Tablets and methods for manufacturing the same

Abstract

The object of the present invention is to suppress the formation of related substances and improve the disintegration properties of tablets containing bilastine; more preferably, to provide a simple method for manufacturing such tablets. [Solution] The present invention provides a tablet comprising bilastine (A), polyvinyl alcohol powder (B), crospovidone (C), and a silicate compound (D), wherein the mass content ratio of crospovidone (C) to bilastine (A) is 10 to 80%. Preferably, the tablet of the present invention is a direct-compression tablet manufactured by a direct-compression method.

Description

Technical Field

[0001] The present invention relates to tablets, more specifically, tablets containing bilastine and a method for producing the same.

Background Art

[0002] Bilastine is known as an active ingredient of a therapeutic agent for allergic diseases and is a compound having the following structure. Ordinary tablets or orally disintegrating tablets containing bilastine are clinically used under the brand name "Bilanoa". Bilanoa is used for the treatment of allergic rhinitis, urticaria, itching associated with skin diseases, etc.

Chemical formula

[0003] Patent Document 1 discloses an orally disintegrating tablet containing bilastine; the orally disintegrating tablet contains bilastine, a granulated product composed of D-mannitol, low-substituted hydroxypropyl cellulose, and a complete saponification product of polyvinyl alcohol, and a disintegrant. Patent Document 2 discloses an orally disintegrating tablet containing bilastine anhydride; it is stated that the particle size of bilastine anhydride is adjusted to control its elution property. Patent Document 3 discloses an orally disintegrating tablet containing bilastine and hydroxypropyl cellulose, and it is stated that the elution delay is suppressed. Patent Document 4 discloses an orally disintegrating tablet containing bilastine and sodium stearyl fumarate, and it is stated that the elution delay is suppressed and tablet pressing failure in production is prevented. Patent Document 5 discloses a tablet containing bilastine and magnesium aluminometasilicate, and it is stated that bilastine is stabilized.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Patent Document 2

[0005] Although several proposals have been made for tablets containing bilastine, there is still a need to improve the physical properties of these tablets and suppress the formation of bilastine-related substances. Therefore, the present invention aims to suppress the formation of related substances and improve the disintegration properties of bilastine-containing tablets. Furthermore, preferably, the present invention aims to manufacture such bilastine-containing tablets simply, preferably by a direct compression method. [Means for solving the problem]

[0006] The present invention relates to the following tablets. <1> A tablet comprising bilastine (A), polyvinyl alcohol powder (B), crospovidone (C), and a silicate compound (D), wherein the mass content ratio of crospovidone (C) to bilastine (A) (C / A) is 10-80%.

[0007] Preferably, the present invention relates to the tablets shown below. <2> Polyvinyl alcohol powder (B) is subject to the following conditions (i) and (ii): (i) 95% or more by mass of the polyvinyl alcohol powder (B) is a powder that passes through a 100-mesh sieve. (ii) The maximum particle size of a single particle of polyvinyl alcohol powder (B) is less than 150 μm. Satisfying at least one of the above <1> The tablets described above. <3> The aforementioned tablet is an orally disintegrating tablet. <1> or <2> The tablets described above. <4> The mass content ratio of polyvinyl alcohol powder (B) to the aforementioned tablets is 0.05 to 0.5%. <1> ~ <3> A tablet as described in any of the following. <5> The mass content ratio of crospovidone (C) in the aforementioned tablets is 2-8%. <1> ~ <4> A tablet as described in any of the following. <6> The polyvinyl alcohol powder (B) is a powder of at least one of the partially saponified and intermediate saponified products of polyvinyl alcohol, as described above. <1> ~ <5> A tablet as described in any of the following. <7> The silicic acid compound (D) is at least one of light anhydrous silicic acid and magnesium aluminometasilicate, <1> ~ <6> A tablet as described in any of the following. <8> The mass content ratio of silicate compound (D) to the aforementioned tablets is 0.2 to 1%. <1> ~ <7> A tablet as described in any of the following. <9> The above is a direct-compression tablet. <1> ~ <8> A tablet as described in any of the following.

[0008] Furthermore, the present invention relates to a method for producing tablets as described below. <10> A method for producing tablets containing bilastine (A), The process includes a mixing step of mixing bilastine (A), polyvinyl alcohol powder (B), crospovidone (C), and silicate compound (D) in powder form. A method for manufacturing tablets in which the mass content ratio (C / A) of crospovidone (C) to bilastine (A) is 10-80%.

[0009] Preferably, the present invention relates to a method for producing tablets as shown below. <11> Polyvinyl alcohol powder (B) is subject to the following conditions (i) and (ii): (i) 95% or more by mass of the polyvinyl alcohol powder (B) is a powder that passes through a 100-mesh sieve. (ii) The maximum particle size of individual polyvinyl alcohol particles is less than 150 μm. Satisfying at least one of the following conditions, <10> The manufacturing method described above. <12>The tablet is an orally disintegrating tablet, the production method according to <10> or <11>. <13>The mass content ratio of the polyvinyl alcohol powder (B) with respect to the tablet is 0.05 to 0.5%, the production method according to any one of <10> to <12>. <14>The mass content ratio of the crospovidone (C) with respect to the tablet is 2 to 8%, the production method according to any one of <10> to <13>. <15>The polyvinyl alcohol powder (B) is at least one powder of a partially saponified product and an intermediate saponified product of polyvinyl alcohol, the production method according to any one of <10> to <14>. <16>The silicic acid compound (D) is at least one of light anhydrous silicic acid and magnesium aluminometasilicate, the production method according to any one of <10> to <15>. <17>The mass content ratio of the silicic acid compound (D) with respect to the tablet is 0.2 to 1%, the production method according to any one of <10> to <16>. <18>Furthermore, it includes a compression molding step, The compression molding step is to table the mixture obtained in the mixing step, the production method according to any one of <10> to <17>.

Advantages of the Invention

[0010] The present invention can be used as a pharmaceutical preparation containing viralastin, the production of analogs of viralastin is suppressed, and due to its high disintegrability, it can also be used as an orally disintegrating tablet.

Modes for Carrying Out the Invention

[0011] Hereinafter, the tablet and its production method according to the present invention will be described. However, the tablet and its production method of the present invention are not construed as being limited to the descriptions of the following embodiments and examples. Hereinafter, the tablet of the present invention and the tablet obtained by the production method of the present invention are also collectively referred to as "the tablet of the present invention".

[0012] 1. Regarding the composition, properties, etc. of the tablet The tablets of the present invention contain bilastine (A), polyvinyl alcohol powder (B), crospovidone (C), and a silicate compound (D), and may further contain any other additives.

[0013] 1-1. Bilastine (A) Bilastine is a compound represented by the following structural formula. The powder of bilastine may be a white powder, is almost insoluble in water or ethanol, and is sparingly soluble in methanol.

Chemical formula

[0014] The bilastine contained in the tablets of the present invention may be in a crystalline form or an amorphous form, but is preferably in a crystalline form. Polymorph 1, polymorph 2, polymorph 3, etc. (see Japanese Patent No. 5142448) are known as the crystalline forms of bilastine, and the bilastine contained in the tablets of the present invention may be any of them, but is preferably polymorph 1.

[0015] The particle size of bilastine contained in the tablets of the present invention may be appropriately set so that the dissolution profile of bilastine from the tablets is as desired. As a guideline, the volume-based D50 of bilastine is preferably 30 μm or more and 100 μm or less; the volume-based D90 is preferably 70 μm or more and 250 μm or less.

[0016] The content ratio of bilastine in the tablets of the present invention is preferably 3% by mass or more, more preferably 5% by mass or more, and still more preferably 9% by mass or more; on the other hand, it is preferably 35% by mass or less, more preferably 25% by mass or less, and still more preferably 20% by mass or less. Also, the content of bilastine in the tablets can be 20 mg per tablet.

[0017] 1-2. Polyvinyl alcohol powder (B) The polyvinyl alcohol contained in the tablets of the present invention is preferably included in powder form. Generally, polyvinyl alcohol contained in pharmaceutical solid dosage forms is often dissolved in water or the like during the manufacturing process of the formulation, but the polyvinyl alcohol in the tablets of the present invention is included in powder form. For example, as described later, the tablets of the present invention can be manufactured by direct tableting. The polyvinyl alcohol powder can act as a binder in the tablets of the present invention, but its purpose of inclusion is not particularly limited.

[0018] The degree of saponification of the polyvinyl alcohol powder contained in the tablets is not particularly limited. In other words, the polyvinyl alcohol may be fully saponified or partially saponified (including intermediate saponified). Fully saponified polyvinyl alcohol means polyvinyl alcohol with a degree of saponification of 97 mol% or more, while partially saponified polyvinyl alcohol preferably has a degree of saponification of 69 mol% or more and less than 97 mol%, and more preferably 78 to 96 mol%. However, the polyvinyl alcohol contained in the tablets may be preferably partially saponified in order to prevent tableting problems (such as sticking) during the tableting process in its manufacture.

[0019] The particle size of individual polyvinyl alcohol powder particles contained in the tablets is preferably less than 300 μm, more preferably less than 180 μm, even more preferably less than 150 μm, and even more preferably less than 106 μm. The maximum particle size can be determined by measuring the longest diameter of the powder particles by optical microscope observation. Furthermore, it is preferable that 95% by mass or more (preferably 99% by mass or more) of the individual polyvinyl alcohol powder particles contained in the tablets can pass through a sieve with a mesh size of 83 (83 mesh), more preferably through a sieve with a mesh size of 100, and even more preferably through a sieve with a mesh size of 140. The measurement of particle size by sieving may be performed in accordance with JIS Z 8815. "Mesh" refers to the number of sieve openings per inch. By keeping the particle size of the polyvinyl alcohol powder below a certain level, the tablets of the present invention can be manufactured by direct tableting, simplifying the manufacturing process.

[0020] The polyvinyl alcohol content in the tablets is preferably 0.05% by mass or more, more preferably 0.1% by mass or more; on the other hand, it is preferably 0.5% by mass or less, and more preferably 0.2% by mass or less. Polyvinyl alcohol can impart appropriate tablet hardness to the tablets.

[0021] 1-3. Crospovidone (C) The crospovidone contained in the tablets of the present invention is not particularly limited in its purpose, but it can act as a disintegrant in the tablets.

[0022] The crospovidone content in the tablets is usually 10% by mass or more, preferably 20% by mass or more, more preferably 30% by mass or more, and even more preferably 40% by mass or more, relative to the bilastine content; on the other hand, it is usually 80% by mass or less, preferably 70% by mass or less, more preferably 60% by mass or less, and even more preferably 50% by mass or less. Furthermore, the crospovidone content in the tablets is preferably 1% by mass or more, more preferably 2% by mass or more, and even more preferably 3% by mass or more, relative to the weight of the tablet; on the other hand, it is preferably 9% by mass or less, more preferably 8% by mass or less, and even more preferably 6% by mass or less.

[0023] When the crospovidone content is above a certain level, the disintegration properties of the tablet improve, making it easier to ensure disintegration as an orally disintegrating tablet. On the other hand, when the crospovidone content is below a certain level, the stability of bilastine in the tablet improves, making it easier to suppress the formation of bilastine-related substances, for example.

[0024] Crospovidone can enhance the disintegration properties of the tablets of the present invention compared to other components known as disintegrants. For example, compared to disintegrants such as sodium starch glycolate or starch (such as corn starch), crospovidone may enhance the disintegration properties of the tablets of the present invention.

[0025] 1-4. Silicate compounds (D) The silicic acid compound contained in the tablets of the present invention is not particularly limited in its purpose of inclusion, but it can act as a lubricant or fluidizer in the tablets to prevent tableting problems during the tableting process in tablet manufacturing.

[0026] Examples of silicic acid compounds include light anhydrous silicic acid, magnesium aluminometasilicate, anhydrous silicic acid, calcium silicate, magnesium silicate, and fine silicon dioxide; however, light anhydrous silicic acid or magnesium aluminometasilicate is preferred; and light anhydrous silicic acid is even more preferred.

[0027] The content of the silicate compound in the tablet is preferably 0.2% by mass or more, more preferably 0.3% by mass or more; on the other hand, it is preferably 3% by mass or less, more preferably 2% by mass or less, and even more preferably 1% by mass or less.

[0028] 1-5. Other Additives The tablets of the present invention may contain bilastine (A), polyvinyl alcohol powder (B), crospovidone (C), and a silicate compound (D), along with any other additives. Examples of other additives include excipients, disintegrants, lubricants, binders, and sweeteners.

[0029] Excipients are not particularly limited as long as they are pharmaceutically acceptable; examples include one or more selected from the group consisting of D-mannitol, crystalline cellulose, trehalose, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, D-sorbitol, lactose monohydrate, anhydrous lactose, sucrose, corn starch, pregelatinized starch, partially pregelatinized starch, and low-substituted hydroxypropyl cellulose.

[0030] The disintegrants are not particularly limited as long as they are pharmaceutically acceptable; examples include one or more additives selected from the group consisting of crospovidone, corn starch, potato starch, sodium starch glycolate, carmellose, carmellose calcium, carmellose sodium, low-substituted hydroxypropyl cellulose, hydroxypropyl starch, croscarmellose, croscarmellose sodium, pregelatinized starch, and partially pregelatinized starch.

[0031] The lubricant is not particularly limited as long as it is pharmaceutically acceptable; examples include one or more additives selected from the group consisting of magnesium stearate, sodium stearate, calcium stearate, stearic acid, palmitic acid, talc, sodium stearyl fumarate, sucrose fatty acid esters, and glycerin fatty acid esters. In one embodiment, it is magnesium stearate and / or sodium stearyl fumarate.

[0032] The binder is not particularly limited as long as it is pharmaceutically acceptable; however, it may include hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone, polyvinyl alcohol (not in powder form; e.g., granules, granules with other components, solutions, etc.), polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, gum arabic, xanthan gum, hydroxyethylcellulose, polyethylene glycol, pregelatinized starch, etc.

[0033] Examples of sweeteners include aspartame, sucralose, sodium saccharin, acesulfame potassium, dipotassium glycyrrhizin, stevia, and thaumatin.

[0034] The tablets of the present invention may be ordinary tablets, orally disintegrating tablets, sustained-release tablets, chewable tablets, etc., but are preferably ordinary tablets or orally disintegrating tablets, and more preferably orally disintegrating tablets. The total weight of the tablets of the present invention is preferably in the range of 100 mg to 300 mg, and more preferably in the range of 125 to 200 mg.

[0035] The tablets of the present invention have sufficient tablet hardness. Sufficient tablet hardness is preferably 5.0 kp or higher, more preferably 5.5 kp or higher, and even more preferably 6.0 kp or higher. Furthermore, the tablets of the present invention retain sufficient tablet hardness even after storage. For example, they retain sufficient tablet hardness even after a 4-week accelerated drug test (40°C, 75% relative humidity). Tablet hardness can be measured by applying pressure along the diameter of the tablet using a Schleuniger tablet hardness tester.

[0036] The tablets of the present invention have good disintegration properties. Good disintegration properties refer to a tablet disintegration time of preferably 40 seconds or less, more preferably 30 seconds or less, and even more preferably 25 seconds or less, as measured by the disintegration test method listed in the Japanese Pharmacopoeia General Test Methods Formulation Test Method (test solution: water (37±2℃), without auxiliary disc). Furthermore, the tablets of the present invention maintain good disintegration properties even after storage. For example, they maintain good disintegration properties even after a 4-week accelerated drug testing period (40℃, relative humidity 75%).

[0037] The tablets of the present invention have a suppressed content of bilastine analogs. For example, the tablets of the present invention have a suppressed content of the N-oxide form, which is one of the bilastine analogs. The content of bilastine analogs can be measured by liquid chromatography as described in the General Test Methods of the Japanese Pharmacopoeia; it can be expressed as the ratio of the peak area of ​​the analog to the peak area of ​​bilastine. For example, the peak with a relative retention time of approximately 0.5 relative to bilastine is the peak of the N-oxide form of bilastine, and the content of the N-oxide form in the tablets of the present invention is preferably 0.050% or less, more preferably 0.040% or less, and even more preferably 0.035% or less relative to bilastine after a 4-week accelerated drug test (40°C, 75% relative humidity).

[0038] 2. Regarding the manufacture of tablets The tablets of the present invention can be obtained, for example, by the manufacturing method of the present invention. The manufacturing method of the present invention involves mixing bilastine (A), polyvinyl alcohol powder (B), crospovidone (C), and a silicate compound (D) in powder form, and then compressing the resulting mixture into tablets (i.e., compression molding). In other words, the tablets of the present invention are preferably tablets obtained by a so-called direct compression method (direct compression tablets). More specifically, the tablets of the present invention can be obtained by mixing bilastine (A), polyvinyl alcohol powder (B), crospovidone (C), and a silicate compound (D) in powder form, further adding and mixing an optional additive (such as a lubricant), and then compressing the resulting mixture into tablets. The means of mixing are not particularly limited, and mixing methods such as diffusion mixing, convection mixing, and shear mixing can be employed.

[0039] Furthermore, the tablets of the present invention may be coated tablets obtained by compressing tablets into uncoated tablets and then forming a coating film on them.

[0040] In the manufacturing method of the present invention described above, each component (for example, "bilastine (A)", "polyvinyl alcohol powder (B)", "crospovidone (C)", "silicic acid compound (D)", etc.) is described in "1. Composition and properties of the tablets, etc.".

[0041] The tablet manufacturing method of the present invention can produce tablets with sufficient hardness and good disintegration properties, similar to the tablets of the present invention described above. Furthermore, the tablet manufacturing method of the present invention can suppress the content of bilastine-related substances.

[0042] 3. Regarding the use of tablets, etc. The tablets of the present invention can be used as a pharmaceutical product administered to humans (preferably adults). For example, the target humans may be patients suffering from allergic rhinitis, urticaria, or itching associated with skin diseases (eczema, dermatitis, pruritus). The dosage of the tablets of the present invention for humans may be 20 mg of bilastine once daily. Therefore, it is preferable that the tablets of the present invention contain 20 mg of bilastine per tablet.

[0043] The tablets of the present invention are packaged and stored in any packaging form. Examples of packaging forms include bulk packaging, PTP packaging, and blister packaging, but PTP packaging is preferred. Packaged tablets of the present invention can be stored at room temperature and preferably have a shelf life of 3 years. [Examples]

[0044] The present invention will be described more specifically below with reference to examples, but the technical scope of the present invention is not limited by the description of the examples.

[0045] A. Ingredients used in the manufacture of the tablets The ingredients used in the manufacture of the tablets in the examples and comparative examples are shown below. [Table 1]

[0046] Component (A), bilastine, had a crystalline form of polymorph I (see Japanese Patent No. 5142448), with a median diameter D50 in the range of 30 to 100 μm.

[0047] The polyvinyl alcohol of component (B) was pulverized as needed to obtain a powder in which 99% by mass could pass through a 100-mesh sieve, and this powder was used in each example and comparative example.

[0048] B. Manufacturing of tablets The tablets for each example and comparative example were manufactured as follows.

[0049] [Example 1] 40g of bilastine, 268.2g of D-mannitol, 18g of low-substituted hydroxypropylcellulose, 0.6g of polyvinyl alcohol (partially hydrolyzed), 18g of crospovidone, 8g of aspartame, and 1.8g of light anhydrous silicic acid were mixed in a diffusion mixer, and then 5.4g of magnesium stearate was added and dispersed in a diffusion mixer. The resulting dispersion was compressed into tablets using a rotary tablet press to obtain the tablets of Example 1, with each tablet weighing 180mg, having a tablet thickness of 2.9mm, and a diameter of 8mm.

[0050] [Example 2] 40g of bilastine, 268.2g of D-mannitol, 18g of low-substituted hydroxypropylcellulose, 0.6g of polyvinyl alcohol (fully saponified), 18g of crospovidone, 8g of aspartame, and 1.8g of light anhydrous silicic acid were mixed in a diffusion mixer, and then 5.4g of magnesium stearate was added and dispersed in a diffusion mixer. The resulting dispersion was compressed into tablets with a weight of 180mg per tablet, a tablet thickness of 2.9mm, and a diameter of 8mm using a rotary tablet press to obtain the tablets of Example 2.

[0051] [Example 3] 40g of bilastine, 268.2g of D-mannitol, 18g of low-substituted hydroxypropylcellulose, 0.6g of polyvinyl alcohol (intermediate saponified product), 18g of crospovidone, 8g of aspartame, and 1.8g of light anhydrous silicic acid were mixed in a diffusion mixer, and then 5.4g of magnesium stearate was added and dispersed in a diffusion mixer. The resulting dispersion was compressed into tablets using a rotary tablet press to obtain the tablets of Example 3, with each tablet weighing 180mg, having a tablet thickness of 2.9mm, and a diameter of 8mm.

[0052] [Example 4] 40g of bilastine, 266.4g of D-mannitol, 18g of low-substituted hydroxypropylcellulose, 0.6g of polyvinyl alcohol (partially hydrolyzed), 18g of crospovidone, 8g of aspartame, and 3.6g of light anhydrous silicic acid were mixed in a diffusion mixer, and then 5.4g of magnesium stearate was added and dispersed in a diffusion mixer. The resulting dispersion was compressed into tablets using a rotary tablet press to obtain the tablets of Example 4, with each tablet weighing 180mg, having a tablet thickness of 2.9mm, and a diameter of 8mm.

[0053] [Example 5] 40 g of bilastine, 274.2 g of D-mannitol, 18 g of low-substituted hydroxypropyl cellulose, 0.6 g of polyvinyl alcohol (partially hydrolyzed), 12 g of crospovidone, 8 g of aspartame, and 1.8 g of light anhydrous silicic acid were mixed in a diffusion mixer, and then 5.4 g of magnesium stearate was added and dispersed in a diffusion mixer. The resulting dispersion was compressed into tablets with a weight of 180 mg per tablet, a tablet thickness of 2.9 mm, and a diameter of 8 mm using a rotary tablet press to obtain the tablets of Example 5.

[0054] [Example 6] 40g of bilastine, 262.2g of D-mannitol, 18g of low-substituted hydroxypropylcellulose, 0.6g of polyvinyl alcohol (partially hydrolyzed), 24g of crospovidone, 8g of aspartame, and 1.8g of light anhydrous silicic acid were mixed in a diffusion mixer, and then 5.4g of magnesium stearate was added and dispersed in a diffusion mixer. The resulting dispersion was compressed into tablets with a weight of 180mg per tablet, a tablet thickness of 2.9mm, and a diameter of 8mm using a rotary tablet press to obtain the tablets of Example 6.

[0055] [Example 7] 40 g of bilastine, 268.2 g of D-mannitol, 18 g of low-substituted hydroxypropyl cellulose, 0.6 g of polyvinyl alcohol (partially hydrolyzed), 18 g of crospovidone, 8 g of aspartame, and 1.8 g of magnesium aluminometasilicate were mixed in a diffusion mixer, and then 5.4 g of magnesium stearate was added and dispersed in a diffusion mixer. The resulting dispersion was compressed into tablets using a rotary tablet press to obtain the tablets of Example 7, with each tablet weighing 180 mg, having a tablet thickness of 2.9 mm, and a diameter of 8 mm.

[0056] [Comparative Example 1] 40 g of bilastine, 270 g of D-mannitol, 18 g of low-substituted hydroxypropyl cellulose, 0.6 g of polyvinyl alcohol (partially hydrolyzed), 18 g of crospovidone, and 8 g of aspartame were mixed in a diffusion mixer, and then 5.4 g of magnesium stearate was added and dispersed in a diffusion mixer. The resulting dispersion was compressed into tablets with a weight of 180 mg per tablet, a tablet thickness of 2.9 mm, and a diameter of 8 mm using a rotary tablet press to obtain the tablets of Comparative Example 1.

[0057] [Comparative Example 2] 40g of bilastine, 284.4g of D-mannitol, 18g of low-substituted hydroxypropylcellulose, 0.6g of polyvinyl alcohol (partially hydrolyzed), 1.8g of crospovidone, 8g of aspartame, and 1.8g of light anhydrous silicic acid were mixed in a diffusion mixer, and then 5.4g of magnesium stearate was added and dispersed in a diffusion mixer. The resulting tablets were compressed using a rotary tablet press to obtain tablets of Comparative Example 2, with each tablet weighing 180mg, having a thickness of 2.9mm, and a diameter of 8mm.

[0058] [Comparative Example 3] 40g of bilastine, 250.2g of D-mannitol, 18g of low-substituted hydroxypropylcellulose, 0.6g of polyvinyl alcohol (partially hydrolyzed), 36g of crospovidone, 8g of aspartame, and 1.8g of light anhydrous silicic acid were mixed in a diffusion mixer, and then 5.4g of magnesium stearate was added and dispersed in a diffusion mixer. The resulting dispersion was compressed into tablets with a weight of 180mg per tablet, a tablet thickness of 2.9mm, and a diameter of 8mm using a rotary tablet press to obtain the tablets of Comparative Example 3.

[0059] [Comparative Example 4] 40 g of bilastine, 268.2 g of D-mannitol, 18 g of low-substituted hydroxypropyl cellulose, 0.6 g of polyvinyl alcohol (partially saponified), 18 g of sodium starch glycolate, 8 g of aspartame, and 1.8 g of light anhydrous silicic acid were mixed in a diffusion mixer, and then 5.4 g of magnesium stearate was added and dispersed in a diffusion mixer. The resulting dispersion was compressed into tablets with a weight of 180 mg per tablet, a tablet thickness of 2.9 mm, and a diameter of 8 mm using a rotary tablet press to obtain the tablets of Comparative Example 4.

[0060] [Comparative Example 5] 40g of bilastine, 268.2g of D-mannitol, 18g of low-substituted hydroxypropylcellulose, 0.6g of polyvinyl alcohol (partially hydrolyzed), 18g of corn starch, 8g of aspartame, and 1.8g of light anhydrous silicic acid were mixed in a diffusion mixer, and then 5.4g of magnesium stearate was added and dispersed in a diffusion mixer. The resulting dispersion was compressed into tablets with a weight of 180mg per tablet, a tablet thickness of 2.9mm, and a diameter of 8mm using a rotary tablet press to obtain the tablets of Comparative Example 5.

[0061] C. Storage of Tablets The tablets obtained in each example and comparative example were heat-sealed using a PTP packaging machine with polypropylene film and aluminum foil, and the sealed products were cut to form PTP packages. The resulting PTP packages were stored for 1 week, 2 weeks, and 4 weeks under conditions of 40°C / 75% relative humidity.

[0062] D. Evaluation of tablets D-1. Measurement of tablet hardness The tablets obtained in each example and comparative example were measured for diametrically using a Schleuniger tablet hardness tester immediately after compression (Initial), after 1 week of storage, after 2 weeks of storage, and after 4 weeks of storage. The tablet hardness (kp) was determined from the average value of 10 tablets.

[0063] D-2. Measurement of tablet disintegration time For each example and comparative example, the time it took for six tablets to completely disintegrate was measured using the disintegration test method listed in the Japanese Pharmacopoeia General Test Methods (test solution: water (37±2℃), without auxiliary disc) for tablets immediately after compression (Initial), stored for 1 week, stored for 2 weeks, and stored for 4 weeks.

[0064] D-3. Measurement of related substances The tablets obtained in each example and comparative example were tested for related substances using the liquid chromatography method listed in the General Test Methods of the Japanese Pharmacopoeia, immediately after compression (Initial), after 1 week of storage, after 2 weeks of storage, and after 4 weeks of storage. The liquid chromatography measurement conditions are shown below. [Formula 1] Amount of related substances (%) = AT / AS AT: Peak area of ​​a related substance in the sample solution (relative retention time to bilastin approximately 0.5) AS: Peak area of ​​bilastin in standard solution Note that AT is the peak corresponding to bilastine N-oxide (the oxide form of bilastine with nitrogen atom N in the piperidine skeleton).

[0065] Analysis method Sample solution: Add diluent to the tablet to disintegrate it, then filter (bilastine approximately 2 mg / mL). Standard solution: Sample solution diluted 100-fold with diluent. Diluent: Methanol / water mixture (7:3) Injection volume: 10 μL

[0066] Test conditions Detector: UV absorbance spectrophotometer (measurement wavelength: 275 nm) Column: Octadecylsilylated silica gel (3 μm), inner diameter 4.6 mm, length 25 cm Column temperature: around 30°C Mobile phase: Ammonium acetate solution (pH 7.6) / acetonitrile / methanol (14:5:1) Flow rate: Bilastin retention time approximately 28 minutes

[0067] Tables 2 and 3 below show the composition of each tablet and the evaluation results.

[0068] [Table 2]

[0069] [Table 3]

[0070] As shown in Comparative Example 1 in Table 3, tablets without component (D) silicate compound experienced tableting problems, resulting in a significant decrease in productivity or manufacturability. In contrast, as shown in each example in Table 2, tablets containing component (D) did not experience tableting problems.

[0071] As shown in Comparative Example 2 of Table 3, tablets with a low content of component (C) crospovidone (4.5% by mass relative to bilastine) exhibited poor disintegration, with disintegration times of 52 seconds after 2 weeks of storage and 68 seconds after 4 weeks of storage. On the other hand, as shown in Comparative Example 3 of Table 3, tablets with a high content of component (C) crospovidone (90% by mass relative to bilastine) resulted in bilastine instability and a significantly increased generation of related substances. Furthermore, as shown in Comparative Examples 4 and 5 of Table 3, tablets containing sodium starch glycolate or corn starch without component (C) crospovidone exhibited poor disintegration. In contrast, as shown in each example of Table 2, tablets containing a predetermined amount of component (C) crospovidone suppressed the generation of bilastine related substances and exhibited sufficient disintegration.

[0072] As can be seen from Examples 1-3 in Table 2, the component (B) polyvinyl alcohol powder contained in the tablets, regardless of its degree of saponification, provided tablets with sufficient hardness, good disintegration, and suppressed the formation of related substances, without causing tableting problems. While the tablets of Example 2, which contained fully saponified polyvinyl alcohol, sometimes showed visual defects, no such defects were observed in the tablets of Examples 1 and 3, which contained partially or intermediately saponified polyvinyl alcohol. Even tablets containing 1% by mass of component (D) light anhydrous silicic acid, as in Example 4, exhibited sufficient hardness, good disintegration, suppressed the formation of related substances, and showed no visual defects, without causing tableting problems.

[0073] As can be seen from Examples 1, 5, and 6 in Table 2, tablets with component (C) crospovidone content of 45% by mass, 30% by mass, and 60% by mass relative to bilastine all exhibited sufficient disintegration properties, and the formation of bilastine-related substances was also suppressed.

[0074] As shown in Example 7 of Table 2, tablets containing magnesium aluminometasilicate as component (D) performed well in each evaluation, similar to tablets containing light anhydrous silicic acid, without causing tableting problems. [Industrial applicability]

[0075] The tablets of the present invention, as a pharmaceutical formulation containing bilastine, can be used to treat allergic rhinitis, urticaria, and itching associated with skin diseases (eczema, dermatitis, pruritus). Furthermore, based on the physiological activity of bilastine, the development of new indications and effects for the tablets of the present invention is expected.

Claims

1. A tablet comprising bilastine (A), polyvinyl alcohol (B) in powder form, crospovidone (C), and a silicate compound (D): Tablets containing crospovidone (C) in a mass ratio (C / A) of bilastine (A) to 70%.

2. Polyvinyl alcohol (B) formulated as a powder is subject to the following conditions (i) and (ii): (i) 95% or more by mass of the polyvinyl alcohol (B) blended as a powder is a powder that passes through a 100-mesh sieve. (ii) The maximum particle size of individual particles of polyvinyl alcohol (B) as a powder is less than 150 μm. A tablet according to claim 1, satisfying at least one of the following conditions.

3. The tablet according to claim 1 or 2, wherein the tablet is an orally disintegrating tablet.

4. The tablet according to claim 1 or 2, wherein the mass content ratio of polyvinyl alcohol (B) formulated as a powder to the tablet is 0.05 to 0.5%.

5. The tablet according to claim 1 or 2, wherein the mass content ratio of crospovidone (C) to the tablet is 2 to 8%.

6. The tablet according to claim 1 or 2, wherein the polyvinyl alcohol (B) incorporated as a powder is a powder of at least one of a partially saponified product and an intermediate saponified product of polyvinyl alcohol.

7. The tablet according to claim 1 or 2, wherein the silicate compound (D) is at least one of light anhydrous silicic acid and magnesium aluminometasilicate.

8. The tablet according to claim 1 or 2, wherein the mass content ratio of the silicate compound (D) to the tablet is 0.2 to 1%.

9. The tablet according to claim 1 or 2, wherein the mass content ratio of crospovidone (C) to bilastine (A) (C / A) is 30 to 60%.

10. A tablet according to claim 1 or 2, which is a direct-compression tablet.

11. A method for producing tablets containing bilastine (A), The process includes a mixing step of mixing bilastine (A), polyvinyl alcohol powder (B), crospovidone (C), and silicate compound (D) in powder form. A method for manufacturing tablets in which the mass content ratio (C / A) of crospovidone (C) to bilastine (A) is 20-70%.

Images