JPH10330288A - Metal fine particle complex and contrast media by using the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject complex useful as an X-ray contrast media, etc., excellent in safety and stability by including a specific transition metal element as a form of metal fine particles. SOLUTION: This complex comprises O-valent transition metal fine particles and a nonionic hydrophilic ligand for dispersing and stabilizing the metal fine particles in water. For example, the O-valent transition metal fine particles is preferably iron, cobalt, nickel, etc., having 0.3-1,000 nm average particle diameter. The nonionic hydrophilic ligand is preferably a compound having one mercapto group in a molecule, e.g. 2-mercaptoethanol, or a compound having a nitrile group, e.g. 2-cyanoethanol.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a metal fine particle composite comprising zero-valent transition metal fine particles and a nonionic hydrophilic ligand for stabilizing the dispersion in water, and a contrast agent using the same. . The metal fine particle composite of the present invention can be stably dispersed in water or an aqueous electrolyte solution.
Such a feature provides a means for dispersing a zero-valent transition metal element extremely finely in the bloodstream, and is useful in an X-ray contrast technique or a contrast technique utilizing a nuclear magnetic resonance phenomenon.

[0002]

2. Description of the Related Art Recently, metal fine particles having a particle size on the order of nanometers (nm) have attracted attention as a material candidate applied to a new nanoelectronic technology utilizing a quantum effect such as a one-electron transfer device. However, there is no example of other uses of such metal fine particles, for example, application to a contrast agent. As a similar technique, only a method of coating fine particles of a ferromagnetic metal oxide such as magnetite with a water-soluble polymer has been proposed. It was only. The limitation of the application of metal fine particles to a contrast agent was limited, in part, by the nonionic hydrophilic ligand required for the development of a contrast agent used in the human body, in water or in an aqueous electrolyte solution. This is because a technique for stably dispersing zero-valent metal fine particles has not been known.

The X-ray contrast technique (hereinafter abbreviated as XRI technique) is a technique for obtaining an image by injecting an element having a high X-ray scattering ability and a high atomic number into a living body by any method, and then irradiating with an X-ray. . An imaging technique (hereinafter, abbreviated as MRI technique) using a nuclear magnetic resonance phenomenon (hereinafter, abbreviated as NMR phenomenon) is a technique for paramagnetic chemical species (for example, a paramagnetic transition element cation such as a gadolinium cation) that causes an NMR phenomenon. This is a technique of obtaining an image by injecting into a living body by some method and then applying a magnetic field. In any case, a technique for stably dispersing the imaging chemical species in the bloodstream, that is, in the aqueous electrolyte solution, is essential to perform good imaging at a specific examination site.

[0004] In the initial XRI technology, iodide ions in the blood (I ^-) is a method of injecting a salt is made, shock symptoms patients administered this, pain sensation, or thyroid disorders etc. There was a problem to cause. For the purpose of alleviating such serious side effects, nonionic iodine compounds, for example, organic compounds containing iodine atoms at a high concentration and imparting hydrophilicity are widely used at present. However, even in such organic iodine compounds, side effects considered to be caused by iodine have been reported, and development of a new XRI contrast agent is desired.

[0005] In the MRI technique, as a contrast chemical species
Trivalent gadolinium cation (Gd ³⁺) Stable in the bloodstream
Various methods have been proposed. For example,
Diamine triacetic acid (EDTA), diethylene triamid
Polyaminocarboxylic acids such as pentaacetic acid (DTPA)
Complexes as ligands have been put to practical use. Such a complex is
Three carbohydrates to neutralize the trivalent positive charge of the cation
The xyl group is a carboxylate anion (COO^-) And
The oxygen atom of the remaining carboxyl group in the ligand
The nitrogen atom of the amino group coordinated to the remaining coordination site of the cation
Has a structure, but the stability of the complex is not enough,
Side effects such as absorption of the cations from the bloodstream and deposition on bone
It has been known. Chemistry of lanthanoids such as gadolinium
Properties are generally alkaline, such as magnesium and calcium.
Although it is similar to that of the earth element, its toxicity and safety
Gd is not fully understood,³⁺Blood of
Is important in MRI technology
It was an issue.

[0006]

An object of the present invention is to contain a transition metal element having a desired large atomic number in the form of fine particles of zero-valent metal without using iodine which is considered to be a cause of side effects. XRI contrast agent excellent in safety and stability that can be obtained, and excellent in safety and stability without a problem of cation release because the transition metal element is contained in the form of zero-valent metal fine particles. It is to provide a contrast agent for MRI.

[0007]

Means for Solving the Problems In the study for solving the above-mentioned problems, the present inventors have studied that a transition metal element can be stabilized in an aqueous solution by a nonionic hydrophilic ligand in the form of zero-valent metal fine particles. We found a phenomenon of decentralization. Then, the above problem was solved by utilizing this phenomenon. That is, the gist of the present invention is a metal fine particle composite comprising a zero-valent transition metal fine particle and a nonionic hydrophilic ligand for stabilizing and dispersing the same in water; .3n
the fine metal particle composite having a diameter of not less than m and not more than 1,000 nm; the transition metal of the zero-valent transition metal fine particles is arbitrarily selected from the group consisting of iron group elements, cobalt group elements, nickel group elements, copper group elements, and lanthanoid elements. The metal fine particle composite, wherein the transition metal of the zero-valent transition metal fine particles is arbitrarily selected from the group consisting of iron, cobalt, nickel, copper, silver, gadolinium, platinum, and gold; The metal fine particle composite wherein the hydrophilic ligand has one mercapto group or a nitrile group in the molecule; the nonionic hydrophilic ligand has an active hydrogen atom-containing functional group or a polyalkylene oxide group in the molecule. An in-vivo diagnostic comprising the metal fine particle complex; a contrast agent comprising the metal fine particle composite; and the metal fine particle composite and a pharmaceutically acceptable carrier. It consists in pharmaceutical compositions.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail. (Transition Metal) In the present invention, a transition metal is an element belonging to each group of 3A, 4A, 5A, 6A, 7A, 8, 1B, and 2B in the periodic table. Specifically, scandium group elements such as scandium (Sc) and yttrium (Y), titanium group elements such as titanium (Ti), zirconium (Zr) and hafnium (Hf), vanadium (V), niobium (Nb), Vanadium group positive element such as tantalum (Ta), chromium group element such as chromium (Cr), molybdenum (Mo) and tungsten (W), and manganese group element such as manganese (Mn), technetium (Tc) and rhenium (Re) , Iron (Fe), ruthenium (Ru), osmium (O
s), an iron group element such as cobalt (Co), rhodium (R
h), cobalt group elements such as iridium (Ir), nickel group elements such as nickel (Ni), palladium (Pd) and platinum (Pt); copper such as copper (Cu), silver (Ag) and gold (Au) Group elements, zinc (Zn), cadmium (Cd), mercury (Hg) and other zinc group elements, lanthanum (La), cerium (Ce), praseodymium (Pr), neodymium (Nd),
Promethium (Pm), samarium (Sm), europium (Eu), gadolinium (Gd), terbium (T
b), dysprosium (Dy), holmium (Ho),
Lanthanide elements such as erbium (Er), thulium (Tm), ytterbium (Yb), lutetium (Lu), actinium (Ac), thorium (Th), protactinium (Pa), uranium (U), neptunium (Np), Plutonium (Pu), Americium (A
m), Curium (Cm), Bercurium (Bk), Californium (Cf), Ainsteinium (Es),
Actinoid elements such as fermium (Fm), mendelevium (Md), and nobelium (No).

For the purpose of increasing the X-ray scattering power as a contrast agent for XRI, the higher the atomic number of the above elements, the more effective. Specifically, the fourth of the periodic table,
Elements belonging to the fifth, sixth and seventh periods are listed. However, cations of elements belonging to the sixth period are preferable from the viewpoint of the effect and economy, and among them, lanthanum, cerium, praseodymium, neodymium, promethium, samarium, europium, gadolinium, terbium, dysprosium, holmium, erbium, thulium, ytterbium are preferable. And lanthanoid elements such as lutetium and noble metal elements such as gold and platinum are more preferable.

When the metal fine particle composite of the present invention is used as an MRI contrast agent, the metal fine particles need to have paramagnetism. The magnetism of the transition metal shows complex behavior depending on the oxidation number and the nature of the ligand.
Cobalt group elements, nickel group elements, lanthanoid elements and the like can be used, and among them, iron, cobalt, nickel, gadolinium and the like are preferable.

In consideration of the use as a contrast agent,
Since it is desirable that the metal fine particles have a particle size that does not cause a sedimentable aggregate structure in the bloodstream, the average particle size is 0.3 n.
m to 1000 nm, preferably 0.5 nm to 500 n
m, more preferably 0.5 to 100 nm.

(Nonionic hydrophilic ligand) The nonionic hydrophilic ligand, which is a component of the metal fine particle composite of the present invention, stabilizes the above-mentioned zero-valent transition metal fine particles by dispersing and stabilizing them in water. Let it. "Stabilizing dispersion in water" means imparting solubility in water to the zero-valent transition metal fine particles, or imparting a property that does not cause a precipitated aggregate structure in water. Such non-ionic aqueous ligands
It has no ionic bonding structure in the molecule, such as carboxylate, sulfonate, phosphate, ammonium salt, phosphonium salt, etc., has a hydrophilic group, and at the same time has an affinity for a zero-valent transition metal. (Or a compound having a functional group having coordination ability).

The term "hydrophilic group" as used herein means a solubility when the metal fine particle composite of the present invention is injected into a bloodstream as a contrast agent, or a property which does not cause a sedimentable aggregate structure in the bloodstream. It is a structure to be granted. Specifically, a functional group having an active hydrogen atom such as a hydroxyl group, an amino group, a hydrazide group, a carboxyl group, a sulfonic acid group, an amide group, a carbamate group, a urea group, or a carbonyl group, an ester group, a nitrile group, or a nitro group And a functional group having no active hydrogen atom such as an aldehyde group and a polyalkylene oxide group. Preferred examples of the polyalkylene oxide group referred to herein include a polyethylene oxide group, a polypropylene oxide group, a polybutylene oxide group, a polypentylene oxide group, a polyhexylene oxide group, a polyisopropylene oxide group, a polyisobutylene oxide group,
Examples include a monomer unit structure having an alkylene group having 6 or less carbon atoms such as a polycyclopentylene oxide group and a polycyclohexylene oxide group, and two or more of these monomer unit structures may be copolymerized. Of these, preferred are polyalkylene oxide groups such as hydroxyl group, amino group, urea group and polyethylene oxide group, and most preferred are hydroxyl group and polyalkylene oxide group such as polyethylene oxide group. In addition, as long as the hydrophilicity of the metal fine particle composite of the present invention is not impaired, a nonionic hydrophilic ligand having two or more kinds of the above hydrophilic groups in one molecule may be used as a component thereof. Alternatively, different types of nonionic hydrophilic ligands may be used as a mixture.

The functional group having an affinity for a zero-valent transition metal is not particularly limited as long as it can stably generate a bond or an interaction with a specific zero-valent transition metal in the bloodstream. , Mercapto group (thiol group), selenol group, disulfide group, sulfide group,
Diselenide group, selenide group, nitrile group (cyano group),
Examples thereof include an isonitrile group, a nitro group, a trivalent phosphorus atom, an isothiocyanate group, a xanthate group, a thiocarbamate group, a thioacid group (-COSH), and a dithioacid group (-CSSH). Among them, preferred in terms of safety and affinity for transition metals are mercapto group, disulfide group, sulfide group, nitrile group, isonitrile group, nitro group, xanthate group, thiocarbamate group, thioic acid group, and dithioic acid group. Etc., among which mercapto group, disulfide group,
Sulfide, nitrile, isonitrile, thiocarbamate and the like are more preferred, and the most preferred are mercapto and nitrile. It is desirable that only one such functional group having an affinity for a zero-valent transition metal exists in the ligand molecule. This is because, when two or more such functional groups are present in the ligand molecule, the ligand cross-links a plurality of metal fine particle composites to form an aggregated structure,
This is presumed to be due to a decrease in the imaging efficiency, and possibly to the formation of a sedimentable aggregate structure.

Specific examples of the compound having one of the mercapto groups in the molecule as a nonionic hydrophilic ligand satisfying the above conditions include 2-mercaptoethanol, 3-mercapto-n-propanol, and 4-mercaptoethanol. Ω-mercapto alcohols having 6 or less carbon atoms, such as mercapto-n-butanol, 5-mercapto-n-pentanol and 6-mercapto-n-hexanol, 2-hydroxymethyl-3-mercapto-n-propanol, bis ( 2-hydroxymethyl)
-3-mercapto-n-propanol, 1-mercapto-1-deoxyglucose, 1-mercapto-1-deoxygalactose, 1-mercapto-1-deoxymannose, 1-mercapto-1-deoxyfucose, 1-
Mercapto-1-deoxyxylose, 1-mercapto-1-deoxyribose, 1-mercapto-1-deoxyarabinose, 2-mercapto-2-deoxyglucose, 3-mercapto-3-deoxyglucose, 4-
Mercapto-4-deoxyglucose, 6-mercapto-6-deoxyglucose, 6-mercapto-6-deoxygalactose, 6-mercapto-6-deoxymannose, 4-O- (6-mercapto-6-deoxyglucosyl) glucose and the like Having one mercapto group in the molecule, saccharides, 2-mercaptoethylamine, 3-mercapto-n-propylamine, 4-mercapto-n-butylamine, 5-mercapto-n-pentylamine, 6-mercapto Ω-mercaptoalkylamines such as -n-hexylamine, N- (2-aminoethyl) -N- (2-mercaptoethyl) amine, N, N
-Bis (2-aminoethyl) -N- (2-mercaptoethyl) amine, N- {2- (N'-2'-aminoethyl) aminoethyl} -N- (2-mercaptoethyl) amine, N, Polyamines having one mercapto group in the molecule, such as N-bis {2- (N'-2'-aminoethyl) aminoethyl} -N- (2-mercaptoethyl) amine, mercaptoacetic acid, 3-mercaptopropion Acid, 4
-Mercaptobutanoic acid, 5-mercaptopentanoic acid, 6
-Ω-mercapto fatty acids such as mercaptohexanoic acid,
Polycarboxylic acids having one mercapto group in the molecule, such as thiomalic acid and thiocitric acid, 2-mercaptoethanesulfonic acid, 3-mercaptopropanesulfonic acid,
Ω such as mercaptobutanesulfonic acid, 5-mercaptopentanesulfonic acid, and 6-mercaptohexanesulfonic acid
-Mercapto aliphatic sulfonic acids, the above-mentioned ω-mercapto fatty acids, polycarboxylic acids having one mercapto group in the molecule, and ω-mercapto aliphatic sulfonic acids with ammonia, methylamine, lower amines such as dimethylamine and the like. Acid amides having one mercapto group in the molecule obtained by the reaction, ω-mercapto alcohols described above, and mercapto obtained by carbamate-forming hydroxyl groups of polyalcohols and saccharides having one mercapto group in the molecule Carbamates having one group in the molecule,
The above-mentioned ω-mercaptoalkylamines, and the ureas having one mercapto group in the molecule obtained by ureaizing the polyamines having one mercapto group in the molecule, the above-mentioned ω-mercapto alcohols, and the mercapto group A thiocarbamate having one mercapto group in a molecule obtained by converting a hydroxyl group of a polyalcohol or a saccharide having one thiocarbamate in the molecule, the ω-mercaptoalkylamines described above, and a mercapto group in the molecule. A molecule having a mercapto group such as a thiourea having one mercapto group in the molecule, a polyethylene oxide having a mercapto group at one end, and a polypropylene oxide having a mercapto group at one end obtained by thiourea-forming a polyamine having one. Polyalkylene oxides having one in the Mercapto-1-deoxy-glucuronic acid, 2-mercapto-2-deoxy-glucuronic acid, 3
Sugar carboxylic acids having one mercapto group in the molecule, such as -mercapto-3-deoxyglucuronic acid and 4-mercapto-4-deoxyglucuronic acid, 1-mercapto-1
-Deoxyglucosamine, 1-mercapto-1-deoxygalactosamine, 1-mercapto-1-deoxymannosamine, 1-mercapto-1-deoxyfucosamine,
1-mercapto-1-deoxyxylosamine, 1-mercapto-1-deoxyribosamine, 1-mercapto-1
-Deoxyarabinosamine, 3-mercapto-3-deoxyglucosamine, 4-mercapto-4-deoxyglucosamine, 6-mercapto-6-deoxyglucosamine, 4-O- (6-mercapto-6-deoxyglucosyl) glucosamine, etc. Aminodeoxy sugars having one mercapto group in the molecule, the above-mentioned ω-mercapto alcohols, polyalcohols and sugars having one mercapto group in the molecule, ω-mercaptoalkylamines, and mercapto group in the molecule One or all of hydroxyl groups or amino groups of one polyamine or the like esterified with an acetyl group or the like, cysteine, ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), or 1,4,7,10- Tori (acetic acid) tetra Azacyclododecane (DOT
Compounds having a plurality of hydrophilic groups, such as aminocarboxylic acids having one mercapto group, such as one in which one carboxyl group of a polyaminocarboxylic acid such as A) is converted to a mercapto group, and the like.

Specific examples of a compound having one nitrile group in a molecule as a nonionic hydrophilic ligand satisfying the above conditions include 2-cyanoethanol, 3-cyano-n-propanol, and 4-cyanoethanol. Ω-cyano alcohols having 6 or less carbon atoms such as cyano-n-butanol, 5-cyano-n-pentanol, 6-cyano-n-hexanol, 2-hydroxymethyl-3-cyano-n-propanol, bis ( 2
-Hydroxymethyl) -3-cyano-n-propanol, 1-cyano-1-deoxyglucose, 1-cyano-1-deoxygalactose, 1-cyano-1-deoxymannose, 1-cyano-1-deoxyfucose,
-Cyano-1-deoxyxylose, 1-cyano-1-
Deoxyribose, 1-cyano-1-deoxyarabinose, 2-cyano-2-deoxyglucose, 3-cyano-3-deoxyglucose, 4-cyano-4-deoxyglucose, 6-cyano-6-deoxyglucose,
6-cyano-6-deoxygalactose, 6-cyano-
6-deoxymannose, 4-O- (6-cyano-6-
Polyalcohols and sugars having one cyano group in the molecule, such as deoxyglucosyl) glucose, 2-cyanoethylamine, 3-cyano-n-propylamine, 4-cyano-n-butylamine, 5-cyano-n-pentyl Amines, ω-cyanoalkylamines such as 6-cyano-n-hexylamine, N- (2-aminoethyl) -N- (2
-Cyanoethyl) amine, N, N-bis (2-aminoethyl) -N- (2-cyanoethyl) amine, N- {2-
(N'-2'-aminoethyl) aminoethyl｝ -N-
(2-cyanoethyl) amine, N, N-bis {2-
(N'-2'-aminoethyl) aminoethyl｝ -N-
A cyano group such as (2-cyanoethyl) amine
Polyamines, cyanoacetic acid, 3-cyanopropionic acid, 4-cyanobutanoic acid, 5-cyanopentanoic acid,
Ω-cyano fatty acids such as 6-cyanohexanoic acid, ω such as 2-cyanoethanesulfonic acid, 3-cyanopropanesulfonic acid, 4-cyanobutanesulfonic acid, 5-cyanopentanesulfonic acid, and 6-cyanohexanesulfonic acid. -Cyano aliphatic sulfonic acids, ω-cyano fatty acids described above, and ω-cyano aliphatic sulfonic acids with ammonia,
Acid amides having one cyano group in the molecule obtained by reacting with lower amines such as methylamine and dimethylamine, the above-mentioned ω-cyano alcohols, and polyalcohols having one cyano group in the molecule And ω-cyanoalkylamines having one cyano group in the molecule obtained by carbamate-forming hydroxyl groups of saccharides and saccharides, and cyanates obtained by ureating the polyamines having one cyano group in the molecule. Ureas having one group in the molecule, ω-cyano alcohols described above, and cyano groups obtained by thiocarbamate-forming hydroxyl groups of polyalcohols and saccharides having one cyano group in the molecule are contained in the molecule. Thiocarbamates, the above-mentioned ω-cyanoalkylamines, and polyamines having one cyano group in the molecule as thiourine Polyalkylene oxides having one cyano group in the molecule, such as thioureas having one cyano group in the molecule, polyethylene oxide having one cyano group at one end, and polypropylene oxide having one cyano group at one end. Or 1-cyano-1-
Deoxyglucuronic acid, 2-cyano-2-deoxyglucuronic acid, 3-cyano-3-deoxyglucuronic acid, 4
Sugar carboxylic acids having one cyano group in the molecule, such as -cyano-4-deoxyglucuronic acid, 1-cyano-1-deoxyglucosamine, 1-cyano-1-deoxygalactosamine, 1-cyano-1-deoxymanno Samin, 1
-Cyano-1-deoxyfucosamine, 1-cyano-1-
Deoxyxylosamine, 1-cyano-1-deoxyribosamine, 1-cyano-1-deoxyarabinosamine, 3
-Cyano-3-deoxyglucosamine, 4-cyano-4
Aminodeoxy sugars having one cyano group in the molecule, such as -deoxyglucosamine, 6-cyano-6-deoxyglucosamine, 4-O- (6-cyano-6-deoxyglucosyl) glucosamine, and the above-mentioned ω-cyano alcohols Some or all of hydroxyl groups or amino groups such as polyalcohols and saccharides having one cyano group in the molecule, ω-cyanoalkylamines, and polyamines having one cyano group in the molecule; And a plurality of hydrophilic groups such as aminocarboxylic acids having one cyano group such as those obtained by converting one carboxyl group of a polyaminocarboxylic acid such as ethylenediaminetetraacetic acid or diethylenetriaminepentaacetic acid into a cyano group. And the like. Specific examples of the functional groups having an affinity for the other zero-valent transition metal described above are also preferable according to the structural examples of the nonionic hydrophilic ligands exemplified herein, for example, a disulfide group such as cystine. Needless to say, an amino acid having the formula can be easily assumed.

Among the specific examples of the above-mentioned nonionic hydrophilic ligands, those suitable for use as a contrast agent include 2
4 carbon atoms such as mercaptoethanol, 3-mercapto-n-propanol and 4-mercapto-n-butanol
The following ω-mercapto alcohols, bis (2-hydroxymethyl) -3-mercapto-n-propanol, 1
-Mercapto-1-deoxyglucose, 1-mercapto-1-deoxygalactose, 1-mercapto-1-
Deoxymannose, 1-mercapto-1-deoxyfucose, 1-mercapto-1-deoxyxylose, 1
Mercapto groups such as -mercapto-1-deoxyribose, 1-mercapto-1-deoxyarabinose, 6-mercapto-6-deoxyglucose, 6-mercapto-6-deoxygalactose and 6-mercapto-6-deoxymannose in the molecule; , Ω-mercapto fatty acids such as mercaptoacetic acid, 3-mercaptopropionic acid, and 4-mercaptobutanoic acid; and polycarboxylic acids having one mercapto group such as thiomalic acid and thiocitric acid in the molecule. Acids, polyalkylene oxides having one mercapto group in the molecule such as polyethylene oxide having a mercapto group at one end, or 1-mercapto-1-deoxyglucuronic acid,
Sugar carboxylic acids having one mercapto group in the molecule such as mercapto-4-deoxyglucuronic acid;
Among them, 2-mercaptoethanol and 3-mercapto-n
-Ω-mercapto alcohols such as propanol, bis (2-hydroxymethyl) -3-mercapto-n-propanol, 1-mercapto-1-deoxyglucose,
1-mercapto-1-deoxygalactose, 6-mercapto-6-deoxyglucose, 6-mercapto-6
A mercapto group such as deoxygalactose in the molecule
And polyalkylene oxides having one mercapto group in the molecule, such as polyalcohols and saccharides having one compound, and polyethylene oxide having a mercapto group at one end.

Examples of preferred combinations of the transition metal and the nonionic hydrophilic ligand for use in the contrast agent are arbitrarily selected from the group consisting of iron, cobalt, nickel, copper, silver, gadolinium, platinum, and gold. Transition metals, ω-mercapto alcohols such as 2-mercaptoethanol and 3-mercapto-n-propanol, bis (2-hydroxymethyl) -3-mercapto-n-propanol, 1-mercapto-1-deoxyglucose, -Mercapto-1
Polyalcohols and sugars having one mercapto group in the molecule, such as -deoxygalactose, 6-mercapto-6-deoxyglucose, 6-mercapto-6-deoxygalactose, and mercapto such as polyethylene oxide having a mercapto group at one end. Combination with a non-ionic hydrophilic ligand arbitrarily selected from the group consisting of polyalkylene oxides having one group in the molecule, among which safe use of any of gadolinium, platinum or gold is safe. Optimum in terms of sex and contrast effect.

(Method for Producing Metal Fine Particle Composite and Use as Contrast Agent) The method for producing the metal fine particle composite of the present invention is not particularly limited, but usually a salt of a corresponding metal cation and a ligand are simultaneously prepared. It is produced by dissolving and reacting with an appropriate reducing agent to convert the cation to a zero-valent metal. It is particularly preferable that the counter anion of the metal cation becomes volatile or decomposable when an acid is formed together with the proton generated by the action of the reducing agent. This is because the counter anion can be easily removed by distillation or the like. Examples of such counter anions include halide ions such as chloride ion, bromide ion and iodide ion, fatty acid ions such as formate ion, acetate ion and oxalate ion, carbonate ion and hydrogen carbonate ion. It is desirable that the reducing agent is water-soluble and has low toxicity to the human body. This is because such a reducing agent may be difficult to remove from the target metal fine particle complex. That is, it is desirable that the complex can be used for the human body together with the complex. Suitable reducing agents satisfying such conditions include ethanol, n-propanol,
Oxidation of lower alcohols such as isopropyl alcohol, easily oxidizable organic acids such as citric acid, ascorbic acid (vitamin C) and vitamin E, easily oxidized amino acids such as cysteine, hydroquinone, tocol and tocopherols (or vitamin E). Phenols which are easily formed into a quinone structure can be exemplified. Among them, particularly preferred are ethanol, citric acid, ascorbic acid, vitamin E and cysteine.

As a reaction solvent in the above-mentioned production method using a reducing agent, water, methanol, ethanol, n
Water-soluble solvents such as lower alcohols such as propanol and isopropyl alcohol, or mixed solvents containing these are preferred. In such a solvent system, a suitable additive such as a surfactant, an antioxidant, a salt and the like may be coexisted as necessary.

When the metal fine particle composite of the present invention is used as a contrast medium, a method of parenteral administration such as intravenous administration is usually used, but oral administration can also be used. Preparations for parenteral administration, that is, solvents used for the production of injections and the like,
Alternatively, examples of the suspending agent include water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, lecithin and the like. Preparation of the preparation may be performed by a conventional method. For oral administration, alone or in combination with a pharmaceutically acceptable carrier, for example, granules, fine granules, powders, tablets, hard syrups, soft capsules, syrups, emulsions, suspensions, liposomes Orally in the form of a liquid or the like. Excipients used in producing solid preparations include, for example, lactose, sucrose, starch, talc, cellulose, dextrin, kaolin, calcium carbonate and the like. Liquid preparations for oral administration, ie emulsions, syrups, suspensions, solutions and the like, contain commonly used inert diluents, such as vegetable oils.
The preparation may also contain, in addition to the inert diluent, auxiliary substances such as wetting agents, suspending aids, sweetening agents, flavoring agents, coloring agents or preservatives. Liquid preparations may be included in capsules of absorbable substances such as gelatin.

The contrast agent according to the present invention is generally administered at a dose that provides the desired contrast effect without side effects. The specific value should be determined at the discretion of the physician, but is generally 0.1 mg per adult per diagnosis.
10 to 10 g, preferably 1 mg to 5 g. The compound of the present invention is used as an active ingredient in one diagnosis per adult.
mg to 5 g, more preferably 3 mg to 3 g, and may be administered.

[0023]

EXAMPLES Hereinafter, the present invention will be described specifically with reference to examples, but the present invention is not limited to these examples unless it exceeds the gist thereof. In addition, the raw material reagent and the solvent which were manufactured by Kishida Chemical Co., Ltd. were used without purification unless otherwise specified.

[Transmission Electron Microscope Observation] Preparation of Copper Mesh for Electron Microscope Observation A collodion film having a film thickness of 100 to 200 ° obtained by developing a solution of collodion in isoamyl acetate (2%) on a water surface at room temperature was prepared. Fixed on a copper mesh. On top of this, carbon was deposited to a thickness of about 100 °. Observation Transmission electron microscope H-9000NA manufactured by Hitachi, Ltd.
(Acceleration voltage: 300 kV), the particle size of the synthetic gold fine particles described below was measured.

EXAMPLE 1 An aqueous solution of chloroauric acid (concentration: 5.6 mM, 20 mL)
Was heated to reflux with stirring under a nitrogen atmosphere, and an aqueous solution of 3-mercaptopropionic acid (concentration: 16.8 m
M, 20 mL) in which 2% by weight of citric acid was dissolved. Thereafter, the heating reflux was continued for 3 hours. A part of the obtained homogeneous solution was diluted 1000 times with water, spread on the above-mentioned copper mesh for electron microscope observation, and dried to obtain an electron microscope observation sample. As a result, the average particle size was 2.5 n.
m, a gold cluster having a standard deviation of the particle size of 0.8 nm was observed.

Evaluation of Performance as Contrast Agent The aqueous solution containing the fine gold particles obtained in the above example was concentrated, and the aqueous solution in which sodium chloride was dissolved so as to have a physiological saline concentration was still uniform and exhibited a high X-ray contrast effect.

[0027]

Industrial Applicability The metal fine particle composite according to the present invention is useful as a contrast agent in which a zero-valent transition metal element that is stable even in the bloodstream is extremely finely dispersed. It is suitably used as an imaging technique utilizing the technique which is excellent in safety and an imaging effect.

Claims (8)

[Claims] 1. A metal fine particle composite comprising zero-valent transition metal fine particles and a nonionic hydrophilic ligand for stabilizing the dispersion in water. 2. The zero-valent transition metal fine particles have an average particle size of 0.3.
2. The metal fine particle composite according to claim 1, having a thickness of not less than nm and not more than 1,000 nm. 3. The method according to claim 1, wherein the transition metal of the zero-valent transition metal fine particles is arbitrarily selected from the group consisting of an iron group element, a cobalt group element, a nickel group element, a copper group element, and a lanthanoid element. Metal fine particle composite. 4. The transition metal of the zero-valent transition metal fine particles is iron,
The metal fine particle composite according to any one of claims 1 to 3, which is arbitrarily selected from the group consisting of cobalt, nickel, copper, silver, gadolinium, platinum, and gold. 5. The method according to claim 1, wherein the nonionic hydrophilic ligand has one molecule in the molecule.
The metal fine particle composite according to any one of claims 1 to 4, which has two mercapto groups or nitrile groups. 6. The metal fine particle composite according to claim 1, wherein the nonionic hydrophilic ligand has an active hydrogen atom-containing functional group or a polyalkylene oxide group in the molecule. 7. A contrast agent comprising the metal fine particle composite according to claim 1 as an essential component. 8. A pharmaceutical composition for in-vivo diagnosis, comprising the metal fine-particle composite according to claim 1 and a pharmaceutically acceptable carrier.