JP6943834B2 - シリコーン系腸管ct造影材料 - Google Patents
シリコーン系腸管ct造影材料 Download PDFInfo
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- JP6943834B2 JP6943834B2 JP2018230672A JP2018230672A JP6943834B2 JP 6943834 B2 JP6943834 B2 JP 6943834B2 JP 2018230672 A JP2018230672 A JP 2018230672A JP 2018230672 A JP2018230672 A JP 2018230672A JP 6943834 B2 JP6943834 B2 JP 6943834B2
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Description
[0001] 本出願は、35 USC119(e)の下で、あらゆる目的のため、全体として参照により本明細書に組み込まれる2013年8月16日に出願された米国仮特許出願第61/866,806号の利益を主張する。
[0042] 二重エネルギーおよびスペクトルCTは、現代のスキャナーの標準的な性能である。現行の二重エネルギー技術により、1つのX線スペクトルを生成するために一方のX線管電位を80kVpに設定した後、第2のX線スペクトルを生成するために他方のX線管電位を140kVpに設定することにより生成されるものなど、2種以上の異なるエネルギースペクトルのX線で患者を同時に撮像することが可能である。あるいは、X線管電位を、低いkVp設定と高いkVp設定の間で急速に変化させることができる。これらの管電位からのX線エネルギースペクトルを、高KvpのX線ビーム上でのスズフィルターの使用などにより、低または高kVpのX線ビームを選択的にフィルタリングすることによってさらに改変して、より良いスペクトル分離を達成することができる。二重エネルギーおよびスペクトルCT撮像は、X線スペクトルの異なる部分におけるX線の減弱を定量するサンドイッチ検出器または光子計数などの他の方法を用いて獲得することもできる。体内の材料は、その高管電位と低管電位のCT数比(例えば、80:140kVpのCT数比)の差異に基づいて識別される。この差異は材料中の原子の原子番号に関連している。臨床用CTスキャナーについてのCT数比のシミュレーションは、ヨウ素およびバリウムが、Hounsfield単位として測定されるCT数と共に、現行の臨床用スキャナーについて予測される最大値に近い、約1.7の高い80:140kVpのCT数比を示すことを示している。より大きく異なる比を有する材料は、DECTによってより明確に識別され、したがって、ヨウ素およびバリウムは、80:140kVpのCT数比が約1.0である水または大部分の軟組織と極めてよく識別することができる。中間の80:140kVpのCT数比(1.25〜1.45)を有する材料は、3物質弁別アルゴリズムの使用により、水または大部分の軟組織ならびにヨードまたはバリウム造影材料の両方からある程度識別することができる。造影材料に組み込んでヨウ素およびバリウムと識別することができる最良の元素は、1.0に近い低い比(高原子番号、例えば、71〜83に対応する、または低原子番号、例えば、3〜20にも対応する)を有すると考えられた。そのような造影材料の対を、単純な2物質弁別アルゴリズムにより分離することができるが、これらの低い80:140kVpのCT数比の物質は、3物質または多物質弁別アルゴリズムを用いた場合であっても、水および軟組織から容易に分離することができない。
[0048] 別途定義しない限り、本明細書で用いられる全ての技術用語および科学用語は、一般に本発明が属する分野の当業者によって普遍的に理解されるものと同じ意味を有する。一般に、本明細書で用いられる命名法ならびに有機化学、医薬製剤、および医学撮像における実験室的手順は、当業界で周知であり、一般に用いられるものである。
A.組成物
[0083] 様々な実施形態において、本発明は、市場にある市販のCT造影材料と容易に識別することができるか、またはかくして文献中にさらに記載された非ヨード腸管/非血管CT造影材料を提供する。これらのケイ素ポリマー系材料は、従来のヨード/バリウムCT造影材料および重金属に基づく造影材料と異なるkVp設定において顕著に異なる相対X線減弱を有する。新しいケイ素ポリマー系造影材料は、二重エネルギーCTにおいて従来のヨードおよびバリウムCT造影材料ならびに軟組織および水と容易に識別され、これらの薬剤は、二重エネルギー/スペクトルCT画像が得られた場合、市販の、または「自家製」の二重エネルギーCT(DECT)/スペクトルCTソフトウェアにより識別することができる。40keVなどの、低エネルギー仮想単色CT画像において、材料は「ポジティブ」造影シグナルを示し、100〜140keVなどの高エネルギー仮想単色CT画像においては、材料は「ネガティブ」造影シグナルを示し得る。かくして、本発明の薬剤により、1つまたは複数の以下の利益:
1)腸管または非血管構造を不透明化して、CTにおいてこれらの構造を不透明化された血管構造と識別することができること;
2)浸出した造影材料の起源を、起源が血管または非血管であるものとして容易に識別することができること;
3)血管および非血管構造のコントラストが強調されたCT画像を同時に/ほぼ同時に取得し、それによって、これらの構造のさらなる差異を完全に同時登録することができること;ならびに
4)腸管/非血管構造を、静脈内造影剤からのこれらの構造(腸管壁、膀胱壁、他の壁構造)の壁面強調の評価を阻害することなく、CTのための造影剤を用いて不透明化することができること
を有する広範囲の改善されたCT適用への初めてのアクセスが可能になる。
を有する。様々な実施形態において、R1およびR2の一方または両方は、置換または非置換アルキル、例えば、C1〜C30アルキルである。ここで、下付き記号「x」は、含ケイ素ポリマーに関する重合度を指す。
(a)カルボキシル基およびその様々な誘導体、例えば、限定されるものではないが、N−ヒドロキシスクシンイミドエステル、N−ヒドロキシベンゾトリアゾールエステル、酸ハライド、アシルイミダゾール、チオエステル、p−ニトロフェニルエステル、アルキル、アルケニル、アルキニルおよび芳香族エステル;
(b)例えば、エステル、エーテル、アルデヒドなどに転換できるヒドロキシル基;
(c)ハライドが後で例えば、アミン、カルボキシレートアニオン、チオールアニオン、カルバニオン、またはアルコキシドイオンなどの求核基に置き換えられ、それによりハロゲン原子の官能基における新たな基の共有結合をもたらすことができる、ハロアルキル基;
(d)例えば、マレイミド基などの、Diels−Alder反応に関与することができる、ジエノフィル基;
(e)例えば、イミン、ヒドラゾン、セミカルバゾンもしくはオキシムなどのカルボニル誘導体の形成によって、またはGrignard付加もしくはアルキルリチウム付加などの機構によって、その後の誘導体化が可能である、アルデヒドまたはケトン基;
(f)引き続いてアミンと反応させ、例えば、スルホンアミドを形成するためのスルホニルハライド基;
(g)例えば、ジスルフィドに転換し、またはアルキルおよびアシルハライドと反応させることができるチオール基;
(h)例えば、アシル化、アルキル化または酸化することができる、アミンまたはスルフヒドリル基;
(i)例えば、環化付加、アシル化、Michael付加などを受けることができる、アルケン;ならびに
(j)例えば、アミンおよびヒドロキシル化合物と反応させることができる、エポキシド;
が挙げられる。
[00162] 本発明はまた、本発明の製剤を用いて、本発明の製剤が投与される対象から臨床的に意義のあるCT画像を獲得し、強調する方法を提供する。かくして、例示的な実施形態において、本発明はコントラストが強調された対象のCT投影データを獲得した後、CT画像に再構成する方法を提供する。この方法は、前記本発明の腸管造影媒体製剤の診断的有効量を対象に投与する工程と、対象のCT投影データを獲得した後、CT画像に再構成する工程とを含む。様々な実施形態において、腸管造影媒体は、DECT撮像実験における前記画像で2.0超の80:140kVpのCT数比を有する。
[00172] (方法1)1パーセントの界面活性剤Tween 20(Sigma-Aldrich)水性溶液を、蒸留水4.95g中にTween−20 50mgを溶解することによって調製した。この透明な溶液(50mlの遠心管中)に、23Gの針と結合した20mlの注射筒を通して、穏やかにボルテックスしながら、ケイ素系ポリマー(25℃で50cSt、Fisher Scientific)15.0gを滴下添加した。添加の完了後、混合物を室温で3分間、激しくボルテックスし、0.25wt%のTween 20界面活性剤を含む75wt%水中油(o/w)型エマルジョンを得た(注記:非減圧調製条件では小さい気泡は避けられない)。このエマルジョンを測定して、Malvern 3000 ZetaSizer上で60μmとして平均粒径を得た。このエマルジョンを、少なくとも3ヶ月にわたって相を分離させることなく室温で安定に保存することができる。CTスキャンはその均一性を証明した(小さい気泡の存在を除く)。
[00176] 実施例1の手順を、Triton X−100を用いて行った。
[00177] 実施例1の手順を、Triton X−100およびフッ素化ケイ素系ポリマーFS−1265(粘度350cSt、Dow Corning)を用いて行った。
[00178] ある範囲のケイ素系ポリマーを、CTファントム中に組み込み、撮像した。ケイ素系ポリマーは、非常に高く、一貫した80:140kVpのCT数比および100:140kVpのCT数比を示した(図7)。
[00179] ラットにおけるin vivoでの撮像実験により、本発明のケイ素系ポリマーに基づく造影剤が、単一のDECTスキャンにおいて同時的なポジティブ、ニュートラルおよびネガティブな腸管造影を提供することが示された。図3は、40keVの仮想単色画像(左の画像、矢頭)上の明るいシグナルとしての、70keVの仮想単色画像(中央の画像、矢頭)上の水と類似するニュートラルシグナルとしての、および90keVの仮想単色画像(右の画像、矢印)上の脂肪と類似するネガティブシグナルとしての、本発明のケイ素系ポリマーに基づく造影剤を示す。3つ全ての画像上で、血管内ヨード造影材料(矢印)は、明るいシグナルのままである。これらの画像をCTスキャン投影データを用いて生成し、これを2物質弁別のために用いて仮想単色40、70および90keVのCT画像を再構成させた。
Claims (36)
- 対象のコントラストが強調されたX線またはコンピューター断層撮影または二重エネルギーコンピューター断層撮影またはスペクトルコンピューター断層撮影の投影データを獲得する方法であって、
前記対象の腹部に対して実施される医学的撮像手順の前に前記対象に経口送達するために製剤化される腸管造影媒体製剤を診断的有効量投与された前記対象の前記投影データを獲得する工程を含み、
前記製剤は、少なくとも1つのケイ素系ポリマーのエマルジョンまたは懸濁液、水性ビヒクル成分、および薬学的に許容される水性ビヒクルである前記水性成分を含む水中油エマルジョンまたは懸濁液中に前記少なくとも1つのケイ素系ポリマーを維持する乳化剤または分散剤を含み、前記ケイ素系ポリマーが、ケイ素系ポリマー成分を含む直鎖状の、分枝状の、または架橋された構造およびケイ素系ポリマーまたはコポリマーを含むポリマーブレンド、ならびにその組合せから選択されるメンバーである、腸管造影媒体を含み、
前記製剤は、少なくとも30%重量/重量の前記ケイ素系ポリマーを含み、
前記腸管造影媒体が2.1超の80:140kVpのCT数比を有する、方法。 - 前記腸管造影媒体製剤は、診断的有効量の前記腸管造影媒体を含む単位用量製剤である、請求項1に記載の方法。
- 前記腸管造影媒体製剤は、成人ヒト用量あたり800mL〜1200mLの単位用量製剤である、請求項1に記載の方法。
- 前記腸管造影媒体製剤は、50〜100mLの容量の単位用量製剤である、請求項1に記載の方法。
- 前記腸管造影媒体製剤は、100mL〜800mLの容量の単位用量製剤である、請求項1に記載の方法。
- 前記ケイ素系ポリマーが室温または体温で液体である、請求項1に記載の方法。
- 前記腸管造影媒体製剤は、少なくとも60%重量/重量の前記ケイ素系ポリマーを含む、請求項1に記載の方法。
- 前記乳化剤および分散剤が、0〜20の親水性−親油性バランス(HLB)値を有する、請求項1に記載の方法。
- 前記乳化剤が、Tween(登録商標)界面活性剤である、請求項1に記載の方法。
- 前記腸管造影媒体製剤は、口腔ケア製剤として有用ではない、請求項1に記載の方法。
- 前記腸管造影媒体製剤は、鼓腸を防止するのに有用ではない、請求項1に記載の方法。
- 前記腸管造影媒体製剤は、単位用量製剤であり、前記ケイ素系ポリマー25g超を含有する、請求項1に記載の方法。
- 前記ケイ素系ポリマーが、エマルジョン粒子/液滴の主成分であるが、固体粒子上には吸着されない、請求項1に記載の方法。
- 前記製剤の重量の30%(w/w)〜100%(w/w)が前記ケイ素系ポリマーである、請求項1に記載の方法。
- 前記乳化剤が水溶性ポリマーを含む、請求項1に記載の方法。
- 前記乳化剤が1つまたは複数のポリ(エチレングリコール)鎖を含む、請求項1に記載の方法。
- 前記薬学的に許容されるビヒクルが、添加剤、香味剤、甘味剤、増粘剤、懸濁化剤、流動剤、pH緩衝剤、緩下剤、浸透圧調整剤、およびその組合せをさらに含む、請求項1に記載の方法。
- 前記ケイ素系ポリマーが0.9〜1.1の比重を有する、請求項1に記載の方法。
- 前記ケイ素系ポリマーが室温で0.5cSt〜200cStの粘度を有する、請求項1に記載の方法。
- 前記ケイ素系ポリマーが室温で200cSt〜600cStの粘度を有する、請求項1に記載の方法。
- 前記ケイ素系ポリマーが室温で600cSt〜1200cStの粘度を有する、請求項1に記載の方法。
- 前記ケイ素系ポリマーが室温で1200cSt〜100,000cStの粘度を有する、請求項1に記載の方法。
- 前記ケイ素系ポリマーが0.4kDa〜5kDaの分子量を有する、請求項1に記載の方法。
- 前記ケイ素系ポリマーが5kDa〜50kDaの分子量を有する、請求項1に記載の方法。
- 前記ケイ素系ポリマーが50kDa〜1000kDaの分子量を有する、請求項1に記載の方法。
- 前記X線またはコンピューター断層撮影または二重エネルギーコンピューター断層撮影またはスペクトルコンピューター断層撮影の投影データが、コンピューター断層撮影画像に再構成される、請求項1に記載の方法。
- 前記造影剤が、X線ビームのエネルギースペクトルを改変する異なる材料または厚さ(0を含む)のX線フィルターを用いる二重エネルギーまたはスペクトルCTスキャナーを用いて撮像される、請求項1に記載の方法。
- 前記X線またはコンピューター断層撮影または二重エネルギーコンピューター断層撮影またはスペクトルコンピューター断層撮影の投影データが、2物質、3物質、または多物質弁別のために用いられ、CT画像に再構成される、請求項1に記載の方法。
- 前記コンピューター断層撮影画像が、2物質、3物質、または多物質弁別のために用いられ、さらなるCT画像を再構成する、請求項1に記載の方法。
- 前記コンピューター断層撮影画像が、腹部における他の材料から前記腸管造影媒体製剤を識別するために用いられる、請求項1に記載の方法。
- 前記画像が、前記対象の腹部および骨盤から選択される領域の画像である、請求項1に記載の方法。
- 前記対象は、前記腸管造影媒体と異なる第2の造影媒体をさらに投与されたものであり、前記第2の造影媒体が、経口投与、髄腔内投与、膀胱内投与、腸内投与、肛門投与、カテーテル内投与、デバイス内投与、血管内投与、瘻孔への投与、および外科的に作出されたパウチへの投与から選択される経路により投与される、請求項1に記載の方法。
- 前記第2の造影媒体がヨード造影媒体、Ba系、Gd系、W系、Bi系、Mg系、Yb系およびTa系造影媒体ならびにケイ素系造影媒体から選択されるメンバーである、請求項32に記載の方法。
- 前記腸管造影媒体と前記第2の造影媒体とが、異なるX線スペクトルにおけるそれらの相対的X線減弱に基づいて前記画像において互いに識別可能である、請求項1に記載の方法。
- 前記対象は、前記腸管造影剤が、
(a)口、膣、膀胱、直腸および尿道から選択される天然の空洞;
(b)回腸嚢、および人工膀胱から選択される外科的に作出された空間;
(c)瘻孔、洞管、および膿瘍から選択される傷害により作出された空間;または
(d)カテーテル、チューブ、リザバー、パウチおよびポンプから選択される医療用デバイス
を介する送達によって投与されたものである、請求項1に記載の方法。 - 前記腸管造影剤が、
(a)前記腸管造影媒体を含有する第1のバイアルまたはバイアルのセット;
(b)第2の造影媒体を含有する第2のバイアル;および
(c)前記第2の造影媒体を含むか、または含まない前記腸管造影媒体を製剤化するための指示書
を含むキットから投与される前に準備される、請求項1に記載の方法。
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US201361866806P | 2013-08-16 | 2013-08-16 | |
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JP2016534885A JP2016528259A (ja) | 2013-08-16 | 2014-08-18 | シリコーン系腸管ct造影材料 |
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JP6943834B2 true JP6943834B2 (ja) | 2021-10-06 |
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JP2016534885A Pending JP2016528259A (ja) | 2013-08-16 | 2014-08-18 | シリコーン系腸管ct造影材料 |
JP2018230672A Active JP6943834B2 (ja) | 2013-08-16 | 2018-12-10 | シリコーン系腸管ct造影材料 |
JP2021146604A Pending JP2021193113A (ja) | 2013-08-16 | 2021-09-09 | シリコーン系腸管ct造影材料 |
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US (3) | US20160193366A1 (ja) |
EP (1) | EP3033012A4 (ja) |
JP (3) | JP2016528259A (ja) |
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EP3984560A1 (en) * | 2013-03-15 | 2022-04-20 | The Regents of the University of California | Enteric ct contrast material based on low-z atoms |
EP3073927A4 (en) * | 2013-11-26 | 2017-08-16 | The Johns Hopkins University | Dual-energy cone-beam computed tomography with a multiple source, single-detector configuration |
WO2016172256A1 (en) | 2015-04-20 | 2016-10-27 | The Regents Of The University Of California | Encapsulated gas or partial vacuum ct contrast material |
WO2017223343A1 (en) * | 2016-06-22 | 2017-12-28 | Board Of Regents, The University Of Texas System | Contrast agents and methods of making the same for spectral ct that exhibit cloaking and auto-segmentation |
US10398394B2 (en) | 2017-01-06 | 2019-09-03 | General Electric Company | Energy-discriminating photon-counting detector and the use thereof |
JP2020103571A (ja) * | 2018-12-27 | 2020-07-09 | キヤノンメディカルシステムズ株式会社 | 医用処理装置及びx線診断システム |
KR20240024802A (ko) * | 2021-05-05 | 2024-02-26 | 더 리전트 오브 더 유니버시티 오브 캘리포니아 | X선 감쇠 변화가 적은 하드쉘형 경구 조영제 |
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JPS6238172A (ja) | 1985-08-12 | 1987-02-19 | 株式会社 高研 | 抗血栓性医用材料の製造方法 |
GB9006671D0 (en) * | 1990-03-24 | 1990-05-23 | Univ Manchester | Diagnostic method and compositions |
US5205290A (en) * | 1991-04-05 | 1993-04-27 | Unger Evan C | Low density microspheres and their use as contrast agents for computed tomography |
CN1047094C (zh) * | 1992-05-21 | 1999-12-08 | 天津市滨江医院 | 结肠运输试验标记物的制备方法 |
US5318769A (en) * | 1993-03-31 | 1994-06-07 | Sterling Winthrop Inc. | Compositions of iodophenyl esters for X-ray visualization of the gastrointestinal tract |
US5472682A (en) * | 1993-03-31 | 1995-12-05 | Sterling Winthrop Inc. | Compositions of iodophenyl esters and iodophenyl sulfonates and pharmaceutically acceptable clays for visualization of the gastrointestinal tract |
CN1146159A (zh) * | 1994-02-25 | 1997-03-26 | 耐克麦德英梅金公司 | 含有纤维素衍生物的x-射线造影组合物 |
JPH09512029A (ja) * | 1994-04-21 | 1997-12-02 | ニコメド イマギング アクスイェ セルスカプ | 薬理学的に許容される粘土を含むx線造影組成物 |
US5736121A (en) * | 1994-05-23 | 1998-04-07 | Imarx Pharmaceutical Corp. | Stabilized homogenous suspensions as computed tomography contrast agents |
WO1996040285A1 (en) * | 1995-06-07 | 1996-12-19 | Imarx Pharmaceutical Corp. | Novel targeted compositions for diagnostic and therapeutic use |
GB9603547D0 (en) | 1996-02-20 | 1996-04-17 | Nycomed Imaging As | Contrast media |
FR2910320B1 (fr) * | 2006-12-21 | 2009-02-13 | Galderma Res & Dev S N C Snc | Emulsion comprenant au moins un retinoide et du peroxyde de benzole |
CN101314049B (zh) * | 2008-06-13 | 2010-11-10 | 许川山 | 一种靶向微泡造影剂 |
US10071174B2 (en) * | 2011-06-06 | 2018-09-11 | Portland State University | Bismuth particle X-ray contrast agents |
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2014
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- 2014-08-18 CN CN201480056062.2A patent/CN105848582A/zh active Pending
- 2014-08-18 US US14/912,258 patent/US20160193366A1/en not_active Abandoned
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2018
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Also Published As
Publication number | Publication date |
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JP2021193113A (ja) | 2021-12-23 |
JP2016528259A (ja) | 2016-09-15 |
US20220233725A1 (en) | 2022-07-28 |
JP2019072505A (ja) | 2019-05-16 |
EP3033012A1 (en) | 2016-06-22 |
US20160193366A1 (en) | 2016-07-07 |
CN105848582A (zh) | 2016-08-10 |
US20190070319A1 (en) | 2019-03-07 |
WO2015024025A1 (en) | 2015-02-19 |
EP3033012A4 (en) | 2017-04-19 |
CN117018234A (zh) | 2023-11-10 |
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