JP2022166159A - Vegfアンタゴニストを含む液体組成物 - Google Patents
Vegfアンタゴニストを含む液体組成物 Download PDFInfo
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- JP2022166159A JP2022166159A JP2022128071A JP2022128071A JP2022166159A JP 2022166159 A JP2022166159 A JP 2022166159A JP 2022128071 A JP2022128071 A JP 2022128071A JP 2022128071 A JP2022128071 A JP 2022128071A JP 2022166159 A JP2022166159 A JP 2022166159A
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- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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Abstract
Description
リン酸ナトリウム、ヒスチジン、又はそれらの組合せを含む緩衝液、及び
塩化ナトリウムを含まない、かつ/又はトレハロース、スクロース、マンニトール及びそれらの組合せからなる群から選択される少なくとも1つを含む、安定剤。
(1)5mg/ml~100mg/mlのタンパク質;
(2)pH4~8の緩衝液;及び
(3)安定剤、
ここで、緩衝液はリン酸ナトリウム、ヒスチジン、又はそれらの組合せを含み、
かつ、安定剤は塩化ナトリウムを含まない、かつ/又はトレハロース、スクロース及びマンニトールからなる群から選択される少なくとも1つを含む。
液体組成物は、界面活性剤を、例えば、全組成物に基づいて0.01~3%(w/v)の量でさらに含んでもよい。
(1)タンパク質;
(2)リン酸ナトリウム、ヒスチジン又はそれらの組合せを含む緩衝液;及び
(3)塩化ナトリウムを含まない、かつ/又はトレハロース、スクロース、及びマンニトールからなる群から選択される1以上を含む、安定剤。
液体組成物は、塩化ナトリウムを含まなくてもよい。
SDTGRPFVEM YSEIPEIIHM TEGRELVIPC RVTSPNITVT LKKFPLDTLI PDGKRIIWDS RKGFIISNAT YKEIGLLTCE ATVNGHLYKT NYLTHRQTNT IIDVVLSPSH
GIELSVGEKL VLNCTARTEL NVGIDFNWEY PSSKHQHKKL VNRDLKTQSG SEMKKFLSTL TIDGVTRSDQ GLYTCAASSG LMTKKNSTFV RVHEKDKTHT CPPCPAPELL GGPSVFLFPP KPKDTLMISR TPEVTCVVVD VSHEDPEVKF NWYVDGVEVH NAKTKPREEQ YNSTYRVVSV LTVLHQDWLN GKEYKCKVSN KALPAPIEKT ISKAKGQPRE PQVYTLPPSR DELTKNQVSL TCLVKGFYPS DIAVEWESNG QPENNYKTTP PVLDSDGSFF LYSKLTVDKS RWQQGNVFSC SVMHEALHNH YTQKSLSLSP G
(ジスルフィド架橋:30-79;124-185;246-306;352-410、二量体:211;214)
(1)タンパク質;
(2)リン酸ナトリウム、ヒスチジン、又はそれらの組合せを含む緩衝液;
(3)塩化ナトリウムを含まない、かつ/又はトレハロース、スクロース及びマンニトールからなる群から選択される1以上を含む、安定剤;そして
(4)任意で、界面活性剤。
VEFGアンタゴニストとして機能する融合タンパク質である、タンパク質薬物としてのアフリベルセプト(ヒトVEGF受容体1及び2の細胞外ドメインに由来するVEGF結合部位とヒトIgG1のFc領域の融合タンパク質;CAS番号:862111-32-8;配列番号1)を用いて、タンパク質薬物の液体組成物1~14を、以下の表2の組成物として調製した:
実施例1で調製した組成物1~14の安定性を試験するために、組成物中のタンパク質薬物の凝集度を示す%HMW(%高分子量;重量に基づく)を、タンパク質薬剤濃度40mg/mL、pH6.2、40℃の条件で4週間の貯蔵の最中にSE-HPLCで測定した。
(n=3)、そして得られた結果を表4に示す:
表5に示すように、組成物1-10(タンパク質薬物濃度:40mg/mL;pH6.2;界面活性剤:0.03%(w/v)PS20)を、優れた安定化効果が実施例1及び表3で確認された安定剤としてのマンニトール、スクロース、又はトレハロースを用いて、及び対照の安定剤としてのデキストロースを用いて、調製した。これらの組成物の安定性をテストするために、組成物中のタンパク質薬物の変性度を示す%酸性(%酸性バリアント含有量;重量に基づく)及び%メイン(電荷バリアントアスペクトの初期状態の表面電荷を維持するタンパク質の含有量(重量に基づく))を、40℃で4週間貯蔵中に、画像化キャピラリー等電点電気泳動(icIEF)を用いて測定した。
実施例1で調製した表2の組成物1~14中の薬理活性成分であるアフリベルセプトの活性の維持を試験するために、VEFGに対する組成物中のアフリベルセプトの%RBA(相対結合活性)及び%RPA(相対効力活性)を、タンパク質薬物濃度40mg/mL
、pH6.2、40℃の条件で4週間貯蔵の最中に測定した。
ドされた96ウェルプレート中にKDR293細胞(Promega)をロードしてインキュベートした後、%RPA(相対効力分析)をEnvisionマイクロプレートリーダー(Perkin Elmer、Envision 2014)を用いて分析した。
実施例1で調製した組成物のうち、実施例2~4で優れた安定性が確認された6種類の組成物(表2における組成物4、5、6、8、9及び10)の%メインを、CE-SDS(キャピラリー電気泳動ドデシル硫酸ナトリウム)を用いて測定した(40℃、4週間)。
software(Beckman Coulter)を用いて、220nm未満で検
出された%全タンパク質面積を分析した。
Claims (28)
- 以下を含む液体組成物:
(1)5mg/ml~100mg/mlのタンパク質;
(2)pH4~8の緩衝液;及び
(3)安定剤、
であって、前記緩衝液は、リン酸、酢酸、クエン酸、コハク酸、前記酸の薬学的に許容される塩、及びヒスチジンからなる群から選択される少なくとも1つを含み、
かつ前記安定剤は、塩化ナトリウムを含まない、液体組成物。 - 前記安定剤が、トレハロース、スクロース、及びマンニトールからなる群から選択される少なくとも1つを含む、請求項1に記載の液体組成物。
- 前記タンパク質の量が、20mg/ml~60mg/mlである、請求項1に記載の液体組成物。
- 前記緩衝液のpHが、5.2~7.2である、請求項1に記載の液体組成物。
- 前記組成物中の緩衝液の濃度が、1~50mMである、請求項1に記載の液体組成物。
- 前記組成物中の緩衝液の濃度が、1~20mMである、請求項5に記載の液体組成物。
- 前記安定剤が、1~20%(w/v)トレハロース、1~20%(w/v)スクロース、及び0.5~10%(w/v)マンニトールからなる群から選択される少なくとも1つを含む、請求項2に記載の液体組成物。
- 前記安定剤が、5~12%(w/v)トレハロース、5~12%(w/v)スクロース、及び2~7%(w/v)マンニトールからなる群から選択される少なくとも1つを含む、請求項7に記載の液体組成物。
- 前記安定剤が、5~12%(w/v)スクロースを含む、請求項8に記載の液体組成物。
- 前記緩衝液が、1~20mMリン酸ナトリウムを含む、請求項1に記載の液体組成物。
- 前記安定剤が、5~12%(w/v)トレハロース、5~12%(w/v)スクロース、及び2~7%(w/v)マンニトールからなる群から選択される少なくとも1つを含む、請求項10に記載の液体組成物。
- 前記安定剤が、5~12%(w/v)スクロースを含む、請求項11に記載の液体組成物。
- 前記緩衝液が、1~20mMのヒスチジンを含む、請求項1に記載の液体組成物。
- 前記安定剤が、5~12%(w/v)トレハロース、5~12%(w/v)スクロース、及び2~7%(w/v)マンニトールからなる群から選択される少なくとも1つを含む、請求項13に記載の液体組成物。
- 前記安定剤が、5~12%(w/v)スクロースを含む、請求項14に記載の液体組成物。
- 界面活性剤をさらに含む、請求項1に記載の液体組成物。
- 前記界面活性剤が、全組成物に基づいて、0.001~3%(w/v)の量で含まれる、請求項16に記載の液体組成物。
- 水性かつ等張性である、請求項1に記載の液体組成物。
- 前記組成物が、水性であり、かつ200~400mOsm/kgの浸透圧を有する、請求項1に記載の液体組成物。
- 前記タンパク質が、10~500kDaの分子量を有する、請求項1~19のいずれか一項に記載の液体組成物。
- 前記タンパク質が、VEGFアンタゴニストである、請求項1~19のいずれか一項に記載の液体組成物。
- 前記VEGFアンタゴニストが、アフリベルセプトである、請求項21に記載の液体組成物。
- 硝子体内投与用である、請求項22に記載の液体組成物。
- 請求項23に記載の液体組成物を含む、硝子体内投与用注射剤。
- 以下を含む、液体組成物
(1)30mg/ml~50mg/mlのアフリベルセプト;
(2)pH5.2~7.2の緩衝液;
(3)安定剤;及び
(4)0.01~0.1%(w/v)の界面活性剤、
であって、前記緩衝液は、1~20mMリン酸ナトリウム、1~20mMヒスチジン、又はそれらの組合せであり、
かつ前記安定剤は、塩化ナトリウムを含まない、液体組成物。 - 安定剤が、5~12%(w/v)トレハロース、5~12%(w/v)スクロース、及び2~7%(w/v)マンニトールからなる群から選択される少なくとも1つを含む、請求項25に記載の液体組成物。。
- 安定剤が、5~12%(w/v)スクロースを含む、請求項26に記載の液体組成物。
- 硝子体内投与用である、請求項25~27のいずれか一項に記載の液体組成物。
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