WO1989003675A1 - Superparamagnetic particles, a way of producing said particles and their use - Google Patents

Superparamagnetic particles, a way of producing said particles and their use Download PDF

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Publication number
WO1989003675A1
WO1989003675A1 PCT/SE1988/000561 SE8800561W WO8903675A1 WO 1989003675 A1 WO1989003675 A1 WO 1989003675A1 SE 8800561 W SE8800561 W SE 8800561W WO 8903675 A1 WO8903675 A1 WO 8903675A1
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particles
superparamagnetic particles
superparamagnetic
particles according
solution
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PCT/SE1988/000561
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French (fr)
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Ulf SCHRÖDER
Gunilla Nyberg
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Carbomatrix Ab
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
    • B01J20/28014—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their form
    • B01J20/28016—Particle form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
    • A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
    • A61K49/1821—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
    • A61K49/1824—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles
    • A61K49/1827—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle
    • A61K49/1851—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with an organic macromolecular compound, i.e. oligomeric, polymeric, dendrimeric organic molecule
    • A61K49/1863—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with an organic macromolecular compound, i.e. oligomeric, polymeric, dendrimeric organic molecule the organic macromolecular compound being a polysaccharide or derivative thereof, e.g. chitosan, chitin, cellulose, pectin, starch
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5094—Microcapsules containing magnetic carrier material, e.g. ferrite for drug targeting
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
    • B01J20/28002—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their physical properties
    • B01J20/28004—Sorbent size or size distribution, e.g. particle size
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
    • B01J20/28002—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their physical properties
    • B01J20/28009—Magnetic properties
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2400/00—Assays, e.g. immunoassays or enzyme assays, involving carbohydrates
    • G01N2400/10—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • G01N2400/12—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar
    • G01N2400/14—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar alpha-D-Glucans, i.e. having alpha 1,n (n=3,4,6) linkages between saccharide units, e.g. pullulan
    • G01N2400/16—Starch, amylose, amylopectin
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2446/00—Magnetic particle immunoreagent carriers
    • G01N2446/20—Magnetic particle immunoreagent carriers the magnetic material being present in the particle core
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2446/00—Magnetic particle immunoreagent carriers
    • G01N2446/30—Magnetic particle immunoreagent carriers the magnetic material being dispersed in the polymer composition before their conversion into particulate form

Definitions

  • This invention relates to magnetically responsive superparam agnetic particles, away of producing said particles and their use.
  • the invention describes a method for the production of superparamagnetic particles which are made of a metal oxide surrounded by a surface layer of a biologically acceptable polymer.
  • the particles may be used as a contrast agent in medical diagnostics in particular in Magnetic Resonance Imaging (MRI). They may also be used as a matrix for biological molecules, thus functioning as a separation device.
  • Another area for their use is by combining said particles with a drug which after injection into the blood stream is stopped in an predetermined area using an external magnet,
  • the invention is based on magnetically responsive particles which are superparamagnetie, indicating that they are not permanently magnetized when subjected to a magnetic field. This means that the particles, after withdrawing of the magnetic field, are easily resuspended, Using magnetically responsive particles within the areas mentioned above, it is of utmost importance that the particles are superparamagnetic m order to avoid permanent aggregation,
  • Magnetic particles has for long times been discussed as a extremely effective separation device (Hirschbein et al. Chemtech . March 1982 , 172- 179).
  • prior art regarding magnetic particles lack one or several of the demands needed in order for the technology to obtain general acceptance,
  • Avrameas & G ⁇ esdon (USTatent 4,241,176, Dec , 28, 19801 describes magnetic polymer particles where magnetite has been entrapped in a polyacrylamide-agarose polymer in an emulsion process, The sue of the spheres is 50-500 ⁇ m, Widder et al (US Patent 4,230,686. Oct. 28, 1980) describes away of producing magnetic particles where the magnetite is entrapped into albumin/protein-A with subsequent covalent stabilization of the polymer mixture.
  • Ugelstad et al (PCT/HO83/00014) describes away of producing particles where the magnetic material is precipitated within prefabricated polymer particles of a defined size.
  • Molday (US Patent 4,462,773. Jun.6, 1984) described sway of producing magnetite particles with a size of 10-70 nm, which are surface coated with a dextran polymer. Dextran has a high molecular weight and is not degraded in the body, thus particles produced in this way are less suitable for medical applications. After production these particles are further processed by centrifugation at 2S.000 rpm, alternatively the particles are allowed to pass a gel chromatography column in connection with the couphng of affinity ligands. Both of these methods may be used in laboratory scale production, however, the technologies are not suitable in the production of particles to be used in large scale separation of fermentation suspensions or the production of superparamagnetic particles for the use as a contrast agent, as discussed in this invention.
  • the particles may not be separated with conventional magnets. This is also seen in the examples presented, where only examples referring to the separation of cells or cell organells are described.
  • a large, number of magnetic particles are associated to the surface of one cell, whereby the total amount of magnetic material attached to a cell makes it responsive to the magnetic field obtained by conventional cobalt-samarium magnets.
  • Schroder & Borrebaeck (EPC 83901116.0) describes the entrappment of magnetite particles within a carbohydrate matrix by an emulsion process with subsequent stabilization try crystallization of the carbohydrate polymer.
  • Chagnon et al (EP 0 126 995) describes a process for the production of magnetic particles in a two step procedure: in the first step the magnetic particles are produced, and in step two, these particles are, after extensive washing, subjected to a surface coating with one or several silicone polymers. Two steps in the process of Chagnon thus differs significantly from the present invention:
  • an contrast agent for the liver and the spleen there is primarily a wish to obtain an contrast agent for the liver and the spleen. This can be accomplished using injection of particles into the blood stream having a size of 0.4-1.0 ⁇ m, since particles having this size are eliminated from the blood stream by these organs.
  • the size should, however , not be below 0.3 ⁇ m , since the magnetically responsive particle thus contains too small amounts of magnetic material to be attracted be a magnetic field. Furthermore, particles having a size below 0.3 ⁇ m possess particle/liquid interactions resulting in a suspension behaving more like a magnetic fluid and not as a suspension where the particles easily can be retrieved.
  • the superparamagnetic particles will aggregate, however, due to the superparamagnetic property, the particles will be resuspended as soon as the magnetic field is switched off, thereby allowing for the affinity attached protein to be recovered.
  • the structure of the particle renders a system where the affinity ligand is associated only to the surface of the particle.
  • the final product is economically advantageous as compared to macroporous particles since the amount of affinity ligand (e.g. a monoclonal antibody) used can be reduced.
  • the surface association of the monoclonal antibody renders rapid adsorption of the substance of interest due to the lack of the diffusion barriers.
  • the present invention relates to superparamagnetic particles, made of a core of magnetite, surrounded by a pharmacologically acceptable carbohydrate polymer, the superparamagnetic particle having a size of 0.1- 2.0 ⁇ m produced by precipitation of iron salts dissolved in a starch solution,
  • the process for fabrication of the superparamagnetic particles according to the present invention is based on optimization of parameters resulting in particles which all fulfills the demands mentioned above.
  • the process renders a high yield where further secondary purification steps in order to obtain optimal superparamagnetie particles having the adequate size and magnetic properties are not needed.
  • the process is based on the well known technology of precipitating iron salts in alkali, whereby the metal oxide is formed, However , this precipitation is performed in a way that both the starch and the iron salts simultaneously are added to the alkali solution (e.g, MaOH) while sonicating, The obtained solution is neutralized to pH 7.
  • the suspension containing a monodispers suspension of superparamagnetic particles in a solution of carbohydrates in an alkali or neutral environment, directly or after a concentration step, can be emulsified in an organic solvent, a crosslinker may added to the emulsion or the water solution of superparamagnetic particles, whereafter these ere stabilized into a water-insoluble three dimensional crosslinked superparamagnetic microsphere.
  • the size of the obtained monodisperse suspension of superparamagnetic particles is measured in an Coulter Counter Multisizer with the following result:
  • Average size 0.775 ⁇ m.
  • Dry weight 25 mg/ml, where 85% is magnetite.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nanotechnology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Immunology (AREA)
  • Molecular Biology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Radiology & Medical Imaging (AREA)
  • Solid-Sorbent Or Filter-Aiding Compositions (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

The present invention relates to superparamagnetic particles, a way of producing said particles and their use. More specifically, the invention describes a process for fabrication of said particles, said process yielding particles with a high recovery in a simple one step procedure.

Description

SUPERPARAMAGNETIC PARTICLES, A WAY OF PRODUCING SAID PARTICLES AND THEIR USE.
This invention relates to magnetically responsive superparam agnetic particles, away of producing said particles and their use.
More specifically the invention describes a method for the production of superparamagnetic particles which are made of a metal oxide surrounded by a surface layer of a biologically acceptable polymer. In this form the particles may be used as a contrast agent in medical diagnostics in particular in Magnetic Resonance Imaging (MRI). They may also be used as a matrix for biological molecules, thus functioning as a separation device. Another area for their use is by combining said particles with a drug which after injection into the blood stream is stopped in an predetermined area using an external magnet,
The invention is based on magnetically responsive particles which are superparamagnetie, indicating that they are not permanently magnetized when subjected to a magnetic field. This means that the particles, after withdrawing of the magnetic field, are easily resuspended, Using magnetically responsive particles within the areas mentioned above, it is of utmost importance that the particles are superparamagnetic m order to avoid permanent aggregation,
Magnetic particles has for long times been discussed as a extremely effective separation device (Hirschbein et al. Chemtech . March 1982 , 172- 179). However, prior art regarding magnetic particles lack one or several of the demands needed in order for the technology to obtain general acceptance,
The above mentioned superparamagnetic property is thereby one of the most important.
Ithakissios (US Patent 4,115,634. Sep. 19, 1978) describes magnetic polymer particles in the size range 10-100 μm where the polymer material is covalently crosslinked,
Avrameas & Gυesdon (USTatent 4,241,176, Dec , 28, 19801 describes magnetic polymer particles where magnetite has been entrapped in a polyacrylamide-agarose polymer in an emulsion process, The sue of the spheres is 50-500 μm, Widder et al (US Patent 4,230,686. Oct. 28, 1980) describes away of producing magnetic particles where the magnetite is entrapped into albumin/protein-A with subsequent covalent stabilization of the polymer mixture.
Ugelstad et al (PCT/HO83/00014) describes away of producing particles where the magnetic material is precipitated within prefabricated polymer particles of a defined size.
Czerlinski (US Patent 4,454,234. June 12, 1984) describes magnetite particles which has been surface coated with a crosslinked polymer of acrylamide,
Molday (US Patent 4,462,773. Jun.6, 1984) described sway of producing magnetite particles with a size of 10-70 nm, which are surface coated with a dextran polymer. Dextran has a high molecular weight and is not degraded in the body, thus particles produced in this way are less suitable for medical applications. After production these particles are further processed by centrifugation at 2S.000 rpm, alternatively the particles are allowed to pass a gel chromatography column in connection with the couphng of affinity ligands. Both of these methods may be used in laboratory scale production, however, the technologies are not suitable in the production of particles to be used in large scale separation of fermentation suspensions or the production of superparamagnetic particles for the use as a contrast agent, as discussed in this invention.
As is discussed in the Molday patent above, the particles may not be separated with conventional magnets. This is also seen in the examples presented, where only examples referring to the separation of cells or cell organells are described. In the separation of cells or cell organells, a large, number of magnetic particles are associated to the surface of one cell, whereby the total amount of magnetic material attached to a cell makes it responsive to the magnetic field obtained by conventional cobalt-samarium magnets.
Schroder & Borrebaeck (EPC 83901116.0) describes the entrappment of magnetite particles within a carbohydrate matrix by an emulsion process with subsequent stabilization try crystallization of the carbohydrate polymer.
Chagnon et al (EP 0 126 995) describes a process for the production of magnetic particles in a two step procedure: in the first step the magnetic particles are produced, and in step two, these particles are, after extensive washing, subjected to a surface coating with one or several silicone polymers. Two steps in the process of Chagnon thus differs significantly from the present invention:
1, On Page 20 is described the ratio between FeCl2 and FeCl3 to be used in order to obtain an optimal recovery. In the text and in the examples, the best particles are achieved using a ratio Fe2+/Fe3+ of 2/1 or 4/1. If Chagnon is using a ratio of Fe2+/Fe3+ of 1/2 or 1/4, heterogeneous particles which "bleeds", finally being totally dissolved in the washing steps (page 20, line 15-25) is obtained. This is in contrast to our own results where optimal particles are obtained with ratios of Fe2+/Fe3+ contradictory to Chagnon,
2, On page 20 is described how the recently prepared particles are washed in an NaCl solution in order to ensure that the final product is resuspendable to particles in the size of interest. However, this is not necessary according to the present invention.
3, On page 35 is described hew Chagnon prior to the surface coating of silicone has to suspend the particles by powerful homogenization in order to obtain a final product consisting of particles which upon suspension forms a monodisperse suspension,
This is also an experience from the inventors of the present invention: if you don't perform the precipitation of metal salts to metal oxide in the presence of a protective colloids, such as starch, the ferromagnetic particles obtained have a size of 5-50 μm, making them unusable for the purposes as described in this invention.
Using superparamagnetic particles in the areas, as described in this invention, the size of the particles and the choice of polymer is of great importance.
Within medical diagnostics there is primarily a wish to obtain an contrast agent for the liver and the spleen. This can be accomplished using injection of particles into the blood stream having a size of 0.4-1.0 μm, since particles having this size are eliminated from the blood stream by these organs.
Using superparamagnetic particles within biotechnology separation it is also a wish to have particles in the same size range due to the large area per volume obtained. As an example, reducing the size of a particle from 10 to 0.5 μm, the area accessible for attachment of affinity ligands is enhanced 20 times, as calculated on a defined volume packed spherical particles.
The size should, however , not be below 0.3 μm , since the magnetically responsive particle thus contains too small amounts of magnetic material to be attracted be a magnetic field. Furthermore, particles having a size below 0.3 μm possess particle/liquid interactions resulting in a suspension behaving more like a magnetic fluid and not as a suspension where the particles easily can be retrieved.
Despite what is known about magnetic separation, as described in the above mentioned patents/patentapplications, the magnetic separation technology has not yet been used in large scale separation, such as in fermentation, since the particles has to be to produced in a simple way in large quantities with the subsequent attachment of affinity ligands. In large scale separation, separation of e.g. human proteins produced by genetically engineered bacteria in fermentation volumes of several thousands of liters is discussed.
In the separation process, under the influence of the magnetic field, the superparamagnetic particles will aggregate, however, due to the superparamagnetic property, the particles will be resuspended as soon as the magnetic field is switched off, thereby allowing for the affinity attached protein to be recovered.
Another item using the present invention is that the structure of the particle (a core of metal oxide surface coated with a polymer) renders a system where the affinity ligand is associated only to the surface of the particle. Thus, the final product is economically advantageous as compared to macroporous particles since the amount of affinity ligand (e.g. a monoclonal antibody) used can be reduced. Furthermore, the surface association of the monoclonal antibody renders rapid adsorption of the substance of interest due to the lack of the diffusion barriers.
Thus, magnetic separation using the particles according to the present invention will give the following advantages:
- the number of separation steps can be reduced
- higher yield
- faster processing
This combination thus leads to reduced costs for the separation using the particles according to the present invention.
By the use of the process for the fabrication of superparamagnetic particles according to the present invention, it is now possible to achieve this. Thus, the present invention relates to superparamagnetic particles, made of a core of magnetite, surrounded by a pharmacologically acceptable carbohydrate polymer, the superparamagnetic particle having a size of 0.1- 2.0 μm produced by precipitation of iron salts dissolved in a starch solution,
The process for fabrication of the superparamagnetic particles according to the present invention is based on optimization of parameters resulting in particles which all fulfills the demands mentioned above. Thus, the process renders a high yield where further secondary purification steps in order to obtain optimal superparamagnetie particles having the adequate size and magnetic properties are not needed.
Thus, the process according the this invention, results in particles in a. high yield in a simple one step procedure.
The process is based on the well known technology of precipitating iron salts in alkali, whereby the metal oxide is formed, However , this precipitation is performed in a way that both the starch and the iron salts simultaneously are added to the alkali solution (e.g, MaOH) while sonicating, The obtained solution is neutralized to pH 7. The suspension obtained, containing a monodisperse suspension of superparamagnetic particles, having a size of 0.2-2.0 μm, is thereby ready for use.
For the person skilled in the art it is now easy the use the suspension for various purposes, As an example, the suspension, containing a monodispers suspension of superparamagnetic particles in a solution of carbohydrates in an alkali or neutral environment, directly or after a concentration step, can be emulsified in an organic solvent, a crosslinker may added to the emulsion or the water solution of superparamagnetic particles, whereafter these ere stabilized into a water-insoluble three dimensional crosslinked superparamagnetic microsphere.
EXAMPLE 1.
2.7 g FeCl3 × 7 H2O, 4.5 g FeCl2 × 4 H2O and 3.0 g of starch is dissolved in 10 ml of water by gentle heating, This solution is added dropwise to 100 ml of 1,0 M NaOH while sonicating. After adding all of the iron-chloride/starch solution the suspension is sonicated for another 5 minutes whereafter the suspension is neutralized with HCl to pH 7.0,
The size of the obtained monodisperse suspension of superparamagnetic particles is measured in an Coulter Counter Multisizer with the following result:
Average size: 0.775 μm.
99% of the particles is found in the size range 0.35 - 1.22 μm.
Dry weight: 25 mg/ml, where 85% is magnetite.
Number of particles /ml: 7 × 108

Claims

CLAIMS,
1, Superparamagnetic particles, constituting of a core of magnetically responsive material, surrounded by a coating of a biologically acceptable carbohydrate polymer, the particles having a size in the range of 0.1 - 2,0 μm.
2, Superparamagnetic particles according to claim 1, characterized by, that the magnetically responsive material consists of a metal oxide of iron, nickel or cobalt.
3, Superparamagnetic particles according to claim 1, characterized by, that the biologically acceptable, carbohydrate polymer is chosen from the group of starch, pullullan or glycogen,
4, A way of producing superparamagnetic particles according to claim 1-3, characterized by, that the particle is produced by precipitation of a solution of a metal salt, dissolved in a water solution of the biologically acceptable carbohydrate polymer, into an alkali solution while having a high energy input into the alkali solution,
5, Away of producing superparamagnetic particles according to claim 1-4, characterized by, that the energy input is performed by sonication of the alkali solution.
6, A way of producing superparamagnetic particles according to claim 1-5, characterized by, that the alkali solution consists of a solution of sodium hydroxide.
7, Superparamagnetic particles according to claim 1-6, characterized by, that the particles upon use is suspended in physiologically acceptable solution,
8, The use of the superparamagnetic particles according to claim 1-7 within medical diagnostics.
9. The use of the superparamagnetic particles according to claim 1-8 within affinity separation.
PCT/SE1988/000561 1987-10-26 1988-10-24 Superparamagnetic particles, a way of producing said particles and their use WO1989003675A1 (en)

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SE8704157A SE8704157L (en) 1987-10-26 1987-10-26 SUPERPARAMAGNETIC PARTICLES AND PROCEDURES FOR PREPARING THEREOF AND APPLICATION
SE8704157-0 1987-10-26

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WO1991001148A1 (en) 1989-07-21 1991-02-07 Nycomed As Contrast medium composition
EP0517740A1 (en) * 1990-02-06 1992-12-16 Advanced Magnetics Inc Low molecular weight carbohydrates as additives to stabilize metal oxide compositions.
EP0525199A1 (en) * 1991-01-19 1993-02-03 Meito Sangyo Kabushiki Kaisha Composition containing ultrafine particles of magnetic metal oxide
WO1993005815A1 (en) * 1991-09-16 1993-04-01 Syngenix Limited Synthetic transfection vectors
WO1995031220A1 (en) * 1994-05-12 1995-11-23 Otsuka Pharmaceutical Co., Ltd. Contrast medium for magnetic resonance imaging
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US6123920A (en) * 1996-01-10 2000-09-26 Nycomed Imaging As Superparamagnetic contrast media coated with starch and polyalkylene oxides
US6423296B1 (en) 1996-01-10 2002-07-23 Amersham Health As Constrast media
US6849400B1 (en) 1997-07-23 2005-02-01 Gen-Probe Incorporated Methods for detecting and measuring spliced nucleic acids
AU2001294068B2 (en) * 2000-10-16 2005-12-22 Consejo Superior De Investigaciones Cientificas Nanoparticles
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EP1683572A1 (en) * 2003-10-14 2006-07-26 Mikhail Vladimirovich Kutushov Magnetically operated absorbent and method for the production thereof
EP2277181A4 (en) * 2008-04-16 2016-03-09 Stemcell Technologies Inc Magnetic particles

Citations (1)

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WO1988000060A1 (en) * 1986-07-03 1988-01-14 Advanced Magnetics, Inc. Biodegradable superparamagnetic materials used in clinical applications

Patent Citations (1)

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