WO1995020981A1 - Moyen de marquage visuel de tissus corporels - Google Patents

Moyen de marquage visuel de tissus corporels Download PDF

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Publication number
WO1995020981A1
WO1995020981A1 PCT/EP1995/000123 EP9500123W WO9520981A1 WO 1995020981 A1 WO1995020981 A1 WO 1995020981A1 EP 9500123 W EP9500123 W EP 9500123W WO 9520981 A1 WO9520981 A1 WO 9520981A1
Authority
WO
WIPO (PCT)
Prior art keywords
agent
marking
colored
dye
tissue
Prior art date
Application number
PCT/EP1995/000123
Other languages
German (de)
English (en)
Inventor
Sylvia HEYWANG-KÖBRUNNER
Werner Weitschies
Ulrich Speck
Thomas Fritzsch
Original Assignee
Schering Aktiengesellschaft
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Schering Aktiengesellschaft filed Critical Schering Aktiengesellschaft
Priority to EP95906937A priority Critical patent/EP0742724A1/fr
Priority to JP7520342A priority patent/JPH09508397A/ja
Publication of WO1995020981A1 publication Critical patent/WO1995020981A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/04—X-ray contrast preparations
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
    • A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
    • A61K49/223—Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B90/00—Instruments, implements or accessories specially adapted for surgery or diagnosis and not covered by any of the groups A61B1/00 - A61B50/00, e.g. for luxation treatment or for protecting wound edges
    • A61B90/39—Markers, e.g. radio-opaque or breast lesions markers
    • A61B2090/3933—Liquid markers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B90/00—Instruments, implements or accessories specially adapted for surgery or diagnosis and not covered by any of the groups A61B1/00 - A61B50/00, e.g. for luxation treatment or for protecting wound edges
    • A61B90/39—Markers, e.g. radio-opaque or breast lesions markers
    • A61B2090/3937—Visible markers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B90/00—Instruments, implements or accessories specially adapted for surgery or diagnosis and not covered by any of the groups A61B1/00 - A61B50/00, e.g. for luxation treatment or for protecting wound edges
    • A61B90/39—Markers, e.g. radio-opaque or breast lesions markers
    • A61B2090/3954—Markers, e.g. radio-opaque or breast lesions markers magnetic, e.g. NMR or MRI
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B90/00—Instruments, implements or accessories specially adapted for surgery or diagnosis and not covered by any of the groups A61B1/00 - A61B50/00, e.g. for luxation treatment or for protecting wound edges
    • A61B90/39—Markers, e.g. radio-opaque or breast lesions markers

Definitions

  • the invention relates to the subject matter characterized in the patent claims, that is to say the use of colored NMR or X-ray contrast media or of dye-containing ultrasound contrast media for the production of a diagnostic agent for the visual marking of body tissue.
  • a needle or wire (generally with anchoring options) is brought to the stove and left there until the operation.
  • the tissue to be excised is marked directly by injecting a dye.
  • Method 1 is inaccurate for lesions in deep tissue, especially tissue with significant breathability (e.g. breast cancer).
  • Method 2 overcomes this disadvantage, but there is increased
  • Method 3 is currently the most frequently used method.
  • an injection needle is inserted directly into the hearth and the dye in question is injected under radiological control.
  • the dye is injected under radiological control.
  • a contrast medium NMR, X-ray
  • Dyes for tissue marking have so far been used on the one hand with water-soluble dyes, such as indigo carmine or methylene blue, etc., or with insoluble substances, such as sterile activated carbon that has been suspended.
  • water-soluble dyes Apart from a few allergic reactions, water-soluble dyes have the advantage of being tolerable. They are clearly visible to the surgeon and are completely excreted. Their main disadvantage is that they diffuse very quickly in the tissue. Already with a relatively short interval (from 1-2 hours) Between the radiological marking and the operation, the dye spreads quickly into the environment, so that large areas are stained and an exact assignment is then no longer possible.
  • the sterile activated carbon suspended in physiological saline remains largely at the injection site until it is removed by the surgeon. This facilitates the time planning between radiological marking and e.g. an operation in routine operation. In addition, with good labeling, an exact histopathological correlation is generally possible without difficulty.
  • the disadvantages of activated carbon are that it cannot be excreted by the body and can lead to reactive changes in the tissue or in draining lymph nodes.
  • fine particulate activated carbon tends to clump, possibly due to electrostatic effects. This is a clear disadvantage, since needles up to 18 gauge often become clogged and a new marking has to be carried out again.
  • the object of the present invention is therefore to provide a marking agent which overcomes the disadvantages of the prior art, i.e. to find a marker that
  • black or colored contrast media for magnetic resonance tomography or X-ray diagnostics as well as gas / dye or gas-containing microparticles, such as are suitable for ultrasound diagnostics, meet the stated requirements surprisingly well and are therefore outstanding are suitable for visually marking body tissues for the purpose of later finding such tissues.
  • the invention thus relates to the use of colored NMR or X-ray contrast media or of dye-containing ultrasound contrast media for the production of a diagnostic agent for the visual marking of body tissue. Examples of such agents are mentioned below.
  • Suitable are e.g. Suspensions of magnetites, i.e. colloidal solutions or mixtures of FeO and Fe2 ⁇ 3, which are stabilized by a more or less hydrophilic coating with usually organic molecules. Because of their strong influence on the relaxation of protons or because of their X-ray absorbing effect, they not only have an imaging effect in radiological procedures, they are also, due to their dark brown to black color, also visually recognizable, so that they are particularly good at
  • Suitable for marking light tissues e.g. fat, glandular tissue, muscle, connective tissue.
  • magnetites usually have particle diameters of well below 1 ⁇ m and are easily suspended in water and are therefore transportable, they remain largely undiluted at the injection site for a surprisingly long time (days to months) after injection into the tissue and are clearly visible there with the eye . Magnetites are well tolerated locally. In the long term, the iron oxides are dissolved and the iron is converted into the natural iron metabolism.
  • Marking with magnetites additionally opens up the possibility in histological sections to stain the iron contained in the magnetites with potassium rhodanide as "Berlin blue".
  • Magnetites suitable for medical use and processes for their production are e.g. in US 4,731,239, US 4,770,183, US 4,827,945, US 4,767,611, EP 0 186 616, SE 83 070 60, SE 84 054 99, GB 84-08127, DE 35 79 899, WO 91/05807.
  • metal porphyrins are also suitable for the stated purpose. Depending on the metal they contain, these can be easily detected either by X-ray analysis or, if the complexed metals are paramagnetic metal ions, such as Fe3 + , manganese + , gadolinium ⁇ "1 " etc., using magnetic resonance tomography. Porphyrins also absorb light in the visible frequency range, so that they are also visually recognizable. Intensely colored complexes such as are described, for example, in EP 0 336 879 or EP 0 355 041 are particularly suitable.
  • ultrasound contrast media which, in addition to the encapsulated echo-giving gas, also contain a dye. Contrast agents of this type are described in DE 43 30 958. In principle, all are physiologically suitable as a dye compatible dyes, such as hemoglobin, chlorophyll, etc. Also suitable are dyes that would diffuse quickly in unencapsulated form (such as methylene blue). The encapsulation prevents diffusion, ie the dye remains at the injection site and can only be released there directly before the operation, as described in DE 43 30 958, by irradiation with ultrasound of a suitable frequency and wavelength.
  • the abovementioned means are outstandingly suitable for marking tissue, in particular in regions of the body which are not accessible to direct visual inspection. Surprisingly, they are also stable over a longer period of time, ie they do not diffuse or are negligibly slow in the time interval between marking and surgery.
  • the agents mentioned are well tolerated and, surprisingly, are already visually recognizable in such a low concentration that they can also be used in imaging radiological processes. This makes it possible to use the dose administered in an injection to use both a control image with an imaging method [such as, for example, X-ray technology including conventional X-ray images, such as mammography or computer tomography, magnetic resonance imaging (MRI) and ultrasound methods] to produce, as well as to create a mark easily recognizable for the surgeon.
  • an imaging method such as, for example, X-ray technology including conventional X-ray images, such as mammography or computer tomography, magnetic resonance imaging (MRI) and ultrasound methods
  • the agents mentioned are therefore of particular value when marking small areas of tissue that are one or more centimeters below the surface of the body, especially if they are easily displaceable (e.g. breast tissue, testicular tissue) due to their location in soft tissue.
  • the agents mentioned are injected through the same cannula immediately after the sample has been taken, the corresponding imaging methods can be used to easily identify whether the sample was actually taken at the intended location.
  • the agents mentioned are generally introduced into the corresponding tissue area through a sufficiently long cannula as a solution, suspension or emulsion, with visual inspection of the imaging processes mentioned.
  • the imaging method used is magnetic resonance imaging
  • cannulas made of non-magnetic material should of course be used because of the strong magnetic fields. Due to the imaging properties of the applied agent, a control image can be taken immediately after the application, from which one can see whether the marking has actually been placed at the desired location. In the event that the lesion was missed, the operating surgeon can easily find the tumor area again using the color marking, since the position of the tumor area relative to the color marking can easily be found in the control image.
  • the agents mentioned are generally easy to see with the naked eye.
  • ultrasound contrast agents based on gas-containing microparticles it is recommended (because of the particles only indistinct marking), instead of visual inspection, the particles are recovered using an ultrasound scanner.
  • Such devices are available in every operating room (in contrast to an MRI scanner or an X-ray machine).
  • Porphyrins recommend that the coloring effect be enhanced by excitation with infrared or ultraviolet light.
  • the aids required for this are also easily accessible in every operating room.
  • All preparations intended for injection into tissue must be sterile. If desired, they can contain the usual pharmaceutical auxiliaries for isotonization (e.g. glucose, NaCl), buffering or stabilization of the solution or emulsion or suspension.
  • auxiliaries for isotonization e.g. glucose, NaCl
  • buffering or stabilization of the solution or emulsion or suspension e.g. glucose, NaCl
  • the applied dose depends primarily on the size of the tissue area to be marked. It can be very low at 50 ⁇ l. Injection volumes of 0.1 to 2 ml are preferred. For larger or multifocal processes, it may be necessary to inject up to 5 or more milliliters of the marking agent. At low volumes, higher concentrations of the individual components are preferred; at higher volumes, lower concentrations are more likely to be used, also to avoid artifacts in imaging diagnostics.
  • the concentrations of the applied agents vary depending on the imaging method chosen in each case.
  • Contrast agents are used for magnetic resonance tomography in concentrations of 0.1-100 ⁇ mol / ml, preferably 1-20 ⁇ mol / ml, X-ray contrast agents in the range of 3-100 mg of contrast element (e.g. iodine, iron etc. ) / ml and ultrasound contrasting preparations in the range from 0.01 to 50 ⁇ l gas / ml, preferably 0.1 to 5 ⁇ l gas / ml.
  • contrast element e.g. iodine, iron etc.
  • Magnetites are used as aqueous solutions with approx. 0.1 ⁇ mol iron / ml to 500 ⁇ mol iron / ml. Strongly colored solutions with approximately 20-500 ⁇ mol iron / ml are preferred.
  • Metalloporphyrins are used in the same concentration range (0.1 ⁇ mol / ml - 500 ⁇ mol / ml), the preferred range being 20-200 ⁇ mol / ml.
  • Other paramagnetic or metal ion-containing or iodine-containing dyes such as rose bengal, erythrosine, tetrachlorotetraiodine fluorescein are preferably used at a slightly higher concentration (50-500 ⁇ mol / ml).
  • the specified concentrations are to be regarded as guidelines; in individual cases they can be exceeded or undershot. They are sufficient to produce a clear imaging effect and, at the same time, a visually recognizable marking of the tissue in the chosen radiological method.
  • a suspicious tissue area is identified on the MRI.
  • a biopsy is performed using a needle, in which cells from the area in question are obtained.
  • 0.5 ml of a 50 mmol dextran magnetite solution (SH U 555, Schering AG, Berlin) is injected to check the exact position of the needle and to facilitate the recovery of the tissue area in question in the event of a subsequent operation.
  • the area in question is shown in the MRI signal arm.
  • the biopsy area can be recognized by the brown discoloration.
  • the pathologist can orientate himself in the surgical material and make the necessary cuts at the correct level.
  • microcalcifications are found in a volume of less than 0.5 cm 3 .
  • the region is stereotactically biopsied.
  • 0.2 ml of 500 mmolar magnetite solution are injected.
  • a breast cancer is detected on the basis of the biopsy.
  • the intraoperative identification of the lesion is facilitated by the clearly black-brown discoloration.
  • the dextran magnetite solution (SH U 555, Schering AG) is injected into muscle tissue in a concentration of A) 500 mmol Fe / liter, B) 250 mmol Fe / liter, C) 125 mmol Fe / liter and a dose of 1 ml by means of computer tomography examined.
  • the magnetite deposit is clearly recognizable in all cases and its shape is sharply defined. After the tissue area in question has been exposed, the magnetite is easily recognizable by the brown discoloration.
  • Microparticles of poly (D, L-lactic acid-glycolic acid) containing methylene blue are irradiated in vitro with ultrasound in a tissue sample (sound pressure> 50dB, frequency 2.5 MHz) and thereby release methylene blue in the tissue.
  • the methylene blue-containing particles can be prepared as disclosed in DE 43 30 958 (Example 8) by dissolving 4 g of poly (D, L-lactic acid-glycolic acid) (50:50) (Resomer RG 503, Boehringer Ingelheim) in 50 ml CH 2 C1 2 . be emulsified with 20 mg of methylene blue, dissolved in 4 ml of an aqueous 4% gelatin solution, with stirring using a high-speed stirrer. A further 200 ml of a 4% autoclaved gelatin solution are then added. The emulsion is stirred for 8 hours at room temperature. The resulting particles are filtered through a 5 ⁇ m filter, separated by centrifugation, resuspended in 50 ml of 4% autoclaved gelatin solution, frozen at -78 ° C and freeze-dried.
  • poly (D, L-lactic acid-glycolic acid) 50:50
  • the gas-containing microparticles are separated by centrifugation (at 1000 rpm, 30 min).
  • the particles obtained in this way are taken up in 20 ml of water for injection purposes and can be used directly for marking body tissue.
  • a dog is injected with 0.05 ml of a suspension of gas-filled hollow bodies with a casing made of biodegradable poly-2-cyanoacrylic acid ester (WO93 / 25242; Example 1) and an average particle size of approx. 2 ⁇ m in the thigh muscles.
  • Transducer found a sharply delineated dts contrast medium that is found in all
  • Levels can be localized well.

Abstract

La présente invention concerne l'utilisation de substances colorées destinées à la RMN, la radiographie ou, le cas échéant, de substances destinées à la production d'images par ultrasons, contenant des colorants, pour le marquage de tissus corporels.
PCT/EP1995/000123 1994-02-03 1995-01-13 Moyen de marquage visuel de tissus corporels WO1995020981A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP95906937A EP0742724A1 (fr) 1994-02-03 1995-01-13 Moyen de marquage visuel de tissus corporels
JP7520342A JPH09508397A (ja) 1994-02-03 1995-01-13 体組織を視覚的に標識化するための薬剤

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DEP4403789.9 1994-02-03
DE4403789A DE4403789A1 (de) 1994-02-03 1994-02-03 Mittel zur visuellen Markierung von Körpergewebe

Publications (1)

Publication Number Publication Date
WO1995020981A1 true WO1995020981A1 (fr) 1995-08-10

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PCT/EP1995/000123 WO1995020981A1 (fr) 1994-02-03 1995-01-13 Moyen de marquage visuel de tissus corporels

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EP (1) EP0742724A1 (fr)
JP (1) JPH09508397A (fr)
CA (1) CA2182686A1 (fr)
DE (1) DE4403789A1 (fr)
WO (1) WO1995020981A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5900228A (en) * 1996-07-31 1999-05-04 California Institute Of Technology Bifunctional detection agents having a polymer covalently linked to an MRI agent and an optical dye
US6022526A (en) * 1997-07-30 2000-02-08 Pharmacyclics, Inc. Use of texaphyrins in detection of melanin and melanin metabolites diagnostic of melanotic melanoma

Families Citing this family (15)

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JPH10508504A (ja) 1994-09-16 1998-08-25 バイオプシス メディカル インコーポレイテッド 組織を特定しおよびマーキングする方法および装置
US6770261B2 (en) 1995-06-02 2004-08-03 Research Corporation Technologies Magnetic resonance imaging agents for the detection of physiological agents
US6493570B1 (en) * 1998-11-02 2002-12-10 Photogen, Inc. Method for improved imaging and photodynamic therapy
US6713046B1 (en) 1997-10-27 2004-03-30 Research Corporation Technologies Magnetic resonance imaging agents for the delivery of therapeutic agents
US6270464B1 (en) 1998-06-22 2001-08-07 Artemis Medical, Inc. Biopsy localization method and device
AU752812B2 (en) 1997-11-17 2002-10-03 Research Corporation Technologies, Inc. Magnetic resonance imaging agents for the detection of physiological agents
US6986740B2 (en) 1998-11-02 2006-01-17 Xantech Pharmaceuticals, Inc. Ultrasound contrast using halogenated xanthenes
US6371904B1 (en) 1998-12-24 2002-04-16 Vivant Medical, Inc. Subcutaneous cavity marking device and method
US6356782B1 (en) 1998-12-24 2002-03-12 Vivant Medical, Inc. Subcutaneous cavity marking device and method
US9669113B1 (en) 1998-12-24 2017-06-06 Devicor Medical Products, Inc. Device and method for safe location and marking of a biopsy cavity
DE19925311B4 (de) 1999-05-27 2004-06-09 Schering Ag Mehrstufen-Verfahren zur Herstellung von gasgefüllten Mikrokapseln
US6673333B1 (en) 2000-05-04 2004-01-06 Research Corporation Technologies, Inc. Functional MRI agents for cancer imaging
AU2001276956A1 (en) 2000-07-17 2002-01-30 California Institute Of Technology Macrocyclic mri contrast agents
WO2002028441A2 (fr) 2000-10-04 2002-04-11 California Institute Of Technology Agents d'imagerie par resonance magnetique pour la detection et l'etiquetage in vivo de depots amyloides
ITMO20010060A1 (it) * 2001-03-30 2002-09-30 H S Hospital Service S R L Metodo e mezzi per l'individuazione e la segnalazione di una lesione non palpabile in tessuti molli

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5900228A (en) * 1996-07-31 1999-05-04 California Institute Of Technology Bifunctional detection agents having a polymer covalently linked to an MRI agent and an optical dye
US6123921A (en) * 1996-07-31 2000-09-26 California Institute Of Technology Bifunctional detection agents having an optical dye linked to an MRI contrast agent
US6521209B1 (en) 1996-07-31 2003-02-18 California Institute Of Technology Bifunctional detection agents
US6022526A (en) * 1997-07-30 2000-02-08 Pharmacyclics, Inc. Use of texaphyrins in detection of melanin and melanin metabolites diagnostic of melanotic melanoma

Also Published As

Publication number Publication date
JPH09508397A (ja) 1997-08-26
DE4403789A1 (de) 1995-08-10
CA2182686A1 (fr) 1995-08-10
EP0742724A1 (fr) 1996-11-20

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