CN1174510A - Contrast agent - Google Patents

Abstract

This invention relates to particulate contrast agents, particularly contrast agents for MR imaging, comprising a metal oxide core, preferably a superparamagnetic iron oxide core, coated with a low-density polyelectrolyte coating material selected from structural polysaccharides and synthetic polymers, especially polyamino acids. Unlike commonly used coated particles, these new particles reduce or eliminate the effects on cardiovascular parameters, thrombocytopenia, complement activation, and coagulation.

Description

contrast agent

The present invention relates to contrast agents, in particular to metal oxide contrast agent particles coated with polyelectrolytes, which can be used in MR, X-ray, EIT and magnetic research, especially the metal oxide particles have superparamagnetism.

It is known that contrast agents can be used in medical diagnostic techniques to enhance the light-dark contrast between tissues or to facilitate the study of in vivo processes. In this method, the contrast intensity varies according to different imaging methods, but in magnetic resonance imaging, the contrast ability of most commonly used contrast agents is obtained by their influence on tissue selection time.

A great advantage of MR imaging is the pronounced intratissue contrast effect exhibited by tissue relaxation times. The initial view is that even without adding contrast agents, normal tissues and diseased tissues can be distinguished by using relaxation parameters (see Damadian, Science 171: 1151-1153 (1971)). However, according to the first MR imaging obtained by Lauterbur (see Nature 242:190-191 (1973)), it was found that diseased tissue could not be clearly distinguished from normal tissue. Consequently, more recent interest has been in the use of materials that enhance contrast by affecting key contrast parameters. The use of MR contrast agents in animals was first described by Lauterbur et al. (see Lauterbur et al., Frontiers of Biological Energetics, New Yook, Academic Press 1978; p. 752). In 1984, Carr et al. described the possibility of intravenously administered contrast agents in clinical diagnosis (see Carr et al., AJR143:215-224 (1984)), and in 1988, the original MR contrast agent Gd DTPA approved for clinical use.

The use of GdDTPA and its analogues such as GdDTPA-BMA, GdHPD03A, and GdDOTA has been shown to be safe and beneficial for enhanced CNS imaging. Due to their low molecular weight and hydrophilic character, these metal chelates are distributed extracellularly and are rapidly cleared by the kidneys. Currently, other contrast agents with improved pharmacokinetic properties are being developed for more specific organ or disease distributions.

In general, there are two approaches to improving the delivery of MR contrast agents to the target region. A commonly used approach is the direct interaction of paramagnetically-labeled naturally occurring or synthetic molecules or macromolecules with specific localization and aggregation properties (eg, contrast agents, porphyrins acting on hepatobiliary and vascular sites). Another approach is to use strong magnetic labels, such as superparamagnetic particles, which can be aggregated at desired sites either by the properties of the particles or by targeting them with specific molecules. Generally, the diagnostic target area/background ratio of superparamagnetic contrast agents is significantly higher than that of paramagnetic contrast agents, and superparamagnetic contrast agents can be monitored at lower tissue concentrations (see Weissleder et al., Magn. Reson . Quart 8:55-56 (1992)).

Using the superparamagnetic preparation obtained by the manager's combination as an MR contrast agent can affect the intensity of the signal in the tissue, thereby obtaining a stronger contrast enhancement effect and making it have a higher specific targeting. The targeting possibilities of particulate contrast agents are largely dependent on the route of administration and the physicochemical properties of the particulate material, especially its size and surface properties. The two main modes of administration are: enteral administration for gastrointestinal studies, and vascular sites and/or reticuloendothelial system and areas of its physiological distribution (e.g., liver, spleen, bone marrow, and lymph nodes). Parenteral administration for research purposes. Compared with commonly used larger iron oxide particles, extremely small iron oxide particles with a diameter of about less than 30 nm have a longer intravascular half-life. In addition to generally shortening _T2 , the iron oxide particles can also shorten _T1 so as to enhance the signal in blood vessels. More recently attempts have been made to develop receptor ligands or antibodies/antibody fragments. An overview of the use of different superparamagnetic agents is provided by Fahlvik et al., see JMRI 3:187-194 (1993).

Work to date on superparamagnetic contrast agents has focused primarily on optimizing their contrast efficiency and biokinetic parameters. However, little attention has been paid to the safety of the pharmaceutical composition or the granule preparation related to each tissue.

However, for granules for parenteral administration, having sufficiently high contrast potency and biokinetic parameters is not enough by itself, and certain problems need to be overcome. For example, the commonly used iron oxide-dextran formulations that have been tested in clinical trials show low colloidal stability. The particles must be redispersed and/or diluted and filtered prior to use, and the formulation is administered slowly through an in-line filter to prevent severe toxic effects.

While particles can be coated to provide sufficient stability, granular formulations for parenteral administration have a large surface area, and we have found that commonly used coating materials such as storable forms that are considered to be completely nontoxic The polysaccharides starch and dextran and their derivatives themselves have deleterious effects on cardiovascular parameters, thrombocytopenia, coagulation time and on the complement system.

We have found, however, that these problems with the particulate contrast agents can be avoided or reduced by employing certain polyelectrolyte coating materials, such as synthetic polyamino acids, synthetic polymers, especially structured polysaccharides, at lower than usual coating concentrations.

Accordingly, one aspect of the present invention is to provide a diagnostic agent comprising a composite particulate material, wherein the particles comprise: a diagnostically effective, substantially water-insoluble metal oxide crystalline material, and a polyion-coated material, wherein the The particle size of the crystalline material is less than 300nm, the crystal size of the crystalline material is 1-100nm, the weight ratio of the crystalline material to the coating material is 1000:1 to 11:1, and the coating material is selected from Natural and synthetic structural polysaccharides, synthetic polyamino acids, physiologically tolerable synthetic polymers and their derivatives.

Polysaccharides widely exist in nature, and they can generally be divided into two categories: storable polysaccharides (such as starch, glycogen, dextran and their derivatives) and structural polysaccharides, such as pectin and pectin fragments such as polygalactose Glycosaminoglycans and heparinoids (such as heparin, heparan, keratin, dermatan, chondroitin, and hyaluronic acid), cellulose, and marine polysaccharides such as alginate, carrageenan, and polysaccharides Glucosamine and their derivatives.

The second class of polysaccharides to which the present invention relates includes natural and synthetic types of polysaccharides, and includes such polysaccharides that have been fragmented or chemically modified, for example, by bonding metal oxide crystals at attachment points.

Particularly preferred polyionic polysaccharide coating materials are natural and synthetic heparanoid polysaccharides such as heparin, chondroitin (e.g., chondroitin-4-sulfate), and marine polysaccharides: alginate, carrageenan, and polysaccharides. Glucosamine.

Less preferred synthetic polyionomers such as polyamino acids, polyacrylates, and polystyrene sulfonates (and other synthetic polymers described in EP-A-580818) may also be used as coating materials. Homopolymers and copolymers of lysine, glutamic acid and aspartic acid and their esters, such as their methyl and ethyl esters, are preferred among the polyamino acids.

Coating materials should generally contain multiple ionic groups, such as amine, carboxyl, sulfate, sulfonate, phosphonate, or phosphoric acid groups, spaced apart from each other on the polymer to allow interaction with the metal oxide at multiple sites. The crystalline surfaces are linked to form composite particles having an overall net charge, preferably negative, and a measurable zeta potential. The multiple connections ensure a stable thermal connection against pressure and make it storage stable, and the net charge helps to increase the biotolerance of the particle after it enters the vasculature.

The molecular weight of the polyion coating material is generally in the range of 500-2,000,000D, especially 1000-500000, especially 1500-250000, most preferably 2000-150000D.

The surface-bound coating material only accounts for a small portion of the entire composite particle, and the weight ratio of crystalline material to coating material is preferably 1000:1 to 15:1, especially 500:1 to 20:1, especially 100:1 To 25:1, most preferably the weight ratio is at least 20:1 for coating with heparin or chondroitin.

Composite particles are generally produced by one- or two-step coating methods. In the one-step process, a base is added in the presence of the coating material to precipitate the crystalline material at high pH (e.g., above 9, preferably above 11), and in the two-step process, the crystalline material is formed first and then To wrap.

Accordingly, another aspect of the present invention is to provide a process for producing a contrast agent of the present invention comprising: (i) a substantially water-insoluble, diagnostically effective 1-100 nm at a pH above 9 Co-precipitation of metal oxide crystals and coating materials. (ii) Coating diagnostically effective, substantially water-insoluble metal oxide crystals of 1-100 nm in size with a coating material. Thereby obtaining composite particles with particle size lower than 300nm, and the weight ratio of crystal to surface coating material is 1000:1 to 11:1, and said coating material is selected from natural or synthetic structural polysaccharides and derivatives thereof, synthesized Polyamino acids as well as physiologically tolerable synthetic polymers, in general, the preferred coating materials should be structural polysaccharides.

Co-precipitation or post-precipitation coating methods are well known and have been extensively described in the literature, eg in the following documents (see eg US-A-4795698 and US-A-4452773).

Since not all of the coating material can be precipitated, a 1.5 to 7-fold, typically a 2-fold excess of coating material (relative to the amount required for 100% coating bonding) is required to achieve the desired coating density.

The nature of the crystalline material in the compositions of the present invention is determined by the function to be achieved. The present invention is generally suitable for the use of substantially insoluble crystalline materials for parenteral administration, and then it is expected to perform specific targeted release or diffusion in blood vessels, and is particularly suitable for the use of metal oxide diagnostic contrast agents, especially those with super smooth Magnetic metal oxides. The oxide can be used as a diagnostic contrast agent in EIT and magnetic tests, especially during MR imaging.

A large number of metal oxides with superparamagnetism and crystal sizes below the single domain size are known and described in, for example, US-A-4827945 (Groman), EP-A-525199 (Meito Sangyo), and EP-A-580878 ( Both are described in BASF). Mixed ferrites containing more than one metal species, such as crystalline particles from BASF, are particularly effective during the relaxation period. These different metal oxides can be used in the present invention, but superparamagnetic iron oxide crystals are particularly preferred, such as compounds of the formula (FeO) _n Fe ₂ O ₃ , where n is 0 to 1, typically such as iron red (γ-Fe ₂ O ₃ ) and iron black (Fe ₃ O ₄ ) and their mixtures. The iron oxide crystals used are generally absorbed and metabolized through the reticuloendothelial system, and their metabolites will not release abnormal toxic metals, and the iron generally enters the iron reserves in the body.

The size of superparamagnetic crystals is generally in the range of 2-50 nm, especially 3-35 nm, especially 4-20 nm. The crystal/coating material composite particles may contain only crystals or, if desired, complex cluster crystals. In the latter case, the cluster "core" of the composite particles should have a particle size of less than 100 nm.

The particle size of crystals, clusters and composite particles can be readily determined using standard techniques such as electron microscopy, laser light scattering or fluid chromatography, for example as discussed in the section preceding the Examples below.

Elemental analysis methods such as inductively coupled plasma analysis can be used, for example, comparing the signal of the metal in the metal oxide with the signal of sulfur in the sulfate associated with the cladding material (or, if not sulfate, with the cladding material). Compared with other similar characteristic molecules or groups in the coating material), the weight ratio of the metal oxide crystals to the coating material can be easily determined. Similarly, the ratio can also be determined gravimetrically.

The polyionic nature of the capping compound allows each polymer molecule to attach to multiple sites on the crystal surface. This allows the formation of a strong bond between the coating material and the crystal, which can withstand the usual hot-press conditions for diagnostic agents (15 minutes at 121°C) and the resulting product (dextran:iron oxide product as described above) Will not have poor colloidal stability.

Due to the polyionic nature of the coating material, the composite particle has a net charge and thus a measurable non-zero zeta potential. Especially when the concentration of the coating material is low, the net charge on the coating material will neutralize the charge on the metal oxide crystal. It is also found that at the isoelectric point, the stability of the particles is poor, and when the particle size exceeds 1000nm aggregation will occur. This phenomenon is undesirable, but agglomeration can be avoided because the effect of coating level on particle size can be easily monitored. The absolute value of the zeta potential is generally at least 10 mV (ie <-10 mV or >+10 mV), particularly preferably 20-100 mV, especially 30-70 mV.

A preferred embodiment of the contrast agent according to the invention therefore comprises an iron oxide core and it is coated and stabilized with polyionic polysaccharides or polyamino acids. The coated iron oxide particles exhibit good stability under conditions of high temperature, dilution and long-term storage. Compared with conventional iron oxide preparations coated and stabilized by storage polysaccharide dextran (or its derivatives) and starch, the new contrast agent has lower toxicity and higher biocompatibility.

To prepare iron oxide preparations with specific chemical composition and structure, careful control of the preparation conditions is required. Various industrial uses of iron oxide colloidal suspensions (ferrous solutions), such as dyes and paint components and in electromechanical devices, are described in the prior art. Various methods of synthesizing and stabilizing iron oxides for industrial use exist, but none of them are suitable for use as iron oxides for pharmaceutical use, mainly because of their non-aqueous properties and/or due to the coating materials and surfaces used therein caused by the toxicity of the active agent.

The most common synthesis of superparamagnetic iron oxide contrast agents for labeling and distinguishing biomolecules and cells, originally described by Molday (see Molday and Mackinzie, J. Immunol. Meth 52:353-367 (1982) and US-A -4452773 (Molday)). This method, called the Molday method or one-step co-precipitation method, is based on the principle that iron oxides will precipitate in alkaline solutions containing water-soluble polysaccharides, preferably dextran. The colloid-sized composite particles contain one or more iron oxide crystals encapsulated in or coated with dextran. The crystals are generally iron black or iron black/iron red structure with a particle size of 3-30nm. The diameter of the entire particle can range from as low as about 10 nm to as high as hundreds of nm. Iron oxide formulations prepared by the Molday process are generally inhomogeneous and particle fractions of various particle sizes are found in these formulations. Centrifugation, filtration, or colloidal or filtration methods can be used to separate the particles into a more uniform size range (see Weissleder et al., Radiology 175:489-493 (1990)).

It is determined by experiments that the diameter of the coated iron oxide particles commonly used in liver and spleen contrast agents is generally 50-1000 nm. The isolated smaller particles have an increased half-life in the blood and an increased ability to pass through capillary walls. The uses of these agents are numerous, such as for imaging of lymph nodes and bone marrow, for imaging of cardiac/vascular sites, and for automated targeted delivery. Formulations containing dextran are less stable and thus have significant adverse effects. For example, a formulation currently in clinical trials cannot be formulated as a back-up product. Dosage units are diluted just prior to use and infused slowly through an in-line filter to reduce the frequency and severity of adverse effects (eg, blood pressure depression, lower back pain, and blood changes).

We have found that the granules of the present invention have improved stability and toxicity compared to conventional granules. The particles used in the present invention can be synthesized by, for example, a common two-step method, wherein the first step is that the metal oxide particles are precipitated from the alkaline solution, and the second step is to use a polymer with polyelectrolyte properties to coat the crystals, Alternatively, the particles can also be synthesized by co-precipitation of metal oxide crystals and polyelectrolyte-coated polymers.

When a base is added to an aqueous solution containing a soluble metal salt, the metal oxide will generally precipitate out of the solution. The alkali is quickly added to the aqueous solution containing the iron salt mixture until the pH value is above 10, and at the same time, the superparamagnetic iron oxide crystals are precipitated from the aqueous solution through vigorous stirring or ultrasonic vibration. Various iron salts such as FeCl ₂ nH ₂ O, FeCl ₃ nH ₂ O, iron (III) citrate, iron (II) gluconate, FeSO ₄ nH ₂ O, Fe ₂ (SO ₄ ) ₃ can be used , iron (II) oxalate, Fe(NO ₃ ) ₃ , iron (II) acetylacetonate, iron (II) ethylenediamine sulfate, iron (II) fumarate, iron (III) phosphate, iron pyrophosphate ( III), ammonium iron(III) citrate, ammonium iron(II) sulfate, ammonium iron(III) sulfate and ammonium iron(II) oxalate. The ratio of ferrous iron to ferric iron is preferably from 1:5 to 5:1. The precipitated iron oxide crystals can be expressed by the following formula: (FeO) _x Fe ₂ O ₃ where x is 0≤x≤1, and when the value of x is low, it represents iron red γ-Fe ₂ O ₃ , and the value of x is high Time represents iron black Fe ₃ O ₄ .

The base used is selected from various inorganic or organic strong bases, such as NaOH, NH ₄ OH, LiOH, KOH, triethylamine and guanidine. Metal and base counterions should generally be physiologically acceptable so as to minimize toxic side effects from precipitated crystals to be removed.

Precipitation of iron oxides or co-precipitation of iron oxides and polymers can be carried out in water, water and organic solvent mixtures or in viscous media. For example, usable organic solvents are methanol, ethanol, acetone, ether and hexane. Viscous media may contain hydrogels of polysaccharides or polyamines, aromatic triiodides, glycerol or polyethylene glycol, and polypropylene glycol. Precipitation is preferably repeated in an aqueous solution free of non-physiologically acceptable salt miscible solvents, so that purification processes in post-production can be reduced.

From the standpoint of stability and toxicity, it is advantageous that the cladding material as one of the components of the new iron oxide formulation has a multi-electrolyte structure. Polyelectrolytes include those polyanionic and polycationic compounds or mixtures thereof that can bind firmly to the iron oxide surface through multiple attachment points.

Coating materials can be classified according to their charge and the functional groups they contain, such as polymers that are negatively charged and have functional groups containing trivalent phosphorus atoms or sulfur atoms or hydroxyl groups, and polymers that are positively charged and have functional groups containing nitrogen atoms. thing. Examples of negatively charged polymers include certain modified hydroxycelluloses, alginates, carrageenans, polygalacturonates, heparin, and heparinoid compounds such as chondroitin-4-sulfate, dermatan sulfate , keratan sulfate and hyaluronate, synthetic polymers such as polystyrene sulfonate, and polyamino acids such as polyglutamic acid and polyaspartic acid. Positively charged polymers include polyglucosamine and polylysins.

As mentioned above, the degree of substitution and the charge density of the polyelectrolyte polymer should not be too low when the toxicity and stability of the particles are the main considerations. Therefore, the polymer should contain multiple (more than one) functional groups to ensure multiple attachment points to the metal oxide and thereby charge the particle surface.

The superparamagnetic iron oxide core typically has a diameter of about 4 nm to about 100 nm. Smaller nuclei contain only one subdomain of superparamagnetic crystals, while larger nuclei will contain clustered crystals. Small diameter single crystal cores can be stabilized with a small amount of low or high molecular weight polymers, while clustered crystals require a large amount of polymers to coat and stabilize them due to their density and high magnetic properties per particle. stabilization. Depending on the preparation conditions and the molecular weight, structure and amount of the polymer, the diameter of the composite particle (including the iron oxide core and polymer coating) should generally be about 5 nm to 300 nm.

The relaxivity of particles containing superparamagnetic iron oxide crystals will vary with the size and composition of the core and cladding particles. At 0.5T, the T ₁ relaxivity (r ₁ ) can be as low as 5 and as high as 200, and the T ₂ relaxivity (r ₂ ) can be from 5 to 500 (given as S ^-1 mM ^{- 1} Fe). The ratio r ₂ /r ₁ may be from 1 to 100, preferably from 2 to 10. The r ₂ /r ₁ ratio is low for small monocrystalline grains and high for large and polycrystalline grains. When the iron oxide crystal has superparamagnetism, the magnetization of the particle is basically independent of the particle itself and the crystal size. At IT, the magnetization is about 20-100, preferably 30-90 emu/g iron oxide.

In another aspect, the present invention provides a diagnostic composition comprising the diagnostic agent of the present invention and at least one physiologically acceptable carrier or excipient, eg, water for injection.

The composition of the present invention can be any conventional pharmaceutical dosage form, such as suspension, dispersion, powder, etc., and can contain water carrier (such as water for injection) and/or components for adjusting permeability, pH, viscosity and stability . The composition is preferably a suspension which should be isotonic and isohydric with the blood. For example, isotonic suspensions can be prepared by adding sodium chloride, low molecular weight sugars such as glucose (dextrose), lactose, maltose, or mannitol, or the soluble fraction of the polymer-coated tablet or mixtures thereof. Isohydric suspensions may be obtained by the addition of an acid such as hydrochloric acid or, if a mild adjustment of the pH is desired, a base such as sodium hydroxide. Buffers such as phosphate, citrate, acetate, borate, tartrate and gluconate buffers can also be used. The chemical stability of the granular suspension can be improved by adding antioxidants such as ascorbic acid or pyrosulfate and chelating agents such as citric acid, EDTA sodium salt and EDTA calcium salt sodium salt. Excipients may also be added to improve the physical stability of the formulation. The most commonly used excipients in parenteral suspensions are surfactants such as polysorbates, lecithin, or sorbitan esters, viscosity modifiers such as glycerol, propylene glycol, and polyethylene glycols (macrogols), or turbidity A point improver, preferably a nonionic surfactant.

Compositions according to the invention suitably contain metal oxides in a diagnostically effective metal concentration, generally 0.1 to 250 mg Fe/ml, preferably 1 to 100 mg Fe/ml, particularly preferably 5 to 75 mg Fe/ml.

The present invention also provides a method for enhancing imaging of a human or non-human body (preferably a mammal), said method comprising administering to said body a contrast agent suspension of the invention, preferably parenterally The drug is administered, particularly preferably intravenously, so that at least a portion of the body in which the contrast agent is dispersed can be imaged by, for example, MR, ET or magnetic measurements.

The dose used in the method of the present invention should be the contrast effective dose required by the imaging method. Generally the dosage is 1 to 500 μmol Fe/kg, preferably 2 to 250 μmol Fe/kg, and particularly preferably 5 to 50 μmol Fe/kg.

Dosages and concentrations commonly used in the art can be used.

Many iron oxide preparations prepared according to the prior art are known to produce significant deleterious effects when administered intravenously. The most common are systemic blood pressure depression and acute thrombocytopenia. We found that these side effects were physiological and hematologic responses to particle-induced activation of the complement system. Commonly used iron oxide particles can strongly activate the complement cascade, and the composite particles of the present invention have little or no effect on the number of circulating platelets, while common preparations can cause acute significant and temporary thrombocytopenia. The outer surface of carbohydrates, such as unmodified dextrans and certain modified dextrans, are potent complement activators similar to many strains of Gram-positive and Gram-negative bacteria. Since nucleophilic surface groups (such as OH) can form covalent bonds with C36 complement proteins, such outer surfaces can activate other pathways (see Immunology (2nd ed.), published by Gower Medical, New York, 1989; 13.3) . Activation of the complement system is beneficial in the setting of sepsis because the complement system is an important part of the body's response to injury, such as intrusion by infectious agents. But after injection of particulate contrast agents, activation of complement was detrimental rather than beneficial.

Unexpectedly, the coated particles of the present invention had no effect on the complement system or parameters related to the complement system such as blood pressure and platelet count. The selected coating material does not trigger complement activation on the particle surface under the same conditions as conventional particles. Likewise, the small amount of polyelectrolyte polymer used to stabilize the particle also had the effect of inhibiting complement activation compared to the conventional particle, due to a change in modulin action (variation in degree and type of modulin).

The invention will be further illustrated with reference to the following non-limiting examples.

In the following examples, the iron concentration was determined by ICP analysis after the iron oxide particles were digested. pH was measured using a Beckman φ10 pH tester equipped with an Orion Sureflow Ross pH electrode. Particle size distribution can be determined by fluid chromatography (HDC) (see Small and Langhorst, Analytical Chem. 54:892A-898A (1982)) or by laser light scattering (PCS) using a Malvern Zetasizer 4 . Particle surface charge, expressed by Zeta-potential and electrophoretic mobility, can also be determined by Malvern Zetasizer 4. Under the conditions of 37°C and 0.47T (Minispec PC-20), the relaxivities r ₁ and r ₂ of T ₁ and T ₂ were measured using aqueous samples. T ₁ uses IR pulse results, and T ₂ uses CPMG results (TE=4ms). At room temperature, under the condition of a magnetic field ranging from +1 to -1 T, the magnetization curve was obtained by using a vibrating sample magnetometer (Molspin). Reference Example 1

Dextran (5 g, manufactured by Sigma) having an average molecular weight of 9000 D was dissolved in water (10 ml). At a temperature of 60°C, FeCl ₃ ·6H ₂ O (1.35g) and FeCl ₂ ·4H ₂ O (0.81g) were dissolved in the sugar solution, and then the mixture was dissolved in 0.18M NaOH (100ml) under ultrasonic vibration Slow precipitation. Continue to sonicate for 10 minutes, and then centrifuge at 4000 rpm for 5 minutes. The supernatant was collected and partially dialyzed against 0.9% NaCl (5 x 1 L). As determined by HDC, the dextran particles have a variety of particle size distributions, including parts smaller than 12nm and parts larger than 300nm. Reference Example 2 (according to Example 7.3 of US-A-5314679)

Add 1M sodium carbonate in the aqueous solution (8.5ml) of FeCl ₃ 6H ₂ O (1.17g) and FeCl ₂ 4H ₂ O (0.53g), make the pH value reach 2.3, then add the average molecular weight 9000D (5.00g) of dextran. The solution was heated to 60-70°C and then cooled to about 40°C. 7.5% _NH4OH was added to a pH of approximately 9.5, and the suspension was heated to 95°C for 15 minutes. The dispersion was dialyzed (to 15000 Daltons) with water (5 x 1 L). Reference Example 3 (according to Example 6.1 of US-A-54770183)

To 50 ml of 7.5% _NH4OH was added 50 ml of a solution containing 0.28M _FeCl3 , 0.16M _FeCl2 and 6.25g of an average molecular weight of 70000D (Pharmacia, Uppsala, Sweden) over 3 minutes. The suspension was stirred for 5 minutes and then heated at 700°C for 30 minutes. After centrifugation at 5000 rpm for 15 minutes, the supernatant was dialyzed against water (5×1 L). Reference Example 4

Starch (3 g, Reppe Glucose, Sweden) with an average molecular weight of 70000 D was dissolved in water (10 ml). At 60°C, FeCl ₃ ·6H ₂ O (2.7g) and FeCl ₂ ·4H ₂ O (4.5g) were dissolved in the sugar solution, and then the mixture was dissolved in 1.2M NaOH ( 50ml) slowly precipitated. Continue to sonicate for 10 minutes, and then centrifuge at 5000 rpm for 5 minutes. The supernatant was collected and dialyzed against 0.9% aqueous NaCl. From the magnetization curve, it can be seen that the starch granules are superparamagnetic granules. The particle size was determined by PCS to be 450 nm. The iron black crystal size was determined to be about 10 nm. Reference Example 5a) the iron black particle dispersion (equivalent to 0.3g iron black particle) prepared in embodiment 1a is diluted with water (50ml), and the carboxyl dextran ( 30 mg, Pharmacia Ab, Uppsala, Sweden) was added to the dispersion. The dispersion was ultrasonically oscillated, centrifuged at 5000 rpm for 13 minutes, and the supernatant was filtered out (0.22 μm filter). The average diameter of carboxydextran particles measured by HDC was 88nm. The measured zeta potential was -26mV. b) Dilute the iron black particle dispersion (equivalent to 0.3g iron black particle) prepared in Example 1a with water (50ml), and dissolve carboxydextran (50mg, Pharmacia Ab, Uppsala, Sweden) was added to the dispersion. The dispersion was ultrasonically oscillated, centrifuged at 5000 rpm for 13 minutes, and the supernatant was filtered out (0.22 μm filter). The average diameter of carboxydextran particles measured by HDC was 74nm. The measured zeta potential was -32mV. r ₁ was 35.2(mM.sec) ^-1 , and r ₂ was 358(mM.sec) ^-1 . c) The iron black particle dispersion (equivalent to 0.3g iron black particle) prepared in embodiment 1a is diluted with water (50ml), and the molecular weight that is dissolved in water (1.5ml) is the carboxy dextran (15mg ) into the dispersion. The dispersion was ultrasonically oscillated, centrifuged at 5000 rpm for 13 minutes, and the supernatant was filtered off. Reference Example 6a) the iron black particle dispersion (equivalent to 0.5g iron black particle) prepared in embodiment 1a is diluted with water (85ml), and the average molecular weight that is dissolved in water (5ml) is the phosphate dextran ( 50 mg, Phamacia Ab, Uppsala, Sweden) was added to the dispersion. The dispersion was sonicated, centrifuged and the supernatant was filtered off (0.22 μm filter). The magnetization curve shows that the phosphate dextran particles are superparamagnetic particles. The particle size was determined to be 74nm by PCS. b) The iron black particle dispersion (equivalent to 0.3g iron black particle) prepared in embodiment 1a is diluted with water (50ml), and the average molecular weight that is dissolved in water (5ml) is phosphate dextran (50mg, TdB Consultancy AS, Uppsala, Sweden) was added to the dispersion. The dispersion was ultrasonically oscillated, centrifuged at 5000 rpm for 13 minutes, and the supernatant was filtered out (0.22 μm filter). The average diameter of the phosphate dextran particles was determined to be 48 nm by HDC. The measured zeta potential was -51 mV. r ₁ is 37(mM.sec) ^-1 , and r ₂ is 342(mM.sec) ^-1 . c) The iron black particle dispersion (equivalent to 0.3g iron black particle) prepared in embodiment 1a is diluted with water (50ml), and the average molecular weight that is dissolved in water (1.5ml) is phosphate dextran (15mg, TdB Consultancy AB, Uppsala, Sweden) was added to the dispersion. The dispersion was ultrasonically oscillated, centrifuged at 5000 rpm for 13 minutes, and the supernatant was filtered out (0.22 μm filter). The average diameter of the phosphate dextran particles was determined to be 48 nm by HDC. The measured zeta potential was -36mV. Reference Example 7

The iron black particle dispersion (equivalent to 0.3g iron black particle) prepared in embodiment 1a is diluted with water (50ml), and the average molecular weight dissolved in water is dextran sulfate (30mg, Sigma, D-6001) of 500000D Add to this dispersion. The dispersion was ultrasonically oscillated, centrifuged at 5000 rpm for 13 minutes, and the supernatant was filtered out (0.22 μm filter). The magnetization curve indicated that the dextran sulfate particles were superparamagnetic particles, and the average diameter was 42nm as determined by HDC. The measured zeta potential was -57mV. 56% of dextran sulfate was adsorbed by the particle surface. The r ₁ relaxivity was 37.7 (mM·sec) ^-1 , and the r ₂ was 307 (mM·sec) ^-1 . Example 1a) NH ₄ OH (28-30%, 72ml) was added rapidly to FeCl ₂ .4H ₂ O (12.50g, 6.29×10 ^-2 mol) and FeCl ₃ .6H ₂ O (33.99 g, 1.26×10 ^-1 mol) in an aqueous solution (500ml) until the pH reaches 10, from which iron black particles precipitate. The particles were collected under the action of a magnetic field and washed with water to pH 6-7. These particles were dispersed in about 200 ml of water. The reaction mixture should be kept under nitrogen except for decanting and redispersing. Bare iron black particles were stabilized with HCl (pH 3.5) and had an average hydrodynamic diameter of 97 nm. The measured zeta potential was +36mV. r ₁ was 27.8 (mM·sec) ^-1 , and r ₂ was 324 (mM·sec) ^-1 . b) Dilute the iron black particle dispersion (equivalent to 0.5g iron black particle) prepared in Example 1a with water (70ml), add heparin (2ml, Heparin 5000 1U/ml, Prod.noF1 NA, Nycomed Pharma, Oslo, Norway). The dispersion was ultrasonically oscillated, centrifuged at 4000 rpm for 13 minutes, and the supernatant was filtered out (0.22 μm filter). The magnetization curve indicated that the heparin particles were superparamagnetic particles, and the average diameter was 48nm as determined by HDC. The size of iron black crystals was determined to be about 10nm by electron microscopy. The measured zeta potential was -61 mV. 54% of the heparin was adsorbed by the particle surface. Equivalent to 10 μg sulfur/mg iron. r ₁ was 40.5 (mM·sec) ^-1 , and r ₂ was 304 (mM·sec) ^-1 . c) Dilute the iron black particle dispersion (equivalent to 0.5g iron black particle) prepared in Example 1a with water (90ml), add low molecular weight heparin (0.8ml Fragmin 10000 1U/ml, Kabi Pharmacia AB, Sweden). The dispersion was sonicated, centrifuged at 4000 rpm for 13 minutes, and the supernatant was filtered off (0.22 μm filter). The magnetization curve indicated that the heparin particles were superparamagnetic particles. The saturation magnetization was measured to be 78 emu/g iron oxide. The particle size measured by PCS was 85nm. The measured zeta potential was -40mV. 16% of the added polyelectrolyte was adsorbed by the particle surface. d) Dilute the iron black particle dispersion (equivalent to 0.5g iron black particle) prepared in Example 1a with water (70ml), add heparin (1ml, Heparin 5000 IU/ml, Prod.no.F1 NA, Nycomed Pharma, Oslo, Norway). The dispersion was sonicated, centrifuged at 4000 rpm for 13 minutes and the supernatant was filtered off (0.22 μm filter). The magnetization curve indicated that the heparin particles were superparamagnetic particles, and the average diameter was 64nm as measured by PCS. 69% of the heparin was adsorbed by the particle surface, corresponding to 7 μg sulfur/mg iron. r ₁ was 38 (mM·sec) ^-1 , and r ₂ was 273 (mM·sec) ^-1 . Example 2

The iron black particle dispersion (equivalent to 0.3 g of iron black particles) prepared in Example 1a was diluted with water (50 ml), and dermatan sulfate (36 mg, Sigma C-2413) dissolved in water (5 ml) was added thereto. The dispersion was sonicated, centrifuged at 5000 rpm for 13 minutes and the supernatant was filtered off (0.22 μm filter). The diameter of dermatan sulfate measured by HDC is 49nm. 40% of dermatan sulfate was adsorbed on the particle surface. The measured zeta potential was -58mV. Example 3

The iron black particle dispersion (equivalent to 0.3 g of iron black particles) prepared in Example 1a was diluted with water (50 ml), and hyaluronic acid (60 mg, Sigma H-4015) dissolved in water (6 ml) was added thereto. The dispersion was sonicated, centrifuged at 5000 rpm for 13 minutes and the supernatant was filtered off (0.22 μm filter). The magnetization curve shows that the hyaluronic acid particles are superparamagnetic particles, and the average diameter measured by HDC is 123nm. The measured zeta potential was -55mV. r ₁ was 33.7 (mM·sec) ^-1 , and r ₂ was 318 (mM·sec) ^-1 .

Example 4

The iron black particle dispersion (corresponding to 0.3 g iron black particle) prepared in Example 1a was diluted with water (50 ml), and chondroitin-4-sulfate (60 mg, Sigma C- 8529). The dispersion was sonicated, centrifuged at 5000 rpm for 13 minutes and the supernatant was filtered off (0.22 μm filter). The magnetization curve shows that the chondroitin-4-sulfate particles are superparamagnetic particles, and the average diameter measured by HDC is 54nm. The measured zeta potential was -52mV. 29% of chondroitin-4-sulfate was adsorbed by the particle surface. r ₁ was 40.4 (mM·sec) ^-1 , and r ₂ was 314 (mM·sec) ^-1 . Example 5

Human plasma was used to incubate the iron oxide compositions of Reference Example 7 (dextran sulfate iron oxide) and Examples 1b and d (heparin iron oxide) at a concentration corresponding to a dose of 1 mgFe/kg, and Cephotest ^™ (Nycomed Pharma AS) was used to study their effect on the coagulation parameter - factor III partial activation time (APTT). The heparin iron oxide compositions of Examples 1b and d prolong APTT in a heparin dose-dependent manner by factors of 4.5 and 2.5, respectively. This clearly demonstrates the desirability of minimizing the coating density employed. The composition of Reference Example 7 prolongs the APTT by a factor of 2.7. Example 6

The iron oxide composition (heparin iron oxide) of the embodiment 1b and d of 1mg Fe/kg (only to embodiment 1b) and 2mgFe/kg intravenous injection dose to rat (n=3), and before injection and Blood samples were drawn at 10, 30 and 60 minutes post-injection. The effect of the composition on the coagulation parameter - factor III partial activation time (APTT) was studied in vitro using Chepotest ^™ (NycomedPharma AS). The composition prolongs the APTT in a dose-dependent and time-dependent manner. The compositions of Examples 1b and d at 2 mg Fe/kg prolonged the APTT in coagulation factors by a factor of 4 and 1.5, respectively, 10 and 30 minutes after injection. The composition of Example 1b at 1 mg Fe/kg prolongs the APTT by a factor of 1.3 at 10 minutes after injection. Example 7

The iron black particle dispersion (equivalent to 0.1 g of iron black particles) prepared in Example 1a was diluted with water (15 ml), and heparan sulfate (20 mg, Sigma H-7641) dissolved in water was added thereto. The dispersion was sonicated and centrifuged. Collect the supernatant. Example 8

The iron black particle dispersion (corresponding to 0.1 g of iron black particles) prepared in Example 1a was diluted with water (15 ml), and keratan sulfate (15 mg, Sigma K-3001) dissolved in water was added thereto. The dispersion was sonicated and centrifuged. Collect the supernatant. Example 9a) The iron black particle dispersion (equivalent to 0.3 g iron black particles) prepared in Example 1a was diluted with water (50 ml), and λ-carrageenan (30 mg, Sigma C-3889). The dispersion was sonicated, centrifuged at 4000 rpm for 13 minutes and filtered (0.22 μm filter). The average diameter of the λ-carrageenan particles measured by HDC was 53 nm. The measured zeta potential was -56mV. b) Dilute the iron black particle dispersion (equivalent to 0.3 g iron black particles) prepared in Example 1a with water (50 ml), add λ-carrageenan (50 mg, Sigma C -3889). The dispersion was sonicated, centrifuged at 4000 rpm for 13 minutes and filtered (0.22 μm filter). The average diameter of the λ-carrageenan particles measured by HDC was 61 nm. The measured zeta potential was -61 mV. r ₁ was 38.6 (mM·sec) ^-1 , and r ₂ was 309 (mM·sec) ^-1 . c) Dilute the iron black particle dispersion (equivalent to 0.3 g iron black particles) prepared in Example 1a with water (50 ml), add λ-carrageenan (15 mg, Sigma C-3889). The dispersion was sonicated, centrifuged at 4000 rpm for 13 minutes and filtered (0.22 μm filter). The average diameter of the λ-carrageenan particles measured by HDC was 52 nm. The measured zeta potential was -50mV. Example 10a) The iron black particle dispersion (corresponding to 0.3 g iron black particles) prepared in Example 1a was diluted with water (50 ml), and iota-carrageenan dissolved in water (3 ml) was added thereto (30 mg, Fluka Prod 22045). The dispersion was sonicated, centrifuged at 5000 rpm for 13 minutes and filtered (0.22 μm filter). The average diameter of the iota-carrageenan particles measured by HDC is 63nm. The measured zeta potential was -47mV. b) The iron black particle dispersion (equivalent to 0.3 g iron black particles) prepared in Example 1a was diluted with water (50 ml), and iota-carrageenan (15 mg, Fluka 22045). The dispersion was sonicated, centrifuged at 5000 rpm for 13 minutes and filtered (0.22 μm filter). The mean diameter of the iota-carrageenan particles measured by HDC was 54 nm. The measured zeta potential was -39mV. Embodiment 11a) Dilute the iron black particle dispersion (equivalent to 0.5g iron black particle) prepared in Example 1a with water (80ml), and dissolve the alginate Protanal LF with an average molecular weight of about 180000D in water (10ml) 10/60 (50 mg, Pronova, Drammen Norway) was added to the dispersion. The dispersion was ultrasonically oscillated, centrifuged at 5000 rpm for 13 minutes, and the supernatant was filtered out (0.22 μm filter). The average diameter of the alginate particles measured by HDC was 57 nm. The measured zeta potential was -63mV. r ₁ was 39.9 (mM·sec) ^-1 , and r ₂ was 305 (mM·sec) ^-1 . b) Dilute the iron black particle dispersion (equivalent to 0.5g iron black particle) prepared in embodiment 1a with water (80ml), and dissolve the alginate Protanal LF 60 ( 25 mg, Pronova, Drammen Norway) was added to the dispersion. The dispersion was ultrasonically oscillated, centrifuged at 5000 rpm for 13 minutes, and the supernatant was filtered out (0.22 μm filter). The average diameter of the alginate particles measured by HDC is 67nm. The measured zeta potential was -58mV. c) Dilute the iron black particle dispersion (equivalent to 0.5g iron black particle) prepared in Example 1a with water (50ml), and dissolve the alginate Protanal LFR 5/ 60 (15 mg, Pronova, Drammen Norway) was added to the dispersion. The dispersion was ultrasonically oscillated, centrifuged at 5000 rpm for 13 minutes, and the supernatant was filtered out (0.22 μm filter). The average diameter of the alginate particles measured by HDC was 62 nm. The measured zeta potential was -53mV. Embodiment 12a) Dilute the iron black particle dispersion (equivalent to 0.3g iron black particle) prepared in Example 1a with water (50ml), add carboxycellulose sodium (30mg) dissolved in water (3ml) therein, and The dispersion was sonicated, centrifuged at 5000 rpm for 13 minutes, and the supernatant was filtered off (0.22 μm filter). The average diameter of the sodium carboxycellulose particles measured by HDC is 56 nm. The measured zeta potential was -57mV. r ₁ was 40.1 (mV·sec) ^-1 , and r ₂ was 303 (mV·sec) ^-1 . b) Dilute the iron black particle dispersion (equivalent to 0.3g iron black particle) prepared in Example 1a with water (50ml), add carboxycellulose sodium (15mg) dissolved in water (1.5ml) to it, and the The dispersion was sonicated, centrifuged at 5000 rpm for 13 minutes, and the supernatant was filtered (0.22 μm filter). The average diameter of the sodium carboxycellulose particles measured by HDC is 65 nm. The measured zeta potential was -53mV. Embodiment 13a) Dilute the iron black particle dispersion (equivalent to 0.3g iron black particle) prepared in Example 1a with water (50ml), and dissolve the polyamino group with an average molecular weight of about 2,000,000D dissolved in 1% acetic acid (4.5ml) Glucose (30 mg, Fluka 22743) was added to the dispersion. The dispersion was ultrasonically shaken, centrifuged at 5000 rpm for 13 minutes, and the supernatant was filtered off (0.22 μm filter). The magnetization curve shows that the polyglucosamine particles are superparamagnetic particles. The particle size measured by PCS is 64nm. The measured zeta potential was +48mV. r ₁ was 35.1 (mM·sec) ^-1 , and r ₂ was 281 (mM·sec) ^-1 . b) Dilute the iron black particle dispersion (equivalent to 0.3g iron black particle) prepared in Example 1a with water (50ml), and dissolve polyglucosamine with an average molecular weight of about 2000000D in 1% acetic acid (7.5ml) (50 mg, Fluka 22743) was added to the dispersion. The dispersion was sonicated, centrifuged at 5000 rpm for 13 minutes and the supernatant was filtered off (0.22 μm filter). The magnetization curve shows that the polyglucosamine particles are superparamagnetic particles. The particle size measured by PCS is 64nm. The measured zeta potential was +47mV. c) Dilute the iron black particle dispersion (equivalent to 0.3g iron black particle) prepared in Example 1a with water (50ml), and dissolve polyglucosamine with an average molecular weight of about 2000000D in 1% acetic acid (7.5ml) (15 mg, Fluka 22743) was added to the dispersion. The dispersion was ultrasonically oscillated, centrifuged at 5000 rpm for 13 minutes, and the supernatant was filtered off (0.22 μm filter). The magnetization curve shows that the polyglucosamine particles are superparamagnetic particles. The particle size measured by PCS is 64nm. The measured zeta potential was +47mV. Embodiment 14a) Dilute the iron black particle dispersion (equivalent to 0.3g iron black particle) prepared in Example 1a with water (50ml), and dissolve the polyamino acid with an average molecular weight of about 750000D in 1% acetic acid (7.5ml) Glucose (50 mg, Fluka 22742) was added to the dispersion. The dispersion was ultrasonically oscillated, centrifuged at 5000 rpm for 13 minutes, and the supernatant was filtered off (0.22 μm filter). The magnetization curve shows that the polyglucosamine particles are superparamagnetic particles. The particle size measured by PCS is 62nm. The measured zeta potential was +48mV. r ₁ was 33.4 (mM·sec) ^-1 , and r ₂ was 279 (mM·sec) ^-1 . b) Dilute the iron black particle dispersion (equivalent to 0.3g iron black particle) prepared in Example 1a with water (50ml), and dissolve polyglucosamine with an average molecular weight of about 750000D in 1% acetic acid (7.5ml) (15 mg, Fluka 22742) was added to the dispersion. The dispersion was ultrasonically shaken, centrifuged at 5000 rpm for 13 minutes, and the supernatant was filtered off (0.22 μm filter). The magnetization curve shows that the polyglucosamine is a superparamagnetic particle. The particle size measured by PCS is 64nm. The measured zeta potential was +49mV. Example 15a) Dilute the iron black particle dispersion (equivalent to 0.3g iron black particle) prepared in Example 1a with water (50ml), and dissolve the polyamino acid with an average molecular weight of about 70000D in 1% acetic acid (4.5ml) Glucose (30 mg, Fluka 22742) was added to the dispersion. The dispersion was ultrasonically oscillated, centrifuged at 5000 rpm for 13 minutes, and the supernatant was filtered off (0.22 μm filter). The magnetization curve shows that the polyglucosamine particles are superparamagnetic particles. The particle size measured by PCS is 62nm. The measured zeta potential was +49mV. r ₁ was 34.3 (mM·sec) ^-1 , and r ₂ was 327 (mM·sec) ^-1 . b) Dilute the iron black particle dispersion (equivalent to 0.3g iron black particle) prepared in Example 1a with water (50ml), and dissolve polyglucosamine with an average molecular weight of about 70000D in 1% acetic acid (2.25ml) (15 mg, Fluka 22742) was added to the dispersion. The dispersion was ultrasonically oscillated, centrifuged at 5000 rpm for 13 minutes, and the supernatant was filtered off (0.22 μm filter). The magnetization curve shows that the polyglucosamine particles are superparamagnetic particles. The particle size measured by PCS is 64nm. The measured zeta potential was +48mV. Example 16a) The iron black particle dispersion (equivalent to 0.3g iron black particles) prepared in Example 1a was diluted with water (50ml), and poly(styrene-4-sulfonate) dissolved in water (3ml) (30 mg, Janssen 22.227.14) was added to the dispersion. The dispersion was ultrasonically oscillated, centrifuged at 5000 rpm for 13 minutes, and the supernatant was filtered out (0.22 μm filter). The average diameter of the poly(sodium styrene-4-sulfonate) particles was measured by HDC to be 43 nm. The measured zeta potential was -53mV. b) Dilute the iron black particle dispersion (equivalent to 0.3g iron black particle) prepared in Example 1a with water (50ml), and dissolve poly(styrene-4-sodium sulfonate) dissolved in water (1.5ml) ( 15 mg, Janssen 22.227.14) were added to the dispersion. The dispersion was ultrasonically oscillated, centrifuged at 5000 rpm for 13 minutes, and the supernatant was filtered out (0.22 μm filter). The average diameter of the poly(sodium styrene-4-sulfonate) particles measured by HDC was 36 nm. The measured zeta potential was -49mV. Embodiment 17a) Dilute the iron black particle dispersion (equivalent to 0.3g iron black particle) prepared in embodiment 1a with water (50ml), dissolve the poly L- Glutamic acid (30 mg, Sigma, p-4636) was added to the dispersion. The dispersion was ultrasonically oscillated, centrifuged at 4000 rpm for 13 minutes, and the supernatant was filtered out (0.22 μm filter). The magnetization curve shows that the poly-L-glutamic acid particles are superparamagnetic particles and the average diameter of the particles is 37nm as measured by HDC. The measured zeta potential was -68mV. b) Dilute the iron black particle dispersion (equivalent to 0.3g iron black particle) prepared in Example 1a with water (50ml), and dissolve the poly-L-glutamine with an average molecular weight of about 2000-15000D in water (5ml) Acid (50 mg, Sigma, P-4636) was added to the dispersion. The dispersion was ultrasonically oscillated, centrifuged at 4000 rpm for 13 minutes, and the supernatant was filtered out (0.22 μm filter). The average diameter of the poly-L-glutamic acid particles measured by HDC was 38 nm. The measured zeta potential was -66mV. r ₁ was 40.4 (mM·sec) ^-1 , and r ₂ was 281 (mM·sec) ^-1 . c) Dilute the iron black particle dispersion (equivalent to 0.3g iron black particle) prepared in Example 1a with water (50ml), and dissolve the poly-L- Glutamic acid (15 mg, Sigma, P-4636) was added to the dispersion. The dispersion was ultrasonically oscillated, centrifuged at 4000 rpm for 13 minutes, and the supernatant was filtered out (0.22 μm filter). The average diameter of the poly-L-glutamic acid particles measured by HDC was 38 nm. The measured zeta potential was -65mV. Embodiment 18a) the iron black particle dispersion (equivalent to 0.3g iron black particle) prepared in embodiment 1a is diluted with water (50ml), the average molecular weight that is dissolved in water (3ml) is about the poly-L of 15000-50000D - Glutamic acid (30 mg, Sigma, P-4761 ) was added to the dispersion. The dispersion was ultrasonically oscillated, centrifuged at 4000 rpm for 13 minutes, and the supernatant was filtered out (0.22 μm filter). The average diameter of the poly-L-glutamic acid particles measured by HDC was 37 nm. The measured zeta potential was -66mV. b) Dilute the iron black particle dispersion (equivalent to 0.3g iron black particle) prepared in Example 1a with water (50ml), and dissolve the poly-L-valley with an average molecular weight of about 15000-50000D in water (5ml) Acid (50 mg, Sigma, P4761) was added to the dispersion. The dispersion was ultrasonically oscillated, centrifuged at 4000 rpm for 13 minutes, and the supernatant was filtered out (0.22 μm filter). The average diameter of the poly-L-glutamic acid particles measured by HDC was 36 nm. The measured zeta potential was -66mV. r ₁ was 41.7 (mM·sec) ^-1 , and r ₂ was 286 (mM·sec) ^-1 . c) Dilute the iron black particle dispersion (equivalent to 0.3g iron black particle) prepared in Example 1a with water (50ml), and dissolve the poly-L- Glutamic acid (15 mg, Sigma, P4761) was added to the dispersion. The dispersion was ultrasonically oscillated, centrifuged at 4000 rpm for 13 minutes, and the supernatant was filtered out (0.22 μm filter). The average diameter of the poly-L-glutamic acid particles measured by HDC was 36 nm. The measured zeta potential was -63mV. Embodiment 19a) Dilute the iron black particle dispersion (equivalent to 0.3g iron black particle) prepared in Example 1a with water (50ml), and dissolve the poly-L with an average molecular weight of about 50000-100000D in water (3ml) - Glutamic acid (30 mg, Sigma, P-4886) was added to the dispersion. The dispersion was ultrasonically oscillated, centrifuged at 4000 rpm for 13 minutes, and the supernatant was filtered out (0.22 μm filter). The magnetization curve shows that the poly-L-glutamic acid particles are superparamagnetic particles. The average diameter measured by HDC is 40nm. The measured zeta potential was -70mV. r ₁ was 39.6 (mM·sec) ^-1 , and r ₂ was 289 (mM·sec) ^-1 . b) Dilute the iron black particle dispersion (equivalent to 0.3g iron black particle) prepared in Example 1a with water (50ml), and dissolve the poly-L- Glutamic acid (15 mg, Sigma, P-4886) was added to the dispersion. The dispersion was ultrasonically oscillated, centrifuged at 4000 rpm for 13 minutes, and the supernatant was filtered out (0.22 μm filter). The average diameter of the poly-L-glutamic acid particles measured by HDC was 39 nm. The measured zeta potential was -66mV. Embodiment 20a) the iron black particle dispersion (equivalent to 0.3g iron black particle) prepared in embodiment 1a is diluted with water (50ml), the average molecular weight that is dissolved in water (3ml) is about the poly-L of 15000-50000D - Glutamic acid (30 mg, Sigma, P-6762) was added to the dispersion. The dispersion was ultrasonically oscillated, centrifuged at 4000 rpm for 13 minutes, and the supernatant was filtered out (0.22 μm filter). The average diameter of the poly-L-glutamic acid particles measured by HDC was 42 nm. The measured zeta potential was -65mV. b) Dilute the iron black particle dispersion (equivalent to 0.3g iron black particle) prepared in Example 1a with water (50ml), and dissolve the poly-L-valley with an average molecular weight of about 15000-50000D in water (5ml) Acid (50 mg, Sigma, P6762) was added to the dispersion. The dispersion was ultrasonically oscillated, centrifuged at 4000 rpm for 13 minutes, and the supernatant was filtered out (0.22 μm filter). The average diameter of the poly-L-glutamic acid particles measured by HDC was 40 nm. The measured zeta potential was -67mV. r ₁ was 40.8 (mM·sec) ^-1 , and r ₂ was 332 (mM·sec) ^-1 . c) Dilute the iron black particle dispersion (equivalent to 0.3g iron black particle) prepared in Example 1a with water (50ml), and dissolve the poly-L- Glutamic acid (15 mg, Sigma, P-6762) was added to the dispersion. The dispersion was ultrasonically oscillated, centrifuged at 4000 rpm for 13 minutes, and the supernatant was filtered out (0.22 μm filter). The average diameter of the poly-L-glutamic acid particles measured by HDC was 44 nm. The measured zeta potential was -66mV. Embodiment 21a) Dilute the iron black particle dispersion (equivalent to 0.3g iron black particle) prepared in embodiment 1a with water (50ml), dissolve the poly-L - Aspartic acid (30 mg, Sigma, P5387) was added to the dispersion. The dispersion was ultrasonically oscillated, centrifuged at 4000 rpm for 13 minutes, and the supernatant was filtered out (0.22 μm filter). The average diameter of the poly-L-aspartic acid particles measured by HDC was 38 nm. The measured zeta potential was -67mV. r ₁ was 41.1 (mM·sec) ^-1 , and r ₂ was 303 (mM·sec) ^-1 . b) Dilute the iron black particle dispersion (equivalent to 0.3g iron black particle) prepared in Example 1a with water (50ml), and dissolve the poly-L-day with an average molecular weight of about 5000-15000D in water (5ml) Partic acid (50 mg, Sigma, P5387) was added to the dispersion. The dispersion was sonicated, centrifuged at 4000 rpm for 13 minutes and filtered (0.22 μm filter). The average diameter of the poly-L-aspartic acid particles measured by HDC was 37 nm. The measured zeta potential was -70mV. c) Dilute the iron black particle dispersion (equivalent to 0.3g iron black particle) prepared in Example 1a with water (50ml), and dissolve the poly-L- Aspartic acid (15 mg, Sigma, P5387) was added to the dispersion. The dispersion was ultrasonically oscillated, centrifuged at 4000 rpm for 13 minutes, and the supernatant was filtered out (0.22 μm filter). The average diameter of the poly-L-aspartic acid particles measured by HDC was 37 nm. The measured zeta potential was -65mV. Embodiment 22a) Dilute the iron black particle dispersion (equivalent to 0.3g iron black particle) prepared in Example 1a with water (50ml), and dissolve polyacrylic acid (30mg, 30mg, Aldrich 32, 366-7) was added to the dispersion. The dispersion was ultrasonically oscillated, centrifuged at 5000 rpm for 13 minutes, and the supernatant was filtered out (0.22 μm filter). The average diameter of the polyacrylic acid particles was measured by HDC to be 50 nm. The measured zeta potential was -36mV. r ₁ is 29.1(mM·sec) ^-1 , r ₂ is 323(mM·sec) ^-1 b) the iron black particle dispersion (equivalent to 0.3g iron black particle) prepared in Example 1a is watered (50ml) For dilution, polyacrylic acid (50 mg, Aldrich 32, 366-7), having an average molecular weight of about 2000D, dissolved in water (5 ml) was added to the dispersion. The dispersion was ultrasonically oscillated, centrifuged at 5000 rpm for 13 minutes, and the supernatant was filtered out (0.22 μm filter). The average diameter of the polyacrylic acid particles was measured by HDC to be 57 nm. The measured zeta potential was -29mV. c) Dilute the iron black particle dispersion (equivalent to 0.3g iron black particle) prepared in embodiment 1a with water (50ml), and dissolve polyacrylic acid (30mg, Aldrich 19 , 205-8) was added to the dispersion, the dispersion was ultrasonically oscillated, centrifuged and the supernatant was filtered off. Embodiment 23a) Dilute the iron black particle dispersion (equivalent to 0.3g iron black particle) prepared in embodiment 1a with water (50ml), and dissolve the polygalactose with an average molecular weight of about 25000-50000D in water (3ml) Alkyd acid (30 mg, Fluka 8 1325) was added to the dispersion and 1M NaOH was added dropwise. The dispersion was ultrasonically oscillated, centrifuged at 5000 rpm for 13 minutes, and the supernatant was filtered out (0.45 μm filter). The average diameter of the polygalacturonic acid particles measured by HDC is 55nm. The measured zeta potential was -60mV. b) Dilute the iron black particle dispersion (equivalent to 0.3g iron black particle) prepared in embodiment 1a with water (50ml), the average molecular weight that will be dissolved in the water (1.5ml) that adds a few drops of 1M NaOH is about 25000 - 50000D polygalacturonic acid (15 mg, Fluka 81325) was added to the dispersion. The dispersion was ultrasonically oscillated, centrifuged at 5000 rpm for 13 minutes, and the supernatant was filtered out (0.45 μm filter). The average diameter of the polygalacturonic acid particles measured by HDC is 61 nm. The measured zeta potential was -55mV. Embodiment 24a) the iron black particle dispersion (equivalent to 0.3g iron black particle) prepared in embodiment 1a is diluted with water (50ml), the average molecular weight that is dissolved in water (3ml) is about the poly-L of 1000-4000D - Lysine (30 mg, Sigma P-0879) was added to the dispersion. The dispersion was ultrasonically oscillated, centrifuged at 4000 rpm for 13 minutes, and the supernatant was filtered out (0.45 μm filter). The average diameter of the poly-L-lysine particles measured by PCS was 102 nm. The measured zeta potential was +47mV. b) Dilute the iron black particle dispersion (equivalent to 0.3g iron black particle) prepared in Example 1a with water (50ml), and dissolve the poly-L- Lysine (15 mg, Sigma P-0879) was added to the dispersion. The dispersion was ultrasonically oscillated, centrifuged at 4000 rpm for 13 minutes, and the supernatant was filtered off (0.45 μm filter). The average diameter of the poly-L-lysine particles measured by PCS was 108 nm. The measured zeta potential was +46mV. Embodiment 25a) the iron black particle dispersion (equivalent to 0.3g iron black particle) prepared in embodiment 1a is diluted with water (50ml), the average molecular weight that is dissolved in water (5ml) is about 15000-30000 poly-L - Lysine (50 mg, Sigma P-7890) was added to the dispersion. The dispersion was ultrasonically oscillated, centrifuged at 4000 rpm for 13 minutes, and the supernatant was filtered off (0.22 μm filter). The magnetization curve shows that the poly-L-lysine particles are superparamagnetic particles. The particle size of warm water measured by PCS is 78nm. The measured zeta potential was +56mV. r ₁ was 38.3 (mM·sec) ^-1 , and r ₂ was 295 (mM·sec) ^-1 . b) Dilute the iron black particle dispersion (equivalent to 0.3g iron black particle) prepared in Example 1a with water (50ml), and dissolve the poly-L- Lysine (15 mg, Sigma P-7890) was added to the dispersion. The dispersion was ultrasonically oscillated, centrifuged at 4000 rpm for 13 minutes, and the supernatant was filtered out (0.22 μm filter). The average diameter of the poly-L-lysine particles measured by PCS was 89 nm. The measured zeta potential was +57mV. Embodiment 26a) Dilute the iron black particle dispersion (equivalent to 0.3g iron black particle) prepared in embodiment 1a with water (50ml), dissolve the poly-L with an average molecular weight of about 70000-150000D in water (3ml) - Lysine (30 mg, Sigma P-1274) was added to the dispersion. The dispersion was ultrasonically oscillated, centrifuged at 4000 rpm for 13 minutes, and the supernatant was filtered out (0.22 μm filter). The average diameter of the alginate particles measured by PCS is 94nm. The measured zeta potential was +57mV. b) Dilute the iron black particle dispersion (equivalent to 0.3g iron black particle) prepared in embodiment 1a with water (50ml), and dissolve the poly-L-lysine with an average molecular weight of about 70000-150000D in water (5ml) Amino acid (50 mg, Sigma P-1274) was added to the dispersion. The dispersion was ultrasonically oscillated, centrifuged at 4000 rpm for 13 minutes, and the supernatant was filtered out (0.22 μm filter). The average diameter of the alginate particles measured by PCS was 86 nm. The measured zeta potential was +62mV. r ₁ was 36.9 (mM·sec) ^-1 , and r ₂ was 294 (mM·sec) ^-1 . c) Dilute the iron black particle dispersion (equivalent to 0.3g iron black particle) prepared in Example 1a with water (50ml), and dissolve the poly-L- Lysine (15 mg, Sigma P1274) was added to the dispersion. The dispersion was ultrasonically oscillated, centrifuged at 4000 rpm for 13 minutes, and the supernatant was filtered off (0.22 μm filter). The particle size measured by PCS is 96nm. The measured zeta potential was +61 mV. Embodiment 27a) the iron black particle dispersion (equivalent to 0.3g iron black particle) prepared in embodiment 1a is diluted with water (50ml), the average molecular weight that is dissolved in water (3ml) is about 1: 1 of 5000-15000D Poly(sodium aspartate, sodium glutamate) (30 mg, Sigma P1408) was added to the dispersion. The dispersion was ultrasonically oscillated, centrifuged at 5000 rpm for 13 minutes, and the supernatant was filtered out (0.22 μm filter). The magnetization curve shows that the poly(sodium aspartate, sodium glutamate) particles are superparamagnetic particles. The particle size measured by HDC is 38nm. The measured zeta potential was -58mV. r ₁ was 40.4 (mM·sec) ^-1 , and r ₂ was 277 (mM·sec) ^-1 . b) Dilute the iron black particle dispersion (equivalent to 0.3g iron black particle) prepared in Example 1a with water (50ml), and dissolve in water (1.5ml) a 1:1 polymer with an average molecular weight of about 5000-15000D (sodium aspartate, sodium glutamate) (15 mg, Sigma P1408) was added to the dispersion. The dispersion was ultrasonically oscillated, centrifuged at 5000 rpm for 13 minutes, and the supernatant was filtered out (0.22 μm filter). The average diameter of the poly(sodium aspartate, sodium glutamate) particles measured by HDC is 40 nm. The measured zeta potential was -60mV. Example 28a) Dilute the iron black particle dispersion (equivalent to 0.3g iron black particle) prepared in Example 1a with water (50ml), and dissolve the 4:1 polymer with an average molecular weight of 70000-150000D dissolved in ethanol (3ml) (glutamic acid, ethyl glutamate) (30 mg, Sigma P4910) was added to the dispersion and a few drops of HCl were added. The dispersion was sonicated and centrifuged, and the supernatant was collected. Embodiment 29a) the iron black particle dispersion (equivalent to 0.3g iron black particle) prepared in embodiment 1a is diluted with water (50ml), and the average molecular weight that is dissolved in water (5.7ml) is about 1:1 of 150000-300000D 4 poly(glutamic acid, lysine) (30 mg, Sigma P0650) was added to the dispersion. The dispersion was ultrasonically oscillated, centrifuged at 5000 rpm for 13 minutes, and the supernatant was filtered out (0.22 μm filter). The average diameter of the poly(glutamic acid, lysine) particles measured by HDC was 79 nm. The measured zeta potential was +65mV. b) Dilute the iron black particle dispersion (equivalent to 0.3g iron black particle) prepared in Example 1a with water (50ml), and dissolve in water (9.5ml) the average molecular weight of about 150000-300000D (glutamic acid, lysine) (50 mg, Sigma P0650) was added to the dispersion. The dispersion was ultrasonically oscillated, centrifuged at 5000 rpm for 13 minutes, and the supernatant was filtered out (0.22 μm filter). The average diameter of the poly(glutamic acid, lysine) particles measured by HDC was 77 nm. The measured zeta potential was +63mV. r ₁ was 35.5 (mM·sec) ^-1 , and r ₂ was 255 (mM·sec) ^-1 . Example 30 The iron black particle dispersion (equivalent to 0.3 g iron black particles) prepared in Example 1a was diluted with water (50 ml), and the water-soluble dendrimer (prepared according to US-A-4507466 (The DowChemical Corporation)) (30 mg) was added to the dispersion. The dispersion was sonicated, centrifuged at 5000 rpm for 13 minutes and the supernatant was filtered off. Stability Example 31

The stability of the following iron oxide compositions was determined by hot pressing at 121°C for 15 minutes: Reference Examples 5b and 6b, Examples 1a, 1b, 2, 3, 4, 9a, 10a, 11a, b and c, 12a, 13a, b and c, 14b, 15a, 16a, 17a and b, 18b, 19a, 20a, 21b, 22a, 23a, 25a, 26a, 27b and 29a.

The uncoated iron oxide particles of Example 1a were dispersed using HCl before the experiment. Other compositions need not be treated. The composition should be observed closely both before and after heat pressing, as well as a day thereafter and a week later. After hot pressing, the sample of Example 1a was completely isolated. The other compositions were not affected by the overheating condition and exhibited a uniform particle size distribution at all observed time points before and after hot pressing. Example 32

The absorption of poly(styrene-4-sodium sulfonate) (PSSNa), a typical example of the polyelectrolyte of the present invention, was investigated. Absorption isotherms, electrophoretic mobility and particle size were determined as a function of polymer concentration. As described in Example 16, the uncoated iron oxide particles in Example 1 were coated with PSSNa, but the dispersion process was not ultrasonically oscillated. The amount ratio of PSSNa and iron oxide is 9×10 ^-3 /2.5. Figure 1 shows the absorption isotherms of PSSNa on iron oxide crystals.

The particle size of the coated iron oxide particles measured by PCS is 130±5 nm. Using a particle density of 5.2 g/l, the surface area of the particles can be estimated by:

Surface area (m ² /ml) = mA/ρ.V

where m is the particle mass per milliliter, ρ is the particle density, and A and V are the area and volume of a single particle, respectively. The estimated surface area in suspension was 9.5 x 10 ^-3 m ² /ml. The maximum absorption capacity is 26 mg/m ² , referring to the multilayer formed by the absorbed polymer, or the polymer wire/ring formed on the surface.

Figures 2 and 3 show particle electrophoretic mobility and its hydrodynamic diameter as a function of polymer concentration. It was found that the electrophoretic mobility of uncoated iron oxide was 4.2±0.6μm.cm/v.s, and decreased rapidly with the increase of polymer concentration. As determined by PCS, at high polymer concentration, the electrophoretic mobility is -4μm.cm/v.s, and the particle size is stable at 230±20nm. The results of Figures 1-3 are illustrated in Table 1 below.

Figure 4 shows the results of electrophoretic mobility measurements of uncoated iron oxide particles and PSSNa-coated particles as a function of the pH of the suspension. The uncoated iron oxide surface has a typical amphoteric character, with high positive electrophoretic mobility at low pH, which becomes increasingly negative electrophoretic mobility at higher pH. The isoelectric point is at pH 7. When coated with PSSNa, the character of the particle surface becomes completely constant acidity. The surface has high negative electrophoretic mobility even at low pH, and at high pH the surface will be more negative. The results of Figure 4 combined with the results of Figures 1 to 3 show that, at this polymer concentration, the uncoated oxide surface can be completely coated with acidic polymer molecules. Table 1: Effects of different PSSNa concentrations on iron oxide colloidal suspensions

    Polymer Concentration     Observations

＜0.01mg/ml     High positive electrophoretic mobility, stable suspension

Set, 0-0.5mg polymer/m ²

0.03-0.10mg/ml Mobility is close to 0, the suspension is unstable,

1-5mg polymer/m ²

Above 0.3mg/ml High negative electrophoretic mobility, stable suspension

10-20mg polymer/m ² Figure 1: The absorption of PSSNa by colloidal iron oxide. Absorption (mg/ml) is a function curve of PSSNa concentration (mg/ml). ■ and ◆ are centrifuged fractions, and ▲ is a filtered fraction. Figure 2: Electrophoretic mobility (μm.cm/Vs) of colloidal iron oxide as a function of PSSNa concentration (mg/ml). Figure 3: Particle size (nm) of colloidal iron oxides as a function of PSSNa concentration (mg/ml). Figure 4: The electrophoretic mobility (μm.cm/Vs) of pure colloidal iron oxide (X) and the electrophoretic mobility (μm.cm/Vs) of PSSNa-coated colloidal iron oxide (X) versus pH function curve. Example 33

The uptake of a typical polyelectrolyte-heparin by iron oxide particles was studied. The electrophoretic mobility and particle size of iron oxides were determined, and the function curve was plotted against the heparin concentration. The bare particles of Example 1a were stabilized with HCl and coated with heparin as in Example 1b, but with rotational agitation for 30 seconds instead of sonication. Figures 5 and 6 show plots of electrophoretic mobility and particle size versus heparin concentration.

The plots of electrophoretic mobility and particle size versus the amount of heparin show the uptake of the polymer on the particle surface. The increasing number of negatively charged molecules on the positively charged iron oxide surface first reduces the electrophoretic mobility of the particle and then becomes oppositely charged. The suspension is unstable near the isoelectric point. Figure 5: Curve of electrophoretic mobility (μm.cm/V.s) versus concentration of added heparin (μl/ml). Figure 6: Particle size (μm) plotted against the concentration of added heparin (μl/ml). Security Example 34

The iron oxide compositions of Reference Example 4 (starch iron oxide) and Example 1b (heparin iron oxide) were rapidly intravenously administered to rabbits (n4-5) in the form of concentrated boluses. The doses of 1, 2.5 and 10 mg Fe/kg were injected, and the mean systemic arterial pressure (SAP) and mean pulmonary arterial pressure (PAP) were recorded within 60 minutes after injection. The composition of Reference Example 4 had a dose-dependent effect on PAP. No changes were observed at the 1 mg Fe/kg dose, and minor changes were noted at the 2.5 mg Fe/kg dose, from 20 ± 1 mm Hg to 23 ± 1 mm Hg. At the 10 mg Fe/kg dose, mean PAP changed from 22 ± 3 mm Hg to 33 ± 6 mm Hg. Higher doses slowly decreased mean SAP from 129±10 mm Hg to 117±8 mm Hg. The maximal effect on PAP and SAP was recorded at 3-4 minutes after injection, with a short response time (within 10 minutes). The composition of Example 1b had no effect on the recorded hydrodynamic parameters. Example 35

Reference will be made to Example 1 (dextran iron oxide), 4 (starch iron oxide), 5b (carboxydextran iron oxide), and 6b (dextran phosphate iron oxide) and Example 1b (heparin iron oxide). oxide), 4 (chondroitin-4-sulfate iron oxide) and 25a (poly-L-lysine iron oxide) iron oxide preparations were administered to rats (n=2-3) by intravenous injection, dose It is 1mg Fe/kg. Circulating platelet counts were recorded at 3, 5, 10 and 15 minutes after injection. The compositions of Reference Examples 1 and 4 significantly reduced platelet counts to 10-17% of pre-injection values at 3 and 5 minutes after injection. The compositions of Reference Examples 5b and 6b also caused a significant decrease in the number of platelets at 3 and 5 minutes after injection, corresponding to 50-60% of the control value. This response returned rapidly in all mice, with platelet counts regaining 75-100% of control values within 15 minutes. The compositions of Examples 1b, 4 and 25a had no or little effect on circulating platelet counts. Example 36

At 37°C, refer to Examples 1 (iron dextran oxide), 4 (iron starch oxide), 5b (iron carboxydextran oxide) and 6b (iron phosphate dextran oxide), and implement Example 1b, 3a (heparin iron oxide), 4 (chondroitin-4-sulfate iron oxide), 11a (alginate iron oxide), 13a (polyglucosamine iron oxide), 17a (poly- L-glutamate iron oxide) and 25a (poly-L-lysine iron oxide) were incubated with human serum for 60 minutes in test tubes at a concentration equivalent to a dose of 1 mg Fe/kg (total substance) and 10 mg Fe /kg (refer to Examples 4 and 5b). All compositions are autoclaved and endotoxin free. Human SC5b-a complement complex (TCC) (Bering) was measured by enzyme immunoassay to study the activation of complement. Zymosan A (Sigma) was used as positive control and dextrose (5%) or water as negative controls. The compositions of the reference examples all significantly increased the TCC level. The sample of reference example 5b has the most obvious effect, compared with the negative control, TCC will be increased to 6 times even at a lower dose of 1mg Fe/kg. The compositions of Reference Examples 1 and 4 were found to have a dose-dependent effect on TCC. A 2-fold increase in TCC was determined at low doses and a 6-fold increase in TCC at high doses. The composition of Reference Example 6b tripled the TCC at a low dose of 1 mg Fe/kg. Other tested compositions had no or little effect on TCC compared to the negative control.

Claims (15)

1. A diagnostic agent comprising a composite particulate material, wherein the particles comprise: a diagnostically effective, substantially water-insoluble metal oxide crystalline material, and a polyion-coated material, wherein said particle size is less than 300nm, said The crystal size of the crystalline material is 1-100nm, the weight ratio of the crystalline material to the coating material is 1000:1 to 11:1, and the coating material is selected from natural and synthetic structural polysaccharides, Synthetic polyamino acids, physiologically tolerated synthetic polymers and their derivatives. 2. The diagnostic agent of claim 1, wherein said coating material is a natural or synthetic structural polysaccharide selected from the group consisting of pectin, polygalacturonic acid, glycosaminoglycan, heparin, cellulose, and Marine polysaccharides. 3. The diagnostic agent of claim 2, wherein said coating material is selected from the group consisting of dermatan, heparin, heparan, keratin, hyaluronic acid, carrageenan and polyglucosamine. 4. The diagnostic agent of claim 2, wherein said coating material is chondroitin. 5. The diagnostic agent of claim 1, wherein said coating material is a homopolymer or copolymer of aspartic acid, glutamic acid or lysine. 6. The diagnostic agent according to any one of claims 1 to 5, wherein the coating material has a molecular weight of 500 to 2,000,000D. 7. The diagnostic agent of any one of claims 1 to 6, wherein the weight ratio of said metal oxide crystals to coating material associated with the surface is at least 15:1. 8. The diagnostic agent according to any one of claims 1 to 6, wherein the weight ratio of the metal oxide crystals to the coating material bound to the surface is 500:1 to 20:1. 9. The diagnostic agent according to any one of claims 1 to 6, wherein the weight ratio of the metal oxide crystals to the coating material bound to the surface is 100:1 to 25:1. 10. The diagnostic agent according to any one of claims 1 to 9, wherein said metal oxide crystals are superparamagnetic. 11. The diagnostic agent according to claim 10, wherein said superparamagnetic crystal is an iron oxide crystal. 12. The diagnostic agent according to any one of claims 1 to 11, wherein said particles have a Zeta potential lower than -10 mV or higher than +10 mV. 13. A diagnostic agent composition comprising the diagnostic agent of any one of claims 1 to 12 and at least one physiologically acceptable carrier or excipient. 14. A method of producing the diagnostic agent of claim 1, said method comprising: or (ii) A diagnostically effective, substantially water-insoluble diagnostic agent of 1-100 nm is coated with a coating material to obtain composite particles with a particle size of less than 300 nm, and the weight ratio of the crystal to the surface-bound coating material is 1000:1 to 11:1, the coating material is selected from natural or synthetic structural polysaccharides and their derivatives, synthetic polyamino acids and physiologically tolerable synthetic polymers. 15. A method for enhancing contrast imaging of human and non-human bodies, said method comprising administering to said body a suspension of any one of the contrast agents of claims 1 to 13, whereby the contrast agent can be distributed in At least a portion of the body is imaged.

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