JP6355645B2 - 活性成分としてテトラゾール誘導体を含む、溶解性が改善された固体分散体 - Google Patents
活性成分としてテトラゾール誘導体を含む、溶解性が改善された固体分散体 Download PDFInfo
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- JP6355645B2 JP6355645B2 JP2015547856A JP2015547856A JP6355645B2 JP 6355645 B2 JP6355645 B2 JP 6355645B2 JP 2015547856 A JP2015547856 A JP 2015547856A JP 2015547856 A JP2015547856 A JP 2015547856A JP 6355645 B2 JP6355645 B2 JP 6355645B2
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- 235000011002 L(+)-tartaric acid Nutrition 0.000 description 1
- FEWJPZIEWOKRBE-LWMBPPNESA-N L-(+)-Tartaric acid Natural products OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 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
- 241000124008 Mammalia Species 0.000 description 1
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- 235000021355 Stearic acid Nutrition 0.000 description 1
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- 229940045799 anthracyclines and related substance Drugs 0.000 description 1
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- 235000010338 boric acid Nutrition 0.000 description 1
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- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
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- 238000010586 diagram Methods 0.000 description 1
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- 210000002889 endothelial cell Anatomy 0.000 description 1
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- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
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- 125000005456 glyceride group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
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- OSILBMSORKFRTB-UHFFFAOYSA-N isoquinolin-1-amine Chemical group C1=CC=C2C(N)=NC=CC2=C1 OSILBMSORKFRTB-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
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- 239000002075 main ingredient Substances 0.000 description 1
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- 239000004530 micro-emulsion Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
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- 239000003960 organic solvent Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Chemical group COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 208000016691 refractory malignant neoplasm Diseases 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- BAZAXWOYCMUHIX-UHFFFAOYSA-M sodium perchlorate Chemical compound [Na+].[O-]Cl(=O)(=O)=O BAZAXWOYCMUHIX-UHFFFAOYSA-M 0.000 description 1
- 229910001488 sodium perchlorate Inorganic materials 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229930192474 thiophene Chemical group 0.000 description 1
- 229950004288 tosilate Drugs 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
Images
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Description
本発明は、活性成分としてテトラゾール誘導体を含む、溶解性が改善された固体分散体に関し、より特定的には、活性成分として式(I)のテトラゾール誘導体またはその薬学的に許容可能な塩を含む非晶質固体分散体と、これを含む医薬製剤とに関する。
式(I)の以下のテトラゾール誘導体およびその薬学的に許容可能な塩は、癌細胞における多剤耐性に対して阻害活性を有するp−糖タンパク質阻害剤として公知である(韓国特許第10−0557093号を参照)。
P−糖タンパク質は、胃腸管などの内皮細胞において発見されるものであって、いくつかの薬剤の経口吸収を制限することが知られている。パクリタキセル、ドセタキセルなどの主要な抗癌剤のうちのいくつかは、経口投与された場合、P−糖タンパク質の作用のせいで、身体にほとんど吸収させることができない(シンケル(Schinkel)他、「細胞(Cell)」、77号、491〜502頁、1994年)。抗癌治療における重大な問題のうちの1つとして、癌細胞における抗癌剤に対する耐性の発現が挙げられる。中でも、最も重大な問題は、P−糖タンパク質の過剰発現によってもたらされる多剤耐性(MDR:multi-drug resistance)である。一般的に、抗癌剤の使用が増えるのに応じて癌細胞におけるMDRが高まり、これが、癌生存率を実質的に低下させる原因因子となる。
したがって、本発明の目的は、上述のテトラゾール誘導体およびその薬学的に許容可能な塩の溶解性および生体内吸収率を向上させることである。
mおよびnは各々が独立して0〜4の整数であり、
XはCH2、OまたはSである。
以下に本発明を詳細に説明する。
表1に列挙された成分に従って、活性成分としてHM30181A;水溶性高分子としてヒプロメロースP−645;賦形剤としてシリケートを、塩化メチレン(MC:methylene chloride)、エタノール(EtOH:ethanol)および蒸留水(DW:distilled water)からなる混合溶液中において完全に溶解および分散させ、次いで、結果として得られた溶液を小型の噴霧乾燥器B−290(Buchi;スイス(Switzerland))を用いて噴霧乾燥させることによって、実施例1〜6の固体分散体を調製した。
表2に列挙された成分に従って、活性成分としてHM30181A;酸としてリン酸、DL−リンゴ酸、クエン酸、L(+)−酒石酸、フマル酸またはシュウ酸;および水溶性高分子としてヒプロメロースP−645を、MC、EtOHおよびDWからなる混合溶液中において完全に溶解および分散させ、次いで、結果として得られた溶液を噴霧乾燥器を用いて噴霧乾燥させることによって、実施例7〜13の固体分散体を調製した。
表3に列挙された成分に従って、活性成分としてHM30181A;酸としてリン酸;および水溶性高分子としてヒプロメロースP−645を、MC、EtOHおよびDWからなる混合溶液中において完全に溶解および分散させ、次いで、結果として得られた溶液を、噴霧乾燥器を用いて噴霧乾燥させることによって固体分散体を調製した。
表5に列挙された成分に従って、活性成分としてHM30181A;酸性の可溶化剤としてリン酸;水溶性高分子としてヒプロメロースP−645;賦形剤としてD−マンニトール;崩壊剤としてクロスポビドン;賦形剤として軽質無水ケイ酸;および潤滑剤としてフマル酸ステアリルナトリウムを混合し、次いで、結果として得られた混合物を錠剤化することによって、比較例1の錠剤を調製した。
固体分散体に最も適した溶媒を見つけ出すために、過剰量のHM30181Aを活性成分として溶媒に追加し、2時間振り混ぜ、次いで、結果として得られた混合物を遠心分離機にかけ、HPLCによって分析して溶解性を測定した。溶解度試験のために用いられた溶媒は、MC、メタノール、EtOH、ヘキサン、ジエチルエーテル、イソプロピルアルコール、アセトンおよびDWであった。結果を表6に示す。
実施例1〜6において調製された固体分散体は、150mgのHM30181Aに対応する適量の各サンプルを用いることによって、溶解について分析された。次いで、溶解性が比較された。
−溶出溶媒:蒸留水を900mL
−テストシステム:サンプル容器を100rpmで回転
−温度:37℃
<分析条件>
−カラム:LC(5μmの直径)のためにオクタデシルシリルシリカゲルが充填されたステンレス鋼カラム(約4.6mmの内径および15cmの長さ)
−移動相:アセトニトリル:pH2.5の緩衝剤(56:44)
−カラム温度:40℃
−流量:1.0mL/分
−注入量:10μL
*pH2.5の緩衝剤:7.0gの過塩素酸ナトリウム(NaClO4)および1.7gのリン酸二水素カリウム(KH2PO4)を900mLの蒸留水に溶解させ、これにリン酸を加えてpHを2.5に調節し、次いで、蒸留水を加えて総容積を1Lとした。
実施例7〜13において調製された固体分散体は、試験実施例2において記載されたのと同じ条件下で、150mgのHM30181Aに対応する適量の各サンプルを用いることによって、溶解について分析された。結果を図2に示す。
CuX線、40kVおよび100mAの条件下で、6°/分の走査速度で、M18XHF−SRA(Macsciences株式会社;日本)を用いることによって、活性成分、すなわちHM30181Aと、実施例8の固体分散体とについてのX線回折パターンが決定された。
実施例1〜13の固体分散体の平均粒度は、4.5バール条件下でR1レンズを備えたHELOS/BR(Sypatec(ドイツ(Germany))を用いたレーザー回折によって測定された。
比較例1および実施例14において調製された錠剤は、溶解について分析され、比較された。
−溶出溶媒:蒸留水を900mL
−テストシステム:100rpmで攪拌
−温度:37℃
<分析条件>
試験実施例2の条件と同じである。
Claims (12)
- 固体分散体がさらに水溶性高分子を含む、請求項1に記載の非晶質固体分散体。
- 水溶性高分子が、ヒプロメロース、ヒドロキシプロピルセルロース、ポリビニルピロリドン、ポリビニルアセタール、ジエチルアミノアセテート、ポリエチレングリコールおよびそれらの混合物からなる群から選択される、請求項2に記載の非晶質固体分散体。
- 水溶性高分子は、活性成分の1重量部を基準として0.1〜4重量部の量で含まれる、請求項2に記載の非晶質固体分散体。
- 固体分散体は酸を含む、請求項1に記載の非晶質固体分散体。
- 酸は、リン酸、塩酸、硫酸、硝酸、酢酸、ホウ酸などの無機酸、ならびに、クエン酸、リンゴ酸、酒石酸、乳酸、トシラート、コハク酸、アスコルビン酸、グルタミン酸、アルギン酸、マレイン酸、アジピン酸などの有機酸からなる群から選択される、請求項5に記載の非晶質固体分散体。
- 酸は、活性成分の1重量部を基準として0.1〜3重量部の量で含まれる、請求項5に記載の非晶質固体分散体。
- 固体分散体の平均粒径が150μm未満である、請求項1に記載の非晶質固体分散体。
- 請求項1に記載の固体分散体を含む医薬組成物。
- 医薬組成物が癌細胞における多剤耐性を低減させるために用いられる、請求項9に記載の医薬組成物。
- 請求項1に記載の固体分散体および抗癌剤を含む医薬組成物。
- 抗癌剤は、パクリタキセル、ドセタキセル、ビンクリスチン、ビンブラスチン、ビノレルビン、ダウノマイシン、ドキソルビシン、トポテカン、イリノテカン、アクチノマイシンおよびエトポシドからなる群から選択される、請求項11に記載の医薬組成物。
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EP3761961A4 (en) * | 2018-03-07 | 2022-01-05 | Andrew Xian Chen | AQUEOUS FORMULATIONS FOR INSOLUBLE DRUGS |
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WO2022011221A1 (en) | 2020-07-10 | 2022-01-13 | Teva Czech Industries S.R.O | Solid state forms of n-[2-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-2(1h)-isoquinolinyl)ethyl]phenyl}-2h-tetrazol-5-yl)-4,5-dimethoxyphenyl]-4-oxo-4h-chromene-2-carboxamide mesylate salt |
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KR20230104185A (ko) * | 2020-10-30 | 2023-07-07 | 아테넥스 알앤디, 엘엘씨 | Hm30181 메실레이트의 다형성(polymorphisms of hm30181 mesylate) |
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