WO2022168967A1 - 新規なコポリマー - Google Patents
新規なコポリマー Download PDFInfo
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- WO2022168967A1 WO2022168967A1 PCT/JP2022/004592 JP2022004592W WO2022168967A1 WO 2022168967 A1 WO2022168967 A1 WO 2022168967A1 JP 2022004592 W JP2022004592 W JP 2022004592W WO 2022168967 A1 WO2022168967 A1 WO 2022168967A1
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- copolymer
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- optionally substituted
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Images
Classifications
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Abstract
Description
[1]次の式(A)、(B)及び(C)で示される構造単位を有するコポリマー。
[2]次の一般式(1)~(3):
で示される3種のモノマーの重合によって形成されるコポリマー。
[3]R1が水素原子である前記[1]又は[2]に記載のコポリマー。
[4]R2が水素原子である前記[1]~[3]のいずれかに記載のコポリマー。
[5]R3が水素原子である前記[1]~[4]のいずれかに記載のコポリマー。
[6]R4がメチル基である前記[1]~[5]のいずれかに記載のコポリマー。
[7]R5が置換基を有してもよいC6-18アリール基である前記[1]~[6]のいずれかに記載のコポリマー。
[8]R5がフェニル基である前記[1]~[7]のいずれかに記載のコポリマー。
[9]R6が、水素原子である前記[1]~[8]のいずれかに記載のコポリマー。
[10]R6の脱離基が、次式(4):
[11]R6のリンカーが、次式(5)~(7):
[12]X1が酸素原子である前記[1]~[11]のいずれかに記載のコポリマー。
[13]X2が酸素原子である前記[1]~[12]のいずれかに記載のコポリマー。
[14]X3が酸素原子である前記[1]~[13]のいずれかに記載のコポリマー。
[15]mが4~22の整数である前記[1]~[14]のいずれかに記載のコポリマー。
[16]nが1である前記[1]~[15]のいずれかに記載のコポリマー。
[17]構造単位(A)、(B)、(C)の比率が、(A)1質量部に対して、0.01~100質量部の(B)と、0.1~100質量部の(C)で構成されている前記[1]~[16]に記載のコポリマー。
[18]モノマー(1)の1質量部に対して、0.01~100質量部のモノマー(2)と、0.1~100質量部のモノマー(3)を重合させてなる前記[2]~[16]のいずれかに記載のコポリマー。
[19]数平均分子量が、5000~150000である前記[1]~[18]のいずれかに記載のコポリマー。
[20]前記[1]~[19]のいずれかに記載のコポリマーを含むsingle chain nanoparticle。
[21]前記[1]~[19]のいずれかに記載のコポリマーを含む医薬組成物。
本明細書において「ナノ粒子」とは、100nm以下の粒子径を示す構造体を指す。
X1は、酸素原子、硫黄原子又はN-R7を示すが、酸素原子、硫黄原子又はNHが好ましく、酸素原子がより好ましい。
mは1~100の整数を示すが、3~100の整数が好ましく、良好な親水性を付与する点から3~80が好ましく、4~60がより好ましく、4~40がさらに好ましく、4~22がよりさらに好ましい。
R4は、C1-3アルキル基を示し、具体的にはメチル基、エチル基、n-プロピル基又はイソプロピル基であり、メチル基又はエチル基が好ましく、メチル基がより好ましい。
X2は、酸素原子、硫黄原子又はN-R7を示すが、酸素原子、硫黄原子又はNHが好ましく、酸素原子がより好ましい。
nは0~3の整数を示すが、1~3の整数が好ましく、1がより好ましい。
R5は、水素原子、C1-18アルキル基、置換基を有してもよい3~8員シクロアルキル基、アダマンチル基、置換基を有してもよいC6-18アリール基又は置換基を有してもよい5~10員へテロアリール基を示すが、構造単位(B)に疎水性を付与する点から、C1-18アルキル基、置換基を有してもよい3~8員シクロアルキル基、アダマンチル基、置換基を有してもよいC6-18アリール基又は置換基を有してもよい5~10員へテロアリール基が好ましく、C1-18アルキル基、置換基を有していてもよい3~8員シクロアルキル基、アダマンチル基、置換基を有していてもよいC6-18アリール基又は置換基を有していてもよい5~10員へテロアリール基がより好ましく、C1-18アルキル基、3~8員シクロアルキル基、アダマンチル基又はC6-18アリール基がよりさらに好ましい。また一方で、置換基を有してもよい3~8員シクロアルキル基、アダマンチル基、置換基を有してもよいC6-14アリール基又は置換基を有してもよい6~10員へテロアリール基も好ましい。ここで、置換基としては、ハロゲン原子、炭素数1~6のアルキル基、炭素数2~6のアルケニル基及び炭素数2~6のアルキニル基から選ばれる1種又は2種以上が好ましい。
X3は、酸素原子、硫黄原子又はN-R7を示すが、酸素原子、硫黄原子又はNHが好ましく、酸素原子がより好ましい。
R6は、水素原子、脱離基又はリンカーを示す。この脱離基は、構造単位(C)が薬物(生理活性物質)と結合するときに脱離し得る基であり、リンカーは、構造単位(C)が薬物(生理活性物質)と結合するときに架橋に使用できる基である。これら脱離基又はリンカーとしては、置換基を有していてもよいC1-18アルキル基、置換基を有してもよい3~8員シクロアルキル基、置換基を有していてもよいC7-19アラルキル基が好ましい。ここで、置換基としては、例えば、ハロゲン原子、炭素数1~6のアルキル基、炭素数2~6のアルケニル基、炭素数2~6のアルキニル基、水酸基、炭素数1~6のアルコキシ基、アミノ基、炭素数1~6のアルキルアミノ基、アルキル基が同一又は異なるジ炭素数1~6のアルキルアミノ基、チオール基、炭素数1~6のアルキルチオ基、カルボキシル基、炭素数1~6のアルコキシカルボニル基、カルバモイル基等が挙げられる。これらの基のうち、リンカーとしては、置換基として、水酸基、アミノ基、チオール基、カルボキシル基などの官能基を有する基が好ましい。
R6の脱離基の好ましい具体例としては、次式(4):
R6の脱離基の好ましい具体例としては、次式(4):
本発明の医薬組成物において、薬物は、静電的相互作用、水素結合、疎水的相互作用又は共有結合といった作用等により、コポリマーに担持されていればよい。
(1)1-Ethoxyethyl acrylate(EEA)の合成
アルゴン雰囲気下にて、Ethyl vinyl ether(28.725mL)を秤取し、氷冷下にてPhosphoric acid(50mg)を加えた。その後、Acrylic acid(17.15mL)を加え、室温にて48時間攪拌した。Hydrotalcite(3g)を加えて、さらに2時間攪拌し、反応を停止した。セライトろ過後、エバポレーションにより、未反応のEthyl vinyl etherを除去した。重合禁止剤としてPhenothiazineを500ppmとなるように加え、水素化カルシウムと共に減圧蒸留することにより精製した(蒸留温度 28-32℃)。得られた1-Ethoxyethyl acrylateはガラスバイヤルに分取し、―30℃にて保管した。
13C NMR(400MHz,CDCl3),δ, ppm:15.29(-OCH2CH3), 21.16(-COOCH(CH3)), 64.98(-OCH2-), 96.73(-COOCH(CH3)), 128.84(CH2CH-), 131.43(CH2CH-), 166.00(-COO).
100mgの2-(Dodecylthiocarbonothioylthio)-2-methylpropionic acid(DDMAT)を秤取し、Toluene17.3mLに溶かしてDDMAT/Toluene stock solution(DDMAT濃度として5.78mg/mL)とした。同様に、22mgの2,2’-Azobis(2-methylpropionitrile)(AIBN)を秤取し,Toluene17.3mLに溶かしてAIBN/Toluene stock solution(AIBN濃度として1.27mg/mL)とした。別に、poly(ethylene glycol)methyl ether acrylate(mPEGA,エチレングリコールの繰り返し数の平均値(n)は9である。)1.296g、Benzyl acrylate(BnA)0.394g、1-Ethoxyethyl acrylate 0.039g、DDMAT/Toluene stock solution 1.73mL及びAIBN/Toluene stock solution 1.73mLを加え、70℃の油浴にて重合を行った。90分経過後、重合を停止した後、反応溶液を再沈殿法またはメタノールに対し透析することでコポリマーを回収した。得られたコポリマーは基本的に粘稠体であるため、再沈殿法については、貧溶媒(ヘキサン/酢酸エチル=7/3[v/v])を加えた遠沈管に反応溶液を滴下し、遠心分離(2,000×g、5min)により回収する操作を3回繰り返し、最終的に真空乾燥を行ない、poly[(benzyl acrylate)-co-(poly(ethylene glycol)methyl ether acrylate)-co-(1-ethoxyethyl acrylate)]を1.223g得た。
得られたコポリマーについて、NMRを用いて測定した1H-NMRスペクトルより各モノマーの重合度、並びに数平均分子量(Mn,NMR)を解析した結果、mPEGA(n=9)の重合度は102、BnAの重合度は94、EEAの重合度は9であり、Mn,NMRは65,900であった。さらに、得られたコポリマーについて、GPCを用いて、分子量分散度(Mw/Mn)を測定した結果1.53であった。
(1)1H-NMR測定
装置 :JNM-ECX400(400MHz)/日本電子
溶媒 :Dimethyl sulfoxide-d6 containing 0.03% tetramethylsilane/関東化学
試料濃度 :20mg/mL
測定温度 :25℃
積算回数 :256回
結果 :図1
(2)GPC測定
装置 :HPLC-Prominence system/島津製作所
検出器 :RID-10A Refractive index detector/島津製作所
カラム :TSKgel α-2500 column/東ソー
(カラムサイズ 7.8mm × 300mm,粒子径 7μm,
排除限界分子量 5 × 103)
TSKgel α-4000 column/東ソー
(カラムサイズ 7.8mm × 300mm,粒子径 10μm,
排除限界分子量 4 × 105)
TSKgel guardcolum/東ソー
移動相 :10mmol/Lの臭化リチウムを含有するN,N-dimethyformamide(DMF)
温度 :40℃
流速 :0.5mL/min
試料濃度 :6mg/mL
標準物質 :Poly(methyl methacrylate)standard ReadyCal set, Mp 800-2,200,000Da/SIGMA
結果 :図2
実施例1で用いたモノマー(mPEGA、BnA、EEA)の種類、仕込み量、反応温度、重合時間を適宜変更し、実施例1と同様の方法を用いることにより、下表に示す、組成比率や平均分子量の異なるポリマーを製造した。
poly[(benzyl acrylate)-co-(poly(ethylene glycol) methyl ether acrylate)-co-(acrylic acid)]の製造
実施例1で得たpoly[(benzyl acrylate)-co-(poly(ethylene glycol) methyl ether acrylate)-co-(1-ethoxyethyl acrylate)]を室温にて0.5N HClで処理することにより、ethoxyethyl基を脱離してカルボキシル基を有する3元共重合体1.176gを得た。得られた3元共重合体の水中におけるZ平均粒子径、並びに多分散指数を動的光散乱法(Dynamic light scattering,DLS)により測定した結果、8.5nm(多分散指数 0.14)であった。
(1)DLS測定
装置 :Zetasizer NanoZS/Malvern Instruments Ltd.
測定温度 :25℃
試料濃度 :10mg/mL
結果 :図3
(1,2-diaminocyclohexane)platinum(II)内包SCNPの製造方法
(1,2-diaminocyclohexane)platinum(II)(以下、DACHPtと略記する)のCl(H2O)体(DACHPt・Cl・H2O)65.28mgを精製水20mLに溶解し、70℃にて2時間撹拌した。この溶液5mLに対し、実施例69で得た3元共重合体287.4mgを添加し、50℃にて一晩撹拌した。撹拌終了後、反応溶液を、精製水を外液として透析精製し、DACHPt内包SCNPを5mL得た。精製後に得られたDACHPt内包SCNPのPt含量は誘導結合プラズマ発光分析(Inductively coupled plasma-atomic emission spectrometry,ICP-AES)により測定し、720μg/mL(DACHPtとして1.14mg/mL)であった。別途、DACHPt内包SCNP200μLを凍結乾燥し、固形分濃度を算出した後、Pt含量との比をとりポリマーあたりのPt結合量を算出した結果、3.4mol/molであった。また、得られたDACHPt内包SCNPのZ平均粒子径、並びに多分散指数を動的光散乱法(Dynamic light scattering,DLS)により測定した結果、8.7nm(多分散指数 0.14)であった。DACHPt内包前後のSCNPの粒子径を図3に示す。SCNPの粒子径は、DACHPt内包前後でほとんど変動しなかった。結果を下表にまとめた。
(1)ICP-AES測定
装置 :シーケンシャル高周波プラズマ発光装置 ICPE-9000/島津製作所
前処理装置 :マイクロ波試料前処理装置 ETHOS EASY/マイルストーン ゼネラル
測定波長 :342nm
標準溶液 :ガドリニウム標準液(Gd1000) ICP分析用/富士フィルム和光純薬
(2)DLS測定
装置 :Zetasizer NanoZS/Malvern Instruments Ltd.
測定温度 :25℃
試料濃度 :10mg/mL
結果 :図3
オキサリプラチン溶液の調製
エルプラット点滴静注液50mg((株)ヤクルト本社)1mLを5.9(w/v)%グルコース溶液5.58mLに添加し、オキサリプラチンとして760μg含有5(w/v)%グルコース溶液を調製した。
雌性ヌードマウス(BALB/c-nu nu/nu,7週齢;日本チャールス・リバー(株))にマウス大腸がん細胞株C26(American Type Culture Collection)を皮下移植した担癌モデルを薬効試験に用いた。
CO2インキュベーター内で継代培養したマウス大腸がん細胞株C26を液体培地(Dulbecco's Modified Eagle's Medium-high glucose, Sigma-Aldrich)に懸濁し、一匹あたり細胞数として1×106/100μLとなるようにヌードマウスの背部皮下に注射した。その後約1週間ヌードマウスを飼育した後、腫瘍体積の平均値が約30mm3に生育したところで薬剤の投与を開始した。DACHPt内包SCNP(実施例70のコポリマーを使用して調製したDACHPt内包SCNP)を尾静脈内投与し(隔日3回)、腫瘍体積から抗腫瘍効果を評価した(1群4~5匹)。比較としてオキサリプラチン溶液(比較例1)を用いて、同様に投与した。各製剤の投与量は、オキサリプラチン溶液については、投与可能な最高用量として8mg/kg(Pt換算で3.9mg/kg)、DACHPt内包SCNPについては、Pt換算で3mg/kgとした。
腫瘍体積の経時変化を図4に示した。DACHPt内包SCNPの場合、投与14日後にT/C=0.4であった[T/C:薬物投与群(T)とControl群(C)の腫瘍体積の比]。オキサリプラチン溶液(比較例1)の場合、投与14日後にT/C=1.1であった。また、投与14日後においてDACHPt内包SCNPはControlに比較して有意に腫瘍の増大を抑制することを確認した(student's t-test)。以上の結果は、DACHPt内包SCNPはオキサリプラチン溶液に比較して優れた抗腫瘍効果を有することを示している。
Claims (21)
- 次の一般式(1)~(3):
で示される3種のモノマーの重合によって形成されるコポリマー。 - R1が水素原子である請求項1又は2に記載のコポリマー。
- R2が水素原子である請求項1~3のいずれか1項に記載のコポリマー。
- R3が水素原子である請求項1~4のいずれか1項に記載のコポリマー。
- R4がメチル基である請求項1~5のいずれか1項に記載のコポリマー。
- R5が置換基を有してもよいC6-18アリール基である請求項1~6のいずれか1項に記載のコポリマー。
- R5がフェニル基である請求項1~7のいずれか1項に記載のコポリマー。
- R6が水素原子である請求項1~8のずれか1項に記載のコポリマー。
- X1が酸素原子である請求項1~11のいずれか1項に記載のコポリマー。
- X2が酸素原子である請求項1~12のいずれか1項に記載のコポリマー。
- X3が酸素原子である請求項1~13のいずれか1項に記載のコポリマー。
- mが4~22の整数である請求項1~14のいずれか1項に記載のコポリマー。
- nが1である請求項1~15のいずれか1項に記載のコポリマー。
- 構造単位(A)、(B)、(C)の比率が、(A)1質量部に対して、0.01~100質量部の(B)と、0.1~100質量部の(C)で構成されている請求項1~16のいずれか1項に記載のコポリマー。
- モノマー(1)の1質量部に対して、0.01~100質量部のモノマー(2)と、0.1~100質量部のモノマー(3)を重合させてなる請求項2~16のいずれか1項に記載のコポリマー。
- 数平均分子量が、5000~150000である請求項1~18のいずれか1項に記載のコポリマー。
- 請求項1~19のいずれか1項に記載のコポリマーを含むsingle chain nanoparticle。
- 請求項1~19のいずれか1項に記載のコポリマーを含む医薬組成物。
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WO2024034684A1 (ja) * | 2022-08-10 | 2024-02-15 | 興和株式会社 | 新薬物複合体 |
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WO2024034684A1 (ja) * | 2022-08-10 | 2024-02-15 | 興和株式会社 | 新薬物複合体 |
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