JP5670335B2 - ベンダムスチン液体製剤 - Google Patents
ベンダムスチン液体製剤 Download PDFInfo
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- JP5670335B2 JP5670335B2 JP2011529180A JP2011529180A JP5670335B2 JP 5670335 B2 JP5670335 B2 JP 5670335B2 JP 2011529180 A JP2011529180 A JP 2011529180A JP 2011529180 A JP2011529180 A JP 2011529180A JP 5670335 B2 JP5670335 B2 JP 5670335B2
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- formulation
- bendamustine
- aqueous
- cancer
- pharmaceutically acceptable
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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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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- 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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Description
ベンダムスチン凍結乾燥粉末の水戻しは、時間がかかり面倒である。さらに工業規模での固形物の凍結乾燥は特殊な装置を必要とし、かなりのコストが発生する。したがって、凍結乾燥および/または水戻しを必要としないベンダムスチンの製剤形態が求められている。
不活性ガス雰囲気下で調製された無水プロピレングリコール中のベンダムスチン塩酸塩の溶液が報告されている(旧東ドイツ特許第159289号明細書)。薄層クロマトグラフィー、ブタノール/酢酸/水(4:1:5)での溶出、およびDragendorff試薬とUV(360nm)検出を使用したこれらの溶液の分析は、いかなる分解も示唆しないことが報告されている。しかし興味深いことに、プロピレングリコール製剤の商業的開発は、今まで報告されていない。したがってベンダムスチンの改善された液体製剤が依然として必要である。
この出願の発明に関連する先行技術文献情報としては、以下のものがある(国際出願日以降国際段階で引用された文献及び他国に国内移行した際に引用された文献を含む)。
【先行技術文献】
【特許文献】
【特許文献2】 旧東独国特許発明第159289号明細書
【特許文献3】 米国特許第5162115号明細書
【特許文献4】 国際公開第2009/120386号明細書
【特許文献5】 米国特許第4670262号明細書
【特許文献6】 米国特許第5162115号明細書
【特許文献7】 米国特許第5204335号明細書
【特許文献8】 米国特許第5227373号明細書
【特許文献9】 米国特許第5750131号明細書
【特許文献10】米国特許第5770230号明細書
【特許文献11】米国特許第5776456号明細書
【特許文献12】米国特許第5955504号明細書
【特許文献13】米国特許第5972912号明細書
【特許文献14】米国特許第6034256号明細書
【特許文献15】米国特許第6077850号明細書
【特許文献16】米国特許第6090365号明細書
【特許文献17】米国特許第6271253号明細書
【特許文献18】米国特許第6380210号明細書
【特許文献19】米国特許出願公開第2002/0102215号明細書
【特許文献20】米国特許第6492390号明細書
【特許文献21】米国特許第6545034号明細書
【特許文献22】米国特許第6569402号明細書
【特許文献23】米国特許第6573292号明細書
【特許文献24】米国特許第6613927号明細書
【特許文献25】米国特許出願公開第2003/0232874号明細書
【特許文献26】米国特許出願公開第2004/0053972号明細書
【特許文献27】米国特許出願公開第2004/0058956号明細書
【特許文献28】米国特許出願公開第2004/072889号明細書
【特許文献29】米国特許出願公開第2004/0096436号明細書
【特許文献30】米国特許出願公開第2004/152672号明細書
【特許文献31】米国特許出願公開第2004/0247600号明細書
【特許文献32】米国特許出願公開第2005/0020615号明細書
【特許文献33】米国特許出願公開第2005/0060028号明細書
【特許文献34】米国特許出願公開第2005/0176678号明細書
【特許文献35】米国特許出願公開第2006/0051412号明細書
【特許文献36】米国特許出願公開第2006/0159713号明細書
【特許文献37】米国特許出願公開第2011/0190363号明細書
【特許文献38】独国特許発明第80967号明細書
【特許文献39】***国特許第159289号明細書
【特許文献40】***国特許第159877号明細書
【特許文献41】***国特許第293808号明細書
【特許文献42】欧州特許出願公開第293808号明細書
【特許文献43】国際公開第96/28148号明細書
【特許文献44】独国特許発明第10016077号明細書
【特許文献45】国際公開第03/066027号明細書
【特許文献46】独国特許発明第10306724号明細書
【特許文献47】国際公開第03/081238号明細書
【特許文献48】欧州特許出願公開第1354952号明細書
【特許文献49】国際公開第03/086470号明細書
【特許文献50】国際公開第03/094990号明細書
【特許文献51】独国特許発明第10304403号明細書
【特許文献52】欧州特許出願公開第1444989号明細書
【特許文献53】国際公開第2006/076620号明細書
【特許文献54】国際公開第2009/120386号明細書
【特許文献55】国際公開第2010/036702号明細書
【非特許文献】
【非特許文献2】 Barman Balfour et al., "Bendamustine", Drugs, 2001, 61(5), 631−638, Auckland, New mckimZealand
【非特許文献3】 Bremer, Karl, "High rates of long−lasting remissions after 5−day bendamustine chemotherapy cycles in pre−treated low−grade non−hodgkin 's−lymphomas", Journal of Cancer Research and Clinical Oncology, 2002, 128(11), 603−609
【非特許文献4】 Chow et al., "Anti−CD20 antibody (IDEC−C2B8, rituximab) enhances efficacy of cytotoxic drugs on neoplastic lymphocytes in vitro: role of cytokines complement, and caspases", Haematologica, January 2002, 87(1), 33−43
【非特許文献5】 Chow et al., "In AML Cell Lines Ara−C Combined with Purine Analogues is Able to Exert Synergistic as Well as Antagonistic Effects on Proliferation, Apoptosis and Disruption of Mitochondrial Membrane Potential", Leukemia & Lymphoma, 2003, 44(1), 165−173
【非特許文献6】 Chow et al., "In vitro induction of apoptosis of neoplastic cells in low−grade non−Hodkin's lymphomas by combinations of established cytotoxic drugs with bendamustine", Haematologica, May 2001, 86(5), 485−493
【非特許文献7】 Chow et al., "Synergistic effects of chemotherapeutic drugs in lymphoma cells are associated with down−regulation of inhibitor of apoptosis proteins (IAPs), prostate−apoptosis−response−gene 4 (Par−4), death−associated protein (Dazz) and with enforced caspase activation", Biochemical Pharmacology, January 2003, 66(5), 711−724
【非特許文献8】 Diehl et al., "Bendamustine in the Treatment of Hematologic Malignancies", Semin. Oncol., August 2002, 29(4), 1−3, Suppl. 13, Saundes, Philadelphia, PA
【非特許文献9】 Fichtner et al., "Antineoplastic activity and toxicity of some alkylating cytostatics (cyclophosphamide, CCNU, cytostasan) encapsulated in liposomes in different murine tumor models", Journal of Microencapsulation, January 1986, 3(2), 77−87
【非特許文献10】 Gandhi, Varsha, "Metabolism and mechanisms of action of bendamustine: Rationales for combination therapies", Seminars in Oncology, August 2002, 29(4), 4−11, Suppl. 13
【非特許文献11】 Gust et al., "Investigations on the Stability of Bendamustin, a Cytostatic Agent of the Nitrogen Mustard Type, I. Synthesis, Isolation, and Characterization of Reference Substances", Monatshefte fur Chemie, 1997, 128(3), 291−299
【非特許文献12】 Heider et al., "Efficacy and toxicity of bendamustine in patients with relapsed low−grade non−Hodgkin's lymphomas", Anti−Cancer Drugs, 2001, 12(9), 725−729
【非特許文献13】 International Patent Application No. PCT/US2009/058023: International Search Report dated February 8, 2010, 4 pages
【非特許文献14】 Kath et al., "Bendamustine monotherapy in advanced and refractory chronic lymphocytic leukemia", Journal of Cancer Research and Clinical Oncology, 2001, 127(1), 48−54
【非特許文献15】 Koenigsman et al., "Fludarabine and Bendamustine in Refractory and Relapsed Indolent Lymphoma a Multicenter Phase IIII Trial of the East German Society of Hematology and Oncology (OSHO)", Leukemia & Lymphoma, 2004, 45(9), 1821−1827
【非特許文献16】 Kollmannsberger et al., "Phase II study of bendamustine in patients with relapsed or cisplatin−refractory germ cell cancer", Anti−Cancer Drugs, 2000, 11(17), 535−539
【非特許文献17】 Konstantinov et al., Cytotoxic efficacy of bendamustine in human leukemia and breast cancer eel/lines", Journal of Cancer Research and Clinical Oncology, 2002, 128(5), 271−278
【非特許文献18】 Koster et al., "Carboplatin in combination with bendamustine in previously untreated patients with extensive−stage small lung cancer (SCLC)", Clinical Drug Investigation, 2004, 24(10), 611−618
【非特許文献19】 Leoni et al., "Sdx−105 (Trenda), Active in Non−Hodgkins Lymphoma Cells, Induces the Mitotic Catastrophe Death Pathway", Blood, 104(11), 2004, Abs 4593, p. 232b
【非特許文献20】 Maas, "Stabilitat von Benamustinhydrochlorid in Infusionslosungen", Pharmazie, 1994, 49(10), 775−777
【非特許文献21】 McKim et al., "Dimethyl Sulfoxide USP, PhEur in Approved Pharmaceutical Products and Medical Devices," Pharmaceutical Technology, May 2, 2008, 1−7
【非特許文献22】 Mottu et al., "Organic solvents for pharmaceutical parenterals and embolic liquids: A review of toxicity data," PDA J. Pharma. Sci. & Tech. 54(6) Nov.−Dec. 2000, 456−469
【非特許文献23】 Niemeyer et al., "SDX−105 (bendamustine) is a clinically active chemotherapeutic agent with a distinct mechanism of action", Proc Annu meet Am Assoc Cancer, Res, March 2004, 45, 1st ed., 2 pages
【非特許文献24】 Nowak et al., "Upon Drug−Induced Apoptosis in Lymphoma Cells X−linked Inhibitor of Apoptosis (XIAP) Translocates from the Cytosol to the Nucleus", Leukemia & Lymphoma, July 2004, 45(7), 1429−1436
【非特許文献25】 Ponisch et al., "Bendamustine in the treatment of Multiple Myeloma: Results and future perspectives", Seminars in Oncology, August 2002, 29(4), 23−26, Suppl. 13.
【非特許文献26】 Preiss et al., "Pharmacokinetics of bendamustin (Cytostasan) in patients", Pharmazie, March 1985, 40(11), 782−784
【非特許文献27】 Ribomustin: Bendamustine Product Monograph, January 2002, 3−58, Ribosepharm GMBH, Munchen, Germany
【非特許文献28】 Ribomustin: Bendamustine Product Monograph, March 2005, 3−73 , Ribosepharm MBH, Munchen, Germany
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ベンダムスチンの安定した液体製剤が発見され、本明細書で報告される。
1−メチル−2−ピロリドン(NMP)、1,3−ジメチル−2−イミダゾリジノン(DMI)、ジメチルアセトアミド(DMA)、ジメチルスルホキシド(DMSO)、アセトン、テトラヒドロフラン(THF)、ジメチルホルムアミド(DMF)、および炭酸プロピレン(PC)をはじめとする溶剤について平衡状態溶解度を測定した。ベンダムスチン塩酸塩の溶解度はまた、DMA中の25mg/mLナイアシンアミド、および66%DMA/34%プロピレングリコール(PG)中の25mg/mLナイアシンアミドの2種の溶液についても測定した。ベンダムスチン塩酸塩の飽和溶液は各溶剤または溶液について三連で作成し、Lab−Quake上で穏やかな混合および低剪断により室温で3日間混合した。各懸濁液のサンプルを微小遠心管に入れ、Eppendorf微量遠心機上で10,000rpmで5分間遠沈させた。上清を取り出して清潔なバイアルに入れた。50%:50%のNMPと0.1%トリフルオロ酢酸の水溶液であるサンプル溶剤で、各溶液を希釈した。ベンダムスチン塩酸塩のための逆相法を使用して、標準から計算した各サンプル濃度を判定した。分析は希釈サンプル調製の18時間以内に実施した。溶解度を下の表Iに列挙する。各値は3つのサンプルの平均である。
4匹の(18〜23時間)絶食させた薬剤未感作オスのカニクイザルに、3種の異なる製剤から調製したベンダムスチン塩酸塩の3mg/kg単一ボーラス静脈内用量を逐次投与した。本研究で評価した製剤は、次のとおりであった。1)TREANDA(ベンダムスチン塩酸塩およびマンニトールの凍結乾燥混合物;25mg(ベンダムスチン塩酸塩))バイアル;2)66%ジメチルアセトアミド(DMA)/34%プロピレングリコール(PG)(w/w)溶液(90mg(ベンダムスチン塩酸塩)/mL原液);および3)100%のDMA溶液(45mg(ベンダムスチン塩酸塩)/mL原液)。用量投与の直前に、ベンダムスチン塩酸塩の凍結乾燥粉末および原液を必要に応じて0.9%食塩水で戻し、または希釈して3mg/mlのベンダムスチン塩酸塩溶液を得た。得られた溶液を1.0mL/kgの固定容積で、伏在静脈を通じてボーラスとして投与した。逐次用量を隔てる、少なくとも7日間の休薬期間があった。3つの投与相全てにおいて、投与直前および投与後12時間内のあらかじめ選択された時点で、ベンダムスチンおよびその2種の活性循環代謝産物であるγ−ヒドロキシベンダムスチン(M3)およびN−des−メチルベンダムスチン(M4)の薬物動態学的プロファイリングのための血液サンプルを大腿静脈を通じて収集した。タンデム質量分光測定の検出(LC−MS/MS)付きの検証済み高速液体クロマトグラフィー法を使用して、次のように血漿サンプル中のベンダムスチン、M3およびM4濃度を測定した。アセトニトリルを用いてタンパク質沈殿によって、血漿からベンダムスチン、M3、およびM4の代謝産物を抽出した。抽出後、等分したサンプルトを1%ギ酸で酸性化し、カルボン酸鎖中に1個の炭素が付加しているベンダムスチンを内部基準として添加した。サンプルを蒸発させて乾燥し、残留物をアセトニトリル/水/ギ酸/ギ酸アンモニウム混合物に溶解した。サンプルをLC/MS/MS検出付きのHPLCシステムに注入して、アセトニトリル/水/ギ酸/ギ酸アンモニウムを移動相としてPhenomenex Synergi Max−RPカラムを使用し、無隔壁法を用いて薬物動態学的分析を実施した。
0.9%塩化ナトリウム(500mLバッグ)中の混和材料を高用量(360mgベンダムスチン塩酸塩)で調製し、Zorbax Bonus−RPカラムを使用して、93%:7%の水中0.1%トリフルオロ酢酸(移動相A)とアセトニトリル中0.1%トリフルオロ酢酸(移動相B)から、10%:90%の移動相A/移動相Bへの勾配でHPLCを使用して、最高8時間まで室温で純度を経時的に判定した。
Claims (32)
- 癌を治療するための安定した非水液体医薬製剤であって、ベンダムスチンまたはその薬学的に許容できる塩と、極性非プロトン性溶剤とを有し、前記製剤は、癌の治療を必要とする患者への注射に適するように薬学的に許容できる注射可能な希釈剤で希釈されるものである製剤。
- 前記極性非プロトン性溶剤が、1−メチル−2−ピロリドン、1,3−ジメチル−2−イミダゾリジノン、ジメチルアセトアミド、ジメチルスルホキシド、アセトン、テトラヒドロフラン、1,4−ジオキサン、アセトニトリル、ジメチルホルムアミド、炭酸プロピレン、またはそれらの混合物である、請求項1に記載の製剤。
- 請求項1に記載の製剤であって、前記製剤は、さらに、
非水性極性プロトン性溶剤を含むものである製剤。 - 前記非水性極性プロトン性溶剤が、アルコール、ポリアルキレングリコール、アミド、またはそれらの混合物である、請求項3に記載の製剤。
- 前記製剤が製剤の90容積%以下の非水性極性プロトン性溶剤を含んでなる、請求項3に記載の製剤。
- 前記極性非プロトン性溶剤がジメチルアセトアミドであり、かつ前記非水性極性プロトン性溶剤がプロピレングリコールである、請求項3に記載の製剤。
- 請求項1に記載の製剤において、この製剤は、さらに、
薬学的に許容できる抗酸化剤を含むものである製剤。 - 約5mg/ml〜約200mg/mLのベンダムスチンまたはその薬学的に許容できる塩を含むものである、請求項1に記載の製剤。
- 前記製剤の分析によれば、前記製剤は、約5℃で少なくとも約180日間の保存条件に曝露される前に存在した量の約90%以上のベンダムスチンを含有することを示唆するものである、請求項1に記載の製剤。
- 前記製剤の分析によれば、前記製剤は、約5℃で少なくとも約180日間の保存条件に曝露される前に存在した量の約95%以上のベンダムスチンを含有することを示唆するものである、請求項1に記載の製剤。
- 請求項1および3のいずれか一項に記載の製剤において、この製剤は、さらに、
少なくとも1種の薬学的に許容できる賦形剤を含んでなる、製剤。 - 請求項1および3のいずれか一項に記載の製剤において、この製剤は、さらに、
抗酸化剤、界面活性剤、脂質、増量剤、有機酸、親水性ポリマー、錯化剤、保存料、またはそれらの組み合わせを含むものである、製剤。 - 前記製剤は、1Lあたり10モル若しくはそれ未満の非水性極性プロトン性溶剤を含むものである、請求項3に記載の製剤。
- 前記製剤は、1Lあたり約4.6モルの非水性極性プロトン性溶剤を含むものである、請求項3に記載の製剤。
- 前記製剤は、前記製剤の90体積%若しくはそれ未満の非水性極性プロトン性溶剤を含むものである、請求項3に記載の製剤。
- ベンダムスチンまたはその薬学的に許容できる塩を有する癌を治療するための安定した非水性の注射用製剤を調製する方法であって、
ベンダムスチンまたはその薬学的に許容できる塩と非水性溶剤とを有する非水液体医薬製剤を提供する工程と、
前記非水液体医薬製剤を薬学的に許容できる注射用希釈剤によって希釈する工程と
を有する方法。 - 前記非水性溶剤は極性非プロトン性溶剤である、請求項20に記載の方法。
- 前記極性非プロトン性溶剤は、1−メチル−2−ピロリドン、1,3−ジメチル−2−イミダゾリジノン、ジメチルアセトアミド、ジメチルスルホキシド、アセトン、テトラヒドロフラン、1,4−ジオキサン、アセトニトリル、ジメチルホルムアミド、炭酸プロピレン、またはそれらの混合物である、請求項21に記載の方法。
- 前記液体医薬製剤は、非水性極性プロトン性溶剤をさらに含むものである、請求項20に記載の方法。
- 前記非水性極性プロトン性溶剤は、アルコール、ポリアルキレングリコール、一級アミド、またはそれらの混合物である、請求項23に記載の方法。
- 前記薬学的に許容できる注射用希釈剤は塩化ナトリウム注射剤である、請求項20に記載の方法。
- 治療的有効量のベンダムスチンまたはその薬学的に許容できる塩と非水溶性溶媒とを有する非水液体医薬製剤を含む安定した非水薬学的製剤であって、前記非水液体医薬製剤は、薬学的に許容できる注入用希釈剤によって希釈され、癌治療用に使用されるものである、薬学的製剤。
- 請求項1記載の製剤において、前記癌は慢性リンパ球性白血病、ホジキン病、非ホジキンリンパ腫、多発性骨髄腫、または乳癌である、製剤。
- 請求項27記載の製剤において、前記癌は慢性リンパ球性白血病または非ホジキンリンパ腫である、製剤。
- 請求項20記載の方法において、前記癌は慢性リンパ球性白血病、ホジキン病、非ホジキンリンパ腫、多発性骨髄腫、または乳癌である、方法。
- 請求項29記載の方法において、前記癌は慢性リンパ球性白血病または非ホジキンリンパ腫である、方法。
- 請求項26記載の薬学的製剤において、前記癌は慢性リンパ球性白血病、ホジキン病、非ホジキンリンパ腫、多発性骨髄腫、または乳癌である、薬学的製剤。
- 請求項31記載の薬学的製剤において、前記癌は慢性リンパ球性白血病または非ホジキンリンパ腫である、薬学的製剤。
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US20210113530A1 (en) | 2021-04-22 |
EP2889029A1 (en) | 2015-07-01 |
AU2016247123A1 (en) | 2016-11-03 |
EP2326306A1 (en) | 2011-06-01 |
AU2009296734A1 (en) | 2010-04-01 |
US20120129904A1 (en) | 2012-05-24 |
AU2015207940B2 (en) | 2016-11-10 |
AU2016203246A1 (en) | 2016-06-09 |
JP2012503666A (ja) | 2012-02-09 |
AU2015207940A1 (en) | 2015-08-20 |
CN104224703A (zh) | 2014-12-24 |
AU2009296734B2 (en) | 2016-02-18 |
US20210008035A1 (en) | 2021-01-14 |
US20110190363A1 (en) | 2011-08-04 |
CA2735899A1 (en) | 2010-04-01 |
US8344006B2 (en) | 2013-01-01 |
US20130041004A1 (en) | 2013-02-14 |
US20180125824A1 (en) | 2018-05-10 |
US20140128443A1 (en) | 2014-05-08 |
WO2010036702A1 (en) | 2010-04-01 |
AU2016203246B2 (en) | 2017-09-21 |
CN102164579B (zh) | 2014-10-15 |
US20140206733A1 (en) | 2014-07-24 |
CN102164579A (zh) | 2011-08-24 |
HK1211462A1 (en) | 2016-05-27 |
US20140080881A1 (en) | 2014-03-20 |
MX2011002936A (es) | 2011-04-11 |
US20150335750A1 (en) | 2015-11-26 |
AU2018202107A1 (en) | 2018-04-19 |
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