WO1999042139A2 - Conjugues d'amidon hydroxyethyle, leur procede de production et produits pharmaceutiques les contenant - Google Patents

Conjugues d'amidon hydroxyethyle, leur procede de production et produits pharmaceutiques les contenant Download PDF

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Publication number
WO1999042139A2
WO1999042139A2 PCT/EP1999/000853 EP9900853W WO9942139A2 WO 1999042139 A2 WO1999042139 A2 WO 1999042139A2 EP 9900853 W EP9900853 W EP 9900853W WO 9942139 A2 WO9942139 A2 WO 9942139A2
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WO
WIPO (PCT)
Prior art keywords
hydroxyethyl starch
general formula
mmol
carboxymethyl
compounds
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.)
Ceased
Application number
PCT/EP1999/000853
Other languages
German (de)
English (en)
Other versions
WO1999042139A3 (fr
Inventor
Peter Mareski
Johannes Platzek
Bernd Radüchel
Ulrich Niedballa
Hanns-Joachim Weinmann
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
Schering AG
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 AG filed Critical Schering AG
Priority to AU28328/99A priority Critical patent/AU2832899A/en
Publication of WO1999042139A2 publication Critical patent/WO1999042139A2/fr
Publication of WO1999042139A3 publication Critical patent/WO1999042139A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B31/00—Preparation of derivatives of starch
    • C08B31/08—Ethers
    • C08B31/12—Ethers having alkyl or cycloalkyl radicals substituted by heteroatoms, e.g. hydroxyalkyl or carboxyalkyl starch
    • 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
    • A61K49/085—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier conjugated systems
    • 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
    • A61K49/12—Macromolecular compounds
    • A61K49/126—Linear polymers, e.g. dextran, inulin, PEG
    • A61K49/128—Linear polymers, e.g. dextran, inulin, PEG comprising multiple complex or complex-forming groups, being either part of the linear polymeric backbone or being pending groups covalently linked to the linear polymeric backbone

Definitions

  • the invention relates to the subject matter characterized in the patent claims, that is to say new hydroxyethyl starch conjugates, agents containing these compounds, the use of the complexes in diagnosis and therapy and methods for producing these compounds and agents.
  • MRI magnetic resonance imaging
  • CT computed tomography
  • Magnnevist®, Pro Hance®, Ultravist® and Omniscan® are distributed throughout the extracellular space of the body (intravascular space and interstitium) about 20% of the body volume
  • Extracellular MRI contrast agents were first used clinically successfully in the diagnosis of cerebral and spinal disease processes, since this results in a very special situation with regard to the regional distribution area.
  • extracellular contrast agents in healthy tissue cannot leave the intravascular space due to the blood-brain barrier.
  • regions with increased blood vessel permeability (permeability) for these extracellular contrast agents Schomiedl et al., MRI of blood -brain bar ⁇ er permeabi ty in astrocytic giiomas: application of small and large molecular weight contrast media, Magn. Reson. Med. 22: 288, 1991).
  • a contrast medium that is distributed exclusively in the vasal space would be desirable especially for the imaging of vessels.
  • vascular space Such a blood pool agent should make it possible to use MRI to differentiate between well-perfused and poorly perfused tissue and thus also diagnose ischemia infarcted tissue could be differentiated from the surrounding healthy or ischemic tissue due to its anemia, if a vasal contrast medium is used. This is particularly important when it comes to differentiating a heart attack from an ischemia, for example
  • NMR contrast media which can mark the vasal space (blood pool agent). These compounds are to be distinguished by good tolerability and high activity (high increase in signal intensity in MRI)
  • Macromolecules can generally be suitable as contrast media for angiography.
  • Albumm-GdDTPA Radiology 1987, 162 205
  • eg 24 hours after intravenous injection in the rat shows an accumulation in the liver tissue that accounts for almost 30% of the dose.
  • 24 hours only 20% of the dose eliminated
  • the macromolecule polylysine-GdDTPA (European patent application, publication no. 0 233 619) also proved to be suitable as a blood pool agent. However, due to the production process, this compound consists of a mixture of molecules of different sizes. In excretion experiments in the rat, it was shown that this macromolecule is excreted unchanged via the kidney by glomerular filtration. Due to its synthesis, polylysine-GdDTPA can also contain macromolecules that are so large that they cannot pass through the capillaries of the kidney during glomerular filtration and thus remain in the body
  • the object was therefore to provide new diagnostic means, especially for the detection and localization of vascular diseases, which do not have the disadvantages mentioned. This object is achieved by the present invention
  • K represents a radical of the general formula II ( " ⁇
  • N preferably stands for the numbers 240 to 750.
  • K is a metal complex
  • at least two of the radicals Z are metal ion equivalents of atomic numbers 20-29, 39, 42, 44 or 57-83, preferably the atomic numbers of paramagnetic metals. Gadolinium is particularly preferred.
  • the monomer unit of the hydroxyethyl starch conjugates according to the invention preferably contains statistically 0.05 to 1 radicals a 4 and 0.05 to 1 radicals a 5.
  • B is preferably one of the radicals
  • hydroxyethyl starch conjugates according to the invention have the desired properties described at the outset
  • contrast agents according to the invention can be used as solutions Isoosmolar to the blood and thereby reduce the osmotic load on the body, which is reflected in a reduced toxicity of the substance (higher toxic threshold).
  • Lower doses and higher toxic threshold lead to a significant increase in the safety of contrast medium applications in modern imaging methods
  • macromolecular contrast agents based on carbohydrates, eg dextran European patent application, publication no.
  • the polymer complexes according to the invention have a content of generally about 20% of the paramagnetic cation.
  • the macromolecules according to the invention bring about a very much higher signal amplification per molecule, which at the same time means that the dose required for nuclear spin tomography is considerably smaller compared to other macromolecular contrast agents
  • the hydroxyethyl starch conjugates according to the invention are distinguished by improved excretion behavior, greater effectiveness, greater stability and / or better tolerance
  • a further advantage of the present invention is that complexes with hydrophilic, macrocyclic, high molecular weight ligands have now become accessible. This makes it possible to control the compatibility and pharmacokinetics of these polymer complexes by chemical substitution
  • hydroxyethyl starch conjugates according to the invention are prepared by the processes known to the person skilled in the art by base-catalyzed etherification of commercially available hydroxyethyl starches - preferably with a degree of substitution of 0.5 - with haloacetic acids, preferably
  • the desired metals are introduced by the methods known to the person skilled in the art, as disclosed, for example, in German Offenlegungsschnft 34 01 052, by adding the metal oxide or a metal salt (for example the nitrate, acetate, carbonate, Chloride or sulfate) of the element of atomic numbers 20 - 29, 39, 42, 44, 57 - 83 dissolved or suspended in water and / or a lower alcohol (such as methanol, ethanol or isopropanol) and with the solution or suspension of the equivalent amount of complex-forming ligands and then, if desired, existing acidic hydrogen atoms of the acid groups substituted by cations of inorganic and / or organic bases, amino acids or amino acid amides
  • a metal salt for example the nitrate, acetate, carbonate, Chloride or sulfate
  • a lower alcohol such as methanol, ethanol or isopropanol
  • inorganic bases for example hydroxides, carbonates or bicarbonates
  • inorganic bases for example sodium, potassium, lithium, magnesium or calcium
  • organic bases such as primary, secondary and tertiary nurses, for example
  • the acidic complex salts in aqueous solution or suspension can be added with as much of the desired base that the neutral point is reached.
  • the solution obtained can then be evaporated to dryness in vacuo.
  • the neutral salts formed of water-miscible solvents such as, for example, lower alcohols (methanol, ethanol, isopropanol and others), lower ketones (acetone and others), polar ethers (tetrahydrofuran, dioxa ⁇ , 1, 2-dimethoxyethane and others) to precipitate and are easy to isolate and to obtain easily cleanable systems
  • lower alcohols methanol, ethanol, isopropanol and others
  • lower ketones acetone and others
  • polar ethers tetrahydrofuran, dioxa ⁇ , 1, 2-dimethoxyethane and others
  • compositions according to the invention are also prepared in a manner known per se by using the complex compounds according to the invention
  • Suitable additives are, for example, physiologically acceptable buffers (such as tromethamine), additions of complexing agents or weak complexes (such as diethylene) - t ⁇ aminpentaacetic acid or its Ca complex) or - if necessary - electrolytes such as sodium chloride or - if necessary - antioxidants such as ascorbic acid
  • suspensions or solutions of the agents according to the invention in water or physiological salt solution are desired for enteral administration or other purposes, they are mixed with one or more auxiliary agents (for example methyl cellulose, lactose, mannitol) and / or tenside which are common in galenics (s) [for example lecithins, Tween®, Myrj®] and / or flavoring (s) for flavor correction [for example essential oils] mixed
  • auxiliary agents for example methyl cellulose, lactose, mannitol
  • tenside which are common in galenics (s) [for example lecithins, Tween®, Myrj®] and / or flavoring (s) for flavor correction [for example essential oils] mixed
  • the pharmaceutical compositions according to the invention without isolating the complex salts.
  • particular care must be taken to carry out the chelation so that the salts and salt solutions according to the invention are practically free of non-complexed, toxic-acting metal ions This can be ensured, for example, with the aid of color indicators such as xylenol orange through control titrations during the production process.
  • the invention therefore also relates to processes for the preparation of the complex compounds and their salts. As a last resort, cleaning of the isolated complex salt remains
  • compositions according to the invention preferably contain 1 ⁇ mol - 1.3 mol / l of the complex salt and are generally dosed in amounts of 0.0001 - 5 mmol / kg. They are intended for enteral and parenteral administration.
  • the complex compounds according to the invention are used
  • the agents according to the invention meet the diverse requirements for suitability as contrast agents for magnetic resonance imaging.
  • they are excellently suited to improve the meaningfulness of the image obtained with the aid of the magnetic resonance tomograph.
  • they show the high effectiveness, which is necessary to burden the body with the smallest possible amount of foreign substances and the good tolerability which is necessary to maintain the non-vasive character of the examinations
  • the agents according to the invention not only have high stability in vitro, but also a surprisingly high stability in vivo, so that a release or an exchange of those not covalently bound in the complexes
  • the agents according to the invention are used for use as NMR diagnostics in amounts of 0.0001-5 mmol / kg, preferably 0.005- 0.5 mmol / kg, dosed. Details of the application are described, for example, in H.J. Weinmann et al., Am. J. of Roentgenology 142, 619 (1984).
  • Particularly low doses (below 1 mg / kg body weight) of organism-specific NMR diagnostics can be used, for example, to detect tumors and heart attacks.
  • the complex compounds according to the invention can advantageously be used as susceptibility reagents and as shift reagents for in vivo NMR spectroscopy.
  • the compounds according to the invention are surprisingly also suitable for differentiating malignant and benign tumors in areas without a blood-brain barrier.
  • the agents according to the invention are outstandingly suitable as X-ray contrast agents, in particular for computed tomography (CT), whereby it should be emphasized that they show no signs of the anaphylaxis-like reactions known from the iodine-containing contrast agents in biochemical-pharmacological examinations. They are particularly valuable for digital subtraction techniques due to their favorable absorption properties in areas with higher tube voltages.
  • CT computed tomography
  • the agents according to the invention for use as X-ray contrast media are dosed in amounts of 0.1 to 5 mmol / kg, preferably 0.25 to 1 mmol / kg, in analogy to, for example, meglumine diatrizoate.
  • a solution of 8.17 g (30 mmol) of the title compound from Example 1 a is dissolved in 200 ml of water and at room temperature with 3 42 g (5 97 mmol) of the gadolinium complex of 10- (2-hydroxy-3- aminopropyl) -4,7,10- tr ⁇ s (carboxymethyl) -1, 4,7, 10-tetraazacyclododecane, 1 N aqu hydrochloric acid is added to pH 6.5.
  • a total of 1 14 g (5 97 mmol) EDCI is then added in portions After the EDCI addition has ended, the mixture is stirred for a further 12 hours at room temperature.
  • the pH is brought to pH 7.2 by adding 1 N aqueous sodium hydroxide solution.
  • the reaction solution is then made up to a total volume of 500 ml with distilled water. After three times ultrafiltration against distilled water over a YM 3 ultrafiltration membrane (AMICON ®), the remaining residue is freeze-dried
  • Polyamide made from O-carboxymethyl-hydroxyethyl starch and the gadolinium complex of 10- (2-hydroxy-3-ami ⁇ opropyl) -4 7, 10-t ⁇ s (carboxymethyl) - _-j 5 _
  • Polyamide made from O-carboxymethyl-hydroxyethyl starch and the gadolinium complex of 10- (2-hydroxy-3-aminopropyl) -4,7,10-tr ⁇ s (carboxymethyl) - 1, 4,7, 10-tetraazacyclododecane (backbone 40 KD / Degree of substitution on gadolinium complex K 0 3) a) Sodium-O-carboxymethyl-hydroxyethyl-strong (ds ⁇ M 2 - 3 )
  • the pH is brought to pH 7.2 by adding 1 N aqueous sodium hydroxide solution is then made up to a total volume of 500 ml with distilled water. After three times ultrafiltration against distilled water over a YM 3 ultrafiltration membrane (AMICON®), the remaining residue is freeze-dried. 10.51 g of the title compound is obtained as an amorphous, colorless powder water content ( Karl-Fischer) 6.8% Gd determination (AAS) 8.89% T-
  • a pH of 10 0 is obtained by adding 10% aqueous hydrochloric acid to the aqueous product solution thus obtained adjusted and made up to a total volume of 500 ml with distilled water. After three times ultrafiltration against distilled water over a YM10 ultrafiltration membrane (AMICON®), the remaining residue is freeze-dried. 12.63 g of the title compound is obtained as an amorphous, colorless powder water content (Karl-Fischer ) 6.8%
  • Gadolinium complex K 0.25) A solution of 6.53 g (24 mmol) of the title compound from Example 4a is dissolved in 200 ml of water and at room temperature with 3.42 g (5.97 mmol) of the gadolinium complex of 10- (2-hydroxy-3 -am ⁇ nopropyl) -4,7,10- tr ⁇ s (carboxymethyl) -1,4,7,10-tetraazacyclododecane are added. 1 N aqu. Hydrochloric acid to pH 6.5. A total of 1 14 g (5.97 mmol) of EDCI is then added in portions. After the EDCI addition has ended, the mixture is stirred for a further 12 hours at room temperature.
  • Polyamide made from O-carboxymethyl-hydroxyethyl starch and the gadolinium complex of 10- (2-hydroxy-3-aminopropyl) -4,7,10-t ⁇ s (carboxymethyl) -1,4,7,10-tetraazacyclododecane (backbone 100 KD / Degree of substitution on gadolinium complex K 0.32)
  • a solution of 4.61 g (12.0 mmol) of the title compound from Example 6a is dissolved in 200 ml of water and at room temperature with 3.42 g (5.97 mmol) of the gadolinium complex of 10- (2-hydroxy -3-aminopropyl) -4,7,10-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane.
  • the pH is adjusted to 6.5 with 1 N aqueous hydrochloric acid, and a total of 1.14 g (5.97 mmol) of EDCI is then added in portions. After the EDCI addition has ended, the mixture is stirred for a further 12 hours at room temperature.
  • the pH is adjusted by adding 1 N aqu.
  • Polyamide made from O-carboxymethyl-hydroxyethyl starch and the gadolinium complex of 10- (2-hydroxy-3-aminopropyl) -4,7, 10-tr ⁇ s (carboxymethyl) - 1, 4,7,10-tetraazacyclododecane (backbone. 200 KD / Degree of substitution on gadolinium complex K. 0.25)
  • a solution of 6.87 g (24.0 mmol) of the title compound from Example 7a is dissolved in 200 ml of water and at room temperature with 3.42 g (5.97 mmol) of the gadolinium complex of 10- (2-hydroxy-3-aminopropyl ) -4.7, 10- tris (carboxymethyl) -1, 4.7, 10-tetraazacyclododecane. It is made with 1 N aqu. Hydrochloric acid to pH 6.5. A total of 1.14 g (5.97 mmol) of EDCI is then added in portions. After the EDCI addition has ended, the mixture is stirred for a further 12 hours at room temperature. The pH is adjusted by adding 1 N aqu.
  • a solution of 3.98 g (11.0 mmol) of the title compound from Example 8a is dissolved in 200 ml of water and at room temperature with 3.42 g (5.97 mmol) of the gadolinium complex of 10- (2-hydroxy -3-aminopropyl) -4,7,10-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane.
  • the pH is adjusted to 6.5 with 1 N aqueous hydrochloric acid.
  • a total of 1.14 g (5.97 mmol) of EDCI is then added in portions. After the EDCI addition has ended, stirring is continued for a further 12 hours at room temperature.
  • the pH is adjusted by adding 1 N aqu.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Radiology & Medical Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Materials Engineering (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Polymers & Plastics (AREA)
  • Organic Chemistry (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)

Abstract

L'invention concerne de nouveaux conjugués d'amidon hydroxyéthyle et leur utilisation dans le diagnostic médical.
PCT/EP1999/000853 1998-02-20 1999-02-09 Conjugues d'amidon hydroxyethyle, leur procede de production et produits pharmaceutiques les contenant Ceased WO1999042139A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU28328/99A AU2832899A (en) 1998-02-20 1999-02-09 Hydroxyethyl starch conjugate, method for the production thereof and pharmaceuticals containing the same

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19808079.4 1998-02-20
DE19808079A DE19808079A1 (de) 1998-02-20 1998-02-20 Hydroxyethylstärke-Konjugate, Verfahren zu ihrer Herstellung und diese enthaltende pharmazeutische Mittel

Publications (2)

Publication Number Publication Date
WO1999042139A2 true WO1999042139A2 (fr) 1999-08-26
WO1999042139A3 WO1999042139A3 (fr) 1999-09-30

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AU (1) AU2832899A (fr)
DE (1) DE19808079A1 (fr)
WO (1) WO1999042139A2 (fr)

Cited By (1)

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RU2655810C2 (ru) * 2016-10-12 2018-05-29 Федеральное государственное бюджетное научное учреждение "Томский национальный исследовательский медицинский центр Российской академии наук" (Томский НИМЦ) Средство, увеличивающее мозговой кровоток

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DE10112825A1 (de) 2001-03-16 2002-10-02 Fresenius Kabi De Gmbh HESylierung von Wirkstoffen in wässriger Lösung
DE10209821A1 (de) 2002-03-06 2003-09-25 Biotechnologie Ges Mittelhesse Kopplung von Proteinen an ein modifiziertes Polysaccharid
DE10209822A1 (de) 2002-03-06 2003-09-25 Biotechnologie Ges Mittelhesse Kopplung niedermolekularer Substanzen an ein modifiziertes Polysaccharid
BR0314227A (pt) 2002-09-11 2005-10-25 Fresenius Kabi De Gmbh Derivados de amido de hidroxialquila
US7538092B2 (en) 2002-10-08 2009-05-26 Fresenius Kabi Deutschland Gmbh Pharmaceutically active oligosaccharide conjugates
WO2005014655A2 (fr) 2003-08-08 2005-02-17 Fresenius Kabi Deutschland Gmbh Conjugues d'amidon d'hydroxyalkyle et de proteine
JP5191729B2 (ja) 2004-03-11 2013-05-08 フレゼニウス・カビ・ドイチュラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング 還元的アミノ化によって製造される、ヒドロキシアルキルデンプンとタンパク質とのコンジュゲート
DE102007015282B4 (de) * 2007-03-29 2017-10-05 Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. Viskositätsregulator, Verfahren zu dessen Herstellung und dessen Verwendung
EP2070950A1 (fr) 2007-12-14 2009-06-17 Fresenius Kabi Deutschland GmbH Dérivés hydroxyalkylés de l'amidon et leur procédé de préparation
WO2012139030A1 (fr) 2011-04-06 2012-10-11 Cedars-Sinai Medical Center Nanoconjugués à base d'acide polymalique pour l'imagerie
CN102321185B (zh) * 2011-08-09 2012-12-19 武汉华科大生命科技有限公司 一种中分子量羟乙基淀粉的合成方法

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Publication number Priority date Publication date Assignee Title
RU2655810C2 (ru) * 2016-10-12 2018-05-29 Федеральное государственное бюджетное научное учреждение "Томский национальный исследовательский медицинский центр Российской академии наук" (Томский НИМЦ) Средство, увеличивающее мозговой кровоток

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AU2832899A (en) 1999-09-06
DE19808079A1 (de) 1999-08-26
WO1999042139A3 (fr) 1999-09-30

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