Formulation for preventing or treating pigmentation disorder

Abstract

To provide a tranexamic acid -, ascorbic acid -, calcium pantothenate -, L-cysteine - and pyridoxine hydrochloride-containing tablet suppressed in discoloration and free from tableting trouble.SOLUTION: The tablet contains a granulated material A and a granulated material B and has a water content of ≤ 2%, wherein the granulated material A contains tranexamic acid and calcium pantothenate, the granulated material B contains ascorbic acid, and the granulated materials A and B separately contain L-cysteine and pyridoxine hydrochloride.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical preparation for the prevention or treatment of pigmentation disorders such as melasma and age spots. [Background technology]

[0002] Tranexamic acid has antihemorrhagic and anti-inflammatory effects due to its antiplasmin activity, and has been used as a pharmaceutical product since 1964. Dermatologists have reported that tranexamic acid is effective against age spots caused by melasma, and therefore a composition containing tranexamic acid as the main ingredient, ascorbic acid, L-cysteine, pyridoxine hydrochloride, and calcium pantothenate has become a composition for preventing or treating skin pigmentation (Patent Document 1), and has been on the market since 2007 as a pharmaceutical product for treating melasma (Non-Patent Document 1).

[0003] Ascorbic acid is also said to be effective in reducing pigmentation caused by age spots, freckles, sunburn, and rashes, and pharmaceuticals containing calcium pantothenate, pyridoxine hydrochloride, and L-cysteine ​​are commercially available (Non-Patent Documents 2 and 3).

[0004] However, when tranexamic acid and ascorbic acid are mixed, there is a problem of discoloration (reddening) over time. As methods for avoiding such discoloration, a method of adding a polyvinyl alcohol copolymer and / or a partially saponified polyvinyl alcohol (Patent Document 2), a method of adding an antioxidant such as citric acid, tartaric acid, or malic acid (Patent Document 3), a method of having tranexamic acid and ascorbic acid exist through a boundary (Patent Document 4), and the like have been reported. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Japanese Patent Application Laid-Open No. 2005-314403 [Patent Document 2] International Publication No. 2010 / 029930 [Patent Document 3] International Publication No. 2010 / 016509 [Patent Document 4] International Publication No. 2010 / 027010 [Non-patent literature]

[0006] [Non-Patent Document 1] Transino® Package Insert [Non-patent document 2] Guidance Required: OTC Drug Manufacturing and Sales Approval Standards and Application Practice Guide 2017 [Non-patent document 3] Hythiol (registered trademark) C package insert Summary of the Invention [Problem to be solved by the invention]

[0007] The present invention relates to providing a tablet containing tranexamic acid, ascorbic acid, calcium pantothenate, L-cysteine ​​and pyridoxine hydrochloride that is inhibited from discoloring and free from tableting problems. [Means for solving the problem]

[0008] Patent Document 4 discloses that discoloration of the preparation can be suppressed by adding L-cysteine ​​and pyridoxine, or L-cysteine ​​and pantothenic acid, to either or both of granules a made of tranexamic acid and granules b made of ascorbic acid. Specifically, when granules a and b contain pyridoxine, discoloration can be suppressed by adding L-cysteine ​​to the granules containing pyridoxine; and when L-cysteine ​​is contained, discoloration can be suppressed by adding pantothenic acid to the granules containing L-cysteine. However, it has been shown that discoloration cannot be suppressed in 1) a formulation containing granules a consisting of tranexamic acid, L-cysteine, calcium pantothenate, crystalline cellulose, and hydroxypropyl cellulose, and granules b consisting of ascorbic acid, pyridoxine hydrochloride, crystalline cellulose, and hydroxypropyl cellulose (Comparative Example 8), and 2) a formulation containing granules a consisting of tranexamic acid, calcium pantothenate, pyridoxine hydrochloride, crystalline cellulose, and hydroxypropyl cellulose, and granules b consisting of ascorbic acid, L-cysteine, crystalline cellulose, and hydroxypropyl cellulose (Comparative Example 7).

[0009] As a result of extensive research, the present inventors have found that by blending L-cysteine ​​and pyridoxine hydrochloride separately into granules A containing tranexamic acid and calcium pantothenate and granule B containing ascorbic acid, respectively, and keeping the moisture content of the tablets to 2% or less, discoloration can be suppressed and tablets with sufficient moldability and no tableting problems can be produced.

[0010] That is, the present invention relates to the following 1) to 16). 1) A tablet containing granulated material A and granulated material B, with a moisture content of 2% or less, wherein granulated material A contains tranexamic acid and calcium pantothenate, and granulated material B contains ascorbic acid, and further contains L-cysteine ​​and pyridoxine hydrochloride separately. 2) The tablet described in 1), which contains granulated material A containing tranexamic acid, calcium pantothenate, and L-cysteine, and granulated material B containing ascorbic acid and pyridoxine hydrochloride. 3) The tablet described in 1), which contains granulated material A containing tranexamic acid, calcium pantothenate and pyridoxine hydrochloride, and granulated material B containing ascorbic acid and L-cysteine. 4) The tablet described in 1), containing 187.5 mg of tranexamic acid, 6 mg of calcium pantothenate, and 75 to 83 mg of ascorbic acid per tablet. 5) The tablet described in 4), containing 60 mg of L-cysteine ​​and 1.5 to 2 mg of pyridoxine hydrochloride per tablet. 6) The tablet according to any one of 1) to 3), wherein the calcium pantothenate is a granule containing calcium pantothenate and calcium lactate. 7) The tablet according to any one of 1) to 3), wherein granulated material A and granulated material B contain a binder. 8) The tablet according to 7), wherein the binder is one or more selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, polyvinyl alcohol, macrogol, and gum arabic. 9) A tablet according to any one of 1) to 3), comprising granulated material A, granulated material B, crystalline cellulose, a disintegrant and a lubricant, and containing 5 to 12% by mass of crystalline cellulose and 1 to 7% by mass of disintegrant relative to the tablet. 10) The tablet according to 9), wherein the bulk density of the crystalline cellulose is 0.08 to 0.38 g / mL. 11) The tablet according to 9), wherein the bulk density of the crystalline cellulose is 0.10 to 0.26 g / mL. 12) The tablet according to 9), wherein the disintegrant is one or more selected from croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, and sodium starch glycolate. 13) The tablet according to 9), wherein the lubricant is one or more selected from magnesium stearate, calcium stearate, sucrose fatty acid esters, and sodium stearyl fumarate. 14) The tablet according to 9), wherein the lubricant content is 1.2 to 5% of the entire tablet. 15) The tablet according to 9), wherein the lubricant content is 2 to 4% of the entire tablet. 16) The tablet according to any one of 1) to 3), which is a film-coated tablet. [Effects of the Invention]

[0011] According to the present invention, it is possible to provide a tablet containing tranexamic acid, ascorbic acid, calcium pantothenate, L-cysteine, and pyridoxine hydrochloride as active ingredients, which is inhibited from discoloring over time, is free from tableting problems, and is easy to produce. DETAILED DESCRIPTION OF THE INVENTION

[0012] The tablet of the present invention contains granulated material A and granulated material B and has a moisture content of 2% or less, and granulated materials A and B contain tranexamic acid and calcium pantothenate in granulated material A, and ascorbic acid in granulated material B, and further contains L-cysteine ​​and pyridoxine hydrochloride separately. As will be shown in the examples described below, the tablets of the present invention are inhibited from discoloration due to the active ingredient, and can be produced without causing tableting problems such as sticking or capping during tableting, even when the content of the active ingredient is 75% by mass or more of the entire tablet. Here, "discoloration caused by an active ingredient is inhibited" means that the color change from white to brown over time due to contact with a specific active ingredient is inhibited, and the color stops at white or whitish yellow. For example, discoloration is inhibited under a severe stability test at 60°C for one month. "Does not cause problems during tableting" means that sticking, capping, cracking, chipping, adhesion to the mortar and pestle, etc. do not occur during tableting.

[0013] In the present invention, granulated product A contains at least tranexamic acid and calcium pantothenate. The tranexamic acid is at least one selected from the group consisting of tranexamic acid and salts thereof, and is preferably tranexamic acid. Tranexamic acid is a known compound and can be produced by known methods or commercially available, and is listed as tranexamic acid in the 18th edition of the Japanese Pharmacopoeia.

[0014] Calcium pantothenate is a known compound and can be produced by known methods or commercially available. Calcium pantothenate is listed in the 18th edition of the Japanese Pharmacopoeia as calcium pantothenate. Calcium pantothenate can be in the form of granules. The granules contain calcium pantothenate and a calcium salt. Examples of calcium salts include calcium lactate, calcium silicate, calcium phosphate, calcium hydrogen phosphate, and anhydrous calcium hydrogen phosphate, with calcium lactate being preferred. The blending ratio of calcium pantothenate to calcium salt in the granules containing calcium pantothenate and a calcium salt is calcium pantothenate:calcium salt=50-80:20-50, preferably calcium pantothenate:calcium salt=65:35. The calcium pantothenate granules are preferably spherical, with a sphericity of 0.8 or greater, preferably 0.9 or greater. Sphericity is determined by measuring the major and minor axes of the particles using SEM photographs and calculating the ratio of minor axis to major axis. The static specific volume of the granules containing calcium pantothenate and a calcium salt is 2.4 to 3.2 mL / g, preferably 2.6 to 3.0 mL / g. The static specific volume is measured according to the bulk density measurement method of the Japanese Pharmacopoeia and is the reciprocal of the obtained bulk density. The particle size distribution is such that sieve size No. 42 or larger is 5% or less, and No. 200 or smaller is 30% or less.

[0015] Granulated product B contains at least ascorbic acid. The ascorbic acid is at least one selected from the group consisting of ascorbic acid and salts thereof, and is preferably ascorbic acid or sodium ascorbate. Ascorbic acid or sodium ascorbate is a known compound and can be produced by a known method, or commercially available ascorbic acid or sodium ascorbate. It is listed as ascorbic acid in the 18th revised Japanese Pharmacopoeia, and as sodium ascorbate in the Japanese Pharmacopoeia Non-prescription Pharmaceutical Standards 2002 and Pharmaceutical Excipients Standards 2018.

[0016] The daily doses of tranexamic acid, ascorbic acid, and calcium pantothenate are 750 mg, 300 mg, and 24 mg, respectively. The content in one tablet may be the amount corresponding to the number of tablets administered per day. For example, when two tablets are administered twice a day, the contents of tranexamic acid, ascorbic acid, and calcium pantothenate in one tablet are 187.5 mg, 75 mg, and 6 mg, respectively.

[0017] Granules A and B further contain L-cysteine ​​and pyridoxine hydrochloride, respectively. Therefore, specific examples of the tablet of the present invention include those containing granulated substances A and B shown below. 1) Granulated substance A containing tranexamic acid, calcium pantothenate, and L-cysteine, and granulated substance B containing ascorbic acid and pyridoxine hydrochloride. 2) Granulated material A containing tranexamic acid, calcium pantothenate, and pyridoxine hydrochloride, and granulated material B containing ascorbic acid and L-cysteine.

[0018] L-cysteine ​​is a known compound and can be produced by known methods, or commercially available L-cysteine ​​can be used; for example, L-cysteine ​​according to the standards set forth in the 18th Edition of the Japanese Pharmacopoeia can be used.

[0019] Pyridoxine hydrochloride is a known compound and can be produced by known methods, or commercially available products can be used; for example, pyridoxine hydrochloride according to the standards set forth in the 18th Edition of the Japanese Pharmacopoeia can be used. The daily dose of L-cysteine ​​and pyridoxine hydrochloride is 240 mg and 6 mg, respectively. If you take a total of four tablets twice a day, for example, the L-cysteine ​​and pyridoxine hydrochloride contents per tablet are 60 mg and 1.5 mg, respectively.

[0020] Granules A and B may contain, in addition to tranexamic acid, ascorbic acid, calcium pantothenate, L-cysteine, and pyridoxine hydrochloride, other active ingredients, such as vitamin E or its derivatives, such as d-α-tocopherol succinate, dl-α-tocopherol succinate, dl-α-tocopherol calcium succinate, d-α-tocopherol acetate, dl-α-tocopherol acetate, d-α-tocopherol, and dl-α-tocopherol, thiamine hydrochloride, thiamine nitrate, bisthiamine nitrate, thiamine disulfide, thiamine diacetyl sulfate, fursultiamine hydrochloride, dicethiamine hydrochloride, octotiamine, sicotiamine, bis-ibuthiamine, bis-bentiamine, and benfotiamine. Examples of suitable vitamin B1 or derivatives thereof include amines; vitamin B2 or derivatives thereof, such as riboflavin, riboflavin butyrate, and riboflavin sodium phosphate; vitamin B12 or derivatives thereof, such as cyanocobalamin, hydroxocobalamin hydrochloride, hydroxocobalamin acetate, and mecobalamin; nicotinic acid or derivatives thereof, such as nicotinic acid and nicotinamide; coix seed, orotic acid, biotin, gamma-oryzanol, glucuronolactone, glucuronic acid amide, and ubidecarenone. One or more of these may be used. Among these, nicotinamide is preferred because it acts as a coenzyme that broadly supports various redox reactions in the body, maintains healthy skin and mucous membranes, and improves blood flow. The daily dose of nicotinamide is 40 mg. For example, when taking a total of four tablets twice daily, each tablet contains 10 mg. Nicotinamide is preferably incorporated into a granulated product containing pyridoxine hydrochloride.

[0021] Granules A and B may contain binders, fluidizing agents, etc. in addition to the above-mentioned active ingredients. Examples of binders include one or more of hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, polyvinyl alcohol, macrogol, Pluronic (registered trademark) F68, gum arabic, gelatin, starch, etc., and preferred are hydroxypropylmethylcellulose, hydroxypropylcellulose, and methylcellulose, and more preferred are hydroxypropylmethylcellulose and hydroxypropylcellulose. The content of the binder is 0.1 to 20% by mass, preferably 0.3 to 10% by mass, and more preferably 0.5 to 7% by mass, based on the total mass of the granules.

[0022] Examples of the fluidizing agent include talc, hydrous silicon dioxide, light anhydrous silicic acid, magnesium aluminometasilicate, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium alumina hydroxide, stearic acid, calcium stearate, and magnesium stearate.

[0023] To prevent discoloration, it is preferable that granules A and B are substantially free of crystalline cellulose. "Substantially free" means that even if crystalline cellulose is present in granules A and B, the amount is such that discoloration of the drug does not occur, and examples include no intentional presence of crystalline cellulose during production, or that the amount of crystalline cellulose in granules A or B is 2% by mass or less, preferably 1% by mass or less, and more preferably 0.5% by mass or less, relative to the drug.

[0024] In addition to granules A and B, the tablet of the present invention may contain crystalline cellulose, a binder, a lubricant, a disintegrant, and other pharmaceutical additives (these may also be referred to as later-added ingredients).

[0025] Here, it is preferable to use crystalline cellulose having a bulk density within a certain range in order to improve the moldability of granulated product A, granulated product B, and the pharmaceutical additives and to prevent tableting problems, and for example, a bulk density of 0.08 to 0.46 g / mL, more preferably a bulk density of 0.10 to 0.38 g / mL, even more preferably a bulk density of 0.10 to 0.33 g / mL, and most preferably a bulk density of 0.10 to 0.26 g / mL. The amount of crystalline cellulose to be added is 5 to 12% by mass, preferably 6 to 11% by mass, and more preferably 7 to 10% by mass, based on the total mass of the tablet.

[0026] Examples of the binder include the same as those mentioned above, and preferred are hydroxypropylmethylcellulose, hydroxypropylcellulose, and methylcellulose. The content of the binder is 3 to 10% by mass, preferably 4 to 9% by mass, and more preferably 5 to 8% by mass, based on the total mass of the tablet.

[0027] The lubricant may be, for example, one or more of magnesium stearate, calcium stearate, sodium stearyl fumarate, sucrose fatty acid ester, talc, glycerin monostearate, or macrogol, preferably magnesium stearate, calcium stearate, or sodium stearyl fumarate, and most preferably magnesium stearate. Lubricants can be used either when mixing with granules A and B and other post-added ingredients during tableting, or as an external lubricant by spraying (applying) the lubricant to the upper and lower punches and dies of the tableting machine, as described below. When mixing the tableting powder, the amount of lubricant added is 1 to 5% by mass, preferably 1.2 to 5% by mass, more preferably 1.5 to 4.5% by mass, and most preferably 2 to 4% by mass, of the entire tablet. In the case of external lubrication, the lubricant segregates on the surface of the uncoated tablet, and the content of the lubricant in the tablet is 0.2% by mass or less, preferably 0.1% by mass or less, of the entire tablet.

[0028] Examples of disintegrants include one or more of starches such as corn starch and potato starch, partially pregelatinized starch, carboxymethyl starch sodium, carmellose, carmellose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, sodium starch glycolate, crystalline cellulose, hydroxypropyl starch, and the like, and preferred are croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, and sodium starch glycolate. The amount of the disintegrant to be added is 1 to 7% by mass, preferably 1.5 to 6% by mass, and more preferably 2 to 5% by mass, based on the total mass of the tablet.

[0029] Other pharmaceutical additives include, for example, excipients, plasticizers, fluidizing agents, surfactants, light-blocking agents, pH adjusters, colorants, antistatic agents, etc., and specific examples are as follows.

[0030] Glidants: For example, talc, hydrous silicon dioxide, light anhydrous silicic acid, magnesium aluminometasilicate, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium alumina hydroxide, stearic acid, calcium stearate, magnesium stearate, and the like.

[0031] Light-shielding agents include, for example, titanium oxide, zinc oxide, talc, iron oxides such as yellow ferric oxide, ferric oxide, and black ferric oxide, Food Yellow No. 5, Food Red No. 102, and the like, and preferably titanium oxide.

[0032] pH adjusters: Examples include acids such as succinic acid, maleic acid, tartaric acid, citric acid, and aspartic acid, and alkalis such as sodium hydroxide, ammonia, magnesium oxide, silicon dioxide, and sodium hydrogen carbonate.

[0033] Coloring agents: For example, food blue No. 1, food blue No. 2, food yellow No. 4, food red No. 2, food red No. 3, food blue No. 1 aluminum lake, food blue No. 2 aluminum lake, food red No. 2 aluminum lake, ferric oxide (red), titanium oxide, yellow ferric oxide, caramel, talc, etc.

[0034] The tablet of the present invention may be film-coated to improve the stability of the active ingredient and to prevent odors derived from L-cysteine, etc. The film coating layer may be one or more layers, preferably two layers. The base of the film-coating portion that forms the film-coating layer can be a conventional aqueous film-coating base. Examples of aqueous film-coating agents include hypromellose (hydroxypropyl methylcellulose), propyl cellulose, methyl cellulose, ethyl acrylate-methyl methacrylate copolymer, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer dispersion, aminoalkyl methacrylate copolymer RS ​​aqueous dispersion, ethyl cellulose aqueous dispersion, aminoalkyl methacrylate copolymer E, povidone, and copolyvidone, with hypromellose (hydroxypropyl methylcellulose) being preferred. In addition to the base, the film-coating portion can contain a plasticizer and a lubricant, and may also contain a small amount of a light-shielding agent and a trace amount of a colorant, if necessary.

[0035] Examples of the plasticizer include triacetin, polyethylene glycol, and triethyl citrate. These compounds may be used alone or in combination. Among them, triacetin is a preferred plasticizer. Examples of the lubricant that can be used include those mentioned above. The light-shielding agent is preferably titanium oxide. Examples of colorants include yellow to red compounds such as yellow ferric oxide and ferric oxide.

[0036] The amounts of base, plasticizer, lubricant, light-shielding agent, and colorant in the film coating portion may be in accordance with the basic, conventional amounts.

[0037] In film-coated tablets, there is no clear limit to the amount of coating applied to the film coating portion, but for example, it is preferable that a plain tablet with a mass of 400 mg / tablet be coated with a coating amount in the range of 2 to 40 mg / tablet, and more preferably in the range of 5 to 30 mg / tablet.

[0038] The tablets of the present invention are plain tablets or film-coated tablets, and have a moisture content of 2% by mass or less, preferably 1.5% by mass or less, more preferably 1% by mass or less, and even more preferably 0.5% by mass or less, based on the total weight of the tablet. By keeping the moisture content below these certain values, discoloration can be suppressed or prevented. The moisture content was measured by heating at 105°C in accordance with the Loss on Drying in the 18th Edition of the Japanese Pharmacopoeia. Specifically, the loss in moisture content was measured by powdering the tablets and drying them at 105°C for 4 hours. If conditions were set to obtain an equivalent value, the moisture content could be measured using an infrared moisture meter (Infrared Moisture Meter FD-660, Kett Electric Laboratory Co., Ltd.).

[0039] The tablets of the present invention can be produced by (1) separately producing granulated material A and granulated material B containing the above-mentioned active ingredients, (2) mixing granulated material A, granulated material B, and the above-mentioned post-added ingredients, followed by compression molding, and (3) film coating as necessary.

[0040] The granulation method for granulated product A and granulated product B is not particularly limited, and any granulation method commonly used in pharmaceutical manufacturing can be used. Conventional granulation methods may be dry granulation methods, but wet granulation methods are preferred. Wet granulation methods may be any method that granulates raw materials for granulation using a solvent, and examples include extrusion granulation, tumbling granulation, fluidized bed granulation, mixing / agitation granulation, spray-drying granulation, and vibration granulation. These wet granulation methods may also be used in combination.

[0041] Among these wet granulation methods, from the viewpoint of productivity, mixing / stirring granulation method, fluidized bed granulation method, etc. are preferred, fluidized bed granulation method is more preferred, and mixing / stirring granulation method and fluidized bed granulation method may be combined.

[0042] The fluidized bed granulation method is not particularly limited as long as it is a method of spraying a granulating liquid onto raw material powder fluidized by an air current to obtain a granulated product, and any conventional method can be used. The method for preparing the raw material powder is not particularly limited, and the raw material powder may be prepared in a fluidized bed granulator or by other granulation methods. As another granulation method, a mixing and stirring granulation method is preferred from the viewpoint of simplicity, etc.

[0043] In the fluidized bed granulation method, the granulation liquid may contain a binder and a granulation solvent, and is usually an aqueous dispersion or solution containing a binder and a granulation solvent.

[0044] The granulation solvent is not particularly limited, but from the viewpoint of safety, water, aqueous solvents, etc. can be used. Examples of aqueous solvents include lower alcohols (e.g., ethanol, isopropanol, etc.) and aliphatic ketones (e.g., acetone, etc.). These solvents can be used alone or in combination of two or more.

[0045] Granulated Products A and B can be suppressed from tableting problems such as sticking, capping, and binding by adjusting the particle size of the granulated products after granulation. These tableting problems can be suppressed by removing portions with relatively large particle sizes and insufficiently granulated fine powder from the granulated products to be subjected to the tableting process. For example, one method for regulating the size of the granulated products is to remove granulated products with a size of 710 μm or more using a sieve.

[0046] In the tablet of the present invention, the moisture content can be adjusted by drying at the end of the above-mentioned granulation process or at the end of the coating process described below. The endpoint of drying in these processes can be determined by monitoring the exhaust temperature, and the endpoint is the point at which the exhaust temperature has risen to a certain level. The endpoint temperature can be appropriately selected depending on the size of the equipment, the air flow rate, and the amount of material charged. For example, the endpoint can be determined when the exhaust temperature reaches 43°C in a 3L fluidized bed, 60°C in a 45L fluidized bed, or 50°C in a 30-type pan coating machine.

[0047] Granulated material A, granulated material B, and post-added ingredients (crystalline cellulose, binder, lubricant, disintegrant, and other pharmaceutical additives) are mixed and compressed using a tablet press to obtain uncoated tablets. Here, mixing can be performed by a commonly used mixing method, such as mixing, kneading, granulation, etc. Mixing can be performed using, for example, a high-speed stirring mixer, a universal kneader, a fluidized bed granulator, a V-type mixer, a tumbler mixer, a double cone mixer, a ribbon mixer, a rotary screw mixer, manual mixing in a bag, etc.

[0048] The lubricant may be added externally during compression molding. External lubrication is a method in which the lubricant is added by spraying (applying) it onto the upper and lower punches and die of a tablet press. By spraying the lubricant directly onto the upper and lower punches and die, a film of the lubricant can be formed on the surface that comes into contact with the powder. In addition to blending the lubricant inside the tablet, external lubrication may also be performed.

[0049] Compression molding can be performed using a rotary tablet press or the like that is commonly used for pharmaceuticals. The molding pressure during tableting varies depending on the size of the tablet, but for example, for a tablet with a diameter of 9.5 mm, it is 2 to 20 kN, and preferably 7 to 15 kN.

[0050] The obtained uncoated tablets can be subjected to film coating to produce film-coated tablets. Film coating can be performed using equipment typically used for aqueous tablet coating, such as a pan-coating type coating equipment. In the film coating process of the present invention, a suspension prepared by dissolving and dispersing the components of the film coating portion, specifically, a base, plasticizer, lubricant, light-shielding agent, colorant, etc., in a solvent such as water or ethanol, is sprayed into a coating pan containing uncoated tablets while maintaining the inlet air temperature described in detail below, and hot air is blown onto the tablet surface to remove the solvent from the tablet surface and dry it, thereby uniformly adhering the film coating portion to the surface of the uncoated tablets, and then drying as necessary, thereby forming a film coating layer. [Example]

[0051] The present invention will be described in more detail below with reference to Examples, Comparative Examples, Test Examples and Preparations, but the present invention is not limited to these. The samples obtained in the Examples were evaluated by the following methods.

[0052] Example 1 187.5 parts by mass of tranexamic acid, 9.23 parts by mass of calcium pantothenate-calcium lactate granules (calcium pantothenate 65% by mass, calcium lactate 35% by mass) (Calcium Pantothenate-S, manufactured by DSM), and 60 parts by mass of L-cysteine ​​were charged into a fluidized bed granulator and mixed, and 80 parts by mass of a 6% aqueous hydroxypropyl cellulose solution was sprayed onto the mixture, followed by drying until the exhaust temperature reached 45°C, to obtain granulated product A. Separately, 75 parts by mass of ascorbic acid and 1.5 parts by mass of pyridoxine hydrochloride were charged into a fluidized bed granulator and mixed, and 29.2 parts by mass of a 6% aqueous hydroxypropyl cellulose solution was sprayed onto the mixture, followed by drying until the exhaust temperature reached 45°C, to obtain granulated product B. The moisture content of granulated product A was 0.60%, and the moisture content of granulated product B was 0.43%. Granulated material A 261.53 parts by mass, granulated material B 78.25 parts by mass, crystalline cellulose (CEOLUS (registered trademark) KG-1000, manufactured by Asahi Kasei Corporation, bulk density: 0.129 g / cm 336.22 parts by mass of granulated sugar, 12 parts by mass of croscarmellose sodium, and 12 parts by mass of magnesium stearate were mixed and compressed into uncoated tablets using a rotary tablet press under conditions of φ9.5 mm, set hardness of 90N, and room humidity of 40%. No powder adhered to the mortar and pestle, and the moisture content of the tablets was 1.3%.

[0053] Example 2 The uncoated tablets of Example 1 were coated with a first layer by spraying a coating solution containing 7.3% hypromellose, 1.2% triacetin, 0.3% red ferric oxide, and 1.2% talc onto the tablets in a coating device at an inlet air temperature of 45°C and an exhaust air temperature of 34 to 36°C. Next, a coating solution containing 5.5% hypromellose, 0.9% triacetin, 2.7% titanium oxide, 0.02% red ferric oxide, and 0.9% talc was sprayed onto the tablets under the same conditions, and the tablets were dried until the exhaust air temperature reached 50°C. Then, the tablets were polished with a small amount of carnauba wax to obtain film-coated tablets weighing 420 mg each.

[0054] Example 3 187.5 parts by mass of tranexamic acid, 9.23 parts by mass of calcium pantothenate-calcium lactate granules (calcium pantothenate 65% by mass, calcium lactate 35% by mass), and 1.5 parts by mass of pyridoxine hydrochloride were charged into a fluidized bed granulator and mixed, and 80 parts by mass of a 6% aqueous hydroxypropyl cellulose solution was sprayed onto the mixture, followed by drying until the exhaust temperature reached 45°C, yielding granulated product A. Separately, 75 parts by mass of ascorbic acid and 60 parts by mass of L-cysteine ​​were charged into a fluidized bed granulator and mixed, and 29.2 parts by mass of a 6% aqueous hydroxypropyl cellulose solution was sprayed onto the mixture, followed by drying until the exhaust temperature reached 45°C, yielding granulated product B. Granulated material A 261.53 parts by mass, granulated material B 78.25 parts by mass, crystalline cellulose (CEOLUS (registered trademark) KG-800, manufactured by Asahi Kasei Corporation, bulk density: 0.204 g / cm 3 36.22 parts by mass of granulated sugar, 12 parts by mass of croscarmellose sodium, and 12 parts by mass of magnesium stearate were mixed and compressed into uncoated tablets using a rotary tablet press under conditions of φ9.5 mm, set hardness of 90N, and room humidity of 40%. No powder adhered to the mortar and pestle, and the moisture content of the tablets was 1.5%.

[0055] Example 4 The uncoated tablets of Example 3 were coated with a first layer by spraying a coating solution containing 7.3% hypromellose, 1.2% triacetin, 0.3% red ferric oxide, and 1.2% talc onto the tablets in a coating device at an inlet air temperature of 45°C and an exhaust air temperature of 34 to 36°C. Next, a coating solution containing 5.5% hypromellose, 0.9% triacetin, 2.7% titanium oxide, 0.02% red ferric oxide, and 0.9% talc was sprayed onto the tablets under the same conditions, and the tablets were dried until the exhaust air temperature reached 50°C. Then, the tablets were polished with a small amount of carnauba wax to obtain film-coated tablets weighing 420 mg each.

[0056] (Comparative Example 1) Tranexamic acid 187.5 parts by mass, calcium pantothenate 6 parts by mass, pyridoxine hydrochloride 1.5 parts by mass, ascorbic acid 75 parts by mass, L-cysteine ​​60 parts by mass, crystalline cellulose (Ceolus® HP-301, manufactured by Asahi Kasei Corporation, bulk density: 0.391 g / cm 3 36.22 parts by weight of croscarmellose sodium and 4.8 parts by weight of hydroxypropyl cellulose were mixed, and an appropriate amount of water was added and further mixed, followed by drying to obtain granules. 376 parts by weight of the granules were mixed with 12 parts by weight of croscarmellose sodium and 12 parts by weight of magnesium stearate, and compressed into uncoated tablets using a rotary tablet press under conditions of φ9.5 mm, set hardness 90N, and room humidity 50%. Powder was found to adhere to the mortar and pestle, and the tablets were sticking. The moisture content of the tablets was 3.1%.

[0057] (Comparative Example 2) In accordance with Comparative Example 5 of WO 2010 / 027010, 187.5 parts by mass of tranexamic acid, 60 parts by mass of L-cysteine, and 10 parts by mass of microcrystalline cellulose were charged into a fluidized bed granulator, mixed, and then 80 parts by mass of a 6% aqueous solution of hydroxypropyl cellulose was sprayed onto the mixture to obtain granules A. Separately, 75 parts by mass of ascorbic acid, 6 parts by mass of calcium pantothenate, 1.5 parts by mass of pyridoxine hydrochloride, and 3 parts by mass of microcrystalline cellulose were charged into a fluidized bed granulator, mixed, and then 29.2 parts by mass of a 6% aqueous solution of hydroxypropyl cellulose was sprayed onto the mixture to obtain granules B. Granulated material A 271.53 parts by mass, granulated material B 81.25 parts by mass, crystalline cellulose (CEOLUS (registered trademark) HP-301, manufactured by Asahi Kasei Corporation, bulk density: 0.391 g / cm 3 29.22 parts by mass of granulated sugar, 14 parts by mass of croscarmellose sodium, and 4 parts by mass of magnesium stearate were mixed and compressed into uncoated tablets using a rotary tablet press under conditions of φ9.5 mm, set hardness of 90N, and room humidity of 50%. Some of the tablets had chips.

[0058] (Discoloration test) The granules and uncoated tablets of Examples 1 and 3 and the uncoated tablets of Comparative Examples 1 and 2 were kept sealed at 50°C for one month, and the degree of discoloration was visually confirmed.

[0059] [Table 1]

[0060] [Table 2]

[0061] (Moisture-adjusted discoloration test) Granulated material A, granulated material B, and a mixture of granulated material A and granulated material B with the following water contents were prepared according to the method of Example 1. The mixture was kept sealed at 60°C for 1 week, and the degree of discoloration was visually confirmed.

[0062] [Table 3]

[0063] Discoloration was sufficiently suppressed for granules A and B and the mixture of granules A and B, which had a moisture content of 2% or less. In contrast, discoloration progressed for granules A and B and the mixture of granules A and B, which had a moisture content of 2% or more.

[0064] The simply mixed tablet of Comparative Example 1 and the tablet of Comparative Example 2 containing 75 parts by mass of ascorbic acid, calcium pantothenate, and a granule of pyridoxine hydrochloride and having a moisture content of 2.6% or more discolored, whereas the tablets of Examples 1 and 3 containing granule A containing tranexamic acid and calcium pantothenate and granule B containing ascorbic acid and having a moisture content of 2% or less did not discolor. Furthermore, the tablets of Examples 1 and 3 were able to be manufactured without any tableting problems such as sticking.

[0065] (Formulation example) Film-coated tablets are prepared in the same manner as in Examples 1 and 3, except that the ingredients are changed to those shown in Table 4.

[0066] [Table 4]

Claims

1. A tablet containing granulated material A and granulated material B and having a moisture content of 2% or less, wherein granulated material A contains tranexamic acid and calcium pantothenate, and granulated material B contains ascorbic acid, and further contains L-cysteine ​​and pyridoxine hydrochloride separately.

2. 2. The tablet according to claim 1, comprising a granulated substance A containing tranexamic acid, calcium pantothenate, and L-cysteine, and a granulated substance B containing ascorbic acid and pyridoxine hydrochloride.

3. 2. The tablet according to claim 1, comprising a granulated substance A containing tranexamic acid, calcium pantothenate, and pyridoxine hydrochloride, and a granulated substance B containing ascorbic acid and L-cysteine.

4. 2. The tablet according to claim 1, wherein each tablet contains 187.5 mg of tranexamic acid, 6 mg of calcium pantothenate, and 75 to 83 mg of ascorbic acid.

5. 5. The tablet according to claim 4, wherein each tablet contains 60 mg of L-cysteine ​​and 1.5 to 2 mg of pyridoxine hydrochloride.

6. The tablet according to any one of claims 1 to 3, wherein the calcium pantothenate is a granulated product containing calcium pantothenate and calcium lactate.

7. The tablet according to any one of claims 1 to 3, wherein granulated material A and granulated material B contain a binder.

8. 8. The tablet according to claim 7, wherein the binder is one or more selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, polyvinyl alcohol, macrogol, and gum arabic.

9. The tablet according to any one of claims 1 to 3, comprising granulated material A, granulated material B, crystalline cellulose, a disintegrant, and a lubricant, and containing 5 to 12% by mass of crystalline cellulose and 1 to 7% by mass of the disintegrant relative to the tablet.

10. The tablet according to claim 9, wherein the bulk density of the crystalline cellulose is 0.08 to 0.38 g / mL.

11. The tablet according to claim 9, wherein the bulk density of the crystalline cellulose is 0.10 to 0.26 g / mL.

12. 10. The tablet according to claim 9, wherein the disintegrant is one or more selected from the group consisting of croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, and sodium starch glycolate.

13. 10. The tablet according to claim 9, wherein the lubricant is one or more selected from magnesium stearate, calcium stearate, sucrose fatty acid esters, and sodium stearyl fumarate.

14. 10. The tablet according to claim 9, wherein the content of the lubricant is 1.2 to 5% of the entire tablet.

15. 10. The tablet according to claim 9, wherein the content of the lubricant is 2 to 4% of the entire tablet.

16. The tablet according to any one of claims 1 to 3, which is a film-coated tablet.

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