JP5529762B2 - 活性化一酸化窒素ドナーならびにその作製および使用方法 - Google Patents
活性化一酸化窒素ドナーならびにその作製および使用方法 Download PDFInfo
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- JP5529762B2 JP5529762B2 JP2010549867A JP2010549867A JP5529762B2 JP 5529762 B2 JP5529762 B2 JP 5529762B2 JP 2010549867 A JP2010549867 A JP 2010549867A JP 2010549867 A JP2010549867 A JP 2010549867A JP 5529762 B2 JP5529762 B2 JP 5529762B2
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/655—Azo (—N=N—), diazo (=N2), azoxy (>N—O—N< or N(=O)—N<), azido (—N3) or diazoamino (—N=N—N<) compounds
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- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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Description
本願は、2008年3月7日に出願された米国仮特許出願第61/034,617号明細書に対する優先権を主張する。本願は、その教示内容のすべてに対して、その全体が参照により本明細書に援用される。
本発明に至る研究は、国立衛生研究所(National Institutes of Health)助成金番号RO1 CA129611によって一部資金提供を受けた。米国政府は、本発明における特定の権利を有する場合がある。
抗癌処置にとって有用な医薬組成物が本明細書中に記載される。組成物は、インビボでNOを被検体に送達するのに有用である。NOは、微生物および腫瘍細胞の成長に対する宿主の免疫防御に寄与する強力な細胞毒素である(Moncada S.ら (1991年) Pharmacological Reviews 43:109−142頁;(Nathan C. (1992年) FASEB Journal 6:3051−3064頁)。実際、NOは、インビトロで腫瘍細胞に対して強力な細胞毒性を示す(Rangei−Yagui C.O.ら (2005年) J.Pharm.Pharma.Sci.8(2):147−63頁)。NOは、AML細胞において、成長を阻害し、分化およびアポトーシスを誘導する(Magrinal G.ら (1992年) Blood 80:1980−1986頁;Shami P.J.ら (1995年) Leukemia Research 19;527−533頁;Shami P.J.ら (1998年) Leukemia 12:1461−1466頁)。NOは、複数の細胞内標的を有し、細胞成長を阻害しうるため、標的送達の場合、抗新生物剤として使用するための非常に魅力的な分子である(Henry Y.ら (1993年) FASEB Journal 7:1124−1134頁);17−28頁)。これらの機序および標的は、(スーパーオキシドの存在下でペルオキシ亜硝酸を生成することによる)タンパク質チロシンニトロソ化、タンパク質チオールニトロシル化、ADPリボシル化、ミトコンドリア呼吸の阻害、リボヌクレオチドレダクターゼの阻害、タンパク質グルタチオン化、およびDNA鎖破壊の誘導を含む(Henry Y.ら (1993年) FASEB Journal 7:1124−1134頁);17−28頁)。
ジアゼニウムジオレートは、N2O2官能基を有する化合物である。米国特許第6,610,660号明細書に開示されるO2−アリール置換ジアゼニウムジオレートおよびそれを調製するための方法は、本明細書中で使用してもよく、その教示内容は参照により援用される。一態様では、O2−アリール置換ジアゼニウムジオレートは、式Iを有する。
本明細書において有用な両親媒性物質は、ミセルまたはリポソームを形成することが可能な親水性および親油性基を有する化合物である。両親媒性物質は、最小の毒性を有するように生体適合性である必要がある。リポソームおよびミセルを調製するための、本明細書において有用な両親媒性物質は、生体適合性かつ生体分解性の物質から生成されるホモポリマー、共重合体、ブロック共重合体を含む。かかるポリマーの例として、限定はされないが、ポリ(アミノ酸);ポリ乳酸;ポリ(エチレンイミン);ポリ(メタクリル酸2−(ジメチルアミノ)エチル)(poly(dimethylaminoethylmethacrylates))、ポリエチレングリコールとヒドロキシアルキルアクリレートとアクリルアミドの共重合体(例えばN−(2−ヒドロキシプロピル)メタクリルアミド)、PEG−β−ポリ(α−アミノ酸)、ポリ(L−乳酸)−ポリ(エチレングリコール)ブロック共重合体、またはポリ(L−ヒスチジン)−ポリ(エチレングリコール)ブロック共重合体が挙げられる。
HO(C2H4O)b(C3H6O)a(C2H4O)bOH
(式中、aは、10〜100、20〜80、25〜70、もしくは25〜70、または50〜70であり;bは、5〜250、10〜225、20〜200、50〜200、100〜200、または150〜200である)を有する。別の態様では、ポロキサマーは、2,000〜15,000、3,000〜14,000、または4,000〜12,000の分子量を有する。本明細書において有用なポロキサマーは、BASFによって製造される商標名Pluronic(登録商標)の下で販売されている。本明細書において有用なポロキサマーの非限定例として、限定はされないが、表1に記載のものが挙げられる。
本明細書中に記載の組成物は、O2−アリール置換ジアゼニウムジオレートと両親媒性物質とを、溶媒中、適切な濃度で混合し、ミセルまたはリポソームを生成することにより、容易に調製することが可能である。特定の態様では、O2−アリール置換ジアゼニウムジオレートおよび両親媒性物質は、水中で混合され、次いで加熱によってミセルを生成する。O2−アリール置換ジアゼニウムジオレートおよび両親媒性物質の量は、変化しうる。一態様では、両親媒性物質の量は、臨界ミセル濃度(CMC)が低下するのに十分である必要がある。臨界ミセル濃度(CMC)は、上部でミセルが自発的に形成される界面活性剤の濃度として定義される。表1は、両親媒性物質として本明細書において有用なポロキサマーのCMCを提供する。特定の態様では、使用される両親媒性物質の濃度は、両親媒性物質のCMCより数倍高い可能性がある。O2−アリール置換ジアゼニウムジオレートに加え、追加的な生物活性剤をミセルまたはリポソームに取り込むことが可能であると考えられる。例えば、本態様では、下記の他の抗癌剤を本明細書で使用してもよい。
一態様では、本明細書中に記載の組成物のいずれかを少なくとも1つの薬学的に許容されるキャリアと組み合わせることで、医薬組成物を生成することが可能である。医薬組成物は、当該技術分野で公知の技術を用いて調製してもよい。一態様では、組成物は、組成物を薬学的に許容されるキャリアと混合することによって調製される。用語「混合する(admixing)」は、化学反応または物理的相互作用が全く生じないように、2つの成分を共に混合することとして定義される。用語「混合する」はまた、式Iを有する化合物と薬学的に許容されるキャリアとの間の化学反応または物理的相互作用を含む。
本明細書中に記載の組成物は、有効な抗癌剤である。化学療法剤に耐性がある腫瘍細胞は、臨床腫瘍学における主要な課題を示す。本発明の方法および組成物を使用し、細胞成長を阻害するか、細胞分化を誘発するか、アポトーシスを誘発するか、MDR表現型を阻害するか、転移を阻害するか、血管新生を阻害するかまたはそれ以外に腫瘍細胞の悪性表現型を無効にするかもしくは低下させるため、「標的」細胞を、本明細書中に記載の1種以上の組成物と接触させる。特定の態様では、O2−アリールジアゼニウムジオレート化合物と少なくとも1種の他の作用剤から構成される組成物を投与してもよい。本明細書中に記載の組成物は、化学および放射線療法の有効性を改善することが可能である。1つのアプローチは、本明細書中に記載の組成物を化学または放射線治療的介入と併用することを含む。この処置のオプションは、DNA損傷剤と共にコンビナトリアルな治療的効果を提供しうる。さまざまな癌治療剤およびかかる作用剤を使用する処置の方法は、当該技術分野で周知である。
本実施例は、ミセル中でのJS−Kの負荷の範囲について例示する。JS−Kを、Pluronic(登録商標)P123およびL121ポリマー中に負荷し、ミセルを形成した。溶液中のJS−K対Pluronic(登録商標)ポリマーの割合は10重量%であった。次いで、JS−Kミセル調製物を2時間透析した。遊離JS−Kを用いた同じ手順に従う並行実験を対照として設定した。透析の2時間後、JS−KレベルをHPLCによって測定し、保持されるJS−Kのパーセントを評価した。遊離JS−Kのパーセント保持は、Pluronic(登録商標)P123およびL121ミセルの各々におけるJS−Kについての75±10%および78±11%と比べて31%に過ぎなかったが、それについては図2を参照のこと。結果は、ミセル調製物中のJS−Kが透析後に保持される一方、遊離JS−Kは透析の間に大部分が失われることを示した。
本実施例は、Pluronic(登録商標)ミセルに対する濾過の効果について例示する。JS−KはP123ミセル中に負荷された(溶液中のJS−K対Pluronic(登録商標)ポリマーは1.57重量%であった)。次いで、一定分量のJS−K調製物を0.2μMの膜フィルタを通して濾過し、室温で保持した。一定間隔で、調製物からの20μLの一定分量を回収し、JS−KレベルをHPLCによって測定した。濾過されていないP123 Pluronic(登録商標)ミセル中の類似のJS−K調合物に対して並行測定を行った。測定されたJS−Kレベルは経時的に低下した。結果は、濾過ミセルと未濾過ミセルの間にJS−K濃度における差異が全くないことを示し、これはこれらのミセルが分解されることなく濾過されうることを示唆しており、それについては図3を参照のこと。
本実施例は、Pluronic(登録商標)ミセルがGSHの存在下でJS−Kを安定化させることを例示する。これらの実験では、Pluronic(登録商標)P−123ミセル中で調合された遊離JS−KおよびJS−Kを、pH7.4および室温で、PBS中、4.0mM GSHとともに、10mMの濃度でインキュベートした。溶液中のJS−K対Pluronic(登録商標)ポリマーの割合は1.57重量%であった。一定間隔で、JS−KレベルをHPLCによって測定した。これらの条件下で、遊離JS−Kは、GSHの存在下で6分間の半減期を有した。同じ条件下、GSHの存在下でのP−123ミセル中のJS−Kは、37分間の半減期を有した。これらの結果は、Pluronic(登録商標)ミセルが、GSHによって表される遊離チオールによる求核攻撃の極めてストリンジェントな条件下で、JS−Kの半減期を実質的に(P−123の場合には6倍)延長することを示す。
本実施例は、血清中、Pluronic(登録商標)ミセル中での遊離JS−K対JS−Kの安定性について例示する。JS−Kを、L121およびP123 Pluronic(登録商標)ミセル中に負荷した。溶液中のJS−K対Pluronic(登録商標)ポリマーの割合は0.98重量%であった。次いで、Pluronic(登録商標)JS−Kを、8mLの全容量でFBSとともに37℃でインキュベートした。JS−Kの最終濃度は100μMであった。FBSの最終濃度は90% v/vであった。pHは7.6であった。対照を、同じ濃度での遊離JS−Kを使用し、同じ条件下で設定した。1mLの一定分量を一定間隔で採取した。ジクロロメタン抽出後、JS−Kレベルを、上で概説したプロトコルを用いるHPLCによって測定した。実験を2通りに行い、測定値を使用し、血清中の異なるJS−Kの調合物の半減期を計算した。
本実施例では、Pluronic(登録商標)ミセル中のJS−Kの粒子サイズおよびpH効果を測定する。Malvern 3000 Zetasizer(Malvern Instruments(Worstershire,UK))を使用する動的光散乱を用い、異なるpH条件下、JS−Kを有する場合と有しない場合とでPluronic(登録商標)P123ミセルの粒子サイズを測定した。3mLの体積のPBS中の4つの別々の試料に対し、測定を行った。1つの実験セットでは、(JS−Kを有しない)P123ミセルに対し、4.5〜7.4の範囲の異なるpH条件下で行った。室温で4時間の平衡化後、粒子サイズを測定した。凝集は全く認められず、これはミセルの完全性が保持されることを示した。表2における結果は、pHがP123 Pluronic(登録商標)ミセルのサイズ(ひいては安定性)に影響を与えないことを示す。
本実施例では、Pluronic(登録商標)ミセル中でのJS−Kのインビトロ細胞毒性を試験した。上記のように、JS−Kを、F68、P105、またはF127 Pluronic(登録商標)ミセル中に負荷した。溶液中のJS−K対Pluronic(登録商標)ポリマーの割合は4重量%であった。次いで、遊離JS−KまたはミセルJS−Kを、0.5μMの濃度でHL−60細胞に加えた。同様の対照実験を、等しい濃度の、JS−Kを有しない各Pluronic(登録商標)ミセルで設定した。3日のインキュベーション後、細胞成長を、MTSアッセイを使用して測定した。遊離JS−Kは、白血病細胞の成長を62%阻害した(図4)。F68ミセルはJS−Kの細胞毒性効果を増大させなかった一方、P105またはF127ミセル中に調合したJS−Kは細胞成長をそれぞれ約90%阻害した(図4)。等しい濃度(0.08% w/v)での等価な空のミセルは細胞成長に対する有意な効果を全く有さなかった(示さない)。
本実施例は、全身血圧に対するPluronic(登録商標)ミセル中のJS−Kの効果について例示する。JS−Kを、Pluronic(登録商標)P123ミセルに負荷し、インビボ実験において使用し、JS−KのPluronic(登録商標)ミセル調製物が全身血圧に対するJS−Kの効果に作用するか否かを判定した。溶液中のJS−K対Pluronic(登録商標)ポリマーの割合は1.53重量%であった。
本実施例は、Pluronic(登録商標)ミセル中のJS−Kのインビボでの抗白血病活性について例示する。NOD/SCID IL2Rγnullマウスの各横腹に、5×106個のHL−60細胞を接種した。腫瘍が触知可能になったとき、処置を、1−空のPluronic(登録商標)P123ミセルを注射した対照(マウス4匹);2−遊離JS−Kを注射したマウス(マウス3匹);および3−Pluronic(登録商標)P123ミセル中に調合されたJS−Kを注射したマウス(マウス3匹)のような3つの変数の場合で開始した。溶液中のJS−K対Pluronic(登録商標)ポリマーの割合は2.0重量%であった。注射を、静脈内に1週につき3回与えた。遊離JS−Kおよびミセルに調合されたJS−Kの用量は4μモル/kgであった。ミセルに調合されたJS−Kでの処置は、腫瘍成長において遊離薬剤より大きい遅延をもたらした。SAS PROC MIXEDを用いる線形混合モデルを、ランダム効果を用いて図8におけるデータに適合させ、同じ動物内での測定値間での相関を明らかにした。このモデルでは、時間の一次および二次効果によって適合させた腫瘍成長の速度は、遊離JS−Kで処置した動物中では、Pluronic(登録商標)P123ミセル中に調合されたJS−Kで処置した動物より有意に高いことが判明した(F検定によるとp=0.01)。
インビトロでの異なる媒体中でのJS−Kの安定性を評価した。JS−Kを、Pluronic(登録商標)P123ミセル中に、2.25%のJS−K対P123の比で負荷した。ミセルに可溶化されたJS−Kまたは遊離JS−Kを、それぞれ50および10μモルの濃度で、異なる媒体中で、37℃でインキュベートした。遊離JS−Kは、その溶解性に限界があるため、より低い濃度を使用した。異なる媒体中のJS−Kの濃度を、高圧液体クロマトグラフィ−(HPLC)を用い、最大で60分間の間隔で測定した。曲線下面積(AUC)HPLCの測定値を使用し、異なる媒体中のJS−Kの半減期(T1/2)およびパーセント回復(percent recovery)を判定した。遊離JS−Kおよびミセルに可溶化されたJS−Kは、10%ウシ胎仔血清を有するRPMI媒体に加えたとき、それぞれ9.6+/−1.3分間および53.4+/−1.96分間のT1/2を有した(6つの別々の実験の平均およびSEM、P=0.00004)(図9)。遊離およびミセルに可溶化されたJS−Kの、RPMI/10%FBS中での60分間のインキュベーション後におけるパーセント回復は、10.53+/−1.42および50.71+/−8.27であった(6つの別々の実験の平均およびSEM、P=0.0001)。遊離JS−Kおよびミセルに可溶化されたJS−Kは、プールされたヒト血漿に加えたとき、それぞれ26+/−0分間および80+/−3分間のT1/2を有した(2つの別々の実験の平均およびSEM、P=0.0353)(図9)。遊離およびミセルに可溶化されたJS−Kの、プールされたヒト血漿中での60分間のインキュベーション後におけるパーセント回復は、39+/−0および59.5+/−1.5であった(2つの別々の実験の平均およびSEM、P=0.05)(図9)。
Claims (12)
- (a)O 2−(2,4−ジニトロフェニル)1−[(4−エトキシカルボニル)ピペラジン−1−イル]ジアゼン−1−イウム−1,2−ジオレート(JS-K)又はその医薬として許容される塩若しくはエステル;及び
(b)以下の式:
HO(C 2 H 4 O) b (C 3 H 6 O) a (C 2 H 4 O) b OH
{式中、aが50〜80であり、そしてbが10〜50である}
を有するポロキサマー
を混合するステップを含む方法によって生成される組成物であって、
ポロキサマーの量がミセルを生成するのに十分である、前記組成物。 - 前記ポロキサマーが、Pluronic(登録商標)P123である、請求項1に記載の組成物。
- aが50〜70であり、そしてbが10〜25である、請求項1に記載の組成物。
- JS−Kの量が、前記ミセルの0.98質量%であるか、又はそれ未満である、請求項1に記載の組成物。
- JS−Kの量が、前記ミセルの0.52質量%であるか、又はそれ未満である、請求項1に記載の組成物。
- 請求項1に記載の組成物及び医薬として許容される担体を含む、医薬組成物。
- 請求項1〜6のいずれか一項に記載の組成物を含む、癌治療用の医薬組成物。
- 請求項1〜6のいずれか一項に記載の組成物を含む、癌細胞の殺傷するための医薬組成物。
- 請求項1〜6のいずれか一項に記載の組成物を含む、癌細胞の成長を予防又は低減するための医薬組成物。
- 前記癌が、前立腺、白血病、骨髄増殖性障害、骨髄異形成症候群、リンパ腫、睾丸癌、頭頸部癌、食道癌、胃癌、肝癌、小腸癌、胆嚢癌、直腸癌、肛門癌、肉腫、子宮癌、頸癌、膀胱癌、骨肉腫、腎癌、メラノーマ、結腸癌、卵巣癌、肺癌、中枢神経系癌、多発性骨髄腫、皮膚癌、または乳癌を含む、請求項7〜9のいずれか1項に記載の組成物。
- 前記組成物が低血圧を誘発しない、請求項7〜9のいずれか1項に記載の組成物。
- 前記組成物が、非経口、経口、皮下、病巣内、腹腔内、静脈内、または筋肉内に投与用である、請求項7〜9のいずれか一項に記載の組成物。
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JP2011513424A (ja) | 2011-04-28 |
EP2262478B1 (en) | 2014-11-05 |
CA2717867A1 (en) | 2009-09-17 |
US20110182978A1 (en) | 2011-07-28 |
WO2009114368A3 (en) | 2009-11-19 |
EP2262478A2 (en) | 2010-12-22 |
CN102014870A (zh) | 2011-04-13 |
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WO2009114368A2 (en) | 2009-09-17 |
KR20110005798A (ko) | 2011-01-19 |
CA2717867C (en) | 2017-05-30 |
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