JP5689052B2 - 光安定性の向上した組成物 - Google Patents
光安定性の向上した組成物 Download PDFInfo
- Publication number
- JP5689052B2 JP5689052B2 JP2011283072A JP2011283072A JP5689052B2 JP 5689052 B2 JP5689052 B2 JP 5689052B2 JP 2011283072 A JP2011283072 A JP 2011283072A JP 2011283072 A JP2011283072 A JP 2011283072A JP 5689052 B2 JP5689052 B2 JP 5689052B2
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- JP
- Japan
- Prior art keywords
- oral solid
- solid composition
- amlodipine
- iron oxide
- starch
- 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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- 239000000203 mixture Substances 0.000 title claims description 22
- 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 claims description 59
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 claims description 58
- 229960000528 amlodipine Drugs 0.000 claims description 53
- 239000008247 solid mixture Substances 0.000 claims description 51
- 238000002360 preparation method Methods 0.000 claims description 45
- 229920002472 Starch Polymers 0.000 claims description 24
- 235000019698 starch Nutrition 0.000 claims description 23
- 239000008107 starch Substances 0.000 claims description 22
- 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 claims description 12
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 11
- 235000010355 mannitol Nutrition 0.000 claims description 10
- 229930195725 Mannitol Natural products 0.000 claims description 9
- 238000002845 discoloration Methods 0.000 claims description 9
- 239000000594 mannitol Substances 0.000 claims description 9
- 239000011247 coating layer Substances 0.000 claims description 8
- 229920002261 Corn starch Polymers 0.000 claims description 7
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims description 7
- 239000008120 corn starch Substances 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- NDLPOXTZKUMGOV-UHFFFAOYSA-N oxo(oxoferriooxy)iron hydrate Chemical compound O.O=[Fe]O[Fe]=O NDLPOXTZKUMGOV-UHFFFAOYSA-N 0.000 claims description 7
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 claims description 7
- 229960004005 amlodipine besylate Drugs 0.000 claims description 6
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 6
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 6
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 5
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 5
- 239000000811 xylitol Substances 0.000 claims description 5
- 235000010447 xylitol Nutrition 0.000 claims description 5
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 5
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- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 4
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 4
- 239000000600 sorbitol Substances 0.000 claims description 4
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- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims description 3
- 239000000845 maltitol Substances 0.000 claims description 3
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- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 claims description 3
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- 238000000034 method Methods 0.000 description 19
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- 150000003839 salts Chemical class 0.000 description 18
- 235000013980 iron oxide Nutrition 0.000 description 17
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- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 9
- 150000005846 sugar alcohols Chemical class 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 8
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- YOBAEOGBNPPUQV-UHFFFAOYSA-N iron;trihydrate Chemical compound O.O.O.[Fe].[Fe] YOBAEOGBNPPUQV-UHFFFAOYSA-N 0.000 description 8
- 230000008859 change Effects 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 230000006641 stabilisation Effects 0.000 description 7
- 238000011105 stabilization Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 239000006191 orally-disintegrating tablet Substances 0.000 description 6
- 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 5
- 239000003963 antioxidant agent Substances 0.000 description 5
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- 239000004386 Erythritol Substances 0.000 description 4
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- 235000019414 erythritol Nutrition 0.000 description 4
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- 238000009472 formulation Methods 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- -1 pyridine compound Chemical class 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- UJMBCXLDXJUMFB-UHFFFAOYSA-K trisodium;5-oxo-1-(4-sulfonatophenyl)-4-[(4-sulfonatophenyl)diazenyl]-4h-pyrazole-3-carboxylate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)C1=NN(C=2C=CC(=CC=2)S([O-])(=O)=O)C(=O)C1N=NC1=CC=C(S([O-])(=O)=O)C=C1 UJMBCXLDXJUMFB-UHFFFAOYSA-K 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 229920000881 Modified starch Polymers 0.000 description 3
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- 239000004480 active ingredient Substances 0.000 description 3
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- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 3
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
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- SPSPIUSUWPLVKD-UHFFFAOYSA-N 2,3-dibutyl-6-methylphenol Chemical compound CCCCC1=CC=C(C)C(O)=C1CCCC SPSPIUSUWPLVKD-UHFFFAOYSA-N 0.000 description 2
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- 108010011485 Aspartame Proteins 0.000 description 2
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Landscapes
- Medicinal Preparation (AREA)
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Description
従来、光に対して不安定な薬物の製剤化に関しては、薬物の安定化を図るため種々の方法が知られている。例えば、特許文献1には皮膜中に着色剤を分散した軟カプセルに光に不安定な薬物であるニフェジピンを封入した光による分解や変質を防止したニフェジピンの軟カプセルが開示されている。また、特許文献2にはタール系色素やベンガラ等を含有する硬カプセルにより活性型ビタミンD3類を安定化したカプセル製剤が開示されている。これらの技術はいずれも光に不安定な薬物を覆うカプセル皮膜中に着色剤を含有させたものであり、錠剤、顆粒剤、細粒剤、散剤等への適用は困難である。
〔1〕 (a)アムロジピンまたはその薬学上許容される塩、および(b)酸化鉄を含有し、かつ被覆層を有しない経口固形組成物。
〔2〕 実質的に酸化チタンを含有しない経口固形組成物である、〔1〕記載の経口固形組成物。
〔3〕 口腔内崩壊型製剤である、〔1〕または〔2〕記載の経口固形組成物。
〔4〕 以下の(a)〜(d)の成分を含有する、〔1〕〜〔3〕のいずれかに記載の経口固形組成物。
(a)アムロジピンまたはその薬学上許容される塩
(b)酸化鉄
(c)マンニトール
(d)トウモロコシデンプン
〔5〕 さらにフマル酸ステアリルナトリウムを含有し、経口固形組成物が口腔内崩壊錠である、〔1〕〜〔4〕のいずれかに記載の経口固形組成物。
〔6〕 (a) アムロジピンまたはその塩の経口固形組成物中含量がアムロジピンとして2〜5重量%であり、
(b)酸化鉄の経口固形組成物中含量が0.03〜2重量%であり、
(c)マンニトールの経口固形組成物中含量が70〜90重量%であり、
(d)トウモロコシデンプンの経口固形組成物中含量が5〜15重量%であり、かつ
(e)フマル酸ステアリルナトリウムの経口固形組成物中含量が1〜3重量%である、
〔5〕記載の経口固形組成物。
〔7〕 酸化鉄が黄色三二酸化鉄である、〔1〕〜〔6〕のいずれかに記載の経口固形組成物。
〔8〕 (a)アムロジピンまたはその薬学上許容される塩、および(b)酸化鉄の混合物を含有する、〔1〕〜〔7〕のいずれかに記載の経口固形組成物。
〔9〕 (a)アムロジピンまたはその薬学上許容される塩、および(b)酸化鉄の混合物を造粒して得られる組成物を含有する、〔1〕〜〔8〕のいずれかに記載の経口固形組成物。
アムロジピンの薬学上許容される塩としては、塩酸、臭化水素酸、硫酸、リン酸、酢酸、マレイン酸、フマル酸、乳酸、酒石酸、クエン酸、グルコン酸、コハク酸、サリチル酸、メタンスルホン酸、ベンゼンスルホン酸、トルエンスルホン酸との塩が挙げられる。好ましくはベンゼンスルホン酸との塩、即ちベシル酸アムロジピンが挙げられる。
具体的には例えば主薬、賦形剤、崩壊剤、結合剤等を乾式造粒または湿式造粒等し、必要に応じて打錠等の成形をして得られる経口固形組成物にフィルム形成性の高分子溶液を噴霧、乾燥するなどして当該経口固形組成物の外側に施す当該経口固形組成物とは異なる組成で形成される外層が挙げられる。フィルム形成性高分子溶液には、通常フィルム形成を阻害しない範囲で各種添加剤が添加される。コーティングとはこのような被覆層の形成を指す。
その他の被覆層としては軟カプセルや硬カプセル等のカプセルが挙げられる。
本発明における口腔内崩壊型粒状製剤、口腔内崩壊錠の口腔内での溶解または崩壊時間は通常1分以内、好ましくは45秒以内、より好ましくは30秒以内であることが挙げられる。
本発明における口腔内崩壊型製剤においては、服用性の観点から賦形剤として水溶性賦形剤の添加が好ましい。水溶性賦形剤としては、服用の際良好な甘味を有する水溶性糖アルコール、糖類、甘味を有するアミノ酸類及びこれらの混合物が挙げられ、好ましくは水溶性糖アルコール、糖類、グリシン及びこれらの混合物が挙げられ、特に好ましくは水溶性糖アルコールが挙げられる。
2.商品名コーンスターチ(XX16)W(日本食品化工株式会社)
3.商品名プルーブ(Penwest Pharmaceuticals社(米国))
4.商品名黄色三二酸化鉄(癸巳化成化成株式会社)
5.商品名三二酸化鉄(キシ化成株式会社)
6.商品名精製脱砒酸化チタン(ザクトレーベンケミエ社(ドイツ))
7.商品名3-t-ブチル-4-ヒドロキシアニソール(ナカライテスク株式会社)
8.商品名2,6-ジ-t-ブチル-p-クレゾール(ナカライテスク株式会社)
9.商品名食用黄色5号(三栄源エフ・エフ・アイ株式会社)
10.商品名食用黄色5号アルミニウムレーキ(三栄源エフ・エフ・アイ株式会社)
11.商品名食用赤色5号(三栄源エフ・エフ・アイ株式会社)
12.商品名食用赤色102号(三栄源エフ・エフ・アイ株式会社)
実施例1〜3および比較例1〜8に関しては表1の処方に従い、処方の12倍量の各成分を乳鉢にてよく混合した後、1錠処方量を秤取して油圧式プレス機(理研製)を用いて50kgfの圧力で圧縮し、直径7mmの錠剤を得た。
実施例1〜3および比較例1〜8の製剤について光安定性試験を実施した。蛍光灯4000ルクス×2週間における外観及び酸化体の生成量の結果を表2に示す。なお、酸化体(2-[(2-アミノエトキシ)メチル]-4-(o-クロロフェニル)-6-メチル-3,5-ピリジンジカルボン酸 3-エチルエステル 5-メチルエステル)の定量は液体クロマトグラフ法により分析した。
HPLC分析法
カラム:オクタデシル基結合型シリカゲル(平均粒径5μm、内径4.6×長さ150mm)(ナカライテスク株式会社 商品名COSMOSIL 5C18)
A液:30mmol/Lリン酸塩緩衝液(pH6.0)/メタノール混液(1:1)
B液:メタノール/30mmolリン酸緩衝液(pH6.0)混液(19:1)
B液:80%→0%のグラジェント
検出器:UV
検出波長:237nm
Claims (16)
- (a) ベシル酸アムロジピン、(b) 酸化鉄、並びに(c) ソルビトール、マルチトール、キシリトール、エリスリトール、及びリン酸水素カルシウムからなる群より選ばれる少なくとも一つの賦形剤を含有し、かつ被覆層を有しない経口固形組成物(但し、マンニトールを含まない組成物である)。
- 酸化チタンを含有しない経口固形組成物である、請求項1に記載の経口固形組成物。
- 口腔内崩壊型製剤である、請求項1又は2記載の経口固形組成物。
- さらに、(d) デンプンを含有する、請求項1〜3いずれか記載の経口固形組成物。
- (d) デンプンがトウモロコシデンプンである、請求項4記載の経口固形組成物。
- さらにフマル酸ステアリルナトリウムを含有する、請求項1〜5いずれか記載の経口固形組成物。
- (a) ベシル酸アムロジピンの経口固形組成物中含量がアムロジピンとして2〜5重量%であり、
(b) 酸化鉄の経口固形組成物中含量が0.03〜2重量%であり、
(d) デンプンの経口固形組成物中含量が2〜30重量%であり、かつ
(e) フマル酸ステアリルナトリウムの経口固形組成物中含量が1〜3重量%である、
請求項6記載の経口固形組成物。 - 酸化鉄が黄色三二酸化鉄である、請求項1〜7いずれか記載の経口固形組成物。
- (a) ベシル酸アムロジピン、および(b) 酸化鉄の混合物を含有する、請求項1〜8いずれか記載の経口固形組成物。
- (a) ベシル酸アムロジピン、および(b) 酸化鉄の混合物を造粒して得られる組成物を含有する、請求項1〜9いずれか記載の経口固形組成物。
- ベシル酸アムロジピンとソルビトール、マルチトール、キシリトール、エリスリトール、及びリン酸水素カルシウムからなる群より選ばれる少なくとも一つの賦形剤とを含有する経口固形組成物の調製に際して、酸化鉄を配合することを特徴とする、請求項1〜10いずれか記載の経口固形組成物の製造方法(但し、マンニトールを含む組成物の場合を除く)。
- 経口固形組成物が口腔内崩壊型製剤である、請求項11記載の製造方法。
- 酸化鉄が黄色三二酸化鉄である、請求項11又は12記載の製造方法。
- 請求項1〜10いずれか記載の経口固形組成物の調製における、光による変色が抑制された組成物とするための酸化鉄の使用。
- 経口固形組成物が口腔内崩壊型製剤である、請求項14記載の使用。
- 酸化鉄が黄色三二酸化鉄である、請求項14又は15記載の使用。
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