TW202203924A - Solid preparation and manufacturing method thereof - Google Patents

Abstract

The present invention relates to a solid preparation that contains 2-{4-[N-(5,6-diphenyl pyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide (generic name "selexipag"), and a manufacturing method thereof. This solid preparation contains (A) selexipag, (B) starch, and (C) a granulated substance containing at least one type of binder selected from the group consisting of hydroxypropyl cellulose and hypromellose, wherein the content ratio of component (B) per 100 parts by mass of the granulated substance is at least 20 parts by mass (but excluding 30.2-30.4 parts by mass), and the content ratio of component (C) per 100 parts by mass of the granulated substance is at most 4 parts by mass.

Description

Solid preparation and method for producing the same

The present invention relates to a kind of compound containing 2-{4-[N-(5,6-diphenylpyridine-2-yl)-N-isopropylamino]butoxy}-N-(methylsulfonic acid base) acetamide (commonly known as "Selexipag", hereinafter also referred to as "Compound I" in this specification) as a solid preparation. In a preferred embodiment, the present invention relates to a solid preparation that can inhibit the decomposition of Compound I, stably contain the compound, and has good disintegrability.

ICompound I represented by the following structural formula is known to have excellent prostaglandin I ₂ (also known as PGI ₂ ) receptor agonist action, and exhibit platelet aggregation inhibitory action, vasodilator action, bronchial smooth muscle dilation action, and lipid deposition inhibitory action Various medicinal effects such as action and leukocyte activation inhibitory action (Patent Document 1 to Patent Document 7). [hua 1]

I

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 formed to be 1.0 m ² or less. Thereby, the decomposition of Compound I in the tablet containing D-mannitol can be inhibited. [Prior Art Literature] [Patent Literature]

[Patent Document 1] International Publication No. 2002/088084 [Patent Document 2] International Publication No. 2009/157398 [Patent Document 3] International Publication No. 2017/098998 [Patent Document 4] International Publication No. 2009/157396 [Patent Document 5] International Publication No. 2009/157398 [Patent Document 6] International Publication No. 2009/157397 [Patent Document 7] International Publication No. 2009/107736 [Non-patent literature]

[Non-Patent Document 1] Hepatology, 2007, Vol. 45, No. 1, p159 - 169. [Non-Patent Document 2] Folia Pharmacologica Japonica, Vol. 117, No. 2, p. 123 - 130, 2001, Abstract. [Non-Patent Document 3] International Angiology, 29, Suppl. 1 to No. 2, p. 49 - 54, 2010. [Non-Patent Document 4] Jpn. J. Clin. Immunol., 16(5), 409-414, 1993. [Non-Patent Document 5] Jpn. J. Thromb. Hemost., 1: 2, p. 94 - 105, 1990, Abstract. [Non-Patent Document 6] J. Rheumatol., 2009, 36 (10), 2244 - 2249. [Non-Patent Document 7] Japan J. Pharmacol., 43, p. 81 - 90, 1987. [Non-Patent Document 8] New Engl. J. Med., 2015, 24, 2522 - 2533. [Non-Patent Document 9] CHEST 2003, 123, 1583 - 1588. [Non-Patent Document 10] Br. Heart J., 53, p. 173 - 179, 1985. [Non-Patent Document 11] The Lancet, 1, 4880, pt 1, p. 569 - 572, 1981. [Non-Patent Document 12] Eur. J. Pharmacol., 449, p. 167 - 176, 2002. [Non-Patent Document 13] The Journal of Clinical Investigation, 117, p. 464 - 472, 2007. [Non-Patent Document 14] Am. J. Physiol. Lung Cell Mol. Physiol., 296: L648-L656, 2009.

[Problems to be Solved by Invention]

In recent years, in order to further improve the convenience of administration for children, the elderly, and patients with dysphagia, solid preparations with good disintegration properties have been desired. The present inventors considered that the disintegration property was reduced by the binder in the solid preparation, and therefore studied by removing the binder from the solid preparation containing Compound I. As a result, although the disintegrability of the solid preparation is improved, the compound I in the solid preparation is decomposed to generate a similar substance, and the content of the compound I is reduced. That is, it was found that when the binder was removed from the solid preparation containing the compound I, the disintegrability was improved, but on the other hand, the stability of the compound I in the solid preparation was reduced.

The object of the present invention is to provide a solid preparation containing Compound I and a method for producing the same. Another object of the present invention is to provide a solid preparation in which the disintegration property is improved and the decrease in the stability of Compound I in the solid preparation is suppressed, and a method for producing the same. [Technical means to solve problems]

The inventors of the present invention have repeatedly conducted intensive studies in order to solve the above-mentioned problems, and as a result, have confirmed that the compound I, starch, and a binder selected from the group consisting of hydroxypropyl cellulose and hypromellose are used in a specific ratio. At least one of the group can be used as a granulation component of the solid preparation, and can exhibit good disintegration properties in the solid preparation, and can inhibit the decomposition of the compound I and keep the compound I stably. The present invention has been completed by further repeated studies based on this knowledge. Some embodiments of the present invention include those described below.

(I) Solid preparation containing celecipaz (I-1) A solid preparation comprising granules containing: (A) 2-{4-[N-(5,6-diphenylene) pyridin-2-yl)-N-isopropylamino]butoxy}-N-(methylsulfonyl)acetamide (Compound I), (B) starch, and (C) selected from At least one binder in the group consisting of hydroxypropyl cellulose (hereinafter also referred to as "HPC") and hypromellose; and the content ratio of the above-mentioned (B) component per 100 parts by mass of granules is 20 mass parts or more (however, 30.2-30.4 mass parts are excluded), and the content rate of the said (C)component per 100 mass parts of granules is 4 mass parts or less. (I-2) The solid preparation according to (I-1), wherein the granulated product is a wet granulated product. (I-3) The solid preparation according to (I-1) or (I-2), wherein the content ratio of the component (B) per 100 parts by mass of the granulation is greater than 30.4 parts by mass. (I-4) The solid preparation according to any one of (I-1) to (I-3), wherein the component (C) is HPC, and the content ratio of the HPC per 100 parts by mass of the granules is 1 to 4 parts by mass. (I-5) The solid preparation according to any one of (I-1) to (I-3), wherein the component (C) is HPC, and the content ratio of the HPC per 100 parts by mass of the granules is 2 to 3 parts by mass. (I-6) The solid preparation according to any one of (I-1) to (I-3), wherein the component (C) is hypromellose, and the content ratio of the hypromellose is It is 1-4 mass parts in 100 mass parts of granules. (I-7) The solid preparation according to any one of (I-1) to (I-6), wherein the granulated product further contains (D) an excipient other than starch. (I-8) The solid preparation according to (I-7), wherein the above-mentioned (D) excipient is D-mannitol. (I-9) The solid preparation according to (I-7) or (I-8), wherein the mass ratio of the (B) component in the above-mentioned granulation to the (D) component other than the starch is the (B) component : (D) component other than starch = 10:0-2:8. (I-10) The solid preparation according to any one of (I-1) to (I-9), wherein the granulated product further contains (E) a disintegrant. (I-11) The solid preparation according to any one of (I-1) to (I-10), which has a tablet shape. (I-12) The solid preparation according to any one of (I-1) to (I-10), which has a tablet shape and whose surface is covered with a coating agent. (I-13) The solid preparation according to any one of (I-1) to (I-12), comprising the above-mentioned granulated product and an excipient selected from (D) as an external additive to the granulated product , (E) at least one of the group consisting of disintegrants and (F) lubricants. (I-14) The solid preparation according to any one of (I-1) to (I-13), wherein the content of the above-mentioned component (A) is less than 0.2 mg. (I-15) The solid preparation according to any one of (I-1) to (I-14), which is a tablet with a total mass of 30 mg or less. (I-16) The solid preparation according to any one of (I-1) to (I-15), which is a tablet having a diameter of 4 mm or less and a circular plane shape. (I-17) The solid preparation according to any one of (I-1) to (I-16), which is used for the treatment of concomitant diseases selected from the group consisting of diabetic neuropathy, diabetic gangrene, peripheral circulation disorder, and chronic arterial occlusion , intermittent claudication, scleroderma, thrombosis, pulmonary hypertension, myocardial infarction, angina pectoris, glomerulonephritis, diabetic nephropathy, chronic renal failure, bronchial asthma, interstitial pneumonia (pulmonary fibrosis), chronic obstructive Symptoms of at least one disease in the group consisting of pulmonary disease, tubulointerstitial nephritis, inflammatory bowel disease, and spinal stenosis. (I-18) The solid preparation according to (I-17), which is used for the treatment of pulmonary hypertension. (I-19) The solid preparation according to (I-17), which is used for the treatment of peripheral circulatory disorders. (I-20) The solid preparation according to (I-17), which is used for the treatment of chronic arterial occlusion. (I-21) The solid preparation according to (I-17), which is used for the treatment of intermittent claudication. (I-22) The solid preparation according to (I-17), which is used for the treatment of symptoms associated with spinal stenosis. (I-23) The solid preparation according to (I-17), which is used for the treatment of pulmonary fibrosis. (I-24) The solid preparation according to (I-17), which is used for the treatment of scleroderma. (I-25) The solid preparation according to (I-17), which is used for the treatment of chronic renal failure. (I-26) The solid preparation according to (I-17), which is used for the treatment of tubulointerstitial nephritis.

(II) Method for producing a solid preparation containing celecipaz (II-1) A method for producing a solid preparation comprising granules containing: (A) 2-{4-[N -(5,6-Diphenylpyridine-2-yl)-N-isopropylamino]butoxy}-N-(methylsulfonyl)acetamide (Compound I), (B) Starch, and (C) at least one binder selected from the group consisting of HPC and hypromellose, the manufacturing method of the above-mentioned solid preparation comprises the following steps: (1) Prepare the above-mentioned (A) component and (B) component and (2) adding a solution containing the above-mentioned component (C) to the above-mentioned powder mixture to granulate to obtain a granulated product; and in the above-mentioned (1) step, granulate per 100 parts by mass The powder mixture was prepared so that the content ratio of the component (B) in the material was 20 parts by mass or more (excluding 30.2 to 30.4 parts by mass), and in the step (2) above, the powder mixture was granulated per 100 parts by mass. The solution containing the said (C)component was added so that the content rate of (C)component in it might become 4 mass parts or less. (II-2) The manufacturing method as described in (II-1) whose content rate of the said (B) component is more than 30.4 mass parts per 100 mass parts of granules. (II-3) The manufacturing method as described in (II-1) or (II-2) whose solution containing the said (C)component contains this (C)component in the ratio of 1-10 mass %. (II-4) The production method according to any one of (II-1) to (II-3), wherein the component (C) is HPC, and has the step of: per 100 parts by mass of the granules The HPC-containing solution is sprayed into the powder mixture of (A) component and (B) component so that the content ratio of HPC is 1 to 4 parts by mass, preferably 2 to 3 parts by mass. (II-5) The production method according to any one of (II-1) to (II-3), wherein the component (C) is hypromellose, and has the step of: producing a hypromellose per 100 parts by mass The hypromellose-containing solution is sprayed on the powder mixture of (A) component and (B) component so that the content ratio of the hypromellose in the granules is 1 to 4 parts by mass. (II-6) The production method according to (II-5), wherein when the measurement is carried out under the conditions of the Japanese Pharmacopoeia, Seventeenth Revised Edition, Viscometry Method 1 (capillary viscometer method), it contains 2 mass % The viscosity of the above-mentioned aqueous solution of hypromellose at 20℃±1℃ is less than 4 mPa·s. (II-7) The production method according to any one of (II-1) to (II-6), wherein the powder mixture further contains (D) an excipient other than starch. (II-8) The production method according to (II-7), wherein the above (D) is D-mannitol. (II-9) The manufacturing method as described in (II-7) or (II-8), wherein the mass ratio of the (B) component in the powder mixture to the (D) component other than the starch is the (B) component: (D) component other than starch = 10:0-2:8. (II-10) The production method according to any one of (II-1) to (II-9), wherein the powder mixture further contains (E) a disintegrant. (II-11) The production method according to any one of (II-1) to (II-10), which, after the above-mentioned (2) granulation step, is optionally subjected to (3) granulation step, and has (4) ) A step of adding at least one granulation external additive selected from the group consisting of (D) excipients, (E) disintegrants, and (F) lubricants (post addition step). (II-12) The production method according to (II-11), which has (5) a compression molding step after the above-mentioned (4) post-addition step. (II-13) The production method according to (II-12), further comprising the step of coating the compression-molded product obtained by the compression-molding step (5) above. (II-14) The production method according to any one of (II-1) to (II-13), wherein the solid preparation is used for the treatment of concomitant diseases selected from the group consisting of diabetic neuropathy, diabetic gangrene, peripheral circulatory disorder, Chronic arterial obstruction, intermittent claudication, 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, and a preparation for the symptoms of at least one disease of the group consisting of spinal stenosis.

( III) Method for inhibiting the decomposition of xeloxipa in a solid preparation containing xeloxipa (III-1) A method for inhibiting the decomposition of component (a) in a solid preparation comprising a granulated material, the Granules contain: (a) 2-{4-[N-(5,6-diphenylpyridine-2-yl)-N-isopropylamino]butoxy}-N-(methylsulfonic acid Acyl)acetamide (compound I), (b) starch, and (c) a binder; the method uses at least one compound selected from the group consisting of HPC and hypromellose as the above (c) Element. (III-2) The method as described in (III-1) whose compounding quantity of the said (c) component is 1-4 mass parts per 100 mass parts of granules. (III-3) The method according to (III-1) or (III-2), comprising the steps of: spraying the aqueous solution containing the above-mentioned (c) component onto the powder mixture of the (a) component and (b) component and wet granulation. (III-4) The method according to (III-3), wherein the component (c) is hypromellose and is measured under the conditions of the Japanese Pharmacopoeia, Seventeenth Revised Edition, Viscometry Method No. 1 In this case, the viscosity of the aqueous solution containing 2% by mass of hypromellose at 20°C±1°C is less than 4 mPa·s. (III-5) The method according to any one of (III-1) to (III-4), wherein the granulated product may further contain D-mannitol as an (d) excipient other than starch, and The mass ratio of (b) component and (d) component other than starch is (b) component: (d) component other than starch=10:0-2:8. (III-6) The method according to any one of (III-1) to (III-5), wherein the content of component (a) in the solid preparation is less than 0.2 mg. (III-7) The method according to any one of (III-1) to (III-6), wherein the above-mentioned solid preparation is used for the treatment of concomitant diseases selected from the group consisting of diabetic neuropathy, diabetic gangrene, peripheral circulatory disorder, chronic Arterial obstruction, intermittent claudication, 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, and a preparation for the symptoms of at least one disease of the group consisting of spinal stenosis.

(IV) Method for Inhibiting Decomposition of Xeloxipa and Improving Disintegration in Solid Preparations Containing Xeloxipa (IV-1) A method for inhibiting decomposition of (a) component and improving disintegration in solid preparations , the solid preparation comprises granules containing: (a) 2-{4-[N-(5,6-diphenylpyridine-2-yl)-N-isopropylamino] Butoxy}-N-(methylsulfonyl)acetamide (compound I), (b) starch, and (c) binder; the method uses a compound selected from the group consisting of HPC and hypromellose At least one compound in the group is used as the above-mentioned (c) component. (IV-2) The method according to (IV-1), wherein the compounding amount of the component (c) is 1 to 4 parts by mass per 100 parts by mass of the granules. (IV-3) The method according to (IV-1) or (IV-2), wherein the component (c) is HPC, and the compounding amount thereof is 2 to 3 parts by mass per 100 parts by mass of the granules. (IV-4) The method according to (IV-1) or (IV-2), wherein the component (c) is hypromellose, and the compounding amount thereof is 1 part by mass per 100 parts by mass of the granulated material . (IV-5) The method according to (IV-4), wherein the component (c) is hypromellose, and the measurement is carried out under the conditions of the Japanese Pharmacopoeia, Seventeenth Revised Edition, Viscometry Method No. 1. In this case, the viscosity of the aqueous solution containing 2% by mass of hypromellose at 20°C±1°C is less than 4 mPa·s. (IV-6) The method according to any one of (IV-1) to (IV-5), wherein the granulated product may further contain D-mannitol as an (d) excipient other than starch, and The mass ratio of (b) component and (d) component other than starch is (b) component: (d) component other than starch=10:0-2:8. (IV-7) The method according to any one of (IV-1) to (IV-6), wherein the content of component (a) in the solid preparation is less than 0.2 mg. (IV-8) The method according to any one of (IV-1) to (IV-7), wherein the solid preparation is a lozenge having a diameter of 4 mm or less and a circular planar shape. (IV-9) The method according to any one of (IV-1) to (IV-8), wherein the above-mentioned solid preparation is used for the treatment of concomitant diseases selected from the group consisting of diabetic neuropathy, diabetic gangrene, peripheral circulatory disorder, chronic Arterial obstruction, intermittent claudication, 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, and a preparation for the symptoms of at least one disease of the group consisting of spinal stenosis. [Effect of invention]

According to the present invention, it is possible to provide a solid preparation capable of improving disintegration and suppressing degradation of the stability of Compound I in the solid preparation, and a method for producing the same.

(I) Solid Formulation Containing Celecipa The solid formulation of the present invention (hereinafter sometimes abbreviated as "the present solid formulation") comprises granules containing: (A) Compound I, (B) starch, and (C) at least one binder selected from the group consisting of HPC and hypromellose; and the content ratio of the above-mentioned (B) component per 100 parts by mass of granulation is 20 parts by mass or more (wherein, 30.2-30.4 mass parts are excluded), and the content rate of the said (C)component per 100 mass parts of granules is 4 mass parts or less.

In the present invention, as long as it is not specifically mentioned, "solid preparation" means a solid preparation of a certain shape for oral administration, which, in addition to ordinary tablets, also includes orally disintegrating tablets, chewing tablets, buccal tablets, Sublingual lozenges, foaming lozenges, dispersible lozenges, dissolving lozenges, sustained-release lozenges (these are sometimes collectively referred to above as "lozenges"), granules and capsules. Preferably it is a lozenge, more preferably an ordinary lozenge. Moreover, the solid preparation made into object of this invention includes the single-layer tablet which has a single-layer structure, and the multilayer tablet which has a plural-layer structure of two or more layers. Monolayer ingots are preferred. Furthermore, in addition to uncoated plain lozenges (naked lozenges), the solid preparations of the present invention also include sugar-coated lozenges, gelatin-coated lozenges, and film-coated lozenges (including enteric-coated lozenges and stomach-coated lozenges) (relative to plain lozenges, These are also collectively referred to as "coated tablets"). The planar shape of the solid preparation is not particularly limited, and may be various shapes such as a circle, an ellipse, a caplet type, and a doughnut type. Moreover, a solid preparation contains the said granulated material (core particle), and the granulated material external additive added to the said granulated material.

Each component constituting the solid preparation of the present invention will be described below.

(A) Compound I Compound I can be produced, for example, by the method described in Patent Document 1 or 2, and crystals of the following three forms are known. The relevant descriptions in these patent documents can be incorporated into the present specification. (1) Form I crystal of compound I: the powder X-ray diffraction pattern is obtained by using Cu Kα radiation (λ=1.54 Å). In the powder X-ray diffraction pattern of compound I, the following diffraction angle 2θ: 9.4 Diffraction peaks are shown at 9.8 degrees, 17.2 degrees and 19.4 degrees. (2) Form II crystal of compound I: the powder X-ray diffraction pattern is obtained by using Cu Kα radiation (λ=1.54 Å). In the powder X-ray diffraction pattern of compound I, the diffraction angle 2θ is as follows: 9.0 Diffraction peaks are displayed at 12.9 degrees, 20.7 degrees, and 22.6 degrees. (3) Type III crystal of compound I: the powder X-ray diffraction pattern is obtained by using Cu Kα radiation (λ=1.54 Å). In the powder X-ray diffraction pattern of compound I, the diffraction angle 2θ is as follows: 9.3 Diffraction peaks are displayed at 9.7 degrees, 16.8 degrees, 20.6 degrees and 23.5 degrees.

The compound I that can be used in this solid preparation may be any of the above crystals, a mixture of these crystals, or an amorphous system. Among them, the I-type crystal is preferred.

In addition, the content ratio of Compound I is not limited in terms of the content per 100 parts by mass of granules contained in the cost solid preparation, but may be in the range of 0.1 to 70 parts by mass. When the present solid preparation is a tablet produced by the following production method A, the ratio of Compound I in 100 parts by mass of granules is preferably 0.1 to 12 parts by mass, more preferably 0.1 to 2 parts by mass . When the present solid preparation is a tablet produced by the following production method B, the ratio of Compound I in 100 parts by mass of granules is preferably 0.1 to 40 parts by mass, more preferably 0.1 to 5 parts by mass .

In addition, the ratio of the compound I contained in the present solid preparation is not limited, but is preferably selected from the range of 0.1 to 25% by mass per 100% by mass of the total solid preparation, more preferably 0.1 to 12% by mass , and more preferably 0.1 to 2 mass %. Here, "the total amount of solid preparation" means "the total amount of plain tablet" when the solid preparation is a tablet (the same applies hereinafter).

(B) Starch In the present invention, starch (hereinafter also abbreviated as "component (B)") may be a component that can be used as a pharmaceutical additive for the production of solid preparations, and includes, for example, corn starch, potato starch as natural starches Starch, rice starch, wheat starch, and hydroxypropyl starch as modified starch, dextrin, maltodextrin, α-starch, partially α-starch. Starch is preferably used as an excipient, preferably including corn starch. The form of starch is not limited, including powder and granules, preferably powder.

The content ratio of the component (B) is 20 parts by mass or more (excluding 30.2 to 30.4 parts by mass) in terms of content per 100 parts by mass of granules contained in the cost solid preparation. When the present solid preparation is a tablet manufactured by the manufacturing method A, the ratio of the component (B) in 100 parts by mass of granules is preferably more than 30.4 parts by mass, more preferably more than 36 parts by mass. Moreover, when the present solid preparation is a tablet manufactured by the manufacturing method B, the ratio range of the component (B) in 100 parts by mass of granules is preferably 20 to 40 parts by mass (wherein, 30.2 to 30.4 30.5-40 mass parts are more preferable, and 36-40 mass parts are still more preferable.

The ratio of the (B) component contained in this solid preparation is not limited, but is 20 mass % or more per 100 mass % of the total solid preparation. Preferably it is 30-40 mass %, More preferably, it is 36-40 mass %.

Furthermore, in the case where the following (D) excipients other than starch are contained in the granulated product (core granules) as components other than the components (A) to (C), although there is no limitation, (B) ) The compounding ratio (mass ratio) of the component and the (D) excipient other than starch is preferably in the range of (B) component: (D) excipient other than starch = 10:0 to 2:8 choose. More preferably, it is 8:2-3:7, More preferably, it is 7:3-3:7. Here, as the (D) excipient other than starch, D-mannitol is preferably exemplified.

(C) Binder In the present invention, the binder is at least one selected from the group consisting of hydroxypropyl cellulose (HPC) and hypromellose (hereinafter also simply referred to as "component (C)"). The component (C) may be a component that can be used as a binding agent in the production of solid preparations as a pharmaceutical additive. (C)component may be used individually by 1 type, and may be used in combination of 2 or more types.

Commercially available HPCs as pharmaceutical additives include those with a molecular weight (GPS) in the range of 40,000 to 2,500,000 (viscosity when prepared as a 20°C/2% aqueous solution: 2 to 6,000 mPa·s) (for example, NISSO HPCSSL). , SL, L, M, H, VH, etc.; all manufactured by Japan Soda Co., Ltd.). In the present invention, it is preferable to use HPC whose molecular weight (GPS) is in the range of 40,000 to 140,000 (above viscosity: 2 to 10 mPa·s); HPC in the range of 5.9 mPa·s); especially, HPC with a molecular weight (GPS) of 40,000 (above viscosity: 2-2.9 mPa·s).

Hypromellose commercially available as a pharmaceutical additive includes methoxy groups with a degree of substitution of 28.0-30.0% and hydroxypropoxy groups with a degree of substitution of 7.0-12.0%, and is prepared at 20°C/2 Hypromellose (such as Hypromellose TC-5 (registered trademark) [variety: E, M, R, S] with a viscosity in the range of 2.5 to 17.5 mPa·s in % aqueous solution; all are Shin-Etsu Chemical manufactured by Industrial Co., Ltd.). In the present invention, it is preferable to use hypromellose whose viscosity is in the range of 2.5-7.0 mPa·s; it is more preferable to use hypromellose whose viscosity is in the range of 2.5-5.1 mPa·s; To use hypromellose whose viscosity is in the range of 2.5 to 3.5 mPa·s. In addition, the hypromellose commercially available as a pharmaceutical additive also includes: the degree of substitution of methoxy groups is 19.0-24.0%, and the degree of substitution of hydroxypropoxy groups is 4.0-12.0%. Hypromellose (such as Hypromellose SB-4) with a viscosity in the range of 3.2 to 4.8 mPa·s at 20°C/2% aqueous solution; Hypromellose (for example, hypromellose 65SH) having a degree of substitution of propoxy groups of 4.0 to 7.5% (all manufactured by Shin-Etsu Chemical Co., Ltd.).

The content ratio of (C)component is 4 parts by mass or less in terms of content per 100 parts by mass of granules contained in the cost solid preparation.

When the present solid preparation is a tablet produced by the production method A, the ratio of the component (C) in 100 parts by mass of the granules is not limited, but for HPC, 0.5 to 4 parts by mass can be exemplified. Preferably, it is 0.5 to 3.5 parts by mass; for hypromellose, it is 0.5 to 4 parts by mass, and preferably 0.5 to 3.5 parts by mass.

When the present solid preparation is a tablet produced by the production method B, the ratio of the component (C) in 100 parts by mass of the granules is 0.5 to 4 parts by mass for HPC, preferably 0.5 to 4 parts by mass. For example, 0.5 to 3.5 parts by mass; for hypromellose, 0.5 to 4 parts by mass, preferably 0.5 to 3.5 parts by mass.

In addition, in any production method, when HPC and hypromellose are used in combination as the component (C), it is preferable to appropriately adjust the total amount of both to be 4 parts by mass or less.

The component (C) is used in a state of being dissolved in water. Specifically, by adding the (C) component in an aqueous solution state to the powder mixture containing the above-mentioned (A) component and (B) component, and granulating (wet granulation method), at least (A) can be prepared by ) ~ (C) the granulated product. Although it does not restrict|limit as an aqueous solution density|concentration of the (C)component used, Usually, it can select suitably from the range of 0.5-20 mass %. Preferably it is 0.5-10 mass %. As shown in the following experimental example 5, when the content of component (C) in 100 parts by mass of granulation is 1.1 parts by mass or less and is small, by using (C) in the aqueous solution for wet granulation ) component is adjusted to a low concentration of 0.5 to 5 mass %, preferably 1 to 5 mass %, so that the decomposition inhibition effect (stabilization effect) of compound I can be enhanced.

(Other pharmaceutical additives) This solid preparation may contain other pharmaceutical additives as optional components to the extent that the effects described in this specification are not impaired. Examples of the pharmaceutical additive preferably include (D) excipients other than starch, (E) disintegrants, and (F) lubricants. In addition, examples of optional pharmaceutical additives include solubilizers, plasticizers, wetting agents, adsorbents, surfactants, pH adjusters, plasticizers, antioxidants, preservatives, and colorants , flavoring agents, sweeteners, flavoring agents, etc. These pharmaceutical additives can be used alone or in any combination of two or more.

(D) Excipients (D) Examples of excipients include, without limitation, sugar alcohols (eg, D-mannitol, erythritol, D- Sorbitol, maltitol, isomalt, lactitol, xylitol, and powdered reduced maltose syrup, etc.), sugars (eg: lactose, glucose, fructose, white sugar, etc.), crystalline cellulose, powdered cellulose , β-cyclodextrin, sodium carboxymethyl cellulose, light anhydrous silicic acid, hydrous silica, silica, precipitated calcium carbonate, anhydrous calcium hydrogen phosphate, magnesium oxide, titanium oxide, calcium lactate, aluminum silicate Magnesium, synthetic hydrotalcite, talc and kaolin, etc. These excipients can be used alone or in combination of two or more as the formulation components of the solid preparation. In addition, the said (B) component (starch) also corresponds to (D) an excipient. In this specification, when it is described only as "(D) excipient" or "(D) component", it means the entire excipient including (B) component, and when it is described as "except starch" (D) Excipient" or "(D) component other than starch" means an excipient other than (B) component (starch). (D) The excipient can be used as a compounding component of the granulated product during the production of the present solid preparation, and can also be used as a component to be added and prepared to the granulated product (core granules) later (additive to the granulated product) .

As (D)component other than starch, a sugar alcohol and a saccharide are mentioned preferably. D-mannitol is more preferable as (D)component other than starch used as a formulation component of a granulated material. The specific surface area of D-mannitol is not particularly limited as long as it does not interfere with the effects described in this specification. In addition, the above-mentioned specific surface area is a value measured by the Boett method, and can be measured using, for example, a specific surface area measuring apparatus Macsorb HM-model 1220 (manufactured by Mounttech).

Examples of D-mannitol commercially available as a pharmaceutical additive include Mannite C (average particle size: 20 μm), Mannite P (average particle size: 50 μm), and Mannite S (average particle size: 150 μm) (The above are manufactured by Mitsubishi Shoji Foodtech Co., Ltd.); Pearlitol 25C (average particle size: 25 μm), Pearlitol 50C (average particle size: 50 μm), Pearlitol 160C (average particle size: 160 μm) (the above are manufactured by ROQUETTE Corporation ); Nonpareil 108(100) (average particle size: 100 μm), Nonpareil 108(200) (average particle size: 200 μm) (the above are manufactured by Freund Co., Ltd.), and the like.

The ratio of the component (D) (the total amount including the component (B)) contained in this solid preparation is not limited, and can be selected from the range of 20 to 99% by mass per 100% by mass of the total amount of the solid preparation . Preferably it is 60-99 mass %, More preferably, it is 80-99 mass %.

In the case where the solid preparation is a tablet manufactured by the manufacturing method A, the ratio of the component (D) (the total amount including the component (B)) contained in the solid preparation is not limited, and per 100 mass The % solid preparation total amount can be selected from the range of 20 to 99% by mass. Preferably it is 60-99 mass %, More preferably, it is 85-99 mass %. When the content ratio of (D)component is converted into content per 100 mass parts of granules contained in this tablet, 20-99 mass parts can be mentioned. Preferably it is 60-99 mass parts, More preferably, it is 85-99 mass parts. Here, as the component (D), D-mannitol is preferably used in addition to the starch as the component (B).

In the case where the solid preparation is a tablet manufactured by the production method B, the ratio of the component (D) (the total amount including the component (B)) contained in the solid preparation is not limited, and per 100 mass The % solid preparation total amount can be selected from a range of 20% by mass or more, preferably 60 to 99% by mass, more preferably 80 to 99% by mass. Among them, the ratio of the component (D) contained in the granulated product is 20 to 99 parts by mass per 100 parts by mass of the granulated product, preferably 60 to 99 parts by mass, more preferably 80 to 99 parts by mass . Here, as the component (D), D-mannitol is preferably used in addition to the starch as the component (B).

(E) Disintegrant Examples of the (E) disintegrant are not specifically limited, for example, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, cross-linked Sodium carboxymethyl cellulose, sodium starch glycolate, crospovidone, cation exchange resin, crystalline cellulose, and low-substituted hydroxypropyl cellulose, etc. These disintegrants may be used alone or in combination of two or more. In addition, (E) the disintegrant can be used as a compounding component of the granulated material when the present solid preparation is produced, and can also be used as a component (extragranular additive) to be added to the granulated material (core granules) later. ).

As the component (E), preferably, low-substituted hydroxypropyl cellulose, crospovidone, and croscarmellose sodium can be mentioned. As the component (E) used as a formulation component of the granulated product, low-substituted hydroxypropyl cellulose and crospovidone are more preferred.

The ratio of the (E) component contained in this solid preparation is not limited, and can be selected from the range of 0 to 20% by mass per 100% by mass of the total solid preparation. Preferably it is 0-15 mass %, More preferably, it is 0-10 mass %.

When the present solid preparation is a tablet manufactured by the production method A, the ratio of the component (E) contained in the present solid preparation is not limited, and may be 0 to 100% by mass of the total amount of the solid preparation. It is selected in the range of 20 mass %, Preferably it is 0-15 mass %, More preferably, it is 0-10 mass %, More preferably, it is 2-7 mass parts. When the content ratio of (E) component is converted into content per 100 mass parts of granules contained in this tablet, 0-20 mass parts can be mentioned. Preferably it is 0-15 mass parts, More preferably, it is 0-10 mass parts, More preferably, it is 3-8 mass parts.

When the present solid preparation is a tablet manufactured by the production method B, the ratio of the component (E) contained in the present solid preparation is not limited, and may be 0 to 100% by mass of the total amount of the solid preparation. It is selected in the range of 20 mass %, Preferably it is 0-15 mass %, More preferably, it is 0-10 mass %. Among them, the ratio of the (E) component contained in the granules can be, for example, 0 to 20 parts by mass per 100 parts by mass of the granules. Preferably it is 0-15 mass parts, More preferably, it is 0-10 mass parts.

(F) Lubricant (F) Examples of lubricants include stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, waxes, DL-leucine, and lauryl sulfate. Sodium, magnesium lauryl sulfate, polyethylene glycol, light anhydrous silicic acid. These may be used alone or in combination of two or more. Magnesium stearate is preferred.

In the production of the present solid preparation, (F) the lubricant is not limited, but can be generally used as a component (additive outside the granulation material) to be added to the granulated material (core granules) and formulated later.

The ratio of the (F) component contained in this solid preparation is not limited, and can be selected from the range of 0.1 to 10% by mass per 100% by mass of the total amount of the solid preparation. Preferably it is 0.2-5 mass %, More preferably, it is 0.2-3 mass %.

(G) Optional pharmaceutical additives other than the above (D) to (F) As other optional components, pharmaceutical additives that are usually formulated in solid preparations can be formulated. These pharmaceutical additives include, without limitation, solubilizers, plasticizers, surfactants, pH adjusters, plasticizers, colorants, and flavoring agents.

Examples of the solubilizer include magnesium oxide, calcium oxide, sodium citrate, magnesium chloride, sodium carbonate, sodium bicarbonate, and the like.

Examples of plasticizers include, for example, light anhydrous silicic acid, hydrous silica, synthetic aluminum silicate, talc, and aluminum magnesium silicate.

Examples of the surfactant include polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene, polyoxyethylene fatty acid ester, glycerol monostearate, sorbitan fatty acid ester (sorbitan monostearate, Sorbitan monolaurate, etc.), polysorbates, sodium lauryl sulfate, polyethylene glycols, sucrose fatty acid esters, etc., nonionic surfactants such as sodium alkyl sulfate, and anionic surfactants, etc. .

Examples of pH adjusters include organic acids such as glycine, sodium bicarbonate, calcium hydrogen phosphate, sodium hydrogen phosphate, acetic acid, succinic acid, tartaric acid, fumaric acid, or citric acid, or salts thereof.

Examples of the plasticizer include triethyl citrate, polyethylene glycol, triacetin, and cetyl alcohol.

Examples of colorants include titanium oxide, talc, ferric oxide, yellow ferric oxide, edible yellow No. 4, edible yellow No. 4 aluminum lake, preferably titanium oxide, ferric oxide, Yellow iron oxide. The content of the colorant was less than 0.1% by weight of the total weight of the solid preparation.

As the flavoring agent, sweeteners such as aspartame and stevia, ascorbic acid, menthol, crude licorice extract, simple syrup, etc. can be exemplified without limitation; as the sweetener, sucrose and D-sorbose can be exemplified without limitation Natural or synthetic sweeteners such as alcohol, xylitol, and aspartame; as flavoring agents, menthol, peppermint, etc. can be exemplified without limitation.

(H) Coating layer As described above, this solid preparation may be a plain tablet or a coated tablet (sugar-coated tablet, gelatin-coated tablet, film-coated tablet) having a coating layer (coating layer) on its surface. .

In the case where the present solid preparation is a coated tablet, the coating agent for forming the coating layer can be appropriately selected and used based on the technical common sense in the industry according to the purpose.

For example, sugars, such as white sugar, D-mannitol, erythritol, sorbitol, xylitol, and trehalose, can be used for the preparation of sugar-coated tablets. In addition, when preparing the film-coated tablet, it can be used: water-soluble coating agents such as hydroxypropyl cellulose (HPC), hypromellose, polyvinyl alcohol, and pullulan; hypromellose phthalic acid Esters (HPMCP), Hypromellose Acetate Succinate (HPMCAS), Carboxymethyl Ethyl Cellulose (CMEC), Methacrylic Acid Copolymer, Cellacefate (Cellacefate) (Acetate Phthalate) Enteric coating agents such as cellulose formate) and shellac; polyvinyl acetal diethylamino acetate, aminoalkyl methacrylate copolymer, polyvinyl acetate diethylamino acetate and other gastric-soluble coating agents; macromolecular compounds such as slow-release coating agents such as ethyl cellulose and aminoalkyl methacrylate copolymers.

Furthermore, in these coating agents, if necessary, one of colorants, flavoring agents, sweeteners, flavoring agents, opacifiers, plasticizers, etc., or a combination of two or more of them can also be prepared. deployment. The mixing ratio of these colorants and the like in the coating layer is not limited, but is appropriately prepared so as to be in the range of 0 to 20 mass % in the total amount of 100 mass % of the components forming the coating layer.

In the coated tablet, the ratio of the coating layer (coating layer, film) is not limited, and can be appropriately selected from the range of 1 to 12 parts by mass relative to 100 parts by mass of the plain tablet, preferably 1 to 10 parts by mass parts, more preferably 2 to 8 parts by mass.

( Use of this solid preparation ) Compound I is known to have excellent prostaglandin I ₂ (also known as PGI ₂ ) receptor agonist action, and exhibits platelet aggregation inhibitory action, vasodilator action, bronchial smooth muscle dilation action, and lipid deposition inhibitory action Various medicinal effects such as action and leukocyte activation inhibitory action (Patent Document 1 to Patent Document 7).

Therefore, the present solid preparation is useful as a preventive or therapeutic agent for diseases related to PGI ₂ , such as transient ischemic attack (TIA), diabetic neuropathy (for example, refer to Non-Patent Document 1), and diabetic gangrene (for example, refer to Non-patent document 1), peripheral circulatory disorders (eg, chronic arteriosclerosis, chronic arterial occlusion) (eg, see non-patent document 2), intermittent claudication (eg, see non-patent document 3), peripheral arterial embolism, Raynaud's disease (For example, see Non-Patent Document 4 and Non-Patent Document 5), collagen diseases (for example, systemic lupus erythematosus, scleroderma) (for example, see Patent Document 3 and Non-Patent Document 6), mixed connective tissue disease, vascular inflammatory syndrome, Re-occlusion/restenosis after percutaneous coronary angioplasty (PTCA), arteriosclerosis, thrombosis (eg, acute cerebral thrombosis, pulmonary embolism) (eg, see Non-Patent Document 5, Non-Patent Document 7), hypertension , pulmonary hypertension such as pulmonary hypertension or chronic thromboembolic pulmonary hypertension (for example, Non-Patent Document 8, Non-Patent Document 9), ischemic diseases (for example, cerebral infarction, myocardial infarction) (for example, see Non-Patent Document 10), angina pectoris (eg stable angina, unstable angina) (eg, see Non-Patent Document 11), glomerulonephritis (eg, see Non-Patent Document 12), diabetic nephropathy (eg, see Non-Patent Document 1), chronic renal failure (eg, see Non-Patent Document 1) Refer to Patent Document 4), allergies, bronchial asthma (for example, refer to Non-Patent Document 13), ulcers, bedsores (pressure ulcers), restenosis after coronary intervention such as atherectomy and stent placement, and dialysis Thrombocytopenia, diseases related to fibrosis of organs or tissues [eg, kidney diseases (eg, tubulointerstitial nephritis) (eg, refer to Patent Document 3), respiratory diseases (eg, interstitial pneumonia (pulmonary fibrosis)) (for example, see Patent Document 3), chronic obstructive pulmonary disease (for example, see Non-Patent Document 14), etc.], digestive diseases (for example, liver cirrhosis, viral hepatitis, chronic pancreatitis, sclerosing gastric cancer), cardiovascular diseases (for example, Cardiac fibrosis), bone/joint disorders (eg, myelofibrosis, rheumatoid arthritis), skin disorders (eg, postoperative scars, burn scars, keloids, hypertrophic scars), obstetric disorders (eg, uterus fibroids), urinary organ diseases (e.g. prostatic hypertrophy), other diseases (e.g. Alzheimer's disease, sclerosing peritonitis, type I diabetes, post-operative organ adhesions), erectile dysfunction (e.g. diabetic erectile dysfunction, psychogenic Erectile dysfunction, psychogenic erectile dysfunction, erectile dysfunction due to chronic renal failure, erectile dysfunction after pelvic surgery to remove the prostate, vascular erectile dysfunction associated with aging or arteriosclerosis) (for example, refer to patent documents 7), inflammatory bowel diseases (eg, ulcerative colitis, Crohn's disease, intestinal tuberculosis, ischemic colitis, intestinal ulcer with Bessie's disease) (eg, refer to Patent Document 5), gastritis, gastric ulcer, ischemia eye disease (eg retinal arterial occlusion, retinal vein obstructive disorder, ischemic optic neuropathy), sudden deafness, avascular osteonecrosis, concomitant nonsteroidal anti-inflammatory drugs (NSAIDs) (eg, diclofenac, meloxicam, oxaprozin, nabumetone, Indomethacin, ibuprofen, ketoprofen, naproxen, celecoxib) administration of intestinal injury (for example, as long as it is an injury that occurs in the duodenum, small intestine, and large intestine, there is no particular limitation). , such as mucosal damage or ulcers such as erosions in the duodenum, small intestine, and large intestine) (for example, refer to Patent Document 8), associated with spinal stenosis (for example, cervical spinal stenosis, thoracic spinal stenosis, lumbar spinal stenosis, extensive Spinal stenosis, sacral stenosis) symptoms (eg, paralysis, dysesthesia, pain, numbness, decreased walking ability) (eg, refer to Patent Document 6). In addition, the solid preparation of the present invention can also be used as a promoter of angiogenesis therapy such as gene therapy and autologous bone marrow cell transplantation, and a promoter of angiogenesis in peripheral revascularization or angiogenesis therapy.

( Characteristics of this solid preparation ) This solid preparation has at least the following properties (a) and (b).

(a) Good disintegration Specifically, the present solid preparation has the following disintegration properties. (i) In the case of plain ingots In the disintegration test specified in the Japanese Pharmacopoeia using water at 37° C. as the test liquid (without using the auxiliary plate), it disintegrated within 2 minutes. Here, with regard to "disintegration", all 6 tested lozenges disintegrated in one disintegration test; or if 1 or 2 did not disintegrate, further 12 tested lozenges were used for disintegration In the disintegration test, when 16 or more of the 18 tested lozenges disintegrated, it can be judged as "disintegrated". Regarding the disintegration time, in the case of the solid preparation produced by the production method A, it is preferable to have the property of disintegrating within 1 minute, more preferably to have the property of disintegrating within 0.9 minutes, and still more preferably It has the property of disintegrating within 0.8 minutes. In the case of a solid preparation manufactured by the manufacturing method B, it is preferable to have the property of disintegrating within 2 minutes, more preferably within 1.8 minutes, and still more preferably within 1.7 minutes Disintegrating properties. (ii) In the case of coated tablets Disintegrates within 2 minutes in the above-mentioned disintegration test (without the use of the auxiliary tray). Preferably, it has the property of disintegrating within 1.8 minutes, and more preferably has the property of disintegrating within 1.7 minutes.

(b) Good stability (inhibition of the formation of analogous substances due to the decomposition of compound I) Specifically, the present solid preparation inhibits the generation of analogous substances due to decomposition of the component (A) (compound I) which may be generated over time. The stability can be judged by comparing the content of similar substances formed in the solid preparation before and after the storage test. Specifically, it can be determined based on the following criteria based on the content ratio of the analogous substance contained in 100 mass % of the solid preparation after the storage test.

(i) After being stored for 1 month under open conditions at 40° C. and 75% RH in a dark place, the content of the above-mentioned similar substances is 1.5 mass % or less. (ii) The content of the above-mentioned similar substances is 1.5 mass % or less after being stored for 1 month under open conditions at 60° C. and under dark conditions. In addition, here, "40 degreeC, 75%RH open conditions" means that a solid preparation is put into an uncapped container, and a specimen is exposed under the conditions of 40 degreeC, 75%RH. In addition, "60 degreeC open condition" means that a solid preparation is put into an uncapped container, and a specimen is exposed under the condition of 60 degreeC. The determination of the content of the analogous substance in the solid preparation is explained in detail in the following example. The amount is quantified and obtained.

(Effect of solid preparation) According to the present solid preparation, the content ratio of starch in the granulation containing Compound I, starch, and at least one binder selected from the group consisting of hydroxypropyl cellulose and hypromellose per 100 parts by mass is: 20 parts by mass or more (excluding 30.2 to 30.4 parts by mass), and the content ratio of the binder per 100 parts by mass of the above-mentioned granules is 4 parts by mass or less. Thereby, the disintegration time of the solid preparation can be shortened, and the generation of similar substances due to the decomposition of Compound I in the solid preparation can be suppressed. Therefore, according to the present solid preparation, the disintegration property can be improved, and the decrease in stability of the compound I, which is an active ingredient in the solid preparation, can be suppressed.

This solid preparation is preferably in the form of a tablet, more preferably a relatively small and small tablet with a total mass of about 20 to 35 mg per tablet. The total mass per tablet is preferably 30 mg or less. The lozenge includes, for example, the following lozenges, characterized in that: the total mass of each lozenge is 18-22 mg, the content of component (A) in one lozenge is 80-120 μg, and the diameter is 2.5-22 mg. 3.5 mm, and the thickness is 1.5 to 2.5 mm.

When this solid preparation is a lozenge, its shape is not particularly limited, for example, it includes a lozenge with any shape such as a circle, an ellipse, and a rhombus when viewed from the front (upper surface), preferably a flat shape. is circular.

When this solid preparation is a tablet, it can be administered once a day or divided into multiple times (for example, 2 to 6 times) and administered. Furthermore, the dose per dose (single dose) can be selected according to gender, age, degree of disease, etc. 2 to 6 ingots).

(II) Manufacturing method of solid preparation containing celecipac This solid preparation can be manufactured according to the conventional method in this technical field according to its shape. The preferred embodiment of the solid preparation is a lozenge. In this case, the present solid preparation is preferably produced using a wet granule compression method.

A preferred embodiment of the production method of the present invention (hereinafter also referred to as "this production method") includes the following method: the components (A) and (B) and other components (for example, other than starch) that are further added as needed (D) component or (E) component, etc.) are mixed with powder, the (C) component prepared as a solution is added thereto, granulated (wet granulation), dried and granulated, and then (F) is prepared. ) component, compression-molding (ingot pressing), and manufacture (in this specification, this is also referred to as "manufacturing method A").

In addition, another preferred embodiment of the production method of the present invention (the present production method) includes the following method: adding components (A) and (B), and other components (for example, (D) other than starch, if necessary. ) component or (E) component, etc.) are mixed with powder, the (C) component prepared as a solution is added thereto, granulated (wet granulation), dried and granulated, and then the (F) component is removed. In addition, other components (for example, (D) component, (E) component, etc.) are mix|blended, and it manufactures by performing compression molding (ingot pressing) (it is also called "manufacturing method B" in this specification).

The above-mentioned manufacturing method is described as follows. (1) A step (mixing step) of mixing at least components (A) and (B) in powder to prepare a powder mixture; (2) A step of adding a solution containing the component (C) to the above-mentioned powder mixture and granulating to obtain a granulated product (granulation step); (3) the step of drying and granulating the above-mentioned granulated material as needed (granulating step); (4) a step of formulating an external additive of the granulated material into the granulated material (core granules) subjected to the above-mentioned granulation (post-addition step); and (5) A step of compression-molding the mixture obtained in the above-mentioned post-addition step (compression-molding step).

Furthermore, in the case where the granulated material external additive added and prepared in the above-mentioned step (4) is the component (F), the production method corresponds to the above-mentioned "production method A". In addition, in the case where the additives other than the granulated material added and prepared in the step (4) above also contain other components (for example, the (D) component or the (E) component, etc.) in addition to the (F) component, the production method meets the In the above-mentioned "manufacturing method B".

This solid preparation can also be a plain tablet without coating, but can be coated if necessary. When the present solid preparation is a coated tablet having a coating layer, the coated tablet can be produced by subjecting the tablet (plain tablet) obtained in the above (5) step to the (6) coating step. .

Each step is briefly described below. (1) Mixing step At least the components (A) and (B), and other optional components to be used as needed, powder mixed components for granulation can be preliminarily used in a pulverizer (chopper, roller mill, hammer mill) , roller mill, shear mill, ball mill, jet mill, etc.) to pulverize, and, if necessary, can be classified.

The mixing method of components (A) and (B) in the mixing step and other components used as needed is not particularly limited as long as it is a method that can uniformly mix the powders of these components. Although it does not restrict|limit, the method of putting a raw material into a fluidized bed granulation dryer, and mixing it while making it flow can be illustrated. Moreover, the method of mixing using mixers, such as a rotary mixer (for example, a V-type mixer, a double cone mixer), a stationary mixer (belt mixer, a screw mixer), can be illustrated.

Here, the mixing ratio of (A) and (B) components, and the mixing ratio of other optional components (for example, (D) component other than starch) are as described in the above-mentioned column (I), and this description can be used for this.

(2) Granulation step Granulation can be performed by adding a solution-like (C) component, preferably a The (C) component of the aqueous solution is granulated (wet granulation method). Although the concentration of the aqueous solution of the component (C) to be used varies depending on the component (C) to be used, it is not limited, but it is usually appropriately selected from the range of 0.5 to 20 mass %. The compounding quantity of the component (C) is as described in the above-mentioned column (I), and the ratio of the component (C) in 100% by mass of the total amount of the solid preparation to be finally produced can be in the range of 0.5 to 4% by mass by dry weight. way to adjust. Preferably it is 0.5-3.5 mass %. In addition, the ratio of the (C) component in 100 mass parts of granules is as described in the above-mentioned column (I), and can be appropriately set and selected according to the production methods A and B.

The granulation method may be a wet granulation method generally used in this technical field, and for example, the following methods can be exemplified without limitation: an extrusion granulation method in which a solution-like (C) is added to a raw material powder mixture. ) ingredients and kneading, extruding the kneaded material from the screen to carry out the method of forming and granulating; the crushing granulation method, which uses the rotary knife of the granulator to cut the kneading block prepared by the above-mentioned method for kneading. The method of breaking and ejecting from the outer spiral hole by centrifugal force; the rolling granulation method, which is to add a solution-like binder to the raw powder mixture and humidify it to obtain a powder, and apply a rotary motion or The method of vibrating to make it agglomerate to obtain nearly spherical particles; the fluidized bed granulation method, which is to make the raw material powder mixture flow from below by hot air flow, and spray the binder in the form of a solution to granulate it. Method; stirring granulation method, which is a method of putting raw material powder into a container, stirring with rotating blades, adding water or granulating liquid, and making raw material powder and granule agglomerate into a spherical shape.

(3) Granulation step For the drying of the granulated product prepared by the above step (2), a drying method commonly used in this technical field can be employed. For example, drying can be performed using various drying apparatuses such as a parallel flow box type dryer, a ventilation box type dryer, a fluidized bed dryer, and a vacuum type dryer. Among the above-mentioned box type, ventilation type, and fluidized bed system, it is preferable to blow and dry the granulated product by blowing air (hot air) heated to about 80 to 90° C. usually.

The granulation is also not particularly limited, and the granulation method commonly used in the technical field can be adopted without any particular limitation. It is preferable to granulate to a particle size such that there are no coarse particles of 1000 μm or more, and the average particle diameter of the granulated product is in the range of 50 to 400 μm. In addition, here, "average particle size" means the average particle size calculated according to the result of the sieving method of the powder particle size measurement method 2 method prescribed|regulated by the Japanese Pharmacopoeia 17th revision general test method.

(4) Post-addition step This step is followed by adding various powdery ingredients (additives to granules) (also simply referred to as “post-addition ingredients”) to the granules prepared by the above-mentioned (3) granulation step ) and carry out the mixing step.

In the manufacturing method A, powdery (F) component is added as a post-addition component, and it mixes. In the manufacturing method B, as a post-addition component, in addition to the powdery (F) component, powdery other components (for example, (D)component, (E)component, etc.) are also mixed. The mixing is the same as the above-mentioned step (1), as long as it is a method that can uniformly mix the granulated granulated material and the powdery granulated material with external additives, for example, by using a rotary mixer or Mixing is performed by a mixer such as a stationary mixer.

(5) Compression molding step The compression molding step can be performed by ingot pressing. The ingot pressing method commonly used in the industry is used for ingot pressing. Specifically, ingot pressing can be performed using a conventional ingot pressing machine such as a single-shot ingot pressing machine and a rotary ingot pressing machine.

Here, the tablet pressing pressure and other tablet pressing conditions are not limited as long as the tablet having the effects of the present invention can be produced, and the following conditions can be exemplified.

The ingot pressing pressure is usually 9.8 to 784 N/mm ² , preferably 93 to 694 N/mm ² . More preferably, it is 147-462 N/mm ² . Furthermore, the external lubrication method can also be used, that is, the (F) component is not mixed in the post-addition step (4), and the (F) component is sprayed on the pestle and the mortar and applied before the (5) compression molding step, Thereafter, (5) the compression molding step is performed.

(6) Coating step The coating method commonly used in this technical field is used for the coating. Specifically, the pan coating method, the fluidized bed coating method, the ventilating drying pan coating method, etc. are mentioned, and the coating can be performed using a coating apparatus suitable for these methods.

The coating can be carried out by coating a coating liquid obtained by blending the above-mentioned coating agent with a coloring agent, a flavoring agent, a sweetening agent, a flavoring agent, etc., if necessary, on the coating agent (1) to (5) The surface of the plain ingot produced by the step.

The coating is prepared so that the ratio of the coating layer to 100 parts by mass of the plain tablet is usually 1 to 12 parts by mass by dry weight. Preferably it is 1-10 mass parts, More preferably, it is 2-8 mass parts.

(Effect of the manufacturing method of the solid preparation) The method for producing a solid preparation according to the present invention includes a step (mixing step) of powder mixing (A) component and (B) component, and a step of granulating the obtained powder mixture using (C) component (Granulation step), in the mixing step, the powder mixture is prepared so that the content ratio of the component (B) per 100 parts by mass of the granulation is 20 parts by mass or more (excluding 30.2 to 30.4 parts by mass) Moreover, in a granulation process, the solution containing (C)component is added so that the content ratio of (C)component in 100 mass parts of granules may be 4 parts by mass or less. Thereby, the disintegration time is short, and the solid preparation which suppresses the generation|occurence|production of the analogous substance by decomposition|disassembly of (A) component (compound I) in a solid preparation can be manufactured. Therefore, according to the manufacturing method of this solid preparation, the solid preparation which can improve the disintegration property and can suppress the fall of the stability of the compound I in a solid preparation can be manufactured.

(III) Method for Inhibiting Decomposition of Xeloxipa in Solid Preparation Containing Xeloxipa The present invention provides a solid containing a granulated product containing (a) compound I, (b) starch, and (c) a binding agent A method for inhibiting the decomposition of the above-mentioned (a) component in a preparation. This method is characterized by using at least one compound selected from the group consisting of HPC and hypromellose as the component (c). The above-mentioned granulated product may further contain D-mannitol as an (d) excipient other than starch. In this case, the mass ratio of (b) component and (d) component other than starch is not limited, but (b) component: (d) component other than starch = 10:0 to 2: range of 8.

Here, (a) compound I, (b) starch, (c) binding agent, and (d) excipient correspond to the above-mentioned columns (I) and (II) as (A) component and (B), respectively. Component, (C) component, and (D) component demonstrated. Therefore, the above-mentioned descriptions can be referred to about the types and the mixing ratios thereof, and the manufacturing method of the solid preparation containing these components. According to the method of the present invention, for a solid preparation containing a granulated material comprising (a) Compound I, (b) starch, and (c) a binding agent, it is possible to remarkably inhibit (a) component (Compound I) in the solid preparation. The formation of similar substances as a result of decomposition. That is, according to the method of the present invention, the decrease in stability of the compound I in the above-mentioned solid preparation can be suppressed.

(IV) Inhibition of Xeloxipa Decomposition and Disintegration Improvement Method in Solid Formulation Containing Xeloxipa In the solid preparation of the granulated material of the binder, the decomposition of the component (a) above is suppressed and the disintegrability in an aqueous solution is improved. This method is characterized by using at least one compound selected from the group consisting of HPC and hypromellose as the component (c). The solid preparation to be targeted here is preferably a lozenge. The above-mentioned granulated product may further contain D-mannitol as an (d) excipient other than starch. In this case, the mass ratio of (b) component and (d) component other than starch is not limited, but (b) component: (d) component other than starch = 10:0 to 2: range of 8.

Here, (a) compound I, (b) starch, (c) binding agent, and (d) excipient correspond to the above-mentioned columns (I) and (II) as (A) component and (B), respectively. Component, (C) component, and (D) component demonstrated. Therefore, the above-mentioned descriptions can be referred to about the types and the mixing ratios thereof, and the manufacturing method of the solid preparation containing these components.

According to the method of the present invention, for a solid preparation containing a granulated material comprising (a) Compound I, (b) starch, and (c) a binding agent, it is possible to remarkably inhibit (a) component (Compound I) in the solid preparation. The formation of similar substances caused by decomposition can improve the disintegration property of solid preparations, especially lozenges, so that they can be disintegrated in a short time. That is, according to the method of the present invention, the decrease in stability of the compound I in the above-mentioned solid preparation can be suppressed, and the disintegrability of the solid preparation can be improved.

As mentioned above, in this specification, the terms "comprising" and "containing" include the meanings of "consisting of" and "substantially consisting of". [Example]

Hereinafter, regarding the structure and effect of the present invention, the present invention will be described using an experimental example for easy understanding. However, the present invention is not limited by these experimental examples. In the following experiments, unless otherwise specified, the experiments were carried out under the conditions of room temperature (25±5° C.) and atmospheric pressure. In addition, unless mentioned otherwise, "%" described below means "mass %", and "part" means "mass part".

The materials used in the following experimental examples are listed in Table 1. [Table 1] Element Material Product name grade manufacturer (A) Compound I Selexipag (type I crystal) - Nippon New Drug (Shares) (B) corn starch eclipse cornstarch W Nippon Foods Chemical Co., Ltd. (C) Hydroxypropyl cellulose HPC SSL Nippon Soda (Shares) Hypromellose TC- ^5R E Shin-Etsu Chemical Industry Co., Ltd. (D) D-Mannitol 1 Mannite P (specific surface area: 0.37 m ² /g) Mitsubishi Shoji Foodtech (Shares) D-Mannitol 2 Granutol ^R R (specific surface area: 0.67 m ² /g) Freund (shares) Lactose Hydrate 1 Dilactose ^R R Freund (shares) Lactose Hydrate 2 Tabletose ^R 100 Meggle Mixture of lactose and powdered cellulose Cellactose 80 Meggle (E) Hydroxypropyl cellulose with low degree of substitution L-HPC LH-11 Shin-Etsu Chemical Industry Co., Ltd. Crospovidone Kollidon ^R CL-F BASF Japan (shares) (F) Magnesium stearate Vegetable Magnesium Stearate special Taiping Chemical Industry (Shares) (G) Propylene Glycol Propylene Glycol - Asahi Glass (Shares) Hypromellose TC- ^5R E Shin-Etsu Chemical Industry Co., Ltd. Aqueous trehalose solution trehalose G Nagase Industry (stock) Titanium oxide Tipaque ^R A-100 Ishihara Sangyo Co., Ltd. (shares) yellow iron oxide yellow iron oxide - Guisi Chemicals (Shares) In the table, a name marked with an " ^R " means that it is a "registered trademark".

Test Methods The following test methods were used for the evaluation of the properties of the solid preparations (tablets) performed in the following Experimental Examples 1 to 7.

(1) Disintegration test Using water heated to 37°C as the test solution, the experiment was conducted in accordance with the general test method [disintegration test method] of the Japanese Pharmacopoeia, 17th Revised Edition (without using an auxiliary plate). When all 6 tested lozenges disintegrated or 1 or 2 did not disintegrate in one disintegration test, then 12 tested lozenges were used for disintegration test, and a total of 18 tested lozenges When more than 16 test tablets disintegrated, it was judged as "disintegration".

(2) Stability test The manufactured solid preparations (tablets) were left unpackaged at 40°C 75%RH open conditions (referred to as "40°C/75%RH" in the following table), or/and 60°C open conditions ( It was left to stand for 1 month under the conditions described as "60°C" in the following table (all in a dark place). The content of Compound I and similar substances in the solid preparation before and after the preservation test was determined by high performance liquid chromatography. Here, the "similar substance" corresponds to the case where the solid preparation containing Compound I was placed under the above conditions for 1 month and then subjected to high performance liquid chromatography, and the plurality of substances detected in the HPLC chromatogram Among the peaks, other than the peak derived from Compound I, the peak (main peak) was mainly detected.

The measurement of the content of Compound I and the like in the solid preparation by HPLC was performed by subjecting a sample (test sample) obtained by dissolving the solid preparation in a solvent to HPLC, but the test sample was Contains a solvent for dissolution, or components other than Compound I and the like (hereinafter referred to as "other components"). Therefore, other components or solvents contained in the solid preparation were previously subjected to HPLC under the same conditions used for the measurement, and the positions of the respective peaks were confirmed. Then, the respective peaks of the other components and the solvent were excluded from the HPLC chromatogram obtained for the above-mentioned test sample, whereby the respective peaks could be detected. However, regarding the analogous substance, the content of the analogous substance contained in the solid preparation can be obtained from the ratio of the peak area derived from the analogous substance to the total area of the peaks excluding the solvent peak. On the other hand, the content of Compound I is derived based on a standard substance.

In addition, the measurement by high performance liquid chromatography is performed under the conditions which can isolate|separate and detect compound I and a similar substance from other components. Specifically, the above-mentioned test sample is subjected to HPLC using a solvent commonly used in HPLC (eg, acetonitrile, etc.) as a mobile phase, and detected by a UV (ultraviolet, ultraviolet) detector.

Experimental Example 1 Evaluation of the presence or absence of a binding agent and the granulation method According to the formulations described in Table 2, various lozenges (plain lozenges) (tested formulations 1-1 to 1-4) were produced. ) component: corn starch) and its addition method were evaluated on the stability of Compound I (component (A)) and the effect on the disintegration of the tablet.

[Table 2] Test preparation 1-1 1-2 1-3 1-4 With binder solution added With binder powder added Binder-free water granulation Binder-free direct tablet compression (A) Compound I 0.022 0.022 0.022 0.022 (B) corn starch 5.333 5.333 5.333 5.333 (C) Hydroxypropyl cellulose ¹⁾ 0.6 0.6 - - (D) D-Mannitol 1 8.067 8.067 8.067 8.067 (E) Hydroxypropyl cellulose with low degree of substitution 0.756 0.756 0.756 0.756 (F) Magnesium stearate 0.222 0.222 0.222 0.222 total 15 mg 15 mg 14.4 mg 14.4 mg 1) Prepared as a 10% aqueous solution for use (wherein, the numbers in the table are the dry matter conversion values)

(1) Preparation of granules (core granules) [mixing, granulation, and granulation] About the test sample 1-1, (A) component, (B) component, (D) component, and (E) component were put into a fluidized bed granulation dryer (MP-01, Powrex Co., Ltd.), While mixing, the 10% hydroxypropylcellulose aqueous solution prepared previously dissolved in water as the component (C) was added by spraying, and granulation was performed. Next, the obtained granules were granulated by a screen granulator (Type Co-mill QC-197S, Powrex Co., Ltd.: screen size 991 μm, rotational speed 25 Hz) to prepare granules (nuclear granules) . About the test sample 1-2, the powdered component (C), the above (A), (B), ( D) and (E) components were mixed for 10 minutes to prepare a powder mixture. The test sample 1-3 was granulated by spraying and adding water to the powder mixture of the components (A), (B), (D) and (E) without using the component (C). About the test sample 1-4, the powder mixture was prepared by mixing only the components (A), (B), (D) and (E) described above without using the component (C).

(2) Preparation of plain ingots (mixing with extragranular additives, ingot pressing) Using a container rotary mixer (Bohle Container Mixer LM-20, HIROSHIMA METAL & MACHINERY Co., Ltd.) to the above-mentioned (1) The powdered (F) component was mixed with the granules (core granules) or the powder mixture for 10 minutes to prepare granules for tablet pressing. Next, using a rotary ingot press (Correct 12HUK manufactured by Kikusui Seisakusho: rotating speed 40 rpm), with a mass of 15 mg/ingot, a circular ingot mold with a diameter of 3 mm was used, and the ingot was ingot-molded with an ingot load of 378 N/mm ² . , to obtain a round-shaped plain tablet (tested formulations 1-1 to 1-4).

(3) Evaluation of tablet properties According to the above test method, the disintegration time of the manufactured test preparations 1-1 to 1-4, and the content (%) of similar substances and the content (%) of compound I in the test preparations (all converted into dry matter content) ) to measure. The results are shown in Table 3.

[table 3] Disintegration time (min) Similar substance content (%) Compound I content (%) When the test starts 40℃/75%RH 60℃ 40℃/75%RH 60℃ Test preparation 1-1 1.3 0.20 1.07 0.41 97.2 100.3 Tested preparations 1-2 Not determined 0.19 3.81 1.06 94.5 98.1 Test preparations 1-3 Not determined 0.20 5.63 1.73 91.4 96.1 Test preparations 1-4 Not determined 0.20 4.76 1.23 94.4 98.7

As shown in Table 3, the test preparations 1-3 and 1-4 produced by the water granulation method or the direct tableting method without adding the component (C) were stored in the stability test for 1 month, and the similar substances increased significantly , it was confirmed that the content of compound I decreased. In addition, the test preparation 1-2 produced by adding the component (C) in powder form and granulated was also stored in the stability test for 1 month, and the similar substances significantly increased, and it was confirmed that the content of the compound I decreased. From this result, it was confirmed that in order to improve the stability of Compound I in the solid preparation (suppress the decomposition of Compound I) and suppress the generation of similar substances, it is preferable to add ( C) Ingredient (wet granulation).

Experimental Example 2 Study and Evaluation of Types of Binders Stability of Compound I (Component (A)) in Solid Formulations (Tablets) with respect to the types of binders (component (C)) used for granulation, and tablets The effect of the disintegration of the agent was evaluated.

(1) Preparation of granulated material (core granules) and plain lozenges According to the formulations described in Table 4, components (A) to (E) were used, and the same wet granulation method as the above-mentioned test preparation 1-1 was used. Granulates (core granules) were prepared. The powdered component (F) is prepared therein, and by the same method as the above-mentioned test preparation 1-1, tableting is carried out with a tableting load of 378 N/mm ² to obtain a plain tablet (tested preparation) whose plane shape is a circular shape. 2-1 to 2-10).

[Table 4] Test preparations 2-1 to 2-10 (A) Compound I 0.022 (B) corn starch 5.333 (C) Binder (refer to Table 5) ^{1 )} 0.6 (D) D-Mannitol 1 8.067 (E) Hydroxypropyl cellulose with low degree of substitution 0.756 (F) Magnesium stearate 0.222 total 15 mg 1) Prepared as a 10% aqueous solution for use (wherein, the numbers in the table are the dry matter conversion values)

(2) Evaluation of tablet properties According to the above test method, the disintegration time of the manufactured test preparations 2-1 to 2-10, as well as the content (%) of similar substances and the content (%) of compound I in the test preparation (all converted into dry matter content) ) to measure. The results are shown in Table 5.

[table 5] Binder (component (C)) Disintegration time (min) Similar substance content (%) Compound I content (%) When the test starts 40℃/75%RH 60℃ 40℃/75%RH 60℃ Test preparation 2-1 Hydroxypropyl cellulose 1.3 0.20 1.07 0.41 97.2 100.3 Test preparation 2-2 Hypromellose 2.6 0.20 0.61 0.53 98.4 100.0 Test preparations 2-3 polyvinyl alcohol 1.8 0.20 2.31 1.00 95.7 97.4 Test preparations 2-4 Povidone 1.2 0.19 2.63 1.01 94.5 98.8 Test preparations 2-5 refined sugar Not determined 0.20 6.72 1.31 91.7 98.0 Test preparations 2-6 Isomalt Not determined 0.20 7.94 1.57 90.3 96.1 Test preparations 2-7 trehalose Not determined 0.20 6.38 1.96 93.0 96.9 Tested preparations 2-8 Erythritol Not determined 0.21 8.21 2.15 88.2 94.5 Test preparations 2-9 Xylitol Not determined 0.20 7.56 1.74 90.0 96.9 Tested preparations 2-10 Sorbitol Not determined 0.22 6.63 1.78 91.6 97.0

As shown in Table 5, when granulation was carried out using binders other than hydroxypropyl cellulose and hypromellose, after being stored for 1 month in the stability test, the similar substances increased significantly, and the content of Compound I was confirmed. reduce. From this result, it was confirmed that in order to improve the stability of Compound I in the solid preparation (suppress the decomposition of Compound I) and suppress the generation of similar substances, in the granulation step of producing the present solid preparation, as a binding agent ((C) component ), preferably hydroxypropyl cellulose or hypromellose.

Experimental Example 3 Evaluation of the blending ratio of (B) component and ( D) component ratio) to evaluate the stability of Compound I (component (A)) in a solid preparation (tablet) and the effect on the disintegration of the tablet.

(1) Preparation of granules (core granules) and plain lozenges According to the formulations described in Table 6, components (A) to (D) were used, and the same wet granulation method as the above-mentioned test preparation 1-1 was used. Granulates (core granules) were prepared. The powdered component (F) is prepared therein, and by the same method as the above-mentioned test preparation 1-1, tableting is carried out with a tableting load of 378 N/mm ² to obtain a plain tablet (tested preparation) whose plane shape is a circular shape. 3-1 to 3-6).

[Table 6] Test preparation 3-1 3-2 3-3 3-4 3-5 3-6 (B) component: (D) component (mass ratio) 0:10 2:8 4:6 6:4 8:2 10:0 (A) Compound I ¹⁾ 0.025 0.025 0.025 0.025 0.025 0.025 (B) corn starch - 2.83 5.66 8.49 11.32 14.15 (C) Hypromellose ²⁾ 0.6 0.6 0.6 0.6 0.6 0.6 (D) D-Mannitol 1 14.15 11.32 8.49 5.66 2.83 - (F) Magnesium stearate 0.225 0.225 0.225 0.225 0.225 0.225 total 15 mg 15 mg 15 mg 15 mg 15 mg 15 mg 1) 25 μg / plain tablet 2) Prepared as a 10% aqueous solution for use (wherein, the numbers in the table are the dry matter conversion value)

(2) Evaluation of tablet properties According to the above test method, the disintegration time of the test preparations 3-1 to 3-6, the content of similar substances (%) and the content of compound I (residual rate) (%) in the test preparations (all converted dry matter content). The results are shown in Table 7.

[Table 7] Allocation ratio (B): (D) Disintegration time (min) Similar substance content (%) Compound I content (%) When the test starts 40℃/75%RH 60℃ 40℃/75%RH 60℃ Test preparation 3-1 0:10 1.9 0.20 1.73 0.62 97.7 98.6 Test preparation 3-2 2:8 1.9 0.20 0.74 0.70 99.5 100.1 Test preparation 3-3 4:6 2.3 0.20 0.60 0.56 99.8 101.3 Test preparations 3-4 6:4 1.6 0.19 0.55 0.43 98.0 103.4 Test preparations 3-5 8:2 1.7 0.20 0.48 0.36 98.2 106.0 Test preparations 3-6 10:0 2.1 0.20 0.35 0.30 100.0 111.3 Test preparation 2-2 (reference) 4:6 2.6 0.20 0.61 0.53 98.4 100.0

As shown in Table 7, it was confirmed that even if D-mannitol (component (D)) was not used during granulation, the stability of Compound I in the solid preparation was high (decomposition of Compound I was suppressed), and similar substances were found to have high stability. Production was inhibited (Test Formulations 3-6). It was confirmed that there is a tendency that by increasing the ratio of (B) component (or the blending ratio of (B) component to (D) component other than starch) in the solid preparation (core particles), the stability of compound I becomes worse high. According to the results of the test preparation 3-2, it is considered that the component (B) (solid preparation 100%) is prepared in a ratio of 15 parts or more, preferably 19 parts or more per 100 parts of the granulated material (core granules). 14% or more, preferably 18% or more), a solid preparation with higher stability of compound I can be obtained. However, even if the blending of the component (B) was increased, it was not confirmed that the disintegrability of the solid preparation was greatly affected. On the other hand, it was confirmed that the disintegration time was shortened by mixing D-mannitol as the (D) excipient in addition to the starch formulated as the (B) component. However, when only D-mannitol was added without the (B) component, the stability of the compound I in the solid preparation decreased (compound I was decomposed), and it was confirmed that a similar substance was produced (test preparation 3-1).

From this, it is considered that in the present solid preparation, starch (component (B)) mainly contributes to the stability (decomposition inhibition) of Compound I in the solid preparation. Therefore, in order to prepare a solid preparation having both the stability (decomposition inhibition) of the compound I in the solid preparation and the good disintegrability of the solid preparation, it is considered that (B) used in the production of the granulated material (core granule) is required. The blending balance of the components and (D) components other than starch (especially D-mannitol) is effective. In addition, according to the comparison of the results of the test preparation 3-3 recorded in Table 7 and the test preparation 2-2 recorded as a reference, it was not confirmed whether the granules were formulated with low-substituted hydroxypropyl cellulose ((( D) Influence of ingredient) on stability and disintegration.

Experimental Example 4 Evaluation of the addition amount of HPC ( component (C ) ) In the case of using hydroxypropyl cellulose (HPC) as the The stability of the compound I (component (A)) in the formulation (tablet) and the effect on the disintegration of the tablet were evaluated.

(1) Preparation of granulated material (core granules) and plain lozenges According to the formulations described in Table 8, components (A) to (E) were used, and the same wet granulation method as the above-mentioned test preparation 1-1 was used. Granulates (core granules) were prepared. The powdered component (F) is prepared therein, and by the same method as the above-mentioned test preparation 1-1, tableting is carried out with a tableting load of 378 N/mm ² to obtain a plain tablet (tested preparation) whose plane shape is a circular shape. 4-1 to 4-5).

[Table 8] Test preparation 4-1 4-2 4-3 4-4 4-5 HPC dosage tablet 100% granulated 100 parts 4% 4.060 servings 3% 3.076 servings 2% 2.072 servings 1% 1.047 servings 0.5% 0.526 copies (A) Compound I 0.022 0.022 0.022 0.022 0.022 (B) corn starch 5.333 5.333 5.333 5.333 5.333 (C) HPC ¹⁾ 0.6 0.45 0.3 0.15 0.075 (D) D-Mannitol 1 8.067 8.067 8.067 8.067 8.067 (E) Low degree of substitution HPC 0.756 0.756 0.756 0.756 0.756 (F) Magnesium stearate 0.222 0.222 0.222 0.222 0.222 total 15 mg 14.85 mg 14.7 mg 14.55 mg 14.475 mg 1) Prepared as a 10% aqueous solution for use (wherein, the numbers in the table are the dry matter conversion values)

(2) Evaluation of tablet properties According to the above test method, the disintegration time of the test preparations 4-1 to 4-5, the content of similar substances (%) and the content of compound I (residual rate) (%) in the test preparations (all converted dry matter content). The results are shown in Table 9.

[Table 9] HPC dosage tablet 100% / 100 granules Disintegration time (min) Similar substance content (%) Compound I content (%) When the test starts 40℃/75%RH 60℃ 40℃/75%RH 60℃ Test preparation 4-1 4%/4.060 servings 1.3 0.20 1.07 0.41 97.2 100.3 Test preparation 4-2 3%/3.076 servings 1.0 0.19 1.35 0.68 97.5 99.1 Test preparation 4-3 2%/2.072 servings 0.8 0.20 1.50 0.81 96.8 98.7 Test preparations 4-4 1%/1.047 servings 0.3 0.20 2.16 1.09 96.1 98.5 Tested preparations 4-5 0.5%/0.526 copies 0.2 0.20 3.27 1.39 94.0 96.1

As shown in Table 9, by reducing the amount of HPC used as component (C) during granulation, the disintegration time is shortened and the disintegration property is improved, but if the ratio to the tablet (plain tablet) is 1% or less (the ratio with respect to the granulated material was 1.047 parts or less), after storage for 1 month in the stability test, the amount of similar substances increased significantly, and it was confirmed that the content of Compound I decreased.

Therefore, it is considered that HPC not only acts as a binding agent during granulation, but also contributes to the maintenance or improvement of the stability of Compound I in the solid preparation (inhibiting the decomposition of Compound I). Furthermore, from the above results, it is considered that if the addition amount of HPC relative to 100 parts of the granulated material is adjusted to 2 parts or more, preferably 2 to 4.1 parts, more preferably 2 to 3.1 parts, it is possible to prepare a solid preparation with The stability (decomposition inhibition) of compound I and the good disintegration of solid preparations are solid preparations.

Experimental Example 5 Evaluation of the addition amount of hypromellose ( component (C) ) When hypromellose was used as the component (C) in the production of the granulated product (core granules), The stability of the compound I (component (A)) in the solid preparation (tablet) and the influence of the disintegration of the tablet were evaluated.

(1) Preparation of granulated material (core granules) and plain tablet According to the formulations described in Table 10, components (A) to (D) were used, and the wet granulation method similar to the above-mentioned test preparation 1-1 was used. Granulates (core granules) were prepared. The powdered component (F) is prepared therein, and by the same method as the above-mentioned test preparation 1-1, tableting is carried out with a tableting load of 378 N/mm ² to obtain a plain tablet (tested preparation) whose plane shape is a circular shape. 5-1 to 5-6).

[Table 10] Test preparation 5-1 5-2 5-3 5-4 5-5 5-6 Hypromellose dosage tablet 100% / 100 granules 4% / 4.061 servings 2%/ 2.073 servings 1% / 1.047 servings 1% / 1.047 servings 1% / 1.047 servings 1% / 1.047 servings Hypromellose Aqueous Concentration ¹⁾ 10% 10% 10% 5% 2.5% 1% (A) Compound I 0.025 0.025 0.025 0.025 0.025 0.025 (B) corn starch 5.66 5.66 5.66 5.66 5.66 5.66 (C) Hypromellose 1 0.6 0.3 0.15 0.15 0.15 0.15 (D) D-Mannitol 1 8.49 8.49 8.49 8.49 8.49 8.49 (F) Magnesium stearate 0.225 0.225 0.225 0.225 0.225 0.225 total 15 mg 14.7 mg 14.55 mg 14.55 mg 14.55 mg 14.55 mg 1) The concentration of hypromellose in the aqueous solution used for granulation (wherein, the numbers in the table are the dry matter conversion values)

(2) Evaluation of tablet properties According to the above test method, the disintegration time of the test preparations 5-1 to 5-6, the content of similar substances (%) and the content of compound I (residual rate) (%) in the test preparations (all converted dry matter content). The results are shown in Table 11.

[Table 11] Hypromellose Disintegration time (min) Addition of similar substances (%) Compound I content (%) added amount Aqueous solution concentration When the test starts 40℃/75%RH 60℃ 40℃/75%RH 60℃ Test preparation 5-1 4% 2% 2.3 0.20 0.60 0.56 99.8 101.3 Test preparation 5-2 2% 10% 1.3 0.21 0.83 0.67 99.2 101.1 Test preparation 5-3 1% 10% 0.8 0.21 1.66 0.90 97.0 99.2 Tested preparations 5-4 1% 5% 1.0 0.20 1.21 0.80 96.6 99.9 Test preparations 5-5 1% 2.5% 0.8 0.20 1.03 0.75 97.8 98.4 Tested preparations 5-6 1% 1% 0.9 0.20 0.83 0.65 97.6 100.4

As shown in Table 11, the disintegration time was shortened and the disintegration property was reduced by reducing the amount of hypromellose used as the component (C) during granulation, as in the results of HPC shown in the above-mentioned Experimental Example 4. However, when the ratio relative to the tablet (plain tablet) was 1% or less (the ratio relative to the granulated material was 1.047 parts or less), the similar substances increased significantly after being stored in the stability test for 1 month, and it was confirmed that until the content of Compound I decreased (Test Formulation 5-3). Therefore, it is considered that hypromellose, like HPC, not only acts as a binding agent during granulation, but also contributes to the maintenance or improvement of the stability of Compound I in the solid preparation (inhibits the decomposition of Compound I).

However, it was confirmed that even when the amount of hypromellose added to the tablet (vegetarian tablet) was 1% or less (the ratio to the granulated material was 1.047 parts or less), by reducing the amount of granulation When the concentration of hypromellose in the aqueous solution used is set to 5% or less, the stability of Compound I can also be improved while maintaining good disintegrability. It is considered that such an effect is also confirmed in the HPC shown in the above-mentioned Experimental Example 4.

Experiment Example 6 Evaluation of Production Method B According to the formulations described in Table 12, Production Method B was used instead of Production Method A used in Experimental Examples 1 to 5 to produce various lozenges (plain lozenges) (Test Formulations 6-1 to 6 -4), the stability of compound I (component (A)) and the disintegration property of the tablet were evaluated.

[Table 12] Test preparation 6-1 6-2 6-3 6-4 Hypromellose addition amount (in plain tablet: mass %) 1% 1% 1% 1% Hypromellose addition amount (in granulation: parts by mass) 3.3% 3.3% 3.3% 3.3% Granules (A) Compound I 0.025 0.025 0.025 0.025 (B) corn starch 1.73 1.73 1.73 1.73 (C) Hypromellose ¹⁾ 0.15 0.15 0.15 0.15 (D) D-Mannitol 1 2.595 2.595 2.595 2.595 External Additives for Granules (D) D-Mannitol 2 9.525 - - - (D) Lactose Hydrate 1 - 9.525 - - (D) Lactose Hydrate 2 - - 9.525 - (D) Mixture of lactose and powdered cellulose - - - 9.525 (E) Crospovidone 0.75 0.75 0.75 0.75 (F) Magnesium stearate 0.225 0.225 0.225 0.225 total 15 mg 15 mg 15 mg 15 mg 1) Prepared into a 2.5% aqueous solution for use (wherein, the numbers in the table are the dry matter conversion values)

(1) Preparation of granules (core granules) (mixing, granulation, and granulation) The components (A), (B), and (D) of the components of the granulated product (core particles) described in Table 12 were put into a fluidized bed granulation dryer (MP-01, Powrex Co., Ltd.) , while mixing, spraying and adding (C) component preliminarily dissolved in water and prepared as a 2.5% aqueous solution for granulation. Next, the obtained granules were granulated by a screen-type granulator (Model Co-mill QC-197S, Powrex Co., Ltd.) to prepare granules (core granules).

(2) Preparation of plain pellets (mixing with extragranular additives, pelletizing) The pellets prepared in the above (1) were granulated using a container rotary mixer (Bohle Container Mixer LM-20, HIROSHIMA METAL & MACHINERY Co., Ltd.). The granules (core granules) and extragranular additives (component (D), component (E), and component (F)) were mixed for 10 minutes to prepare granules for tablet pressing. Here, the extragranular additives are all used in powder form. Next, using a rotary ingot press (Correct 12HUK manufactured by Kikusui Seisakusho: rotating speed 40 rpm), with a mass of 15 mg/ingot, a circular ingot mold with a diameter of 3 mm was used, and the ingot was ingot-molded with an ingot load of 378 N/mm ² . , to obtain a round-shaped ingot.

(3) Evaluation of tablet properties According to the above test method, the disintegration time of the test preparations 6-1 to 6-4, the content of similar substances (%) and the content of compound I (residual rate) (%) in the test preparations (all converted dry matter content). The results are shown in Table 13.

[Table 13] Disintegration time (min) Similar substance content (%) Compound I content (%) When the test starts 40℃/75%RH 60℃ 40℃/75%RH 60℃ Test preparation 6-1 0.3 0.19 0.94 0.62 97.0 96.6 Test preparation 6-2 0.4 0.19 1.03 0.91 98.7 97.4 Test preparation 6-3 0.4 0.20 0.95 0.88 95.9 96.7 Test preparations 6-4 0.4 0.19 0.86 0.80 100.3 97.7

As shown in Table 13, all formulations can be prepared with the stability of Compound I (decomposition Inhibition) and good disintegration of solid preparations. In particular, by the production method B, the disintegration time can be further shortened, and it is considered that the ratio of the (B) component used at the time of granulation can also be increased.

Moreover, as shown in this result, by adjusting so that the ratio of the hypromellose in 100% of the solid preparation (plain tablet) is 1% (3.3 parts with respect to 100 parts of granules), it can be prepared. A solid preparation having both the stability (decomposition inhibition) of Compound I and good disintegration properties, therefore, as the ratio of the hypromellose used for granulation, it is preferable to enumerate: per 100% of the solid preparation (sugar ) is in the range of 0.5 to 4%, preferably in the range of 0.5 to 3.5%; relative to 100 parts of granules, it is in the range of 0.5 to 4 parts, preferably in the range of 0.5 to 3.5 parts.

Experimental Example 7 Evaluation of Coating Formulation Coating films were applied to the lozenges (plain lozenges) produced in Experimental Example 6 (test formulations 6-1 to 6-4) to stabilize compound I (component (A)). properties, and tablet disintegration properties were evaluated.

(1) Preparation of coated tablets (coating) Using a tablet coating machine (manufactured by Powrex Co., Ltd., vented coater DRC650, air supply temperature 50-60°C, air volume 4 m ³ /min), The plain tablets (tested formulations 6-1 to 6-4) produced in Experimental Example 6 contained hypromellose (64 parts), propylene glycol (13 parts), seaweed per 100 parts (converted to dry matter) of the coating film. Aqueous solution (coating liquid) of sugar hydrate (13 parts), titanium oxide (10 parts), and yellow ferric oxide (trace).

(2) Evaluation of tablet properties According to the above test method, the disintegration time of the test preparations 7-1 to 7-4, the content of similar substances (%) and the content of compound I (residual rate) (%) in the test preparations (all converted dry matter content). The results are shown in Table 14.

[Table 14] Disintegration time (min) Addition of similar substances (%) Compound I content (%) When the test starts 40℃/75%RH 60℃ 40℃/75%RH 60℃ Tested preparation 7-1 0.8 0.08 0.64 0.38 98.9 100.6 Test preparation 7-2 0.9 0.09 0.66 0.23 99.7 98.3 Test preparation 7-3 0.5 0.09 0.72 0.50 98.8 98.5 Tested preparations 7-4 1.7 0.09 0.67 0.47 98.4 100.0

As shown in Table 14, all formulations (tested formulations 7-1 to 7-4) can be prepared with both the stability (decomposition inhibition) and good disintegration properties of Compound I without being affected by the coating film. solid preparations. It is thought that the ratio of (C)component used at the time of granulation can also be increased by manufacturing method B, since the disintegration time can be shortened further similarly to a plain tablet.

Claims (21)

A solid preparation comprising granules comprising: (A) 2-{4-[N-(5,6-Diphenylpyridine-2-yl)-N-isopropylamino]butoxy}-N-(methylsulfonyl)ethyl amide, (B) starch, and (C) at least one binder selected from the group consisting of hydroxypropyl cellulose and hypromellose; and The content ratio of the above-mentioned (B) component per 100 parts by mass of the granules is 20 parts by mass or more (excluding 30.2 to 30.4 parts by mass), The content rate of the said (C)component per 100 mass parts of granules is 4 mass parts or less. The solid preparation according to claim 1, wherein the granulated product is a wet granulated product. The solid preparation according to claim 1 or 2, wherein the granulated product further contains (D) excipients other than starch. The solid preparation according to claim 3, wherein the above-mentioned (D) excipient is D-mannitol. The solid preparation of claim 3 or 4, wherein the mass ratio of component (B) in the granulation to component (D) other than starch is (B) component: component (D) other than starch = 10: 0 to 2:8. The solid preparation according to any one of claims 1 to 5, wherein the granulated product further contains (E) a disintegrant. The solid preparation of any one of claims 1 to 6, which has the shape of a lozenge. The solid preparation according to any one of claims 1 to 7, which has the shape of a lozenge, and the surface is covered with a coating agent. The solid preparation according to any one of Claims 1 to 8, which contains the above-mentioned granules, and as an external additive to the granules, selected from (D) excipients, (E) disintegrants and (F) lubricants at least one of the group consisting of agents. The solid preparation according to any one of claims 1 to 9, which is used for the treatment of concomitant diseases selected from the group consisting of diabetic neuropathy, diabetic gangrene, peripheral circulatory disorder, chronic arterial occlusion, intermittent claudication, 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 Symptoms of at least one disease in the group consisting of bowel disease and spinal stenosis. A method for producing a solid preparation comprising granules containing: (A) 2-{4-[N-(5,6-diphenylpyridine-2-yl)-N- Isopropylamino]butoxy}-N-(methylsulfonyl)acetamide, (B) starch, and (C) selected from the group consisting of hydroxypropyl cellulose and hypromellose At least one of the binding agents, the manufacturing method of the above-mentioned solid preparation comprises the following steps: (1) Prepare a powder mixture of the above-mentioned (A) components and (B) components; and (2) adding the solution containing the above-mentioned (C) component to the above-mentioned powder mixture and granulating to obtain a granulated product; and In the above step (1), the powder mixture is prepared so that the content ratio of the component (B) per 100 parts by mass of the granules is 20 parts by mass or more (excluding 30.2 to 30.4 parts by mass), and , In the said (2) process, the solution containing the said (C)component is added so that the content rate of the (C)component per 100 mass parts of granules may be 4 parts by mass or less. The production method of claim 11, wherein the solution containing the component (C) described above contains the component (C) in a ratio of 1 to 10% by mass. The production method according to claim 11 or 12, wherein the component (C) is hydroxypropyl cellulose, and has the step of: the content ratio of hydroxypropyl cellulose per 100 parts by mass of the granules is 1 to 4 The hydroxypropyl cellulose-containing solution was sprayed into the powder mixture of (A) component and (B) component by mass parts. The production method according to claim 11 or 12, wherein the component (C) is hypromellose, and has the step of: the content ratio of hypromellose per 100 parts by mass of the granules is 1 to 4 The hypromellose-containing solution was sprayed into the powder mixture of (A) component and (B) component in mass parts. The production method according to any one of claims 11 to 14, wherein the powder mixture further contains (D) excipients other than starch. The production method according to claim 15, wherein the component (D) is D-mannitol. The production method of claim 15 or 16, wherein the mass ratio of component (B) in the powder mixture to component (D) excluding starch is (B) component: component (D) excluding starch = 10:0 ~2:8. The production method according to any one of claims 11 to 17, wherein the powder mixture further contains (E) a disintegrant. The production method according to any one of claims 11 to 18, wherein after the above-mentioned (2) granulation step, after (3) granulation step as necessary, there is (4) an addition selected from (D) excipients, (E) A step of at least one granulation external addition of the group consisting of a disintegrant and (F) a lubricant (post addition step). The production method according to claim 19, wherein (5) a compression molding step is provided after the above-mentioned (4) post-addition step. The production method of claim 20, further comprising the step of coating the compression-molded product obtained by the compression-molding step (5).