Selexipag tablet and method for producing same

Abstract

Provided are: a tablet containing 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide (compound I); and a method for producing the same. The tablet is an uncoated tablet containing the (A) compound I, (B) starch and a crystalline cellulose, and a (C) binder, or is a coated tablet obtained by providing a coating material on the uncoated tablet. The (C) component is contained in an amount of 1 mass% or more with respect to 100 mass% of the uncoated tablet. The proportion of the crystalline cellulose with respect to 1 part by mass of the starch in the (B) component is 1-5 parts by mass.

Description

Selexipag tablets and their manufacturing method

[0001] The present disclosure relates to a tablet containing 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide (generic name "Selexipag," hereinafter also referred to as "Compound I" in this specification). In a preferred embodiment, the present disclosure relates to a tablet that stably contains Compound I and has good hardness and disintegrability.

[0002] The following structural formula: Compound I represented by the formula: ２ (P.G.I. ２ It is known that these compounds have a receptor agonist effect and exhibit various medicinal effects such as platelet aggregation inhibitory effect, vasodilatory effect, bronchial smooth muscle dilation effect, lipid deposition inhibitory effect, and leukocyte activation inhibitory effect (Patent Documents 1 to 8).

[0003] Patent Document 3 discloses a tablet containing Compound I and D-mannitol. In this tablet, D-mannitol is used as an excipient, and the specific surface area of ​​D-mannitol is 1.0 m ２ The compound I in the tablet containing D-mannitol is formed as follows: This can suppress the decomposition of Compound I in the tablet containing D-mannitol.

[0004] Patent Document 8 discloses a tablet containing, as granulation components, Compound I, starch, and at least one binder selected from the group consisting of hydroxypropyl cellulose and hypromellose. Patent Document 8 describes that by setting the proportions of starch and binder per 100 parts by mass of the granules to 20 parts by mass or more and 4 parts by mass or less, respectively, a tablet can be provided that exhibits good disintegrability while suppressing the decomposition of Compound I.

[0005] International Publication No. WO 2002 / 088084, International Publication No. WO 2009 / 157398, International Publication No. WO 2017 / 098998, International Publication No. WO 2009 / 157396, International Publication No. WO 2009 / 157398, International Publication No. WO 2009 / 157397, International Publication No. WO 2009 / 107736, International Publication No. WO 2021 / 206159, International Publication No. WO 2022 / 211052

[0006] Hepatology, 2007, Vol. 45, No. 1, p159-169. Folia Pharmacologica Japonica, Vol. 117, No. 2, p. 123-130, 2001, Abstract. International Angiology, 29, Suppl. 1 to No. 2, p. 49-54, 2010. Jpn. J. Clin. Immunol. , 16(5), 409-414, 1993. Jpn. J. Thromb. Hemost. , 1:2, p. 94-105, 1990, Abstract. J. Rheumatol. , 2009, 36(10), 2244-2249. Japan J. Pharmacol. , 43, p. 81-90, 1987. New Engl. J. Med. , 2015, 24, 2522-2533. CHEST 2003, 123, 1583-1588. Br. Heart J. , 53, p. 173-179, 1985. The Lancet, 1, 4880, pt 1, p. 569-572, 1981. Eur. J. Pharmacol. , 449, p. 167-176, 2002. The Journal of Clinical Investigation, 117, p. 464-472, 2007. Am. J. Physiol. Lung Cell Mol. Physiol. , 296:L648-L656, 2009.

[0007] In recent years, there has been a demand for tablets that are easier to administer for children, the elderly, or patients with swallowing difficulties. To this end, it is necessary to develop tablets that have the desired formulation properties (hardness, disintegrability) so that the tablets can be made smaller and easily suspended and administered while maintaining the efficacy (effectiveness) of the active ingredient. Therefore, an object of the present disclosure is to provide a tablet that stably contains Compound I and has good hardness and disintegrability.

[0008] In the course of intensive research to solve the above-mentioned problems, the present inventors have found that, while omitting a binder from a tablet containing Compound I improves disintegration, the decomposition of Compound I in the tablet proceeds, producing related substances, reducing the content of Compound I, i.e., decreasing the stability of Compound I in the tablet. Therefore, while a binder is essential for maintaining the stability of Compound I in a tablet, its incorporation tends to delay disintegration. Therefore, intensive research was conducted to develop a tablet that maintains the stability of Compound I while exhibiting good disintegration properties by incorporating a binder. It was found that by incorporating a specific amount of binder and starch and crystalline cellulose in a specific ratio, tablets that maintain the stability of Compound I and have good disintegration properties and a desired hardness can be prepared. Based on these findings, the present disclosure has been completed through further research. Some embodiments of the present disclosure include the following:

[0009] (I) Selexipag-Containing Tablet 1 (I-1) A tablet containing (A) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide (Compound I), (B) starch and crystalline cellulose, and (C) a binder, wherein the tablet is an uncoated tablet or a coated tablet in which a coating material is applied to the uncoated tablet, the content of component (C) is 1% by mass or more, preferably 1 to 10% by mass, and more preferably 1 to 5% by mass per 100% by mass of the uncoated tablet, and the ratio of crystalline cellulose to 1 part by mass of starch in component (B) is 1 to 5 parts by mass. (I-2) The tablet according to (I-1), further containing an excipient (excluding starch and crystalline cellulose), a disintegrant, and a lubricant. (I-3) The tablet according to (I-1) or (I-2), which contains the components (A), (B), and (C), and an excipient (excluding starch and crystalline cellulose) as intragranular components, and an excipient (excluding starch and crystalline cellulose), a disintegrant, and a lubricant, or a disintegrant and a lubricant as extragranular components. (I-4) The tablet according to any one of (I-1) to (I-3), in which the content of the starch is 20% by mass or less, preferably 5% to 20% by mass, per 100% by mass of the uncoated tablet. (I-5) The tablet according to any one of (I-1) to (I-4), in which the hardness of the uncoated tablet is 30 N or more and the disintegration time of the uncoated tablet is 180 seconds or less. (I-6) The tablet according to any one of (I-1) to (I-5), wherein the uncoated tablet has a tablet diameter of 4 mmφ or more (preferably 4 to 8 mmφ) and a porosity of 10% or less (preferably 5 to 10%). (I-7) The tablet according to any one of (I-1) to (I-6), wherein the coated tablet is a film-coated tablet obtained by applying a film coating to an uncoated tablet.(I-8) The tablet according to any one of (I-1) to (I-7), which is a pharmaceutical composition used for improving or treating symptoms associated with arteriosclerosis obliterans, intermittent claudication, diabetic neuropathy, diabetic gangrene, peripheral circulatory disorder, chronic arterial occlusion, scleroderma, thrombosis, pulmonary hypertension, myocardial infarction, angina pectoris, glomerulonephritis, diabetic nephropathy, chronic renal failure, bronchial asthma, interstitial pneumonia (pulmonary fibrosis), chronic obstructive pulmonary disease, tubulointerstitial nephritis, inflammatory bowel disease, or spinal canal stenosis.

[0010] (II) Selexipag-Containing Tablet 2 (II-1) A tablet containing (A) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide (Compound I), (B) starch and crystalline cellulose, and (C) a binder, wherein the tablet is a coated tablet obtained by applying a coating material to an uncoated tablet, and the ratio of starch and crystalline cellulose is adjusted so that the disintegration time of the coated tablet is 300 seconds or less. (II-2) The tablet according to (II-1), further containing an excipient (excluding starch and crystalline cellulose), a disintegrant, and a lubricant. (II-3) The tablet according to (II-1) or (II-2), which contains the components (A), (B), and (C), and an excipient (excluding starch and crystalline cellulose) as intragranular components, and contains an excipient (excluding starch and crystalline cellulose), a disintegrant, and a lubricant, or a disintegrant and a lubricant, as extragranular components. (II-4) The tablet according to any of (II-1) to (II-3), wherein the coated tablet is a film-coated tablet obtained by applying a film coating to an uncoated tablet.

[0011] (III) Selexipag-Containing Tablet 3 (III-1) A tablet containing (A) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide (Compound I), (B) starch and crystalline cellulose, and (C) a binder, wherein the tablet is an uncoated tablet or a coated tablet in which a coating material is applied to the uncoated tablet, the content of component (C) is 1% by mass or more per 100% by mass of the uncoated tablet, and the proportions of starch and crystalline cellulose are adjusted so that the hardness of the uncoated tablet is 30 N or more and the disintegration time of the uncoated tablet is 180 seconds or less. (III-2) The tablet according to (III-1), further containing an excipient (excluding starch and crystalline cellulose), a disintegrant, and a lubricant. (III-3) The tablet according to (III-1) or (III-2), which contains the components (A), (B), and (C), and an excipient (excluding starch and crystalline cellulose) as intragranular components, and contains an excipient (excluding starch and crystalline cellulose), a disintegrant, and a lubricant, or a disintegrant and a lubricant as extragranular components. (III-4) The tablet according to any one of (III-1) to (III-3), wherein the coated tablet is a film-coated tablet obtained by applying a film coating to an uncoated tablet.

[0012] (IV) Manufacturing Method of Selexipag-Containing Tablets (IV-1) A manufacturing method of a tablet containing (A) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide (Compound I), (B) starch and crystalline cellulose, and (C) a binder, wherein the tablet is an uncoated tablet or a coated tablet obtained by applying a coating material to the uncoated tablet, the manufacturing method comprises: (1) a step of preparing a powder mixture of the component (A) and the component (B); and (2) a step of adding a solution containing the component (C) to the powder mixture and granulating to obtain a granulated product, wherein in the step (1), the blending ratio of starch to crystalline cellulose in the powder mixture is adjusted to 1 to 5 parts by mass of crystalline cellulose per 1 part by mass of starch, (IV-2) The production method according to (IV-1), wherein in step (1), the starch content in the powder mixture is adjusted to 20% by mass or less, preferably 5% by mass or more and 20% by mass or less, per 100% by mass of the uncoated tablets. (IV-3) The production method according to (IV-1) or (IV-2), wherein the solution containing the component (C) contains the component (C) in an amount of 1 to 10% by mass. (IV-4) The method according to any one of (IV-1) to (IV-3), wherein the step (1) is a step of preparing a powder mixture containing, in addition to the components (A) and (B), a (D) excipient (excluding starch and microcrystalline cellulose). (IV-5) The method according to any one of (IV-1) to (IV-4), wherein, after the step (2) of granulation and, if necessary, after a step (3) of sizing, a step of adding (4) a (E) disintegrant and an (F) lubricant, or (D) an excipient (excluding starch and microcrystalline cellulose), an (E) disintegrant, and an (F) lubricant (extragranular component mixing step). (IV-6) The method according to (IV-5), wherein, after the step (4) of extragranular component mixing, a step (5) of compression molding is added.(IV-7) A method for producing a coated tablet, the method comprising a step of coating the compression-molded product obtained in the compression molding step (5) with a coating material, as described in (IV-6). (IV-8) A method for producing a tablet in which the hardness of the uncoated tablet is 30 N or more and the disintegration time of the uncoated tablet is 180 seconds or less, as described in any of (IV-1) to (IV-7). (IV-9) A method for producing a tablet in which the diameter of the uncoated tablet is 4 mmφ or more (preferably 4 to 8 mmφ) and the porosity is 10% or less (preferably 5 to 10%), as described in any of (IV-1) to (IV-8).

[0013] (V) Method for inhibiting decomposition of selexipag and improving hardness and disintegration property of selexipag-containing tablet (V-1) A method for inhibiting decomposition of the (A) component and adjusting the hardness and disintegration time to a desired range in a tablet containing (A) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide (Compound I), (B) starch and crystalline cellulose, (C) a binder, (E) a disintegrant, and (F) a lubricant, wherein the tablet is an uncoated tablet or a coated tablet obtained by applying a coating material to the uncoated tablet, the desired range of the hardness is 30 N or more when converted to the hardness of an uncoated tablet, and the desired range of the disintegration time is 180 seconds or less when converted to the disintegration time of an uncoated tablet, and the (C) component is blended in a solution state so that the dry weight of the (C) component per 100% by mass of the uncoated tablet is 1% by mass or more, and The method, characterized in that the ratio of starch to crystalline cellulose in component (B) is adjusted so that the hardness and disintegration time of the uncoated tablet are within the desired range. (V-2) The method described in (V-1), wherein the tablet is a coated tablet obtained by applying a coating material to an uncoated tablet, and the disintegration time of the coated tablet is 300 seconds or less. (V-3) The method described in (V-2), wherein the tablet is a coated tablet obtained by applying a coating material to an uncoated tablet, and the disintegration time of the divided pieces obtained by equally dividing the coated tablet is 180 seconds or less. (V-4) The method described in any of (V-1) to (V-3), wherein the ratio of starch to crystalline cellulose in component (B) is in the range of 1 to 5 parts by mass of crystalline cellulose per 1 part by mass of starch. (V-5) The method described in any of (V-1) to (V-4), wherein the solution of component (C) is an aqueous solution containing component (C) in a ratio of 0.5 to 20% by mass. (V-6) The method according to any one of (V-1) to (V-5), characterized in that the blending ratio of the starch is adjusted to 20% by mass or less per 100% by mass of the uncoated tablet. (V-7) The method according to any one of (V-1) to (V-6), wherein the tablet is an uncoated tablet further containing (D) an excipient (excluding starch and crystalline cellulose), or a coated tablet obtained by applying a coating material to the uncoated tablet.

[0014] According to the present invention, it is possible to provide a tablet of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide (generic name "selexipag") (Compound I) that maintains its stability while exhibiting good disintegrability and a desired hardness, and a method for producing the same.

[0015] (I) The tablet of the present disclosure (hereinafter, sometimes simply referred to as "the tablet") is a tablet containing (A) Compound I, (B) starch and crystalline cellulose, and (C) a binder. The tablet may further contain (D) an excipient (excluding starch and crystalline cellulose), (E) a disintegrant, and (F) a lubricant.

[0016] In this disclosure, unless otherwise specified, the term "tablet" refers to a solid preparation of a certain shape for oral administration, including regular tablets, orally disintegrating tablets, chewable tablets, troche tablets, sublingual tablets, effervescent tablets, dispersible tablets, dissolving tablets, and sustained-release tablets. Regular tablets are preferred. Tablets covered by this disclosure also include monolayer tablets with a single layer structure and multilayer tablets with two or more layers. Monolayer tablets are preferred. Tablets include uncoated tablets (commonly referred to as "plain tablets" or "naked tablets") as well as coated tablets whose surfaces are coated with a coating material, such as sugar-coated tablets, gelatin-coated tablets, and film-coated tablets (including enteric-coated tablets and gastrosoluble tablets). The planar shape of the tablet is not particularly limited and may be various shapes, such as round, oval, caplet-shaped, diamond-shaped, or doughnut-shaped. The present tablet can be manufactured using a wet granulation method (wet granule compression method) and contains components that constitute the granules (core granules) (hereinafter also referred to as "intragranular components") and components outside the granules (hereinafter also referred to as "extragranular components") that are added to the prepared granules.

[0017] The components of the tablet are described below. (A) Compound I (intragranular component) Compound I can be prepared, for example, according to the methods described in Patent Document 1 or 2, and the following three crystalline forms are known. The relevant descriptions in these patent documents are incorporated herein by reference. (1) Form I crystal of Compound I, whose powder X-ray diffraction pattern is obtained using Cu Kα radiation (λ=1.54 Å) and whose powder X-ray diffraction spectrum shows diffraction peaks at diffraction angles 2θ: 9.4 degrees, 9.8 degrees, 17.2 degrees, and 19.4 degrees. (2) Form II crystal of Compound I, whose powder X-ray diffraction pattern is obtained using Cu Kα radiation (λ=1.54 Å) and whose powder X-ray diffraction spectrum shows diffraction peaks at diffraction angles 2θ: 9.0 degrees, 12.9 degrees, 20.7 degrees, and 22.6 degrees. (3) A type III crystal of Compound I, whose powder X-ray diffraction pattern is obtained using Cu Kα radiation (λ=1.54 Å) and which shows diffraction peaks at diffraction angles 2θ of 9.3 degrees, 9.7 degrees, 16.8 degrees, 20.6 degrees, and 23.5 degrees in the powder X-ray diffraction spectrum of Compound I.

[0018] Compound I that can be used in the present tablet may be any of the above crystals or a mixture of these crystals. Among them, type I crystal is preferred. Compound I that can be used in the present tablet may also be an amorphous compound or a mixture of at least one of the above crystals and an amorphous compound.

[0019] The proportion of Compound I (hereinafter also referred to simply as "Component (A)") in the present tablet is not limited, but can be in the range of 0.1 to 70 parts by mass when converted into the content per 100 parts by mass of the granules. It is preferably 0.1 to 12 parts by mass, more preferably 0.1 to 2 parts by mass, and even more preferably 0.1 to 1 part by mass. In this specification, "content per 100 parts by mass of granules" refers to the proportion (parts by mass) of the corresponding component in the granules when the total amount of the components (intragranular components) constituting the granules is 100 parts by mass. Furthermore, although not limited, the proportion of Component (A) per 100% by mass of the total amount of the uncoated tablet can be selected from the range of 0.1 to 70% by mass. It is preferably 0.1 to 12% by mass, more preferably 0.1 to 2% by mass, and even more preferably 0.1 to 1.6% by mass.

[0020] Component (B) The present tablet contains starch and crystalline cellulose. For example, the present tablet contains starch and crystalline cellulose as intragranular components. These components are collectively referred to as "component (B)."

[0021] (B) Starch (intragranular component) In the present disclosure, the starch may be any starch that can be used as a pharmaceutical additive in the production of tablets. For example, natural starches include corn starch, potato starch, rice starch, and wheat starch; modified starches include hydroxypropyl starch, dextrin, maltodextrin, pregelatinized starch, and partially pregelatinized starch. Among pharmaceutical additives, starch is preferably used as an excipient, and among these, natural starch (unmodified starch) is preferred, and corn starch is preferably used. The form of starch is not limited and includes powder and granules, with powder being preferred.

[0022] The proportion of starch in the present tablet is adjusted to 20% by mass or less per 100% by mass of the total weight of the uncoated tablet, although this is not limited. It is preferably 15% by mass or less, and more preferably 10% by mass or less. The lower limit may be 1% by mass or more, for example, 2% by mass or more, preferably 3% by mass or more, more preferably 4% by mass or more, and even more preferably 5% by mass or more. These upper and lower limits can be arbitrarily combined. Although not limited, it can be appropriately set within ranges of, for example, 1 to 20% by mass, 2 to 20% by mass, 3 to 20% by mass, 4 to 20% by mass, and 5 to 20% by mass. Furthermore, when the proportion of starch is converted into the content per 100 parts by mass of the granules, it can be within the range of 5 to 30 parts by mass, although this is not limited. It is preferably 7 to 25 parts by mass, more preferably 10 to 22 parts by mass, and particularly preferably 10 to 20 parts by mass.

[0023] (B) Microcrystalline Cellulose (Intragranular Component) Microcrystalline cellulose is purified by partially depolymerizing α-cellulose obtained from fibrous plants with acid. It is a water-soluble polymer of the β-glucan family consisting of the crystalline portion of cellulose, in which glucose is linked by β-1,4 bonds (also known as microcrystalline cellulose). In the present disclosure, any crystalline cellulose may be used as long as it can be used as a pharmaceutical additive, preferably as an excipient, in the manufacture of tablets, and commercially available crystalline cellulose can be used. Examples of such crystalline cellulose include, but are not limited to, Ceolus® PH grade (e.g., PH-101, PH-102, PH-301, PH-302, PH-F20JP, etc.) (all manufactured by Asahi Kasei Corporation) and Avicel® PH grade (manufactured by IFF's Pharma Solutions). These crystalline celluloses have, but are not limited to, an average particle size (D50) of 20 to 100 μm, preferably 40 to 80 μm; a bulk density of 0.1 to 0.5 g / cm. ２ , preferably 0.2 to 0.4 g / cm ２ Contains crystalline cellulose.

[0024] The blending ratio of crystalline cellulose can be selected from a range of 1 to 5 parts by mass relative to 1 part by mass of starch in component (B). It is preferably 1 to 4 parts by mass, more preferably 1 to 3 parts by mass. As shown in Experimental Example 2 described below, blending crystalline cellulose can increase tablet hardness, but tends to decrease disintegration (prolong disintegration time) (Comparative Example 2-3). This problem can be improved by blending starch in addition to crystalline cellulose, and by using crystalline cellulose and starch in combination in the above-mentioned predetermined ratio, tablets with the desired hardness and disintegration properties can be prepared.

[0025] The content of crystalline cellulose in the present tablet is not particularly limited, as long as the blending ratio with starch in component (B) is within the above-mentioned range. For example, when the content of crystalline cellulose is converted to the content per 100 parts by mass of the granules, it can be in the range of 3 to 50 parts by mass. Preferably, it is, for example, 4 to 40 parts by mass, 4 to 35 parts by mass, 4 to 25 parts by mass, or 4 to 20 parts by mass, and more preferably, it is, for example, 10 to 40 parts by mass, 10 to 35 parts by mass, 10 to 25 parts by mass, or 5 to 15 parts by mass. Furthermore, although not limited thereto, it can be selected from the range of 1 to 40% by mass per 100% by mass of the total amount of the uncoated tablet. Preferably, it is 15 to 35% by mass or 15 to 30% by mass, and more preferably 20 to 30% by mass.

[0026] (C) Binder (Intragranular Component) The present tablet contains a binder. For example, the present tablet contains a binder as an intragranular component. This component is also referred to as "component (C)." Component (C) may be any pharmaceutical additive that can be used as a binder in the production of tablets. Although not limited thereto, it is preferably at least one selected from the group consisting of hydroxypropyl cellulose (HPC) and hypromellose. These may be used alone or in combination of two or more.

[0027] HPCs commercially available as pharmaceutical additives include HPCs having a molecular weight (GPS) in the range of 40,000 to 2,500,000 (viscosity when prepared in a 2% aqueous solution at 20°C: 2 to 6,000 mPa·s) (e.g., NISSO HPCSSL, SL, L, M, H, VH, etc.; all manufactured by Nippon Soda Co., Ltd.). In the present disclosure, preferably, HPCs having a molecular weight (GPS) in the range of 40,000 to 140,000 (said viscosity: 2 to 10 mPa·s); more preferably, HPCs having a molecular weight (GPS) in the range of 40,000 to 100,000 (said viscosity: 2 to 5.9 mPa·s); and particularly preferably, HPCs having a molecular weight (GPS) of 40,000 (said viscosity: 2 to 2.9 mPa·s) can be used.

[0028] Hypromellose commercially available as a pharmaceutical additive includes hypromellose having a degree of substitution of 28.0 to 30.0% for methoxy groups and 7.0 to 12.0% for hydroxypropoxy groups, and having a viscosity of 2.5 to 17.5 mPa s when prepared in a 2% aqueous solution at 20°C (e.g., Hypromellose TC-5 (registered trademark) [varieties: E, M, R, S]; all manufactured by Shin-Etsu Chemical Co., Ltd.). In the present disclosure, preferably, hypromellose having a viscosity in the range of 2.5 to 7.0 mPa s can be used; more preferably, hypromellose having a viscosity in the range of 2.5 to 5.1 mPa s can be used; and particularly preferably, hypromellose having a viscosity in the range of 2.5 to 3.5 mPa s can be used. Other commercially available hypromelloses as pharmaceutical additives include those having a degree of substitution of methoxy groups of 19.0 to 24.0% and a degree of substitution of hydroxypropoxy groups of 4.0 to 12.0%, and having a viscosity of 3.2 to 4.8 mPa s when prepared as a 2% aqueous solution at 20°C (e.g., hypromellose SB-4); and those having a degree of substitution of methoxy groups of 27.0 to 30.0% and a degree of substitution of hydroxypropoxy groups of 4.0 to 7.5% (e.g., hypromellose 65SH) (both manufactured by Shin-Etsu Chemical Co., Ltd.).

[0029] From the viewpoint of inhibiting the decomposition (stability) of component (A) in the tablet, component (C) is preferably blended in at a ratio of 1% by mass or more, preferably 1 to 10% by mass, and more preferably 1 to 5% by mass per 100% by mass of the total amount of the uncoated tablet.

[0030] When the content of component (C) is converted to the content per 100 parts by mass of the granulated product, it can be in the range of 1 to 10 parts by mass, although this is not limited thereto. Specifically, when HPC is used as component (C), the content can be in the range of 1 to 10 parts by mass, preferably 1 to 8 parts by mass, and more preferably 1 to 6 parts by mass per 100 parts by mass of the granulated product. When hypromellose is used as component (C), the content can be in the range of 1 to 6 parts by mass, preferably 1 to 4 parts by mass, and more preferably 1 to 3 parts by mass per 100 parts by mass of the granulated product. When HPC and hypromellose are used in combination as component (C), it is preferable to adjust the ratio and total amount of the two so that the hardness and disintegration property (disintegration time) of the tablet fall within the desired ranges described below. Although not limited thereto, it is preferable to adjust the total amount of HPC and hypromellose to 10 parts by mass or less per 100 parts by mass of the granulated product.

[0031] Component (C) is used in a state dissolved in water. Specifically, a granulated product containing components (A) to (C) can be prepared by adding component (C) in an aqueous solution to a powder mixture containing at least the aforementioned components (A) and (B) and granulating the mixture (wet granulation method). The concentration of the aqueous solution of component (C) used is not limited, but can usually be selected appropriately from the range of 0.5 to 20% by mass. It is preferably 1 to 15% by mass, and more preferably 2 to 10% by mass.

[0032] As shown in Experimental Example 1 described below, when preparing a granule, in both cases where component (C) was not used (Reference Comparative Example 1-2) and where component (C) was used in powder form without being dissolved in water (Reference Comparative Example 1-1), the stability of compound I (component (A)) in the produced tablet was low, and the production of related substances increased due to decomposition of compound I. In contrast, when preparing a granule, by spraying component (C) in solution form into a powder mixture containing components (A) and (B), the stability of compound I (component (A)) in the tablet can be increased and decomposition can be suppressed. In other words, in order to suppress the decomposition of component (A) in the tablet and maintain the stability and efficacy of component (A), it is important to incorporate component (C) in solution form, preferably in the form of an aqueous solution.

[0033] (Other Pharmaceutical Additives) The present tablet may contain other pharmaceutical additives as optional ingredients, provided that the effects described herein are not impaired. Examples of such pharmaceutical additives preferably include (D) excipients (excluding starch and crystalline cellulose), (E) disintegrants, and (F) lubricants. Other examples of pharmaceutical additives that can be optionally added include solubilizers, fluidizers, wetting agents, adsorbents, surfactants, pH adjusters, plasticizers, antioxidants, preservatives, colorants, flavoring agents (including sweeteners), and flavoring agents. These pharmaceutical additives can be used alone or in any combination of two or more.

[0034] (D) Excipients (excluding starch and crystalline cellulose) (intragranular component, extragranular component) The present tablet may contain an excipient (excluding starch and crystalline cellulose). For example, the present tablet may contain an excipient (excluding starch and crystalline cellulose) as an intragranular component, or as an intragranular component and an extragranular component. This component is also referred to as "component (D)." The component (D) may be any pharmaceutical additive that can be used as an excipient in the production of tablets (however, starch and crystalline cellulose are excluded). Non-limiting examples of component (D) include sugar alcohols (e.g., D-mannitol, erythritol, D-sorbitol, maltitol, isomalt, lactitol, xylitol, and powdered reduced maltose syrup), sugars (e.g., lactose, glucose, fructose, and sucrose), powdered cellulose, β-cyclodextrin, carmellose sodium, light anhydrous silicic acid, hydrous silicon dioxide, silicon dioxide, precipitated calcium carbonate, anhydrous calcium hydrogen phosphate, magnesium oxide, titanium oxide, calcium lactate, magnesium aluminometasilicate, synthetic hydrotalcite, talc, and kaolin. These components (D) can be used alone or in combination as ingredients of the tablet.

[0035] Preferred examples of component (D) include sugar alcohols and sugars. Preferred sugar alcohols are D-mannitol, and preferred sugars are lactose, more preferably D-mannitol.

[0036] D-mannitol commercially available as a pharmaceutical additive includes, for example, Mannit C (average particle size [D50, hereinafter the same]: 20 μm), Mannit P (average particle size: 50 μm), Mannit S (average particle size: 150 μm) (all manufactured by Mitsubishi Corporation Life Sciences Co., Ltd.), Pearitol 25C (average particle size: 25 μm), Pearitol 50C (average particle size: 50 μm), Pearitol 100SD (average particle size: 100 μm), and Pearitol 160 C (average particle size: 160 μm) (all manufactured by ROQUETTE), Nonpareil 108 (100) (average particle size: 100 μm), Nonpareil 108 (200) (average particle size: 200 μm), Granutol F (average particle size: 65 μm), Granutol S (average particle size: 83 μm), Granutol R (average particle size: 154 μm) (all manufactured by Freund Corporation), and Partec M200 (average particle size: 150 μm) (Merck).

[0037] The proportion of component (D) contained in the present tablet is not limited and can be selected from the range of 20 to 80% by mass per 100% by mass of the uncoated preparation, preferably 30 to 80% by mass, 40 to 80% by mass, 30 to 70% by mass, more preferably 40 to 60% by mass, 50 to 75% by mass, for example.

[0038] When component (D) is blended as an intragranular component, the proportion of component (D) per 100 parts by mass of the granules is not limited, but can be selected from the range of 25 to 70 parts by mass. It is preferably 35 to 65 parts by mass, and more preferably 40 to 60 parts by mass or 50 to 60 parts by mass. Furthermore, when component (D) is blended as an extragranular component in addition to the intragranular component, the total amount of component (D) per 100% by mass of the uncoated preparation can be appropriately set and adjusted so that it falls within the aforementioned range. Furthermore, when the component (D) blended as the intragranular component and the extragranular component is D-mannitol, the intragranular D-mannitol is preferably Mannit P (Mitsubishi Corporation Life Sciences Co., Ltd.), and the extragranular D-mannitol is preferably a direct compression grade mannitol, for example, Pearitol (ROQUETTE), Partec (Merck), or Granutol (Freund Corporation).

[0039] (E) Disintegrant The present tablet may contain a disintegrant. For example, the present tablet may contain a disintegrant as an extragranular component. This component is also referred to as "component (E)." Component (E) may be any pharmaceutical additive that can be used as a disintegrant in tablet production. Specific examples include, but are not limited to, carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, sodium starch glycolate, crospovidone, cation exchange resins, and low-substituted hydroxypropyl cellulose. These disintegrants may be used alone or in combination. As described above, component (E) is an extragranular component that is subsequently added to the granules (core granules) during the production of the present tablet. It is not necessarily required to be used as an intragranular component of the core granules, but it may also be used as an intragranular component of the granules, provided that the effects of the present invention are not impaired.

[0040] Preferred examples of the component (E) include low-substituted hydroxypropyl cellulose, crospovidone, and croscarmellose sodium, and more preferred are low-substituted hydroxypropyl cellulose and crospovidone.

[0041] The proportion of component (E) contained in the present tablet is not limited, but can be selected from the range of 1 to 20% by mass per 100% by mass of the uncoated tablet, preferably 1 to 15% by mass, more preferably 1 to 10% by mass, or 3 to 7% by mass.

[0042] (F) Lubricant (Extragranular Component) The present tablet may contain a lubricant. For example, the present tablet may contain a lubricant as an extragranular component. This component is also referred to as "component (F)." Component (F) may be any pharmaceutical additive that can be used as a lubricant in the production of tablets. Examples include stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, waxes, DL-leucine, sodium lauryl sulfate, magnesium lauryl sulfate, macrogol, and light anhydrous silicic acid. These may be used alone or in combination of two or more. Magnesium stearate is preferred.

[0043] The proportion of component (F) contained in the present tablet is not limited, but can be selected from the range of 0.1 to 10% by mass per 100% by mass of the uncoated tablet, preferably 0.2 to 5% by mass, and more preferably 0.5 to 3% by mass.

[0044] (G) Optional Pharmaceutical Additives Other Than (D) to (F) Pharmaceutical additives typically used in tablets can be added as other optional components. These pharmaceutical additives include, without limitation, solubilizers, fluidizing agents, surfactants, pH adjusters, plasticizers, colorants, flavoring agents (including sweeteners), and flavoring agents.

[0045] Examples of the solubilizing agent include magnesium oxide, calcium oxide, sodium citrate, magnesium chloride, sodium carbonate, and sodium bicarbonate.

[0046] Examples of flow agents include, for example, light anhydrous silicic acid, hydrous silicon dioxide, synthetic aluminum silicate, talc, and magnesium aluminometasilicate.

[0047] Examples of the surfactant include nonionic surfactants and anionic surfactants such as polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene, polyoxyethylene fatty acid esters, glycerin monostearate, sorbitan fatty acid esters (sorbitan monostearate, sorbitan monolaurate, etc.), polysorbates, sodium lauryl sulfate, macrogols, sucrose fatty acid esters, sodium alkyl sulfate, etc.

[0048] Examples of the pH adjuster include glycine, sodium bicarbonate, calcium hydrogen phosphate, sodium hydrogen phosphate, organic acids such as acetic acid, succinic acid, tartaric acid, fumaric acid, and citric acid, or salts thereof.

[0049] Examples of plasticizers include, for example, triethyl citrate, propylene glycol, polyethylene glycol, triacetin, and cetanol.

[0050] Examples of coloring agents include titanium oxide, talc, ferric oxide, yellow ferric oxide, food yellow No. 4, and aluminum lake food yellow No. 4, and preferably titanium oxide, ferric oxide, and yellow ferric oxide are used. The content of the coloring agent is less than 0.1% by weight of the total tablet weight.

[0051] Examples of flavoring agents include natural or synthetic sweeteners such as sucrose, D-sorbitol, xylitol, aspartame, and stevia (all of which are referred to as sweeteners), ascorbic acid, menthol, crude licorice extract, simple syrup, etc.; and examples of flavoring agents include, but are not limited to, menthol and mint.

[0052] (H) Coating Layer The present tablet may be an uncoated tablet (plain tablet, naked tablet) or a coated tablet (sugar-coated tablet, gelatin-coated tablet, film-coated tablet, etc.) having a coating layer (coating layer) on its surface.

[0053] When the present tablet is a coated tablet, the coating material used to form the coating layer can be appropriately selected and used based on the technical common sense in the art depending on the purpose.

[0054] For example, sugars such as sucrose, D-mannitol, erythritol, sorbitol, xylitol, and trehalose are used to prepare sugar-coated tablets, while water-soluble coating agents such as hydroxypropyl cellulose (HPC), hypromellose, polyvinyl alcohol, and pullulan are used to prepare film-coated tablets.

[0055] If necessary, these coating materials may contain one or more of a colorant, a flavoring agent (including a sweetener), a fragrance, a light-blocking agent, a plasticizer, etc. The blending ratio of these colorants, etc. in the coating layer is not limited, but is appropriately adjusted so that it falls within the range of 0 to 20% by mass relative to 100% by mass of the total amount of the components forming the coating layer.

[0056] In coated tablets, the proportion of the coating layer (coating layer, film) is not limited and can usually be appropriately selected from the range of 1 to 12 parts by mass per 100 parts by mass of the uncoated tablet, preferably 1 to 10 parts by mass, and more preferably 2 to 8 parts by mass.

[0057] (Use of the present tablet) Compound I is an excellent prostaglandin I ２ (P.G.I. ２ It is known that these compounds have a receptor agonist effect and exhibit various medicinal effects such as platelet aggregation inhibition, vasodilatory effect, bronchial smooth muscle dilation, lipid deposition inhibition, and leukocyte activation inhibition (Patent Documents 1 to 9, Non-Patent Documents 1 to 14).

[0058] Therefore, the present tablet is PGI ２Diseases involving cerebrovascular disease, for example, arteriosclerosis obliterans (Patent Document 9), transient ischemic attack (TIA), diabetic neuropathy (see, for example, Non-Patent Document 1), diabetic gangrene (see, for example, Non-Patent Document 1), peripheral circulatory disorders (for example, chronic arteriosclerosis, chronic arterial occlusion) (see, for example, Non-Patent Document 2), intermittent claudication (see, for example, Non-Patent Document 3), peripheral arterial embolism, Raynaud's disease (see, for example, Non-Patent Document 4 and Non-Patent Document 5), collagen diseases (for example, systemic lupus erythematosus, scleroderma) (see, for example, Patent Document 3 and Non-Patent Document 6), mixed connective tissue disease, vasculitis syndrome , re-occlusion / restenosis after percutaneous coronary intervention (PTCA), arteriosclerosis, thrombosis (e.g., acute cerebral thrombosis, pulmonary embolism) (see, for example, Non-Patent Documents 5 and 7), hypertension, pulmonary hypertension such as pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension (see, for example, Non-Patent Documents 8 and 9), ischemic diseases (e.g., cerebral infarction, myocardial infarction) (see, for example, Non-Patent Document 10), angina pectoris (e.g., stable angina pectoris, unstable angina pectoris) (see, for example, Non-Patent Document 11), glomerulonephritis (see, for example, Non-Patent Document 12), diabetic nephropathy (see, for example, Non-Patent Document 1), chronic The following diseases are also known: renal failure (see, for example, Patent Document 4), allergies, bronchial asthma (see, for example, Non-Patent Document 13), ulcers, bedsores, restenosis after coronary interventions such as atherectomy and stent placement, thrombocytopenia due to dialysis, diseases involving organ or tissue fibrosis [for example, kidney diseases (e.g., tubulointerstitial nephritis) (see, for example, Patent Document 3), respiratory diseases (e.g., interstitial pneumonia (pulmonary fibrosis) (see, for example, Patent Document 3), chronic obstructive pulmonary disease (see, for example, Non-Patent Document 14), etc.], digestive diseases (e.g., liver cirrhosis, viral hepatitis, chronic pancreatitis, stomach ulcers, etc.), and the like. gastric cancer), cardiovascular diseases (e.g., myocardial fibrosis), bone and joint diseases (e.g., myelofibrosis, rheumatoid arthritis), skin diseases (e.g., postoperative scars, burn scars, keloids, hypertrophic scars), obstetric diseases (e.g., uterine fibroids), urinary diseases (e.g., benign prostatic hyperplasia), other diseases (e.g., Alzheimer's disease, sclerotic peritonitis, type I diabetes, postoperative organ adhesions), erectile dysfunction (e.g., diabetic erectile dysfunction, psychogenic erectile dysfunction, psychotic erectile dysfunction, erectile dysfunction due to chronic renal failure, erectile dysfunction after pelvic surgery for prostate removal, vascular erectile dysfunction due to aging or arteriosclerosis) (e.g.,see Patent Document 7), inflammatory bowel diseases (e.g., ulcerative colitis, Crohn's disease, intestinal tuberculosis, ischemic colitis, intestinal ulcers associated with Behcet's disease) (see, for example, Patent Document 5), gastritis, gastric ulcer, ischemic eye disease (e.g., retinal artery occlusion, retinal vein occlusion, ischemic optic neuropathy), sudden hearing loss, avascular bone necrosis, nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., diclofenac, meloxicam, oxaprozin, nabumetone, indomethacin, ibuprofen, ketoprofen, naproxen, The present tablet is useful as a preventive or therapeutic agent for intestinal injury (for example, ulcers and mucosal injury such as erosion occurring in the duodenum, small intestine, or large intestine, but is not particularly limited as long as the injury occurs in the duodenum, small intestine, or large intestine) associated with administration of celecoxib (see, for example, Patent Document 8), and symptoms (for example, paralysis, hypoesthesia, pain, numbness, and decreased walking ability) associated with spinal canal stenosis (for example, cervical spinal canal stenosis, thoracic spinal canal stenosis, lumbar spinal canal stenosis, diffuse spinal canal stenosis, and sacral stenosis) (see, for example, Patent Document 6). The tablet is also useful as a promoter of angiogenesis therapy such as gene therapy or autologous bone marrow cell transplantation, and as an angiogenesis promoter in peripheral vascular reconstruction or angiogenesis therapy.

[0059] (Characteristics of the tablet) The tablet has at least the following characteristics (a), (b), and (c). Therefore, the tablet is characterized by having desired hardness and disintegrability while suppressing a decrease in the stability of Compound I, the active ingredient in the tablet (while maintaining stability and efficacy).

[0060] (A) Good stability (inhibition of the production of related substances due to decomposition of Compound I) The present tablet has high stability of component (A) (compound I), and the production of related substances (related substances of component (A)) due to the decomposition of component (A) that may occur over time is inhibited. The stability can be determined by comparing the content of related substances produced in the tablet before and after a storage test. Specifically, the stability can be determined according to the following criteria (i) and (ii) based on the content ratio of related substances relative to the total amount of component (A) and related substances (100%) contained in the tablet after the storage test. When determined based on these criteria, if both (i) and (ii) are satisfied, the present tablet can be evaluated as having characteristic (A).

[0061] (i) After storage for one month under open conditions at 40°C and 75% RH in a dark place, the content of the related substances is 1.5% or less, based on 100% of the total amount of component (A) and related substances. (ii) After storage for one month under open conditions at 60°C in a dark place, the content of the related substances is 1.5% or less, based on 100% of the total amount of component (A) and related substances. Here, "open conditions at 40°C and 75% RH" means that the tablet is placed in an open container and the sample is exposed to conditions of 40°C and 75% RH. "Open conditions at 60°C" means that the tablet is placed in an open container and the sample is exposed to conditions of 60°C. The measurement of the content of related substances in the tablet will be explained in detail in the Examples section below, but simply, it can be determined by quantifying the amount of related substances contained in the tablet after storage using high-performance liquid chromatography.

[0062] (a) Good Hardness: The hardness of the present tablet is not particularly limited, but it is desirable that it be practically sufficient. For example, uncoated tablets (plain tablets) preferably have a hardness that does not cause tableting problems such as scratches, cracks, or chips when subjected to the compression molding process by tableting. More specifically, when hardness is measured according to the tablet hardness test method (G6-4-180) described in the Reference Information (G6, Preparations) of the 18th Edition of the Japanese Pharmacopoeia, it is preferable that the hardness exhibits a hardness of 30 N or more. The hardness can be measured using a load cell tablet hardness tester (Okada Seiko).

[0063] (c) Good disintegrability: In administration by the simple suspension method, the drug is generally placed in a syringe or container, an appropriate amount of warm water (approximately 55°C) is added, and the drug is left for 5 to 10 minutes, shaken, and then the suspended drug is administered directly or via a tube, etc. To enable administration by the simple suspension method, it is desirable for the tablet to exhibit rapid disintegration. Specifically, this tablet has the following disintegration characteristics:

[0064] (i) Uncoated tablets: The tablets have the property of disintegrating within a specified time in the disintegration test (without using auxiliary discs) specified in the 18th edition of the Japanese Pharmacopoeia using water at 37±2°C as the test liquid. If an uncoated tablet disintegrates within 180 seconds (disintegration time: within 180 seconds), it can be determined that the tablet meets the formulation standards for this tablet. The preferred disintegration time is within 150 seconds, and the more preferred disintegration time is within 120 seconds. Here, "disintegration time" refers to the time required for all six test tablets to disintegrate in one disintegration test. Specifically, one tablet is placed in each of six glass tubes, and the test starts when the tester is activated. The time from this point until all test tablets have disintegrated is measured as the disintegration time (seconds).

[0065] (ii) In the case of coated tablets, the coated tablets after coating have the property of disintegrating within 300 seconds in the disintegration test (without using an auxiliary disc). Preferably, they have the property of disintegrating within 240 seconds, more preferably within 180 seconds. If the disintegration time of a coated tablet is within 300 seconds, the tablet can be determined to meet the tablet formulation standards. Preferably, the disintegration time of an uncoated tablet before coating is within 180 seconds, and the disintegration time of a coated tablet after coating is within 300 seconds.

[0066] The following method can be used to estimate the disintegration time of an uncoated tablet before coating from a coated tablet. For example, a coated tablet is divided into equal halves using a tablet cutter or the like, and the two divided pieces are placed in the same glass tube and subjected to the disintegration test. The disintegration time is the time required for both divided pieces to disintegrate. In other words, if both pieces disintegrate within 180 seconds, it can be determined that the disintegration time of the uncoated tablet before coating of the coated tablet is within 180 seconds.

[0067] (Size, etc. of the Tablet) The tablet preferably has a total mass of about 40 to 200 mg, preferably about 40 to 150 mg, and more preferably about 40 to 60 mg per tablet. Examples of such tablets include uncoated tablets characterized by a total mass of 45 to 55 mg per tablet, a content of component (A) of 50 to 1000 μg, preferably 75 to 800 μg, more preferably 100 to 600 μg, and even more preferably 180 to 220 μg per tablet, a tablet diameter of 4 mmφ or more (e.g., a tablet diameter of 4 to 8 mmφ, 4 to 7 mmφ, 4 to 6 mmφ, etc.), and a porosity of 10% or less, and coated tablets in which the uncoated tablets are coated with a coating material. The porosity of the uncoated tablets may be 10% or less, but is preferably 5 to 10%, and more preferably 6 to 9%.

[0068] The porosity of an uncoated tablet can be calculated by the following formula: Porosity (%) = (1 - theoretical volume / actual volume) x 100

[0069] Here, "actual volume" refers to the actual volume (capacity) of an uncoated tablet, and can be calculated, for example, from the short side, long side, and thickness of the uncoated tablet. For example, if the uncoated tablet has a disc-like (cylindrical) shape, the actual volume can be calculated from the circle area calculated from the radius of the circle and the thickness. It can also be calculated using tablet volume calculation software or online websites (https: / / www.notter.com / jp / tablettenvolumen-berechnung / ).

[0070] "Theoretical volume" refers to the volume calculated by dividing the mass of an uncoated tablet by true density. True density refers to a density calculated using only the volume occupied by the solid itself, excluding surface pores and internal voids. True density can be measured by thoroughly pulverizing a test sample to eliminate open pores and using a gas displacement pycnometer. Specifically, true density can be determined by completely degassing and replacing the voids in the test sample with helium, and then calculating the relationship between its weight and volume.

[0071] The present tablet is not particularly limited as long as the total mass per tablet is within the above range and the porosity is adjusted to be within the above range, but it is desirable that the tablet thickness is within the range of 2 to 3 mm. The thickness is the maximum distance between the upper and lower ends of the tablet as viewed from the side, sandwiched perpendicularly between two parallel surfaces.

[0072] The shape of the tablet is not particularly limited, and includes tablets having any shape such as a circle, an oval, or a diamond when viewed from the front (top), preferably a circle when viewed from the front. In the case of a circle, the tablet diameter is the diameter, and in the case of an oval or diamond, the tablet diameter is the major axis.

[0073] The tablets may be administered once or multiple times (e.g., 2 to 6 times) per day. The dosage per dose (single dose) can be selected depending on the sex, age, severity of the disease, etc., and may be administered, for example, one tablet or multiple tablets (e.g., 2 to 6 tablets) per dose.

[0074] (II) Manufacturing Method of the Tablet The tablet can be manufactured according to a conventional method in the art depending on its shape. The tablet can be preferably manufactured using a wet granulation method (wet granule compression method).

[0075] An embodiment of the manufacturing method according to the present disclosure (hereinafter also referred to as "the manufacturing method") includes a method of manufacturing by powder mixing components (A) and (B), and optionally other components (e.g., component (D), etc.), adding component (C) prepared in a solution form to the mixture, granulating (wet granulation), drying, optionally sizing the particles, and then blending components (E) and (F) with the mixture, followed by compression molding (tabletting). Another embodiment of the manufacturing method includes a method of manufacturing by powder mixing components (A) and (B), and optionally other components (e.g., component (D), etc.), adding component (C) prepared in a solution form to the mixture, granulating (wet granulation), drying, optionally sizing the particles, and then blending components (E) and (F) with other components (e.g., component (D)) with the mixture, followed by compression molding (tabletting).

[0076] This process can be described step by step as follows: (1) a step of powder-mixing at least components (A) and (B) to prepare a powder mixture (mixing step), (2) a step of adding a solution containing component (C) to the powder mixture and granulating the mixture to obtain a granulated product (granulation step), (3) a step of drying the granulated product and, if necessary, sizing the product (sizing step), (4) a step of blending at least components (E) and (F) with the sizing granulated product (core granules) (extragranular component mixing step), and (5) a step of compression-molding the mixture obtained in the extragranular component mixing step (compression molding step).

[0077] In the step (1) (mixing step), component (D) can be blended in addition to components (A) and (B). Also in the step (4) (extragranular component blending step), component (D) can be blended in addition to components (E) and (F).

[0078] The present tablet may be an uncoated tablet that is not coated, but may be coated if necessary. When the present tablet is a coated tablet having a coating layer, the tablet can be produced by further subjecting an uncoated tablet (plain tablet) produced by the above steps (1) to (5) to the coating step (6).

[0079] Each step is briefly described below: (1) Mixing Step The powder mixture components used for granulation, including at least the components (A) and (B), and optionally other optional components, may be previously pulverized using a pulverizer (such as a cutter mill, rotary mill, hammer mill, roll mill, shear mill, ball mill, or jet mill), and may also be classified as needed.

[0080] In the mixing step, components (A) and (B), and optionally other components (e.g., component (D)), can be mixed by any method that can uniformly mix the powders of these components, and there are no particular limitations on the mixing method. An example of a method that involves feeding the raw materials into a fluidized bed granulation dryer and mixing them while fluidizing them is not particularly limited. Other examples of mixing methods include using a mixer such as a rotary mixer (e.g., a V-type mixer or a double cone mixer) or a stationary mixer (e.g., a ribbon mixer or a screw mixer).

[0081] The mixing ratio of components (A) and (B) and the mixing ratio of other optional components (e.g., component (D)) are as described in section (I) above, and the descriptions therein are incorporated herein by reference. As described in section (I), in step (1), the mixing ratio of starch to crystalline cellulose in the powder mixture is adjusted so that 1 to 5 parts by mass of crystalline cellulose is present per 1 part by mass of starch. The ratio is preferably 1 to 4 parts by mass, and more preferably 1 to 3 parts by mass.

[0082] (2) Granulation Step Granulation can be carried out by adding a solution of component (C), preferably an aqueous solution of component (C), to the powder mixture containing at least components (A) and (B) prepared above (wet granulation). The concentration of the aqueous solution of component (C) used is not limited, but can be selected appropriately from the range of typically 0.5 to 20% by mass, preferably 1 to 15% by mass, and more preferably 2 to 10% by mass. The amount of component (C) can be adjusted so that the content per 100% by mass of the uncoated preparation produced is 1% by mass or more, calculated on a dry weight basis. For example, the proportion per 100 parts by mass of the granulated product can be selected from the range of 1 to 10 parts by mass, calculated on a dry weight basis. As described in section (I) above, the amount of component (C) can be set within a suitable range depending on the type of component (C).

[0083] The granulation method may be any wet granulation method (wet granule compression method) commonly used in the technical field, and examples thereof include, without limitation, an extrusion granulation method in which a solution of component (C) is added to a raw material powder mixture, the mixture is kneaded, and the kneaded mixture is extruded through a screen to form granules; a crushing granulation method in which the kneaded mass prepared by the above method is cut with the rotating blade of a granulator and ejected through the outer screw holes by centrifugal force; a tumbling granulation method in which a solution of component (C) is added to a raw material powder mixture, the humidified powder is subjected to rotational motion or vibration to agglomerate, and nearly spherical particles are obtained; a fluidized bed granulation method in which a raw material powder mixture is fluidized from below by a hot air current, and then a solution of component (C) is sprayed onto it to granulate; and an agitation granulation method in which the raw material powder is placed in a container, and while stirring with a rotating blade, a solution of component (C) is added, and the raw material powder particles are agglomerated into spherical particles.

[0084] (3) Sizing Step The granules prepared in step (2) above can be dried using a drying method commonly used in the art. For example, various drying devices such as a parallel flow box dryer, a through-flow box dryer, a fluidized bed dryer, or a vacuum dryer can be used. In the box, through-flow, and fluidized bed methods, the granules are preferably dried by applying air (hot air) heated to about 60 to 90°C.

[0085] The sizing method is not particularly limited, and any sizing method commonly used in the art can be used. Preferably, the sizing is performed to a particle size such that there are no coarse particles of 1000 μm or more and the average particle size of the granulated product is in the range of 50 to 400 μm. Here, the "average particle size" refers to the average particle size calculated from the results of the sieving method of Method 2 of the Powder Particle Size Measurement Method specified in the General Test Methods of the Japanese Pharmacopoeia, 18th Edition.

[0086] (4) Extragranular Component Mixing Step This step is a step in which various powdery components (extragranular components) are added to and mixed with the granules prepared in the above (3) sizing step.

[0087] Examples of the extragranular component to be added to the granules include component (E) and component (F). In addition to component (E) and component (F), other components (e.g., component (D)) can also be added. It is preferable that all of these components are in powder form. Powdered components (D), (E), and (F) are preferred as extragranular components. As shown in Experimental Example 5 below, by using component (D) as the extragranular component to be added to the granules, the disintegration property of the produced tablets can be improved (the disintegration time can be shortened).

[0088] As in the step (1) above, the mixing may be carried out by any method that can uniformly mix the sized granules and the powdery extragranular component, and can be carried out by using a mixer such as a rotary mixer or a static mixer.

[0089] (5) Compression molding step The compression molding step can be carried out by tableting. Tableting can be carried out by a tableting method generally used in the industry. Specifically, it can be carried out using a conventional tableting machine such as a single punch tableting machine or a rotary tableting machine.

[0090] Here, the tableting pressure and other tableting conditions are not limited as long as they can produce tablets having the effects of the present invention, but examples include tableting pressures and tableting conditions that result in a porosity of 10% or less in uncoated tablets.

[0091] Alternatively, an external lubrication method may be used in which component (F) is not mixed in the (4) extragranular component mixing step, but component (F) is sprayed onto the punch and die before the (5) compression molding step, and then the (5) compression molding step is carried out.

[0092] (6) Coating Step For coating, a coating method generally used in the technical field can be adopted. Specific examples include pan coating, fluidized bed coating, and ventilated dry pan coating, and coating can be performed using a coating device suitable for these methods.

[0093] The coating can be carried out by coating the surface of the uncoated tablets produced in the steps (1) to (5) with a coating liquid prepared by blending the coating material described in the above section (I) with a colorant, a flavoring agent (including a sweetener), and / or a fragrance, etc., as needed.

[0094] The proportion of the coating layer (degree of coating) is preferably such that the disintegration property of the uncoated tablet is not significantly impaired, and is preferably adjusted so that the disintegration time of the coated tablet produced in the coating step is within 300 seconds, for example. The proportion of the coating layer per 100 parts by mass of the uncoated tablet is usually adjusted to 1 to 12 parts by mass in dry weight, preferably 1 to 10 parts by mass, more preferably 2 to 8 parts by mass.

[0095] (Effects of tablet manufacturing method) According to the present tablet manufacturing method, the production of related substances due to decomposition of component (A) (compound I) in the tablet is suppressed (the decrease in stability of component (A) is suppressed), and tablets having the desired hardness and disintegrability can be manufactured.

[0096] (III) Method for inhibiting decomposition of selexipag and improving hardness and disintegration property of selexipag-containing tablets The present invention provides a method for inhibiting decomposition of component (A) and adjusting hardness and disintegration time within desired ranges in a tablet containing (A) Compound I, (B) starch and crystalline cellulose, (C) a binder, (E) a disintegrant, and (F) a lubricant (hereinafter also referred to as "the method"). The tablet may further contain (D) an excipient. The tablet is an uncoated tablet or a coated tablet in which a coating material is applied to the uncoated tablet.

[0097] Here, the desired range of tablet hardness is 30 N or more, converted into the hardness of an uncoated tablet. The method for measuring and evaluating the hardness of an uncoated tablet is as described in section (I) above, and details thereof are described in the Examples section. The desired range of the disintegration time of an uncoated tablet is within 180 seconds. The method for measuring and evaluating the disintegration time of an uncoated tablet is as described in section (I) above, and details thereof are described in the Examples section. The desired range of the disintegration time of a coated tablet is within 300 seconds. It is preferable that the coated tablet is adjusted so that the disintegration time of the uncoated tablet before coating is within 180 seconds, and the disintegration time of the uncoated tablet can be determined by dividing the coated tablet equally in half and measuring the disintegration time of the divided pieces, as described above.

[0098] This method is characterized in that component (C) prepared in the form of a solution (preferably an aqueous solution) is added to a powder mixture containing at least components (A) and (B) (preferably a powder mixture containing components (A), (B), and (D)) so that the content is 1% by mass or more, calculated as the dry weight per 100% by mass of the uncoated tablet, preferably 1 to 10% by mass, and more preferably 1 to 5% by mass.

[0099] When the blending ratio of component (C) is converted into the content per 100 parts by mass of a granulated product containing at least components (A), (B), and (C) (preferably a granulated product containing components (A), (B), (D), and (C)), the range is, but is not limited to, 1 to 10 parts by mass. Specifically, when HPC is used as component (C), the range is 1 to 10 parts by mass, preferably 1 to 8 parts by mass, and more preferably 1 to 6 parts by mass per 100 parts by mass of the granulated product. Furthermore, when hypromellose is used as component (C), the range is 1 to 6 parts by mass, preferably 1 to 4 parts by mass, and more preferably 1 to 3 parts by mass per 100 parts by mass of the granulated product. By blending component (C) in the above-mentioned ratio in the form of a solution, the stability of component (A) in the tablet can be increased and the generation of related substances due to its decomposition can be suppressed.

[0100] This method is also characterized in that the ratio of starch to crystalline cellulose in component (B) is adjusted so that the hardness and disintegration time of the uncoated tablet fall within the desired ranges.

[0101] The ratio of starch to crystalline cellulose in component (B) is not limited, but can be adjusted so that the ratio of crystalline cellulose to 1 part by mass of starch is preferably in the range of 1 to 5 parts by mass. It is preferably 1 to 4 parts by mass, more preferably 1 to 3 parts by mass. In tablets containing components (A), (C), (E), and (F), and preferably also component (D), adding crystalline cellulose as component (B) can produce uncoated tablets with the desired hardness, but tends to reduce disintegration properties and make it impossible to achieve the desired disintegration time. In contrast, by using starch in addition to crystalline cellulose as component (B) and setting the ratio of crystalline cellulose to 1 part by mass of starch within the above range, it is possible to maintain the stability of component (A) in the tablet as described above, while achieving improved hardness due to the addition of crystalline cellulose and ameliorating the decrease in disintegration properties due to the addition of crystalline cellulose, thereby obtaining uncoated tablets and coated tablets with the desired hardness and disintegration properties.

[0102] In this method, the components (A), (B), (C), (D), (E), and (F) are all as described in sections (I) and (II), and the types and blending ratios thereof, as well as the method for producing tablets containing these components, can be determined from the above descriptions.

[0103] As described above, in this specification, the terms "comprise" and "contain" encompass the meanings of "consist of" and "consist essentially of."

[0104] The present invention will be described below using experimental examples to aid in understanding the configuration and effects of the present invention. However, the present invention is not limited by these experimental examples. Unless otherwise specified, the following experiments were carried out at room temperature (25±5°C) and atmospheric pressure. Unless otherwise specified, "%" and "parts" in the following descriptions mean "% by mass" and "parts by mass," respectively.

[0105] The materials used in the following experimental examples are listed in Table 1.

[0106] Test Methods The following test methods were used to evaluate the tablet properties in Experimental Examples 1 to 6 below.

[0107] (1) Disintegration Test: Using water heated to 37°C as the test liquid, the experiment was conducted according to the General Test Method [Disintegration Test] (Method A) (without using an auxiliary disc) of the 18th Edition of the Japanese Pharmacopoeia. Specifically, one test sample (test tablet) was placed in each of six glass tubes containing the test liquid, and the tester was operated at 37°C. The test was started when the tester was operated, and the time from when all the test tablets disintegrated was measured as the disintegration time (seconds). Disintegration was determined by observing the condition of the test tablet in the glass tube. Specifically, the test tablet was considered to have disintegrated if no test tablet residue was found in the glass tube, or if residue was found but was a soft substance that clearly did not retain its original shape, or if it was fragments of insoluble tablet coating. For coated tablets, the above disintegration test was also performed on two tablet slices prepared by dividing the tablets equally in half using a tablet cutter.

[0108] If the test tablet (the undivided tablet in the case of an uncoated tablet, or both the halves of the tablet slices in the case of a coated tablet) disintegrated within 180 seconds, it was judged to have good disintegration properties "◯", and if not, it was evaluated as poor disintegration properties "×". Note that the undivided coated tablet was used as the test tablet, and if this test tablet disintegrated within 300 seconds, it was judged to have good disintegration properties "◯", and if not, it was evaluated as poor disintegration properties "×".

[0109] (2) Hardness Test This test was carried out in accordance with the tablet hardness test method (G6 preparation related <G6-4-180>) described in the reference information of the 18th edition of the Japanese Pharmacopoeia. Specifically, a tablet was sandwiched between two pressure plates, and one of the pressure plates was moved at a constant speed to obtain the force (N) just before the tablet broke. Here, "breakage" refers to the state in which a break occurs in the tablet cross section.

[0110] Hardness tester used: Load cell tablet hardness tester (manufactured by Okada Seiko Co., Ltd.). Pressure plates: Two parallel pressure plates with smooth contact surfaces with the tablet and larger than the actual tablet contact area were used. While the pressure plates were moving, the tablet was prevented from being deformed by bending or twisting. Load application rate: Measurements were performed using a device (cylinder: manufactured by SMC Corporation) capable of maintaining a constant pressure plate movement speed. The pressure plates were moved at a slow speed (0.5 mm / sec) from just before contact with the tablet, thereby suppressing fluctuations in the load application rate. Tablet orientation: Round tablets without a score line were typically measured between two pressure plates to allow compression relative to the tablet diameter. For scored tablets, the tablet was placed so that the score line was perpendicular to the pressure plates. For irregularly shaped or complex-shaped tablets, measurements were preferably performed in an orientation that was easily reproducible, and the load was applied parallel to the diameter or major axis. This procedure was performed on 10 samples, and the average value was taken as the tablet hardness (N).

[0111] If the hardness of the test tablet was 30 N or more, it was judged to have a good hardness (◯), and if not, it was evaluated as having a poor hardness (×).

[0112] (3) Stability test The produced tablets were stored in an unpackaged state in a dark environment for one month under open conditions of 40°C / 75% RH (referred to as "40°C / 75% RH" in the tables below) and / or under open conditions of 60°C (referred to as "60°C" in the tables below). The contents of Compound I and related substances in the tablets before and after storage were measured using high performance liquid chromatography.

[0113] Here, the "related substance" refers to a substance that corresponds to the peak (main peak) that is mainly detected, other than the peak derived from Compound I, among multiple peaks detected in the HPLC chromatogram when a tablet containing Compound I is left to stand for one month under the above conditions and then subjected to high performance liquid chromatography.

[0114] The content of Compound I and related substances in tablets is measured by HPLC by dissolving the tablet in a solvent to obtain a sample (test sample) and subjecting it to HPLC. The test sample contains the solvent used for dissolution and components other than Compound I and related substances (hereinafter referred to as "other components"). Therefore, the other components and solvent contained in the tablet are subjected to HPLC in advance under the same conditions as those used for measurement, and the positions of each peak are confirmed. Next, the peaks of the other components and the solvent can be separated from the HPLC chromatogram obtained for the test sample to detect the peaks of Compound I and related substances. For the related substances, the ratio of the related substances is determined by the area percentage method. In the area percentage method, the sum of the peak areas of each component obtained on the chromatogram, excluding the solvent peak, is set to 100, and the content ratio of the related substances contained in the tablet can be determined from the ratio of the peak areas of each component.

[0115] The measurement by high performance liquid chromatography was carried out under conditions that allowed Compound I and related substances to be separated and detected from the solvent peak and other components. Specifically, the test sample was subjected to HPLC using a solvent commonly used in HPLC (e.g., acetonitrile) as the mobile phase, and detection was carried out with a UV detector.

[0116] If the following conditions (i) and (ii) were met, the product was judged to have good stability (◯), and if these conditions were not met, the product was rated as having poor stability (×): (i) After storage for one month in an open place at 40°C and 75% RH, the content of the related substance is 1.5% or less; (ii) After storage for one month in an open place at 60°C, the content of the related substance is 1.5% or less.

[0117] (4) Measurement of Porosity of Uncoated Tablets The porosity of uncoated tablets was determined by the following formula: [Formula] Porosity (%) = (1 - theoretical volume / actual volume) x 100 The theoretical volume was calculated from the true density measured using a gas displacement pycnometer.

[0118] Experimental Example 1 Evaluation of the stability of Compound I depending on the blending and addition method of binder Various tablets (uncoated tablets) (Reference Examples 1-1 and 1-2, Reference Comparative Examples 1-1 and 1-2) were produced according to the formulations shown in Table 2, and the effects of the blending of binder (component (C)) and its addition method on the stability of Compound I (component (A)) in the tablets were evaluated.

[0119]

[0120] (1) Preparation of Powder Mixture [Mixing and Granulation, or Mixing] (a) Reference Examples 1-1 and 1-2: Components (A), (B), and (D) were placed in a fluidized bed granulation dryer (MP-01, Powrex Corporation), and a 5% aqueous solution of component (C), which had been dissolved in water in advance, was added by spraying to granulate. The resulting granules were then placed in a plastic bag, and components (E) and (F) were blended therein and simply mixed for 1 minute to prepare a granulated mixture containing components (A) to (F).

[0121] (b) Reference Comparative Example 1-1: The components (A), (B), (D), and powdered components (C), (E), and (F) were simply mixed in a plastic bag for 1 minute to prepare a powder mixture.

[0122] (c) Reference Comparative Example 1-2: Without using component (C), component (A), component (B), component (D), component (E), and component (F) were simply mixed in a plastic bag for 1 minute to prepare a powder mixture.

[0123] (2) Preparation of Tablets (Uncoated Tablets) [Tableting] The granulated mixture and powder mixture prepared in (1) above were compressed into tablets with a mass of 50 mg / tablet using a rotary tablet press (VELA5, Kikusui Seisakusho Co., Ltd.: rotation speed 30 rpm) in a circular tablet mold with a diameter of 5 mm so that the tablet porosity was 10% or less, and disc-shaped uncoated tablets (Reference Examples 1-1 to 1-2, Reference Comparative Examples 1-1 to 1-2) were obtained. For example, a true density of 1.45 g / cm ３ When this occurs, the actual volume is 38.1 mm ３ Compression mold as follows:

[0124] (3) Evaluation of stability of Compound I According to the stability test method described above, the ratio (%) of related substances in the uncoated tablets (Reference Examples 1-1 to 1-2, Reference Comparative Examples 1-1 to 1-2) produced was measured to evaluate stability. The results are shown in Table 3-1. The actual measured values ​​are shown in Table 3-2.

[0125]

[0126]

[0127] As shown in Table 3-1, an increase in related substances was observed in tablets produced without blending component (C) as a binder (Reference Comparative Example 1-2), confirming that the stability of Compound I in the tablet was low. Furthermore, an increase in related substances was also observed in tablets produced by blending component (C) in powder form (Reference Comparative Example 1-1), confirming that the stability of Compound I in the tablet was low. In contrast, in tablets produced by blending component (C) in the form of an aqueous solution as a binder (Reference Examples 1-1 and 1-2), the increase in related substances was suppressed (decomposition of Compound I in the tablet was suppressed), confirming that the stability of Compound I in the tablet was high. Furthermore, the content of component (C) differed between Reference Examples 1-1 and 1-2, and it was confirmed that the higher the content of component (C), the more the increase in related substances was suppressed.

[0128] From the above, it was found that in tablets containing Compound I, in order to increase the stability of Compound I in the tablet (suppress the decomposition of Compound I) and suppress the generation of related substances, it is necessary to add a binder, and moreover, it is necessary to add the binder in the form of a solution in the tablet manufacturing process (particularly the granulation process) (wet granulation). It was also found that the decomposition of Compound I is suppressed depending on the amount of binder added.

[0129] Experimental Example 2: Investigation and evaluation of the blending ratio of starch and crystalline cellulose The effect of the ratio of starch to crystalline cellulose in component (B) used in the production of tablets on the stability of Compound I in the tablets, as well as the hardness and disintegration properties of the tablets, was evaluated.

[0130] (1) Preparation of Granulated Product (Core Granules) and Uncoated Tablets Granulated products (core granules) were prepared using the components (A) to (D) according to the formulations shown in Table 4, using the same wet granulation method as in Reference Example 1-1. This was placed in a plastic bag, and the powdered components (E) and (F) were added and mixed to prepare a granulated mixture. The prepared granulated mixture was compressed into tablets using the same rotary tablet press as in Reference Example 1-1 under the same conditions, using a circular tablet mold with a diameter of 5 mm, so that the tablet porosity was 10% or less, and uncoated tablets (Examples 2-1 to 2-2, Comparative Examples 2-1 to 2-3) with a mass of 50 mg / tablet were prepared.

[0131]

[0132] (2) Evaluation of Compound I Stability and Tablet Properties (Hardness, Disintegration Time) The stability, hardness, and disintegration time of Compound I were measured and evaluated for the uncoated tablets (Examples 2-1 to 2-2, Comparative Examples 2-1 to 2-3) produced according to the above-described method in accordance with the test methods (stability test, hardness test, disintegration test) described above. The results are shown in Table 5-1. The actual measured values ​​are shown in Table 5-2.

[0133]

[0134]

[0135] As shown in Table 5-1, regardless of the blending ratio of starch and crystalline cellulose, by blending a binder in solution during tablet production, the stability of Compound I was good even after storage under open conditions (40°C / 75% RH open conditions, 60°C open conditions). As shown in Table 5-1, the hardness of Comparative Examples 2-1 and 2-2 did not meet the formulation standard (30N or more). Furthermore, although the hardness of Comparative Example 2-3 met the formulation standard, the disintegration standard was not met. In contrast, tablets (Examples 2-1 and 2-2) in which the ratio of starch to crystalline cellulose was 1:1 to 1:3 (mass ratio), in other words, the ratio of crystalline cellulose to 1 part by mass of starch was 1 to 3 parts by mass, met the formulation standard for both hardness and disintegration.

[0136] These results show that when starch and crystalline cellulose are used alone as tablet manufacturing components (particularly intragranular components), the formulation standards for at least one of hardness and disintegration property are not met, whereas by using a combination of starch and crystalline cellulose in a ratio of 1:1 to 1:5, preferably 1:1 to 1:3 (mass ratio), an increase in hardness and a shortened disintegration time can be achieved without impairing the stability of Compound I in the tablet.

[0137] Experimental Example 3 Investigation and Evaluation of Types of Binders The effects of the type of binder (component (C)) used in granulation on the stability of Compound I in tablets, as well as the hardness and disintegration properties of the tablets, were evaluated.

[0138] (1) Preparation of granulated material (core granules) and uncoated tablets (a) Preparation of uncoated tablets of Examples 3-1 and 3-2 According to the formulations listed in Table 6, components (A) to (D) were used to prepare granulated material (core granules) using the same wet granulation method as in Reference Example 1-1. This was placed in a plastic bag, and powdered components (E) and (F) were added and mixed to prepare a granulated mixture. The prepared granulated mixture was compressed into tablets using the same rotary tablet press under the same conditions as in Reference Example 1-1 using a circular tablet mold with a diameter of 5 mm so that the tablet porosity was 10% or less, and uncoated tablets (Examples 3-1 to 3-2) with a mass of 50 mg / tablet were prepared.

[0139] (b) Preparation of uncoated tablets of Examples 3-3 and 3-4 According to the formulations shown in Table 6, components (A), (B), and (D) were placed in a fluidized bed granulation dryer (WSG-15, Powrex Corporation), and a 5% aqueous solution of component (C), which had been dissolved in water in advance, was sprayed onto the components and granulated to obtain core granules. The resulting core granules were then sized using a screen-type granulator (Co-Mill QC-197S, Powrex Corporation: screen size 1391 μm, rotation speed 2400 rpm) to obtain sized granules. The sized granules and components (E) and (F) were mixed for 10 minutes in a container rotary mixer (Bohle Container Mixer PM-100, Hiroshima Metal & Machinery Co., Ltd.) to prepare a granulated mixture. The prepared granulated mixture was tableted using a rotary tablet press (VIRGO, Kikusui Seisakusho Co., Ltd.: rotation speed 60 rpm) in a circular tablet mold with a diameter of 5 mm so that the tablet porosity was 10% or less, and uncoated tablets (Examples 3-3 to 3-4) with a mass of 50 mg / tablet were prepared.

[0140]

[0141] (2) Evaluation of Compound I Stability and Tablet Properties (Hardness, Disintegration Time) The stability, hardness, and disintegration time of Compound I were measured and evaluated for the uncoated tablets (Examples 3-1 to 3-4) produced according to the above method, according to the test methods described above. The results are shown in Table 7-1. Table 7-1 also shows the results of Example 2-2. The actual measured values ​​are shown in Table 7-2.

[0142]

[0143]

[0144] As shown in Table 7-1, whether hypromellose or hydroxypropyl cellulose was used as a binder, the decomposition of Compound I in the tablets was suppressed, and the stability met the formulation standards. As the proportion of binder in the uncoated tablets increased, an increase in tablet hardness was observed, but it was confirmed that both tablets met the standard values ​​for hardness and disintegration time. Furthermore, as with Experimental Example 1 above, it was confirmed that the decomposition of Compound I was suppressed depending on the amount of binder used.

[0145] Experimental Example 4 Investigation and Evaluation of Types of Disintegrants The effects of the types of disintegrants (component (E)) used in granulation on the stability of Compound I in tablets, as well as the hardness and disintegrability of tablets were evaluated.

[0146] (1) Preparation of Granulated Product (Core Granules) and Uncoated Tablets Uncoated tablets (Examples 4-1 to 4-2) weighing 50 mg / tablet were prepared according to the formulations shown in Table 8 and the same manufacturing method as in Example 3-3. Specifically, components (A) to (D) were used to prepare granulated products (core granules) using the same wet granulation method as in Example 3-3. The granulated products were then sized using a screen-type granulator to prepare sized granules, which were then placed in a plastic bag and mixed with powdered components (E) and (F) to prepare a granulated mixture. The prepared mixture was compressed into tablets using the same rotary tablet press as in Example 3-3 under the same conditions using a 5 mm diameter circular tablet mold so that the tablet porosity was 10% or less, and uncoated tablets weighing 50 mg / tablet (Examples 4-1 to 4-2) were prepared.

[0147]

[0148] (2) Evaluation of Compound I Stability and Tablet Properties (Hardness, Disintegration Time) The stability, hardness, and disintegration time of Compound I were measured and evaluated for the uncoated tablets (Examples 4-1 and 4-2) produced according to the above method according to the test methods described above. The results are shown in Table 9-1. The results of Example 3-3 are also shown. The actual measured values ​​are shown in Table 9-2.

[0149]

[0150]

[0151] As shown in Table 9-1, it was found that when low-substituted hydroxypropyl cellulose or croscarmellose sodium was used as a disintegrant in addition to crospovidone, an increase in hardness and a shortened disintegration time could be achieved without impairing the stability of Compound I in the tablet, and a formulation that met the formulation standards could be obtained.

[0152] Experimental Example 5 Evaluation of Manufacturing Method Tablets (Examples 5-1 to 5-4) were manufactured according to the formulations shown in Table 10, and the effects of the compound I on the stability and physical properties of the tablets were evaluated.

[0153] (1) Preparation of granulated material (core granules) and uncoated tablets Component (A), component (B), and component (D) were placed in a fluidized bed granulation dryer (MP-01, Powrex Corporation), and a 5% aqueous solution of component (C), which had been dissolved in water in advance, was added by spraying to granulate. The granulated material (core granules) was placed in a plastic bag, and the extragranular components (components (D), (E), and (F)) were added thereto and mixed for 1 minute to prepare a mixture. The prepared granulated mixture was compressed into tablets using a rotary tablet press (VELA5, Kikusui Seisakusho Co., Ltd.) in a circular tablet mold with a diameter of 5 mm so that the tablet porosity was 10% or less, and a mass of 50 mg / tablet was prepared (Examples 5-1 to 5-4).

[0154]

[0155] (2) Evaluation of Compound I Stability and Tablet Properties (Hardness, Disintegration Time) The stability, hardness, and disintegration time of Compound I were measured and evaluated for the uncoated tablets (Examples 5-1 to 5-4) produced according to the above-mentioned method according to the test methods described above. The results are shown in Table 11-1. The actual measured values ​​are shown in Table 11-2.

[0156]

[0157]

[0158] As shown in Table 11-1, all formulations were able to prepare tablets that had the stability of Compound I (decomposition suppression) as well as good hardness and disintegrability, without the influence of excipients (extragranular components) added later to the granules (core granules). In particular, it was confirmed that the disintegration time could be further shortened by incorporating an excipient as an extragranular component. From this, it is believed that incorporating an excipient as an extragranular component can also increase the proportion of component (B) used during granulation.

[0159] Experimental Example 6 Evaluation of Coated Tablets Film-coated tablets were produced (Examples 6-1 to 6-3) and the stability of Compound I, as well as the hardness and disintegration properties of the tablets, were evaluated.

[0160] (1) Preparation of Granulated Product (Core Granules), Uncoated Tablets, and Coated Tablets According to the formulations in Table 12, components (A), (B), and (D) were placed in a fluidized bed granulation dryer (WSG-15, Powrex Corporation), and a 5% aqueous solution of component (C), which had been dissolved in water in advance, was added by spraying to granulate (core granules). The resulting core granules were then sized using a screen-type sieving machine (Co-Mill QC-197S, Powrex Corporation: screen size 1391 μm, rotation speed 2400 rpm) to obtain sized granules. The resulting sized granules were mixed with components (E) and (F) in a container rotary mixer (Bohle Container Mixer PM-100, Hiroshima Metal & Machinery Co., Ltd.) for 10 minutes to prepare a mixture. The prepared granulated mixture was compressed into tablets using a rotary tablet press (VIRGO, Kikusui Seisakusho Co., Ltd.) in a 5 mm diameter circular tablet mold so that the tablet porosity was 10% or less, and a mass of 50 mg / tablet (uncoated tablet) was prepared. An aqueous solution containing component (G) was sprayed as a coating liquid onto the prepared uncoated tablets using a tablet coating machine (DRC-650, Powrex Corporation), and a coating of 3 mg / tablet was applied to obtain film-coated (FC) tablets (53 mg / tablet) (Examples 6-1 to 6-3).

[0161]

[0162] (2) Evaluation of Compound I Stability and Tablet Properties (Hardness, Disintegration) For the FC tablets (Examples 6-1 to 6-3) produced according to the above method, the stability, hardness, and disintegration time of Compound I were measured according to the test methods described above, and tablet properties were evaluated. Furthermore, the hardness and disintegration time were similarly measured and evaluated for uncoated tablets before film coating. Furthermore, for the disintegration time, a disintegration test was similarly performed on the divided pieces (two pieces) prepared by dividing the FC tablet equally in half, and the case where both pieces disintegrated within 180 seconds was evaluated as "Good". The results are shown in Table 13-1. The actual measured values ​​for the FC tablets are shown in Table 13-2.

[0163]

[0164]

[0165] As shown in Table 13-1, it was confirmed that the stability (decomposition inhibition) of Compound I was maintained in all formulations (Examples 6-1 to 6-3) without the influence of the coating film. On the other hand, it was confirmed that the application of coating improved the hardness and prolonged the disintegration time compared to uncoated tablets, but coated tablets that met the formulation standards in all cases could be prepared. From the results of Experimental Example 6, it is considered that even when producing a coated formulation, the disintegration time can be further shortened by incorporating component (D) as an extragranular component.

Claims

1. A tablet containing (A) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide, (B) starch and crystalline cellulose, and (C) a binder, wherein the tablet is an uncoated tablet or a coated tablet in which a coating material is applied to the uncoated tablet, the content of component (C) is 1% by mass or more per 100% by mass of the uncoated tablet, and the ratio of crystalline cellulose to 1 part by mass of starch in component (B) is 1 to 5 parts by mass.

2. The tablet according to claim 1, further comprising an excipient (excluding starch and crystalline cellulose), a disintegrant, and a lubricant.

3. The tablet according to claim 1 or 2, comprising the components (A), (B), and (C), and an excipient (excluding starch and crystalline cellulose) as intragranular components, and an excipient (excluding starch and crystalline cellulose), a disintegrant, and a lubricant, or a disintegrant and a lubricant, as extragranular components.

4. A tablet according to claim 1 or 2, wherein the starch content is 20% by weight or less per 100% by weight of the uncoated tablet.

5. The tablet according to claim 1 or 2, wherein the hardness of the uncoated tablet is 30 N or more and the disintegration time of the uncoated tablet is 180 seconds or less.

6. The tablet according to claim 1 or 2, wherein the uncoated tablet has a tablet diameter of 4 mm or more and a porosity of 10% or less.

7. The tablet according to claim 1 or 2, wherein the coated tablet is a film-coated tablet.

8. The tablet according to claim 1 or 2, which is a pharmaceutical composition used for improving or treating symptoms associated with arteriosclerosis obliterans, intermittent claudication, diabetic neuropathy, diabetic gangrene, peripheral circulatory disorder, chronic arterial occlusion, scleroderma, thrombosis, pulmonary hypertension, myocardial infarction, angina pectoris, glomerulonephritis, diabetic nephropathy, chronic renal failure, bronchial asthma, interstitial pneumonia (pulmonary fibrosis), chronic obstructive pulmonary disease, tubulointerstitial nephritis, inflammatory bowel disease, or spinal stenosis.

9. A method for producing a tablet containing (A) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide (Compound I), (B) starch and crystalline cellulose, and (C) a binder, wherein the tablet is an uncoated tablet or a coated tablet obtained by applying a coating material to the uncoated tablet, the method comprising: (1) preparing a powder mixture of the components (A) and (B); and (2) adding a solution containing the component (C) to the powder mixture and granulating to obtain a granulated product, wherein in the step (1), the blending ratio of starch to crystalline cellulose in the powder mixture is adjusted so that 1 to 5 parts by mass of crystalline cellulose is used per 1 part by mass of starch, In the step (2), the solution containing the component (C) is added so that the content of the component (C) per 100% by mass of the uncoated tablet is 1% by mass or more in terms of dry weight.

10. A manufacturing method as described in claim 9, wherein in step (1), the starch content in the powder mixture is adjusted to 20% by mass or less per 100% by mass of the uncoated tablet.

11. The production method according to claim 9 or 10, wherein the solution containing component (C) contains component (C) in a proportion of 1 to 10% by mass.

12. A manufacturing method according to claim 9 or 10, wherein step (1) is a step of preparing a powder mixture containing component (A) and component (B) as well as excipient (D) (excluding starch and crystalline cellulose).

13. The method of claim 9 or 10, further comprising the following step (4) after the (2) granulation step and, if necessary, after the (3) sizing step: (4) adding (E) a disintegrant and (F) a lubricant, or (D) an excipient (excluding starch and crystalline cellulose), (E) a disintegrant, and (F) a lubricant.

14. The manufacturing method according to claim 13, further comprising a compression molding step (5) after step (4).

15. A method for producing coated tablets according to claim 14, comprising a step of coating the compressed product obtained in step (5) with a coating material.

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