tablet

Abstract

A tablet containing chenodeoxycholic acid is provided. [Solution] The tablet satisfies the requirement that the dissolution rate of chenodeoxycholic acid after 15 minutes of dissolution is 50% or more in a dissolution test conducted by the paddle method of the 18th edition of the Japanese Pharmacopoeia Dissolution Test, using the Japanese Pharmacopoeia Dissolution Test Fluid No. 2 (pH 6.8) as the test fluid at a rotation speed of 50 rpm.

Description

[Technical Field]

[0001] The present invention relates to tablets. [Background technology]

[0002] Chenodeoxycholic acid (3α,7α-dihydroxy-5β-cholic acid, hereinafter also referred to as "CDCA") exists in the human body as a primary bile acid.

[0003] As a preparation containing such chenodeoxycholic acid, a capsule preparation containing powder containing chenodeoxycholic acid as the content is known (Non-Patent Document 1). [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Chino® Capsule 125 Package Insert (https: / / www.fujimoto-pharm.co.jp / jp / iyakuhin / cn / pdf / chino_tenpu.pdf) Summary of the Invention [Problem to be solved by the invention]

[0005] An object of the present invention is to provide a tablet containing chenodeoxycholic acid. [Means for solving the problem]

[0006] As mentioned above, chenodeoxycholic acid has conventionally been formulated as a powder or a capsule containing the powder. In this context, the present inventors investigated dosage forms other than powders (pulverized drugs) and capsules as formulations containing chenodeoxycholic acid, and found that tablets containing chenodeoxycholic acid (as an active ingredient) could be obtained. After further investigations, they completed the present invention.

[0007] That is, the present invention relates to the following inventions. [1] A tablet containing chenodeoxycholic acid at a ratio of 30% by mass or more. [2] A tablet containing chenodeoxycholic acid, in which the dissolution rate of chenodeoxycholic acid is 50% or more after 15 minutes of dissolution testing using the paddle method of the 18th revised Japanese Pharmacopoeia Dissolution Test Method, Japanese Pharmacopoeia Dissolution Test Fluid No. 2 (pH 6.8) as the test fluid and at a rotation speed of 50 rpm. [3] A tablet containing chenodeoxycholic acid and having a hardness of 5N or more. [4] A tablet containing chenodeoxycholic acid with a friability of 1% or less. [5] Contains chenodeoxycholic acid at a ratio of 30% by mass or more, A tablet in which the dissolution rate of chenodeoxycholic acid after 15 minutes of dissolution is 50% or more in a dissolution test using the paddle method of the 18th revised Japanese Pharmacopoeia Dissolution Test, Japanese Pharmacopoeia Dissolution Test Fluid No. 2 (pH 6.8) as the test fluid and at a rotation speed of 50 rpm, and which satisfies at least one of the following (A) and (B): (A) Hardness of 5N or more (B) Friability is 1% or less [6] A tablet containing chenodeoxycholic acid that has a disintegration time of 10 minutes or less according to the disintegration test method of the 18th edition of the Japanese Pharmacopoeia. [7] Contains chenodeoxycholic acid at a ratio of 30% by mass or more, According to the 18th revised Japanese Pharmacopoeia disintegration test method, the disintegration time is within 10 minutes. A tablet that satisfies at least one of the following (A) and (B): (A) Hardness of 5N or more (B) Friability is 1% or less [8] Contains chenodeoxycholic acid at a ratio of 30% by mass or more, In a dissolution test using the paddle method of the 18th revised Japanese Pharmacopoeia Dissolution Test, the Japanese Pharmacopoeia Dissolution Test No. 2 fluid (pH 6.8) is used as the test fluid and the rotation speed is 50 rpm, the dissolution rate of chenodeoxycholic acid after 15 minutes of dissolution is 50% or more, According to the 18th revised Japanese Pharmacopoeia disintegration test method, the disintegration time is within 10 minutes. A tablet that satisfies at least one of the following (A) and (B): (A) Hardness of 5N or more (B) Friability is 1% or less [9] Contains chenodeoxycholic acid at a ratio of 40% by mass or more, In a dissolution test using the paddle method of the 18th edition of the Japanese Pharmacopoeia Dissolution Test, the Japanese Pharmacopoeia Dissolution Test No. 2 fluid (pH 6.8) is used as the test fluid and the rotation speed is 50 rpm, the dissolution rate of chenodeoxycholic acid after 15 minutes of dissolution is 60% or more, Hardness is 5 to 150N, The tablet according to any one of [1] to [8], having a friability of 0.5% or less.

[10] The tablet according to any one of [1] to [8], wherein the dissolution rate of chenodeoxycholic acid after 30 minutes of dissolution is 70% or more in a dissolution test using the paddle method of the 18th edition of the Japanese Pharmacopoeia Dissolution Test, the Japanese Pharmacopoeia Dissolution Test No. 2 Fluid (pH 6.8) as the test fluid and at a rotation speed of 50 rpm.

[11] The tablet according to any one of [1] to [8], wherein in a dissolution test according to the 18th edition of the Japanese Pharmacopoeia Dissolution Test, paddle method, using the Japanese Pharmacopoeia Dissolution Test Fluid No. 2 (pH 6.8) as the test fluid and rotating at a speed of 50 rpm, the ratio ((B) / (A)) of the dissolution rate of chenodeoxycholic acid after a dissolution time of 5 minutes (B) to the dissolution rate of chenodeoxycholic acid after a dissolution time of 15 minutes (A) is 0.7 or more.

[12] In a dissolution test using the 18th revised Japanese Pharmacopoeia Dissolution Test Paddle Method, the Japanese Pharmacopoeia Dissolution Test No. 2 Fluid (pH 6.8) is used as the test fluid and the rotation speed is 50 rpm, the dissolution rate of chenodeoxycholic acid after 30 minutes is 70% or more, The tablet according to any one of [1] to [8], wherein the ratio ((B) / (A)) of the dissolution rate of chenodeoxycholic acid (A) in a dissolution time of 15 minutes to the dissolution rate of chenodeoxycholic acid (B) in a dissolution time of 5 minutes is 0.7 or more.

[13] The tablet according to any one of [1] to [8], containing chenodeoxycholic acid in an amount of 50% by mass or more.

[14] The tablet according to any one of [1] to [8], which has a disintegration time of 5 minutes or less according to the disintegration test method of the 18th edition of the Japanese Pharmacopoeia.

[15] The tablet according to any one of [1] to [8], which contains at least one selected from carboxymethylcellulose, carboxymethylcellulose sodium, carmellose calcium, and croscarmellose sodium.

[16] At least one selected from sugar alcohols, cellulose, starch, and starch derivatives; The tablet according to any one of [1] to [8], which contains at least one selected from carboxymethylcellulose, carboxymethylcellulose sodium, carmellose calcium, and croscarmellose sodium.

[17] The tablet according to any one of [1] to [8], which contains a sucrose fatty acid ester.

[18] At least one selected from sugar alcohols, cellulose, and starch; At least one selected from carmellose calcium and croscarmellose sodium; The tablet according to any one of [1] to [8], containing a sucrose fatty acid ester.

[19] The tablet according to any one of [1] to [8], which is a coated tablet.

[20] The tablet according to any one of [1] to [8], which is a coated tablet, and the coating layer constituting the coated tablet contains at least one selected from cellulose derivatives, talc, and macrogol.

[21] The tablet according to any one of [1] to [8], having a major axis of 7 mm or less.

[22] The tablet according to any one of [1] to [8], which contains 15 mg or more of chenodeoxycholic acid and has a major axis of 7 mm or less.

[23] A tablet according to any one of [1] to [8] for taking 10,000 mg or less of chenodeoxycholic acid three times a day.

[24] The tablet according to any one of [1] to [8], which has a major axis of 7 mm or less and is intended for administration to children.

[25] The tablet according to any one of [1] to [8], which has a major axis of 7 mm or less and is used for the prevention or treatment of cerebrotendinous xanthomatosis. [Effects of the Invention]

[0008] The present invention can provide a tablet containing chenodeoxycholic acid. As mentioned above, since powders and capsules are common formulations containing chenodeoxycholic acid, it was expected that tableting would be extremely difficult. However, the present inventors have found that tableting can be performed efficiently (for example, without any particular problems such as serious tableting problems). In particular, it was extremely unexpected that such efficient tableting could be achieved even when a relatively high proportion of chenodeoxycholic acid was contained, possibly due to the properties of chenodeoxycholic acid itself.

[0009] Such tablets of the present invention can not only be simply tableted (tablets can be obtained), but also, as described above, can incorporate a high proportion of chenodeoxycholic acid and achieve excellent (or sufficient) properties (e.g., dissolution, strength, disintegration, etc.). Such tablets may achieve at least one of these properties, but it is also possible to achieve two or more properties (for example, a high proportion of the compound and one property selected from dissolution, strength, and disintegration properties, or at least one property selected from dissolution, strength, and disintegration properties). For example, in one embodiment of the tablet of the present invention, it is possible to achieve tablet properties that are difficult to achieve simultaneously, such as excellent dissolution and disintegration properties and excellent strength. In particular, it is extremely surprising that such tablet properties can be achieved while containing a high proportion of chenodeoxycholic acid. DETAILED DESCRIPTION OF THE INVENTION

[0010] The tablet of the present invention contains chenodeoxycholic acid.

[0011] Chenodeoxycholic acid may be a commercially available product or may be prepared by manufacturing. The method for manufacturing chenodeoxycholic acid is not particularly limited, and it may be prepared by a method known per se. When bile is used as a raw material, bile from mammals (e.g., cows, pigs, bears), birds (e.g., chickens, geese), fish, etc. may be used as the raw material. The form of chenodeoxycholic acid is not particularly limited as long as it is pharmaceutically acceptable, and may be a crystalline form (e.g., form A (melting point: approximately 165-168°C), form C (melting point: approximately 143°C)), an amorphous form (e.g., form B (melting point: approximately 119°C)), a pharmaceutically acceptable salt (e.g., sodium salt, potassium salt), a hydrate or solvate, a conjugate (glycine conjugate or taurine conjugate), or other derivative, and those conforming to the specifications for chenodeoxycholic acid in the Japanese Pharmacopoeia may be used.

[0012] In this disclosure, the term "about" is used to encompass small deviations, for example. These terms can refer to, for example, within ±10%, ±5%, ±2%, ±1%, ±0.5%, ±0.2%, ±0.1%, or ±0.05%. Such ranges also include within the experimental error inherent in standard methods used to measure and / or quantify a given value or range.

[0013] The form of the tablet of the present invention is not particularly limited, and may be an uncoated tablet, a coated tablet (for example, a tablet coated with a coating layer such as a sugar coating, a film coating, or an enteric coating), a multilayer tablet, or a dry-coated tablet. Furthermore, the tablet may be a tablet (a tableted product) made from a powder [for example, a powder of an active ingredient, or a mixed powder (for example, a mixed powder containing an active ingredient, an excipient, a disintegrant, etc.)], or a tablet (a tableted product) made from a granulated powder (or granules). In particular, the tablet may be a coated tablet (or a tablet with a coating layer, for example, a tablet composed of a plain tablet and a coating layer coating the plain tablet (a tablet in which the plain tablet is coated with a coating layer)). In the present invention, even such coated tablets can be formulated with a high proportion of chenodeoxycholic acid and can achieve excellent (or sufficient) properties (e.g., dissolution property, strength, disintegration property, etc.) (and even achieve a balance between these properties), as described below.

[0014] In one embodiment, the tablet of the present invention can exhibit excellent (sufficient) dissolution properties.

[0015] The dissolution properties of the tablets of the present invention can be measured (confirmed) by measuring the dissolution rate of chenodeoxycholic acid at a specific time point when a dissolution test is conducted using the Japanese Pharmacopoeia Dissolution Test Fluid No. 2 (pH 6.8) according to the Japanese Pharmacopoeia Dissolution Test Method, Paddle Method, 18th Edition. Specifically, 900 mL of the second dissolution test fluid (one volume of phosphate buffer, pH 6.8 (3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous disodium hydrogen phosphate dissolved in water to make 1000 mL) plus one volume of water) is used as the test fluid, and the test is carried out using a sinker by the paddle method at 50 revolutions per minute, and the dissolution time can be confirmed by measuring the dissolution rate of chenodeoxycholic acid after, for example, 5 minutes, 10 minutes, 15 minutes, 30 minutes, etc.

[0016] In the tablet of the present invention, the lower limit of the dissolution rate of chenodeoxycholic acid 5 minutes after the start of the above dissolution test may be selected from the range of, for example, 40% or more, 50% or more (e.g., 52% or more, 54% or more), preferably 55% or more, more preferably 60% or more (e.g., 63% or more), particularly preferably 65% ​​or more, or may be 68% or more, 70% or more, 71% or more, etc. The upper limit of the dissolution rate is not particularly limited, and may be, for example, 100% or less, 95% or less, 93% or less, 90% or less, 85% or less, 80% or less, 75% or less, etc. In the present disclosure, when simply "%" is used, it may be "% by mass."

[0017] In the tablet of the present invention, the lower limit of the dissolution rate of chenodeoxycholic acid 10 minutes after the start of the above dissolution test may be selected from the range of, for example, 55% or more (e.g., 60% or more, 63% or more), preferably 65% ​​or more, more preferably 70% or more (e.g., 73% or more), particularly preferably 75% or more, or may be 78% or more, 80% or more, 82% or more, 83% or more, 84% or more, 85% or more, 86% or more, 87% or more, 88% or more, etc. The upper limit of the dissolution rate is not particularly limited, and may be, for example, 100% or less, 98% or less, 95% or less, 90% or less, etc.

[0018] In the tablet of the present invention, the lower limit of the dissolution rate of chenodeoxycholic acid 15 minutes after the start of the above dissolution test may be selected from a range of, for example, 50% or more (e.g., 52% or more, 54% or more, 55% or more), or 60% or more (e.g., 62% or more, 63% or more), preferably 65% ​​or more (e.g., 68% or more), more preferably 70% or more (e.g., 75% or more), particularly preferably 80% or more, 82% or more, 83% or more, 84% or more, 85% or more, 87% or more, 88% or more, 89% or more, 90% or more, 91% or more, 92% or more, 93% or more, etc. The upper limit of the dissolution rate is not particularly limited, and may be, for example, 100% or less, 99% or less, 98% or less, 95% or less, 90% or less, etc.

[0019] In the tablet of the present invention, the lower limit of the dissolution rate of chenodeoxycholic acid 30 minutes after the start of the above dissolution test may be selected from the range of, for example, 70% or more (e.g., 73% or more), preferably 75% or more, more preferably 80% or more (e.g., 82% or more), particularly preferably 85% or more, or may be 88% or more, 89% or more, 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more, etc. The upper limit of the dissolution rate is not particularly limited, and the dissolution rate may be, for example, 100% or less, 99% or less, etc. In particular, in the case of the tablets of the present invention, in the above-mentioned dissolution test, a high dissolution rate can often be achieved in a relatively short time, and excellent dissolution properties can be achieved, with most or all (substantially all) of the chenodeoxycholic acid being dissolved in approximately 15 minutes or 30 minutes (particularly, at least 30 minutes).

[0020] In the tablet of the present invention, when the above-mentioned dissolution test is carried out, the ratio ((B) / (A)) of the dissolution rate of chenodeoxycholic acid in (B) a dissolution time of 5 minutes to the dissolution rate of chenodeoxycholic acid in (A) a dissolution time of 15 minutes may be, for example, 0.5 or more, 0.6 or more (e.g., more than 0.68), 0.7 or more (e.g., 0.72 or more, 0.74 or more, 0.75 or more, 0.76 or more), or 0.8 or more. In the tablet of the present invention, the ratio ((B) / (C)) of the dissolution rate of chenodeoxycholic acid in (B) a dissolution time of 5 minutes to the dissolution rate of chenodeoxycholic acid in (C) a dissolution time of 30 minutes may be, for example, 0.4 or more (e.g., 0.45 or more, 0.5 or more, 0.55 or more), 0.6 or more (e.g., 0.65 or more, 0.68 or more, 0.69 or more), 0.7 or more (e.g., 0.71 or more, 0.72 or more), or 0.75 or more.

[0021] When the tablet of the present invention is a coated tablet, the dissolution rate of the tablet may be measured on a tablet (plain tablet) (before coating) that does not contain a coating layer (coating agent, plasticizer, etc.) (it may be the value on the tablet (plain tablet, etc.) before a coating layer is formed). In the case of the tablet (coated tablet) of the present invention, the dissolution rate often does not change significantly before and after the formation of a coating layer.

[0022] In one embodiment, the tablet of the present invention can exhibit excellent (sufficient) disintegration properties. The disintegration time of such a tablet may be about 60 minutes or less (e.g., 40 minutes or less, 30 minutes or less, 25 minutes or less, 20 minutes or less, or 15 minutes or less) in the above-mentioned tablet dissolution test, preferably 10 minutes or less, more preferably 5 minutes or less, particularly preferably 3 minutes or less, or may be 2 minutes 30 seconds or less, 2 minutes or less, etc. The dissolution properties of the tablet of the present invention can be confirmed by the measurement method described in "2.1. Immediate-release preparations" in "Disintegration test method <6.09>" of the general test method dissolution test in the 18th edition of the Japanese Pharmacopoeia.

[0023] In one embodiment, the tablets of the present invention may have good (sufficient) strength (eg, strength and / or friability).

[0024] The hardness of the tablet of the present invention was measured according to the "Tablet Hardness Measurement Method" in the Reference Information of the 18th Edition of the Japanese Pharmacopoeia. <g6-4-180>" can be measured (confirmed) by the measurement method described in the ".

[0025] In the tablet of the present invention, the lower limit of the hardness measured by the above-mentioned measurement method is, for example, preferably 5N or more, more preferably 10N or more (13N or more), even more preferably 15N or more, and may be 20N or more, 25N or more, 30N or more, or 40N or more. The upper limit of the hardness is preferably 150N or less, more preferably 100N or less, even more preferably 70N or less, and may be 65N or less. From the viewpoint of achieving appropriate dissolution, 10 to 100N, 13 to 80N, 20 to 70N, 20 to 40N, 25 to 35N, or 15 to 70N are preferred.

[0026] The friability of the tablets of the present invention was determined in accordance with the "Testing Method for Tablet Friability" in the Reference Information of the 18th Edition of the Japanese Pharmacopoeia. <g6-5-181>This can be confirmed by the measurement method described in . The friability of the tablet of the present invention can be selected, for example, from a range of about 2% or less, and may be 1.5% or less (e.g., 1.2% or less), preferably 1% or less (e.g., 0.8% or less), and more preferably 0.5% or less (e.g., 0.4% or less, 0.3% or less, 0.2% or less, 0.1% or less, 0.05% or less, 0.02% or less).

[0027] When the tablet of the present invention is a coated tablet, the hardness and friability of the tablet may be measured on a tablet (plain tablet) (before coating) that does not contain a coating layer (coating agent, plasticizer, etc.) (the values ​​may be on the tablet (plain tablet, etc.) before a coating layer is formed). In the case of the tablet (coated tablet) of the present invention, the hardness and friability often do not change substantially significantly before and after the formation of a coating layer.

[0028] The tablet of the present invention may satisfy any one or more of the above-mentioned excellent (sufficient) dissolution properties, excellent (sufficient) disintegration properties, and excellent (sufficient) strength (e.g., strength and / or friability).

[0029] In the tablet, the content of chenodeoxycholic acid (proportion relative to the entire tablet) may be, for example, 10% by mass or more (e.g., 15% by mass or more, 20% by mass or more, 25% by mass or more), and can also be a high proportion, particularly such as 30% by mass or more [e.g., 40% by mass or more (e.g., 45% by mass or more), preferably 50% by mass or more (e.g., 55% by mass or more, more than 55% by mass), and more preferably 60% by mass or more (e.g., 65% by mass or more, 66.5% by mass or more, 66.8% by mass or more, 67% by mass or more), etc.]. In the tablet, the content (upper limit) of chenodeoxycholic acid may be 100% by mass, or may be less than 100% by mass, for example, 99% by mass or less, 95% by mass or less, 90% by mass or less, 88% by mass or less, 85% by mass or less, 80% by mass or less, 77% by mass or less, 75% by mass or less, 73% by mass or less, 72% by mass or less, 70% by mass or less, etc. Surprisingly, in the present invention, even if the tablet contains such a high proportion of chenodeoxycholic acid, it can be efficiently tableted (particularly while ensuring sufficient dissolution and hardness as described above). The ability to contain such a high proportion of the active ingredient can also lead to the miniaturization of tablets. Moreover, in one embodiment of the tablet of the present invention, it is surprisingly possible to realize the above-mentioned excellent (sufficient) properties (e.g., dissolution property, disintegration property, and / or strength) while containing such a high proportion of chenodeoxycholic acid.

[0030] The tablet of the present invention may contain, as needed, ingredients other than chenodeoxycholic acid (the active ingredient), such as additives (e.g., pharmaceutically acceptable carriers). Examples of such other ingredients (additives) include excipients, disintegrants, binders, lubricants, flow agents, flavoring agents, flavorings, colorants, preservatives, antioxidants, sweeteners, and stabilizers (e.g., cyclodextrin (β-cyclodextrin)). These additives can be added singly or in combination in appropriate amounts. By appropriately selecting such additives in combination with chenodeoxycholic acid, it is possible to more efficiently incorporate a high proportion of chenodeoxycholic acid and to impart the above-mentioned excellent (sufficient) properties (e.g., dissolution property, disintegration property, and / or strength).

[0031] Examples of the "excipient" used in the tablet of the present invention include organic substances such as sugars (lactose, sucrose, glucose, trehalose, etc.), sugar alcohols (D-mannitol, D-sorbitol, etc.), cellulose (crystalline cellulose), starch and starch derivatives (corn starch, pregelatinized starch, sodium carboxymethyl starch, etc.), dextrin, cellulose derivatives (carboxymethyl cellulose, hydroxypropyl cellulose, etc.), and gum arabic; and inorganic substances such as kaolin, calcium hydrogen phosphate, and calcium carbonate. These may be used alone or in combination of two or more. From the viewpoint of efficient tableting and efficient imparting of excellent (sufficient) properties, it is preferable to use an excipient (such as crystalline cellulose or D-mannitol), and it is more preferable to use one or more selected from sugar alcohols, cellulose, and starch and starch derivatives, and it is particularly preferable to use crystalline cellulose, D-mannitol, or corn starch.

[0032] Examples of the "disintegrants" used in the tablets of the present invention include starch and processed starch (e.g., sodium carboxymethyl starch, partially pregelatinized starch, crosslinked starch, etc.), cellulose and its derivatives (e.g., carboxymethyl cellulose, sodium carboxymethyl cellulose, carmellose calcium, low-substituted hydroxypropyl cellulose, croscarmellose sodium), starch derivatives (e.g., sodium carboxymethyl starch), polyvinylpyrrolidone derivatives (e.g., crospovidone), inorganic salts (e.g., calcium carbonate, calcium bicarbonate), sugar alcohols (e.g., mannitol), and other known disintegrants (e.g., alginates, carbonates including those in combination with organic acids). These may be used alone or in combination of two or more. From the viewpoint of efficient tableting and efficient imparting of excellent (sufficient) properties, it is preferable to use a disintegrant (cellulose and its derivatives such as carmellose calcium and croscarmellose sodium), more preferably cellulose and its derivatives, and particularly preferably carmellose calcium or croscarmellose sodium. The cellulose and derivatives thereof may be those excluding hydroxyalkyl cellulose (for example, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylethyl cellulose, etc.) and those excluding low-substituted hydroxypropyl cellulose.

[0033] Examples of the "binder" used in the tablet of the present invention include hydroxypropyl cellulose, hypromellose, polyvinylpyrrolidone, sucrose, glucose, dextrin, starch, pregelatinized starch, partially pregelatinized starch, methyl cellulose, gelatin, sodium carboxymethyl cellulose, gum arabic, pullulan, sodium alginate, polyvinyl alcohol, etc. These binders can be used alone or in combination of two or more.

[0034] Examples of "lubricants" used in the tablets of the present invention include stearic acid, stearates (magnesium stearate, calcium stearate, etc.), stearic acid esters (sodium stearyl fumarate, etc.), sucrose fatty acid esters, talc, wax, etc. From the viewpoint of efficient tableting and efficiently imparting excellent (sufficient) properties, it is preferable to use lubricants (magnesium stearate, sucrose fatty acid esters, etc.). These lubricants can be used alone or in combination of two or more.

[0035] Examples of the "fluidizer" used in the tablet of the present invention include light anhydrous silicic acid, magnesium stearate, etc.

[0036] Examples of the "flavoring agent" used in the tablet of the present invention include lactose, glucose, sucrose, fructose, mannitol, sorbitol, and the like.

[0037] The "flavoring" used in the tablet of the present invention includes vegetable oil and the like.

[0038] Examples of the "coloring agent" used in the tablet of the present invention include food dyes (e.g., Food Red No. 2 or No. 3, Food Yellow No. 4 or No. 5, etc.), β-carotene, and the like.

[0039] Examples of the "preservative" used in the tablet of the present invention include ethyl parahydroxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, sorbic acid, and the like.

[0040] Examples of the "antioxidant" used in the tablet of the present invention include sodium sulfite, ascorbic acid, etc.

[0041] Examples of the "sweetener" used in the tablet of the present invention include saccharin sodium, dipotassium glycyrrhizinate, aspartame, etc.

[0042] It should be noted that these components do not necessarily have to be classified into the above categories (for example, they may be components belonging to other categories, or may be components belonging to multiple categories).

[0043] The tablet of the present invention [in the case of a coated tablet, the components constituting the tablet other than the coating layer (such as the uncoated tablet)] preferably contains at least one selected from sugar alcohols, cellulose, starch, starch derivatives, and cellulose derivatives. In particular, from the viewpoint of containing chenodeoxycholic acid in a high proportion as described above and efficiently imparting excellent (sufficient) properties, the tablet of the present invention preferably contains at least a cellulose derivative (e.g., carboxymethylcellulose, carboxymethylcellulose sodium, carmellose calcium, croscarmellose sodium), and preferably contains a combination of (1) at least one selected from sugar alcohols (D-mannitol, D-sorbitol, etc.), cellulose, starch, and starch derivatives (corn starch, pregelatinized starch, carboxymethylstarch sodium, etc.) and (2) a cellulose derivative (e.g., carboxymethylcellulose, carboxymethylcellulose sodium, carmellose calcium, croscarmellose sodium). More specific combinations include sugar alcohol and carmellose calcium, cellulose and carmellose calcium, starch and / or starch derivative and carmellose calcium, cellulose (such as crystalline cellulose) and a cellulose derivative, corn starch and cellulose and / or a cellulose derivative, and mannitol and cellulose and / or a cellulose derivative, and even more preferred are combinations that include at least a cellulose derivative (e.g., carmellose calcium) [for example, combinations of cellulose (such as crystalline cellulose) and carmellose calcium, corn starch and carmellose calcium, mannitol and carmellose calcium, cellulose (such as crystalline cellulose) and croscarmellose sodium, or mannitol and croscarmellose sodium]. Furthermore, the tablet of the present invention [in the case of a coated tablet, the components constituting the tablet other than the coating layer (such as the uncoated tablet)] preferably contains at least one selected from stearic acid, stearates, stearic acid esters, and sucrose fatty acid esters [particularly, at least a sucrose fatty acid ester (e.g., sucrose fatty acid ester only, or a sucrose fatty acid ester and a stearate)] in terms of containing a high proportion of chenodeoxycholic acid as described above and efficiently imparting excellent (sufficient) properties. Furthermore, from the viewpoint of efficiently imparting multiple or high levels of excellent (sufficient) properties, the tablet of the present invention preferably contains a combination of at least one selected from sugar alcohols, cellulose, starch, starch derivatives, and cellulose derivatives {for example, a combination including at least a cellulose derivative (e.g., carmellose calcium)} and at least one selected from stearic acid, stearates, stearic acid esters, and sucrose fatty acid esters [particularly, at least a sucrose fatty acid ester (e.g., sucrose fatty acid ester only, or sucrose fatty acid ester and stearate)].

[0044] When the tablet of the present invention contains an additive, the content ratio of the additive (ratio to the entire tablet) may be, for example, 70% by mass or less (e.g., less than 70% by mass), 60% by mass or less, 50% by mass or less, 40% by mass or less (e.g., less than 40% by mass), 35% by mass or less, 33% by mass or less, 31% by mass or less, or 1% by mass or more, 3% by mass or more, 5% by mass or more, 7% by mass or more, 10% by mass or more, 15% by mass or more, 20% by mass or more, 25% by mass or more, 27% by mass or more, 28% by mass or more, etc.

[0045] When the tablet contains an excipient, the proportion of the excipient (e.g., at least one selected from sugar alcohols, cellulose, starch, and starch derivatives) may be, for example, 0.01% by mass or more, 0.05% by mass or more, 0.1% by mass or more, 2% by mass or more, 5% by mass or more, 7% by mass or more, etc., or 25% by mass or less, 20% by mass or less, 15% by mass or less, 10% by mass or less, 9% by mass or less, etc.

[0046] When the tablet contains a disintegrant, the proportion of the disintegrant (e.g., a cellulose derivative such as carmellose calcium) may be, for example, 0.01% by mass or more, 0.05% by mass or more, 0.1% by mass or more, 1% by mass or more, 10% by mass or more, 15% by mass or more, or 30% by mass or less, 25% by mass or less, 20% by mass or less, etc. In addition, the tablet [in the case of a coated tablet, the components that normally constitute the tablet other than the coating layer (such as a plain tablet)] may not contain hydroxyalkyl cellulose (e.g., hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl ethyl cellulose, etc.), or if it does contain hydroxyalkyl cellulose, it may contain only a small amount {for example, less than 0.5% by mass (e.g., 0.4% by mass or less) of the tablet [in the case of a coated tablet, the components that normally constitute the tablet other than the coating layer (such as a plain tablet)]}.

[0047] When the tablet contains a binder, the proportion of the binder may be, for example, 0.01% by mass or more, 0.05% by mass or more, 0.1% by mass or more, 0.5% by mass or more, 0.7% by mass or more, 0.8% by mass or more, or 10% by mass or less, 5% by mass or less, 3% by mass or less, 2% by mass or less, 1% by mass or less, or less than 1% by mass.

[0048] When the tablet contains a lubricant, the proportion of the lubricant {e.g., at least one selected from stearic acid, stearate salts, stearate esters, and sucrose fatty acid esters [particularly, at least a sucrose fatty acid ester (e.g., only a sucrose fatty acid ester, or a sucrose fatty acid ester and a stearate salt)], etc.} may be, for example, 0.01% by mass or more, 0.05% by mass or more, 0.1% by mass or more, 0.5% by mass or more, 1% by mass or more, etc., or 10% by mass or less, 5% by mass or less, 3% by mass or less, 2% by mass or less, 1.8% by mass or less, etc.

[0049] When the tablet contains one or more (e.g., two or more, three or more) additives selected from excipients, disintegrants, binders, and lubricants in addition to chenodeoxycholic acid, the content ratio of each additive (percentage relative to the entire tablet) may be, for example, 2 to 20% by mass of excipients (e.g., crystalline cellulose, corn starch, D-mannitol, etc.), 10 to 30% by mass of disintegrants (e.g., carmellose calcium, hydroxypropyl cellulose, etc.), 0.1 to 5% by mass of binders (e.g., magnesium stearate, sucrose fatty acid esters, etc.), or 0.5 to 5% by mass of lubricants (e.g., magnesium stearate, sucrose fatty acid esters, etc.). The tablet may also contain excipients, disintegrants, binders, and lubricants in addition to chenodeoxycholic acid. In this case, the content ratio of each component is the same as above.

[0050] The tablet may be free of surfactants (for example, polyoxyl 40 stearate, polysorbate 80). When a surfactant is contained, the amount may be, for example, less than 30% by mass. The tablet may not contain an aqueous organic solvent (an organic solvent that dissolves chenodeoxycholic acid and is freely miscible with water, such as a solvent containing 30 to 70% by mass of water containing methanol, ethanol, isopropanol, acetone, etc.). When the tablet contains an aqueous organic solvent, it may not contain hydroxyacetylcellulose or a surfactant. The tablet may not contain cyclodextrin (such as β-cyclodextrin). When cyclodextrin (such as β-cyclodextrin) is contained, it may contain, for example, less than 0.8% by mass of chenodeoxycholic acid. In the present invention, even when no inclusion compound such as cyclodextrin (such as β-cyclodextrin) is contained, or when only a small amount of such compound is contained, a tablet containing a high amount of chenodeoxycholic acid has excellent properties (such as dissolution property).

[0051] When the tablet is a coated tablet, the tablet (the coating layer constituting the tablet) may contain a coating agent, a plasticizer, and the like.

[0052] The "coating agent" used in the tablets of the present invention depends on the type of coating, such as sugar coating or film coating, but examples include sugars (sucrose, maltitol, etc.), cellulose derivatives (hypromellose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, etc.), polyvinyl alcohol, talc, etc. These coating agents can be used alone or in combination of two or more.

[0053] Examples of the "plasticizer" used in the tablet of the present invention include triethyl citrate, glycerin, glycerin fatty acid esters, D-sorbitol, medium-chain fatty acid triglycerides, triacetin, concentrated glycerin, castor oil, polyoxyethylene hydrogenated castor oil 60, propylene glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polysorbate 80, macrogol (or polyethylene glycol, e.g., macrogol 400, macrogol 600, macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000NF), glycerin monostearate, isopropyl linoleate, liquid paraffin, etc. These plasticizers can be used alone or in combination of two or more.

[0054] When the tablet of the present invention contains a coating agent, it may be used in combination with, but not limited to, a plasticizer. Among these, from the viewpoint of efficiently coating tablets (plain tablets, etc.) containing chenodeoxycholic acid (especially at a high content) (and further efficiently imparting the above-mentioned properties to coated tablets), cellulose derivatives (hypromellose, hydroxypropyl cellulose, etc.), talc, macrogol, etc. can be preferably used. Therefore, the coated tablet (the coating layer constituting the coated tablet) may contain at least one selected from cellulose derivatives (hypromellose, hydroxypropyl cellulose, etc.), talc, and macrogol.

[0055] When the tablet is a coated tablet, the content ratio of the coating layer (ratio to the entire tablet) may be in the range of, for example, 1 to 10 mass %, 2 to 6 mass %, or 3 to 5 mass %.

[0056] The coating layer may contain, for example, a coating agent and a plasticizer, and the content ratio of each component (ratio to the entire tablet) may be, for example, 2 to 8 mass%, 2.5 to 5 mass%, 3 to 4 mass%, etc. for the coating agent (e.g., hypromellose), and 0.2 to 2 mass%, 0.4 to 1 mass%, 0.5 to 0.7 mass%, etc. for the plasticizer (e.g., macrogol 400).

[0057] In addition to chenodeoxycholic acid, the tablet may contain an excipient, a disintegrant, a binder, a lubricant, a coating agent, and a plasticizer. The content ratio of each ingredient (percentage relative to the total tablet) may be, for example, 2 to 20% by mass for excipients (e.g., crystalline cellulose, corn starch, D-mannitol, etc.), 10 to 30% by mass for disintegrants (e.g., carmellose calcium, hydroxypropyl cellulose, etc.), 0.1 to 5% by mass for binders (e.g., methylcellulose), 0.5 to 5% by mass for lubricants (e.g., magnesium stearate, sucrose fatty acid esters, etc.), or may be in the ranges of 5 to 15% by mass for excipients, 15 to 25% by mass for disintegrants, 0.5 to 2% by mass for binders, and 1 to 3% by mass for lubricants; 2.5 to 5% by mass for coating agents (e.g., hypromellose); and 0.4 to 1% by mass for plasticizers (e.g., macrogol 400).

[0058] The size of the tablet can be selected depending on, for example, the content ratio of chenodeoxycholic acid, the desired dose (effective intake amount), etc. The major axis (diameter, etc.) of the tablet may be, for example, 1 mm or more (e.g., 2 mm or more, 3 mm or more, 5 mm or more) or 30 mm or less (e.g., 25 mm or less, 20 mm or less, 15 mm or less, 10 mm or less), etc., specifically, 1 to 20 mm, 3 to 18 mm, 4 to 15 mm, 8 to 9 mm, etc. The tablets may also be mini-tablets. In such cases, the size of the tablet can be selected depending on, for example, the content of chenodeoxycholic acid and the desired dosage (effective intake amount), and for example, the major axis (diameter, etc.) of the tablet may be 7 mm or less, specifically 1 to 7 mm, 2 to 6 mm, 3 to 5 mm, 4 to 6 mm, etc. Mini-tablets are preferred because they allow fine adjustment of the dosage per dose and can be administered in small doses to children and the like without crushing or dividing the tablets. In the present invention, even if the tablet is miniaturized (reduced in size) in this way, it is possible to achieve a high proportion of chenodeoxycholic acid and excellent (sufficient) tablet properties, as described above.

[0059] The mass of the tablet (one tablet) can be selected depending on the content of chenodeoxycholic acid and the desired dosage (effective intake amount), but may be, for example, 1000 mg or less, preferably 700 mg or less, more preferably 500 mg or less (e.g., 400 mg or less), particularly 300 mg or less (e.g., 280 mg or less), and particularly preferably 250 mg or less (e.g., less than 250 mg, less than 230 mg), or may be 220 mg or less, 200 mg or less, 180 mg or less, 160 mg or less, 140 mg or less, 120 mg or less, 100 mg or less, less than 100 mg, 80 mg or less, 60 mg or less, 50 mg or less, less than 50 mg, 40 mg or less, 38 mg or less, etc.

[0060] The lower limit of the tablet mass is not particularly limited, but may be, for example, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 7 mg, 10 mg, 13 mg, preferably 15 mg or more (e.g., 17 mg, 18 mg), and more preferably 20 mg or more (e.g., 23 mg, 25 mg, 27 mg, 30 mg, 33 mg, etc.). In tablets, the mass of chenodeoxycholic acid can be selected depending on the size of the tablet, etc., and may be selected, for example, from a range of about 3 mg or more (e.g., 4 mg or more), 5 mg or more (e.g., 7 mg or more), preferably 10 mg or more (e.g., 12 mg or more), more preferably 15 mg or more (e.g., 18 mg or more), and particularly 20 mg or more (e.g., 25 mg or more). Since the tablet of the present invention can contain chenodeoxycholic acid at a high ratio as described above, even small tablets (for example, tablets with a major axis of 7 mm or less) can contain a sufficient mass of chenodeoxycholic acid. In tablets, the mass (upper limit) of chenodeoxycholic acid can also be selected depending on the size of the tablet, etc., and may be selected from a range of, for example, about 1000 mg or less (e.g., 800 mg or less), 500 mg or less (e.g., 400 mg or less), preferably 300 mg or less (e.g., 250 mg or less), etc., or may be less than 250 mg (e.g., 240 mg or less, 200 mg or less, 180 mg or less, 150 mg or less, 120 mg or less, 100 mg or less, 80 mg or less, 70 mg or less, 60 mg or less, 50 mg or less, 40 mg or less, 35 mg or less, 30 mg or less, 25 mg or less), etc.

[0061] The tablet of the present invention can be in a dosage form described in the 18th revised Japanese Pharmacopoeia Preparation Regulations, etc., such as a preparation for oral administration (e.g., tablet, fast-dissolving tablet, chewable tablet, effervescent tablet, sustained-release tablet, orally disintegrating tablet, dispersible tablet) or a preparation for oral application (e.g., oral tablet, troche, sublingual tablet, buccal tablet, adhesive tablet, gum).

[0062] The tablet (tablet shape) is not particularly limited, and may be, for example, a round tablet (so-called ordinary tablet), an irregularly shaped tablet (caplet, ring tablet, flower-shaped, star-shaped, heart-shaped, etc.), or the like.

[0063] Uses of the tablet of the present invention (or efficacy or effects of the tablet, or target symptoms or diseases for which the tablet is used) include, for example, cholelithiasis [dissolution of gallstones (e.g., cholesterol-based gallstones without exoskeleton calcification)], cerebrotendinous xanthomatosis (CTX), etc. In other words, the tablet of the present invention can be used for the prevention, treatment, etc. of such target symptoms or diseases (dissolution of cholesterol-based gallstones, cerebrotendinous xanthomatosis, etc.). Among these diseases, CTX and the like are said to frequently occur in childhood. Therefore, when the target population is children (and further, when the target disease is CTX, etc.), the small tablets (mini-tablets) described above are highly useful.

[0064] The subjects to which the tablet of the present invention is administered are mainly humans (e.g., adults and children), but may also be mammals other than humans (e.g., mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, pigs, cows, horses, sheep, and monkeys). In the present invention, "adults" refers to men and women aged 15 or over, and "children" refers to men and women under 15 years of age.

[0065] The dosage of chenodeoxycholic acid in the tablet of the present invention is adjusted appropriately depending on the use of the tablet, the subject to be administered, the symptoms, age, weight, sex, etc. of the subject to be administered.

[0066] The daily dose of chenodeoxycholic acid in the present invention may be 0.1 to 2000 mg, 1 to 1700 mg, 3 to 1500 mg, 5 to 750 mg, 100 to 1300 mg, 100 to 800 mg, 200 to 500 mg, 250 to 1000 mg, 500 to 1000 mg, 750 to 1000 mg, or 300 to 600 mg.

[0067] In a specific embodiment, the dosage of chenodeoxycholic acid is adjusted, for example, within the range of 50 to 1000 mg, preferably 200 to 800 mg, and more preferably 300 to 600 mg per day administered to an adult. In a specific embodiment, the dosage of chenodeoxycholic acid is adjusted, for example, in the range of 100 to 2000 mg, preferably 200 to 1500 mg, and more preferably 250 to 1000 mg per day administered to an adult. In a specific embodiment, the dosage of chenodeoxycholic acid is adjusted within the range of, for example, 0.1 to 1000 mg, preferably 1 to 850 mg, 5 to 250 mg, 10 to 500 mg, or 15 to 750 mg per day administered to children. In an embodiment, the dosage of chenodeoxycholic acid is adjusted within the range of, for example, 1 to 30 mg / kg, 3 to 20 mg / kg, or 5 to 15 mg / kg per day when administered to a child.

[0068] The dosage of the tablets mentioned above is a daily dosage, but the same amount may be administered to a subject in a single dose or multiple doses, for example, two, three or four times a day, preferably three times a day.

[0069] The dosage of the tablets may be a constant dosage from the start of administration, or may be increased stepwise (e.g., every 3 days, every week, every 2 weeks, every 3 weeks, or every 4 weeks) from the initial dosage (e.g., 1 mg, 5 mg, 100 mg, 200 mg, 250 mg), or may be increased stepwise and then administered at a constant dosage as a maintenance dose. The maintenance dosage may be selected from the same dosages as those described above.

[0070] The number of tablets per day (number taken, number administered, number ingested) depends on the effective intake amount, the content ratio in the tablets, etc., but may be selected from a range of approximately 500 tablets or less, 300 tablets or less, 200 tablets or less (e.g., 150 tablets or less, 120 tablets or less), for example, 100 tablets or less (e.g., 80 tablets or less, 60 tablets or less), preferably 50 tablets or less (e.g., 40 tablets or less, 30 tablets or less), or may be 18 tablets or less, 15 tablets or less, 10 tablets or less, etc.

[0071] The lower limit of the number of tablets per day may be, for example, 1 tablet, 3 tablets, 6 tablets, 9 tablets, 12 tablets, 15 tablets, 50 tablets, 100 tablets, etc.

[0072] The number of tablets per dose (number taken, number administered, number ingested) may be selected from a range of approximately 500 tablets or less, 300 tablets or less, 200 tablets or less, 100 tablets or less, 50 tablets or less, or 20 tablets or less (e.g., 19 tablets or less), depending on the method of use, etc., and may be, for example, 18 tablets or less (e.g., 17 tablets or less), preferably 16 tablets or less (e.g., 15 tablets or less), more preferably 14 tablets or less (e.g., 13 tablets or less), particularly 12 tablets or less (e.g., 11 tablets or less), particularly preferably 10 tablets or less (e.g., 9 tablets or less), and most preferably 8 tablets or less (e.g., 7 tablets or less, 6 tablets or less, 5 tablets or less, 4 tablets or less, etc.). The lower limit of the number of tablets per dose may be, for example, 1 tablet, 2 tablets, 3 tablets, 4 tablets, 5 tablets, etc.

[0073] In a specific embodiment, adult patients may be administered a starting dose of 250 mg of chenodeoxycholic acid per day, increasing the dose by 250 mg each time, and then maintaining a daily dose of 750 mg orally, divided into three doses per day. The daily dose may not exceed 1000 mg. Furthermore, the single dose may not exceed 375 mg. In a specific embodiment, children may be administered an initial daily dose of 5 mg / kg of chenodeoxycholic acid, which may be increased by 5 mg / kg increments, followed by a maintenance dose of 15 mg / kg, administered orally three times daily. The daily dose may be adjusted depending on the patient's condition, and may not exceed either 15 mg / kg or 750 mg. A single dose may not exceed 250 mg. In certain embodiments, the pediatric dose of chenodeoxycholic acid may be administered at a daily escalation rate of not more than 250 mg at a 5 mg / kg dose, 500 mg at a 10 mg / kg dose, or 750 mg at a 15 mg / kg dose. In a specific embodiment, chenodeoxycholic acid may be orally administered to an adult in a dose of 300 to 400 mg in two to three divided doses per day.

[0074] The present invention also includes multiple tablets (multiple tablets, combination tablets) corresponding to such dosage regimens.

[0075] For example, if the daily dose of tablet X is A mg, the multiple tablets would be tablets obtained by combining multiple tablets X to provide A mg of chenodeoxycholic acid (multiple tablets for taking a daily dose of A mg). The specific number of tablets (number of tablets per day) of multiple tablets can be selected, for example, from the range exemplified above.

[0076] Furthermore, if the dose of tablet X per administration is B mg, the multiple tablets are tablets obtained by combining multiple tablets X to provide B mg of chenodeoxycholic acid (multiple tablets for taking a dose of B mg per administration). The specific number of tablets (number of tablets per dose) of multiple tablets can be selected, for example, from the range exemplified above.

[0077] The tablet can be manufactured by any conventional method (molding method) as long as the tablet contains the active ingredient (chenodeoxycholic acid). Examples of such molding methods (tablet molding methods) include, but are not limited to, direct powder compression (direct compression), granule compression (e.g., dry granule compression, wet granule compression), etc. The tablet production method of the present invention may include a step of granulating or mixing chenodeoxycholic acid with an excipient, a disintegrant, a binder, etc. Alternatively, the method may include a step of hydrolyzing and mixing chenodeoxycholic acid with a binder and water, a wet granulation step, a drying step, etc. The tablet production method of the present invention may include a wet granulation step. When a drying step is included, the drying temperature is not particularly limited and may be, for example, 25 to 100°C, 30 to 95°C, 35 to 90°C, 36 to 85°C, etc., or may be higher than 35°C, 40°C or higher, 45°C or higher, 50°C or higher, etc. The drying time may be, for example, 5 hours or more, 7 hours or more, 10 hours or more, 13 hours or more, or 15 hours or more. The upper limit of the drying time may be, for example, less than 24 hours, 20 hours or less, 18 hours or less, 16 hours or less, etc. The method for producing tablets of the present invention may include a sizing step after the drying step, and may also include a lubricant mixing step (for example, after the sizing step). Thereafter, the tablet of the present invention may be produced by compression molding (including, for example, a tableting step) using a method known per se. Furthermore, the tablets may be coated with a coating agent.

[0078] The method for producing tablets of the present invention may include a tableting step. The tableting conditions are not particularly limited, but a pressure of 10 to 300 kgf, 20 to 200 kgf, 30 to 180 kgf, 40 to 150 kgf, 50 to 130 kgf, 60 to 120 kgf, or the like may be applied for 10 seconds or less, 5 seconds or less (e.g., less than 3 seconds), or 1 second or less (e.g., less than about 1 second) so as to achieve the above-mentioned hardness. The tablet press used is not particularly limited, but for example, a fully automatic single-punch tablet press (for example, AUTOTAB-500, manufactured by Ichihashi Seiki Co., Ltd.), a rotary tablet press, etc. can be used.

[0079] In a specific embodiment, the present invention provides a method for preventing or treating a disease (e.g., cholelithiasis, cerebrotendinous xanthomatosis) comprising administering the tablet to a human or non-human animal.

[0080] In a specific embodiment, the present invention provides a method for preventing or treating a disease (e.g., cholelithiasis, cerebrotendinous xanthomatosis) by administering the tablet to a human or non-human animal (e.g., 10,000 mg of chenodeoxycholic acid per day, administered in three divided doses).

[0081] In such a method, the form and shape of the tablet, the subject of administration, the administration method, etc. can be selected from the same as those described above. [Example]

[0082] The present invention will be explained in more detail below by way of examples, but the present invention is not limited to these examples, and many modifications can be made by those skilled in the art within the technical spirit of the present invention.

[0083] [Test Example 1. Production of tableted products or mixed powder]

[0084] <Experimental Example 1> Based on the formulation shown in Table 1, 25 parts by mass of CDCA (JP), crystalline cellulose (JP, average degree of polymerization: 100-300, loss on drying: 2.0-6.0%, bulk density: 0.28-0.33 g / cm 3 2.88 parts by mass of PEG-400 Calcium Carbonate (JP) and 7.2 parts by mass of Calcium Carboxylate (JP) were mixed together. The mixed powder mixture was then compressed into tablets using a tablet press (fully automatic single-punch tablet press AUTOTAB-500, manufactured by Ichihashi Seiki Co., Ltd.) under tableting conditions of approximately 64 to 111 kgf for approximately 1 second, with each tablet having a diameter of approximately 4 mm, a weight of approximately 35 mg, and a hardness of 20 to 40 N, to produce mixed powder tablets (Experimental Example 1). Surprisingly, despite the high CDCA content, none of the tablets experienced tableting problems such as capping or lamination, and were successfully tableted (the same applies hereinafter).

[0085] <Experimental Example 2> 25 parts by mass of CDCA (JP), 2.88 parts by mass of corn starch (JP), and 7.2 parts by mass of carmellose calcium (JP) were mixed together according to the formulation shown in Table 1. The mixed powder mixture was then compressed using a tablet press (fully automatic single-punch tablet press AUTOTAB-500, manufactured by Ichihashi Seiki Co., Ltd.) under tableting conditions of approximately 91 to 111 kgf for approximately 1 second, so that each tablet had a diameter of approximately 4 mm, a weight of approximately 35 mg, and a hardness of 20 to 40 N, to produce a mixed powder tablet (Experimental Example 2).

[0086] <Experimental Example 3> 25 parts by mass of CDCA (JP), 2.88 parts by mass of D-mannitol (JP), and 7.2 parts by mass of carmellose calcium (JP) were mixed together based on the formulation shown in Table 1. The mixed powder mixture was then compressed using a tablet press (fully automatic single-punch tablet press AUTOTAB-500: manufactured by Ichihashi Seiki Co., Ltd.) under tableting conditions of approximately 91 to 103 kgf for approximately 1 second, so that each tablet had a diameter of approximately 4 mm, a weight of approximately 35 mg, and a hardness of 20 to 40 N, to produce a mixed powder tablet (Experimental Example 3).

[0087] <Experimental Example 4> Based on the formulation shown in Table 1, 25 parts by mass of CDCA (JP), crystalline cellulose (JP, average degree of polymerization: 100-300, loss on drying: 2.0-6.0%, bulk density: 0.28-0.33 g / cm 3 2.88 parts by mass of croscarmellose sodium (Japanese Pharmacopoeia) and 7.2 parts by mass of croscarmellose sodium (Japanese Pharmacopoeia) were mixed together. The mixed powder mixture was then compressed using a tablet press (fully automatic single-punch tablet press AUTOTAB-500: manufactured by Ichihashi Seiki Co., Ltd.) under tableting conditions of approximately 91 to 106 kgf for approximately 1 second, so that each tablet had a diameter of approximately 4 mm, a weight of approximately 35 mg, and a hardness of 20 to 40 N, to produce a mixed powder tablet (Experimental Example 4).

[0088] <Experimental Example 5> 25 parts by mass of CDCA (JP), 2.88 parts by mass of D-mannitol (JP), and 7.2 parts by mass of croscarmellose sodium (JP) were mixed together based on the formulation shown in Table 1. The mixed powder mixture was then compressed using a tablet press (fully automatic single-punch tablet press AUTOTAB-500: manufactured by Ichihashi Seiki Co., Ltd.) under tableting conditions of approximately 93 to 100 kgf for approximately 1 second, so that each tablet had a diameter of approximately 4 mm, a weight of approximately 35 mg, and a hardness of 20 to 40 N, to produce a mixed powder tablet (Experimental Example 5).

[0089] <Experimental Example 6> Based on the formulation shown in Table 1, 25 parts by mass of CDCA (JP), crystalline cellulose (JP, average degree of polymerization: 100-300, loss on drying: 2.0-6.0%, bulk density: 0.28-0.33 g / cm 3 2.88 parts by mass of hydroxypropyl cellulose (Japanese Pharmacopoeia) and 7.2 parts by mass of hydroxypropyl cellulose (Japanese Pharmacopoeia) were mixed together. The mixed powder mixture was then compressed into tablets using a tablet press (fully automatic single-punch tablet press AUTOTAB-500, manufactured by Ichihashi Seiki Co., Ltd.) under tableting conditions of approximately 89 to 99 kgf for approximately 1 second, so that each tablet had a diameter of approximately 4 mm, a weight of approximately 35 mg, and a hardness of 20 to 40 N, to produce a mixed powder tablet (Experimental Example 6).

[0090] <Experimental Example 7> 25 parts by mass of CDCA (JP), 2.88 parts by mass of corn starch (JP), and 7.2 parts by mass of hydroxypropyl cellulose (JP) were mixed together based on the formulation shown in Table 1. The mixed powder mixture was then compressed using a tablet press (fully automatic single-punch tablet press AUTOTAB-500, manufactured by Ichihashi Seiki Co., Ltd.) under tableting conditions of approximately 93 to 108 kgf for approximately 1 second, so that each tablet had a diameter of approximately 4 mm, a weight of approximately 35 mg, and a hardness of 20 to 40 N, to produce a mixed powder tablet (Experimental Example 7).

[0091] <Experimental Example 8> Based on the formulation shown in Table 2, 25 parts by mass of CDCA (JP), crystalline cellulose (JP, average degree of polymerization: 100-300, loss on drying: 2.0-6.0%, bulk density: 0.28-0.33 g / cm 3 2.88 parts by mass of methylcellulose (JP, viscosity: 25 mPa s) and 7.2 parts by mass of carmellose calcium (JP) were mixed. Then, 0.32 parts by mass of methylcellulose (JP, viscosity: 25 mPa s) and purified water were added to obtain a granulated powder, which was then sized and dried at 55°C for 15 hours to obtain a dry powder. After sieving the dried powder, 0.30 parts by mass of magnesium stearate (JP, vegetable magnesium stearate) and 0.30 parts by mass of sucrose fatty acid ester (JP, Pharmaceutical Additives Standards) were mixed to obtain a lubricated mixed powder. The lubricated mixed powder was then compressed using a tablet press (fully automatic single-punch tablet press AUTOTAB-500: Ichihashi Seiki Co., Ltd.) under tableting conditions of approximately 77 to 96 kgf for 1 second to produce uncoated tablets (Experimental Example 8).

[0092] <Experimental Example 9> Based on the formulation shown in Table 2, 25 parts by mass of CDCA (JP), crystalline cellulose (JP, average degree of polymerization: 100-300, loss on drying: 2.0-6.0%, bulk density: 0.28-0.33 g / cm 3 2.88 parts by mass of methylcellulose (JP, viscosity: 25 mPa·s) and 7.2 parts by mass of carmellose calcium (JP) were mixed. Then, 0.32 parts by mass of methylcellulose (JP, viscosity: 25 mPa·s) and purified water were added to obtain a granulated powder, which was then sieved. The granulated powder was then dried at 55°C for 15 hours to obtain a dry powder. After sieving the dried powder, 0.30 parts by mass of magnesium stearate (JP, vegetable magnesium stearate) and 0.30 parts by mass of sucrose fatty acid ester (JP, Pharmaceutical Additives) were mixed to obtain a lubricated mixed powder. The lubricated mixed powder was then compressed using a tablet press (fully automatic single-punch tablet press, AUTOTAB-500, manufactured by Ichihashi Seiki Co., Ltd.) under tableting conditions of approximately 72 to 90 kgf for approximately 1 second to obtain tablets with a diameter of approximately 4 mm, a diameter of approximately 36 mg, and a hardness of 20 to 40 N, yielding five uncoated tablets. The obtained plain tablets were film-coated with 1.11 parts by mass of hypromellose (JP, degree of substitution: 2910, viscosity: 6 mPa s), 0.22 parts by mass of macrogol 400, and 0.11 parts by mass of talc to prepare film-coated tablets (Experimental Example 9).

[0093] <Comparative Example 1> Based on the formulation shown in Table 2, 25 parts by mass of CDCA (JP), crystalline cellulose (JP, average degree of polymerization: 100-300, loss on drying: 2.0-6.0%, bulk density: 0.28-0.33 g / cm 3 2.88 parts by mass of methylcellulose (JP, viscosity: 25 mPa s) and 7.2 parts by mass of carmellose calcium (JP) were mixed together. 0.32 parts by mass of methylcellulose (JP, viscosity: 25 mPa s) and purified water were then added to obtain a granulated powder, which was then sized and dried at 55°C for 15 hours to obtain a dry powder. After sizing the dried powder, it was mixed with 0.30 parts by mass of magnesium stearate (JP, vegetable magnesium stearate) and 0.30 parts by mass of sucrose fatty acid ester (JP, Pharmaceutical Additives Regulations) to obtain a lubricant-mixed powder (Comparative Example 1).

[0094] [Table 1]

[0095] [Table 2]

[0096] [Test Example 2. Dissolution Measurement] The dissolution properties of CDCA in the prepared tableted products, coated tablets, and mixed powders of the experimental and comparative examples were evaluated as follows: Specifically, the dissolution tests were performed according to the "Dissolution Test Method (Paddle Method)" described in the 18th Edition of the Japanese Pharmacopoeia. The test solution used was 900 mL of the second dissolution test fluid, and the test was conducted at 50 revolutions per minute using a sinker and the paddle method. Approximately 35 mg of the prepared mixed powder (Comparative Example 1), one tablet (Experimental Examples 1-8), or one coated tablet (Experimental Example 9) was taken and the test was initiated. At specified times (0, 5, 10, 15, and 30 minutes), at least 10 mL of the dissolution solution was taken and filtered through a membrane filter with a pore size of 0.45 μm or less. The first 2 mL of filtrate was discarded, and the next filtrate was used as the sample solution. Separately, approximately 28 mg of chenodeoxycholic acid for assay was precisely weighed and dissolved in acetonitrile to make exactly 50 mL. 5 mL of this solution was accurately weighed, and the test solution was added to make exactly 100 mL, creating the standard solution. Exactly 200 μL of the sample solution and standard solution were taken and tested by liquid chromatography under the following conditions. The peak area A of chenodeoxycholic acid in each solution was measured. T and A S was measured.

[0097] Dissolution rate (%) of chenodeoxycholic acid per tablet (25 mg) = M S / C×A T / A S ×90 M S : Amount of chenodeoxycholic acid taken for quantitative analysis (mg) C: Amount of chenodeoxycholic acid in one tablet (mg)

[0098] Test conditions Detector: ultraviolet absorption photometer (measurement wavelength: 220 nm) Column: A stainless steel tube having an inner diameter of 4.6 mm and a length of 15 cm was packed with 5 μm octadecylsilanized silica gel for liquid chromatography. Column temperature: constant temperature around 40°C Mobile phase: Acetonitrile / diluted phosphoric acid (1→500) mixture (3:2) Flow rate: Adjusted so that the retention time of chenodeoxycholic acid was approximately 5 minutes.

[0099] The results are shown in Tables 3 and 4 below. In the table, the dissolution rate is the average value of n=6.

[0100] [Table 3]

[0101] [Table 4]

[0102] As is clear from the results in Table 3, the mixed powder tablet product (Experimental Example 1) had an excellent (high) dissolution rate at all times: 5 minutes, 10 minutes, 15 minutes, and 30 minutes after the start of the test. This tendency was also observed in Experimental Examples 2 to 5. Forming tablets involves the application of molding pressure (e.g., tableting pressure) during the process of tableting powder raw materials. Therefore, it is generally known that tablets have a smaller specific surface area and a lower dissolution rate than powders. Therefore, in this test, it was expected that the dissolution rate would decrease due to tableting (tabletting). However, unexpectedly, the dissolution rate did not decrease, but rather improved, after tableting.

[0103] As is clear from the results in Table 4, even when a lubricant component was contained, the uncoated tablets (Experimental Example 8) that had undergone the tableting process had an excellent (high) dissolution rate at 5, 10, 15 and 30 minutes after the start of the test, compared to the lubricant-mixed powder that had not been tableted (Comparative Example 1).

[0104] The results of Experimental Example 8, Experimental Example 9 and Comparative Example 1 in Table 4 show that even when a coating agent component was included, the tablets had superior (high) dissolution rates at 5, 10, 15 and 30 minutes after the start of the test, compared to the non-compressed lubricant-mixed powder (Comparative Example 1).

[0105] From the above results, it was found that the dissolution properties of the coated tablets were superior to those of the mixed powder, as were the uncoated tablets and the mixed powder tableted products. Furthermore, when a dissolution test was conducted on capsules containing the same ingredients as in Experimental Example 8 in the filling powder at the same ratio, the dissolution rate 15 minutes after the start of dissolution showed similar behavior to the dissolution rate in Experimental Example 9. When the capsule filling powder was made into tablets, it was predicted that the dissolution rate would decrease and that the tablets would not have the same dissolution properties as the capsules, but unexpectedly, the dissolution rate did not decrease.

[0106] [Test Example 3. Hardness Measurement] The 18th edition of the Japanese Pharmacopoeia, Reference Information, "Tablet Hardness Measurement Method" <g6-4-180>The hardness was measured by the method described in the "Journal of Hardness Testing, Vol. 1, No. 1, pp. 111-114, 2003" (n=6). The hardness of Experimental Example 8 was 25 to 35 N, and the hardness of Experimental Example 9 was 42 to 64 N. In Experimental Examples 1 to 7, the same results as in Experimental Example 8 were obtained.

[0107] [Test Example 4. Friability Measurement] The 18th edition of the Japanese Pharmacopoeia, Reference Information, "Testing Method for Tablet Friability" <g6-5-181>The degree of wear was measured by the method described in (n=6). The abrasion rate in Experimental Example 8 was −0.11 to 0.02%. In Experimental Examples 1 to 7, the same results as in Experimental Example 8 were obtained. In Experimental Example 9, the abrasion rate was smaller than in Experimental Example 8.

[0108] [Test Example 5. Disintegration Measurement]

[0109] Disintegration was measured by the measurement method described in the "Disintegration Test Method" of the General Test Methods of the Japanese Pharmacopoeia, 18th Edition (n=6). The disintegration time was 47 to 63 seconds in Experimental Example 8, and 92 to 109 seconds in Experimental Example 9. In Experimental Examples 1 to 7, the same results as in Experimental Example 8 were obtained.

[0110] Because tablets are subjected to tableting pressure during the manufacturing process, they are generally thought to have higher hardness and lower dissolution properties compared to powder raw materials. Increasing the dissolution rate of tablets requires lowering the hardness, making it difficult to produce chenodeoxycholic acid tablets with a desired hardness. However, the results of this example show that the tablets of the present invention, which contain chenodeoxycholic acid as an active ingredient, were unexpectedly and efficiently tableted (without any particular problems, such as serious tableting problems). Furthermore, as described above, the tablets of the present invention were able to incorporate a high proportion of chenodeoxycholic acid and achieve excellent properties (dissolution properties, hardness, friability, disintegration, etc.). [Industrial Applicability]

[0111] The present invention can provide a novel tablet.

Claims

1. Contains chenodeoxycholic acid in a proportion of 50% by mass or more, In a dissolution test according to the Japanese Pharmacopoeia Dissolution Test Method, 18th Edition, by the paddle method, using Japanese Pharmacopoeia Dissolution Test Fluid No. 2 (pH 6.8) as the test fluid and at a rotation speed of 50 rpm, the dissolution rate of chenodeoxycholic acid after a dissolution time of 15 minutes is 50% or more, A tablet that satisfies at least one of the following (A) and (B): A tablet in which the form of chenodeoxycholic acid is not in the form of a pharmaceutically acceptable salt. (A) Hardness of 5N or more (B) Friability is 1% or less

2. Contains chenodeoxycholic acid in a proportion of 50% by mass or more, In a dissolution test according to the Japanese Pharmacopoeia, 18th Edition, using the paddle method with the Japanese Pharmacopoeia Dissolution Test No. 2 Fluid (pH 6.8) as the test fluid and at a rotation speed of 50 rpm, the dissolution rate of chenodeoxycholic acid after 15 minutes of dissolution is 50% or more, containing at least one selected from carmellose calcium and croscarmellose sodium, A tablet satisfying at least one of the following (A) and (B): (A) Hardness of 5N or more (B) Friability is 1% or less

3. The tablet contains 50% by mass or more of chenodeoxycholic acid, and has a disintegration time of 10 minutes or less according to the disintegration test method of the 18th edition of the Japanese Pharmacopoeia, In a dissolution test according to the Japanese Pharmacopoeia Dissolution Test Method, 18th Edition, by the paddle method, using Japanese Pharmacopoeia Dissolution Test Fluid No. 2 (pH 6.8) as the test fluid and at a rotation speed of 50 rpm, the dissolution rate of chenodeoxycholic acid after a dissolution time of 15 minutes is 50% or more, containing at least one selected from carmellose calcium and croscarmellose sodium, A tablet satisfying at least one of the following (A) and (B): (A) Hardness of 5N or more (B) Friability is 1% or less

4. In a dissolution test according to the 18th revised Japanese Pharmacopoeia Dissolution Test Paddle Method, using Japanese Pharmacopoeia Dissolution Test Fluid No. 2 (pH 6.8) as the test fluid and at a rotation speed of 50 rpm, the dissolution rate of chenodeoxycholic acid after a dissolution time of 15 minutes is 60% or more, The hardness is 5 to 150 N, The tablet according to any one of claims 1 to 3, having a friability of 0.5% or less.

5. The tablet according to any one of claims 1 to 3, wherein the dissolution rate of chenodeoxycholic acid after 30 minutes of dissolution is 70% or more in a dissolution test according to the paddle method of the Japanese Pharmacopoeia Dissolution Test, 18th Edition, using Japanese Pharmacopoeia Dissolution Test Fluid 2 (pH 6.8) as the test fluid at a rotation speed of 50 rpm.

6. The tablet according to any one of claims 1 to 3, wherein in a dissolution test conducted by the paddle method of the Japanese Pharmacopoeia Dissolution Test, 18th Edition, using Japanese Pharmacopoeia Dissolution Test Fluid No. 2 (pH 6.8) as the test fluid and at a rotation speed of 50 rpm, the ratio ((B) / (A)) of the dissolution rate of chenodeoxycholic acid at a dissolution time of 5 minutes (B) to the dissolution rate of chenodeoxycholic acid at a dissolution time of 15 minutes (A) is 0.7 or more.

7. In a dissolution test according to the Japanese Pharmacopoeia, 18th Edition, using the paddle method with the Japanese Pharmacopoeia Dissolution Test No. 2 Fluid (pH 6.8) as the test fluid and at a rotation speed of 50 rpm, the dissolution rate of chenodeoxycholic acid after a dissolution time of 30 minutes is 70% or more, The tablet according to any one of claims 1 to 3, wherein the ratio ((B) / (A)) of the dissolution rate of chenodeoxycholic acid in a dissolution time of 5 minutes to the dissolution rate of chenodeoxycholic acid in a dissolution time of 15 minutes is 0.7 or more.

8. The tablet according to any one of claims 1 to 3, which has a disintegration time of 5 minutes or less according to the disintegration test method of the 18th edition of the Japanese Pharmacopoeia.

9. 2. The tablet according to claim 1, comprising at least one selected from the group consisting of carboxymethylcellulose, sodium carboxymethylcellulose, carmellose calcium, and croscarmellose sodium.

10. The tablet according to any one of claims 1 to 3, comprising at least one selected from the group consisting of sugar alcohols, cellulose, starch, and starch derivatives.

11. The tablet according to any one of claims 1 to 3, which contains a sucrose fatty acid ester.

12. At least one selected from sugar alcohol, cellulose, and starch; At least one selected from carmellose calcium and croscarmellose sodium; The tablet according to claim 1, further comprising a sucrose fatty acid ester.

13. At least one selected from sugar alcohols, cellulose, and starch; The tablet according to claim 2 or 3, which contains a sucrose fatty acid ester.

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

15. The tablet according to any one of claims 1 to 3, which is a coated tablet, and the coating layer constituting the coated tablet contains at least one selected from a cellulose derivative, talc, and macrogol.

16. The tablet according to any one of claims 1 to 3, wherein the major axis is 7 mm or less.

17. The tablet according to any one of claims 1 to 3, which contains 15 mg or more of chenodeoxycholic acid and has a major axis of 7 mm or less.

18. The tablet according to any one of claims 1 to 3, for taking 10,000 mg or less of chenodeoxycholic acid three times a day.

19. The tablet according to any one of claims 1 to 3, which has a major axis of 7 mm or less and is intended for administration to children.

20. The tablet according to any one of claims 1 to 3, which has a major axis of 7 mm or less and is for use in the prevention or treatment of cerebrotendinous xanthomatosis.

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