JP7161176B2 - Orally disintegrating tablet and manufacturing method thereof - Google Patents

Description

The present invention provides an orally disintegrating tablet that rapidly disintegrates in the oral cavity even when taken with a small amount of water or without water, and contains tolvaptan that maintains good disintegration even when stored under humidified conditions. It relates to an internal disintegrating tablet and a method for producing the same.

Tolvaptan is a vasopressin receptor antagonist represented by the following formula (1), and is effective in improving fluid retention associated with congestive heart failure/liver cirrhosis (Non-Patent Document 1). Many patients with congestive heart failure and cirrhosis that cause fluid retention are elderly, and many patients have dysphagia. Therefore, orally disintegrating tablets containing tolvaptan that can be taken with or without water are desired. ing.

On the other hand, in recent years, when a patient takes a plurality of medicines at the time of dispensing, efforts have often been made to improve adherence to the medicine by packaging the medicines in one package. As a result, the period from when the drug is taken out of the package or PTP sheet to when the patient takes it increases, increasing the possibility of long-term exposure to unfavorable conditions for drug storage, such as high humidity conditions. ing. Under such conditions, conventional orally disintegrating tablets may lose their properties due to delay in disintegration time. Against this background, it is desired to create a tolvaptan orally disintegrating tablet that maintains its disintegrating properties even when stored for a long period of time under high humidity conditions, which are not preferable for drug storage.

Due to its usefulness, there have been several reports on formulation techniques for tolvaptan. For example, Patent Document 1 discloses that a pharmaceutical solid dispersion produced by blending tolvaptan and hydroxypropylcellulose and spray drying is superior to a pharmaceutical solid dispersion produced by replacing hydroxypropylcellulose with other polymer components. It is disclosed to have solubility and absorbability.

Patent Document 2 discloses that a pharmaceutical solid preparation containing tolvaptan, a methacrylic acid-based enteric polymer compound, and a sugar and/or a sugar alcohol has a high degree of controlled release in the intestine.

Patent Document 3 discloses a gradually disintegrating sustained-release pharmaceutical solid preparation containing tolvaptan, polycarbophil calcium, and sugar and/or sugar alcohol.

Patent Document 4 discloses that a pharmaceutical solid dispersion containing tolvaptan, crospovidone, and a water-soluble polymer has excellent dissolution properties.

Patent Document 5 discloses that a pharmaceutical solid dispersion containing tolvaptan and povidone or a graft copolymer composed of polyethylene glycol, polyvinylcaprolactam, and polyvinyl acetate has excellent dissolution properties.

However, Patent Documents 1 to 5 do not describe or suggest tolvaptan orally disintegrating tablets that do not change in disintegration even after long-term storage under high humidity conditions.

JP-A-11-21241 WO 2009/051022 pamphlet WO 2010/026971 pamphlet International Publication No. 2011/160541 Pamphlet International Publication No. 2014/068586 pamphlet

Samsca Tablets Drug Interview Form Revised March 2017 (16th edition)

The present invention has been made based on such problems, and a stable orally disintegrating tolvaptan-containing preparation that can maintain good disintegration properties in the oral cavity even under high-humidity storage conditions for a long period of time. The object is to provide a lock and its manufacturing method.

The orally disintegrating tablet of the present invention comprises (a) tolvaptan, (b) at least one component selected from the group consisting of hydroxypropylmethylcellulose and polyvinyl alcohol, and (c) from the group consisting of D-mannitol and lactose. It contains at least one selected component and (d) light anhydrous silicic acid.

According to the present invention, since the above components are contained, it is possible to provide an orally disintegrating tablet containing tolvaptan that has good disintegration properties even under high-humidity storage conditions. For example, the disintegration time in the reference state is within 40 seconds, and the difference between the disintegration time in the reference state and the disintegration time after storage for one week under the conditions of 40 ° C. and 75% relative humidity from the reference state is 15 seconds. can be within

Further, if hydroxypropylmethylcellulose is contained as the component (b), sufficient hardness can be obtained. Furthermore, if hydroxypropylmethylcellulose and polyvinyl alcohol are contained as the component (b), a good dissolution rate can be obtained, and the stability of the disintegration time after storage under high humidity conditions is also improved. can be improved.
Furthermore, disintegration can be improved by containing (e) a disintegrant.

In addition, (f) containing at least one component selected from the group consisting of crystalline cellulose, low-substituted hydroxypropylcellulose and corn starch, the content of each component in the orally disintegrating tablet A higher effect can be obtained by setting it within a predetermined range.

Furthermore, if a solid dispersion of tolvaptan and hydroxypropylmethylcellulose is contained, and if the weight ratio of tolvaptan and hydroxypropylmethylcellulose in the solid dispersion is within a predetermined range, High effect can be obtained.

In addition, it is manufactured by a manufacturing method including a mixing granulation step of granulating a mixture containing at least tolvaptan as a component, and a tableting step of compressing and molding the granules after the mixing granulation step, and a tableting step In the above, if the granules are mixed with at least light anhydrous silicic acid and then compression-molded, better disintegration properties can be obtained.

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, embodiments of the present invention will be described in detail.

The orally disintegrating tablet according to the present embodiment is selected from the group consisting of (a) tolvaptan, and (b) hydroxypropylmethylcellulose (HPMC; hereinafter referred to as HPMC) and polyvinyl alcohol (PVA; hereinafter referred to as PVA). (c) at least one component selected from the group consisting of D-mannitol and lactose; and (d) light silicic anhydride.

Tolvaptan used in the present embodiment has the general name N-{4-[(5RS)-7-chloro-5-hydroxy-2,3,4,5-tetrahydro-1H represented by formula (1). -benzo[b]azepine-1-carbonyl]-3-methylphenyl}-2-methylbenzamide or a pharmaceutically acceptable salt thereof, but a compound of formula (1) (i.e. educt) is preferred. Furthermore, in the present embodiment, tolvaptan can be used in various forms of crystals, solid dispersions with HPMC, or amorphous forms of tolvaptan alone. When a solid dispersion of tolvaptan and HPMC is used, the weight ratio of tolvaptan and HPMC in the solid dispersion is preferably 1:1 to 5:1, more preferably 1.5:1 to 3:1.

When amorphous tolvaptan such as a solid dispersion with HPMC or an amorphous form of tolvaptan alone is used, the method for producing amorphous tolvaptan is not particularly limited. It can be produced by known methods such as a solvent distillation method using a granulator or the like, a melting method using a twin-screw extruder or the like, or a pulverization method using a vibration mill or planetary mill. When using the solvent distillation method, the solvent to be used is not particularly limited, but halogenated hydrocarbons such as dichloromethane and dichloroethane, ketones such as acetone and methyl ethyl ketone, lower alcohols such as methanol and ethanol, and mixtures thereof. A solution etc. are mentioned. Also, if necessary, water can be added. Among these solvents, mixed solutions of halogenated hydrocarbons or ketones and lower alcohols are preferred from the viewpoint of solubility and solvent distillation. Specifically, dichloromethane and methanol or ethanol, acetone and methanol or ethanol. A mixed solution is mentioned.

The content of tolvaptan in the orally disintegrating tablet is not particularly limited, but the lower limit of the content is preferably 3% by weight, more preferably 5% by weight, relative to the orally disintegrating tablet. The upper limit of the content is preferably 25% by weight, more preferably 20% by weight, and even more preferably 15% by weight relative to the orally disintegrating tablet. In addition, from the viewpoint of exhibiting the effect of maintaining good disintegrability in the oral cavity under high-humidity storage conditions, the content of tolvaptan should be in the range of 3% by weight or more of the orally disintegrating tablet. % by weight or less, more preferably 5% by weight or more and 20% by weight or less, and even more preferably 5% by weight or more and 15% by weight or less. On the other hand, if the tolvaptan content is less than 3% by weight, the tablet may become too large, resulting in poor usability.

In the orally disintegrating tablet, the total content of at least one component selected from the group consisting of HPMC and PVA is not particularly limited, but the lower limit of the total content is 0.2% by weight relative to the orally disintegrating tablet. Preferably, it is more preferably 0.5% by weight, and the upper limit of the total content is preferably 10% by weight, more preferably 8% by weight, relative to the orally disintegrating tablet . The range of the total content of at least one component selected from the group consisting of HPMC and PVA is preferably 0.2% by weight or more and 10% by weight or less with respect to the orally disintegrating tablet, and 0.5% by weight. % or more and 8 wt % or less. If the total content of at least one component selected from the group consisting of HPMC and PVA is more than 10% by weight, it may not have good rapid disintegration properties, and the content is less than 0.2% by weight. and may not have excellent solubility.

When the orally disintegrating tablet contains HPMC, the content is not particularly limited, but the lower limit of the content is preferably 0.2% by weight, preferably 0.5% by weight, relative to the orally disintegrating tablet. is more preferable, and the upper limit of the content is preferably 8% by weight, more preferably 7% by weight, relative to the orally disintegrating tablet. In addition, when HPMC is contained, the content range is preferably 0.2% by weight or more and 8% by weight or less, and 0.5% by weight or more and 7% by weight or less, relative to the orally disintegrating tablet. is more preferred.

When the orally disintegrating tablet contains PVA, the content is not particularly limited, but the lower limit of the content is preferably 0.1% by weight, preferably 0.2% by weight, relative to the orally disintegrating tablet. is more preferable, and the upper limit of the content is preferably 7% by weight, more preferably 5% by weight, relative to the orally disintegrating tablet. In addition, when PVA is contained, the content range is preferably 0.1% by weight or more and 7% by weight or less, and 0.2% by weight or more and 5% by weight or less with respect to the orally disintegrating tablet. is more preferred.

The orally disintegrating tablet preferably contains HPMC as the component (b). This is because sufficient hardness can be obtained. Moreover, it is particularly preferable that the orally disintegrating tablet contains both HPMC and PVA as the component (b). When both HPMC and PVA are included, dissolution, oral disintegration time and stability of disintegration time when stored under high humidity conditions for a long period of time are the best.

In the orally disintegrating tablet, the total content of at least one component selected from the group consisting of D-mannitol and lactose is not particularly limited, but the lower limit of the total content is 40% by weight with respect to the orally disintegrating tablet. is preferably 50% by weight, more preferably 60% by weight, and the upper limit of the total content is preferably 85% by weight with respect to the orally disintegrating tablet, and 80 % by weight is more preferred. In addition, the total range of the content of at least one component selected from the group consisting of D-mannitol and lactose is preferably 40% by weight or more and 85% by weight or less with respect to the orally disintegrating tablet, and 50% by weight % or more and 85 wt % or less, more preferably 60 wt % or more and 80 wt % or less. If the total content of at least one component selected from the group consisting of D-mannitol and lactose is more than 85% by weight, tableting failure may occur, and if the total content is less than 40% by weight, it is favorable. It may not be able to have rapid disintegration properties.

The orally disintegrating tablet preferably contains D-mannitol as component (c) from the viewpoint of stability during disintegration time.
Moreover, when using lactose as a (c) component, lactose hydrate is preferable as lactose.

In the orally disintegrating tablet, the content of light anhydrous silicic acid is not particularly limited, but the lower limit of the content is preferably 0.1% by weight, more preferably 0.2% by weight, relative to the orally disintegrating tablet. More preferably, the upper limit of the content is 8% by weight, more preferably 5% by weight, relative to the orally disintegrating tablet. Also, from the viewpoint of exhibiting the effect of maintaining good disintegrability in the oral cavity under high-humidity storage conditions, the range of the content of light silicic anhydride is 0.00 for the orally disintegrating tablet. It is preferably 1% by weight or more and 8% by weight or less, more preferably 0.2% by weight or more and 5% by weight or less.

The orally disintegrating tablet preferably contains (e) a disintegrant in addition to the above components. The disintegrant is not particularly limited, but includes crospovidone, low-substituted hydroxypropyl cellulose, partially pregelatinized starch, croscarmellose sodium, carmellose calcium, and carmellose. Crospovidone is preferred from the viewpoint of disintegration time.

In the orally disintegrating tablet, the content of (e) the disintegrant is not particularly limited, but the lower limit of the content is preferably 0.5% by weight, more preferably 1% by weight, relative to the orally disintegrating tablet. Preferably, the upper limit of the content is preferably 10% by weight, more preferably 7% by weight, relative to the orally disintegrating tablet. In addition, from the viewpoint of exhibiting the effect of maintaining good disintegrability in the oral cavity under high humidity storage conditions, the range of the content of the disintegrant is 0.5% by weight with respect to the orally disintegrating tablet. It is preferably 10% by weight or more, more preferably 1% by weight or more and 7% by weight or less.

In addition to the above components, the orally disintegrating tablet further contains (f) crystalline cellulose, low-substituted hydroxypropyl cellulose (L-HPC; hereinafter referred to as L-HPC) and at least one selected from the group consisting of corn starch. Ingredients are preferred.

When the orally disintegrating tablet contains at least one component selected from the group consisting of crystalline cellulose, L-HPC and corn starch, the total content thereof is not particularly limited, but the lower limit of the content is the orally disintegrating tablet. It is preferably 5% by weight, more preferably 8% by weight, still more preferably 10% by weight, and the upper limit of the total content is 25% by weight with respect to the orally disintegrating tablet. It is preferably 20% by weight, more preferably 20% by weight. In addition, when it contains at least one component selected from the group consisting of crystalline cellulose, L-HPC and corn starch, it has the effect of maintaining good disintegration properties in the oral cavity under high humidity storage conditions. From the viewpoint of better performance, the total content range is preferably 5% by weight or more and 25% by weight or less, more preferably 8% by weight or more and 20% by weight or less, relative to the orally disintegrating tablet. , more preferably 10% by weight or more and 20% by weight or less. Moreover, if the total content of at least one component selected from the group consisting of crystalline cellulose, L-HPC and corn starch is less than 5% by weight, tableting problems may occur.

When the orally disintegrating tablet contains at least one component selected from the group consisting of crystalline cellulose, L-HPC and corn starch, it preferably contains crystalline cellulose. When crystalline cellulose is contained, its content is not particularly limited, but the lower limit of the content is preferably 2% by weight, more preferably 4% by weight, relative to the orally disintegrating tablet, and the upper limit of the content is It is preferably 20% by weight, more preferably 15% by weight, relative to the orally disintegrating tablet. When crystalline cellulose is contained, the content thereof is preferably 2% to 20% by weight, more preferably 2% to 15% by weight, relative to the orally disintegrating tablet. , 4% by weight or more and 15% by weight or less.

In addition to the above, the orally disintegrating tablet preferably further contains a lubricant. Lubricants include magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, talc, sucrose fatty acid ester and polyethylene glycol, with magnesium stearate and sodium stearyl fumarate being preferred. These lubricants may be used alone, or two or more of them may be used in combination.

In addition, in the orally disintegrating tablet of the present embodiment, non-toxic and inert additives that are commonly used in the pharmaceutical field other than the above ingredients are added as long as they do not affect the effects of the present embodiment. In order to further improve the feeling of ingestion, a method of coating the drug-containing core particles with a sweetener or flavoring agent, a method of coating the drug-containing core particles with a gastrosoluble polymer, an enteric polymer or water It is also possible to apply a known method for improving the feeling of taking, such as a coating method of coating with a film containing an insoluble polymer.

Additives to be used may be those that are pharmaceutically acceptable, and examples thereof include excipients, fluidizing agents, sweeteners, corrigents, flavoring agents/perfumes, coloring agents, and stabilizers. . Fluidizing agents include, for example, light anhydrous silicic acid and magnesium aluminometasilicate. Examples of sweeteners and flavoring agents include aspartame, saccharin, sodium saccharin, dipotassium glycyrrhizinate, stevia, thaumatin, sucralose, acesulfame K, etc. Aspartame and sucralose are preferred. Flavoring agents and fragrances include, for example, peppermint, spearmint, menthol, peppermint oil, lemon, orange, grapefruit, pineapple, fruit, and yogurt, with menthol and peppermint oil being preferred. Gastric polymers include, for example, polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E, and the like. Examples of enteric polymers include hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, methacrylic acid copolymer L, methacrylic acid copolymer LD, and methacrylic acid copolymer S. Examples of water-insoluble polymers include ethyl cellulose, aminoalkyl methacrylate copolymer RS, and ethyl acrylate/methyl methacrylate copolymer dispersions. A more favorable ingestion feeling may be obtained by blending the aforementioned sweetening agent, flavoring agent, flavoring agent, flavoring agent, or coating with a sweetening agent, flavoring agent, gastrosoluble polymer, enteric polymer, or water-insoluble polymer. . These additives can be added in an appropriate amount either singly or in combination of two or more.

The method for producing the orally disintegrating tablet according to the present embodiment is not particularly limited. and a tableting step for molding. Specifically, for example, after mixing and pulverizing a fluidizing agent such as light silicic anhydride and the active ingredient tolvaptan, at least one component selected from the group consisting of D-mannitol and lactose, a group consisting of HPMC and PVA At least one component selected from the above, a fluidizer such as light silicic anhydride, and, if necessary, an additive such as water, crystalline cellulose, L-HPC, corn starch, etc. are added and mixed and granulated. Then, if necessary, it is dried. To the obtained granules, a disintegrant and, if necessary, additives such as D-mannitol, light silicic anhydride and a lubricant are added, mixed and compression-molded. You can get tablets by If there is a possibility that the content uniformity of the active ingredient may be hindered, such as if the ingredients used are cohesive or have large crystals or granules, each ingredient should be pulverized before or after mixing. It is desirable to adjust the particle size to ensure content uniformity by using a technique such as the following. The granulation method is not particularly limited, but tumbling granulation, fluid bed granulation, stirring granulation and the like can be used.

The method for molding tablets is not particularly limited, but in the case of commercial production, a compression molding method using a rotary tableting machine can be used. The orally disintegrating tablet according to the present embodiment can be compression-molded without using the external lubrication method, but can of course also be molded using the external lubrication method. In this case, after mixing the ingredients except the lubricant, tableting is performed while spraying the lubricant onto a punch or die, or part of the lubricant is premixed and the remaining lubricant is added. is sprayed onto the punch and die for tableting. The compression molding force is not particularly limited as long as it gives the tablet sufficient strength, but a compression force of 2.5 kN (about 250 kg) or more is preferable.

The shape of the orally disintegrating tablet according to the present embodiment is not particularly limited, and may be any shape such as a round tablet, a triangular tablet, a bullet tablet, a circular tablet, a circular R tablet, a circular square tablet, and various irregularly shaped tablets. Moreover, it is good also as a split tablet.

In the present embodiment, an orally disintegrating tablet means a tablet that rapidly disintegrates in the oral cavity without ingestion of water or with a small amount of water in order to take the tablet. For example, the collapse time in the reference state is preferably within 60 seconds, more preferably within 40 seconds, and even more preferably within 35 seconds. By reference condition is meant a condition that has not deteriorated due to moisture absorption, such as immediately after being removed from the package.

Moreover, the orally disintegrating tablet preferably has sufficient hardness so as not to be chipped or cracked during normal operations. Here, the normal operation includes transportation and storage in a packaged state, removal from the PTP, packaging by an automatic packaging machine, and the like. In the present embodiment, the hardness of the orally disintegrating tablet is preferably 2.0 kgf or more, more preferably 3.0 kgf or more in the standard state. Further, in the present embodiment, the hardness of the orally disintegrating tablet is preferably 2.0 kgf or more even after storage for 2 weeks under conditions of 25° C. and 93% relative humidity (93% RH).

Furthermore, the orally disintegrating tablet of the present embodiment is a tablet capable of maintaining rapid disintegration and hardness even when stored under humidified conditions. For example, the difference between the disintegration time after storage for one week under the conditions of 40° C. and 75% relative humidity (75% RH) from the standard state and the disintegration time in the standard state before storage is preferably within 20 seconds, More preferably within 15 seconds. In addition, the hardness of the orally disintegrating tablet after storage for 2 weeks under the conditions of 25 ° C. and 93% relative humidity (93% RH) from the reference state and the hardness of the orally disintegrating tablet in the reference state before storage. The difference is preferably 3.0 kgf or less, more preferably 2.5 kgf or less.

Thus, according to the present embodiment, (a) tolvaptan, (b) at least one component selected from the group consisting of HPMC and PVA, and (c) selected from the group consisting of D-mannitol and lactose and (d) light silicic anhydride, good disintegration properties can be obtained even under high-humidity storage conditions.
Furthermore, disintegration can be improved by containing (e) a disintegrant.

Further, if HPMC is contained as the component (b), sufficient hardness can be obtained. Furthermore, if HPMC and PVA are contained as components (b), a good dissolution rate can be obtained, and the stability of the disintegration time and the stability of the disintegration time after storage under high humidity conditions can be obtained. can also be improved.

In addition, (f) containing at least one component selected from the group consisting of crystalline cellulose, low-substituted hydroxypropylcellulose and corn starch, the content of each component in the orally disintegrating tablet A higher effect can be obtained by setting it within a predetermined range.

Furthermore, if a solid dispersion of tolvaptan and HPMC is contained, and if the weight ratio of tolvaptan and HPMC in the solid dispersion is within a predetermined range, a higher effect can be obtained. be able to.

In addition, it is manufactured by a manufacturing method including a mixing granulation step of granulating a mixture containing at least tolvaptan as a component, and a tableting step of compressing and molding the granules after the mixing granulation step, and a tableting step In the above, if the granules are mixed with at least light anhydrous silicic acid and then compression-molded, better disintegration properties can be obtained.

EXAMPLES The present invention will be described in more detail below with reference to Examples, which are not intended to limit the scope of the present invention.

In this example, D-mannitol, lactose, light anhydrous silicic acid, synthetic aluminum silicate, anhydrous calcium hydrogen phosphate, hydrated silicon dioxide, calcium silicate, magnesium aluminometasilicate, copolyvidone, polyvinylpyrrolidone, crospovidone, L -HPC, partially pregelatinized starch, croscarmellose sodium, sodium starch glycolate, carmellose calcium, carmellose, cornstarch, aspartame, sucralose, L-menthol, peppermint oil, blue No. 2, magnesium stearate, stearyl fumarate The following sodium was used unless otherwise specified.

D-mannitol: Granutol S (Freund), Lactose: SuperTab11SD (DFE Pharma), Light anhydrous silicic acid: Adsolider 101 (Freund), Synthetic aluminum silicate: Synthetic aluminum silicate (extra light) (Kyowa Chemical Industry) , Anhydrous calcium hydrogen phosphate: Anhydrous calcium hydrogen phosphate (standard) (Kyowa Chemical Industry), Hydrous silicon dioxide: Adsolider 102 (Freund Sangyo), Calcium silicate: Fluorite R (Tomita Pharmaceutical), Magnesium aluminometasilicate: Neusilin UFL2 (Fuji Chemical Industry), copolyvidone: Kollidon VA64 (BASF), polyvinylpyrrolidone: PLASDONE K-25 (ISP), crospovidone: Kollidon CL-F (BASF), L-HPC: NBD-022 (Shin-Etsu Chemical) , partially pregelatinized starch: PC-10 (Asahi Kasei), croscarmellose sodium: Ac-Di-Sol (FMC), sodium starch glycolate: Primojel (DFE Pharma), carmellose calcium: ECG-505 (Gotoku Yakuhin), Carmellose: NS-300 (Gotoku Yakuhin), Corn starch: ST Starch C (Nidori Kagaku), Aspartame: Ajinomoto KK Aspartame (Ajinomoto), Sucralose: Sucralose P (Sanei Gen FFI), l-menthol: JP l-Menthol (Toyo Hakka Kogyo), Peppermint oil: Peppermint oil "Yoshida" (Yoshida Pharmaceutical), Blue No. 2: Blue No. 2 aluminum lake (Kisumi Kasei), Magnesium stearate: Magnesium stearate-S (Taihei Kagaku) industry), sodium stearyl fumarate: PRUV (JRS PHARMA).

In this example, HPMC uses at least one selected from the group consisting of TC-5E (Shin-Etsu Chemical Co., Ltd.) and METOLOSE SR90SH-100SR (Shin-Etsu Chemical Co., Ltd.), PVA is Partek SRP80 (Merck), Poval PE-05JPS ( Japan Vinyl Acetate Poval), and Gohsenol EG-03P (Nippon Synthetic Chemical) are used, and crystalline cellulose is Ceorus PH-301 (Asahi Kasei), Ceorus KG-802 (Asahi Kasei) and Ceorus UF-702 ( Asahi Kasei) was used.

(Examples 1 to 20, Comparative Examples 1 to 3)
As Example 1, an orally disintegrating tablet weighing about 90 mg (diameter 6 mm, angle R) was obtained by the following steps.
(1) 0.113 g of amorphous tolvaptan and 0.007 g of light anhydrous silicic acid were mixed and pulverized (mixed pulverization step).
(2) 0.681 g of D-mannitol, 0.007 g of light anhydrous silicic acid, 0.075 g of microcrystalline cellulose, 0.075 g of L-HPC and 0.027 g of HPMC (METOLOSE SR90SH-100SR) were added and mixed, and then HPMC (TC 0.210 mL of purified water in which 0.014 g of 5E) was dissolved was added for granulation (mixing granulation step).
(3) The granules were dried (drying process) and granulated (granule regulating process).
(4) 0.068 g of crospovidone, 0.270 g of D-mannitol and 0.015 g of magnesium stearate were added to the granulated product and mixed, followed by compression molding (tabletting) (tabletting step).

As Examples 2 to 20, according to Example 1, according to the ratios described in Tables 1 and 2, the additives added in the mixing pulverization step, the mixing granulation step, and the tableting step were changed to produce an orally disintegrating tablet. was prepared. However, in Example 20, a solid dispersion of tolvaptan and HPMC (TC-5E) was used. Further, as Comparative Examples 1 to 3, orally disintegrating tablets were prepared in the same manner as in Example 1 based on the ratios shown in Table 3. However, in Comparative Example 2, a solid dispersion of tolvaptan and polyvinylpyrrolidone was used. In Comparative Example 3, a solid dispersion of tolvaptan and copolypidone was used. When preparing the orally disintegrating tablets of Examples 1 to 20 and Comparative Examples 1 to 3, 0.113 to 0.300 g of tolvaptan was used. The numbers shown in Tables 1 to 3 are weight percentages with the weight of the orally disintegrating tablet taken as 100%.

(Examples 21-29, Comparative Examples 4-8)
As Example 21, an orally disintegrating tablet weighing about 180 mg (diameter 8 mm, angle R) was obtained by the following steps.
(1) 22.50 g of amorphous tolvaptan and 1.35 g of light anhydrous silicic acid were mixed and pulverized (mixed pulverization step).
(2) After adding and mixing 141.33 g of D-mannitol, 1.35 g of light silicic anhydride, 15.00 g of microcrystalline cellulose (PH-301), 15.00 g of L-HPC and 2.70 g of HPMC (TC-5E) , and 42 mL of purified water were added to granulate (mixed granulation step).
(3) The granules were dried (drying step) and sized (granule sizing step).
(4) 13.50 g of crospovidone, 39.15 g of D-mannitol, 1.35 g of light anhydrous silicic acid, 0.27 g of blue No. 2, 13.50 g of microcrystalline cellulose (UF-702) and stearyl fumarate in the granules 3.00 g of sodium was added and mixed, and compression molding (tabletting) was carried out (tabletting step).

As Examples 22 to 29, orally disintegrating tablets were prepared by changing the additives added in the mixing pulverization step, the mixing granulation step, and the tableting step according to the ratios shown in Table 4 according to Example 21. did. However, in Example 25, Fujicalin SG (Fuji Chemical Industry Co., Ltd.) was used as anhydrous calcium hydrogen phosphate. Further, as Comparative Examples 4 to 8, orally disintegrating tablets were prepared in the same manner as in Example 21 based on the ratios shown in Table 5. When preparing the orally disintegrating tablets of Examples 21-29 and Comparative Examples 4-8, 22.50-30.00 g of tolvaptan was used.

(Examples 30 to 36, Comparative Example 9)
As Example 30, an orally disintegrating tablet weighing about 180 mg (diameter 8 mm, angle R) was obtained by the following steps.
(1) 355.80 g of D-mannitol, 30.00 g of crystalline cellulose (PH-301), 30.00 g of L-HPC, 30.00 g of corn starch, 5.40 g of aspartame and 5.40 g of HPMC (TC-5E) were mixed. 45.00 g of tolvaptan, 5.40 g of light anhydrous silicic acid, and 0.54 g of blue No. 2 dissolved and dispersed in a solvent, and then 84 mL of purified water in which 1.62 g of PVA (EG-03P) was dissolved, Granulation was performed by adding a solvent in which 0.54 g of l-menthol was dissolved (mixing granulation step).
(2) The granules were dried (drying process) and granulated (granule regulating process).
(3) 16.20 g of crospovidone, 5.40 g of light anhydrous silicic acid and 6.00 g of sodium stearyl fumarate were added to the granulated product and mixed, followed by compression molding (tabletting step).

As Examples 31 to 35, orally disintegrating tablets were prepared by changing the additives added in the mixing pulverization step, the mixing granulation step, and the tableting step according to the ratios shown in Table 6 according to Example 30. did. The solvents used in Examples 30, 31, 32, 33, 34 and 35 were acetone/methanol (7:3), ethanol, methanol and acetone/ethanol (7:3). ), dichloromethane/ethanol (7:3) and dichloromethane/ethanol (7:3) were used. Further, 22.50 to 45.00 g of tolvaptan was used when preparing the orally disintegrating tablets of Examples 30 to 35.

In addition, as Example 36 and Comparative Example 9, orally disintegrating tablets were prepared by changing the additives added in the mixing granulation step and tableting step according to the ratios shown in Table 6 according to Example 30. did. As a solvent for Example 36 and Comparative Example 9, dichloromethane/ethanol (7:3) was used. Moreover, when preparing the orally disintegrating tablets of Example 36 and Comparative Example 9, 45.00 g of tolvaptan was used.

(Examples 37-42)
As Example 37, an orally disintegrating tablet weighing about 180 mg (diameter 8 mm, angle R) was obtained by the following steps. As a solvent, dichloromethane/ethanol (7:3) was used.
(1) 361.20 g of D-mannitol, 30.00 g of microcrystalline cellulose (PH-301), 30.00 g of L-HPC, 30.00 g of corn starch, 2.70 g of light silicic anhydride and 5.40 g of HPMC (TC-5E) After adding a solvent in which 45.00 g of tolvaptan and 5.40 g of light silicic anhydride are dissolved and dispersed, 84 mL of purified water in which 2.70 g of PVA (EG-03P) is dissolved is added, Granulated (mixed granulation process).
(2) The granules were dried (drying process) and granulated (granule regulating process).
(3) 1.62 g of L-HPC, 0.54 g of light anhydrous silicic acid, and 0.60 g of sodium stearyl fumarate were added to 51.24 g of the granulated product and mixed, followed by compression molding (tabletting). process).

As Examples 38 to 42, 51.24 g of the granules obtained in the sizing step of Example 37 were used, and the additives added in the tableting step were changed according to the ratios shown in Table 7. An internally disintegrating tablet was prepared.

(Examples 43-45)
As Example 43, an orally disintegrating tablet weighing about 180 mg (diameter 8 mm, angle R) was obtained by the following steps.
(1) Mix 513.04 g of D-mannitol, 40.00 g of microcrystalline cellulose (UF-702), 40.00 g of corn starch, 3.60 g of light anhydrous silicic acid and 7.20 g of HPMC (TC-5E) to prepare tolvaptan. 60.00 g, 7.20 g of light silicic anhydride, and 0.72 g of Blue No. 2 dissolved and dispersed in a solvent, then 200 mL of purified water and 216 mL of purified water in which 2.16 g of PVA (EG-03P) is dissolved. was added to granulate (mixing granulation step).
(2) The granules were dried (drying process) and granulated (granule regulating process).
(3) 21.60 g of crospovidone, 7.20 g of light silicic anhydride, 7.20 g of sucralose, 0.72 g of l-menthol and 10.80 g of sodium stearyl fumarate are added to the granules and mixed, followed by compression molding ( Tableting) was performed (tabletting step).

As Example 44, an orally disintegrating tablet was prepared according to Example 43 by changing the additives added in the mixing granulation step and tableting step according to the ratios shown in Table 8. Ethanol was used as the solvent in Examples 43-44. Also, 60.00 g of tolvaptan was used when preparing the orally disintegrating tablet of Example 44.

As Example 45, an orally disintegrating tablet weighing about 180 mg (diameter 8 mm, angle R) was obtained by the following steps.
(1) 511.36 g of D-mannitol, 80.00 g of crystalline cellulose (PH-301), 3.60 g of light anhydrous silicic acid and 7.20 g of HPMC (TC-5E) were mixed to obtain 60.00 g of tolvaptan and light anhydrous. After adding a solvent in which 7.20 g of silicic acid is dissolved and dispersed, 200 mL of purified water in which 0.72 g of Blue No. 2 is dissolved and 240 mL of purified water in which 2.40 g of PVA (EG-03P) is dissolved are added. and granulated (mixed granulation step).
(2) The granules were dried (drying process) and granulated (granule regulating process).
(3) 21.60 g of crospovidone, 7.20 g of light silicic anhydride, 7.20 g of sucralose, 0.72 g of l-menthol and 10.80 g of sodium stearyl fumarate are added to the granules and mixed, followed by compression molding ( Tableting) was performed (tabletting step).
Ethanol was used as the solvent in Example 45.

(characteristic test)
In the following characteristic tests, the hardness was measured using a load cell type tablet hardness tester (Okada Seiko PORTABLE CHECKER PC-30), the tablet was broken in the diameter direction at a speed of 0.5 mm / sec, and the maximum breaking force was measured. It was measured. In addition, in the following property tests, unless otherwise specified, disintegration time was measured using water as the test liquid according to the disintegration test method of the 17th revision of the Japanese Pharmacopoeia. , or the time (disintegration time) to become a soft substance that clearly does not retain its original shape even if it is recognized.

(Characteristic test 1)
For the orally disintegrating tablets obtained in Examples 1 to 19 and Comparative Example 1, immediately after compression molding was performed as a reference condition (before storage), and after compression molding was performed, from the reference condition at 40 ° C. and 75% RH. The disintegration time and hardness before and after storage (after storage) and after storage for one week under (open) conditions were measured, respectively. Table 9 shows the results.

As shown in Table 9, all of the orally disintegrating tablets of each example exhibited a disintegration time of 40 seconds or less under standard conditions (before storage), indicating excellent disintegration properties. In addition, the difference in disintegration time between the reference state after storage under humidified conditions and the reference state (before storage) was within 15 seconds in all examples, indicating excellent stability of disintegration time. On the other hand, the orally disintegrating tablet containing neither HPMC nor PVA of Comparative Example 1 was not satisfactory in terms of disintegration and stability of disintegration time.

(Characteristic test 2)
For the orally disintegrating tablets obtained in Examples 21 to 42, Examples 45 and Comparative Examples 4 to 9, immediately after performing compression molding as a reference state (before storage), and after performing compression molding, from the reference state After two weeks of storage at 40° C. and 75% RH (open) (after storage), the disintegration time and hardness before and after storage were measured. Table 10 shows the results.

As shown in Table 10, all of the orally disintegrating tablets of each example exhibited a disintegration time of 40 seconds or less under standard conditions (before storage), indicating excellent disintegration properties. In addition, the difference in disintegration time between the reference state after storage under humidified conditions and the reference state (before storage) was within 15 seconds in all examples, indicating excellent stability of disintegration time. On the other hand, the orally disintegrating tablets of each comparative example were not satisfactory in terms of stability of disintegration time.

(Characteristic test 3)
The orally disintegrating tablets obtained in Example 20 and Comparative Examples 2 and 3 were subjected to compression molding immediately after compression molding as a reference condition (before storage), and after compression molding from the reference condition at 40 ° C. and 75% RH. After storage for 4 weeks under (open) and after storage (after storage), the disintegration times before and after storage were measured, respectively. Table 11 shows the results.

As shown in Table 11, the orally disintegrating tablet of Example 20 exhibited a disintegration time of 40 seconds or less under standard conditions (before storage), demonstrating excellent disintegration properties. In addition, in Example 20, the difference in disintegration time between the standard state after storage under humidified conditions and the standard state (before storage) was within 15 seconds, indicating excellent stability of the disintegration time. On the other hand, the orally disintegrating tablets of Comparative Examples 2 and 3 did not satisfy all of the disintegration time and the stability of the disintegration time.

(Characteristic test 4)
For the orally disintegrating tablets obtained in Examples 43 and 44, immediately after compression molding was performed as a reference condition (before storage), and after compression molding was performed from the reference condition at 40 ° C. and 75% RH (open). The disintegration time and hardness were measured before and after storage (after storage) for 3 days at . Table 12 shows the results. In characteristic test 4, the disintegration time was measured using an orally disintegrating tablet disintegration test device (Tricorp Tester, Okada Seiko), and artificial saliva was added to the orally disintegrating tablet sandwiched between meshes with a load of 40 g at a rate of 6 mL / min. , and measured by dropping a fixed amount under the conditions of a dropping height of 80 mm.

As shown in Table 12, all of the orally disintegrating tablets of each example exhibited a disintegration time of 40 seconds or less under standard conditions (before storage), indicating excellent disintegration properties. In addition, the difference in disintegration time between the reference state after storage under humidified conditions and the reference state (before storage) was within 15 seconds in all examples, indicating excellent stability of disintegration time.

(Characteristic test 5)
For the orally disintegrating tablets selected from the examples, immediately after compression molding as a reference condition (before storage), and after compression molding from the reference condition at 25 ° C., 93% RH (open) 2 The disintegration time and hardness before and after storage and after storage for a week were measured. The results are shown in Table 13.

As shown in Table 13, the orally disintegrating tablet of each example had an excellent disintegration time, with a difference of 15 seconds or less in the disintegration time after storage under humidified conditions from the standard state and in the standard state (before storage). showed stability. In addition, the orally disintegrating tablets of Examples 21 to 26 and Examples 30 to 35 had a hardness difference of 2.5 kgf or less between the standard state and the standard state (before storage) after storage under humidified conditions. , the hardness after storage under humidified conditions was 2.0 kgf or more. On the other hand, in Example 28, the difference in hardness between the standard state and after storage under humidified conditions and the standard state (before storage) was greater than 2.5 kgf, and the hardness after storage under humidified conditions was 2. It was lower than 0 kgf. That is, it was found that if HPMC is contained as the component (b), sufficient hardness can be obtained even after storage under humidified conditions.

(Characteristic test 6)
For the orally disintegrating tablet selected from the examples, 900 ml of water was used as the test liquid, and according to the 17th revision of the Japanese Pharmacopoeia Dissolution Test Method 2, it was stirred at a paddle rotation speed of 50 rpm, and after each time was measured. The dissolution rate was determined by the ratio of the peak areas to the tolvaptan standard solution using the HPLC method. The results are shown in Table 14.

As shown in Table 14, the dissolution properties of the orally disintegrating tablets of Examples were satisfactory. Further, it was found that higher dissolution was obtained in Examples 29, 30, 32-34, 36-42, and 45 containing HPMC and PVA as components (b).

(Characteristic test 7)
The oral absorbability of the tolvaptan solid dispersions used in Example 20 and Comparative Examples 2 and 3 in rats was measured. The solid dispersion of tolvaptan used in this test was obtained by dissolving tolvaptan and one selected from the group consisting of HPMC, polyvinylpolyvidone, and copolypidone in dichloromethane/ethanol (7:3), and using a rotary evaporator. It was produced by distilling off the solvent and pulverizing with a jet mill. Male SD rats were used. Rats were acclimated for at least one week before being used for testing. Solid feed (F-2, Funabashi Farm) was freely given as feed, and tap water was given as drinking water. Eight-week-old animals were used for the study.

0.5 hours, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours and 24 hours after oral administration of the test substance at 10 mg/kg Later, blood was collected from either the left or right jugular vein with a 1 mL syringe treated with sodium heparin and a 25 G venous needle attached. The blood was cooled and centrifuged (4°C, 12000 rpm, 10 min) to obtain rat plasma. Using the obtained plasma as a sample, a plasma concentration-time curve of tolvaptan was created using the HPLC method, and Cmax (ng/mL) and AUC (ng·hr/mL) were calculated. Table 15 shows the results.

As shown in Table 15, rat oral absorption of solid dispersions of tolvaptan and HPMC was superior to other solid dispersions.

Although the present invention has been described above with reference to the embodiments and examples, the present invention is not limited to the above-described embodiments and examples, and various modifications are possible.

INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide an orally disintegrating tablet of tolvaptan that maintains rapid disintegrability and oral disintegrability even under humidified conditions.

Claims (12)

(a) tolvaptan, (b) hydroxypropylmethylcellulose and polyvinyl alcohol , (c) at least one component selected from the group consisting of D-mannitol and lactose, and (d) light anhydrous silicic acid An orally disintegrating tablet characterized by: The disintegration time in the reference state is within 40 seconds, and the difference between the disintegration time in the reference state and the disintegration time after storage for one week under conditions of 40° C. and 75% relative humidity from the reference state is within 15 seconds. The orally disintegrating tablet according to claim 1, characterized in that 3. The orally disintegrating tablet according to claim 1, comprising D-mannitol as the component (c). 4. The orally disintegrating tablet according to any one of claims 1 to 3 , further comprising (e) a disintegrant. 5. The orally disintegrating tablet according to claim 4 , which contains crospovidone as the component (e). The content of each component in 100% by weight of the orally disintegrating tablet is as follows: (a) tolvaptan is 3% by weight or more and 25% by weight or less; (b) the total of components is 0.2% or more and 10% by weight or less; (d) 0.1% to 8% by weight of light silicic anhydride, and (e) 0.5% to 10% by weight of disintegrant. The orally disintegrating tablet according to claim 4 or 5 , characterized by: 7. The composition according to any one of claims 1 to 6 , further comprising (f) at least one component selected from the group consisting of crystalline cellulose, low-substituted hydroxypropylcellulose and corn starch. orally disintegrating tablet. 8. The orally disintegrating tablet according to claim 7 , wherein the total content of component (f) in 100% by weight of the orally disintegrating tablet is 5% by weight or more and 25% by weight or less. 9. The orally disintegrating tablet according to any one of claims 1 to 8 , comprising a solid dispersion of tolvaptan and hydroxypropylmethylcellulose. 10. The orally disintegrating oral disintegrant according to claim 9 , comprising a solid dispersion of tolvaptan and hydroxypropylmethylcellulose in a weight ratio of 1:1 to 5:1 in the solid dispersion of tolvaptan and hydroxypropylmethylcellulose. lock. A method for producing an orally disintegrating tablet for producing the orally disintegrating tablet according to any one of claims 1 to 10 ,
a mixing granulation step of granulating a mixture containing at least tolvaptan as a component;
and a tableting step of compressing and molding the granulated product after the mixed granulation step. 12. The method for producing an orally disintegrating tablet according to claim 11 , wherein in the tableting step, the granulated material is mixed with at least light silicic anhydride and compression-molded.