JP2018524320A - カルボプラチンベースの共結晶の医薬組成物及びその用途 - Google Patents
カルボプラチンベースの共結晶の医薬組成物及びその用途 Download PDFInfo
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- MBWXNTAXLNYFJB-NKFFZRIASA-N phylloquinone Chemical compound C1=CC=C2C(=O)C(C/C=C(C)/CCC[C@H](C)CCC[C@H](C)CCCC(C)C)=C(C)C(=O)C2=C1 MBWXNTAXLNYFJB-NKFFZRIASA-N 0.000 description 1
- 239000002897 polymer film coating Substances 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0086—Platinum compounds
- C07F15/0093—Platinum compounds without a metal-carbon linkage
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- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/267—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
【選択図】なし
Description
式中、nは、1〜12から選択される整数であり、n≧2であるとき、環状アミド上の炭素原子は、単結合又は二重結合によって連結され、R1,R2、及びR3は、互いに同じであるか、又は異なり、各々が独立して水素、ハロゲン、アミノ基、C1−C6アルキル基、C3−C6シクロアルキル基、シアニド基、ヒドロキシル基、アシル基、ホスホリル基、ホスホロアミド基、ヒドロキシカルボキシル基、フェニル基、又は脂肪族基を表わす。
式中、Rは、水素、ハロゲン、アミノ基、C1−C6アルキル基、C3−C6シクロアルキル基、シアニド基、ヒドロキシル基、アシル基、ホスホリル基、ホスホロアミド基、ヒドロキシルカルボキシル基、フェニル基、又は脂肪族基を表わす。
共結晶CBP−NMPは、ドセタキセル及びシスプラチン(前立腺がん患者のために広く許容される薬剤)と比較して前立腺がんの治療において試験された。
細胞培養:前立腺がん細胞株LNCaP及びPC−3は、ATCC(Manassas,VA)から購入された。胎児肝細胞HL−7002及びヒト胚腎臓細胞HEK393は、ATCCから購入された。細胞は、RPMI+5%胎児ウシ血清(FBS)で培養された。
PC−3(骨転移を有する進行した前立腺がん患者由来の細胞株)に対して、CBP−NMPは、ドセタキセルより優れた細胞毒性を示したが、シスプラチンより弱かった。LNCaP(リンパ節転移を有する進行した前立腺がん患者由来の細胞株)に対して、CBP−NMPの細胞毒性は、ドセタキセル及びシスプラチンより弱い。HL−7002(不死化ヒト胎児肝細胞株)に対して、CBP−NMPは、低いレベルの細胞毒性を有することが検出されたが、ドセタキセル及びシスプラチンよりずっと弱かった。HEK293(不死化ヒト胎児腎臓細胞株)に対して、CBP−NMPは、低いレベルの細胞毒性を有することが検出されたが、ドセタキセル及びシスプラチンよりずっと弱かった。
共結晶CBP−NMPは、オキサリプラチン及びフルオロウラシル(5−FU)(大腸がん患者を治療する際に広く使用される薬剤)と比較して大腸がんの治療で試験された。
細胞培養:大腸がん細胞株HCT−116及びHT−29は、ATCC(Manassas,VA)から購入された。胎児肝細胞HL−7002及びヒト胚腎臓細胞HEK393は、ATCCから購入された。細胞は、RPMI+5%胎児ウシ血清(FBS)で培養された。
大腸がん細胞株HCT−116に対して、CBP−NMPは、オキサリプラチン及び5−FUより弱い毒性を示した。大腸がん細胞株HT−29に対して、CBP−NMPは、オキサリプラチンより少し弱い毒性を示し、5−FUより弱い毒性を示した。HL−7002(不死化ヒト胎児肝細胞株)に対して、CBP−NMPは、低いレベルの毒性を有することが検出された。HEK293(不死化ヒト胚腎臓細胞株)に対して、CBP−NMPは、低いレベルの毒性を有することが検出された。
本発明の共結晶は、共結晶形成体としてのカルボプラチン及び環状アミドから形成された。包括的な共結晶スクリーニングは、スラリー/攪拌、加熱及び冷却、回転式蒸発、凍結乾燥、冷却、及び蒸発によって実施された。
X線粉末回折(XRPD):偏光顕微鏡写真は、室温(RT)で撮影された。X線強度データは、Bruker APEX II CCD回折計(MoKα放射線、λ=0.71073Å)を使用して296(2)Kで収集された。XRPDパターンは、RTでPanalytical Empyreanシステムによって収集された。F2に対して直接法構造解、差分フーリエ計算、及び完全行列最小二乗精密化が、SHELXTL及びOLEX2で実施された(Sheldrick GM.,Acta Crystallogr A,64:112−122,2008;及びO.V.Dolomanovら,J.Appl.Cryst.42,339−341,2009;及びBrandenburg,K.DIAMOND,1999,Crystal Impact GbR,Bonn,Germany参照)。分子グラフィックスは、Brandenburg,K.DIAMOND,1999,Crystal Impact GbR,Bonn,ドイツに従って作られた。
DSCは、試料の温度を上昇させるために必要な熱の量の差を測定するための熱分析方法として使用された。参照は、温度の関数として測定された。DSCの一般的なプロセスは、公知である。以下の実施例で使用された特定の機器及び条件は、以下の通りである:
分析機器:TA Instruments Q2000 DSC;
加熱速度:10℃/分;及び
パージガス:窒素。
TGAは、(一定の加熱速度での)上昇する温度の関数としての、又は(一定の温度及び/又は一定の質量損失での)時間の関数としての、試料の物理的及び化学的特性の変化を測定するために使用された。TGAの一般的なプロセスは、公知である。以下の実施例で使用された特定の機器及び条件は、以下の通りである:
分析機器:TA Instruments Q5000 TGA;
加熱速度:10℃/分;及び
パージガス:窒素。
本発明の水性又は固体医薬組成物は、少なくとも一種の追加の治療薬又はアジュバント療法薬の適切な量を有して又は有さずに、有効量の本発明の共結晶(例えばCBP−NMP)を含む。共結晶、並びに治療薬又はアジュバント療法薬は、医薬的に許容可能な担体又は水性媒体中に溶解又は分散されることができる。
医薬組成物試料A:70gのCBP−NMPを予め処理された生理食塩水又は5%の水性グルコース(水中)に溶解し、溶液の最終体積を5.0Lに調整した。次いで、溶液を0.22μmフィルターで濾過し、アンプル瓶にそれぞれ50mLで分散した。
Claims (21)
- カルボプラチン(CBP)及び環状アミドを含む共結晶であって、環状アミドが、以下のものから選択される、共結晶:
式中、Rは、水素、ハロゲン、アミノ基、C1−C6アルキル基、C3−C6シクロアルキル基、シアニド基、ヒドロキシル基、アシル基、ホスホリル基、ホスホロアミド基、ヒドロキシルカルボキシル基、フェニル基、又は脂肪族基を表わす。 - 環状アミドが、式CF−05である、請求項1に記載の共結晶。
- 環状アミドが、N−メチル−2−ピロリドン(NMP)であり、カルボプラチンと環状アミドが、1:1の比で結合される、請求項1に記載の共結晶。
- 共結晶が、16.0°の回折角2−シータでのピーク及び24.5°±0.2の回折角2−シータでのピークを含むX線回折パターンを有する、請求項3に記載の共結晶。
- 共結晶の固体状態が、いかなる結晶多形形態も含む、請求項1〜3のいずれかに記載の共結晶。
- 請求項1〜5のいずれかに記載の共結晶の化合物を含む医薬組成物であって、カルボプラチンが活性医薬成分(API)である、医薬組成物。
- 共結晶が、いかなる結晶多形形態も有するか、又は非晶形態に作られている、請求項6に記載の医薬組成物。
- 少なくとも一種の治療薬又はアジュバント療法薬をさらに含む、請求項6又は7に記載の医薬組成物。
- 治療薬又はアジュバント療法薬が、葉酸、補酵素Q10、クルクミン、グルタチオン(GSH)、アロエ、オリザノール、5−フルオロウラシル、及びボルテゾミブからなる群から選択される、請求項8に記載の医薬組成物。
- 請求項6〜10のいずれかに記載の医薬組成物を対象に投与することを含む、対象における疾患をその必要において治療する方法であって、共結晶の化合物が、治療有効量である、方法。
- 疾患が、がんである、請求項10に記載の方法。
- がんが、前立腺がん、大腸がん、腎臓腺がん、及び白血病からなる群から選択される、請求項11に記載の方法。
- がんが、前立腺がんである、請求項12に記載の方法。
- がんが、大腸がんである、請求項12に記載の方法。
- がんが、腎臓腺がんである、請求項12に記載の方法。
- がんが、白血病である、請求項12に記載の方法。
- 疾患が、ウイルス感染である、請求項10に記載の方法。
- ウイルス感染が、B型肝炎ウイルス(HBV)、C型肝炎ウイルス(HCV)、ヒト免疫不全ウイルス(HIV)、又はハンターンウイルスによって起こされる、請求項16に記載の方法。
- 化合物の治療有効量が、約0.01〜約10mg/kg体重である、請求項10〜18のいずれかに記載の方法。
- 化合物の治療有効量が、約0.01〜約5mg/kg体重である、請求項10〜18のいずれかに記載の方法。
- 医薬組成物が、請求項4に記載の共結晶の化合物の有効量、及び医薬的に許容可能な担体又は水性媒体に溶解又は分散された少なくとも一種の治療薬又はアジュバント療法薬の医薬的に許容可能な量を含む水性組成物である、請求項10〜18のいずれかに記載の方法。
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CN107847508B (zh) | 2020-10-02 |
AU2016279099A1 (en) | 2018-01-04 |
US20180179240A1 (en) | 2018-06-28 |
EP3297636A1 (en) | 2018-03-28 |
EP3297636B1 (en) | 2021-02-17 |
US10421770B2 (en) | 2019-09-24 |
AU2016279099B2 (en) | 2021-09-23 |
BR112017027285A2 (pt) | 2018-09-11 |
WO2016205785A1 (en) | 2016-12-22 |
CA2988992A1 (en) | 2016-12-22 |
JP6768716B2 (ja) | 2020-10-14 |
KR20180018800A (ko) | 2018-02-21 |
EP3297636A4 (en) | 2018-11-14 |
CN107847508A (zh) | 2018-03-27 |
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