KR101790554B1

KR101790554B1 - Silica nano particles having biocompatible material shell

Info

Publication number: KR101790554B1
Application number: KR1020150101737A
Authority: KR
Inventors: 유영철; 권오성; 서정원; 김연주
Original assignee: (주)석경에이티
Priority date: 2015-05-29
Filing date: 2015-07-17
Publication date: 2017-10-26
Also published as: KR20160140295A

Abstract

(A) mixing a silica precursor with a solvent to obtain a transparent silicate precursor solution; (b) adding a catalyst to the precursor solution and hydrolyzing to form silica nanoparticles; And (c) drying and calcining the silica nanoparticles, wherein the average particle diameter is 300 to 2000 nm. The present invention also relates to a method of preparing a monodisperse high-purity silica fine particle core having an average particle size of 300 to 2000 nm, , Zinc phosphate and ZnO, the functional silica nanoparticles comprising a shell coated uniformly with one or two or more biocompatible materials selected from the group consisting of dental bone graft materials, implants, artificial joint surface coating materials, and toothpastes for medical use Lt; / RTI >

Description

SILICA NANO PARTICLES HAVING BIOCOMPATIBLE MATERIAL SHELL < RTI ID = 0.0 >

The present invention relates to spherical functional silica nanoparticles comprising silica shells coated with a biocompatible material.

Generally, as an example of particles having a function of transferring a substance with a core structure, in the case of polymer micelles, a hydrophobic core is trapped in a poorly soluble core.

A method in which the drug is dissolved in an organic solvent (e.g., ethanol, N, N-dimethylformamide (DMF)) mixed with water and then dialysis is performed in an aqueous solution. Second, the insoluble drug is dissolved in an organic solvent (O / W type emulsion-solvent evaporation method in which an organic solution prepared by dissolving an organic solvent in an organic solvent (e.g., dichloromethane or chloroform) is added to an aqueous solution of a block copolymer to form an O / W type emulsion and then the organic solvent is slowly evaporated. Kwon et al., G. Kwon et al., Physical entrapment of Adriamycin in AB block copolymer micelles, Pharm. Res. 12 (1997) (1995) 192-195).

(A) an inner core; And (b) a shell surrounding the inner core, wherein the shell is formed by cross-linking a nonionic polymer and an albumin into which a functional group has been introduced by covalent bonding In this case, the particles having the core-shell structure carry the functional material to the core and carry it (Korean Patent Laid-Open No. 10-2016-0030848).

An object of the present invention is to prepare SiO ₂ spherical particle cores by uniformly coating a functional material with shell particles to produce particles having various functions.

The functional particles of the present invention can be applied to various fields such as dental bone graft materials, implants, artificial joint surface coating materials, and medical toothpaste.

According to an aspect of the present invention, there is provided a method for preparing a silica precursor solution, comprising: (a) mixing a silica precursor with a solvent to obtain a transparent silicate precursor solution; (b) adding a catalyst to the precursor solution and hydrolyzing to form silica nanoparticles; And (c) drying and calcining the silica nanoparticles, wherein the average particle size of the silica nanoparticles is 300 to 2000 nm.

The silica precursor may be selected from the group consisting of silicon alkoxide such as tetramethyl orthosilicate (TMOS), tetraethylorthosilicate (TEOS), 3-mercaptopropyltrimethoxysilane (MPTMS), phenyltrimethoxysilane (PTMS) Methoxy silane (VTMS), methyltrimethoxysilane (MTMS), 3-aminopropyltrimethoxysilane (APTMS), 3-glycidyloxypropyltrimethoxysilane (GPTMS), (3-trimethoxysilyl ) Propyl methacrylate (TMSPMA), 3-mercaptopropyl trimethoxysilane (MPTMS), and 3- (trimethoxysilyl) propyl isocyanate (TMSPI).

The reaction temperature in step (b) is preferably from 35 to 50 ° C., and in step (c), preliminary drying is performed at 50 to 60 ° C. for 1 to 3 hours and then drying is performed at 100 to 150 ° C. for 4 to 24 hours .

And calcining at 800 to 1000 ° C for 1 to 6 hours in the step (c).

In order to stabilize the alkoxide in the step (b), 2-aminopropanol, 2- (methylphenylamino) ethanol, 2- (ethylphenylamino) ethanol, 2- -Diethylaminoethanol, 4-aminophenylaminoisopropanol, N-ethylaminoethanol, monoethanolamine, diethanolamine, triethanolamine, monoisopropanolamine, diisopropanolamine, triisopropanolamine, methyldiethanolamine, dimethylmonoethanol And an amino alcohol such as amine, ethyldiethanolamine, diethylmonoethanolamine and the like.

The catalyst for stabilizing the alkoxide is 0.01 to 20 parts by weight based on 100 parts by weight of the total reaction solution.

In the step (b), the catalyst is a basic catalyst.

The silica nanoparticles produced according to the production method of the present invention are monodisperse high purity silica nanoparticles having a sphericity of 0.6 to 1 and an average particle size of 300 to 2000 nm.

The present invention also provides a method for producing a functional silica nanoparticle, comprising: preparing a slurry using high purity silica fine particle monodisperse high purity silica nanoparticles having a sphericity of 0.6 to 1 and an average particle size of 300 to 2000 nm using pure water;

And attaching a biocompatible material to the slurry to uniformly coat the biocompatible material on the surface of the monodisperse high-purity silica nanoparticle core to form a shell.

The functional biocompatible material may be at least one selected from the group consisting of HA (Hydroxyapatite), FA (Fluorapatite), FHA (Fluorapatite), CIA (Chlorapatite), CHA (Carbonate apatite), AP (Calcium-deficient apatite) And may be selected from the group consisting of octacalcium phosphate (OCP), dicalcium phosphate dihydrate (DCPD), dicalcium phosphate (DCP), calcium pyrophosphate dihydrate (CPPD), zirconium phosphate, aluminum phosphate, zinc phosphate and ZnO.

The silica nanoparticles prepared according to the process for producing functional silica nanoparticles of the present invention are characterized by comprising a monodisperse high purity silica fine particle core having an average particle size of 300 to 2000 nm and a hydrophobic silica fine particle core having a hydrophobic functional group such as HA (Hydroxyapatite), FA (Fluorapatite) (PHA), octacalcium phosphate (OCP), dicalcium phosphate dihydrate (DCPD), dicalcium phosphate (DCP), and the like. , And a shell coated uniformly with one or two or more biocompatible materials selected from the group consisting of calcium pyrophosphate dihydrate (CPPD), zirconium phosphate, aluminum phosphate, zinc phosphate and ZnO.

According to the present invention, core-shell spherical functionalities (HAP / TCP / ZP) uniformly coated (adjusted pH and zeta-potential) with shell particles on a monodispersed SiO ₂ spherical particle core made of a sol- Nanoparticles can be produced.

The functional nanoparticles of the present invention can be utilized in various medical fields such as dental bone graft materials, implants, surface coating materials for hip joints and spine systems, and medical toothpastes.

1 is a SEM photograph of nanoparticles according to Example 1 of the present invention.
2 is a SEM photograph of nanoparticles according to Example 2 of the present invention.
3 is an SEM photograph of the functional nanoparticles according to Example 3 of the present invention.
4 is an SEM photograph of the functional nanoparticles according to Example 4 of the present invention.
5 is an SEM photograph of the functional nanoparticles according to Example 5 of the present invention.
6 is an XRD photograph of the functional nanoparticles according to Example 5 of the present invention.
7 is an SEM photograph of the functional nanoparticles according to Example 6 of the present invention.
8 is an XRD photograph of the functional nanoparticle according to Example 6 of the present invention.
9 is a schematic diagram of the functional silica nanoparticles of the present invention.
10 is an SEM photograph of the resultant particles according to Comparative Example 1. Fig.
11 to 19 are SEM photographs of the resultant particles and compositions of decomposition materials according to Examples 8 to 12 of the present invention.

The monodisperse high purity silica nanoparticles of the present invention can be prepared by (a) mixing a silica precursor with a solvent to obtain a transparent silicate precursor solution; (b) adding a catalyst to the precursor solution and hydrolyzing to form silica fine particles; And (c) drying and calcining the silica fine particles, wherein the average particle size is 300 to 2000 nm.

1. Silica precursor

In the present invention, the silica precursor may be a silicon alkoxide, and examples thereof include tetramethyl orthosilicate (TMOS), tetraethyl orthosilicate (TEOS), 3-mercaptopropyl trimethoxysilane (MPTMS) (PTMS), vinyltrimethoxysilane (VTMS), methyltrimethoxysilane (MTMS), 3-aminopropyltrimethoxysilane (APTMS), 3-glycidyloxypropyltrimethoxysilane (GPTMS) (Trimethoxysilyl) propyl methacrylate (TMSPMA), 3-mercaptopropyl trimethoxysilane (MPTMS), 3- (trimethoxysilyl) propyl isocyanate (TMSPI) Preferably, it is tetraethylorthosilicate (TEOS). The mixing ratio of one or more of the silicon alkoxide to be used may be appropriately selected depending on the structure and particle size of the silica fine particles.

The silica precursor is provided in a solution state, and the silica precursor solution preferably contains 1 to 70% by weight of the silica precursor and 30 to 99% by weight of the organic solvent, more preferably 2 to 30% by weight of the silica precursor, 70 to 98% by weight.

Examples of the organic solvent include aliphatic hydrocarbon solvents such as n-pentane, i-pentane, n-hexane, i-hexane, 2,2,4-trimethylpentane, cyclohexane and methylcyclohexane; Aromatic hydrocarbon solvents such as benzene, toluene, xylene, trimethylbenzene, ethylbenzene, and methylethylbenzene; Methyl alcohol, ethyl alcohol, n-propanol, i-propanol, n-butanol, i-butanol, sec- Alcohol-based solvents; Ketone solvents such as acetone, methyl ethyl ketone, methyl-n-propyl ketone, methyl-n-butyl ketone, methyl-i-butyl ketone, diethyl ketone, cyclohexanone, metal cyclohexanone or acetylacetone; Propyl ether, n-butyl ether, diglyme, dioxin, dimethyl dioxin, ethylene glycol monomethyl ether, ethylene glycol (ethylene glycol) Propylene glycol monoethyl ether, propylene glycol monopropyl ether, propylene glycol-dimethyl ether, propylene glycol di (meth) acrylate, diethylene glycol monoethyl ether, ethylene glycol n-propyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, Ether solvents such as ethyl ether, propylene glycol dipropyl ether and the like; Diethyl carbonate, methyl acetate, ethyl acetate, n-propyl acetate, i-propyl acetate, n-butyl acetate, ethyl lactate, ethylene glycol monomethyl etheracetate, ethylene glycol monoethyl ether acetate, propylene glycol monomethyl ether acetate Ester solvents such as propylene glycol monoethyl ether acetate, propylene glycol monopropyl ether acetate, ethylene glycol diacetate, and propylene glycol diacetate; Or N-methylpyrrolidone, formamide, N-methylformamide, N-ethylformamide, N, N-dimethylformamide, N, Amide, N, N-dimethylacetamide, N, N-diethylacetamide, and the like can be used.

2. Preparation of silica fine particles

Silica fine particles having a particle size of 300 to 2000 nm are prepared by a sol-gel process using the high purity silica precursor obtained through the above process.

The silica precursor is mixed with a suitable solvent, and examples of such a solvent include water, an alcohol, or a mixture thereof. As the alcohol, solvents such as methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol and butyl alcohol may be used alone or in combination. Of these, ethyl alcohol, propyl alcohol and isopropyl alcohol are preferably used.

The silica precursor may be mixed with a solvent to obtain a transparent silica precursor solution. In this case, a catalyst may be added to stabilize the alkoxide. Examples of such catalysts include 2-aminopropanol, 2- (methylphenylamino) ethanol, 2- (ethylphenylamino) ethanol, 2-amino-1-butanol, (diisopropylamino) , 4-aminophenylamino isopropanol, N-ethylaminoethanol, monoethanolamine, diethanolamine, triethanolamine, monoisopropanolamine, diisopropanolamine, triisopropanolamine, methyldiethanolamine, dimethylmonoethanolamine, ethyldiethanol Amines, and amino alcohols such as diethyl monoethanol amine.

For the preparation of the silica fine particles, the reaction is preferably carried out at about 30 to 50 ° C for 1 to 6 hours. If the temperature is kept below 30 ° C, the sphericity is low and the particles may be uneven. When the temperature is more than 50 ° C It is difficult to grow the particles, which may cause the particles to become excessively small.

When the alkoxide stabilizing catalyst is added to the reaction, the content thereof is preferably 0.01 to 20 parts by weight based on 100 parts by weight of the total reaction solution. When the content of the catalyst is less than 0.01 part by weight, it is difficult to expect stabilization of the alkoxide. When the amount of the catalyst is more than 20 parts by weight, the yield may be reduced, the particles may become uneven or the spheroidization may decrease.

A basic catalyst may be added to the reaction solution for the formation of silica fine particles. Basic catalysts help control the rate of hydrolysis of each component during the hydrolysis of two or three alkoxides or salts. However, the acid catalyst (c-HNO ₃ , HCl, CH ₃ COOH, etc.) may also be used in the reaction process of the present invention (in this case, a transparent reaction is performed after hydrolysis with an acid catalyst) The degree of sphericity and uniformity of the particles obtained by the method of the present invention is lowered, so that a basic catalyst is preferable.

Thus, it is preferable to adjust the pH of the solution to 7 to 10 by adding a base.

Examples of the basic catalyst to be used in the reaction include a compound containing an amine group and a hydroxy group or an aqueous solution thereof, and typical examples of the substance containing an amine group and a hydroxy group include ammonia, sodium hydroxide, alkylamine, .

The silica microparticles obtained in the above process are preliminarily dried at 50 to 60 ° C. for 1 to 3 hours, dried at 100 to 150 ° C. for 4 to 24 hours, and then calcined. The calcination step is a step of progressing the silica fine particles to have a crystal phase, and it is preferable to perform calcination at 800 ° C to 1000 ° C for 1 hour to 6 hours.

The thus prepared silica fine particles of the present invention preferably have a spherical shape having an average particle size of 300 to 2000 nm and a center value of the particles of 300 nm, 500 nm, 1000 nm, 1500 nm and 2000 nm. The term " spherical shape " includes not only a perfect spherical shape but also a slightly distorted spherical shape having a spherical shape in a range of 0.6 to 1. Also, the spherical shape means the surface area of the hole having the same volume as the actual particle / actual particle surface area.

3. Manufacture of spherical nanoparticles of Core-Shell

It is possible to produce core-shell spherical nanoparticles uniformly coating (pH controlled and zeta-potential-controlled) materials having biocompatibility with shell particles on the silica fine particle core.

The silica microparticles are slurried using pure water, and then a biocompatible substance is injected through a metering pump into a uniform amount. At this time, the pH is adjusted to adjust the biocompatibility of the silica particles to the isoelectric point region It was possible to manufacture spherical nanoparticles of coated Core-Shell.

Hereinafter, the present invention will be described in detail with reference to Examples, but the scope of the present invention is not limited by these Examples.

[ Example One] Average particle diameter High-purity silica fine particle production of 380nm class

1,200 ml of water, 1800 ml of ethyl alcohol and 100 ml of ammonia water were added to a 5000 ml flask, and the clear mixed solution was heated while stirring to raise the temperature to 45 캜. Another 1000 ml beaker was weighed 220 g of tetraethyl silicate (TEOS). High-purity TEOS was added to the solution (transparent mixed solution) at once to perform condensation polymerization reaction of the hydrolyzate for 4 hours. The reaction temperature of the silica mixed solution was maintained at 45 ° C. The silica fine particles thus obtained were preliminarily dried at 60 ° C for 1 hour and then dried at 100 ° C for 24 hours. The dried silica fine particles were calcined at 1000 ° C for 6 hours to have a crystalline phase. The obtained silica fine particles were analyzed by SEM (SHIMADSU, SS-550), and it was confirmed that they were spherical particles of 380 nm (Fig. 1)

[ Example 2] Average particle diameter Manufacture of high purity silica fine particles at 800nm

500 ml of water, 2000 ml of ethyl alcohol and 500 ml of ammonia water were added to a 5000 ml flask, and the clear mixed solution was heated with stirring and heated to 35 캜. 500 g of tetraethyl silicate (TEOS) obtained in Example 3 was measured in another 1000 ml beaker. High-purity TEOS was added to the solution (transparent mixed solution) at once to perform condensation polymerization reaction of the hydrolyzate for 4 hours. The temperature of the silica mixed solution reaction was maintained at 35 ° C. The silica fine particles thus obtained were preliminarily dried at 60 ° C for 1 hour and then dried at 100 ° C for 24 hours. The dried silica fine particles were calcined at 1000 ° C for 6 hours to have a crystalline phase. The obtained silica fine particles were analyzed by SEM (SHIMADSU, SS-550) and found to be spherical particles of 800 nm. (Fig. 2)

[ Example 3] SiO ₂ @TCP Core shell nanoparticles

139 g of the silica fine particles (380 nm) obtained in Example 1 are placed in 3 L of ultrapure water and ball mill is performed for 6 hours. While stirring the solution, 15.586 g of calcium nitrate tetrahydrate was dissolved in 300 ml of ultrapure water, and 6.246 g of sodium hydrogophosphate was dissolved in 300 ml of ultrapure water. The resulting solution was subjected to measurement using a metering pump at a rate of 10 ml / min . Aging is carried out for 4 hours after all the addition, and then left to stand for 12 hours. After that, it was washed, dried at 100 ° C for 24 hours, and then annealed at 500 ° C for 4 hours to obtain SiO ₂ @TCP core shell nanoparticles. The HA-coated silica microparticles were analyzed by SEM (SHIMADSU, SS-550) and found to be spherical particles of 800 nm. (Fig. 3)

[ Example 4] SiO ₂ @TCP Core shell nanoparticles

SiO ₂ @ TCP core shell nanoparticles were obtained in the same manner as in Example 3 except that the silica fine particles (800 nm) obtained in Example 2 were used.

The HA-coated silica microparticles were analyzed by SEM (SHIMADSU, SS-550) to be spherical particles of 800 nm (FIG. 4)

[ Example 5] 50nm class Hydroxy apatite synthesis

945 g of Ca (NO ₃ ) 2-4H ₂ O and 3.2 kg of ultrapure water are added to a 10 L beaker and the temperature is adjusted to 40 ° C with stirring to make a clear solution.

Separately, 1.6 kg of NaHPO ₄ 341 g of ultrapure water is added to a 2 L beaker and stirred to make a clear solution. An aqueous NaHPO ₄ solution was added to the Ca (NO 3) 2-4H 2 O aqueous solution. At this time, the pH was 4.35 and the pH was adjusted to 9.5 using a 50% aqueous solution of NaOH.

Aging was performed for 20 hours after the calibration, followed by washing, drying at 100 ° C for 24 hours, and heat treatment at 550 ° C for 4 hours to obtain 50 nm-grade hydroxyapatite nanoparticles. The obtained HA fine particles were analyzed by SEM (SHIMADSU, SS-550) to be 50 nm particles (FIG. 5) and confirmed to have a hydroxy apatite crystal structure when XRD (SHIMADSU, XRD-6000) was confirmed. (Fig. 6)

[ Example 6] 100 nm class Hyroxy apatite synthesis

236.15 g of Ca (NO ₃ ) 2-4H ₂ O and ₂ kg of ultrapure water were added to a 1 L beaker, and the temperature was adjusted to 40 ° C while stirring to prepare a transparent solution.

Separately, 1 kg of 79.242 g of ultra-pure water of NaHPO _{4 is} added to a 2 L beaker and stirred to make a clear solution. An aqueous solution of Ca (NO ₃ ) 2 - 4H ₂ O was added to the work in a NaHPO ₄ aqueous solution. The pH at this time was 4.2 and the pH was adjusted to 7 using aqueous NH ₄ OH solution (28%).

Aging was performed for 4 hours after the calibration, followed by washing, drying at 100 ° C for 24 hours, and heat treatment at 750 ° C for 2 hours to obtain 100 nm-sized hydroxyapatite nanoparticles. The obtained HA fine particles were analyzed by SEM (SHIMADSU, SS-550) to be 100 nm particles (FIG. 7) and confirmed to have a hydroxy apatite crystal structure when XRD (SHIMADSU, XRD-6000) was confirmed. (Fig. 8)

[ Comparative Example 1] SO800 @ HA 141001C1 (pH control)

SO800 cleaning slurry HAU / M min 6N HNO ₃ 465.43 g 97.52 g pH control

After SO800, HA slurry solid content was measured, SO800 slurry was stirred. 10% amount of HA slurry of SO800 slurry in stirring was added and after aging for 5 minutes, 6N HNO ₃ Lt; / RTI > After aging for 30 minutes, the mixture was allowed to stand and dried in an oven. The SEM image of the result is shown in Figure 10. (Non-uniform coating)

[ Example 8] SO1000 @ HA 141006C2 (titration)

SO1000 cleaning slurry Ca (NO ₃ ) ₂ -4H ₂ O 6N HNO ₃ 843.97g 10.93 g 3.94 g

The SO1000 washed slurry solids were calculated and stirred. The amount of 5% HA synthesis raw material of SO1000 was titrated, respectively. After fully titrated, the mixture was stirred and aged. For the removal of unreacted materials and acids, DI H ₂ O was rinsed twice or three times, dried in an oven, and calcined at 400 ° C for 2 hours. The SEM photograph of the result is shown in Fig.

[ Example 9] SO800 @ TZP 141017C1 (titration)

SO800 cleaning slurry Zn (NO ₃ ) ₂ -6H ₂ O Na ₂ HPO ₄ 16.57kg 288.55 g 92.27 g

SO800 Washing slurry solid 2.5Kg The corresponding slurry was stirred and the amount of 5% TZP synthesis material SO800 was titrated with a metering pump. After the titration was completed for about 4 hours, the mixture was agitated and agitated for 1 hour. After washing with Filterpress to remove unreacted materials and acid, it was dried in an oven and calcined at 400 ° C for 2 hours. The progress results are shown in FIG. 12 and FIG.

[ Example 10] SO800 @ TCP 141030C1 (titration)

SO800 cleaning slurry Ca (NO ₃ ) ₂ -4H ₂ O Na ₂ HPO ₄ 18.5kg 285.5 g 114.42 g

SO800 2.5Kg The slurry was stirred and the amount of 5% TCP synthesis material SO800 was titrated with a metering pump. After the titration was completed for about 4 hours, the mixture was agitated and agitated for 1 hour. Filterpress washes to remove unreacted materials and acids, dried in an oven, and calcined at 400 ° C for 4 hours. The progress results are shown in Figs. 14 and 15. Fig.

[ Example 11] SO380 @ TCP 150302C1 (titration)

SO380 cleaning slurry Ca (NO ₃ ) ₂ -4H ₂ O Na ₂ HPO ₄ 5.82kg 15.59 g 6.25 g

5.82 Kg of the SO380 slurry was stirred, and the amount of 5% TCP synthesis starting material of SO380 was titrated by a metering pump. After the titration was completed for about 4 hours, the mixture was agitated and agitated for 1 hour. Filterpress washes to remove unreacted materials and acids, dried in an oven, and calcined at 400 ° C for 4 hours. The progress result is shown in FIG. 16 and FIG.

[ Example 12] SO380 @ HA 150303C1 (titration)

SO380 cleaning slurry Ca (NO ₃ ) ₂ -4H ₂ O Na ₂ HPO ₄ 6.48 kg 11.81 g 4.26 g

6.48 Kg of the SO380 slurry was stirred, and the amount of the 5% TCP synthesis material of SO380 was titrated by a metering pump. After the titration was completed for about 4 hours, the mixture was agitated and agitated for 1 hour. Filterpress washes to remove unreacted materials and acids, dried in an oven, and calcined at 400 ° C for 4 hours. The results of the process are shown in Figs. 18 and 19.

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it will be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention as defined in the appended claims. It can be understood that

Claims

delete

Preparing a slurry by adding monodisperse high purity silica nanoparticles having a spherical degree of 0.6 to 1 and an average particle diameter of 300 to 2000 nm into purified water and ball milling;
Adding 5 to 10% by weight of the biocompatible material of the slurry to the slurry at a rate of 10 ml / min through a metering pump;
Adjusting the pH of the slurry to conform to the isoelectric point region to uniformly coat the biocompatible material on the surface of the monodisperse silica fine particle core to form a shell;
Washing and drying and firing to remove unreacted materials and acid.

11. The method of claim 10,
The biocompatible material may be selected from the group consisting of HA (Hydroxy Apatite), FA (Fluorapatite), FHA (Fluorapatite), CIA (Chlorapatite), CHA (Carbonate apatite), AP (Calcium- And one or more selected from the group consisting of octacalcium phosphate, dicalcium phosphate dihydroxide (DCPD), dicalcium phosphate (DCPD), calcium pyrophosphate dihydrate (CPPD), zirconium phosphate, aluminum phosphate, zinc phosphate and ZnO (Method for preparing functional silica nanoparticles).

(FA), Fluorapatite (FA), Fluorapatite (FHA), Chlorapatite (CIA), Carbonate apatite (CHA) and AP (hydroxyapatite) on the surface of a core of a high-purity silica fine particle having an average particle size of 300 to 2000 nm. Calcium-deficient apatite, TCP (Tri-calcium phosphate), OCP (Octacalcium phosphate), DCPD (Dicalcium phosphate dihydrate), DCP (Dicalcium phosphate) and CPPD (Calcium pyrophosphate dihydrate), Zirconium phosphate, Aluminum phosphate, Zinc phosphate &Lt; RTI ID = 0.0 > ZnO < / RTI > is uniformly coated with one or more biocompatible materials selected from the group consisting of ZnO.

13. The functional silica nanoparticle according to claim 12, wherein the functional silica nanoparticles are used in the manufacture of one of dental bone graft materials, implants, surface coating materials for Hip, Knee, Spine system, and medical dentifrices.