JP5365949B2 - Orally disintegrating tablets containing low-dose ramosetron - Google Patents

Description

  The present invention relates to an orally disintegrating tablet comprising a low dose of ramosetron or a pharmaceutically acceptable salt thereof. In particular, the present invention relates to an orally disintegrating tablet with improved absorbability for the treatment of irritable bowel syndrome, containing a low dose of ramosetron or a pharmaceutically acceptable salt thereof.

  Ramosetron has the chemical name (-)-(R) -5-[(1-methyl-1H-indol-3-yl) carbonyl] -4,5,6,7-tetrahydro-1H-benzimidazole.

Patent Document 1 discloses that a series of tetrahydrobenzimidazole derivatives including ramosetron and a pharmaceutically acceptable salt thereof have a 5HT ₃ receptor antagonistic action. Based on this effect, it is suggested that cancer drugs such as cisplatin and the prevention and treatment of vomiting due to radiation may be prevented. Clinical dosage is usually 0.1 mg to 10 mg intravenously per day for adults, 0.5 mg or more orally It is 50 mg or less, and it is described that this is administered once or divided into several times.

  In Non-Patent Documents 1 and 2, an orally disintegrating tablet containing 0.1 mg of ramosetron hydrochloride, which is effective and effective for digestive symptoms (nausea, vomiting) associated with administration of an antineoplastic agent (cisplatin, etc.), is “Nazea ( (Registered trademark) OD tablet 0.1 mg "is described in Japan. The orally disintegrating tablet contains lactose hydrate, D-mannitol, aspartame, agar powder, yellow ferric oxide and ferric oxide in addition to ramosetron hydrochloride.

  Patent Document 2 discloses that a density of 400 mg / ml to 1000 mg / ml of an active ingredient, a sugar composed of lactose and / or D-mannitol, and a solid content of 0.12 w / w% to 1.2 w / w%. An invention relating to an orally disintegrating solid preparation having sufficient strength for handling the preparation is disclosed, and in claim 4, (R) -5-[(1-methyl-3-indolyl) as an active ingredient is disclosed. An invention relating to an orally disintegrating solid preparation containing carbonyl] -4,5,6,7-tetrahydro-1H-benzimidazole hydrochloride (ramosetron hydrochloride) is described. The solid preparation has a structure mainly composed of sugar, and is rapidly weakened by saliva in the oral cavity and gradually disintegrates or dissolves. On the other hand, Kanten, which is an additive other than sugar, facilitates the handling of the preparation in the production process, ensures uniformity of content, does not lose its shape, and has an orally disintegrating solid that has sufficient strength for handling. It has been added to provide a formulation.

  In Patent Document 3, a preparation containing ramosetron hydrochloride of 0.002 mg or more and 0.02 mg or less, or equimolar amount of ramosetron or 0.002 mg or more and 0.02 mg or less of ramosetron or other pharmaceutically acceptable salt is a diarrhea type. It is described as being useful as a therapeutic agent for irritable bowel syndrome. Further, Example 2 of Patent Document 3 describes an orally disintegrating tablet containing ramosetron hydrochloride.

  In Non-Patent Documents 3 and 4, tablets containing 2.5 μg or 5 μg of ramosetron hydrochloride, which are effective for diarrhea-type irritable bowel syndrome, are “Iribo (registered trademark) 2.5 μg” and “Iribo (registered trademark)”. ) Tablets 5 μg ”.

Japanese Patent Publication No. 6-25153 Japanese Patent No. 2807346 Japanese Patent No. 3763360

Nazea OD pharmaceutical package insert Nazea OD pharmaceutical interview form Iribo Tablets package insert Iribo Tablets Drug Interview Form

  An object of the present invention is to provide an orally disintegrating tablet containing a low dose of ramosetron or a pharmaceutically acceptable salt thereof.

  Another object of the present invention is to provide an orally disintegrating tablet containing a low dose of ramosetron or a pharmaceutically acceptable salt thereof and useful as a therapeutic agent for diarrhea-type irritable bowel syndrome.

  Still another object of the present invention is to provide an orally disintegrating tablet containing a low dose of ramosetron or a pharmaceutically acceptable salt thereof and having bioequivalence with Iribo (registered trademark) tablets (ordinary tablets). It is to provide.

  As described in Non-Patent Document 3, Iribo® tablets (ordinary tablets) containing 2.5 μg or 5 μg of ramosetron hydrochloride are used for diarrhea-type irritable bowel syndrome.

  By the way, in recent years, orally disintegrating tablets can be taken without water, and even for patients who have difficulty swallowing, it is relatively easy to take. Attention has been paid.

  An orally disintegrating tablet (nazea OD) already containing a high dose of ramosetron has been found to be bioequivalent (BE) to a normal tablet. Nazea OD is an orally disintegrating tablet disclosed in Patent Document 2, but after that, a simpler production method considering mass production has been selected, and orally disintegrating tablets of other drugs have been marketed. However, in the treatment of diarrhea-type irritable bowel syndrome, there is a concern that the amount of ramosetron or a pharmaceutically acceptable salt thereof is smaller than that of nazea OD and stability is lowered.

  Therefore, in order to develop an orally disintegrating tablet containing a low dose of ramosetron, the present inventors first included a low dose of ramosetron hydrochloride (20 μg as ramosetron) in the preparation, An orally disintegrating tablet comprising a known formulation (Production Example 1 described later) containing the same stabilizer contained in a registered trademark (refer to Japanese Patent No. 3689104 for a method for preparing an orally disintegrating tablet). Was prepared and administered to humans, and it was unexpectedly found that BE was not established as compared with normal tablets (the same formulation as in Production Example 2 described later).

  In order to investigate the cause of the BE failure, the effect of the administration method was examined.

  Specifically, an orally disintegrating tablet composed of a known formulation (Production Example 1 described later) is orally administered to dogs (for gastrointestinal movement, oral gastric forced administration that disintegrates and dissolves in the stomach and moves to the small intestine). In addition, a suspension in which the orally disintegrating tablet is dispersed in water is orally administered to dogs (as for gastrointestinal movement, it is disintegrated / dissolved in the oral cavity and passes through the esophagus and moves to the stomach and small intestine). Then, Pharmacokinetics Parameters compared with normal tablets were compared.

  As a result, Cmax is equivalent in the method in which the normal tablet and the orally disintegrating tablet are orally administered (oral intragastric forced administration), and in the method in which the orally disintegrating tablet is orally administered (oral administration) as a suspension, It was found that it decreased compared to the tablet.

On the other hand, when the disappearance clearance of the substance from the human oral cavity was evaluated using the orally disintegrating tablet containing a radioactive substance ( ¹¹¹ In-DTPA), the components remained in the oral cavity even after the oral disintegrating tablet disintegrated. A tendency to remain was also observed.

  Under the above circumstances, the present inventors conducted extensive studies focusing on the effect of not lowering Cmax of ramosetron compared to ordinary tablets when orally administering a low dose ramosetron orally disintegrating tablet, Surprisingly, it has been found that kantene powder added as a suspending agent to Nazea OD tablets (high dose ramosetron-containing orally disintegrating tablets) has this action. It was also found that orally disintegrating tablets containing low-dose ramosetron hydrochloride and agar powder form normal tablets and BE in humans. As a result of further investigations, the present inventors have completed the present invention.

That is, the present invention
[1] (a) 0.001 mg to 0.05 mg of ramosetron hydrochloride, or (b) 0.001 mg to 0.05 mg of ramosetron hydrochloride and an equimolar amount of ramosetron or a pharmaceutically acceptable salt thereof, and agar and / or Orally disintegrating tablets containing agar powder,
[2] containing (a) 0.00125 mg or more and 0.025 mg or less of ramosetron hydrochloride, or (b) 0.00125 mg or more and 0.025 mg or less of ramosetron hydrochloride and an equimolar amount of ramosetron or a pharmaceutically acceptable salt thereof, Orally disintegrating tablet according to 1],
[3] The oral cavity according to [1] or [2], wherein the amount of kantene and / or kanteng powder is 10% by weight or more and 500,000% by weight or less based on ramosetron or a pharmaceutically acceptable salt thereof. Disintegrating tablets,
[4] The orally disintegrating tablet according to [1] or [2], wherein the amount of agar and / or agar powder is 0.001 wt% or more and 70 wt% or less per unit preparation,
[5] An orally disintegrating tablet according to any one of [1] to [4] for the treatment of diarrhea-type irritable bowel syndrome,
[6] The orally disintegrating tablet according to any one of [1] to [5], which is bioequivalent to 2.5 μg of Iribo (registered trademark) tablet or 5 μg of Iribo (registered trademark) tablet,
[7] The orally disintegrating tablet according to any one of [1] to [6], further comprising a stabilizer,
[8] The orally disintegrating tablet according to [7], wherein the stabilizer is hydroxycarboxylic acid,
[9] The orally disintegrating tablet according to [8], wherein the hydroxycarboxylic acid is one or more substances selected from the group consisting of tartaric acid, malic acid, and citric acid,
[10] The orally disintegrating tablet according to any one of [1] to [9], further comprising a light stabilizer,
[11] The oral disintegration according to [10], wherein the light stabilizer is one or two or more substances selected from the group consisting of yellow ferric oxide, red ferric oxide, and titanium oxide. Tablets,
[12] The orally disintegrating tablet according to any one of [1] to [11], further comprising a saccharide,
[13] The orally disintegrating tablet according to [12], wherein the saccharide is a saccharide having a high moldability and / or a saccharide having a low moldability.
[14] The orally disintegrating tablet according to [13], wherein the saccharide having high moldability is one or two or more substances selected from the group consisting of maltose, maltitol, sorbitol, and trehalose,
[15] The oral cavity according to [13], wherein the saccharide having low formability is one or two or more substances selected from the group consisting of lactose, D-mannitol, glucose, sucrose, xylitol, and erythritol. Disintegrating tablets,
[16] Iribo containing (a) 0.001 mg or more and 0.05 mg or less of ramosetron hydrochloride, or (b) 0.001 mg or more and 0.05 mg or less of ramosetron hydrochloride and an equimolar amount of ramosetron or a pharmaceutically acceptable salt thereof. Use of Kanten and / or Kanten powder for the production of orally disintegrating tablets which are bioequivalent to 2.5 μg of (R) tablets or 5 μg of Iribo® tablets,
[17] An orally disintegrating tablet used for treating diarrhea-type irritable bowel syndrome by administering ramosetron hydrochloride of 0.00125 mg or more and 0.025 mg or less as a daily dose per adult,
An orally disintegrating tablet containing at least 0.00125 mg to 0.025 mg of ramosetron hydrochloride, agar and / or agar powder, D-mannitol, and maltose per unit preparation,
I will provide a.

  The present invention can provide an orally disintegrating tablet containing a low dose of ramosetron or a pharmaceutically acceptable salt thereof and useful as a therapeutic agent for diarrhea-type irritable bowel syndrome. The present invention also provides an orally disintegrating tablet containing ramosetron or a pharmaceutically acceptable salt thereof and having bioequivalence to a normal tablet containing ramosetron hydrochloride. Play.

  Hereinafter, embodiments of the present invention will be described in detail.

  As used herein, “low dose” means that ramosetron or a pharmaceutically acceptable salt thereof is contained and the dose is low (small). Specifically, it means lower (smaller) than the dose of nazea, 0.1 mg.

  In the present specification, the “orally disintegrating tablet” means a tablet that disintegrates or disintegrates / dissolves in the oral cavity. As an oral disintegration time, for example, when a tablet is taken without ingesting water, it is within 3 minutes by saliva only in the oral cavity, within 2 minutes as another embodiment, within 1 minute as another embodiment, and further As an embodiment, it is defined as a tablet that disintegrates within 45 seconds, or a preparation similar to a tablet. The “orally disintegrating tablet” is actually an “orally disintegrating tablet”, but also includes tablets described as orally administered as a usage. Embodiments also include tablets described as oral gastric gavage.

  In the present specification, “ordinary tablet” refers to a tablet that disintegrates and dissolves in the stomach after oral administration with a liquid such as water, for example, as gastrointestinal movement. “Iribo (registered trademark) tablets” containing 2.5 μg or 5 μg of ramosetron hydrochloride are “ordinary tablets”.

  In this specification, “bioequivalent” means that the ratio of geometric average values of AUC and Cmax of ramosetron to a control preparation (for example, normal tablet) of the preparation to be tested is 0.80 or more and 1.25 or less, respectively, in an in vivo test. (80% or more and 125% or less).

  Ramosetron and a pharmaceutically acceptable salt thereof can be easily obtained by the production method described in Patent Document 1 or according thereto.

  Specific examples of pharmaceutically acceptable salts of ramosetron include mineral acid salts such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid, acetic acid, oxalic acid, succinic acid, citric acid, maleic acid, and apples. Examples thereof include salts with acids, fumaric acid, tartaric acid, organic acids such as methanesulfonic acid, and salts with acidic amino acids such as glutamic acid and aspartic acid. Of these, commercially available ramosetron hydrochloride is preferred. These salts can be used alone or in combination of two or more.

  The orally disintegrating tablet of the present invention is 0.001 mg to 0.05 mg, or 0.00125 mg to 0.025 mg, or 0.00125 mg to 0.005 mg, or 0.002 mg to 0.005 mg, or 0.00125 mg per tablet (unit preparation). Or 0.0025 mg, or 0.005 mg, or 0.0226 mg of ramosetron or a pharmaceutically acceptable salt thereof. Alternatively, the content of ramosetron or a pharmaceutically acceptable salt thereof per unit preparation can be 0.0001 wt% or more and 0.01 wt% or less.

  The dose of ramosetron or a pharmaceutically acceptable salt thereof is appropriately determined depending on the individual case in consideration of the administration route, disease symptoms, age, race, sex, etc. of the administration subject.

  For the treatment of diarrhea-type irritable bowel syndrome, the orally disintegrating tablet of the present invention is used, and 0.001 mg to 0.05 mg or less of ramosetron hydrochloride and equimolar amount of ramosetron or a pharmaceutically acceptable product thereof per day Salt can be administered. Ramosetron hydrochloride can be administered at a daily dose of 0.001 mg to 0.05 mg, preferably 0.00125 mg to 0.025 mg, or 0.0025 mg to 0.01 mg, or 0.005 mg to 0.01 mg per adult. It is preferable to administer once a day after meals.

  The orally disintegrating tablet of the present invention contains agar and / or agar powder.

  Kanten (agar) is composed of polysaccharides with galactose as the basic skeleton, and is classified into agarose rich in neutral gelling ability and agaropectin without ionic gelling ability. The structure of agarobiose, which is a repeating unit of agarose, consists of β-D-galactopyranose bonded at the 1st and 3rd positions and 3,6 anhydro-α-L-galactobilanose bonded at the 1st and 4th positions. Agaropectin contains all ionic polysaccharides other than agarose in agar and / or agar powder, and its structure is the same as that of agarose, but is partially sulfated, methoxyl, pyruvate, carboxyl Contains groups. The molecular weight of kanteng and / or kanteng powder varies depending on the degree of hydrolysis when extracted from seaweed, but is generally several thousand or more and tens of thousands or less.

  Kanteng powder is a powdered kanteng powder and is not particularly limited in shape, particle size and the like.

  The agar and / or agar powder used in the present invention can be used alone or in combination.

  The content of agar and / or agar powder in the orally disintegrating tablet of the present invention is not particularly limited as long as it can be added pharmaceutically. For example, 10 wt% or more and 500000 wt% or less with respect to the weight of ramosetron or a pharmaceutically acceptable salt thereof, 100 wt% or more and 36000 wt% or less as another embodiment, and 200 wt% or more and 18000 wt% as a further embodiment % Or less, or 1000 wt% or more and 5000 wt% or less of agar and / or agar powder. In another embodiment, the content of agar and / or agar powder is 0.001% to 70% by weight per unit preparation, 0.01% to 30% by weight in another embodiment, 0.05% to 10% in a further embodiment. It can be less than wt%.

  In the orally disintegrating tablet of the present invention, various kinds of pharmaceutical additives are further appropriately blended as desired. Such a pharmaceutical additive is not particularly limited as long as it is pharmaceutically acceptable and pharmacologically acceptable. Specifically, for example, excipients, stabilizers, binders, disintegrants, acidulants, foaming agents, artificial sweeteners, fragrances, lubricants, colorants, buffers, antioxidants, surfactants Etc.

  Examples of the excipient include D-mannitol and lactose hydrate.

  The stabilizer is, for example, a compound having a carbonyl group, which stabilizes ramosetron or a pharmaceutically acceptable salt thereof. Specific examples of the compound having a carbonyl group include aliphatic carboxylic acids (particularly saturated or unsaturated, linear or branched aliphatic mono-, di- or tri-carboxylic acids. In particular, carbon An aliphatic carboxylic acid having a number of 3 to 36) or an ester thereof, a hydroxycarboxylic acid (specifically a saturated or unsaturated, linear or branched aliphatic hydroxymono-, di- or tri-carboxylic acid) In particular, a hydroxycarboxylic acid having 3 to 36 carbon atoms) or an ester thereof, an acidic amino acid, an enolic acid, an aromatic carboxyl compound (specifically, an alkyl group having 1 to 4 carbon atoms or a hydroxy group is substituted) Aromatic mono-, di- or tri-carboxylic acids, especially aromatic carboxylic acids having 7 to 20 carbon atoms) or their esters, polymeric substances having a carboxyl group The recited, these compounds may be appropriately used in combination of two or more. In particular, the specific compound having a carbonyl group is preferably a hydroxycarboxylic acid or an ester thereof, a polymer substance having a carboxyl group, an aromatic carboxyl compound or an ester thereof, or an enolic acid, particularly a hydroxycarboxylic acid or an ester thereof, a carboxyl A polymer substance having a group, an aromatic carboxyl compound or an ester thereof is preferred, and a hydroxycarboxylic acid or an ester thereof, or a polymer substance having a carboxyl group is more preferred. The aliphatic carboxylic acid is preferably maleic acid, malonic acid, succinic acid, or fumaric acid. As the hydroxycarboxylic acid, tartaric acid, malic acid and citric acid are preferable, and tartaric acid and citric acid are more preferable. More preferred is citric acid. The acidic amino acid is preferably glutamic acid or aspartic acid. The aromatic carboxyl compound is preferably phthalic acid or propyl gallate, and more preferably propyl gallate. Preferred as the polymer substance having a carboxyl group is carboxymethyl cellulose or alginic acid, and more preferred is carboxymethyl cellulose. Further, enolic acid is preferably ascorbic acid or erythorbic acid, and more preferably ascorbic acid. As for the above carbonyl compounds, it has been clarified that hydrates and anhydrides having no water of crystallization, such as citric acid hydrate or citric acid anhydride, also exhibit the stabilizing effect of the present invention. A hydrate, an anhydride, or a mixture thereof is included. Further, the degree of polymerization and the molecular weight of the polymer substance are not particularly limited, but in the case of carboxymethyl cellulose, a weight average molecular weight of about 110,000 is particularly preferable, and that of alginic acid is preferably about 200,000.

  Examples of the binder include gum arabic, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, maltose and the like.

  Examples of the disintegrant include corn starch, potato starch, carmellose calcium, carmellose sodium, and low-substituted hydroxypropylcellulose.

  Examples of the sour agent include citric acid, tartaric acid, malic acid and the like.

  Examples of the foaming agent include baking soda.

  Examples of the artificial sweetener include saccharin sodium, dipotassium glycyrrhizin, aspartame, stevia and thaumatin.

  Examples of the fragrances include lemon, lemon lime, orange and menthol.

  Examples of the lubricant include light anhydrous silicic acid, magnesium stearate, calcium stearate, sucrose fatty acid ester, polyethylene glycol, talc, stearic acid and the like.

  Examples of the colorant include yellow ferric oxide, red ferric oxide, black iron oxide, titanium oxide, edible yellow No. 4, No. 5, edible red No. 3, No. 102, and edible blue No. 3. Among them, yellow iron sesquioxide, red iron sesquioxide, black iron oxide, and titanium oxide also act as light stabilizers. Preferred light stabilizers are yellow ferric oxide and red ferric oxide.

  Buffers include citric acid, succinic acid, fumaric acid, tartaric acid, ascorbic acid or salts thereof, glutamic acid, glutamine, glycine, aspartic acid, alanine, arginine or salts thereof, magnesium oxide, zinc oxide, magnesium hydroxide, phosphoric acid Boric acid or a salt thereof.

  Examples of the antioxidant include ascorbic acid, dibutylhydroxytoluene, propyl gallate and the like.

  Examples of the surfactant include polysorbate 80, sodium lauryl sulfate, polyoxyethylene hydrogenated castor oil, and the like.

  The pharmaceutical additives can be appropriately added in an appropriate amount by combining one or more kinds.

  The blending amount of the stabilizer is not limited as long as it stabilizes ramosetron or a pharmaceutically acceptable salt. For example, it is 0.01 wt% or more and 90 wt% or less per unit preparation, preferably 0.01 wt% or more and 50 wt% or less, more preferably 0.1 wt% or more and 10 wt% or less.

  The blending amount of the light stabilizer is determined appropriately depending on the type of colorant and the addition method. For example, it is usually 0.1 to 20% by weight, preferably 0.2 to 10% by weight, more preferably 0.2 to 5% by weight, based on the entire composition.

  Other additives are also used in amounts that achieve the desired effect of the present invention.

  Orally disintegrating tablets are generally roughly classified into a mold type, a moist type, and a normal tableting type, but the orally disintegrating tablet of the present invention may be any type. The mold-type orally disintegrating tablet is prepared by filling a mold with a solution or suspension such as an excipient as disclosed in, for example, Japanese Patent No. 2807346 (US Patent No. 5466464). Can be manufactured by drying.

  The mold-type orally disintegrating tablet comprises, for example, a solution or suspension containing ramosetron or a pharmaceutically acceptable salt thereof, agar or agar powder, and various pharmaceutical additives blended as necessary. After filling the PTP pocket, it can be produced by removing moisture by a method such as freeze drying, drying under reduced pressure, or low temperature drying.

  Wet type orally disintegrating tablets are moistened with excipients such as saccharides as shown in Patent No. 3069458 (U.S. Pat. No. 5,018,618, U.S. Pat. No. 5,720,974). The tablet is produced by tableting under low pressure and then drying. Thus, for example, ramosetron or a pharmaceutically acceptable salt thereof, an excipient such as a saccharide, and agar and / or agar powder are moistened with a small amount of water or a mixture of water and alcohol, and the moist mixture is subjected to low pressure. After molding, it can be produced by drying.

  In the case of a normal tableting type, International Publication No. WO95 / 20380 pamphlet (US corresponding patent No. 5576014 specification), International Publication No. WO2002 / 92057 pamphlet (US corresponding patent application No. 2003/099701 specification), Japanese Patent Application Laid-Open No. 10-182436 (US Patent No. 5958543), Japanese Patent Application Laid-Open No. 9-48726, Japanese Patent Application Laid-Open No. 8-19589 (US Patent No. 5672364), Patent 2919771, Patent No. 3069458 (US-corresponding patent No.5501861 specification, US-corresponding patent number 5720974 specification), International Publication No. WO2008 / 032767 pamphlet (US correspondence patent application publication No. 2008/0085309 specification), It is prepared through a normal tableting process.

  In order to prepare a normal tablet type orally disintegrating tablet, for example, as disclosed in International Publication No. WO95 / 20380 (US Patent No. 5576014) and Japanese Patent No. 2919771, Ramosetron Alternatively, a pharmaceutically acceptable salt, agar and / or agar powder, and an excipient such as a low moldability saccharide, and a solution or suspension of a high moldability saccharide or a water-soluble polymer are used. After granulation, the granulated product can be compression-molded to form a compressed molded product, or the compressed molded product can be further humidified and dried to produce an orally disintegrating tablet. In order to prepare a normal tablet type orally disintegrating tablet as shown in International Publication No. WO99 / 47124 (US Pat. No. 6,658,954), for example, ramosetron or its pharmaceutical Orally-acceptable salts, sugar and / or agar powder, saccharides such as D-mannitol, maltitol, erythritol, and xylitol, and amorphous saccharides. Can be made. Furthermore, in order to prepare a normal tablet-type orally disintegrating tablet as disclosed in WO 2002/92057 pamphlet (US 2003/099701 specification), for example, ramosetron or A mixture of the pharmaceutically acceptable salt, agar and / or agar powder, and an excipient and a saccharide having a “melting point having a lower melting point” than that of the excipient is compression-molded and heated. An orally disintegrating tablet can be prepared by forming a crosslink by melting and solidifying a saccharide having a low melting point. By such humidification drying or heat treatment, the tablet strength of the orally disintegrating tablet can be improved. Furthermore, in order to prepare a normal tablet type orally disintegrating tablet as disclosed in International Publication No. WO2008 / 032767 (U.S. Patent Application Publication No. 2008/0085309), for example, ramosetron or Oral disintegration by compression molding a mixture of the pharmaceutically acceptable salt, agar and / or agar powder, and excipients and processed starches having a pregelatinization degree of 30% to 60% Tablets can be prepared.

  As the excipient used in the orally disintegrating tablet of the present invention, a general excipient can be used, but it is particularly preferable to use a pharmaceutically acceptable saccharide, and a technique utilizing the moldability of the saccharide. In the case of using saccharides with low moldability, crystalline / amorphous saccharides, and tablet strength improvement technology by humidification drying, it is common to use cross-linking technology with crystalline saccharides and saccharide melt-solidified products. In addition to typical excipients, high melting point saccharides can be used.

Here, “the saccharide having low moldability” means, for example, when tableting 150 mg of saccharide with a punch having a diameter of 8 mm at a tableting pressure of 10 kg / cm ² or more and 50 kg / cm ² or less, the tablet hardness is 0 kp or more and 2 kp or less In addition, the term “highly moldable saccharide” means that the hardness by the same method is 2 kp or more. Saccharides with low moldability are pharmaceutically acceptable, and examples thereof include lactose, D-mannitol, glucose, sucrose, xylitol, erythritol and the like. One or more of these may be used in appropriate combination. Saccharides with high moldability are pharmaceutically acceptable, and examples thereof include maltose, maltitol, sorbitol, oligosaccharides and trehalose. These saccharides can also be used alone or in combination of two or more.

  “Amorphous saccharides” are pharmaceutically acceptable and include, for example, lactose, sucrose, glucose, sorbitol, maltose, trehalose and the like, and these saccharides may be used alone or in combination of two or more. It is also possible to use it.

  “Saccharides having a low melting point” are pharmaceutically acceptable, and examples thereof include xylitol and trehalose. These saccharides can also be used alone or in combination of two or more. Examples of binders for orally disintegrating tablets include maltitol and copolyvidone. Such binders can be used alone or in combination of two or more.

  When a water-soluble polymer is used in place of a highly moldable saccharide, for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, polyvinyl alcohol, gum arabic powder, gelatin, pullulan and the like are suitable.

  In addition, “α-ized” means that when physical treatment is applied to starch, water enters between the molecules and swells (gelatinizes). Become. Examples of the processed starch include corn starch, wheat starch, potato starch, rice starch, tapioca starch and the like.

  The amount of excipient used in the orally disintegrating tablet of the present invention is appropriately adjusted. For example, it is usually 20 mg to 1000 mg per tablet, 50 mg to 900 mg as another embodiment, and 70 mg to 800 mg as a further embodiment. Hereinafter, it is 35 mg or more and 400 mg or less as another aspect.

  The blending amount of highly moldable saccharides, water-soluble polymers, amorphous saccharides, and saccharides with a low melting point is 0.5 wt. % Or more and 40% by weight or less is preferable, and in another aspect, it is 2% by weight or more and 30% by weight or less, and in a further aspect, it is 5% by weight or more and 20% by weight or less, or % Or less is preferred.

  Below, the manufacturing method of the orally disintegrating tablet of this invention is demonstrated.

  The timing of adding kanteng and / or kanteng powder is not particularly limited as long as it can produce a preparation that achieves the desired effect of the present invention. A pulverization process, a mixing process, or a granulation process is preferred.

The pulverization step is not particularly limited as long as it is a pharmaceutically pulverization method, as long as it is a pharmaceutically pulverization method. Examples of the pulverizer include a hammer mill, a ball mill, and a jet mill. The grinding conditions are not particularly limited as long as they are appropriately selected.

The mixing method is not particularly limited as long as it is a method in which each component is generally uniformly mixed pharmacologically. Examples of the mixing apparatus include a V-type mixer, a ribbon-type mixer, a container mixer, and a high-speed stirring mixer. The mixing conditions are not particularly limited as long as they are appropriately selected.

Examples of the granulating step granulator include a fluidized bed granulator. As granulation methods, for example, fluidized bed granulation method, melt granulation method, high speed stirring granulation method, crushing (pulverization) granulation method, extrusion granulation method, rolling granulation method, spray granulation method, dry method Examples include granulation methods. Another embodiment is a fluidized bed granulation method.

  Since the amount of ramosetron or a pharmaceutically acceptable salt thereof is very small, a method of dissolving and spraying a drug in a binder solution may be adopted. For example, the method includes a method of dissolving citric acid in a binder solution for drug stabilization (see WO2004 / 066998 for stabilization of ramosetron with citric acid).

  The binder solution is prepared by dissolving or dispersing the binder in a solvent such as water, ethanol, methanol or the like. Further, these solvents can be appropriately mixed and used.

  The preparation conditions of the spray liquid are not particularly limited as long as they are appropriately selected.

  It can also be dried after granulation. The drying method is not particularly limited as long as it is a pharmaceutically drying method. For example, ventilation drying and reduced pressure drying are mentioned.

Molding process In the molding process, a granulated product or a mixture of granulated products mixed with various pharmaceutical additives is filled into capsules to form capsules, or compressed into tablets using a rotary tableting machine. be able to.

  The compression step is not particularly limited as long as it is a method for molding the pharmaceutical composition of the present invention. Specifically, for example, a direct tableting method in which a tablet is obtained by compression molding after mixing a drug and an appropriate pharmaceutical additive, and a method in which a lubricant is further mixed with the granulated product and then compression molding is performed to produce a tablet. It is done.

  Examples of the tableting device include a rotary tableting machine, a single tableting machine, and an oil press. Tableting conditions such as tableting pressure are not particularly limited as long as the tablet can be molded and the tableting pressure does not damage the tablet during the production process.

Humidification and drying process As described in International Publication No. WO95 / 20380 pamphlet (US corresponding patent No. 5576014), when an orally disintegrating tablet is produced using a sugar having low moldability, In order to increase the hardness, humidification and drying processes can be employed. “Humidification” is determined by the apparent critical relative humidity of the saccharides contained, but usually humidifies above its critical relative humidity. For example, the humidity is 30 RH% or more and 100 RH% or less, and in another aspect, it is 50 RH% or more and 90 RH% or less. The temperature at this time is preferably 15 ° C. or more and 50 ° C. or less, and in another embodiment, it is 20 ° C. or more and 40 ° C. or less. The treatment time is 1 hour or more and 36 hours or less, and in another aspect, 12 hours or more and 24 hours or less. “Drying” is not particularly limited as long as it is a step of removing moisture absorbed by humidification. For example, the drying temperature condition can be set to 10 ° C. or more and 100 ° C. or less, and in another embodiment, 20 ° C. or more and 60 ° C. or less can be set. The treatment time can be 0.5 hours or more and 6 hours or less, and in another aspect, it can be 1 hour or more and 4 hours or less.

  In addition, for example, as disclosed in International Publication No. WO2002 / 92057 pamphlet (US patent application publication No. 2003/099701 specification), an orally disintegrating tablet is produced using an excipient with a high melting point and a low sugar. In this case, a heating step can be employed to increase the hardness of the prepared molded product. “Heating” is determined by the melting point of the saccharide having a low melting point, and is usually heated to a temperature not lower than the melting point of the excipient having a high melting point and not lower than the melting point of the saccharide having a low melting point. The treatment time can be 0.5 minutes or more and 120 minutes or less, and in another aspect, it can be 1 minute or more and 60 minutes or less.

  In the orally disintegrating tablet of the present invention, agar and / or agar powder is used. Thereby, an orally disintegrating tablet having bioequivalence to a normal tablet can be provided. This is thought to be because Kanten and / or Kanten powder have a function of suppressing the delay of movement speed and absorption of ramosetron or a pharmaceutically acceptable salt thereof in the oral cavity or esophagus.

  Hereinafter, the present invention will be described in more detail with reference to production examples and experimental examples, but the present invention is not limited thereto.

  Ramosetron was produced by the method described in Example 44 of JP-B-6-25153.

<Preparation of formulation>
Production Example 1
Ramosetron hydrochloride 0.01883 parts (0.0226 mg)
D-mannitol 87.8 parts (105.3374 mg)
0.2 parts of anhydrous citric acid (0.24mg)
10 parts maltose (12.0mg)
Red iron sesquioxide 1 part (1.20mg)
Magnesium stearate 1 part (1.20mg)

  To produce 6,000 tablets, 7 parts of maltose (Sanmalto S, manufactured by Sanwa Starch Co., Ltd., unless otherwise specified), 0.01883 parts of Ramosetron hydrochloride and anhydrous citric acid (Citric acid of Japan Pharmacopoeia, Unless otherwise specified, the same one was used.) A spray solution was prepared by stirring and dissolving 0.2 parts in 40 parts of water using a magnetic stirrer. Next, D-mannitol (Pearlitol 50C, manufactured by Rocket, unless otherwise specified, 8 parts), 3 parts maltose, red iron sesquioxide (iron sesquioxide S, manufactured by Hatake Kasei, especially hereafter) If there is no description, the same one was used.) After mixing and grinding 1 part, 79.8 parts of D-mannitol was charged into a fluidized bed granulator (FLOW COATER, manufactured by Freund) and sprayed with the spray solution. Fluidized bed granulated. After granulation, the granulated product was dried until the product temperature reached 40 ° C, and then 1 part of magnesium stearate (Parteck LUB MST, manufactured by Merck, unless otherwise specified) was used. Mixed. The mixed powder was tableted at 120 mg per tablet using a rotary tableting machine (X-20, manufactured by Hata Iron Works) to obtain a tablet having an initial hardness of about 10N. The tablet was stored at 25 ° C. and 62% relative humidity for 15 hours, and then stored at 30 ° C. for 3 hours to obtain an orally disintegrating tablet containing 22.6 μg of ramosetron hydrochloride as a comparative example.

Production Example 2
Ramosetron hydrochloride 0.0226 parts (0.0226 mg)
0.5 parts of anhydrous citric acid (0.5mg)
Hydroxypropylcellulose 3 parts (3.0mg)
86 parts of crystalline cellulose (86.0mg)
Low-substituted hydroxypropylcellulose 10 parts (10.0 mg)
Magnesium stearate 0.5 parts (0.5 mg)

  To produce 6,000 tablets, 0.0226 parts of ramosetron hydrochloride, 3 parts of hydroxypropylcellulose (HPC-SL, manufactured by Nippon Soda, unless otherwise specified) and 0.5 parts of anhydrous citric acid in 27 parts of water A spray solution was prepared by stirring and dissolving using a magnetic stirrer. Next, 86 parts of crystalline cellulose (Theoras PH302, manufactured by Asahi Kasei, unless otherwise specified), low-substituted hydroxypropylcellulose (L-HPC, LH31, manufactured by Shin-Etsu Chemical Co., Ltd., specifically described below) In the absence, there was used a similar one.) 10 parts were charged in a fluidized bed granulator (FLOW COATER, manufactured by Freund) and sprayed with the spray solution to perform fluidized bed granulation. After granulation, the granulated product was dried and mixed with 0.5 part of magnesium stearate. The mixed powder was tableted at 100 mg per tablet using a rotary tableting machine (X-20, manufactured by Hata Iron Works) to obtain a conventional tablet containing 22.6 μg of ramosetron hydrochloride as a comparative example.

Production Example 3
Ramosetron hydrochloride 0.0028 parts (0.005 mg)
D-mannitol 87.9 parts (158.215 mg)
0.2 part (0.36 mg) anhydrous citric acid
10 parts maltose (18.0mg)
Kanteng powder 0.1 parts (0.18mg)
Red iron sesquioxide 0.8 parts (1.44mg)
Magnesium stearate 1 part (1.80mg)

  In order to produce 100,000 tablets, 7 parts of maltose, 0.0028 parts of ramosetron hydrochloride and 0.2 parts of anhydrous citric acid were stirred and dissolved in 28 parts of water using a magnetic stirrer to prepare a spray solution. Next, 8 parts of D-mannitol, 3 parts of maltose, 0.8 parts of red iron sesquioxide, Kanten (Ultra Kanten AX200F, Ina Food Industry Co., Ltd. After mixing and pulverizing (made by Hosokawa Micron), it was charged into a fluidized bed granulator (GPCG15, manufactured by Glatt) together with 79.9 parts of D-mannitol, and fluidized bed granulated by spraying the spray solution. After granulation, the granulated product was dried until the product temperature reached 40 ° C., and then 1 part of magnesium stearate was mixed. The mixed powder was tableted at 180 mg per tablet using a rotary tableting machine (X-20, manufactured by Hata Iron Works) to obtain a tablet having an initial hardness of about 10N. The tablet was stored at 25 ° C. and 62% relative humidity for 15 hours, and then stored at 30 ° C. for 3 hours to obtain an orally disintegrating tablet containing 5 μg of ramosetron hydrochloride of the present invention.

Production Example 4
Ramosetron hydrochloride 0.005 parts (0.005 mg)
0.5 parts of anhydrous citric acid (0.5mg)
Hydroxypropylcellulose 3 parts (3.0mg)
86 parts of crystalline cellulose (86.0mg)
Low-substituted hydroxypropylcellulose 10 parts (10.0 mg)
Magnesium stearate 0.5 parts (0.5 mg)

  In order to produce 6,000 tablets, 0.005 part of ramosetron hydrochloride, 3 parts of hydroxypropylcellulose and 0.5 part of anhydrous citric acid were stirred and dissolved in 27 parts of water using a magnetic stirrer to prepare a spray solution. Next, 86 parts of crystalline cellulose and 10 parts of low-substituted hydroxypropyl cellulose were charged into a fluidized bed granulator (FLOW COATER, manufactured by Freund), and fluidized bed granulated by spraying the spray solution. After granulation, the granulated product was dried and mixed with 0.5 part of magnesium stearate. The mixed powder was tableted at 100 mg per tablet using a rotary tableting machine (X-20, manufactured by Hata Iron Works) to obtain a conventional tablet containing 5 μg of ramosetron hydrochloride as a comparative example.

Production Example 5
Ramosetron hydrochloride 0.0028 parts (0.005 mg)
D-mannitol 87.9 parts (158.215 mg)
0.2 part (0.36 mg) anhydrous citric acid
10 parts maltose (18.0mg)
Kanteng powder 0.1 parts (0.18mg)
Red iron sesquioxide 0.5 parts (0.90mg)
Yellow ferric oxide 0.3 parts (0.54mg)
Magnesium stearate 1 part (1.80 mg)

  In order to produce 170,000 tablets, a spray solution was prepared by stirring and dissolving 7 parts maltose, 0.0028 parts ramosetron hydrochloride and 0.2 parts anhydrous citric acid in 28 parts water using a magnetic stirrer. Next, 8 parts of D-mannitol, 3 parts of maltose, 0.5 part of red iron sesquioxide, yellow iron sesquioxide (Yellow sesquioxide S, manufactured by Kasei Chemical Co., Ltd., unless otherwise specified) 0.3 And 0.1 parts of Kanteng powder were mixed and pulverized with a sample mill (Hosokawa Micron), then charged with 79.9 parts of D-mannitol into a fluidized bed granulator (GPCG30, manufactured by Glatt) and sprayed with the spray solution to prepare a fluidized bed. Grained. After granulation, the granulated product was dried until the product temperature reached 40 ° C., and then 1 part of magnesium stearate was mixed. The mixed powder was tableted at 180 mg per tablet using a rotary tableting machine (X-20, manufactured by Hata Iron Works) to obtain a tablet having an initial hardness of about 10N. The tablet was stored at 25 ° C. and 62% relative humidity for 15 hours, and then stored at 30 ° C. for 3 hours to obtain an orally disintegrating tablet containing 5 μg of ramosetron hydrochloride of the present invention.

Production Example 6
The mixed powder of Production Example 3 was tableted at 90 mg per tablet using a rotary tableting machine (X-20, manufactured by Hata Iron Works) to obtain a tablet having an initial hardness of about 10N. The tablet was stored at 25 ° C. and 62% relative humidity for 15 hours, and then stored at 30 ° C. for 3 hours to obtain an orally disintegrating tablet containing 2.5 μg of ramosetron hydrochloride of the present invention.

Production Example 7
Ramosetron hydrochloride 0.00139 parts (0.00125 mg)
D-mannitol 87.9 parts (79.1088 mg)
0.2 parts of anhydrous citric acid (0.18mg)
Maltose 10 parts (9.0mg)
Kanteng powder 0.1 parts (0.09mg)
Red iron sesquioxide 0.5 parts (0.45mg)
Yellow iron sesquioxide 0.3 parts (0.27mg)
Magnesium stearate 1 part (0.90mg)

  In order to produce 200,000 tablets, 7 parts of maltose, 0.00139 parts of ramosetron hydrochloride and 0.2 parts of anhydrous citric acid were stirred and dissolved in 28 parts of water using a magnetic stirrer to prepare a spray solution. Next, 8 parts of D-mannitol, 3 parts of maltose, 0.5 part of red ferric oxide, 0.3 part of yellow ferric oxide and 0.1 part of Kanteng powder were mixed and ground by a sample mill (manufactured by Hosokawa Micron) and then flowed together with 79.9 parts of D-mannitol. Fluidized bed granulation was performed by charging in a layer granulator (GPCG15, manufactured by Glatt) and spraying the spray solution. After granulation, the granulated product was dried until the product temperature reached 40 ° C., and then 1 part of magnesium stearate was mixed. The mixed powder was tableted at 90 mg per tablet using a rotary tableting machine (X-20, manufactured by Hata Iron Works) to obtain a tablet having an initial hardness of about 10N. The tablet was stored at 25 ° C. and 62% relative humidity for 15 hours and then stored at 30 ° C. for 3 hours to obtain an orally disintegrating tablet containing 1.25 μg of ramosetron hydrochloride of the present invention.

<Evaluation>
Experimental example 1
Oral gastric gavage was administered to a beagle dog fasted for 18 hours or more together with 50 mL of water with a normal tablet containing 22.6 μg of ramosetron hydrochloride produced in Production Example 2. In addition, pentagastrin (0.015 mg / kg) was intravenously administered 30 minutes before, 30 minutes, and 90 minutes after oral gavage administration of the tablets, and the gastric pH of the beagle dog was treated to be acidic. After oral intragastric forced administration, blood was collected over time, and the plasma ramosetron concentration obtained by centrifugation was measured. The results are shown in Table 1.

Experimental example 2
The oral disintegrating tablet containing 22.6 μg of ramosetron hydrochloride produced in Production Example 1 was forcibly orally administered to the beagle dog fasted for 18 hours or more together with 50 mL of water. In addition, pentagastrin (0.015 mg / kg) was intravenously administered 30 minutes before, 30 minutes, and 90 minutes after oral gavage administration of the tablets, and the gastric pH of the beagle dog was treated to be acidic. After oral intragastric forced administration, blood was collected over time, and the plasma ramosetron concentration obtained by centrifugation was measured. The results are shown in Table 1.

Experimental example 3
The orally disintegrating tablet containing 22.6 μg of ramosetron hydrochloride produced in Production Example 1 was placed in a syringe for injection together with 2 mL of water, and then uniformly dispersed by pumping. The suspension was administered orally to beagle dogs that had been fasted for at least 18 hours. In addition, pentagastrin (0.015 mg / kg) was intravenously administered 30 minutes before, 30 minutes, and 90 minutes before oral administration of the tablet, and the gastric pH of the beagle dog was treated to be acidic. After intraoral administration, blood was collected over time, and the plasma ramosetron concentration obtained by centrifugation was measured. The results are shown in Table 1.

Experimental Example 4
An agar powder suspension (0.05 mg / mL) was prepared. Next, the orally disintegrating tablet containing 22.6 μg of ramosetron hydrochloride produced in Production Example 1 was placed in a syringe for injection together with 2 mL of the above Kanteng powder suspension, and then uniformly dispersed by pumping. The suspension was administered orally to beagle dogs that had been fasted for at least 18 hours. In addition, pentagastrin (0.015 mg / kg) was intravenously administered 30 minutes before, 30 minutes, and 90 minutes before oral administration of the tablet, and the gastric pH of the beagle dog was treated to be acidic. After intraoral administration, blood was collected over time, and the plasma ramosetron concentration obtained by centrifugation was measured. The results are shown in Table 1.

  In Experimental Example 1, AUC was 323 ± 92 pg · h / mL, and Cmax was 156 ± 51 pg / mL.

  In Experimental Example 2, AUC is 338 ± 66, Cmax is 153 ± 53, and the ratio of the respective geometric mean values (GMR, Comparative Example 1 is 0.98 (98%), 1.07 (107%)) Meet the BE criteria.

  In Experimental Example 3, AUC is 262 ± 57 and Cmax is 116 ± 28, and the ratio of the geometric mean values (GMR, Comparative Example 1 is 0.87) is 0.77 (77%) and 0.82 (82%). I did not meet the BE criteria.

  In Experimental Example 4, AUC is 319 ± 37, Cmax is 139 ± 20, and the ratio of the respective geometric mean values (GMR, Comparative Example 1 of Experimental Example 1) is 0.94 (94%) and 1.02 (102%). Meet the BE criteria.

  In Experimental Example 2, the AUC and Cmax when the orally disintegrating tablet was orally administered to the dog by oral stomach were both the same as the AUC and Cmax of Experimental Example 1, and biologically equivalent. On the other hand, in Experimental Example 3, a suspension of the orally disintegrating tablet produced in Production Example 1 dispersed in water was orally administered to dogs. As a result, AUC was lower than that of ordinary tablets, and the bioequivalence criteria were reduced. Did not meet. Since Experimental Example 3 is different from Experimental Example 2 in that the intra-oral and esophagus are included as the ramosetron movement route, it is considered that the ramosetron's moving speed was delayed in the oral cavity or the esophagus and the absorption was decreased. On the other hand, according to Experimental Example 4, AUC and Cmax when the oral disintegrating tablet containing agar powder was orally administered was equivalent to that of the normal tablet. This is thought to be due to the fact that Kanten powder suppressed the slowing of the movement speed and the decrease in absorption of ramosetron in the oral cavity or esophagus.

Experimental Example 5
The usual tablet containing 5 μg of ramosetron hydrochloride produced in Production Example 4 was forcibly orally administered to a beagle dog fasted for 18 hours or more together with 50 mL of water. In addition, pentagastrin (0.015 mg / kg) was intravenously administered 30 minutes before, 30 minutes, and 90 minutes before oral administration of the tablet, and the gastric pH of the beagle dog was treated to be acidic. After oral intragastric forced administration, blood was collected over time, and the plasma ramosetron concentration obtained by centrifugation was measured. The results are shown in Table 2.

Experimental Example 6
The orally disintegrating tablet containing 5 μg of ramosetron hydrochloride containing agar powder produced in Production Example 3 was placed in a syringe for injection together with 2 mL of water, and then uniformly dispersed by pumping. The suspension was administered orally to beagle dogs that had been fasted for at least 18 hours. In addition, pentagastrin (0.015 mg / kg) was intravenously administered 30 minutes before, 30 minutes, and 90 minutes before oral administration of the tablet, and the gastric pH of the beagle dog was treated to be acidic. After intraoral administration, blood was collected over time, and the plasma ramosetron concentration obtained by centrifugation was measured. The results are shown in Table 2.

  In Experimental Example 5, AUC was 30.3 ± 15.7 pg · h / mL, and Cmax was 17.1 ± 6.0 pg / mL.

  In Experimental Example 6, AUC was 30.0 ± 7.5, Cmax was 14.7 ± 3.4, and the ratio of the respective geometric mean values (GMR, Comparative Example 5) was 0.89 (89%) and 1.12 (112%). Meet the BE criteria.

  As mentioned above, the orally disintegrating tablet containing ramosetron or a pharmaceutically acceptable salt thereof achieved BE with the normal tablet by containing agar powder.

Experimental Example 7
When the oral disintegrating tablet containing 5 μg of Ramosetron hydrochloride containing Kanten powder produced in Production Example 5 and 5 μg of iribo tablet (commercial product, normal tablet) were orally administered to humans, the ratio of geometric average values of AUC and Cmax was 80. % And below 125%. From the above, the orally disintegrating tablet produced in Production Example 5 achieved a normal tablet and BE.

  According to the present invention, it is possible to provide an orally disintegrating tablet with improved absorbability comprising a low dose of ramosetron or a pharmaceutically acceptable salt thereof and having bioequivalence to a normal tablet. it can.

Claims (18)

  (a) 0.001 mg or more and 0.05 mg or less of ramosetron hydrochloride, or (b) 0.001 mg or more and 0.05 mg or less of ramosetron hydrochloride and an equimolar amount of ramosetron or a pharmaceutically acceptable salt thereof, and agar and / or agar powder. Orally disintegrating tablets.   2. It contains (a) 0.00125 mg or more and 0.025 mg or less ramosetron hydrochloride, or (b) 0.00125 mg or more and 0.025 mg or less ramosetron hydrochloride and an equimolar amount of ramosetron or a pharmaceutically acceptable salt thereof. The orally disintegrating tablet described.   The orally disintegrating tablet according to claim 1 or 2, wherein the amount of kantene and / or kanteng powder is 10% by weight or more and 500,000% by weight or less based on ramosetron or a pharmaceutically acceptable salt thereof.   The orally disintegrating tablet according to claim 1 or 2, wherein the amount of Kanten and / or Kanten powder is 0.001 wt% or more and 70 wt% or less per unit preparation.   The orally disintegrating tablet according to any one of claims 1 to 4, for the treatment of diarrhea-type irritable bowel syndrome.   The orally disintegrating tablet according to any one of claims 1 to 5, which is bioequivalent to 2.5 µg of Iribo (registered trademark) tablets or 5 µg of Iribo (registered trademark) tablets.   The orally disintegrating tablet according to any one of claims 1 to 6, further comprising a stabilizer.   The orally disintegrating tablet according to claim 7, wherein the stabilizer is hydroxycarboxylic acid.   The orally disintegrating tablet according to claim 8, wherein the hydroxycarboxylic acid is one or more substances selected from the group consisting of tartaric acid, malic acid, and citric acid.   The orally disintegrating tablet according to any one of claims 1 to 9, further comprising a light stabilizer.   The orally disintegrating tablet according to claim 10, wherein the light stabilizer is one or more substances selected from the group consisting of yellow ferric oxide, red ferric oxide, and titanium oxide.   The orally disintegrating tablet according to any one of claims 1 to 11, further comprising a saccharide.   The orally disintegrating tablet according to claim 12, wherein the saccharide is a saccharide having a high moldability and / or a saccharide having a low moldability.   The orally disintegrating tablet according to claim 13, wherein the highly moldable saccharide is one or more substances selected from the group consisting of maltose, maltitol, sorbitol, and trehalose.   The orally disintegrating tablet according to claim 13, wherein the saccharide having low moldability is one or more substances selected from the group consisting of lactose, D-mannitol, glucose, sucrose, xylitol, and erythritol. .   Iribo (Registered Trademark) containing (a) 0.001 mg to 0.05 mg of ramosetron hydrochloride, or (b) 0.001 mg to 0.05 mg of ramosetron hydrochloride and an equimolar amount of ramosetron or a pharmaceutically acceptable salt thereof. ) Use of agar and / or agar powder for the production of orally disintegrating tablets that are bioequivalent to 2.5 μg of tablets or 5 μg of Iribo® tablets. An orally disintegrating tablet used to treat diarrhea-type irritable bowel syndrome by administering ramosetron hydrochloride of 0.00125 mg or more and 0.025 mg or less as a daily dose per adult,
An orally disintegrating tablet containing at least 0.00125 mg to 0.025 mg of ramosetron hydrochloride, agar and / or agar powder, D-mannitol, and maltose per unit preparation. The oral cavity according to any one of claims 1 to 15 and 17, obtained by compression molding a mixture containing ramosetron hydrochloride, ramosetron or a pharmaceutically acceptable salt thereof and agar and / or agar powder. Disintegrating tablets.