JP2021161103A - Film coated tablet containing azisartan and amlodipine besylate - Google Patents
Film coated tablet containing azisartan and amlodipine besylate Download PDFInfo
- Publication number
- JP2021161103A JP2021161103A JP2020073113A JP2020073113A JP2021161103A JP 2021161103 A JP2021161103 A JP 2021161103A JP 2020073113 A JP2020073113 A JP 2020073113A JP 2020073113 A JP2020073113 A JP 2020073113A JP 2021161103 A JP2021161103 A JP 2021161103A
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- Prior art keywords
- film
- manufactured
- azilsartan
- coated
- tablet
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- ZPBWCRDSRKPIDG-UHFFFAOYSA-N amlodipine benzenesulfonate Chemical compound OS(=O)(=O)C1=CC=CC=C1.CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl ZPBWCRDSRKPIDG-UHFFFAOYSA-N 0.000 title claims abstract description 49
- 239000007941 film coated tablet Substances 0.000 title claims abstract description 38
- 229960004005 amlodipine besylate Drugs 0.000 title claims abstract description 18
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims abstract description 60
- 239000003826 tablet Substances 0.000 claims abstract description 49
- 239000005485 Azilsartan Substances 0.000 claims abstract description 45
- KGSXMPPBFPAXLY-UHFFFAOYSA-N azilsartan Chemical compound CCOC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NOC(=O)N1 KGSXMPPBFPAXLY-UHFFFAOYSA-N 0.000 claims abstract description 45
- 229960002731 azilsartan Drugs 0.000 claims abstract description 45
- 235000013772 propylene glycol Nutrition 0.000 claims abstract description 19
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- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000000654 additive Substances 0.000 claims abstract description 13
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Abstract
Description
本発明は、アジルサルタン及びアムロジピンベシル酸塩を含有するフィルムコーティング錠に関する。 The present invention relates to film-coated tablets containing azilsartan and amlodipine besylate.
アジルサルタンは、化学名２‐Ｅｔｈｏｘｙ‐１‐｛［２′‐（５‐ｏｘｏ‐４，５‐ｄｉｈｙｄｒｏ‐１，２，４‐ｏｘａｄｉａｚｏｌ‐３‐ｙｌ）ｂｉｐｈｅｎｙｌ‐４‐ｙｌ］ｍｅｔｈｙｌ｝‐１Ｈ‐ｂｅｎｚｏ［ｄ］ｉｍｉｄａｚｏｌｅ‐７‐ｃａｒｂｏｘｙｌｉｃ ａｃｉｄと称され、既に医薬品として医療の現場に提供されている。アジルサルタンは、アンジオテンシンＩＩ受容体拮抗薬であり、高血圧症の治療剤として知られている（非特許文献１）。 Azil sultan has the chemical name 2-Ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxodiazol-3-yl) biphenyl-4-yl] methyl} -1H. It is called -benzo [d] imidazole-7-carboxylic acid, and has already been provided as a pharmaceutical product in the medical field. Azilsartan is an angiotensin II receptor blocker and is known as a therapeutic agent for hypertension (Non-Patent Document 1).
アムロジピンベシル酸塩は、化学名３‐Ｅｔｈｙｌ ５‐ｍｅｔｈｙｌ（４ＲＳ）‐２‐［（２‐ａｍｉｎｏｅｔｈｏｘｙ）ｍｅｔｈｙｌ］‐４‐（２‐ｃｈｌｏｒｏｐｈｅｎｙｌ）‐６‐ｍｅｔｈｙｌ‐１，４‐ｄｉｈｙｄｒｏｐｙｒｉｄｉｎｅ‐３，５‐ｄｉｃａｒｂｏｘｙｌａｔｅ ｍｏｎｏｂｅｎｚｅｎｅｓｕｌｆｏｎａｔｅと称され、こちらも既に医薬品として医療の現場に提供されている。アムロジピンは、ジヒドロピリジン系カルシウム拮抗薬としての作用を示すことから、高血圧症、狭心症の治療剤として知られている（非特許文献２）。 Amlodipine besylate has the chemical name 3-Ethyl 5-methyl (4RS) -2-[(2-aminoethoxy) methyl] -4- (2-chromopheneyl) -6-methyl-1,4-dihydropyridine-3,5. -Dicarboxylate It is called monobenenesulfonate, which is also already provided as a medicine in the medical field. Amlodipine is known as a therapeutic agent for hypertension and angina because it acts as a dihydropyridine calcium channel blocker (Non-Patent Document 2).
特許文献１には、アンジオテンシンＩＩ受容体拮抗作用を有するベンズイミダソール誘導体（アジルサルタン）と、カルシウム拮抗薬（アムロジピン）とを安定に含有し、消化管における、薬物の製剤からの溶出性が適切にコントロールされたアジルサルタン、アムロジピンベシル酸塩を有効成分し、ヒプロメロース、マクロゴール６０００、酸化チタン、黄色三二酸化鉄のフィルム層により被覆されたフィルムコーティング錠（二層錠）に関する発明が記載されている。具体的な実施例として、ポリエチレングリコールを含むフィルム層により被覆されたフィルムコーティング錠が記載されている。 Patent Document 1 stably contains a benzimidazolan derivative (azilsartan) having an angiotensin II receptor antagonistic activity and a calcium channel blocker (amlodipine), and has a drug elution property in the digestive tract from a drug preparation. Described is an invention relating to a film-coated tablet (two-layer tablet) in which an appropriately controlled azilsartan, amlodipine besylate is used as an active ingredient and coated with a film layer of hypromerose, macrogol 6000, titanium oxide, and yellow iron sesquioxide. ing. As a specific example, a film-coated lock coated with a film layer containing polyethylene glycol is described.
また、特許文献２には、アムロジピンとアジルサルタンの二層錠において、アムロジピンの安定性を高めて、アムロジピンのＮ−ホルミル体の経時的生成を抑制するために、アジルサルタン含有層とアムロジピン含有層とを含んでなる二層錠であって、該二層錠の重量中、アムロジピン含有層の重量が３５〜８５％を占めるものである二層錠に関する発明が記載され、更にタルクが分散されたヒプロメロース及びトリアセチンを含むフィルム層の被覆されたフィルムコーティング錠が記載されている。 Further, in Patent Document 2, in a bilayer tablet of amlodipine and azilsartan, in order to enhance the stability of amlodipine and suppress the time-dependent production of N-formyl form of amlodipine, the azilsartan-containing layer and the azilsartan-containing layer are described. An invention relating to a two-layer tablet comprising the above, wherein the weight of the amlodipine-containing layer occupies 35 to 85% of the weight of the two-layer tablet is described, and talc is further dispersed. A film-coated tablet coated with a film layer containing hypromerose and triacetin is described.
本発明の目的は、保存安定性（例えば、温湿度条件あるいは熱条件下）に優れたアジルサルタン及びアムロジピンベシル酸塩を含有するフィルムコーティング錠を提供することにある。 An object of the present invention is to provide a film-coated lock containing azilsartan and amlodipine besylate, which have excellent storage stability (for example, temperature and humidity conditions or thermal conditions).
本発明の錠剤を検討するにあたって、本発明者らは、アジルサルタン及びアムロジピンベシル酸塩の安定性に着目して検討を行い、先ずはアジルサルタンの保存安定性に効果のあるとされているポリエチレングリコールが、意外にもアムロジピンベシル酸塩由来の分解物（Ｎ−ホルミル体）を温湿度条件下に経時的に生成させ、該分解物量が増大することを知った。本発明者らは、更に鋭意検討を行った結果、ヒドロキシプロピルセルロース、プロピレングリコール、クエン酸トリエチルからなる群より一種以上選択される添加剤を含むフィルム層が、アムロジピン由来の分解物の生成を抑制して、安定性の改善されたフィルムコーティング錠が得られること等を知見して、本発明を完成させるに至った。 In examining the tablets of the present invention, the present inventors focused on the stability of azilsartan and amlodipine besylate, and first of all, polyethylene which is said to be effective for the storage stability of azilsartan. It was found that glycol unexpectedly produced a decomposition product (N-formyl compound) derived from amlodipine besylate over time under temperature and humidity conditions, and the amount of the decomposition product increased. As a result of further diligent studies, the present inventors have found that a film layer containing one or more additives selected from the group consisting of hydroxypropyl cellulose, propylene glycol, and triethyl citrate suppresses the formation of decomposition products derived from amlogipin. As a result, they have found that a film-coated tablet having improved stability can be obtained, and have completed the present invention.
すなわち、本発明は、
（１）アジルサルタン及びアムロジピンベシル酸塩を含む素錠、ヒドロキシプロピルセルロース、プロピレングリコール、クエン酸トリエチルからなる群より一種以上選択される添加剤を含むフィルム層を含有してなるフィルムコーティング錠、
（２）前記素錠が、アジルサルタンを含む層及びアムロジピンベシル酸塩を含む層を含有してなる前記（１）に記載のフィルムコーティング錠、
（３）前記素錠が、アジルサルタンを含む層及びアムロジピンベシル酸塩を含む層を含有してなる二層錠である前記（１）又は（２）のいずれかに記載のフィルムコーティング錠、
（４）前記添加剤が、フィルム層１００質量部あたり１〜４０％である前記（１）〜（３）のいずれかに記載のフィルムコーティング錠、
（５）前記添加剤が、プロピレングリコールである前記（１）〜（４）のいずれかに記載のフィルムコーティング錠、
（６）更に、フィルム層に、酸化チタン、黄色三二酸化鉄、三二酸化鉄からなる群より一種以上選択される遮光剤を含有してなる前記（１）〜（５）のいずれかに記載のフィルムコーティング錠、
に関する。That is, the present invention
(1) An uncoated tablet containing azilsartan and amlodipine besylate, a film-coated tablet containing a film layer containing one or more additives selected from the group consisting of hydroxypropyl cellulose, propylene glycol, and triethyl citrate.
(2) The film-coated lock according to (1) above, wherein the uncoated tablet contains a layer containing azilsartan and a layer containing amlodipine besilate.
(3) The film-coated tablet according to any one of (1) and (2) above, wherein the uncoated tablet is a two-layer tablet containing a layer containing azilsartan and a layer containing amlodipine besilate.
(4) The film-coated lock according to any one of (1) to (3) above, wherein the additive is 1 to 40% per 100 parts by mass of the film layer.
(5) The film-coated lock according to any one of (1) to (4) above, wherein the additive is propylene glycol.
(6) The method according to any one of (1) to (5) above, wherein the film layer contains a light-shielding agent selected from the group consisting of titanium oxide, yellow iron sesquioxide, and iron sesquioxide. Film-coated tablets,
Regarding.
本発明によれば、保存安定性（例えば、温湿度条件あるいは熱条件下）に優れたアジルサルタン及びアムロジピンベシル酸塩を含有するフィルムコーティング錠を提供することができる。 According to the present invention, it is possible to provide a film-coated tablet containing azilsartan and amlodipine besilate having excellent storage stability (for example, temperature / humidity conditions or thermal conditions).
本明細書における「安定性」とは、アジルサルタン及びアムロジピンの分解等に起因する類縁物質量の増大及び／又は未知物質の生成・増加を抑制することを意味する。評価方法としては、例えば、温湿度条件下、例えば、後記実施例に記載の試験条件下等に錠剤を保管した後、高速液体クロマトグラフ法（ＨＰＬＣ法）により試験を行い、類縁物質量を算出して、試験開始時の総類縁物質量と比較する等して、アジルサルタン及びアムロジピン含有フィルムコーティング錠の安定性を評価する。次に、評価基準は、例えば、温湿度条件下、例えば、４０℃７５％ＲＨで７日間又は１４日間、あるいは６０℃で７日間又は１４日間保管するとき、アジルサルタン由来の類縁物質（デスエチル体）、アムロジピンベシル酸塩由来の類縁物質（Ｎ−ホルミル体）及び総類縁物質量が特定量以下として規定される。例えば、アジルサルタン由来の類縁物質（デスエチル体）について、ある態様として０％〜０．４％、アムロジピンベシル酸塩由来の類縁物質（Ｎ−ホルミル体）について、ある態様として０％〜０．２％、総類縁物質量について、ある態様として０％〜０．９％と規定する。 The term "stability" as used herein means suppressing an increase in the amount of related substances and / or an increase in the production / increase of unknown substances due to decomposition of azilsartan and amlodipine. As an evaluation method, for example, after storing the tablet under temperature and humidity conditions, for example, the test conditions described in Examples described later, a test is performed by a high performance liquid chromatograph method (HPLC method), and the amount of related substances is calculated. Then, the stability of the film-coated tablets containing azyl sultan and amlogipin is evaluated by comparing with the total amount of related substances at the start of the test. Next, the evaluation criteria are, for example, when stored under temperature and humidity conditions, for example, at 40 ° C. 75% RH for 7 days or 14 days, or at 60 ° C. for 7 days or 14 days, an azilsartan-derived related substance (desethyl compound). ), Amlodipine besilate-derived related substances (N-formyl) and total related substances are specified as specified amounts or less. For example, for azilsartan-derived related substances (desethyl form), 0% to 0.4% in some embodiments, and for amlodipine besilate-derived relative substances (N-formyl form), 0% to 0.2% in certain embodiments. %, The total amount of related substances is defined as 0% to 0.9% in a certain embodiment.
本明細書における「安定性に影響を及ぼさない」あるいは「安定性に影響の少ない」とは、有効成分に由来する類縁物質量について、製品供給の観点から、安全性が寛容される範囲内であることを意味する。例えば、後記試験方法に記載された方法に従って類縁物質量を算出することにより、類縁物質量の許容値が、ある態様として０％〜０．９％と規定される。 In the present specification, "does not affect stability" or "does not affect stability" means the amount of related substances derived from the active ingredient within the range where safety is tolerated from the viewpoint of product supply. It means that there is. For example, by calculating the amount of related substances according to the method described in the test method described later, the permissible value of the amount of related substances is defined as 0% to 0.9% in some embodiments.
本明細書における「ポリエチレングリコールを実質的に含まない」とは、アムロジピンベシル酸塩の安定性に影響を及ぼさない範囲内のポリエチレングリコールの量を意味する。例えば、フィルム層１００質量部あたりポリエチレングリコールを１％未満、ある態様として０．５％未満、ある態様として０．１％未満、と規定される。 As used herein, "substantially free of polyethylene glycol" means an amount of polyethylene glycol within a range that does not affect the stability of amlodipine besylate. For example, polyethylene glycol is defined as less than 1% per 100 parts by mass of the film layer, less than 0.5% in some embodiments, and less than 0.1% in some embodiments.
以下に、本発明のアジルサルタン及びアムロジピンベシル酸塩を含むフィルムコーティング錠に関して説明する。 The film-coated lock containing azilsartan and amlodipine besylate of the present invention will be described below.
本発明に用いられるアジルサルタンは、化学名２‐Ｅｔｈｏｘｙ‐１‐｛［２′‐（５‐ｏｘｏ‐４，５‐ｄｉｈｙｄｒｏ‐１，２，４‐ｏｘａｄｉａｚｏｌ‐３‐ｙｌ）ｂｉｐｈｅｎｙｌ‐４‐ｙｌ］ｍｅｔｈｙｌ｝‐１Ｈ‐ｂｅｎｚｏ［ｄ］ｉｍｉｄａｚｏｌｅ‐７‐ｃａｒｂｏｘｙｌｉｃ ａｃｉｄと称され、既に医薬品として医療の現場に提供され、臨床で使用されている。アジルサルタンは、特許第２５１４２８２号公報に記載の製造方法に従って、容易に製造することができる。 The azilsartan used in the present invention has a chemical name of 2-Ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxodiazol-3-yl) biphenyl-4-yl). ] Methyl} -1H-benzo [d] It is called imidazole-7-carboxylic acid, and it has already been provided as a pharmaceutical product in the medical field and is used clinically. Azilsartan can be easily produced according to the production method described in Japanese Patent No. 251482.
アジルサルタンの効能及び効果は、「高血圧症」である。用法及び用量は、上記効能及び効果に対して、通常、成人にはアジルサルタンとして２０ｍｇを１日１回経口投与する。なお、年齢、症状により適宜増減するが、１日最大投与量は４０ｍｇとする。 The indication of azilsartan is "hypertension". For the above indications and effects, the usual dosage and administration for adults is 20 mg of azilsartan orally administered once daily. The dose may be adjusted according to the patient's age and symptoms, but the maximum daily dose is 40 mg.
アジルサルタンの配合量は、フィルムコーティング錠全量あたり、ある態様として５％〜１５％、ある態様として８％〜１０％である。 The blending amount of azilsartan is 5% to 15% in some embodiments and 8% to 10% in some embodiments, based on the total amount of the film-coated tablets.
本発明に用いられるアムロジピンベシル酸塩は、化学名３‐Ｅｔｈｙｌ ５‐ｍｅｔｈｙｌ（４ＲＳ）‐２‐［（２‐ａｍｉｎｏｅｔｈｏｘｙ）ｍｅｔｈｙｌ］‐４‐（２‐ｃｈｌｏｒｏｐｈｅｎｙｌ）‐６‐ｍｅｔｈｙｌ‐１，４‐ｄｉｈｙｄｒｏｐｙｒｉｄｉｎｅ‐３，５‐ｄｉｃａｒｂｏｘｙｌａｔｅ ｍｏｎｏｂｅｎｚｅｎｅｓｕｌｆｏｎａｔｅと称され、既に医薬品として医療の現場に提供され、臨床で使用されている。アムロジピンは、特許第１６４５８２２号公報に記載の製造方法に従って、容易に製造することができる。 The amlodipine besylate used in the present invention has the chemical name 3-Ethyl 5-methyl (4RS) -2-[(2-aminoethoxy) methyl] -4- (2-chromopheneyl) -6-methyl-1,4-. It is called dihydropyridine-3,5-dicarboxylate monobenzenesulfonate, and has already been provided as a pharmaceutical product in the medical field and used clinically. Amlodipine can be easily produced according to the production method described in Japanese Patent No. 1645822.
アムロジピンベシル酸塩の効能及び効果は、「高血圧症、狭心症」である。用法及び用量は、高血圧症に対して、成人には、通常、アムロジピンとして２．５〜５ｍｇを１日１回経口投与する。なお、症状に応じ適宜増減するが、効果不十分な場合には１日１回１０ｍｇまで増量することができる。６歳以上の小児には、通常、アムロジピンとして２．５ｍｇを１日１回経口投与する。なお、年齢、体重、症状により適宜増減する。狭心症に対して、成人には、通常、アムロジピンとして５ｍｇを１日１回経口投与する。なお、症状に応じ適宜増減する。 The indication of amlodipine besilate is "hypertension, angina". For hypertension, the usual dosage and administration for adults is 2.5 to 5 mg of amlodipine orally administered once daily. The dose may be adjusted according to the patient's symptoms, but if the effect is insufficient, the dose can be increased up to 10 mg once a day. For children 6 years and older, 2.5 mg of amlodipine is usually orally administered once daily. The dose may be adjusted according to the patient's age, weight and symptoms. For angina, the usual adult dosage is 5 mg of amlodipine given orally once daily. The dose may be adjusted according to the patient's symptoms.
アムロジピンベシル酸塩の配合量は、アムロジピンの配合量として、錠剤全量あたり、ある態様として０．５％〜１５％、ある態様として１％〜１０％である。 The blending amount of amlodipine besilate is 0.5% to 15% in some embodiments and 1% to 10% in some embodiments, based on the total amount of tablets.
アジルサルタン及びアムロジピンベシル酸塩含有フィルムコーティング錠については、効能又は効果として「高血圧症」というものであり、用法及び用量として「成人には１日１回１錠（アジルサルタン／アムロジピンとして２０ｍｇ／２．５ｍｇ又は２０ｍｇ／５ｍｇ）を経口投与する。本剤は高血圧治療の第一選択薬として用いない。」というものである。 Regarding film-coated tablets containing azilsartan and amlodipine besilate, the indication is "hypertension", and the dosage and administration is "1 tablet once a day for adults (20 mg / 2 as azilsartan / amlodipine). .5 mg or 20 mg / 5 mg) is orally administered. This drug is not used as a first-line drug for the treatment of hypertension. "
本発明に用いるヒドロキシプロピルセルロース、プロピレングリコール、クエン酸トリエチルからなる群より一種以上選択される添加剤としては、製薬学的に許容され、アジルサルタン及びアムロジピンベシル酸塩の安定性に影響を与えるものでなければ、あるいは安定性に影響の少ないものであれば、特に制限されない。 The additive selected from the group consisting of hydroxypropyl cellulose, propylene glycol, and triethyl citrate used in the present invention is pharmaceutically acceptable and affects the stability of azilsartan and amlodipine besylate. Otherwise, or as long as it has little effect on stability, there is no particular limitation.
ヒドロキシプロピルセルロースとしては、製薬的に許容されるものである。例えば、ＨＰＣ−ＳＳＬ（例えば、日本曹達株式会社製 製品名ＮＩＳＳＯ ＨＰＣ−ＳＳＬ）を含む。プロピレングリコールとしては、製薬的に許容されるものである。例えば、局方プロピレングリコール（例えば、ＡＤＥＫＡ製）を含む。クエン酸トリエチルとしては、製薬的に許容されるものである。例えば、森村商事製・製品名シトロフレックス２ ＳＣ−６０を含む。好適には、ある態様としてプロピレングリコールが挙げられる。 Hydroxypropyl cellulose is pharmaceutically acceptable. For example, HPC-SSL (for example, product name NISSO HPC-SSL manufactured by Nippon Soda Corporation) is included. Propylene glycol is pharmaceutically acceptable. For example, it contains Japanese propylene glycol (eg, manufactured by ADEKA). As triethyl citrate, it is pharmaceutically acceptable. For example, the product name Citroflex 2 SC-60 manufactured by Morimura Brothers is included. Preferably, propylene glycol is mentioned as an embodiment.
配合量は、フィルムコーティング層１００質量部あたり、ある態様として１〜４０％、ある態様として５〜３０％、ある態様として１０〜２５％である。 The blending amount is 1 to 40% in some embodiments, 5 to 30% in some embodiments, and 10 to 25% in some embodiments per 100 parts by mass of the film coating layer.
本発明に用いられるフィルムコーティング錠は、医薬品錠剤の周囲がフィルム層により被覆されている錠剤である。フィルム層は、例えば、可塑剤、着色剤、遮光剤等からなる群より選択される一種以上の添加剤を含む。 The film-coated tablet used in the present invention is a tablet in which the periphery of a pharmaceutical tablet is coated with a film layer. The film layer contains, for example, one or more additives selected from the group consisting of plasticizers, colorants, shading agents, and the like.
フィルム層には、フィルム基剤の他、例えば、可塑剤、着色剤、遮光剤等が必要に応じて配合される。フィルム基剤（コーティング剤）としては、例えば、ヒプロメロース、メチルセルロース等が挙げられる。可塑剤としては、製薬的に許容され、アジルサルタン及びアムロジピンベシル酸塩の安定性に影響を与えるものでなければ、あるいは両有効成分の安定性に与える影響の少ないものであれば、特に制限されない。具体的には、例えば、ヒドロキシプロピルセルロース、プロピレングリコール、クエン酸トリエチルからなる群より選択される一種以上の添加物が挙げられる。ある態様としてプロピレングリコールである。着色剤あるいは遮光剤としては、製薬的に許容され、アジルサルタン及びアムロジピンベシル酸塩の安定性に影響を与えるものでなければ、あるいは両有効成分の安定性に与える影響の少ないものであれば、特に制限されない。具体的には、例えば、酸化チタン、黄色三二酸化鉄、三二酸化鉄からなる群より一種以上選択される添加物が挙げられる。ある態様として酸化チタン、黄色三二酸化鉄である。 In addition to the film base, for example, a plasticizer, a colorant, a light-shielding agent, and the like are blended in the film layer as needed. Examples of the film base (coating agent) include hypromellose and methyl cellulose. The plasticizer is not particularly limited as long as it is pharmaceutically acceptable and does not affect the stability of azilsartan and amlodipine besilate, or has little effect on the stability of both active ingredients. .. Specifically, for example, one or more additives selected from the group consisting of hydroxypropyl cellulose, propylene glycol, and triethyl citrate can be mentioned. One embodiment is propylene glycol. As the colorant or light-shielding agent, if it is pharmaceutically acceptable and does not affect the stability of azilsartan and amlodipine besilate, or if it has little effect on the stability of both active ingredients. There are no particular restrictions. Specifically, for example, an additive selected by one or more from the group consisting of titanium oxide, yellow iron sesquioxide, and iron sesquioxide can be mentioned. In one embodiment, titanium oxide and yellow iron sesquioxide.
ある態様として、フィルム層には、あるいはフィルムコーティング錠には、ポリエチレングリコールを実質的に含まない。具体的態様としては、例えば、アムロジピンベシル酸塩の近傍にない状態でポリエチレングリコールを含有する錠剤を含む。例えば、アジルサルタンを含む層及びポリエチレングリコールを含む層の二層錠の場合、アジルサルタンを含む層中に偏在する状態で含有したり、また、アジルサルタンを含む造粒物中に偏在する状態で含有する造粒物を、例えば、水溶性物質（例えば、糖類（糖、糖アルコール）、高分子）等により被覆されてなる状態（例えば、アジルサルタンとは遮断された状態）で含有される態様を含む。後記実施例又は試験方法の記載から、フィルムコーティング錠において、アムロジピンに由来する分解物量（温湿度条件下保管後）について、ポリエチレングリコールを実質的に含まない錠剤では、ポリエチレングリコールを含む錠剤よりも、該分解物の増加が抑制されていることが示された。 In some embodiments, the film layer, or film-coated tablets, is substantially free of polyethylene glycol. Specific embodiments include, for example, tablets containing polyethylene glycol in a state not in the vicinity of amlodipine besylate. For example, in the case of a two-layer tablet containing a layer containing azilsartan and a layer containing polyethylene glycol, it may be contained in a layer containing azilsartan in a state of being unevenly distributed, or in a state of being unevenly distributed in a granulated product containing azilsartan. An embodiment in which the contained granulated product is contained in a state of being coated with, for example, a water-soluble substance (for example, sugar (sugar, sugar alcohol), polymer) or the like (for example, in a state of being shielded from azilsartan). including. From the description of the examples or test methods described below, in film-coated tablets, the amount of decomposition products derived from amlodipine (after storage under temperature and humidity conditions) is higher in tablets that do not substantially contain polyethylene glycol than in tablets that contain polyethylene glycol. It was shown that the increase of the decomposition products was suppressed.
本発明のフィルムコーティング錠には、本発明の所望の効果が達成される範囲で各種医薬品添加物が適宜使用される。具体的には、例えば、賦形剤、崩壊剤、界面活性剤、結合剤、酸味料、発泡剤、甘味剤、香料、着色剤、緩衝剤、抗酸化剤、滑沢剤等が挙げられる。 In the film-coated lock of the present invention, various pharmaceutical additives are appropriately used as long as the desired effects of the present invention are achieved. Specific examples thereof include excipients, disintegrants, surfactants, binders, acidulants, foaming agents, sweeteners, fragrances, colorants, buffers, antioxidants, lubricants and the like.
賦形剤としては、例えば、Ｄ−マンニトール、トウモロコシデンプン、結晶セルロース、トレハロース、無水リン酸水素カルシウム、Ｄ−ソルビトール、乳糖、白糖、デンプン、α化デンプン、低置換度ヒドロキシプロピルセルロース、カルメロースナトリウム、アラビアゴム、デキストリン、プルラン、軽質無水ケイ酸、合成ケイ酸アルミニウム、メタケイ酸アルミン酸マグネシウム等が挙げられる。 Excipients include, for example, D-mannitol, corn starch, crystalline cellulose, trehalose, anhydrous calcium hydrogen phosphate, D-sorbitol, lactose, sucrose, starch, pregelatinized starch, low-substituted hydroxypropyl cellulose, carmellose sodium. , Arabic rubber, dextrin, pullulan, light anhydrous silicic acid, synthetic aluminum silicate, magnesium aluminometasilicate and the like.
崩壊剤としては、例えば、トウモロコシデンプン、バレイショデンプン、カルメロース、カルメロースカルシウム、クロスカルメロース、クロスカルメロースナトリウム、低置換度ヒドロキシプロピルセルロース、部分アルファー化デンプン、クロスポビドン等が挙げられる。 Examples of the disintegrant include corn starch, potato starch, carmellose, carmellose calcium, croscarmellose, croscarmellose sodium, low-degree-of-substitution hydroxypropyl cellulose, partially pregelatinized starch, crospovidone and the like.
界面活性剤としては、例えば、ポリソルベート８０、ラウリル硫酸ナトリウム、ポリオキシエチレン硬化ヒマシ油等が挙げられる。 Examples of the surfactant include polysorbate 80, sodium lauryl sulfate, polyoxyethylene hydrogenated castor oil and the like.
結合剤としては、例えば、ポリビニルアルコール、ヒプロメロース、アラビアゴム、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、ポリビニルピロリドン等が挙げられる。 Examples of the binder include polyvinyl alcohol, hypromellose, gum arabic, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone and the like.
酸味料としては、例えば、クエン酸、酒石酸、リンゴ酸等が挙げられる。 Examples of the acidulant include citric acid, tartaric acid, malic acid and the like.
発泡剤としては、例えば、重層等が挙げられる。 Examples of the foaming agent include multiple layers.
甘味剤としては、例えば、スクラロース、サッカリンナトリウム、グリチルリチン二カリウム、アスパルテーム、ステビア、ソーマチン等が挙げられる。 Examples of the sweetener include sucralose, sodium saccharin, dipotassium glycyrrhizin, aspartame, stevia, thaumatin and the like.
香料としては、例えば、レモン、レモンライム、オレンジ、メントール等が挙げられる。 Examples of the fragrance include lemon, lemon lime, orange, menthol and the like.
着色剤としては、例えば、黒酸化鉄、酸化チタン、食用黄色４号、食用黄色５号、食用赤色３号、食用赤色１０２号、食用青色３号等が挙げられる。 Examples of the colorant include black iron oxide, titanium oxide, edible yellow No. 4, edible yellow No. 5, edible red No. 3, edible red No. 102, edible blue No. 3, and the like.
緩衝剤としては、例えば、クエン酸、コハク酸、フマル酸、酒石酸、アスコルビン酸又はその塩類、グルタミン酸、グルタミン、グリシン、アスパラギン酸、アラニン、アルギニン又はその塩類、酸化マグネシウム、酸化亜鉛、水酸化マグネシウム、リン酸、ホウ酸又はその塩類等が挙げられる。 Examples of the buffer include citric acid, succinic acid, fumaric acid, tartrate acid, ascorbic acid or salts thereof, glutamate, glutamine, glycine, aspartic acid, alanine, arginine or salts thereof, magnesium oxide, zinc oxide, magnesium hydroxide, etc. Examples thereof include phosphoric acid, boric acid or salts thereof.
抗酸化剤としては、例えば、アスコルビン酸、ジブチルヒドロキシトルエン、没食子酸プロピル等が挙げられる。 Examples of the antioxidant include ascorbic acid, dibutylhydroxytoluene, propyl gallate and the like.
滑沢剤としては、例えば、フマル酸ステアリルナトリウム、ステアリン酸、ステアリン酸ナトリウム、タルク、ステアリン酸マグネシウム、ステアリン酸カルシウム、硬化油、ショ糖脂肪酸エステル等が挙げられる。 Examples of the lubricant include stearyl sodium fumarate, stearic acid, sodium stearate, talc, magnesium stearate, calcium stearate, hydrogenated oil, sucrose fatty acid ester and the like.
本発明のフィルムコーティング錠は、粉砕、混合、造粒、乾燥、成形（打錠）、コーティング等の工程を含む、自体公知の方法により、製造することができる。 The film-coated tablet of the present invention can be produced by a method known per se, which includes steps such as pulverization, mixing, granulation, drying, molding (locking), and coating.
本発明のフィルムコーティング錠は、通常の錠剤の製造方法により製造することが可能であるが、安定性の観点から、素錠は二層錠として製造することが好ましい。 The film-coated tablet of the present invention can be produced by a usual method for producing a tablet, but from the viewpoint of stability, the uncoated tablet is preferably produced as a two-layer tablet.
具体的には、本発明のアジルサルタン、アムロジピンベシル酸塩含有フィルムコーティング錠は、例えば、アジルサルタンと賦形剤を混合し、結合剤を精製水に溶解した液を噴霧しながらから流動層造粒機で造粒、当該造粒物を篩により、整粒物とし、当該整粒物に、賦形剤、崩壊剤、及び滑沢剤を混合し、アジルサルタン混合末を得る。同様に、アムロジピンベシル酸塩についても、混合、造粒、整粒、混合を行い、アムロジピンベシル酸塩混合末を得る。次に、当該アジルサルタン混合末とアムロジピンベシル酸塩混合末をロータリー打錠機で打錠し、アジルサルタン、アムロジピンベシル酸塩含有二層錠が得られる。次に、得られた二層錠に、ヒドロキシプロピルセルロース、プロピレングリコール、クエン酸トリエチルからなる群より一種以上選択される添加剤、ヒプロメロース、遮光剤などを精製水に溶解・分散して調製したフィルムコーティング液を、コーティング機を用いて、噴霧することで、本件発明のフィルムコーティング錠が得られる。 Specifically, the azilsartan and amlodipine besilate-containing film-coated tablets of the present invention are, for example, mixed with azilsartan and an excipient, sprayed with a solution of a binder in purified water, and then fluidized. Granulation is performed with a granulator, the granulated product is sieved to obtain a sizing product, and the sized product is mixed with an excipient, a disintegrant, and a lubricant to obtain an azilsartan mixed powder. Similarly, the amlodipine besylate is also mixed, granulated, sized, and mixed to obtain a mixed powder of amlodipine besilate. Next, the mixed powder of azilsartan and the mixed powder of amlodipine besilate are tableted with a rotary tableting machine to obtain a bilayer tablet containing azilsartan and amlodipine besilate. Next, a film prepared by dissolving and dispersing an additive, hypromellose, a light-shielding agent, etc. selected by one or more from the group consisting of hydroxypropyl cellulose, propylene glycol, and triethyl citrate in the obtained two-layer tablet in purified water. The film-coated tablet of the present invention can be obtained by spraying the coating liquid using a coating machine.
アジルサルタン及びアムロジピンを含有し、安定なフィルムコーティング錠を製造するためのプロピレングリコールの使用に関する各成分の配合量、配合方法等については、本発明のフィルムコーティング錠における当該説明をそのまま適用することができる。 Regarding the blending amount, blending method, etc. of each component regarding the use of propylene glycol containing azilsartan and amlodipine to produce a stable film-coated tablet, the description in the film-coated tablet of the present invention may be applied as it is. can.
以下に、実施例により本発明をさらに具体的に説明するが、本発明は下記の実施例に何ら限定されるものではない。 Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to the following Examples.
流動層造粒コーティング装置（パウレック社製；ＭＰ−０１）にアムロジピンベシル酸塩４２ｇ、Ｄ−マンニトール（ロケットジャパン製：ペアリトール５０Ｃ）２７８ｇ、トウモロコシデンプン（日本食品化工製；日食局方コンスターチ）４２ｇ及び結晶セルロース（旭化成製；セオラスＵＦ−７１１）１８ｇを投入し混合後、水１３８ｇにヒドロキシプロピルセルロース（日本曹達製；ＨＰＣ−ＳＳＬ）１２ｇを溶解させた結合液で造粒・乾燥した。得られた造粒・乾燥品を、スクリーン径５００μｍの篩にて整粒した。得られた整粒品に、結晶セルロース（旭化成製；セオラスＵＦ−７１１）４２ｇ、部分アルファー化デンプン（旭化成製；ＰＣＳ ＰＣ−１０）４２ｇ、ステアリン酸マグネシウム（太平化学産業製；ステアリン酸マグネシウム 植物性）３．６ｇを加えてポリ袋にて混合し、打錠用混合品を得た。
打錠用混合品をロータリー式打錠機（菊水製作所製；ＶＥＬ５）にて、１錠質量２３０ｍｇ、錠径Φ８．０ｍｍの素錠を得た。Fluidized bed granulation coating device (manufactured by Paulec; MP-01), amlogipin besilate 42 g, D-mannitol (manufactured by Rocket Japan: Pairitol 50C) 278 g, corn starch (manufactured by Nihon Shokuhin Kako; And 18 g of crystalline cellulose (manufactured by Asahi Kasei; Theoras UF-711) was added and mixed, and then granulated and dried with a binding solution in which 12 g of hydroxypropyl cellulose (manufactured by Nihon Soda; HPC-SSL) was dissolved in 138 g of water. The obtained granulated / dried product was sized with a sieve having a screen diameter of 500 μm. The obtained sized product contains 42 g of crystalline cellulose (Asahi Kasei; Theoras UF-711), 42 g of partially pregelatinized starch (Asahi Kasei; PCS PC-10), magnesium stearate (Taipei Chemical Industry; magnesium stearate). ) 3.6 g was added and mixed in a plastic bag to obtain a mixture for tableting.
A mixture for locking was obtained with a rotary locking machine (manufactured by Kikusui Seisakusho; VEL5) as an uncoated tablet having a mass of 230 mg and a lock diameter of Φ8.0 mm.
得られた素錠に、ヒプロメロース（信越化学工業製；ＴＣ−５Ｒ）５５ｇ、ヒドロキシプロピルセルロース（日本曹達製；ＨＰＣ−ＳＳＬ）１１ｇ、酸化チタン（フロイント産業製；ＦＧ）５ｇ、タルク（松村産業製；クラウンタルク）１９ｇ、黄色三二酸化鉄（癸巳化成製；黄色三二酸化鉄）０．４５ｇを精製水７５０ｇに溶解・分散して調製したフィルムコーティング溶液を、コーティング機（パウレック社製；ＤＲＣ−３００）を用いて、１錠質量９ｍｇまで噴霧し、本発明のフィルムコーティング錠を得た。 Hypromellose (manufactured by Shin-Etsu Chemical Co., Ltd .; TC-5R) 55 g, hydroxypropyl cellulose (manufactured by Nippon Soda; HPC-SSL) 11 g, titanium oxide (manufactured by Freund Sangyo; FG) 5 g, talc (manufactured by Matsumura Sangyo) in the obtained uncoated tablets. A film coating solution prepared by dissolving and dispersing 19 g of crown talc) and 0.45 g of yellow iron sesquioxide (manufactured by Shin-Etsu Chemical Co., Ltd .; ) Was sprayed to a mass of 9 mg per tablet to obtain a film-coated tablet of the present invention.
実施例１で得られた素錠に、ヒプロメロース（信越化学工業製；ＴＣ−５Ｒ）５５ｇ、プロピレングリコール（ＡＤＥＫＡ製；局方プロピレングリコール）１１ｇ、酸化チタン（フロイント産業製；ＦＧ）５ｇ、タルク（松村産業製；クラウンタルク）１９ｇ、黄色三二酸化鉄（癸巳化成製；黄色三二酸化鉄）０．４５ｇを精製水７５０ｇに溶解・分散して調製したフィルムコーティング溶液を、コーティング機（パウレック社製；ＤＲＣ−３００）を用いて、１錠質量９ｍｇまで噴霧し、本発明のフィルムコーティング錠を得た。 Hypromerose (manufactured by Shin-Etsu Chemical Co., Ltd .; TC-5R) 55 g, propylene glycol (manufactured by ADEKA; manufactured by Japanese Pharmacopoeia propylene glycol) 11 g, titanium oxide (manufactured by Freund Sangyo; FG) 5 g, and talc (manufactured by Freund Sangyo; FG) were added to the uncoated tablets obtained in Example 1. A film coating solution prepared by dissolving and dispersing 19 g of Crown Talk (manufactured by Matsumura Sangyo Co., Ltd.) and 0.45 g of yellow ferric dioxide (manufactured by Shin-Etsu Chemical Co., Ltd.) in 750 g of purified water was prepared by a coating machine (manufactured by Paulec Co., Ltd .; Using DRC-300), one tablet was sprayed to a mass of 9 mg to obtain a film-coated tablet of the present invention.
実施例１で得られた素錠に、ヒプロメロース（信越化学工業製；ＴＣ−５Ｒ）５５ｇ、クエン酸トリエチル（森村商事製；シトロフレックス２ ＳＣ−６０）１１ｇ、酸化チタン（フロイント産業製；ＦＧ）５ｇ、タルク（松村産業製；クラウンタルク）１９ｇ、黄色三二酸化鉄（癸巳化成製；黄色三二酸化鉄）０．４５ｇを精製水７５０ｇに溶解・分散して調製したフィルムコーティング溶液を、コーティング機（パウレック社製；ＤＲＣ−３００）を用いて、１錠質量９ｍｇまで噴霧し、本発明のフィルムコーティング錠を得た。 The uncoated tablet obtained in Example 1 contains 55 g of hypromerose (manufactured by Shin-Etsu Chemical Co., Ltd .; TC-5R), 11 g of triethyl citrate (manufactured by Morimura Shoji Co., Ltd .; Citroflex 2 SC-60), and titanium oxide (manufactured by Freund Sangyo; FG). A film coating solution prepared by dissolving and dispersing 5 g, talc (manufactured by Matsumura Sangyo; crown talc) 19 g, and 0.45 g of yellow iron sesquioxide (manufactured by Shin-Etsu Chemical; yellow sesquioxide) in 750 g of purified water was applied to a coating machine (coating machine (manufactured by Matsumura Sangyo Co., Ltd .; crown talc)). A film-coated tablet of the present invention was obtained by spraying up to a mass of 9 mg per tablet using Paulec Co., Ltd .; DRC-300).
≪比較例１≫
実施例１で得られた素錠に、ヒプロメロース（信越化学工業製；ＴＣ−５Ｒ）５５ｇ、マクロゴール６０００（三洋化成工業製；マクロゴール６０００ＳＰ）１１ｇ、酸化チタン（フロイント産業製；ＦＧ）５ｇ、タルク（松村産業製；クラウンタルク）１９ｇ、黄色三二酸化鉄（癸巳化成製；黄色三二酸化鉄）０．４５ｇを精製水７５０ｇに溶解・分散して調製したフィルムコーティング溶液を、コーティング機（パウレック社製；ＤＲＣ−３００）を用いて、１錠質量９ｍｇまで噴霧し、比較例のフィルムコーティング錠を得た。<< Comparative Example 1 >>
Hypromerose (manufactured by Shin-Etsu Chemical Co., Ltd .; TC-5R) 55 g, Macrogol 6000 (manufactured by Sanyo Chemical Industries; manufactured by Macrogol 6000SP) 11 g, titanium oxide (manufactured by Freund Sangyo; FG) 5 g, in the uncoated tablet obtained in Example 1. A film coating solution prepared by dissolving and dispersing 19 g of talc (manufactured by Matsumura Sangyo; crown talc) and 0.45 g of yellow sesquioxide (manufactured by Shinmi Kasei; yellow sesquioxide) in 750 g of purified water was applied to a coating machine (Paurek Co., Ltd.). Manufacture; DRC-300) was used to spray up to a mass of 9 mg per tablet to obtain a film-coated tablet of Comparative Example.
＜試験例１＞
（評価方法）
実施例１〜３及び比較例１で得られた錠剤を各々５錠ずつ遮光した容器にとり、メタノール／水混液（４：１）を加え、時々振り混ぜながら超音波処理を行った後、メタノール／水混液（４：１）を加えて１００ｍＬとした。この液を遠心分離し、上澄液を孔径０．４５μｍ以下のメンブランフィルターでろ過した。初めのろ液５ｍＬを除き、次のろ液を試料溶液とした。この液１ｍＬを正確に量り、メタノール／水混液（４：１）を加えて正確に１００ｍＬとし、標準溶液とした。試料溶液及び標準溶液１０μＬずつを正確にとり、次の条件で液体クロマトグラフィーにより試験を行った。それぞれの液の各々のピーク面積を自動積分法により測定した。結果を表３に示す。
試験条件
検出器：紫外吸光光度計（測定波長：２３７ｎｍ）
カラム：内径４．６ｍｍ、長さ２５ｃｍのステンレス管に５μｍの液体クロマトグラフ ィー用オクタデシルシリル化シリカゲルを充填する。
カラム温度：３５℃付近の一定温度
移動相Ａ：リン酸二水素ナトリウム二水和物３．１ｇを水１０００ｍＬに溶かし、薄め たリン酸（１→１０）を加えてｐＨ３．０に調整する。
移動相Ｂ：液体クロマトグラフィー用アセトニトリル
移動相Ｃ：液体クロマトグラフィー用メタノール
移動相の送液：移動相Ａ、移動相Ｂ及び移動相Ｃの混合比を次のように変えて濃度勾配制御した。
(Evaluation method)
Take the tablets obtained in Examples 1 to 3 and Comparative Example 1 in a light-shielded container of 5 tablets each, add a methanol / water mixture (4: 1), perform ultrasonic treatment with occasional shaking, and then methanol / water. A water mixture (4: 1) was added to make 100 mL. This liquid was centrifuged, and the supernatant was filtered through a membrane filter having a pore size of 0.45 μm or less. 5 mL of the first filtrate was removed, and the next filtrate was used as a sample solution. 1 mL of this solution was accurately weighed, and methanol / water mixture (4: 1) was added to make exactly 100 mL, which was used as a standard solution. Accurately 10 μL each of the sample solution and the standard solution were taken and tested by liquid chromatography under the following conditions. The peak area of each liquid was measured by the automatic integration method. The results are shown in Table 3.
Test conditions Detector: Ultraviolet absorptiometer (measurement wavelength: 237 nm)
Column: A stainless steel tube having an inner diameter of 4.6 mm and a length of 25 cm is filled with 5 μm of octadecylsilylated silica gel for liquid chromatography.
Column temperature: Constant temperature around 35 ° C. Mobile phase A: Dissolve 3.1 g of sodium dihydrogen phosphate dihydrate in 1000 mL of water, and add diluted phosphoric acid (1 → 10) to adjust the pH to 3.0.
Mobile phase B: acetonitrile mobile phase C for liquid chromatography: methanol mobile phase for liquid chromatography Liquid transfer: The mixing ratio of mobile phase A, mobile phase B and mobile phase C was changed as follows to control the concentration gradient.
表３に示す通り、ヒドロキシプロピルセルロース（実施例１）、プロピレングリコール（実施例２）、クエン酸トリエチル（実施例３）をフィルムコーティング層に含むフィルムコーティング錠は、マクロゴール６０００（比較例１）をフィルムコーティング層に含むフィルムコーティング錠よりも有効成分に由来する類縁物質量（Ｎ−ホルミル体）は少ない傾向を示し、総類縁物質量の増加量においても少ない傾向を示した。 As shown in Table 3, a film-coated tablet containing hydroxypropyl cellulose (Example 1), propylene glycol (Example 2), and triethyl citrate (Example 3) in the film coating layer is Macrogol 6000 (Comparative Example 1). The amount of related substances (N-formyl body) derived from the active ingredient tended to be smaller than that of the film-coated tablets containing the above, and the amount of increase in the total amount of related substances also tended to be smaller.
流動層造粒コーティング装置（フロイント産業社製；ＮＦＬＯ−１５）にアジルサルタン１５００ｇ、Ｄ−マンニトール（ロケットジャパン製：ペアリトール５０Ｃ）５９１０ｇ、トウモロコシデンプン（日本食品化工製；日食局方コンスターチ）９００ｇ及び結晶セルロース（旭化成製；セオラスＵＦ−７１１）３７５ｇを投入し混合後、水８３２５ｇにヒドロキシプロピルセルロース（日本曹達製；ＨＰＣ−Ｌ）３３７．５ｇ、マクロゴール６０００（日油製：マクロゴール６０００Ｐ）３３７．５ｇを溶解させた結合液で造粒・乾燥を実施した。上述した工程を１バッチとし、この工程を２バッチ分製造した。得られた２バッチ分の造粒・乾燥品（アジルサルタン層）を、スクリーン径８１３μｍのコーミル（パウレック社製；ＱＣ−１９７Ｓ）にて整粒し、バッチ混合した。得られた整粒品１８７２０ｇに、結晶セルロース（旭化成製；セオラスＵＦ−７１１）１８００ｇ、部分アルファー化デンプン（旭化成製；ＰＣＳ ＰＣ−１０）１８００ｇ、ステアリン酸マグネシウム（太平化学産業製；ステアリン酸マグネシウム 植物性）１８０ｇを加えてＶ型混合機（徳寿工作所製；Ｖ−６０）にて混合し、打錠用混合品（アジルサルタン層）を得た。 A fluidized layer granulation coating device (manufactured by Freund Sangyo Co., Ltd .; NFLO-15) containing 1500 g of azil sultan, D-mannitol (manufactured by Rocket Japan: Pearitol 50C) 5910 g, corn starch (manufactured by Nihon Shokuhin Kako; After adding 375 g of crystalline cellulose (Asahi Kasei; Theoras UF-711) and mixing, hydroxypropyl cellulose (manufactured by Nihon Soda; HPC-L) 337.5 g and Macrogol 6000 (Nippon Oil: Macrogol 6000P) 337 in 8325 g of water. Granulation and drying were carried out with a binder solution in which 5.5 g was dissolved. The above-mentioned process was regarded as one batch, and this process was produced for two batches. The obtained two batches of granulated / dried product (azilsartan layer) were sized with a Komil (manufactured by Paulec Co., Ltd .; QC-197S) having a screen diameter of 813 μm and mixed in batches. In 18720 g of the obtained sized product, 1800 g of crystalline cellulose (Asahi Kasei; Theoras UF-711), 1800 g of partially pregelatinized starch (Asahi Kasei; PCS PC-10), magnesium stearate (manufactured by Taihei Kagaku Sangyo; magnesium stearate) (Sex) 180 g was added and mixed with a V-type mixer (manufactured by Tokuju Kosakusho; V-60) to obtain a mixture for tableting (azylsartane layer).
流動層造粒コーティング装置（フロイント産業社製；ＮＦＬＯ−５）にアムロジピンベシル酸塩５１９．７５ｇ、Ｄ−マンニトール（ロケットジャパン製：ペアリトール５０Ｃ）３４８５．２５ｇ、トウモロコシデンプン（日本食品化工製；日食局方コンスターチ）５２５ｇ及び結晶セルロース（旭化成製；セオラスＵＦ−７１１）２２５ｇを投入し混合後、水２８５０ｇにヒドロキシプロピルセルロース（日本曹達製；ＨＰＣ−Ｌ）１５０ｇを溶解させた結合液で造粒・乾燥した。上述した工程を１バッチとし、この工程を２バッチ分製造した。得られた２バッチ分の造粒・乾燥品（アムロジピンベシル酸塩層）を、スクリーン径８１３μｍのコーミル（パウレック社製；ＱＣ−１９７Ｓ）にて整粒し、バッチ混合した。得られた整粒品９８１０ｇに、結晶セルロース（旭化成製；セオラスＵＦ−７１１）１０５０ｇ、部分アルファー化デンプン（旭化成製；ＰＣＳ ＰＣ−１０）１０５０ｇ、ステアリン酸マグネシウム（太平化学産業製；ステアリン酸マグネシウム 植物性）９０ｇを加えてＶ型混合機（徳寿工作所製；ＴＣＶ−３０）にて混合し、打錠用混合品（アムロジピンベシル酸塩層）を得た。 Fluid layer granulation coating device (Freund Sangyo Co., Ltd .; NFLO-5) contains 518.75 g of amlogipin besilate, D-mannitol (Rocket Japan: Pearitor 50C) 3485.25 g, corn starch (Nihon Shokuhin Kako; Nihon Shokuhin) 525 g of Japanese Pharmacopoeia Starch) and 225 g of crystalline cellulose (Asahi Kasei; Theoras UF-711) are added and mixed, and then granulated with a binder solution in which 150 g of hydroxypropyl cellulose (manufactured by Nihon Soda; HPC-L) is dissolved in 2850 g of water. It was dry. The above-mentioned process was regarded as one batch, and this process was produced for two batches. The obtained two batches of granulated / dried product (amlodipine besylate layer) were sized with a Komil (manufactured by Paulec Co., Ltd .; QC-197S) having a screen diameter of 813 μm and mixed in batches. In addition to 9810 g of the obtained sized product, 1050 g of crystalline cellulose (Asahi Kasei; Theoras UF-711), 1050 g of partially pregelatinized starch (Asahi Kasei; PCS PC-10), magnesium stearate (manufactured by Taihei Kagaku Sangyo; magnesium stearate) (Sex) 90 g was added and mixed with a V-type mixer (manufactured by Tokuju Kosakusho; TCV-30) to obtain a tableting mixture (amlogipine besylate layer).
打錠用混合品（アジルサルタン層）及び打錠用混合品（アムロジピンベシル酸塩層）ロータリー式打錠機（菊水製作所製；ＡＱＵＡ ０８５５２Ｌ２Ｋ１）にて１層目質量１５０ｍｇ、２層目質量８０ｍｇ、１錠質量２３０ｍｇ、錠径Φ８．０ｍｍの素錠を得た。 Mixing product for tableting (azilsartan layer) and mixture for tableting (amlogodipine besilate layer) Rotary type tableting machine (manufactured by Kikusui Seisakusho; AQUA 08552L2K1), 1st layer mass 150mg, 2nd layer mass 80mg, An uncoated tablet having a mass of 230 mg and a tablet diameter of Φ8.0 mm was obtained.
得られた素錠に、ヒプロメロース（信越化学工業製；ＴＣ−５Ｒ）６６ｇ、ヒドロキシプロピルセルロース（日本曹達製；ＨＰＣ−Ｌ）１３．２ｇ、酸化チタン（フロイント産業製；ＦＧ）６．０ｇ、タルク（松村産業製；クラウンタルク）２２．８ｇ、黄色三二酸化鉄（癸巳化成製；黄色三二酸化鉄）０．５４ｇを精製水８８０ｇに溶解・分散して調製したフィルムコーティング溶液を、コーティング機（パウレック社製；ＤＲＣ−３００）を用いて、１錠質量９ｍｇまで噴霧し、本発明のフィルムコーティング錠を得た。 Hypromellose (manufactured by Shin-Etsu Chemical Co., Ltd .; TC-5R) 66 g, hydroxypropyl cellulose (manufactured by Nippon Soda; HPC-L) 13.2 g, titanium oxide (manufactured by Freund Sangyo; FG) 6.0 g, talc in the obtained uncoated tablets. A film coating solution prepared by dissolving and dispersing 22.8 g of (Matsumura Sangyo; Crown Talk) and 0.54 g of yellow sesquioxide (manufactured by Shin-Etsu Chemical; yellow sesquioxide) in 880 g of purified water was applied to a coating machine (Paurek). A film-coated tablet of the present invention was obtained by spraying up to a mass of 9 mg per tablet using DRC-300).
実施例４で得られた素錠に、ヒプロメロース（信越化学工業製；ＴＣ−５Ｒ）６６ｇ、プロピレングリコール（ＡＤＥＫＡ製；局方プロピレングリコール）１３．２ｇ、酸化チタン（フロイント産業製；ＦＧ）６．０ｇ、タルク（松村産業製；クラウンタルク）２２．８ｇ、黄色三二酸化鉄（癸巳化成製；黄色三二酸化鉄）０．５４ｇを精製水８８０ｇに溶解・分散して調製したフィルムコーティング溶液を、コーティング機（パウレック社製；ＤＲＣ−３００）を用いて、１錠質量９ｍｇまで噴霧し、フィルムコーティング錠を得た。 Hypromellose (manufactured by Shin-Etsu Chemical Co., Ltd .; TC-5R) 66 g, propylene glycol (manufactured by ADEKA; manufactured by Japanese Pharmacopoeia propylene glycol) 13.2 g, titanium oxide (manufactured by Freund Sangyo; FG) 6. A film coating solution prepared by dissolving and dispersing 0 g, talc (manufactured by Matsumura Sangyo; crown talc) 22.8 g, and 0.54 g of yellow sesquioxide (manufactured by Shin-Etsu Chemical; yellow sesquioxide) in 880 g of purified water is coated. Using a machine (manufactured by Paulec Co., Ltd .; DRC-300), one tablet was sprayed to a mass of 9 mg to obtain a film-coated tablet.
実施例４で得られた素錠に、ヒプロメロース（信越化学工業製；ＴＣ−５Ｒ）６６ｇ、クエン酸トリエチル（森村商事製；シトロフレックス２ ＳＣ−６０）１３．２ｇ、酸化チタン（フロイント産業製；ＦＧ）６．０ｇ、タルク（松村産業製；クラウンタルク）２２．８ｇ、黄色三二酸化鉄（癸巳化成製；黄色三二酸化鉄）０．５４ｇを精製水８８０ｇに溶解・分散して調製したフィルムコーティング溶液を、コーティング機（パウレック社製；ＤＲＣ−３００）を用いて、１錠質量９ｍｇまで噴霧し、本発明のフィルムコーティング錠を得た。 In the uncoated tablet obtained in Example 4, 66 g of hypromerose (manufactured by Shin-Etsu Chemical Co., Ltd .; TC-5R), 13.2 g of triethyl citrate (manufactured by Morimura Brothers; Citroflex 2 SC-60), titanium oxide (manufactured by Freund Sangyo; Film coating prepared by dissolving and dispersing 6.0 g of FG), 22.8 g of talc (manufactured by Matsumura Sangyo; crown talc), and 0.54 g of yellow iron sesquioxide (manufactured by Shin-Etsu Chemical; yellow citrate) in 880 g of purified water. The solution was sprayed to a mass of 9 mg per tablet using a coating machine (manufactured by Paulec Co., Ltd .; DRC-300) to obtain a film-coated tablet of the present invention.
≪比較例２≫
実施例４で得られた素錠に、ヒプロメロース（信越化学工業製；ＴＣ−５Ｒ）６６ｇ、マクロゴール６０００（日油製；マクロゴール６０００Ｐ）１３．２ｇ、酸化チタン（フロイント産業製；ＦＧ）６．０ｇ、タルク（松村産業製；クラウンタルク）２２．８ｇ、黄色三二酸化鉄（癸巳化成製；黄色三二酸化鉄）０．５４ｇを精製水８８０ｇに溶解・分散して調製したフィルムコーティング溶液を、コーティング機（パウレック社製；ＤＲＣ−３００）を用いて、１錠質量９ｍｇまで噴霧し、比較例のフィルムコーティング錠を得た。<< Comparative Example 2 >>
Hypromellose (manufactured by Shin-Etsu Chemical Co., Ltd .; TC-5R) 66 g, Macrogol 6000 (manufactured by NOF; Macrogol 6000P) 13.2 g, titanium oxide (manufactured by Freund Sangyo; FG) 6 in the uncoated tablets obtained in Example 4. A film coating solution prepared by dissolving and dispersing 0.0 g, talc (manufactured by Matsumura Sangyo; Crown Talk) 22.8 g, and 0.54 g of yellow ferrous sesquioxide (manufactured by Shin-Etsu Chemical; yellow sesquioxide) in 880 g of purified water was prepared. Using a coating machine (manufactured by Paulec Co., Ltd .; DRC-300), one tablet was sprayed to a mass of 9 mg to obtain a film-coated tablet of Comparative Example.
実施例４で製造された素錠の成分及び配合量を表４に、実施例４〜６、比較例２で得られたフィルムコーティング錠のフィルムコーティング部の成分及び配合量を表５に示す。 Table 4 shows the components and blending amounts of the uncoated tablets produced in Example 4, and Table 5 shows the components and blending amounts of the film-coated portion of the film-coated tablets obtained in Examples 4 to 6 and Comparative Example 2.
＜試験例２＞
試験例１と同様の操作により、実施例４〜６及び比較例２で得られたフィルムコーティング錠について、試験を行った。結果を表６に示す。<Test Example 2>
The film-coated locks obtained in Examples 4 to 6 and Comparative Example 2 were tested by the same operation as in Test Example 1. The results are shown in Table 6.
表６に示す通り、ヒドロキシプロピルセルロース（実施例４）、プロピレングリコール（実施例５）、クエン酸トリエチル（実施例６）をフィルムコーティング層に含むフィルムコーティング錠剤は、マクロゴール６０００（比較例２）をフィルムコーティング層に含むフィルムコーティング錠よりもＮ−ホルミル体（アムロジピンベシル酸塩由来の類縁物質）の増加量を抑制し、総類縁物質量においても増加量を抑制した。 As shown in Table 6, a film-coated tablet containing hydroxypropyl cellulose (Example 4), propylene glycol (Example 5), and triethyl citrate (Example 6) in the film coating layer is Macrogol 6000 (Comparative Example 2). The increase in the amount of N-formyl compound (related substance derived from amlogipin besilate) was suppressed as compared with the film-coated tablet containing the above in the film coating layer, and the increase in the total amount of related substances was also suppressed.
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