JP7402218B2 - 安定な濃厚放射性核種錯体溶液 - Google Patents
安定な濃厚放射性核種錯体溶液 Download PDFInfo
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- JP7402218B2 JP7402218B2 JP2021504167A JP2021504167A JP7402218B2 JP 7402218 B2 JP7402218 B2 JP 7402218B2 JP 2021504167 A JP2021504167 A JP 2021504167A JP 2021504167 A JP2021504167 A JP 2021504167A JP 7402218 B2 JP7402218 B2 JP 7402218B2
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- INBJJAFXHQQSRW-STOWLHSFSA-N rucaparib camsylate Chemical compound CC1(C)[C@@H]2CC[C@@]1(CS(O)(=O)=O)C(=O)C2.CNCc1ccc(cc1)-c1[nH]c2cc(F)cc3C(=O)NCCc1c23 INBJJAFXHQQSRW-STOWLHSFSA-N 0.000 description 1
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- 108700014314 sandostatinLAR Proteins 0.000 description 1
- 229950006896 sapacitabine Drugs 0.000 description 1
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- 230000001953 sensory effect Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- NHXLMOGPVYXJNR-ATOGVRKGSA-N somatostatin Chemical class C([C@H]1C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N1)[C@@H](C)O)NC(=O)CNC(=O)[C@H](C)N)C(O)=O)=O)[C@H](O)C)C1=CC=CC=C1 NHXLMOGPVYXJNR-ATOGVRKGSA-N 0.000 description 1
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- 229940063683 taxotere Drugs 0.000 description 1
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- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- OQUFJVRYDFIQBW-UHFFFAOYSA-N trametinib dimethyl sulfoxide Chemical compound CS(C)=O.CC(=O)NC1=CC=CC(N2C(N(C3CC3)C(=O)C3=C(NC=4C(=CC(I)=CC=4)F)N(C)C(=O)C(C)=C32)=O)=C1 OQUFJVRYDFIQBW-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
- A61K51/121—Solutions, i.e. homogeneous liquid formulation
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
- A61K51/083—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins the peptide being octreotide or a somatostatin-receptor-binding peptide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
- A61K51/088—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins conjugates with carriers being peptides, polyamino acids or proteins
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
Description
(ai)放射性核種と、
(aii)キレート化剤にリンクされた細胞レセプター結合有機部分と、
により形成された錯体と、
(b)放射線分解劣化に対する少なくとも1種の安定化剤と、
を含み、
前記放射性核種が、少なくとも100MBq/mL、好ましくは少なくとも250MBq/mLの体積放射能を提供する濃度で存在する、
医薬水性溶液。
(ai)250~500MBq/mLの体積放射能を提供する濃度で存在する放射性核種177ルテチウム(Lu-177)と、
(aii)キレート化剤にリンクされたソマトスタチンレセプター結合有機部分DOTA-TATE(オキソドトレオチド)又はDOTA-TOC(エドトレオチド)と、
により形成された錯体と、
(bi)0.5~1mg/mLの濃度で存在する放射線分解劣化に対する第1の安定化剤としてのゲンチシン酸又はその塩と、
(bii)2.0~5.0mg/mLの濃度で存在する放射線分解劣化に対する第2の安定化剤としてのアスコルビン酸又はその塩と、
を含む医薬水性溶液。
(1.1)放射性核種を含む水性溶液を調製することと、
(1.2)キレート化剤にリンクされた細胞レセプター結合有機部分と、第1の安定化剤と、任意選択的に第2の安定化剤と、を含む水性溶液を調製することと、
(1.3)工程(1.1)及び(1.2)で得られた溶液を混合して得られた混合物を加熱することと、
により、放射性核種と、キレート化剤にリンクされた細胞レセプター結合有機部分と、の錯体を形成するプロセス工程と、
(2)以下:
(2.1)第2の安定化剤を任意選択的に含む水性希釈溶液を調製することと、
(2.2.)工程(1)により得られた錯体溶液と、工程(2.1)により得られた希釈溶液と、を混合することと、
により、工程(1)により得られた錯体溶液を希釈するプロセス工程と、
を含む、以上に定義される前記医薬水性溶液の製造プロセス。
(ai)放射性核種と、
(aii)キレート化剤にリンクされた細胞レセプター結合有機部分と、
により形成された錯体と、
(b)放射線分解劣化に対する少なくとも1種の安定化剤と、
を含み、
前記放射性核種が、少なくとも100MBq/mL、好ましくは少なくとも250MBq/mLの体積放射能を提供する濃度で存在する、
医薬水性溶液。
実施形態1に記載の医薬水性溶液。
実施形態1~4のいずれか1つに記載の医薬水性溶液。
実施形態1~5のいずれか1つに記載の医薬水性溶液。
(ai)250~500MBq/mLの体積放射能を提供する濃度で存在する放射性核種177ルテチウム(Lu-177)と、
(aii)キレート化剤にリンクされたソマトスタチンレセプター結合有機部分DOTA-TATE(オキソドトレオチド)又はDOTA-TOC(エドトレオチド)と、
により形成された錯体と、
(bi)0.5~1mg/mLの濃度で存在する放射線分解劣化に対する第1の安定化剤としてのゲンチシン酸又はその塩と、
(bii)2.0~5.0mg/mLの濃度で存在する放射線分解劣化に対する第2の安定化剤としてのアスコルビン酸又はその塩と、
を含む医薬水性溶液。
をさらに含む、実施形態23に記載の医薬水性溶液。
をさらに含む、実施形態23又は24に記載の医薬水性溶液。
(1.1)放射性核種を含む水性溶液を調製することと、
(1.2)キレート化剤にリンクされた細胞レセプター結合有機部分と、第1の安定化剤と、任意選択的に第2の安定化剤と、を含む水性溶液を調製することと、
(1.3)工程(1.1)及び(1.2)で得られた溶液を混合して得られた混合物を加熱することと、
により、放射性核種と、キレート化剤にリンクされた細胞レセプター結合有機部分と、の錯体を形成するプロセス工程と、
(2)以下:
(2.1)第2の安定化剤を任意選択的に含む水性希釈溶液を調製することと、
(2.2.)工程(1)により得られた錯体溶液と、工程(2.1)により得られた希釈溶液と、を混合することと、
により、工程(1)により得られた錯体溶液を希釈するプロセス工程と、
を含む、実施形態1~31のいずれか1つに記載の医薬水性溶液の製造プロセス。
(4)工程(3)により得られた濾過溶液を、5.0~10MBq、好ましくは7.0~8.0MBq、より好ましくは7.3~7.7MBq、さらにより好ましくは7.4~7.5MBqの放射線量を送達するのに必要な量で、線量単位容器にディスペンスするプロセス工程であって、好ましくは前記量が10~50mL、より好ましくは15~30mL、さらにより好ましくは20~25mLである、プロセス工程と、
をさらに含む、実施形態32~39のいずれか1つに記載のプロセス。
(ai)放射性核種177Lu(ルテチウム-177)と、
(aii)キレート化剤DOTAにリンクされたソマトスタチンレセプター結合ペプチドと、
により形成された錯体と、
(b)放射線分解劣化に対する少なくとも2種の異なる安定化剤と、
を含み、
前記放射性核種が250~500MBq/mLの体積放射能を提供する濃度で存在し、且つ
前記安定化剤が0.2~20.0mg/mLの合計濃度で存在する、
医薬水性溶液。
(bi)ゲンチシン酸又はその塩と、
(bii)アスコルビン酸又はその塩と、
を含む、
実施形態E1に記載の医薬水性溶液。
(bii)アスコルビン酸が2.0~5.0mg/mLの濃度で存在する、
実施形態E2に記載の医薬水性溶液。
(a)以下:
(ai)250~500MBq/mLの体積放射能を提供する濃度の放射性核種177Lu(ルテチウム-177)と、
(aii)キレート化剤DOTAにリンクされたソマトスタチンレセプター結合ペプチドと、
により形成された錯体と、
(b)放射線分解劣化に対する安定化剤、
(bi)0.5~1mg/mLの濃度のゲンチシン酸と、
(bii)2.0~5.0mg/mLの濃度のアスコルビン酸と、
を含む医薬水性溶液、
を提供する。
をさらに含む、実施形態E3に記載の医薬水性溶液。
(di)0.3~0.7mg/mLの濃度の酢酸と、
(dii)0.4~0.9mg/mLの濃度の酢酸ナトリウムと、
から構成された酢酸塩緩衝剤、
をさらに含み、
好ましくは前記酢酸塩緩衝剤が、4.5~6.0、好ましくは4.7~6.0、より好ましくは5.0~6.0、さらにより好ましくは5.0~5.5のpHを提供する、
実施形態E3又はE4に記載の医薬水性溶液。
(a)以下:
(ai)250~500MBq/mLの体積放射能を提供する濃度の放射性核種177Lu(ルテチウム-177)と、
(aii)キレート化剤DOTAにリンクされたソマトスタチンレセプター結合ペプチドと、
により形成された錯体と、
(b)放射線分解劣化に対する安定化剤、(bi)0.5~1mg/mLの濃度のゲンチシン酸と、(bii)2.0~5.0mg/mLの濃度のアスコルビン酸と、
(c)0.01~0.10mg/mLの濃度のジエチレントリアミン五酢酸(DTPA)又はその塩と、
(d)以下:
(di)0.3~0.7mg/mLの濃度の酢酸と、
(dii)0.4~0.9mg/mLの濃度の酢酸ナトリウムと、
から構成された酢酸塩緩衝剤と、
を含み、
好ましくは前記酢酸塩緩衝剤が5.0~5.5のpHを提供する、
医薬水性溶液を提供する。
(a)以下:
(ai)250~500MBq/mLの体積放射能を提供する濃度の放射性核種177Lu(ルテチウム-177)と、
(aii)キレート化剤DOTAにリンクされたソマトスタチンレセプター結合ペプチドと、
により形成された錯体と、
(b)放射線分解劣化に対する安定化剤、
(bi)0.5~1mg/mL(最終溶液中)の濃度のゲンチシン酸と、
(bii)2.0~5.0mg/mL(最終溶液中)の濃度のアスコルビン酸と、
を含み、
成分(ai)及び(aii)の錯体形成時にゲンチシン酸が存在し、且つ成分(ai)及び(aii)の錯体形成後にアスコルビン酸が添加される、
医薬水性溶液を提供する。
(a)以下:
(ai)250~500MBq/mLの体積放射能を提供する濃度の放射性核種177Lu(ルテチウム-177)と、
(aii)キレート化剤DOTAにリンクされたソマトスタチンレセプター結合ペプチドと、
により形成された錯体と、
(b)放射線分解劣化に対する安定化剤、(bi)0.5~1mg/mLの濃度のゲンチシン酸と、(bii)2.0~5.0mg/mLの濃度のアスコルビン酸と、
(c)0.01~0.10mg/mLの濃度のジエチレントリアミン五酢酸(DTPA)又はその塩と、
(d)以下:
(di)0.3~0.7mg/mLの濃度の酢酸と、
(dii)0.4~0.9mg/mLの濃度の酢酸ナトリウムと、
から構成された酢酸塩緩衝剤と、
を含み、
好ましくは前記酢酸塩緩衝剤が5.0~5.5のpHを提供し、
成分(ai)及び(aii)の錯体形成時にゲンチシン酸が存在し、且つ成分(ai)及び(aii)の錯体形成後にアスコルビン酸が添加される、
医薬水性溶液。
(a)以下:
(ai)250~500MBq/mLの体積放射能を提供する濃度の放射性核種177Lu(ルテチウム-177)と、
(aii)キレート化剤DOTAにリンクされたソマトスタチンレセプター結合ペプチドと、
により形成された錯体と、
(b)放射線分解劣化に対する安定化剤、(bi)0.5~1mg/mLの濃度のゲンチシン酸と、(bii)2.0~5.0mg/mLの濃度のアスコルビン酸と、
(c)0.01~0.10mg/mLの濃度のジエチレントリアミン五酢酸(DTPA)又はその塩と、
(d)以下:
(di)0.3~0.7mg/mLの濃度の酢酸と、
(dii)0.4~0.9mg/mLの濃度の酢酸ナトリウムと、
から構成された酢酸塩緩衝剤と、
を含み、
好ましくは前記酢酸塩緩衝剤が5.0~5.5のpHを提供し、
成分(ai)及び(aii)の錯体形成時にゲンチシン酸が存在し、且つ成分(ai)及び(aii)の錯体形成後にアスコルビン酸が添加され、且つ成分(ai)及び(aii)の錯体形成時に存在する唯一の安定化剤がゲンチシン酸であり、且つ錯体配合時に20~40mg/mL、好ましくは25~35mg/mLの濃度で存在する、
医薬水性溶液。
(a)以下:
(ai)250~500MBq/mL(最終溶液中)の体積放射能を提供する濃度の放射性核種177Lu(ルテチウム-177)と、
(aii)キレート化剤DOTAにリンクされたソマトスタチンレセプター結合ペプチドと、
により形成された錯体と、
(b)放射線分解劣化に対する安定化剤、(bi)0.5~1mg/mLの濃度のゲンチシン酸と、(bii)2.0~5.0mg/mLの濃度のアスコルビン酸と、
(c)0.01~0.10mg/mLの濃度のジエチレントリアミン五酢酸(DTPA)又はその塩と、
(d)以下:
(di)0.3~0.7mg/mLの濃度の酢酸と、
(dii)0.4~0.9mg/mLの濃度の酢酸ナトリウムと、
から構成された酢酸塩緩衝剤と、
を含み、
好ましくは前記酢酸塩緩衝剤が5.0~5.5のpHを提供し、
成分(ai)及び(aii)の錯体形成時にゲンチシン酸が存在し、且つ成分(ai)及び(aii)の錯体形成後にアスコルビン酸が添加され、且つ成分(ai)及び(aii)の錯体形成時に存在する唯一の安定化剤がゲンチシン酸であり、且つ錯体配合時に20~40mg/mLの濃度で存在し、且つ放射性核種が錯体形成時に10~20GBq/mLの体積放射能を提供する濃度で存在する、
医薬水性溶液。
(1.1)放射性核種を含む水性溶液を調製することと、
(1.2)キレート化剤にリンクされたソマトスタチンレセプター結合ペプチドと、放射線分解劣化に対する少なくとも1種の安定化剤と、を含む水性溶液を調製することと、
(1.3)工程(1.1)及び(1.2)で得られた溶液を混合して、得られた混合物を加熱することと、
により、放射性核種177Luと、キレート化剤DOTAにリンクされたソマトスタチンレセプター結合ペプチドと、の錯体を形成するプロセス工程と、
(2)以下:
(2.1)放射線分解劣化に対する少なくとも1種の安定化剤を任意選択的に含む水性希釈溶液を調製することと、
(2.2.)工程(1)により得られた錯体溶液と、工程(2.1)により得られた希釈溶液と、を混合して最終溶液を得ることと、
により、工程(1)により得られた錯体溶液を希釈するプロセス工程と、
を含み、
(1.2)の下で調製された溶液が1種の安定化剤のみを含む場合、(2.1)の下で調製された溶液が少なくとも1種の安定化剤を含む、
実施形態E1~E14のいずれか1つに記載の医薬水性溶液の製造プロセス。
(4)工程(3)により得られた濾過溶液を、5.0~10MBq、好ましくは7.0~8.0MBq、より好ましくは7.3~7.7MBq、さらにより好ましくは7.4~7.5MBqの放射線量を送達するのに必要な量で、線量単位容器にディスペンスするプロセス工程であって、好ましくは前記量が10~50mL、より好ましくは15~30mL、さらにより好ましくは20~25mLである、プロセス工程と、
をさらに含む、実施形態E15~E23のいずれか1つに記載のプロセス。
以下では、本明細書で用いられる用語の意味が定義される。
(aii)キレート化剤にリンクされた細胞レセプター結合有機部分と、
により形成された錯体」:
放射性核種金属イオンは、アミン又はカルボン酸などのキレート化剤の官能基と非共有結合を形成している。キレート化剤は、キレート錯体を形成できるように少なくとも2個のかかる錯体化官能基を有する。
DOTA:1,4,7,10-テトラアザシクロドデカン-1,4,7,10-四酢酸、
DTPA:ジエチレントリアミン五酢酸、
NTA:ニトリロ三酢酸、
EDTA:エチレンジアミン四酢酸、
DO3A:1,4,7,10-テトラアザシクロドデカン-1,4,7-三酢酸、
NOTA:1,4,7-トリアザシクロノナン-1,4,7-三酢酸、
トリゾキセタン、
テトラキセタン、
又はそれらの混合物、
でありうるとともに、好ましくは、DOTAである。
DOTA-OC:[DOTA0,D-Phe1]オクトレオチド、
DOTA-TOC:以下の式により表される[DOTA0,D-Phe1,Tyr3]オクトレオチド及びエドトレオチド(INN):
DOTA-NOC:[DOTA0,D-Phe1,1-Nal3]オクトレオチド、
DOTA-TATE:以下の式により表される[DOTA0,D-Phe1,Tyr3]オクトレオテート、DOTA-Tyr3-オクトレオテート、DOTA-d-Phe-Cys-Tyr-d-Trp-Lys-Thr-Cys-Thr(シクロ2,7)、オキソドトレオチド(INN):
DOTA-LAN:[DOTA0,D-β-Nal1]ランレオチド、
DOTA-VAP:[DOTA0,D-Phe1,Tyr3]バプレオチド。
177LuCl3は、I.D.B.Holland BVなどの供給業者から得られうる。DOTA0-Tyr3-オクトレオテートは、piCHEM Forschungs-und Entwicklungs GmbH,Austriaなどの供給業者から入手しうる。薬剤製品の他の成分はすべて、各種供給元から市販されている。
薬剤製品(177Lu-DOTA0-Tyr3-オクトレオテート370MBq/mL注入用溶液)は、参照日及び参照時刻(キャリブレーション時刻(tc))で370MBq/mLの体積放射能を有する薬剤物質として177Lu-DOTA0-Tyr3-オクトレオテートを含有する注入用無菌即使用可能溶液として設計される。キャリブレーション時刻(tc)は、第1のQCバイアルの放射能の測定時刻である製造終了時(EOP=t0)に対応する。薬剤製品の貯蔵寿命は、キャリブレーション時刻後の72時間として定義される。薬剤製品は、注射時に7.4GBqの放射能の送達を可能にする好適量の溶液を含有する単一線量バイアルである。
74GBqバッチサイズ(2Ciバッチサイズ)では、177LuCl3溶液(HCl中約74GBq)と、DOTA-Tyr3-オクトレオテート(約2mg)溶液と、反応緩衝剤溶液(抗酸化剤(及び放射線分解劣化に対する安定化剤)(すなわちゲンチシン酸、約157mg)と緩衝剤系(すなわち酢酸塩緩衝剤系)とを含有する)と、を混合一体化し、合計約5.5mLの溶液を生成し、これを約90~約98℃の温度で15分間未満のうちに行われる放射性標識に使用する。
以下の表は、実施例2に記載のプロセスに従って74GBqバッチサイズで製造されたバッチの安定性試験データを提供する。
本発明は、以下の態様を含み得る。
[1]
(a)以下:
(ai)放射性核種 177 Lu(ルテチウム-177)と、
(aii)キレート化剤DOTAにリンクされたソマトスタチンレセプター結合ペプチドと、
により形成された錯体と、
(b)放射線分解劣化に対する少なくとも2種の異なる安定化剤と、
を含み、
前記放射性核種が250~500MBq/mLの体積放射能を提供する濃度で存在し、且つ
前記安定化剤が0.2~20.0mg/mLの合計濃度で存在する、
医薬水性溶液。
[2]
前記成分(b)が、安定化剤:
(bi)ゲンチシン酸又はその塩と、
(bii)アスコルビン酸又はその塩と、
を含む、[1]に記載の医薬水性溶液。
[3]
(bi)ゲンチシン酸が0.5~2mg/mL、好ましくは0.5~1mg/mLの濃度で存在し、且つ
(bii)アスコルビン酸が2.0~5.0mg/mLの濃度で存在する、
[2]に記載の医薬水性溶液。
[4]
(c)0.01~0.10mg/mLの濃度のジエチレントリアミン五酢酸(DTPA)又はその塩、
をさらに含む、[3]に記載の医薬水性溶液。
[5]
(d)以下:
(di)0.3~0.7mg/mLの濃度の酢酸と、
(dii)0.4~0.9mg/mLの濃度の酢酸ナトリウムと、
から構成された酢酸塩緩衝剤、
をさらに含み、
好ましくは前記酢酸塩緩衝剤が、4.5~6.0、好ましくは5.0~5.5のpHを提供する、
[3]又は[4]に記載の医薬水性溶液。
[6]
少なくとも1種の安定化剤が成分(ai)及び(aii)の錯体形成時に存在し、且つ少なくとも1種の安定化剤が成分(ai)及び(aii)の錯体形成後に添加される、[1]~[5]のいずれか一項に記載の医薬水性溶液。
[7]
成分(ai)及び(aii)の錯体形成時に少なくともゲンチシン酸が存在し、且つ成分(ai)及び(aii)の錯体形成後に少なくともアスコルビン酸が添加される、[1]~[5]のいずれか一項に記載の医薬水性溶液。
[8]
成分(ai)及び(aii)の錯体形成時に存在する唯一の安定化剤がゲンチシン酸であり、且つ成分(ai)及び(aii)の錯体形成後に添加される唯一の安定化剤がアスコルビン酸である、[1]~[5]のいずれか一項に記載の医薬水性溶液。
[9]
成分(ai)及び(aii)の錯体形成時に存在する1種/複数種の安定化剤が、15~50mg/mL、好ましくは20~40mg/mLの合計濃度で前記錯体配合時に存在する、[6]~[8]のいずれか一項に記載の医薬水性溶液。
[10]
成分(ai)及び(aii)の錯体形成時に存在する唯一の安定化剤がゲンチシン酸であり、且つ前記錯体配合時に20~40mg/mL、好ましくは25~35mg/mLの濃度で存在する、[9]に記載の医薬水性溶液。
[11]
≦25℃で貯蔵したときに少なくとも72h、とくに25℃で貯蔵したときに少なくとも72hの貯蔵寿命を有する、[1]~[10]のいずれか一項に記載の医薬水性溶液。
[12]
25℃で貯蔵したときに放射化学的純度(HPLCにより決定)が少なくとも72hにわたり≧95%に維持される、[1]~[11]のいずれか一項に記載の医薬水性溶液。
[13]
前記溶液が商業製造スケールで製造される、とくに少なくとも20GBq、少なくとも50GBq、少なくとも70GBqのバッチサイズで製造される、[1]~[12]のいずれか一項に記載の医薬水性溶液。
[14]
即使用可能である、[1]~[13]のいずれか一項に記載の医薬水性溶液。
[15]
(1)以下:
(1.1)放射性核種を含む水性溶液を調製することと、
(1.2)キレート化剤にリンクされたソマトスタチンレセプター結合ペプチドと、放射線分解劣化に対する少なくとも1種の安定化剤と、を含む水性溶液を調製することと、
(1.3)工程(1.1)及び(1.2)で得られた溶液を混合して得られた混合物を加熱することと、
により、放射性核種 177 Luと、キレート化剤DOTAにリンクされたソマトスタチンレセプター結合ペプチドと、の錯体を形成するプロセス工程と、
(2)以下:
(2.1)放射線分解劣化に対する少なくとも1種の安定化剤を任意選択的に含む水性希釈溶液を調製することと、
(2.2.)工程(1)により得られた錯体溶液と、工程(2.1)により得られた希釈溶液と、を混合して最終溶液を得ることと、
により、工程(1)により得られた錯体溶液を希釈するプロセス工程と、
を含み、
(1.2)の下で調製された溶液が1種の安定化剤のみを含む場合、(2.1)の下で調製された溶液が少なくとも1種の安定化剤を含む、
[1]~[14]のいずれか一項に記載の医薬水性溶液の製造プロセス。
[16]
工程(1.2)で調製された溶液が少なくとも1種の安定化剤を含み、且つ工程(2.1)で調製された溶液が少なくとも1種の安定化剤を含む、[15]に記載のプロセス。
[17]
工程(1.2)で調製された溶液が少なくとも安定化剤ゲンチシン酸を含み、且つ工程(2.1)で調製された溶液が少なくとも安定化剤アスコルビン酸を含む、[15]に記載のプロセス。
[18]
工程(1.2)で調製された溶液が、ゲンチシン酸である1種の安定化剤のみを含み、且つ工程(2.1)で調製された溶液が、アスコルビン酸である1種の安定化剤のみを含む、[15]に記載のプロセス。
[19]
工程(1.2)で調製された溶液が、15~50mg/mL、好ましくは20~40mg/mLの合計濃度で1種/複数種の安定化剤を含む、[15]~[18]のいずれか一項に記載のプロセス。
[20]
工程(1.2)で調製された溶液が、20~40mg/mL、好ましくは25~35mg/mLの濃度でゲンチシン酸である1種の安定化剤のみを含む、[15]~[18]のいずれか一項に記載のプロセス。
[21]
工程(1.2)の溶液が緩衝剤、好ましくは酢酸塩緩衝剤をさらに含む、[15]~[20]のいずれか一項に記載のプロセス。
[22]
工程(1.3)で、得られた混合物が、2~59分、好ましくは10~15分にわたり、70~99℃、好ましくは90~98℃の温度に加熱される、[15]~[21]のいずれか一項に記載のプロセス。
[23]
工程(2.1)の溶液がジエチレントリアミン五酢酸(DTPA)又はその塩をさらに含む、[15]~[22]のいずれか一項に記載のプロセス。
[24]
(3)工程(2)により得られた溶液を0.2μmに通して濾過するプロセス工程と、
(4)工程(3)により得られた濾過溶液を、5.0~10MBq、好ましくは7.0~8.0MBq、より好ましくは7.3~7.7MBq、さらにより好ましくは7.4~7.5MBqの放射線量を送達するのに必要な量で、線量単位容器にディスペンスするプロセス工程であって、好ましくは前記量が10~50mL、より好ましくは15~30mL、さらにより好ましくは20~25mLである、プロセス工程と、
をさらに含む、[15]~[23]のいずれか一項に記載のプロセス。
[25]
工程(1.1)の溶液がLuCl 3 とHClとを含む、[15]~[24]のいずれか一項に記載のプロセス。
[26]
工程(1.2)の溶液が、 177 Lu-DOTA-TATE又は 177 Lu-DOTA-TOCと、ゲンチシン酸と、酢酸と、酢酸ナトリウムと、を含む、[15]~[25]のいずれか一項に記載のプロセス。
[27]
工程(2.1)の溶液がDTPAとアスコルビン酸とを含む、[15]~[26]のいずれか一項に記載のプロセス。
[28]
工程(4)の線量単位容器が、鉛容器内に封入されたストッパー付きバイアルである、[24]~[27]のいずれか一項に記載のプロセス。
[29]
[15]~[28]のいずれか一項に記載のプロセスにより得られた医薬水性溶液。
Claims (20)
- (a)以下:
(ai)放射性核種177Lu(ルテチウム-177)と、
(aii)DOTA-TATE(オキソドトレオチド)またはDOTA-TOC(エドトレオチド)と、
により形成された錯体と、
(b)放射線分解劣化に対する少なくとも2種の異なる安定化剤と、
を含み、
前記放射性核種が250~500MBq/mLの体積放射能を提供する濃度で存在し、
前記成分(b)が、安定化剤:
(bi)ゲンチシン酸又はその塩と、
(bii)アスコルビン酸又はその塩と、
を含み、
前記安定化剤が1.0~5.0mg/mLの合計濃度で存在し、25℃で貯蔵したときに前記医薬水性溶液の放射化学的純度(HPLCにより決定)が少なくとも72時間にわたり≧95%に維持され、最終溶液のエタノール濃度が1%未満であり、
(bi)ゲンチシン酸が0.5~2mg/mLの濃度で存在し、且つ
(bii)アスコルビン酸が2.0~5.0mg/mLの濃度で存在する、医薬水性溶液。 - (bi)ゲンチシン酸が0.5~1mg/mLの濃度で存在する、
請求項1に記載の医薬水性溶液。 - (c)0.01~0.10mg/mLの濃度のジエチレントリアミン五酢酸(DTPA)又はその塩、
をさらに含む、請求項2に記載の医薬水性溶液。 - (d)以下:
(di)0.3~0.7mg/mLの濃度の酢酸と、
(dii)0.4~0.9mg/mLの濃度の酢酸ナトリウムと、
から構成される酢酸塩緩衝剤、
をさらに含み、
前記酢酸塩緩衝剤が、4.5~6.0のpHを提供する、
請求項2又は3に記載の医薬水性溶液。 - ≦25℃で貯蔵したときに少なくとも72時間の貯蔵寿命を有する、請求項1~4のいずれか一項に記載の医薬水性溶液。
- 即使用可能である、請求項1~5のいずれか一項に記載の医薬水性溶液。
- (1)以下:
(1.1)放射性核種を含む水性溶液を調製することと、
(1.2)DOTA-TATE(オキソドトレオチド)またはDOTA-TOC(エドトレオチド)と、放射線分解劣化に対する少なくとも1種の安定化剤と、を含む水性溶液を調製することと、
(1.3)工程(1.1)及び(1.2)で得られた溶液を混合して得られた混合物を加熱することと、
により、放射性核種177Luと、DOTA-TATE(オキソドトレオチド)またはDOTA-TOC(エドトレオチド)と、の錯体を形成するプロセス工程と、
(2)以下:
(2.1)放射線分解劣化に対する少なくとも1種の安定化剤を任意選択的に含む水性希釈溶液を調製することと、
(2.2.)工程(1)により得られた錯体溶液と、工程(2.1)により得られた希釈溶液と、を混合して最終溶液を得ることと、
により、工程(1)により得られた錯体溶液を希釈するプロセス工程と、
を含み、
(1.2)の下で調製された溶液が1種の安定化剤のみを含む場合、(2.1)の下で調製された溶液が工程(1.2)で使用された安定化剤とは異なる少なくとも1種の安定化剤を含み、且つ
前記安定化剤が1.0~5.0mg/mLの合計濃度で最終溶液中に存在し、前記最終溶液のエタノール濃度が1%未満であり、前記安定化剤がゲンチシン酸又はその塩、およびアスコルビン酸又はその塩から選択され、ゲンチシン酸が0.5~2mg/mLの濃度で存在し、且つアスコルビン酸が2.0~5.0mg/mLの濃度で存在する、
請求項1~6のいずれか一項に記載の医薬水性溶液の製造プロセス。 - 工程(1.2)で調製された溶液が少なくとも1種の安定化剤を含み、且つ工程(2.1)で調製された溶液が少なくとも1種の安定化剤を含む、請求項7に記載のプロセス。
- 工程(1.2)で調製された溶液が少なくとも安定化剤ゲンチシン酸を含み、且つ工程(2.1)で調製された溶液が少なくとも安定化剤アスコルビン酸を含む、請求項7に記載のプロセス。
- 工程(1.2)で調製された溶液が、ゲンチシン酸である1種の安定化剤のみを含み、且つ工程(2.1)で調製された溶液が、アスコルビン酸である1種の安定化剤のみを含む、請求項7に記載のプロセス。
- 工程(1.2)で調製された溶液が、15~50mg/mLの合計濃度で1種または複数種の安定化剤を含む、請求項7~10のいずれか一項に記載のプロセス。
- 工程(1.2)で調製された溶液が、20~40mg/mLの濃度でゲンチシン酸である1種の安定化剤のみを含む、請求項7~10のいずれか一項に記載のプロセス。
- 工程(1.2)の溶液が緩衝剤をさらに含む、請求項7~12のいずれか一項に記載のプロセス。
- 工程(1.3)で、得られた混合物が、2~59分にわたり、70~99℃の温度に加熱される、請求項7~13のいずれか一項に記載のプロセス。
- 工程(2.1)の溶液がジエチレントリアミン五酢酸(DTPA)又はその塩をさらに含む、請求項7~14のいずれか一項に記載のプロセス。
- (3)工程(2)により得られた溶液を0.2μmに通して濾過するプロセス工程と、
(4)工程(3)により得られた濾過溶液を、5.0~10MBqの放射線量を送達するのに必要な量で、線量単位容器にディスペンスするプロセス工程であって、前記量が10~50mLである、プロセス工程と、
をさらに含む、請求項7~15のいずれか一項に記載のプロセス。 - 工程(1.1)の溶液がLuCl3とHClとを含む、請求項7~16のいずれか一項に記載のプロセス。
- 工程(1.2)の溶液が、DOTA-TATE又はDOTA-TOCと、ゲンチシン酸と、酢酸と、酢酸ナトリウムと、を含む、請求項7~17のいずれか一項に記載のプロセス。
- 工程(2.1)の溶液がDTPAとアスコルビン酸とを含む、請求項7~18のいずれか一項に記載のプロセス。
- 工程(4)の線量単位容器が、鉛容器内に封入されたストッパー付きバイアルである、請求項16~19のいずれか一項に記載のプロセス。
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