JP2002137910A - Hydroxy-apatite nano particle and its manufacturing method - Google Patents

Abstract

PROBLEM TO BE SOLVED: To manufacture hydroxy-apatite nano particles in a certain shape, large crystallization with large surface area. SOLUTION: A hydroxy-atatite nano particle is 50 nm-5 μm in a maximum diameter of a minor axis and 75 nm-10 μm in a maximum diameter of a major axis. The particle is grown in a c-axis direction with a 1-5 aspect ratio (c-axis length/a-axis length) of crystallization, and is truncated column structure having an oblique angle plane at a top-end angle. In manufacturing the hydroxy-apatite fine particles, a calcium solution and a phosphoric acid solution are dissolved in, mixed with, and reacted to a surfactant/water/oil type emulsion phase at a surfactant clouding point or more. By changing ratio of a surfactant functional group and a hydrophile/hydrophobe ratio, a size of hydroxy-apatite nano particles is controlled. The hydroxy-apatite nano particles are used for surface modification of organic high polymer in order to enhance reaction of the particles and the matrix, and are suitable as chromatography packing agents.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to hydroxyapatite nanoparticles, a method for producing the same, and uses of the hydroxyapatite nanoparticles.

[0002]

2. Description of the Related Art Hydroxyapatite is used as a material for restoring bone and teeth. It is also used as a packing material for chromatography used for separation and purification of biopolymer compounds, and as a carrier for carrying a pharmaceutical agent or protein and transporting it in a living body. Further, it is also known that a portion of a catheter base made of a polymer material, which comes into contact with a living tissue when attached to a living body, is coated with hydroxyapatite by a vapor deposition method or the like (Japanese Patent Laid-Open No. 10-28).
728).

Method for producing hydroxyapatite fine particles
As a surfactant-water-non-polar organic liquid system, or
Surfactant-water-alkanol non-polar organic liquid W / O
In the microemulsion phase, Ca (NO_Three)_Two/ Ammo
Near aqueous solution and (NH_Four) _TwoHPO_Four/ Ammonia water
Solubilize each solution and mix these lysates
Spherical hydroxyapatite with a particle size of 100 nm or less
A method for producing fine particles is known (JP-A-5-17 / 1990).
No. 111). Also, in the a and b axis directions by hydrothermal method
Growing plate-like apatite (JP-A-6-206713)
Report) and plate-like apatite with preferentially grown a-plane
JP-A-10-45405) is also known.

[0004]

DISCLOSURE OF THE INVENTION The present inventors aimed at the development of osteosynthetic and soft tissue compatible materials, and conducted research on the synthesis of hydroxyapatite (Hap) -polymer composites via covalent bonds. I went. As described above, the form of the hydroxyapatite ultrafine particles varies depending on the production method, but the emulsion method is a preferable method because extensive equipment and equipment are not required.

In the above-mentioned method for producing hydroxyapatite ultrafine particles by the emulsion method, synthesis conditions at a reaction temperature lower than the cloud point of the surfactant are used. However, under such conditions, since the micelles composed of the surfactant have a thermodynamically stable structure, the crystal growth of hydroxyapatite occurring in the micelles of the surfactant is suppressed, which is obtained. The fine particles have a spherical to irregular shape. Moreover, the size of the crystal is 20 to 1 in diameter.
Due to the restriction to 00 nm, a crystal having a large specific shape could not be obtained. Hap with ionic and covalent bonds
In order to enhance the reaction between the Hap particles and the substrate when the particles are bound to a polymer gas, a larger adhesion surface area of Ha
It is necessary to make p particles.

[0006]

Means for Solving the Problems In the method for producing hydroxyapatite nanoparticles by the emulsion method, the present inventor controlled the morphology of the obtained fine particles to improve the adhesion between the polymer surface and the Hap fine particles. It has been found that nano-order fine particles having an excellent truncated columnar structure can be produced.

That is, according to the present invention, the maximum diameter of the short axis is 5
0 nm to 5 μm, the major axis is 75 nm to 10 μm, c
It is a hydroxyapatite nanoparticle that grows in the axial direction, has a crystal aspect ratio (c-axis length / a-axis length) of 1 to 5, and has a truncated columnar structure having a beveled tip angle.

The present invention also relates to a method for synthesizing hydroxyapatite fine particles by solubilizing and mixing a calcium solution and a phosphoric acid solution in a surfactant / water / oil emulsion phase and reacting the same. 2. The method for producing hydroxyapatite nanoparticles according to claim 1, wherein the reaction is performed at a temperature higher than the cloud point of the agent.

Further, the present invention provides the above-mentioned hydroxyapatite nano-particle, wherein the size of the hydroxyapatite nano-particle is controlled by changing the functional group of the surfactant and the ratio of the hydrophilic / hydrophobic ratio. This is a method for producing particles.

[0010] The present invention is also a chromatography packing comprising the above hydroxyapatite nanoparticles.

[0011] The present invention is also an organic polymer surface-modified with the above hydroxyapatite nanoparticles.

The hydroxyapatite nanoparticles obtained by the production method of the present invention have a maximum minor axis diameter of 50 nm.
５5 μm, desirably 90 to 150 nm, and the long axis is 75 n
m to 10 μm, desirably 100 to 300 nm, grows in the c-axis direction, and has a crystal aspect ratio (c-axis length /
It is a single crystal having a truncated columnar structure having an a-axis length of 1 to 5 and a tip angle having a bevel.

The form of the hydroxyapatite nanoparticles of the present invention is completely different from the form of hydroxyapatite fine particles obtained by the conventional emulsion method, and the form is suitable as a filler for chromatography separation.

Further, the hydroxyapatite nanoparticles of the present invention have a much larger area for bonding than conventional fine particles, so that the adhesiveness to a polymer base material can be improved. Therefore, biocompatible medical materials such as catheters and the like can be used. Suitable for modifying a polymer surface. As a method of modifying the polymer surface, active groups of hydroxyapatite nanoparticles and a polymer substrate, for example, a silicone rubber obtained by graft polymerization of a vinyl polymerizable monomer having a carboxyl group on the surface,
And a method using a curable adhesive, a method in which a polymer base material is heated to near the melting point and embedded in the base material, and the like.

In the method of solubilizing and mixing a calcium solution and a phosphoric acid solution in a surfactant / water / oil emulsion phase and reacting them to synthesize hydroxyapatite fine particles, the surfactant micelle is used. Then, the nucleus of hydroxyapatite grows and crystal grows. Features of the method for producing hydroxyapatite nanoparticles of the present invention,
The point is that the thermodynamic stability of the micelles was controlled by setting the reaction temperature to the cloud point of the surfactant or higher.

Increasing the reaction temperature above the cloud point of the surfactant means lowering the surfactant's ability to form micelles. Then, it is considered that the driving force for crystal growth of apatite, which has been restricted in the micelle frame, is larger than the driving force for maintaining the micelle frame. The crystal shape can be controlled using the mechanism. The upper limit of the reaction temperature is not particularly limited as long as the solution does not boil since the reaction is an aqueous solution, and may be about 90 ° C. or less.

The cloud point of a surfactant differs depending on the type. The type of surfactant used in the method of the present invention,
There is no particular limitation, and it can be appropriately selected from other kinds of known anions, cations, and nonionic surfactants disclosed in the above-mentioned JP-A-5-17111.
When making micelles of surfactants, the functional groups (hydrophilic sites) of the surfactants and the hydrophilic / hydrophobic ratio in the molecule are important, and the differences result in different micelle stability and cloud point. .

When the reaction is performed at a temperature higher than the cloud point of the surfactant, the hydrophobicity of the surfactant molecule is increased, and the formed micelle becomes thermodynamically unstable, and the crystal growth of Hap is further emphasized. Surfactants instantaneously reach 10% at their cloud point.
It does not become 0% hydrophobic, but gradually becomes hydrophobic as the temperature rises. The degree depends on the functional group of the surfactant, the hydrophilic / hydrophobic ratio, and the molecular weight.

[0019]

EXAMPLE 1 Dodecane [CH as continuous oil phase_Three(CH_Two)_TenCH
_ThreePentane having a cloud point of 31 ° C. as a nonionic surfactant
Ethylene glycol dodecyl ether [CH_Three(C
H_Two)_TenCH_TwoO (CH_TwoCH_TwoO)_FourCH_TwoCH_TwoO
H] was used. At room temperature, containing 0.5 g of a surfactant.
After preparing 40 ml of the il phase, Ca (OH) _TwoWater dispersion
10 ml of the liquid (2.5 M) was added. After thorough stirring,
1.5M-KH in water / oil (W / O) solution_TwoPO_Four
Add 10 ml of the solution and stir for 24 hours at a reaction temperature of 50 ° C.
Reacted.

The reaction product was purified by centrifugation, dried at 60 ° C., and calcined at 800 ° C. for 1 hour. The obtained hydroxyapatite sintered body was B-type carbonate apatite, and was confirmed to have high biological activity. The elemental analysis revealed that the Ca / P ratio was 1.61, and the apatite was a calcium-deficient apatite.

FIG. 1 shows a transmission electron microscope (TEM) image of the obtained Hap nanoparticles. It was confirmed from TEM observation that the particle diameter was 100 to 200 nm and that the tip angle had a truncated columnar structure having a bevel. Further, as a result of analysis by electron beam diffraction, the obtained particles were oriented in the c-axis direction.

Comparative Example 1 The hydroxyapatite nanoparticles obtained under the same conditions as in Example 1 except that the reaction temperature was 25 ° C., were observed from TEM observation shown in FIG. ~
It was 60 nm.

[0023]

As described above, the nano-sized fine particles having a truncated columnar structure according to the present invention have a much larger area for bonding at the polymer interface than conventional spherical particles, and the apatite firing on the polymer base material is greatly improved. Demonstrates excellent properties in bonding of consolidated particles. Further, the method of the present invention has made it possible to control the size and morphology of hydroxyapatite nanoparticles by selecting the reaction temperature. In addition, by changing the type of the surfactant in addition to the reaction temperature conditions, the produced Ha
The morphology and size of p-particles can be controlled more finely.

[Brief description of the drawings]

FIG. 1 is a drawing substitute photograph showing a transmission electron microscope (TEM) image of the Hap nanoparticles obtained in Example 1.

FIG. 2 is a drawing substitute photograph showing a transmission electron microscope (TEM) image of the Hap nanoparticles obtained in Comparative Example 1.

 ────────────────────────────────────────────────── ─── Continued on the front page (72) Inventor Tsutomu Furuzono 3-50 D12-206 Aoyamadai, Suita-shi, Osaka F-term (reference) 4C081 AB04 BB04 CF031 DA11 DB02 EA02 4C089 AA06 BA03 BA15 CA02 CA05

Claims (5)

[Claims] The maximum diameter of the minor axis is 50 nm to 5 μm, the major axis is 75 nm to 10 μm, the crystal grows in the c-axis direction, and the crystal has an aspect ratio (c-axis length / a-axis length) of 1 to 5. ,
Hydroxyapatite nanoparticles having a truncated columnar structure with a beveled tip angle. 2. A method for solubilizing and mixing a calcium solution and a phosphoric acid solution in a surfactant / water / oil emulsion phase and reacting them to produce hydroxyapatite fine particles. The method for producing hydroxyapatite nanoparticles according to claim 1, wherein the reaction is performed as described above. 3. The size of the hydroxyapatite nanoparticles is controlled by changing the functional group of the surfactant and the ratio of the hydrophilicity / hydrophobicity ratio.
A method for producing the hydroxyapatite nanoparticles according to the above. 4. A chromatography packing comprising the hydroxyapatite nanoparticles according to claim 1. 5. An organic polymer surface-modified with the hydroxyapatite nanoparticles according to claim 1.