JP2018165280A - アントラサイクリン製剤 - Google Patents
アントラサイクリン製剤 Download PDFInfo
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- JP2018165280A JP2018165280A JP2018145172A JP2018145172A JP2018165280A JP 2018165280 A JP2018165280 A JP 2018165280A JP 2018145172 A JP2018145172 A JP 2018145172A JP 2018145172 A JP2018145172 A JP 2018145172A JP 2018165280 A JP2018165280 A JP 2018165280A
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- emch
- doxo
- cancer
- reconstituted
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- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A61K9/0012—Galenical forms characterised by the site of application
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
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Abstract
Description
アントラサイクリンとは、特定の型のストレプトマイセス属の細菌に由来する抗生物質のクラスである。アントラサイクリンは、がん治療薬として使用されることも多く、また、一部において、核酸インターカレート剤、およびDNA修復酵素トポイソメラーゼIIの阻害剤として機能し、それにより、がん細胞内の核酸に損傷を与え、その細胞の複製を防ぐ。アントラサイクリンがん治療薬の一例はドキソルビシンであり、これは、乳がん、肺がん、卵巣がん、リンパ腫、および白血病を含めた様々ながんを処置するために使用される。ドキソルビシンの6−マレイミドカプロイルヒドラゾン(DOXO−EMCH)は、ドキソルビシンと、腫瘍抗原に対するモノクローナル抗体との免疫コンジュゲートを調製するために使用することができる酸感受性リンカーをもたらすために元来合成されたものである(Willnerら、Bioconjugate Chem 4巻:521〜527頁(1993年))。この場合、抗体ジスルフィド結合はジチオスレイトールで還元されて遊離のチオール基を形成し、それが今度はDOXO−EMCHのマレイミド基と反応して安定なチオエーテル結合を形成する。投与されると、ドキソルビシン−抗体コンジュゲートは、当該抗体によって認識される抗原を含有する腫瘍にターゲティングされる。抗原−抗体結合の後、コンジュゲートは腫瘍細胞内に内部移行し、リソソームに輸送される。酸性のリソソーム環境では、酸感受性ヒドラゾンリンカーの加水分解によってドキソルビシンがコンジュゲートから細胞内に放出される。放出されると、ドキソルビシンは細胞核に到達し、その腫瘍細胞を死滅させることができる。ドキソルビシンおよびDOXO−EMCHに関する追加的な記載については、例えば、そのそれぞれの全体が参照により本明細書に組み込まれる、米国特許第7,387,771号および同第7,902,144号および米国特許出願第12/619,161号を参照されたい。
DOXO−EMCH内の酸により切断可能なリンカーの感受性に起因して、長期保管下で、ならびに再構成(例えば、予め凍結乾燥した組成物の)および投与の間に安定な製剤形態を有することが望ましい。DOXO−EMCHは、現行の製剤に使用される組成物、希釈剤および投与液体中に存在する場合、低温で保持されたときにのみ安定である。DOXO−EMCHをそのような温度に維持する必要性により、医師が低温(4℃)のDOXO−EMCH組成物を患者に投与することを強いられるという主要な問題が生じる。DOXO−EMCHを低温で維持することは、DOXO−EMCHを4℃で保持し、4℃で希釈して、患者への使用を不適当にさせる分解を予防することが必要であるという点で、その投与を複雑にする。さらに、4℃で投与することは、体温が有意に高い(37℃)患者にとって有害であり得る。
本発明は、アントラサイクリン化合物の再構成製剤および注射可能組成物を提供する。
例えば、本発明は、アントラサイクリン化合物と再構成液剤とを含む再構成製剤であって、このアントラサイクリン化合物の凍結乾燥組成物を、エタノールおよび水を含む再構成液剤で再構成することによって調製される再構成製剤を提供する。例示的な再構成製剤は、DOXO−EMCHと再構成液剤とを含む。
本発明は、例えば以下を提供する。
(項目1)
アントラサイクリン化合物と再構成液剤とを含む再構成製剤であって、該アントラサイクリン化合物の凍結乾燥組成物を、エタノールおよび水を含む再構成液剤で再構成することによって調製される、再構成製剤。
(項目2)
前記アントラサイクリン化合物がDOXO−EMCHである、項目1に記載の再構成製剤。
(項目3)
エタノール:水の体積比が約10:90〜約90:10である、項目1または項目2に記載の再構成製剤。
(項目4)
エタノール:水の体積比が約40:60〜約60:40である、項目3に記載の再構成製剤。
(項目5)
エタノール:水の体積比が約45:55〜約55:45である、項目4に記載の再構成製剤。
(項目6)
エタノール:水の体積比が約50:50である、項目5に記載の再構成製剤。
(項目7)
前記再構成製剤中の前記アントラサイクリン化合物の濃度が約1mg/mlから約30mg/mlまでである、項目1から項目6までのいずれか一項に記載の再構成製剤。
(項目8)
前記再構成製剤中の前記アントラサイクリン化合物の濃度が約5mg/mlから約25mg/mlまでである、項目7に記載の再構成製剤。
(項目9)
前記再構成製剤中の前記アントラサイクリン化合物の濃度が約10mg/mlである、項目8に記載の再構成製剤。
(項目10)
項目1から項目9までのいずれか一項に記載の再構成製剤と乳酸リンゲル液とを含む、アントラサイクリン化合物の注射可能組成物。
(項目11)
前記アントラサイクリン化合物がDOXO−EMCHである、項目10に記載の注射可能組成物。
(項目12)
前記注射可能組成物中の前記アントラサイクリン化合物の濃度が約0.1mg/mlから約25mg/mlまでである、項目10に記載の注射可能組成物。
(項目13)
前記注射可能組成物中の前記アントラサイクリン化合物の濃度が約7mg/mlから約17mg/mlまでである、項目10に記載の注射可能組成物。
(項目14)
前記注射可能組成物中の前記アントラサイクリン化合物の濃度が約0.1mg/mlから約5mg/mlまでである、項目10に記載の注射可能組成物。
(項目15)
前記注射可能組成物中の前記アントラサイクリン化合物の濃度が約0.25mg/mlから約4.5mg/mlまでである、項目14に記載の注射可能組成物。
(項目16)
前記注射可能組成物中の前記アントラサイクリン化合物の濃度が約2.4mg/mlである、項目15に記載の注射可能組成物。
(項目17)
患者におけるがんの処置において使用するための、項目1から項目9までのいずれか一項に記載の再構成製剤、または項目10から項目16までのいずれか一項に記載の注射可能組成物。
(項目18)
前記がんが、固形腫瘍がん、乳がん、肺がん、子宮体がん、卵巣がん、膵がん、副腎皮質のがん、非ホジキンリンパ腫、多発性骨髄腫、白血病、カポジ肉腫、ユーイング肉腫、軟部肉腫、腎芽腫、神経膠芽腫、前立腺がん、肝がん、骨がん、軟骨肉腫、腎がん、膀胱がん、および胃がんから選択される、項目17に記載の再構成製剤または注射可能組成物。
(項目19)
前記がんが固形腫瘍がんおよび軟部肉腫から選択される、項目18に記載の再構成製剤または注射可能組成物。
(項目20)
前記膵がんが膵管腺がんである、項目18に記載の再構成製剤または注射可能組成物。
(項目21)
患者におけるがんを処置するための医薬の製造における、項目1から項目9までのいずれか一項に記載の再構成製剤、または項目10から項目16までのいずれか一項に記載の注射可能組成物の使用。
(項目22)
前記がんが、固形腫瘍がん、乳がん、肺がん、子宮体がん、卵巣がん、膵がん、副腎皮質のがん、非ホジキンリンパ腫、多発性骨髄腫、白血病、カポジ肉腫、ユーイング肉腫、軟部肉腫、腎芽腫、神経膠芽腫、前立腺がん、肝がん、骨がん、軟骨肉腫、腎がん、膀胱がん、および胃がんから選択される、項目21に記載の使用。
(項目23)
前記がんが固形腫瘍がんおよび軟部肉腫から選択される、項目22に記載の使用。
(項目24)
前記膵がんが膵管腺がんである、項目22に記載の使用。
(項目25)
患者におけるがんを処置するための方法であって、項目1から項目9までのいずれか一項に記載の再構成製剤、または項目10から項目16までのいずれか一項に記載の注射可能組成物を患者に投与する工程を含む方法。
(項目26)
前記再構成製剤または前記注射可能組成物を静脈内に投与する、項目25に記載の方法。
(項目27)
前記がんが、固形腫瘍がん、乳がん、肺がん、子宮体がん、卵巣がん、膵がん、副腎皮質のがん、非ホジキンリンパ腫、多発性骨髄腫、白血病、カポジ肉腫、ユーイング肉腫、軟部肉腫、腎芽腫、神経膠芽腫、前立腺がん、肝がん、骨がん、軟骨肉腫、腎がん、膀胱がん、および胃がんから選択される、項目25または項目26のいずれか一項に記載の方法。
(項目28)
前記がんが固形腫瘍がんおよび軟部肉腫から選択される、項目27に記載の方法。
(項目29)
前記膵がんが膵管腺がんである、項目27に記載の方法。
(項目30)
アントラサイクリン化合物の再構成製剤を調製する方法であって、該アントラサイクリン化合物の凍結乾燥組成物を、エタノールおよび水を含む再構成液剤で再構成する工程を含む、方法。
(項目31)
前記アントラサイクリン化合物がDOXO−EMCHである、項目30に記載の方法。(項目32)
エタノール:水の体積比が約10:90〜約90:10である、項目30または項目31に記載の方法。
(項目33)
エタノール:水の体積比が約40:60〜約60:40である、項目32に記載の方法。
(項目34)
エタノール:水の体積比が約45:55〜約55:45である、項目33に記載の方法。
(項目35)
エタノール:水の体積比が約50:50である、項目34に記載の方法。
(項目36)
前記再構成製剤中の前記アントラサイクリン化合物の濃度が約1mg/mlから約30mg/mlまでである、項目25から項目35までのいずれか一項に記載の方法。
(項目37)
前記再構成製剤中の前記アントラサイクリン化合物の濃度が約5mg/mlから約25mg/mlまでである、項目36に記載の方法。
(項目38)
前記再構成製剤中の前記アントラサイクリン化合物の濃度が約10mg/mlである、項目37に記載の方法。
(項目39)
アントラサイクリン化合物の注射可能組成物を調製する方法であって、項目1から項目9までのいずれか一項に記載の再構成製剤を乳酸リンゲル液で希釈する工程を含む方法。
(項目40)
前記アントラサイクリン化合物がDOXO−EMCHである、項目39に記載の方法。(項目41)
前記注射可能組成物中の前記アントラサイクリン化合物の濃度が約1mg/mlから約25mg/mlまでである、項目39または項目40に記載の方法。
(項目42)
前記注射可能組成物中の前記アントラサイクリン化合物の濃度が約1mg/mlから約5mg/mlまでである、項目41に記載の方法。
(項目43)
前記注射可能組成物中の前記アントラサイクリン化合物の濃度が約7mg/mlから約17mg/mlまでである、項目42に記載の方法。
本明細書において特に定義されていなければ、本出願において使用される科学技術用語は当業者に一般に理解される意味を有するものとする。一般に、本明細書に記載されている化学、分子生物学、細胞およびがん生物学、免疫学、微生物学、薬理学、ならびにタンパク質および核酸化学に関連して使用される命名法ならびにその技法は当技術分野で周知であり、一般に使用されているものである。
本発明の化合物
再構成製剤
注射可能組成物
賦形剤
可溶化剤
緩衝液
pH調整剤
増量剤
界面活性物質
カプセル封入剤
張度調整剤
安定化剤
保護剤
粘度調整剤
疾患および/または状態の処置
注射可能組成物の投与
アントラサイクリン化合物製剤の調製および使用
アントラサイクリン化合物組成物の安定性
変更および改変
例証
等価物
溶液中でのDOXO−EMCHの挙動を分析するために、DOXO−EMCHおよび種々の不純物ならびに分解生成物を定量化するための逆相(RP)HPLC法を利用した。試料(注入量1.0μL)を、毎分0.3mLの流速でPhenomenex Gemini C18カラム、100×2.0mm、3μmに適合させたHPLC系においてアッセイした。使用した移動相は酢酸/アセトニトリル勾配であった。分解生成物EMCHは、上記のHPLC法を使用して検出することができず、したがって、液体クロマトグラフィー−質量分析(LC−MS)法を使用して決定した。
(実施例1)
Claims (1)
- 本明細書に記載の発明。
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US5977082A (en) | 1985-08-02 | 1999-11-02 | Pharmacia & Upjohn Company | Injectable ready-to-use solutions containing an antitumor anthracycline glycoside |
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JP2010526845A (ja) * | 2007-05-16 | 2010-08-05 | カーテーベー トゥモーアフォルシュングス ゲゼルシャフト ミット ベシュレンクテル ハフツング | 低粘度アントラサイクリン製剤 |
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"Anti-myeloma effects of the novel anthracycline derivative INNO-206", BLOOD, vol. 118, no. 21, JPN6017039798, 18 November 2011 (2011-11-18), pages 5107, ISSN: 0004328251 * |
新・薬剤学総論, vol. 改訂第3版, JPN6019036979, 10 April 1987 (1987-04-10), pages 326 - 335, ISSN: 0004328252 * |
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US20170340655A1 (en) | 2017-11-30 |
US10328093B2 (en) | 2019-06-25 |
JP2021120415A (ja) | 2021-08-19 |
EP2931042B1 (en) | 2021-04-28 |
CA2894548A1 (en) | 2014-06-19 |
HK1209973A1 (en) | 2016-04-15 |
CA2894548C (en) | 2021-01-12 |
DK2931042T3 (da) | 2021-06-07 |
JP6433913B2 (ja) | 2018-12-05 |
JP6833768B2 (ja) | 2021-02-24 |
EP2931042A4 (en) | 2016-06-01 |
JP7213303B2 (ja) | 2023-01-26 |
EP2931042A1 (en) | 2015-10-21 |
US20150342975A1 (en) | 2015-12-03 |
JP2021120414A (ja) | 2021-08-19 |
EP3915369A1 (en) | 2021-12-01 |
WO2014093815A1 (en) | 2014-06-19 |
AU2013359048A1 (en) | 2015-07-02 |
JP2016503026A (ja) | 2016-02-01 |
JP2019206583A (ja) | 2019-12-05 |
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