JP2022500376A - タンパク質及びポリアルコキシ脂肪酸アシル界面活性剤を含む組成物 - Google Patents
タンパク質及びポリアルコキシ脂肪酸アシル界面活性剤を含む組成物 Download PDFInfo
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Abstract
Description
したがって、本発明は、タンパク質と、一般式Iのポリアルコキシ脂肪酸アシル界面活性剤
ポリアルコキシ化合物は、構−(−A−O)m−を有する1つ又は複数の基を含有する化合物であり、mは3以上であり、Aは未置換アルキル基である。A基は直鎖状、分岐状、環状又はその組み合わせであり得る。種々のA基、特に種々の−(−A−O)−基は互いに同じ又は異なり得る。
式Iのポリアルコキシ脂肪酸化合物において、R1は好ましくは、置換若しくは未置換脂肪族基である。置換脂肪族基の中でも、好ましい置換基はヒドロキシルである。より好ましくは、R1は、未置換脂肪族基;より好ましくは、R1は未置換アルキル基である。好ましくは、R1は、炭素原子9〜22個、好ましくは炭素原子10〜18個、より好ましくは炭素原子10〜16個を有する直鎖状アルキル基である。
好ましくは、R3は数平均分子量600〜5000ダルトン、より好ましくは800〜3000ダルトンを有する。
別段の指定がない限り、すべての材料はシグマ・アルドリッチ社(Sigma−Aldrich)又はフィッシャー社(Fisher)から入手し、さらに精製することなく使用した。ジェファーミン(Jeffamine)M−1000がハンツマン社(Huntsman)によって提供された。ポリソルベート80(PS80)及びポリソルベート20(PS20)は、それぞれシグマ・アルドリッチ製品番号59924及び44112の「Ph.Eur準拠試験済み」グレードであった。それらは、酸化を最小限に抑えるために窒素ヘッドスペース下にて保管した。ポロキサマー188(PO188)は、シグマ社(Sigma)製品番号P5556の10%滅菌濾過水溶液として購入した。工業グレードのウシIgGをMP Biomedicals(カリフォルニア州サンタアナ(Santa Ana,CA))から購入した。
0.9%塩化ナトリウム水溶液中でIgG20mg/mLの濃度で試料を調製した。界面活性剤濃度は実施例に示す。動的光散乱(DLS)測定を以下の通りに実施した。光散乱測定は、Wyatt DynaPro(商標)高処理DLS装置で実施した。各試料30μLをコーニング社(Corning)96穴プレートのウェルに入れた。分析前に1000rpmにて3分間、プレートを遠心した。分析前に25℃で5分間、試料を平衡化した。DLS測定値が連続的に得られ、5×3秒取得/ウェル/サイクルでウェルからウェルへと繰り返した。
製剤600μLを1mLガラスバイアル内に調製した。分析(t=0)のために100μLを除去し、次いで試料を35℃にて200rpmにて一晩、その側で振とうした。それぞれのバイアルに対して相の透明度を測定し、サイズに関して、100μLアリコートをDLSによって測定した。結果を以下の表に示す。
実施例1と同様であるが、1セットの界面活性剤濃度:0.05mg/mL(400:1比)にて、実験をセットアップした。それぞれの時点で、試料を振盪機から取り出し、光散乱によって流体力学的半径について分析した。100の値を読み取り不能なデータに入力した。
実施例1と同様に実験をセットアップしたが、アミノ酸残基を含有しない式(I)のポリアルコキシ脂肪酸アシル界面活性剤(OM1000、n=0、X1=NH2)を賦形剤として使用し、FM1000を比較した。IgGの濃度は20mg/mLであり;界面活性剤濃度は0.05mg/mLであった(タンパク質と界面活性剤の比は400:1であった)。ポリソルベート20も対照として調べた。試料500μLを他の実施例と同様に18時間振とうした。そのデータは以下の通りである。
実施例3と同様に実験をセットアップしたが、溶液は0.9%塩化ナトリウムではなく25mMクエン酸塩(pH6)を含有した。IgGの濃度は20mg/mLであり;界面活性剤濃度は0.05mg/mLであった(タンパク質と界面活性剤の比は400:1であった)。これらの試料については、透明度を測定しなかった。そのデータは以下の通りである:
セツキシマブの安定性に対する界面活性剤の効果
セツキシマブは商品名Erbitux(登録商標)で市販されており、薬局で入手できた。それは、10mMリン酸緩衝液及び145mM塩化ナトリウム中の2mg/mL溶液(pH7.2)として配合される。
Claims (25)
- 前記タンパク質と前記ポリアルコキシ脂肪酸アシル界面活性剤との重量比が、250:1〜900:1の範囲である、請求項1に記載の組成物。
- 前記タンパク質と前記ポリアルコキシ脂肪酸アシル界面活性剤との重量比が、300:1〜800:1の範囲である、請求項1又は2に記載の組成物。
- 前記タンパク質と前記ポリアルコキシ脂肪酸アシル界面活性剤との重量比が、400:1〜700:1の範囲である、請求項1〜3のいずれか一項に記載の組成物。
- タンパク質と前記ポリアルコキシ脂肪酸アシル界面活性剤との重量比が、201:1〜250:1の範囲である、請求項1又は2に記載の組成物。
- タンパク質と前記ポリアルコキシ脂肪酸アシル界面活性剤との重量比が、205:1〜245:1の範囲である、請求項5に記載の組成物。
- タンパク質と前記ポリアルコキシ脂肪酸アシル界面活性剤との重量比が、210:1〜240:1の範囲である、請求項5又は6に記載の組成物。
- R1がC9〜22直鎖状アルキルである、請求項1〜7のいずれか一項に記載の組成物。
- X2はNHである、請求項1〜8のいずれか一項に記載の組成物。
- nは1、2、3、4又は5、好ましくは1である、請求項1〜9のいずれか一項に記載の組成物。
- X1はNHである、請求項1〜10のいずれか一項に記載の組成物。
- nは1であり、且つ式Iの基におけるR2が天然アミノ酸の側鎖を表す、請求項1〜11のいずれか一項に記載の組成物。
- R2がHであり、未置換C1〜4アルキル又は−CH2−(C6H5)である、請求項1〜12のいずれか一項に記載の組成物。
- R3が、数平均分子量600〜5000、好ましくは800〜3000を有する、請求項1〜13のいずれか一項に記載の組成物。
- プロピレンオキシド(PO)単位とエチレンオキシド(EO)単位の比が、0.01:1〜2:1、好ましくは0.05:1〜1:1、より好ましくは0.1:1〜0.5:1である、請求項1〜14のいずれか一項に記載の組成物。
- 式Iにおいて、R1がCH3−(CH2)11−CH2−であり、nが1であり、X1及びX2はどちらもNHであり、R2は−CH2(C6H5)であり、R3が、近似の分子量1000及びPO:EO比3:19を有する、CH3でキャップされたPO及びEO単位のコポリマーである、請求項1〜15のいずれか一項に記載の組成物。
- 式Iにおいて、R1がCH3−(CH2)11−CH2−であり、nが0であり、X2がNHであり、且つR3が、近似の分子量1000及びPO:EO比3:19を有する、CH3でキャップされたPO及びEO単位のコポリマーである、請求項1〜15のいずれか一項に記載の組成物。
- 前記タンパク質が、モノクローナル抗体、ポリクローナル抗体、抗体薬物複合体、成長因子、インスリン、免疫グロブリン、ペプチドホルモン、酵素、ポリペプチド、融合タンパク質、グリコシル化タンパク質、抗原、抗原サブユニット及びその組み合わせからなる群から選択される、請求項1〜18のいずれか一項に記載の組成物。
- タンパク質の量が、0.01mg/ml〜400mg/ml、好ましくは0.1mg/ml〜300mg/ml、より好ましくは1mg/ml〜250mg/mlの範囲である、請求項1〜18のいずれか一項に記載の組成物。
- ショ糖、グルコース、マンノース、トレハロース、マルトース、ブドウ糖、デキストラン、ソルビトール、マンニトール、及びキシリトールからなる群から選択される糖又は糖アルコールをさらに含む、請求項1〜19のいずれか一項に記載の組成物。
- 塩、例えばフッ化物、塩化物、臭化物、ヨウ化物、リン酸、カルボン酸、酢酸、クエン酸、硫酸の、水素、ナトリウム、カリウム、マグネシウム、カルシウム又はアンモニウム塩をさらに含む、請求項1〜20のいずれか一項に記載の組成物。
- 天然アミノ酸、好ましくはリジン、グリシン、アルギニン又はヒスチジンをさらに含む、請求項1〜21のいずれか一項に記載の組成物。
- 前記タンパク質がセツキシマブである、請求項1〜21のいずれか一項に記載の組成物。
- 式(I)(式中、R1はCH3−(CH2)11−CH2−であり、nは1であり、X1及びX2はどちらもNHであり、R2は−CH2(C6H5)であり、且つR3は、近似の数平均分子量1000及びPO/EO比3:19を有する、CH3でキャップされたPO及びEO単位のコポリマーである)のポリアルコキシ脂肪酸アシル界面活性剤を含む、請求項23に記載の組成物。
- セツキシマブとポリアルコキシ脂肪酸アシル界面活性剤の比が300:1〜750:1である、請求項23又は24に記載の組成物。
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- 2019-09-06 CN CN201980059505.6A patent/CN112672734B/zh active Active
- 2019-09-06 WO PCT/US2019/049904 patent/WO2020055679A2/en unknown
- 2019-09-06 KR KR1020217007252A patent/KR20210056349A/ko not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
CN112672734A (zh) | 2021-04-16 |
WO2020055679A2 (en) | 2020-03-19 |
EP3849519B1 (en) | 2022-09-21 |
CN112672734B (zh) | 2023-04-11 |
KR20210056349A (ko) | 2021-05-18 |
WO2020055679A3 (en) | 2020-05-28 |
EP3849519A2 (en) | 2021-07-21 |
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