WO2017098998A1 - 2-{4-[n-(5,6-ジフェニルピラジン-2-イル)-n-イソプロピルアミノ]ブチルオキシ}-n-(メチルスルホニル)アセトアミドを含有する医薬組成物 - Google Patents
2-{4-[n-(5,6-ジフェニルピラジン-2-イル)-n-イソプロピルアミノ]ブチルオキシ}-n-(メチルスルホニル)アセトアミドを含有する医薬組成物 Download PDFInfo
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Definitions
- the present invention relates to 2- ⁇ 4- [N- (5,6-diphenylpyrazin-2-yl) -N-isopropylamino] butyloxy ⁇ -N- (methylsulfonyl) acetamide (hereinafter referred to as “compound (I)”).
- compound (I) 2- ⁇ 4- [N- (5,6-diphenylpyrazin-2-yl) -N-isopropylamino] butyloxy ⁇ -N- (methylsulfonyl) acetamide
- the compound (I) represented by the above has an excellent prostaglandin I 2 (also referred to as PGI 2 ) receptor action, platelet aggregation inhibitory action, vasodilator action, bronchial muscle dilator action, lipid deposition inhibitory action, leukocyte It is known to show various medicinal effects such as activation suppressing action (Patent Document 1).
- sugar alcohols such as lactose, corn starch, crystalline cellulose, and D-mannitol are used for diluting active ingredients.
- compound (I) itself is stable against temperature and humidity, but depending on the type of D-mannitol, compound (I) in the solid preparation It turned out that decomposition
- the object of the present invention is to provide a stabilized solid preparation of compound (I).
- stabilized means that a decrease in content due to decomposition of compound (I) contained in the solid preparation is suppressed.
- the present inventors have used D-mannitol having a specific surface area of 1.0 m 2 / g or less as an excipient for compound (I), thereby producing a solid preparation. It was found that the stability of the compound (I) therein was improved, and the present invention was completed. That is, the present invention is as follows.
- (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 excipient contained in the solid preparation is D-mannitol.
- E The content of D-mannitol is (A) The weight of D-mannitol is 5 to 10,000 parts by weight relative to 1 part by weight of compound (I), (B) 10 to 99% by weight of the total weight of the solid preparation, (C) The solid preparation according to (A), which is 20% or more of the total weight of excipients contained in the solid preparation.
- (F) The solid preparation according to any one of (A) to (E), which further contains an excipient 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, purified sucrose, and crystalline cellulose.
- (H) The solid preparation according to (F), wherein the binder is hydroxypropylcellulose.
- (I) (A) One or two selected from the group consisting of corn starch, refined sucrose, and crystalline cellulose, and (b) hydroxypropylcellulose further, (A) to (E) Solid formulation.
- (J) (A) the content of 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; (D) The solid preparation according to (I), wherein the content of hydroxypropylcellulose is 1 to 5% by weight of the total weight of the solid preparation. (K) The solid preparation according to (J), wherein compound (I) is a type I crystal. (L) The solid preparation according to any one of (A) to (K), wherein the solid preparation is a tablet or a granule.
- M Diabetic neuropathy, diabetic gangrene, peripheral circulatory disorder, chronic arterial occlusion, intermittent claudication, scleroderma, thrombosis, pulmonary hypertension, myocardial infarction, angina, glomerulonephritis, diabetic nephropathy, chronic For the treatment of symptoms associated with renal failure, bronchial asthma, interstitial pneumonia (pulmonary fibrosis), chronic obstructive pulmonary disease, tubulointerstitial nephritis, inflammatory bowel disease, or spinal stenosis (A ) To (L). (N) The solid preparation according to (M), which is used for treatment of pulmonary hypertension.
- P The solid preparation according to (M), which is used for treatment of chronic arterial occlusion.
- Q The solid preparation according to (M), which is used for treatment of intermittent claudication.
- R The solid preparation according to (M), which is used for treatment of symptoms associated with spinal stenosis.
- S The solid preparation according to (M), which is used for treatment of pulmonary fibrosis.
- T The solid preparation according to (M), which is used for treatment of scleroderma.
- U The solid preparation according to (M), which is used for treatment of chronic renal failure.
- V The solid preparation according to (M), which is used for treatment of tubulointerstitial nephritis.
- 1 represents a powder X-ray diffraction spectrum chart of type I crystal of compound (I).
- the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
- 1 represents a powder X-ray diffraction spectrum chart of a type II crystal of compound (I).
- the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
- 3 shows a powder X-ray diffraction spectrum chart of compound (I) type III crystal.
- the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
- Compound (I) can be produced, for example, according to the method described in Patent Document 1 or 2, and the following three forms of crystals are known.
- the following diffraction angle 2 ⁇ 9.4 Form I crystals of compound (I) exhibiting diffraction peaks at degrees, 9.8 degrees, 17.2 degrees and 19.4 degrees.
- Compound (I) that can be used in the solid preparation of the present invention may be any of the above crystals, a mixture of these crystals, or an amorphous system. Of these, type I crystals are preferred.
- powder X-ray diffraction spectrum charts of the above three types of crystals are shown in FIGS. These powder X-ray diffraction spectra were measured by 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.
- 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 at most 0.7 m 2 / g, and even more preferably less than greater than 0.7m 2 / g 0.2m 2 / g .
- 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 1220 (Mounttech).
- D-mannitol used in the present invention examples include, for example, Mannit C (Mitsubishi Corporation Food Tech Co., Ltd., average particle size: 20 ⁇ m), Mannit P (Mitsubishi Corporation Food Tech Co., Ltd., 50 ⁇ m), Mannit S (Mitsubishi Corporation Foodtech Co., Ltd., average particle size: 150 ⁇ m), Peeritol 25C (ROQUETTE, average particle size: 25 ⁇ m), Peeritol 50C (ROQUETTE, average particle size: 50 ⁇ m), Peeritol 160C (ROQUETTE, average particle) (Diameter: 160 ⁇ m), non-parrel 108 (100) (Freund Sangyo Co., Ltd., average particle size: 100 ⁇ m), non-parrel 108 (200) (Freund Sangyo Co., Ltd., average particle size: 200 ⁇ m).
- Mannit K, Mannit S, Peeritol 50C, and Peeritol 160C are examples
- D-mannitol having a specific surface area of 1.0 m 2 / g or less is used.
- the D-mannitol may be 20% by weight or more of the total weight of the excipient 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.
- excipients that can be used in addition to D-mannitol include corn starch, crystalline cellulose, purified white sugar, erythritol, isomalt and the like, preferably corn starch, purified white sugar and crystalline cellulose. More preferred is corn starch.
- the content of corn starch is preferably 0.5 to 45% of the total weight of the solid preparation, more preferably 15 to 40%.
- the solid preparation of the present invention is a solid preparation containing compound (I) and D-mannitol, and D-mannitol is 5 to 10,000 parts by weight, preferably 10 parts by weight based on 1 part by weight of compound (I). ⁇ 9500 parts by weight.
- 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. It is preferably 15 to 95% by weight, and more preferably 20 to 80% by weight.
- solid preparation means a solid preparation having a certain shape for oral administration unless otherwise specified, and is an ordinary tablet, orally disintegrating tablet, chewable tablet, troche, sublingual tablet, foaming Tablets, dispersible tablets, dissolving tablets, powders, granules, and capsules are included.
- the solid preparation of the present invention includes a single-layer tablet having a single-layer structure and a multilayer tablet having a plurality of layer structures of two or more layers.
- the shape of the solid preparation thus obtained is not particularly limited, and may be various shapes such as a circle, an ellipse, a caplet type, and a donut type.
- the solid preparation of the present invention may be given 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 with various coating agents or sugar coatings by a known method for the purpose of improving light stability, improving appearance, ensuring discrimination, or controlling release. . Furthermore, the solid preparation of the present invention may be blended with pigments for the purpose of improving light stability and ensuring discriminability, and is blended with flavoring agents and flavors for the purpose of improving the flavor. It may be.
- the solid preparation of the present invention can contain a pharmaceutically acceptable carrier (additive) in addition to the above components as long as the effects of the present invention are not impaired.
- a pharmaceutically acceptable carrier additive
- additives can be blended as appropriate and in appropriate amounts as, for example, a binder, a disintegrant, a fluidizing agent, a lubricant, a coating agent, a release controlling agent, a plasticizer, a coloring agent, a corrigent, and a fragrance.
- additives can be used alone or in combination of two or more.
- binder examples include gelatin, pullulan, hydroxypropyl cellulose, methyl cellulose, polyvinyl pyrrolidone, macrogol, gum arabic, dextran, polyvinyl alcohol, pregelatinized starch and hypromellose, preferably hydroxypropyl cellulose, polyvinyl alcohol. Hypromellose, more preferably hydroxypropylcellulose.
- the binder is preferably 0.1 to 10% by weight of the total weight of the solid preparation, more preferably 1 to 8% by weight, still more preferably 1 to 5%.
- Hydroxypropylcellulose is preferably from 0.1 to 10% by weight, more preferably from 1 to 8% by weight, even more preferably from 1 to 5% by weight, based on the total weight of the solid preparation.
- Disintegrants include, for example, carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, sodium starch glycolate, crospovidone, cation exchange resin, partially pregelatinized starch, and low substituted hydroxypropylcellulose Preferred is low-substituted hydroxypropylcellulose.
- the disintegrant is preferably 0.1 to 10% by weight, more preferably 1 to 8% by weight, based on the total weight of the solid preparation.
- the low-substituted hydroxypropyl cellulose is preferably 0.1 to 10% by weight, more preferably 1 to 8% by weight, still more preferably 3 to 7% by weight based on the total weight of the solid preparation.
- fluidizing agent examples include light anhydrous silicic acid, hydrous silicon dioxide, synthetic aluminum silicate, and magnesium aluminate metasilicate.
- lubricants examples include stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, waxes, DL-leucine, sodium lauryl sulfate, magnesium lauryl sulfate, macrogol, and light anhydrous silicic acid.
- it is magnesium stearate.
- the lubricant is preferably 0.1 to 10% by weight, more preferably 0.2 to 5% by weight, based on 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 still more preferably 0.5 to 3% by weight of the total weight of the solid preparation.
- the coating agent examples include ethyl cellulose, ethyl acrylate / methyl methacrylate copolymer, methacrylic acid copolymer LD, and hypromellose acetate succinate.
- release controlling agent examples include hydroxypropyl cellulose, ethylene / vinyl acetate copolymer, and polyethylene oxide.
- plasticizer examples include triethyl citrate, propylene glycol, and macrogol, preferably propylene glycol.
- the colorant examples include titanium oxide, talc, iron sesquioxide, yellow iron sesquioxide, edible yellow No. 4, edible yellow No. 4 aluminum lake, and preferably titanium oxide, iron sesquioxide, yellow sesquioxide. It is iron.
- the content of the colorant is less than 0.1% by weight of the total weight of the solid preparation.
- flavoring agents include fructose, xylitol, glucose, and DL-malic acid.
- fragrances examples include l-menthol and peppermint.
- the solid preparation of the present invention can be produced by a conventional method in the pharmaceutical field. Although an example of the manufacturing method is shown below, this invention is not restrict
- the solid preparation of the present invention is a powder of the active ingredient compound (I), (1) Mix with additives such as excipients to make powders, or add additives such as disintegrants and binders to the mixed powder, and granulate them by various known granulation methods. To do. (2) The obtained mixed powder or granule is mixed as it is, or additives such as a lubricant and a fluidizing agent are mixed and filled into capsules to form capsules. Alternatively, it is compression-molded (tablet) to obtain a tablet. (3) If necessary, the surface of the obtained mixed powder, granule, capsule or tablet is coated with a coating agent or sugar coating by a known coating method.
- Compound (I) has an excellent PGI 2 receptor agonistic action, and diseases involving PGI 2 , such as transient cerebral ischemic attack (TIA), diabetic neuropathy (eg, non-patent literature) 1), diabetic gangrene (for example, see Non-Patent Document 1), peripheral circulatory disorder (for example, chronic arteriosclerosis, chronic arterial occlusion (for example, see Non-Patent Document 2), intermittent claudication (for example, Non-patent document 3), peripheral arterial embolism, Raynaud's disease) (for example, see non-patent document 4 and non-patent document 5), collagen disease (for example, systemic lupus erythematosus, scleroderma) (for example, patent) Reference 3 and Non-Patent Document 6), mixed connective tissue disease, vasculitis syndrome, reocclusion / restenosis after percutaneous coronary angioplasty (PTCA), arteriosclerosis, thrombosis (eg, acute phase) Cere
- LH-11 (Shin-Etsu Chemical Co., Ltd.) was used as the low-substituted hydroxypropyl cellulose.
- Magnesium stearate used was magnesium stearate vegetable (special) (Taihei Chemical Industry Co., Ltd.). Purified white sugar is T. T.A. G. H granule (Toyo Seika Co., Ltd.) was used. Yellow iron sesquioxide used was yellow iron sesquioxide (Hana Kasei Co., Ltd.). Titanium oxide A-100 (Ishihara Sangyo Co., Ltd.) was used as the titanium oxide. Propylene glycol (Asahi Glass Co., Ltd.) was used as propylene glycol.
- Example 1 Type and stability of D-mannitol (1) Preparation of tablets Predetermined amounts of compound (I), various D-mannitol, corn starch and low-substituted hydroxypropylcellulose, fluidized bed granulator / dryer (MP -01, POWREC Co., Ltd.) and sprayed with a 5% hydroxypropylcellulose aqueous solution while mixing to prepare granules. A predetermined amount of magnesium stearate was mixed with the obtained granules, and tableted with 800 kg using a rotary tableting machine (collect, Kikusui Seisakusho Co., Ltd.) to give tablets (diameter 7 mm, 120 mg tablets).
- Table 1 shows the types of D-mannitol used in each example and comparative example.
- the bulk density (g / mL) shown in Table 1 means the ratio between the mass of the powder sample in the untapped (loosened) state and the volume of the powder including the interparticle void volume factor.
- the tap density (g / mL) shown in Table 1 is a bulk density obtained by mechanically tapping a container containing a powder sample. Specifically, the tap density is changed until no change in volume is recognized. The volume at that time was measured and calculated.
- the ingredients and content of the tablet are as shown in Table 2.
- Example 2 Stability when D-mannitol and other excipients are blended (1) Preparation of tablet Compound (I) and D-mannitol (Mannit P, Mitsubishi Corporation Foodtech Co., Ltd.), corn starch A predetermined amount of crystalline cellulose was put into a fluidized bed granulator / dryer (MP-01, POWREC Co., Ltd.) and sprayed with a 10% aqueous hydroxypropylcellulose solution while mixing to produce granules.
- MP-01 fluidized bed granulator / dryer
- Predetermined amounts of low-substituted hydroxypropylcellulose and magnesium stearate are mixed into the obtained granules, and tableted with 1000 kg using a rotary tableting machine (collect, Kikusui Seisakusho Co., Ltd.), tablets (diameter 8 mm, 190 mg). Tablet).
- the content of each component is as shown in Table 4.
- Example 2-3 When only D-mannitol was used as an excipient (Example 2-1), corn starch (Example 2-2) and crystalline cellulose (Example 2-3) were blended with D-mannitol. In some cases, a high survival rate was exhibited.
- Example 3 Stability of granules (1) Preparation of granules Example 3-1 Predetermined amount of Compound (I) and D-mannitol (Mannit P, Mitsubishi Corporation Foodtech Co., Ltd.), corn starch, refined sucrose (pulverized with sample mill (AP-S, Hosokawa Micron Corporation, screen diameter 3 mm)) was put in a fluidized bed granulator / dryer (MP-01, Powrec Co., Ltd.) and sprayed with a 10% hydroxypropylcellulose aqueous solution while mixing to produce granules.
- a fluidized bed granulator / dryer MP-01, Powrec Co., Ltd.
- Example 3-2 While mixing a predetermined amount of compound (I), D-mannitol (Mannit P, Mitsubishi Corporation Foodtech Co., Ltd.) and corn starch into a fluidized bed granulator / dryer (MP-01, Powrec Co., Ltd.) A 10% hydroxypropyl cellulose aqueous solution in which a predetermined amount of yellow iron sesquioxide was dispersed was sprayed to produce granules.
- the components of the granules and their contents are as shown in Table 6.
Abstract
Description
で示される化合物(I)は、優れたプロスタグランジンI2(PGI2ともいう)受容体作動作用を有し、血小板凝集抑制作用、血管拡張作用、気管支筋拡張作用、脂質沈着抑制作用、白血球活性化抑制作用等、種々の薬効を示すことが知られている(特許文献1)。
すなわち、本発明は以下の通りである。
(A)
化合物(I)と、比表面積が1.0m2/g以下であるD-マンニトールとを含有する固形製剤。
(B)
化合物(I)1重量部に対し、D-マンニトールが5~10000重量部である、(A)に記載の固形製剤。
(C)
D-マンニトールの含有量が、固形製剤総重量の10~99重量%である、(A)または(B)に記載の固形製剤。
(D)
固形製剤中に含まれる賦形剤総重量の20重量%以上がD-マンニトールである、(A)~(C)のいずれかに記載の固形製剤。
(E)
D-マンニトールの含有量が、
(a)化合物(I)1重量部に対し、D-マンニトールの重量が5~10000重量部であり、
(b)固形製剤総重量の10~99重量%であり、
(c)固形製剤中に含まれる賦形剤総重量の20%以上である、(A)に記載の固形製剤。
(F)
D-マンニトール以外の賦形剤、および結合剤をさらに含有する(A)~(E)のいずれかに記載の固形製剤。
(G)
D-マンニトール以外の賦形剤が、トウモロコシデンプン、精製白糖、および結晶セルロースからなる群から選択される1種または2種である、(F)に記載の固形製剤。
(H)
結合剤がヒドロキシプロピルセルロースである(F)に記載の固形製剤。
(I)
(a)トウモロコシデンプン、精製白糖、および結晶セルロースからなる群から選択される1種または2種、および
(b)ヒドロキシプロピルセルロース
をさらに含有する、(A)~(E)のいずれかに記載の固形製剤。
(J)
(a)化合物(I)の含有量が固形製剤総重量の0.1~2重量%であり、
(b)D-マンニトールの含有量が、固形製剤総重量の20~80重量%であり、
(c)トウモロコシデンプンの含有量が、固形製剤総重量の15~40重量%であり、
(d)ヒドロキシプロピルセルロースの含有量が、固形製剤総重量の1~5重量%である、(I)に記載の固形製剤。
(K)
化合物(I)がI型の結晶である、(J)に記載の固形製剤。
(L)
固形製剤が錠剤または顆粒剤である、(A)~(K)に記載の固形製剤。
(M)
糖尿病性神経障害、糖尿病性壊疽、末梢循環障害、慢性動脈閉塞症、間欠性跛行、強皮症、血栓症、肺高血圧症、心筋梗塞、狭心症、糸球体腎炎、糖尿病性腎症、慢性腎不全、気管支喘息、間質性肺炎(肺線維症)、慢性閉塞性肺疾患、尿細管間質性腎炎、炎症性腸疾患、又は脊柱管狭窄症に伴う症状の治療用である、(A)~(L)に記載の固形製剤。
(N)
肺高血圧症の治療用である、(M)に記載の固形製剤。
(O)
末梢循環障害の治療用である、(M)に記載の固形製剤。
(P)
慢性動脈閉塞症の治療用である、(M)に記載の固形製剤。
(Q)
間欠性跛行の治療用である、(M)に記載の固形製剤。
(R)
脊柱管狭窄症に伴う症状の治療用である、(M)に記載の固形製剤。
(S)
肺線維症の治療用である、(M)に記載の固形製剤。
(T)
強皮症の治療用である、(M)に記載の固形製剤。
(U)
慢性腎不全の治療用である、(M)に記載の固形製剤。
(V)
尿細管間質性腎炎の治療用である、(M)に記載の固形製剤。
化合物(I)は、例えば、特許文献1、または2に記載の方法に従って製造することができ、以下の3つの形態の結晶が知られている。
(1)粉末X線回折図がCu Kα放射線(λ=1.54Å)を用いて得られるものであって、化合物(I)の粉末X線回折スペクトルにおいて、次の回折角2θ:9.4度、9.8度、17.2度及び19.4度で回折ピークを示す、化合物(I)のI型結晶。
(2)粉末X線回折図がCu Kα放射線(λ=1.54Å)を用いて得られるものであって、化合物(I)の粉末X線回折スペクトルにおいて、次の回折角2θ:9.0度、12.9度、20.7度及び22.6度で回折ピークを示す、化合物(I)のII型結晶。
(3)粉末X線回折図がCu Kα放射線(λ=1.54Å)を用いて得られるものであって、化合物(I)の粉末X線回折スペクトルにおいて、次の回折角2θ:9.3度、9.7度、16.8度、20.6度及び23.5度で回折ピークを示す、化合物(I)のIII型結晶。
参考までに上記3つの形態の結晶の粉末X線回折スペクトルチャートを図1~3に示す。
これらの粉末X線回折スペクトルは、RINT-UltimaIII((株)リガク製)(ターゲット:Cu,電圧:40kV,電流:40mA,スキャンスピード:4度/分)で測定した。
本発明の固形製剤の賦形剤は比表面積が1.0m2/g以下のD-マンニトールを使用する。比表面積は0.7m2/g以下であることがより好ましく、0.2m2/gより大きく0.7m2/gより小さいことが更に好ましい。
トウモロコシデンプンの含有量は、好ましくは固形製剤総重量の0.5~45%であり、より好ましくは15~40%である。
本発明の固形製剤は化合物(I)、およびD-マンニトールを含有する固形製剤であって、D-マンニトールは、化合物(I)1重量部に対して5~10000重量部であり、好ましくは10~9500重量部であることを特徴とする。
結合剤は、固形製剤総重量の0.1~10重量%が好ましく、1~8重量%がより好ましく、1~5%がさらに好ましい。
ヒドロキシプロピルセルロースは、固形製剤総重量の0.1~10重量%が好ましく、1~8重量%がより好ましく、1~5重量%がさらに好ましい。
崩壊剤は、固形製剤総重量の0.1~10重量%が好ましく、1~8重量%がより好ましい。
低置換度ヒドロキシプロピルセルロースは、固形製剤総重量の0.1~10重量%が好ましく、1~8重量%がより好ましく、3~7重量%がさらに好ましい。
滑沢剤は、固形製剤総重量の0.1~10重量%が好ましく、0.2~5重量%がより好ましい。
着色剤の含有量は、固形製剤総重量の0.1重量%未満である。
本発明の固形製剤は、製剤分野における慣用の方法により製造することができる。以下にその製法の一例を示すが、本発明はこの製造方法になんら制約されるものではない。
本発明の固形製剤は、有効成分である化合物(I)の粉末に、
(1)賦形剤等の添加物と混合して散剤としたり、あるいは、その混合末に崩壊剤および結合剤等の添加物を加え、公知の各種造粒方法により造粒して顆粒剤とする。
(2)得られた混合末または顆粒をそのまま、あるいは滑沢剤および流動化剤等の添加物を混合し、カプセルに充填してカプセル剤とする。あるいは、圧縮成型(打錠)して錠剤とする。
(3)必要に応じて、得られた混合末、顆粒、カプセルあるいは錠剤の表面を、コーティング剤あるいは糖衣により、公知のコーティング方法でコーティングする。
本発明に使用する化合物(I)は、上記I型結晶を使用した。
実施例、比較例で特に記載のない場合は以下の添加剤を使用した。トウモロコシデンプンは日食コーンスターチW(日本食品化工株式会社)を使用した。結晶セルロースはセオラスPH-101(旭化成ケミカルズ株式会社)を使用した。ヒドロキシプロピルセルロースはHPC-SSL(日本曹達株式会社)を使用した。低置換度ヒドロキシプロピルセルロースはLH-11(信越化学工業株式会社)を使用した。ステアリン酸マグネシウムはステアリン酸マグネシウム植物性(特製)(太平化学産業株式会社)を使用した。精製白糖はT.T.G.Hグラニュー(東洋精糖株式会社)を使用した。黄色三二酸化鉄は黄色三二酸化鉄(癸巳化成株式会社)を使用した。酸化チタンはタイペークA-100(石原産業株式会社)を使用した。プロピレングリコールはプロピレングリコール(旭硝子株式会社)を使用した。
(1)錠剤の調製
化合物(I)と各種D-マンニトール、トウモロコシデンプン、低置換度ヒドロキシプロピルセルロースを所定量、流動層造粒乾燥機(MP-01、株式会社パウレック)に入れ、混合しながら5%ヒドロキシプロピルセルロース水溶液をスプレー噴霧し、顆粒を調製した。得られた顆粒にステアリン酸マグネシウムを所定量混合し、ロータリー式打錠機(コレクト、株式会社菊水製作所)を用いて、800kgで打錠し錠剤(直径7mm、120mg錠)とした。各実施例、比較例で使用したD-マンニトールの種類を表1に示す。表1に記載のかさ密度(g/mL)は、タップしない(ゆるみ)状態での粉体試料の質量と粒子間空隙容積の因子を含んだ粉体の体積との比を意味し、予め試料を目開き1000μmの篩にて篩過したものを25g秤りとり、試料を濾斗を介してメスシリンダーに投入したときの容積を測定して算出した。また、表1記載のタップ密度(g/mL)は、粉体試料を入れた容器を機械的にタップすることにより得られるかさ密度であり、具体的には体積の変化が認められなくなるまでタップし、そのときの容積を測定して算出した。
錠剤の成分とその含量については、表2に記載の通りである。
(2)評価方法と結果
得られた錠剤をプラスチックボトルに入れ、栓をしない状態で、40℃/75%RHの開放した条件、および60℃の開放した条件で、1か月保存した。保存前後の錠剤中の化合物(I)の類縁物質を、高速液体クロマトグラフィーを用いて測定し、試験開始時からの類縁物質の増加量を評価した。なお、表中、類縁物質の増加量(%)は、保存前後の製剤中に含まれる化合物(I)の減少量(ピーク面積)を表す。その結果と使用した各種D-マンニトールの比表面積を表3に示す。実施例1-1から1-5のいずれの錠剤においても類縁物質の生成量は3%未満であることが示された。これらの実施例で使用したD-マンニトールの比表面積は概ね1.0m2/g以下であり、これらの物性を有するD-マンニトールを用いた場合には製剤の安定性が向上することが確認できた。
(1)錠剤の調製
化合物(I)とD-マンニトール(マンニットP、三菱商事フードテック株式会社)、トウモロコシデンプン、結晶セルロースの所定量を流動層造粒乾燥機(MP-01、株式会社パウレック)に入れ、混合しながら10%ヒドロキシプロピルセルロース水溶液をスプレー噴霧し、顆粒を製造した。得られた顆粒に、低置換度ヒドロキシプロピルセルロースおよびステアリン酸マグネシウムを所定量混合し、ロータリー式打錠機(コレクト、株式会社菊水製作所)を用いて1000kgで打錠し、錠剤(直径8mm,190mg錠)とした。各成分の含量については、表4に記載の通りである。
(1)で調製した錠剤を、プラスチックボトルに乾燥剤(ドライヤーンタブレットPW2010、山仁薬品株式会社)とともに入れて密栓し、40℃/75%RHの条件(加速試験)で6か月保存した。また、錠剤を、プラスチックボトルに入れ、栓をしない状態で、40℃/75%RHの条件、および60℃の条件で、1か月保存した。保存前後の錠剤中の化合物(I)の含量を高速液体クロマトグラフィーを用いて測定し、試験開始時に対する化合物(I)の残存率を評価した。
その結果を表5に示す。賦形剤としてD-マンニトールのみ用いた場合(実施例2-1)のみでなく、トウモロコシデンプン(実施例2-2)や結晶セルロース(実施例2-3)を、D-マンニトールと配合させた場合においても高い残存率を示した。
(1)顆粒剤の調製
実施例3-1
所定量の化合物(I)とD-マンニトール(マンニットP、三菱商事フードテック株式会社)、トウモロコシデンプン、精製白糖(サンプルミル(AP-S、ホソカワミクロン株式会社、スクリーン径3mm)で粉砕したもの)を流動層造粒乾燥機(MP-01、株式会社パウレック)に入れ、混合しながら10%ヒドロキシプロピルセルロース水溶液をスプレー噴霧し、顆粒を製造した。
実施例3-2
所定量の化合物(I)とD-マンニトール(マンニットP、三菱商事フードテック株式会社)、トウモロコシデンプン、を流動層造粒乾燥機(MP-01、株式会社パウレック)に入れて混合しながら、所定量の黄色三二酸化鉄を分散させた10%ヒドロキシプロピルセルロース水溶液をスプレー噴霧し、顆粒を製造した。
顆粒剤の成分とその含量については、表6に記載の通りである。
(2)評価方法と結果
得られた顆粒剤を乾燥剤(ドライヤーンタブレットPW2010、山仁薬品株式会社)とともにプラスチックボトルに入れて密栓し、40℃/75%RHの条件(加速試験)で2か月、または開放した状態で1か月保存した。保存前後の顆粒剤中の化合物(I)の含量を高速液体クロマトグラフィーを用いて測定し、試験開始時に対する化合物(I)の残存率(%)を評価した。その結果を表7に示す。その結果、顆粒剤とした場合にも高い安定性を確保することがわかった。
Claims (22)
- 2-{4-[N-(5,6-ジフェニルピラジン-2-イル)-N-イソプロピルアミノ]ブチルオキシ}-N-(メチルスルホニル)アセトアミドと、
比表面積が1.0m2/g以下であるD-マンニトールとを含有する固形製剤。 - 2-{4-[N-(5,6-ジフェニルピラジン-2-イル)-N-イソプロピルアミノ]ブチルオキシ}-N-(メチルスルホニル)アセトアミド1重量部に対し、D-マンニトールが5~10000重量部である、請求項1に記載の固形製剤。
- D-マンニトールの含有量が、固形製剤総重量の10~99重量%である、請求項1または2に記載の固形製剤。
- 固形製剤中に含まれる賦形剤総重量の20重量%以上がD-マンニトールである、請求項1~3のいずれかに記載の固形製剤。
- D-マンニトールの含有量が、
(a)2-{4-[N-(5,6-ジフェニルピラジン-2-イル)-N-イソプロピルアミノ]ブチルオキシ}-N-(メチルスルホニル)アセトアミド1重量部に対し、D-マンニトールの重量が5~10000重量部であり、
(b)固形製剤総重量の10~99重量%であり、
(c)固形製剤中に含まれる賦形剤総重量の20%以上である、請求項1に記載の固形製剤。 - D-マンニトール以外の賦形剤、および結合剤をさらに含有する請求項1~5のいずれかに記載の固形製剤。
- D-マンニトール以外の賦形剤が、トウモロコシデンプン、精製白糖、および結晶セルロースからなる群から選択される1種または2種である、請求項6に記載の固形製剤。
- 結合剤がヒドロキシプロピルセルロースである請求項6に記載の固形製剤。
- (a)トウモロコシデンプン、精製白糖、および結晶セルロースからなる群から選択される1種または2種、および
(b)ヒドロキシプロピルセルロース
をさらに含有する、請求項1~5のいずれかに記載の固形製剤。 - (a)2-{4-[N-(5,6-ジフェニルピラジン-2-イル)-N-イソプロピルアミノ]ブチルオキシ}-N-(メチルスルホニル)アセトアミドの含有量が固形製剤総重量の0.1~2重量%であり、
(b)D-マンニトールの含有量が、固形製剤総重量の20~80重量%であり、
(c)トウモロコシデンプンの含有量が、固形製剤総重量の15~40重量%であり、
(d)ヒドロキシプロピルセルロースの含有量が、固形製剤総重量の1~5重量%である、請求項9に記載の固形製剤。 - 2-{4-[N-(5,6-ジフェニルピラジン-2-イル)-N-イソプロピルアミノ]ブチルオキシ}-N-(メチルスルホニル)アセトアミドがI型の結晶である、請求項10に記載の固形製剤。
- 固形製剤が錠剤または顆粒剤である、請求項1~11のいずれかに記載の固形製剤。
- 糖尿病性神経障害、糖尿病性壊疽、末梢循環障害、慢性動脈閉塞症、間欠性跛行、強皮症、血栓症、肺高血圧症、心筋梗塞、狭心症、糸球体腎炎、糖尿病性腎症、慢性腎不全、気管支喘息、間質性肺炎(肺線維症)、慢性閉塞性肺疾患、尿細管間質性腎炎、炎症性腸疾患、又は脊柱管狭窄症に伴う症状の治療用である、請求項1~12のいずれかに記載の固形製剤。
- 肺高血圧症の治療用である、請求項13に記載の固形製剤。
- 末梢循環障害の治療用である、請求項13に記載の固形製剤。
- 慢性動脈閉塞症の治療用である、請求項13に記載の固形製剤。
- 間欠性跛行の治療用である、請求項13に記載の固形製剤。
- 脊柱管狭窄症に伴う症状の治療用である、請求項13に記載の固形製剤。
- 肺線維症の治療用である、請求項13に記載の固形製剤。
- 強皮症の治療用である、請求項13に記載の固形製剤。
- 慢性腎不全の治療用である、請求項13に記載の固形製剤。
- 尿細管間質性腎炎の治療用である、請求項13に記載の固形製剤。
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BR112018009534-6A BR112018009534B1 (pt) | 2015-12-02 | 2016-12-01 | Composição farmacêutica contendo 2-{4-[n-(5,6-difenilpirazin-2-il)-nisopropilamino]butiloxi }-n-(metilsulfonil)acetamida |
RU2018123304A RU2735547C2 (ru) | 2015-12-02 | 2016-12-01 | Фармацевтическая композиция, содержащая 2-{ 4-[n-(5,6-дифенилпиразин-2-ил)-n-изопропиламино]бутилокси} -n-(метилсульфонил)ацетамид |
JP2017555036A JP6825574B2 (ja) | 2015-12-02 | 2016-12-01 | 2−{4−[n−(5,6−ジフェニルピラジン−2−イル)−n−イソプロピルアミノ]ブチルオキシ}−n−(メチルスルホニル)アセトアミドを含有する医薬組成物 |
EP23214939.3A EP4331607A2 (en) | 2015-12-02 | 2016-12-01 | Pharmaceutical composition containing 2-{4-[n-(5,6-diphenylpyrazin-2-yl)-n-isopropylamino]butyloxy}-n-(methylsulfonyl)acetamide |
US15/777,711 US10821108B2 (en) | 2015-12-02 | 2016-12-01 | Pharmaceutical composition containing 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide |
CN201680068849.XA CN108289890B (zh) | 2015-12-02 | 2016-12-01 | 含有2-{4-[n-(5,6-二苯基吡嗪-2-基)-n-异丙基氨基]丁氧基}-n-(甲磺酰基)乙酰胺的医药组合物 |
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UAA201807264A UA124002C2 (uk) | 2015-12-02 | 2016-12-01 | Твердий препарат, що містить 2-{4-[n-(5,6- дифенілпіразин-2-іл)-n-ізопропіламіно]бутилокси}-n-(метилсульфоніл)ацетамід |
MX2018006343A MX2018006343A (es) | 2015-12-02 | 2016-12-01 | Composicion farmaceutica que contiene 2-{4-[n-(5,6-difenilpirazin- 2-il)-n-isopropilamino]butiloxi}-n-(metilsulfonil)acetamida. |
EP16872896.2A EP3384911A4 (en) | 2015-12-02 | 2016-12-01 | PHARMACEUTICAL COMPOSITION CONTAINING 2- {4- [N- (5,6-DIPHENYLPYRAZIN-2-YL) -N-ISOPROPYLAMINO] BUTYLOXY} -N- (METHYLSULFONYL) ACETAMIDE |
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KR1020187017182A KR20180081141A (ko) | 2015-12-02 | 2016-12-01 | 2-{4-[n-(5,6-디페닐피라진-2-일)-n-이소프로필아미노]부틸옥시}-n-(메틸술포닐)아세트아미드를 함유하는 의약 조성물 |
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CONC2018/0006834A CO2018006834A2 (es) | 2015-12-02 | 2018-06-29 | Composición farmacéutica que contiene 2-{4-[n-(5,6-difenilpirazin-2-il)-n-isopropilamino]butiloxi}-n-(metilsulfonil)acetamida |
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WO2019098300A1 (ja) | 2017-11-16 | 2019-05-23 | 日本新薬株式会社 | 放出制御製剤 |
WO2019163822A1 (ja) * | 2018-02-21 | 2019-08-29 | 日本新薬株式会社 | 粒状組成物、粒状組成物の製造方法、および粒状組成物の溶出性改善方法 |
WO2021206159A1 (ja) * | 2020-04-10 | 2021-10-14 | 日本新薬株式会社 | 固形製剤及びその製造方法 |
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US20210069187A1 (en) * | 2019-05-11 | 2021-03-11 | RK Pharma Solutions LLC | Stable pharmaceutical composition of Selexipag |
IL292354A (en) * | 2019-10-23 | 2022-06-01 | Actelion Pharmaceuticals Ltd | A pharmaceutical preparation containing Selexifag |
CN112220770B (zh) * | 2020-12-17 | 2021-04-09 | 上海翰森生物医药科技有限公司 | 司来帕格的药物组合物及其制备方法 |
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