Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Magnetic imaging agent
Patent
1995-02-06
1998-06-16
Hollinden, Gary E.
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Magnetic imaging agent
424493, 436173, A61B 5055
Patent
active
057665729
DESCRIPTION:
BRIEF SUMMARY
This Application is a 371 of PCT/JP93/01092 filed Aug. 4, 1993.
TECHNICAL FIELD
The present invention relates to a water-soluble carboxypolysaccharide-magnetic iron oxide complex having a small particle diameter, which is useful in the fields of biology, medical treatment, etc. as a contrast medium for nuclear magnetic resonance imaging (hereinafter abbreviated to MRI), an X-ray contrast medium, etc.
PRIOR ART
A complex of a magnetic iron oxide having a colloid size has superparamagnetism, and an aqueous sol thereof (i.e. a magnetic fluid) has drawn attention in recent years in the fields of medical treatment, biology and engineering as an MRI contrast medium, in particular. When a magnetic iron oxide complex is used as an MRI contrast medium, for example, when the complex is administered intravascularly to allow liver Kupffer's cells to capture it, the complex may have a relatively large particle diameter; in that case, a large particle diameter is rather advantageous because there can be obtained a large T.sub.2 -relaxivity (the T.sub.2 -relaxivity is a yardstick for contrast ability). However, when the complex is used as an MRI contrast medium moving between cells and/or tissues, it is desired that the particle diameter of the magnetic iron oxide core and/or the total particle diameter of the complex is small and that the T.sub.2 -relaxivity is as large as possible.
There have hitherto been made various disclosures with respect to compounds between magnetic iron oxide ultrafine particles and polysaccharide. For example, Japanese Patent Publication No. 13521/1984 (U.S. Pat. No. 4,101,435) discloses a complex between agnetic iron oxide prepared beforehand and dextran or alkali-treated dextran. No specific particle diameter is mentioned in the literature, but the complex obtained by the method described in the Examples of said literature has a core (magnetic iron oxide) diameter of about 7 to about 12 nm and a total diameter of about 80 to about 200 nm when measured by methods described later.
U.S. Pat. No. 4,452,773 discloses microspherical magnetic iron oxide coated with dextran. According to this literature, the core diameter is about 10 to about 20 nm and the total diameter by SEM is about 30 to about 40 nm. P. Kronick and R. W. Gilpin, Journal of Biochemical and Biophysical Methods, 12, 73-80 (1986) reports a dextran-magnetite complex used for cell-separation, particularly antibody-bonding. The core diameter is 3 nm according to the literature, but it is feared that the total diameter is large because of dextran use and that the complex is high in acute toxicity (which is an important property of drug).
Japanese Patent Application Kokai (Laid-Open) No. 141119/1991 discloses a process for producing magnetite ultrafine particles having an average particle diameter of 10 nm or more by controlling the ratio of iron ion during reaction and the reaction temperature. Japanese Patent Application Kokai (Laid-Open) No. 242327/1991 discloses a process for producing magnetic ultrafine particles having a particle diameter of 10-15 nm by controlling the iron ion concentration and dextran concentration during reaction.
Further, R. Weissleder et al., Radiology, 175, 489493 (1990) and R. Weissleder et al., Radiology, 181, 245249 (1991) each disclose an approach to produce a complex of small particle diameter by subjecting a dextran-magnetic iron oxide complex to gel filtration fractionation. However, the obtained complex certainly has a small core diameter, but it is feared that the complex has a large total diameter because of dextran use and the employment of gel filtration fractionation and has strong acute toxicity and low stability. Further problems remain in procedure and yield.
Hence, the present inventors made an extensive study in order to develop a water-soluble carboxypolysaccharide-magnetic iron oxide complex having a small particle diameter (hereinafter abbreviated to "magnetic complex" or simply to "complex" in some cases) which can have wider applications to living bodies, and a process for effici
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Ebert Wolfgang
Hasegawa Masakatsu
Hino Yukari
Hokukoku Shusaburo
Ito Yoshio
Hollinden Gary E.
Meito Sangyo Kabushiki Kaisha
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