JP5764328B2 - 改良された放射性医薬組成物 - Google Patents
改良された放射性医薬組成物 Download PDFInfo
- Publication number
- JP5764328B2 JP5764328B2 JP2010525359A JP2010525359A JP5764328B2 JP 5764328 B2 JP5764328 B2 JP 5764328B2 JP 2010525359 A JP2010525359 A JP 2010525359A JP 2010525359 A JP2010525359 A JP 2010525359A JP 5764328 B2 JP5764328 B2 JP 5764328B2
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- JP
- Japan
- Prior art keywords
- tetrofosmin
- dose
- radiopharmaceutical
- kit
- syringe
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 238000009826 distribution Methods 0.000 description 1
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- 125000001033 ether group Chemical group 0.000 description 1
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- 238000011990 functional testing Methods 0.000 description 1
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- 150000002334 glycols Chemical class 0.000 description 1
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
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- 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
- 229960000367 inositol Drugs 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000012633 leachable Substances 0.000 description 1
- 150000002634 lipophilic molecules Chemical class 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
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- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 238000009206 nuclear medicine Methods 0.000 description 1
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- 238000010979 pH adjustment Methods 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
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- 230000035699 permeability Effects 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-M phenolate Chemical compound [O-]C1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-M 0.000 description 1
- 229940031826 phenolate Drugs 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229920001084 poly(chloroprene) Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 238000002600 positron emission tomography Methods 0.000 description 1
- WSHYKIAQCMIPTB-UHFFFAOYSA-M potassium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical compound [K+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 WSHYKIAQCMIPTB-UHFFFAOYSA-M 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 238000007342 radical addition reaction Methods 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 230000005258 radioactive decay Effects 0.000 description 1
- 238000000163 radioactive labelling Methods 0.000 description 1
- 238000003608 radiolysis reaction Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010058 rubber compounding Methods 0.000 description 1
- 230000002000 scavenging effect Effects 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
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000002603 single-photon emission computed tomography Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
- UPMFZISCCZSDND-JJKGCWMISA-M sodium gluconate Chemical compound [Na+].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O UPMFZISCCZSDND-JJKGCWMISA-M 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 229940007163 stannous tartrate Drugs 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 239000010937 tungsten Substances 0.000 description 1
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
- A61K51/02—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
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
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- 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
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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
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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
- A61K51/02—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
- A61K51/025—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 inorganic Tc complexes or compounds
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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
- A61K9/0012—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
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Description
(i)99mTcと金属錯体を形成するリガンド、及び
(ii)過テクネチウム酸塩(即ち、Tc(VII))を所望の99mTc金属錯体生成物のそれより低い酸化状態に還元できる生体適合性還元剤。
テトロフォスミン 0.23mg
塩化第一スズ二水和物 30μg
スルホサリチル酸二ナトリウム 0.32mg
D−グルコン酸ナトリウム 1.0mg
炭酸水素ナトリウム 1.8mg
再構成後のpH 8.3〜9.1
この製剤は窒素ガスUSP/NF下で10mlガラスバイアル内に封入されていて、これを無菌(99mTc)過テクネチウム酸ナトリウム注射液USP/Ph.Eur.で再構成すれば、心臓イメージング用の放射性医薬品99mTc−テトロフォスミンを含む溶液が得られる。テトロフォスミンのモル濃度は、再構成体積に応じて変化する。製造業者の説明書(パッケージリーフレット)通りに再構成した場合、凍結乾燥Myoview(商標)製剤を再構成するために使用される体積は4〜8mlの範囲内にある。これは0.15mMテトロフォスミン(1Mテトロフォスミン=382.45g/L)の最大モル濃度を与える。
一態様では、本発明は、
(i)生体適合性キャリヤー中にあるテトロフォスミンの99mTc錯体、
(ii)テトロフォスミン、並びに
(iii)アスコルビン酸及びそれの生体適合性陽イオンとの塩から選択される放射線防護剤
を含んでなる放射性医薬組成物であって、テトロフォスミンと放射線防護剤とのモル比が0.10:1.0〜1.0:1.0の範囲内にある放射性医薬組成物を提供する。
(i)一定範囲の臨床グレードプラスチック注射器に対する保持放射能が減少すること、
(ii)公知の放射線防護剤含有99mTc−テトロフォスミン組成物に比べて放射化学安定性が向上すること、及び
(iii)公知の99mTc−テトロフォスミン組成物に比べて放射化学純度が向上すること。
本発明の別の態様は本発明の放射性医薬組成物を調製するための非放射性キットであって、前記キットは
(i)テトロフォスミン、
(ii)アスコルビン酸及びそれの生体適合性陽イオンとの塩から選択される放射線防護剤、並びに
(iii)生体適合性還元剤
を含む製剤を内部に収容した適当な容器を含んでなり、テトロフォスミンと放射線防護剤とのモル比は本発明の放射性医薬組成物に関して上記に定義した通りである。
好ましい実施形態では、本発明のキットは多用量キットである。この「多用量キット」は、溶液の添加及び抜取りが可能なクロージャを備えた密封無菌容器内に本発明の製剤を含んでいて、1つの多用量キットから99mTc−テトロフォスミン放射性医薬品の4〜30回分の単位患者用量を得ることができるようなものである。多用量キットの容器及びクロージャーの好ましい態様は、本発明のキットに関して上記に記載した通りである。
本発明の別の態様は、99mTc−テトロフォスミン放射性医薬品の複数回分の単位患者用量の調製方法であって、
(i)本発明の多用量キットを99mTc−過テクネチウム酸塩の無菌溶液で再構成するか、或いは最初に生体適合性キャリヤーで、次いで99mTc−過テクネチウム酸塩の無菌溶液で再構成する段階、
(ii)任意には、段階(i)を抗菌保存剤の存在下で実施する段階、
(iii)99mTc−テトロフォスミン錯体を形成させて、所望の99mTc−テトロフォスミン放射性医薬品のバルク供給材料を含む溶液を得る段階、
(iv)任意には、99mTc−テトロフォスミン錯体のバルク供給材料の放射化学純度を確認する段階、
(v)段階(iii)のバルク供給材料から単位用量を適当な注射器又は容器内に抜き取る段階、及び
(vi)後の時点で追加の注射器又は容器を用いて段階(v)を繰り返すことで追加の単位用量を得る段階
を含んでなる方法である。
(a)調製された99mTc−テトロフォスミンは、使い捨てプラスチック注射器に対して付着性の減少を示す。
(b)放射能(99mTc−過テクネチウム酸塩)が関与する操作の数が格段に減少する。
(c)空気導入段階を必要としない。
(d)投与量ごとのQC決定と異なり、単位用量のバッチごとにただ1回のQC決定しか必要とされない。
(e)製剤が一定範囲の99mTcジェネレータ溶出液条件に耐え得るようにしてバルクバイアルが処方される。
(f)必要とされる段階が減少するので、自動化が容易となる。
(g)必要とされる非放射性キットバイアルが減少するので、冷蔵庫の貯蔵空間が節約される。
本発明はまた、1人の患者のイメージングに適した99mTc放射能含有量を有する本発明の放射性医薬組成物を含んでなる99mTc−テトロフォスミン放射性医薬品の単位用量を提供する。
実施例1では、テトロフォスミンの合成を記載する。
すべての反応及び操作は、真空中又は酸素を含まない窒素雰囲気下で行った。溶媒は乾燥し、使用前に窒素パージによって脱気した。α−アゾイソブチロニトリル(AIBN)及びエチルビニルエーテルは、それぞれBDH社及びAldrich社から入手した。ビス(ジホスフィノ)エタンは、文献(Inorganic Synthesis,Vol 14,10)に従って製造した。
下記の凍結乾燥製剤を調製した。
下記の凍結乾燥製剤を調製した。
下記の凍結乾燥製剤を調製した。
Claims (15)
- (i)生体適合性キャリヤー中にあるテトロフォスミンの99mTc錯体、
(ii)テトロフォスミン、並びに
(iii)アスコルビン酸及びそれの生体適合性陽イオンとの塩から選択される放射線防護剤
を含んでなる放射性医薬組成物であって、(i)及び(ii)に存在するテトロフォスミンの合計量と(iii)中の放射線防護剤とのモル比が0.10:1.0〜1.0:1.0の範囲内にある放射性医薬組成物。 - さらに生体適合性還元剤を含む、請求項1記載の放射性医薬組成物。
- さらにpH調整剤を含む、請求項1又は請求項2記載の放射性医薬組成物。
- さらに、5−スルホサリチル酸及びグルコン酸並びにこれらの生体適合性陽イオンとの塩から選択される1種以上のトランスキレーターを含む、請求項1乃至請求項3のいずれか1項記載の放射性医薬組成物。
- 放射線防護剤がアスコルビン酸である、請求項1乃至請求項4のいずれか1項記載の放射性医薬組成物。
- 請求項1乃至請求項5のいずれか1項記載の放射性医薬組成物を臨床グレードの容器又は注射器内に収容してなる99mTc−テトロフォスミン放射性医薬品の単位患者用量。
- 施術者を放射線量から保護するためのシリンジシールドを有する注射器に入れて供給される、請求項6記載の単位患者用量。
- 請求項1乃至請求項5のいずれか1項記載の放射性医薬組成物を調製するための非放射性キットであって、当該キットが、
(i)テトロフォスミン、
(ii)アスコルビン酸及びそれの生体適合性陽イオンとの塩から選択される放射線防護剤、並びに
(iii)生体適合性還元剤
を含む製剤を内部に収容した適当な容器を含んでなり、テトロフォスミンと放射線防護剤とのモル比は請求項1に定義した通りである、非放射性キット。 - 前記製剤が凍結乾燥されている、請求項8記載の非放射性キット。
- 前記容器が、無菌健全性を維持しながら溶液の添加及び抜取りを許すクロージャーを備えた密封無菌容器である、請求項8又は請求項9記載の非放射性キット。
- 前記クロージャーは、容器内容物に接触するその表面がエチレン−テトラフルオロエチレンコポリマー(ETFE)を含むコーティングで被覆されている、請求項10記載の非放射性キット。
- 単一の多用量キットから4〜30回分の単位患者用量の99mTc−テトロフォスミン放射性医薬品を得ることができるように処方された多用量キットであり、前記単位用量が請求項6又は請求項7で定義した通りである、請求項10又は請求項11記載のキット。
- 容器が容積20〜40cm3の隔膜封止バイアルである、請求項12記載のキット。
- 99mTc−テトロフォスミン放射性医薬品の複数回分の単位患者用量の調製方法であって、
(i)請求項12又は請求項13のいずれかに記載の多用量キットを99mTc−過テクネチウム酸塩の無菌溶液で再構成するか、或いは最初に生体適合性キャリヤーで、次いで99mTc−過テクネチウム酸塩の無菌溶液で再構成する段階、
(ii)任意には、段階(i)を抗菌保存剤の存在下で実施する段階、
(iii)99mTc−テトロフォスミン錯体を形成させて、所望の99mTc−テトロフォスミン放射性医薬品のバルク供給材料を含む溶液を得る段階、
(iv)任意には、99mTc−テトロフォスミン錯体のバルク供給材料の放射化学純度を確認する段階、
(v)段階(iii)のバルク供給材料から単位用量を適当な注射器又は容器内に抜き取る段階、及び
(vi)後の時点で追加の注射器又は容器を用いて段階(v)を繰り返すことで追加の単位用量を得る段階
を含んでなる方法。 - 段階(i)で使用する99mTc−過テクネチウム酸塩が0.2〜100GBqの範囲内の放射能含有量を有する、請求項14記載の方法。
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US7344702B2 (en) | 2004-02-13 | 2008-03-18 | Bristol-Myers Squibb Pharma Company | Contrast agents for myocardial perfusion imaging |
US7485283B2 (en) * | 2004-04-28 | 2009-02-03 | Lantheus Medical Imaging | Contrast agents for myocardial perfusion imaging |
WO2009110984A2 (en) * | 2008-02-29 | 2009-09-11 | Lantheus Medical Imaging, Inc. | Contrast agents for applications including perfusion imaging |
LT2419096T (lt) | 2009-04-15 | 2020-04-10 | Lantheus Medical Imaging, Inc. | Radiofarmacinės kompozicijos stabilizavimas naudojant askorbo rūgštį |
EP3323810B1 (en) | 2010-02-08 | 2022-01-05 | Lantheus Medical Imaging, Inc. | Automated reaction system, cassette and apparatus for synthesizing imaging agents |
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JPS60248710A (ja) * | 1984-05-22 | 1985-12-09 | Daikin Ind Ltd | 新規エチレン/テトラフルオロエチレン系共重合体 |
JP4269456B2 (ja) * | 1999-12-24 | 2009-05-27 | 日立電線株式会社 | カテーテルチューブの製造方法 |
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HK1149203A1 (en) | 2011-09-30 |
CN101861170B (zh) | 2012-09-26 |
CN101861170A (zh) | 2010-10-13 |
GB0718386D0 (en) | 2007-10-31 |
JP2010539222A (ja) | 2010-12-16 |
EP2190484A2 (en) | 2010-06-02 |
WO2009037336A2 (en) | 2009-03-26 |
EP2190484B1 (en) | 2015-12-09 |
US20100236958A1 (en) | 2010-09-23 |
US9549999B2 (en) | 2017-01-24 |
ES2562441T3 (es) | 2016-03-04 |
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