JP4464639B2 - CT and MRI contrast medium and contrast fat emulsion for the same - Google Patents
CT and MRI contrast medium and contrast fat emulsion for the same Download PDFInfo
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Description
本発明は、ＣＴ（コンピューター断層撮影）およびＭＲＩ（磁気共鳴映像）による画像診断法に利用するためのＣＴおよびＭＲＩ両用造影剤及び造影用脂肪乳剤に関する。 The present invention relates to a contrast medium for CT and MRI and a fat emulsion for contrast for use in diagnostic imaging methods based on CT (Computer Tomography) and MRI (Magnetic Resonance Imaging).
癌などの疾患を早期診断する画像診断法として、ＣＴおよびＭＲＩが広く使用されている。ＣＴはＸ線で身体の回りをスキャンしながら、得られたデジタル信号をコンピューターに取り込み、身体の断面の画像を作り出すものである。ＣＴには、形態学的検査に優れ、検査測定時間が短いという利点がある。
一方、ＭＲＩは、磁石（Ｎ極およびＳ極）と電波を使用して人体の断層像を撮影するものである。ＭＲＩでは、人体の横断像だけでなく、縦断像や斜めに切った像など、任意な方向から断層像が得られ、またＣＴのように骨からのアーチファクト（偽像）がなく、病変の質的な判断が可能であるという利点がある。
CT and MRI are widely used as diagnostic imaging methods for early diagnosis of diseases such as cancer. CT scans around the body with X-rays, captures the obtained digital signals into a computer, and creates an image of a cross section of the body. CT has the advantages of excellent morphological examination and short examination measurement time.
On the other hand, MRI takes a tomographic image of a human body using magnets (N pole and S pole) and radio waves. In MRI, a tomographic image can be obtained from any direction, such as a longitudinal image and an obliquely cut image, as well as a transverse image of the human body, and there is no artifact from the bone as in CT, and the quality of the lesion. There is an advantage that it is possible to make a judgment.
このように、ＣＴとＭＲＩは、画像診断においてそれぞれ異なる利点を有するため、両診断法を併用することにより、より正確な診断が可能になる。ところが、ＣＴとＭＲＩを同日に施行することは、それぞれに異なる造影剤を使用しているため、副作用のおそれがある。このため、通常は２日程度間を空けてから施行されていた。その結果、診断に時間がかかり、患者の負担も大きかった。 Thus, since CT and MRI have different advantages in image diagnosis, more accurate diagnosis is possible by using both diagnostic methods together. However, performing CT and MRI on the same day uses different contrast agents, which may cause side effects. For this reason, it was normally enforced after about two days. As a result, the diagnosis took time and the burden on the patient was great.
造影剤としては、下記特許文献１に、油相が油性Ｘ線造影剤を主成分とするＯ／Ｗ型エマルション製剤が開示されている。しかし、ＣＴおよびＭＲＩ両用造影剤は知られていない。
本発明は、同じ日にＣＴおよびＭＲＩの施行が可能なＣＴおよびＭＲＩ両用造影剤及びその為の造影用脂肪乳剤を提供することを課題とする。 An object of the present invention is to provide a CT and MRI contrast medium capable of performing CT and MRI on the same day, and a contrast fat emulsion for the same.
本発明のＣＴおよびＭＲＩ両用造影剤は、Ｘ線造影剤と、常磁性金属とを含有することを特徴とする。ここで、Ｘ線造影剤はＣＴ造影用として、また常磁性金属はＭＲＩ造影用としてそれぞれ機能する。
前記Ｘ線造影剤は、水溶性又は脂溶性のヨウ素化された造影剤であるのがよく、例えばヨード付加された油脂であるのがよい。
前記常磁性金属は、プロトン緩和効果を有する２価又は３価のイオンとなり得る鉄、クロム、マンガン、ガドリニウム、テルビウム、ジスプロシウム、ホルミウムおよびエルビウムから選ばれる少なくとも１種であるのがよく、特に鉄が有用である。
常磁性金属がキレート剤などの安定化剤によって安定化されているの好ましい。具体的には、常磁性金属は安定化剤によってキレートを形成しているか又はコロイド状態であるのがよい。前記安定化剤は、(1)多糖類、(2)クエン酸、(3)EDTA、(4)DTPA、(5)環状アミン、(1)〜(5)の誘導体および(1)〜(5)の塩から選ばれる少なくとも１種である。
The CT and MRI contrast medium of the present invention is characterized by containing an X-ray contrast medium and a paramagnetic metal. Here, the X-ray contrast agent functions for CT contrast, and the paramagnetic metal functions for MRI contrast.
The X-ray contrast agent may be a water-soluble or fat-soluble iodinated contrast agent, for example, an iodine-added fat.
The paramagnetic metal may be at least one selected from iron, chromium, manganese, gadolinium, terbium, dysprosium, holmium, and erbium, which can be a divalent or trivalent ion having a proton relaxation effect. Useful.
It is preferred that the paramagnetic metal is stabilized by a stabilizer such as a chelating agent. Specifically, the paramagnetic metal may be chelated by a stabilizer or in a colloidal state. The stabilizer includes (1) polysaccharide, (2) citric acid, (3) EDTA, (4) DTPA, (5) cyclic amine, (1) to (5) derivatives and (1) to (5 ) At least one selected from the salts.
本発明のＣＴおよびＭＲＩ両用造影剤は脂肪乳剤の形態で使用されるのがよい。すなわち、本発明の造影用脂肪乳剤は、Ｘ線造影剤と、常磁性金属とを含有することを特徴とするものであり、本発明で利用されるＸ線造影剤は、水溶性造影剤又は油性造影剤のいずれをも使用できる。特に前記ヨード付加した油脂をＸ線造影剤として用い、鉄を常磁性金属として用いる場合に、本発明の好ましいＣＴおよびＭＲＩ両用造影剤及びその為の造影用脂肪乳剤を提供できる。本発明の造影用脂肪乳剤の形態は、ヨード付加した油脂と常磁性金属からなるＯ／Ｗ型又はＷ/Ｏ/Ｗ型エマルジョンであるのがよい。脂肪乳剤の粒子径は７μm以下、特に１μｍ以下であるのが好ましい。
本発明の前記造影剤または前記脂肪乳剤は、これを体内に投与し、関心領域、例えば肝実質、脾、傍脊柱筋などのＣＴ撮影およびＭＲＩ撮影を行うものである。ＣＴとＭＲＩの施行の間隔は４〜６時間、好ましくは１〜２時間程度であるのがよい。
本発明の造影用脂肪乳剤は、これらの組成物に適性な乳化剤の適量を加え、常法に従って乳化することで調製することができる。脂肪乳剤の粒子径は、乳化剤の添加量または乳化方法によって各種調整することができる。
The CT and MRI contrast medium of the present invention is preferably used in the form of a fat emulsion. That is, the contrast fat emulsion of the present invention is characterized by containing an X-ray contrast agent and a paramagnetic metal, and the X-ray contrast agent used in the present invention is a water-soluble contrast agent or Any oil-based contrast agent can be used. In particular, when the oil and fat to which iodine is added is used as an X-ray contrast medium and iron is used as a paramagnetic metal, the preferred CT and MRI contrast medium of the present invention and a contrast fat emulsion for the same can be provided. The form of the contrast-use fat emulsion of the present invention is preferably an O / W type emulsion or a W / O / W type emulsion made of iodine-added oil and fat and a paramagnetic metal. The particle diameter of the fat emulsion is preferably 7 μm or less, particularly 1 μm or less.
The contrast agent or the fat emulsion of the present invention is administered into the body, and CT imaging and MRI imaging of a region of interest, for example, liver parenchyma, spleen, paraspinal muscles, and the like are performed. The interval between CT and MRI is 4 to 6 hours, preferably about 1 to 2 hours.
The contrast fat emulsion of the present invention can be prepared by adding an appropriate amount of an appropriate emulsifier to these compositions and emulsifying according to a conventional method. The particle size of the fat emulsion can be variously adjusted by the amount of emulsifier added or the emulsification method.
本発明によれば、同じ日にＣＴおよびＭＲＩの施行が可能になり、正確な診断を迅速に行えるので、肝臓癌等の病巣の早期発見に有用であると共に、診断の迅速化により患者の負担も軽減できるという効果がある。 According to the present invention, CT and MRI can be performed on the same day, and an accurate diagnosis can be quickly performed. Therefore, the present invention is useful for early detection of a lesion such as liver cancer, and the burden of the patient is increased by speeding up the diagnosis. Can also be reduced.
本発明の造影剤は、ヨード付加した油脂と、常磁性金属とを含有する脂肪乳剤、特にＯ／Ｗ型又はＷ/Ｏ/Ｗ型エマルジョンの形態で使用するのがよい。この脂肪乳剤においては、油相に前記ヨード付加した油脂を用い、水相に常磁性金属を配合することになる。 The contrast agent of the present invention is preferably used in the form of a fat emulsion containing an iodine-added oil and fat and a paramagnetic metal, particularly an O / W type or W / O / W type emulsion. In this fat emulsion, the oil added with iodine is used in the oil phase, and a paramagnetic metal is added to the water phase.
ヨード付加した油脂としては、ＣＴ撮影において造影剤として使用されるものであれば、特別な制限なく使用可能であり、例えばヨード化ケシ油脂肪酸エチルエステル（ゲルベ社（フランス）製の「リピオドール ウルトラフルイド」など）が挙げられる。ヨード付加した油脂におけるヨード量は、油脂１ｍＬに対して３００〜６００ｍｇ程度であればよい。 The iodine-added oil and fat can be used without any particular limitation as long as it is used as a contrast agent in CT imaging. Etc.). The iodine amount in the oil added with iodine may be about 300 to 600 mg per 1 mL of the oil.
油相には、本発明の効果を妨げない限りにおいて、他の油脂成分が含まれていてもよい。このような成分としては、薬理学上許容される油脂類等が挙げられる。該油脂類としては、例えば大豆油、オリーブ油、ゴマ湯、トウモロコシ油などの植物油、タラ肝油などの魚油、中鎖脂肪酸トリグリセリドなどがあげられる。
また、Ｏ／Ｗ型又はＷ/Ｏ/Ｗ型エマルジョンを作成するための乳化剤としては、薬理学上許容される乳化剤が挙げられる。例えば卵黄または大豆レシチンなどのリン脂質類、ポロキサマー１８８などの非イオン性の合成界面活性剤などが使用可能であるが、これらに限定されるものではなく、生体にとって安全性の確認されたものであればいずれも使用できる。
As long as the effects of the present invention are not hindered, the oil phase may contain other oil and fat components. Examples of such components include pharmacologically acceptable oils and fats. Examples of the fats and oils include vegetable oils such as soybean oil, olive oil, sesame water, and corn oil, fish oils such as cod liver oil, and medium chain fatty acid triglycerides.
Moreover, as an emulsifier for preparing an O / W type or a W / O / W type | mold emulsion, the emulsifier accept | permitted pharmacologically is mentioned. For example, phospholipids such as egg yolk or soybean lecithin, and nonionic synthetic surfactants such as poloxamer 188 can be used, but are not limited to these, and have been confirmed to be safe for the living body. Any can be used.
前記常磁性金属としては、例えばプロトン緩和効果を有する２価又は３価のイオンとなり得る鉄、クロム、マンガン、ガドリニウム、テルビウム、ジスプロシウム、ホルミウム、エルビウムなどがあげられ、特に鉄であるのが好ましい。鉄は、生体内で直接利用されるからである。
常磁性金属は水酸化物、酸化物などの形態で使用するのがよく、鉄の場合には、例えばFe(OH)2、Fe2(OH)2、FeO、Fe2O3およびコロイド状の鉄から選ばれる１種または２種以上が挙げられる。また、一般に常磁性金属は金属毒性が発現することから、安定化剤によって安定化されているのがよい。すなわち、前記常磁性金属は安定化剤によってキレートを形成しているか又はコロイド状態で使用するのが好ましい。
前記安定化剤としては、(1)多糖類、(2)クエン酸、(3)EDTA、(4)DTPA、(5)環状アミンなどが挙げられる。これらの化合物は、例えばエステル、エーテルなどの誘導体の形態でも使用可能であり、さらにナトリウム塩、カリウム塩、塩酸塩、硝酸塩などの塩の形態でも使用可能である。
本発明では、コンドロイチン硫酸等の安定化剤を含むコロイド状の鉄又は含糖酸化鉄（例えば三菱ウェルファーマ社製の「フェジン」）の様なキレート化された鉄などが使用可能である。通常、これらの鉄は水相に含有されることになる。
Examples of the paramagnetic metal include iron, chromium, manganese, gadolinium, terbium, dysprosium, holmium, and erbium that can be a divalent or trivalent ion having a proton relaxation effect, and iron is particularly preferable. This is because iron is directly used in vivo.
Paramagnetic metals should be used in the form of hydroxides, oxides, etc. In the case of iron, for example, Fe (OH) 2 , Fe 2 (OH) 2 , FeO, Fe 2 O 3 and colloidal 1 type or 2 types or more chosen from iron are mentioned. In general, paramagnetic metals exhibit metal toxicity and are preferably stabilized with a stabilizer. That is, the paramagnetic metal is preferably used in the form of a chelate with a stabilizer or in a colloidal state.
Examples of the stabilizer include (1) polysaccharides, (2) citric acid, (3) EDTA, (4) DTPA, and (5) cyclic amine. These compounds can be used in the form of derivatives such as esters and ethers, and also in the form of salts such as sodium salts, potassium salts, hydrochlorides and nitrates.
In the present invention, colloidal iron containing a stabilizer such as chondroitin sulfate or chelated iron such as sugar-containing iron oxide (for example, “Fedin” manufactured by Mitsubishi Pharma Corporation) can be used. Usually, these irons will be contained in the aqueous phase.
水相には、脂肪粒子の安定化を損わない様な他の成分を加えることができる。例えばＮａＣｌ、グリセリン、ブドウ糖、ソルビトール、Ｄ−マンニトール等の注射用等張化剤やアミノ酸等のpH安定化剤を含有させてもよい。 Other components that do not impair the stabilization of the fat particles can be added to the aqueous phase. For example, an isotonic agent for injection such as NaCl, glycerin, glucose, sorbitol, D-mannitol and a pH stabilizer such as amino acid may be contained.
本発明の脂肪乳剤は、例えば前記ヨード付加した油脂を１〜５０％程度（ｗ／ｖ％である。以下同じ）、好ましくは５〜３０％、常磁性金属を０．０５〜５％、好ましくは０．１〜３％、乳化剤を０．０１から１０％、好ましくは０．０５〜８％の割合でそれぞれ含有しているのがよい。それぞれ関心領域でのコントラストが得られるような適正な配合量が確保できればよい。 The fat emulsion of the present invention is, for example, about 1 to 50% (w / v%; the same applies hereinafter) of the oil and fat added with iodine, preferably 5 to 30%, and paramagnetic metal 0.05 to 5%, preferably May contain 0.1 to 3% and an emulsifier in a proportion of 0.01 to 10%, preferably 0.05 to 8%. It is only necessary to ensure an appropriate blending amount so that a contrast in each region of interest can be obtained.
脂肪乳剤の調製は、従来公知の方法を使用すればよい。具体的には、例えば、ヨード付加した油脂を、乳化剤および必要に応じて油脂その他の成分と共に水に加えて、攪拌して乳化液を調製する。さらに微細な粒子に調製する必要がある場合には、攪拌以外に超音波乳化法、高圧乳化法または膜乳化法などの公知の方法を採用することができる。
また、脂肪乳剤の平均粒子径の大きさは、安全性や標的臓器への集積性と密接に関与することから、本発明で得られる脂肪乳剤の平均粒子径は７μm以下、好ましくは１μｍ以下であるのがよい。油相の平均粒子径がこの範囲を超えると、副作用の発現が高くなり安全性が懸念される。
A fat emulsion may be prepared by a conventionally known method. Specifically, for example, an iodine-added oil and fat is added to water together with an emulsifier and, if necessary, the oil and fat and other components, and stirred to prepare an emulsion. When it is necessary to prepare finer particles, a known method such as an ultrasonic emulsification method, a high-pressure emulsification method, or a membrane emulsification method can be employed in addition to stirring.
Further, since the average particle size of the fat emulsion is closely related to safety and accumulation in the target organ, the average particle size of the fat emulsion obtained in the present invention is 7 μm or less, preferably 1 μm or less. There should be. If the average particle size of the oil phase exceeds this range, the occurrence of side effects is increased and there is concern about safety.
ＣＴおよびＭＲＩの撮影を行うには、例えば肝実質の場合には、本発明造影剤を動脈又は静脈投与にて所要量を投与し、投与から３０〜６０分の間にＣＴを施行し、さらに投与から６０〜３６０分の間にＭＲＩを実施する。ＣＴとＭＲＩを施行する間隔は前記したとおりである。 In order to perform CT and MRI imaging, for example, in the case of liver parenchyma, the required amount of the contrast medium of the present invention is administered by arterial or intravenous administration, CT is performed for 30 to 60 minutes after administration, MRI is performed between 60 and 360 minutes after administration. The interval between CT and MRI is as described above.
本発明造影剤の投与量は、撮影部位によって異なるが、前記ヨード付加した油脂は、ヨードに換算して３０〜６００ｍｇ／回程度、好ましくは２４０〜４８０ｍｇ／回程度であるのがよい。
本発明造影剤の撮影部位は、従来、ＣＴやＭＲＩによる撮影が行われていた部位であれば、全て適用可能であり、特に肝臓などでのＣＴやＭＲＩの施行には好適である。
The dose of the contrast agent of the present invention varies depending on the region to be imaged, but the iodine added fat is about 30 to 600 mg / time, preferably about 240 to 480 mg / time in terms of iodine.
The imaging part of the contrast agent of the present invention can be applied to any part that has been conventionally imaged by CT or MRI, and is particularly suitable for performing CT or MRI in the liver or the like.
以下、実施例を挙げて本発明の薬剤を説明するが、本発明は以下の実施例のみに限定されるものではない。 Hereinafter, although the chemical | medical agent of this invention is demonstrated using an Example, this invention is not limited only to a following example.
ケタラール：ドミトールを容量比で１０：３で混合した麻酔剤１ｃｃをウサギ（雌、体重１ｋｇ）３羽に筋肉注射した。
一方、含糖酸化鉄水溶液（前出の「フェジン」、２ｍＬ中含糖酸化鉄４０ｍｇを含有）１ｍＬ、ヨード化ケシ油脂肪酸エチルエステル（前出の「リピオドール ウルトラフルイド」）１ｍＬ、大豆油５００ｍｇ、レシチン２４０ｍｇ、グリセリン１２５ｍｇに蒸留水を混合して、総量５ｍＬのＯ／Ｗ型エマルションである脂肪乳剤を得た。この脂肪乳剤の油相の粒子径は３６０ｎｍとほぼ均一であった。造影剤として、前記脂肪乳剤０．２ｍＬ、０．４ｍＬ、０．８ｍＬをそれぞれ用意し、投与時に蒸留水にて５倍希釈して（すなわち全量で１ｍＬ、2ｍＬ、４ｍＬ）投与した。投与は耳静脈から行った。
造影剤投与前および投与後、ＣＴは５分ごとに施行し、ＭＲＩは投与から５２分後に施行した。
ＣＴ撮影装置：ＧＥ社製のLight Speed Ultra
ＭＲＩ撮影装置：ＧＥ社製の１．５Ｔ Signa Horizon
Three rabbits (female, body weight 1 kg) were injected intramuscularly with 1 cc of anesthetic prepared by mixing ketalal: dmitol at a volume ratio of 10: 3.
On the other hand, 1 mL of sugar-containing iron oxide aqueous solution (containing the above-mentioned “Fedin”, 40 mL of sugar-containing iron oxide in 2 mL), 1 mL of iodinated poppy oil fatty acid ethyl ester (the above-mentioned “Lipiodol Ultrafluid”), 500 mg of soybean oil, Distilled water was mixed with 240 mg of lecithin and 125 mg of glycerin to obtain a fat emulsion which was an O / W emulsion having a total amount of 5 mL. The particle size of the oil phase of this fat emulsion was almost uniform at 360 nm. As the contrast agent, 0.2 mL, 0.4 mL, and 0.8 mL of the fat emulsion were prepared, respectively, and diluted 5 times with distilled water at the time of administration (that is, 1 mL, 2 mL, and 4 mL in total amount). Administration was via the ear vein.
Before and after contrast agent administration, CT was performed every 5 minutes, and MRI was performed 52 minutes after administration.
CT imaging device: Light Speed Ultra manufactured by GE
MRI imaging equipment: 1.5T Signa Horizon made by GE
＜ＣＴ撮影の条件＞
１２０ｋＶ、ＦＯＶ＝２０ｃｍ、５ｍｍスライスでＸ線管球は１回転５秒で回し、８．７５ｍｍ／秒で移動。
＜MRI撮影の条件＞
TＲ４０００、ＴＥ３４．０、Ｔ２ ７１．３、ＥＴＬ８回、ＦＯＶ＝２０、スライス５ｍｍ、space １ｍｍ、ＮＥ（励起回数）２回、マトリックス ５１２×１６０
試験結果を以下に示す。
<Conditions for CT imaging>
120kV, FOV = 20cm, 5mm slice, X-ray tube rotates at 5 seconds per rotation and moves at 8.75mm / second.
<Conditions for MRI photography>
TR4000, TE34.0, T2 71.3, ETL 8 times, FOV = 20, slice 5 mm, space 1 mm, NE (excitation number) 2 times, matrix 512 × 160
The test results are shown below.
１．ＣＴ
表１はＣＴの試験結果を示す。
Table 1 shows the test results of CT.
２．ＭＲＩ
造影剤投与前後において、肝臓の信号強度（ＳＩ）および背景ノイズの標準偏差（ＳＤ）を測定し、ＳＮＲ（signal to noise ratio）＝ＳＩ／ＳＤを求めた。造影剤投与後のSNRが投与後のSNRより低い値であれば、信号強度比（ＳＥＲ）に優れていることを示している。ちなみに、信号強度比（ＳＥＲ）は以下の式から求められる。
Before and after contrast agent administration, the signal intensity (SI) of the liver and the standard deviation (SD) of background noise were measured, and SNR (signal to noise ratio) = SI / SD was determined. If the SNR after administration of the contrast agent is lower than the SNR after administration, it indicates that the signal intensity ratio (SER) is excellent. Incidentally, the signal intensity ratio (SER) is obtained from the following equation.
＜Ｔ２強調画像の信号強度＞
（1）造影剤を投与する前
肝臓 ３０３．８７
背景 ２２．８６（平均値）／１１．９２（標準偏差）
ＳＮＲ(pre)＝３０３．８７／１１．９２＝２５．４９
（2）造影剤0.8mL（全量で4.0mL）を投与してから５２分後
肝臓 ３０３．６７
背景 ２８．３４（平均値）／１５．１５（標準偏差）
ＳＮＲ（post）＝３０３．６７／１５．１５＝２０．０４
この結果から、造影剤０．８ｍＬの投与が肝実質の信号強度比（ＳＥＲ）に優れていることがわかる。
<Signal strength of T2-weighted image>
(1) Before administration of contrast medium Liver 303.87
Background 22.86 (average value) / 11.92 (standard deviation)
SNR (pre) = 303.87 / 11.92 = 25.49
(2) 52 minutes after administration of 0.8 mL of contrast agent (total volume of 4.0 mL) liver 303.67
Background 28.34 (average value) /15.15 (standard deviation)
SNR (post) = 303.67 / 15.15 = 20.04
From this result, it can be seen that administration of contrast medium 0.8 mL is excellent in the signal intensity ratio (SER) of the liver parenchyma.
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