JP7590950B2 - Orally disintegrating tablets containing bilastine - Google Patents

Description

The present invention relates to an orally disintegrating tablet having high tablet hardness, rapid disintegration and good storage stability, and a method for producing the same.

As a compound showing excellent antihistamine activity, 2-[4-(2-{4-[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]piperidin-1-yl}ethyl
[phenyl]-2-methylpropanoic acid (hereinafter also referred to as "bilastine" or "compound 1" in this specification) has been reported (Patent Documents 1 and 2).

In modern aging society, as the number of elderly people who have to take many medicines daily due to various diseases increases, the number of patients who have difficulty "taking medicine" due to the decline in swallowing function associated with aging is also increasing. This situation is one of the factors that lead to a decline in medication adherence. For such patients with decreased swallowing function, granules such as granules and fine granules, or orally disintegrating tablets that disintegrate quickly in the mouth with a small amount of water or saliva are preferred over tablets and capsules. Orally disintegrating tablets are desired to have both rapid disintegration and high hardness. In addition, they are required to maintain a moderate hardness and sufficient disintegration that can withstand practical use even under high humidity conditions. Therefore, the manufacturing process of orally disintegrating tablets can be complicated. Various methods have been developed to overcome these problems.

For example, Patent Document 3 shows that by mixing a disintegrating particle composition with a medicament active substance and compressing the mixture, an orally disintegrating tablet having high disintegrability and reduced cracking to a practical level can be easily obtained. When mixing a disintegrating particle composition with a medicament active substance and compressing the mixture as in Patent Document 3, the disintegrability and hardness of the orally disintegrating tablet obtained are thought to vary depending on the amount of the medicament active substance, but no consideration has been given to the optimal amount. In addition, although orally disintegrating tablets are generally likely to have a reduced hardness or delayed disintegration under high humidity conditions, no mention has been made of their storage stability.

Patent Document 4 discloses an orally disintegrating tablet comprising a medicinal ingredient-containing composition selected from the group consisting of medicinal ingredient-containing powders and medicinal ingredient-containing granules, rapidly disintegrating granules, and a lubricant.
It has been shown that by incorporating rapidly disintegrating granules, an orally disintegrating tablet having rapid disintegration properties and high hardness can be obtained. However, even in Patent Document 4, there is no mention of storage stability under high humidity conditions.

In view of the above, there is still room for improvement in order to obtain, by a simple method, an orally disintegrating tablet that has rapid disintegrability and high hardness, and that retains appropriate hardness and sufficient disintegrability for practical use even under high humidity conditions.

As for the dosage form of Compound 1 or a salt thereof, in addition to tablets, other dosage forms have been reported (
(Patent Documents 5 and 6) However, no preparation having the rapid disintegrability and high hardness of the composition disclosed in this specification has been reported.

Japanese Patent Application Publication No. 10-059961 Special Publication No. 2005-529120 JP 2017-226600 A International Publication No. WO2017/217494 No. CN104398481 No. CN104398512

The object of the present invention is to develop a food product that has rapid disintegration properties in the oral cavity, is not damaged during distribution, and
The present invention provides an orally disintegrating tablet of Compound 1 or a salt thereof, which has a suitable hardness for practical use even under high humidity conditions and does not cause a delay in disintegration time, and a method for producing the same.

As a result of intensive research aimed at solving the above problems, the present inventors have found that by combining bilastine (compound 1); an additive (a granule composed of D-mannitol, low-substituted hydroxypropyl cellulose, and polyvinyl alcohol (completely saponified)); and crospovidone, an orally disintegrating tablet containing bilastine that has high tablet hardness, rapid disintegration, and good storage stability can be obtained, despite being produced by a simple method.

That is, the present invention relates to the following [1] to [18].
[1] (1) 2-[4-(2-{4-[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]piperidin-1-yl}ethyl)phenyl]-2-methylpropanoic acid or a salt thereof,
(2) A granule consisting of D-mannitol, low-substituted hydroxypropyl cellulose and polyvinyl alcohol (completely saponified), and (3) an orally disintegrating tablet containing a disintegrant.
[2] The orally disintegrating tablet according to [1], wherein the disintegrant is crospovidone.
[3] The total amount of the orally disintegrating tablet is 100.0% by mass,
(1) The orally disintegrating tablet according to [1] or [2], containing 5.0 to 23.0% by mass of 2-[4-(2-{4-[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]piperidin-1-yl}ethyl)phenyl]-2-methylpropanoic acid or a salt thereof.
[4] The total amount of the orally disintegrating tablet is 100.0% by mass,
(3) The orally disintegrating tablet according to [2] or [3], containing 1.0 to 10.0% by mass of crospovidone.
[5] The total amount of the orally disintegrating tablet is 100.0% by mass,
(3) The orally disintegrating tablet according to any one of [2] to [4], containing 1.0 to 5.0% by mass of crospovidone.
[6] The total amount of the orally disintegrating tablet is 100.0% by mass,
(3) The orally disintegrating tablet according to any one of [2] to [5], containing 3.0% by mass of crospovidone.
[7] The total amount of the orally disintegrating tablet is 100.0% by mass,
(2) A composition comprising 90.0 to 95.0% by mass of D-mannitol, 5.0 to 7.0% by mass of low-substituted hydroxypropyl cellulose, and 0.10 to 0.5% by mass of polyvinyl alcohol (completely saponified).
The orally disintegrating tablet according to any one of [1] to [6], comprising 72.0 to 88.0% by mass of granulated material having a molecular weight of 0.30% by mass.
[8] The total amount of the orally disintegrating tablet is 100.0% by mass,
(2) 64.0 to 84.0% by mass of D-mannitol, 3.0 to 6.2% by mass of low-substituted hydroxypropyl cellulose, and 0.07 to 0.05% by mass of polyvinyl alcohol (completely saponified).
The orally disintegrating tablet according to any one of [1] to [7], containing 30% by mass of glycerin.
[9] The orally disintegrating tablet according to any one of [1] to [8], having a tablet hardness of 60 N or more.
[10] The orally disintegrating tablet according to any one of [1] to [9], which has a disintegration time of 30 seconds or less.
[11] The orally disintegrating tablet according to any one of [1] to [10], which has a disintegration time of 25 seconds or less.

[12] (1) 2-[4-(2-{4-[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]piperidin-1-yl}ethyl)phenyl]-2-methylpropanoic acid or a salt thereof,
(2) A method for producing an orally disintegrating tablet containing a granule consisting of D-mannitol, low-substituted hydroxypropyl cellulose, and polyvinyl alcohol (completely saponified), and (3) crospovidone, the method comprising the steps of mixing the components (1) to (3) and compressing the mixture into tablets.
[12-1] A method for producing an orally disintegrating tablet, comprising the steps of:
A step of mixing the following components (1) to (3):
(1) 2-[4-(2-{4-[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]piperidin-1-yl}ethyl)phenyl]-2-methylpropanoic acid or a salt thereof,
(2) a granule consisting of D-mannitol, low-substituted hydroxypropylcellulose and polyvinyl alcohol (completely saponified), and (3) crospovidone; and the above method comprising the steps of compressing the resulting mixture into tablets.

[13] (1) 2-[4-(2-{4-[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]piperidin-1-yl}ethyl)phenyl]-2-methylpropanoic acid or a salt thereof,
(2) A granule comprising D-mannitol, low-substituted hydroxypropyl cellulose, and polyvinyl alcohol (completely saponified), and (3) a pharmaceutical composition which is an orally disintegrating tablet comprising crospovidone.
[14] The pharmaceutical composition according to [13] for treating an allergic disease or its symptoms.
[15] The orally disintegrating tablet according to any one of [1] to [11] for use as a pharmaceutical.
[16] The orally disintegrating tablet according to any one of [1] to [11] for use in treating an allergic disease or a symptom thereof.
[17] A method for treating a subject, comprising orally administering to the subject the orally disintegrating tablet according to any one of [1] to [11].
[18] A method for treating an allergic disease or a symptom thereof in a subject, comprising orally administering to the subject the orally disintegrating tablet according to any one of [1] to [11].

The present invention provides an orally disintegrating tablet of bilastine and a method for producing the same. The orally disintegrating tablet of the present invention has rapid disintegration and high hardness, and maintains a suitable hardness and sufficient disintegrability for practical use even under high humidity conditions, and therefore has good storage stability. In addition, the orally disintegrating tablet of the present invention can be easily produced by a conventional pharmaceutical process without requiring a special production device.

1 is a graph showing the results of measuring the hardness (N) of tablets prepared in Examples 2 to 6 and Comparative Example 4 immediately after tableting (initial) and after leaving the tablets unpackaged under 40°C and 75% relative humidity conditions for 1 day (40°C/75%RH (open) 1 day). FIG. 1 is a graph showing the results of measuring the disintegration time of tablets prepared in Examples 2 to 6 and Comparative Example 4 immediately after tableting (initial) and after leaving the tablets unpackaged under 40° C. and 75% relative humidity conditions for 1 day (40° C./75% RH (open) 1 day). 1 is a photograph showing the appearance of tablets produced in Examples 2 to 6 and Comparative Example 4 after being left unpackaged under conditions of 40° C. and 75% relative humidity for 1 day (40° C./75% RH (open) 1 day). 1 is a graph showing the results of measuring the hardness (N) of tablets produced in Examples 7 to 9 immediately after tableting (initial) and after leaving them unpackaged under 40°C and 75% relative humidity conditions for 1 day (40°C/75%RH (open) 1 day). FIG. 1 is a graph showing the results of measuring the disintegration time of tablets prepared in Examples 7 to 9 immediately after tableting (initial) and after leaving them unpackaged under 40° C. and 75% relative humidity conditions for 1 day (40° C./75% RH (open) 1 day).

This application claims priority to Japanese Patent Application No. 2020-209788, filed on December 18, 2020, the entire contents of which are incorporated herein by reference.
The orally disintegrating tablet and its manufacturing method according to the present invention will be described below. However, the orally disintegrating tablet and its manufacturing method according to the present invention should not be construed as being limited to the description of the following embodiments and examples.

In the present invention, the orally disintegrating tablet means a tablet that can be taken by disintegrating in the oral cavity without water or with a small amount of water. Preferably, the tablet can be taken by disintegrating in the oral cavity only with saliva in the oral cavity without ingesting water. The dosage form of the orally disintegrating tablet is not particularly limited, but may be plain tablet, chewable tablet, film-coated tablet, etc. The shape is also not particularly limited, and may be disk-shaped, doughnut-shaped, spherical, elliptical, etc.

In the present invention, the active ingredient of the orally disintegrating tablet is 2-[4-(2-{4-[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]piperidin-1-yl}ethyl)phenyl]-2-methylpropanoic acid ("Compound 1" or "bilastine") or a salt thereof, which is represented by the following structural formula (I):

Compound 1 or a salt thereof is a known compound, and is described, for example, in Patent Document 1 (JP-A-10-05535).
The compound can be synthesized according to the method described in the Japanese Patent Application Laid-Open No. 9961.

Compound 1 or a salt thereof may be a solvate (for example, a hydrate) or a non-solvate, and in the present invention, either form is encompassed by "Compound 1 or a salt thereof."

In the present invention, a salt of compound 1 means a pharma- ceutically acceptable salt.

Pharmaceutically acceptable salts refer to salts that possess the desired pharmacological activity of a compound and that are prepared from pharma- ceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids.

Pharmaceutically acceptable salts of Compound 1 include, but are not limited to, addition salts with inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as acetic acid, citric acid, tartaric acid, and maleic acid, salts with alkali metals such as potassium and sodium, salts with alkaline earth metals such as calcium and magnesium, and salts with organic bases such as ammonium salts, ethylamine salts, and arginine salts.

The orally disintegrating tablet containing compound 1 or a salt thereof in the present invention comprises compound 1 or a salt thereof,
Contains D-mannitol, low-substituted hydroxypropyl cellulose, polyvinyl alcohol (fully saponified) and a disintegrant.

In a preferred embodiment of the present invention, the orally disintegrating tablet containing Compound 1 or a salt thereof is
The pharmaceutical composition contains Compound 1 or a salt thereof; a granule made of D-mannitol, low-substituted hydroxypropyl cellulose and polyvinyl alcohol (completely saponified); and crospovidone.

In the present invention, the content of Compound 1 in an orally disintegrating tablet containing Compound 1 or a salt thereof is 1 to 90 mg/tablet, preferably 3 to 60 mg/tablet, more preferably 9 to 50 mg/tablet.
, for example, 10 mg/tablet, 20 mg/tablet or 40 mg/tablet.

The content of Compound 1 or a salt thereof used in the present invention is preferably 1.0 to 50.0% by mass, more preferably 2.0 to 30.0% by mass, even more preferably 5.0 to 23.0% by mass, still more preferably 6.0 to 22.0% by mass, and most preferably 10.0 to 12.0% by mass, based on 100.0% by mass of the total amount of the orally disintegrating tablet, in terms of dissolution property, stability, absorbability, and manufacturability.

The orally disintegrating tablet containing Compound 1 or a salt thereof of the present invention contains, as additives, D-mannitol, low-substituted hydroxypropylcellulose, granulated polyvinyl alcohol, and a disintegrant. The orally disintegrating tablet according to the present invention may contain various additives in addition to the above. Examples of the additives include excipients, disintegrants, binders, colorants, flavoring agents, flavoring agents, sweeteners, lubricants, flow agents, coating agents, etc.

In the present invention, the excipient is preferably water-soluble or water-compatible in consideration of the mouthfeel, etc. For example, sugar alcohols such as mannitol, erythritol, sorbitol, and xylitol, trehalose, cyclodextrin, corn starch, sucrose, crystalline cellulose, anhydrous calcium hydrogen phosphate, calcium carbonate, etc. can be used alone or in appropriate combination. In the present invention, sugar alcohols are preferred, mannitol is more preferred, and D-mannitol is particularly preferred.

The content of D-mannitol is 10% by weight of the orally disintegrating tablet containing Compound 1 or a salt thereof.
As 0.0 mass%, 64.0 to 84.0 mass% is preferable, and 64.8 to 83.6 mass% is preferable.
More preferably, 68.0 to 81.0% by mass, and more preferably, 68.4 to 80.8% by mass.
is more preferable, and 74.7 to 78.9 mass % is particularly preferable.

In the present invention, the disintegrant may be selected from, for example, low-substituted hydroxypropyl cellulose, crospovidone, carmellose calcium, carmellose sodium, croscarmellose sodium, carmellose, various starches, etc. These disintegrants may be used alone or in combination of two or more. In the present invention, low-substituted hydroxypropyl cellulose and crospovidone are preferred.

The content of low-substituted hydroxypropyl cellulose is preferably 3.0 to 6.2% by mass, and more preferably 3.6 to 6.2% by mass, based on 100.0% by mass of the total amount of the orally disintegrating tablet containing Compound 1 or a salt thereof.
6.2% by mass is more preferable, 3.8 to 6.0% by mass is more preferable, and 4.2 to 5.8% by mass is particularly preferable.

The content of crospovidone was determined by dividing the total amount of the orally disintegrating tablet containing Compound 1 or a salt thereof by 100.
As 0.0 mass%, 1.0 to 10.0 mass% is preferable, 1.0 to 5.0 mass% is more preferable, 1.0 to 4.0 mass% is even more preferable, 1.0 to 3.0 mass% is still more preferable, and 3.0 mass% is particularly preferable.

In the present invention, examples of the binder include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, and polyvinyl alcohol (completely saponified).
, macrogol, and the compounds listed above as excipients. These binders can be used alone or in appropriate combination. In the present invention, polyvinyl alcohol (completely saponified) is preferred.

In the present invention, the polyvinyl alcohol may be either polyvinyl alcohol or polyvinyl alcohol (completely saponified), but is preferably polyvinyl alcohol (completely saponified).

The content of polyvinyl alcohol (completely saponified product) is preferably 0.07 to 0.30% by mass, and more preferably 0.05 to 0.50% by mass, based on 100.0% by mass of the total amount of the orally disintegrating tablet containing Compound 1 or a salt thereof.
More preferably, the content is 0.07 to 0.26 mass%, and even more preferably, the content is 0.08 to 0.26 mass%, and 0.07 to 0.26 mass% is more preferably, the content is 0.07 to 0.26 mass% is further ...
A content of 0.08 to 0.25 mass% is particularly preferred.

In the present invention, the lubricant may be selected from, for example, magnesium stearate, stearic acid, calcium stearate, light anhydrous silicic acid, sodium stearyl fumarate, talc, hydrogenated vegetable oil, microcrystalline wax, sucrose fatty acid ester, polyethylene glycol, etc. These lubricants may be used alone or in appropriate combination. In the present invention, magnesium stearate is preferred.

The content of magnesium stearate is preferably 0.5 to 1.5% by mass, particularly preferably 1.0% by mass, relative to 100.0% by mass of the total amount of the orally disintegrating tablet containing Compound 1 or a salt thereof.

In the orally disintegrating tablet containing Compound 1 or a salt thereof of the present invention, the flavoring agent can be selected from, for example, aspartame, saccharin, sodium saccharin, dipotassium glycyrrhizinate, stevia, thaumatin, sucralose, acesulfame K, 1-menthol, camphor, mint, etc. These flavoring agents can be used alone or in appropriate combination. In the present invention, aspartame and sucralose are preferred, and aspartame is more preferred.

The content of the flavoring agent is preferably 0.1 to 5.0% by mass, more preferably 1.0 to 5.0% by mass, based on 100.0% by mass of the total amount of the orally disintegrating tablet containing Compound 1 or a salt thereof.
0 mass% is even more preferable.

In the present invention, examples of the fluidizing agent include silicon dioxide, sodium silicate, talc, magnesium stearate, and the like.

In the present invention, examples of the coloring agent include food yellow No. 5, food blue No. 2, food lake color, ferric oxide, yellow ferric oxide, and titanium oxide.

In the present invention, examples of the coating agent include hydroxypropyl methylcellulose (hypromellose, TC-5, METOLOSE (registered trademark), etc.) and polyethylene glycol (PEG 400, PEG 1500, PEG 4000, PEG 6000, macrogol 400, macrogol 1500, macrogol 4000, macrogol 6000, etc.).

The orally disintegrating tablet of the present invention is made of orange,
Various flavorings such as lemon, lime, etc. can be used as flavoring agents.

In a preferred embodiment, the orally disintegrating tablet contains 64.0 to 84.0% by mass of D-mannitol and 3.0 to 84.0% by mass of low-substituted hydroxypropyl cellulose, with the total amount being 100.0% by mass.
0 to 6.2% by mass, polyvinyl alcohol (completely saponified) 0.07 to 0.30% by mass
Contains.

In the present invention, other additives may also be used, such as sweeteners, flavorings, antistatic agents, surfactants, wetting agents, fillers, extenders, adsorbents, moisture-proofing agents, antioxidants, preservatives (e.g., antiseptics), and buffers.

In preparing the orally disintegrating tablet of the present invention, a premix of excipients, disintegrants, binders, etc. may be used. For example, SmartEx (registered trademark)
D-mannitol, low-substituted hydroxypropyl cellulose, polyvinyl alcohol (
In the present invention, when an additive in which a filler, a disintegrant, and a binder are mixed in advance is used, the amount of the additive should be appropriately adjusted in consideration of the composition and physical properties of the additive. In order to adjust the moldability and disintegrability of the orally disintegrating tablet, a binder and a disintegrant can be further added.

The granules consisting of D-mannitol, low-substituted hydroxypropyl cellulose, and polyvinyl alcohol (completely saponified) contain 90.0 to 95.0% by mass of D-mannitol,
The additive contains 5.0 to 7.0% by mass of low-substituted hydroxypropyl cellulose and 0.10 to 0.30% by mass of polyvinyl alcohol (completely saponified).
x (registered trademark), SmartEx (registered trademark) QD-50 and QD-100
is commercially available.

The content of the granules consisting of D-mannitol, low-substituted hydroxypropyl cellulose and polyvinyl alcohol (completely saponified) is more preferably 70.0 to 90.0% by mass, and more preferably 72.0 to 90.0% by mass, based on the total amount of the orally disintegrating tablet containing Compound 1 or a salt thereof being 100.0% by mass.
Up to 88.0% by mass is more preferable, 76.0 to 85.0% by mass is even more preferable, and 83.
0% by weight is particularly preferred.

These additives can be used without any particular limitation as long as their quality is guaranteed for pharmaceutical formulations. These additives may be used alone or in combination. For details of these additives, see, for example, Pharmaceutical Excipients Standards 20.
This can be confirmed by 18.

The orally disintegrating tablet of the present invention can be manufactured by a known manufacturing method for a preparation. For example, a method of mixing the components and then compressing the components, a method of mixing the components, granulating the components, and then compressing the components, a method of granulating some of the components, mixing them with other components, and then compressing the components, and the like can be used. For example, the granulation method can be a fluidized bed granulation method, an agitation granulation method, a rolling fluidized bed granulation method, an extrusion granulation method, or the like.
Granulated materials can be produced using spray drying granulation and dry granulation. The granulated materials obtained after granulation may be dried. Tableting is carried out using a known tablet press, adjusting the hardness so that the resulting tablets have an appropriate hardness and can be rapidly disintegrated as orally disintegrating tablets. As the tablet press, for example, a rotary tablet press, a single punch tablet press, a hydraulic press, etc. can be appropriately selected and used. The tableting pressure depends on the tableting method, the tablet press used, the size and thickness of the tablets,
The dosage is adjusted appropriately depending on the type of active ingredient, etc.

Therefore, the method for producing an orally disintegrating tablet according to the present invention includes a step of mixing the above-mentioned ingredients for the orally disintegrating tablet and a step of compressing the mixture into tablets. The method for producing an orally disintegrating tablet according to the present invention may further include a step of granulating a part or all of the ingredients, a step of coating the tablets, etc.

The stability in the present invention includes both the physical stability of the formulation and the chemical stability of the active ingredient, Compound 1 or its salt. The improvement of stability can be judged by comparing the state of the formulation before and after storage under the same conditions, and by comparing the chemical purity of Compound 1 or its salt by high performance liquid chromatography or the like. Considering the storage and distribution of pharmaceuticals, the improvement of stability is always a very important issue for orally disintegrating tablets or pharmaceutical compositions.

The hardness in the present invention is a standard known in the field of tablets, and refers to a value measured by the method described in the following test example, for example. Specifically, the hardness refers to the load (N) at which the tablet breaks when a tablet is clamped laterally with a tablet hardness tester (e.g., PC-30, manufactured by Okada Seiko Co., Ltd.) and gradually pressurized.

From the viewpoint of practicality in production, transportation and clinical use, the tablet hardness must be high to a certain degree. The tablet hardness of the orally disintegrating tablet of the present invention is preferably about 60 N or more.
More preferably, it is about 70 N or more, and further preferably, it is 80 N or more. The upper limit of the hardness is not particularly limited, but is generally 200 N or less.

The disintegration time in the present invention is the time measured by the disintegration test method specified in the Japanese Pharmacopoeia, for example, the time measured by the method described in the following Test Example 2. In the present invention, the disintegration time was measured using a disintegration tester (NT-4H, NT-4H(P), manufactured by Toyama Sangyo Co., Ltd.).

In the orally disintegrating tablet of the present invention, the disintegration time is preferably 30 seconds or less, more preferably 25 seconds or less.

The oral disintegration time in the present invention is the time taken to measure the disintegration of a tablet that has been disintegrated to simulate the disintegration behavior in the oral cavity, and refers to the time measured, for example, by the method described in the following Test Example 1. In the present invention, the measurement was performed using an oral disintegrating tablet tester (ODT-101, manufactured by Toyama Sangyo Co., Ltd.).

In the orally disintegrating tablet of the present invention, the oral disintegration time is preferably 30 seconds or less, more preferably 25 seconds or less.

The orally disintegrating tablet of the present invention preferably has both a certain level of tablet hardness and a rapid oral disintegration time, for example, a tablet hardness of about 60 N or more and an oral disintegration time of 30 seconds or less.

The tablet friability is a standard known in the tablet field, and was tested according to the Tablet Friability Test Method of the Japanese Pharmacopoeia.

Compound 1 or a salt thereof is manufactured and sold in various countries around the world as a therapeutic agent for allergic diseases. Therefore, the orally disintegrating tablet according to the present invention can be used as a pharmaceutical composition, for example, as a pharmaceutical composition for treating allergic diseases or their symptoms. More specifically, the orally disintegrating tablet according to the present invention can be used as a pharmaceutical composition for treating allergic rhinitis (hay fever), urticaria, skin diseases (
It can be used as a therapeutic agent for itching associated with eczema, dermatitis, and cutaneous pruritus.

When used as a pharmaceutical composition for the treatment of a subject, the orally disintegrating tablet according to the present invention is orally administered to the subject. The dosage varies depending on the age, weight, condition, etc. of the subject, the purpose of the treatment (e.g., treatment or prevention of a disease or symptom), etc., and can be appropriately determined by a person skilled in the art. For example, 10 to 40 mg, preferably 20 mg, is administered per day in terms of the amount of Compound 1.

The present invention will now be described in detail with reference to examples, but the present invention is not limited to these examples.

[Example 1: Production of tablet A]
Bilastine (manufactured by SAI LIFE SCIENCES LIMITED) 2 g; granules consisting of D-mannitol, low-substituted hydroxypropylcellulose and polyvinyl alcohol (completely saponified) (SmartEx (registered trademark) QD-50; manufactured by Shin-Etsu Chemical Co., Ltd.) 12.75 g (D-mannitol 90.0-95.0%, low-substituted hydroxypropylcellulose 5.0-7.0%, polyvinyl alcohol (completely saponified) 0.1-0.
The mixture was thoroughly mixed with 0.1 g of flavoring agent and 0.15 g of magnesium stearate (vegetable-based, manufactured by Taihei Chemical Industry Co., Ltd.), and compressed into tablets with a weight of 150 mg per tablet and 20 mg of bilastine using a hydraulic press (manufactured by Riken Seiki Co., Ltd.) at a compression force of 500 kgf to form tablets with a diameter of 8 mm and a weight of 1.5 kg.
Tablet A having a mass of 150 mg was obtained.

[Comparative Example 1: Production of tablet a]
Bilastine (manufactured by SAI LIFE SCIENCES LIMITED) 2 g; a mixture of D-mannitol, carmellose, crystalline cellulose and crospovidone (Grandfiller D (registered trademark): manufactured by Daicel Corporation) 12.75 g (D-mannitol was adjusted to 53.0 to 53.0 g)
59.0%, carmellose 15.0-25.0%, and crystalline cellulose 17.0-23.
0.0%, containing crospovidone 3.4-4.6%, 0.1 g of flavoring agent, and 0.15 g of magnesium stearate (vegetable-based, manufactured by Taihei Chemical Industry Co., Ltd.) were thoroughly mixed, and the tablets were compressed at a compression force of 5 using a hydraulic press (manufactured by Riken Seiki Co., Ltd.) with a mass of 150 mg per tablet and 20 mg of bilastine.
The mixture was compressed at 00 kgf to obtain tablet a having a diameter of 8 mm and a mass of 150 mg.

[Comparative Example 2: Production of tablet b]
Bilastine (manufactured by SAI LIFE SCIENCES LIMITED) 2 g; granules consisting of D-mannitol and corn starch (PEARLITOL (registered trademark)
Flash; manufactured by ROQUETTE) 12.75 g (D-mannitol 78.0 to 82
0.0%, corn starch 15.0-19.0%, 0.1 g of flavoring agent, and 0.15 g of magnesium stearate (vegetable-based, manufactured by Taihei Chemical Industry Co., Ltd.) were thoroughly mixed and mixed to obtain a 1
The tablets each weighed 150 mg and contained 20 mg of bilastine. They were compressed at a compression force of 500 kgf using a hydraulic press (manufactured by Riken Seiki Co., Ltd.) to obtain tablet b having a diameter of 8 mm and a mass of 150 mg.

[Comparative Example 3: Production of tablet c]
Bilastine (manufactured by SAI LIFE SCIENCES LIMITED) 2 g; a mixture of D-mannitol, xylitol, crystalline cellulose, crospovidone and magnesium aluminometasilicate (F-MELT (registered trademark); manufactured by Fuji Chemical Industry Co., Ltd.) 12.75 g (D
- Mannitol 62.3-67.2%, xylitol 4.2-5.8%, crystalline cellulose 13.5-16.5%, crospovidone 6.8-9.2%, magnesium aluminometasilicate 5.9-8.0%, flavoring agent 0.1 g, magnesium stearate (vegetable, manufactured by Taihei Chemical Industry Co., Ltd.) 0.15 g are thoroughly mixed to form a tablet of mass 150
20 mg of bilastine was compressed at 500 kPa using a hydraulic press (manufactured by Riken Seiki Co., Ltd.).
The mixture was compressed at 1000 gf to obtain tablet C having a diameter of 8 mm and a mass of 150 mg.

[Test Example 1: Measurement of tablet hardness and disintegration time]
The tablets produced in Example 1 and Comparative Examples 1 to 3 were subjected to a tablet hardness test using a tablet hardness tester (PC-30,
The hardness in the diameter direction was measured using a tablet disintegrating tester (manufactured by Okada Seiko Co., Ltd.), and the hardness (N) was calculated from the average value of three tablets. The disintegration time was measured using an orally disintegrating tablet tester (ODT-101, manufactured by Toyama Sangyo Co., Ltd.) under the following conditions: test liquid: water (37.0±1° C.), weight of weight: 10 g, and rotation speed: 20 rpm, from the time when the weight came into contact with the tablet until the tablet completely disintegrated. The results are shown in Table 1. In Table 1, the numerical values of the components are in mass %.

As is clear from the results in Table 1, it was confirmed that the tablet of Example 1 had both high hardness and rapid disintegration property.

[Example 2: Production of tablet B]
Bilastine (manufactured by SAI LIFE SCIENCES LIMITED) 40g; D-
Granules consisting of mannitol, low-substituted hydroxypropyl cellulose, and polyvinyl alcohol (completely saponified) (SmartEx (registered trademark) QD-50; containing 90.0 to 95.0% D-mannitol, 5.0 to 7.0% low-substituted hydroxypropyl cellulose, and 0.1 to 0.3% polyvinyl alcohol (completely saponified), manufactured by Shin-Etsu Chemical Co., Ltd.)
304.8 g of crospovidone (Kollidon (registered trademark) CL-SF, manufactured by BASF) 3.6 g, aspartame (manufactured by Ajinomoto Co., Inc.) 8 g, and magnesium stearate (vegetable-based, manufactured by Taihei Chemical Industry Co., Ltd.) 3.6 g were thoroughly mixed to obtain a tablet having a mass of 180 mg per tablet.
Bilastine 20mg, Crospovidone 1.8mg, rotary tablet press "12TU-AW
(Kikusui Seisakusho Co., Ltd.) was used to compress the tablet at a compression force of 930 kgf, resulting in a diameter of 8 mm and a mass of 1
Tablet B weighing 80 mg was obtained.

[Example 3: Production of tablet C]
Bilastine (manufactured by SAI LIFE SCIENCES LIMITED) 40g; D-
Granules consisting of mannitol, low-substituted hydroxypropyl cellulose, and polyvinyl alcohol (completely saponified) (SmartEx (registered trademark) QD-50; containing 90.0 to 95.0% D-mannitol, 5.0 to 7.0% low-substituted hydroxypropyl cellulose, and 0.1 to 0.3% polyvinyl alcohol (completely saponified), manufactured by Shin-Etsu Chemical Co., Ltd.)
297.6 g, crospovidone (Kollidon (registered trademark) CL-SF, manufactured by BASF) 10.8 g, aspartame (manufactured by Ajinomoto Co., Inc.) 8 g, magnesium stearate (
(vegetable, manufactured by Taihei Chemical Industry Co., Ltd.) 3.6 g was thoroughly mixed to give a tablet with a mass of 180 mg.
, bilastine 20 mg, crospovidone 5.4 mg, and a rotary tablet press "12TU-A
The tablets were compressed using a compression press (manufactured by Kikusui Seisakusho Co., Ltd.) at a compression force of 920 kgf to obtain tablet C having a diameter of 8 mm and a mass of 180 mg.

[Example 4: Production of tablet D]
Bilastine (manufactured by SAI LIFE SCIENCES LIMITED) 40g; D-
Granules consisting of mannitol, low-substituted hydroxypropyl cellulose, and polyvinyl alcohol (completely saponified) (SmartEx (registered trademark) QD-50; containing 90.0 to 95.0% D-mannitol, 5.0 to 7.0% low-substituted hydroxypropyl cellulose, and 0.1 to 0.3% polyvinyl alcohol (completely saponified), manufactured by Shin-Etsu Chemical Co., Ltd.)
294 g, Crospovidone (Kollidon® CL-SF, manufactured by BASF) 1
The mixture was thoroughly mixed with 4.4 g of crospovidone, 8 g of aspartame (manufactured by Ajinomoto Co., Inc.), and 3.6 g of magnesium stearate (vegetable-based, manufactured by Taihei Chemical Industry Co., Ltd.), and the mixture was pressed into a rotary tablet press "12TU-AW" with a mass of 180 mg per tablet, 20 mg of bilastine, and 7.2 mg of crospovidone.
(manufactured by Kikusui Seisakusho Co., Ltd.) was used to compress the tablets at a compression force of 910 kgf to obtain tablets with a diameter of 8 mm and a mass of 18
Tablet D weighing 0 mg was obtained.

[Example 5: Production of tablet E]
Bilastine (manufactured by SAI LIFE SCIENCES LIMITED) 40g; D-
Granules consisting of mannitol, low-substituted hydroxypropyl cellulose, and polyvinyl alcohol (completely saponified) (SmartEx (registered trademark) QD-50; containing 90.0 to 95.0% D-mannitol, 5.0 to 7.0% low-substituted hydroxypropyl cellulose, and 0.1 to 0.3% polyvinyl alcohol (completely saponified), manufactured by Shin-Etsu Chemical Co., Ltd.)
290.42 g, Crospovidone (Kollidon® CL-SF, BASF
The mixture was thoroughly mixed to obtain a tablet having a mass of 180 mg each.
Bilastine 20 mg and crospovidone 9 mg were used in a rotary tablet press "12TU-AW" (
The tablet was compressed with a compression force of 900 kgf using a machine manufactured by Kikusui Seisakusho Co., Ltd., and the diameter was 8 mm and the mass was 180 g.
Tablet E weighing 100 mg was obtained.

[Example 6: Production of tablet F]
Bilastine (manufactured by SAI LIFE SCIENCES LIMITED) 40g; D-
Granules consisting of mannitol, low-substituted hydroxypropyl cellulose, and polyvinyl alcohol (completely saponified) (SmartEx (registered trademark) QD-50; containing 90.0 to 95.0% D-mannitol, 5.0 to 7.0% low-substituted hydroxypropyl cellulose, and 0.1 to 0.3% polyvinyl alcohol (completely saponified), manufactured by Shin-Etsu Chemical Co., Ltd.)
272.43 g, Crospovidone (Kollidon® CL-SF, BASF
The mixture was thoroughly mixed to obtain a tablet having a mass of 180 mg each.
Bilastine 20mg, Crospovidone 18mg, rotary tablet press "12TU-AW"
(manufactured by Kikusui Seisakusho Co., Ltd.) was used to compress the tablets at a compression force of 820 kgf to obtain tablets with a diameter of 8 mm and a mass of 18
Tablet F weighing 0 mg was obtained.

[Comparative Example 4: Production of Tablet X]
Bilastine (manufactured by SAI LIFE SCIENCES LIMITED) 40g; D-
A granule consisting of mannitol, low-substituted hydroxypropyl cellulose, and polyvinyl alcohol (completely saponified) (SmartEx (registered trademark) QD-50; manufactured by Shin-Etsu Chemical Co., Ltd.) (308.4 g), aspartame (manufactured by Ajinomoto Co., Inc.) (8 g), and magnesium stearate (vegetable-based, manufactured by Taihei Chemical Industry Co., Ltd.) (3.6 g) were thoroughly mixed and a weight of 1 tablet was obtained.
The mixture was compressed with a rotary tablet press "12TU-AW" (manufactured by Kikusui Seisakusho Co., Ltd.) at a compression force of 970 kgf to produce tablet X having a diameter of 8 mm and a mass of 180 mg.
obtained.

The amounts of ingredients in Examples 2 to 6 and Comparative Example 4 are summarized in Table 2. The values in Table 2 are in mass %.

[Test Example 2: Measurement of tablet hardness and disintegration time]
The tablets produced in Examples 2 to 6 and Comparative Example 4 were subjected to a tablet hardness test using a tablet hardness tester (PC-30,
The hardness in the diameter direction was measured using a disintegration tester (manufactured by Okada Seiko Co., Ltd.), and the hardness (N) was calculated from the average value of five tablets. The disintegration time was measured using a disintegration tester (NT-4H, NT-4H(P), manufactured by Toyama Sangyo Co., Ltd.) under the conditions of test liquid: water (37±2°C) and no disk, and the time from when the tablet was put into the tester until it completely disintegrated. The hardness and disintegration time were measured immediately after tableting (Initial
), and after leaving it unpackaged under 40°C and 75% relative humidity for 1 day (40°C/75%RH
The results are shown in Figures 1 and 2, respectively.

[Test Example 3]
The tablets produced in Examples 2 to 6 and Comparative Example 4 were left unpackaged under conditions of 40°C and 75% relative humidity for 1 day (40°C/75% RH (open) 1 day), and then their appearances were observed. The results are shown in Figure 3.

[Test Example 4: Measurement of the amount of related substances]
The tablets produced in Examples 2 to 6 and Comparative Example 4 were subjected to room temperature or severe conditions (40°C/7
After storage at 5% RH (open) for one month, the amount of related substances formed was measured by the liquid chromatography method listed in the physical testing method of the Japanese Pharmacopoeia. The results are shown in Table 3.

[Test Example 5: Measurement of wear degree]
The tablets produced in Example 6 were subjected to severe conditions (40°C/75% RH (open)).
After storage at 4° C. for 1 day, the tablet friability was measured according to the tablet friability test method prescribed in the Japanese Pharmacopoeia.

As is clear from the results of Figures 1 and 2, when the amount of crospovidone was in the range of 1 to 10% by mass, the preparation had both high hardness and rapid disintegration properties, and when humidified (40°C/75% RH (
It was confirmed that the tablet maintained sufficient hardness and rapid disintegration even after 1 day of storage.
The friability of the tablet containing 10% by mass of crospovidone (Tablet F) upon moisture absorption was 0.20%. Furthermore, as is clear from the results of Fig. 3 and Table 3, no change in properties or significant increase in the amount of related substances due to moisture absorption was observed, confirming that the tablet has good storage stability.

[Example 7: Production of tablet H]
Bilastine (manufactured by SAI LIFE SCIENCES LIMITED) 20g, D-
Mannitol/low-substituted hydroxypropyl cellulose/polyvinyl alcohol (completely saponified) granules (SmartEx (registered trademark) QD-50, manufactured by Shin-Etsu Chemical Co., Ltd.) 3
17.6 g, Crospovidone (Kollidon® CL-SF, manufactured by BASF)
10.8 g of glycerin, 8 g of aspartame (manufactured by Ajinomoto Co., Inc.), and 3.6 g of magnesium stearate (vegetable-based, manufactured by Taihei Chemical Industry Co., Ltd.) were thoroughly mixed to give a tablet having a mass of 180 mg.
Bilastine 10mg, rotary tablet press "12TU-AW" (manufactured by Kikusui Seisakusho Co., Ltd.)
The mixture was compressed using a compression force of 850 kgf to obtain tablet H having a diameter of 8 mm and a mass of 180 mg.

[Example 8: Preparation of tablet I]
Bilastine (manufactured by SAI LIFE SCIENCES LIMITED) 40g, D-
Mannitol/low-substituted hydroxypropyl cellulose/polyvinyl alcohol (fully saponified) granules (SmartEx (registered trademark) QD-50, manufactured by Shin-Etsu Chemical Co., Ltd.) 2
97.6 g, Crospovidone (Kollidon® CL-SF, manufactured by BASF)
10.8 g of glycerin, 8 g of aspartame (manufactured by Ajinomoto Co., Inc.), and 3.6 g of magnesium stearate (vegetable-based, manufactured by Taihei Chemical Industry Co., Ltd.) were thoroughly mixed to give a tablet having a mass of 180 mg.
Bilastine 20mg, rotary tablet press "12TU-AW" (manufactured by Kikusui Seisakusho Co., Ltd.)
The mixture was compressed using a compression force of 920 kgf to obtain tablet I having a diameter of 8 mm and a mass of 180 mg.

[Example 9: Production of tablet J]
Bilastine (manufactured by SAI LIFE SCIENCES LIMITED) 80g, D-
Mannitol/low-substituted hydroxypropyl cellulose/polyvinyl alcohol (fully saponified) granules (SmartEx (registered trademark) QD-50, manufactured by Shin-Etsu Chemical Co., Ltd.) 2
57.6 g, Crospovidone (Kollidon® CL-SF, manufactured by BASF)
10.8 g of glycerin, 8 g of aspartame (manufactured by Ajinomoto Co., Inc.), and 3.6 g of magnesium stearate (vegetable-based, manufactured by Taihei Chemical Industry Co., Ltd.) were thoroughly mixed to give a tablet having a mass of 180 mg.
Bilastine 40mg, rotary tablet press "12TU-AW" (manufactured by Kikusui Seisakusho Co., Ltd.)
The mixture was compressed using a compression force of 880 kgf to obtain tablet J having a diameter of 8 mm and a mass of 180 mg.

The amounts of ingredients in Examples 7 to 9 are summarized in Table 4. The values in Table 4 are in mass percent.

The hardness and disintegration time of the tablets were measured according to Test Example 2. The results are shown in Figures 4 and 5, respectively.

The amount of related substances was measured according to Test Example 4. The results are shown in Table 5.

As is clear from the results of Figures 4 and 5, the amount of the drug substance (bilastine) blended was 6 to 22% by mass.
Within this range, the formulation has both high hardness and rapid disintegration, and when humidified (40°C/75% RH)
It was confirmed that the tablet (open for 1 day) also maintained sufficient hardness and rapid disintegration. In addition, as is clear from the results in Table 5, no significant increase in the amount of related substances due to moisture absorption was observed, and it was confirmed that the tablet had good storage stability.

Claims (13)

(1) 2-[4-(2-{4-[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]piperidin-1-yl}ethyl)phenyl]-2-methylpropanoic acid or a salt thereof,
(2) a granule consisting of D-mannitol, low-substituted hydroxypropyl cellulose and polyvinyl alcohol (completely saponified), and (3) crospovidone
An orally disintegrating tablet comprising: The total amount of the orally disintegrating tablet is 100.0% by mass.
(1) The orally disintegrating tablet according to claim 1 , containing 5.0 to 23.0% by mass of 2-[4-(2-{4-[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]piperidin-1-yl}ethyl)phenyl]-2-methylpropanoic acid or a salt thereof. The total amount of the orally disintegrating tablet is 100.0% by mass.
(3) The orally disintegrating tablet according to claim 1 or 2 , containing 1.0 to 10.0% by mass of crospovidone. The total amount of the orally disintegrating tablet is 100.0% by mass.
(3) The orally disintegrating tablet according to any one of claims 1 to 3 , containing 1.0 to 5.0% by mass of crospovidone. The total amount of the orally disintegrating tablet is 100.0% by mass.
(3) The orally disintegrating tablet according to any one of claims 1 to 4 , containing 3.0% by mass of crospovidone. The total amount of the orally disintegrating tablet is 100.0% by mass.
(2) The orally disintegrating tablet according to any one of claims 1 to 5, comprising 72.0 to 88.0% by mass of a granule containing 90.0 to 95.0% by mass of D-mannitol, 5.0 to 7.0% by mass of low-substituted hydroxypropyl cellulose, and 0.10 to 0.30 % by mass of polyvinyl alcohol (completely saponified). The total amount of the orally disintegrating tablet is 100.0% by mass.
(2) The orally disintegrating tablet according to any one of claims 1 to 6 , comprising 64.0 to 84.0% by mass of D-mannitol, 3.0 to 6.2% by mass of low-substituted hydroxypropyl cellulose, and 0.07 to 0.30% by mass of polyvinyl alcohol (completely saponified). The orally disintegrating tablet according to any one of claims 1 to 7 , having a tablet hardness of 60 N or more. The orally disintegrating tablet according to any one of claims 1 to 8 , which has a disintegration time of 30 seconds or less. The orally disintegrating tablet according to any one of claims 1 to 9 , which has a disintegration time of 25 seconds or less. (1) 2-[4-(2-{4-[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]piperidin-1-yl}ethyl)phenyl]-2-methylpropanoic acid or a salt thereof,
(2) A method for producing an orally disintegrating tablet containing a granule consisting of D-mannitol, low-substituted hydroxypropyl cellulose, and polyvinyl alcohol (completely saponified), and (3) crospovidone, the method comprising the steps of mixing the components (1) to (3) and compressing the mixture into tablets. (1) 2-[4-(2-{4-[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]piperidin-1-yl}ethyl)phenyl]-2-methylpropanoic acid or a salt thereof,
(2) A granule comprising D-mannitol, low-substituted hydroxypropyl cellulose, and polyvinyl alcohol (completely saponified), and (3) a pharmaceutical composition which is an orally disintegrating tablet comprising crospovidone. 13. A pharmaceutical composition according to claim 12 for the treatment of an allergic disease or its symptoms.