JP6709216B2 - 金属錯体製剤 - Google Patents
金属錯体製剤 Download PDFInfo
- Publication number
- JP6709216B2 JP6709216B2 JP2017526513A JP2017526513A JP6709216B2 JP 6709216 B2 JP6709216 B2 JP 6709216B2 JP 2017526513 A JP2017526513 A JP 2017526513A JP 2017526513 A JP2017526513 A JP 2017526513A JP 6709216 B2 JP6709216 B2 JP 6709216B2
- Authority
- JP
- Japan
- Prior art keywords
- chelating agent
- lanthanide
- dota
- gadolinium
- metal
- 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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- 229910052747 lanthanoid Inorganic materials 0.000 claims description 75
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- 229910052751 metal Inorganic materials 0.000 claims description 40
- 239000002184 metal Substances 0.000 claims description 40
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 claims description 38
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- 230000002588 toxic effect Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
- A61K49/101—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/244—Lanthanides; Compounds thereof
-
- 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
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/547—Chelates, e.g. Gd-DOTA or Zinc-amino acid chelates; Chelate-forming compounds, e.g. DOTA or ethylenediamine being covalently linked or complexed to the pharmacologically- or therapeutically-active agent
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/0002—General or multifunctional contrast agents, e.g. chelated agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
- A61K49/101—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals
- A61K49/106—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals the complex-forming compound being cyclic, e.g. DOTA
- A61K49/108—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals the complex-forming compound being cyclic, e.g. DOTA the metal complex being Gd-DOTA
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/28—Compounds containing heavy metals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
- A61K49/101—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals
- A61K49/106—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals the complex-forming compound being cyclic, e.g. DOTA
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- Chemical & Material Sciences (AREA)
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- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
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- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Magnetic Resonance Imaging Apparatus (AREA)
- Medicinal Preparation (AREA)
Description
b)大環状キレートとランタニドとの錯体、及び賦形剤X[X’,L](式中、Lは大環状キレートであり、X及びX’は、特にカルシウム、ナトリウム、亜鉛及びマグネシウムから無関係に選ばれる金属イオンである。)の形でない遊離大環状キレート、及び遊離ランタニドを含む液体医薬組成物を、遊離大環状キレートの溶液及び遊離ランタニドの溶液を混合することにより調製し、それによって、大環状キレートによるランタニドの錯化が得られ、遊離大環状キレートの量及び遊離ランタニドの量は、すべてのランタニドが錯化されるような量ではないステップと、
c)ステップb)において得られた医薬製剤中の遊離ランタニドの濃度Clan lを測定し、遊離大環状キレートの濃度Cch lは0に等しいステップと、
d)第1に、ステップb)において得られた製剤に、必要な遊離大環状キレートの量を加えることで、Cch l及びClan lを調整して、遊離ランタニドの錯化を完了し、それによって、Clan l=0を達成し、及び、
第2に、Cch l=Ct ch l(式中、Ct ch lは、最終的な液体医薬製剤中の遊離大環状キレートの目標濃度であり、0.002%〜0.4% mol/molの間の範囲で選択される。)を達成し、
最終的な液体医薬製剤中の遊離大環状キレートの量は、最終的な液体医薬製剤中の錯化された大環状キレートの量に対する遊離大環状キレートの割合に対応するステップ。
(i)適した溶媒中で、キレート剤と過剰のランタニド金属とを錯化して、過剰のランタニドを含む金属錯体の第1の溶液を与えるステップと、
(ii)溶液を、固相結合スカベンジングキレート剤と1回又は複数回接触させることにより、ステップ(i)の第1の溶液から過剰のランタニドを除去して、過剰のランタニドをスカベンジングキレート剤と錯化させるステップと、
(iii)ステップ(ii)の第1の溶液から固相を分離して、過剰のランタニドを含まない金属錯体を含む第2の溶液を与えるステップと、
(iv)ステップ(iii)の第2の溶液に対して0.002〜0.4mol/mol%の間の範囲の未錯化形キレート剤を添加して、液体医薬製剤を与えるステップと、
未錯化形キレート剤は、配位金属イオンを含まない。
わずかに過剰のガドリニウムがDOTAを完全に錯化させてGd−DOTAを与え、DOTA配位不純物金属イオン(カルシウムなど)が、あまり有利でない熱力学的安定性により、遊離イオンとして溶液中に効果的にトランスメタル化される。
第1の態様の方法において、ステップ(i)のランタニド金属の過剰量は、好ましくは0.01〜5、より好ましくは0.01〜1、最も好ましくは0.05〜0.5mol/mol%である。
(a)第1の態様の方法を実施して、そこに記載の液体医薬製剤を得るステップと、
(b)適宜、ステップ(a)の液体医薬製剤を生体適合性担体で希釈するステップと、
(c)ステップ(b)の製剤を医薬として許容される容器又はシリンジに分注して、分注された容器又はシリンジを与えるステップと、
(d)無菌製造条件下でステップ(a)〜(c)、或いはステップ(c)の分注された容器又はシリンジの最終滅菌のいずれかを実施して、哺乳動物の投与に適した形の医薬として許容される容器又はシリンジ内のMRI造影剤を与えるステップと
を含む、MRI造影剤の調製方法を提供する。
BT−DO3A:10−(2,3−ジヒドロキシ−1−ヒドロキシメチルプロピル)−1,4,7,10−テトラアザシクロドデカン−1,4,7−三酢酸;
Cyclen:1,4,7,10−テトラアザシクロドデカン;
DO3A:1,4,7,10−テトラアザシクロドデカン−1,4,7−三酢酸;
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;
EDTA:エチレンジアミン四酢酸;
GMP:優良製造規範;
HP−DO3A:1,4,7,10−テトラアザシクロドデカン−1,4,7−三酢酸−10−(2−ヒドロキシプロピル);
HPLC:高性能液体クロマトグラフィー;
HPLC−CAD:HPLC荷電化粒子検出器;
ICP−AES:誘導結合プラズマ原子発光分光法
ICP−MS:誘導結合プラズマ質量分析法;
MeCN:アセトニトリル;
min:分;
MRI:磁気共鳴画像法;
NOTA:1,4,7−トリアザシクロノナン−1,4,7−三酢酸;
PCTA:3,6,9,15−テトラアザビシクロ[9.3.1]ペンタデカ−1,11,13−トリエン−3,6,9−三酢酸;
WFI:注射用水。
焼結ガラスフィルター上のChelex−100樹脂(Sigma−Aldrich;100g)を1M HCl(1L)で4回に分けて4時間にわたり処理した。次いで、溶出液がpH6.5になるまで樹脂を水で洗い、水(400mL)中のメグルミン(10g)の溶液を1時間にわたり樹脂と平衡化させた。樹脂をpH8になるまで再び水で洗い、次いで、濾過して真空下で1分間乾燥し、湿った樹脂を得た。この樹脂は、この形(「Meg−Chelex」)で使用される。
塩化ガドリニウム標準液を標準的なChelex(ナトリウムイオン形;「Na−Chelex」又はメグルミン化Chelex(実施例1;「Meg−Chelex」)のいずれかで処理した。
既知の過剰の遊離ガドリニウム(160μg/mL)を含むGd−DOTA−メグルミン反応混合物(濃度〜380mg/mL)を、標準的な(Na−Chelex)Chelex又はメグルミン化(Meg−Chelex)Chelexで処理した。
検出器:ESA Corona、荷電化粒子検出器;
カラム:SeQuant ZIC−pHILIC(5μm、150*4.6mm)。
注入量:20μL;
移動相:100mM酢酸アンモニウム(A)、アセトニトリル(B)。
勾配:
保持時間(min)
メグルミン 21.3
GdDOTA 23.2
ZnDOTA* 28.1
*DOTAは、ZnDOTA錯体として間接的に分析した。
DOTA(211kg)を沸騰水(1600kg)に溶解し、Gd2O3(94,8kg)を加えた。温度を70℃に設定し、スラリーを一晩撹拌した。溶液中の遊離ガドリニウムイオン(1390μg/g)の存在を比色滴定により確認した。
Puropack C150樹脂を、標準的な手順にしたがってプロトン形にコンディショニングした。樹脂床から中性の水が溶出されるまで樹脂を水ですすいだ。
Claims (22)
- ランタニド金属と大環状キレート剤との金属錯体を、金属錯体の0.002〜0.4m
ol/mol%の間の範囲の量の未錯化形の大環状キレート剤と共に含む液体医薬製剤の
調製方法であって、前記方法が、
(i)適した溶媒中で、大環状キレート剤と過剰のランタニド金属とを錯化して、過剰
のランタニドを含む金属錯体の第1の溶液を与えるステップと、
(ii)溶液を、スカベンジャー樹脂と1回又は複数回接触させることにより、ステッ
プ(i)の第1の溶液から過剰のランタニドを除去して、過剰のランタニドをスカベンジ
ャー樹脂と錯化させるステップと、
(iii)ステップ(ii)の第1の溶液から固相を分離して、過剰のランタニドを含
まない金属錯体を含む第2の溶液を与えるステップと、
(iv)ステップ(iii)の第2の溶液に対して0.002〜0.4mol/mol
%の間の範囲の未錯化形の大環状キレート剤を添加して、液体医薬製剤を与えるステップ
と
を含み、
未錯化形の大環状キレート剤は、配位金属イオンを含まず、
スカベンジャー樹脂が、スカベンジャーキレート剤のメグルミン塩として存在する固相
結合スカベンジャーキレート剤である、
調製方法。 - ステップ(i)のランタニド金属の過剰量が0.001〜5mol/mol%である、
請求項1に記載の方法。 - 未錯化形の大環状キレート剤が、0.025〜0.25mol/mol%の間の範囲の
量である、請求項1又は請求項2に記載の方法。 - 未錯化形の大環状キレート剤が、ランタニドイオン、カルシウムイオン、亜鉛イオン及
びマグネシウムイオンを含まない、請求項1乃至請求項3のいずれか1項に記載の方法。 - ランタニド金属がガドリニウムである、請求項1乃至請求項4のいずれか1項に記載の
方法。 - 大環状キレート剤が、DOTA、NOTA、DO3A、BT−DO3A、HP−DO3
A及びPCTAを含む、請求項1乃至請求項5のいずれか1項に記載の方法。 - 大環状キレート剤がDOTAを含む、請求項6に記載の方法。
- スカベンジャー樹脂が固相結合スカベンジャーキレート剤である、請求項1乃至請求項
7のいずれか1項に記載の方法。 - スカベンジャーキレート剤が、イミノ二酢酸、EDTA又はDTPAを含む、請求項8
に記載の方法。 - スカベンジャーキレート剤がイミノ二酢酸を含む、請求項9に記載の方法。
- ステップ(i)の過剰のランタニドが、1以上の任意の配位した不純物金属を大環状キ
レート剤から置換し、各不純物金属は、ランタニドよりも小さい、大環状キレート剤との
生成定数を有する、請求項1乃至請求項10のいずれか1項に記載の方法。 - ランタニド金属と大環状キレート剤との金属錯体が、ガドリニウム−DOTA錯体であ
り、
前記ガドリニウム−DOTA錯体において、ランタニド金属がガドリニウムであり、及
び大環状キレート剤がDOTAを含む、請求項1乃至請求項11のいずれか1項に記載の
方法。 - ガドリニウム−DOTA錯体が、ガドリニウム−DOTAのメグルミン塩を含む、請求
項12に記載の方法。 - スカベンジャーキレート剤がイミノ二酢酸を含む、請求項1乃至請求項13のいずれか
1項に記載の方法。 - ステップ(i)の錯化が、メグルミンを用いてpHを4.5〜5.5に調整することに
より完了される、請求項1乃至請求項14のいずれか1項に記載の方法。 - MRI造影剤の調製方法であって、
(a)請求項1乃至請求項15のいずれか1項に記載の方法を実施して、請求項1乃至請
求項15のいずれか1項に記載された液体医薬製剤を得るステップと、
(b)ステップ(a)の製剤を医薬として許容される容器又はシリンジに分注して、分注
された容器又はシリンジを与えるステップと、
を含み、
ステップ(a)およびステップ(b)を無菌製造条件下で実施するか、或いはステップ
(b)の分注された容器又はシリンジを最終滅菌するか、のいずれかを実施することによ
り、哺乳動物の投与に適した形の、医薬として許容される容器又はシリンジ内のMRI造
影剤を得る、
を含む方法。 - ステップ(a)とステップ(b)との間に、ステップ(a)の液体医薬製剤を生体適合
性担体で希釈するステップをさらに含む、請求項16に記載の方法。 - 前記希釈するステップが、無菌製造条件下で実施される、請求項17に記載の方法。
- 最終滅菌が利用される、請求項16又は請求項17に記載の方法。
- 請求項1乃至請求項19のいずれか1項に記載の方法に用いるための、固相結合スカベ
ンジャーキレート剤であって、スカベンジャーキレート剤のメグルミン塩として存在する
、固相結合スカベンジャーキレート剤。 - イミノ二酢酸を含む、請求項20に記載の固相結合スカベンジャーキレート剤。
- 請求項1乃至請求項15のいずれか1項に記載の医薬製剤の調製方法、或いは
請求項16乃至請求項19のいずれか1項に記載のMRI造影剤の調製方法
のいずれかの調製方法における、請求項20又は請求項21に記載の固相結合スカベンジャーキレート剤の使用。
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GB201421161D0 (en) | 2014-11-28 | 2015-01-14 | Ge Healthcare As | Metal complex formulations |
WO2018069176A1 (en) | 2016-10-12 | 2018-04-19 | T2Pharma Gmbh | Method of preparing formulations of lanthanide metal complexes of macrocyclic chelates |
WO2018069179A1 (en) | 2016-10-12 | 2018-04-19 | T2Pharma Gmbh | Method of preparing formulations of lanthanide metal complexes of macrocyclic chelates |
WO2019020662A1 (de) * | 2017-07-27 | 2019-01-31 | Sanochemia Pharmazeutika Ag | Zubereitung enthaltend ein kontrastmittel, und verfahren zum herstellen |
AT521001B1 (de) * | 2018-02-23 | 2020-10-15 | Sanochemia Pharmazeutika Ag | Herstellungsverfahren für ein Kontrastmittel |
EP3784294A4 (en) * | 2018-04-27 | 2022-01-05 | University of Iowa Research Foundation | COMPOSITIONS FOR CHELATING METALS AT LOW TEMPERATURES |
CN108940221A (zh) * | 2018-07-27 | 2018-12-07 | 福建省微生物研究所 | 壳聚糖磁性吸附剂除去钆塞酸二钠注射液中游离钆的方法 |
CN110286168B (zh) * | 2019-07-03 | 2023-03-03 | 浙江普利药业有限公司 | 显影剂中多氨基多羧基化合物的测定方法 |
CN114829346A (zh) * | 2019-12-20 | 2022-07-29 | 核研究和咨询集团 | 使用基于doat的螯合剂色谱分离金属 |
GB201919073D0 (en) * | 2019-12-20 | 2020-02-05 | Ge Healthcare As | Novel manufacturing process |
CN113801071B (zh) * | 2021-09-14 | 2023-04-07 | 安徽普利药业有限公司 | 一种钆特酸葡甲胺的精制方法 |
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ATE152623T1 (de) * | 1986-12-17 | 1997-05-15 | Glaxo Group Ltd | Verwendung von heterozyklischen derivaten zur herstellung von arzneimitteln |
US10925977B2 (en) | 2006-10-05 | 2021-02-23 | Ceil>Point, LLC | Efficient synthesis of chelators for nuclear imaging and radiotherapy: compositions and applications |
WO2008144728A1 (en) | 2007-05-21 | 2008-11-27 | Bracco Imaging S.P.A. | Conjugates which bind a blood protein such as human serum albumin and methods of using the same in diagnostic and therapeutic applications |
FR2921271A1 (fr) * | 2007-09-20 | 2009-03-27 | Guerbet Sa | Formulation d'agents de contraste pour l'irm contenant une polybase organique |
US20090208421A1 (en) * | 2008-02-19 | 2009-08-20 | Dominique Meyer | Process for preparing a pharmaceutical formulation of contrast agents |
FR2945448B1 (fr) * | 2009-05-13 | 2012-08-31 | Guerbet Sa | Procede de preparation d'une formulation pharmaceutique de chelate de lanthanide sous forme de poudre. |
EP2338874A1 (en) * | 2009-12-16 | 2011-06-29 | Bracco Imaging S.p.A | Process for the preparation of chelated compounds |
GB201421161D0 (en) | 2014-11-28 | 2015-01-14 | Ge Healthcare As | Metal complex formulations |
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CA2967873C (en) | 2023-04-04 |
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JP2017538685A (ja) | 2017-12-28 |
RU2017116217A3 (ja) | 2019-06-04 |
RU2017116217A (ru) | 2018-12-28 |
WO2016083597A1 (en) | 2016-06-02 |
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