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WO2007026533A1 - Comprimé soluble contenant des particules de nanosilicium et son procédé de fabrication - Google Patents

Comprimé soluble contenant des particules de nanosilicium et son procédé de fabrication 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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Prior art keywords
nanosilicon
particles
nano
treatment
silicon
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Japanese (ja)
Inventor
Keisuke Sato
Kenji Hirakuri
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Tokyo Denki University
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Tokyo Denki University
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Priority to JP2007533166A priority Critical patent/JP4931015B2/ja
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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

La présente invention concerne un comprimé comprenant une poudre de chlorure de sodium et une abondance de particules de nanosilicium ayant une taille particulaire dans la plage de 1,5 à 2,0 nm, 2,0 à 2,5 nm ou 2,5 à 3,5 nm mélangées dans la poudre, pouvant émettre une lumière fluorescente ayant une couleur bleue, verte ou rouge dans le sang lors d’une irradiation avec un rayon ultraviolet ou de la lumière visible. Le comprimé peut être fabriqué en immergeant des particules de nanosilicium dans une solution mixte contenant un agent thérapeutique et un composé polymère tel qu’un polysaccharide ou une protéine, en soumettant le mélange résultant à un traitement thermique, puis en mélangeant le produit résultant à une poudre de chlorure de sodium.
PCT/JP2006/315980 2005-08-30 2006-08-07 Comprimé soluble contenant des particules de nanosilicium et son procédé de fabrication Ceased WO2007026533A1 (fr)

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JP2007137700A (ja) * 2005-11-16 2007-06-07 Univ Nagoya 蛍光性シリコン粒子の製造方法、蛍光性シリコン粒子およびそれを用いて生体物質を観察する方法
JP2010254972A (ja) * 2009-04-02 2010-11-11 National Institute For Materials Science 蛍光発光性シリコンナノ粒子とその製造方法
JP2010248325A (ja) * 2009-04-14 2010-11-04 National Institute For Materials Science シート状発光体
CN113426312A (zh) * 2015-12-04 2021-09-24 Ｋｉｔ股份有限公司 含氢溶液、含氢溶液的制造方法、含氢溶液的制造装置、及活体用氢生成材料
JP7222053B2 (ja) 2016-01-29 2023-02-14 株式会社ボスケシリコン 固形製剤、飼料、サプリメント、食品添加物、及び食品
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US11752170B2 (en) 2016-01-29 2023-09-12 Bosquet Silicon Corp. Solid preparation, method for producing solid preparation, and method for generating hydrogen
EP3409282A4 (fr) * 2016-01-29 2019-08-28 Hikaru Kobayashi Préparation solide, procédé de production de la préparation solide, et procédé pour générer de l'hydrogène
JP2019142861A (ja) * 2016-01-29 2019-08-29 株式会社ボスケシリコン 固形製剤、固形製剤の製造方法及び水素発生方法
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TWI728041B (zh) * 2016-01-29 2021-05-21 小林光 固體製劑、固體製劑的製造方法及析氫方法
JP2021119143A (ja) * 2016-01-29 2021-08-12 株式会社ボスケシリコン 固形製剤及びその製造方法、並びに飼料及びサプリメント
CN113262204A (zh) * 2016-01-29 2021-08-17 株式会社Kit 固体制剂、固体制剂的制备方法及析氢方法
TWI811631B (zh) * 2016-01-29 2023-08-11 小林光 固體製劑、固體製劑的製造方法及析氫方法
CN108601798A (zh) * 2016-01-29 2018-09-28 小林光 固体制剂、固体制剂的制备方法及析氢方法
JP2019069959A (ja) * 2016-01-29 2019-05-09 小林　光 経口製剤、飼料、サプリメント、食品添加物、健康食品
US11311572B2 (en) 2016-01-29 2022-04-26 Bosquet Silicon Corp. Preparation, method for producing preparation, and method for generating hydrogen
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CN116159073A (zh) * 2016-01-29 2023-05-26 株式会社Kit 固体制剂、固体制剂的制备方法及析氢方法
CN115919894A (zh) * 2016-01-29 2023-04-07 株式会社Kit 固体制剂、固体制剂的制备方法及析氢方法
US11583483B2 (en) 2016-08-23 2023-02-21 Bosquet Silicon Corp. Hydrogen supply material and production therefor, and hydrogen supply method
WO2018037819A1 (fr) * 2016-08-23 2018-03-01 小林　光 Composé, son procédé de production et procédé d'alimentation en hydrogène
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