Patent Description:
It is known that Compound (I) represented by the following structural formula has an excellent prostaglandin I<NUM> (also referred to as PGI<NUM>) receptor agonistic activity and shows various medicinal effects such as a platelet aggregation inhibitory effect, a vasodilating effect, a bronchial smooth muscle dilating effect, a lipid deposition inhibitory effect, and a leukocyte activation inhibitory effect (PTL <NUM>). <CHM>
<CHM>.

In general, as diluents for a solid preparation, lactose, cornstarch, crystalline cellulose, and sugar alcohols such as D-mannitol are used for diluting an active ingredient. In the process for studying the formulation of a solid preparation containing Compound (I), it was found that Compound (I) itself is stable to temperature and humidity, however, depending on the type of D-mannitol, the decomposition of Compound (I) in the solid preparation proceeds, and the content thereof decreases. <NPL> discloses immediate release film-coated tablets (i.e. a solid preparation) comprising selexipag for oral administration in <NUM> different strengths (<NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM>µg), whereby the excipients include D-mannitol, corn starch, low substituted hydroxypropylcellulose, hydroxypropylcellulose and magnesium stearate. <NPL>, relates to the bioequivalence of different dose-strength tablets of selexipag in a multiple-dose up-titration study. <NPL>, discloses solid formulations comprising amorphous selexipag. <CIT> discloses Form-I, -II and III crystal of selexipag a method for producing the crystal, and a pharmaceutical composition containing the crystal as an active ingredient. Certain properties such as compressability, density and flowability for powder and granular qualities of specific mannitol types are disclsoed in <NPL>. <NPL> pertain to the role of water in the physical stability of solid dosage formulations.

An object of the present invention is to provide a stabilized solid preparation containing Compound (I). Here, the term "stabilized" means that the decrease in the content of Compound (I) contained in the solid preparation due to decomposition thereof is suppressed.

As a result of intensive studies for achieving the above object, the present inventors found that the stability of Compound (I) in a solid preparation is improved by using D-mannitol having a specific surface area of <NUM><NUM>/g or less as a diluent for Compound (I), and thus completed the present invention.

Compound (I) can be produced in accordance with the method described in, for example, PTL <NUM> or <NUM>, and the following crystals of three forms are known (PTL <NUM>).

Compound (I) which can be used in the solid preparation of the present invention may be any of the above-mentioned crystals, and further, it may be a mixture of these crystals or may be amorphous. Above all, the Form-I crystal is preferred.

The powder X-ray diffraction spectrum charts of the above-mentioned crystals of three forms are shown in <FIG> for reference.

The powder X-ray diffraction spectra of these crystals were measured using RINT-Ultima III (manufactured by Rigaku Corporation) (target: Cu, voltage: <NUM> kV, current: <NUM> mA, scan speed: <NUM>°/min).

The amount of Compound (I) contained in the solid preparation of the present invention is preferably from <NUM> to <NUM> wt%, more preferably from <NUM> to <NUM> wt% of the total weight of the solid preparation.

As a diluent for the solid preparation of the present invention, D-mannitol having a specific surface area of <NUM><NUM>/g or less is used. The specific surface area is more preferably <NUM><NUM>/g or less, further more preferably larger than <NUM><NUM>/g and smaller than <NUM><NUM>/g.

In the present invention, the specific surface area is a value measured by the BET method, and can be measured using, for example, a specific surface area measuring device Macsorb HM model-<NUM> (Mountech Co.

As an example of D-mannitol to be used in the present invention, for example, Mannit C (Mitsubishi Shoji Foodtech Co. , average particle diameter: <NUM>), Mannit P (Mitsubishi Shoji Foodtech Co. , <NUM>), Mannit S (Mitsubishi Shoji Foodtech Co. , average particle diameter: <NUM>), Pearlitol 25C (Roquette Pharma, average particle diameter: <NUM>), Pearlitol 50C (Roquette Pharma, average particle diameter: <NUM>), Pearlitol 160C (Roquette Pharma, average particle diameter: <NUM>), Nonpareil <NUM> (<NUM>) (Freund Corporation, average particle diameter: <NUM>), and Nonpareil <NUM> (<NUM>) (Freund Corporation, average particle diameter: <NUM>) can be exemplified. Among these, Mannit P, Mannit S, Pearlitol 50C, and Pearlitol 160C are preferred.

As the diluent for the solid preparation of the present invention, D-mannitol having a specific surface area of <NUM><NUM>/g or less is used. The D-mannitol accounts for <NUM> wt% or more, and preferably accounts for <NUM> wt% or more of the total weight of diluents contained in the solid preparation of the present invention. The diluents may be a mixture of two or more types. As the diluents which can be used other than D-mannitol, cornstarch, crystalline cellulose, sucrose, erythritol, isomalt, and the like can be exemplified, and cornstarch, sucrose, and crystalline cellulose are preferred. Cornstarch is more preferred.

The content of cornstarch is preferably from <NUM> to <NUM>%, more preferably <NUM> to <NUM>% of the total weight of the solid preparation.

The solid preparation of the present invention is a solid preparation containing Compound (I) and D-mannitol, and is characterized in that the amount of D-mannitol is from <NUM> to <NUM> parts by weight, preferably from <NUM> to <NUM> parts by weight with respect to <NUM> part by weight of Compound (I).

The content of D-mannitol in the solid preparation of the present invention is from <NUM> to <NUM> wt%, and is preferably from <NUM> to <NUM> wt%, more preferably from <NUM> to <NUM> wt% of the total weight of the solid preparation.

In the present invention, unless otherwise specified, the "solid preparation" refers to a solid preparation in a given form to be orally administered, and includes a conventional tablet, an orally disintegrating tablet, a chewable tablet, a troche tablet, a sublingual tablet, an effervescent tablet, a dispersible tablet, a soluble tablet, a powder, a granule, and a capsule. The solid preparation of the present invention includes a single-layer tablet having a single-layer structure and a multi-layer tablet having a multi-layer structure including two or more layers. The shape of the thus obtained solid preparation is not particularly limited, and can be various shapes such as a circle, an ellipse, a caplet, or a doughnut. In order to control the dissolution property of Compound (I), a sustained release property or an enteric release property may be imparted to the solid preparation of the present invention by a known method. Further, the solid preparation of the present invention may be coated with any of various coating agents or a sugar coating agent by a known method for the purpose of improvement of light stability, improvement of appearance, ensuring of discriminability, release control, or the like. Further, in the solid preparation of the present invention, a pigment may be blended for the purpose of improvement of light stability, ensuring of discriminability, or the like, and also, a taste masking agent and a flavoring agent may be blended for the purpose of improvement of flavor, or the like.

In the solid preparation of the present invention, other than the above-mentioned components, pharmaceutically acceptable carriers (excipients) can be blended as long as the effect of the present invention is not inhibited. These excipients can be blended as appropriate in appropriate amounts as, for example, a binder, a disintegrant, a fluidizing agent, a lubricant, a coating agent, a release control agent, a plasticizer, a coloring agent, a taste masking agent, and a flavoring agent. These excipients can be used alone or two or more types thereof can be used in combination.

As the binder, for example, gelatin, pullulan, hydroxypropyl cellulose, methyl cellulose, polyvinylpyrrolidone, macrogol, gum Arabic, dextran, polyvinyl alcohol, pregelatinized starch, and hypromellose can be exemplified, and hydroxypropyl cellulose, polyvinyl alcohol, and hypromellose are preferred, and hydroxypropyl cellulose is more preferred.

The amount of the binder is preferably from <NUM> to <NUM> wt%, more preferably from <NUM> to <NUM> wt%, further more preferably from <NUM> to <NUM> wt% of the total weight of the solid preparation.

The amount of hydroxypropyl cellulose is preferably from <NUM> to <NUM> wt%, more preferably from <NUM> to <NUM> wt%, further more preferably from <NUM> to <NUM> wt% of the total weight of the solid preparation.

As the disintegrant, for example, carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, sodium starch glycolate, crospovidone, a cation exchange resin, partially pregelatinized starch, and low-substituted hydroxypropyl cellulose can be exemplified, and low-substituted hydroxypropyl cellulose is preferred.

The amount of the disintegrant is preferably from <NUM> to <NUM> wt%, more preferably from <NUM> to <NUM> wt% of the total weight of the solid preparation.

The amount of low-substituted hydroxypropyl cellulose is preferably from <NUM> to <NUM> wt%, more preferably from <NUM> to <NUM> wt%, further more preferably from <NUM> to <NUM> wt% of the total weight of the solid preparation.

As the fluidizing agent, for example, light anhydrous silicic acid, hydrated silicon dioxide, synthetic aluminum silicate, and magnesium aluminometasilicate can be exemplified.

As the lubricant, for example, 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 can be exemplified, and magnesium stearate is preferred.

The amount of the lubricant is preferably from <NUM> to <NUM> wt%, more preferably from <NUM> to <NUM> wt% of the total weight of the solid preparation.

The amount of magnesium stearate is preferably from <NUM> to <NUM> wt%, more preferably from <NUM> to <NUM> wt%, further more preferably from <NUM> to <NUM> wt% of the total weight of the solid preparation.

As the coating agent, ethyl cellulose, ethyl acrylate-methyl methacrylate copolymer, methacrylic acid copolymer LD, hypromellose acetate succinate, and the like can be exemplified.

As the release control agent, for example, hydroxypropyl cellulose, an ethylene-vinyl acetate copolymer, and polyethylene oxide can be exemplified.

As the plasticizer, for example, triethyl citrate, propylene glycol, and macrogol can be exemplified, and propylene glycol is preferred.

As the coloring agent, for example, titanium oxide, talc, iron sesquioxide, yellow iron sesquioxide, Food Yellow No. <NUM>, and Food Yellow No. <NUM> Aluminum Lake can be exemplified, and titanium oxide, iron sesquioxide, yellow iron sesquioxide are preferred.

The content of the coloring agent is preferably less than <NUM> wt% of the total weight of the solid preparation.

As the taste masking agent, for example, fructose, xylitol, glucose, and DL-malic acid can be exemplified.

As the flavoring agent, for example, L-menthol and peppermint can be exemplified.

The solid preparation of the present invention can be produced by a conventional method in the pharmaceutical field. One example of the production method for the solid preparation will be shown below; however, the present invention is by no means limited to this production method.

The solid preparation of the present invention is produced as follows using a powder of Compound (I) which is the active ingredient.

The Compound (I) has an excellent PGI<NUM> receptor agonistic effect and is useful as a preventive agent or a therapeutic agent for a PGI<NUM>-related disease, for example, transient ischemic attack (TIA), diabetic neuropathy (see, for example, NPL <NUM>), diabetic gangrene (see, for example, NPL <NUM>), a peripheral circulatory disturbance (for example, chronic arteriosclerosis, chronic arterial occlusion (see, for example, NPL <NUM>), intermittent claudication (see, for example, NPL <NUM>), peripheral embolism, or Raynaud' s disease) (see, for example, NPL <NUM> or NPL <NUM>), a connective tissue disease (for example, systemic lupus erythematosus or scleroderma) (see, for example, PTL <NUM> or NPL <NUM>), a mixed connective tissue disease, a vasculitic syndrome, reocclusion/restenosis after percutaneous transluminal coronary angioplasty (PTCA), arteriosclerosis, thrombosis (for example, acute-phase cerebral thrombosis or pulmonary embolism) (see, for example, NPL <NUM> or NPL <NUM>), hypertension, pulmonary hypertension such as pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension (for example, NPL <NUM> or NPL <NUM>), an ischemic disease (for example, cerebral infarction or myocardial infarction (see, for example, NPL <NUM>)), angina pectoris (for example, stable angina pectoris or unstable angina pectoris) (see, for example, NPL <NUM>), glomerulonephritis (see, for example, NPL <NUM>), diabetic nephropathy (see, for example, NPL <NUM>), chronic renal failure (see, for example, PTL <NUM>), allergy, bronchial asthma (see, for example, NPL <NUM>), ulcer, pressure ulcer (bedsore), restenosis after coronary intervention such as atherectomy or stent implantation, thrombocytopenia by dialysis, a disease in which fibrogenesis in an organ or a tissue is involved [for example, a renal disease (for example, tubulointerstitial nephritis) (see, for example, PTL <NUM>), a respiratory disease (for example, interstitial pneumonia (pulmonary fibrosis) (see, for example, PTL <NUM>), a chronic obstructive pulmonary disease (see, for example, NPL <NUM>), or the like), a digestive disease (for example, hepatocirrhosis, viral hepatitis, chronic pancreatitis, or scirrhous gastric cancer), a cardiovascular disease (for example, myocardial fibrosis), a bone or articular disease (for example, bone marrow fibrosis or rheumatoid arthritis), a skin disease (for example, postoperative cicatrix, burn cicatrix, keloid, or hypertrophic cicatrix), an obstetric disease (for example, uterine fibroid), a urinary disease (for example, prostatic hypertrophy), other diseases (for example, Alzheimer's disease, sclerosing peritonitis, type I diabetes, or postoperative organ adhesion)], erectile dysfunction (for example, diabetic erectile dysfunction, psychogenic erectile dysfunction, psychotic erectile dysfunction, erectile dysfunction due to chronic renal failure, erectile dysfunction after pelvic operation for resection of the prostate, or vascular erectile dysfunction associated with aging or arteriosclerosis) (see, for example, PTL <NUM>), an inflammatory bowel disease (for example, ulcerative colitis, Crohn's disease, intestinal tuberculosis, ischemic colitis, or intestinal ulcer associated with Behcet disease) (see, for example, PTL <NUM>), gastritis, gastric ulcer, an ischemic eye disease (for example, retinal artery occlusion, retinal vein occlusion, or ischemic optic neuropathy), sudden hearing loss, avascular necrosis of bone, an intestinal damage caused by administration of a non-steroidal anti-inflammatory agent (NSAID) (for example, diclofenac, meloxicam, oxaprozin, nabumetone, indomethacin, ibuprofen, ketoprofen, naproxen, or celecoxib) (there is no particular limitation as long as it is a damage occurring in, for example, the duodenum, small intestine, or large intestine; however, for example, a mucosal damage such as erosion or ulcer occurring in the duodenum, small intestine, or large intestine) (see, for example, PTL <NUM>), or a symptom (for example, paralysis, dullness in sensory perception, pain, numbness, or a decrease in walking ability) associated with spinal canal stenosis (for example, cervical spinal canal stenosis, thoracic spinal canal stenosis, lumbar spinal canal stenosis, coexisting cervical and lumbar spinal stenosis, or sacral spinal stenosis) (see, for example, PTL <NUM>).

Hereinafter, the present invention will be described in more detail with reference to Comparative Examples, Examples; and Test Examples.

As Compound (I) used in the present invention, the above-mentioned Form-I crystal was used.

Unless otherwise stated, the following excipeints were used in Examples and Comparative Examples. As cornstarch, Nisshoku Cornstarch W (Nihon Shokuhin Kako Co. ) was used. As crystalline cellulose, Ceolus PH-<NUM> (Asahi Kasei Chemicals Co. ) was used. As hydroxypropyl cellulose, HPC-SSL (Nippon Soda Co. ) was used. As low-substituted hydroxypropyl cellulose, LH-<NUM> (Shin-Etsu Chemical Co. ) was used. As magnesium stearate, vegetable magnesium stearate (specially manufactured) (Taihei Chemical Industrial Co. ) was used. As sucrose, T. H granulated sugar (Toyo Sugar Refining Co. ) was used. As yellow iron sesquioxide, yellow iron sesquioxide (Kishi Kasei Co. ) was used. As titanium oxide, Tipaque A-<NUM> (Ishihara Sangyo Kaisha, Ltd. ) was used. As propylene glycol, propylene glycol (Asahi Glass Co. ) was used.

Predetermined amounts of Compound (I), each type of D-mannitol, cornstarch, and low-substituted hydroxypropyl cellulose were placed in a fluidized bed granulation/drying machine (MP-<NUM>, Powrex Corporation), and a <NUM>% aqueous hydroxypropyl cellulose solution was sprayed thereon while mixing, whereby granules were prepared. In the obtained granules, a predetermined amount of magnesium stearate was mixed, and the resulting mixture was tableted at <NUM> using a rotary tableting machine (Correct, Kikusui Seisakusho, Ltd. ), whereby a tablet (diameter: <NUM>, <NUM>/tablet) was prepared. The types of D-mannitol used in the respective Examples and Comparative Examples are shown in Table <NUM>. The bulk density (g/mL) shown in Table <NUM> means the ratio of the mass of a powder sample in a state where the powder is not tapped (loosened) to the volume of the powder including the factor of an inter-particle void volume, and it was obtained by weighing <NUM> of a sample having passed through a sieve with a mesh size of <NUM> in advance, placing the sample in a measuring cylinder through a funnel, and measuring the volume at that time, followed by calculation. Further, the tap density (g/mL) shown in Table <NUM> is a bulk density obtained by mechanically tapping a container in which the powder sample is placed, and specifically, it was obtained by tapping the container until no change in the volume was observed, and measuring the volume at that time, followed by calculation.

The components of each tablet and the contents thereof are as shown in Table <NUM>.

The obtained tablet was placed in a plastic bottle and stored for <NUM> month in an uncapped state under open conditions at <NUM>/<NUM>% RH or under open conditions at <NUM>. The related substances of Compound (I) in the tablet were measured before and after the storage using high-performance liquid chromatography, and the increased amount of related substances from the start of the test was evaluated. Incidentally, as the "increased amount of related substances (%)" in the table, the decreased amount (peak area) of Compound (I) contained in the preparation before and after the storage is shown. The results and the specific surface area of each type of D-mannitol used are shown in Table <NUM>. It was shown that the produced amount of the related substances was less than <NUM>% in each of the tablets of Examples <NUM>-<NUM> to <NUM>-<NUM>. The specific surface area of D-mannitol used in each of these Examples was <NUM><NUM>/g or less, and it could be confirmed that in a case where D-mannitol having such physical properties was used, the stability of the preparation is improved.

Predetermined amounts of Compound (I), D-mannitol (Mannit P, Mitsubishi Shoji Foodtech Co. ), cornstarch, and crystalline cellulose were placed in a fluidized bed granulation/drying machine (MP-<NUM>, Powrex Corporation), and a <NUM>% aqueous hydroxypropyl cellulose solution was sprayed thereon while mixing, whereby granules were produced. In the obtained granules, predetermined amounts of low-substituted hydroxypropyl cellulose and magnesium stearate were mixed, and the resulting mixture was tableted at <NUM> using a rotary tableting machine (Correct, Kikusui Seisakusho, Ltd. ), whereby a tablet (diameter: <NUM>, <NUM>/tablet) was prepared. The contents of the respective components are as shown in Table <NUM>.

The tablet prepared in (<NUM>) was placed in a plastic bottle along with a desiccant (Dryern tablet PW <NUM>, Yamani Yakuhin Co. ) and airtightly sealed, and then, stored for <NUM> months under conditions of <NUM>/<NUM>% RH (accelerated test). Further, the tablet was placed in a plastic bottle and stored for <NUM> month in an uncapped state under conditions of <NUM>/<NUM>% RH or under conditions of <NUM>. The content of Compound (I) in the tablet was measured before and after the storage using high-performance liquid chromatography, and the residual ratio of Compound (I) relative to the amount at the start of the test was evaluated.

The results are shown in Table <NUM>. Not only in a case where only D-mannitol was used as the diluent (Example <NUM>-<NUM>), but also in a case where cornstarch (Example <NUM>-<NUM>) or crystalline cellulose (Example <NUM>-<NUM>) was blended along with D-mannitol, a high residual ratio was shown.

Predetermined amounts of Compound (I), D-mannitol (Mannit P, Mitsubishi Shoji Foodtech Co. ), cornstarch, and sucrose (obtained by grinding using a sample mill (AP-S, Hosokawa Micron Corporation, screen diameter: <NUM>)) were placed in a fluidized bed granulation/drying machine (MP-<NUM>, Powrex Corporation), and a <NUM>% aqueous hydroxypropyl cellulose solution was sprayed thereon while mixing, whereby a granule was produced.

Predetermined amounts of Compound (I), D-mannitol (Mannit P, Mitsubishi Shoji Foodtech Co. ), and cornstarch were placed in a fluidized bed granulation/drying machine (MP-<NUM>, Powrex Corporation), and a <NUM>% aqueous hydroxypropyl cellulose solution in which a predetermined amount of yellow iron sesquioxide was dispersed was sprayed thereon while mixing, whereby a granule was produced.

The components of each granule and the contents thereof are as shown in Table <NUM>.

The obtained granule was placed in a plastic bottle along with a desiccant (Dryern tablet PW <NUM>, Yamani Yakuhin Co. ) and hermetically sealed, and then, stored for <NUM> months under conditions of <NUM>/<NUM>% RH (acceleration test) or stored for <NUM> month in an open state. The content of Compound (I) in the granule was measured before and after the storage using high-performance liquid chromatography, and the residual ratio (%) of Compound (I) relative to the amount at the start of the test was evaluated. The results are shown in Table <NUM>. As a result, it was found that high stability is ensured also in a case where it is formulated into a granule.

Claim 1:
A solid preparation comprising:
<NUM>-{<NUM>-[N-(<NUM>,<NUM>-diphenylpyrazin-<NUM>-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide; and
D-mannitol having a specific surface area of <NUM><NUM>/g or less, wherein the content of D-mannitol is from <NUM> to <NUM> wt% of the total weight of the solid preparation and wherein D-mannitol accounts for <NUM> wt% or more of the total weight of diluents contained in the solid preparation.