WO2006051732A1 - 被覆磁性粒子含有製剤およびその製造方法、並びに診断治療システム - Google Patents
被覆磁性粒子含有製剤およびその製造方法、並びに診断治療システム Download PDFInfo
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- WO2006051732A1 WO2006051732A1 PCT/JP2005/020263 JP2005020263W WO2006051732A1 WO 2006051732 A1 WO2006051732 A1 WO 2006051732A1 JP 2005020263 W JP2005020263 W JP 2005020263W WO 2006051732 A1 WO2006051732 A1 WO 2006051732A1
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- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
- A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/26—Iron; Compounds thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- Coated magnetic particle-containing preparation method for producing the same, and diagnostic treatment system
- the present invention relates to a preparation containing coated magnetic particles obtained by coating magnetic fine particles bound with an organic compound with a lipid film, a method for producing the same, and a diagnostic treatment system.
- Magnetic nanobeads are being developed as one of the promising medical materials used in next-generation medical technology.
- Magnetic nanobeads also referred to herein as “magnetic fine particles” are nano-sized fine particles of ferrite (a solid solution of Fe 2 O and ⁇ —Fe 2 O).
- Patent Document D o Such coated magnetic particles coated with dextran, lipids, ribosomes, polymers, etc.
- Medical magnetic nanobeads in which drugs, physiologically active substances, etc. are immobilized (bonded or included) have been proposed (Patent Documents 1 and 2), which are magnetic particles and have been applied in the medical field.
- thermotherapy using fever based on the hysteresis loss of magnetic particles in a high-frequency magnetic field, and combining cancer diagnosis and treatment at the same time It is also considered to be used (Non-Patent Document 1).
- Hyperthermia of cancer is one of the cancer therapies that have been proposed and studied for decades.
- the principle of treatment is based on artificially treating the cancer cells in a high-temperature environment by utilizing the property that cancer cells are more susceptible to heat than normal cells.
- Cancer hyperthermia is a noninvasive treatment compared to surgical excision, which is generally used for cancer treatment, and is selective compared to chemotherapy or radiation therapy, where side effects are likely to be problematic. But with fewer side effects. In this way, organ preservation is possible, and this is a treatment method that improves the quality of life of patients. Therefore, it is suitable for the treatment of early cancer, or cancer treatment of the elderly and infants who cannot tolerate surgical invasion and side effects.
- Non-Patent Document 1 Non-Patent Document 1
- Patent Document 1 Japanese Patent Laid-Open No. 2002-128523
- Patent Document 2 Japanese Patent Laid-Open No. 09-110722
- Non-Patent Document 1 ": BIO INDUSTRY" 21 ⁇ , No. 8, pp. 48-54, 2004
- the present invention can enable selective delivery (targeting ability) to a tumor site, and is applied to a contrast medium and a drug transporter, as well as thermotherapy using fever, and further
- An object of the present invention is to provide a coated magnetic particle-containing agent that can be used for cancer diagnosis and treatment in combination with the above, a method for producing the same, and a diagnostic treatment system. Means for solving the problem
- the coated magnetic particle-containing preparation according to the present invention has a hydroxyl group, carboxyl group, carbamoyl group, amino group, mercapto group, sulfo group, dithio group, thiocarboxy group, and dithiocarboxy group strength in the molecule.
- a preparation containing coated magnetic particles in which a magnetic fine particle to which an organic compound having at least two linking groups is bonded is coated with a lipid film.
- the coated magnetic particles have the following formula:
- R represents the average particle diameter of the coated magnetic particles, and r represents the average particle diameter of the magnetic fine particles contained in the coated magnetic particles).
- the coated magnetic particles have the following formula: 0. 05 ⁇ R / (rX 100) ⁇ l. 0
- R represents the average particle diameter of the coated magnetic particles, and r represents the average particle diameter of the magnetic fine particles.
- the magnetic fine particles have a hydroxyl group, a carboxyl group, a force rubamoyl group, an amino group in the molecule.
- C / 30 ° C is preferred to be generated under the condition! /.
- the average particle size of the magnetic fine particles is Inn! It is also preferable that it is in the range of ⁇ 30 nm and its main component is ferrite.
- the coated magnetic particles are preferably lipid membrane ribosomes containing magnetic fine particles, and the surface charge of the ribosomes is preferably positive.
- the coated magnetic particle-containing preparation of the present invention is preferably used as an imaging agent and / or a therapeutic agent for tumors.
- the coated magnetic particle-containing preparation of the present invention is preferably an imaging agent in which a physiologically functional substance and Z or an antitumor active substance are bound to the surface of a lipid membrane directly or via a connecting substance.
- a contrast agent it is desirable to be used as a contrast agent for an ultrasound diagnostic imaging apparatus, a nuclear magnetic resonance imaging diagnostic apparatus, or an X-ray diagnostic imaging apparatus.
- the coated magnetic particle-containing preparation of the present invention is used as an imaging agent
- the administration of the coated magnetic particle-containing preparation into the subject's vein is started within 1 minute to 48 hours,
- an ultrasound diagnostic imaging apparatus a nuclear magnetic resonance imaging diagnostic apparatus, or an X-ray diagnostic imaging apparatus, the detection ability of tumor tissue can be improved.
- an ultrasonic imaging apparatus a nuclear magnetic resonance imaging apparatus
- the coated magnetic particle-containing preparation of the present invention comprises a physiologically functional substance, an additional stabilizing substance, a pharmacologically active substance, a pharmacologically active chelate substance, directly or via a connecting substance on the outermost layer of the lipid membrane.
- Antitumor active substances, immune enhancing substances, cell fusion substances and gene transfer mediators It is preferable to combine at least one substance selected from these.
- the therapeutic agent is a therapeutic agent for thermotherapy.
- This thermotherapy is a method using energy irradiation, and the temperature of the tumor tissue adjacent to the coated magnetic particles is increased by the energy irradiation. It becomes possible to make it.
- the energy irradiation is alternating magnetic field irradiation or ultrasonic irradiation, and it is preferable that the irradiation is an alternating magnetic field irradiation with a frequency of 25 to 500 kHz.
- the coated magnetic particle-containing preparation of the present invention is used as a therapeutic agent, the test is performed within 1 minute to 48 hours after the administration of the coated magnetic particle-containing preparation into the subject's vein is started. By performing alternating magnetic field irradiation or ultrasonic irradiation on the subject, the temperature of the tumor tissue adjacent to the coated magnetic particles can be raised.
- the coated magnetic particle-containing preparation when used as a therapeutic agent, the injection of the coated magnetic particle-containing preparation is started in the vicinity of the tumor tissue of the subject within 0.5 minutes to 36 hours, By subjecting the subject to alternating magnetic field irradiation or ultrasonic irradiation, the temperature of the tumor tissue adjacent to the coated magnetic particles can be increased.
- the method for producing a coated magnetic particle-containing preparation comprises mixing a lipid membrane component and supercritical carbon dioxide and adding a dispersion of magnetic fine particles to which an organic compound is chemically bonded.
- the magnetic fine particles are covered with a lipid membrane by discharging carbon dioxide and carbon dioxide.
- the magnetic fine particles have a hydroxyl group, a carboxyl group, a force rubamoyl group, an amino group in the molecule.
- C / 30 ° C is preferred to be generated under the condition! /.
- a diagnostic treatment system is a system for diagnosing and treating a tumor part of a subject using the coated magnetic particle-containing preparation
- the diagnostic treatment system includes an automatic injection device that automatically administers a coated magnetic particle-containing preparation to a subject,
- a first irradiation unit that irradiates a subject into which the preparation is injected with ultrasonic waves, electromagnetic waves, or X-rays, and an imaging unit that scans a tumor site where the coated magnetic particles accumulate!
- Preparation A diagnostic device,
- a second irradiation part that irradiates an alternating magnetic field or ultrasonic wave to the tumor site where the coated magnetic particles accumulate! / Sound, and a tumor part and a normal part in the vicinity thereof when the alternating magnetic field or ultrasonic wave is irradiated.
- a treatment device comprising a temperature measuring unit for measuring temperature;
- a control device that is connected to the automatic injection device, the diagnostic device, and the treatment device via a network, controls the operation of these devices, and controls each device;
- the temperature measurement unit performs non-invasive temperature measurement on the subject.
- the non-invasive temperature measurement is performed by a signal intensity method using a nuclear magnetic resonance imaging apparatus. It is also preferable to use a method that is calculated from values measured by longitudinal relaxation time, proton chemical shift in phase method, diffusion coefficient in diffusion imaging method, or microwave geometry measured at multiple frequencies.
- the temperature measurement unit measures the temperature of the tumor part and a normal part in the vicinity thereof, and sequentially transmits the measurement results to the control device, and the control device determines the temperature of the tumor part from the received measurement results.
- the control device determines the temperature of the tumor part from the received measurement results.
- the second irradiation unit When the second irradiation unit is irradiating an alternating magnetic field or an ultrasonic wave to the tumor site where the coated magnetic particles are accumulated! /,
- the first irradiation unit is more than the tumor site.
- the imaging unit By irradiating sound waves, electromagnetic waves, or X-rays, the imaging unit is controlled to perform treatment while confirming the tumor site by scanning the tumor site where the coated magnetic particles accumulate due to the irradiation. I also like it.
- the coated magnetic particles contained in the preparation of the present invention selective delivery to a disease site or a tumor lesion can be made possible (targeting ability).
- it can be used for hyperthermia using fever, and for combining it with cancer diagnosis and treatment.
- the coated magnetic particle can be prepared without using an organic solvent. Is highly safe for living organisms.
- the diagnostic treatment system of the present invention can be implemented as a single system from the examination of the disease site, tumor lesion, diagnosis to treatment. Therefore, diagnosis and treatment, which have been performed separately until now, can be performed simultaneously or sequentially, and the burden on the patient can be reduced.
- Fig. 1 is a diagram schematically showing the concept of coated magnetic particles contained in the preparation of the present invention. An example in which a plurality of magnetic fine particles are encapsulated is shown.
- FIG. 2 shows a preferred embodiment of coated magnetic particles contained in the preparation of the present invention.
- the physiologically active substance 5 and the antitumor active substance 6 may be included in the membrane.
- FIG. 3 shows a preferred embodiment of the diagnostic treatment system using the coated magnetic particle-containing preparation of the present invention.
- the coated magnetic particle-containing preparation of the present invention is a preparation containing coated magnetic particles.
- formulation aids are included as necessary.
- the coated magnetic particle 1 has a hydroxyl group, carboxyl group, carbamoyl group, amino group, mercapto group, sulfo group, dithio group, thiocarboxy group, and dithiocarboxy group in the molecule.
- the magnetic fine particle 2 in which an organic compound 3 having at least two selected bonding groups (hereinafter simply referred to as the organic compound 3) is bonded by a chemical bond is covered with the lipid film 4, that is, the magnetic fine particle Is encapsulated in a lipid membrane.
- the coated magnetic particle shows an embodiment in which a plurality of magnetic fine particles are coated with a lipid film, but one magnetic fine particle may be coated with a lipid film. This coated magnetic particle is further represented by the following formula:
- R represents the average particle diameter of the coated magnetic particles
- r represents the average particle diameter of the magnetic fine particles contained in all the coated magnetic particles.
- the coated magnetic particle 1 used in the present invention is coated with a magnetic particle 2 chemically bonded with an organic compound 3 with a lipid film 4, and on the surface thereof, a linking substance is formed.
- a physiologically functional substance 5 such as an antibody is bound to the antitumor active substance 6 through 7.
- FIG. 2 also shows a state in which a plurality of magnetic fine particles are covered with a lipid membrane, but one magnetic fine particle may be covered with a lipid membrane.
- FIG. 2 shows an embodiment in which a physiologically functional substance and an antitumor active substance are bound to each other.
- a physiologically functional substance As described later, a physiologically functional substance, an additional stabilizing substance, a pharmacologically active substance, and a pharmacologically active substance are shown. It is only necessary that at least one physiologically active substance selected as a chelate substance, an antitumor active substance, an immunopotentiating substance, a cell fusion substance, and a gene transfer mediating substance be combined. Thus, by binding the physiologically active substance, the coated magnetic particles can act specifically on the tumor tissue not only being delivered to the tumor site for detection.
- the temperature of the tumor tissue adjacent to the coated magnetic particles can be specifically determined by thermotherapy using energy irradiation such as alternating magnetic field irradiation or ultrasonic irradiation. And can be used as a therapeutic agent that can be applied to tumor tissue with a physiologically active substance.
- 1 and 2 schematically show the concept of the coated magnetic particles contained in the preparation of the present invention, and the specific embodiment is not limited thereto.
- cancer refers to a malignant tumor, sometimes simply referred to as “tumor” !.
- Encapsulated within a lipid membrane or ribosome membrane means an aqueous phase encapsulated within the lipid membrane or ribosome and associated with the lipid membrane or confined within the lipid membrane (internal It shall include both of the conditions present in the aqueous phase).
- magnetic fine particles are mainly composed of magnetite, Fe 2 O, Fe 2 O, mixed ferrite.
- Force Fe O which shows the maximum magnetic force, has good magnetic response and is particularly preferred.
- Nano-level ferrite solid solution of Fe 2 O and ⁇ -Fe 2 O
- Patent Document 1 A technology has been developed that can synthesize fine particles of particles by controlled precipitation under mild conditions around 4-25 ° C and near neutral pH (Patent Document 1).
- such mixed ferrite fine particles are used as suitable magnetic fine particles.
- Magnetic fine particles with ferrite as a core The magnetic properties can be controlled by adding various metal elements such as Zn, Co, and Ni.
- the average particle size of the magnetic fine particles is Inn! ⁇ 30nm, preferably 5 ⁇ ! Desirably, it should be in the range of ⁇ 25nm, more preferably 5nm ⁇ 20nm! /.
- the coated magnetic particles contain at least one magnetic fine particle as a ferrite core.
- the number varies depending on the average particle size of the magnetic fine particles, the average particle size of the coated magnetic particles, and the magnetic properties required for the preparation of the present invention, and is adjusted as necessary.
- the average particle size of the coated magnetic particles containing one or more such magnetic fine particles it is necessary to consider sizing of the particle size in order to provide passive targeting capability.
- Patent No. 2619037 discloses that embolization in pulmonary capillaries is avoided by eliminating ribosomes having a particle size of 3000 nm or more.
- ribosomes in the 150-3000 nm particle size range are not necessarily antitumor.
- the particle size needs to be set appropriately according to the purpose of the contrast agent.
- the average particle size of the coated magnetic particles is usually 50 to 300 nm, preferably 50 to 200 nm, more preferably 50 to 150 nm.
- the coated magnetic particles can be selectively concentrated on the cancer tissue (“EPR effect”).
- the pores of the neovascular wall in solid cancer tissue are the size of the capillary wall window (fenestra) of normal tissue, which is abnormally larger than the size of about 30-80 nm, even with molecules of about lOOnm to about 200 nm in size. Power leaks out.
- the EPR effect is due to the fact that the neovascular wall in cancer tissue is more permeable than the microvessel wall of normal tissue, so it is necessary to improve the blood retention. Since the coated magnetic particles are not particularly large particles, they are difficult to capture by reticuloendothelial cells.
- the preparation of the present invention When the preparation of the present invention is used as a contrast agent, the ability to detect tumor tissue is improved when the average particle diameter of the coated magnetic particles is in the above range.
- the preparation of the present invention when used as a therapeutic agent for thermotherapy for tumors, if the average particle diameter is in this range, the temperature of the tumor tissue adjacent to the coated magnetic particles is limitedly increased by energy irradiation, and normal cells In The temperature of the tumor tissue can be raised with little effect.
- the energy irradiation is an alternating magnetic field irradiation
- the average particle diameter is preferably lOnm or more from the viewpoint of the rotation of the magnetic fine particles by the alternating magnetic field.
- the average particle diameter is in the range of 10 nm to 30 nm, preferably 10 nm to 25 nm, more preferably 10 nm to 20 nm.
- magnetic fine particles have a particle diameter, a magnetic moment, and a magnetic moment from the aspect of contrast performance (particularly T2 relaxation time) of a contrast agent for nuclear magnetic resonance imaging (MRI) or a function as a heating element of thermotherapy.
- the particle size should be as large as possible.
- the particle diameter of the coated magnetic particles is restricted to be less than or equal to the size of the entire diameter due to various biological characteristics, particularly target directivity. Therefore, as a preferable range of the average particle diameter for finding a compromise between the two parameters, this covered magnetic particle is required to satisfy the following formula indicating the relationship between the particle diameter of the magnetic fine particle and the particle diameter of the coated magnetic particle. Is done.
- R represents the average particle diameter of the coated magnetic particles
- r represents the average particle diameter of the magnetic fine particles.
- the coated magnetic particles satisfy the above formula, it is ensured that the size of the magnetic fine particles of the member and the size of the whole particles are within suitable ranges.
- the coated magnetic particles can be delivered specifically to the affected area of the tumor, and as a contrast agent that can improve the detection ability of the tumor tissue, or hyperthermia with energy irradiation such as alternating magnetic field irradiation or ultrasonic irradiation
- it can also be used as a therapeutic agent that can raise the temperature of the tumor tissue adjacent to the coated magnetic particles in a limited manner.
- the organic compound chemically bonded to the magnetic fine particle has a hydroxyl group (-0H), a force ruboxyl group (-COOH), a force rubermoyl group (-CONH), an amino group (-NH), a mercapto group in the molecule.
- the organic compound since at least two or more binding groups (a) are bonded to the magnetic fine particles, they are firmly bonded to the magnetic fine particles through these bonding groups.
- a polyvalent organic compound serves as a so-called “connector” because it binds a plurality of magnetic fine particles and also binds to the lipid membrane 4 covering the magnetic fine particles 2.
- the coated magnetic particles as a whole are structurally stable. Due to the presence of such organic compound 3, the magnetic fine particles are stably encapsulated in the lipid membrane.
- the organic compound 3 bound to the magnetic fine particles may be bound with a physiologically active substance or a medicinal substance described later at the other end. If the physiologically active substance or medicinal substance delivered using the coated magnetic particles as a carrier is lipophilic, it is expected to interact preferably with the lipid membrane 4 that coats the magnetic fine particles 2.
- the strong organic compound is not particularly limited as long as it has two or more bonding groups (a).
- the linking group (a) may be the same functional group or a combination of different functional groups. Specifically, an organic compound having a hydrogen atom or an organic group (b) at a predetermined carbon atom position of the compound (A) having at least two bonding groups (a). A compound having a structure in which at least one end of the compound skeleton is branched is preferable.
- phthalic acid As the basic skeleton of compound (A), phthalic acid, isophthalic acid, terephthalic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, fumaric acid, maleic acid, 2-mercaptoamine, 6- Amamine hexanethiol, 2-Mercaptopropionic acid, Aspartic acid, Gnoretamic acid, Asnolagin, Gnoretamine, Malic acid, Oxaguchi acetic acid, 2-Ketognoletanolic acid, Serine, Threnin, Cysteine, Cystic acid, Cystine, Naseti Nolestine, cysteine ethyl ester, dithiothreitol and the like.
- the organic group (b) is not particularly limited, and examples thereof include an alkyl group, an aralkyl group, an alkoxy group, an aryl group, an alkyleneoxy group, an aliphatic hydrocarbon group, a polyoxyalkylene group, and the like. It may have a group.
- the organic compound has a role of binding the magnetic fine particles and the lipid membrane by allowing the organic group (b) and the lipid membrane to interact through various bonds such as a covalent bond, an ionic bond, a hydrophobic bond, and a hydrogen bond. I prefer that.
- a hydrophobic medium or long chain alkyl group or a dissociable group capable of interacting with the phospholipid of the lipid membrane is preferable as the organic group (b). Therefore, among these organic groups (b), a side chain is formed on the compound (A) using a linear aliphatic hydrocarbon group or polyoxyalkylene group having about 3 to 30 carbon atoms. Is desirable.
- the organic compound having the organic group (b) at the predetermined carbon atom position of the compound (A) is not particularly limited and is prepared by a conventionally known method.
- the organic compound 3 is chemically bonded to the surface of the magnetic microparticle 2 via a bonding group (a) having two or more, and the lipid membrane 4 is one of the organic groups (b). Since the part is taken in, it is firmly joined to the lipid membrane 4. Therefore, the magnetic particles and the lipid membrane are tightly bound via the organic compound, so the stability in the human body and during storage is enhanced.
- the coated magnetic particles are decomposed by energy irradiation during thermotherapy, for example. Therefore, it is possible to efficiently perform thermotherapy.
- Such magnetic fine particles to which an organic compound is chemically bonded are produced by generating magnetic fine particles under a predetermined condition in the presence of the organic compound.
- an aqueous solution containing metal ions such as Fe 2+ ions is dropped into an aqueous solution or dispersion of an organic compound having two or more functional groups described above and stirred and mixed.
- the reaction solution it is preferable to manage the reaction solution so that the pH is 7 to 10 and the temperature of the reaction solution is 3 ° C to 30 ° C so as not to impair the activity of the organic compound.
- the pH is adjusted to be within the above range using a mixed solution of ammonium acetate, potassium acetate, salty ammonium, hydroxyammonium, etc. as a pH buffer solution. .
- the acid / oxidation conditions at this time may be mild or strong enough to take in oxygen in the air by stirring, so that the organic compound is added to the ferrite without altering the organic compound or impairing its activity. Can be fixed. Magnetic fine particles formed under such mild conditions have a uniform composition and magnetic properties. A product with uniform characteristics can be obtained.
- the oxidation conditions may be used in combination with known methods using nitrous acid or hydrogen peroxide as long as the object of the invention is not impaired.
- various ferritic ions can be prepared by adding other metal ions such as Co 2+ ions, Ni 2+ ions, and Zn 2+ ions. Can do. The reaction is performed until the magnetic fine particles have a predetermined size.
- the magnetic fine particles may be prepared by previously existing an organic compound in which the organic group (b) is bonded to the basic skeleton of the compound (A) when the magnetic fine particles are formed. ) After forming magnetic fine particles with only an organic compound having the basic skeleton of (), the organic group (b) may be bonded to the compound (A).
- ferrite fine particles are dispersed in advance in the aqueous solution or dispersion of an organic compound as nuclei of magnetic fine particles, and a spinel ferrite layer bonded with the organic compound is formed on the surface of the ferrite fine particles according to the above-described method. It is also preferable to form it.
- Magnetic fine particles chemically bonded with organic compounds obtained by this manufacturing method have a nucleus of a fly crystal with a uniform crystal structure. Therefore, a nuclear magnetic resonance imaging method that creates a tomographic image of the whole body by applying electromagnetic waves (MRI) When used as a diagnostic contrast agent, accurate imaging can be performed.
- MRI electromagnetic waves
- the magnetic fine particles to which the organic compound is chemically bonded, obtained as described above, can be obtained in the form of a dispersion.
- the magnetic fine particles are used for the production of coated magnetic particles described later, the magnetic fine particles are used. It is preferable to purify by a predetermined method and disperse in an aqueous medium.
- the aqueous medium water such as distilled water, pharmacopoeia water and pure water, physiological saline, various buffer solutions, salts, and the like are used.
- the magnetic fine particles 2 bound with the organic compound 3 are further coated with the lipid membrane 4 via the organic compound (FIGS. 1 and 2).
- This lipid film is well dispersed in an aqueous medium by coating with magnetic fine particles, and has excellent dispersion stability. It enables preparations containing magnetic fine particles. In the case of magnetic fine particles with large remanent magnetization, they will magnetically aggregate with each other, and precipitation is likely to occur in the liquid.
- lipid membranes are inherently biocompatible and can impart magnetic microparticles with a high affinity for living tissues, especially for hydrophobic tissues. There is also an advantage that physiologically active substances, medicinal substances, etc. can be added by designing the constituents of the lipid membrane and the modification of the membrane surface.
- the lipid membrane covering the magnetic fine particles is generally a lipid multi-layer membrane.
- it is a multi-layered lipid membrane formed of amphiphilic molecules having two medium and long chain fatty acid residues or medium and long chain alkyl groups and a hydrophilic group.
- Such lipid membrane components are usually phospholipids and
- ribosomes composed of lipid bilayers based on such phospholipids are generally called “ribosomes”.
- Examples of phospholipids include phospholipids typified by phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol, phosphatidic acid, cardiolipin, and sphingomyelin. It is used without limitation to phospholipids derived from egg yolk, soybeans and other animal and plant materials, hydrogenated products thereof, semi-synthetic phospholipids such as hydroxide derivatives, or synthetic processed products.
- the fatty acid constituting the phospholipid is not particularly limited, and may be either a saturated fatty acid or an unsaturated fatty acid.
- Specific neutral phospholipids include dipalmitoyl phosphatidylcholine (DPPC), distearoyl phosphatidylcholine (DSPC), dimyristol phosphatidylcholine (DMPC), dioleyl phosphatidylcholine (DOPC), dioleyl phosphatidylethanolamido. (DOPE), dimyristoyl phosphatidylethanolamine, dipalmitoyl phosphatidylethanolamine, distearoyl phosphatidylethanolamine, and the like.
- DPPC dipalmitoyl phosphatidylcholine
- DSPC distearoyl phosphatidylcholine
- DMPC dimyristol phosphatidylcholine
- DOPC dioleyl phosphatidylcholine
- DOPE dioleyl phosphatidylethanolamido.
- the ribosome which is preferably a lipid membrane caposome, more preferably has a positive surface charge.
- the ribosome in addition to the above neutral phospholipid, at least one selected from cationic phospholipids, cationic lipids, and long-chain cationic compounds compatible with phospholipids. It is preferable to use it. Since the liposomal membrane has a positive surface charge, the coating contained in the formulation of the present invention Magnetic particles can be specifically introduced into negatively charged tumor cells.
- Cationic phospholipids include esters of phosphatidic acid and amino alcohols, such as esters of dipalmitoyl phosphatidic acid (DPPA) or distearoyl phosphatidic acid (D SPA) and hydroxyethylene diamine. .
- esters of phosphatidic acid and amino alcohols such as esters of dipalmitoyl phosphatidic acid (DPPA) or distearoyl phosphatidic acid (D SPA) and hydroxyethylene diamine.
- examples of cationic lipids include 1,2 dioleoyloxy 3- (trimethylammonium) propan (DOTAP), N, N dioctadecylamide glycylspermine (DOGS), dimethyldi Octadecylammobromide (DDAB), N— [l— (2,3 dioleyloxy) propyl] —N, N, N Trimethylammo-um chloride (DOTMA), 2, 3 dioleyloxy—N— [2 (spermine —Carboxamido) ethyl] N, N dimethyl 1-propane amyl trifluoroacetate (DOSPA) and N— [1— (2,3 dimyristyloxy) propyl] N, N dimethyl N— (2-hydroxyethyl) ) Ammobromide (DMRIE).
- examples of the long-chain cationic compound include, for example, ammonium salts having a carbon number of 10 or more and onium salts
- glycolipids examples include glycolipids.
- glycated oral lipids such as digalatatosyl diglyceride and galactosyl diglyceride sulfate ester, galactosylceramide, galactosylceramide sulfate ester, latatosylceramide, contoside G7, ganglioside G6, ganglioside G4 and other sphingo Examples thereof include glycolipids.
- the above-described phospholipid may be introduced with a functional group capable of binding to a physiologically active substance in a range without departing from the purpose of the present invention in order to bind a physiologically active substance described later. .
- a ribosome membrane constituent in addition to the above lipids, other substances may be added as necessary.
- Daricols such as ethylene glycol and propylene glycol
- sterols that act as membrane stabilizers
- cholesterol dihydrocholesterol
- cholesterol esters Sterol derivatives have also been shown to be effective in ribosome stability (Japanese Patent Laid-Open No. 5-245357).
- cholesterol is particularly preferred.
- the amount of sterols to be used is from 0.05 to 1 part by weight of phospholipid: 5 parts by weight of L, preferably 0.2 to 1 part by weight, more preferably 0.3 to 0.8 part by weight.
- the proportion of parts is desirable. When less than 0.05 parts by weight, stability due to sterols that improve the dispersibility of mixed lipids is demonstrated. If the amount exceeds 1.5 parts by weight, it becomes unstable even if a force that inhibits ribosome formation is formed.
- dialkyl phosphates such as dicetyl phosphate, which are negatively charged substances
- aliphatic amines such as stearylamine
- polyethylene glycol can be used as one component of the ribosome that coats the magnetic fine particles. That is, by attaching PEG to the ribosome, a role as a “linking substance” described later or a new function can be given. For example, effects such as the ability of ribosomes to have a hydrophilic tendency, the difficulty of being recognized by the immune system, or increased blood stability can be expected. Specifically, since lipid components are easily stored in the liver, PEG is not used or ribosome with a low PEG content is used for the purpose of accumulation in the liver.
- PEGylated ribosomes is recommended because it collects in the liver by using PEG.
- the function can be adjusted by changing the length of oxyethylene unit of PEG, the ratio of introduction, or by adding some modification to PEG.
- PEG polyethylene glycol having 10 to 3500 oxyethylene units is preferred.
- the amount of PEG used is 0.1 to 30% by mass, preferably about 1 to 15% by mass with respect to the lipid constituting the ribosome.
- Cholesterol in the ribosome membrane can also serve as an anchor for introducing polyalkylene oxide.
- a polyalkylene oxide group may be bonded to the cholesterol contained in the membrane as a ribosome membrane constituent component, if necessary, via a linker.
- a linker a short-chain alkylene group, an oxyalkylene group or the like is used.
- Japanese Patent Application Laid-Open No. 09-3093 discloses a novel functional substance that can be efficiently immobilized by covalent bonding at the end of a polyoxyalkylene chain and can be used as a ribosome-forming component. Cholesterol derivatives are disclosed.
- a known technique can be used for PEGylation of a ribosome.
- An PEG-binding anchor eg, cholesterol or phospholipid
- a phospholipid that is a membrane component to prepare a liposome, and the activated PEG may be bound to the anchor.
- Ribosome Since the polyethylene glycol group introduced on the surface does not react with the “bioactive substance” described later, it is difficult to fix the “bioactive substance” on the ribosome surface.
- a ribosome can also be produced by binding PEG with some modification on the PEG tip to phospholipid and including it as a ribosome component.
- Examples of the oxyalkylene group having 2 to 4 carbon atoms include, for example, an oxyethylene group, an oxypropylene group, an oxytrimethylene group, an oxytetramethylene group, an oxy 1 -ethylethylene group, an oxy ; L, 2-dimethylethylene group and the like can be mentioned.
- n is a positive number of 1 to 2000, preferably 10 to 500, and more preferably 20 to 200.
- Y is a hydrogen atom, an alkyl group, or a functional functional group.
- alkyl group include an optionally branched aliphatic hydrocarbon group having 1 to 5 carbon atoms.
- Functional functional groups are used to attach “bioactive substances” such as sugars, glycoproteins, antibodies, lectins, and cell adhesion factors to the tips of polyalkyleneoxide chains.
- bioactive substances such as sugars, glycoproteins, antibodies, lectins, and cell adhesion factors
- amino groups, oxycarboximidazole groups examples thereof include N-hydroxysuccinimide groups and functional groups rich in reactivity.
- the various polyalkyleneoxide groups introduced into the lipid membrane are the same as in polyethylene glycol. In the same way, it plays a role as a “linking substance” described later. Ribosomes with a polyalkyleneoxide chain (linking substance) that has a “bioactive substance” attached to the tip are blocked by the polyalkyleneoxide chain, reflecting the effect of introducing the polyalkyleneoxide chain.
- the functions of the “physiologically active substance”, for example, the action of specific organ directivity, cancer tissue directivity, etc. are sufficiently exerted as a “recognition element”.
- Phospholipids or compounds having a polyalkyleneoxide group can be used alone or in combination of two or more. Its content is the total amount of ribosomal film forming component, 0.001 to 50 mol%, preferably 0.01 to 25 Monore 0/0, more preferably ⁇ or 0.1 to 10 Monore 0/0 . 0.001 Monore 0/0 less effect is ⁇ or expectations in decreases.
- a known technique can be used to introduce a polyalkylene oxide chain into the ribosome.
- An anchor for example, cholesterol or phospholipid
- An anchor for example, cholesterol or phospholipid
- a phospholipid that is a membrane component to produce a ribosome and an active polyalkylene oxide may be bonded to the anchor.
- it is necessary to perform a multi-step chemical reaction on the surface of the ribosome membrane after the preparation of the ribosome, so that the amount of the target “bioactive substance” introduced is limited to a low level, and a by-product generated by the reaction
- There are problems such as contamination of impurities and large damage to the ribosome membrane.
- ribosomes in advance by including a phospholipid polyalkyleneoxide derivative in the raw material phospholipids.
- modified phospholipids such as polyethyleneoxide ( ⁇ ) derivatives such as phosphatidylethanolamine, such as distearoylphosphatidylethanolamine polyethyleneoxide (DSPE——) were proposed ( JP-A-7-165770).
- JP-A-2002-37883 discloses a high-purity polyalkyleneoxide-modified phospholipid for producing a water-soluble polymer-modified ribosome with increased blood retention. It is described that, when such a liposome is produced, the monoacyl body content is low, and if a polyalkylene oxide-modified phospholipid is used, the aging stability of the ribosome dispersion is good.
- the "linking substance” refers to various physiologically active substances as a linker, Combines medicinal substances.
- the physiologically active substance or medicinal substance is a low molecular weight compound, access may be hindered due to steric hindrance by the coated magnetic particles when they bind to a receptor as a ligand. If the ligand is bound to the coated magnetic particle via a connecting substance as a spacer having an appropriate length, such obstacles can be avoided.
- the linking substance the polyethylene glycol chain and polyalkylene oxide chain described above, for example, ethylene glycol diglycidyl ether (EGDE) derivatives are preferable.
- It may be a hydrocarbon chain that may contain heteroatoms (oxygen, nitrogen, iow, phosphorus, etc.). Such a hydrocarbon chain has 2 to 50 carbon atoms, preferably 3 to 40 carbon atoms, more preferably 4 to 30 carbon atoms, and may be further substituted with a functional group, an alkyl group or an aryl group as necessary. .
- a linking group such as a thiol group, an epoxy group, an amino group, a carboxy group, histidine tag avidin, streptavidin, or piotin may be further provided at the terminal end or in the middle of the chain. It may also be an oligonucleotide modified with an amino group, carboxyl group, thiol group, etc. (number of nucleobase: 3 to: LOO) or polypeptide (number of amino acid residues: 3 to 50).
- the linking substance may be a member constituting the lipid membrane as a lipid derivative constituting the lipid membrane, or may be bound to phospholipid, cholesterol or the like as described above.
- the coated magnetic particles of the present invention are obtained by binding a “bioactive substance” via the above-mentioned linking substance 7 or organic compound 3! /
- the coated magnetic particles coated with a lipid layer such as ribosome may further bind a “bioactive substance” directly to the lipid membrane surface of the ribosome.
- the physiologically active substance may be in a form bound to the organic compound 3 and present in the lipid membrane or in the membrane.
- “Physiologically active substances” include physiologically functional substances, additional stabilizing substances, pharmacologically active substances, pharmacologically active chelating substances, antitumor active substances, immune enhancing substances, cell fusion substances, and gene transfer mediators. Can be mentioned. It is also possible to bind such physiologically active substances to the coated magnetic particles and selectively concentrate them on the target site by magnetic operation.
- Preferred antibodies include antibodies against "WT1 protein", which is present in a large amount in various types of cancer cells not present in normal cells, leukemia cells, and the like.
- WT1 protein A part of the WT1 protein (9 amino acids-WT1 peptide) is bound to a molecule called HLA on the surface of cancer cells, which has been proven to be a marker for cancer cells.
- HLA a molecule on the surface of cancer cells, which has been proven to be a marker for cancer cells.
- the above antibody can be prepared by a conventional method using the WT1 peptide.
- the additional stabilizing substance is a substance that stabilizes the structure of the magnetic fine particles bound by solvation or the like.
- polybulal alcohol polybulurpyrrolidone, polyethylene glycol, polyalkylene oxide, dextran
- examples thereof include cellulose derivatives, mucopolysaccharides, proteins, polypeptides, polyamino acids, and polynucleotides.
- the pharmacologically active substance is a compound mainly having a therapeutic biological activity or medicinal effect, for example, an antitumor active substance, an anti-infective compound, an antiviral substance, an antibiotic, an anti-inflammatory compound, a chemical substance.
- Therapeutic agents, circulatory drugs, gastrointestinal drugs, nerve drugs and the like can be mentioned.
- the pharmacologically active chelating substance is a substance having a detoxifying action by complex formation and a stabilizing action by complexation, such as EDTA, DTPA, cyclen, polycarboxylic acid, polyamino acid, porphyrin, catecholamine, etc. Is mentioned.
- the antitumor active substance is a substance having a tumor shrinking effect.
- an antitumor agent containing an antibiotic, a plant alkali, an alkylating agent, an antimetabolite, an angiogenesis inhibitor, a tumor necrosis factor, etc. Is mentioned.
- Angiogenesis inhibitors include TNP-470 (AGM — 1470, a synthetic analogue of fumagillin, a fungal secretion; Takeda Pharmaceutical Co., Ltd. (Osaka)), Angiostatin (Noichiichi Bird Medical School Children's Hospital, Surgical Research Lab) .) And integrin a j8 antagonists (eg, monochrome of integrin a j8
- V 3 V 3 Nanole antibody The Scripps Research Institute, Lajolla, CA).
- the immunopotentiator enhances the activity of immune cells including lymphocytes and macrophages.
- immune cells including lymphocytes and macrophages.
- examples of such substances include interferon, krestin, picibanil, lentinan, IFA, and OK-432.
- the cell fusion substance is a substance that is used for cell fusion operation and promotes cell fusion.
- polyalkylene glycol alkyl polyalkylene glycol, aryl polyalkylene glycol, alkyl aryl polyalkylene glycol and the like. And derivatives thereof.
- Gene transfer mediators are substances that serve as carriers for gene transfer, such as polyalkylene glycol (polyethylene glycol, etc.), polyimine (spermine, spermidine, pentaethylenehexamine, polyethyleneimine, protamine sulfate, etc.) ), Viral vectors, plasmid vectors and the like.
- photosensitizers for photodynamic therapy both Photodynamic therapy and PDT
- ribosomes containing phospholipids with a transition temperature and cancer hyperthermia
- a photosensitizing compound such as porphyrins, 5-aminolevulinic acid, chlorins, phthalocyanines, etc.
- the preparation of the coated magnetic particle-containing preparation of the present invention pharmacologically acceptable buffers, stabilizers, antioxidants such as human coferol, and the like as further formulation aids when necessary. Viscosity modifiers, chelating agents and the like may also be included. These are appropriately used to prevent oxidation-reduction reaction, alteration, for example, aggregation and precipitation.
- the preparation of the present invention is characterized in that the organic solvent is substantially not contained in the lipid membrane or the internal aqueous phase contained therein.
- the coated magnetic particle-containing preparation of the present invention is not particularly limited as long as the surface of the magnetic fine particles to which the organic compound is chemically bonded can be coated with a lipid film, and a conventionally known shaking method or the like is used. It can also be prepared.
- the conventional method requires the phospholipid to be dissolved in a chlorinated solvent such as black mouth form, which may leave a strong chlorinated solvent that cannot be removed in the preparation. There may be problems with safety. I got it. Therefore, the coated magnetic particle-containing preparation of the present invention can be prepared by a production method using supercritical diacid-carbon, which can be produced substantially without using an organic solvent such as a chlorinated solvent. preferable. “Substantially” means that the upper limit of the concentration of residual organic solvent in the preparation is 10 gZL. In the following description, supercritical nitric acid carbon includes subcritical carbon dioxide.
- a preferred method for producing the coated magnetic particle-containing preparation of the present invention is as follows.
- the pressure vessel While mixing the lipid membrane component and liquefied carbon dioxide in the pressure vessel, the pressure vessel is heated and pressurized to bring the liquefied carbon dioxide into a supercritical state, and the lipid membrane component and the supercritical diacid salt are mixed.
- the first step of adding and mixing the dispersion of “magnetic fine particles with organic compounds chemically bonded” produced as described above, and then mixing the mixed solution in the above step A second step of preparing an aqueous dispersion of the coated magnetic particles by coating the magnetic fine particles with a lipid film by depressurizing the inside of the pressure vessel and discharging carbon dioxide and removing the carbon dioxide. .
- the lipid membrane constituent and liquefied carbon dioxide are mixed in the pressure vessel, and the pressure and temperature are adjusted so that the carbon dioxide is in a critical state in the pressure vessel. Mix membrane constituents with supercritical carbon dioxide.
- Suitable pressure diacid I ⁇ oxygen supercritical used in the production method of the present invention, 50 ⁇ 5 OOkg / cm 2, preferably 100 ⁇ 400kg / cm 2.
- the temperature of carbon dioxide in a suitable critical state is 25 to 200 ° C, preferably 31 to 100 ° C, and more preferably 35 to 80 ° C. Within these ranges, it is preferable to establish a supercritical state by appropriately selecting and combining temperature and pressure. Further, the stirring conditions are not particularly limited, and it is carried out by appropriately selecting suitable conditions.
- the lipid membrane component and supercritical carbon dioxide are mixed, and a dispersion of magnetic fine particles in which an organic compound is chemically bonded is added and mixed.
- the dispersion may be added at a time or may be added intermittently, but in a controlled manner so that the supercritical state is maintained.
- the inside of the pressure vessel is depressurized to discharge the carbon dioxide and the magnetic fine particles are covered with the lipid membrane. An aqueous dispersion of coated magnetic particles is formed.
- the organic compound bonded to the magnetic fine particles has the organic group (b) as described above, and when it is joined to the lipid membrane, a part thereof is taken in when forming the lipid membrane. Conceivable. Therefore, the magnetic fine particles and the lipid membrane are firmly bonded via the organic compound, so that the stability in the human body and during storage is high, and the coated magnetic particles are decomposed by, for example, energy irradiation during thermotherapy. Therefore, the thermal treatment can be performed efficiently.
- one magnetic fine particle or a plurality of magnetic fine particles are coated with a lipid film, and such coated magnetic particles are dispersed to obtain an aqueous dispersion.
- the aqueous dispersion of coated magnetic particles obtained in the second step is filtered through a filtration membrane having a pore size of 100 to lOOOnm.
- the Etasuto extruder equipped with a filter having a pore size of 100 ⁇ 1000nm as a filtration membrane, it can be efficiently prepared coated magnetic particles of 10 0 to 150 nm.
- the intended effect of the coated magnetic particle-containing preparation can be obtained.
- coated magnetic particles have the advantage that the dose of coated magnetic particles, in other words, the amount of lipid to be administered does not increase, compared with coated magnetic particles composed of multilamellar vesicles (MLV). is there.
- MLV multilamellar vesicles
- the conventional ribosome production method in order to increase the ratio of single-layer or multi-layer liposomes in which MLVs of various sizes and forms are often present in a powerful ratio, In addition, operations such as the ability to irradiate ultrasonic waves and passing through a filter with a fixed pore size many times were required.
- the coated magnetic particle-containing preparation of the present invention can be prepared by filtering the aqueous dispersion of coated magnetic particles obtained in this way through the filtration membrane as described above. , The aqueous medium may be separated and concentrated using a method such as centrifugation or ultrafiltration.
- the coated magnetic particle-containing preparation of the present invention can be used as an imaging agent and a therapeutic agent for examination diagnosis as a medical preparation. Specifically, it should be used as an X-ray contrast agent, a contrast agent for MRI (nuclear magnetic resonance imaging) or a contrast agent such as an ultrasound contrast agent, a therapeutic agent for cancer, etc., preferably a therapeutic agent for thermotherapy. Can do.
- X-ray contrast agents are administered to luminal sites such as blood vessels, ureters, oviducts, etc., and are used for diagnosis of lumen shape, stenosis, and the like.
- luminal sites such as blood vessels, ureters, oviducts, etc.
- conventional compounds are useful for the purpose of more detailed diagnosis of tissues and diseased sites, especially cancerous tissues, because the luminal site force is rapidly expelled without interacting with tissues and diseased sites. Absent. Therefore, there is a demand for an X-ray contrast medium that selectively accumulates in a target tissue or diseased site and provides an image that can be distinguished from the surrounding or other sites with a clear contrast.
- MRI Magnetic Resonance Imaging
- MRI contrast agents that vary the relaxation time, such as protons
- Gd-DTPA gadolinium monodiethylenetriaminepentaacetic acid
- Ultrasound diagnostic imaging is usually based on the fact that ultrasound in the frequency range of 1 to: LOMHz penetrates into the body of the subject through a transducer, and the ultrasound interacts with the interface of body tissues and fluids. It is. In other words, the dyed image of the ultrasonic signal originates from the differential reflection / absorption of sound waves at such an interface.
- an ultrasound contrast agent in which a gas or a bubble is enclosed in a microcapsule is used.
- the amount of gas or bubbles enclosed is not necessarily large because it depends on other factors. Therefore, a contrast effect cannot be obtained sufficiently that a large amount is not administered!
- the coated magnetic particles of the present invention are introduced into the body and used as an X-ray contrast agent, an MRI (nuclear magnetic resonance imaging) contrast agent, or an ultrasonic contrast agent, the target tissue or disease is obtained. It is possible to provide an image that can be selectively accumulated at the affected area and distinguished from the surrounding area or other areas with a clear contrast. That is, the coated magnetic particles of the present invention can be selectively accumulated in a tissue or a diseased site depending on the particle size or surface charge, and impart the ability to identify the tissue with a physiologically active substance bound to the lipid membrane surface.
- the magnetic fine particles can effectively contrast the tumor tissue by utilizing the fact that the propagation speed of ultrasonic waves is faster than that of the living body (water).
- the coated magnetic particle-containing preparation of the present invention can be suitably used as an X-ray contrast agent, a superparamagnetic MRI (nuclear magnetic resonance imaging) contrast agent or an ultrasonic contrast agent.
- ultrasound is administered within 1 minute to 48 hours, preferably 10 minutes to 36 hours after the start of the administration of the coated magnetic particle-containing preparation of the present invention into the subject's vein.
- an image diagnostic apparatus a nuclear magnetic resonance image diagnostic apparatus, or an X-ray image diagnostic apparatus
- the detection ability of tumor tissue can be improved.
- the injection is started even if the preparation containing the coated magnetic particles is injected directly in the vicinity of the tumor tissue of the subject, and the force is also within 0.5 to 36 hours, preferably within 10 to 24 hours.
- the detection ability of the tumor tissue can be improved by performing scanning in the ultrasonic diagnostic imaging apparatus, the nuclear magnetic resonance diagnostic apparatus, or the X-ray diagnostic apparatus.
- the coated magnetic particle-containing preparation of the present invention is used as an imaging agent for the above-described examination diagnosis, and at the same time, binds or encapsulates a physiologically active substance or a medicinal substance such as an antitumor agent inside or outside the lipid membrane. Therefore, it can be used as a therapeutic agent for various diseases. Since the coated magnetic particles are selectively accumulated in a lesion site or a lesion such as a tumor tissue, the effects of physiologically active substances and medicinal substances are effectively exhibited and side effects are reduced. Specific application examples thereof are shown below, but the application of the preparation of the present invention is not limited thereto.
- thermotherapy for cancer is a treatment that has unique characteristics and excellent aspects, but it has not always been actively adopted in the field of cancer treatment. Rather than using thermotherapy alone, radiation therapy is currently used in combination with anticancer drugs for the purpose of strengthening the effects of anticancer drugs. There are several reasons for this, but the results are not necessarily as good as other treatments. It is safe to say that there was no reason to replace the conventional method. For this reason, there is still room for improvement in the components, drugs, and devices used in cancer thermotherapy.
- hyperthermia a method that warms the whole body (whole body thermotherapy) and a method that warms the cancer and its vicinity (local thermotherapy).
- local hyperthermia is mainly performed, and the local area is heated with a device that uses microwaves, electromagnetic waves (alternating magnetic field), and ultrasonic waves. Heating from the outside of the body is the most common method, but there are other methods such as putting the device in the lumen of the esophagus, rectum, uterus, bile duct and heating, and several electrode needles in the cancer tissue.
- a method that warms the whole body whole body thermotherapy
- local thermotherapy a method that warms the cancer and its vicinity
- local thermotherapy mainly performed, and the local area is heated with a device that uses microwaves, electromagnetic waves (alternating magnetic field), and ultrasonic waves. Heating from the outside of the body is the most common method, but there are other methods such as putting the device in the lumen of the esophagus, rectum, uterus,
- the administration of the coated magnetic particle-containing preparation of the present invention into the subject's vein is 1 minute to 48 hours, preferably 30 minutes to 36 hours after the start of administration.
- the examiner By irradiating the examiner with energy, it is possible to increase the temperature of the tumor tissue adjacent to the coated magnetic particles and perform treatment with little effect on normal cells.
- the injection in the vicinity of the tumor tissue of the subject, even if the injection containing the coated magnetic particle-containing preparation is started directly, the injection is started for 0.5 minutes to 36 hours, preferably 10 minutes to 24 hours.
- the energy irradiation is preferably an alternating magnetic field irradiation or ultrasonic irradiation, and the alternating magnetic field irradiation is preferably performed at a frequency of 25 to 500 kHz.
- the diagnostic treatment system 10 of the present invention includes:
- An automatic injection device 20 that automatically administers a preparation containing coated magnetic particles to a subject, and a first irradiation unit 3 that irradiates the subject into which the preparation is injected with ultrasonic waves, electromagnetic waves, or X-rays 3
- a diagnostic device 30 comprising: 2 and an imaging unit 34 that scans a tumor site where the coated magnetic particles are accumulated by the irradiation!
- a second irradiation unit 42 that irradiates an alternating magnetic field or ultrasonic wave to the tumor site where the coated magnetic particles accumulate! /, And a normal part near the tumor part when the alternating magnetic field or ultrasonic wave is irradiated
- a treatment device 40 comprising a temperature measurement unit 44 for measuring the temperature of
- the automatic injection device 20, the diagnostic device 30, and the treatment device 40 are connected to each other through a network 60.
- the control device 50 controls the operation of these devices and controls each device.
- the automatic injection apparatus 20 a conventionally known automatic injection apparatus can be used, and as the diagnostic apparatus 30, an X-ray image diagnostic apparatus, a nuclear magnetic resonance image diagnostic apparatus, or an ultrasonic image diagnostic apparatus is used.
- the treatment device 40 a focused ultrasonic heating device or an alternating magnetic field heating device can be used.
- the automatic injection device 20, the diagnosis device 30, and the treatment device 40 are preferably integrated so that diagnosis and treatment for the patient can be performed simultaneously.
- the control device 50 is not particularly limited as long as it is a device including a control unit (CPU), an operation unit such as a keyboard and a mouse, a display unit such as a memory and a display, and includes, for example, a computer.
- the network 60 may be connected by an information communication network such as the Internet or a LAN (Local Area Network) ⁇ WAN (Wide Area Network). The connection between these terminals is not limited to wired wireless.
- the diagnostic treatment system 10 of the present invention preferably has a patient information database.
- the control device 50 can access the database as necessary to obtain the information of the subject, and can check in advance the major position of the tumor part, the patient's constitution and health status.
- the coated magnetic particle-containing preparation is automatically administered to a patient who performs a therapeutic diagnosis of a tumor site in the automatic injection device 20.
- information that identifies the patient is obtained by biometrics authentication such as the IC tag, fingerprint, and iris of the patient.
- the control device 50 accesses the database to identify the patient, determines the type and dose of the coated magnetic particle-containing preparation from the patient data (medical chart), and sends it to the automatic injection device 20 .
- the automatic injection device 20 When the automatic injection device 20 receives the type, dosage, etc. of the preparation from the control device 50, the automatic injection device 20 administers the coated magnetic particle-containing preparation to the patient according to predetermined items. When the administration of the coated magnetic particle-containing preparation is completed, the automatic injection device 20 issues a signal to the control device 50 that the administration has been completed, and the received control device 50 then starts diagnosing the tumor site to the diagnostic device 30. Signal to do.
- the received diagnostic apparatus 30 irradiates the patient with ultrasonic waves, electromagnetic waves, or X-rays by the first irradiation unit 32, and scans the tumor site where the coated magnetic particles are accumulated by the imaging unit 34. .
- the image scanned by the imaging unit 34 is transmitted as data to the control device 50, and the control device 50 confirms the contrast of the image based on the previously input data and identifies the tumor site where the coated magnetic particles are accumulated.
- control device 50 stores the location information of the tumor site in the patient database and transmits the location information of the tumor site to the treatment device 40.
- the treatment device 40 that has received the position information of the tumor site irradiates the patient with an alternating magnetic field or an ultrasonic wave by the second irradiation unit 42, and at the same time, the temperature measurement unit 44 Measure the temperature.
- the temperature measurement by the temperature measurement unit 44 applies the fact that the change in temperature is expressed as a change in resonance frequency, and measures the temperature inside the living body non-invasively without embedding a sensor or the like.
- the temperature measurement by the temperature measurement unit 44 is performed by using a nuclear magnetic resonance imaging (MRI) diagnostic device, the longitudinal relaxation time by the signal intensity method, the opening chemical shift in the phase method, the diffusion coefficient in the diffusion imaging method, or a plurality of diffusion coefficients.
- the method is preferably calculated from values measured with microwave geometry measured at frequency.
- the first control is performed.
- the irradiation unit 32 irradiates the tumor site with ultrasonic waves, electromagnetic waves, or X-rays, and the imaging unit accumulates coated magnetic particles by the irradiation!
- the second irradiation unit is controlled to irradiate an alternating magnetic field or ultrasound to the tumor site while scanning the tumor site.
- the temperature measurement unit 44 When the temperature measurement unit 44 measures the temperature of the tumor part and the normal part in the vicinity thereof, the temperature measurement unit 44 sequentially transmits the measurement results to the control device 50.
- the control device 50 receives the measurement result and confirms that the tumor part has risen to a predetermined temperature (for example, 42 ° C), it issues a command to stop the irradiation of the alternating magnetic field or the ultrasonic wave to the second irradiation part 42. .
- a predetermined temperature for example, 42 ° C
- control may be performed so as to irradiate an alternating magnetic field or ultrasonic waves for a certain period of time.
- the control device 50 applies an alternating magnetic field or A command to stop the irradiation of ultrasonic waves is issued.
- the ability to confirm the tumor site can be performed with a single system, so the diagnosis and treatment that have been performed separately can be performed simultaneously, and the burden on the patient is reduced. Therefore, it is possible to effectively and efficiently carry out diagnosis and treatment with a small amount.
- malic acid (A-1) modified with tetraethylenedaricol monomethyl ether.
- hexamethylene glycol monomethyl ether-modified malic acid (A-2) and decaethylene glycol monomethyl ether-modified malic acid (A-3) were prepared in the same manner.
- the amino group of aspartic acid and the hydroxyl group of hexamethylene glycol monomethyl ether Aspartate (A-4) modified with hexamethylene glycol monomethyl ether was prepared by reaction via sulfonate.
- octanoic acid modified phosphoric acid (A-5) was prepared by reacting malic acid hydroxyl group with octanoic acid chloride.
- Aspartic acid-modified (A-6) was prepared by reacting the amino group of aspartic acid with stearic acid chloride.
- A-4 Aspartic acid modified with hexamethylene glycol monomethyl ether
- Solution 1 was prepared by mixing an equal volume of 0. ImolZL salt-iron ferrous solution and 0. ImolZL salt-iron ferric solution.
- the diluted solution 2 was prepared with distilled water ammonia solution of 28 weight 0/0 such that 0.01 weight 0/0.
- an aqueous solution containing the organic compound A described in Table 1 at an ImmolZ L concentration was prepared, and this aqueous solution was adjusted to pH 8.4 with an ImolZL buffer solution composed of hydroxylated ammonium salt and salted ammonia.
- Solution 3 was obtained by adjusting to L0.0.
- the dropping speed was adjusted so that the stirring speed, the pH and the temperature of the solution 3 when the solution 1 and the solution 2 were dropped were within the above-described ranges, and the particle diameter (r) described in Table 1 was adjusted. Magnetic ferrite particles were formed.
- the particle size (r) was determined by observing 20 formed magnetic fine particles with a transmission electron microscope and calculating the average particle size.
- Solution 1 and Solution 2 were prepared in the same manner as in Magnetic Particle Formation Method 1. Separately, prepare an aqueous solution containing the organic compound A listed in Table 1 at an ImmolZL concentration, and adjust the pH to 8.4 ⁇ : LO. 0 with an ImolZL buffer solution that is also composed of hydroxylammonium hydroxide and ammonium chloride. The solution was adjusted to make Solution 3. Further, the aqueous solution was adjusted to pH 8.4 ⁇ : LO. 0 with an lmol ZL concentration buffer consisting of hydroxyammonium and salt-ammoumuka to obtain a solution 4.
- the magnetic fine particles were separated by magnetic separation and washed thoroughly with distilled water to prepare magnetic fine particles in which organic compound A having at least two specific bonding groups was chemically bonded.
- the dropping temperature was adjusted so that the stirring speed, the pH of the solution 4 or the solution 5 at the time of dropping the solution 1 and the solution 2 and the temperature of the solution 5 were within the above-mentioned range, and are shown in Table 1.
- Magnetic ferrite particles with a particle size were formed. The particle size was determined as the average particle size by observing 20 particles (r) at the time of preparing Solution 5 and the particle size (r) of the finally formed magnetic particles with a transmission electron microscope. (Method 3 for forming magnetic fine particles)
- Solution 1 and Solution 2 were prepared in the same manner as in Magnetic Particle Formation Method 1. Separately, prepare an aqueous solution containing the organic compound B shown in Table 1 at an ImmolZL concentration, and adjust the pH to 8.4-10. 0 with an ImolZL buffer solution that also contains hydroxylated ammonium and hydrated ammonia. Solution 3 was obtained. Next, the solution was mixed in the same manner as in magnetic fine particle formation method 1 to prepare magnetic fine particles in which organic compound B having at least two specific bonding groups was chemically bonded.
- the magnetic fine particles were dried and then charged into hexane and dispersed with an ultrasonic disperser.
- acid chloride organic compound C shown in Table 1 diluted to 1% by weight with hexane is added to react organic compound B and organic compound C chemically bonded to magnetic fine particles. I let you.
- the magnetic fine particles are separated by magnetic separation, washed well with acetone and distilled water, and the magnetic fine particles in which organic compound B is chemically bonded are separated. Magnetic fine particles in which organic compound C was further chemically bonded to organic compound B were prepared.
- the dropping speed was adjusted so that the stirring speed, the pH of the solution 3 and the liquid temperature when the solutions 1 and 2 were dropped were within the above-described range, and are shown in Table 1.
- Magnetic particles with particle size (r) were formed.
- the particle diameter (r) was measured by the same method as in Method 1 for forming magnetic fine particles.
- Solution 1 Solution 2 and Solution 4 were prepared in the same manner as Magnetic Particle Formation Method 2 except that Organic Compound B was used, and Solution 3 was prepared in the same manner as Magnetic Particle Formation Method 3.
- magnetic fine particles chemically bonded to the organic compound B having at least two specific bonding groups were formed by the same method as the magnetic fine particle formation method 2.
- the organic compound B and the organic compound C chemically bonded to the magnetic fine particles in hexane are reacted in the same manner as the magnetic fine particle formation method 3. It was.
- the magnetic fine particles are separated by magnetic separation, washed well with acetone and distilled water, and the magnetic fine particles in which organic compound B is chemically bonded are separated. Then, magnetic fine particles in which the organic compound B was further chemically bonded to the organic compound B were prepared.
- the dropping temperature was adjusted so that the stirring speed, the pH of the solution 4 or the solution 5 when the solutions 1 and 2 were added dropwise, and the temperature of the solution 5 were within the above-mentioned ranges.
- Magnetic fine particles having the particle diameter described in 1 were formed.
- the particle size was measured by observing 20 particle sizes (r) of the magnetic fine particles formed at the time (rl) when the solution 5 was prepared in the same manner as the magnetic fine particle formation method 2 with a transmission electron microscope. It calculated
- magnetic fine particles having stearic acid adhered to the surface were prepared by the following method.
- coated magnetic fine particles were prepared by the following preparation method.
- DPPC dipalmitoylphosphatidylcholine
- This slurry suspension was placed in a nurse flask in the range of 0.5 to 6.01, and 0.4 ml of 10 times the concentration of phosphate buffered saline was added.
- the mixed solution was subjected to ultrasonic stirring for 60 seconds for 60 minutes with a pause of 30 seconds.
- the mixture after ultrasonic stirring is centrifuged using a centrifuge for 15 minutes at a rotational speed of 3,300 rpm, and the resulting supernatant is centrifuged at a rotational speed of 7,500 rpm for 50 minutes.
- magnetic fine particles coated with a phospholipid membrane having a particle size (R) shown in Table 2 as a precipitate were obtained.
- the particle diameter (R) of the magnetic fine particles coated on the phospholipid membrane was determined by observing 20 formed particles with a transmission electron microscope and calculating the average particle diameter.
- distilled water was added to the magnetic fine particles shown in Table 2 prepared by the above-described method to obtain a slurry suspension containing magnetic fine particles at a concentration of 10.
- This slurry suspension is placed in a nurse flask in the range of 0.5 to 6.01, and 10 times the concentration of phosphate buffered physiological saline is added to the slurry aqueous solution of magnetic fine particles at 1Z10 volume.
- the mixed solution was subjected to ultrasonic stirring for 60 seconds for 60 minutes with a pause of 30 seconds.
- the particle diameter (R) of the magnetic fine particles coated with the phospholipid membrane was determined by the same method as in Preparation 1 of coated magnetic particles coated with the lipid membrane.
- a stainless steel autoclave was charged, the inside of the autoclave was heated to 60 ° C, and then 13 g of liquid carbon dioxide was added. Pressurizing the pressure in the autoclave from 50KgZcm 2 to the 200kgZc m 2, and stirred in the autoclave to dissolve the DPPC to supercritical diacid I ⁇ Motochu.
- phosphate buffered saline was added to the magnetic fine particles shown in Table 2 prepared by the above-described method to obtain a slurry suspension containing magnetic fine particles at a concentration of lOmgZml.
- the slurry suspension was continuously injected in the range of 0.5 to 6. Oml. Thereafter, the system is depressurized to discharge carbon dioxide and finally centrifuged at a rotational speed of 3,300 rpm for 15 minutes in a centrifuge. The obtained supernatant is 50 at a rotational speed of 7,500 rpm. Centrifugation was performed to obtain magnetic fine particles coated with a phospholipid membrane having a particle size (R) shown in Table 2 as a precipitate.
- R particle size
- the particle diameter (R) of the magnetic fine particles coated with the phospholipid membrane was determined in the same manner as in Preparation 1 of coated magnetic particles coated with the lipid membrane.
- the slurry suspension was continuously injected in the range of 0.5 to 6.0 ⁇ 1. Then, the system is depressurized to discharge carbon dioxide and finally centrifuged at a rotational speed of 3,300 rpm for 15 minutes in a centrifuge. The obtained supernatant is centrifuged at a rotational speed of 7,500 rpm for 50 minutes. Centrifugation was performed to obtain magnetic fine particles coated with a phospholipid membrane having a particle size (R) shown in Table 2 as a precipitate.
- R particle size
- the particle diameter (R) of the magnetic fine particles coated on the phospholipid membrane was determined in the same manner as in Preparation 1 of the covered magnetic particles coated with the lipid membrane. [0156] (Method 5 for preparing coated magnetic particles)
- a lipid having a maleimide group (EMC-DPPE) was prepared.
- EMC-DPPE 1.5 mg, phosphatidylethanolamine 8.5 mg, phosphatidylcholine 20 mg and 900 mg ethanol were charged into a stainless steel autoclave, the autoclave was heated to 60 ° C, and then liquid carbon dioxide 13 g Was added. The pressure in the autoclave was increased from 50 kgZcm 2 to 200 kg Zcm 2 and the autoclave was stirred to dissolve lipids in supercritical carbon dioxide.
- phosphate buffered physiological saline was added to the magnetic fine particles shown in Table 2 prepared by the above-described method to obtain a slurry suspension containing magnetic fine particles at a concentration of lOmgZml.
- G22 monoclonal antibody was bound to this solution according to the method described in Example 1 of JP-A-11-106391, and finally centrifuged at a rotational speed of 3,300 rpm for 15 minutes with a centrifuge. The resulting supernatant was centrifuged at a rotational speed of 7,500 rpm for 50 minutes to obtain magnetic fine particles coated with a phospholipid membrane having a particle size (R) shown in Table 2 as a precipitate.
- the particle diameter (R) of the magnetic fine particles coated with the phospholipid membrane was determined in the same manner as in Preparation 1 of coated magnetic particles coated with the lipid membrane.
- the coated magnetic particles coated with the lipid membrane of the present invention have a distinguishable tumor size compared to the comparative example, and can be distinguished from the comparative example even after a lapse of time. It turns out that there is little change in the size of the tumor.
- the coated magnetic particles shown in Table 4 were diluted with isotonic glucose solution to give a concentration of lOmg iron / ml. This solution was locally injected into a breast cancer tumor site of a mouse transplanted subcutaneously with a human breast cancer cell line, and observed with a nuclear magnetic resonance imaging apparatus after the time shown in Table 4 to measure the size of the distinguishable tumor. The results are shown in Table 4. [0166] As can be seen from Table 4, it can be seen that the coated magnetic particles coated with the lipid membrane of the present invention can be identified as compared with the comparative example over time.
- the coated magnetic particles shown in Table 5 were diluted with isotonic glucose solution to a concentration of 10 mg iron / ml. This solution was intravenously injected into rats transplanted with human malignant Dario cell lines. After the time shown in Table 5, the size of the tumor that can be identified was measured by observation with a nuclear magnetic resonance imaging apparatus. The results are shown in Table 5.
- Example 13 30 minutes later 1 hour later 6 hours later 1 2 hours later 3 6 hours later Example 13 14 5 5 5 8 10 10
- Example 29 31 5 5 5 5 10
- Example 30 32 5 5 5 5 & 10
- Example 31 33 5 5 5 5 8 10
- Example 32 34 5 5 5 5 8 10
- Example 35 37 5 5 5 5 8 10
- Example 36 38 5 5 5 ⁇ 10
- Example 39 41 5 5 5 5 5 8
- Example 40 42 5 5 5 5 5 5 8
- Example 41 43 5 5 5 5 5 5 5 5
- Example 44 46 5 5 5 5 5 5 5 Comparative example 7 51 5 5 8 10 ⁇ * ⁇ One * 1 Comparative example 8 52 5 5 8 10 ⁇ * 1 One * ⁇ Comparative example 9 53 5 5 8 8 10 One comparison
- Example 10 54 5 5 8 10 One * 1
- the coated magnetic particles shown in Table 6 were diluted with isotonic glucose solution to a concentration of 10 mg iron / ml. O This solution was locally injected into the lung cancer site of a mouse transplanted with a human lung-derived low-molecular-weight linear cancer cell line directly under the pleura, and after 30 minutes or 24 hours, it was irradiated with an alternating magnetic field under the following conditions: o
- Frequency 375KHz
- coil for generating magnetic field diameter 300mm
- magnetic field strength 6mT
- current 225A
- output 3KW
- distance from applicator 20mm
- the coated magnetic particles coated with the lipid membrane of the present invention efficiently increased the temperature of only the tumor part in a shorter time compared to the comparative example when performing thermotherapy. It can be seen that it is possible to perform an effective thermotherapy regardless of the time after the local injection.
- Example 9 9 32.8 5.0 34.5 10.5 36.9
- Example 10 10 33.5 6.0 35.2 12.5 37.8 Comparative Example 1 12 32.9 15.0 38.5 25,0 42.5
- Example 13 14 33.3 5.0 35.1 10.0 36.9
- Example 21 23 33.8 3.5 34.2 7.5 35.6
- the coated magnetic particles shown in Table 7 were diluted with isotonic glucose solution to a concentration of 10 mg iron Zml. This solution was intravenously injected into a rat transplanted with a human malignant Dario cell line, and after 1 hour and after the time shown in Table 7, alternating magnetic field irradiation was continuously performed under the following conditions.
- the coated magnetic particles coated with the lipid membrane of the present invention efficiently increased the temperature of only the tumor part in a shorter time compared to the comparative example when performing thermotherapy. It can be seen that, because of its high accumulation in the tumor area, it can be seen that even when several thermal treatments are performed, the treatment can be efficiently performed without supplying new magnetic particles.
- Example 13 14 33.5 5.0 34. B 12.0 37.6 25.0 42.4
- Example 23 25 32.6 5.0 34.4 10.0 36.8 18.0 39.8 29
- 31 33.1 5.0 34.3 8.5 36.8 15.0 38.4
- Example 30 32 33.0 5.0 35.0 8.5 36.4 15.0 38. ⁇
- Example 31 33 32.6 4.0 34.5 7.0 35.4 13.0 37.5
- Example 35 37 32.8 4.0 34.3 7.0 35.9 12.0 37.4
- Example 36 38 33.5 3.5 34.1 5.5 35.1 13.0 37.9
- the coated magnetic particles shown in Table 8 were diluted with isotonic glucose solution to a concentration of lOmg iron / ml.
- This solution was injected intravenously for the first time into mice subcutaneously transplanted with human breast cancer cell lines, and irradiated with an alternating magnetic field under the same conditions as in Test Example 5 after 2 hours and after 24 hours. Sarakuko, the first intravenous injection force 6 days later, the second intravenous injection was performed, and after 2 hours and 24 hours had passed, alternating magnetic field irradiation was performed under the same conditions as in Test Example 5. In addition, the second intravenous injection force was also given a third intravenous injection 15 days later.
- the coated magnetic particles of the present invention not only have the functions of both a contrast agent and a therapeutic agent, but also effectively act as a therapeutic agent.
- the configuration of the present invention enables selective delivery (targeting ability) to a tumor site, and is applied to a contrast medium and a drug transporter, as well as a thermotherapy using fever, and Can provide a coated magnetic particle-containing preparation that can be used for diagnosis and treatment of cancer combining these, a method for producing the same, and a diagnostic treatment system.
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Abstract
Description
Claims
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JP2006544867A JP5082446B2 (ja) | 2004-11-10 | 2005-11-04 | 被覆磁性粒子含有製剤およびその製造方法、並びに診断治療システム |
EP05800454A EP1810688A1 (en) | 2004-11-10 | 2005-11-04 | Pharmaceutical preparation containing coated magnetic particles and method for production thereof, and diagnosis therapy system |
AU2005303251A AU2005303251A1 (en) | 2004-11-10 | 2005-11-04 | Pharmaceutical preparation containing covered magnetic particles, manufacturing method thereof and diagnostic therapeutic system |
NO20072915A NO20072915L (no) | 2004-11-10 | 2007-06-07 | Farmasoytisk preparat som inneholder belagte magnetiske partikler og fremgangsmate for fremstilling av disse, og diagnoseterapisystem |
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EP (1) | EP1810688A1 (ja) |
JP (1) | JP5082446B2 (ja) |
AU (1) | AU2005303251A1 (ja) |
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Also Published As
Publication number | Publication date |
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US7560097B2 (en) | 2009-07-14 |
JPWO2006051732A1 (ja) | 2008-05-29 |
NO20072915L (no) | 2007-08-09 |
US20080260648A1 (en) | 2008-10-23 |
AU2005303251A1 (en) | 2006-05-18 |
US7427393B2 (en) | 2008-09-23 |
EP1810688A1 (en) | 2007-07-25 |
US20060099145A1 (en) | 2006-05-11 |
JP5082446B2 (ja) | 2012-11-28 |
US20090238764A1 (en) | 2009-09-24 |
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