WO2007026533A1 - Soluble tablet containing nanosilicon particles and process for production thereof - Google Patents

Soluble tablet containing nanosilicon particles and process for production thereof Download PDF

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Publication number
WO2007026533A1
WO2007026533A1 PCT/JP2006/315980 JP2006315980W WO2007026533A1 WO 2007026533 A1 WO2007026533 A1 WO 2007026533A1 JP 2006315980 W JP2006315980 W JP 2006315980W WO 2007026533 A1 WO2007026533 A1 WO 2007026533A1
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nanosilicon
particles
nano
treatment
silicon
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PCT/JP2006/315980
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French (fr)
Japanese (ja)
Inventor
Keisuke Sato
Kenji Hirakuri
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Tokyo Denki University
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Priority to JP2007533166A priority Critical patent/JP4931015B2/en
Publication of WO2007026533A1 publication Critical patent/WO2007026533A1/en

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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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6923—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being an inorganic particle, e.g. ceramic particles, silica particles, ferrite or synsorb
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6927—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
    • A61K47/6929—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
    • A61K49/0054—Macromolecular compounds, i.e. oligomers, polymers, dendrimers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
    • A61K49/0056—Peptides, proteins, polyamino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
    • A61K49/0065—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the luminescent/fluorescent agent having itself a special physical form, e.g. gold nanoparticle
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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

  • the present invention relates to a dissolution tablet containing nanosilicon particles that emit red, green, and blue (three primary colors) fluorescence in blood by irradiating light from ultraviolet light to visible light, and
  • the present invention relates to a dissolved tablet containing nanosilicon particles having a surface attached with a polymer compound such as a drug, a polysaccharide, or a protein, and also relates to a method for manufacturing these tablets.
  • bioimaging for visualizing and observing the dynamic state of blood, arteries, and cells is visualized as a pathogenic site (cancer cell), and a drug delivery system that treats the site with a drug ( Research and development of DDS) is being promoted with the aim of commercialization.
  • semiconductor nanoparticles have been developed as a marker material capable of emitting visible light in a living body. These semiconductor nanoparticles are particles obtained by finely pulverizing a semiconductor material to a nanometer-scale size, and have a function of emitting light.
  • semiconductor nanoparticle materials are very expensive because they are made by combining multiple elements.
  • nanosilicon particles have been developed as a semiconductor nanomaterial having a light emitting function that satisfies the above-described factors (see Japanese Patent Laid-Open No. 11-210972).
  • nano-silicon particles emit high-intensity fluorescence in the visible region (blue to red) in the atmosphere or in solution (2 1st Century Joint Symposium Proceedings (900, 2002), Tokyo) , P. 4 7 7 to 4 7
  • nanosilicon particles have a particle size of about 3.5 nm or less in diameter, they can circulate freely within the blood vessel even when injected into the blood vessel, and are stored in the living body. There is no. Therefore, nanosilicon particles are promising as a single material.
  • nanosilicon particles themselves are composed of silicon, they are abundant in terms of resources and environmentally friendly, and are also environmentally friendly, especially for living organisms. Material. In this way, nanosilicon particles are non-toxic and non-hazardous materials, and have the greatest advantage as inexpensive materials.
  • nanosilicon particles that fluoresce in the air or in solution have adsorbed hydrogen, which is very unstable to heat and changes over time, on their surfaces. It has the characteristic that the emission color and the emission luminance are likely to change.
  • nanosilicon particles are manufactured using this method.
  • the material that is stable and dissolves in vivo on the surface of the nanosilicon particles Can not form. Disclosure of the invention
  • Nano-silicon particles that are surrounded by materials that are stable and soluble in the living body and emit red, green, and blue (trinary colors) fluorescence are environmentally and biologically friendly and inexpensive. Accelerate the development of dissolution tablets that have a wide range of applications in the field of cancer treatment and observation of various parts of the body.
  • the present invention provides (i) surrounding the nanosilicon particles with a material that is stable and soluble in the living body, and (ii) attaching a polymer compound such as a drug, a polysaccharide, or a protein to the surface of the nanosilicon particles. And (iii) dissolving a dissolution tablet containing nanosilicon particles in vivo.
  • the problem (or purpose) is to make red, green, and blue (the three primary colors) fluoresce in blood with high brightness and stability.
  • Another object of the present invention is to establish a production method for producing a dissolving tablet containing nanosilicon particles that emit fluorescence of three primary colors, which can be applied in various fields in the medical field.
  • the present inventor has processed nano-silicon particles whose particle size has been reduced to about 1.5 to 3.5 nm by treating powder-like silicon particles in a solution. Dissolving tablets containing, when injected into a living body, dissolve the tablets, and the nanosilicon particles that appear after dissolution are red, green, or blue (three primary colors) in the blood with high brightness and It was found that stable fluorescence was emitted.
  • the present inventor has formed a nano-particle of about 1.5 to 3.5 nm formed using a high-frequency sputtering method while controlling the particle size by a series of hydrofluoric acid aqueous solution treatment, solution treatment, and stirring treatment. Dissolved tablets containing silicon particles dissolve when injected into the body, and the nanosilicon particles that appear after dissolution are one of red, green, and blue (three primary colors) in the blood. It was found that the fluorescent light was emitted stably and stably.
  • Nano-silicon particles when nano-silicon particles are subjected to a thermal treatment, and dissolved tablets containing nano-silicon particles having a polymer compound such as drugs, polysaccharides, and proteins attached to the surface are injected into the body.
  • the present invention has been made on the basis of the above findings, and the gist thereof is as follows.
  • nanosilicon particles having a large number of unbonded hands are immersed in a solution in which a polymer compound such as a drug, polysaccharide, or protein is mixed, and subjected to thermal treatment again, and then
  • the nano-silicon particles are formed by subjecting an amorphous silicon oxide film produced by a high-frequency sputtering method to a heat treatment, followed by hydrofluoric acid solution treatment, solution treatment, and stirring treatment.
  • the concentration of the hydrofluoric acid aqueous solution is 1 to 50%
  • the treatment temperature is 10 to 70 ° C
  • the treatment time is 10 to 60 (9) or (10)
  • the particle size that has been difficult to manufacture by the conventional method is the particle size that has been difficult to manufacture by the conventional method.
  • Nanosilicon particles of about 1.5 to 3.5 nm can be surrounded by a stable and dissolvable material. Further, according to the present invention, a high molecular compound such as a drug, a polysaccharide or a protein can be attached to the surface of the nanosilicon particle.
  • the dissolving tablet containing eggplant silicon particles of the present invention dissolves when injected into a living body, and the nanosilicon particles that appear after dissolution are red, green, and blue in blood.
  • the fluorescence emission can be used to observe each part in the living body or to detect cancer cells by color or visually.
  • the present invention greatly expands the application range of nanosilicon particles in the medical field related to measurement of each part in a living body, detection and treatment of cancer.
  • FIG. 1 is a diagram showing the production process of the nanosilicone-containing dissolving tablet of the present invention.
  • A is a diagram showing a dispersion mode of nanosilicon particles in a solution in the initial stage of the manufacturing process
  • B is a diagram showing a mode in which nanosilicon particles are mixed into sodium chloride powder.
  • C is a diagram showing a mode of mixing sodium chloride powder
  • D is a diagram showing a processing mode by a press machine
  • E is a manufacturing method. It is a figure which shows the aspect of the sodium chloride containing the nano silicon particle in the final stage of a process.
  • FIG. 2 is a diagram showing a production process of a solution in which nano-silicon having a particle shape according to the present invention is dispersed.
  • A is a diagram showing an example of a raw material for producing a nanosilicon dispersion solution
  • B is an illustration in the initial stage of the production process.
  • C is a diagram showing a treatment mode in which silicon powder is treated with a mixed solution
  • D is a diagram of nanosilicon in the final stage of the manufacturing process. This is a diagram showing the state of dispersion in particle units.
  • FIG. 3 is a diagram showing a production process of a solution in which nano-silicon having a particle shape according to the present invention is dispersed.
  • A is a diagram showing the state of nanosilicon in the initial stage of the production process
  • B is a diagram showing the state of hydrofluoric acid aqueous solution treatment
  • C is after hydrofluoric acid aqueous solution treatment.
  • D is a diagram showing an embodiment of a solution treatment
  • (E) is a diagram showing an embodiment of a stirring treatment
  • F) is a production process.
  • FIG. 3 is a diagram showing a dispersion mode of nano silicon particles in the final stage of the process.
  • Figure 4 shows the drug by thermal treatment for the nano IJ particles of the present invention.
  • FIG. 3 is a diagram showing an adhesion process of a high molecular compound such as a polysaccharide / protein.
  • (A) is a diagram showing the mode of nanosilicon particles in the initial stage of the deposition process.
  • (B) is a diagram showing the mode of nanosilicon particles in the final stage of the deposition process.
  • FIG. 5 is a diagram showing the existence mode (transmission electron micrograph) of particle-shaped nanosilicon dispersed in the solution of the present invention.
  • FIG. 6 is a diagram showing a fluorescence emission spectrum in the blood of nanosilicon particles contained in the dissolution tablet of the present invention.
  • FIG. 7 is a diagram showing an aspect of the high-frequency sputtering device.
  • FIG. 8 is a diagram showing an aspect of the target material used in the high-frequency sputtering apparatus.
  • FIG. 9 is a diagram showing a light emission mode of the nano-U-contained dissolution tablet of the present invention.
  • FIG. 10 shows the fluorescence emission spectrum of the nanosilicone-containing dissolution tablet of the present invention.
  • FIG. 11 is a diagram showing a light emission mode of nano-cone particles dispersed by dissolving the nano-silicone-containing dissolution tablet of the present invention in physiological saline.
  • FIG. 12 is a diagram showing a fluorescence emission spectrum of nanosilicon particles dispersed by dissolving the nanosilicon-containing dissolution tablet of the present invention in physiological saline.
  • FIG. 13 is a diagram showing a light emission mode in a state where the nanosilicon-containing dissolution tablet of the present invention is dissolved in physiological saline, and the dispersed nanon U-con particle flows into the coronary artery of an animal. .
  • FIG. 14 shows a luminescence spectrum obtained by dissolving the nanosilicone-containing dissolution tablet of the present invention in physiological saline and allowing the dispersed nanosilicon particles to flow into the coronary artery of the animal.
  • the best mode for carrying out the invention is the best mode for carrying out the invention.
  • the important point in the present invention is that the nano-silicon particles that fluoresce red, green, and blue are surrounded by a stable and dissolvable material, and the dissolution tablet (nano-silicon) containing the nano-silicon particles is contained.
  • the tablet is dissolved by injecting the tablet into the living body, and the nanosilicon particles that appear after dissolution are fluorescently emitted stably and with high brightness in the blood.
  • hydrofluoric acid, nitric acid, acetic acid, and silicon particles obtained by finely pulverizing solid silicon for example, silicon wafer
  • heat treatment is performed with a mixed solution in which pure water is mixed to form nano-silicon particles, and the nano-silicon particles are mixed into the sodium chloride powder.
  • an amorphous silicon oxide film produced by a high-frequency sputtering method is used. Heat treatment is performed, and further, hydrofluoric acid aqueous solution treatment, solution treatment, and stirring treatment are performed to form nanosilicon particles, and the nanosilicon particles are mixed into the sodium chloride powder.
  • the nanosilicon particles are subjected to a heat treatment, and a polymer compound such as a drug, a polysaccharide, or a protein is attached to the nanosilicon particle surface, and thereafter The nanosilicon particles are mixed into the sodium chloride powder.
  • the nanosilicone-containing dissolution tablet of the present invention When the nanosilicone-containing dissolution tablet of the present invention is injected into a living body, the tablet dissolves and nanosilicon particles appear, and the nanosilicon particles stably and stably have high brightness in blood. Fluorescent light is emitted in red, green and blue colors.
  • the affected part is treated in vivo using the nanosilicone-containing dissolving tablet of the present invention. It becomes possible.
  • the nanosilicone-containing dissolution tablet of the present invention lays the foundation for innovative medical technology in the medical field such as visualization measurement of pathogenic sites and cancer treatment. .
  • Figure 1 shows an overview of the manufacturing process for manufacturing nanosilicone-containing dissolving tablets.
  • a particulate solution dispersed in a container 3 containing a solution 1 such as pure water or ethanol, or a mixed solution 2 of a high molecular compound such as a drug, polysaccharide or protein is contained.
  • Nanosilicon 4 is used (see Fig. 1 (A)).
  • solid silicon for example, silicon wafer
  • heat treatment is applied to the amorphous silicon oxide film formed by processing in a solution or by high-frequency sputtering, followed by hydrofluoric acid aqueous solution treatment, solution treatment, and stirring treatment. Two types of methods can be used.
  • Figure 2 shows the manufacturing process for producing a solution in which particulate nanosilicon is dispersed by pulverizing a silicon wafer and treating it in the solution.
  • this manufacturing process for example, an n-type or p-type silicon wafer having a specific resistivity of 0.01 to 20 ⁇ cm and a plane orientation of (1 0 0), (1 1 0), (1 1 1) Use 1-8 (see Fig. 2 (A)).
  • the silicon wafer 8 is finely pulverized to produce a silicon chip 9, put in a mortar 10 and sprinkled with a pestle 1 1. Silicon powder 1 2 is produced (see Fig. 2 (B)). '
  • the particle size of the silicon powder at this time is preferably 50 m or less, and more preferably 2 to 20 / X m.
  • the particle size of the particle ⁇ is further reduced (see Fig. 2 (C)).
  • the concentrations of hydrofluoric acid, nitric acid, and acetic acid at this time are all about 1 to 50%, preferably 20 to 40%, and more preferably 30%.
  • the treatment time is 30 to 300 minutes, preferably 60 to 240 minutes, and more preferably 120 to 180 minutes.
  • nitric acid and acetic acid in the mixed solution 2 efficiently oxidize the surface of the silicon powder 1 2, and a silicon oxide film is formed on the particle surface.
  • the hydrofluoric acid gradually etches this silicon oxide film from the outermost surface side, so the particle size of the silicon compounder 12 is reduced to the nanometer size.
  • Con 4 is formed.
  • the particle size of nano and silicon 4 is in the range of 1.5 to 35 nm, and in particular, the particle size of 1.5 to 2.0 nm, 9.0 to 2
  • a large number of nano-sized particles of 5 nm and 2.5 nm to 3.5 nm are formed.
  • the emission color can be freely selected by freely controlling the particle size during the nano-silicon manufacturing process.
  • the concentration of hydrofluoric acid, nitric acid and acetic acid is 30%, and the treatment time is 180 minutes.
  • the concentration of hydrofluoric acid, nitric acid, and acetic acid is 30%, and the treatment time is 150 minutes.
  • the concentration of hydrofluoric acid, nitric acid, and acetic acid is 30%, and the treatment time is 120 minutes.
  • a thermostatic water bath as a method of forming the nano silicon 4 from the silicon powder 12.
  • a resin container 14 is placed in a constant temperature water bath, and solution treatment is performed with a mixed solution 2 of hydrofluoric acid, nitric acid, acetic acid, and pure water.
  • the concentrations of hydrofluoric acid, nitric acid, and acetic acid at this time are all about 1 to 50%, preferably 20 to 40%, and more preferably 30%.
  • the treatment temperature in the above solution treatment is 10 to 70 ° C, preferably 30 to 50 ° C, more preferably 40 ° C.
  • the force S is between 1 and 120 minutes, preferably between 15 and 90 minutes, and more preferably between 30 and 60 minutes.
  • nitric acid and acetic acid in the mixed solution 2 form a silicon oxide film on the surface of the silicon powder 1 2 in a short time, The silicon oxide film is gradually etched from the outermost surface by hydrofluoric acid.
  • nano-silicone 4 can be formed in a short time from silicon powder 12.
  • the particle size of nanosilicon 4 formed at this time is 1.5-3
  • a large number of nanosilicon particles having a particle size of 5 nm or 25 nm to 3.5 nm are formed.
  • the concentration of hydrofluoric acid, nitric acid and acetic acid is 30%, and the treatment temperature is 40
  • the concentration of hydrofluoric acid, nitric acid and acetic acid is 30. 0, treatment temperature 4 0
  • treatment time is 45 minutes.
  • the concentration of hydrofluoric acid, nitric acid and acetic acid is 30? .
  • the processing temperature is 40
  • treatment time is 30 minutes.
  • the nanosilicon 4 Since the surface of the nanosilicon 4 formed in this way has particles of hydrofluoric acid, nitric acid, and acetic acid attached thereto, the nanosilicon 4 is immersed in a solution 1 such as pure water or ethanol. Then, the particles of hydrofluoric acid, nitric acid, and acetic acid are completely removed (see Fig. 2 (D)).
  • a solution 1 such as pure water or ethanol.
  • particulate nanosilicon 4 dispersed in a solution 1 such as pure water or ethanol can be obtained.
  • the amorphous silicon oxide film prepared by the high-frequency sputtering method is subjected to heat treatment, followed by hydrofluoric acid aqueous solution treatment, solution treatment, and stirring treatment to disperse the particulate nanosilicon.
  • a production method for producing the prepared solution will be described.
  • Figure 3 shows an overview of the manufacturing process for manufacturing a solution in which particulate nanosilicon is dispersed by the above series of treatments.
  • An amorphous silicon oxide film formed on the substrate 15 using a high-frequency sputtering method is heat-treated in an atmosphere of an inert gas (argon, helium, etc.) to produce an oxidation cage.
  • an inert gas argon, helium, etc.
  • the particle size is 1.5 to 3.5 nm, in particular, the particle size is 1.5 to 2.0 nm, 2.0 to 2.5 nm, 2.5 to 3.5 nm.
  • Many nanosilicones 4 are formed (see Fig. 3 (A)).
  • the particle size that directly contributes to the emission color can be freely controlled at the initial stage of nanosilicon production, and therefore various emission colors can be easily realized in the present invention. It is possible. .
  • FIG. 7 shows one mode of the high-frequency sputtering system.
  • This apparatus is roughly divided into (a) a vacuum chamber 30 having an argon gas inlet 28 and an exhaust 29 at the bottom of the side surface, and (b) an insulating material 31 on the upper surface of the vacuum chamber 30.
  • the substrate holder 3 4 cooled by the cooling water 3 3 introduced and discharged from the cooling pipe 3 2, and (c) attached to the lower surface of the vacuum chamber 1 3 0 via the insulating material 3 1
  • the high-frequency electrode 3 6 includes a cathode shield 3 5 that is cooled by cooling water 3 3 introduced and discharged from the cooling pipe 3 2.
  • argon gas is introduced into the vacuum chamber 30.
  • Argon gas is ionized by the high-frequency controller 3 7, introduced from the Gon gas inlet 2 8, and the ionized Argon ion is converted into silicon chip 3 8 a, which is the target material 3 8 on the high-frequency electrode 3 6 3 8 b (see Fig. 8)
  • Silica chips 3 8 a are arranged at a predetermined interval on quartz glass 3 S b, and are discharged from the target material 3 8 in the evening. Then, silicon atoms and silicon oxide molecules are deposited on the substrate 15 held in the substrate holder 3 4 to form an amorphous silicon oxide film.
  • an inert gas (argon, helium, etc.) is applied to the above oxide film.
  • the heat treatment temperature is set to 90 ° C to 120 ° C, but preferably 100 ° C to 1100 ° C, and the heat treatment time is 120 minutes or less. However, it is preferably 1510 minutes, more preferably 30 to 80 minutes, and most preferably ⁇ 50 to 60 minutes.
  • Particle size of the nano-silicon co down particles, P This area ratio can be controlled by changing the area ratio of the silicon chip 3 8 a and the quartz glass 3 8 b constituting the evening Ge' Bok material 3 8 shown in FIG. 8 Is usually a force of 1 to 50%, preferably 5 to 30%, and more preferably 10 to 15%. '
  • the particle size can be controlled even by changing the high peripheral power and gas pressure (pressure during production, argon gas pressure in this manufacturing process) under sputtering conditions.
  • high frequency power is varied in the range of 1 0 ⁇ 5 0 0 W
  • the gas pressure is 1 XI 0- 4 ⁇ 1 XI 0 - vary within a range of 1 torr.
  • Nanosilicon particles containing a large number of nanosilicon particles having a particle size of 5 to 2.0 nm, 2.0 to 2.5 nm, or 2.5 to 3.5 nm can be produced.
  • the substrate 15 on which the silicon oxide film 16 on which the nanosilicon 4 having a particle size in the range of 1.5 to 3.5 nm is formed is pasted on the acrylic plate 17. (Refer to FIG. 3 (A)).
  • the resin film 14 containing the hydrofluoric acid aqueous solution 19 is mounted with the above-mentioned silicon oxide film 16 facing down.
  • the concentration of the hydrofluoric acid aqueous solution 19 is 1 to 50%, preferably 10 to 40%, and more preferably 20 to 30%.
  • the resin container 14 is installed in a thermostatic water tank 2 2 equipped with a hygiene 20 and containing pure water 2 1, and a hydrofluoric acid aqueous solution treatment 18 is performed (FIG. 3 (
  • the treatment temperature is 10 to 70 ° C, preferably 3
  • the temperature is 0 to 50 ° C, more preferably 40 ° C.
  • the processing time is 10 to 600 seconds, preferably 30 to 300 seconds, and more preferably 60 to 120 seconds.
  • the fluoric acid particles evaporated from the hydrofluoric acid aqueous solution 19 in the resin container 14 adhere to the surface of the silicon oxide film 16, and the silicon oxide film 16.
  • the silicon oxide inside is gradually etched from the surface.
  • the substrate 15 on which nanosilicon., 4 is aggregated and exposed is immersed in a container 3 containing a solution 1 such as pure water or ethanol, and the container 3 is placed in a stirrer or ultrasonic cleaner 13. Place the solution and perform solution treatment 2 3 to completely remove the hydrofluoric acid particles remaining on the substrate 1 5 and nanosilicon 4 (Refer to Fig. 3 (D)).
  • a solution 1 such as pure water or ethanol
  • this solution treatment 2 3 is performed to ensure non-toxicity and harmlessness to the environment and living organisms. By sufficiently performing this solution treatment 23, it is possible to ensure the environmental conservation inherent in nanosilicon particles.
  • the substrate 15 on which the nanosilicone 4 is aggregated and exposed is again immersed in a container 3 containing a solution 1 such as pure water or ethanol, and the container 3 is placed on a stirrer or ultrasonic cleaner 1 3. Then, perform the stirring process 24 (see Fig. 3 (E)). .
  • the treatment time of the stirring treatment 24 is usually 10 to 600 seconds, preferably 30 to 300 seconds, and more preferably 60 to 120 seconds. .
  • the nanosilicone 4 exposed in agglomerated state on the substrate 15 due to the stirring treatment 24 is separated and separated from the substrate 15 and dispersed in the solution 1 such as pure water or ethanol. (Refer to Fig. 3 (E)).
  • the particulate nanosilicon 4 can be obtained in a dispersed state in a solution 1 such as pure water or ethanol (FIG. 3 (F ), See).
  • FIG. 5 shows transmission electron micrographs of the solution prepared by the above-described two kinds of manufacturing methods in which particulate nanosilicon is dispersed.
  • the part marked with ⁇ is nanosilicon particles.
  • the nanosilica particles are uniformly dispersed in the form of particles and still exist in a spherical shape.
  • the particle size of the nanosilicon particles was 1.5 to 3.511 m.
  • Fig. 4 shows the thermal treatment of particulate nanosilicon to produce nanosilicon Shows the attachment process of attaching high-molecular compounds such as drugs, polysaccharides and proteins to the surface.
  • the particulate nanosilicon 4 of the present invention is manufactured by solution treatment with a mixed solution of hydrofluoric acid, nitric acid, acetic acid, and pure water or a hydrofluoric acid aqueous solution, the surface of the nanosilicone 4 is Oxygen atoms and a lot of hydrogen atoms are in a 'bonded state'.
  • the hydrogen atoms dissociate from the silicon atoms due to heat and changes over time. This is because the bond energy between the silicon atom and the hydrogen atom is much weaker than the bond energy with other elements.
  • Nanosilicone 4 in which a large number of unbonded hands 25 are formed in this manner is immersed in a container 3 containing a mixed solution 2 of a polymer compound such as a drug, a polysaccharide, or a protein, and container 3 is placed in a heater. It is installed in a constant temperature water tank 2 2 containing 20 and containing pure water 2 1, and thermal heat treatment 26 is performed again (see FIG. 4 (A)).
  • a polymer compound such as a drug, a polysaccharide, or a protein
  • the treatment temperature is 30 to 100 ° C., preferably 40 to 80 ° C., and more preferably 50 ° C.
  • the time is from '10 to 60 minutes, preferably from 20 to 50 minutes, more preferably about 30 minutes.
  • hydroxyl groups can be attached to the surface of nanosilicon 4 (Fig. 4 (B), see).
  • the nanosilicon 4 is mixed in the mold container 6 containing the powdered sodium chloride 5 while the nanosilicon 4 is dispersed in the solution 1 or the mixed solution 2 (FIG. 1 (B ), See).
  • Sodium chloride 5 used here is a material that dissolves easily in solution and in the body.
  • potassium bromide which is soluble and used as a sedative hypnotic drug, can also be used.
  • the solution 1 and the mixed solution 2 adhering to the sodium chloride 5 evaporate in a short time, so that a large amount of the sodium chloride 5 is contained in the treatment by dividing the treatment into several times.
  • Nanosilicon 4 can be mixed.
  • nanosilicon 4 mixed in the powdered sodium chloride 5 is filtered through an aqueous solution or mixed solution in which the particulate nanosilicon 4 is dispersed. Silicon 4 can also be used. .
  • the powdered sodium chloride 5 mixed with a large amount of nanosilicon 4 is further placed in the mold container 6 containing the powdered sodium chloride 5 and further powdered sodium chloride 5. (See Fig. 1 (C)).
  • Figure 6 shows the fluorescence spectrum in the blood of the nanosilicon particles contained in the dissolution tablet.
  • the nano-silicon particles present in the dissolution tablet are red (wavelength: 660 nm), green (wavelength: 560 nm), and blue (wavelength: 4400 nm) fluorescence in blood. Luminescence can be obtained.
  • This difference in emission color is due to the difference in the particle size of the nanosilicon particles for each emission color.
  • the emission color obtained from a semiconductor material directly depends on the band gap energy of the material, and the wavelength of the emission color is inversely proportional to the band gap energy.
  • the band gap energy increases with decreasing particle size. That is, when the nanosilicon particle size is large, its bandgap energy is small and the wavelength of the emitted color is on the long wavelength side.
  • the nanosilicon particle size is small, its node gap energy increases, and an emission color having a wavelength on the short wavelength side can be obtained.
  • the particle size of the nanosilicon particles that emit red light is in the range of 2.5 to 3.5 nm, and the nano particles that emit green light.
  • the particle size of the silicon particles is in the range of 2.0 to 2.5 nm, and the particle size of the nanosilicon particles exhibiting blue emission is in the range of 1.5 to 2. O nm.
  • the luminance of each emission color is strong enough that it can be clearly seen with the naked eye under room lighting by irradiating light from ultraviolet light to visible light, and its emission lifetime is long. And stable.
  • nanosilicone-containing dissolution tablet of the present invention can be effectively used as bioimaging or DDS in the field of visualization and measurement of pathogenic sites in the living body or in the medical field related to cancer treatment.
  • the conditions of the embodiment are one example of conditions adopted to confirm the feasibility and effects of the present invention, and the present invention is limited to this one example Is not to be done.
  • the present invention can adopt various conditions as long as the object of the present invention is achieved without departing from the gist of the present invention.
  • Fig. 9 shows a dissolution tablet containing nanosilicone (particle size: 2.5 to 3.5 nm) prepared according to the present invention.
  • the light emission mode is shown when the agent is directly irradiated with ultraviolet rays.
  • the nano-silicone-containing tablets fluoresce in a red color with a luminance that can be clearly seen with the naked eye under room lighting. Moreover, it was confirmed that the emission lifetime was long and stable.
  • Figure 10 shows the fluorescence emission spectrum of the nanosilicon-containing dissolution tablet when irradiated with ultraviolet light. From FIG. 10, it can be confirmed from the nanosilicon particles in the tablet that red light having a peak at a wavelength of 660 nm is emitting fluorescence.
  • Fig. 11 shows that the nano-silicone-containing dissolution tablet prepared in the present invention is poured into physiological saline to dissolve the tablet, and the physiological saline solution in which nano-silicon particles are dispersed is directly irradiated with ultraviolet rays. The light emission mode is shown.
  • the nano-silicon particles dispersed in the physiological saline solution fluoresce with a bright red color that can be clearly seen with the naked eye under room lighting. Moreover, it was confirmed that the light emission lifetime was long and stable.
  • Figure 12 shows the fluorescence emission spectrum of the physiological saline solution when irradiated with ultraviolet light. Disperse in the physiological saline solution. From the nanosilicon particles, confirm that the red light having a peak at a wavelength of 6600 nm is emitted in the same manner as when incorporated in the tablet. be able to.
  • Fig. 13 shows that the nanosilicone-containing dissolution tablet of the present invention was dissolved in physiological saline, and the nanosilicon particles dispersed in the solution were allowed to flow directly into the coronary artery of an animal (sheep).
  • the light emission mode in the state is shown. This in vivo flow observation was performed while irradiating the animal (sheep) with ultraviolet rays directly from the outside.
  • Figure 13 shows that even when the nanosilicon particles are flowing in the coronary arteries, the nanosilicon particles fluoresce with a bright red color that can be clearly seen with the naked eye under room lighting. I understand that In addition, it was confirmed that the emission lifetime was long and stable. +
  • Figure 14 shows the fluorescence emission spectrum of nanosilicon particles during flow to the coronary arteries.
  • Figure 14 shows that the nanosilicon particles in the coronary artery fluoresce red with a peak at a wavelength of 66 nm, as in the tablet or solution. Can be confirmed.
  • the nano-silicone-containing dissolution tablet of the present invention dissolves when injected into a living body, and the nano-silicon particles that appear after dissolution are highly bright and stable in blood. It exhibits a full color (red, green, blue) fluorescence.
  • Nanosilicon particles are gentle to the environment and living organisms, and can be manufactured from inexpensive materials. Therefore, bioimaging promotes the development of dissolution tablets with DDS functions, Contribute to the development of technologies related to site observation and cancer treatment.
  • the nano-silicone-containing dissolving tablet of the present invention has a surface on which medicines and many Since a high molecular compound such as sugar / protein is attached, the visualized pathogenic site (for example, cancer cell) can be treated as it is.
  • a dissolution material sodium bromide powder, which is used as a pharmaceutical product such as a sedative hypnotic, may be used depending on the application field in addition to sodium chloride powder.
  • nanosilicon particles with sodium chloride or potassium bromide For tablets containing nanosilicon particles with sodium chloride or potassium bromide, just before use, use sodium chloride or potassium bromide in a solution such as pure water ethanol. It is possible to use nano-silicon particles that have been dissolved and that have emerged after dissolution.
  • the present invention has great applicability in pathological site measurement technology and treatment technology, and in other technical fields.

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Abstract

Disclosed is a tablet comprising a sodium chloride powder and an abundance of nanosilicon particles having a particle size in the range of 1.5 to 2.0 nm, 2.0 to 2.5 nm or 2.5 to 3.5 nm blended into the powder, which can emit a fluorescent light with blue, green or red color in the blood upon being irradiated with ultraviolet ray or visible light. The tablet can be produced by immersing nanosilicon particles in a mixed solution containing a therapeutic agent and a polymeric compound such as a polysaccharide or protein, subjecting the resulting mixture to a thermal treatment and then mixing the resulting product with a sodium chloride powder.

Description

ナノ シリ コン含有溶解錠剤とその製造方法 技術分野 TECHNICAL FIELD OF THE INVENTION Technical Field
本発明は、 紫外光から可視光までの光を照射することにより、 血 液内において、 赤色、 緑色、 青色 （三原色） を蛍光発光するナノ シ リ コン粒子を含有する溶解錠明剤、 及び、 表面に、 薬剤や多糖 ， 蛋白 質などの高分子化合物を付着させたナノシリ コン粒子を含有する溶 解錠剤、 さ らに、 それら錠剤の製造方室法に関する。 背景技術  The present invention relates to a dissolution tablet containing nanosilicon particles that emit red, green, and blue (three primary colors) fluorescence in blood by irradiating light from ultraviolet light to visible light, and The present invention relates to a dissolved tablet containing nanosilicon particles having a surface attached with a polymer compound such as a drug, a polysaccharide, or a protein, and also relates to a method for manufacturing these tablets. Background art
近年、 ナノテクノ ロジ一を取り入れたマテリ アルサイエンスの研 究開発の発展は著しく、 その分野は、 光学、 工学、 医学、 化学、 物 理学などの広い範囲にわたっている。 特に、 医学分野においては、 ナノ メディ シン · プロジェク ト研究が活発に行われている。  In recent years, research and development of material science incorporating nanotechnology has been remarkable, and its fields cover a wide range of fields such as optics, engineering, medicine, chemistry, and physics. In particular, nanomedicine project research is actively conducted in the medical field.
そのプロジェク トの中で、 血液、 動脈、 細胞の動的状態を可視化 して観察するためのバイオイ メージングゃ病原部位 （癌細胞） の可 視化と、 その部位を薬剤により治療する薬物送達システム （D D S ) の研究開発が、 実用化を目途に推進されている。  In the project, bioimaging for visualizing and observing the dynamic state of blood, arteries, and cells is visualized as a pathogenic site (cancer cell), and a drug delivery system that treats the site with a drug ( Research and development of DDS) is being promoted with the aim of commercialization.
そして、 上記可視化のために、 生体内において可視光を発するこ とのできるマーカー材料として、 半導体ナノ粒子が開発されている 。 この半導体ナノ粒子は、 半導体材料を、 ナノメー トルスケールの 大きさに微粉砕した粒子であり、 光を発する機能を備えている。  For the above visualization, semiconductor nanoparticles have been developed as a marker material capable of emitting visible light in a living body. These semiconductor nanoparticles are particles obtained by finely pulverizing a semiconductor material to a nanometer-scale size, and have a function of emitting light.
しかし、 半導体ナノ粒子の原材料には、 重金属元素や有害物質が 含まれているので、 半導体ナノ粒子を生体内で使用する場合、 生体 への安全性が危惧されている。 半導体ナノ粒子の毒性を抑制する方法として、 粒子表面を保護膜 で包囲する方法があるが、 保護膜で包囲すると、 粒子サイズ自体が 数十ナノメー トルと大きくなり、 生体内に半導体材料が貯留する恐 れがある。 However, since the raw materials of semiconductor nanoparticles contain heavy metal elements and harmful substances, there are concerns about safety to living organisms when semiconductor nanoparticles are used in vivo. As a method for suppressing the toxicity of semiconductor nanoparticles, there is a method in which the particle surface is surrounded by a protective film. However, if the particle surface is surrounded by a protective film, the particle size itself increases to several tens of nanometers, and the semiconductor material is stored in the living body. There is a fear.
さ らに、 半導体ナノ粒子材料は、 複数の元素が組み合わされて作 製されているため、 材料が非常に高価である。  In addition, semiconductor nanoparticle materials are very expensive because they are made by combining multiple elements.
このようなことから、 .マ 力 —材料として、 生体に対し無毒性 · 無害性で、 粒子サイズが小さ < 、 かつ、 安価な材料の開発が待たれ ている。 .  For this reason, the development of materials that are non-toxic and harmless to the living body, have a small particle size, and are inexpensive has been awaited. .
そこで、 上記要因を満足し 、 発光機能をもつ半導体ナノ材料と し て、 ナノシリ コン粒子が開発された （特開平 1 1 - 2 0 1 9 7 2号 公報、 参照） 。  Therefore, nanosilicon particles have been developed as a semiconductor nanomaterial having a light emitting function that satisfies the above-described factors (see Japanese Patent Laid-Open No. 11-210972).
このナノ シリコン粒子は 、 可視領域 （青色〜赤色） において、 大 気中や溶液中で、 高輝度の蛍光発光を発するものである ( 2 1 世紀 連合シンポジウム論文集 （ 9 0 0 2年、 東京） 、 P . 4 7 7 〜 4 7 These nano-silicon particles emit high-intensity fluorescence in the visible region (blue to red) in the atmosphere or in solution (2 1st Century Joint Symposium Proceedings (900, 2002), Tokyo) , P. 4 7 7 to 4 7
8、 平成 1 6年度照明学会第 3 7 回全国大会講演論文集 ( 2 0 0 4 年 8 月 4 日） 、 p . 2 3 3 2 3 4、 第 5 1 回応用物理学関係連合 講演会講演予稿集 N o . 3 ( 2 0 0 4 ) 、 2 8 p— P 6 ― 4、 東海 大学総合科学技術研究所研究 資料集 2 4 ( 2 0 0 5年 3 月 3 1 曰8. Proceedings of the 37th National Convention of the Illuminating Society of Japan (Aug. 4, 2004), p. 2 3 3 2 3 4, p. 5 3 3 2 3 4 Proceedings N o. 3 (2 0 0 4), 2 8 p— P 6 4, Tokai University Research Institute for Science and Technology Research Materials 2 4 (2 March 2005
；) 、 p . 4 0 〜 4 6、 参照） 。 ;), P. 40-46, see).
そして、 そのナノシリ コン粒子は、 粒子サイズが、 直径で約 3 . 5 n m以下であるので、 血管内に注入されても、 血管内を自由に循 環することができ、 生体内に貯留することはない。 したがって、 ナ ノシリコン粒子は、 マ一力一材料として有望である。  Since the nanosilicon particles have a particle size of about 3.5 nm or less in diameter, they can circulate freely within the blood vessel even when injected into the blood vessel, and are stored in the living body. There is no. Therefore, nanosilicon particles are promising as a single material.
さ らに、 ナノシリ コン粒子は、 それ自体がシリ コンで構成されて いるので、 資源面で豊富であり、 かつ、 環境面で優しく、 また、 環 境面以外でも、 特に、 生体に対して優しい材料である。 このように、 ナノシリコン粒子は、 無毒性 ， 無害性の物質で、 し かも、 安価な物質として、 最大のメリ ッ トを有している。 Furthermore, since nanosilicon particles themselves are composed of silicon, they are abundant in terms of resources and environmentally friendly, and are also environmentally friendly, especially for living organisms. Material. In this way, nanosilicon particles are non-toxic and non-hazardous materials, and have the greatest advantage as inexpensive materials.
しかし、 大気中や溶液中で蛍光発光するナノシリコン粒子のほと んどは、 その表面に、 熱や経時的変化に対して非常に不安定な水素 が吸着されているため、 時間経過とともに、 発光色や発光輝度が変' 化し易いという特性を有している。  However, most nanosilicon particles that fluoresce in the air or in solution have adsorbed hydrogen, which is very unstable to heat and changes over time, on their surfaces. It has the characteristic that the emission color and the emission luminance are likely to change.
それ故、 発光色や発光輝度が長期間安定した蛍光発光を実現する ためには、 ナノシリコン粒子の表面を、 より安定な材料で包囲する 必要がある。  Therefore, in order to realize fluorescence emission with stable emission color and emission luminance for a long period of time, it is necessary to surround the surface of nanosilicon particles with a more stable material.
また、 安定な材料で包囲したナノシリコン粒子を、 生体内で使用 可能にするためには、 包囲材料として、 生体内で溶解する材料を使 用する必要がある。  In addition, in order to use nano-silicon particles surrounded by a stable material in vivo, it is necessary to use a material that dissolves in vivo as the surrounding material.
従来は、 溶液中で化学エッチング処理を行うウエッ トプロセス法 Conventionally, a wet process method in which chemical etching is performed in solution
(特開平 1 1 _ 2 0 1 9 7 2号公報、 参照） を用いてナノシリコン 粒子を製造しているが、 この方法では、 ナノシリコン粒子の表面に 、 安定でかつ生体内で溶解する材料を形成することができない。 発明の開示 (Refer to Japanese Patent Laid-Open No. 11_2 0 1 9 7 2), nanosilicon particles are manufactured using this method. In this method, the material that is stable and dissolves in vivo on the surface of the nanosilicon particles Can not form. Disclosure of the invention
安定でかつ生体内で溶解する材料で包囲され、 赤色、 緑色、 青色 (三原色） を蛍光発光するナノシリコン粒子は、 環境や生体に対し て優しく、 かつ、 安価な材料によるバイオイメージングゃ D D Sの 機能を有する溶解錠剤の開発を促進して、 生体内の各部位の観察や 、 癌治療の分野への幅広い応用を可能にする。  Nano-silicon particles that are surrounded by materials that are stable and soluble in the living body and emit red, green, and blue (trinary colors) fluorescence are environmentally and biologically friendly and inexpensive. Accelerate the development of dissolution tablets that have a wide range of applications in the field of cancer treatment and observation of various parts of the body.
そこで、 本発明は、 （ i ) ナノシリコン粒子を、 安定でかつ生体 内で溶解する材料で包囲すること、 （i i ) ナノシリコン粒子の表面 に、 薬剤や多糖 ， 蛋白質などの高分子化合物を付着すること、 及び 、 ( i i i ) ナノシリコン粒子を含有する溶解錠剤を、 生体内で溶解 し、 血液中で、 高輝度でかつ.安定的な赤色、 緑色、 青色 （三原色） を蛍光発光させること、 を課題 （又は目的） とする。 Therefore, the present invention provides (i) surrounding the nanosilicon particles with a material that is stable and soluble in the living body, and (ii) attaching a polymer compound such as a drug, a polysaccharide, or a protein to the surface of the nanosilicon particles. And (iii) dissolving a dissolution tablet containing nanosilicon particles in vivo. The problem (or purpose) is to make red, green, and blue (the three primary colors) fluoresce in blood with high brightness and stability.
また、 本発明は、 医療分野において多方面にわたる応用が可能な 、 三原色を蛍光発光するナノシリコン粒子を含有する溶解錠剤を製 造する製造方法を確立すること、 も課題 （又は目的） とする。  Another object of the present invention is to establish a production method for producing a dissolving tablet containing nanosilicon particles that emit fluorescence of three primary colors, which can be applied in various fields in the medical field.
本発明者は、 上記課題を解決すべく鋭意研究を重ねた結果、 パゥ ダ一状のシリコン粒子を溶液中で処理して粒子サイズを 1 . 5 〜 3 . 5 n m程度に縮小したナノシリコン粒子を含有する溶解錠剤は、 生体内に注入されると錠剤が溶解し、 溶解後に現出したナノシリコ ン粒子は、 血液内において、 赤色、 緑色、 青色 （三原色） の何れか を、 高輝度でかつ安定的に蛍光発光することを見いだした。  As a result of intensive research to solve the above problems, the present inventor has processed nano-silicon particles whose particle size has been reduced to about 1.5 to 3.5 nm by treating powder-like silicon particles in a solution. Dissolving tablets containing, when injected into a living body, dissolve the tablets, and the nanosilicon particles that appear after dissolution are red, green, or blue (three primary colors) in the blood with high brightness and It was found that stable fluorescence was emitted.
また、 本発明者は、 一連のフッ酸水溶液処理、 溶液処理及び攪拌 処理により、 高周波スパッ夕リ ング法を用いて粒子サイズを制御し つつ形成した 1 . 5 〜 3 .. 5 n m程度のナノシリコン粒子を含有す る溶解錠剤は、 体内に注入されると錠剤が溶解し、 溶解後に現出し たナノシリコン粒子は、 血液内において、 赤色、 緑色、 青色 （三原 色） の何れかを、 高輝度でかつ安定的に蛍光発光することを見いだ した。  In addition, the present inventor has formed a nano-particle of about 1.5 to 3.5 nm formed using a high-frequency sputtering method while controlling the particle size by a series of hydrofluoric acid aqueous solution treatment, solution treatment, and stirring treatment. Dissolved tablets containing silicon particles dissolve when injected into the body, and the nanosilicon particles that appear after dissolution are one of red, green, and blue (three primary colors) in the blood. It was found that the fluorescent light was emitted stably and stably.
さらに、 本発明者は、 ナノシリコン粒子に温熱処理を施して、 表 面に薬剤や多糖 ， 蛋白質などの高分子化合物を付着させたナノシリ コン粒子を含有ずる溶解錠剤は、 体内に注入されると錠剤が溶解し 、 溶解後に現出した、 薬剤や多糖 · 蛋白質などの高分子化合物を付 着したナノシリコン粒子は、 血液内において、 赤色、 緑色、 青色 （ 三原色） の何れかを、 高輝度でかつ安定的に蛍光発光することを見 いだした。  Furthermore, the present inventor, when nano-silicon particles are subjected to a thermal treatment, and dissolved tablets containing nano-silicon particles having a polymer compound such as drugs, polysaccharides, and proteins attached to the surface are injected into the body. Nano-silicon particles with a high molecular weight compound such as drugs and polysaccharides / proteins that are dissolved after the tablet dissolves, in the blood, red, green, blue (three primary colors), with high brightness We also found stable and stable fluorescence.
本発明は、 上記知見に基づいてなされたもので、 その要旨は以下 のとおりである。 ( 1 ) 粒子サイズ 1. 5〜 2. 0 n m、 2. 0〜 2. 5 n m、 2 . 5〜 3. 5 n mの何れかのナノ シリコン粒子を多数含むナノシリ コン粒子を塩化ナ ト リ ウム粉末に混入した錠剤であって、 紫外光線 又は可視光線の照射によ り、 血液内において、 青色、 緑色、 赤色の 何れかを蛍光発光することを特徴とするナノ シリ コン含有溶解錠剤 The present invention has been made on the basis of the above findings, and the gist thereof is as follows. (1) Particle size 1.5 to 2.0 nm, 2.0 to 2.5 nm, 2.5 to 3.5 nm Nano-silicone-containing dissolution tablet mixed with powder, which emits blue, green, or red fluorescence in the blood by irradiation with ultraviolet light or visible light
( 2 ) 前記ナノ シリ コン粒子が凝集していることを特徴とする前 記 （ 1 ) に記載のナノ シリ コン含有溶解錠剤。 (2) The nanosilicon-containing dissolution tablet according to (1), wherein the nanosilicon particles are aggregated.
( 3 ) 前記ナノシリ コン粒子の表面に、 薬剤や多糖 ， 蛋白質など の高分子化合物が付着していることを特徴とする前記 （ 1 ) スは （ 2 ) に記載のナノ シリ コン含有溶解錠剤。  (3) The nanosilicon-containing dissolved tablet according to (2), wherein a polymer compound such as a drug, a polysaccharide, or a protein is attached to the surface of the nanosilicon particle.
( 4 ) 水溶液中で、 粒子サイズ 1. 5〜 2. 0 n m、 2. 0〜 2 5 n m、 2. 5〜 3. 5 nmの何れかのナノ シリ コン粒子を多数 含むナノシリコン粒子に温熱処理を施し、 ナノ シリ コン粒子の表面 に未結合手を多数形成し、 次いで、  (4) In aqueous solution, heat is applied to nanosilicon particles containing a large number of nanosilicon particles with particle sizes of 1.5 to 2.0 nm, 2.0 to 25 nm, and 2.5 to 3.5 nm. Treatment to form many dangling bonds on the surface of the nanosilicon particles,
上記未結合手を多数有するナノシリ コン粒子を塩化ナ ト リ ウム粉 末に混入する  Incorporate the above nano-silicon particles with many unbonded hands into the sodium chloride powder.
ことを特徴とするナノ シリ コン含有溶解錠剤の製造方法。 A method for producing a nano-silicone-containing dissolving tablet characterized by the above.
( 5 ) 水溶液中で、 粒子サイズ 1. 5〜 2. O n m、 2. 0〜 2 . 5 n m、 2. 5〜 3. 5 n mの何れかのナノ シリ コ ン粒子を多数 含むナノシリ コン粒子に温熱処理を施し、 ナノ シリ コ ン粒子の表面 に未結合手を多数形成し、 次いで、  (5) Nanosilicon particles containing a large number of nanosilicon particles with particle sizes of 1.5 to 2. O nm, 2.0 to 2.5 nm, and 2.5 to 3.5 nm in aqueous solution To the surface of the nanosilicon particles to form many dangling bonds,
上記未結合手を多数有するナノシリ コン粒子を、 薬剤や多糖 ， 蛋 白質などの高分子化合物を混合した溶液に浸漬して、 再度、 温熱処 理を施し、 その後、  The nanosilicon particles having a large number of unbonded hands are immersed in a solution in which a polymer compound such as a drug, polysaccharide, or protein is mixed, and subjected to thermal treatment again, and then
上記温熱処理後のナノシリコン粒子を塩化ナ ト リ ウム粉末に混入 する ことを特徴とするナノ シリ コン含有溶解錠剤の製造方法。 Incorporate nano-silicon particles after thermal treatment into sodium chloride powder A method for producing a nano-silicone-containing dissolving tablet characterized by the above.
( 6 ) 前記ナノ シリ コン粒子が、 シリ コンを微粉砕して溶液中で 処理することによ り形成されたものであることを特徴とする前記 （ 4 ) 又は （ 5 ) に記載のナノ シリ コン含有溶解錠剤の製造方法。  (6) The nanosilicon described in (4) or (5), wherein the nanosilicon particles are formed by pulverizing silicon and treating it in a solution. A method for producing a kon-containing dissolution tablet.
( 7 ) 前記微粉砕後のシリ コン粒子の粒子サイズが 1 0 0 m以 下であることを特徴とする前記 （ 6 ) に記載のナノ シリ コン含有溶 解錠剤の製造方法。  (7) The method for producing a nanosilicone-containing dissolved tablet according to (6) above, wherein the finely pulverized silicon particles have a particle size of 100 m or less.
( 8 ) 前記溶液が、 フッ酸、 硝酸、 酢酸、 及び、 純水の混合溶液 であることを特徴とする前記 （ 6 ) 又は （ 7 ) に記載のナノシリ コ ン含有溶解錠剤の製造方法。 ，  (8) The method for producing a nanosilicone-containing dissolution tablet according to (6) or (7), wherein the solution is a mixed solution of hydrofluoric acid, nitric acid, acetic acid, and pure water. ,
( 9 ) 前記ナノ シリ コン粒子が、 高周波スパッタ リ ング法で作製 したアモルファス酸化ケィ素膜に熱処理を施し、 次いで、 フッ酸水 溶液処理、 溶液処理、 攪拌処理を施して形成されたものであること を特徴とする前記 （ 4 ) 又は （ 5 ) に記載のナソシリ コン含有溶解 錠剤の製造方法。  (9) The nano-silicon particles are formed by subjecting an amorphous silicon oxide film produced by a high-frequency sputtering method to a heat treatment, followed by hydrofluoric acid solution treatment, solution treatment, and stirring treatment. The method for producing a dissolved tablet containing nasallikon according to (4) or (5) above,
( 1 0 ) 前記熱処理の温度が 9 0 0〜 1 2 0 0 °Cで、 かつ、 同時 間が 1 2 0分以下であることを特徴とする前記 （ 9 ) に記載のナノ シリ コン含有溶解錠剤の製造方法。  (1 0) The nanosilicon-containing dissolution according to (9), characterized in that the temperature of the heat treatment is 90 ° C. to 120 ° C., and the time is 1 20 minutes or less. Tablet manufacturing method.
( 1 1 ) 前記フッ酸水溶液処理において、 フッ酸水溶液の濃度が 1〜 5 0 %であり、 処理温度が 1 0〜 7 0 °Cであり、 かつ、 処理時 間が 1 0〜 6 0 0秒であることを特徴とする前記 （ 9 ) 又は （ 1 0 ) に記載のナノシリ コン含有溶解錠剤の製造方法。 '  (11) In the hydrofluoric acid aqueous solution treatment, the concentration of the hydrofluoric acid aqueous solution is 1 to 50%, the treatment temperature is 10 to 70 ° C, and the treatment time is 10 to 60 (9) or (10) The method for producing a nanosilicone-containing dissolution tablet according to (9) or (10), wherein '
( 1 2 ) 前記攪拌処理の時間が 1 0〜 6 0 0秒であることを特徴 とする前記 （ 9 ) 〜 （.1 1 ) のいずれかに記載のナノ シリ コン含有 溶解錠剤の製造方法。  (12) The method for producing a nanosilicone-containing dissolution tablet according to any one of (9) to (.11), wherein the stirring treatment time is 10 to 60 seconds.
( 1 3 ) 前記温熱処理の温度が 3 0〜 1 0 0 °Cで、 同時間が 1 0 〜 6 0分であることを特徴とする前記 （ 4 ) 〜 （ 1 2 ) のいずれか に記載のナノシリ コン含有溶解錠剤の製造方法。 (1 3) Any one of the above (4) to (12), wherein the temperature of the heat treatment is 30 to 100 ° C and the same time is 10 to 60 minutes The manufacturing method of the nano silicon containing melt | dissolution tablet of description.
本発明によれば、 従来の手法では製造が困難であつた粒子サイズ According to the present invention, the particle size that has been difficult to manufacture by the conventional method.
1 . 5〜 3 . 5 n m程度のナノ シリ コン粒子を、 安定でかつ溶解可 能な材料で包囲することができる。 また、 本発明によれば、 ナノ シ リ コン粒子の表面に、 薬剤や多糖 · 蛋白質などの高分子化合物を付 着させることができる。 Nanosilicon particles of about 1.5 to 3.5 nm can be surrounded by a stable and dissolvable material. Further, according to the present invention, a high molecular compound such as a drug, a polysaccharide or a protein can be attached to the surface of the nanosilicon particle.
そして、 本発明のナスシリコン粒子を含有する溶解錠剤は、 生体 内に注入されると錠剤が溶解し、 溶解後に現出したナノ シリ コン粒 子は、 血液内において、 赤色、 緑色、 青色の各色を蛍光発光するの で、 該蛍光発光を利用 して、 生体内の各部位を観察したり、 癌細胞 を色別に又は可視的に検出することができる。  The dissolving tablet containing eggplant silicon particles of the present invention dissolves when injected into a living body, and the nanosilicon particles that appear after dissolution are red, green, and blue in blood. Thus, the fluorescence emission can be used to observe each part in the living body or to detect cancer cells by color or visually.
したがって、 本発明は、 生体内の各部位の計測や、 癌の検出 ， 治 療に係る医療分野において、 ナノシリ コン粒子の応用範囲を大きく 広げるものである。 図面の簡単な説明  Therefore, the present invention greatly expands the application range of nanosilicon particles in the medical field related to measurement of each part in a living body, detection and treatment of cancer. Brief Description of Drawings
図 1 は、 本発明のナノ シリ コン含有溶解錠剤の製造過程を示す図 である。 （A ) は、 製造過程の初期段階における溶液中でのナノシ リ コン粒子の分散態様を示す図であり、 （B ) は、 ナノ シリ コン粒 子を塩化ナ ト リ ウム粉末に混入する態様を示す図であり、 （ C ) は 、 塩化ナ ト リ ウム粉末を混入する態様を示す図であり、 （D ) は、 プレス機による処理態様を示す図であり、 そして、 （E ) は、 製造 過程の終期段階におけるナノシリコン粒子を含有した塩化ナ ト リ ウ ムの態様を示す図である。  FIG. 1 is a diagram showing the production process of the nanosilicone-containing dissolving tablet of the present invention. (A) is a diagram showing a dispersion mode of nanosilicon particles in a solution in the initial stage of the manufacturing process, and (B) is a diagram showing a mode in which nanosilicon particles are mixed into sodium chloride powder. (C) is a diagram showing a mode of mixing sodium chloride powder, (D) is a diagram showing a processing mode by a press machine, and (E) is a manufacturing method. It is a figure which shows the aspect of the sodium chloride containing the nano silicon particle in the final stage of a process.
図 2 は、 本発明の粒子形状のナノシリ コンを分散した溶液の製造 過程を示す図である。 （A ) は、 ナノシリ コン分散溶液の製造用原 料の一例を示す図であり、 （ B ) は、 製造過程の初期段階における パウダー化の工程を示す図であり、 （ C ) は、 シリ コンパウダーを 混合液で処理する処理態様を示す図であり、 そして、 （D ) は、 製 造過程の終期段階におけるナノ シリ コンの粒子単位での分散態 示す図でめる。 FIG. 2 is a diagram showing a production process of a solution in which nano-silicon having a particle shape according to the present invention is dispersed. (A) is a diagram showing an example of a raw material for producing a nanosilicon dispersion solution, and (B) is an illustration in the initial stage of the production process. (C) is a diagram showing a treatment mode in which silicon powder is treated with a mixed solution, and (D) is a diagram of nanosilicon in the final stage of the manufacturing process. This is a diagram showing the state of dispersion in particle units.
図 3 は 、 本発明の粒子形状のナノ シリ コンを分散した溶液の製造 過程を示す図である。 （A ) は、 製造過程の初期段階におけるナノ シリ コンの状態を示す図'であり、 ( B ) は、 フッ酸水溶液処理の 様を示す図であり、 （ C ) は、 フッ酸水溶液処理後のナノシリ コ ン の存在態様を示す図であり、 （D ) は、 溶液処理の態様を示す図で あり、 （ E ) は、 攪拌処理の態様を示す図であり、 そして、 F ) は、 製造過程の終期段階におけるナノ シリ コンの粒子単位での分散 態様を示す図である。  FIG. 3 is a diagram showing a production process of a solution in which nano-silicon having a particle shape according to the present invention is dispersed. (A) is a diagram showing the state of nanosilicon in the initial stage of the production process, (B) is a diagram showing the state of hydrofluoric acid aqueous solution treatment, and (C) is after hydrofluoric acid aqueous solution treatment. (D) is a diagram showing an embodiment of a solution treatment, (E) is a diagram showing an embodiment of a stirring treatment, and F) is a production process. FIG. 3 is a diagram showing a dispersion mode of nano silicon particles in the final stage of the process.
図 4 は、 本発明のナノ IJ コン粒子に対する温熱処理による薬剤 Figure 4 shows the drug by thermal treatment for the nano IJ particles of the present invention.
、 多糖 · 蛋白質などの高分子化合物の付着過程を示す図である。 （FIG. 3 is a diagram showing an adhesion process of a high molecular compound such as a polysaccharide / protein. (
A ) は、 付着過程の初期段階におけるナノ シリ コン粒子の態様を示 す図であり （ B ) は 付着過程の終期段階におけるナノ シリコン 粒子の態様を示す図である (A) is a diagram showing the mode of nanosilicon particles in the initial stage of the deposition process. (B) is a diagram showing the mode of nanosilicon particles in the final stage of the deposition process.
図 5 は、 本発明の溶液内に分散された粒子形状のナノ シリ コンの 存在態様 （透過型電子顕微鏡写真） を示す図である。  FIG. 5 is a diagram showing the existence mode (transmission electron micrograph) of particle-shaped nanosilicon dispersed in the solution of the present invention.
図 6 は、 本発明の溶解錠剤内に含有'されるナノ シリ コン粒子の血 液中における蛍光発光スぺク 卜ルを示す図である。  FIG. 6 is a diagram showing a fluorescence emission spectrum in the blood of nanosilicon particles contained in the dissolution tablet of the present invention.
図 7 は、 高周波スパッ夕 U ング装置の態様を示す図である。  FIG. 7 is a diagram showing an aspect of the high-frequency sputtering device.
図 8 は、 高周波スパッ夕 '」 ング装置において使用するターゲッ 卜 材料の態様を示す図である  FIG. 8 is a diagram showing an aspect of the target material used in the high-frequency sputtering apparatus.
図 9 は、 本発明のナノ シ U コン含有溶解錠剤の発光態様を示す図 である。  FIG. 9 is a diagram showing a light emission mode of the nano-U-contained dissolution tablet of the present invention.
図 1 0 は 、 本発明のナノシリ コン含有溶解錠剤の蛍光発光スぺク トルを示す図である。 FIG. 10 shows the fluorescence emission spectrum of the nanosilicone-containing dissolution tablet of the present invention. FIG.
図 1 1 は、 本発明のナノ シリ コン含有溶解錠剤を生理食塩水内で 溶解し 、 分散したナノ u コン粒子の発光態様を示す図である。 図 1 2 は、 本発明のナノ シリ コン含有溶解錠剤を生理食塩水内で 溶解し 、 分散したナノ シ U コン粒子の蛍光発光スぺク 卜ルを示す図 である  FIG. 11 is a diagram showing a light emission mode of nano-cone particles dispersed by dissolving the nano-silicone-containing dissolution tablet of the present invention in physiological saline. FIG. 12 is a diagram showing a fluorescence emission spectrum of nanosilicon particles dispersed by dissolving the nanosilicon-containing dissolution tablet of the present invention in physiological saline.
図 1 3 は、 本発明のナノ シリ コン含有溶解錠剤を生理食塩水内で 溶解し 、 分散したナノ ン' U コン粒子を動物の冠動脈に流動させた状 態での発光態様を示す図である。  FIG. 13 is a diagram showing a light emission mode in a state where the nanosilicon-containing dissolution tablet of the present invention is dissolved in physiological saline, and the dispersed nanon U-con particle flows into the coronary artery of an animal. .
図 1 4 は、 本発明のナノ シリ コン含有溶解錠剤を生理食塩水内で 溶解し 、 分散したナノ シリ コン粒子を動物の冠動脈に流動させた状 態での虫光発光スぺク ルを示す図であ 発明を実施するための最良の形態  FIG. 14 shows a luminescence spectrum obtained by dissolving the nanosilicone-containing dissolution tablet of the present invention in physiological saline and allowing the dispersed nanosilicon particles to flow into the coronary artery of the animal. In the drawings, the best mode for carrying out the invention
本発明において重要な点は、 赤色、 緑色、 青色の各色を蛍光発光 するナノ シリ コン粒子を、 安定でかつ溶解可能な材料で包囲し、 そ のナノ シリ コン粒子を含有する溶解錠剤 （ナノ シリ コン含有溶解錠 剤） を生体内に注入して錠剤を溶解し、 .溶解後に現出したナノ シリ コン粒子を、 血液中において、 高輝度でかつ安定的に蛍光発光させ るという ことである。  The important point in the present invention is that the nano-silicon particles that fluoresce red, green, and blue are surrounded by a stable and dissolvable material, and the dissolution tablet (nano-silicon) containing the nano-silicon particles is contained. The tablet is dissolved by injecting the tablet into the living body, and the nanosilicon particles that appear after dissolution are fluorescently emitted stably and with high brightness in the blood.
このことを達成するため、 本発明のナノ シリ コン含有溶解錠剤の 製造方法においては、 固体シリ コン （例えば、 シリ コンウェハー） を 微粉砕したシリ コ ン粒子に、 フッ酸、 硝酸、 酢酸、 及び、 純水を混 合した混合溶液で温熱処理を施してナノ シリ コン粒子を形成し、 該 ナノ シリ コン粒子を塩化ナ 卜 リ ゥム粉末に混入する。  In order to achieve this, in the method for producing a nanosilicon-containing dissolution tablet according to the present invention, hydrofluoric acid, nitric acid, acetic acid, and silicon particles obtained by finely pulverizing solid silicon (for example, silicon wafer) are used. Then, heat treatment is performed with a mixed solution in which pure water is mixed to form nano-silicon particles, and the nano-silicon particles are mixed into the sodium chloride powder.
また、 本発明のナノ シリ コン含有溶解錠剤の製造方法においては 、 高周波スパッタ リ ング法で作製したアモルファス酸化ケィ素膜に 熱処理を施し、 さ らに、 フッ酸水溶液処理、 溶液処理、 攪拌処理を 施してナノ シリ コン粒子を形成し、 該ナノ シリ コ ン粒子を塩化ナ ト リ ゥム粉末に混入する。 ' In addition, in the method for producing a nanosilicon-containing dissolving tablet of the present invention, an amorphous silicon oxide film produced by a high-frequency sputtering method is used. Heat treatment is performed, and further, hydrofluoric acid aqueous solution treatment, solution treatment, and stirring treatment are performed to form nanosilicon particles, and the nanosilicon particles are mixed into the sodium chloride powder. '
また、 本発明のナノシリ コ ン含有溶解錠剤の製造方法においては 、 ナノ シリ コン粒子に温熱処理を施して、 ナノ シリ コン粒子表面に 、 薬剤や多糖 ， 蛋白質などの高分子化合物を付着させ、 その後、 該 ナノシリ コン粒子を塩化ナ ト リ ゥム粉末に混入する。  Further, in the method for producing a nanosilicone-containing dissolving tablet of the present invention, the nanosilicon particles are subjected to a heat treatment, and a polymer compound such as a drug, a polysaccharide, or a protein is attached to the nanosilicon particle surface, and thereafter The nanosilicon particles are mixed into the sodium chloride powder.
本発明のナノ シリ コ ン含有溶解錠剤を生体内に注入すると、 錠剤 が溶解してナノ シリ コン粒子が現出し、 該ナノ シリ コ ン粒子は、 血 液中において、 高輝度でかつ安定的に、 赤色、 緑色、 青色の各色を 蛍光発光する。  When the nanosilicone-containing dissolution tablet of the present invention is injected into a living body, the tablet dissolves and nanosilicon particles appear, and the nanosilicon particles stably and stably have high brightness in blood. Fluorescent light is emitted in red, green and blue colors.
しかも、 ナノ シリ コン粒子の表面には、 薬剤や多糖 · 蛋白質など の高分子化合物を付着させることができるので、 本発明のナノシリ コ ン含有溶解錠剤を用いて、 生体内における患部の治療を行う こと が可能となる。  In addition, since a high molecular compound such as a drug or a polysaccharide / protein can be attached to the surface of the nanosilicon particles, the affected part is treated in vivo using the nanosilicone-containing dissolving tablet of the present invention. It becomes possible.
してみれば、 本発明のナノ シリ コ ン含有溶解錠剤は、 病原部位の 可視化計測や、 癌治療などの医学分野において、 革新的な医療技術 の基盤を築く ものである。 .  Thus, the nanosilicone-containing dissolution tablet of the present invention lays the foundation for innovative medical technology in the medical field such as visualization measurement of pathogenic sites and cancer treatment. .
'以下に、 本発明のナノシリ コ ン含有溶解錠剤の製造方法について 説明する。  Hereinafter, a method for producing the nanosilicone-containing dissolution tablet of the present invention will be described.
図 1 に、 ナノ シリ コン含有溶解錠剤を製造する製造過程の概要を 示す。 ナノシリ コン含有溶解錠剤の製造においては、 '純水又はエタ ノールなどの溶液 1 や、 薬剤や多糖 · 蛋白質などの高分子化合物の 混合溶液 2 を収容した,容器 3 内に分散させた粒子状のナノ シリ コ ン 4 を用いる （図 1 ( A ) 、 参照） 。  Figure 1 shows an overview of the manufacturing process for manufacturing nanosilicone-containing dissolving tablets. In the production of nano-silicone-containing dissolving tablets, a particulate solution dispersed in a container 3 containing a solution 1 such as pure water or ethanol, or a mixed solution 2 of a high molecular compound such as a drug, polysaccharide or protein is contained. Nanosilicon 4 is used (see Fig. 1 (A)).
この容器内に分散した粒子状のナノ シリ コンの製造方法として、 本発明では、 固体シリ コン （例えば、 シリ コンウェハー） を微粉砕 して溶液中で処理して形成する方法や、 高周波スパッタ リ ング法で 作製したアモルファス酸化ケィ素膜に熱処理を施し、 次いで.、 フッ 酸水溶液処理、 溶液処理、 攪拌処理を施して形成する.方法の 2種類 を用いることができる。 As a method for producing particulate nanosilicon dispersed in the container, in the present invention, solid silicon (for example, silicon wafer) is finely pulverized. Then, heat treatment is applied to the amorphous silicon oxide film formed by processing in a solution or by high-frequency sputtering, followed by hydrofluoric acid aqueous solution treatment, solution treatment, and stirring treatment. Two types of methods can be used.
図 2 に、 シリ コンウェハーを微粉砕して溶液中で処理することに より、 粒子状のナノ シリ コンを分散した溶液を製造する製造過程を 示す。 この製造過程においては、 例えば、 比抵抗率 0 . 0 1 〜 2 0 Ω c mで、 面方位 （ 1 0 0 ) 、 （ 1 1 0 ) 、 （ 1 1 1 ) の n型又は p型のシリ コンウェハ一 8 を用いる （図 2 ( A ) 、 参照） 。  Figure 2 shows the manufacturing process for producing a solution in which particulate nanosilicon is dispersed by pulverizing a silicon wafer and treating it in the solution. In this manufacturing process, for example, an n-type or p-type silicon wafer having a specific resistivity of 0.01 to 20 Ωcm and a plane orientation of (1 0 0), (1 1 0), (1 1 1) Use 1-8 (see Fig. 2 (A)).
上記製造過程の初期段階において、 シリ コンウェハー 8 を細かく 粉砕し、 シリ コンチップ 9 を作製し、 乳鉢 1 0 内に入れ、 すり棒 1 1 で擂り、 例えば、 1 0 0 /i m以下の細粒のシリコンパウダー 1 2 を作製する （図 2 ( B ) 、 参照） 。 '  In the initial stage of the above manufacturing process, the silicon wafer 8 is finely pulverized to produce a silicon chip 9, put in a mortar 10 and sprinkled with a pestle 1 1. Silicon powder 1 2 is produced (see Fig. 2 (B)). '
この時のシリコンパゥダ一 1 2 の粒子サイズは、 好ましく は 5 0 m以下、 さ らに好ましく は 2 〜 2 0 /X mであ  The particle size of the silicon powder at this time is preferably 50 m or less, and more preferably 2 to 20 / X m.
このサイズのシリ コンパウダ一 1 2 を、 ス夕一ラー又は超音波洗 浄器 1 3上に載置した樹脂容器 1 4内のフッ酸 、 硝酸、 酢酸、 及び Hydrochloric acid, nitric acid, acetic acid, and a plastic container 14 in a resin container 14 in which a silicon powder 1 2 of this size is placed on a slider or ultrasonic cleaner 1 3
、 純水の混合溶液 2 に混合し、 A , Mix with pure water 2
Π溶液.2 を攪拌しながら、 . シリ コ ンパウダ一 1 2 、、  While stirring the soot solution 2, the silicon powder 1 2,
の粒子サイス ^、 さ らに縮小する （図 2 ( C ) 、 参 照） 。  The particle size of the particle ^ is further reduced (see Fig. 2 (C)).
この時のフッ酸、 硝酸、 及び、 酢酸の濃度は、 いずれも 1 〜 5 0 %程度であるが、 好ましく は 2 0 〜 4 0 %であり、 さ らに好ましく は 3 0 %である。 また、 処理時間は 3 0 〜 3 0 0分であるが、 好ま しく は 6 0 〜 2 4 0分であり、 さ らに好ましく は 1 2 0 〜 1 8 0分 である。  The concentrations of hydrofluoric acid, nitric acid, and acetic acid at this time are all about 1 to 50%, preferably 20 to 40%, and more preferably 30%. The treatment time is 30 to 300 minutes, preferably 60 to 240 minutes, and more preferably 120 to 180 minutes.
上記溶液処理において、 混合溶液 2 中の硝酸と酢酸が、 効率よく シリ コンパウダー 1 2 の表面を酸化し、 粒子表面に酸化ケィ素膜が 形成された状態になるが、 この酸化ケィ素膜を、 フッ酸が最表面側 から徐々にエッチングしていく ので、 シリ コンパゥダー 1 2 の粒子 サイズは、 ナノ メー トルサイズにまで縮小され、 ナノ シ Uコ ン 4が 形成される。 In the above solution treatment, nitric acid and acetic acid in the mixed solution 2 efficiently oxidize the surface of the silicon powder 1 2, and a silicon oxide film is formed on the particle surface. Although formed, the hydrofluoric acid gradually etches this silicon oxide film from the outermost surface side, so the particle size of the silicon compounder 12 is reduced to the nanometer size. Con 4 is formed.
この時のナノ，シリ コン 4の粒子サイズは、 1 . 5 〜 3 5 n mの 範囲内にあり、 特に、 粒子サイズ 1 . 5 〜 2 . 0 n m、 9 . 0 〜 2 At this time, the particle size of nano and silicon 4 is in the range of 1.5 to 35 nm, and in particular, the particle size of 1.5 to 2.0 nm, 9.0 to 2
. 5 n m、 及び、 2 . 5.〜 3 . 5 n mの何れかのナノ シ U コン粒子 が多数形成されている。 A large number of nano-sized particles of 5 nm and 2.5 nm to 3.5 nm are formed.
この粒子サイズのナノシリ コン粒子が、 発光色に直接口 3与してい るので、 ナノ シリ コンの製造過程で、 粒子サイズを自在に制御する ことにより、 発光色を自在に選択することができる。  Since the nano-silicon particles of this particle size directly affect the emission color, the emission color can be freely selected by freely controlling the particle size during the nano-silicon manufacturing process.
例えば、 粒子サイズ 1 . 5 〜 2 . 0 n mのナノ シリ コン 4 を製造 する場合には、 フッ酸、 硝酸、 及び、 酢酸の濃度を 3 0 %、 処理時 間を 1 8 0分とする。 粒子サイズ 2 . 0 〜 2 . 5 n mのナノ シリ コ ン 4 を製造する場合には、 フッ酸、 硝酸、 及び、 酢酸の濃度を 3 0 %、 処理時間を 1 5 0分とする。 粒子サイズ 2 . 5 〜 3 . 5 n mの ナノシリ コン 4 を製造する場合には、 フッ酸、 硝酸、 及び、 酢酸の 濃度を 3 0 %、 処理時間を 1 2 0分とする。  For example, in the case of producing nanosilicon 4 having a particle size of 1.5 to 2.0 nm, the concentration of hydrofluoric acid, nitric acid and acetic acid is 30%, and the treatment time is 180 minutes. In the case of producing nanosilicon 4 having a particle size of 2.0 to 2.5 nm, the concentration of hydrofluoric acid, nitric acid, and acetic acid is 30%, and the treatment time is 150 minutes. In the case of producing nanosilicon 4 having a particle size of 2.5 to 3.5 nm, the concentration of hydrofluoric acid, nitric acid, and acetic acid is 30%, and the treatment time is 120 minutes.
'また、 シリ コンパウダー 1 2からナノ シリ コン 4 を形成する方法 と して、 上記方法以外に、 恒温水槽を使用する方法がある。 この方 法では、 樹脂容 1 4 を恒温水槽内に設置して、 フッ酸、 硝酸、 酢 酸、 及び、 純水の混合溶液 2 による溶液処理を行う。 '  'In addition to the above method, there is a method of using a thermostatic water bath as a method of forming the nano silicon 4 from the silicon powder 12. In this method, a resin container 14 is placed in a constant temperature water bath, and solution treatment is performed with a mixed solution 2 of hydrofluoric acid, nitric acid, acetic acid, and pure water. '
この時のフッ酸、 硝酸、 及び、 酢酸の濃度は、 いずれも 1 〜 5 0 %程度であるが、 好ましく は 2 0 〜 4 0 %であり、 さ らに好ましく は 3 0 %である。  The concentrations of hydrofluoric acid, nitric acid, and acetic acid at this time are all about 1 to 50%, preferably 20 to 40%, and more preferably 30%.
上記溶液処理における処理温度は 1 0 〜 7 0 °Cであるが、 好まし く は 3 0 〜 5 0 °Cであり、 さ らに好ましく は 4 0 °Cである。 処理時 間は 1 〜 1 2 0分である力 S、 好ましく は 1 5 〜 9 0分であり、 さ ら に好ましく は 3 0 〜 6 0分である。 The treatment temperature in the above solution treatment is 10 to 70 ° C, preferably 30 to 50 ° C, more preferably 40 ° C. During processing The force S is between 1 and 120 minutes, preferably between 15 and 90 minutes, and more preferably between 30 and 60 minutes.
上記溶液処理は、 樹脂容器 1 4 を温めながら行う '（温熱処理） の で、 混合溶液 2 中の硝酸と酢酸が、 短時間でシリ コンパウダ一 1 2 の表面に酸化ケィ素膜を形成し、 この酸化ケィ素膜を、 フッ酸が最 表面側から徐々にエッチングする。  Since the above solution treatment is performed while warming the resin container 14 (thermal treatment), nitric acid and acetic acid in the mixed solution 2 form a silicon oxide film on the surface of the silicon powder 1 2 in a short time, The silicon oxide film is gradually etched from the outermost surface by hydrofluoric acid.
その結果、 刖記方法と同様に、 シリ コンパウダー 1 2からナノ シ リ コン 4 を、 しかも 、 短時間で形成することができる  As a result, similar to the method described in the above, nano-silicone 4 can be formed in a short time from silicon powder 12.
この時に形成されるナノ シリ コン 4の粒子サイズは 、 1 . 5 〜 3 The particle size of nanosilicon 4 formed at this time is 1.5-3
. 5 n mの範囲内にあり、 特に、 1 . 5 〜 2 . 0 11 m 9 . 0 〜 2In the range of 5 nm, in particular 1.5 to 2.0 11 m 9.0 to 2
. 5 n m、 2 5 〜 3 . 5 n mの何れかの粒子サイズのナノシリ コ ン粒子が多数形成される。 A large number of nanosilicon particles having a particle size of 5 nm or 25 nm to 3.5 nm are formed.
粒子サイズ 1 . 5 2 . 0 n mのナノ シリ コ ン 4 を製造する場合 には、 フッ酸 、 硝酸 、 及び、 酢酸の濃度を 3 0 %、 処理温度を 4 0 When producing nanosilicon 4 with a particle size of 1.5 2.0 nm, the concentration of hydrofluoric acid, nitric acid and acetic acid is 30%, and the treatment temperature is 40
°C、 処理時間を 6 0分とする。 ° C, treatment time 60 minutes.
粒子サイズ 2 . 0 〜 2 . 5 n mのナノ シリ コン 4 を製造する場合 には、 フッ酸 、 硝酸 、 及び、 酢酸の濃度を 3 0 。0、 処理温度を 4 0 In the case of producing nanosilicon 4 having a particle size of 2.0 to 2.5 nm, the concentration of hydrofluoric acid, nitric acid and acetic acid is 30. 0, treatment temperature 4 0
°C、 処理時間を 4 5分とする。 ° C, treatment time is 45 minutes.
粒子サイズ 2 . 5 〜 3 . 5 n mのナノ シリ コン 4 を製造する場合 には、 フッ酸 、 硝酸 、 及び、 酢酸の濃度を 3 0 ？。、 処理温度を 4 0 When producing nanosilicon 4 with a particle size of 2.5 to 3.5 nm, the concentration of hydrofluoric acid, nitric acid and acetic acid is 30? . The processing temperature is 40
°c、 処理時間を 3 0分とする。 ° C, treatment time is 30 minutes.
このようにして形成したナノシリ 3 ン 4の表面には 、 フッ酸、 硝 酸、 及び、 酢酸の粒子が付着しているので、 ナノ シリ コン 4 を、 純 水又はエタノールなど,の溶液 1 に浸漬して洗浄し、 フッ酸、 硝酸、 及び、 酢酸の粒子を完全に除去する （図 2 ( D ) 、 参照） 。  Since the surface of the nanosilicon 4 formed in this way has particles of hydrofluoric acid, nitric acid, and acetic acid attached thereto, the nanosilicon 4 is immersed in a solution 1 such as pure water or ethanol. Then, the particles of hydrofluoric acid, nitric acid, and acetic acid are completely removed (see Fig. 2 (D)).
フッ酸、 硝酸、 及び、 酢酸の粒子は毒性をもっているので、 この 除去は、 環境や生体への安全性を確保するために行う。 このようにして、 純水又はエタノールなどの溶液 1 中に分散した 粒子状のナノシリコン 4 を得ることができる。 Since hydrofluoric acid, nitric acid, and acetic acid particles are toxic, this removal should be done to ensure safety for the environment and living organisms. In this way, particulate nanosilicon 4 dispersed in a solution 1 such as pure water or ethanol can be obtained.
次に、 高周波スパッタ リ ング法で作製したァモルフ.ァス酸化ケィ 素膜に熱処理を施し、 次いで、 フッ酸水溶液処理、 溶液処理、 攪拌 処理を施すこと,により、 粒子状のナノ シリ コンを分散した溶液を製 造する製造方法について説明する。  Next, the amorphous silicon oxide film prepared by the high-frequency sputtering method is subjected to heat treatment, followed by hydrofluoric acid aqueous solution treatment, solution treatment, and stirring treatment to disperse the particulate nanosilicon. A production method for producing the prepared solution will be described.
図 3 に、 上記一連の処理により粒子状のナノ シリ コンを分散した 溶液を製造する製造過程の概要を示す。  Figure 3 shows an overview of the manufacturing process for manufacturing a solution in which particulate nanosilicon is dispersed by the above series of treatments.
高周波スパッタ リ ング法 （図 7、 参照） を用いて基板 1 5上に形 成したアモルファス酸化ケィ素膜を不活性ガス （アルゴン、 へリ ウ ム等） の雰囲気中で熱処理して、 酸化ケィ素膜 1 6 内に、 粒子サイ ズ 1 . 5 〜 3 . 5 n m、 特に、 粒子サイズ 1 . 5 〜 2 . 0 n m、 2 . 0 〜 2 . 5 n m、 2 . 5 〜 3 . 5 n mの何れかのナノ シリ コン 4 を多数形成する （図 3 ( A ) 、 参照） 。  An amorphous silicon oxide film formed on the substrate 15 using a high-frequency sputtering method (see Fig. 7) is heat-treated in an atmosphere of an inert gas (argon, helium, etc.) to produce an oxidation cage. In the base film 16, the particle size is 1.5 to 3.5 nm, in particular, the particle size is 1.5 to 2.0 nm, 2.0 to 2.5 nm, 2.5 to 3.5 nm. Many nanosilicones 4 are formed (see Fig. 3 (A)).
高周波スパッタ リ ング法を用いると、 ナノ シリ コンの製造初期の 段階で、 発光色に直接寄与する粒子サイズを自在に制御することが できるので、 本発明では、 様々な発光色を容易に実現することが可 能である。 .  When the high frequency sputtering method is used, the particle size that directly contributes to the emission color can be freely controlled at the initial stage of nanosilicon production, and therefore various emission colors can be easily realized in the present invention. It is possible. .
'図 7 に、 高周波スパッタ リ ング装置の一態様を示す。 この装置は 、 概略、 （a)側面下部にアルゴンガス導入口 2 8 と排気口 2 9 を備 える真空チャンバ一 3 0 、 （b)真空チャ ンバ一 3 0 の上面に絶縁材 料 3 1 を介して取り付けられ、 冷却管 3 2から導入、 排出される冷 却水 3 3で冷却される基板ホルダー 3 4、 及び、 （c)真空チャンバ 一 3 0 の下面に絶縁材料 3 1 を介して取り付けられ、 冷却管 3 2か ら導入、 排出される冷却水 3 3で冷却される陰極シールド 3 5 を備 える高周波電極 3 6、 から構成されている。  'Figure 7 shows one mode of the high-frequency sputtering system. This apparatus is roughly divided into (a) a vacuum chamber 30 having an argon gas inlet 28 and an exhaust 29 at the bottom of the side surface, and (b) an insulating material 31 on the upper surface of the vacuum chamber 30. The substrate holder 3 4 cooled by the cooling water 3 3 introduced and discharged from the cooling pipe 3 2, and (c) attached to the lower surface of the vacuum chamber 1 3 0 via the insulating material 3 1 The high-frequency electrode 3 6 includes a cathode shield 3 5 that is cooled by cooling water 3 3 introduced and discharged from the cooling pipe 3 2.
上記装置において、 アルゴンガスを真空チャ ンバ一 3 0内にアル ゴンガス導入口 2 8から導入し、 高周波コン トローラ 3 7 によりァ ルゴンガスをイオン化し、 イオン化したァルゴンイオンを、 高周波 電極 3 6上のターゲッ 卜材料 3 8であるシリ コンチッ.プ 3 8 a と石 英ガラス 3 8 b (図 8、 参照。 石英ガラス 3 S b上に、 シリ コンチ ップ 3 8 aが所定の間隔で配列されている。 ） へ衝突させ、 夕一ゲ ッ ト材料 3 8から放出されたシリ コ ン原子や酸化ケィ素分子を基板 ホルダ一 3 4 に保特した基板 1 5上に堆積させ、 アモルファス酸化 ケィ素膜を形成する。 In the above device, argon gas is introduced into the vacuum chamber 30. Argon gas is ionized by the high-frequency controller 3 7, introduced from the Gon gas inlet 2 8, and the ionized Argon ion is converted into silicon chip 3 8 a, which is the target material 3 8 on the high-frequency electrode 3 6 3 8 b (see Fig. 8) Silica chips 3 8 a are arranged at a predetermined interval on quartz glass 3 S b, and are discharged from the target material 3 8 in the evening. Then, silicon atoms and silicon oxide molecules are deposited on the substrate 15 held in the substrate holder 3 4 to form an amorphous silicon oxide film.
次に、 上記酸化ケィ素膜に、 不活性ガス (アルゴン、 へリ ゥム等 Next, an inert gas (argon, helium, etc.) is applied to the above oxide film.
) の雰囲気中で熱処理を施して、 該酸化ケィ素膜 1 6内に、 所定粒 子サイズのナノ シリ コ ン 4 を多数形成する (図 3 ( A ) 、 参照） 。 ) To form a large number of nanosilicones 4 having a predetermined particle size in the silicon oxide film 16 (see FIG. 3A).
上記熱処理の際、 熱処理温度は 9 0 0 〜. 1 2 0 0 °Cとするが、 好 ましく は 1 0 0 0〜 1 1 0 0 °Cであ また、 熱処理時間は 1 2 0 分以下であるが 、 好ましく は 1 5 1 0 0分であり、 さ らに好まし く は 3 0〜 8 0分であり、 最も好ま し <は 5 0〜 6 0分である。 ナノ シリ コ ン粒子の粒子サイズは、 図 8 に示す夕ーゲッ 卜材料 3 8 を構成するシリコンチップ 3 8 a と石英ガラス 3 8 bの面積比を 変えることにより制御することができる P この面積比は、 通常、 1 〜 5 0 %とする力 好ましく は 5〜 3 0 %であり、 さ らに好ましく は 1 0〜 1 5 %である。 ' In the above heat treatment, the heat treatment temperature is set to 90 ° C to 120 ° C, but preferably 100 ° C to 1100 ° C, and the heat treatment time is 120 minutes or less. However, it is preferably 1510 minutes, more preferably 30 to 80 minutes, and most preferably <50 to 60 minutes. Particle size of the nano-silicon co down particles, P This area ratio can be controlled by changing the area ratio of the silicon chip 3 8 a and the quartz glass 3 8 b constituting the evening Ge' Bok material 3 8 shown in FIG. 8 Is usually a force of 1 to 50%, preferably 5 to 30%, and more preferably 10 to 15%. '
また、 スパッタリ ング条件の高周 ¾電力やガス圧 （作製中の圧力 であり、 本製造プロセスではアルゴンガスの圧力） を変えても、 粒 子サイズを制御することが可能である。 この時、 高周波電力は 1 0 〜 5 0 0 Wの範囲内で変化させ、 ガス圧は 1 X I 0— 4〜 1 X I 0 - 1 t o r rの範囲内で変化させる。 In addition, the particle size can be controlled even by changing the high peripheral power and gas pressure (pressure during production, argon gas pressure in this manufacturing process) under sputtering conditions. At this time, high frequency power is varied in the range of 1 0 ~ 5 0 0 W, the gas pressure is 1 XI 0- 4 ~ 1 XI 0 - vary within a range of 1 torr.
このように、 高周波スパッタ リ ング装置を用いて、 粒子サイズが 1 . 5〜 3 . 5 n mの範囲内にあるナノ シリ コン粒子、 特に、 1 . 5〜 2 . 0 n m、 2 . 0〜 2 . 5 n m、 2 . 5〜 3 . 5 n mの何れ かの粒子サイズのナノ シリ コン粒子を多数含むナノ シリ コン粒子を 作製することができる。 Thus, using a high frequency sputtering apparatus, nano-silicon particles having a particle size in the range of 1.5 to 3.5 nm, particularly 1. Nanosilicon particles containing a large number of nanosilicon particles having a particle size of 5 to 2.0 nm, 2.0 to 2.5 nm, or 2.5 to 3.5 nm can be produced.
次に、 粒子サイズが 1 . 5〜 3 . 5 n mの範囲内にあるナノシリ コン 4が形成された酸化ケィ素膜 1 6 を載置する基板 1 5 を、 ァク リル板 1 7 に貼り付け （図 3 ( A ) 、 参照） 、 フッ酸水溶液 1 9 を 収容する樹脂容器 1 4 に、 上記酸化ケィ素膜 1 6 を下にして装着す る。  Next, the substrate 15 on which the silicon oxide film 16 on which the nanosilicon 4 having a particle size in the range of 1.5 to 3.5 nm is formed is pasted on the acrylic plate 17. (Refer to FIG. 3 (A)). The resin film 14 containing the hydrofluoric acid aqueous solution 19 is mounted with the above-mentioned silicon oxide film 16 facing down.
この時 、 フッ酸水溶液 1 9の濃度は 1〜 5 0 %とするが、 好まし く は 1 0 〜 4 0 %であり、 さ らに好ましく は 2 0〜 3 0 %である。 そして、 樹脂容器 1 4 を、 ヒ ―夕一 2 0 を備え、 純水 2 1 を収容す る恒温水槽 2 2 内に設置し 、 フッ酸水溶液処理 1 8 を行う （図 3 ( At this time, the concentration of the hydrofluoric acid aqueous solution 19 is 1 to 50%, preferably 10 to 40%, and more preferably 20 to 30%. Then, the resin container 14 is installed in a thermostatic water tank 2 2 equipped with a hygiene 20 and containing pure water 2 1, and a hydrofluoric acid aqueous solution treatment 18 is performed (FIG. 3 (
B ) 、 参ノ昭、、ヽ） B), Sannoaki, 、)
上記処理の際、 処理温度は 1 0〜 7 0 °Cであるが、 好ましく は 3 In the above treatment, the treatment temperature is 10 to 70 ° C, preferably 3
0〜 5 0 °Cであり 、 さ らに好ましく は 4 0 °Cである。 また、 処理時 間は 1 0 〜 6 0 0秒であるが 、 好ましく は 3 0〜 3 0 0秒であり、 さ らに好ましく は 6 0〜 1 2 0秒である。 The temperature is 0 to 50 ° C, more preferably 40 ° C. The processing time is 10 to 600 seconds, preferably 30 to 300 seconds, and more preferably 60 to 120 seconds.
上記フッ酸水溶液処理 1 8 にお.いては， 樹脂容器 1 4内のフッ酸 水溶液 1 9から蒸発したフ 酸粒子が、 酸化ケィ素膜 1 6 の表面に 付着し、 酸化ケィ素膜 1 6 中の酸化ケィ素を表面から徐々にエッチ ングしてい く  In the hydrofluoric acid aqueous solution treatment 18, the fluoric acid particles evaporated from the hydrofluoric acid aqueous solution 19 in the resin container 14 adhere to the surface of the silicon oxide film 16, and the silicon oxide film 16. The silicon oxide inside is gradually etched from the surface.
その結果、 基板 1 5上には、 多数のナノ シリ コン 4が凝集状態で 露出する （図 3 ( C ) 、 参照） 。  As a result, a large number of nanosilicones 4 are exposed in an aggregated state on the substrate 15 (see FIG. 3 (C)).
次に、 ナノ シリ コン., 4が凝集露出した基板 1 5 を、 純水又はエタ ノールなどの溶液 1 を収容した容器 3 に浸漬し、 容器 3 を、 スター ラー又は超音波洗浄器 1 3 に載置して、 溶液処理 2 3 を施し、 基板 1 5及びナノ シリ コン 4上に残留しているフッ酸粒子を完全に除去 する （図 3 ( D ) 、 参照） 。 Next, the substrate 15 on which nanosilicon., 4 is aggregated and exposed is immersed in a container 3 containing a solution 1 such as pure water or ethanol, and the container 3 is placed in a stirrer or ultrasonic cleaner 13. Place the solution and perform solution treatment 2 3 to completely remove the hydrofluoric acid particles remaining on the substrate 1 5 and nanosilicon 4 (Refer to Fig. 3 (D)).
フッ酸粒子は毒性を持っているので、 環境や生体への無毒性や無 害性を確保するため、 この溶液処理 2 3 を行う。 この溶液処理 2 3 を充分に行う ことによ り、 ナノ シリ コン粒子が本来有する環境保全 性を確実に確保することができる。  Since hydrofluoric acid particles are toxic, this solution treatment 2 3 is performed to ensure non-toxicity and harmlessness to the environment and living organisms. By sufficiently performing this solution treatment 23, it is possible to ensure the environmental conservation inherent in nanosilicon particles.
その後、 ナノ シリ コ ン 4が凝集露出した基板 1 5 を、 再び、 純水 又はェタノ一ルなどの溶液 1 を収容した容器 3 に浸漬し、 容器 3 を スターラー又は超音波洗浄器 1 3 に載置して、 攪拌処理 2 4 を施す (図 3 ( E ) 、 参照） 。 .  Thereafter, the substrate 15 on which the nanosilicone 4 is aggregated and exposed is again immersed in a container 3 containing a solution 1 such as pure water or ethanol, and the container 3 is placed on a stirrer or ultrasonic cleaner 1 3. Then, perform the stirring process 24 (see Fig. 3 (E)). .
攪拌処理 2 4の処理時間は、 通常、 1 0 〜 6 0 0秒とするが、 好 ましく は 3 0 〜 3 0 0秒であり、 さ らに好ましく は 6 0 〜 1 2 0秒 である。 攪拌処理 2 4 によ り、 基板 1 5上に凝集状態で露出してい たナノシリ コ ン 4は、 基板 1 5から分離 · 離散し、 純水又はェ夕ノ ールなどの溶液 1 内に分散する （図 3 ( E ) 、 参照） 。  The treatment time of the stirring treatment 24 is usually 10 to 600 seconds, preferably 30 to 300 seconds, and more preferably 60 to 120 seconds. . The nanosilicone 4 exposed in agglomerated state on the substrate 15 due to the stirring treatment 24 is separated and separated from the substrate 15 and dispersed in the solution 1 such as pure water or ethanol. (Refer to Fig. 3 (E)).
そして、 攪拌処理 2 4の後、 容器 3から基板 1 5 を取り出せば、 純水又はエタノールなどの溶液 1 中に分散した状態で粒子状のナノ シリ コン 4 を得ることができる （図 3 ( F ) 、 参照） 。  Then, after the stirring process 2 4, if the substrate 15 is taken out from the container 3, the particulate nanosilicon 4 can be obtained in a dispersed state in a solution 1 such as pure water or ethanol (FIG. 3 (F ), See).
このように、 上記 2種類の製造方法により製造した、 粒子状のナ ノ シリ コンが分散した溶液の透過型電子顕微鏡写真を、 図 5 に示す 。 図 5 中、 〇印の部分がナノシリ コン粒子である。  FIG. 5 shows transmission electron micrographs of the solution prepared by the above-described two kinds of manufacturing methods in which particulate nanosilicon is dispersed. In Fig. 5, the part marked with ○ is nanosilicon particles.
図 5 において、 ナノ シリ ユン粒子は、 粒子状で一様に分散してお り、 しかも、 球形で存在していることが解る。 なお、 ナノ シリ コン 粒子の粒子サイズは、 1 . 5 〜 3 . 5 11 mであった。  In Fig. 5, it can be seen that the nanosilica particles are uniformly dispersed in the form of particles and still exist in a spherical shape. The particle size of the nanosilicon particles was 1.5 to 3.511 m.
次に、 上記 2種類の、製造方法によ り製造した粒子状のナノ シリ コ ン表面に、 薬剤や多糖 · 蛋白質などの高分子化合物を付着させる方 法について説明する。 '  Next, a method for attaching a high molecular compound such as a drug, a polysaccharide or a protein to the surface of the particulate nanosilicon produced by the above two production methods will be described. '
図 4に、 粒子状のナノシリ コンに温熱処理を施し、 ナノ シリ コン 表面に'、 薬剤や多糖 · 蛋白質などの高分子化合物を付着させる付着 過程を示す。 ' Fig. 4 shows the thermal treatment of particulate nanosilicon to produce nanosilicon Shows the attachment process of attaching high-molecular compounds such as drugs, polysaccharides and proteins to the surface. '
本発明の粒子状のナノ シリ コン 4は、 フッ酸、 硝酸、 酢酸、 及び 、 純水の混合溶液やフッ酸水溶液による溶液処理によ り製造されて いるので、 ナノ シリ コン 4の表面は、 酸素原子や多量の水素原子が' 結合した状態になっている。  Since the particulate nanosilicon 4 of the present invention is manufactured by solution treatment with a mixed solution of hydrofluoric acid, nitric acid, acetic acid, and pure water or a hydrofluoric acid aqueous solution, the surface of the nanosilicone 4 is Oxygen atoms and a lot of hydrogen atoms are in a 'bonded state'.
この粒子状のナノシリ コン 4 に温熱処理を施すことにより、 水素 原子の結合を解除し、 ナノシリ コン 4の表面に、 未結合手 2 5 を多 数形成する （図 4 ( A ) 、 参照） 。  By subjecting the particulate nanosilicon 4 to a thermal treatment, the bonding of hydrogen atoms is released, and a large number of dangling bonds 25 are formed on the surface of the nanosilicon 4 (see FIG. 4 (A)).
一般に、 シリ コン原子と水素原子が結合した材料の場合、 熱や経 時的変化によ り、 水素原子がシリ コン原子と解離していく。 これは 、 シリコン原子と水素原子の結合エネルギーが、 他の元素との結合 エネルギーより も非常に弱いためである。  In general, in the case of a material in which silicon atoms and hydrogen atoms are bonded, the hydrogen atoms dissociate from the silicon atoms due to heat and changes over time. This is because the bond energy between the silicon atom and the hydrogen atom is much weaker than the bond energy with other elements.
つまり、 水素原子が結合しているナノ シリ コ ン 4に温熱処理を施 すことにより、 その表面から水素原子を完全に解離することができ る。  In other words, by performing a thermal treatment on nanosilicon 4 to which hydrogen atoms are bonded, hydrogen atoms can be completely dissociated from the surface.
即ち、 本発明の粒子状のナノ シリ コン 4の場合、 その表面には多 量の水素原子が結合して'いるが、 温熱処 により、 この結合を解離 じて、 ナノシリ コン 4の表面に未結合手 2 5 を多数形成することが できる。 '  That is, in the case of the particulate nanosilicon 4 of the present invention, a large amount of hydrogen atoms are bonded to the surface, but this bond is dissociated by heat treatment, and the surface of the nanosilicon 4 is not yet removed. Many bonds 2 5 can be formed. '
このようにして未結合手 2 5 を多数形成したナノ シリ コ ン 4 を、 薬剤や多糖 ， 蛋白質などの高分子化合物の混合溶液 2 を収容した容 器 3 に浸漬し、 容器 3 を、 ヒータ一 2 0 を備え、 純水 2 1 を収容す る恒温水槽 2 2内に設.置し、 再度、 温熱処理 2 6 を行う （図 4 ( A ) 、 参照） 。  Nanosilicone 4 in which a large number of unbonded hands 25 are formed in this manner is immersed in a container 3 containing a mixed solution 2 of a polymer compound such as a drug, a polysaccharide, or a protein, and container 3 is placed in a heater. It is installed in a constant temperature water tank 2 2 containing 20 and containing pure water 2 1, and thermal heat treatment 26 is performed again (see FIG. 4 (A)).
上記処理の際、 処理温度は 3 0 〜 1 0 0 °Cであるカ^ 好ま しく は 4 0 〜 8 0 °Cであり、 さ らに好ましく は 5 0 °Cである。 また、 処理 時間は' 1 0 〜 6 0分であるが、 好ましく は 2 0 〜 5 0分で、 さ らに 好ましく は約 3 0分である。 In the above treatment, the treatment temperature is 30 to 100 ° C., preferably 40 to 80 ° C., and more preferably 50 ° C. Also processing The time is from '10 to 60 minutes, preferably from 20 to 50 minutes, more preferably about 30 minutes.
上記温熱処理 2 6 を行なう ことにより、 ナノ シリ コ.ン 4の表面に は、 薬剤や多糖 · 蛋白質などの高分子化合物 2 7以外に、 水酸基 （ 〇 H基） を付着させることができる （図 4 ( B ) 、 参照） 。  By performing the above heat treatment 26, in addition to high molecular compounds 27 such as drugs, polysaccharides and proteins, hydroxyl groups (O H groups) can be attached to the surface of nanosilicon 4 (Fig. 4 (B), see).
上記製造方法から製造した、 純水又はエタノ一ルなどの溶液 1 内 に分散している粒子状のナノ シリ コン 4、 又は、 薬剤や多糖 ' 蛋白 質などの高分子化合物 2 7 の混合溶液 2内に分散し、 表面に薬剤や 多糖 · 蛋白質などの高分子化合物 2 7が付着している粒子状のナノ シリ コン 4 をピぺッ 卜ですく い取る。  Particulate nanosilicone 4 dispersed in solution 1 such as pure water or ethanol produced from the above production method, or mixed solution 2 of polymer compound 2 7 such as drug or polysaccharide 'protein 2 Pipette the nanosized silicon particles 4 that are dispersed in the surface and have high-molecular compounds 27 such as drugs, polysaccharides, and proteins attached to the surface.
このナノ シリ コン 4 を、 ナノ シリ コン 4が溶液 1 又は混合溶液 2 内に分散した状態のまま、 粉末状の塩化ナ ト リ ウム 5 を収容する型 容器 6 内に混入する （図 1 ( B ) 、 参照） 。  The nanosilicon 4 is mixed in the mold container 6 containing the powdered sodium chloride 5 while the nanosilicon 4 is dispersed in the solution 1 or the mixed solution 2 (FIG. 1 (B ), See).
ここで使用する塩化ナ ト リ ウム 5 は、 溶液や体内において容易に 溶解する材料である。 塩化ナ ト リ ウム 5以外に、 溶解性があり、 鎮 静就眠薬などの医薬品と して使用されている臭化カ リ ウムを使用す ることもできる。  Sodium chloride 5 used here is a material that dissolves easily in solution and in the body. In addition to sodium chloride 5, potassium bromide, which is soluble and used as a sedative hypnotic drug, can also be used.
上記処理において、 塩化ナ ト リ ウム 5に付着した溶液 1及び混合 溶液 2 は、 短時間で蒸発するので、 数回に分けて処理することによ り、 塩化ナ ト リ ウム 5 内に多量のナノ シリ コ ン 4 を混入することが できる。  In the above treatment, the solution 1 and the mixed solution 2 adhering to the sodium chloride 5 evaporate in a short time, so that a large amount of the sodium chloride 5 is contained in the treatment by dividing the treatment into several times. Nanosilicon 4 can be mixed.
また、 粉末状の塩化ナ ト リ ウム 5内に混入するナノ シリ コ ン 4 と して、 粒子状のナノ シリ コン 4が分散した水溶液又は混合溶液に濾 過処理を施して取り出レたナノ シリ コ ン 4 を使用することも可能で ある。 .  In addition, the nanosilicon 4 mixed in the powdered sodium chloride 5 is filtered through an aqueous solution or mixed solution in which the particulate nanosilicon 4 is dispersed. Silicon 4 can also be used. .
その後、 多量のナノ シリ コン 4 を混入した粉末状の塩化ナ ト リ ウ ム 5 を収容する型容器 6内に、 さ らに、 粉末状の塩化ナ ト リ ウム 5 を加える （図 1 ( C ) 、 参照.） 。 Thereafter, the powdered sodium chloride 5 mixed with a large amount of nanosilicon 4 is further placed in the mold container 6 containing the powdered sodium chloride 5 and further powdered sodium chloride 5. (See Fig. 1 (C)).
そして、 型容器 6 にフタ 7 をして、 プレス機によ り、 多量のナノ シリ コン 4を混入した塩化ナ ト リ ウム 5 を凝結状態にする （図 1 ( D) 、 参照） 。 最後に、 凝結したナノ シリ コン 4含有塩化ナ ト リ ウ ム 5 を型容器 6から取り出す （図 1 ( E ) 、 参照） 。  Then, a lid 7 is put on the mold container 6, and sodium chloride 5 mixed with a large amount of nanosilicon 4 is condensed by a press machine (see Fig. 1 (D)). Finally, the condensed nanosilicon 4 containing sodium chloride 5 is removed from the mold container 6 (see Fig. 1 (E)).
こ こで、 図 6 に、 溶解錠剤内に内蔵したナノシリ コン粒子の血液 中における蛍光発光スぺク トルを示す。 溶解錠剤内に存在するナノ シリ コン粒子からは、 血液中において、 赤色 （波長 ： 6 6 0 n m ) 、 緑色 （波長 ： 5 6 0 n m) 、 及び、 青色 （波長 ： 4 4 0 n m) の 蛍光発光を得ることができる。  Figure 6 shows the fluorescence spectrum in the blood of the nanosilicon particles contained in the dissolution tablet. The nano-silicon particles present in the dissolution tablet are red (wavelength: 660 nm), green (wavelength: 560 nm), and blue (wavelength: 4400 nm) fluorescence in blood. Luminescence can be obtained.
この発光色の違いは、 ナノ シリ コン粒子の粒子サイズが各発光色 に対して異なっていることによる。  This difference in emission color is due to the difference in the particle size of the nanosilicon particles for each emission color.
一般に、 半導体材料から得られる発光色は、 その材料のもつバン ドギャ ップエネルギーに直接依存しており、 発光色の波長は、 バン ドギャ ップエネルギーと反比例関係にある。  In general, the emission color obtained from a semiconductor material directly depends on the band gap energy of the material, and the wavelength of the emission color is inversely proportional to the band gap energy.
ナノシリ コ ン粒子の場合、 バン ドギャ ップエネルギーの大きさは 、 粒子サイズの縮小とともに増大する。 即ち、 ナノ シリ コン粒子の 粒子サイズが大きい場合、 そのバン ドギヤ ップエネルギーは小さ く なり、 発光色の波長は長波長側になる。  In the case of nanosilicon particles, the band gap energy increases with decreasing particle size. That is, when the nanosilicon particle size is large, its bandgap energy is small and the wavelength of the emitted color is on the long wavelength side.
逆に、 ナノ シリ コン粒子の粒子サイズが小さい場合、 そのノ ン ド ギャ ップエネルギーは大きくなり、 短波長側に波長を有する発光色 が得られることになる。  Conversely, when the nanosilicon particle size is small, its node gap energy increases, and an emission color having a wavelength on the short wavelength side can be obtained.
各発光色に対するナノ シリ コ ン粒子の粒子サイズの目安について は、 赤色発光を示すナノ シリ コ粒子の粒子サイズは、 2. 5〜 3. 5 n mの範囲であり、 緑色発光を示すナノ シ.リ コン粒子の粒子サイ ズは、 2. 0〜 2. 5 n mの範囲であり、 青色発光を示すナノ シリ コン粒子の粒子サイズは、 1. 5〜 2. O n mの範囲である。 また、 各発光色の輝度は、 紫外光から可視光までの光を照射する ことにより室内照明下において肉眼ではっき り と確認することがで きる程度に強く、 しかも、 その発光寿命は、 長期でかつ安定してい る。 As a guide for the particle size of the nanosilicon particles for each emission color, the particle size of the nanosilicon particles that emit red light is in the range of 2.5 to 3.5 nm, and the nano particles that emit green light. The particle size of the silicon particles is in the range of 2.0 to 2.5 nm, and the particle size of the nanosilicon particles exhibiting blue emission is in the range of 1.5 to 2. O nm. In addition, the luminance of each emission color is strong enough that it can be clearly seen with the naked eye under room lighting by irradiating light from ultraviolet light to visible light, and its emission lifetime is long. And stable.
このように、 ，本発明においては、 血液中において、 高輝度でかつ 安定した赤色から青色までの領域で蛍光発光し、 環境 · 人体に対し 無毒 · 無害のナノ シリ コン粒子を含有した溶解錠剤を、 固体シリ コ ン （例、 シリコンゥェ一ハー） を原料と し、 （a) フッ酸、 硝酸、 酢 酸、 及び、 純水の混合溶液による溶液処理、 又は、 （b)高周波スパ ッ夕 リ ング法、 熱処理、 フッ酸水溶液処理、 溶液処理、 及び、 攪拌 処理を用いた製造プロセスで得ることができる。  As described above, in the present invention, a dissolved tablet containing nano-silicon particles that fluoresce in the blood in a highly bright and stable region from red to blue, and is non-toxic and harmless to the environment / human body. (A) Solution treatment with a mixed solution of hydrofluoric acid, nitric acid, acetic acid, and pure water, or (b) high-frequency sputtering It can be obtained by a manufacturing process using a method, a heat treatment, a hydrofluoric acid aqueous solution treatment, a solution treatment, and a stirring treatment.
さ らに、 温熱処理を用いることにより、 ナノ シリ コ ン粒子の表面 に、 薬剤や多糖 ， 蛋白質などの高分子化合物を容易に付着させるこ とができる。  In addition, by using thermal heat treatment, high molecular compounds such as drugs, polysaccharides, and proteins can be easily attached to the surface of the nanosilicon particles.
本発明のナノ シリ コン含有溶解錠剤は、 生体内の病原部位の可視 化計測や、 癌治療に係る医学分野において、 バイオイ メージングゃ D D S と して有効に用いることができるものである。 実施例  The nanosilicone-containing dissolution tablet of the present invention can be effectively used as bioimaging or DDS in the field of visualization and measurement of pathogenic sites in the living body or in the medical field related to cancer treatment. Example
次に、 本発明の実施例について説明する力 実施例の条件は、 本 発明の実施可能性及び効果を確認するために採用 した一条件例であ り、 本発明は、 この一条件例に限定されるものではない。 本発明は 、 本発明の要旨を逸脱せず、 本発明の目的を達成する限り において 、 種々の条件を採用 し得るものである。  Next, the power of the embodiment of the present invention will be described. The conditions of the embodiment are one example of conditions adopted to confirm the feasibility and effects of the present invention, and the present invention is limited to this one example Is not to be done. The present invention can adopt various conditions as long as the object of the present invention is achieved without departing from the gist of the present invention.
(実施例 1 )  (Example 1)
錠剤の発光特性を確認する実施例である。 図 9 に、 本発明で作製 したナノ シリ コン （粒子サイズ ： 2 . 5 〜 3 . 5 n m ) 含有溶解錠 剤に、 直接、 紫外光線を照射したときの発光態様を示す。 It is an Example which confirms the luminescent property of a tablet. Fig. 9 shows a dissolution tablet containing nanosilicone (particle size: 2.5 to 3.5 nm) prepared according to the present invention. The light emission mode is shown when the agent is directly irradiated with ultraviolet rays.
図 9 に示すように、 ナノ シリ コン含有錠剤は、 室内照明下におい て肉眼ではっきり と確認することができる輝度の赤色.を蛍光発光し ている。 しかも、 発光寿命も、 長期でかつ安定していることを確認 することができた。  As shown in Fig. 9, the nano-silicone-containing tablets fluoresce in a red color with a luminance that can be clearly seen with the naked eye under room lighting. Moreover, it was confirmed that the emission lifetime was long and stable.
図 1 0 に、 紫外光線を照射したときのナノ シリ コン含有溶解錠剤 の蛍光発光スペク トルを示す。 図 1 0 により、 錠剤内のナノ シリ コ ン粒子から、 波長 ： 6 6 0 n mにピークを有する赤色が蛍光発光し ていることを確認することができる。  Figure 10 shows the fluorescence emission spectrum of the nanosilicon-containing dissolution tablet when irradiated with ultraviolet light. From FIG. 10, it can be confirmed from the nanosilicon particles in the tablet that red light having a peak at a wavelength of 660 nm is emitting fluorescence.
図 1 1 に、 本発明で作製したナノ シリ コン含有溶解錠剤を生理食 塩水に投入して錠剤を溶解し、 ナノシリ コン粒子を分散させた生理 食塩溶液に、 直接、 紫外光線を照射したときの発光態様を示す。  Fig. 11 shows that the nano-silicone-containing dissolution tablet prepared in the present invention is poured into physiological saline to dissolve the tablet, and the physiological saline solution in which nano-silicon particles are dispersed is directly irradiated with ultraviolet rays. The light emission mode is shown.
図 1 1 に示すように、 生理食塩溶液内に分散したナノ シリ コン粒 子は、 室内照明下において肉眼ではっきり と確認することができる 輝度の赤色を蛍光発光している。 しかも、 発光寿命も、 長期でかつ 安定していることを確認することができた。  As shown in Fig. 11, the nano-silicon particles dispersed in the physiological saline solution fluoresce with a bright red color that can be clearly seen with the naked eye under room lighting. Moreover, it was confirmed that the light emission lifetime was long and stable.
図 1 2 に、 紫外光線を照射したときの生理食塩溶液の蛍光発光ス ぺク トルを示す。 生理食塩溶液内に分散.したナノ シリ コン粒子から 、 '錠剤内に内蔵されていた状態の時と同様に、 波長 ： 6 6 0 n mに ピークを有する赤色を蛍光発光していることを確認することができ る。  Figure 12 shows the fluorescence emission spectrum of the physiological saline solution when irradiated with ultraviolet light. Disperse in the physiological saline solution. From the nanosilicon particles, confirm that the red light having a peak at a wavelength of 6600 nm is emitted in the same manner as when incorporated in the tablet. be able to.
(実施例 2 )  (Example 2)
本発明のナノ シリ コン粒子が、 動物の生体内において流動すると ともに蛍光発光する様子を観察した実施例である。  This is an example in which the nanosilicon particles of the present invention were observed to emit fluorescence while flowing in an animal body.
図 1 3 に、 本発明のナノシリ コ ン含有溶解錠剤を生理食塩水に溶 解し、 同溶液内に分散したナノ シリ コン粒子を、 動物 （羊） の冠動 脈に、 直接、 流動させた状態での発光態様を示す。 この生体内流動観察は、 動.物 （羊） を開腹した状態で、 外部から 、 直接、 紫外光線を照射しながら行った。 Fig. 13 shows that the nanosilicone-containing dissolution tablet of the present invention was dissolved in physiological saline, and the nanosilicon particles dispersed in the solution were allowed to flow directly into the coronary artery of an animal (sheep). The light emission mode in the state is shown. This in vivo flow observation was performed while irradiating the animal (sheep) with ultraviolet rays directly from the outside.
図 1 3から、 ナノ シリ コン粒子が、 冠動脈で流動している時にお いても、 ナノシリ コン粒子は、 室内照明下で肉眼でもはっき り と確 認することができる輝度の赤色を蛍光発光していることが解る。 し かも、 発光寿命も、 長期でかつ安定していることを確認することが できた。 +  Figure 13 shows that even when the nanosilicon particles are flowing in the coronary arteries, the nanosilicon particles fluoresce with a bright red color that can be clearly seen with the naked eye under room lighting. I understand that In addition, it was confirmed that the emission lifetime was long and stable. +
図 1 4 に、 冠動脈への流動時におけるナノ シリ コン粒子の蛍光発 光スペク トルを示す。 図 1 4から、 冠動脈中でのナノ シリ コ ン粒子 は、 錠剤や溶液内に含有されていた状態の時と同様に、 波長 ： 6 6 O n mにピークを有する赤色を蛍光発光していることを確認するこ とができる。  Figure 14 shows the fluorescence emission spectrum of nanosilicon particles during flow to the coronary arteries. Figure 14 shows that the nanosilicon particles in the coronary artery fluoresce red with a peak at a wavelength of 66 nm, as in the tablet or solution. Can be confirmed.
この生体内流動観察は、 冠動脈以外にも、 マウスゃラッ 卜の各部 位 （小腸壁、 皮下） において流動させた状態でも行った。 その結果 、 動物の各部位において、 ナノ シリ コン粒子から高輝度でかつ安定 的な赤色が蛍光発光していることを確認した。 産業上の利用可能性  This in-vivo flow observation was performed not only in the coronary arteries but also in a state where the fluid flowed in each part (small intestine wall, subcutaneous) of the mouse. As a result, it was confirmed that a high-luminance and stable red fluorescent light was emitted from the nanosilicon particles in each part of the animal. Industrial applicability
'本発明のナノ シリ コ ン含有溶解錠剤は、 生体内に注入されると、 錠剤が溶解し、 溶解後に現出したナノ'シリ コ ン粒子が、 血液中にお いて、 高輝度でかつ安定したフルカラ一 （赤色、 緑色、 青色） の蛍 光発光を呈する。  The nano-silicone-containing dissolution tablet of the present invention dissolves when injected into a living body, and the nano-silicon particles that appear after dissolution are highly bright and stable in blood. It exhibits a full color (red, green, blue) fluorescence.
そして、 ナノ シリ コン粒子は、 環境や生体に対し優しく 、， かつ、 安価な材料から製造することができるから、 バイォイメージングゃ D D Sの機能を有する溶解錠剤の開発を促進し、 生体内の各部位の 観察や癌治療に係る技術の発展に貢献する。  Nanosilicon particles are gentle to the environment and living organisms, and can be manufactured from inexpensive materials. Therefore, bioimaging promotes the development of dissolution tablets with DDS functions, Contribute to the development of technologies related to site observation and cancer treatment.
また、 本発明のナノ シリ コン含有溶解錠剤は、 表面に、 薬剤や多 糖 · 蛋白質などの高分子化合物が付着しているので、 可視化した病 原部位 （例えば、 癌細胞） を、 そのまま治療することができる。 溶解材料としては、 塩化ナ ト リ ウム粉末の他、 応用分野によって は、 鎮静就眠薬などの医薬品と して使用されている臭化力 リ ゥム粉 末を使用することもできる。 In addition, the nano-silicone-containing dissolving tablet of the present invention has a surface on which medicines and many Since a high molecular compound such as sugar / protein is attached, the visualized pathogenic site (for example, cancer cell) can be treated as it is. As a dissolution material, sodium bromide powder, which is used as a pharmaceutical product such as a sedative hypnotic, may be used depending on the application field in addition to sodium chloride powder.
塩化ナ ト リ ウムや臭化カ リ ウムでナノシリ コン粒子を包囲した錠 剤においては.、' 使用直前に、 純水ゃェタノ一ルなどの溶液中で塩化 ナ ト リ ウムや臭化カ リ ウムを溶解し、 溶解後に現出したナノ シリ コ ン粒子を、 作製直後の状態で使用することができる。  For tablets containing nanosilicon particles with sodium chloride or potassium bromide, just before use, use sodium chloride or potassium bromide in a solution such as pure water ethanol. It is possible to use nano-silicon particles that have been dissolved and that have emerged after dissolution.
したがって、 本発明は、 病原部位の計測技術や治療技術、 さ らに 、 その他の技術分野で、 利用可能性が大きいものである。  Therefore, the present invention has great applicability in pathological site measurement technology and treatment technology, and in other technical fields.

Claims

1 . 粒子サイズ 1 . 5 〜 2 . 0 n m、 2 . 0 〜 2： 5 n m、 2 . 5 〜 3 . 5 n mの何れかのナノ シリ コン粒子を多数含むナノ シリ コ ン粒子を塩化ナ ト リ ゥム粉末に混入した錠剤であって、 紫外光線又 は可視光線の照射により、 血液内において、 青色、 緑色、 赤色の何 1. Particle size 1.5 to 2.0 nm, 2.0 to 2: Nanosilicon particles containing many nanosilicon particles of any of 5 nm and 2.5 to 3.5 nm are mixed with sodium chloride. A tablet mixed in a lump powder, which can be blue, green or red in the blood by irradiation with ultraviolet light or visible light.
き口  Mouth
れかを蛍光発光することを特徴とするナノ シリ コン含有溶解錠剤。 A nano-silicone-containing dissolution tablet characterized in that it emits fluorescence.
2 . 前記ナノ シリ コ ン粒子が凝集していることを特徴とする請求 の範囲 1に記載のナノシリ コ ン含有溶解錠剤。  2. The nanosilicone-containing dissolving tablet according to claim 1, wherein the nanosilicon particles are aggregated.
3 . 前記ナノ シリ コン粒子の表面に、 薬剤や多糖 ， 蛋白質などの 高分子化合物が付着していることを特徴とする請求の範囲 1 又は 2 囲  3. A polymer compound such as a drug, a polysaccharide, or a protein is attached to the surface of the nanosilicon particle.
に記載のナノ シリ コン含有溶解錠剤。 A nano-silicone-containing dissolution tablet according to 1.
4 . 水溶液中で、 粒子サイズ 1 . 5 〜 2 . 0 n m、 2 . 0 〜 2 . 4. In aqueous solution, particle size 1.5-2.0 nm, 2.0-2.
5 n m、 2 . 5 〜 3 . 5 n mの何れかのナノ シリ コン粒子を多数含 むナノ シリ コ ン粒子に温熱処理を施し、 ナノ シリ コン粒子の表面に 未結合手を多数形成し、 次いで、 The nanosilicon particles containing a large number of nanosilicon particles of any of 5 nm and 2.5 to 3.5 nm are subjected to thermal heat treatment to form a large number of dangling bonds on the surface of the nanosilicon particles, ,
上記未結合手を多数有するナノ シリ コン粒子を塩化ナ ト リ ゥム粉 末に混入する  Incorporate nano-silicon particles with many unbonded hands into sodium chloride powder
こ'とを特徴とするナノ シリ コ ン含有溶解錠剤の製造方法。 This is a method for producing nano-silicone-containing dissolving tablets.
5 . 水溶液中で、 粒子サイズ 1 . 5 〜 2 . O n m、 2 . 0 〜 2 . 5 n m、 2 . 5 〜 3 . 5 n mの何れかのナノ シリ コン粒子を多数含 むナノ シリ コン粒子に温熱処理を施し、 ナノシリ コン粒子の表面に 未結合手を多数形成し、 次いで、  5. Nano-silicon particles containing a large number of nano-silicon particles of any particle size from 1.5 to 2.5 nm, 2.0 to 2.5 nm, or 2.5 to 3.5 nm in aqueous solution To the surface of the nanosilicon particles to form many dangling bonds,
上記未結合手を多数有するナノ シリ コン粒子を、 薬剤や多糖 · 蛋 白質などの高分子化合物を混合した溶液に浸漬して、 再度、 温熱処 理を施し、 その後、  The nano silicon particles having a large number of unbonded hands are immersed in a solution in which a high molecular compound such as a drug or a polysaccharide / protein is mixed, and again subjected to thermal treatment,
上記温熱処理後のナノシリ コン粒子を塩化ナ ト リ ゥム粉末に混入 する Nanosilicon particles after the above heat treatment are mixed in sodium chloride powder. Do
ことを特徴とするナノシリ コン含有溶解錠剤の製造方法。  A method for producing a nano-silicone-containing dissolving tablet characterized by the above.
6 . 前記ナノ シリ コン粒子が、 シリ コンを微粉砕して溶液中で処 理することによ り形成されたものであることを特徴とする請求の範 囲 4又は 5 に記載のナノ シリ コン含有溶解錠剤の製造方法。  6. The nanosilicon particles according to claim 4 or 5, wherein the nanosilicon particles are formed by pulverizing silicon and processing in a solution. A method for producing a dissolved tablet.
7 . 前記微粉砕後のシリ コン粒子の粒子サイズが 1 0 0 m以下 であることを特徴とする請求の範囲 6 に記載のナノ シリ コン含有溶 解錠剤の製造方法。  7. The method for producing a nanosilicone-containing dissolved tablet according to claim 6, wherein the finely pulverized silicon particles have a particle size of 100 m or less.
8 . 前記溶液が、 フッ酸、 硝酸、 酢酸、 及び、 純水の混合溶液で あることを特徴とする請求の範囲 6 又は 7 に記載のナノシリ コン含 有溶解錠剤の製造方法。  8. The method for producing a nanosilicone-containing dissolution tablet according to claim 6 or 7, wherein the solution is a mixed solution of hydrofluoric acid, nitric acid, acetic acid, and pure water.
9 . 前記ナノシリ コン粒子が、 高周波スパッタ リ ング法で作製し たアモルファス酸化ケィ素膜に熱処理を施し、 次いで、 フッ酸水溶 液処理、 溶液処理、 攪拌処理を施して形成されたものであるこ とを 特徴とする請求の範囲 4又は 5 に記載のナノ シリ コン含有溶解錠剤 の製造方法。  9. The nano-silicon particles are formed by subjecting an amorphous silicon oxide film produced by a high-frequency sputtering method to a heat treatment, followed by a hydrofluoric acid aqueous solution treatment, a solution treatment, and a stirring treatment. The method for producing a nanosilicone-containing dissolution tablet according to claim 4 or 5, wherein
1 0 . 前記熱処理の温度が 9 0 0 〜 1 2 0 0 °Cで、 かつ、 同時間 が 1 2 0分以下であることを特徴とする請求の範囲 9 に記載のナノ シリ コン含有溶解錠剤の製造方法。  10. The nanosilicon-containing dissolving tablet according to claim 9, wherein the temperature of the heat treatment is 90 ° C. to 120 ° C. and the same time is 1 20 minutes or less. Manufacturing method.
1 1 . 前記フッ酸水溶液処理において、 フッ酸水溶液の濃度が 1 〜 5 0 %であり、 処理温度が 1 0 〜 7 0 °Cであり、 かつ、 処理時間 が 1 0 〜 6 0 0秒であることを特徴とする請求の範囲 9又は 1 0 に 記載のナノ シリ コン含有溶解錠剤の製造方法。  11. In the hydrofluoric acid aqueous solution treatment, the hydrofluoric acid aqueous solution concentration is 1 to 50%, the treatment temperature is 10 to 70 ° C, and the treatment time is 10 to 60 seconds. The method for producing a nano-silicone-containing dissolving tablet according to claim 9 or 10, characterized in that it exists.
1 2 . 前記攪拌処理の時間が 1 0 〜 6 0 0秒であることを特徴と する請求の範囲 9 〜 1 1 のいずれかに記載のナノ シリ コン含有溶解 錠剤の製造方法。  12. The method for producing a nanosilicone-containing dissolved tablet according to any one of claims 9 to 11, wherein the stirring treatment time is 10 to 60 seconds.
1 3 . 前記温熱処理の温度が 3 0 〜 1 0 0 °Cで、 同時間が 1 0 〜 6 0分であることを特徴とする請求の範囲 4〜 1 2 のいずれかに記 載のナノシリ コン含有溶解錠剤の製造方法。 1 3. The temperature of the heat treatment is 30 to 100 ° C and the same time is 10 to The method for producing a nanosilicone-containing dissolving tablet according to any one of claims 4 to 12, wherein the time is 60 minutes.
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