KR100584086B1 - Method for fabricating biomedical superparamagnetic nanocomposite powders - Google Patents

Abstract

The present invention relates to a method for producing a superparamagnetic nanocomposite powder, comprising a metal oxide / ceramic nanocomposite powder in which metal oxide nanoparticles of uniform size having superparamagnetism are uniformly dispersed on a ceramic matrix by using ultrasonic spray pyrolysis. It is an object of the present invention to provide a method for economically manufacturing the same. In order to achieve the above object, a method for producing a superparamagnetic nanocomposite powder is prepared by adding and stirring a superparamagnetic dispersed phase and a ceramic matrix phase raw material into a solvent to prepare a solution, spraying the solution with an ultrasonic atomizer, and Spraying the sprayed droplets into a preheated chamber; pyrolyzing the spray; and collecting the powder produced after the pyrolysis.

Ultrasound, Superparamagnetic, Ferrimagnetic, Blocking Temperature, Pyrolysis, Nanocomposite Powder, Local Thermal Therapy, Drug Delivery System

Description

Manufacturing method of medical superparamagnetic nanocomposite powder {METHOD FOR FABRICATING BIOMEDICAL SUPERPARAMAGNETIC NANOCOMPOSITE POWDERS}

1 is a schematic configuration diagram of an ultrasonic spray pyrolysis apparatus for producing a superparamagnetic metal oxide / ceramic nanocomposite powder according to the present invention.

2 is a flow chart of a method for producing a superparamagnetic metal oxide / ceramic nanocomposite powder according to the present invention.

Figure 3 is a transmission electron micrograph of the γ-Fe ₂ O ₃ / MgO nanocomposite powder synthesized at 600 ℃ in accordance with a first embodiment of the present invention.

Figure 4 is a transmission electron micrograph of γ-Fe ₂ O ₃ / MgO nanocomposite powder synthesized at 800 ℃ in accordance with a second embodiment of the present invention.

5 is a graph showing the magnetic properties of γ-Fe ₂ O ₃ / MgO nanocomposite powder synthesized at 800 ℃.

6 is a graph showing the magnetic loss according to the change of frequency under the applied magnetic field of 6mT.

<Explanation of symbols for the main parts of the drawings>

100: ultrasonic nebulizer

110: solution source

120: carrier gas source

130: ultrasonic vibrator

200: reactor

210: chamber

220: burner

230: temperature sensor

240: temperature controller

300: collector

310: capture filter

320: pump

The present invention relates to a method for producing a superparamagnetic nanocomposite powder, and in particular, to prepare a superparamagnetic metal oxide / ceramic nanocomposite powder applied to medical fields such as drug delivery system, magnetic resonance analysis, protein separation purification and heat treatment. It is about a method.

Recently, research on nanocomposites has been carried out around the world. Metal nanoparticle-dispersed ceramic composites are a new concept of composites with excellent mechanical and magnetic properties. In particular, these composite materials include metal nanoparticles such as nickel (Ni), cobalt (Co), tungsten (W) and titanium (Ti) in the order of tens to hundreds of nanometers (nm), and alumina (Al ₂ O ₃ ) and magnesia ( It is a composite material dispersed on ceramic matrix such as MgO) and silica (SiO ₂ ), and the mechanical strength is improved by about 1.3 times and the cohesive force, which is one of the important properties of magnetic properties, is tens or hundreds of times or more. Order).

As a manufacturing process of such a composite material, a metal nitrate to be a metal source is first dissolved in alcohol, then mixed with a ceramic powder to be known as a base material, and then a composite powder is prepared through calcination / reduction, followed by sintering. To prepare. However, such research on nanocomposites is limited to sintered bodies, and research on nanocomposites themselves is insufficient. In addition, the production of nanocomposite particles in which superparamagnetic nanoparticles are dispersed / coated on paramagnetic substrates is almost carried out by a deposition method (PVD, CVD, MOCVD, etc.), which also controls the particle size of metal (or metal oxide) particles. It is not easy, and there is a limit to the control of physical properties as well as economic problems. In particular, research on the practical application of drug delivery system (DDS), protein separation purification, and heat treatment by coating non-metal magnetic metal oxide with nonmagnetic materials is in the early stages of the world. Secondary particle size control is also important for applications, but it is impossible to control dozens of microns in the submicron region.

On the other hand, magnetic particles having superparamagnetic properties tend to aggregate with each other in order to be thermodynamically stable due to the nano-sized particle size. For this reason, a coating method using an organic material or an inorganic material has been proposed to implement the superparamagnetic property. However, as described above, there are various problems.

For example, the preparation of a conventional superparamagnetic powder, using the sol-gel method, using iron nitrate or iron chloride as the starting material on the metal oxide, and using the TEOS as the starting material on the superparamagnetic γ- Fe ₂ O ₃ phase SiO the portrait coating on the _second magnetic γ-Fe ₂ O ₃ / SiO "formed of only the silica matrix dispersed γ-Fe ₂ O ₃ nanoparticles" ₂ composite powder production method of the ( "formation of γ-Fe ₂ O ₃ isolated nanoparticles in a silica matrix, "F. del Monte, MP Morales, D. Levy, A. Fernandez, M. Ocana, A. Roig, E. Moolins, K. O'Grady, and CJ Serna, Langmuir, Vol. 13, No. 14, 1997, 3627-3634.

In addition, Korean Patent Application No. 10-2002-0048079 (superparamagnetic oxide particles, preparation method thereof and use thereof) contains a superparamagnetic metal oxide domain having a diameter of 3 to 20 nm in a nonmagnetic metal or metalloid oxide matrix, and contains a chloride content. Pyrolysis oxide particles having a size of 50 to 1000 ppm, a preparation method thereof, and a use thereof are disclosed. This produces oxide particles by pyrolysis by mixing the precursor of the superparamagnetic domain and the precursor of the nonmagnetic metal or metalloid oxide matrix with air and / or oxygen and fuel gas in the flame and reacting the mixture in the flame.

However, this conventional technique produces superparamagnetic powders using chloride as a precursor and pyrolysis using flames, so that not only γ-Fe ₂ O ₃ but also α-Fe ₂ O ₃ phase are produced and a large amount of the obtained material is obtained. It contains chloride, making it unsuitable for practical medical use. Therefore, the pyrolysis oxide particles, that is, the composite powder, prepared according to the conventional method are not easy to control the particle size, so that it is difficult to obtain particles of uniform size. In addition, the manufacturing method of the superparamagnetic powder according to the prior art takes a lot of time in the process, such as undergoing a heat treatment process for a long time increases the manufacturing cost, which is not suitable for mass production.

An object of the present invention is to solve the above-mentioned problems of the prior art, a metal oxide / ceramic nanocomposite in which metal oxide nanoparticles of uniform size having superparamagnetism are uniformly dispersed on a ceramic matrix by using ultrasonic spray pyrolysis. It is to provide a method for easily preparing a powder.

Another object of the present invention is to provide a method for preparing a metal oxide / ceramic nanocomposite powder which can easily control the particle size and particle size distribution of the powder.

Method for producing a superparamagnetic nanocomposite powder for achieving the above object of the present invention is to prepare a solution by adding and stirring a superparamagnetic dispersed phase and ceramic matrix-based raw material containing a metal nitrate in a solvent, and ultrasonically spraying the solution Spraying with the apparatus, spraying the sprayed droplets into a preheated chamber, pyrolysing the spray, and collecting the powder produced after the pyrolysis.

The metal nitrate of the superparamagnetic dispersed phase raw material may include Fe (NO ₃ ) ₃ 9H ₂ O, Ni (NO ₃ ) ₂ 6H ₂ O, or Co (NO ₃ ) ₂ 6H ₂ O. Meanwhile, the ceramic matrix-based raw material may include Mg (NO ₃ ) ₂ 6H ₂ O or SiCl ₄ . The solvent may include a pure or alcoholic solvent. It may include adjusting the size of the initial powder by appropriately adjusting the mixing ratio of the superparamagnetic dispersed phase and the ceramic matrix phase raw material, the concentration of the solution or the ultrasonic spray by controlling the mixing ratio of the superparamagnetic dispersed phase and ceramic matrix phase raw material and the solvent Adjusting the frequency of the device may include adjusting the size of the final powder is secondary particles. Injecting the sprayed droplets into the preheated chamber may comprise spraying the droplets into a heating chamber using a carrier gas, the carrier gas being air, oxygen, nitrogen, an inert gas or a mixture of these gases. It may include a gas. On the other hand, the temperature of the step of pyrolyzing the spray may be 500 ℃ to 1000 ℃. In addition, the powder produced after the pyrolysis may be a dispersed type in which the superparamagnetic dispersed phase is uniformly dispersed on a ceramic matrix, in which case the produced powder has a size of less than micron.

The superparamagnetic nanocomposite powder for achieving the above object of the present invention is prepared using the above method.

Figure 1 shows a schematic configuration of the ultrasonic spray pyrolysis apparatus used to prepare the superparamagnetic metal oxide / ceramic nanocomposite powder according to the present invention. As shown in FIG. 1, the ultrasonic spray pyrolysis apparatus may be basically divided into three regions, an ultrasonic spraying zone A, a heat treatment zone B, and a collecting zone C. FIG. The process in each of these areas of the ultrasonic spray pyrolysis apparatus is performed in the ultrasonic nebulizer 100, the reactor 200, and the collector 300, respectively. A solution source 110 and a carrier gas source 120 are connected to the ultrasonic nebulizer 100, and an ultrasonic vibrator 130 is mounted below the ultrasonic nebulizer 100. The solution source 110 supplies the ultrasonic nebulizer 100 with a solution in which superparamagnetic dispersed phase and ceramic matrix phase raw materials are dissolved in a solvent. The ultrasonic vibrator 130 at the bottom of the ultrasonic nebulizer 100 sprays the solution supplied from the solution source 110 into droplets of several microns in size. The sprayed droplets are moved into the chamber 210 of the reactor 200 by using a carrier gas supplied from the carrier gas source 120. The reactor 200 is a device for maintaining the temperature in the chamber 210 at a desired value, and includes a heater 220 mounted around the chamber, a temperature sensor 230 and a temperature controller 240 mounted in the chamber. . The temperature controller 240 maintains the temperature in the chamber 210 at the set temperature by controlling the heater 220 based on the temperature in the chamber received from the temperature sensor 230. Droplets introduced into the chamber 210 of the reactor 200 together with the carrier gas are pyrolyzed at a set temperature. A collector 300 including a collecting filter 310 and a pump 320 is provided at the top of the reactor 200 to collect various powders generated at the same time while emitting various gases generated during the pyrolysis reaction. That is, in the chamber 210 of the reactor 200, the reaction powder and the various gases generated during the pyrolysis reaction are passed through the collector 300 by the pump 320, wherein the generated powder is generated after the pyrolysis. The powder is trapped by the collecting filter 310, and various gases generated during the pyrolysis reaction are discharged to the outside through the collecting filter 310.

A method for preparing a superparamagnetic nanocomposite powder according to the present invention will be described with reference to FIG. 2. First, as a starting material for the superparamagnetic nanocomposite powder, Fe (NO ₃ ) ₃ 9H ₂ O, Ni (NO ₃ ) ₂ 6H ₂ O, Co (NO ₃ ) ₂ 6H ₂ O, or the like as a metal (or metal oxide) dispersed phase. Metal nitrate is used, and Mg (NO ₃ ) ₂ 6H ₂ O, SiCl _4, and the like are used as the ceramic matrix. As such, all raw materials that are soluble in nitrate hydrate, as well as other pure water (ultra pure water) or alcohol solvents can be used. The superparamagnetic dispersed phase and ceramic matrix phase raw materials are added to the ultrapure water at an appropriate ratio and sufficiently stirred (S1 in Fig. 2). At this time, the size of the primary magnetic particles can be adjusted by appropriately adjusting the mixing ratio of the superparamagnetic dispersed phase and the ceramic matrix phase raw material. That is, the volume ratio of the dispersed phase to the matrix phase is about 0 to 50%, and as the volume ratio increases, the size of the magnetic particles (primary particles) also increases. In addition, the size of the secondary particles can be adjusted by adjusting the concentration of the solution by the mixing ratio of the starting materials (superparamagnetic dispersed phase and ceramic matrix phase raw materials) and the solvent. In this case, as the concentration of the solution increases, the size of the secondary particles also increases. The prepared solution is sprayed in an ultrasonic spray device (vibrator frequency of several tens kHz to 3MHz) (S2 of FIG. 2). At this time, the droplets sprayed by the ultrasonic vibrator are sized by factors such as the frequency of the vibrator and the concentration of the solution, which can be theoretically calculated. In the present invention, a vibrator having a frequency of 1.67 MHz was used, and the droplet size was about 3 microns. As the oscillation frequency increases, the size of the droplets is reduced, and the size of the secondary particles produced is also reduced. The sprayed droplets are injected by the carrier gas into the chamber previously heated to the set temperature (500 to 1,000 ° C.) (S3 in FIG. 2). This spray produces a pyrolysis reaction in the chamber (S4 in FIG. 2) to produce a metal oxide / ceramic nanocomposite powder in which the superparamagnetic dispersed phase is uniformly dispersed on the ceramic matrix together with NOx and H ₂ O. The resulting nanocomposite powder is collected (S5 in FIG. 2), and NOx and H ₂ O are released to the outside. This entire reaction process is usually carried out under atmospheric pressure.

NOx is generated using an aqueous solution of nitrate as a starting material, but this is relatively environmentally friendly because the main by-product generated during the process is water because it is used in a small concentration below the decimal point. The metal oxide / ceramic nanocomposite powder produced by the ultrasonic spray pyrolysis method forms secondary particles whose primary particles between about 5 and 30 nm are smaller than microns. If the γ-Fe ₂ O ₃ of the γ-Fe ₂ O ₃ / MgO dispersed in the MgO matrix superparamagnetic properties when the particle size of 10nm amount of γ-Fe ₂ O _3.

Example 1

As a specific example, Fe (NO ₃ ) ₃ 9H ₂ O was used as the metal oxide dispersed phase and Mg (NO ₃ ) ₂ 6H ₂ O was used as the ceramic matrix phase. At this time, the reason why Mg (NO ₃ ) ₂ 6H ₂ O was chosen as the ceramic matrix is 1) It is thermodynamically stable when it becomes dispersed magnetic particles from the metal mixed salt by calcination process, so that superparamagnetic / paramagnetic nanocomposite powder can be easily obtained. , 2) MgO and SiO ₂ generated after calcination have the advantage of easily adsorbing OH groups on the surface. The final product (Fe / MgO) was weighed to a volume ratio of 2: 8 and dissolved in ultrapure water at a concentration of 0.2 mol. The prepared solution is sprayed by an ultrasonic atomizer (frequency 1.67 MHz) and moved by a carrier gas into a chamber previously heated to a set temperature (600 ° C.) to cause a pyrolysis reaction. The carrier gas used at this time may include air, oxygen, nitrogen, an inert gas or a mixture of two or more of these gases. NOx and H ₂ O were released by this pyrolysis reaction to form a metal oxide / ceramic nanocomposite powder. The whole reaction process was under atmospheric pressure.

FIG. 3 is observed with a transmission electron microscope of a metal oxide / ceramic nanocomposite powder (γ-Fe ₂ O ₃ / MgO) prepared by the method of Example 1 (synthesis temperature 600 ° C.) in the ultrasonic spray pyrolysis apparatus of FIG. It is a photograph. In the photograph of FIG. 3, B) is a photograph enlarged by 5 times A). As can be seen in the photo, the metal oxide / ceramic nanocomposite powder (γ-Fe ₂ O ₃ / MgO) having a primary particle size of 5 nm or less and a secondary particle size of less than micron can be obtained. can confirm.

Example 2

In Example 2, γ-Fe ₂ O ₃ / MgO nanocomposite powder was prepared in the same manner as in Example 1 except that the pyrolysis temperature of 600 ° C. was changed to 800 ° C.

4 is a photograph taken with a transmission electron microscope of a metal oxide / ceramic nanocomposite powder (γ-Fe ₂ O ₃ / MgO) prepared by the method of Example 2 (synthesis temperature 800 ° C.). In the photograph of FIG. 4, B) is a photograph enlarged by 20 times A). As can be seen from the photograph, it can be seen that the size of the primary particles is slightly larger compared to Example 1 at about 10 nm. This is because the grain growth of the primary particles occurs with the increase of the synthesis temperature from 600 ℃ to 800 ℃. By controlling the temperature, the size of the primary particles can be adjusted from several nanometers to several tens of nanometers.

5 is a hysteresis (MH) loop showing superparamagnetic properties of the γ-Fe ₂ O ₃ / MgO nanocomposite powder prepared in Example 2. FIG. FIG. 5A is a hysteresis loop obtained as a result of measuring magnetization using a superconducting quantum using interference device (SQUID) magnetometer when the applied magnetic field is changed from -50 kOe to 50 kOe at room temperature (300 K). 5B shows the measurement of ZFC (Zero Field Cooled) and FC (Field Cooled) magnetization. At this time, ZFC magnetization measured the magnetic moment by cooling the sample to 5K without applying a magnetic field and gradually increasing the temperature to 300K while applying a weak magnetic field of 50Oe, and the FC magnetization continuously applied the magnetic field to the sample at 300K. The magnetic moment was measured while cooling to 5K. The blocking temperature of the γ-Fe ₂ O ₃ / MgO nanocomposite powder prepared in Example 2 is about 125K.

6 is a measurement of the heat generation characteristics of the γ-Fe ₂ O ₃ / MgO nanocomposite powder prepared in Example 2 by applying a frequency at 40 ~ 140 kHz under an applied magnetic field of 6mT to measure the magnetic loss generated at this time . 0.1 g of γ-Fe ₂ O ₃ / MgO powder was placed in a cylindrical glass bottle having a diameter of 3 cm, filled with distilled water, and placed inside a coil filled with insulation. The standard specimen was filled with only the same amount of distilled water and placed in the coil together. Then, the thermocouple was inserted into the two glass bottle specimens to measure the exothermic temperature of each specimen, and the temperature difference (ΔT) was measured. The temperature difference thus obtained was substituted into Equation 1 below to calculate the power loss according to the frequency change. For comparison, Fe ₂ O ₃ powder was also measured magnetic loss value by the above method.

_{P i = (8 · λ eff} · ΔT max · V V) / r 2 ( Equation 1)

Where V _V is the total volume of the specimen glass bottle and r is the inner radius of the glass bottle. λ _eff is the effective thermal conductivity of the entire specimen to be measured, which is the sum of the thermal conductivity of each component divided by the fraction of each component. As shown in Equation 1, the increase in applied frequency is proportional to the increase in magnetic loss. The calculated magnetic loss is shown in FIG. 6, and the magnetic loss of Fe ₂ O ₃ / MgO powder is much higher than that of Fe ₂ O ₃ powder at the same frequency, γ-Fe ₂ O ₃ / MgO nanocomposite powder In the case of the magnetic particles in the case of having a particle size of about 10nm, is surrounded on the MgO matrix and is uniformly dispersed without interaction between the magnetic particles. In addition, the MgO matrix phase has excellent thermal conductivity (30 W / m · K), which does not contain the generated heat and releases it out of the powder so that it is more thermally treated than other organic and inorganic matrix phases (1.4 W / m · K for SiO ₂ ). Suitable for

The superparamagnetic γ-Fe ₂ O ₃ / MgO nanocomposite powder prepared by the ultrasonic spray pyrolysis method becomes magnetic only when the magnetic field is applied to it.The drug is attached to the powder and the external magnetic field is used as a desired part of the human body. It can be applied to drug delivery system that causes drug reaction by moving. In a similar way, it is possible to use a protein-separated tablet that attaches a substance that reacts with a specific protein to a powder, and then puts it in a solution containing various proteins to separate it using a magnetic field. Representative methods of cancer treatment so far are radiation therapy using radiation, but it is accompanied by side effects due to the use of radiosensitizer. Because of this, thermotherapy began to be applied to cancer treatment, while general cells began to be damaged at 44 ° C or higher, whereas cancer cells were designed to be destroyed between 42.5 and 44 ° C. It is classified into systemic heat therapy and local heat therapy. In the case of systemic heat therapy, local heat therapy is appropriate because of side effects. Existing local thermotherapy has been difficult to apply to specific areas because of the use of ultrasound or electromagnetic heat, and because of the problem of irradiating a large area, other parts of the body (normal cells) are exposed to excessive heat and delivered to the body. This was not easy and did not get a big response. When the frequency is applied to the magnetic nanocomposite powder prepared in the present invention, heat is generated, and this property can be applied to local thermotherapy for cancer treatment. In addition, when using the superparamagnetic nanocomposite powder proposed in the present invention, the heat applied to the normal cells can be suppressed to the maximum through direct injection into the affected area (cancer cells), and the superparamagnetic properties can be released into the body. .

As described above, a superparamagnetic nanocomposite powder, which can be applied to drug delivery systems, protein separation tablets, and heat treatments, can be manufactured by a simple process by the method for preparing a metal oxide / ceramic nanocomposite powder of uniform size according to the present invention. can do. In particular, the manufacturing method according to the present invention can reduce the manufacturing cost and can be suitable for mass production because the superparamagnetic nanocomposite powder can be produced quickly in a simple process.

Furthermore, in the advanced countries, the production of superparamagnetic nanocomposite powders according to the present invention is limited to nanostructured materials and thin film forms, thereby obtaining an advantage in the market of functional high value-added nanocomposite powders.

On the other hand, the production of superparamagnetic nanopowders using the ultrasonic spray pyrolysis method proposed in the present invention is similarly coated with magnesia particles of similar size, and consequently coated with γ-Fe ₂ O ₃ magnetic particles. To be distributed. In addition, by controlling the concentration and temperature, the size of the magnetic particles can be controlled from several nm to several tens of nm in size, thereby realizing various magnetic properties (superparamagnetic, ferrimagnetic, etc.). Secondary particles can also be scaled from submicrons to hundreds of microns in size, facilitating manipulation in a variety of applications and applications.

Claims (14)

Preparing a solution by adding and stirring a superparamagnetic dispersed phase and ceramic matrix-based raw material including a metal nitrate, Spraying the solution with an ultrasonic atomizer; Spraying the sprayed droplets into a preheated chamber; Pyrolyzing the spray; Method for producing a superparamagnetic nanocomposite powder comprising the step of collecting the powder generated after the pyrolysis. delete The superparamagnetic nanoparticles of claim 1, wherein the metal nitrate comprises Fe (NO ₃ ) ₃ 9H ₂ O, Ni (NO ₃ ) ₂ 6H ₂ O, or Co (NO ₃ ) ₂ 6H ₂ O. Method for producing a composite powder. The method of manufacturing a superparamagnetic nanocomposite powder according to claim 1, wherein the raw material on the ceramic matrix comprises Mg (NO ₃ ) ₂ 6H ₂ O or SiCl ₄ . The method of claim 1, wherein the solvent comprises a pure or alcoholic solvent. The method of manufacturing a superparamagnetic nanocomposite powder according to claim 1, comprising adjusting the size of the initial powder by appropriately adjusting the mixing ratio of the superparamagnetic dispersed phase and the ceramic matrix phase raw material. The superparamagnetic nanocomposite powder manufacturing method of claim 1, further comprising adjusting the size of the final powder by adjusting the concentration of the solution by controlling the mixing ratio of the superparamagnetic dispersed phase and the ceramic matrix-based raw material and the solvent. The method of manufacturing a superparamagnetic nanocomposite powder according to claim 1, comprising adjusting the size of the final powder which is secondary particles by adjusting the frequency of the ultrasonic atomizer. The method of claim 1, wherein spraying the sprayed droplets into the preheated chamber comprises spraying the droplets into the heating chamber using a carrier gas. The method of claim 9, wherein the carrier gas comprises air, oxygen, nitrogen, an inert gas, or a mixed gas of the gas. The method of claim 1, wherein the temperature of the pyrolyzing the spray is 500 ° C to 1000 ° C. The method of manufacturing a superparamagnetic nanocomposite powder according to claim 1, wherein the powder produced after pyrolysis is a dispersed type in which a superparamagnetic dispersed phase is uniformly dispersed on a ceramic matrix. The method of manufacturing a superparamagnetic nanocomposite powder according to claim 12, wherein the product powder has a size of micron or less. A superparamagnetic nanocomposite powder prepared using the method according to any one of claims 1 and 3 to 13.

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