Bilastine-containing tablets and method for producing the same

Abstract

To provide bilastine-containing tablets with improved formulation uniformity, or to provide a method for producing bilastine-containing tablets with improved formulation uniformity.SOLUTION: According to one embodiment of the present invention, a bilastine-containing tablet is provided, which contains bilastine and crystalline cellulose having an angle of repose of 42° or more. Alternatively, according to one embodiment of the present invention, a method for producing a bilastine-containing tablet is provided, including mixing bilastine, crystalline cellulose having an angle of repose of 42° or more, and one or more pharmaceutically acceptable additives to prepare a mixed powder; and compressing the mixed powder.SELECTED DRAWING: None

Description

[Technical field]

[0001] One embodiment of the present invention relates to a bilastine-containing tablet. Alternatively, one embodiment of the present invention relates to a method for producing a bilastine-containing tablet. [Background technology]

[0002] Bilastine (2-[4-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)piperidin-1-yl)ethyl)phenyl]-2-methylpropanoic acid) is known to be a compound having excellent antihistamine activity and is used as a therapeutic agent for allergic diseases (e.g., Patent Documents 1 and 2).

[0003] Allergic diseases are one of the diseases that affect many people, and are often seasonal diseases. For seasonal allergic diseases, preventive administration begins about 1 to 2 months before the start of the season, and treatment is administered during the season, and prescriptions for treatment are required for several months each year. Therefore, from the perspective of reducing medical expenses, there is a growing demand for inexpensive medicines to reduce the prices of allergic disease treatments.

[0004] In order to make it possible to supply inexpensive pharmaceuticals, it is preferable that the manufacturing cost of pharmaceuticals is as low as possible. Therefore, various methods have been tried to reduce the manufacturing cost of pharmaceutical preparations. For example, direct compression is a simple manufacturing method known as a manufacturing method with good workability. For example, Patent Document 2 describes a manufacturing method for bilastine-containing tablets using direct compression. However, direct compression is also a manufacturing method in which it is difficult to maintain formulation uniformity compared to granulation. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] JP 2022-097443 A [Patent Document 2] JP 2023-014416 A Summary of the Invention [Problem to be solved by the invention]

[0006] One of the objects of the present invention is to provide a bilastine-containing tablet having improved formulation uniformity. Alternatively, one of the objects of the present invention is to provide a method for producing a bilastine-containing tablet having improved formulation uniformity. [Means for solving the problem]

[0007] According to one embodiment of the present invention, there is provided a bilastine-containing tablet comprising bilastine and microcrystalline cellulose having an angle of repose of 42° or more.

[0008] The crystalline cellulose may have an angle of repose of 42° or more and 49° or less.

[0009] The bilastine-containing tablet may contain 16% by mass or more and 82% by mass or less of crystalline cellulose relative to 100% by mass of the tablet.

[0010] It may further comprise microcrystalline cellulose having an angle of repose of less than 42°.

[0011] It may further include one or more pharma- ceutically acceptable excipients.

[0012] According to one embodiment of the present invention, there is provided a method for producing a bilastine-containing tablet, comprising mixing bilastine, crystalline cellulose having an angle of repose of 42° or more, and one or more pharma- ceutically acceptable additives to prepare a mixed powder, and compressing the mixed powder.

[0013] The crystalline cellulose may have an angle of repose of 42° or more and 49° or less.

[0014] The mixed powder may be prepared by mixing 16% by mass or more and 82% by mass or less of crystalline cellulose with respect to 100% by mass of the bilastine-containing tablet.

[0015] Microcrystalline cellulose having an angle of repose of less than 42° may be further added to prepare the mixed powder. Effect of the Invention

[0016] According to one embodiment of the present invention, a bilastine-containing tablet having improved formulation uniformity is provided. Alternatively, according to one embodiment of the present invention, a method for producing a bilastine-containing tablet having improved formulation uniformity is provided. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] The bilastine-containing tablet and its manufacturing method according to the present invention will be described below. Note that the bilastine-containing tablet and its manufacturing method according to the present invention are not limited to the description of the following embodiment and examples. Note that in the present embodiment and the examples described below, repeated description of the same configuration or configuration having similar function will be omitted.

[0018] In general, various factors such as particle size, bulk density, surface charge, surface structure (unevenness, etc.) and angle of repose of excipients may affect formulation uniformity, and which factors are important for formulation uniformity differs depending on the types of drug substance and excipients. As a result of the study by the present inventors, it was revealed that the angle of repose of crystalline cellulose, which is commonly added as an excipient, affects formulation uniformity in bilastine-containing tablets.

[0019] The bilastine-containing tablet according to one embodiment of the present invention comprises bilastine and crystalline cellulose having a repose angle of 42° or more. In one embodiment of the present invention, the crystalline cellulose contained in the bilastine-containing tablet preferably has a repose angle of 42° or more and 49° or less. When the bilastine-containing tablet contains only crystalline cellulose having a repose angle of less than 42°, the formulation uniformity decreases. Note that crystalline cellulose with a repose angle of more than 50° has poor fluidity and is not suitable for the manufacture of the bilastine-containing tablet according to this embodiment.

[0020] In this specification, the angle of repose of crystalline cellulose is measured according to the method for measuring the angle of repose described in the reference information of the 18th revised Japanese Pharmacopoeia. The angle of repose is used as one of the indicators of powder fluidity. It is known that a powder with good fluidity accumulates at a gentle angle when dropped, resulting in a small angle of repose, while a powder with poor fluidity accumulates at a steep angle when dropped, resulting in a large angle of repose. Table 1 on the method of measuring angle of repose listed in the reference information of the 18th Edition of the Japanese Pharmacopoeia lists the following flow characteristics and corresponding angles of repose: powders having an angle of repose of 25° to 30° have extremely good fluidity, powders having an angle of repose of 31° to 35° have good fluidity, powders having an angle of repose of 36° to 40° have slightly good fluidity, powders having an angle of repose of 41° to 45° have average fluidity, powders having an angle of repose of 46° to 55° have slightly poor fluidity, powders having an angle of repose of 55° to 65° have poor fluidity, and powders having an angle of repose of 66° or more have extremely poor fluidity.

[0021] As mentioned above, when the bilastine-containing tablet contains only crystalline cellulose having a repose angle of less than 42°, which is generally considered to have relatively good fluidity, the formulation uniformity is reduced. On the other hand, the crystalline cellulose contained in the bilastine-containing tablet according to one embodiment of the present invention having a repose angle of 42° or more and 49° or less is classified as a powder having normal or slightly poor fluidity in Table 1 of the repose angle measurement method. In other words, the range of the repose angle of the crystalline cellulose contained in the bilastine-containing tablet according to one embodiment of the present invention is a specific range for obtaining the formulation uniformity of the bilastine-containing tablet, and cannot be easily estimated from technical common sense.

[0022] In one embodiment of the present invention, the bilastine-containing tablet may contain crystalline cellulose having an angle of repose of 42° or more and 49° or less in an amount of 16% by mass or more and 82% by mass or less, based on 100% by mass of the bilastine-containing tablet.

[0023] In addition, in one embodiment of the present invention, when the bilastine-containing tablet contains crystalline cellulose having a repose angle of 42 ° or more and 49 ° or less at a content of 16% by mass to 82% by mass, in addition to the crystalline cellulose having a repose angle of 42 ° or more and 49 ° or less, it may further contain crystalline cellulose having a repose angle of less than 42 °. When the bilastine-containing tablet further contains crystalline cellulose having a repose angle of less than 42 °, the repose angle of the entire crystalline cellulose is lower than the range of 42 ° or more and 49 ° or less, and it is expected that the formulation uniformity of the bilastine-containing tablet will also decrease. However, surprisingly, as shown in the examples described later, when the bilastine-containing tablet according to this embodiment contains crystalline cellulose having a repose angle of 42 ° or more and 49 ° or less at a content of 16% by mass to 82% by mass, even if crystalline cellulose having a repose angle of less than 42 ° is further added, the bilastine-containing tablet can obtain good formulation uniformity.

[0024] In one embodiment of the present invention, the bilastine-containing tablet can contain bilastine or its salt as bilastine. Bilastine may be in the form of an addition salt with inorganic acids such as hydrochloric acid and sulfuric acid, organic acids such as acetic acid, citric acid, tartaric acid, and maleic acid, an alkali metal salt such as potassium and sodium, an alkaline earth metal salt such as calcium and magnesium, an organic base salt such as ammonium salt, ethylamine salt, and arginine salt. Bilastine or its salt may be a non-solvate or a solvate such as a hydrate.

[0025] In addition, in one embodiment of the present invention, a bilastine-containing tablet may contain, for example, 20 mg of bilastine (as bilastine in the case of a salt or solvate) per tablet, but the bilastine content is not limited to this and can be changed as desired within the range in which a therapeutic effect is obtained.

[0026] In one embodiment of the present invention, the bilastine-containing tablet may be a normal tablet (plain tablet) or an orally disintegrating tablet (plain tablet). In one embodiment of the present invention, the bilastine-containing tablet may be a film-coated tablet in which a film is placed on the surface of a plain tablet, or a film-coated orally disintegrating tablet.

[0027] In one embodiment of the present invention, the bilastine-containing tablet may further include one or more pharma- ceutically acceptable additives, such as one or more additives selected from the group consisting of excipients, disintegrants, binders, colorants, flavorings, taste masking agents, lubricants, flow agents, and coating agents.

[0028] In one embodiment, the excipient may be one or more selected from the group consisting of mannitol, erythritol, sorbitol, xylitol, trehalose, cyclodextrin, corn starch, potato starch, sucrose, anhydrous calcium hydrogen phosphate, calcium carbonate, white sugar, partially pregelatinized starch and lactose. The bilastine-containing tablet according to this embodiment may contain these excipients in combination with crystalline cellulose having an angle of repose of 42° to 49°. Even when these excipients are combined, the bilastine-containing tablet according to this embodiment contains crystalline cellulose having an angle of repose of 42° to 49° in an amount of 16% by mass to 82% by mass.

[0029] In one embodiment, the disintegrant can be one or more selected from the group consisting of low-substituted hydroxypropylcellulose, crospovidone, carmellose calcium, carmellose sodium, croscarmellose sodium, carmellose, and starches such as sodium starch glycolate.

[0030] In one embodiment, examples of the binder include one or more selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol (fully saponified), macrogol, sugar alcohols (e.g., mannitol, erythritol, sorbitol, and xylitol), trehalose, cyclodextrin, corn starch, sucrose, crystalline cellulose, anhydrous calcium hydrogen phosphate, and calcium carbonate.

[0031] In one embodiment, examples of the colorant include one or more selected from the group consisting of food yellow No. 5, food blue No. 2, food lake color, ferric oxide, yellow ferric oxide, and titanium oxide.

[0032] In one embodiment, the flavoring agent may be one or more selected from the group consisting of orange, lemon, and lime.

[0033] In one embodiment, examples of the flavoring agent include one or more selected from the group consisting of aspartame, saccharin, sodium saccharin, dipotassium glycyrrhizinate, stevia, thaumatin, sucralose, acesulfame K, l-menthol, camphor, and mint.

[0034] In one embodiment, the lubricant may be one or more selected from the group consisting of magnesium stearate, stearic acid, calcium stearate, light anhydrous silicic acid, sodium stearyl fumarate, talc, hydrogenated vegetable oil, microcrystalline wax, sucrose fatty acid ester, and polyethylene glycol.

[0035] In one embodiment, the fluidizing agent can be one or more selected from the group consisting of silicon dioxide, sodium silicate, talc, and magnesium stearate.

[0036] In one embodiment, examples of the coating agent include hydroxypropylmethylcellulose or polyethylene glycol.

[0037] [Manufacturing method of bilastine-containing tablets] The bilastine-containing tablet according to one embodiment of the present invention is manufactured by direct compression. Direct compression is a method for manufacturing tablets by mixing bilastine, which is a drug substance, with pharmaceutically acceptable additives to obtain a mixed powder, and compressing the mixture. In one embodiment of the present invention, the method for manufacturing bilastine-containing tablets includes mixing bilastine, crystalline cellulose having an angle of repose of 42° or more, and one or more pharmaceutically acceptable additives to prepare a mixed powder (step S1), and compressing the mixed powder (step S2).

[0038] In step S1, crystalline cellulose having an angle of repose of 42° to 49° is mixed with bilastine and one or more pharma- ceutically acceptable additives to prepare a mixed powder. At this time, crystalline cellulose is mixed in an amount of 16% by mass to 82% by mass relative to 100% by mass of the bilastine-containing tablet to prepare the mixed powder.

[0039] In addition, in one embodiment, when the content of crystalline cellulose having an angle of repose of 42° or more and 49° or less is 16% by mass or more and 82% by mass or less, the mixed powder may be prepared by further mixing crystalline cellulose having an angle of repose of less than 42° in addition to the crystalline cellulose having an angle of repose of 42° or more and 49° or less.

[0040] [Evaluation of formulation uniformity of bilastine-containing tablets] In this specification, the formulation uniformity of bilastine-containing tablets is evaluated according to the content uniformity test of the formulation uniformity test method of the Japanese Pharmacopoeia, 18th Edition. The bilastine contained in the bilastine-containing tablets is quantified by high performance liquid chromatography (HPLC). In this specification, bilastine-containing tablets with a judgment value of less than 10% are evaluated as bilastine-containing tablets with high formulation uniformity, and bilastine-containing tablets with a judgment value of 10% or more are evaluated as bilastine-containing tablets with low formulation uniformity. EXAMPLES

[0041] Table 1 shows the main grades of crystalline cellulose commercially available at the time of filing this application, as well as their average particle size, bulk density, and angle of repose. [Table 1]

[0042] [Example 1] 20.0 g of bilastine, 102.1 g of crystalline cellulose (Ceolas® PH-101, Asahi Kasei Corporation), 1.0 g of sodium starch glycolate (Primojel®, DFE Pharma Co., Ltd.), 0.6 g of light anhydrous silicic acid (Adsolider 101®, Freund Corporation), and 1.3 g of magnesium stearate (plant, Taihei Chemical Industry Co., Ltd.) were mixed in a plastic bag and compressed using a tablet press (Kikusui Seisakusho, VELA5) to give tablets weighing 125.0 mg, thereby obtaining bilastine-containing tablets of Example 1, each weighing 125.0 mg.

[0043] [Example 2] The bilastine-containing tablet of Example 2 was obtained by the same production method as in Example 1, except that the crystalline cellulose was changed from Ceolus (registered trademark) PH-101 to Ceolus (registered trademark) PH-102 (Asahi Kasei Corporation).

[0044] [Example 3] The bilastine-containing tablets of Example 3 were obtained by the same manufacturing method as in Example 1, except that the crystalline cellulose was changed from Ceolus (registered trademark) PH-101 to 20.0 g of Ceolus (registered trademark) KG-802 (Asahi Kasei Corporation) and 82.1 g of Ceolus (registered trademark) UF-702 (Asahi Kasei Corporation).

[0045] [Example 4] The bilastine-containing tablets of Example 4 were obtained by the same manufacturing method as in Example 3, except that the amount of CEOLUS (registered trademark) KG-802 (Asahi Kasei Corporation) was changed to 50.0 g and the amount of CEOLUS (registered trademark) UF-702 (Asahi Kasei Corporation) was changed to 52.1 g.

[0046] [Example 5] The bilastine-containing tablets of Example 3 were obtained by the same manufacturing method as in Example 1, except that the crystalline cellulose was changed from Ceolus (registered trademark) PH-101 to 20.0 g of Ceolus (registered trademark) PH-102 (Asahi Kasei Corporation) and 82.1 g of Ceolus (registered trademark) UF-702 (Asahi Kasei Corporation).

[0047] [Comparative Example 1] A bilastine-containing tablet of Comparative Example 1 was obtained by the same production method as in Example 1, except that the crystalline cellulose was changed from Ceolus (registered trademark) PH-101 to Ceolus (registered trademark) PH-301 (Asahi Kasei Corporation).

[0048] [Comparative Example 2] A bilastine-containing tablet of Comparative Example 2 was obtained by the same production method as in Example 1, except that the crystalline cellulose was changed from Ceolus (registered trademark) PH-101 to Ceolus (registered trademark) PH-302 (Asahi Kasei Corporation).

[0049] [Comparative Example 3] A bilastine-containing tablet of Comparative Example 3 was obtained by the same production method as in Example 1, except that the crystalline cellulose was changed from Ceolus (registered trademark) PH-101 to Ceolus (registered trademark) UF-702 (Asahi Kasei Corporation).

[0050] [Evaluation of formulation uniformity of bilastine-containing tablets] The formulation uniformity was evaluated using 10 tablets of each of the bilastine-containing tablets of each Example and Comparative Example. Specifically, each bilastine-containing tablet was dissolved in a water / acetonitrile mixture and filtered through a 0.2 μm filter to prepare a measurement sample. The bilastine content of each bilastine-containing tablet was calculated by HPLC using an InertSustain C18 column (inner diameter: 4.6 mm, length: 50, particle size: 3.0 μm) with 10 mM phosphate buffer (pH 6.8) and acetonitrile as the mobile phase and a photodiode array detector (measurement wavelength: 215 nm). The judgment value was calculated according to the following formula in accordance with the calculation of the judgment value of the content uniformity test of the formulation uniformity test method of the 18th revised Japanese Pharmacopoeia.

number

[0051] The evaluation values ​​of the formulation uniformity of the bilastine-containing tablets of each Example and Comparative Example are shown in Table 2. [Table 2]

[0052] From the results in Table 2, it was revealed that the bilastine-containing tablets of Example 1, to which crystalline cellulose (PH-101) with a repose angle of 45° was added, and the bilastine-containing tablets of Example 2, to which crystalline cellulose (PH-102) with a repose angle of 42° was added, had better formulation uniformity than the bilastine-containing tablets of Comparative Example 1, to which crystalline cellulose (PH-301) with a repose angle of 41° was added, the bilastine-containing tablets of Comparative Example 2, to which crystalline cellulose (PH-302) with a repose angle of 41° was added, and the bilastine-containing tablets of Comparative Example 3, to which crystalline cellulose (UF-702) with a repose angle of 34° was added.

[0053] It was also found that the bilastine-containing tablets of Examples 3 and 4, which contain 16.0% to 40.0% by mass of crystalline cellulose (KG-802) having a repose angle of 49° and further contain crystalline cellulose (UF-702) having a repose angle of 34°, also have good formulation uniformity. Furthermore, it was found that the bilastine-containing tablets of Example 5, which contain 16.0% by mass of crystalline cellulose (PH-102) having a repose angle of 42° and further contain crystalline cellulose (UF-702) having a repose angle of 34°, also have good formulation uniformity.

Claims

1. Bilastine and A bilastine-containing tablet comprising: a crystalline cellulose having an angle of repose of 42° or more.

2. The bilastine-containing tablet according to claim 1, wherein the crystalline cellulose has an angle of repose of 42° or more and 49° or less.

3. The bilastine-containing tablet according to claim 1 or 2, comprising 16% by mass or more and 82% by mass or less of the crystalline cellulose relative to 100% by mass of the bilastine-containing tablet.

4. 4. The bilastine-containing tablet of claim 3, further comprising microcrystalline cellulose having an angle of repose of less than 42°.

5. 2. The bilastine-containing tablet of claim 1, further comprising one or more pharma- ceutically acceptable excipients.

6. Mixing bilastine, crystalline cellulose having an angle of repose of 42° or more, and one or more pharma- ceutically acceptable additives to prepare a mixed powder; A method for producing a bilastine-containing tablet, comprising compressing and molding the mixed powder.

7. The method for producing a bilastine-containing tablet according to claim 6, wherein the crystalline cellulose has an angle of repose of 42° or more and 49° or less.

8. The method for producing a bilastine-containing tablet according to claim 6 or 7, wherein the mixed powder is prepared by mixing 16% by mass or more and 82% by mass or less of the crystalline cellulose with respect to 100% by mass of the bilastine-containing tablet.

9. The method for producing a bilastine-containing tablet according to claim 8, further comprising adding crystalline cellulose having an angle of repose of less than 42° to prepare the mixed powder.

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