JP2015083615A - Coating composition excellent in oral disintegration - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an oral disintegrable tablet in which the outside of an uncoated tablet containing a hormone-like substance as an active ingredient is covered with a coating film.SOLUTION: In an oral disintegrable tablet in which the outside of an uncoated tablet containing a specific hormone-like substance as an active ingredient is covered with a coating film, the outermost layer of the coating film contains trehalose and/or erythritol and a water-insoluble compound having an average particle diameter of 0.1 to 50 μm, which is selected from a group consisting of water-insoluble inorganic salts, silicate compounds, aluminum hydroxides, magnesium oxides, zinc oxides, stearic acid, and stearyl sodium fumarate. The coating film prevents contact with the active ingredient, a tablet applied with the coating film has a smaller slip angle compared with the uncoated tablet, and the coating surface is smooth.

Description

  The present invention relates to an outermost layer coating composition suitably used for forming a thin film as the outermost layer of various orally disintegrating tablets for pharmaceutical use, supplements, etc., an outermost layer coating liquid, and a coating having the outermost layer film It is related with a tablet and its manufacturing method.

  Various coated tablets formed by coating a film on the outside of a tablet such as a sugar-coated tablet have been developed so far. However, although some proposals have been made on coating compositions for improving the handleability and the like while maintaining the characteristics of orally disintegrating tablets, none have been put to practical use. For example, Patent Document 1 discloses an orally disintegrating film-coated tablet including an orally disintegrating tablet core and a film coating layer. By providing such a film coating layer, an orally disintegrating tablet is disclosed. While maintaining the above characteristics, it is possible to provide a tablet having high strength that is stable against abrasion and impact at the time of manufacturing, transporting, storing, packaging, and dispensing. Here, a film made of a water-soluble polymer, a plasticizer (Macrogol 400) and titanium oxide is used as the film formed on the outside of the tablet. However, there are concerns about problems such as a feeling of slimming and disintegration that are characteristic of film coating, delay of disintegration, and peeling of the tablet due to slight swelling of the tablet due to moisture absorption.

On the other hand, a sugar-coated tablet coated with a saccharide such as sucrose, trehalose or erythritol and a binder has been proposed. Patent Document 2 is mainly composed of a sugar coating layer containing 50 mg of α, α-trehalose, 10 mg of talc, 5 mg of precipitated calcium carbonate, 1.5 mg of gum arabic and 0.5 mg of gelatin per 252 mg of uncoated tablet, and sucrose. A sugar-coated tablet is obtained by forming a top sugar-coated layer by a pan coating method. Patent Document 3 discloses an undercoat solution comprising 40 parts by weight of water containing trehalose, 2 parts by weight of pullulan (average molecular weight 200,000), 30 parts by weight of water, 25 parts by weight of talc and 3 parts by weight of titanium oxide, and then water containing trehalose. A coating method is disclosed in which an overcoat liquid comprising 65 parts by weight, 1 part by weight of pullulan and 34 parts by weight of water is used for the uncoated tablet. However, the coating films disclosed in Patent Documents 2 and 3 are not intended for orally disintegrating tablets, and are further used in combination with a binder and are considered to have a layer thickness of several hundreds of μm or more. Whether it is possible to produce a coated tablet that maintains the above characteristics is unclear.
Regarding thin-layer sugar-coated tablets, Patent Document 4 discloses a thin-layer sugar-coated tablet having a sugar-coated layer containing a sugar, an excipient, and a binder in an amount of 5 to 60% of the uncoated tablet weight. It is useful for masking unpleasant odors and preventing whisker generation, can be made sugar-free, has a short manufacturing time, can be downsized, and decomposes with high moisture due to low water content of tablets. It is said to be a thin-layer sugar-coated tablet that can stabilize the drug. In Example 2, a sugar coating solution in which 50 g of erythritol, 28 g of talc, 10 g of crystalline cellulose and 12 g of gum arabic powder were dissolved and suspended in 120 g of purified water was used in 300 g of uncoated tablets, and 35% of the uncoated tablet weight with respect to the uncoated tablets. Further, a sugar coating solution in which 89 g of erythritol, 10 g of gum arabic powder, and 1 g of macrogol 6000 were dissolved in 160 g of purified water was coated on the uncoated tablet in an amount of 5% to obtain a thin-layered sugar-coated tablet, In addition, a thin layer of sugar-coated tablets is coated with a slight amount of a polishing liquid. This sugar-coated film is not intended for orally disintegrating tablets, and it is also used as a thin-layered sugar-coated tablet. The thickness is considered to be several hundred μm or more, and it is completely unknown whether a coated tablet that maintains the characteristics of an orally disintegrating tablet can be produced.

Patent document 5 includes spraying a coating solution or suspension comprising sugar or starch or a mixture of sugar and starch onto a tablet or tablet core to obtain a coated tablet, provided that film formation in the coating solution or suspension Disclosed is a tablet core coating method wherein the material is removed. In Example 1, tablet cores were prepared from mannitol (21.4%), soluble starch (21.4%), silicon dioxide (2.0%), talc (31.8%), titanium dioxide (21.4%). ) And aspartame (2.0%). This sugar-coated film is not intended for orally disintegrating tablets, and it is completely unknown whether a coated tablet that maintains the characteristics of orally disintegrating tablets can be produced. Rather, the advantage of this coated tablet is that the tablet already disintegrates in the patient's mouth, which can be uncomfortable for the patient, such as can occur with uncoated tablets when contacted with saliva or another liquid. It is described that the release of the active compound can be controlled and can be interpreted as delaying disintegration in the oral cavity.
In Patent Document 5, use of mannitol and starch is essential, and trehalose and erythritol are not described at all regarding sugar.
Furthermore, when a coating film is formed on an uncoated tablet by a conventional method, it is necessary to repeatedly apply a coating solution to the uncoated tablet and dry it, which causes a problem that it takes time to form the coating film.

JP 2010-248106 A JP-A-6-227975 Japanese Patent Laid-Open No. 7-143876 JP 2002-179559 A Special table 2003-514848 gazette

The present invention obtains a coated tablet that maintains the characteristics of an orally disintegrating tablet that achieves the contradictory properties of fast disintegration and hardness, and is difficult to crack and has a smooth surface despite the thin coating film. An object of the present invention is to provide an outermost layer coating composition and an outermost layer coating solution that can be applied.
Another object of the present invention is to provide a coated tablet prepared using the outermost layer coating composition and the outermost layer coating solution.
Another object of the present invention is to provide an orally disintegrating tablet in which the outer side of an uncoated tablet containing a hormone-like substance as an active ingredient is covered with a coating film.
Another object of the present invention is to provide an industrially excellent method for producing a coated tablet.

The present invention provides at least one water-insoluble inorganic compound and / or water selected from the group consisting of a specific saccharide and a water-insoluble inorganic salt having a specific average particle diameter, a silicate compound, aluminum hydroxide, magnesium oxide and zinc oxide. When the outermost layer film of a tablet is formed by combining an insoluble fatty acid, a salt thereof or an ester thereof, a specific sugar is used as a matrix to favorably incorporate the water-insoluble inorganic compound and / or the water-insoluble fatty acid, a salt thereof or an ester thereof. This is based on the knowledge that a thin and smooth film can be formed to solve the above-mentioned problems. Moreover, when the coating composition was made to contain titanium oxide in order to further improve the appearance of the coated tablet, a problem was found that the color tone of the coating changes due to ultraviolet rays. This problem is particularly problematic in tablet coating. The present invention is based on the knowledge that the coating composition can contain at least one organic compound selected from an organic binder, a water-soluble polymer, and a disintegrant to solve this color change problem. It was made.
That is, the first aspect of the present invention is the following coating composition.
(1-1) At least one selected from the group consisting of trehalose and / or erythritol and water-insoluble inorganic salts having an average particle diameter of 0.1 to 50 μm, silicate compounds, aluminum hydroxide, magnesium oxide and zinc oxide. An outermost layer coating composition for forming a film having a thickness of 100 μm or less as an outermost layer of a tablet, comprising a water-insoluble inorganic compound and / or a water-insoluble fatty acid, a salt thereof or an ester thereof.
(1-2) Trehalose and / or erythritol: In the above (1-1), the water-insoluble inorganic compound and / or water-insoluble fatty acid, salt or ester thereof is in the range of 1: 3 to 3: 1 (mass ratio). The coating composition as described.
(1-3) Trehalose and / or erythritol: In the above (1-1), the water-insoluble inorganic compound and / or water-insoluble fatty acid, salt or ester thereof is in the range of 1: 2 to 2: 1 (mass ratio). The coating composition as described.
(1-4) The coating composition according to any one of (1-1) to (1-3), wherein the water-insoluble inorganic compound is a silicate compound.
(1-5) The above-described (1- The coating composition as described in 4).

(1-6) Any of the above (1-1) to (1-3), wherein the water-insoluble inorganic compound is one or more selected from the group consisting of dry aluminum hydroxide gel, magnesium oxide, aluminum hydroxide, and zinc oxide. A coating composition according to claim 1.
(1-7) The above (1-1) to (1), wherein the water-insoluble fatty acid, salt or ester thereof is one or more selected from the group consisting of stearic acid or salt thereof, sodium stearyl fumarate, and sucrose fatty acid ester. -3) The coating composition according to any one of the above.
(1-8) The water-insoluble inorganic compound and / or the water-insoluble fatty acid, salt or ester thereof has an average particle diameter in the range of 1 to 20 μm, as described in any of (1-1) to (1-7) above Coating composition.
(1-9) The coating composition according to the above (1-8), wherein the average particle size of the water-insoluble inorganic compound and / or water-insoluble fatty acid, salt or ester thereof is in the range of 5 to 10 μm.
(1-10) The coating composition according to any one of the above (1-1) to (1-9) for forming a film having a thickness of 50 μm or less as the outermost layer of the tablet.
(1-11) The coating composition according to the above (1-10) for forming a film having a thickness of 20 μm or less as the outermost layer of the tablet.
(1-12) The coating composition according to any one of (1-1) to (1-11), which does not contain an organic binder and / or a water-soluble polymer.
(1-13) The coating composition according to any one of (1-1) to (1-12), further comprising a pharmaceutically acceptable colorant and / or a light stabilizer.
(1-14) The colorant is titanium oxide, iron oxide (black iron oxide), iron sesquioxide (red iron oxide), yellow sesquioxide, zinc oxide, water-soluble edible tar dye, water-insoluble lake dye, riboflavin The coating composition according to (1-13), which is at least one water-insoluble inorganic particle or light stabilizer selected from the group consisting of chlorophyll and barium sulfate.

The second aspect of the present invention is the following coating solution.
(2-1) An outermost layer coating solution for forming a film as the outermost layer of a tablet, wherein the coating composition is dissolved and / or dispersed in water and / or alcohol.
(2-2) The coating liquid according to (2-1), wherein water: alcohol is in the range of 1: 1 to 20: 1 (volume ratio).
(2-3) The coating liquid according to (2-1) or (2-2) above, wherein the alcohol is methanol and / or ethanol.

The third aspect of the present invention is the following coated tablet.
(3-1) Trehalose and / or erythritol and at least one selected from the group consisting of water-insoluble inorganic salts having an average particle diameter of 0.1 to 50 μm, silicate compounds, aluminum hydroxide, magnesium oxide and zinc oxide. A coated tablet, wherein a film containing a water-insoluble inorganic compound and / or a water-insoluble fatty acid, a salt thereof or an ester thereof is formed with a thickness of 100 μm or less as the outermost layer of the tablet.
(3-2) Trehalose and / or erythritol: In the above (3-1), the water-insoluble inorganic compound and / or the water-insoluble fatty acid, salt or ester thereof is in the range of 1: 3 to 3: 1 (mass ratio). The coated tablet as described.
(3-3) Trehalose and / or erythritol: In the above (3-1), the water-insoluble inorganic compound and / or water-insoluble fatty acid, salt or ester thereof is in the range of 1: 2 to 2: 1 (mass ratio). The coated tablet as described.
(3-4) The coated tablet according to any one of (3-1) to (3-3), wherein the water-insoluble inorganic compound is a silicate compound.
(3-5) The above (3-) wherein the silicate compound is at least one selected from the group consisting of talc, magnesium aluminate metasilicate, silicon dioxide, kaolin, magnesium silicate, hydrous silicon dioxide, and light anhydrous silicic acid. The coated tablet according to 4).
(3-6) Any of the above (3-1) to (3-3), wherein the water-insoluble inorganic compound is at least one selected from the group consisting of dry aluminum hydroxide gel, magnesium oxide, aluminum hydroxide, and zinc oxide. Coated tablet according to crab.
(3-7) The above (3-1) to (3), wherein the water-insoluble fatty acid, salt or ester thereof is one or more selected from the group consisting of stearic acid or salt thereof, sodium stearyl fumarate, sucrose fatty acid ester. -3) The coated tablet according to any one of the above.

(3-8) The water-insoluble inorganic compound and / or water-insoluble fatty acid, salt thereof, or ester thereof has an average particle diameter in the range of 1 to 20 μm, as described in any one of (3-1) to (3-7) above. Coated tablets.
(3-9) The coated tablet according to (3-8) above, wherein the average particle size of the water-insoluble inorganic compound and / or water-insoluble fatty acid, salt or ester thereof is in the range of 5 to 10 μm.
(3-10) The coated tablet according to any one of the above (3-1) to (3-9) for forming a film having a thickness of 50 μm or less as the outermost layer of the tablet.
(3-11) The coated tablet according to the above (3-10) for forming a film having a thickness of 20 μm or less as the outermost layer of the tablet.
(3-12) The coated tablet according to any one of (3-1) to (3-11), which does not contain an organic binder and / or a water-soluble polymer.
(3-13) Furthermore, at least one water-insoluble inorganic particle selected from the group consisting of titanium oxide, iron oxide (black iron oxide), iron sesquioxide (red iron oxide), yellow iron sesquioxide and zinc oxide, and The coated tablet according to any one of (3-1) to (3-11) above, which contains at least one organic compound selected from the group consisting of an organic binder, a water-soluble polymer, and a disintegrant.
(3-14) The coated tablet according to any one of (3-1) to (3-13) above, wherein the disintegration time measured by the method of Test Example 1 described later is 60 seconds or less.
(3-15) The coated tablet according to (3-14) above, wherein the disintegration time is 40 seconds or less.
(3-16) The coated tablet according to (3-14) above, wherein the disintegration time is 20 seconds or less.
(3-17) The coated tablet according to any one of (3-14) to (3-16), wherein the disintegration time is not more than twice the disintegration time of the uncoated tablet measured by the method of Test Example 1 described later. .

(3-18) The coated tablet according to any one of (3-14) to (3-16) above, wherein the disintegration time of the coated tablet is not delayed by 20 seconds or more compared to the disintegration time of the uncoated tablet.
(3-19) The coated tablet according to (3-18) above, wherein the disintegration time of the coated tablet is not delayed by 10 seconds or more compared to the disintegration time of the uncoated tablet.
(3-20) The coated tablet according to any one of (3-1) to (3-19), wherein the hardness measured by the method of Test Example 2 described later is 30 Newtons (N) or more.
(3-21) The coated tablet according to the above (3-20), which has a hardness of 40 N or more.
(3-22) The coated tablet according to (3-20), wherein the hardness is 50 N or more.
(3-23) The coated tablet according to the above (3-20), which has a hardness of 60 N or more.
(3-24) Any of (3-1) to (3-23) above, wherein the absolute value of the difference between the hardness of the coated tablet and the hardness of the uncoated tablet measured by the method of Test Example 2 described later is within 10N The coated tablet according to 1.
(3-25) The coated tablet according to any one of (3-1) to (3-23) above, wherein the hardness of the coated tablet is not less than the hardness of the uncoated tablet.
(3-26) The coated tablet according to any one of (3-1) to (3-25) above, wherein the sliding angle measured by the method of Test Example 3 described later is 15 degrees or less.
(3-27) The coated tablet according to (3-26), wherein the sliding angle is 14 degrees or less.
(3-28) The above (3-1) to (3-27), wherein the absolute value of the difference between the sliding angle of the coated tablet and the sliding angle of the uncoated tablet measured by the method of Test Example 3 described later is within 1 degree. The coated tablet according to any one of the above.
(3-29) The coated tablet according to any one of (3-1) to (3-28), wherein the sliding angle of the coated tablet is not more than the sliding angle of the uncoated tablet.
(3-30) The above (3-1) to (3) in which the degree of change in the drop test of Test Example 4 described later is no change or very small crushing (cannot be confirmed visually but can be confirmed with a stereomicroscope). -29) The coated tablet according to any one of
(3-31) The coated tablet according to any one of (3-1) to (3-30), wherein the degree of appearance confirmed in Test Example 5 described later is glossy and very smooth or smooth. .

A fourth aspect of the present invention is the following method for producing a coated tablet.
(4-1) A method for producing a coated tablet, wherein the coating liquid is formed as an outermost layer of the tablet with a thickness of 100 μm or less.
(4-2) The manufacturing method of the coated tablet as described in (4-1) whose thickness of an outermost layer is 50 micrometers or less.
(4-3) The method for producing a coated tablet according to (4-1), wherein the outermost layer has a thickness of 20 μm or less.

The fifth aspect of the present invention is the following coating composition that effectively reduces coloring by light, particularly ultraviolet rays.
(5-1) Titanium oxide, iron oxide (black iron oxide), iron sesquioxide (red iron oxide), at least one water-insoluble inorganic particle selected from the group consisting of yellow iron sesquioxide and zinc oxide, and an organic bond A composition for coating a tablet, which contains at least one organic compound selected from the group consisting of an agent, a water-soluble polymer, and a disintegrant, wherein discoloration due to ultraviolet rays of the water-insoluble inorganic particles is reduced .
(5-2) At least one water-insoluble inorganic particle selected from the group consisting of titanium oxide, iron oxide (black iron oxide), iron sesquioxide (red iron oxide), yellow iron sesquioxide and zinc oxide, and an organic bond An outermost layer coating composition for forming an outermost layer of an orally disintegrating tablet, comprising at least one organic compound selected from the group consisting of an agent, a water-soluble polymer and a disintegrant.
(5-3) Furthermore, at least one water selected from the group consisting of polysaccharides, water-insoluble inorganic salts having an average particle size of 0.1 to 50 μm, silicic acid compounds, aluminum hydroxide, magnesium oxide and zinc oxide. The composition according to (5-1) or (5-2), comprising an insoluble inorganic compound and / or a water-insoluble fatty acid, a salt thereof or an ester thereof.

The sixth aspect of the present invention is at least one water selected from the group consisting of titanium oxide, iron oxide (black iron oxide), iron sesquioxide (red iron oxide), yellow iron sesquioxide and zinc oxide. This is a method for reducing discoloration of a composition containing insoluble inorganic particles due to light, particularly ultraviolet rays.
(6-1) A composition containing at least one water-insoluble inorganic particle selected from the group consisting of titanium oxide, iron oxide (black iron oxide), iron sesquioxide (red iron oxide), yellow iron sesquioxide and zinc oxide. A method for reducing discoloration due to ultraviolet rays of a composition containing water-insoluble inorganic particles, wherein at least one organic compound selected from the group consisting of an organic binder, a water-soluble polymer and a disintegrant is added to the product.

A seventh aspect of the present invention is an orally disintegrating tablet in which the outer side of an uncoated tablet containing a hormone-like substance as an active ingredient is covered with a coating film.
(7-1) Element comprising one or more hormone-like substances selected from the group consisting of norethisterone, medroxyprogesterone acetate, methyltestosterone, didrogesterone, estradiol, ethinylestradiol, levonorgestrel, pregnanediol, salivary gland hormone, and dienogest as active ingredients An orally disintegrating tablet in which the outside of the tablet is covered with a coating film,
The outermost layer of the coating film is at least one selected from the group consisting of trehalose and / or erythritol and water-insoluble inorganic salts, silicate compounds, aluminum hydroxide, magnesium oxide, zinc oxide, stearic acid, and sodium stearyl fumarate. Containing a water-insoluble compound having an average particle size of 0.1 to 50 μm,
Contact with the active ingredient is prevented by the coating film,
Tablets with a coating film are orally disintegrating tablets with a smooth coating surface with a reduced sliding angle compared to plain tablets.

According to the present invention, at least one water-insoluble inorganic compound selected from the group consisting of a specific saccharide and a water-insoluble inorganic salt having a specific average particle diameter, a silicate compound, aluminum hydroxide, magnesium oxide and zinc oxide, and / or Alternatively, a film having a thickness of 100 μm or less can be applied as the outermost layer of the tablet by combining only water-insoluble fatty acids, salts thereof or esters thereof. Therefore, there is an advantage that it is not necessary to use a commonly used organic binder and / or water-soluble polymer. There are few problems of delamination. According to the present invention, while satisfying the characteristics required for orally disintegrating tablets, such as fast disintegration and hardness, the storage stability of the active ingredient such as shading and moisture prevention is improved, and contact with active ingredients of persons other than patients is prevented. The effect of can be achieved. Moreover, since the external appearance of the tablet coated with the coating composition of the present invention has few irregularities and good slipperiness, it is excellent in production efficiency and handleability, and excellent in applicability and beauty.
When a colorant and / or a light stabilizer is added to the coating composition of the present invention, the appearance is further improved, and the storage stability of the active ingredient is improved by the light shielding effect. Even when water-insoluble inorganic particles such as titanium oxide are used as a colorant and / or a light stabilizer, by containing at least one organic compound selected from an organic binder, a water-soluble polymer, and a disintegrant. The color change due to ultraviolet rays in the coated tablet is reduced. The coating composition of the present invention has at least one, preferably all of the above preferred properties.

  The coating composition of the present invention comprises trehalose and / or erythritol, water-insoluble inorganic salts having an average particle size of 0.1 to 50 μm, preferably 1 to 20 μm, more preferably 5 to 10 μm, silicic acid compounds, aluminum hydroxide , At least one water-insoluble inorganic compound and / or water-insoluble fatty acid, salt or ester thereof selected from the group consisting of magnesium oxide and zinc oxide is 30% or more, preferably 50% by mass or more of the entire coating composition, More preferably, it is used in an amount of 60% by mass or more, particularly preferably 70% by mass or more.

  Trehalose and / or erythritol used in the coating composition of the present invention is contained as an essential component. Trehalose is a kind of disaccharide formed by combining 1,1-glycoside with glucose, and is a white powdery crystal at normal temperature and pressure. As trehalose, any of α, α-trehalose, α, β-trehalose and β, β-trehalose may be used, but naturally occurring α, α-trehalose is preferably used. Further, a water-containing crystallized product may be used. On the other hand, erythritol is a natural sugar alcohol contained in fruits and the like. Both trehalose and erythritol are readily available from the market. Examples of trehalose include treha (high-purity water-containing crystal α, α-trehalose, Hayashibara Biochemical Laboratories), trehalose (α, α-trehalose, Asahi Kasei Corporation), and the like. An example of erythritol is erythritol (Mitsubishi Corporation Food Tech). Trehalose and erythricol have low hygroscopicity among sugars and can be preferably used in a coating composition for orally disintegrating tablets. Here, the coating composition of the present invention contains trehalose and / or erythritol in an amount of 10% by mass or more, preferably 15% by mass or more, more preferably 20% by mass or more of the entire coating composition. Moreover, Preferably it is 10-90 mass%, More preferably, it is 15-80 mass%, Most preferably, it is 20-70 mass%.

As the water-insoluble inorganic compound used in the coating composition of the present invention, a silicate compound is preferable. Examples of the silicate compound include talc, magnesium aluminate metasilicate, silicon dioxide, kaolin, magnesium silicate, hydrous silicon dioxide, and light anhydrous silicic acid. Talc and magnesium aluminate metasilicate are particularly desirable.
Examples of the inorganic compound other than the silicate compound include dry aluminum hydroxide gel, magnesium oxide, aluminum hydroxide, and zinc oxide. Examples of the water-insoluble inorganic salts include tricalcium phosphate, calcium hydrogen phosphate, magnesium carbonate, and calcium carbonate.
Examples of the water-insoluble fatty acid, salt or ester thereof used in the coating composition of the present invention include stearic acid or a salt thereof, sodium stearyl fumarate, sucrose fatty acid ester and the like. The above water-insoluble inorganic compound and / or water-insoluble fatty acid, salt or ester thereof can be easily obtained from the market. For example, as talc, high filler # 7 (Matsumura Sangyo Co., Ltd., average particle size 5 μm by laser diffraction method), high filler # 12 (Matsumura Sangyo Co., Ltd., average particle size 3 μm by laser diffraction method), high filler # 17 (Matsumura Sangyo Co., Ltd., average particle size 7.4 μm by laser diffraction method), UM talc (Luzenac Pharma, average particle size 3.6 μm by laser diffraction method), M talc (Luzenac Pharma, average particle size 4 by laser diffraction method) .7 μm) and the like. As magnesium metasilicate aluminate, Neusilin type FH1 (Fuji Chemical Industry Co., Ltd., average particle diameter 10.7 μm by laser diffraction method), Neusilin type FL1 (Fuji Chemical Industry Co., Ltd., average particle diameter 5 by laser diffraction method) 0.4 μm), Neusilin type UFL2 (Fuji Chemical Industry Co., Ltd., average particle diameter 4.3 μm by laser diffraction method) and the like. Examples of sodium stearyl fumarate include probe (JRS Pharma, average particle diameter of 22 μm by laser diffraction method), probe CG (JRS Pharma, average particle diameter of 35 μm by laser diffraction method), and the like.

Here, water insolubility is defined by the Japanese Pharmacopoeia. When the powder is passed through a No. 100 (150 μm) sieve, it is placed in a solvent and shaken vigorously every 5 minutes at 20 ± 5 ° C for 30 seconds. The degree of dissolution within 30 minutes means that it is extremely difficult to dissolve (the amount of solvent necessary for dissolving 1 g of solute is 1000 ml or more and less than 10,000 ml) and hardly dissolved (10,000 ml or more).
The average particle diameter of the water-insoluble inorganic compound and / or water-insoluble fatty acid, salt or ester thereof used in the present invention is 0.1-50 μm, preferably 1-20 μm, more preferably 5-10 μm. The average particle size is desirably 80% or less, preferably 60% or less, more preferably 40% or less, and further preferably 20% or less of the thickness of the outermost layer coating film. The average particle diameter can be easily measured by a laser diffraction method using, for example, a laser diffraction / scattering particle diameter / particle size distribution measuring apparatus (for example, Microtrac MT3100 II (Nikkiso Co., Ltd.)).

According to the present invention, at least one selected from the group consisting of trehalose and / or erythritol and water-insoluble inorganic salts having an average particle diameter of 0.1 to 50 μm, silicate compounds, aluminum hydroxide, magnesium oxide, and zinc oxide. Of the water-insoluble inorganic compound and / or water-insoluble fatty acid, salt or ester thereof as the outermost layer coating composition, the outermost layer of the orally disintegrating tablet is 100 μm or less, preferably 50 μm or less, more preferably 20 μm or less. Can be formed. In particular, the thickness is preferably 1 to 50 μm, more preferably 1 to 30 μm, and still more preferably 2 to 20 μm. The thickness is preferably 5 μm or more, preferably 5 to 100 μm, more preferably 5 to 50 μm, still more preferably 10 to 50 μm, and particularly preferably 10 to 30 μm.
Here, the layer thickness of the outermost layer can be measured by using a method and equipment usually used in the scientific and industrial fields. Although the following methods are illustrated, it is not limited to these methods.
The section of the coated tablet cut with a cutter is observed with a digital microscope or a scanning electron microscope, the thickness of the coating layer is measured at a plurality of locations, and the average value of the measured values is taken as the layer thickness. Any two or more measurement locations are preferable, more preferably any three or more locations, and an average value of measurement values at any three locations is usually sufficient.

Using a near-infrared / mid-infrared / far-infrared imaging system or a terahertz imaging system, measure the layer thickness distribution of the coated tablets non-invasively according to the measurement method of each system, and calculate the average value of those measurements. Layer thickness. For example, MatrixNIR ^TM system (Spectraldimentions) as a near infrared imaging system, Spotlight 400N (PerkinElmer), Frontier FT IR / NIR as a near infrared / middle infrared / far infrared imaging system / MIR / FIR system (Perkin Elmer) and others include TAS7500 terahertz imaging system (Advantest) and TPI Image 2000 (TeraView) as terahertz imaging systems.
In the present invention, trehalose and / or erythritol: a water-insoluble inorganic compound and / or a water-insoluble fatty acid, a salt thereof or an ester thereof is preferably used in a range of 1: 4 to 4: 1 (mass ratio). It is more preferable to use in the range of 3: 1 (mass ratio), and still more preferably in the range of 1: 2 to 2: 1 (mass ratio).
The combination of trehalose and / or erythritol and the water-insoluble inorganic compound and / or water-insoluble fatty acid, salt or ester thereof in the coating composition of the present invention is not particularly limited, but the following combinations may be exemplified. it can.

(1) A combination of trehalose and talc;
(2) Combination of trehalose and magnesium aluminate metasilicate;
(3) A combination of trehalose and one or more selected from the group consisting of silicon dioxide, kaolin, magnesium silicate, hydrous silicon dioxide, and light anhydrous silicic acid;
(4) A combination of trehalose and one or more selected from the group consisting of dried aluminum hydroxide gel, magnesium oxide, aluminum hydroxide, magnesium carbonate, zinc oxide and calcium carbonate;
(5) A combination of trehalose and one or more selected from the group consisting of stearic acid or a salt thereof, sodium stearyl fumarate, sucrose fatty acid ester;
(6) A combination of erythritol and talc;
(7) Combination of erythritol and magnesium aluminate metasilicate;
(8) A combination of erythritol and one or more selected from the group consisting of silicon dioxide, kaolin, magnesium silicate, hydrous silicon dioxide, and light anhydrous silicic acid;
(9) A combination of erythritol and one or more selected from the group consisting of dry aluminum hydroxide gel, magnesium oxide, aluminum hydroxide, magnesium carbonate, zinc oxide and calcium carbonate;
(10) A combination of erythritol and one or more selected from the group consisting of stearic acid or a salt thereof, sodium stearyl fumarate, sucrose fatty acid ester;
(11) Combination of trehalose and erythritol with talc;
(12) A combination of trehalose and erythritol with magnesium aluminate metasilicate;
(13) A combination of trehalose and erythritol with one or more selected from the group consisting of silicon dioxide, kaolin, magnesium silicate, hydrous silicon dioxide, and light anhydrous silicic acid;
(14) A combination of trehalose and erythritol with one or more selected from the group consisting of dry aluminum hydroxide gel, magnesium oxide, aluminum hydroxide, magnesium carbonate, zinc oxide, calcium carbonate;
(15) A combination of trehalose and erythritol and one or more selected from the group consisting of stearic acid or a salt thereof, sodium stearyl fumarate, and a sucrose fatty acid ester.

As preferable combinations of the present invention, the following combinations can be exemplified.
(1) A combination of trehalose and talc;
(2) Combination of trehalose and magnesium aluminate metasilicate (3) Combination of erythritol and talc;
(4) A combination of erythritol and magnesium aluminate metasilicate;
(5) Combination of trehalose and erythritol and talc;
(6) A combination of trehalose and erythritol and magnesium aluminate metasilicate.

In addition to the above components, the coating composition of the present invention can contain various components as long as the effects of the present invention are not affected. Examples of such components include water-insoluble inorganic particles other than inorganic compounds such as titanium oxide, iron oxide (black iron oxide), iron sesquioxide (red iron oxide), yellow iron sesquioxide, and zinc oxide. These compounds can be used as a colorant and / or a light stabilizer, and can improve the appearance of the coated tablet or improve the storage stability of the active ingredient due to light shielding. Moreover, as such an auxiliary | assistant inorganic particle, an average particle diameter is 0.1-50 micrometers, Preferably it is 1-20 micrometers. The average particle size of at least one water-insoluble inorganic compound and / or water-insoluble fatty acid, salt or ester thereof selected from the group consisting of water-insoluble inorganic salts, silicate compounds, aluminum hydroxide, magnesium oxide and zinc oxide. It can be measured by the same method as the method of measuring the average particle diameter. In the present invention, the auxiliary inorganic particles are preferably used in an amount of 50% by mass or less, more preferably 1 to 20% by mass.
The coating composition of the present invention comprises at least one water-insoluble inorganic particle selected from the group consisting of titanium oxide, iron oxide (black iron oxide), iron sesquioxide (red iron oxide), yellow iron sesquioxide and zinc oxide. In the case of containing, at least one selected from the group consisting of an organic binder, a water-soluble polymer and a disintegrating agent, which will be described later, causes deterioration of the color tone of the coating composition due to light caused by these inorganic particles, particularly ultraviolet rays. It is preferable to reduce by including an organic compound. At this time, it is preferable to use the organic compound at a ratio of 10 to 1000 parts by mass with respect to 100 parts by mass of the inorganic particles, more preferably 30 to 1000 parts by mass, further preferably 50 to 800 parts by mass, and particularly preferably. 60 to 600 parts by mass.

Among the above organic binders, water-soluble polymers and disintegrants, water-soluble low-viscosity organic binders such as pullulan, crystalline cellulose, powdered cellulose, hypromellose, dextrin, corn starch, pregelatinized starch, and partially pregelatinized Suspending and swelling organic binders such as starch, water-soluble polymers such as Macrogol 6000, and disintegrants such as crospovidone are preferred. This time, in the crystalline cellulose, crospovidone, hypromellose and macrogol 6000, which are representative compounds of organic binders, water-soluble polymers and disintegrants, the effect of suppressing the discoloration of titanium oxide to light blue-white by light These compounds are more preferable.
The coating composition of the present invention is preferably prepared from only the above components and does not contain an organic binder and / or a water-soluble polymer, but can also contain additives usually used in the pharmaceutical field. The particle size of the additive of the coating composition of the present invention is preferably about 50 μm or less, and more preferably about 20 μm or less. Examples of additives used include organic binders and / or water-soluble polymers, excipients, disintegrants, lubricants, surfactants, sweeteners, flavoring agents, flavoring agents / fragrances, and fluidizing agents. , PH adjusting agents, colorants, stabilizers, light stabilizers, moisture-proofing agents, and the like. The coating composition of the present invention is used in the pharmaceutical field as necessary for further improving the appearance of the coated tablet or for improving the storage stability of the active ingredient by shading. An embodiment containing an acceptable colorant and / or a light stabilizer is also preferred. The pharmaceutically acceptable colorant and / or light stabilizer is not particularly limited. For example, the above-described titanium oxide, iron oxide (black iron oxide), iron sesquioxide (red iron oxide), yellow three Examples thereof include water-insoluble inorganic particles other than inorganic compounds such as iron dioxide and zinc oxide, and compounds listed as light stabilizers described later.

  Examples of the organic binder and / or water-soluble polymer include gum arabic powder, pullulan, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose 2208 (HPMC2208), hydroxypropylmethylcellulose 2906 (HPMC2906), hydroxypropylmethylcellulose 2910 (HPMC2910). ), Methyl cellulose (MC), hydroxyethyl cellulose (HEC), crystalline cellulose, powdered cellulose, low substituted hydroxypropyl cellulose, dextrin, corn starch, pregelatinized starch, partially pregelatinized starch, hydroxypropyl starch, polyvinylpyrrolidone (PVP), Carboxyvinyl polymer, polyvinyl alcohol (PVA), crystalline cellulose and carme Sodium, gelatin, xanthan gum, tragacanth, tragacanth end, macrogol 200, macrogol 300, macrogol 400, macrogol 600, macrogol 1000, macrogol 1500, macrogol 1540, macrogol 4000, macrogol 6000, macrogol 20000 And polyoxyethylene [105] polyoxypropylene [5] glycol. The coating composition of the present invention can be produced without adding an organic binder and / or a water-soluble polymer. In the coating composition of the present invention, it is desirable not to add an organic binder and / or a water-soluble polymer because there is a possibility that sliminess or decay delay may occur due to the addition of an organic binder and / or a water-soluble polymer. . However, for example, an organic binder and / or a water-soluble polymer is added to the coating composition to reduce the color tone of the coating composition containing water-insoluble inorganic particles such as titanium oxide. It is also possible to add a binder and / or a water-soluble polymer. When an organic binder and / or a water-soluble polymer is added, it is desirable that the content does not affect the effects of the present invention.

Here, the content that does not affect the effect of the present invention means that the organic binder and / or water-soluble polymer mass is 30% by mass or less, preferably 20% by mass or less, more preferably, the entire coating composition. It is 15 mass% or less, More preferably, it is 10 mass% or less, Most preferably, it is 5% mass or less.
Among organic binders and / or water-soluble polymers, those that are preferably used in the coating composition of the present invention are water-soluble organic binders having low viscosity, and examples thereof include pullulan. Further, among organic binders and / or water-soluble polymers, suspendable and swellable organic binders are more preferable, and examples thereof include crystalline cellulose, powdered cellulose, and dextrin. These materials are less prone to sliminess and decay delay. As one aspect of the present invention, it is also preferable to use an organic binder and / or a water-soluble polymer excluding starches in the coating composition of the present invention.

Examples of excipients include precipitated calcium carbonate, calcium monohydrogen phosphate, calcium hydrogen phosphate, sodium hydrogen phosphate, dipotassium phosphate, potassium dihydrogen phosphate, calcium dihydrogen phosphate, sodium dihydrogen phosphate. , Calcium sulfate, calcium lactate, synthetic aluminum silicate, synthetic hydrosite, dry aluminum hydroxide, magnesium carbonate, magnesium oxide, carmellose, carmellose calcium, carmellose sodium, carboxymethyl ethyl cellulose, carboxy starch sodium and the like.
Examples of the disintegrant include carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch sodium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropyl starch and the like.

Examples of the lubricant include glyceryl monostearate, glyceryl palmitostearate, sodium stearyl fumarate, sucrose fatty acid ester, carnauba wax, L-leucine, macrogol and the like.
Examples of the surfactant include sodium lauryl sulfate, polysorbate 80, hydrogenated oil, polyoxyethylene (105) polyoxypropylene (5) glycol (PEP101), polyoxyethylene (160) polyoxypropylene (30) glycol, and the like. Can be mentioned.
Examples of the sweetener include aspartame, amateur, fructose, xylitol, glycyrrhizic acid or a salt thereof, saccharin, sucralose, stevia extract, sucrose, D-sorbitol, glucose, maltitol, D-mannitol and the like.
Examples of the flavoring agent include ascorbic acid or a salt thereof, sodium chloride, magnesium chloride, citric acid or a salt thereof, glycine, glucono-δ-lactone, L-glutamic acid or a salt thereof, succinic acid or a salt thereof, β-cyclodextrin , Tartaric acid or a salt thereof, skim milk powder, sodium bicarbonate, lactic acid or a salt thereof, fumaric acid or a salt thereof, menthol, DL-malic acid or a salt thereof, and the like.

Examples of the fluidizing agent include calcium carbonate, calcium phosphate, gypsum, magnesium carbonate, synthetic aluminum silicate, magnesium alumina hydroxide, corn starch, calcium hydrogen phosphate granule, and glyceryl monostearate.
Examples of the pH adjuster include citrate, phosphate, carbonate, tartrate, fumarate, acetate, amino acid salt and the like.
Examples of the stabilizer include sodium edetate, tocopherol, cyclodextrin and the like.
Examples of light stabilizers include water-soluble food tar dyes (food yellow No. 5, food blue No. 2 etc.), water-insoluble lake dyes (water-soluble tar dye salts), riboflavin, chlorophyll, talc, zinc oxide, sulfuric acid Examples include barium. An embodiment in which the coating composition of the present invention contains a light stabilizer is also preferable.
Examples of the desiccant include ethyl cellulose, vinyl acetate resin, purified shellac, seraphate, and white shellac.

The coating composition of the present invention is preferably used as an outermost layer coating solution obtained by dissolving and dispersing the above components in water and / or alcohol. At this time, it is preferable to prepare trehalose and / or erythritol at a concentration of 0.5 to 20% by mass, preferably 1 to 10% by mass, more preferably 1 to 5% by mass. . In this case, a lower alcohol such as methanol, ethanol, isopropanol, etc. can be used as the alcohol, and ethanol, particularly anhydrous ethanol is preferred. Here, ethanol means that containing 95% by volume or more of ethanol, and absolute ethanol means that containing 99.5% or more by volume of ethanol. Water: alcohol ranges from 1: 1 to 20: 1, preferably 2: 1 to 10: 1, more preferably 3: 1 to 5: 1. Furthermore, an interfacial tension adjusting agent that lowers the interfacial tension of the coating liquid, for example, a nonionic surfactant, can also be added. When an alcohol solution is used, drying after coating can be performed in a short time, which is advantageous in production.
In the present invention, the coating liquid is applied to an orally disintegrating tablet (plain tablet) by a conventional method, for example, a spray coating method, with a thickness of 100 μm or less as an outermost layer, preferably 2 to 50 μm, more preferably 5 to 20 μm. It is preferable to produce a coated tablet by forming such that The preferred coating film thickness is as described above. Commercially available pan coating devices, fluidized bed coating devices, full-time rotary drum coating devices, and the like can be used, and full-year rotary drum coating devices are particularly suitable.
In the present invention, the coating liquid is preferably applied to the orally disintegrating tablet (uncoated tablet) as a single layer, but the orally disintegrating tablet (uncoated tablet) and a layer (outermost layer) formed of the coating liquid; In between, one or more additional intermediate layers can be provided. In this case, the total thickness of the coating layers provided for the orally disintegrating tablets (plain tablets) is preferably 100 μm or less, more preferably 50 μm or less.

The intermediate layer that can be provided in the present invention is not particularly limited as long as it does not impair the effects of the present invention, but preferably contains trehalose and / or erythritol, and further contains the various components described above. Also good. Particularly preferred can be set according to the embodiment of the outermost layer coating solution of the present invention.
The intermediate layer coating is preferably used as an intermediate layer coating solution obtained by dissolving and dispersing the intermediate layer coating component in water and / or alcohol. In this case, preferable mass% of trehalose and / or erythritol, alcohol type, water: alcohol ratio, and interfacial tension adjuster addition can be set according to the outermost layer coating solution.
The intermediate layer coating solution is formed on an orally disintegrating tablet (plain tablet) by a conventional method such as spray coating so as to have a thickness of 50 μm or less, preferably 1 to 30 μm, more preferably 2 to 20 μm. It is preferable.

  In the present invention, for the purpose of further improving the appearance of the coated tablet or for the purpose of improving the storage stability of the active ingredient due to light shielding, if necessary, the coating composition may contain other than inorganic compounds such as titanium oxide. It is possible to contain water-insoluble inorganic particles. In this case, it is preferable to use an outermost layer coating composition that effectively reduces changes in the color tone of the coated tablet due to light, particularly ultraviolet rays. That is, at least one water-insoluble inorganic particle selected from the group consisting of titanium oxide, iron oxide (black iron oxide), iron sesquioxide (red iron oxide), yellow sesquioxide and zinc oxide, and an organic binder, water-soluble It is the composition for outermost layer coating for forming the outermost layer of an orally disintegrating tablet containing the at least 1 sort (s) of organic compound chosen from the group which consists of a dispersible polymer and a disintegrating agent. Here, as the at least one organic compound selected from the group consisting of an organic binder, a water-soluble polymer, and a disintegrant, those described above are preferable. Furthermore, the preferable ratio of the said inorganic particle and the said organic compound is as above-mentioned. The inorganic particles are preferably contained in an amount of 1 to 67% by mass based on the outermost layer coating composition, more preferably 1 to 50% by mass, still more preferably 5 to 45% by mass, and particularly preferably 10 to 40% by mass. % Content is preferable.

  In addition to trehalose and erythritol, this outermost layer coating composition can contain other polysaccharides. The content of such a polysaccharide is preferably 0.1 to 50% by mass based on the outermost layer coating composition. Further, at least one water-insoluble inorganic compound and / or water-insoluble fatty acid selected from the group consisting of water-insoluble inorganic salts, silicate compounds, aluminum hydroxide, magnesium oxide and zinc oxide having an average particle size of 0.1 to 50 μm The salt or ester thereof is preferably contained in an amount of 1 to 70% by mass, more preferably 5 to 60% by mass, still more preferably 10 to 50% by mass, based on the outermost layer coating composition. The water-insoluble inorganic compound and / or water-insoluble fatty acid, salt or ester thereof are as described above.

The orally disintegrating tablet (plain tablet) to which the coating composition of the present invention is applied is not particularly limited as long as it is within the range normally used as an orally disintegrating tablet (plain tablet) in the industry. Preferably, it is an orally disintegrating tablet as defined in the 16th revised Japanese Pharmacopoeia General Rules for Preparations 1.1.1, and it is rapidly dissolved or disintegrated in the oral cavity with oral saliva or a small amount of water. Possible orally disintegrating tablets can be used. Moreover, the disintegration time measured by the method of Test Example 1 described later is 60 seconds or less, preferably 40 seconds or less, more preferably 20 seconds or less.
For example, an intraoral-dissolving tablet produced by tableting a mixture containing a medicinal ingredient described in JP-A-5-271054, a saccharide, and water having a wetness to the particle surface of the saccharide, WO 95/20380 An oral dissolution-type compression-molded product comprising a low-moldability saccharide and a high-moldability saccharide described in the publication, and having rapid disintegration and solubility in the oral cavity, and a drug described in WO99 / 47124 A mixture of amorphous saccharide (B) obtained by dissolving saccharide (A) and saccharide capable of becoming amorphous in a pharmaceutically acceptable solvent, removing the solvent from the solution and drying. , A rapidly disintegrating buccal tablet manufactured by humidification and drying after molding, a drug described in WO2002 / 092057, a diluent, and a saccharide having a melting point relatively lower than that of the drug and the diluent, The low melting sugar Orally disintegrating tablets produced by forming a cross-link with the drug and / or the diluent particles with a melt-solidified product of the saccharide having a low melting point, JP-A-2001-328948 Use a solid preparation containing a low-substituted hydroxypropyl cellulose having a loose bulk density of 0.40 g / ml or more and a hard bulk density of 0.60 g / ml or more, and a sugar / sugar alcohol, These orally disintegrating tablets (plain tablets) can be easily produced by the method described in the above-mentioned patent document. Moreover, the foamable disintegrating agent described in JP-A-5-50056 can also be contained.

Among these, as orally disintegrating tablets (plain tablets), in addition to the active ingredient drug, contain one or more from the group consisting of mannitol, xylitol, crystalline cellulose, crospovidone, magnesium aluminate metasilicate, and the like. Those are preferred.
The shape and size of the coated tablet formed with the coating composition of the present invention are not particularly limited, but from the viewpoint of ease of taking, a round tablet or an elliptical tablet having a diameter of about 5 to 15 mm and a thickness of about 2 to 5 mm. Preferably, it is a flower-shaped tablet or the like. Moreover, it is also possible to provide one or two secant lines so that the tablet can be divided into two or four as required.
Although the active ingredient contained in the coated tablet of the present invention is not particularly limited, the active ingredient commercially available as an orally disintegrating tablet (droxidopa, cilostazol, selegiline hydrochloride, acarbose, voglibose, glimepiride, pioglidazone, amlodipine, midodrine hydrochloride , Ebastine, olopatadine hydrochloride, cetirizine hydrochloride, fexofenadine hydrochloride, bepotastine besylate, imidafenacin, solifenacin succinate, tamsulosin hydrochloride, naphthopidyl, famotidine, lansoprazole, irsogladine maleate, precipitated calcium carbonate , Polaprezinc, rebamipide, tartyrelin hydrate, ramosetron hydrochloride, risperidone, brotizolam, galantamine hydrobromide, galantamine hydrobromide, etc.), with pharmacological activity In addition, active ingredients that are not preferably exposed to direct contact with non-healthcare or caregiver patients (norethisterone, medroxyprogesterone acetate, methyltestosterone, didrogesterone, estradiol, ethinylestradiol, levonorgestrel, pregnanediol, Hormone-like substances such as salivary gland hormones, dienogest, corticoids such as betamethasone and prednisolone, prostanoids, methyl ergometrine maleate, etc.) or active ingredients that have low light stability and require light shielding (nifedipine, benidipine, cilnidipine) And dihydropyridine antihypertensive drugs such as norfloxacin and ofloxacin, and other quinolone antibacterial drugs such as carbabapine and vitamins.
Furthermore, it is not limited to these active ingredients, The coating composition of this invention is applicable also to a Chinese medicine, an OTC medicine, the food for specified health, or a health food.

Next, although an example and a comparative example are shown and the present invention is explained still more concretely, the present invention is not limited to these.
<Manufacture of uncoated tablets>
(1) Uncoated tablet A
The following ingredients were weighed, mixed and tableted to obtain about 9 kg (about 90,000 tablets) of uncoated tablet A having a diameter of 6.5 mm and a thickness of 3.2 mm of about 100 mg / tablet.
D-mannitol, xylitol, crystalline cellulose, crospovidone, magnesium metasilicate aluminate mixture (F melt type M: Fuji Chemical Industry) 7.200 kg
Crystalline cellulose (Theolas PH-101: Asahi Kasei Chemicals) 2.100 kg
Crospovidone (Kollidon CL-F: BASF) 0.500kg
Talc (High filler # 17 Matsumura Sangyo) 0.200kg
Magnesium stearate (magnesium stearate plant: Ohira Chemical Industry) 0.025 kg
(2) Uncoated tablet B
The following ingredients were weighed, mixed and compressed to obtain about 9 kg (about 90,000 tablets) of about 100 mg / tablet of uncoated tablet B having a diameter of 6.5 mm and a thickness of 3.2 mm.
D-mannitol, xylitol, crystalline cellulose, crospovidone, magnesium metasilicate aluminate mixture (F melt type M: Fuji Chemical Industry) 7.200 kg
Crystalline cellulose (Theolas PH-101: Asahi Kasei Chemicals) 2.100 kg
Crospovidone (Kollidon CL-F: BASF) 0.500kg
Talc (High filler # 17 Matsumura Sangyo) 0.200kg
Sodium stearyl fumarate (PRUV: Kimura Sangyo) 0.100 kg

(3) Uncoated tablet C (dienogest tablet)
0.100 kg of dienogest is added to the ingredients of uncoated tablet B, manufactured in the same manner as uncoated tablet B, and approximately 9 mg (approximately 90,000 tablets) of uncoated tablet C with a diameter of 6.5 mm and a thickness of 3.2 mm of approximately 100 mg / tablet. Obtained.
(4) Uncoated tablet D
The following ingredients were weighed, mixed and tableted to obtain about 9 kg (about 90,000 tablets) of uncoated tablet D having a diameter of 6.5 mm and a thickness of 3.2 mm of about 100 mg / tablet.
D-mannitol (Pertek M200: Merck) 7.120 kg
Crystalline cellulose (Theolas PH-101: Asahi Kasei Chemicals) 2,000 kg
Crospovidone (Kollidon CL-F: BASF) 0.500kg
Talc (High filler # 17 Matsumura Sangyo) 0.200kg
Magnesium stearate (:) 0.080kg

<Coating>
Example 1
Trehalose (product name: Trehalose G: Hayashibara Biochemical Laboratories) 4.5 g was weighed and added to 191.0 g of purified water while stirring with a propeller stirrer to dissolve. Next, 4.5 g of talc (high filler # 17, average particle size 7.4 μm: Matsumura Sangyo) was weighed and added to the trehalose solution, and uniformly dispersed to obtain a coating solution [2.3% by mass of trehalose, talc 2 .3% by mass]. This coating solution was spray-coated on the uncoated tablets A using a coating apparatus (Dria Coater 200: Powrec) under the following conditions to obtain coated tablets. 200 g of uncoated tablet A (about 2000 tablets) was coated by one coating.
Supply air temperature: 56 ° C
Air volume: 40m ³ / min
Spray speed: 4.91 mL / min
Spray pressure: 0.12 MPa
Drum rotation speed: 10rpm

Example 2
Trehalose (product name: Trehalose G: Hayashibara Biochemical Laboratories) 9.0 g was weighed and added to 186.5 g of purified water with stirring with a propeller stirrer, and dissolved. Next, 4.5 g of talc (high filler # 17, average particle size 7.4 μm: Matsumura Sangyo) and 4.5 g of titanium oxide (average particle size 0.6 μm, product name NA65: Toho Titanium) were weighed, respectively, and the above trehalose In addition to the solution, it was uniformly dispersed to form a coating solution [trehalose 4.4 mass%, talc 2.2 mass%, and titanium oxide 2.2 mass%]. This coating solution was spray-coated on the uncoated tablets A using a coating apparatus (Dria Coater 200: Paulek) under the same conditions as in Example 1 to obtain coated tablets. 200 g of uncoated tablet A (about 2000 tablets) was coated by one coating.

Example 3
Erythritol (product name erythritol: Mitsubishi Corporation Foodtech) 6.0 g was weighed and added to 191.0 g of purified water while stirring with a propeller stirrer to dissolve. Next, 6.0 g of talc (high filler # 17, average particle size 7.4 μm: Matsumura Sangyo) and 3.0 g of titanium oxide (average particle size 0.6 μm, product name NA65: Toho Titanium) were weighed, and the above erythritol was measured. In addition to the solution, it was uniformly dispersed to obtain a coating liquid [erythritol 2.9% by mass, talc 2.9% by mass and titanium oxide 1.5% by mass]. A specified amount of this coating solution was spray coated on the uncoated tablet B using the coating apparatus (Dria Coater 200: Powrec) under the same conditions as in Example 1 to obtain coated tablets. 200 g of uncoated tablet B (about 2000 tablets) was coated by one coating.

Example 4
A propeller stirrer is prepared by weighing 10.0 g of trehalose (product name: trehalose G: Hayashibara Biochemical Laboratories) and mixing 125.0 g of purified water and 40.0 g of 99.5% ethanol (reagent special grade: Wako Pure Chemical Industries). The solution was added with stirring at a temperature and dissolved. Next, 20.0 g of talc (high filler # 17, average particle size 7.4 μm: Matsumura Sangyo) and 5.0 g of titanium oxide (average particle size 0.6 μm, product name NA65: Toho Titanium) were weighed, and the above trehalose was measured. In addition to the solution, it was uniformly dispersed to obtain a coating solution [trehalose 5.0 mass%, talc 10.0 mass% and titanium oxide 2.5 mass%]. A specified amount of this coating solution was spray coated on the uncoated tablet B using the coating apparatus (Dria Coater 200: Powrec) under the same conditions as in Example 1 to obtain coated tablets. 200 g of uncoated tablet B (about 2000 tablets) was coated by one coating.

Comparative Example 1
Trehalose (product name: Trehalose G: Hayashibara Biochemical Laboratories) 4.5 g was weighed and added to 191.0 g of purified water while stirring with a propeller stirrer to dissolve. Next, 4.5 g of crospovidone (Kollidon CL-SF, average particle size 17 μm: BASF) was weighed, added to the trehalose solution, and uniformly dispersed to give a coating solution [2.3% by mass of trehalose, crospovidone 2. 3% by mass]. This coating solution was spray-coated on the uncoated tablets A using a coating apparatus (Dria Coater 200: Paulek) under the same conditions as in Example 1 to obtain coated tablets. 200 g of uncoated tablet A (about 2000 tablets) was coated by one coating.

Comparative Example 2
Trehalose (product name: Trehalose G: Hayashibara Biochemical Laboratories) 4.5 g was weighed and added to 191.0 g of purified water while stirring with a propeller stirrer to dissolve. Next, 4.5 g of titanium oxide (average particle size 0.6 μm, product name NA65: Toho Titanium) was weighed and added to the above trehalose solution, and uniformly dispersed to form a coating solution [2.3% by mass of trehalose, titanium oxide. 2.3 mass%]. This coating solution was spray-coated on the uncoated tablets A using a coating apparatus (Dria Coater 200: Paulek) under the same conditions as in Example 1 to obtain coated tablets. 200 g of uncoated tablet A (about 2000 tablets) was coated by one coating.

The properties of the uncoated tablet and the coated tablet were evaluated by the following methods.
Test Example 1 <Disintegration time>
The uncoated tablet or coated tablet was measured under the following conditions using an orally disintegrating tablet tester (ODT-101: Toyama Sangyo). The average value of the measured values of 3 tablets was taken as the disintegration time.
Test solution: Water 37 ° C
Weight: φ20mm 10g 45rpm
Test Example 2 <Hardness>
The plain tablet or the coated tablet was measured by a conventional method using a tablet hardness meter (8M: Dr. Schleuniger Pharmatron AG). The average value of the measured values of 10 tablets was defined as hardness (Newton: N).
Test Example 3 <Slip angle>
A short side of a rectangular stainless steel plate measuring 17 cm × 28.5 cm was placed on a horizontal desk, and the short side facing each other was lifted with a jack to be inclined. Three plain tablets or coated tablets were put on the highest place on the stainless steel plate, and the angle between the stainless steel plate and the desk surface when all three tablets slipped was calculated, and this was taken as the sliding angle.

Test Example 4 <Drop test>
About 10 uncoated tablets or coated tablets, they were dropped onto a stainless steel plate from a height of 1 m, and the presence or absence of cracks was confirmed visually and using a digital microscope (VHX-600: Keyence). The degree of change is indicated by the following symbols.
A: No change, B: Very small crushing at a level that cannot be visually confirmed, B: Crushing and chipping that can be visually confirmed, X: Cracking Test Example 5 <Appearance>
Appearance was confirmed using visual and fingertip palpation. The degree of appearance is indicated by the following symbols.
A: Glossy and very smooth, O: Smooth, Δ: Roughly rough or slightly uneven, X: Roughly rough or uneven Test Example 6 <Layer thickness>
The cross section of the coated tablet cut with a cutter was observed with an electron microscope (S-3400N), and the thickness of the coating layer was measured. The average value of the measured values at three locations was defined as the layer thickness.
Tables 1 and 2 show the evaluation results.

Table 1

Table 2

In the table, “amount of spray solution” is the actual amount of the coating solution used for spraying in the coating apparatus.
“Coating rate (%)” is the ratio of the mass of the solid component increased by coating to the mass of the solid component in the spray liquid amount.
That is, coating rate (%) = (mass of solid component increased by coating) / (mass of solid component in the amount of spray liquid) × 100 (%)

In Examples 1 to 4, the coating was applied without harming the disintegration time and hardness of the uncoated tablets. The appearance was smooth, and in particular, Example 4 was glossy and excellent results were obtained.
In addition, the sliding angle was smaller than that of the uncoated tablet, and it slipped at a gentle angle. On the other hand, in the comparative example, the appearance of Comparative Example 1 was somewhat rough and uneven. Further, the sliding angles of Comparative Examples 1 and 2 were larger by 2 ° or more than the uncoated tablets. In Example 1, the colorant and / or the light stabilizer, titanium oxide, was not contained and the appearance was slightly inferior, but there was no problem with the smoothness of the coating surface.

Example 5
180 g of trehalose (product name: trehalose G: Hayashibara Biochemical Laboratories) was weighed and added to 3780 g of purified water while stirring with a propeller stirrer to dissolve. Next, 180 g of talc (high filler # 17, average particle size 7.4 μm: Matsumura Sangyo) and 60 g of titanium oxide (average particle size 0.6 μm, product name NA65: Toho Titanium) were weighed and added to the trehalose solution. It was uniformly dispersed to form a coating solution [trehalose 4.3 mass%, talc 4.3 mass% and titanium oxide 1.4 mass%]. This coating solution was spray coated on the uncoated tablets B using a coating apparatus (Paurec coater PRC-7: Paulek) under the following conditions to obtain coated tablets. 3000 g of uncoated tablets B (about 30,000 tablets) were coated in one coating.
Supply temperature: 65 ° C
Air volume: 3.5m ³ / min
Spray speed: 30 g / min
Drum rotation speed: 12rpm

Example 6
120 g of trehalose (product name: trehalose G: Hayashibara Biochemical Laboratories) was weighed and added to 2600 g of purified water while stirring with a propeller stirrer to dissolve. Next, 120 g of talc (high filler # 17, average particle size 7.4 μm: Matsumura Sangyo) and 60 g of titanium oxide (average particle size 0.6 μm, product name NA65: Toho Titanium) were weighed and added to the trehalose solution. The coating liquid was uniformly dispersed [trehalose 4.1% by mass, talc 4.1% by mass and titanium oxide 2.1% by mass]. A specified amount of this coating solution was spray coated on the uncoated tablets B under the same conditions as in Example 5 using a coating apparatus (Paurec coater PRC-7: Paulek) to obtain coated tablets. 3000 g of uncoated tablets B (about 30,000 tablets) were coated in one coating.

Example 7
60 g of trehalose (product name: trehalose G: Hayashibara Biochemical Laboratories) was weighed and added to 4020 g of purified water while stirring with a propeller stirrer and dissolved. Next, 60 g of talc (high filler # 17, average particle size 7.4 μm: Matsumura Sangyo) and 60 g of titanium oxide (average particle size 0.6 μm, product name NA65: Toho Titanium) were weighed and added to the trehalose solution. It was uniformly dispersed to give a coating solution [trehalose 1.4% by mass, talc 1.4% by mass and titanium oxide 1.4% by mass]. A specified amount of this coating solution was spray coated on the uncoated tablets B under the same conditions as in Example 5 using a coating apparatus (Paurec coater PRC-7: Paulek) to obtain coated tablets. 3000 g of uncoated tablets B (about 30,000 tablets) were coated in one coating.

Example 8
90 g of trehalose (product name: trehalose G: Hayashibara Biochemical Laboratories) was weighed and added to 6030 g of purified water while stirring with a propeller stirrer to dissolve. Next, 90 g of talc (high filler # 17, average particle size 7.4 μm: Matsumura Sangyo) and 90 g of titanium oxide (average particle size 0.6 μm, product name NA65: Toho Titanium) were weighed and added to the trehalose solution. It was uniformly dispersed to give a coating solution [trehalose 1.4% by mass, talc 1.4% by mass and titanium oxide 1.4% by mass]. This coating solution was spray coated on the uncoated tablets C using a coating apparatus (Paurec coater PRC-7: Paulek) under the same conditions as in Example 5 to obtain coated tablets. 3000 g of uncoated tablets C (about 30,000 tablets) were coated in one coating.
The performance evaluation results of the coated tablets of Examples 5 to 8 are summarized in Table 3.

Table 3

  In Examples 5-8, coating was performed on a 30,000 tablet scale. As a result, as with the 2000 tablet scale, the coating could be applied without harming the disintegration time and hardness of the uncoated tablet, the sliding angle was smaller than that of the uncoated tablet, and the glossiness increased in appearance. In Example 8, uncoated tablet C containing 1% of active ingredient (dienogest) was used, but the same results were obtained as when uncoated tablet B containing no active ingredient was used.

Example 9
Trehalose (product name: Trehalose G: Hayashibara Biochemical Laboratories) 3.0 g was weighed and added to 194.0 g of purified water with stirring with a propeller stirrer, and dissolved. Next, 3.0 g of titanium oxide (average particle size 0.6 μm, product name NA65: Toho Titanium) was weighed, added to the above aqueous solution, and uniformly dispersed to obtain a coating solution for the first layer [trehalose 1.5% by mass And 1.5% by mass of titanium oxide]. The coating solution for the first layer was spray coated on the uncoated tablet B using a coating apparatus (Dria Coater 200: Powrec) under the same conditions as in Example 1 to obtain a first layer coated tablet. Next, 4.5 g of trehalose was weighed and dissolved in 191.0 g of purified water while stirring with a propeller stirrer. Next, 4.5 g of talc (high filler # 17, average particle size 7.4 μm: Matsumura Sangyo) was weighed, added to the above aqueous solution, and uniformly dispersed to obtain a coating solution for the second layer [trehalose 2.3 mass% And 2.3% by mass of talc]. The coating solution for the second layer was spray-coated on the first layer-coated tablet using a coating apparatus (Dria Coater 200: Powrec) under the same conditions as in Example 1 to obtain a two-layer coated tablet. 200 g of uncoated tablet B (about 2000 tablets) was coated with the coating of the first layer and the second layer.

Example 10
Trehalose (product name: Trehalose G: Hayashibara Biochemical Laboratories) 4.5 g and Macrogol 6000 (product name: Macrogol 6000: Sanyo Kasei) 0.9 g were weighed and stirred in 190.4 g of purified water with a propeller stirrer. Add and dissolve. Next, 1.2 g of talc (high filler # 17, average particle size 7.4 μm: Matsumura Sangyo) and 3.0 g of titanium oxide (average particle size 0.6 μm, product name NA65: Toho Titanium) were weighed, respectively, and the above aqueous solution. In addition to the above, it was uniformly dispersed to obtain a coating solution for the first layer [trehalose 2.3 mass%, macrogol 6000 0.5% talc 0.6 mass%, and titanium oxide 1.5 mass%]. The coating solution for the first layer was spray-coated on the uncoated tablet A using a coating apparatus (Dria Coater 200: Powrec) under the same conditions as in Example 1 to obtain a first layer coated tablet. Next, 4.5 g of trehalose and 0.9 g of macrogol 6000 were weighed and added to 193.4 g of purified water while stirring with a propeller stirrer, and dissolved. Next, 1.2 g of magnesium aluminate metasilicate (product name Neusilin UFL2, average particle size 4.3 μm: Fuji Chemical Industry) was weighed, added to the above aqueous solution, and uniformly dispersed to form a coating solution for the second layer [trehalose 2.3 wt%, Macrogol 6000 0.5% and magnesium aluminate metasilicate 0.6 wt%]. The coating solution for the second layer was spray-coated on the first layer-coated tablet using a coating apparatus (Dria Coater 200: Powrec) under the same conditions as in Example 1 to obtain a two-layer coated tablet. 200 g of uncoated tablet A (about 2000 tablets) was coated with the coating of the first layer and the second layer.

Comparative Example 3
2.7 g of trehalose (product name: trehalose G: Hayashibara Biochemical Laboratories) was weighed and added to 189.2 g of purified water while stirring with a propeller stirrer to dissolve. Next, 2.7 g of crystalline cellulose (Theorus PH-F20JP: Asahi Kasei Chemicals), talc (high filler # 17, average particle size 7.4 μm: Matsumura Sangyo) 1.2 g, titanium oxide (average particle size 0.6 μm, product name) NA65: 3.0 g of Toho Titanium) and 1.2 g of crospovidone (Kollidon CLSF, average particle size 17 μm: BASF) were weighed, added to the above aqueous solution, and uniformly dispersed to obtain a coating solution for the first layer [Trehalose 1 .4 mass%, crystalline cellulose 1.4% talc 0.6 mass%, titanium oxide 1.5 mass% and crospovidone 0.6 mass%]. The coating solution for the first layer was spray-coated on the uncoated tablet A using a coating apparatus (Dria Coater 200: Powrec) under the same conditions as in Example 1 to obtain a first layer coated tablet. Next, 2.5 g of trehalose and 60002.5 g of macrogol were weighed, added to 95.0 g of purified water while stirring with a propeller stirrer, and dissolved to obtain a coating solution for the second layer [2.5% by mass of trehalose and Macrogol 6000 2.5% by mass]. The coating solution for the second layer was spray-coated on the first layer-coated tablet using a coating apparatus (Dria Coater 200: Powrec) under the same conditions as in Example 1 to obtain a two-layer coated tablet. 200 g of uncoated tablet A (about 2000 tablets) was coated with the coating of the first layer and the second layer.
Table 4 summarizes the performance evaluation results of the coated tablets of Examples 9 and 10 and Comparative Example 3.

Table 4
* Total 75.7% for the first and second layers

  In Examples 9 and 10, the second layer (outermost layer) contained talc and magnesium aluminate metasilicate, and good results were obtained in all of the decay time, hardness, appearance, and sliding angle. On the other hand, in Comparative Example 3, the first layer contains trehalose and talc, which are good results in Example 1, but the second layer does not contain talc, so the surface has unevenness in appearance. The sliding angle was slightly larger than the uncoated tablet.

Example 11
A propeller stirrer is added to a solution obtained by weighing 40.0 g of trehalose (product name: trehalose G: Hayashibara Biochemical Laboratories) and mixing 97.5 g of purified water and 32.5 g of 99.5% ethanol (reagent special grade: Wako Pure Chemical Industries). The solution was added with stirring at a temperature and dissolved. Next, 20.0 g of talc (high filler # 17, average particle size 7.4 μm: Matsumura Sangyo) and 10.0 g of titanium oxide (average particle size 0.6 μm, product name NA65: Toho Titanium) were weighed, and the above trehalose was measured. In addition to the solution, it was uniformly dispersed to obtain a coating solution [trehalose 20.0% by mass, talc 10.0% by mass and titanium oxide 5.0% by mass]. A specified amount of this coating solution was spray coated on the uncoated tablet B using the coating apparatus (Dria Coater 200: Powrec) under the same conditions as in Example 1 to obtain coated tablets. 200 g of uncoated tablet B (about 2000 tablets) was coated by one coating.

Comparative Example 4
Coating was performed according to the method of Example 11 except that the amount of spray solution of Example 11 was about 2.4 times.

Comparative Example 5
Coating was performed according to the method of Example 11 except that the amount of spray solution of Example 11 was about 3.8 times.
Table 5 summarizes the performance evaluation results of the coated tablets of Example 11 and Comparative Examples 4 and 5.

Table 5

  In Example 11, the disintegration time, hardness, sliding angle, drop test, and appearance were all excellent. On the other hand, in Comparative Examples 4 and 5 having a coating layer thicker than Example 11, the disintegration time was delayed as the layer thickness increased, and surface irregularities tended to be conspicuous in appearance.

Comparative Example 6
Hypromellose (product name TC-5R: Shin-Etsu Chemical) 7.2 g and Macrogol 6000 (product name Macrogol 6000: Sanyo Kasei) 4.2 g were weighed respectively, purified water 127.5 g and 99.5% ethanol 42.5 g. Was added to the mixed liquid while stirring with a propeller stirrer and dissolved. Next, 13.8 g of talc (high filler # 17, average particle size 7.4 μm: Matsumura Sangyo) and 4.8 g of titanium oxide (average particle size 0.6 μm, product name NA65: Toho Titanium) were weighed, and the above solution In addition, the coating solution was uniformly dispersed [hypromellose 3.6% by mass, macrogol 6000 2.1% by mass, talc 6.9% by mass and titanium oxide 2.4% by mass]. This coating solution was spray coated on the uncoated tablets B using a coating apparatus (Paurec coater PRC-7: Paulek) under the following conditions to obtain coated tablets. 200 g of uncoated tablet B (about 2000 tablets) was coated by one coating.
The performance evaluation results of the coated tablet of Comparative Example 6 are shown in Table 6 together with the results of Example 4.

Table 6

  Comparative Example 6 is an example of film coating, but the disintegration time tended to be delayed compared to Example 4 shown above. This is thought to be due to the fact that hypromellose, which is a water-soluble polymer, is blended at a constant level to form a viscous (slimy) layer with a small amount of water, preventing water penetration into the tablet. Further, the sliding angle was 1 ° or more larger than that of the uncoated tablet, and deterioration of the sliding property was recognized.

Example 12
81 g of trehalose (product name: trehalose G: Hayashibara Biochemical Laboratories) was weighed and added to 5922 g of purified water while stirring with a propeller stirrer to dissolve. Next, 81 g of crystalline cellulose (Theorus PH-F20JP: Asahi Kasei Chemicals), 90 g of talc (high filler # 17, average particle size 7.4 μm: Matsumura Sangyo), titanium oxide (average particle size 0.6 μm, product name NA65: Toho Titanium) ) 90 g and 36 g of crospovidone (Kollidon CL-M, average particle size 5.4 μm: BASF) were weighed, added to the above aqueous solution, and uniformly dispersed to obtain a coating solution [trehalose 1.3 mass%, crystalline cellulose 1. 3% 1.4% by mass of talc, 1.4% by mass of titanium oxide, and 0.6% by mass of crospovidone]. The coating solution was spray coated on the uncoated tablets A using a coating apparatus (Paurec coater PRC-7: Paulek) under the following conditions to obtain coated tablets. 3 kg of uncoated tablet A (about 30,000 tablets) was coated by one coating.
Supply temperature: 65 ° C
Air volume: 3.5m ³ / min
Spray speed: 20mL / min
Drum rotation speed: 12rpm
Examples 13 and 14
According to Example 12, coated tablets having the composition described in Table 7 were produced.
Table 7 also shows the performance evaluation results of the coated tablets of Examples 12-14.

Table 7

In Examples 12 to 14, the coating was applied without harming the disintegration time and hardness of the uncoated tablets. Crystalline cellulose tends to cause roughness on the coating surface when the dose is increased, and crospovidone also tends to cause unevenness on the coating surface when the dose is increased. However, the appearance was smooth in Examples 12 to 14 and glossy, and excellent results were obtained.
Even in Example 12 in which 21.4% of the crystalline cellulose as the organic binder was added, the appearance was good and no decay delay was observed, so at least about 21% of the organic binder was added. However, it was considered that appearance and disintegration were not impaired.
In Example 1 where the coating layer thickness was 17.3 μm, and Example 9 where the coating layer thickness was 14.4 μm, etc., the characteristics of the tablets were good, so that the layer thickness was 10 μm or more. It was thought that the effect of the present invention could be exhibited.

Example 15
Trehalose (product name: Trehalose G: Hayashibara Biochemical Laboratories) 4.2 g was weighed and added to 191.6 g of purified water with stirring with a propeller stirrer and dissolved. Next, 4.2 g of talc (high filler # 17, average particle size 7.4 μm: Matsumura Sangyo) was weighed and added to the above trehalose solution and uniformly dispersed to form a coating solution [trehalose 2.1 mass%, talc 2 .1% by mass]. A specified amount of this coating solution was spray-coated on the uncoated tablets B using a coating apparatus (Dria Coater 200: Powrec) under the following conditions to obtain coated tablets. 200 g of uncoated tablet B (about 2000 tablets) was coated by one coating. A coated tablet almost the same as that obtained in Example 1 was obtained.
Supply air temperature: 65 ℃
Air volume: 40m ³
Spray speed: 2.95mL / min
Drum rotation speed: 10rpm

Example 16
Trehalose (product name: Trehalose G: Hayashibara Biochemical Laboratories) 4.2 g was weighed and added to 187.4 g of purified water while stirring with a propeller stirrer and dissolved. Next, 4.2 g of talc (high filler # 17, average particle size 7.4 μm: Matsumura Sangyo) and 4.2 g of titanium oxide (average particle size 0.6 μm, product name NA65: Toho Titanium) were weighed, and the above trehalose was measured. In addition to the solution, it was uniformly dispersed to obtain a coating solution [trehalose 2.1 mass%, talc 2.1 mass% and titanium oxide 2.1 mass%]. A specified amount of this coating solution was spray coated on the uncoated tablet B using the coating apparatus (Dria Coater 200: Paulek) under the same conditions as in Example 14 to obtain coated tablets. 200 g of uncoated tablet B (about 2000 tablets) was coated by one coating.

Example 17
The trehalose of Example 15 was replaced with 4.2 g of erythritol (product name: erythritol fine powder: Mitsubishi Food Chemical), and uncoated tablet B was coated in the same manner.
Test Example 7 <Light Stability Test>
For the coated tablets obtained in Examples 15 to 17 and Example 12, the measurement was performed under the following conditions using an environmental tester No. 20 (light stability test device: LT-120D3CJ: Nagano Scientific Machinery Co., Ltd.). went. The coated tablets were arranged so as not to overlap in a glass petri dish and stored in an environmental tester.
<Irradiation conditions>
Use lamp: D65 lamp (illuminance 5000Lux)
Installation area: Central Temperature: Event Storage period: Up to 10 days (1.2 million Lux · h)
Table 8 shows the results of the photostability tests of Examples 15 to 17 and Example 12.

Table 8

The tablet with the coating containing trehalose and talc (Example 15) was white at the start of the test, and the color of the tablet remained white at the start of the test even with the light irradiation of 1.2 million Lux · h. It was. The tablet (Example 16) provided with a coating containing trehalose, talc, and titanium oxide changed the color of the tablet from white at the start to slightly pale blue by light irradiation. The same discoloration as in Example 16 was observed in the tablet (Example 17) in which trehalose was replaced with erythritol.
However, in the tablet with the coating containing trehalose, talc, titanium oxide, crystalline cellulose, and crospovidone (Example 12), the color of the tablet is the same even when irradiated with 1.2 million Lux · h. The white color remained unchanged.
Only the coating layer was discolored, and the uncoated part did not discolor.
This time, it has been found that crystalline cellulose and / or crospovidone has the effect of suppressing the discoloration of titanium oxide to light blue-white by light.
In addition, when the same study was conducted separately using a tablet coated with trehalose, titanium oxide, hypromellose, and macrogol 6000, the color of the tablet at the start of the test even when irradiated with 1.2 million Lux · h. The white color remained unchanged.
From the above, organic binders and / or water-soluble polymers (including crystalline cellulose, hypromellose, macrogol 6000, etc.) and disintegrants (including crospovidone) have the effect of suppressing discoloration of titanium oxide due to light. I understood.

Example 18
Trehalose (product name: Trehalose G: Hayashibara Biochemical Laboratories) 4.5 g and pullulan (product name: pullulan: Hayashibara Biochemistry Laboratories) 0.9 g were weighed and stirred in 190.4 g of purified water with a propeller stirrer. Add and dissolve. Next, 1.2 g of talc (high filler # 17, average particle size 7.4 μm: Matsumura Sangyo), 3.0 g of titanium oxide average particle size 0.6 μm, product name NA65: Toho Titanium) were weighed, respectively, into the above aqueous solution. In addition, it was uniformly dispersed to obtain a coating liquid for the first layer [trehalose 2.3 mass%, pullulan 0.5 mass%, talc 0.6 mass%, and titanium oxide 1.5 mass%]. The coating solution for the first layer was spray coated on the uncoated tablet A using a coating apparatus (Dria Coater 200: Powrec) under the same conditions as in Example 1 to obtain a first layer coated tablet.
Next, 4.5 g of trehalose and 0.9 g of pullulan were weighed and added to 192.2 g of purified water while stirring with a propeller stirrer to dissolve. Next, 2.4 g of talc was weighed, added to the above aqueous solution, and uniformly dispersed to obtain a coating solution for the second layer [2.3% by mass of trehalose, 0.5% by mass of pullulan, and 1.2% by mass of talc] . The coating solution for the second layer was spray-coated on the first layer-coated tablet using a coating apparatus (Dria Coater 200: Powrec) under the same conditions as in Example 1 to obtain a two-layer coated tablet. 200 g of uncoated tablet A (about 2000 tablets) was coated with the coating of the first layer and the second layer.
The test results of Example 18 are summarized in Table 9.

Table 9

  From these results, it can be seen that Example 18 using pullulan as the organic binder and / or water-soluble polymer is excellent in all of the disintegration time, hardness, sliding angle, drop test, and appearance.

Claims (1)

Coated on the outside of the uncoated tablet containing one or more hormone-like substances selected from the group consisting of norethisterone, medroxyprogesterone acetate, methyltestosterone, didrogesterone, estradiol, ethinylestradiol, levonorgestrel, pregnanediol, salivary hormone, dienogest as an active ingredient An orally disintegrating tablet covered with a coating,
The outermost layer of the coating film is at least one selected from the group consisting of trehalose and / or erythritol and water-insoluble inorganic salts, silicate compounds, aluminum hydroxide, magnesium oxide, zinc oxide, stearic acid, and sodium stearyl fumarate. Containing a water-insoluble compound having an average particle size of 0.1 to 50 μm,
Contact with the active ingredient is prevented by the coating film,
Tablets with a coating film are orally disintegrating tablets with a smooth coating surface with a reduced sliding angle compared to plain tablets.