JP2018519279A - イリノテカン含有経口用固形製剤及びその製造方法 - Google Patents
イリノテカン含有経口用固形製剤及びその製造方法 Download PDFInfo
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- JP2018519279A JP2018519279A JP2017564664A JP2017564664A JP2018519279A JP 2018519279 A JP2018519279 A JP 2018519279A JP 2017564664 A JP2017564664 A JP 2017564664A JP 2017564664 A JP2017564664 A JP 2017564664A JP 2018519279 A JP2018519279 A JP 2018519279A
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- Prior art keywords
- acid
- solid preparation
- irinotecan
- acidifying agent
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- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
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- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
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- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
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- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
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- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
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- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 description 1
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Abstract
Description
下記表1のような組成で、まずイリノテカン塩酸塩三水和物(Dongwoo Fine-Chem、韓国)、乳糖及び微結晶セルロースを予備混合(pre-mixing)し、ポビドンを、エタノール及び水の混合物(エタノール:水=7:3)に溶解させた結合液に、酸性化剤として、クエン酸、乳酸または酢酸を加えて溶解させて酸性化された結合液を加え、練合して乾燥させた後、約20メッシュシーブでシービングし、イリノテカン湿式顆粒を製造した。
下記表2のような組成で、前記実施例1と同一方法で製造するが、酸性化剤としてクエン酸を使用し、その量だけ異ならせ、実施例4ないし6の錠剤を製造した。
下記表3のような組成で、前記実施例1と同一方法で製造するが、酸性化剤を使用しないか(比較例1)、あるいは酸性化剤の代わりに、塩基性化剤である炭酸カルシウム(比較例2)またはメグルミン(比較例3)を使用することを除いては、同一方法で比較例1ないし3の錠剤を製造した。
実施例1ないし6、及び比較例1,2,3で得られた錠剤に対して、米国薬典(USP)溶出試験項目のパドル法により、精製水900mlを利用して溶出試験を実施した。試験開始30分後に、溶出試験液のpHを測定して下記表4に示した。
実施例1ないし6、及び比較例1,2,3で得られた錠剤に対して、米国薬典(USP)溶出試験項目のパドル法により、精製水900mlを利用して溶出試験を実施した。試験開始後30分、溶出試験液サンプルを採取し、以下のような条件で、液体クロマトグラフィを実施し、それぞれのサンプルについて、イリノテカン塩酸塩溶出率を計算し、下記表5及び図1に示した。
−カラム温度:30℃
−試料注入量:20μL
−移動相:0.005mol/Lの1−ヘプタンスルホン酸ナトリウムを含んだメタノール:pH4.0酢酸・酢酸ナトリウム緩衝液の混合液(11:9)
−流速:1.0mL/分
−検出器:紫外部吸光光度計(測定波長254nm)
前記実施例1,2,3,4,5,6及び比較例1,2,3で製造したイリノテカンの製剤に対して、保管安定性を評価するために、未知関連物質及び総関連物質の生成量を測定した。測定方法は、下記表6に示した。前記製剤をHDPE(high-density polyethylene)ビン包装した後、保管安定性を予測するための経時変化を観察するために、60℃チャンバに保管し、2週後、4週後、関連物質の生成量を測定した。測定結果を下記表7,8及び図2,3に示した。
Claims (14)
- イリノテカン、またはその薬学的に許容可能な塩;及び酸性化剤を含む経口投与用固形製剤。
- 前記酸性化剤がカルボン酸基(COOH)またはスルホン酸基(SO3H)を含むC2−C20有機酸であることを特徴とする請求項1に記載の固形製剤。
- 前記酸性化剤が、酢酸、アジピン酸、クエン酸、アスコルビン酸、エリソルビン酸、乳酸、プロピオン酸、酒石酸、フマル酸、ギ酸、シュウ酸、カンシル酸、リンゴ酸、マレイン酸、エジシル酸、パルミチン酸、ステアリン酸、及びそれらの任意の組み合わせからなる群から選択されることを特徴とする請求項2に記載の固形製剤。
- 前記酸性化剤は、酢酸、クエン酸、乳酸、及びそれらの任意の組み合わせからなる群から選択されることを特徴とする請求項2に記載の固形製剤。
- 前記固形製剤に対して、米国薬典(USP)溶出試験項目のパドル法により、精製水900mlを利用して溶出試験を実施するとき、30分後溶出液のpHが、約1ないし5を示すことを特徴とする請求項1に記載の固形製剤。
- 前記酸性化剤が、イリノテカン、またはその薬学的に許容可能な塩1重量部に対して、約0.2ないし10重量部の量で含まれることを特徴とする請求項1に記載の固形製剤。
- 前記固形製剤は、顆粒剤、カプセル剤または錠剤であることを特徴とする請求項1に記載の固形製剤。
- 希釈剤、結合剤、崩壊剤、滑沢剤、及びそれらの任意の組み合わせからなる群から選択された薬剤学的に許容される添加剤をさらに含むことを特徴とする請求項1に記載の固形製剤。
- 固形製剤総量を基準に、前記希釈剤が、約20ないし80重量%、前記結合剤が、約1ないし10重量%、前記崩壊剤が、約2ないし7重量%、または前記滑沢剤が、約0.5ないし5重量%の量で含まれることを特徴とする請求項8に記載の固形製剤。
- 前記固形製剤は、米国薬典(USP)溶出試験項目のパドル法により、精製水900mlを利用しての溶出試験時、30分以内に、約80%以上の活性成分の溶出率を示すことを特徴とする請求項1に記載の固形製剤。
- 癌治療用であることを特徴とする請求項1に記載の固形製剤。
- イリノテカン、またはその薬学的に許容可能な塩、希釈剤、及び結合剤を含む顆粒を製造する製粒段階と、
前記製粒された顆粒を、崩壊剤及び滑沢剤と混合する後混合段階と、
選択的に、前記後混合して得られた混合物を製剤化する製剤化段階と、を含み、
前記製粒段階及び/または後混合段階で酸性化剤を付加する、請求項1ないし11のうちいずれか1項に記載の経口用固形製剤の製造方法。 - 前記製粒段階は、湿式顆粒法または乾式顆粒法によって遂行されることを特徴とする請求項12に記載の製造方法。
- 前記湿式顆粒法は、イリノテカン、またはその薬学的に許容可能な塩、及び希釈剤を含む混合物を、結合剤を含む結合液と練合して製粒し、酸性化剤を、前記混合物及び/または結合液に付加して混合することを特徴とする請求項13に記載の製造方法。
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