JP6346314B2 - Candesartan cilexetil formulation - Google Patents
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- JP6346314B2 JP6346314B2 JP2017001556A JP2017001556A JP6346314B2 JP 6346314 B2 JP6346314 B2 JP 6346314B2 JP 2017001556 A JP2017001556 A JP 2017001556A JP 2017001556 A JP2017001556 A JP 2017001556A JP 6346314 B2 JP6346314 B2 JP 6346314B2
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- GHOSNRCGJFBJIB-UHFFFAOYSA-N Candesartan cilexetil Chemical compound C=12N(CC=3C=CC(=CC=3)C=3C(=CC=CC=3)C3=NNN=N3)C(OCC)=NC2=CC=CC=1C(=O)OC(C)OC(=O)OC1CCCCC1 GHOSNRCGJFBJIB-UHFFFAOYSA-N 0.000 title claims description 28
- 229960004349 candesartan cilexetil Drugs 0.000 title claims description 28
- 239000000203 mixture Substances 0.000 title description 26
- 238000009472 formulation Methods 0.000 title description 7
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 14
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 claims description 12
- 239000001069 triethyl citrate Substances 0.000 claims description 12
- 235000013769 triethyl citrate Nutrition 0.000 claims description 12
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 8
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 7
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 7
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 7
- 235000019359 magnesium stearate Nutrition 0.000 claims description 7
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 claims description 6
- 229920002472 Starch Polymers 0.000 claims description 2
- 239000008107 starch Substances 0.000 claims description 2
- 235000019698 starch Nutrition 0.000 claims description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 235000013869 carnauba wax Nutrition 0.000 description 12
- 239000004203 carnauba wax Substances 0.000 description 12
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 12
- 239000000654 additive Substances 0.000 description 10
- 230000000996 additive effect Effects 0.000 description 10
- 230000000052 comparative effect Effects 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 239000007787 solid Substances 0.000 description 9
- 239000008187 granular material Substances 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 5
- 238000012858 packaging process Methods 0.000 description 5
- 239000011230 binding agent Substances 0.000 description 4
- 238000004811 liquid chromatography Methods 0.000 description 4
- 239000000314 lubricant Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 239000007857 degradation product Substances 0.000 description 3
- 238000013112 stability test Methods 0.000 description 3
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 229950008138 carmellose Drugs 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
- 230000000087 stabilizing effect Effects 0.000 description 2
- -1 sucrose fatty acid ester Chemical class 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 102000008873 Angiotensin II receptor Human genes 0.000 description 1
- 108050000824 Angiotensin II receptor Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 206010007558 Cardiac failure chronic Diseases 0.000 description 1
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- HTIQEAQVCYTUBX-UHFFFAOYSA-N amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-UHFFFAOYSA-N 0.000 description 1
- 229960000528 amlodipine Drugs 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000000679 carrageenan Substances 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- 229940113118 carrageenan Drugs 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 229960002003 hydrochlorothiazide Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 229940093429 polyethylene glycol 6000 Drugs 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 238000000275 quality assurance Methods 0.000 description 1
- 206010038464 renal hypertension Diseases 0.000 description 1
- 238000004513 sizing Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229940083542 sodium Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は、保存安定性が向上されたカンデサルタン シレキセチル製剤に関する。 The present invention relates to a candesartan cilexetil formulation with improved storage stability.
カンデサルタン シレキセチル（Ｃａｎｄｅｓａｒｔａｎ Ｃｉｌｅｘｅｔｉｌ）は、持続性アンジオテンシンＩＩ受容体拮抗作用を有し、高血圧症、腎実質性高血圧症、並びに軽症〜中等症の慢性心不全の治療薬として広く本邦において使用されている。（特許文献１）
ところで、結晶性のカンデサルタン シレキセチルは、それ自体は温度、湿度、光に対して安定であるが、錠剤化した場合、製造工程における圧力、摩擦、熱等により結晶の歪みが生じ、これにより、経日的な分解物増加、含量低下が加速される旨の報告がなされている。（特許文献２）
特許文献２では、ポリエチレングリコール６０００、ステアリールアルコール、ショ糖脂肪酸エステル及びソルビタン脂肪酸エステル等の低融点油脂状物質を配合することで、顕著に有効成分であるカンデサルタン シレキセチルの分解が抑えられ、錠剤の保存安定性が向上した旨、報告している。
一方、特許文献３では、錠剤化の間の劣化に対しカンデサルタン シレキセチルを適切に安定化させる目的でカラゲナンを配合した医薬組成物を報告している。
また、特許文献４では、非イオン性界面活性剤を含んで成る生物学的利用能が改善されたカンデサルタン シレキセチル製剤を報告している。
このように製剤を安定化することは、製品の品質担保に非常に重要であり、製品価値を高めることにも繋がる。
Candesartan cilexetil has a persistent angiotensin II receptor antagonistic action and is widely used in Japan as a therapeutic agent for hypertension, renal parenchymal hypertension, and mild to moderate chronic heart failure. (Patent Document 1)
By the way, crystalline candesartan cilexetil itself is stable to temperature, humidity, and light, but when tableted, crystal distortion occurs due to pressure, friction, heat, etc. in the manufacturing process. It has been reported that daily degradation products increase and content decrease are accelerated. (Patent Document 2)
In Patent Document 2, by blending a low melting point oily substance such as polyethylene glycol 6000, stearyl alcohol, sucrose fatty acid ester and sorbitan fatty acid ester, decomposition of candesartan cilexetil, which is an active ingredient, is remarkably suppressed, Reports that storage stability has been improved.
On the other hand, Patent Document 3 reports a pharmaceutical composition containing carrageenan for the purpose of appropriately stabilizing candesartan cilexetil against deterioration during tableting.
Patent Document 4 reports a candesartan cilexetil preparation with improved bioavailability comprising a nonionic surfactant.
Stabilizing the preparation in this way is very important for quality assurance of the product and leads to an increase in product value.
本発明の課題は保存安定性が向上されたカンデサルタン シレキセチル製剤を提供することにある。 An object of the present invention is to provide a candesartan cilexetil preparation with improved storage stability.
本発明者らは結晶性のカンデサルタン シレキセチルにクエン酸トリエチル、カルナウバロウ及びラウリル硫酸ナトリウムから選択された添加物を配合することで、カンデサルタン シレキセチルの分解が抑えられ、保存安定性が向上した錠剤が得られることを見出し、本発明を完成した。
即ち、本発明は 結晶性のカンデサルタン シレキセチル又はその塩にクエン酸トリエチル、カルナウバロウ及びラウリル硫酸ナトリウムから選択された添加物を配合した経口用固形医薬組成物に関する。
また、本発明は、結晶性のカンデサルタン シレキセチル又はその塩にクエン酸トリエチル、カルナウバロウ及びラウリル硫酸ナトリウムから選択された添加物を配合した錠剤の製造法に関する。
The inventors of the present invention blended crystalline candesartan cilexetil with an additive selected from triethyl citrate, carnauba wax and sodium lauryl sulfate, whereby the decomposition of candesartan cilexetil is suppressed, and a tablet with improved storage stability is obtained. As a result, the present invention has been completed.
That is, the present invention relates to an oral solid pharmaceutical composition comprising crystalline candesartan cilexetil or a salt thereof and an additive selected from triethyl citrate, carnauba wax and sodium lauryl sulfate.
The present invention also relates to a method for producing a tablet in which crystalline candesartan cilexetil or a salt thereof is blended with an additive selected from triethyl citrate, carnauba wax and sodium lauryl sulfate.
本発明を更に詳細に説明する。
本発明組成物としては好ましくは次の組成物が挙げられる。
（１）
（ａ）結晶性のカンデサルタン シレキセチル又はその塩、
（ｂ）賦形剤、
（ｃ）結合剤、
（ｄ）滑沢剤、
（ｅ）クエン酸トリエチル、カルナウバロウ及びラウリル硫酸ナトリウムから選択された添加物を
配合してなる経口用固形医薬組成物。
（２）
錠剤である上記（１）記載の組成物。
（３）
結晶性のカンデサルタン シレキセチル又はその塩を組成物中、１〜１０重量％含有する上記（１）又は（２）記載の組成物。
（４）
クエン酸トリエチル、カルナウバロウ及びラウリル硫酸ナトリウムから選択された添加物を組成物中、０．５〜１５重量％含有する上記（１）〜（３）記載の組成物。
（５）
賦形剤が、乳糖、トウモロコシデンプン、マンニトール、結晶セルロースから選択されるものを含む上記（１）〜（４）記載の組成物。
（６）
結合剤が、ヒドロキシプロピルセルロース又はポビドンから選択されるものを含む上記（１）〜（５）記載の組成物。
（７）
滑沢剤が、ステアリン酸マグネシウムである上記（１）〜（６）記載の組成物。
（８）
添加物として、更に崩壊剤を配合する上記（１）〜（７）記載の組成物。
（９）
崩壊剤がカルメロースカルシウム、クロスカルメロースナトリウムカルメロース、クロスポビドン、低置換度ヒドロキシプロピルセルロース又はカルボキシメチルスターチナトリウムから選択されるものを含む上記（８）記載の組成物。
（１０）添加物として、更に酸化鉄等の着色剤を配合する（１）〜（９）記載の組成物。
（１１）結晶性のカンデサルタン シレキセチル又はその塩、並びにクエン酸トリエチル、カルナウバロウ及びラウリル硫酸ナトリウムから選択された添加物を配合してなる経口用固形医薬組成物。
（１２）結晶性のカンデサルタン シレキセチル又はその塩、賦形剤、結合剤、並びにクエン酸トリエチル、カルナウバロウ及びラウリル硫酸ナトリウムから選択された添加剤を混合、造粒し、造粒物を得た後、滑沢剤を加え、混合後、打錠することによる錠剤の製造法。
The present invention will be described in further detail.
Preferred examples of the composition of the present invention include the following compositions.
(1)
(A) crystalline candesartan cilexetil or a salt thereof,
(B) an excipient,
(C) a binder,
(D) a lubricant,
(E) An oral solid pharmaceutical composition comprising an additive selected from triethyl citrate, carnauba wax and sodium lauryl sulfate.
(2)
The composition according to the above (1), which is a tablet.
(3)
The composition according to (1) or (2) above, wherein 1 to 10% by weight of crystalline candesartan cilexetil or a salt thereof is contained in the composition.
(4)
The composition according to any one of (1) to (3) above, wherein the composition contains an additive selected from triethyl citrate, carnauba wax and sodium lauryl sulfate in an amount of 0.5 to 15% by weight.
(5)
The composition according to any one of (1) to (4) above, wherein the excipient comprises one selected from lactose, corn starch, mannitol, and crystalline cellulose.
(6)
The composition according to any one of (1) to (5) above, wherein the binder comprises one selected from hydroxypropylcellulose or povidone.
(7)
The composition according to any one of (1) to (6) above, wherein the lubricant is magnesium stearate.
(8)
The composition according to any one of (1) to (7), wherein a disintegrant is further added as an additive.
(9)
The composition according to (8) above, wherein the disintegrant comprises one selected from carmellose calcium, croscarmellose sodium carmellose, crospovidone, low-substituted hydroxypropylcellulose, or sodium carboxymethyl starch.
(10) The composition according to (1) to (9), wherein a colorant such as iron oxide is further blended as an additive.
(11) An oral solid pharmaceutical composition comprising crystalline candesartan cilexetil or a salt thereof and an additive selected from triethyl citrate, carnauba wax and sodium lauryl sulfate.
(12) After crystalline candesartan cilexetil or a salt thereof, an excipient, a binder, and an additive selected from triethyl citrate, carnauba wax and sodium lauryl sulfate are mixed and granulated to obtain a granulated product, A method for producing tablets by adding a lubricant, mixing, and tableting.
次に本発明の経口用固形医薬組成物のうち、錠剤の製造法を述べる。
まず、結晶性のカンデサルタン シレキセチル又はその塩、賦形剤、結合剤、並びにクエン酸トリエチル、カルナウバロウ及びラウリル硫酸ナトリウムから選択された添加物を混合し、水を加え造粒する。
得られた造粒物を乾燥、整粒する。ここで得られた顆粒に滑沢剤を加え混合後、打錠する。更に得られた錠剤にフィルムコーテイングを施すことも可能である。
また、本発明の経口用固形医薬組成物は公知の直打法や乾式造粒法で製造することもできる。
Next, the manufacturing method of a tablet is described among the solid pharmaceutical compositions for oral use of this invention.
First, crystalline candesartan cilexetil or a salt thereof, an excipient, a binder, and an additive selected from triethyl citrate, carnauba wax and sodium lauryl sulfate are mixed and granulated by adding water.
The obtained granulated product is dried and sized. A lubricant is added to the granule obtained here and mixed, and then tableted. Furthermore, film coating can be applied to the obtained tablets.
The solid pharmaceutical composition for oral use of the present invention can also be produced by a known direct compression method or dry granulation method.
次に、本発明の経口用固形医薬組成物(錠剤)の安定性試験結果を示す。
表４、７に示すように結晶性のカンデサルタン シレキセチルに、クエン酸トリエチル、カルナウバロウ又はラウリル硫酸ナトリウムを配合した実施例１〜３記載の本発明の経口用固形医薬組成物(錠剤)は、クエン酸トリエチル、カルナウバロウ又はラウリル硫酸ナトリウムを配合しない比較例１、２記載の錠剤に対し、安定性が優れていることが判明した。
従って、本発明の経口用固形医薬組成物は、成形による経日的な分解が抑制された保存安定な向上された製剤である。
なお、本発明の経口用固形医薬組成物は、有効成分としてカンデサルタン シレキセチルのみ含有するものの他、有効成分がカンデサルタン シレキセチルと持続的Ｃａ拮抗剤（アムロジピン）や利尿薬（ヒドロクロロチアジド）等との配合剤も本発明に含まれる。
次に実施例、比較例を挙げて本発明を更に詳細に説明する。
Next, the stability test results of the oral solid pharmaceutical composition (tablet) of the present invention are shown.
As shown in Tables 4 and 7, the oral solid pharmaceutical composition (tablet) of the present invention described in Examples 1 to 3, in which triethyl citrate, carnauba wax or sodium lauryl sulfate was blended with crystalline candesartan cilexetil, It was found that the tablets of Comparative Examples 1 and 2 not containing triethyl, carnauba wax or sodium lauryl sulfate were excellent in stability.
Therefore, the solid pharmaceutical composition for oral use of the present invention is a storage-stable and improved preparation in which the daily degradation due to molding is suppressed.
The solid pharmaceutical composition for oral use of the present invention contains only candesartan cilexetil as an active ingredient, and the active ingredient is a combination of candesartan cilexetil and a continuous Ca antagonist (amlodipine) or diuretic (hydrochlorothiazide). It is included in the present invention.
Next, the present invention will be described in more detail with reference to Examples and Comparative Examples.
実施例１
結晶性のカンデサルタン シレキセチル１ｇ、乳糖水和物２０ｇ、ヒドロキシプロピルセルロース１ｇを小型粉砕機にて混合し、水２ｇ、クエン酸トリエチル１ｇを加えて造粒後、箱型乾燥機にて乾燥し、篩にて整粒した。得られた顆粒に対して、ステアリン酸マグネシウムを０．３％加えて混合し、単発打錠機にて７．０ｍｍφ、重量１３８．４ｍｇであり、包装工程や輸送中の衝撃に耐えられる硬度の錠剤を得た。
実施例１の処方を表１に示す。
Example 1
1 g of crystalline candesartan cilexetil, 20 g of lactose hydrate and 1 g of hydroxypropylcellulose are mixed in a small pulverizer, granulated with 2 g of water and 1 g of triethyl citrate, dried in a box dryer, and sieved. Sizing. 0.3% of magnesium stearate is added to and mixed with the obtained granules, and it is 7.0 mmφ and weight 138.4 mg in a single tableting machine, and has a hardness that can withstand impact during packaging process and transportation. Tablets were obtained.
The formulation of Example 1 is shown in Table 1.
実施例２
結晶性のカンデサルタン シレキセチル１ｇ、乳糖水和物２０ｇ、ヒドロキシプロピルセルロース１ｇ、カルナウバロウ１ｇを小型粉砕機にて混合し、水２ｇを加えて造粒後、箱型乾燥機にて乾燥し、篩にて整粒した。得られた顆粒に対して、ステアリン酸マグネシウムを０．３％加えて混合し、単発打錠機にて７．０ｍｍφ、重量１３８．４ｍｇであり、包装工程や輸送中の衝撃に耐えられる硬度の錠剤を得た。
実施例２の処方を表２に示す。
Example 2
1 g of crystalline candesartan cilexetil, 20 g of lactose hydrate, 1 g of hydroxypropylcellulose and 1 g of carnauba wax are mixed in a small pulverizer, granulated with 2 g of water, dried in a box-type dryer, and sieved. Sized. 0.3% of magnesium stearate is added to and mixed with the obtained granules, and it is 7.0 mmφ and weight 138.4 mg in a single tableting machine, and has a hardness that can withstand impact during packaging process and transportation. Tablets were obtained.
The formulation of Example 2 is shown in Table 2.
比較例１
結晶性のカンデサルタン シレキセチル１ｇ、乳糖水和物２１ｇ、ヒドロキシプロピルセルロース１ｇを小型粉砕機にて混合し、水２ｇを加えて造粒後、箱型乾燥機にて乾燥し、篩にて整粒した。得られた顆粒に対して、ステアリン酸マグネシウムを０．３％加えて混合し、単発打錠機にて７．０ｍｍφ、重量１３８．４ｍｇであり、包装工程や輸送中の衝撃に耐えられる硬度の錠剤を得た。
比較例１の処方を表３に示す。
Comparative Example 1
1 g of crystalline candesartan cilexetil, 21 g of lactose hydrate and 1 g of hydroxypropylcellulose were mixed in a small pulverizer, granulated with 2 g of water, dried in a box dryer, and sized with a sieve. . 0.3% of magnesium stearate is added to and mixed with the obtained granules, and it is 7.0 mmφ and weight 138.4 mg in a single tableting machine, and has a hardness that can withstand impact during packaging process and transportation. Tablets were obtained.
The formulation of Comparative Example 1 is shown in Table 3.
安定性試験１
(試験方法)
実施例１、２及び比較例１で得られた錠剤を４０℃で、１週間及び２週間保存後、主分解物であるデスエチル体の有効成分であるカンデサルタン シレキセチルに対する割合（％）を液体クロマトグラフィーで測定した。液体クロマトグラフィー条件は以下のとおりである。
カラム：内径３．９ｍｍ、長さ１５ｃｍのＯＤＳカラム
移動相A：アセトニトリル/水/酢酸(１００)混液（５７:４３:１）
移動相B：アセトニトリル/水/酢酸(１００)混液（９０:１０:１）
Stability test 1
(Test method)
After the tablets obtained in Examples 1 and 2 and Comparative Example 1 were stored at 40 ° C. for 1 week and 2 weeks, the ratio (%) with respect to candesartan cilexetil, which is the active ingredient of desethyl body, which is the main degradation product, was subjected to liquid chromatography. Measured with The liquid chromatography conditions are as follows.
Column: ODS column with an inner diameter of 3.9 mm and a length of 15 cm Mobile phase A: Acetonitrile / water / acetic acid (100) mixture (57: 43: 1)
Mobile phase B: acetonitrile / water / acetic acid (100) mixture (90: 10: 1)
（試験結果）
試験結果を表４に示す。
表４から明らかなように、クエン酸トリエチル又はカルナウバロウを配合した実施例１及び２記載の本発明組成物(錠剤)は、比較例１記載の錠剤に比べて安定性が優れていることが判明した。
(Test results)
The test results are shown in Table 4.
As is apparent from Table 4, the compositions of the present invention (tablets) described in Examples 1 and 2 containing triethyl citrate or carnauba wax were found to be more stable than the tablets described in Comparative Example 1. did.
実施例３
結晶性のカンデサルタン シレキセチル０．５ｇ、乳糖水和物１０ｇ、ヒドロキシプロピルセルロース０．５ｇ、ラウリル硫酸ナトリウム０．５ｇを小型粉砕機にて混合し、水１ｇを加えて造粒後、箱型乾燥機にて乾燥し、篩にて整粒した。得られた顆粒に対して、ステアリン酸マグネシウムを０．３％加えて混合し、単発打錠機にて７．０ｍｍφ、重量１３８．４ｍｇであり、包装工程や輸送中の衝撃に耐えられる硬度の錠剤を得た。
実施例３の処方を表５に示す。
Example 3
Crystalline candesartan cilexetil 0.5g, lactose hydrate 10g, hydroxypropylcellulose 0.5g, sodium lauryl sulfate 0.5g were mixed in a small pulverizer, granulated with 1g of water, and box-type dryer And dried with a sieve. 0.3% of magnesium stearate is added to and mixed with the obtained granules, and it is 7.0 mmφ and weight 138.4 mg in a single tableting machine, and has a hardness that can withstand impact during packaging process and transportation. Tablets were obtained.
The formulation of Example 3 is shown in Table 5.
比較例２
結晶性のカンデサルタン シレキセチル０．５ｇ、乳糖水和物１０．５ｇ、ヒドロキシプロピルセルロース０．５ｇを小型粉砕機にて混合し、水１ｇを加えて造粒後、箱型乾燥機にて乾燥し、篩にて整粒した。得られた顆粒に対して、ステアリン酸マグネシウムを０．３％加えて混合し、単発打錠機にて７．０ｍｍφ、重量１３８．４ｍｇであり、包装工程や輸送中の衝撃に耐えられる硬度の錠剤を得た。
比較例２の処方を表６に示す。
Comparative Example 2
Crystalline candesartan cilexetil 0.5g, lactose hydrate 10.5g, hydroxypropylcellulose 0.5g was mixed in a small grinder, granulated with 1g of water, dried in a box dryer, The size was adjusted with a sieve. 0.3% of magnesium stearate is added to and mixed with the obtained granules, and it is 7.0 mmφ and weight 138.4 mg in a single tableting machine, and has a hardness that can withstand impact during packaging process and transportation. Tablets were obtained.
The formulation of Comparative Example 2 is shown in Table 6.
安定性試験２
(試験方法)
実施例３及び比較例２で得られた錠剤を４０℃で、１週間及び２週間保存後、主分解物であるデスエチル体の有効成分であるカンデサルタン シレキセチルに対する割合（％）を液体クロマトグラフィーで測定した。液体クロマトグラフィー条件は以下のとおりである。
カラム：内径３．９ｍｍ、長さ１５ｃｍのＯＤＳカラム
移動相A：アセトニトリル/水/酢酸(１００)混液（５７:４３:１）
移動相B：アセトニトリル/水/酢酸(１００)混液（９０:１０:１）
Stability test 2
(Test method)
After the tablets obtained in Example 3 and Comparative Example 2 were stored at 40 ° C. for 1 week and 2 weeks, the ratio (%) to candesartan cilexetil, which is an active ingredient of desethyl body, which is the main degradation product, was measured by liquid chromatography. did. The liquid chromatography conditions are as follows.
Column: ODS column with an inner diameter of 3.9 mm and a length of 15 cm Mobile phase A: Acetonitrile / water / acetic acid (100) mixture (57: 43: 1)
Mobile phase B: acetonitrile / water / acetic acid (100) mixture (90: 10: 1)
（試験結果）
試験結果を表７に示す。
表７から明らかなように、ラウリル硫酸ナトリウムを配合した実施例３記載の本発明組成物（錠剤）は、比較例２記載の錠剤に比べて安定性が優れていることが判明した。
(Test results)
The test results are shown in Table 7.
As is apparent from Table 7, the composition of the present invention described in Example 3 (tablet) containing sodium lauryl sulfate was found to be more stable than the tablet described in Comparative Example 2.
Claims (1)
A pharmaceutical composition comprising crystalline candesartan cilexetil or a salt thereof, lactose hydrate, hydroxypropylcellulose, triethyl citrate and magnesium stearate, and no starch.
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