JP7465309B2 - アフリベルセプト製剤及びその使用 - Google Patents
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- JP7465309B2 JP7465309B2 JP2022120981A JP2022120981A JP7465309B2 JP 7465309 B2 JP7465309 B2 JP 7465309B2 JP 2022120981 A JP2022120981 A JP 2022120981A JP 2022120981 A JP2022120981 A JP 2022120981A JP 7465309 B2 JP7465309 B2 JP 7465309B2
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Description
SDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDS
RKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVVLSPSHGIELSVGEKL
VLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQ
GLYTCAASSGLMTKKNSTFVRVHEKDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISR
TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLN
GKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPS
DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH
YTQKSLSLSPG//配列番号1
重量オスモル濃度=(化合物g/100mL溶液)*(化合物のE値)
化合物のE値は以下の式によって決定される:
E値=(MW NaCl/i値NaCl)×(i値化合物/MW化合物)。
i値は、80%の理論的解離に基づく化合物からのイオンの数である。解離しない化合物、すなわちスクロースの場合、i値は1である。2つのイオンに解離する化合物、すなわちNaClの場合、i値は1.8であり、3つのイオンに解離する化合物の場合、i値は2.6である。重量オスモル濃度は溶液の束一的特性であるので、添加した溶質による凝固点の低下又は蒸気圧の低下が液体中の溶質分子の総数に直接関係する。重量オスモル濃度を測定する有用な機器を開発するためにこれらの原理の各々が当技術分野で利用されてきた。いずれか又は両方の種類の機器を生物学的試料に使用することができる。一例として、10mMリン酸ナトリウム、40mM NaCl、5%(w/v)スクロース及び0.03%(w/v)ポリソルベート20を含む溶液は、263mOsm/kgの理論重量オスモル濃度を有するであろう。本発明者らの実験室では、実際の測定値は、凝固点降下によって測定されるように270mOsm/kgであった。これは、実験値が理論値と厳密に一致することを示し、本発明を実施する目的のために、溶液がその重量オスモル濃度に基づいて硝子体内注射に適しているかどうかを決定するために理論値又は実験値のいずれかを使用することができることをさらに実証している。
(i)約9%(w/v)の濃度のスクロースもしくはトレハロース、又は
(ii)約3%(w/v)の濃度のプロリン
であり;(e)塩化物アニオンの濃度が約1mM未満であり;製剤のpHが約pH6.0~約pH6.5である。この製剤のいくつかの好ましい実施形態では、等張化剤が約9%(w/v)の濃度のスクロース又はトレハロースであり、アフリベルセプト濃度が約30mg/mL~約50mg/mL、例えば、約40mg/mLの濃度である。他の好ましい実施形態では、等張化剤が約3%(w/v)の濃度のプロリンであり、アフリベルセプト濃度が約30mg/mL~約50mg/mL、例えば、約40mg/mLの濃度である。
(i)約9%(w/v)の濃度のスクロースもしくはトレハロース、又は
(ii)約3%(w/v)の濃度のプロリン
であり;(e)塩化物アニオンの濃度が約10mM未満、又はより好ましくは約5mM未満であり;製剤のpHが約pH5.5~約pH6.5、又はいくつかの実施形態では約pH6.0~約pH6.5である。この製剤のいくつかの好ましい実施形態では、等張化剤が約9%(w/v)の濃度のスクロース又はトレハロースであり、アフリベルセプト濃度が約30mg/mL~約50mg/mL、例えば、約40mg/mLの濃度である。他の好ましい実施形態では、等張化剤が約3%(w/v)の濃度のプロリンであり、アフリベルセプト濃度が約30mg/mL~約50mg/mL、例えば、約40mg/mLの濃度である。
(i)約9%(w/v)の濃度のスクロースもしくはトレハロース、又は
(ii)約3%(w/v)の濃度のプロリン
であり;(e)塩化物アニオンの濃度が約1mM未満であり;製剤のpHが約pH5.0~約pH5.5である。この製剤のいくつかの好ましい実施形態では、等張化剤が約9%(w/v)の濃度のスクロース又はトレハロースであり、アフリベルセプト濃度が約30mg/mL~約50mg/mL、例えば、約40mg/mLの濃度である。他の好ましい実施形態では、等張化剤が約3%(w/v)の濃度のプロリンであり、アフリベルセプト濃度が約30mg/mL~約50mg/mL、例えば、約40mg/mLの濃度である。
(a)5~100mg/mLの濃度のアフリベルセプトと;
(b)5~50mM濃度の緩衝剤と;
(c)非イオン性界面活性剤と;
(d)ポリオール及びアミノ酸からなる群から選択される等張化剤と
を含む眼科用製剤であって、その最終重量オスモル濃度が約300mOsm/kgであり、
(e)塩化物アニオンの濃度が約10mM未満であり、そのpHが約pH5.0~約pH6.5である眼科用製剤。
(a)アフリベルセプト濃度が20~80mg/mLであり;
(b)リン酸緩衝液濃度が約10mMであり;
(c)非イオン性界面活性剤がポリソルベート又はポロキサマーであり;
(d)等張化剤が(i)約9%(w/v)の濃度のスクロースもしくはトレハロース、又は(ii)約3%(w/v)の濃度のプロリンであり;
(e)塩化物アニオンの濃度が約1mM未満であり;
そのpHが約pH6.0~約pH6.5である、実施形態4に記載の眼科用製剤。
(a)アフリベルセプト濃度が20~80mg/mLであり;
(b)ヒスチジン緩衝液が約10mMであり;
(c)非イオン性界面活性剤がポリソルベート又はポロキサマーであり;
(d)等張化剤が(i)約9%(w/v)の濃度のトレハロース、又は(ii)約3%(w/v)の濃度のプロリンであり;
そのpHが約pH5.5~約pH6.5である、実施形態5に記載の眼科用製剤。
(a)アフリベルセプト濃度が20~80mg/mLであり;
(b)酢酸緩衝液が約10mMであり;
(c)非イオン性界面活性剤がポリソルベート又はポロキサマーであり;
(d)等張化剤が(i)約9%(w/v)の濃度のスクロースもしくはトレハロース、又は(ii)約3%(w/v)の濃度のプロリンであり;
(e)塩化物アニオンの濃度が約1mM未満であり;
そのpHが約pH5.0~約pH5.5である、実施形態6に記載の眼科用製剤。
[請求項1]
下記(a)~(d)を含む眼科用製剤:
(a)5~100mg/mLの濃度のアフリベルセプト;
(b)5~50mM濃度の緩衝剤;
(c)非イオン性界面活性剤;
(d)ポリオール及びアミノ酸からなる群から選択される等張化剤、
最終重量オスモル濃度は約300mOsm/kgであり、
(e)塩化物アニオンの濃度は約10mM未満であり、
pHは約pH5.0~約pH6.5である。
[請求項2]
塩化物アニオンの濃度が約5mM未満である、請求項1に記載の眼科用製剤。
[請求項3]
塩化物アニオンの濃度が約1mM未満である、請求項1に記載の眼科用製剤。
[請求項4]
緩衝剤がリン酸緩衝液である、請求項1に記載の眼科用製剤。
[請求項5]
緩衝剤が5~20mMの濃度のヒスチジン緩衝液である、請求項1に記載の眼科用製剤。
[請求項6]
緩衝剤が酢酸緩衝液である、請求項1に記載の眼科用製剤。
[請求項7]
緩衝剤がリン酸塩、ヒスチジン、酢酸塩、コハク酸塩、クエン酸塩、グルタミン酸塩及び乳酸塩から選択される、又はこれらの2つ以上の組み合わせから選択される、請求項1に記載の眼科用製剤。
[請求項8]
緩衝剤濃度が5~20mMである、請求項1に記載の眼科用製剤。
[請求項9]
非イオン性界面活性剤がポリソルベート、ポリエチレングリコールドデシルエーテル、ポロキサマー、4-(1,1,3,3-テトラメチルブチル)フェニル-ポリエチレングリコール、アルキルサッカライド及びアルキルグリコシドからなる群から選択される、請求項1に記載の眼科用製剤。
[請求項10]
非イオン性界面活性剤がポロキサマー188である、請求項9に記載の眼科用製剤。
[請求項11]
等張化剤がスクロース、トレハロース、ソルビトール、マンニトール及びグリセロールから選択されるポリオールである、請求項1に記載の眼科用製剤。
[請求項12]
等張化剤がスクロースである、請求項1に記載の眼科用製剤。
[請求項13]
等張化剤がトレハロースである、請求項1に記載の眼科用製剤。
[請求項14]
追加のアミノ酸安定化剤をさらに含む、請求項11に記載の眼科用製剤。
[請求項15]
追加のアミノ酸安定化剤がプロリン、アルギニン、メチオニン、グリシン及びリジンからなる群から選択される、請求項14に記載の眼科用製剤。
[請求項16]
等張化剤がプロリン、アルギニン、アスパラギン酸、グルタミン酸、グリシン、ヒスチジン、イソロイシン及びリジンから選択されるアミノ酸である、請求項1に記載の眼科用製剤。
[請求項17]
等張化剤がプロリンである、請求項16に記載の眼科用製剤。
[請求項18]
(a)アフリベルセプト濃度が20~80mg/mLであり;
(b)リン酸緩衝液濃度が約10mMであり;
(c)非イオン性界面活性剤がポリソルベート又はポロキサマーであり;
(d)等張化剤が
(i)約9%(w/v)の濃度のスクロースもしくはトレハロース、又は
(ii)約3%(w/v)の濃度のプロリン
であり;
(e)塩化物アニオンの濃度が約1mM未満であり;
そのpHが約pH6.0~約pH6.5である、請求項4に記載の眼科用製剤。
[請求項19]
等張化剤が約9%(w/v)の濃度のスクロース又はトレハロースである、請求項18に記載の眼科用製剤。
[請求項20]
等張化剤が約3%(w/v)の濃度のプロリンである、請求項18に記載の眼科用製剤。
[請求項21]
(a)アフリベルセプト濃度が20~80mg/mLであり;
(b)ヒスチジン緩衝液が約10mMであり;
(c)非イオン性界面活性剤がポリソルベート又はポロキサマーであり;
(d)等張化剤が
(i)約9%(w/v)の濃度のトレハロース、又は
(ii)約3%(w/v)の濃度のプロリン
であり;
そのpHが約pH5.5~約pH6.5である、請求項5に記載の眼科用製剤。
[請求項22]
等張化剤が約9%(w/v)の濃度のトレハロースである、請求項21に記載の眼科用製剤。
[請求項23]
等張化剤が約3%(w/v)の濃度のプロリンである、請求項21に記載の眼科用製剤。
[請求項24]
(a)アフリベルセプト濃度が20~80mg/mLであり;
(b)酢酸緩衝液が約10mMであり;
(c)非イオン性界面活性剤がポリソルベート又はポロキサマーであり;
(d)等張化剤が
(i)約9%(w/v)の濃度のスクロースもしくはトレハロース、又は
(ii)約3%(w/v)の濃度のプロリン
であり;
(e)塩化物アニオンの濃度が約1mM未満であり;
そのpHが約pH5.0~約pH5.5である、請求項6に記載の眼科用製剤。
[請求項25]
治療上有効量の請求項1、請求項4、請求項5、請求項6、又は請求項7に記載の眼科用製剤を、治療を必要とする患者に投与するステップを含む、眼障害又は疾患を治療する方法。
[請求項26]
眼障害又は疾患が網膜静脈閉塞症(RVO)後の黄斑浮腫、網膜中心静脈閉塞症(CRVO)、網膜静脈分枝閉塞症(BRVO)、新生血管(滲出型)加齢黄斑変性(AMD)、近視性脈絡膜新生血管による視力低下、糖尿病性黄斑浮腫(DME)、DME患者における糖尿病性網膜症(DR)、及び新生血管加齢黄斑変性(AMD)からなる群から選択される、請求項25に記載の方法。
[請求項27]
眼科用製剤の投与が硝子体内注射によるものである、請求項25に記載の方法。
Claims (8)
- 以下を含む眼科用製剤:
(a)5~100mg/mLの濃度のアフリベルセプト;
(b)5~50mMの濃度のヒスチジン緩衝液又は酢酸緩衝液;
(c)ポリソルベート、ポリエチレングリコールドデシルエーテル、ポロキサマー、4-(1,1,3,3-テトラメチルブチル)フェニル-ポリエチレングリコール、アルキルサッカライド及びアルキルグリコシドからなる群から選択される0.001%(w/v)~5%(w/v)の濃度の非イオン性界面活性剤;
(d)プロリン、アルギニン、アスパルギン酸、グリシン、ヒスチジン、イソロイシン及びリジンのアミノ酸から選択され、2~4%(w/v)の濃度である等張化剤、ただし、最終重量オスモル濃度は300±50mOsm/kgであり、
製剤のpHは、pH5.0~pH6.5である。 - 緩衝液の濃度が5mM~20mMである、請求項1に記載の眼科用製剤。
- 非イオン性界面活性剤がポロキサマー188である、請求項1に記載の眼科用製剤。
- 等張化剤がプロリンである、請求項1に記載の眼科用製剤。
- (a)アフリベルセプトの濃度が20~80mg/mLであり;
(b)ヒスチジン緩衝液又は酢酸緩衝液が10mMであり;
(c)非イオン性界面活性剤がポリソルベート又はポロキサマーであり;
(d)等張化剤が3%(w/v)の濃度のプロリンであり;
製剤のpHがpH5.0~pH6.5である、
請求項1に記載の眼科用製剤。 - 眼障害又は眼疾患の治療に用いるための医薬の調製における、請求項1~5のいずれかに記載の眼科用製剤の使用。
- 眼障害又は眼疾患が網膜静脈閉塞症(RVO)後の黄斑浮腫、網膜中心静脈閉塞症(CRVO)、網膜静脈分枝閉塞症(BRVO)、新生血管(滲出型)加齢黄斑変性(AMD)、近視性脈絡膜新生血管による視力低下、糖尿病性黄斑浮腫(DME)、DME患者における糖尿病性網膜症(DR)、及び新生血管加齢黄斑変性(AMD)からなる群から選択される、請求項6に記載の使用。
- 眼科用製剤の投与が硝子体内注射により行われる、請求項6又は7に記載の使用。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201662497584P | 2016-11-21 | 2016-11-21 | |
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