EP0854732A2 - Kontrastmittel für die nahinfrarot-diagnostik - Google Patents

Kontrastmittel für die nahinfrarot-diagnostik

Info

Publication number
EP0854732A2
EP0854732A2 EP96945477A EP96945477A EP0854732A2 EP 0854732 A2 EP0854732 A2 EP 0854732A2 EP 96945477 A EP96945477 A EP 96945477A EP 96945477 A EP96945477 A EP 96945477A EP 0854732 A2 EP0854732 A2 EP 0854732A2
Authority
EP
European Patent Office
Prior art keywords
dye
agent according
atoms
contrast agent
dyes
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.)
Withdrawn
Application number
EP96945477A
Other languages
German (de)
English (en)
French (fr)
Inventor
Kai Licha
Björn Riefke
Werner Weitschiess
Dieter Heldmann
Violetta Sudmann
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
Original Assignee
Institut fuer Diagnostikforschung GmbH
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 Institut fuer Diagnostikforschung GmbH filed Critical Institut fuer Diagnostikforschung GmbH
Publication of EP0854732A2 publication Critical patent/EP0854732A2/de
Withdrawn legal-status Critical Current

Links

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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
    • A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
    • A61K49/0032—Methine dyes, e.g. cyanine dyes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
    • A61K49/0069—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form
    • A61K49/0076—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form dispersion, suspension, e.g. particles in a liquid, colloid, emulsion
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
    • A61K49/0069—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form
    • A61K49/0076—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form dispersion, suspension, e.g. particles in a liquid, colloid, emulsion
    • A61K49/0078—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form dispersion, suspension, e.g. particles in a liquid, colloid, emulsion microemulsion, nanoemulsion

Definitions

  • the invention relates to colloidal systems loaded with polymethyl dyes, their use as contrast agents in near-infrared diagnostics and methods for their production.
  • the diagnostician Since biological tissue has a relatively high permeability to long-wave light in the wavelength range from 700 to 1000 nm, the diagnostician has a completely different method for imaging tissue imaging in addition to the modern imaging methods such as X-ray, magnetic resonance tomography or ultrasound diagnostics.
  • Both the detection of the non-absorbed radiation in the form of a transmission representation and the fluorescence radiation emitted after irradiation with near-infrared light can provide tissue-specific information.
  • suitable fluorescent color Contribute substances that accumulate in the diseased tissue (especially tumors) and have a specific absorption and emission behavior.
  • Excitation radiation-induced fluorescence is detected and provides the actual tissue-specific information.
  • dyes from the class of polymethines have absorption and fluorescence properties, which are characterized by high absorption coefficients between 700 and 1000 nm and sufficient fluorescence quantum yields.
  • the photosensitizing effect of the polymethines is negligible, the photostability mostly very high.
  • a high degree of hydrophilicity of the dyes is required for application in the form of aqueous solutions in order to be able to introduce sufficient amounts of dye into the body in the form of aqueous solutions for imaging.
  • this object is achieved by creating contrast media which contain colloidal, dye-loaded systems, these colloids having a size range from 5 nm to 10 ⁇ m and at least one dye which absorbs and / or fluoresces in the wavelength range from 600 to 1200 nm contain.
  • colloids see Hunnius, Pharmaceutical Dictionary, 6th Edition, Berlin, de Gruyter 1986, p. 589 f., In the present text also coarsely disperse systems with particle sizes up to 10 ⁇ m are included under the term colloidal systems.
  • colloidal, dye-loaded systems accumulate in the area of local inflammations or tumors. This enrichment is excellently suited for the display of tumors or inflammations with the help of NIR diagnostics.
  • the contrast agents according to the invention are rapidly broken down by certain cells, for example copper cells of the liver, which leads to a rapid decrease in the colloid concentrations in the blood, while the colloid particles which have already been taken up by the target tissue , are degraded much more slowly. This significantly reduces the background noise caused by blood levels, which improves the representation of the lesions and / or makes it possible at an earlier point in time.
  • the invention thus relates to dye-loaded colloidal systems containing colloidal particles with a particle size between 5 nm and 10 ⁇ m, in or on the walls and / or cavities of which dye molecules are integrated, adhered or enclosed.
  • poly- ⁇ -caprolactone polylactic acid, polyglycolic acid, and copolymers of polylactic acid and polyglycolic acid, polyhydroxybutyric acid, polyhydroxyvaleric acid, and copolymers of polyhydroxybutyric acid and polyhydroxyvaleric acid, polyammo acids, polyal- alkyl cyanoacrylates, polyamides, polyacryldextran, polyacrylic starch, polyacrylic saccharide, polyacrylamide, polyesters, poly (ortho) esters, polyphosphorenes, copolymers of lactic acid and / or glycolic acid with polyoxyethylene.
  • proteins such as albumins, collagen, gelatin, hemoglobin or fibrinogen and starches, dextrans, chitin and chitosan are preferred as natural or partially synthetic biodegradable polymer materials.
  • Amphiphilic substances which either enclose the fluorescent dye in colloidal particles or together with the fluorescent dye form colloidal particles are also particularly suitable.
  • Phospholipids, fatty acids, fatty alcohols, cholesterol, esters or ethers from fatty alcohols or fatty alcohols and fatty acids, sugar derivatives with fatty acids or polyoxyethylene, esters or ethers from phospholipids, fatty acids, fatty alcohols with polyoxyethylene, bile acids, derivatives of sorbitan are preferred here with polyoxyethylene or fatty acids or fatty alcohols and their combinations.
  • Preferred contrast agents according to the invention contain colloids of proteins, such as albumins, collagen, gelatin, hemoglobin or fibrinogen, or starches and starch derivatives, dextrans, chitin or chitosan.
  • proteins such as albumins, collagen, gelatin, hemoglobin or fibrinogen, or starches and starch derivatives, dextrans, chitin or chitosan.
  • contrast agents according to the invention contain colloids from phospholipids, fatty acids, fatty alcohols, cholesterol, esters from fatty alcohols and fatty acids, ethers from fatty alcohols, sugar derivatives with fatty acids or polyoxyethylene, esters or ethers from phospholipids, fatty acids or fatty alcohols with polyoxyethylene, bile acids, derivatives of sorbitan with polyoxyethylene, fatty acids or fatty alcohols as well as combinations of the substances mentioned.
  • contrast agents according to the invention are those which contain polyesters of ⁇ -, ⁇ -, ⁇ - or ⁇ -hydroxycarboxylic acids, polyalkylcyanoacrylates, polyamino acids, polyamides, polyacrylated saccharides or poly (ortho) esters as colloids.
  • the dyes used for the colloidal near-infrared diagnosis according to the invention are distinguished by the fact that they absorb and fluoresce in the wavelength range from 600 to 1200 nm, absorption coefficients of approx. 100,000 1 mol "1 cm “ 1 and higher and, if fluorescence is desired has fluorescence quantum yields greater than 5%.
  • the dyes used belong to the class of polymer dyes and are selected from the following group: cyanine, styryl, merocyanine, squarain, oxonol dyes.
  • the contrast agents according to the invention contain a cyanine, a styryl, a merocyanine, a squarain, an oxonol dye or a mixture of the dyes mentioned as the dye.
  • Contrast agents according to the invention which contain a dye from the class of cyanine dyes or squarain dyes are preferred. Also preferred are contrast agents according to the invention in which the dye has one or more unbranched, branched, cyclic or polycyclic alkyl, alkenyl, polyalkenyl, alkynyl, polyalkmyl, aryl, alkylaryl or arylalkyl radicals, each with up to to 60 carbon atoms, which are optionally substituted with halogen atoms, hydroxy, carboxy, aminocarbonyl, alkoxycarbonyl, ammo, aldehyde, oxo, oxy or alkoxy groups with up to 20 carbon atoms and / or optionally interrupted and / or substituted by one or more hetero atoms from the O, N, S or P series.
  • Contrast agents according to the invention are particularly preferred in which at least one dye of the general formula I, II or III
  • R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 and R 10 are identical or different and independently of one another are -COOE 1 , -CONE ⁇ 2 , -NHCOE 1 , -NHCONHE 1, -NE ⁇ 2 - 1 OE, -SO3E 1, -SO2E 1, -S0 2 NE 1 e 2, e 1, for em fluorine, chlorine, bromine or iodine atom or a nitro group STE hen, or in which two adjacent radicals R 1 , R 2 , R 3 or R 4 or R 7 , R 8 , R 9 or R 10 are fused, taking into account the C atoms in between, 5 to 6-membered rings, which are saturated, unsaturated or aromatic and, if appropriate, with the residues -COOE 1 , -CONE ⁇ 2 , -NHCOE 1 , -NHCONHE 1 , -NE ⁇ 2 ,
  • E 1 and E 2 are the same or different and independently of one another for a hydrogen atom, a saturated or unsaturated, branched or unbranched C1-C50-alkyl chain, the chain or parts of this chain optionally being a cyclic C5 -C6- or eme bicyclic Cio-Emheit form, which are interrupted and / or substituted by by oxygen atoms, sulfur atoms, nitrogen atoms, carboxylic acid ester, carboxylic acid amide, urea, thiourea, carbamate ether groups are, or for a hydroxypolyoxyethylene or methoxypolyoxyethylene chain or for a branched or unbranched C 1 -C 4 -alkyl chain which is substituted by 1 to 19 fluorine atoms, R5 and R ⁇ independently of one another represent a radical -E 1 or a C ⁇ -C 4 sulfoalkyl chain,
  • R 11 represents a hydrogen, fluorine, chlorine, bromine or iodine atom, a radical -NE ⁇ 2 , -OE 1 or -E 1 or a nitro group,
  • R 12 represents a hydrogen atom or a radical -E 1 ,
  • b represents the number 0, 2 or 3
  • ChfeR 14 stand in what
  • R 13 and R 14 independently of one another for hydrogen, a saturated or unsaturated, branched or unbranched C 1 -C 4 -alkyl chain, where the radicals R 13 and R 14 optionally forming a 5- or 6-membered chain Ring are linked together, which are optionally interrupted and / or substituted by oxygen atoms and / or by hydroxy groups, alkoxy groups with up to 6 carbon atoms, carboxylic acid ester and / or carboxylic acid amide units,
  • Cations can be sodium, potassium, calcium, magnesium, gadolinium, as well as lysine, glutamine and methylglutamine.
  • Dyes with a positive total charge are preferably present as iodides, bromides or perchlorates.
  • the contrast media according to the invention can furthermore contain at least two dyes which have different photophysical and / or pharmacological properties.
  • the contrast media according to the invention can additionally contain auxiliaries and carriers and diluents customary in galenics.
  • the dyes are prepared by methods known from the literature, such as, for example, Hamer, FM, The Cyanine Dyes and Related Compounds, John Wiley and Sons, New York, 1964; Bioconjugate Chem. 4 (1993) 105-11; Anal biochem. 217 (1994) 197-204; Tetrahedron 45 (1989) 4845-66; Anal. Chim. Acta 282 (1993) 633-641; Dyes Pigm. 21: 227-234 (1993); EP 0 591 820 AI.
  • Another object of the present invention is the use of the contrast agents according to the invention for in vivo fluorescence and absorption diagnostics in the near infrared range.
  • the in vivo diagnosis using the contrast agents according to the invention is preferably carried out after intravenous
  • the diagnostic agent according to the invention is represented on the basis of the methods described in the literature for the representation of colloidal particles, one or more dyes being added to the reaction mixtures.
  • the degree of loading can be varied by the choice of the dye concentration in the reaction system.
  • the organic materials described above are preferably dissolved together with one or more dyes in one or more water-immiscible organic solvents and then, if appropriate, emulsified in water after the addition of a further solvent, it being possible, if appropriate, to add an emulsifier to the emulsion.
  • the colloidal system obtained can then be filtered and optionally through drying measures such. B. freeze-drying can be stabilized.
  • contrast media are produced by methods known to the person skilled in the art, optionally using customary auxiliaries and / or carriers, as well as diluents and the like. These include physiologically compatible electrolytes, buffers, detergents, emulsifiers and substances for adapting the osmolality and for improving the stability and solubility, such as cyclodextrins.
  • auxiliaries and / or carriers as well as diluents and the like.
  • diluents and the like include physiologically compatible electrolytes, buffers, detergents, emulsifiers and substances for adapting the osmolality and for improving the stability and solubility, such as cyclodextrins.
  • the measures customary in pharmacy ensure the sterility of the preparations during manufacture and in particular before application.
  • the suspension After resuspending a portion with 5 ml of 0.9% saline solution, the suspension contains about 10 particles per ml containing hexamethylindotnecarbocyanine iodide with a particle size of about 1 to 10 ⁇ m.
  • Example 2

Landscapes

  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biomedical Technology (AREA)
  • Chemical & Material Sciences (AREA)
  • Dispersion Chemistry (AREA)
  • Nanotechnology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Investigating, Analyzing Materials By Fluorescence Or Luminescence (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
EP96945477A 1995-10-11 1996-09-26 Kontrastmittel für die nahinfrarot-diagnostik Withdrawn EP0854732A2 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19539409A DE19539409C2 (de) 1995-10-11 1995-10-11 Kontrastmittel für die Nahinfrarot-Diagnostik
DE19539409 1995-10-11
PCT/DE1996/001878 WO1997013490A2 (de) 1995-10-11 1996-09-26 Kontrastmittel für die nahinfrarot-diagnostik, enthaltend mit polymethinfarbstoffen beladene kolloidale systeme

Publications (1)

Publication Number Publication Date
EP0854732A2 true EP0854732A2 (de) 1998-07-29

Family

ID=7775535

Family Applications (1)

Application Number Title Priority Date Filing Date
EP96945477A Withdrawn EP0854732A2 (de) 1995-10-11 1996-09-26 Kontrastmittel für die nahinfrarot-diagnostik

Country Status (13)

Country Link
US (2) US6319488B1 (hu)
EP (1) EP0854732A2 (hu)
JP (1) JPH11504656A (hu)
KR (1) KR100290240B1 (hu)
CN (1) CN1075951C (hu)
AU (1) AU711266B2 (hu)
CA (1) CA2233995A1 (hu)
DE (1) DE19539409C2 (hu)
HU (1) HUP9900458A3 (hu)
IL (1) IL119365A (hu)
NO (1) NO981586L (hu)
WO (1) WO1997013490A2 (hu)
ZA (1) ZA968229B (hu)

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Also Published As

Publication number Publication date
ZA968229B (en) 1997-05-14
NO981586D0 (no) 1998-04-07
CN1199341A (zh) 1998-11-18
AU711266B2 (en) 1999-10-07
AU1589297A (en) 1997-04-30
IL119365A (en) 2000-07-26
KR100290240B1 (ko) 2001-05-15
IL119365A0 (en) 1997-01-10
DE19539409A1 (de) 1997-04-17
WO1997013490A2 (de) 1997-04-17
HUP9900458A2 (hu) 1999-06-28
HUP9900458A3 (en) 1999-11-29
CA2233995A1 (en) 1997-04-17
DE19539409C2 (de) 1999-02-18
WO1997013490A3 (de) 1997-10-23
US20020022004A1 (en) 2002-02-21
NO981586L (no) 1998-04-07
CN1075951C (zh) 2001-12-12
JPH11504656A (ja) 1999-04-27
KR19990044581A (ko) 1999-06-25
US6319488B1 (en) 2001-11-20

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