for preparing an orally disintegrating tablet containing the medicinal particles by adjusting the amount to 4% by mass or more in the medicinal particles.