WO2013044341A1

WO2013044341A1 - Nanoparticulate magnetic material for thermal applications

Info

Publication number: WO2013044341A1
Application number: PCT/BR2012/000403
Authority: WO
Inventors: Élio Alberto PÉRIGO; Fernando José Gomes LANDGRAF; Suelanny Carvalho da SILVA; Hidetoshi TAKIISHI; Edésia Martins SOUSA; Anderson Augusto FREITAS
Original assignee: Instituto De Pesquisas Tecnológicas Do Estado De São Paulo; Fundação De Amparo À Pesquisa Do Estado De São Paulo - Fapesp
Priority date: 2011-09-29
Filing date: 2012-10-01
Publication date: 2013-04-04
Also published as: BRPI1104888A2; BRPI1104888B1

Abstract

The invention, "nanoparticulate magnetic material for thermal applications", pertains to the field of specific uses or applications of nanostructures formed by individual manipulation of groups of atoms or molecules as discrete magnetic units composed of metals of the lanthanide group, and relates to a nanoparticulate material coated with an organic or inorganic compound, or with a combination thereof, for heating a localised point or a localized zone on an object exposed to an alternating magnetic field. The product consists of a particulate material, optionally including a biocompatible, organic and/or inorganic coating made from an alloy composed of at least one element of the lanthanide group (LA), at least one transition metal (MT) and at least one metalloid (ML), and represented by LA-MT-ML. The described material can be produced by a physical or a chemical process, or by a combination thereof, and has the novel and inventive feature of allowing the alloy to be heated in a controlled manner, alloy that can be produced from a mixture of pure elements, a mixture of alloys or by recycling already industrialised products. The product described in this patent can be used in applications requiring localised heating or localised magnetic features, such as resin or cement hardening, and in medical applications for the treatment of tumours or imaging diagnosis by means of contrast agents.

Description

NANOPARTICULATED MAGNETIC MATERIAL FOR THERMAL APPLICATIONS

The present invention, pertaining to the sector of specific uses or applications of nanostructures formed by individual manipulation of groups of atoms or molecules as discrete magnetic units composed of lanthanide group elements, refers to nanoparticulate material coated with organic or inorganic compound or their combinations, for heating or generating localized magnetic characteristics of an object or localized region when exposed to an alternating magnetic field.

TECHNICAL STATE

Hard magnetic materials are often used in electric motors, electronic beam collimators in power microwave valves and magnetic resonance equipment. In some applications, as in the case of electric motors, the hard magnetic material may be exposed to an alternating magnetic field, with a portion of energy dissipated by this material from the interaction of electromagnetic radiation-matter in the form of heat. Such an effect is undesirable in the mentioned cases, although it is, under specific conditions of amplitude and field frequency, a possibility of application in other fields of technology. Magnetic materials that exhibit satisfactory energy dissipation when exposed to an alternating magnetic field have application in situations where localized heating or magnetic characteristics are required, such as healing organic compounds or even treating cancer. The amount of energy dissipated depends on the type of material loss: hysteresis or relaxation. An explanation of both can be found in lchiyanagi et al. (Y. ICHIYANAGI et al. Study on increasing temperature of Co-Ti ferrite nanoparticles for magnetic hyperthermia treatment. Therm. Acta, DOI: 10.1016 / j.tca.2011.02.012) .

The figure of merit of the materials used for heating or localized magnetic characteristics, usually in powder form, is called the volumetric absorption rate (TAV) and is defined as the amount of heat released. per unit volume of compound per unit time during exposure to a frequency-defined magnetic field. The heating efficiency or magnetic characteristics of the particles is dictated by a variety of factors, one being the spatial distribution of the magnetic particles within the matrix. The particles should be evenly distributed throughout the matrix to optimize magnetic interactions and to achieve maximum volumetric absorption rate values for each particle.

With respect to application restrictions, when heating of cement or epoxy is required for rapid curing and without heating of surfaces or nearby objects, magnetic particles are homogeneously dispersed throughout the material such that after application of a cyclic magnetic field results in uniform heating of the entire volume of cement, rather than just heating from the outside in. Studies in the area of hyperthermia, for example, suggest the existence of a limit of the product H.f, where H is the applied magnetic field and f the frequency of H, to which the human body may be exposed for physiological reasons.

In fact, the development of micro- or nanometric-scale particulate magnetic materials for medical applications has been stimulated due to the absence of toxicity associated with the hyperthermia process, which does not occur in chemotherapy and radiotherapy; however, the materials used in the art in question should be evaluated a priori for compatibility. In hyperthermia, the body must be warmed to the temperature at which diseased cells are destroyed, keeping healthy tissue as unchanged as possible. For the treatment of hyperthermia to be effective, target tumors must be localized and the heating or magnetic characteristics of the target site maximized while maintaining safe operating limits for the patient. Thus, magnetic particles can be directed to the desired tissue by direct injection or intravenous infusion, and an alternating magnetic field generates heat in the particles, thereby causing the tumor temperature to rise to the therapeutic limit. Magnetic field conditions should be such that they do not cause interactions with the tissue, but only with magnetic particles and thus only tissue containing a concentration of magnetic particles will be heated.

In general, magnetic particles investigated or tested for hyperthermia consist of an iron oxide (Fe _x O _y ) with or without the presence of other chemical elements, such as Zn, Ni and Co, and coated with a biocompatible organic or inorganic material. It is common for these iron oxides to be prepared by chemical processes, such as co-precipitation, which require various chemical reagents, tight control of reaction time, temperature and pH, as well as heat treatments and additional steps. surface coating (T. KIKUCHI et al., Preparation of aqueous magnetite dispersion for magnetic fluid hyperthermia, J. Magn. Magn. Mat. 323 (10) (201 1) p.1216; and DL ZHAO et al. Magnetic and inductive heating properties of Fe ₃ O ₄ / polyethylene glycol composite nanoparticles with core-shell structure, J. AH Compd 502 (2) (2010), p 392). Moreover, although the range of intrinsic coercivity is in the range of 8 kAm ^"1 (approximately 100 Oe) to 24 kAm ^{" 1} (approximately 300 Oe), considered adequate for hyperthermia for technical reasons regarding obtaining such fields, Magnetic mass per unit ( _s ) is generally less than 60 Am ² kg ^"1 (60 emu g ^{" 1} ) without the material coated, which will further reduce this value. It is disclosed in US 6,167,313 that the invention provides an improved method for localized and specific treatment of diseased tissue in a patient, comprising the following steps: (i) selecting at least one magnetic material having a magnetic heating efficiency of about 4.10 ^"8 Jm / Ag when magnetic field conditions are equal to or less than 7.5 x 0 ⁷ A / ms; (ii) transport the magnetic material to the patient's diseased tissue; and (iii) exposing the material inserted into the patient at an alternating magnetic field of a frequency exceeding 10 kHz and a field strength such that the product of the field strength, the frequency and the radius of the exposed region is less than about 7.5.10 ⁷ A / ms to generate warming in diseased tissue Preferably, steps (i) through (iii) of the above method are repeated until the diseased tissue has been destroyed or treated sufficiently to alleviate the disease. Further, which magnetic particles are incorporated into biocompatible microcapsules that are administered so that they concentrate around a tumor vascular network. An external magnetic field is applied and the heat released by the material is conducted to the tumor tissue. The use of properly formulated microcapsules, magnetic field conditions and dosage of these particles ensure that tumors will be heated to lethal temperatures of around 42 ° C while sparing healthy tissue.

The material used is magnetic with a coercivity of less than 314 Oe, a heating efficiency of 4.5.10 ^"8 Jm / Ag and a cyclic magnetic field where the amplitude product and applied field frequency is less than or equal to 5.10 ⁸ A / ms , and the frequency of the applied field is at least 20 kHz. The material used may be a magnetite (Fe ₃ 0 ₄ ) or ferric oxide-γ (v-Fe ₂ 0 ₃ ) with a crystalline lattice in which some of the atoms of If the substituent atom can be from the cobalt, zinc, nickel, manganese, magnesium, copper, chromium, gallium or cadmium group, the magnetic material must have a cubic or and a diameter between 20 nm and 1 pm.

US 11 / 125,488 discloses that heat-generating magnetic nanoparticle compositions have been used in magnetic heating, particularly for magnetic hyperthermia applications in medical treatments, and a composition comprising nanomagnetic particles having a Curie temperature is envisaged. 40 to 46 ° C, preferably 42 ° C. In some experiments, magnetic particles include copper and nickel alloys (71 wt% nickel and 29 wt% copper), ferrite (Zn ferrite, Mn - Zn ferrite, Fe - Zn ferrite) or compositions ( Mn _{, 5} Zn _0.5 Gd _x Fe _(2- x) 0 ₄ , where 0 <x> 1, 5; Zn _x Mn _(1-x) Fe ₂ 0 ₄ , where 0.6 <x> 0.8 Fe ₍ i- _x) Zn _x Fe ₂ 0 ₄ where 0.7 <x> 0.9, or ZnGd _x Fe ₍ 2- _X ) 0 ₄ where 0.01 <x> 0.8) and also that in some publications the nanometer particles have an efficient mean diameter between 5 nm and 400 nm, and are coated or dispersed in a material biocompatible polymeric In some cases, the composition further includes at least one medicament.

The paper suggests some methods for treating patients requiring the use of the hyperthermia technique, one of which includes administering a composition containing magnetic nanoparticles having a Curie temperature between 40 and 46 ° C and exposing these magnetic particles. to an alternating magnetic field effective to generate the heating. It is emphasized that this composition should be administered to a tumor or other tissue-related diseases of the patient. Magnetic nanoparticles are preferably administered in a pharmaceutically acceptable carrier. Particles of the selected Curie temperature are either mixed in a liquid suspension or encapsulated within microcapsules which may then be mixed with a suitable biocompatible medium. Important properties of these microcapsules are diameter, which determines the proximity of the particle in diseased tissue, and density, which affects the efficiency of particle transport through blood flow. Biocompatible coatings have been used to minimize the metallic interaction of alloy particles with the body's biological components, and for in vivo use the biocompatible polymeric material should preferably be biodegradable. Examples of suitable polymers for this function are: ethylcelluloses, polystyrenes, poly (d, 1 - lactic acid) and poly (d, 1 lactic acid co-glycolic acid).

Nanoparticles may be obtained by various techniques, such as (a) by melting a material containing at least two different metals and, after solidification, subjecting the particles to a milling process; or (b) by chemical co-precipitation.

In general, magnetic particles are polymer-coated iron oxides, such as dextran (polysaccharide). Although such complexes have been used in vitro, any use in vivo has been limited due to the breakdown of the polymeric coating within the body.

US 10 / 543,063 discloses a microparticle composition comprising magnetic particles and a matrix which must be have at least one of the following properties: (a) a volumetric absorption rate of at least about 10 W / cm ³ , subject to appropriate field conditions; (b) a density less than or equal to 2.7 g / cm ³ ; or (c) a size in the range 100 nm to 200 pm.

Proper field conditions will depend on the nature of the object to be heated and the level of the selected volumetric absorption rate. In the case of microparticle compositions for human therapy application, the TAV should be at least 10 W / cm ³ when exposed to an alternating magnetic field, preferably between 60 and 120 Oe, and the frequency between about 50 and 300 ° C. kHz.

The particles of the compositions of US 10 / 543,063 are superparamagnetic. The term superparamagnetic is intended for magnetic particles that do not have the properties of remnant, coercivity or hysteresis curve. Thus, the volumetric heating rates resulting from the microparticle compositions are not the result of the hysteresis heating, but rather a physical mechanism called Néel relaxation.

It is known from US 10 / 543,063 document that the superparamagnetic particles are preferably nanometer size selected within the group of ferrites with the general formula MO.Fe ₂ 0 ₃ where M is a divalent metal such as Fe, Co, Ni Mn, Be, Mg, Ca, Ba, Sr, Cu, Zn, Pt, or oxides of the type M0.6Fe20 _3, where M is a large divalent ion such as metallic iron, cobalt or nickel. These particles may also be of Fe, Ni, Cr or Co or in oxides.

US 11 / 235,631 discloses a nanoparticulate material composed of a fatty acid-coated magnetic particle core and surfactant, and method of processing.

The core material may be any metal or a combination of metals including iron, cobalt, zinc, cadmium, nickel, gadolinium, chrome, copper, manganese and their oxides, and a magnetic particle may be composed of an alloy with a metal. like gold, platinum, silver or copper. The document further provides that the magnetic particle may be a free metal ion compound, a metal oxide or an insoluble metal compound. To prepare high saturation polarization (Js) magnetic particles, an inert gas condensation technique was employed. Iron-based nanoparticles produced by inert gas condensation exhibited an average size of 11.6 nm, while cobalt-based nanoparticles had an average size of 42 nm.

Fatty acid has several functions, such as protecting the nucleus of magnetic particles from oxidation and / or hydrolysis in the presence of water, which can significantly reduce magnetization of nanoparticles; stabilize the nanoparticle core; improve biocompatibility; and, serve as an interface for the attachment of surfactant hydrophobic groups. Fatty acid can be applied as a monolayer where the thickness is projected, controlling the length of the chain according to the percentage added to the metal nanoparticles. The amount of fatty acid used is generally 5 to 40% by weight of the magnetic particles. However, high percentages of applied fatty acids are expected to result in multiple coating layers.

Various core coatings may also be used, such as alginates, animal gelatin, polyalkanoates and other biopolymers.

According to US 11 / 235,631, nanoparticle compositions produced in accordance with the invention may be used in a variety of applications, including the delivery of therapeutic agents for the prevention and treatment of localized diseases, tumor heating by magnetic nanoparticles. , or in contrast for better resolution on magnetic resonance imaging. As shown in WO 2009137889, polymer granules incorporating magnetic particles are known by the state of the art and over the years various processes have been developed for their production.

This document deals with microgel polymeric granules having a polymer matrix with uniformly dispersed magnetic particles, where a steric stabilizer is associated with the particle, the steric stabilizer being a polymeric material that is not part of the polymeric matrix of the particles. beads, and magnetic nanoparticle is formed by iron, nickel, chromium, cobalt or their oxides, preferably magnetite (Fe ₃ 0 ₄₎ or magmita (gamma - Fe ₂ 03).

The product is used as a composition for the treatment of hyperthermia performed at a target site of interest such as cancerous tissue and for biomedical and diagnostic imaging applications using contrasts such as tissue hyperthermia induction for application in immunity assays.

"Recovery process of lanthanide-metal-metalloid alloy in nanoparticulate powder with magnetic recovery and product", filed on 07/01/2011 under No. 018110024898 at the National Institute of Intellectual Property - INPI (Brazil), with the Institute of Technological Research of the State of São Paulo - IPT. This patent application discloses the process used for preparing the particulate material disclosed in this invention.

SUMMARY OF THE INVENTION

The product consists of a particulate material, with or without the presence of an organic and / or inorganic biocompatible coating: fatty acids such as oleic acid, polysaccharides, animal or vegetable protein, chitosan, gums (gum arabic, xanthan gum, guar gum, carrageenan gum, cashew gum, tara gum, tragacanth gum, Karaya gum, gati gum), cellulose derivatives (carboxymethyl cellulose, carboxyethyl cellulose, etc.), polyvinylpyrrolidone, poly (meta) acrylates, poly (meta) acrylamides, polyesters, polyvinylcaprolactams, polyamides, polyvinyl alcohol or blends of such polymers, derived from an alloy composed of at least one element of the lanthanide group (LA), at least one transition metal (MT) and at least one metalloid (ML). This league will be represented by LA-MT-ML. The described material may be obtained by a physical, chemical or a combination of both, and its novelty and inventive activity is to control the heat or magnetic characteristics of the alloy, which may be obtained by mixing pure elements, mixtures. It can be used in applications where localized heating is required, for example in resin and cement cures and in applications for the treatment of cancerous tissues and biomedical and diagnostic imaging applications using contrasts. DESCRIPTION OF DRAWINGS

Figure 1 - Graph of the relationship between magnetic properties (magnetic moment per unit mass at μ ₀ Η = 2T and intrinsic coercivity) as a function of milling time. Figure 2 - X-ray diffractograms showing the structural evolution of the particulate material prepared with different milling times.

Figure 3 - Photographs taken by scanning electron microscope (10,000x) showing particles obtained with different grinding times: (a) 10 minutes and (b) 10 hours. Figure 4 - Photographs taken by scanning electron microscope (100,000x) showing particles obtained with different grinding times: (a) 10 minutes and (b) 10 hours.

Figure 5 - Transmission electron microscope photographs showing particles obtained with grinding time of 10 hours: (a) three particles (b) highlighted in one of the particles shown in (a).

Figure 6 - Variation of the temperature increase as a function of the grinding time employed to obtain the particles.

Figure 7 - Graph of cytotoxicity test in two samples.

Figure 8 - Photograph taken by transmission electron microscope of a Pr ₈ Fe86B6 particle obtained after high energy milling for 5 hours.

Figure 9 - Curing of hysteresis powder with nominal composition Pr ₈ Fe86B ₆ , after grinding at 900 rpm for 5 hours.

Figure 10 - X-ray diffractograms of Pr ₈ Fe ₈₆ B6 powders as a function of milling time.

Figure 1 1 - Heating profile Powder of nominal composition Pr ₈ Fe ₈₆ B ₆ processed at 900 rpm for 5 hours.

Figure 12 - Heating profile Pri2Fe ₈₂ B ₆ nominal composition powder processed at 900 rpm for 5 hours. Figure 13 - Hysteresis curve of magnetic powder of nominal composition Pri ₂ Fe ₈ 2B6 after grinding at 900 rpm for 5 hours.

DETAIL OF THE INVENTION

The nanoscale powder preparation process may involve a physical, chemical process or a combination of both. Below is a physical process and methodology for verifying cytotoxicity.

A. Preparation of Nanometric Particles from Discarded Industrial Sintered Magnets

Among the state-of-the-art processes for particle production, the process can be adopted from discarded industrial sintered magnets, such as the "Magnetic Recovery Nanoparticulate Powder Lanthanide-Metal-Metalloid Alloy Recovery Process", filed on July 1, 2011 under No. 018110024898 at the National Institute of Intellectual Property - INPI (Brazil), with the Institute of Technological Research of the State of São Paulo - IPT as the holder, or from the production of magnetic alloy.

This process is initiated with heat treatment demagnetization using a temperature higher than that of the Curie temperature of the LA-MT-ML compound, and the heat treatment time should be as long as necessary for temperature stabilization on the parts. The heat treatment atmosphere may be oxidizing or inert. The chemical composition of the alloy used as a starting material should be such that the LA ₂ -MTi ₄ -ML phase (usually Nd ₂ Fe ₁₄ B, but not exclusively) is present in at least 10% of the volume of material used.

After the demagnetization step, the surface coating of heat treated parts should be removed using chemical means such as solvents or physical means such as sanding. This second process was used in the present invention.

Then sintered magnets without surface coating should be inserted into a pressurization vessel, which must be connected to a gas line for the insertion of hydrogen or any other gas having hydrogen in its composition, as well as to a gas pumping system such as a mechanical vacuum pump. The pressure vessel must be made of a material that does not absorb any kind of gas. Such a system may be considered an oven, the ends of which may be sealed.

Once the pressurization system is sealed, hydrogen or any other hydrogen-containing gas should be inserted into its composition, preferably high purity hydrogen. The hydrogen insertion temperature should be between 25 ° C and 180 ° C, preferably 100 ° C, and the initial hydrogen pressure should be between 0.1 atm and 10.0 atm, preferably 2.0 atm. The exposure time of the material to hydrogen is from 10 minutes to 180 minutes, preferably 60 minutes.

After this step, the final material must have hydrogen in its composition, in addition to the lanthanide, transition metal and metalloid elements, where the amount of hydrogen will depend on the conditions under which the hydrogenation process was performed.

After complete absorption of hydrogen by the sintered magnets, the pressurization system must be opened and the resulting material transferred to a milling equipment. The comminution step should occur on any type of grinding equipment, preferably in a planetary ball mill. The mass ratio of the grinding bodies to the material to be ground may range from 1: 1 to 100: 1, preferably from 20: 1, and the grinding bodies may be of any geometric shape, preferably spherical. The mixture of hydrogenated material and grinding bodies must be immersed in a liquid capable of protecting the particulate material from oxidation, so any non-oxygen containing liquid can be used, preferably cyclohexane. A surfactant may also be added to prevent particle welding during the milling step, preferably oleic acid, in the proportion of 0.01% to 10% by weight of particulate material, preferably 0.1% by weight. Grinding time may range from 5 minutes to 50 hours, preferably from 3 hours to 20 hours, more preferably 10 hours. The rotational speed of the milling process may range from 100 to 1200 rpm, preferably 900 rpm. Oleic acid will remain surrounding the particles avoiding oxidation after grinding.

During the grinding stage, the particulate material will heat up and may lead to disproportionate phase LA ₂ -MTi -ML. This means that there is a possible separation of the magnetically hard phase, generating as possible new hydride phases of the lanthanide element, Fe2B, FesB and other metastable compounds.

Based on the conditions described above, it is possible to prepare a nanoscale powder with particle size ranging from 10 to 1000 nm, magnetic moment between 60 Am ² kg ^"1 and 130 Am ² kg ^{" 1} and intrinsic coercivity between 4 kAm ^" up to 70 kAm ^" . The nanometric material obtained shall be exposed to an alternating magnetic field with an intensity between 8 kAm ^"1 and 55.7 kAm ^{" 1} and a frequency between 10 kHz and 700 kHz. The heating of the described material may be modified from the conditions employed in the preparation of the powder as well as the experimental conditions of the assay. For the first case, for example, process variables such as milling time, milling pot rotation and the amount of oleic acid can be modified individually or together. Referring to the second case one can change the amplitude of the magnetic field applied to the magnetic particles or the frequency of the magnetic field.

B - Cytotoxicity Assay

The cytotoxic activity of two different samples ground for 3 hours or 10 hours (identified as H3 and H10, respectively) was assessed by the MTT [3- (4,5-dimethyl-2-thiazolyl-2,5-diphenyl- 2H-tetrazolium bromide)]. MTT is a yellow-colored salt capable of capturing electrons from the electron transport chain in an oxy-reduction reaction. When reduced by metabolically viable cell dehydrogenase enzymes, it forms purple-colored crystals, Formazan. These Formazan crystals are water insoluble and have an absorption peak at 570 nm. All cells were grown in a CO2 greenhouse (5% CO2 - Cole Parmer) in a humid atmosphere at 37 ° C in Dubelcco's Modified Eagle's Essential Medium (DMEM) supplemented with 10% (by volume) fetal bovine serum (SFB). ) and 1% penicillin / streptomycin (complete DMEM medium). Upon reaching 80% confluence, the cells were trypsinized (cell expansion) and cell viability was assessed by Trypan blue exclusion.

Trypan blue is a high molecular weight dye that is only able to enter dead cells or that have increased membrane permeability. The assessment of cell viability by Trypan blue exclusion consists of incubating the cells for 1 minute with this dye and quantifying them with the aid of a Neubauer chamber. Perfectly alive living cells (impermeable membrane) remain colorless and dead cells or with increased membrane permeability are displayed in blue. Viable (colorless) cells were used in the experiments (passage range: 5-20).

Human pulmonary fibroblast MRC-5 cells were seeded in 2000 cell / well culture plates, 96-well plate and incubated for 24 hours for adherence. After this time, different concentrations of samples H3 and H10 (200; 100; 50; 10 and 1 Mg / mL) were added to the adhered cells. Then the cells were incubated again for a further 48 hours. After this time, cells were incubated with MTT (0.5 mg / mL) for 4 hours in the dark. Subsequently, the MTT-containing supernatant was removed and 100 μΙ DMSO were placed in each well to solubilize Formazan crystals. Samples were measured by spectrophotometry on a UV-visible microplate reader at 570 nm. The survival fraction was calculated as a percentage of control (Absorbance in control = 100% survival). The experiments were done in quadruplicates. The IC 50 value (concentration of compound that produced 50% cell death) of Culac, Lac, Lacm, Lacpt compounds were determined graphically. Morphological aspects of MRC-5 cells were analyzed by optical microscopic observation of control cells and those treated with H3 and H 10. Tests were performed in parallel using dimethylsulfoxide (DMSO) as negative control, as H3 and H10 were pre-dissolved in 0.5% DMSO.

EXAMPLE 1

Ten grams of the compound Ndi _4, ₆ 5Fe79B 5 was hydrogenated with an initial pressure of high purity hydrogen of 2.0 atm in a pressurized vessel at a temperature of 100 ° C for 60 minutes. At the end of this step, the material was transferred to a grinding pot with spherical grinding bodies at a 20: 1 mass ratio. Cyclohexane and oleic acid (the latter in the proportion 0.1% by weight of particulate material) were added to the pool. The grinding pot was closed and taken to a planetary ball mill where the process was carried out for 0 hours at 900 revolutions per minute.

Then the material was dried and characterized.

The material consists of iron nanoparticles along with other phases that have in their composition Nd and B. The magnetic particles have a size ranging between 25nm and 100nm, have a magnetic moment per unit mass of the order of 70 Am ² kg ^"1 and coercivity. 8 kAm ^" . The influence of milling time on the magnetic properties of the prepared powders is shown in Figure. Figure 2 shows the X-ray diffractograms of ground materials. After 15 minutes, there is a variation of the present peaks, indicating the existence of the disproportion process, as mentioned above. Figures 3, 4 and 5 show the agglomerates and particles obtained after 10 minutes and 10 hours of milling.

Heating tests under an applied magnetic field of 3.82 kAm ^"1 and a frequency of 228 kHz: the results, shown in Figure 6, indicated a temperature variation of the order of 45 ° C, much higher than that required for hyperthermia applications. Therefore, the conditions may be reduced, which makes it possible to use a smaller amount of magnetic material. Toxicity tests indicated that the material prepared under the conditions described may not be harmful or that the amount employed in the The test is insufficient to cause acute damage to cells isolated from the body, as shown in Figure 7. However, it cannot be stated that the materials can be considered biocompatible since the in vivo toxicity test was not performed for material analysis. . EXAMPLE 2

A second example was the preparation of a nanoscale magnetic powder whose production process is similar to that described in EXAMPLE 1, only changing the milling time from 10 hours to 3 hours. In this example, the particle size is within the range of the present patent as well as its magnetic properties. With regard to heating, this material exhibited a warming lower than that of the material prepared with 10 hours of grinding, as shown in Figure 6. EXAMPLE 3: Preparation of nanometric particles from the mixture of alloys or elemental powders.

This process is started from crushing LA-MT-ML type alloys with an average diameter of 0.5 cm. The stoichiometric proportions of each alloying element were in the following ranges: LA - from 1% to 16% of the alloy atoms, MT - from 74% to 98% of the alloy atoms and ML - from 1% to 10% of the alloy atoms. alloy atoms.

The alloy pieces were inserted into a pressurization vessel, which should be connected to a gas line. Gas pumping is also required, which can be performed using a vacuum pump connected to the pressure vessel system, which in turn is connected to a gas line. This pressurization vessel must be designed so that it can be inserted into an oven.

Once the alloy has been inserted into the pressurization vessel, and it is inserted and sealed in the oven, high purity hydrogen is preferably injected into the system. The initially injected gas pressure may range from 0.1 atm to 10 atm, preferably 1 atm. The system is heated until hydrogenation of the alloy is achieved. The temperature for the occurrence of this phenomenon is between 60 and 120 ° C, preferably 100 ° C, maintaining at this temperature between 15 and 30 minutes, preferably 23 minutes. After hydrogenation of the alloy, the system was heated to 770 ° C when hydrogen liberation from the alloy occurs. Alloy disproportion occurs with increasing pressurization vessel temperature between 800 and 900 ° C, preferably 840 ° C.

The disproportion and recombination steps of the initially inserted alloy occur at the same temperature as the disproportion under vacuum for a period of from 1 to 180 minutes, preferably 5 minutes and 30 seconds. After this period, the pressurization vessel is cooled.

The dust resulting from this heat treatment is removed from the system and transferred to a grinding pot. The milling process can be carried out in any type of high energy mill, preferably in a planetary type ball mill. The mass ratio of the grinding bodies to the material to be milled may range from 1: 1 to 100: 1, preferably from 10: 1. Grinding bodies may be of any geometric shape, preferably spherical. The heat treatment dust and grinding bodies must be immersed in a liquid capable of protecting the particulate material from oxidation. Therefore, any non-oxygen containing liquid in its composition may be used, preferably cyclohexane. A surfactant may also be added to prevent particle welding during the milling step, preferably oleic acid, in the proportion of 0.01% to 10% by weight of particulate material, preferably 0.1% by weight. Grinding time may range from 5 minutes to 50 hours, preferably 5 hours. The rotational speed of the process may range from 100 to 1200 revolutions per minute, preferably 900 revolutions per minute.

The last step for obtaining nanoparticulate materials is drying, which can be performed under controlled or uncontrolled atmosphere, preferably in a glovebox containing inert gas inside.

The process described above can be carried out not only with commercial alloys but also from alloy mixtures, for example: a Pr ₁₄ Fe ₈ oB ₆ alloy with Fe-α and FeB added or by mixing LA powders + MT + LA according to appropriate stoichiometric calculations to obtain a desired desired compound.

From the experimental conditions described above, nanoscale powders with particle size between 10 and 1000 nm can be obtained. The magnetic moment of the material may range from 60 Am ² kg ^"1 to 50 Am ² kg ^{~ 1.} Intrinsic coercivity may range from 4 kAm ^{" 1} to 70 kAm ^" .

The heating of the material can be controlled / modified by varying the chemical composition of the alloy, the milling time, the amount of surfactant added (oleic acid, for example), the speed of rotation, or by changing the frequency of the magnetic field or the amplitude of the external magnetic field applied to the powder.

An example of preparation of nanomagnetic material is described below.

Ten grams of the Pr ₈ Fes6B6 alloy were subjected to hydrogenation, disproportionation, desorption and recombination treatment according to the following parameters: the system was vacuumed at about 10 ^{~ 1} mbar followed by the addition of 1 atm hydrogen peroxide. high purity. This system was heated at a rate of 0 ° C / min until it reached 100 ° C, where the alloy was subjected to the hydrogenation stage at a 23-minute level. After hydrogenation of the alloy, the system was heated at a rate of 15 ° C / min until hydrogen evolution occurred at 770 ° C (2 min. Level), then heated at a rate of 4 ° C. / min until reaching 840 ° C, maintaining a 15-minute plateau, where the disproportion of the alloy occurred. Then, the alloy desorption and recombination steps were performed at the same temperature, at 840 ° C and under vacuum (until it reached 10 ^"1 mbar) for 5 minutes and 30 seconds. Then, the pressurization vessel was removed from the oven and cooled quickly using a water-cooled copper coil.

The resulting material was transferred to a grinding vessel with spherical grinding bodies at a 10: 1 mass ratio. Cyclohexane and oleic acid (0.1% by weight relative to powder) were added. The grinding pot was closed and taken to a planetary ball mill where the process was carried out for 5 hours with the pot rotating at 900 rpm. After grinding, the powder was dried and characterized. The resulting material has a diameter of the order of 10 nm, as shown in Figure 8. The magnetic properties obtained were: 13.3 kAm ^"1 of coercivity and magnetic saturation moment per mass unit of the order of 118 Am ² kg ^{" 1} , as shown in Figure 9.

From the X-ray analyzes presented in Figure 10, phases of Pr ₂ Fei ₄ B and Fe-α were identified. Heating measurements were performed on equipment that simulates hyperthermia treatment using an alternating magnetic field with intensity of 3.82 kAm ^"1 and frequency of 228 kHz. The heating profile for the powder of nominal composition Pr ₈ Fe ₈ 6B ₆ is shown in Figure 11 and the temperature range was around 41 ° C.

In vitro toxicity tests were performed and indicated that the material obtained from the process route described above may not be harmful to the body cells, or the amount of material required for the treatment of hyperthermia is small such that insufficient to cause acute damage to isolated body cells.

By changing the magnetic powder alloy composition, such as for the Pr ^ FesaBe composition, and processed in the same manner as the example described above, a heating variation was obtained from the simulation of the 34 ° C hyperthermia treatment, as shown in Figure 12. The magnetic properties of said powder can be obtained from its hysteresis curve (at _sat = 86 Am ² kg ^"1 and Hc = 6.69 kAm ^{" 1} ), shown in Figure 13.

Claims

"NANOPARTICULATED MAGNETIC MATERIAL FOR THERMAL APPLICATIONS", obtained by a physical, chemical process or a combination of both, consisting of microparticulate material consisting of an alloy composed of at least one element of the lanthanide (LA) group at least at least one transition metal (MT) and at least one metalloid (ML), obtained from the mixing of pure elements, alloy mixtures or recycling of already manufactured products, having particle size ranging from 10 to 1000 nm, momentum between 60 Am ² kg ^"1 and 130 Am ² kg ^{" 1} and intrinsic coercivity between 4 kAm ^"1 to 70 kAm ^{" 1} , and have been exposed to an alternating magnetic field with intensity between 8 kAm ^"1 and 55.7 kAm ^{" 1} and frequency between 10 kHz and 700 kHz for generating alloy heat control conditions; used for treatment for hyperthermia performed in cancerous tissues or in biomedical and diagnostic imaging applications using contrasts, resin cures and cements;

"NANOPARTICULATED MAGNETIC MATERIAL FOR THERMAL APPLICATIONS" according to claim 1, optionally having organic or inorganic biocompatible coating or combinations thereof;

"NANOPARTICULATED MAGNETIC MATERIAL FOR THERMAL APPLICATIONS" according to Claim 1 or 2, characterized in that the material particle is fatty acid coated when not coated with biocompatible coating;

"NANOPARTICULATED MAGNETIC MATERIAL FOR THERMAL APPLICATIONS" according to Claim 3, characterized in that a fatty acid is oleic acid;

"NANOPARTICULATED MAGNETIC MATERIAL FOR THERMAL APPLICATIONS" according to Claim 1 or 2, characterized in that the biocompatible coating is polysaccharides, a protein of animal origin. or vegetable, chitosan, gums (gum arabic, xanthan gum, guar gum, carrageenan gum, cashew gum, tara gum, tragacanth gum, karaya gum, gati gum), cellulose derivatives (carboxymethyl cellulose, carboxyethyl cellulose, etc.), polyvinylpyrrolidone poly (meta) acrylates, poly (meta) acrylamides, polyesters, polyvinylcaprolactams, polyamides, polyvinyl alcohol or blends of such polymers;

6. "NANOPARTICULATED MAGNETIC MATERIAL FOR THERMAL APPLICATIONS" according to Claim 1, characterized in that the material particle is LA-MT-ML, where the LA content may vary from 1% to 16% of the atoms of alloy, the MT content may range from 74% to 98% of the alloy atoms and the ML content may range from 1% to 10% of the alloy atoms;

"NANOPARTICULATED MAGNETIC MATERIAL FOR THERMAL APPLICATIONS" according to claim 1, characterized in that it contains hydride phases of the lanthanide element, Fe ₂ -3, Fe ₃ B and other metastable compounds due to heating during the grinding process;

8. "NANOPARTICULATED MAGNETIC MATERIAL FOR THERMAL APPLICATIONS" according to claim 1, characterized in that the material is obtained by a physical, chemical process or a combination of both which provides control of the heating of the alloy and is obtained from mixing pure elements, mixing alloys or recycling already processed products;

9. "NANOPARTICULATED MAGNETIC MATERIAL FOR THERMAL APPLICATIONS" according to Claim 1 or 8, characterized in that it is produced by the "Magnetic Recovery Nanoparticulate Powder and Product Recovery Lanthanide-Metalloid Alloy Recovery Process" filed 01/01 07/2011 under number 018110024898 at the National Institute of Intellectual Property - INPI (Brazil), owned by the Institute of Technological Research of the State of São Paulo - IPT.