JPWO2020106948A5 - - Google Patents
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- JPWO2020106948A5 JPWO2020106948A5 JP2021527899A JP2021527899A JPWO2020106948A5 JP WO2020106948 A5 JPWO2020106948 A5 JP WO2020106948A5 JP 2021527899 A JP2021527899 A JP 2021527899A JP 2021527899 A JP2021527899 A JP 2021527899A JP WO2020106948 A5 JPWO2020106948 A5 JP WO2020106948A5
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- protein
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- aqueous
- polysorbate
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- 102000004169 proteins and genes Human genes 0.000 claims description 84
- 108090000623 proteins and genes Proteins 0.000 claims description 84
- 238000009472 formulation Methods 0.000 claims description 71
- 239000000203 mixture Substances 0.000 claims description 71
- 239000012141 concentrate Substances 0.000 claims description 38
- 239000003795 chemical substances by application Substances 0.000 claims description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- 239000000843 powder Substances 0.000 claims description 14
- 230000002209 hydrophobic effect Effects 0.000 claims description 13
- 239000007787 solid Substances 0.000 claims description 13
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical group OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 12
- 230000001225 therapeutic effect Effects 0.000 claims description 10
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 8
- 150000001413 amino acids Chemical class 0.000 claims description 6
- 150000001720 carbohydrates Chemical class 0.000 claims description 6
- 239000002736 nonionic surfactant Substances 0.000 claims description 6
- 229920000136 polysorbate Polymers 0.000 claims description 6
- 229950008882 polysorbate Drugs 0.000 claims description 6
- VLPFTAMPNXLGLX-UHFFFAOYSA-N trioctanoin Chemical compound CCCCCCCC(=O)OCC(OC(=O)CCCCCCC)COC(=O)CCCCCCC VLPFTAMPNXLGLX-UHFFFAOYSA-N 0.000 claims description 5
- 235000019445 benzyl alcohol Nutrition 0.000 claims description 4
- 238000002347 injection Methods 0.000 claims description 4
- 239000007924 injection Substances 0.000 claims description 4
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 claims description 4
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 3
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 3
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims description 3
- DNDWZFHLZVYOGF-KKUMJFAQSA-N Leu-Leu-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O DNDWZFHLZVYOGF-KKUMJFAQSA-N 0.000 claims description 3
- 229930195725 Mannitol Natural products 0.000 claims description 3
- 229920001213 Polysorbate 20 Polymers 0.000 claims description 3
- 229920001219 Polysorbate 40 Polymers 0.000 claims description 3
- 229920001214 Polysorbate 60 Polymers 0.000 claims description 3
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 3
- 229930006000 Sucrose Natural products 0.000 claims description 3
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 claims description 3
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims description 3
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims description 3
- 108010049589 leucyl-leucyl-leucine Proteins 0.000 claims description 3
- 239000000594 mannitol Substances 0.000 claims description 3
- 235000010355 mannitol Nutrition 0.000 claims description 3
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 claims description 3
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 claims description 3
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 3
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 3
- 239000000249 polyoxyethylene sorbitan monopalmitate Substances 0.000 claims description 3
- 235000010483 polyoxyethylene sorbitan monopalmitate Nutrition 0.000 claims description 3
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 claims description 3
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 claims description 3
- 229940068977 polysorbate 20 Drugs 0.000 claims description 3
- 229940101027 polysorbate 40 Drugs 0.000 claims description 3
- 229940113124 polysorbate 60 Drugs 0.000 claims description 3
- 229920000053 polysorbate 80 Polymers 0.000 claims description 3
- 229940068968 polysorbate 80 Drugs 0.000 claims description 3
- 238000001694 spray drying Methods 0.000 claims description 3
- 239000005720 sucrose Substances 0.000 claims description 3
- 125000000185 sucrose group Chemical group 0.000 claims description 3
- LADGBHLMCUINGV-UHFFFAOYSA-N tricaprin Chemical compound CCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCC)COC(=O)CCCCCCCCC LADGBHLMCUINGV-UHFFFAOYSA-N 0.000 claims description 3
- STORWMDPIHOSMF-UHFFFAOYSA-N decanoic acid;octanoic acid;propane-1,2,3-triol Chemical compound OCC(O)CO.CCCCCCCC(O)=O.CCCCCCCCCC(O)=O STORWMDPIHOSMF-UHFFFAOYSA-N 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 6
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 4
- LDVVMCZRFWMZSG-UHFFFAOYSA-N captan Chemical compound C1C=CCC2C(=O)N(SC(Cl)(Cl)Cl)C(=O)C21 LDVVMCZRFWMZSG-UHFFFAOYSA-N 0.000 description 4
- 235000014633 carbohydrates Nutrition 0.000 description 4
- 239000001087 glyceryl triacetate Substances 0.000 description 3
- 235000013773 glyceryl triacetate Nutrition 0.000 description 3
- 229960002622 triacetin Drugs 0.000 description 3
- 150000003626 triacylglycerols Chemical class 0.000 description 3
- -1 Miglyol 812 Chemical compound 0.000 description 2
- 229960002903 benzyl benzoate Drugs 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- PWEOPMBMTXREGV-UHFFFAOYSA-N decanoic acid;octanoic acid;propane-1,2-diol Chemical compound CC(O)CO.CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCCCC(O)=O.CCCCCCCCCC(O)=O PWEOPMBMTXREGV-UHFFFAOYSA-N 0.000 description 2
- LZCLXQDLBQLTDK-UHFFFAOYSA-N ethyl 2-hydroxypropanoate Chemical compound CCOC(=O)C(C)O LZCLXQDLBQLTDK-UHFFFAOYSA-N 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 2
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- 235000019486 Sunflower oil Nutrition 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 229940116333 ethyl lactate Drugs 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 1
- 239000002600 sunflower oil Substances 0.000 description 1
- 125000005457 triglyceride group Chemical group 0.000 description 1
Description
例えば、一例示的な実施形態では、高濃度タンパク質製剤は、（ｉ）少なくとも２００ｍｇ／ｍＬの治療用タンパク質と、（ｉｉ）２５％～７５％ｖ／ｖの疎水性剤と、（ｉｉｉ）２５％～７５％ｖ／ｖの粘度低下剤と、を含み得る。疎水性剤は、ＳＡＳＯＬ、ヒマワリ油、キャスター油、グリセロール、オレイン酸エチル、トリグリセリド、またはこれらの組み合わせから選択され得る。トリグリセリドは、グリセリルトリカプリレート／トリカプレート（Ｍｉｇｌｙｏｌ ８１２、Ｍｉｇｌｙｏｌ ８１０、Ｍｉｇｌｙｏｌ ８１８、Ｍｉｇｌｙｏｌ ８２９、Ｍｉｇｌｙｏｌ ８４０、ＣＡＰＴＥＸ３００、ＣＡＰＴＥＸ ＩＮＪ ３００、ＣＡＰＴＥＸ ＩＮＪ ３３５など）、グリセリルトリカプリレート、及びトリアセチン、またはこれらの組み合わせから選択され得る。一例示的な実施形態では、疎水性剤は、Ｍｉｇｌｙｏｌ ８１２Ｎである。粘度低下剤は、エタノール、ベンジルアルコール、安息香酸ベンジル、酢酸エチル、Ｎ－メチル－２－ピロリドン、乳酸エチル、ＰＥＧ４００、またはこれらの組み合わせから選択され得る。一例示的な実施形態において、粘度低下剤は、ベンジルアルコールである。この実施形態の別の態様では、高濃度タンパク質製剤は、２つ以上のトリグリセリドを含み得る。
For example, in one exemplary embodiment, the high concentration protein formulation comprises (i) at least 200 mg/mL therapeutic protein; (ii) 25% to 75% v/v hydrophobic agent; % to 75% v/v of a viscosity reducing agent. Hydrophobic agents may be selected from SASOL, sunflower oil, castor oil, glycerol, ethyl oleate, triglycerides, or combinations thereof. Triglycerides include glyceryl tricaprylate/ tricaprate (such as Miglyol 812, Miglyol 810, Miglyol 818, Miglyol 829, Miglyol 840, CAPTEX 300, CAPTEX INJ 300, CAPTEX INJ 335), glyceryl tricaprylate, and triacetin, or can be selected from a combination of In one exemplary embodiment, the hydrophobic agent is Miglyol 812N. Viscosity-lowering agents may be selected from ethanol, benzyl alcohol, benzyl benzoate, ethyl acetate, N-methyl-2-pyrrolidone, ethyl lactate, PEG400, or combinations thereof. In one exemplary embodiment, the viscosity-lowering agent is benzyl alcohol. In another aspect of this embodiment, the high concentration protein formulation may contain more than one triglyceride.
本明細書で使用される場合、「トリグリセリド」という用語は、グリセロール及び３つの脂肪酸に由来するエステルを指す。例示的なトリグリセリドは、グリセリルトリカプリレート／トリカプレート（Ｍｉｇｌｙｏｌ ８１２、Ｍｉｇｌｙｏｌ ８１０、Ｍｉｇｌｙｏｌ ８１８、Ｍｉｇｌｙｏｌ ８２９、Ｍｉｇｌｙｏｌ ８４０、ＣＡＰＴＥＸ ３００、ＣＡＰＴＥＸ ＩＮＪ ３００、ＣＡＰＴＥＸ ＩＮＪ ３３５など）、グリセリルトリカプリレート、及びトリアセチンである。
As used herein, the term "triglyceride" refers to an ester derived from glycerol and three fatty acids. Exemplary triglycerides are glyceryl tricaprylate/ tricaprate (such as Miglyol 812, Miglyol 810, Miglyol 818, Miglyol 829, Miglyol 840, CAPTEX 300, CAPTEX INJ 300, CAPTEX INJ 335), glyceryl tricaprylate, and It is triacetin.
本開示は以下の実施形態を含む。
実施形態１
非水性高濃度タンパク質製剤であって、
ａ．微細化固体タンパク質製剤として少なくとも約２００ｍｇ／ｍＬの治療用タンパク質と、
ｂ．疎水性剤と、
ｃ．粘度低下剤と、を含む、前記非水性高濃度タンパク質製剤。
実施形態２
前記微細化固体タンパク質製剤が、噴霧乾燥によって生成されたものである、実施形態１に記載の非水性高濃度タンパク質製剤。
実施形態３
前記疎水性剤が、トリグリセリドである、実施形態１に記載の非水性高濃度タンパク質製剤。
実施形態４
前記疎水性剤が、Ｍｉｇｌｙｏｌ ８１０Ｎ、Ｍｉｇｌｙｏｌ ８１２Ｎ、トリアセチン、またはこれらの組み合わせからなる群から選択される、実施形態１に記載の非水性高濃度タンパク質製剤。
実施形態５
前記疎水性剤が、Ｍｉｇｌｙｏｌ ８１２Ｎである、実施形態１に記載の非水性高濃度タンパク質製剤。
実施形態６
前記疎水性剤が、Ｍｉｇｌｙｏｌ ８１０Ｎである、実施形態１に記載の非水性高濃度タンパク質製剤。
実施形態７
前記粘度低下剤が、エタノール、ベンジルアルコール、酢酸エチル、Ｎ－メチル－２－ピロリドン、またはこれらの組み合わせからなる群から選択される、実施形態１に記載の非水性高濃度タンパク質製剤。
実施形態８
前記粘度低下剤が、エタノールである、実施形態７に記載の非水性高濃度タンパク質製剤。
実施形態９
前記粘度低下剤が、ベンジルアルコールである、実施形態７に記載の非水性高濃度タンパク質製剤。
実施形態１０
前記粘度低下剤が、酢酸エチルである、実施形態７に記載の非水性高濃度タンパク質製剤。
実施形態１１
前記微細化固体タンパク質製剤が、前記疎水性剤及び前記粘度低下剤中に無視可能な程度に可溶性である、実施形態１に記載の非水性高濃度タンパク質製剤。
実施形態１２
前記微細化固体タンパク質製剤が、粉末の形態である、実施形態１に記載の非水性高濃度タンパク質製剤。
実施形態１３
前記粉末が、トリロイシンを使用して製剤化されている、実施形態１２に記載の非水性高濃度タンパク質製剤。
実施形態１４
前記粉末の濃度が、約２００ｍｇ／ｍＬ～約５００ｍｇ／ｍＬである、実施形態１２に記載の非水性高濃度タンパク質製剤。
実施形態１５
前記粉末と前記非水性高濃度タンパク質製剤との重量比（ｗ／ｗ）が、約０．２５０を超える、実施形態１２に記載の非水性高濃度タンパク質製剤。
実施形態１６
前記粉末が、前記治療用タンパク質、炭水化物、アミノ酸、または非イオン性界面活性剤を含む、実施形態１２に記載の非水性高濃度タンパク質製剤。
実施形態１７
前記炭水化物が、スクロース、マンニトール、またはトレハロースである、実施形態１６に記載の非水性高濃度タンパク質製剤。
実施形態１８
前記アミノ酸が、ヒスチジンまたはプロリンである、実施形態１６に記載の非水性高濃度タンパク質製剤。
実施形態１９
前記非イオン性界面活性剤が、ポリソルベートである、実施形態１６に記載の非水性高濃度タンパク質製剤。
実施形態２０
前記ポリソルベートが、ポリソルベート２０、ポリソルベート４０、ポリソルベート６０、ポリソルベート８０、またはこれらの組み合わせからなる群から選択される、実施形態１９に記載の非水性高濃度タンパク質製剤。
実施形態２１
前記タンパク質の濃度（％ｗ／ｗ）が、少なくとも約７０％である、実施形態１６に記載の非水性高濃度タンパク質製剤。
実施形態２２
前記非水性高濃度タンパク質製剤が、約５０ニュートン（Ｎ）未満の注射摺動力を有する、実施形態１に記載の非水性高濃度タンパク質製剤。
実施形態２３
前記注射摺動力が、約３０ニュートン（Ｎ）未満である、実施形態２２に記載の非水性高濃度タンパク質製剤。
実施形態２４
前記治療用タンパク質が、モノクローナル抗体である、実施形態１に記載の非水性高濃度タンパク質製剤。
実施形態２５
非水性高濃度タンパク質製剤であって、
ａ．微細化固体タンパク質製剤として少なくとも約２００ｍｇ／ｍＬの治療用タンパク質と、
ｂ．Ｍｉｇｌｙｏｌ ８１２Ｎと、
ｃ．ベンジルアルコールと、を含む、前記非水性高濃度タンパク質製剤。
実施形態２６
前記微細化固体タンパク質製剤が、噴霧乾燥によって生成されたものである、実施形態２５に記載の非水性高濃度タンパク質製剤。
実施形態２７
前記微細化固体タンパク質製剤が、疎水性剤及び粘度低下剤中に無視可能な程度に可溶性である、実施形態２５に記載の非水性高濃度タンパク質製剤。
実施形態２８
前記微細化固体タンパク質製剤が、粉末の形態である、実施形態２５に記載の非水性高濃度タンパク質製剤。
実施形態２９
前記粉末が、トリロイシンを使用して製剤化されている、実施形態２８に記載の非水性高濃度タンパク質製剤。
実施形態３０
前記粉末の量が、約２００ｍｇ／ｍＬ～約５００ｍｇ／ｍＬである、実施形態２８に記載の非水性高濃度タンパク質製剤。
実施形態３１
前記粉末と前記非水性高濃度タンパク質製剤との重量比（ｗ／ｗ）が、約０．２５０を超える、実施形態２８に記載の非水性高濃度タンパク質製剤。
実施形態３２
前記粉末が、治療用タンパク質、炭水化物、アミノ酸、または非イオン性界面活性剤を含む、実施形態２８に記載の非水性高濃度タンパク質製剤。
実施形態３３
前記炭水化物が、スクロース、マンニトール、またはトレハロースである、実施形態３２に記載の非水性高濃度タンパク質製剤。
実施形態３４
前記アミノ酸が、ヒスチジンまたはプロリンである、実施形態３２に記載の非水性高濃度タンパク質製剤。
実施形態３５
前記非イオン性界面活性剤が、ポリソルベートである、実施形態３３に記載の非水性高濃度タンパク質製剤。
実施形態３６
前記ポリソルベートが、ポリソルベート２０、ポリソルベート４０、ポリソルベート６０、ポリソルベート８０、またはこれらの組み合わせからなる群から選択される、実施形態３５に記載の非水性高濃度タンパク質製剤。
実施形態３７
前記タンパク質の濃度（％ｗ／ｗ）が、少なくとも約７０％である、実施形態３２に記載の非水性高濃度タンパク質製剤。
実施形態３８
非水性高濃度タンパク質製剤であって、
ａ．微細化固体タンパク質製剤として少なくとも約２００ｍｇ／ｍＬの治療用タンパク質と、
ｂ．Ｍｉｇｌｙｏｌ ８１０Ｎ、Ｍｉｇｌｙｏｌ ８１２Ｎ、またはこれらの組み合わせからなる群から選択される疎水性剤と、
ｃ．エタノール、ベンジルアルコール、安息香酸ベンジル、酢酸エチル、Ｎ－メチル－２－ピロリドン、またはこれらの組み合わせからなる群から選択される粘度低下剤と、を含む、前記非水性高濃度タンパク質製剤。
本発明は、以下の実施例を参照することによってより十分に理解されるであろう。しかしながら、それらは、本発明の範囲を限定するものとして解釈すべきではない。
The present disclosure includes the following embodiments.
Embodiment 1
A non-aqueous high-concentration protein formulation comprising:
a. at least about 200 mg/mL of a therapeutic protein as a micronized solid protein formulation;
b. a hydrophobic agent;
c. and a viscosity-lowering agent.
Embodiment 2
2. The non-aqueous high concentration protein formulation of embodiment 1, wherein said micronized solid protein formulation is produced by spray drying.
Embodiment 3
The non-aqueous protein concentrate formulation of embodiment 1, wherein said hydrophobic agent is a triglyceride.
Embodiment 4
2. The non-aqueous protein concentrate formulation of embodiment 1, wherein said hydrophobic agent is selected from the group consisting of Miglyol 810N, Miglyol 812N, triacetin, or combinations thereof.
Embodiment 5
The non-aqueous protein concentrate formulation of embodiment 1, wherein said hydrophobic agent is Miglyol 812N.
Embodiment 6
The non-aqueous protein concentrate formulation of embodiment 1, wherein said hydrophobic agent is Miglyol 810N.
Embodiment 7
The non-aqueous protein concentrate formulation of embodiment 1, wherein said viscosity-lowering agent is selected from the group consisting of ethanol, benzyl alcohol, ethyl acetate, N-methyl-2-pyrrolidone, or combinations thereof.
Embodiment 8
8. The non-aqueous protein concentrate formulation of embodiment 7, wherein said viscosity-lowering agent is ethanol.
Embodiment 9
8. The non-aqueous protein concentrate formulation of embodiment 7, wherein said viscosity-lowering agent is benzyl alcohol.
Embodiment 10
8. The non-aqueous protein concentrate formulation of embodiment 7, wherein said viscosity-lowering agent is ethyl acetate.
Embodiment 11
2. The non-aqueous high concentration protein formulation of embodiment 1, wherein said micronized solid protein formulation is negligibly soluble in said hydrophobic agent and said viscosity-lowering agent.
Embodiment 12
2. The non-aqueous high concentration protein formulation of embodiment 1, wherein said micronized solid protein formulation is in the form of a powder.
Embodiment 13
13. The non-aqueous protein concentrate formulation of embodiment 12, wherein said powder is formulated with trileucine.
Embodiment 14
13. The non-aqueous protein concentrate formulation of embodiment 12, wherein the concentration of said powder is from about 200 mg/mL to about 500 mg/mL.
Embodiment 15
13. The non-aqueous protein concentrate formulation of embodiment 12, wherein the weight ratio (w/w) of said powder to said non-aqueous protein concentrate formulation is greater than about 0.250.
Embodiment 16
13. The non-aqueous protein concentrate formulation of embodiment 12, wherein said powder comprises said therapeutic protein, carbohydrate, amino acid, or nonionic surfactant.
Embodiment 17
17. The non-aqueous protein concentrate formulation of embodiment 16, wherein said carbohydrate is sucrose, mannitol, or trehalose.
Embodiment 18
17. The non-aqueous protein concentrate formulation of embodiment 16, wherein said amino acid is histidine or proline.
Embodiment 19
17. The non-aqueous protein concentrate formulation of embodiment 16, wherein said non-ionic surfactant is a polysorbate.
Embodiment 20
20. The non-aqueous protein concentrate formulation of embodiment 19, wherein said polysorbate is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, or combinations thereof.
Embodiment 21
17. The non-aqueous protein concentrate formulation of embodiment 16, wherein the protein concentration (% w/w) is at least about 70%.
Embodiment 22
3. The non-aqueous protein concentrate formulation of embodiment 1, wherein said non-aqueous protein concentrate formulation has an injection sliding force of less than about 50 Newtons (N).
Embodiment 23
23. The non-aqueous protein concentrate formulation of embodiment 22, wherein said injection sliding force is less than about 30 Newtons (N).
Embodiment 24
The non-aqueous protein concentrate formulation of embodiment 1, wherein said therapeutic protein is a monoclonal antibody.
Embodiment 25
A non-aqueous high-concentration protein formulation comprising:
a. at least about 200 mg/mL of a therapeutic protein as a micronized solid protein formulation;
b. Miglyol 812N;
c. and benzyl alcohol.
Embodiment 26
26. The non-aqueous high concentration protein formulation of embodiment 25, wherein said micronized solid protein formulation is produced by spray drying.
Embodiment 27
26. The non-aqueous high concentration protein formulation of embodiment 25, wherein said micronized solid protein formulation is negligibly soluble in hydrophobic and viscosity reducing agents.
Embodiment 28
26. The non-aqueous high concentration protein formulation of embodiment 25, wherein said micronized solid protein formulation is in the form of a powder.
Embodiment 29
29. The non-aqueous protein concentrate formulation of embodiment 28, wherein said powder is formulated with trileucine.
Embodiment 30
The non-aqueous protein concentrate formulation of embodiment 28, wherein the amount of said powder is from about 200 mg/mL to about 500 mg/mL.
Embodiment 31
29. The non-aqueous protein concentrate formulation of embodiment 28, wherein the weight ratio (w/w) of said powder to said non-aqueous protein concentrate formulation is greater than about 0.250.
Embodiment 32
29. The non-aqueous protein concentrate formulation of embodiment 28, wherein said powder comprises therapeutic proteins, carbohydrates, amino acids, or nonionic surfactants.
Embodiment 33
33. The non-aqueous protein concentrate formulation of embodiment 32, wherein said carbohydrate is sucrose, mannitol, or trehalose.
Embodiment 34
33. The non-aqueous protein concentrate formulation of embodiment 32, wherein said amino acid is histidine or proline.
Embodiment 35
34. The non-aqueous protein concentrate formulation of embodiment 33, wherein said non-ionic surfactant is a polysorbate.
Embodiment 36
36. The non-aqueous protein concentrate formulation of embodiment 35, wherein said polysorbate is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, or combinations thereof.
Embodiment 37
33. The non-aqueous protein concentrate formulation of embodiment 32, wherein the protein concentration (% w/w) is at least about 70%.
Embodiment 38
A non-aqueous high-concentration protein formulation comprising:
a. at least about 200 mg/mL of a therapeutic protein as a micronized solid protein formulation;
b. a hydrophobic agent selected from the group consisting of Miglyol 810N, Miglyol 812N, or combinations thereof;
c. and a viscosity-lowering agent selected from the group consisting of ethanol, benzyl alcohol, benzyl benzoate, ethyl acetate, N-methyl-2-pyrrolidone, or combinations thereof.
The invention will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the invention.
Claims (11)
ａ．微細化固体タンパク質製剤として約２００ｍｇ／ｍＬ～約６００ｍｇ／ｍＬの治療用タンパク質と、
ｂ．グリセリルトリカプリレート／トリカプレートを含む疎水性剤と、
ｃ．エタノール、ベンジルアルコール、酢酸エチル、Ｎ－メチル－２－ピロリドン、またはこれらの組み合わせからなる群から選択される粘度低下剤と、
を含む、前記非水性高濃度タンパク質製剤。 A non-aqueous high-concentration protein formulation comprising:
a. from about 200 mg/mL to about 600 mg/mL of therapeutic protein as a micronized solid protein formulation;
b. a hydrophobic agent comprising glyceryl tricaprylate/tricaprate ;
c. a viscosity-lowering agent selected from the group consisting of ethanol, benzyl alcohol, ethyl acetate, N-methyl-2-pyrrolidone, or combinations thereof ;
The non-aqueous high-concentration protein formulation comprising:
前記アミノ酸が、ヒスチジンまたはプロリンであり、および／または
前記非イオン性界面活性剤が、ポリソルベートであり、好ましくは前記ポリソルベートがポリソルベート２０、ポリソルベート４０、ポリソルベート６０、ポリソルベート８０、またはこれらの組み合わせからなる群から選択される、
請求項６に記載の非水性高濃度タンパク質製剤。 said carbohydrate is sucrose, mannitol, or trehalose , and/or
said amino acid is histidine or proline, and/or
said nonionic surfactant is a polysorbate, preferably said polysorbate is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, or combinations thereof;
The non-aqueous high-concentration protein formulation according to claim 6 .
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
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| US201862770337P | 2018-11-21 | 2018-11-21 | |
| US62/770,337 | 2018-11-21 | ||
| PCT/US2019/062596 WO2020106948A1 (en) | 2018-11-21 | 2019-11-21 | High concentration protein formulation |
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| JP2022532965A JP2022532965A (en) | 2022-07-21 |
| JPWO2020106948A5 true JPWO2020106948A5 (en) | 2022-11-28 |
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| US (2) | US12036280B2 (en) |
| EP (1) | EP3883542A1 (en) |
| JP (1) | JP7637618B2 (en) |
| KR (1) | KR20210093976A (en) |
| CN (1) | CN113164378A (en) |
| AU (1) | AU2019384160B2 (en) |
| BR (1) | BR112021009463A2 (en) |
| CA (1) | CA3118306A1 (en) |
| EA (1) | EA202191403A1 (en) |
| IL (1) | IL283229B2 (en) |
| MX (1) | MX2021005910A (en) |
| SG (1) | SG11202104166QA (en) |
| WO (1) | WO2020106948A1 (en) |
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| MX421310B (en) | 2018-05-10 | 2025-03-14 | Regeneron Pharma | High concentration vegf receptor fusion protein containing formulations |
| KR102735988B1 (en) | 2019-02-18 | 2024-12-03 | 일라이 릴리 앤드 캄파니 | therapeutic antibody preparations |
| WO2023039531A1 (en) * | 2021-09-09 | 2023-03-16 | Xeris Pharmaceuticals, Inc. | Injectable high concentration pharmaceutical formulations and methods of manufacturing and use thereof |
| TW202508633A (en) * | 2023-08-24 | 2025-03-01 | 美商瑞澤路特有限公司 | High concentration formulations for anti-insulin receptor antibody and uses thereof |
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| IT1142172B (en) * | 1978-10-19 | 1986-10-08 | Sandoz Ag | NEW THERAPEUTIC USE OF CYCLOSPORINE-A AND DIHYDROCYCLOSPORINE-C |
| US6659982B2 (en) | 2000-05-08 | 2003-12-09 | Sterling Medivations, Inc. | Micro infusion drug delivery device |
| US6629949B1 (en) | 2000-05-08 | 2003-10-07 | Sterling Medivations, Inc. | Micro infusion drug delivery device |
| KR20030038690A (en) * | 2000-08-07 | 2003-05-16 | 인헤일 테라퓨틱 시스템즈 인크. | Inhaleable spray dried 4-helix bundle protein powders having minimized aggregation |
| US20090208492A1 (en) * | 2007-06-14 | 2009-08-20 | Elan Pharmaceuticals, Inc. | Lyophilized Immunoglobulin Formulations and Methods of Preparation |
| US9072668B2 (en) | 2010-03-09 | 2015-07-07 | Janssen Biotech, Inc. | Non-aqueous high concentration reduced viscosity suspension formulations of antibodies |
| US20110223208A1 (en) * | 2010-03-09 | 2011-09-15 | Beth Hill | Non-Aqueous High Concentration Reduced Viscosity Suspension Formulations |
| WO2012122544A2 (en) * | 2011-03-10 | 2012-09-13 | Board Of Regents, The University Of Texas System | Protein nanoparticle dispersions |
| CN103356490A (en) * | 2012-03-29 | 2013-10-23 | 复旦大学 | Cross-linked food protein stabilized nanometer medicament delivery system capable of being solidified directly |
| MX389346B (en) * | 2012-05-18 | 2025-03-20 | Genentech Inc | HIGH CONCENTRATION MONOCLONAL ANTIBODY FORMULATIONS. |
| UA117466C2 (en) | 2012-12-13 | 2018-08-10 | Мерк Шарп Енд Доме Корп. | STABLE COMPOSITION IN THE VIEW OF AN ANTIBODY ANTIBODY TO IL-23p19 |
| IL312865B2 (en) * | 2013-09-11 | 2025-06-01 | Eagle Biologics Inc | Liquid protein formulations containing viscosity-reducing agents |
| DK2942050T3 (en) * | 2014-05-06 | 2022-11-21 | S I I T S R L Servizio Int Imballaggi Termosaldanti | SPRAYABLE, OIL-CONTAINING COMPOSITION BASED ON FAT-SOLUBLE GROUP D VITAMINS AND USE THEREOF |
| EP3240571A4 (en) * | 2014-12-31 | 2018-06-13 | NovelMed Therapeutics, Inc. | Formulation of aglycosylated therapeutic antibodies |
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