Pharmaceutical composition containing 2-{4n-(5,6- diphenylpyrazin-2-yl)-n-isopropylamino]butyloxy}-n- (methylsulfonyl)acetamide

Abstract

Provided is a stabilized solid preparation of 2-{4-[N-(5,6- diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N- (methylsulfonyl)acetamide. A solid preparation containing 2-{4-[N-(5,6-diphenylpyrazin- 2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl) acetamide and D-mannitol having a specific surface area of 1.0 m2 / g or less.

Description

A pharmaceutical composition containing 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide The present invention relates to a stabilized solid preparation of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide (hereinafter referred to as "Compound (I)"). The following structural formula: Compound (I) represented by the formula has excellent prostaglandin I ２ (PGI ２ also referred to as) receptor agonist activity and is known to exhibit various medicinal effects such as platelet aggregation inhibitory activity, vasodilatory activity, bronchiolar muscle relaxant activity, lipid deposition inhibitory activity, and leukocyte activation inhibitory activity (Patent Document 1). Generally, as excipients for solid preparations, sugar alcohols such as lactose, corn starch, crystalline cellulose, and D-mannitol are used for diluting the active ingredient. In the process of examining the formulation of a solid preparation containing Compound (I), although Compound (I) itself is stable against temperature and humidity, depending on the type of D-mannitol, the decomposition of Compound (I) in the solid preparation progresses and its content decreases. International Publication No. 2002 / 088084 International Publication No. 2009 / 157396 International Publication No. 2009 / 107736 International Publication No. 2009 / 154246 International Publication No. 2009 / 157397 International Publication No. 2009 / 157398 International Publication No. 2009 / 154246 International Publication No. 2009 / 157397 Hepatology, 2007, Vol. 45, No. 1, p159 - 169. Folia Pharmacologica Japonica, Vol. 117, No. 2, p. 123 - 130, 2001, Abstract. International Angiology, 29, Suppl. 1 to No. 2, p. 49 - 54, 2010. Jpn. J. Clin. Immunol., 16(5), 409 - 414, 1993. Jpn. J. Thromb. Hemost., 1:2, p. 94 - 105, 1990, Abstract. J. Rheumatol., 2009, 36(10), 2244 - 2249. Japan J. Pharmacol., 43, p. 81 - 90, 1987. New Engl. J. Med., 2015, 24, 2522 - 2533. CHEST 2003, 123, 1583 - 1588. Br. Heart J., 53, p. 173 - 179, 1985. The Lancet, 1, 4880, pt 1, p. 569 - 572, 1981. Eur. J. Pharmacol., 449, p. 167 - 176, 2002. The Journal of Clinical Investigation, 117, p. 464 - 472, 2007. Am. J. Physiol.Lung Cell Mol. Physiol., 296:L648 - L656, 2009. An object of the present invention is to provide a stabilized solid preparation of compound (I). Here, "stabilized" means that a decrease in the content due to the decomposition of compound (I) contained in the solid preparation is suppressed. As a result of intensive studies to solve the above problems, the present inventors have found that the use of D - mannitol having a specific surface area of 1.0 m ２ / g or less as an excipient for compound (I) improves the stability of compound (I) in the solid preparation, and thus completed the present invention. That is, the present invention is as follows. (A) A solid preparation containing compound (I) and D - mannitol having a specific surface area of 1.0 m ２ / g or less. (B) The solid preparation according to (A), wherein the amount of D-mannitol is 5 to 10,000 parts by weight per 1 part by weight of the compound (I). (C) The solid preparation according to (A) or (B), wherein the content of D-mannitol is 10 to 99% by weight of the total weight of the solid preparation. (D) The solid preparation according to any one of (A) to (C), wherein 20% by weight or more of the total weight of the excipients contained in the solid preparation is D-mannitol. (E) The content of D-mannitol is (a) 5 to 10,000 parts by weight of D-mannitol per 1 part by weight of the compound (I), (b) 10 to 99% by weight of the total weight of the solid preparation, (c) 20% or more of the total weight of the excipients contained in the solid preparation, the solid preparation according to (A). (F) The solid preparation according to any one of (A) to (E), further containing excipients other than D-mannitol and a binder. (G) The solid preparation according to (F), wherein the excipient other than D-mannitol is one or two selected from the group consisting of corn starch, refined sugar, and crystalline cellulose. (H) The solid preparation according to (F), wherein the binder is hydroxypropyl cellulose. (I) (a) One or two selected from the group consisting of corn starch, refined sugar, and crystalline cellulose, and (b) hydroxypropyl cellulose The solid preparation according to any one of (A) to (E), further containing. (J) (a) The content of the compound (I) is 0.1 to 2% by weight of the total weight of the solid preparation, (b) The content of D-mannitol is 20 to 80% by weight of the total weight of the solid preparation, (c) The content of corn starch is 15 to 40% by weight of the total weight of the solid preparation, The solid preparation according to (I), wherein the content of hydroxypropyl cellulose is 1 to 5% by weight of the total weight of the solid preparation. (K) The solid preparation according to (J), wherein the compound (I) is in the form of type I crystals. (L) The solid preparation according to (A) to (K), wherein the solid preparation is a tablet or granules. (M) For the treatment of symptoms associated with diabetic neuropathy, diabetic gangrene, peripheral circulatory disorders, 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 bowel disease, or spinal canal stenosis: the solid preparation according to (A) to (L). (N) The solid preparation according to (M), which is for the treatment of pulmonary hypertension. (O) The solid preparation according to (M), which is for the treatment of peripheral circulatory disorders. (P) The solid preparation according to (M), which is for the treatment of chronic arterial occlusion. (Q) The solid preparation according to (M), which is for the treatment of intermittent claudication. (R) The solid preparation according to (M), which is for the treatment of symptoms associated with spinal canal stenosis. (S) The solid preparation according to (M), which is for the treatment of pulmonary fibrosis. (T) The solid preparation according to (M), which is for the treatment of scleroderma. (U) The solid preparation according to (M), which is for the treatment of chronic renal failure. (V) The solid preparation according to (M), which is for the treatment of tubulointerstitial nephritis. The powder X-ray diffraction spectrum chart of the Form I crystal of Compound (I) is represented. The vertical axis indicates the peak intensity (cps), and the horizontal axis indicates the diffraction angle (2θ [°]). The powder X-ray diffraction spectrum chart of the Form II crystal of Compound (I) is represented. The vertical axis indicates the peak intensity (cps), and the horizontal axis indicates the diffraction angle (2θ [°]). The powder X-ray diffraction spectrum chart of the Form III crystal of Compound (I) is represented. The vertical axis indicates the peak intensity (cps), and the horizontal axis indicates the diffraction angle (2θ [°]). (Compound (I)) Compound (I) can be produced, for example, according to the methods described in Patent Document 1 or 2, and three forms of crystals thereof are known. (1) The powder X-ray diffraction pattern is obtained using Cu Kα radiation (λ = 1.54 Å), and in the powder X-ray diffraction spectrum of Compound (I), diffraction peaks are shown at the following diffraction angles 2θ: 9.4 degrees, 9.8 degrees, 17.2 degrees, and 19.4 degrees. Form I crystal of Compound (I). (2) The powder X-ray diffraction pattern is obtained using Cu Kα radiation (λ = 1.54 Å), and in the powder X-ray diffraction spectrum of Compound (I), diffraction peaks are shown at the following diffraction angles 2θ: 9.0 degrees, 12.9 degrees, 20.7 degrees, and 22.6 degrees. Form II crystal of Compound (I). (3) The powder X-ray diffraction pattern is obtained using Cu Kα radiation (λ = 1.54 Å), and in the powder X-ray diffraction spectrum of Compound (I), diffraction peaks are shown at the following diffraction angles 2θ: 9.3 degrees, 9.7 degrees, 16.8 degrees, 20.6 degrees, and 23.5 degrees. Form III crystal of Compound (I). Compound (I) that can be used in the solid preparation of the present invention may be any of the above crystals, or a mixture of those crystals, or may be amorphous. Among them, Form I crystal is preferred. For reference, the powder X-ray diffraction spectrum charts of the above three forms of crystals are shown in FIGS. 1 to 3. These powder X-ray diffraction spectra were measured with RINT-UltimaIII (manufactured by Rigaku Corporation) (target: Cu, voltage: 40 kV, current: 40 mA, scan speed: 4 degrees / min). The compound (I) contained in the solid preparation of the present invention is preferably 0.1 to 12% by weight, more preferably 0.1 to 2% by weight, based on the total weight of the solid preparation. (D-mannitol) The excipient of the solid preparation of the present invention uses D-mannitol having a specific surface area of 1.0 m ２ / g or less. The specific surface area is more preferably 0.7 m ２ / g or less, and even more preferably greater than 0.2 m ２ / g and less than 0.7 m ２ / g. In the present invention, the specific surface area is a value measured by the BET method, and for example, it can be measured using a specific surface area measuring device Macsorb HM-model 1220 (manufactured by Mountech Co., Ltd.). Examples of D-mannitol used in the present invention include, for example, Mannitol C (Mitsubishi Corporation Foodtech Co., Ltd., average particle size: 20 μm), Mannitol P (Mitsubishi Corporation Foodtech Co., Ltd., 50 μm), Mannitol S (Mitsubishi Corporation Foodtech Co., Ltd., average particle size: 150 μm), Pairitol 25C (ROQUETTE, average particle size: 25 μm), Pairitol 50C (ROQUETTE, average particle size: 50 μm), Pairitol 160C (ROQUETTE, average particle size: 160 μm), Nonpareil 108(100) (Freund Industry Co., Ltd., average particle size: 100 μm), Nonpareil 108(200) (Freund Industry Co., Ltd., average particle size: 200 μm). Among them, Mannitol P, Mannitol S, Pairitol 50C, and Pairitol 160C are preferred. The excipient of the solid preparation of the present invention uses D-mannitol having a specific surface area of 1.0 m ２ / g or less. The D-mannitol may be 20% by weight or more of the total weight of the excipients contained in the solid preparation of the present invention, and more preferably 50% by weight or more. The excipient may be a mixture of two or more kinds. Examples of excipients other than the D-mannitol that can be used include corn starch, crystalline cellulose, refined sugar, erythritol, isomalt, etc., and preferably corn starch, refined sugar, and crystalline cellulose. More preferably, it is corn starch. The content of corn starch is preferably 0.5 to 45% by weight of the total weight of the solid preparation, more preferably 15 to 40% by weight. (Solid preparation) The solid preparation of the present invention is a solid preparation containing compound (I) and D-mannitol, wherein D-mannitol is 5 to 10,000 parts by weight, preferably 10 to 9,500 parts by weight, based on 1 part by weight of compound (I). The content of D-mannitol in the solid preparation of the present invention is usually 10 to 99% by weight of the total weight of the solid preparation. 15 to 95% by weight is preferred, and 20 to 80% by weight is more preferred. In the present invention, the "solid preparation" means a solid preparation having a certain shape for oral administration, unless otherwise specified, and includes ordinary tablets, orally disintegrating tablets, chewable tablets, troches, sublingual tablets, effervescent tablets, dispersible tablets, soluble tablets, powders, granules, and capsules. The solid preparation of the present invention includes single-layer tablets having a single-layer structure and multilayer tablets having a multilayer structure of two or more layers. The shape of the solid preparation thus obtained is not particularly limited and can be various shapes such as circular, elliptical, caplet type, donut type, etc. The solid preparation of the present invention may be provided with sustained-release or enteric properties by a known method in order to control the dissolution characteristics of compound (I). Further, the solid preparation of the present invention may be coated by a known method with various coating agents or sugar coating agents for the purpose of improving light stability, improving appearance, ensuring distinctiveness, or controlling release. Further, the solid preparation of the present invention may be formulated with a pigment for the purpose of improving light stability, ensuring distinctiveness, etc., and may also be formulated with a flavoring agent and a fragrance for the purpose of improving flavor. In addition to the above components, the solid preparation of the present invention can be formulated with a pharmaceutically acceptable carrier (additive) as long as the effects of the present invention are not inhibited. These can be appropriately and appropriately formulated in appropriate amounts as, for example, binders, disintegrants, fluidizing agents, lubricants, coating agents, release control agents, plasticizers, coloring agents, flavoring agents, and fragrances. These additives can be used alone or in combination of two or more. Examples of the binder include gelatin, pullulan, hydroxypropyl cellulose, methyl cellulose, polyvinylpyrrolidone, macrogol, gum arabic, dextran, polyvinyl alcohol, pregelatinized starch, and hypromellose. Preferably, they are hydroxypropyl cellulose, polyvinyl alcohol, and hypromellose, and more preferably hydroxypropyl cellulose. The binder preferably accounts for 0.1 to 10% by weight, more preferably 1 to 8% by weight, and even more preferably 1 to 5% by weight of the total weight of the solid preparation. For hydroxypropyl cellulose, preferably 0.1 to 10% by weight, more preferably 1 to 8% by weight, and even more preferably 1 to 5% by weight of the total weight of the solid preparation. Examples of the disintegrant include carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, sodium starch glycolate, crospovidone, cation exchange resin, partially pregelatinized starch, and low-substituted hydroxypropyl cellulose. Preferably, it is low-substituted hydroxypropyl cellulose. The disintegrant preferably accounts for 0.1 to 10% by weight, and more preferably 1 to 8% by weight of the total weight of the solid preparation. For low-substituted hydroxypropyl cellulose, preferably 0.1 to 10% by weight, more preferably 1 to 8% by weight, and even more preferably 3 to 7% by weight of the total weight of the solid preparation. Examples of the fluidizing agent include light anhydrous silicic acid, hydrous silicon dioxide, synthetic aluminum silicate, and magnesium aluminometasilicate. Examples of the lubricant include stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, waxes, DL-leucine, sodium lauryl sulfate, magnesium lauryl sulfate, macrogol, and light anhydrous silicic acid. Preferably, it is magnesium stearate. The lubricant preferably accounts for 0.1 to 10% by weight, and more preferably 0.2 to 5% by weight of the total weight of the solid preparation. Magnesium stearate is preferably 0.1 to 10% by weight, more preferably 0.2 to 5% by weight, and even more preferably 0.5 to 3% by weight of the total weight of the solid preparation. Examples of the coating agent include ethyl cellulose, ethyl acrylate / methyl methacrylate copolymer, methacrylic acid copolymer LD, hypromellose acetate succinate, and the like. Examples of the release control agent include hydroxypropyl cellulose, ethylene / vinyl acetate copolymer, and polyethylene oxide. Examples of the plasticizer include triethyl citrate, propylene glycol, and macrogol, and preferably propylene glycol. Examples of the coloring agent include titanium oxide, talc, iron sesquioxide, yellow iron sesquioxide, Food Yellow No. 4, and Food Yellow No. 4 aluminum lake, and preferably titanium oxide, iron sesquioxide, and yellow iron sesquioxide. The content of the coloring agent is less than 0.1% by weight of the total weight of the solid preparation. Examples of the flavoring agent include fructose, xylitol, glucose, and DL-malic acid. Examples of the fragrance include l-menthol and peppermint. (Method for producing a solid preparation) The solid preparation of the present invention can be produced by a conventional method in the pharmaceutical field. An example of the production method is shown below, but the present invention is not limited to this production method at all. The solid preparation of the present invention is obtained by adding (1) Additives such as excipients are mixed with the powder of the compound (I) which is the active ingredient to form a powder, or additives such as a disintegrant and a binder are added to the mixed powder, and granulated by various known granulation methods to obtain granules. (2) The obtained mixed powder or granules are either used as they are, or additives such as a lubricant and a fluidizing agent are mixed, and filled into capsules to form capsules. Alternatively, compression molding (tableting) is performed to form tablets. (3) If necessary, coat the surface of the obtained mixed powder, granules, capsules or tablets with a coating agent or sugar coating by a known coating method. Compound (I) has excellent PGI ２ receptor agonist activity and PGI ２diseases involving, for example, transient ischemic attack (TIA), diabetic neuropathy (see, for example, Non-Patent Document 1), diabetic gangrene (see, for example, Non-Patent Document 1), peripheral circulatory disorders (e.g., chronic arteriosclerosis, chronic arterial occlusion (see, for example, Non-Patent Document 2), intermittent claudication (see, for example, Non-Patent Document 3), peripheral arterial embolism, Raynaud's disease) (see, for example, Non-Patent Document 4, Non-Patent Document 5), collagen diseases (e.g., systemic lupus erythematosus, scleroderma) (see, for example, Patent Document 3, Non-Patent Document 6), mixed connective tissue disease, vasculitis syndrome, restenosis and re-narrowing after percutaneous coronary angioplasty (PTCA), arteriosclerosis, thrombosis (e.g., acute cerebral thrombosis, pulmonary embolism) (see, for example, Non-Patent Document 5, Non-Patent Document 7), hypertension, pulmonary hypertension such as pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension (e.g., Non-Patent Document 8, Non-Patent Document 9), ischemic diseases (e.g., cerebral infarction, myocardial infarction (see, for example, Non-Patent Document 10)), angina pectoris (e.g., stable angina pectoris, unstable angina pectoris) (see, for example, Non-Patent Document 11), glomerulonephritis (see, for example, Non-Patent Document 12), diabetic nephropathy (see, for example, Non-Patent Document 1), chronic renal failure (see, for example, Patent Document 4), allergy, bronchial asthma (see, for example, Non-Patent Document 13), ulcers, bedsores (pressure sores), restenosis after coronary intervention such as atelectomy and stent placement, thrombocytopenia due to dialysis, diseases involving fibrosis of organs or tissues [e.g., kidney diseases (e.g., tubulointerstitial nephritis) (see, for example, Patent Document 3), respiratory diseases (e.g., interstitial pneumonia (pulmonary fibrosis) (see, for example, Patent Document 3), chronic obstructive pulmonary disease (see, for example, Non-Patent Document 14), etc.), digestive diseases (e.g., liver cirrhosis, viral hepatitis, chronic pancreatitis, gastric cancer of the Scirrhous type), cardiovascular diseases (e.g., myocardial fibrosis), bone and joint diseases (e.g., myelofibrosis, rheumatoid arthritis), skin diseases (e.g., postoperative scars, burn scars, keloids, hypertrophic scars), obstetric diseases (e.g., uterine fibroids), urological diseases (e.g., benign prostatic hyperplasia), other diseases (e.g., Alzheimer's disease, sclerosing peritonitis, type I diabetes, postoperative organ adhesions)], erectile dysfunction (e.g., diabetic erectile dysfunction, psychogenic erectile dysfunction, psychotic erectile dysfunction, erectile dysfunction due to chronic renal failure, erectile dysfunction after pelvic surgery for prostatectomy, vascular erectile dysfunction associated with aging and arteriosclerosis) (see, for example, Patent Document 7),Agents for preventing or treating inflammatory bowel diseases (e.g., ulcerative colitis, Crohn's disease, intestinal tuberculosis, ischemic colitis, intestinal ulcers associated with Behçet's disease) (see, for example, Patent Document 5), gastritis, gastric ulcers, ischemic eye diseases (e.g., retinal artery occlusion, retinal vein occlusion, ischemic optic neuropathy), sudden deafness, avascular osteonecrosis, enteric injuries associated with administration of non-steroidal anti-inflammatory drugs (NSAIDs) (e.g., diclofenac, meloxicam, oxaprozin, nabumetone, indomethacin, ibuprofen, ketoprofen, naproxen, celecoxib) (e.g., injuries occurring in the duodenum, small intestine, or large intestine are not particularly limited, but for example, mucosal injuries such as erosions and ulcers occurring in the duodenum, small intestine, or large intestine) (see, for example, Patent Document 8), symptoms associated with spinal canal stenosis (e.g., cervical spinal canal stenosis, thoracic spinal canal stenosis, lumbar spinal canal stenosis, extensive spinal canal stenosis, sacral stenosis) (e.g., paralysis, sensory hypoesthesia, pain, numbness, decreased walking ability) (see, for example, Patent Document 6). Further, the solid preparation of the present invention is also useful as an accelerator for angiogenesis therapies such as gene therapy or autologous bone marrow cell transplantation, and as an angiogenesis promoter in peripheral vascular reconstruction or angiogenesis therapy., The present invention will be described in more detail below with reference to Comparative Examples, Examples, and Test Examples, but these do not limit the present invention thereto. Compound (I) used in the present invention was the above-mentioned Form I crystal. The following additives were used unless otherwise specified in the Examples and Comparative Examples. Corn starch used was Nisshin Corn Starch W (Nisshin Food Products Co., Ltd.). Crystalline cellulose used was Ceolus PH-101 (Asahi Kasei Chemicals Corporation). Hydroxypropyl cellulose used was HPC-SSL (Nippon Soda Co., Ltd.). Low-substituted hydroxypropyl cellulose used was LH-11 (Shin-Etsu Chemical Co., Ltd.). Magnesium stearate used was Magnesium Stearate Vegetable (Special Product) (Taihei Chemical Industry Co., Ltd.). Refined sugar used was T.T.G.H Granule (Toyobo Sugar Co., Ltd.). Yellow ferric oxide used was Yellow Ferric Oxide (Kisui Kasei Co., Ltd.). Titanium oxide used was Type-Pake A-100 (Ishihara Sangyo Co., Ltd.). Propylene glycol used was Propylene Glycol (Asahi Glass Co., Ltd.). (Example 1) Types and Stability of D-Mannitol (1) Preparation of Tablets Compound (I), various D-mannitols, corn starch, and low-substituted hydroxypropyl cellulose were placed in a fluidized bed granulator dryer (MP-01, Powrex Corporation) in predetermined amounts, and a 5% aqueous solution of hydroxypropyl cellulose was spray-sprayed while mixing to prepare granules. A predetermined amount of magnesium stearate was mixed with the obtained granules, and tableting was performed at 800 kg using a rotary tableting machine (Collect, Kikusui Seisakusho Co., Ltd.) to obtain tablets (7 mm in diameter, 120 mg tablets). Table 1 shows the types of D-mannitol used in each example and comparative example. The bulk density (g / mL) described in Table 1 means the ratio of the mass of the powder sample in the non-tapped (loose) state to the volume of the powder including the factor of the interparticle void volume. A sample previously sieved through a sieve with a mesh size of 1000 μm was weighed at 25 g, and the volume when the sample was put into a graduated cylinder through a funnel was measured and calculated. The tapped density (g / mL) described in Table 1 is the bulk density obtained by mechanically tapping the container containing the powder sample. Specifically, tapping was performed until no change in volume was observed, and the volume at that time was measured and calculated. Regarding the components and their contents of the tablets, they are as described in Table 2. (2) Evaluation Methods and Results The obtained tablets were placed in plastic bottles and stored for 1 month under the open conditions of 40 °C / 75% RH and 60 °C without capping. The related substances of compound (I) in the tablets before and after storage were measured using high-performance liquid chromatography, and the increase amount of the related substances from the start of the test was evaluated. In the table, the increase amount (%) of the related substances represents the decrease amount (peak area) of compound (I) contained in the preparation before and after storage. Table 3 shows the results and the specific surface areas of the various D-mannitols used. It was shown that the production amount of related substances in any of the tablets from Example 1-1 to 1-5 was less than 3%. The specific surface areas of D-mannitol used in these examples were generally 1.0 m２ It was confirmed that the stability of the preparation was improved when D-mannitol having these physical properties and being 1 g or less was used. (Example 2) Stability when D-mannitol and other excipients are blended (1) Preparation of tablets A predetermined amount of compound (I), D-mannitol (Mannit P, Mitsubishi Corporation Foodtech Co., Ltd.), corn starch, and crystalline cellulose was placed in a fluidized bed granulator dryer (MP-01, Powrex Corporation), and while mixing, an aqueous solution of 10% hydroxypropyl cellulose was spray-sprayed to produce granules. To the obtained granules, a predetermined amount of low-substituted hydroxypropyl cellulose and magnesium stearate were mixed, and tableting was performed at 1000 kg using a rotary tableting machine (Collect, Kikusui Seisakusho Co., Ltd.) to obtain tablets (8 mm in diameter, 190 mg tablets). The content of each component is as described in Table 4. (2) Evaluation method and results The tablets prepared in (1) were placed in a plastic bottle together with a desiccant (Dryernt Tablet PW2010, Yamanishi Pharmaceutical Co., Ltd.), sealed, and stored for 6 months under the conditions of 40 °C / 75% RH (accelerated test). In addition, the tablets were placed in a plastic bottle and stored for 1 month under the conditions of 40 °C / 75% RH and 60 °C without capping. The content of compound (I) in the tablets before and after storage was measured using high performance liquid chromatography, and the residual rate of compound (I) with respect to the start of the test was evaluated. The results are shown in Table 5. High residual rates were shown not only when only D-mannitol was used as the excipient (Example 2-1), but also when corn starch (Example 2-2) or crystalline cellulose (Example 2-3) was blended with D-mannitol. (Example 3) Stability of granules (1) Preparation of granules Example 3-1 A predetermined amount of Compound (I), D-mannitol (Mannitol P, Mitsubishi Corporation Foodtech Co., Ltd.), corn starch, and refined sugar (ground with a sample mill (AP-S, Hosokawa Micron Corporation, screen diameter 3 mm)) were placed in a fluidized bed granulator dryer (MP-01, Paurec Co., Ltd.), and while mixing, an aqueous solution of 10% hydroxypropyl cellulose was spray-sprayed to produce granules. Example 3-2 A predetermined amount of Compound (I), D-mannitol (Mannitol P, Mitsubishi Corporation Foodtech Co., Ltd.), and corn starch were placed in a fluidized bed granulator dryer (MP-01, Paurec Co., Ltd.) and mixed, and while mixing, an aqueous solution of 10% hydroxypropyl cellulose in which a predetermined amount of yellow ferric oxide was dispersed was spray-sprayed to produce granules. The components of the granule agent and their contents are as described in Table 6. (2) Evaluation method and results The obtained granule agent was placed in a plastic bottle together with a desiccant (Dryer N tablet PW2010, Yamanishi Pharmaceutical Co., Ltd.) and sealed, and stored for 2 months under the conditions of 40 °C / 75% RH (accelerated test), or for 1 month in an open state. The content of Compound (I) in the granule agent before and after storage was measured using high performance liquid chromatography, and the residual rate (%) of Compound (I) with respect to the start of the test was evaluated. The results are shown in Table 7. As a result, it was found that high stability was ensured even when the granule agent was used. Industrial applicability According to the present invention, a stabilized solid preparation of Compound (I), that is, a solid preparation having improved storage stability as a preparation, in which a decrease in content due to decomposition of the active ingredient and the production and increase of decomposition products (analogous substances) of the active ingredient are suppressed, can be provided.

Claims

1. A solid preparation containing 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide and D-mannitol having a specific surface area of 1.0 m ２ / g or less.

2. The solid preparation according to claim 1, wherein the amount of D-mannitol is 5 to 10,000 parts by weight with respect to 1 part by weight of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide.

3. The solid preparation according to claim 1 or 2, wherein the content of D-mannitol is 10 to 99% by weight of the total weight of the solid preparation.

4. The solid preparation according to any one of claims 1 to 3, wherein 20% by weight or more of the total weight of the excipients contained in the solid preparation is D-mannitol.

5. The solid preparation according to claim 1, wherein the content of D-mannitol is such that (a) the weight of D-mannitol is 5 to 10,000 parts by weight with respect to 1 part by weight of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide, (b) it is 10 to 99% by weight of the total weight of the solid preparation, and (c) it is 20% or more of the total weight of the excipients contained in the solid preparation.

6. The solid preparation according to any one of claims 1 to 5, further containing excipients other than D-mannitol and a binder.

7. The solid preparation according to claim 6, wherein the excipient other than D-mannitol is one or two selected from the group consisting of corn starch, refined sugar, and crystalline cellulose.

8. The solid preparation according to claim 6, wherein the binder is hydroxypropyl cellulose.

9. The solid preparation according to any one of claims 1 to 5, further containing (a) one or two selected from the group consisting of corn starch, refined sugar, and crystalline cellulose, and (b) hydroxypropyl cellulose.

10. (a) The content of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide is 0.1 to 2% by weight of the total weight of the solid preparation; (b) the content of D-mannitol is 20 to 80% by weight of the total weight of the solid preparation; (c) the content of corn starch is 15 to 40% by weight of the total weight of the solid preparation; (d) the content of hydroxypropyl cellulose is 1 to 5% by weight of the total weight of the solid preparation. The solid preparation according to claim 9.

11. The solid preparation according to claim 10, wherein 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide is in the form of type I crystals.

12. The solid preparation according to any one of claims 1 to 11, wherein the solid preparation is a tablet or granules.

13. For the treatment of symptoms associated with diabetic neuropathy, diabetic gangrene, peripheral circulatory disorders, 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 bowel disease, or spinal canal stenosis. The solid preparation according to any one of claims 1 to 12.

14. The solid preparation according to claim 13, which is for the treatment of pulmonary hypertension.

15. The solid preparation according to claim 13, which is for the treatment of peripheral circulatory disorders.

16. The solid preparation according to claim 13, which is for the treatment of chronic arterial occlusion.

17. The solid preparation according to claim 13, which is for the treatment of intermittent claudication.

18. The solid preparation according to claim 13, which is for the treatment of symptoms associated with spinal canal stenosis.

19. The solid preparation according to claim 13, which is for the treatment of pulmonary fibrosis.

20. The solid preparation according to claim 13, which is for the treatment of scleroderma.

21. The solid preparation according to claim 13, which is for the treatment of chronic renal failure.

22. The solid preparation according to claim 13, which is for the treatment of tubulointerstitial nephritis.

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