JPH03504723A - Magnetic particle-containing composition - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Magnetic particle-containing composition The present invention relates to therapeutic and diagnostic compositions, and more particularly to compositions containing magnetic particles. Parenterally administrable compositions and therapeutic and diagnostic methods thereof, particularly for nuclear magnetic resonance The present invention relates to use in diagnostic methods using radiofrequency (nmr) technology.

Containing magnetic particles, i.e. ferromagnetic (or ferrimagnetic) or superparamagnetic particles Compositions have been widely used in diagnostic studies and therapeutic treatments.

That is, magnetic particles administered parenterally can be prepared using, for example, an externally applied magnetic field. Drug targeting (e.g. Widder et al.: J, Pharm, Sci, 68 : 79-82. 1979; Advancesin Pharmaco logy and Chemotherapy 16:213.1979; and US-A-4247406, as well as Gelstand et al.: WO3 3/03920 (Sintef) and Morris: US-A-43 31654), repair of vascular injuries and “clamping” of arteries during surgery For example, Perry: Proceedings Int, Adv, Cour se Work-shop, pp. 219-230, 19778 and Roth: J, Appl, Physics.

40:1044-1045.1969), blood flow tracing (e.g. N ewbower 2 IEEE Transactions on Magnet ics Mag 9(3): 447-450.1973), and Killing of cancer cells by in vivo use of heat generated by particles placed in a fast alternating magnetic field Applications have been proposed for It has been proposed.

Recently, with the development of medical NMR, magnetic particles have been used in magnetic resonance imaging (IJRI) and It has been shown to be useful for both magnetic resonance spectroscopy (MR5). Ta. For example, in MR5, magnetic particles are used to obtain selective signals from cancer tissues. The use of children is shown in White et al. anqisco Workshop on Magnetic Re5onan ce 5pectro-scopy in vivo - April 4-5, 1987 (Japan, p. 93, 1987) and MRI contrast agents of ferromagnetic and superparamagnetic particles. Its use as described by Nycomed (WO85/04330) There is.

In MRI, it is introduced into the area to be imaged to improve the contrast of the resulting image. The agent that enhances the image is commonly called a contrast agent, which enhances the resonance signals generated by the image. The responding nucleus (“image part”, generally a proton, more specifically a water proton) This affects the spin rebalancing properties of Contrast obtained through the use of contrast agents Increased trust increases the signal level of a particular organ or tissue by increasing its surrounding organs or tissue. I; increases or decreases relative to a particular organ or tissue. can be visualized more clearly. The shield at the target site relative to its surroundings. Contrast agents that increase the signal level are called "positive" contrast agents, whereas contrast agents that increase the Contrast agents that reduce the level of signal present are called "negative" contrast agents.

Most of the substances currently proposed as MRI contrast agents are paramagnetic, superparamagnetic, or A contrast effect is achieved by containing a ferromagnetic material or a ferromagnetic material.

For negative IJRI contrast agents, ferromagnetic and superparamagnetic contrast agents, the image contrast The increase of Decreasing the equilibrium coefficient, for the imaging nucleus of the field caused by ferromagnetic or superparamagnetic particles Derived from the decline resulting from action.

On the other hand, paramagnetic contrast agents are either positive or negative MRI contrast agents. magnetic co The effect of paramagnetic materials on the ring signal strength depends on many factors, the most important of which is What is important is the concentration of paramagnetic material in the imaged area, the properties of the paramagnetic material itself, and the pulse sequence and magnetic field strength used in the imaging procedure. But long Generally, paramagnetic contrast agents are not positive at conventional concentrations, where their T1-lowering effect is dominant. MRI contrast agent, but at higher concentrations where the T2 lowering effect is dominant, negative MRI Can be used as a contrast agent. In both cases, the decrease in relaxation time is caused by the paramagnetic center. This is caused by the action of the magnetic field on the imaging nucleus.

The use of ferromagnetic and superparamagnetic materials as MRI contrast agents is widely supported and widespread. Suitable materials have been suggested in the literature. For example, WO85104330 (Ny comed AS), WO35102772 (Schr5der et al.), LIS -A -4675173 (Widder), WO38100060 (Adva nced Magnetics Inc.), WO86101112 (FOX Chase Cancer Center), DE-A-3443252 ( Schering AG), Widder et al. AJR148: 399-404 (1 987), Renshaw et al.: Magnetic Re5onance in Medicine 3; 217-225 (1986), 5aini et al. Radiology 162: 211-216 (1987), Mend oncaDias et al.: Magnetic Re5onance in Med icine 3: 328-330 (1986), HemmiHemm1n et al. : Acta Radiologica 28: 703-705 (198 7) and Bacon et al.: J, Lab, Cl1n, Med, 110: 164-171 (1987).

There are many suggestions in the literature for formulating parenterally administrable compositions containing magnetic particles. included, especially when administered neat (i.e. without coating or binding to other substances). (uncoated) magnetic particles; coated (e.g. dextran); Coatings (see e.g. US-A-4452773) magnetic particles, matrices polysaccharide, such as WO 85/0 2772) Magnetic particles or organ or tissue targeting species such as antibodies or Magnetic particles bound to biomolecules such as lumon (e.g. Wo 8810006 0) is suggested.

Magnetic particles, which can be administered parenterally, can help the reticuloendothelial system, which removes such particles from the bloodstream. Due to its effects, it is of particular interest in imaging the liver and lungs. However, non-menstrual Magnetic particles that can be administered orally include, for example, particles bound to tissue or organ targeting agents. By using the child it can be located in other organs or tissues and therefore Targeted I; obtain contrasting MR images of the tissue or organ to be imaged be able to.

Furthermore, WO 88100060 describes magnetic particle serum that can be administered parenterally. Increased lifetime and potential for such particles to act as blood-retaining MRI contrast agents sex is suggested.

Prior to administration of magnetic particles, chemically and physiologically similar non-magnetic particles are administered to target the target. This causes the network internal system to be overloaded.

Of course, both in therapeutic treatments and in diagnostic studies using magnetic particles. It is desirable that the magnetic particles be excreted after they have fulfilled their desired function.

Orally administered magnetic particles, organs with excretory conduits to the outside, I; e.g. the bladder. For particles administered into the bladder and uterus, excretion of magnetic particles is not a problem. Not possible. However, particles administered parenterally, especially intravenously, are excreted. To do so, you must first destroy them.

In vivo biological degradation of intravenously administered magnetic particles has been studied in detail. However, the results of various studies indicate that its decomposition gradually occurs over a few days. This occurs over several months, and the rate of decomposition depends on the nature of the particles, especially when they are released. It has been shown that it depends on whether the (see, eg, Bacon et al., supra, and Wo 88100060).

An object of the present invention is to facilitate biological degradation of magnetic particles that can be administered parenterally; or to provide a means for accelerating.

The present inventors have surprisingly found that magnetic particles administered parenterally, particularly intravenously, It has been discovered that the rate of degradation increases in the presence of chelating agents.

That is, according to one aspect of the present invention, treatment of a living body of a human or a non-human animal is possible. In a diagnostic examination method that generates images of a living body or a living body, multiple This is a method of parenterally administering magnetic particles, in which case a chelating agent or provides an improvement in administering the biological precursor;

The term chelating agent or biological precursor refers to the metal species (especially iron ions) in the magnetic particles. Drugs that can chelate or can chelate metal species in magnetic particles after parenteral administration means a drug that liberates a chelating agent that can be However, the following chelating agents The term chelating agents and prochelating agents (i.e., forming the basis of chelating agents) (residues of the chelating agent biological precursor) which are released at the appropriate time. used.

With particular reference to biological precursors, e.g. biologically degradable bonds. For example, ester bonds can bind other substances, such as biomolecules (e.g. antibodies and or biologically relatively inert macromolecules (e.g. polysaccharides) or Mention may be made of chelating agents bound to other matrices or carrier materials. .

The chelating agent is bound on or to or otherwise in the other material. When incorporated into the carrier material, this other material is referred to herein as a carrier material. Sunawa Typical carrier materials include, for example, coatings, matrices and macromolecules. The chelating agent/carrier material mixture may or may not be granular. You don't have to.

The chelate residue of the chelating agent used in the present invention is already present when administered to a living body. If you are chelating an ionic species, this ionic species will obviously have a particular preference. Preferably, the metal type of the magnetic particles, i.e., the chelate, which is thermodynamically more unstable than iron. It is an ionic species that forms, and its chelate formation constant is lower than that of iron ions (depending on biological temperature). , in the bloodstream). This is related to the fact that the chelating residue already has an ionic species. In the case of chelation, the ionic species is Ia, rb, I[a or nb metal metal ions such as Na, K;

Preferably, the ions are Ca, Mg or Zn ions. In general, such The ON species is highly magnetic, non-radioactive, and has a charge of +2 or less.

That is, the method of the present invention is based on the 5th Annual M eating of the 5ociety for Magnetic R e5o-1987, and also by Weissleder et al. Resonance Imaging 87005/01S, 0O135~ 136, paramagnetic MRI contrast agent Gd-DTPA and Ferrite Improvement of MRI contrast enhancement by co-administration of superparamagnetic MRI contrast agent consisting of It is recognized as a technology that pursues excellence.

In the method of the invention, the magnetic particles and the chelating agent or biological precursor are separately Although it is possible to administer both drugs, it is preferable to administer them together. administering them separately chelating agents can be administered parenterally or orally if they are absorbable. May also be administered enterally. In this case, examples of absorbable chelating agents include 1.2- Mention may be made of dimethyl-3-hydroxy-pyrid-4-one.

Additionally, the chelating agent may be administered before, during, or after administration of the magnetic particles. Can be done. That is, for example, if a magnetic particle performs its diagnostic or therapeutic function, ; After the injection, a key is added to ensure rapid degradation of the magnetic particles remaining in the body. Administration of rate agents or continuous administration for hours or days (e.g. up to 48 hours) It is desirable to give

However, it is also preferred to co-administer the magnetic particles and the chelating agent, and according to the invention In other embodiments, magnetic particles and crystals used, for example, in therapy or diagnosis. parenteral drugs containing the anti-inflammatory agent or its biological precursor in a physiologically tolerable dispersion. Orally administrable compositions are provided.

In a preferred embodiment, the composition of the invention comprises a chelating agent and a carrier material or magnetic material. particles, and particularly preferably mixtures consisting of magnetic particles, chelating agent and carrier material. It is a particulate matter.

The use of hybrid particles containing both magnetic particles and a chelating agent is advantageous in this method. Delivery of free chelating agents into the vicinity of magnetic particles is particularly easy during biological degradation of particles. This is particularly preferable.

When administering chelating agents and/or magnetic particles bound to or incorporated into carrier materials, Go! In this case, the carrier is an organ or tissue targeting biomolecule such as a hormone or an antibody. , biologically tolerated and generally relatively biologically inert substances such as polysaccharides (e.g. Kytran or starch), protein (e.g. albumin) or! Nitoe wo 85102772 or Nycorne by Chr5der et al. d described in EP-A-184899 and EP-A-186947 by AS It is particularly convenient to use other natural or synthetic macromolecules, such as be.

If magnetic particles are to be administered so that they enter specific cells, chelating agents can be used as targets. To facilitate entry into target cells, the chelating agent is bound by a biologically degradable bond. Therefore, it is desirable that the particles, lipophilic residues or I; be attached to biomolecules.

If the chelating agent is introduced into the carrier material, this can be done, for example, simply by biological analysis. can be entrapped or encapsulated within a resolvable matrix or coating material. Wear.

In this case, the chelating agent is released, preferably in sustained release, as the carrier material decomposes. be done. Alternatively, the chelating agent may be used substantially as described in EP-A-184899. , matrix particles are retained in the voids and upon particle decomposition or matrix Penetration of body fluids into the solution dissolves and releases the particles. Furthermore, another alternative method or , hybrid particles were prepared from particles of an insoluble derivative of the chelating agent and the inviv.

The chelating agent can also be released by decomposition at .

The chelating agent itself is any agent that can chelate the metal species (especially iron ions) in the magnetic particles. Any biologically resistant chelating agent may be used. In this regard, especially aminopolyacetic acid and many biological systems suggested in the literature for parenteral administration of paramagnetic MRI contrast agents. Mention may be made of well-tolerated chelating agents. For example, EP-A-184899 (Nycomed AS), EP-A-186947 (Nycomed AS), EP-71564 (Schering AG), EP-A-130 934 (Schering AG), GB-A-2137612 (Sch Schering AG), US-A-4647447 (Schering AG) , us-A-4639365 (Sherry), WO85105554 ( Amersham International PLC), WO8710289 3 (University of Texas), WO87101594 (A mersham International PLC), EP-A-136 812 (Technicare Corp) and EP-A-160552 (Vestar Research Inc.) and Nycomed AS. Reference is made to WO89100557. Particularly preferred chelating agents include Sferrin, N, N, N', N", N"-diethylenetriaminopentaacetic acid (DT PA), DTPA N, N”-bismethylamide (DTPA-BMA), ■- Oxer 4.7.10-triaza-cyclododecane-triacetic acid (OTTA), 1. 4.7.10-Tetraazacyclododecane-triacetic acid (DO3A), 1.4.7. 10-tetraazacyclododecane-tetraacetic acid (DOTA), desferrioxamine , ethylene-bis(2-hydroxyphenylglycine) (EHPG) 8 and its derivatives, such as physiologically tolerable counterions, in particular the metal ions mentioned above, or is a non-toxic amine [e.g., tri(hydroxymethylcinaminomethane, ethanol amine, jetanolamine and N-methylglucamine], or halogen or salts with non-toxic organic or inorganic acids.

As mentioned above, in general, paramagnetic MRI contrast agents that can be administered parenterally are The chelating agent used for chelating ions is the chelating agent in the method of the present invention. Can be used as However, of particular interest are Amersham by wo 85105554 and further details by NycomedAS Macromolecular linker residue disclosed in patent application No. 89200168.6 It is a chelating agent compound.

A biologically degradable linkage of the chelating agent to a water-soluble carrier material such as dextran If the chelating agent is conjugated with The carrier material/chelating agent composition preferably has a total molecular weight above the renal threshold, i.e. preferably at least 20,000, particularly preferably from 40,000 to 2,000,0 00, particularly preferably about 50,000 to 150,000. In addition, The rate agent may be in particulate form, such as matrix/clean-1 agent composition particles. When administered, the average particle size is preferably between 0.001 and 10 μm. Particularly preferably 0. It is preferable to set it to 0.05 to 2.0 μm, especially 0.05 to 2.0 μm. Yes.

The magnetic particles used in the present invention are preferably non-radioactive (although the particles may ferromagnetism or superparamagnetism (unless intended to be detected by radioactive decay release) It may be any substance shown. Magnetic particles are magnetic metals! ; is an alloy, I; e.g. It is convenient to use pure iron particles, but magnetite or or ferrite such as gamma ferrite and cobalt, nickel or manganese It is a magnetic compound like gunferrite.

Magnetic particles may be neat, coated, agglomerated, or It may be held or embedded in a matrix. However, the carrier material The total particle diameter is preferably less than 10 μm, preferably 5 nm to 5 μm. Preferably, the magnetic particles themselves have a diameter of 1.5 μm or less, preferably 0.1 μm or less. ; is less than that, particularly preferably in the superparamagnetic dimension rather than the ferromagnetic dimension. (i.e. subdomain size), e.g. 5-50 nm. is preferable.

Particles of superparamagnetic or ferromagnetic material may be coated or coated with a non-magnetic matrix. substances such as polysaccharides or albumins such as dextran or starch It may also be carried in or on particles of proteins such as ferromagnetic or If it is desired to target superparamagnetic materials to specific tissues, Wo 8810 0060; for example, binding to tissue- or organ-specific biomolecules as described; It is desirable to use a superparamagnetic material for the combination t; ferromagnetism or t;

Superparamagnetic or I; is the application of a non-magnetic coating or matrix to a ferromagnetic material. If so, the coating or matrix material may be a polysaccharide material, e.g. pun or dextran (as shown in WO83101738 by 5chr5der) or as suggested in WO 83/03920 by Ugelstad et al. Particularly preferred are biocompatible polymers as suggested.

When applying coatings or matrices to ferromagnetic or superparamagnetic materials The iron content of the total particles is preferably 0.1 to 80% by weight, particularly 1 to 70% by weight. stomach.

However, in general, magnetic particles such as those suggested in the literature, such as Sc to hering AG and Mo1day (US-A-4452773) Therefore, magnetite dextran as suggested, also 5chrader et al., Nycomed AS and Advanced Magnetics In Using carrier-bound or free magnetic particles as suggested by c. I can do it.

Magnetic particles as a particle composition containing a carrier material, a chelating agent and magnetic particles When administered, the particle composition can be prepared, for example, using the method of 5chrQder et al. , produced by precipitating magnetic particles and a chelating agent into a carrier material matrix. Can be built. Alternatively, such particle compositions may include magnetic particle-containing particle compositions containing: It can also be produced by binding a chelating agent using a coupling agent.

Compositions of the invention include a chelating agent, a carrier material, magnetic particles and a dispersion medium (e.g. In addition to water for injection or physiological saline, other ingredients may be included. virtue In addition, this composition contains viscosity modifiers, pH modifiers, osmotic pressure modifiers, stabilizers, and antioxidants. agents, buffering agents, and emulsifying or dispersing agents, as well as other conventional pharmaceutical or veterinary agents. Pharmaceutical auxiliaries can be added. However, the carrier medium is homodominant or Preferably it is slightly hypertonic.

Even when the chelating agent is administered separately from the magnetic particles, the chelating agent can be Oral or enteral dosage forms, e.g. physiologically tolerable vehicles e.g. for injection Parenteral dosage forms such as solutions, suspensions or dispersions in water etc. and tablets, coats As oral dosage forms such as tablets, capsules, solutions, suspensions, dispersions, syrups etc. Preferably, it is administered. When a chelating agent is formulated for enteral administration, the composition includes Of course, diluents, flavorings or colorants, and other additives such as those mentioned above may also be added. Customary pharmaceutical or veterinary auxiliaries can be added. Enteral dosage forms are also If desired, they can be formulated into sustained or delayed release dosage forms using conventional techniques. .

Preferred dosages of chelating agents and magnetic particles used in the present invention vary widely. The choice of dosage depends on the route of administration, the nature of the subject being administered, and the substance being administered. biodistribution, pharmacokinetic and chemical properties, purpose of administration (i.e. therapeutic , diagnostics, etc.) as well as the characteristics of externally applied magnetic fields, e.g. in imaging procedures. depending on factors such as the intensity and pulse sequence used.

Generally, for MRI, the dose of magnetic particles is the same as the conventional dose, but The dose of ferromagnetic or preferably superparamagnetic material is between 0.0001 and 5 mm. Mol/kg body weight, preferably 0.001 to 1 mM Fe/kg body weight. It is convenient to combine the chelating group of the chelating agent in the magnetic particles with the magnetic metal species (e.g. Fe). The molar ratio between should preferably be at least 3. Increase this ratio The half-life of magnetic particles can be reduced by The dose of the rate agent should not exceed the toxic dose level, and preferably should not exceed the toxic dose level. You should not approach it.

According to another aspect of the present invention, the chelating agent or its biological A method for administering precursors and parenterally administering magnetic particles for treatment of living organisms; magnetic particles and/or chelating agents in the manufacture of drugs used in diagnostic methods or the use of biological precursors thereof.

The invention is further illustrated in detail by the following examples, which do not limit the invention. It's not something you can do. In the examples, ratios, percentages and parts are by weight unless otherwise indicated. It is based on

Example l Suspension containing DTPA covalently bound to magnetic particles and crosslinked starch particles Uncoated magnetic particles (manufactured according to the description on page 43 of WO 88100060) superparamagnetic particles) 1001119 and DTPA-containing starch gel beads (1,5 μm ) (manufactured according to the first part of Example 9 of EP-A-184899) 1 ．． Fill 20++2 vials with 09. Particles were soaked in 0.9% NaCl before use. Add to 10 tnQ of a sterile aqueous solution containing 2 and suspend by shaking vigorously for 2 minutes. suspension per 1 mQ, 10 mg of magnetic particles and 100+ DTPA-starch gel beads Contains ++9.

Preferably, this suspension is administered intravenously.

Dextran magnetite (Meito Sangyo, superparamagnetic made in Japan) Granulated paramagnetic particles 0m were mixed with 0.9% NaCl2 and 0.1% Pluronic ■ Suspend in 10 mQ of an aqueous solution of F-18 by sonication.

The suspension is filled into a 10 mQ vial and sterilized by heat.

This suspension contains IOi of dextran magnetite in 1 m+2.

Contains.

(b) 3 vials containing desferrioxamine desferrioxamine methane Dissolve 3.0 g of the sulfonate salt in 30III2 of water. This solution was sterile filtered and Fill three 20raQ vials (lomo each) and freeze-dry the contents of the vials. dry Each vial contains 1000mg of desferrioxamine methanesulfonate. Contains as a white powder.

Before use, dissolve the contents of each vial in 5 mff of sterile water.

Both suspensions of superparamagnetic particles and solutions of desferrioxamine methanesulfonate are Intended for oral administration.

Suspensions are preferably administered intravenously, whereas solutions of desferrioxamine are administered intravenously. It may be administered intravenously or intramuscularly. If the solution is administered intravenously, Subjects weighing 1 kg or more; ribs ferrioxamine methanesulfone [less than 151 Ag It must be administered gradually at a dosage of .

Example 3 Two components: one vial containing magnetic particles and one vial containing a suspension of chelating agent. Kit consisting of vials (a) Vial containing magnetic particles Sterile superparamagnetic particles coated with human serum albumin (0-211-m) (Manufactured according to the description on page 43 of WO88/00060) 150mg at 20rn Fill Q vial.

Before use, the particles are added to a sterile aqueous solution of 0.9% NaCQ lOmQ and vigorously shaken for 2 minutes. Shake to suspend.

This suspension contains 15 mg of superparamagnetic particles per 1 m2.

(b) Suspension of chelating agent Zn (,n)-1,5-bis((1,2-dihydro-1-hydroxy-2- Oxo-pyridin-6-yl)carbonyl]-1,5-diazahene 97 (Z) (ff)-LIHOPO) White et al.: J, Med-Chem, 31:11 (1988) under aseptic conditions.

Zn(n)-LrHOPO (particle size less than 2um) 4.0g with 0.9% Na Suspend in 20 mQ of sterile aqueous solution of Cl2. Pour this suspension into a 10 mQ vial. Fill with fungi.

Both suspensions are intended for parenteral administration. Suspension of superparamagnetic particles is intravenous Preferably, it is administered intravenously. Chelating agent suspensions may be administered intravenously or intramuscularly. (a) Suspension of magnetic particles Heat-denatured human serum albumin microspheres containing magnetite (Us- Manufactured according to A-4675173) 200 mg with 0.9% NaCQ and 0 ．． Added to 10 mff of 2% polysorbate 80 aqueous solution and sonicated for 1 minute. suspend

This suspension contains 20+119 particles per l+11I2.

(b) Capsule of chelating agent 1,2-Dimethyl-3-hydroxy-pyrid-4-one is available from Kontohior Ghes et al.: Arzneimiiiel forschung 37 (11 ), 1099 (1987).

The powder mixture is Prepared from corn starch + appropriate amount.

“Use enough to fill the capsule.

Mix the powder and fill it into hard gelatin capsules (Capsugel [F] No. 0). Ru.

Preferably, the suspension is administered intravenously. Capsules are preferably administered orally .

Example 5 Suspension of magnetic particles and ethylene diamine (ortho-hydroxyphenylacetic acid) ) Kit consisting of a solution of (EHPG) (a) Suspension of magnetic particles DE human serum albumin-magnetite-protein A conjugate in the form of microparticles Manufactured according to -A-3508000.

10+++ g of the particles are filled into a lomff vial.

Before use, particles were sterilized with 0.9% NaCQ and 0.1% polysorbate 80. Suspend in 1 g of aqueous solution IOII.

(b) Solution of ethylene diamine-di(ortho-hydroxyphenylacetic acid) The solution is sterile filtered, filled into loomff vials and lyophilized. before use When the white powder is dissolved in 100m+2 of sterile water, 50+y　E)(PG/i12 A containing solution is produced.

+2 equivalents of acid per 1 equivalent of EHPG 8. Use sufficient amount to achieve isotonicity. Corrected sound translation submission form (Article 184-8 of the Patent Law) December 3, 1990

Claims (1)

[Claims] 1) Parenterally administering multiple magnetic particles to a living body of a human or non-human animal. In the method of generating an image of the living body, the living body is treated with a chelating agent or Improved methods of administering physical precursors. 2) Providing a drug or its biological precursor that can chelate the metal species of magnetic particles to a living body. 2. The method of claim 1, wherein the method of claim 1 is administered. 3) The chelating agent binds to biological molecules or molecules through biologically degradable bonds. Biology bound to a biologically inert macromolecular matrix or carrier material 3. The method according to any one of claims 1 and 2, wherein a chemical precursor is administered. 4) Chelating agents or their biological precursors are sodium, potassium, calcium , magnesium and zinc. 3. The method according to any one of 3 to 3. 5) The magnetic particles are ferromagnetic or superparamagnetic particles, according to any one of claims 1 to 4. the method of. 6) The chelating agent or biological precursor is co-administered with the magnetic particles according to claims 1-5. Any method described. 7) The method according to any one of claims 1 to 6, wherein the magnetic particles are superparamagnetic particles. 8) Consisting of magnetic particles, a chelating agent or its biological precursor, and a carrier material A diagnostic composition that is a particulate composition. 9) The chelating agent and/or magnetic particles are bound to or attached to a carrier material. 9. A composition according to claim 8, wherein the composition is contained within a substance. 10) Claim 8 and above, wherein the chelating agent comprises an aminopolycarboxylic acid or a derivative thereof. and 9. The composition according to any one of 9. 11) Chelating agents connect macromolecules via any biologically degradable linker residue. The composition according to any one of claims 8 to 10, which is a chelating agent residue attached to . 12) The chelating agent according to any one of claims 8 to 11 has a molecular weight equal to or higher than the renal threshold. composition. 13) A claim consisting of a particle composition having an average particle size of 0.001 to 10 μm. The composition according to any one of 8 to 11. 14) Magnetic particles may be provided with a non-magnetic matrix or coating A composition according to any one of claims 8 to 13, comprising superparamagnetic particles. 15) Placing multiple magnetic particles and a chelating agent or treatment or diagnosis of the living organism, which is a method of parenterally administering the biological precursor; Use of magnetic particles in the manufacture of medicaments for use in the method. 16) Parenterally administering multiple magnetic particles to a living human or non-human animal. chelating agents or Improved methods of administering the biological precursors.