JP6835746B2 - 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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- YYRMJZQKEFZXMX-UHFFFAOYSA-L calcium bis(dihydrogenphosphate) Chemical compound [Ca+2].OP(O)([O-])=O.OP(O)([O-])=O YYRMJZQKEFZXMX-UHFFFAOYSA-L 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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- 235000021317 phosphate Nutrition 0.000 description 1
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- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 235000002949 phytic acid Nutrition 0.000 description 1
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- 229940068041 phytic acid Drugs 0.000 description 1
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- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 208000026775 severe diarrhea Diseases 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
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- REFMEZARFCPESH-UHFFFAOYSA-M sodium;heptane-1-sulfonate Chemical compound [Na+].CCCCCCCS([O-])(=O)=O REFMEZARFCPESH-UHFFFAOYSA-M 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 description 1
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Classifications
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
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- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
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- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A61K9/2004—Excipients; Inactive ingredients
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- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
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- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Cosmetics (AREA)
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 (10)
- イリノテカン塩酸塩三水和物;及び、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酸性化剤を含む経口投与用固形製剤。
- 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、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、イリノテカン塩酸塩三水和物1重量部に対して、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、20ないし80重量%、前記結合剤が、1ないし10重量%、前記崩壊剤が、2ないし7重量%、または前記滑沢剤が、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5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、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。
- イリノテカン塩酸塩三水和物、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し、
前記製粒段階は、湿式顆粒法によって遂行され、
前記酸性化剤は、酢酸、クエン酸、乳酸、及びこれらの任意の組み合わせからなる群から選択される、請求項1ないし8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。 - 前記湿式顆粒法は、イリノテカン塩酸塩三水和物、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9に記載の製造方法。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR10-2015-0093413 | 2015-06-30 | ||
KR1020150093413A KR102293907B1 (ko) | 2015-06-30 | 2015-06-30 | 이리노테칸 함유 경구용 고형제제 및 그 제조방법 |
PCT/KR2016/006513 WO2017003120A1 (en) | 2015-06-30 | 2016-06-20 | Oral solid formulation containing irinotecan and method of preparing the same |
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KR102293907B1 (ko) * | 2015-06-30 | 2021-08-26 | 한미약품 주식회사 | 이리노테칸 함유 경구용 고형제제 및 그 제조방법 |
KR102066402B1 (ko) * | 2017-12-22 | 2020-01-15 | 대화제약 주식회사 | 이리노테칸 또는 그의 약제학적으로 허용가능한 염을 포함하는 경구투여용 약제학적 조성물 |
KR102185475B1 (ko) * | 2019-06-20 | 2020-12-02 | 대화제약 주식회사 | 이리노테칸 자유 염기를 포함하는 경구투여용 약학 조성물 |
KR102444073B1 (ko) * | 2020-01-06 | 2022-09-16 | (주)휴온스 | 안정성이 향상된 메틸에르고메트린말레산염 함유 약제학적 제제 및 이의 제조방법 |
KR20220006776A (ko) * | 2020-07-09 | 2022-01-18 | 주식회사유한양행 | 다이아미노피리미딘 유도체 또는 이의 약학적으로 허용가능한 염을 포함하는 약학 조성물 및 이의 제조방법 |
KR20230048032A (ko) * | 2020-08-06 | 2023-04-10 | 에스케이바이오팜 주식회사 | 카바메이트 화합물을 포함하는 경구용 고형 제제 및 이의 제조방법 |
CN116964044A (zh) | 2020-10-07 | 2023-10-27 | 希华医药有限公司 | 乙酰胺基-苯基四唑衍生物及其使用方法 |
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CA2973906C (en) * | 2014-01-17 | 2022-07-26 | Oncoral Pharma Aps | Solid oral dosage form of irinotecan for the treatment of cancer |
KR102293907B1 (ko) * | 2015-06-30 | 2021-08-26 | 한미약품 주식회사 | 이리노테칸 함유 경구용 고형제제 및 그 제조방법 |
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