JPWO2018181876A1 - 水性製剤及び注射器入り水性製剤、並びに、抗体タンパク脱凝集剤及び抗体タンパク脱凝集方法 - Google Patents
水性製剤及び注射器入り水性製剤、並びに、抗体タンパク脱凝集剤及び抗体タンパク脱凝集方法 Download PDFInfo
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- JPWO2018181876A1 JPWO2018181876A1 JP2019510230A JP2019510230A JPWO2018181876A1 JP WO2018181876 A1 JPWO2018181876 A1 JP WO2018181876A1 JP 2019510230 A JP2019510230 A JP 2019510230A JP 2019510230 A JP2019510230 A JP 2019510230A JP WO2018181876 A1 JPWO2018181876 A1 JP WO2018181876A1
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- ustekinumab
- aqueous preparation
- antibody protein
- histidine
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- 230000004069 differentiation Effects 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- WDRWZVWLVBXVOI-QTNFYWBSSA-L dipotassium;(2s)-2-aminopentanedioate Chemical compound [K+].[K+].[O-]C(=O)[C@@H](N)CCC([O-])=O WDRWZVWLVBXVOI-QTNFYWBSSA-L 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
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- 230000005847 immunogenicity Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
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- 230000002401 inhibitory effect Effects 0.000 description 1
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 1
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- 229960003136 leucine Drugs 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229960005337 lysine hydrochloride Drugs 0.000 description 1
- 229910001425 magnesium ion Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
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- 229940098895 maleic acid Drugs 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
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- 210000004962 mammalian cell Anatomy 0.000 description 1
- 229910001437 manganese ion Inorganic materials 0.000 description 1
- 235000013919 monopotassium glutamate Nutrition 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 235000013923 monosodium glutamate Nutrition 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
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- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
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- QEEAPRPFLLJWCF-UHFFFAOYSA-K potassium citrate (anhydrous) Chemical compound [K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QEEAPRPFLLJWCF-UHFFFAOYSA-K 0.000 description 1
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- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
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- 229940043230 sarcosine Drugs 0.000 description 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
- 229960001153 serine Drugs 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- HELHAJAZNSDZJO-OLXYHTOASA-L sodium L-tartrate Chemical compound [Na+].[Na+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O HELHAJAZNSDZJO-OLXYHTOASA-L 0.000 description 1
- 229960004249 sodium acetate Drugs 0.000 description 1
- 229960001790 sodium citrate Drugs 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 229940073490 sodium glutamate Drugs 0.000 description 1
- 239000001540 sodium lactate Substances 0.000 description 1
- 235000011088 sodium lactate Nutrition 0.000 description 1
- 229940005581 sodium lactate Drugs 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
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- 229940074404 sodium succinate Drugs 0.000 description 1
- ZDQYSKICYIVCPN-UHFFFAOYSA-L sodium succinate (anhydrous) Chemical compound [Na+].[Na+].[O-]C(=O)CCC([O-])=O ZDQYSKICYIVCPN-UHFFFAOYSA-L 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000001433 sodium tartrate Substances 0.000 description 1
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- 239000002904 solvent Substances 0.000 description 1
- 230000010473 stable expression Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
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- 239000011975 tartaric acid Substances 0.000 description 1
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- UYPYRKYUKCHHIB-UHFFFAOYSA-N trimethylamine N-oxide Chemical compound C[N+](C)(C)[O-] UYPYRKYUKCHHIB-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229960004799 tryptophan Drugs 0.000 description 1
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Abstract
Description
(1)ウステキヌマブと、ヒスチジン及びその塩から選択される少なくとも1種と、水と、を含有しており、ヒスチジン及び/又はその塩の含有量がヒスチジン換算で50〜90mMである、水性製剤。
(2)メチオニンを更に含有しており、メチオニンの含有量が10〜50mMである(1)に記載の水性製剤。
(3)ウステキヌマブの含有量が80〜100mg/mLである(1)又は(2)に記載の水性製剤。
(4)スクロースを更に含有する(1)〜(3)のうちのいずれか一項に記載の水性製剤。
(5)pHが5.7〜6.3である(1)〜(4)のうちのいずれか一項に記載の水性製剤。
(6)ウステキヌマブ及びヒスチジン緩衝液を配合してなる(1)〜(5)のうちのいずれか一項に記載の水性製剤。
(7)注射器と、前記注射器内に充填された(1)〜(6)のうちの少なくともいずれかに記載の水性製剤と、を備える注射器入り水性製剤。
(8)凝集ウステキヌマブを脱凝集せしめる抗体タンパク脱凝集剤であり、ヒスチジン及びその塩から選択される少なくとも1種と水とを含有しており、ヒスチジン及び/又はその塩の含有量がヒスチジン換算で50〜90mMである、抗体タンパク脱凝集剤。
(9)メチオニンを更に含有しており、メチオニンの含有量が5〜50mMである(8)に記載の抗体タンパク脱凝集剤。
(10)スクロースを更に含有する(8)又は(9)に記載の抗体タンパク脱凝集剤。
(11)pHが5.7〜6.3である(8)〜(10)のうちのいずれか一項に記載の抗体タンパク脱凝集剤。
(12)凝集ウステキヌマブを脱凝集せしめる抗体タンパク脱凝集方法であり、凝集ウステキヌマブに(8)〜(11)のうちのいずれか一項に記載の抗体タンパク脱凝集剤を添加する工程を含む、抗体タンパク脱凝集方法。
各実施例及び比較例で得られた水性製剤について、それぞれ、製造直後、並びに、40℃で2週間、1ヶ月間、及び2ヶ月間保存した後、サイズ排除クロマトグラフィー(SEC、カラム:TSKgel G3000SWXL 7.8×300mm、東ソー株式会社製、カラム温度:25℃、溶離液:20mM Na2HPO4+150mM NaCl(pH7.3)、流量:0.5ml/分))を用いて、各水性製剤中の%凝集体(全タンパク質量に占める凝集体質量の割合[%Aggregate])及び%単量体(全タンパク質量に占める単量体質量の割合[%Monomer])を測定した。なお、%凝集体の値が小さい程、或いは、%単量体の値が大きい程、その水性製剤は保存安定性に優れたものと評価できる。
先ず、ヒスチジン及びヒスチジン塩酸塩・1水和物からヒスチジン緩衝液(pH6.0)を調製した。次いで、ウステキヌマブと前記ヒスチジン緩衝液とを、ウステキヌマブ:90mg/mL、ヒスチジン及び/又はその塩(ヒスチジン換算):50mMの組成となるように配合し、500μLの水性製剤を得た。ウステキヌマブとしては、国際公開第2009/114040号に記載の方法でチャイニーズハムスター卵巣細胞安定発現株を用いて発現させたウステキヌマブを、ProteinAクロマトグラフィー等のクロマトグラフィーによって精製した試料を用いた(以下同じ)。
先ず、実施例1と同様にしてヒスチジン緩衝液(pH6.0)を調製した。次いで、ステラーラ(登録商標)と同様の組成となるように水性製剤を調製した。すなわち、ウステキヌマブと、前記ヒスチジン緩衝液と、ポリソルベート80と、スクロースとを、ウステキヌマブ:90mg/mL、ヒスチジン及び/又はその塩(ヒスチジン換算):6.4mM(1mg/ml)、ポリソルベート80:0.04mg/mL、スクロース:76mg/mLの組成となるように配合し、500μLの水性製剤を得た。
先ず、実施例1と同様にしてヒスチジン緩衝液(pH6.0)を調製した。次いで、ウステキヌマブと前記ヒスチジン緩衝液とを、ウステキヌマブ:90mg/mL、ヒスチジン及び/又はその塩(ヒスチジン換算):6.4mMの組成となるように配合し、500μLの水性製剤を得た。
各種アミノ酸を更に配合したこと以外は比較例2と同様にして、各水性製剤(ウステキヌマブ:90mg/mL+ヒスチジン及び/又はその塩(ヒスチジン換算):6.4mM+各種アミノ酸)をそれぞれ得た。各種アミノ酸としては、比較例3:L−グルタミン酸ナトリウム塩(50mM)、比較例4:L−リジン塩酸塩(50mM)、比較例5:L−プロリン(50mM)、比較例6:L−ロイシン(30mM(製剤調製時の溶解限界濃度))、比較例7:L−トリプトファン(10mM(製剤調製時の溶解限界濃度))、比較例8:グリシン(50mM)、及び比較例9:L−セリン(50mM)を、それぞれ括弧内の濃度となるように用いた。
相対凝集体量=(各水性製剤を40℃で2週間保存した後の%凝集体)/(比較例2の水性製剤を40℃で2週間保存した後の%凝集体)
により、各水性製剤をそれぞれ40℃で2週間保存した後の相対凝集体量、すなわち、比較例2で得られた水性製剤の%凝集体に対する各水性製剤の%凝集体の相対量[Relative Aggregate Amount]を求めた。各水性製剤をそれぞれ40℃で2週間保存した後の相対凝集体量を示すグラフを図1に示す。図1に示す結果から明らかなように、ウステキヌマブ含有水性製剤に高濃度のヒスチジン及び/又はその塩が添加された本発明の水性製剤(実施例1)においては、凝集体(凝集ウステキヌマブ)の生成が顕著に抑制されることが確認された。
各種等張化剤を更に配合したこと以外は比較例2と同様にして、各水性製剤(ウステキヌマブ:90mg/mL+ヒスチジン及び/又はその塩(ヒスチジン換算):6.4mM+各種等張化剤)をそれぞれ得た。各種等張化剤としては、比較例10:スクロース(76mg/mL)、比較例11:マンニトール(30mg/mL(製剤調製時の溶解限界濃度))を、それぞれ括弧内の濃度となるように用いた。
ヒスチジン及び/又はその塩の濃度を変更し、それぞれ下記の表1に示す組成となるようにしたこと以外は実施例1と同様にして各水性製剤を得た。また、実施例1〜3については、更にL−メチオニンを添加し、その濃度が10、25、50mMとなるようにした水性製剤もそれぞれ得た。下記の表1に得られた水性製剤の組成を示す。また、表1には、実施例1及び比較例2で得られた水性製剤の組成も併せて示す。なお、下記の表中、ヒスチジン[mM]は、ヒスチジン緩衝液により配合されたヒスチジン及び/又はその塩のヒスチジン換算での含有量を示す(以下同じ)。
先ず、実施例1と同様にしてヒスチジン緩衝液(pH6.0)を調製した。次いで、ウステキヌマブと、L−メチオニンと、前記ヒスチジン緩衝液と、ポリソルベート80と、スクロースとを、下記の表2に示す組成となるように配合し、500μLの水性製剤をそれぞれ得た。下記の表2に得られた水性製剤の組成を示す。また、表2には、比較例1で得られた水性製剤の組成も併せて示す。
先ず、実施例1と同様にしてヒスチジン緩衝液(pH6.0)を調製した。また、実施例1と同様にして得られたウステキヌマブを37℃において24時間保存して凝集させ、凝集ウステキヌマブとした。次いで、凝集ウステキヌマブと、L−メチオニンと、前記ヒスチジン緩衝液と、ポリソルベート80と、スクロースとを、下記の表3に示す組成となるように配合し、500μLの水性製剤をそれぞれ得た。下記の表3に得られた水性製剤の組成を示す。
Claims (12)
- ウステキヌマブと、ヒスチジン及びその塩から選択される少なくとも1種と、水と、を含有しており、
ヒスチジン及び/又はその塩の含有量がヒスチジン換算で50〜90mMである、
水性製剤。 - メチオニンを更に含有しており、メチオニンの含有量が10〜50mMである請求項1に記載の水性製剤。
- ウステキヌマブの含有量が80〜100mg/mLである請求項1又は2に記載の水性製剤。
- スクロースを更に含有する請求項1〜3のうちのいずれか一項に記載の水性製剤。
- pHが5.7〜6.3である請求項1〜4のうちのいずれか一項に記載の水性製剤。
- ウステキヌマブ及びヒスチジン緩衝液を配合してなる請求項1〜5のうちのいずれか一項に記載の水性製剤。
- 注射器と、前記注射器内に充填された請求項1〜6のうちの少なくともいずれかに記載の水性製剤と、を備える注射器入り水性製剤。
- 凝集ウステキヌマブを脱凝集せしめる抗体タンパク脱凝集剤であり、
ヒスチジン及びその塩から選択される少なくとも1種と水とを含有しており、
ヒスチジン及び/又はその塩の含有量がヒスチジン換算で50〜90mMである、
抗体タンパク脱凝集剤。 - メチオニンを更に含有しており、メチオニンの含有量が5〜50mMである請求項8に記載の抗体タンパク脱凝集剤。
- スクロースを更に含有する請求項8又は9に記載の抗体タンパク脱凝集剤。
- pHが5.7〜6.3である請求項8〜10のうちのいずれか一項に記載の抗体タンパク脱凝集剤。
- 凝集ウステキヌマブを脱凝集せしめる抗体タンパク脱凝集方法であり、
凝集ウステキヌマブに請求項8〜11のうちのいずれか一項に記載の抗体タンパク脱凝集剤を添加する工程を含む、
抗体タンパク脱凝集方法。
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