KR101516754B1 - Organic inorganic hybrid drug delivery system and manufacturing method thereof - Google Patents

Abstract

The present invention relates to an organic-inorganic hybrid drug delivery system and a method of manufacturing the same. More particularly, the present invention relates to an organic-inorganic hybrid drug delivery system and a method of manufacturing the same. More particularly, Organic hybrid drug delivery system and a method for producing the same.
In the organic or inorganic hybrid drug delivery system according to the present invention, the silica shell portion is coated on the surface of the spherical particle core portion containing the calcium phosphate compound so that the outer surface of the silica shell portion is further polymerized with the thermosensitive polymer The rate at which the drug is released can be controlled depending on the temperature.

Description

TECHNICAL FIELD [0001] The present invention relates to an organic / inorganic hybrid drug delivery system and a method for manufacturing the same. BACKGROUND OF THE INVENTION < RTI ID = 0.0 >

The present invention relates to an organic-inorganic hybrid drug delivery system and a method of manufacturing the same. More particularly, the present invention relates to an organic-inorganic hybrid drug delivery system and a method of manufacturing the same. More particularly, Organic hybrid drug delivery system and a method for producing the same.

A temperature-sensitive polymer refers to a polymer in which the phase of a polymer changes with temperature, changing from a sol to a gel or from a gel to a sol. At this time, when the temperature is higher than the predetermined temperature, it is a sole. When the temperature changes to gel, the temperature is referred to as LCST (Low Critical Solution Temperature). On the other hand, when the gel is changed to a gel at a certain temperature or above, (LCST) polymer is the mainstream (K. Park, Controlled Drug Delivery, 485, 1997).

The temperature-sensitive polymer has a LCST that varies depending on the balance between the hydrophobic group and the hydrophilic group bonded to the polymer skeleton. In general, when the hydrophilic group content increases, the phase transition temperature increases. When the hydrophobic group increases, the phase transition temperature decreases. These temperature-sensitive polymers have been actively studied in various fields such as medical materials, environment, and cosmetics centered on drug delivery systems. For example, there is a field of controlling the rate of release of a drug by loading various drugs on a temperature-sensitive polymer gel and then changing the temperature, preparing a temperature-sensitive enzyme by binding a temperature-sensitive polymer to an enzyme, And to increase the reaction efficiency by separating the product and the enzyme easily. To date, dozens of temperature-sensitive polymers have been reported and can be used as temperature-sensitive polymers in the present invention. PNIPAm [poly (N-isopropylacrylamide)] or copolymers thereof are widely used in drug delivery systems due to the LCST of 33.2 ° C. (E.Kokufuta et al., Macromolecules, 26, 1053, (N, N'-diethylaminoethyl) acrylate, poly (2-hydromethacrylic acid), poly polyfumaric acid) can be used.

Hydroxyapatite (HAp), a bioceramic material used as biomaterial, is chemically similar to minerals in bone and hard tissues. It does not cause toxic reactions in vivo and exhibits excellent biocompatibility for soft tissues such as muscles and skin as well as for cervical tissues.

Because CaP microparticles readily accept defective structures and support the proliferation and growth of the surrounding cells, and because they can be degraded to regenerate new bone tissue at the end, they are of interest as a form of clinical use for filling and increasing bone defect sites Sharma CP et al., J Biomater Appl, 2003, 17 (4), 253-64; Kim CH et al., 1999, 10 (7), 383-8; et al., Tissue Enga, 2010, 16 (5), 1681-91).

The chemical formula of HAp is [Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ ] and is the main constituent of bone with an apatite with a chemical ratio of Ca (Ca) and phosphorus (P) of 1.67. It is a ceramic biomaterial which accounts for 70 ~ 90%. It is also one of the most widely used ceramic biomaterials because it can be made into a variety of crystal states depending on the synthesis temperature and various physical properties can be controlled from non-absorbable to bioabsorbable in vivo

In addition, one major advantage of CaP microparticles is their ability to mount and deliver drugs and biomolecules, thus providing therapeutic functionality (Sharma CP et al., J Mater Sci Mater Med 1999, 10 (7), 383-8). Bioceramics such as CaP have been used as a suitable method for local drug delivery since they are non-immunogenic and have a high affinity for the bound drug (Sharma CP. Et al., J Biomater Appl, 2003, 17 4), 253-64).

Several recent studies have shown the availability of CaP microparticles for the effective loading and controllable release of a variety of drugs including proteins, enzymes and antibiotics (Koplik EV. Et al., Biomater, 2002, 23 (16) Tang R. et al., Chem. Mater. 2007, 19 (13), 3081-3), < / RTI > Sharma CP. Et al., J Biomed Mater Res, 2002, 61 (4), 660-2;

It is an object of the present invention to provide a novel organic / inorganic hybrid drug delivery system using calcium phosphate particles and a temperature sensitive polymer.

The present invention also aims at providing a method for producing an organic or inorganic hybrid drug delivery vehicle.

The present invention has been made to solve the above problems

A spherical particle core portion containing a calcium phosphate compound;

A silica shell part formed on the surface of said hydroxyapatite spherical particle core part; And

A temperature-sensitive polymer shell part formed on the surface of the silica shell part; Or a pharmaceutically acceptable salt thereof.

In the organic or inorganic hybrid drug delivery system according to the present invention, the temperature-sensitive polymer is selected from the group consisting of poly (N-isopropylacrylamide) (PNIPAm), polymethacrylic acid, poly (2-hydro methacrylic acid) N'-diethylaminoethyl) acrylate and polyfumaric acid.

In the organic or inorganic hybrid drug delivery system according to the present invention, the calcium phosphate compound is selected from the group consisting of tricalcium phosphate, monocalcium phosphate, tetracalcium phosphate, dicalcium phosphate, hydroxyapatite or a combination thereof.

In the organic or inorganic hybrid drug delivery vehicle according to the present invention, the organic or inorganic hybrid drug delivery vehicle may have a particle size of 550 to 650 μm.

In the organic or inorganic hybrid drug delivery system according to the present invention, the drug is selected from the group consisting of proteins, peptides, synthetic compounds, extracts, and nucleic acids.

In the organic or inorganic hybrid drug delivery system according to the present invention, the drug is selected from the group consisting of an osteoporosis treatment agent, an antibiotic agent, an anticancer agent, an antiinflammatory agent, an antiviral agent, an antibacterial agent and a hormone.

The present invention also relates to

Preparing spherical calcium phosphate compound particles;

Forming a silica shell on the surface of the spherical particles of the calcium phosphate compound;

Supporting the drug in the spherical particles of the calcium phosphate compound; And

Polymerizing the temperature-sensitive polymer at the silica shell surface; And a method for preparing the same.

FIG. 1 schematically shows a process for producing an organic or inorganic hybrid drug delivery system according to the present invention.

In the method for producing an organic or inorganic hybrid drug delivery system according to the present invention,

The step of polymerizing the temperature-sensitive polymer on the silica shell surface

Modifying the surface of the silica shell portion;

And polymerizing the temperature-sensitive polymer in the modified silica shell part.

In the method of preparing an organic or inorganic hybrid drug delivery system according to the present invention, a C = C double bond is formed on the surface of the silica shell using a silane coupling agent having a double bond in the step of modifying the surface of the silica shell part .

In the method for preparing an organic or inorganic hybrid drug delivery system according to the present invention, the silane coupling agent is 3- (trimethoxysilyl) propyl methacrylate.

In the method of preparing an organic or inorganic hybrid drug delivery system according to the present invention, in the step of polymerizing the temperature-sensitive polymer on the surface of the silica shell part, N , N'- methylenebisacrylamide is used as a crosslinking agent and potassium persulfate is used as an initiator. Characterized in that the sensitive polymer is polymerized.

In the method for preparing an organic or inorganic hybrid drug delivery vehicle according to the present invention, the method further comprises a step of supporting the drug on the prepared drug delivery vehicle.

In the organic or inorganic hybrid drug delivery system according to the present invention, the silica shell portion is coated on the surface of the spherical particle core portion containing the calcium phosphate compound so that the outer surface of the silica shell portion is further polymerized with the thermosensitive polymer The rate at which the drug is released can be controlled depending on the temperature.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 schematically shows a process for producing an organic or inorganic hybrid drug delivery system according to the present invention.
2 shows SEM photographs of the calcium phosphate microparticles prepared in one embodiment of the present invention.
3 shows the results of EDS analysis of the calcium phosphate microparticles prepared in one embodiment of the present invention.
FIG. 4 shows the FT-IR spectra of the calcium phosphate microparticles prepared in one embodiment of the present invention before and after heat treatment (a).
5 shows TGA analysis results of the calcium phosphate microparticles prepared in one embodiment of the present invention.
FIG. 6 shows SEM photographs of calcium phosphate microparticles and cross-sections coated with silicon dioxide prepared in one embodiment of the present invention.
7 shows the results of EDS analysis of the calcium phosphate microparticles surface-coated with silicon dioxide prepared in one embodiment of the present invention.
FIG. 8 shows FT-IR analysis results of calcium dioxide microparticles surface-coated with silicon dioxide prepared in one embodiment of the present invention.
FIG. 9 shows SEM photographs of PNIPAm / SiO ₂ -CaP microparticles prepared in an embodiment of the present invention.
10 shows the results of FT-IR measurement of PNIPAm / SiO ₂ -CaP microparticles prepared in one embodiment of the present invention.
FIG. 11 shows the results of analysis of TGA of PNIPAm / SiO ₂ -CaP microparticles prepared in one embodiment of the present invention.
12 shows the results of analyzing the size and particle size of the CaP microparticles prepared in the examples of the present invention.
13 to 15 show the results of drug release experiments of CaP microparticles prepared in the examples of the present invention.

Hereinafter, the present invention will be described in more detail by way of examples. However, the present invention is not limited by the following examples.

< Example  1 > Not supported  Non-existent machine hybrid  Preparation of drug delivery system

< Example  1-1> Calcium phosphate microparticle synthesis

Calcium phosphate microparticles were prepared by recrystallization of hydroxyapatite (HAp) and water-in-oil emulsion by increasing the pH using urease for urea decomposition.

0.2 g of hydroxyapatite (HAp) was added to 40 mL of distilled water and adjusted to pH 2.5 with HCl. After adding 0.2 g of urea to the acid solution containing hydroxyapatite (HAp), stirring was carried out at 400 rpm for 1 hour at room temperature, and pH was adjusted to 4.3 using NaOH to make urea activation condition. Then, 0.1 g of urease was added, Lt; / RTI &gt; When recrystallization of hydroxyapatite (HAp) occurred, a mixture of HAp, urea and urease was added to a solution of 100 g of mineral oil and 1 ml of span, 85, and the mixture was stirred at 1000 rpm for 4 hours.

After the reaction, the oil was separated by centrifugation at 3000 rpm for 10 minutes, and the filtrate was removed to remove the oil remaining as an ether, and the resulting microspheres of calcium phosphate were vacuum-dried at room temperature. In order to remove the organic substances remaining in the calcium phosphate microparticles, the temperature was raised to 700 ° C for 2 hours and the temperature was maintained for 4 hours.

< Experimental Example  1-1> SEM  Photo measurement

SEM photographs of the prepared calcium phosphate microparticles were measured and the results are shown in Fig. 2 (A) and 2 (B) show before the heat treatment, and (C) and (D) show SEM photographs of the calcium phosphate microparticles after the heat treatment. It was confirmed that the calcium phosphate microparticles synthesized in FIG. 2 were spherical.

< Experimental Example  1-2> EDS  Measure

It is already known that calcium phosphate is not suitable for a living body when the mole ratio of Ca / P is 1 or less (Lee, SC, Choi, HJ, Kim, KJ, Jeong YK, "In-situ synthesis of reactive hydroxyapatite nano-crystals for a novel approach of surface grafting polymerization" J. Mater. Chem ., 2007; 17: 174-180).

Elemental analysis and chemical composition of calcium phosphate synthesized by the present invention were confirmed by EDS. The obtained calcium phosphate microparticles were coated with gold and subjected to elemental analysis of particles and CaP at a 15 KV AC voltage with an SEM (Topcon SM-300 Scanning Electron Microscope) connected to EDS, and the surface and cross-sectional area were observed.

Fig. 3 shows the results of EDS analysis of synthesized calcium phosphate microparticles. The results showed that CaP microparticles were composed of C, N, O, P and Ca. The Ca / P molar ratio of the calcium phosphate microparticles synthesized by the present invention was measured to be 1.17, and thus it was confirmed to be suitable for a living body.

< Experimental Example  1-3> FT - IR  Measure

The FT-IR spectra of calcium phosphate microparticles before and after heat treatment (a) and (b) were measured and the results are shown in Fig.

In FIG. 4, the phosphate (PO ₄ ^3- ) peaks of HAp were found at 1214 cm ^-1 , 1063 cm ^-1 and 990 cm ^-1 before and after the heat treatment of the calcium phosphate microparticles, ^{cm -1, 3486 cm -1, 3073} cm -1, 1250 cm - 1 and the OH bond ^{2385 cm -1, carbonyl (C =} O) 1646 cm -1, 1415 cm -1, 875 cm -1, CH of And 2973 cm ^-1 and 2931 cm ^-1 peaks of the bond disappear.

< Experimental Example  1-4> TGA  Measure

TGA analysis of calcium phosphate microparticles can confirm the organic matter content of each sample.

The TGA of the prepared calcium phosphate microparticles was analyzed and the results are shown in FIG. In FIG. 5, the weight change of calcium phosphate microparticles can be largely divided into a change up to 120 ° C and a change after 200 ° C. The initial weight change to 120 ℃ was judged to be the weight loss due to moisture remaining on the surface of calcium phosphate microparticles.

The change after 200 ° C, the main change, resulted in a weight loss of about 13 wt%. The weight loss is caused by the surfactant used in the urea or W / O emulsion that remained undissolved.

< Example  1-2> Silicon dioxide coating of calcium phosphate microparticles

The surface of the calcium phosphate microparticles was coated with silicon dioxide to compensate for the easily breaking property of the calcium phosphate microparticles prepared in the above example.

By the acid catalytic hydrolysis of TEOS, SiO ₂ And 1 mL of 0.1 M HCl were mixed and reacted at room temperature for 15 minutes. Then, 0.1 g of the calcium phosphate microparticles prepared in the above Example was added. The mixture is added dropwise to 300 mL of cyclohexane and reacted for 4 hours at room temperature using a mechanical stirrer. After the reaction, the solution was filtered, washed with methanol, and vacuum dried at room temperature.

< Experimental Example  1-5> SEM  Photo measurement

SEM photographs of particles and cross sections of the calcium phosphate microparticles surface-coated with silicon dioxide prepared in Example 1-2 were measured and the results are shown in FIG.

In FIG. 6, it can be confirmed that not only CaP microparticle surfaces but also CaP microparticles are all surrounded by Silica.

< Experimental Example  1-6> EDS  Measure

The EDS of the silicon dioxide-coated calcium phosphate microparticles prepared in the above examples was analyzed and the results are shown in Fig.

In FIG. 7, the calcium phosphate microparticles coated with silicon dioxide are composed of Si, C, O, P and Ca, and the content of Si is about 31 wt%, indicating that SiO ₂ is synthesized on the surface of calcium phosphate microparticles .

< Experimental Example  1-7> FT - IR  Measure

The FT-IR of the silicon dioxide-coated calcium phosphate microparticles prepared in the above examples was analyzed and the results are shown in FIG.

8, the FT-IR spectrum of silicon dioxide-coated calcium phosphate microparticles is similar to the FT-IR spectrum of calcium phosphate microparticles, but at 795 cm ^-1 , peak. In addition, 1145 cm ^-1 and 1081 cm ^-1 peaks of Si-O-Si bonds and 946 cm ^-1 peaks of Si-OH bonds were broadly observed, indicating that SiO ₂ was coated on CaP microparticles.

< Example  1-3> Surface modification for C = C bond formation

The surface of the silicon dioxide-coated calcium phosphate microparticles synthesized in Example 1-2 was surface-modified with 3-MOP to form C = C.

Add 0.05 g of dried silicon dioxide-coated calcium phosphate microparticles, 2 mL of 3-MOP and 10 mL / 80 mL of water / ethanol, and react at room temperature for 24 hours. After the reaction, 3-MOP modified SiO ₂ -CaP microparticles were synthesized by washing with ethanol to remove unreacted 3-MOP and drying in a vacuum oven at 50 ° C.

< Example  1-4> NIPAm  polymerization

The temperature sensitive polymer NIPAm was polymerized on the surface of 3-MOP surface-modified silicon dioxide-coated calcium phosphate microparticles.

The monomer NIPAm was recrystallized from hexane. In a two-neck flask, 0.1 g of the 3-MOP surface-modified SiO ₂ -CaP microparticles prepared in the above example, 0.2 g of NIPAm as a monomer and 0.1 g of MBA as a cross-linking agent were placed in a 30-mL secondary water, And the mixture was stirred in an atmosphere for 30 minutes. To this mixture was added 0.01 g of KPS, initiator, and 0.01 g of sodium metabisulfite in 1 mL of secondary water, and the mixture was reacted for 4 hours to obtain PNIPAm / SiO ₂ -CaP microparticles surface-polymerized with PNIPAm. In order to remove the unreacted NIPAm of the synthesized PNIPAm / SiO ₂ -CaP microparticles, they were washed with distilled water and vacuum dried.

< Experimental Example  1-8> SEM  Photo measurement

SEM photographs of the PNIPAm / SiO ₂ -CaP microparticles prepared in Example 1-4 were measured and the results are shown in FIG.

In FIG. 9, the surface of the PNIPAm / SiO ₂ -CaP microparticles is uneven and completely surrounded by PNIPAm. The average size of the PNIPAm / SiO ₂ -CaP microparticles was found to be 593.3 탆.

< Experimental Example  1-8> FT - IR  Measure

FT-IR was measured on the PNIPAm / SiO ₂ -CaP microparticles prepared in Example 1-4, and the results are shown in FIG.

In Figure 10 results C = O bond to ^{2984 cm -1, 1650 cm -1,} 1461 cm - was able to be confirmed by the peaks of the ^1, 3080 cm ^-1 bond of a CH PNIPAm and 2973 cm ^{- 1,} the peaks of the Respectively. In addition, ^{3439 cm -1, 3305 cm -1,} 1545 cm -1, 1370 cm - was confirmed NH bond ^1. As a result, it was confirmed that PNIPAm was synthesized on the silicon dioxide-coated calcium phosphate microsphere surface.

< Experimental Example  1-9> TGA  Measure

The TGA of the PNIPAm / SiO ₂ -CaP microparticles prepared in Example 1-4 was analyzed and the results are shown in FIG. As a result of TGA analysis in FIG. 11, weight change due to moisture remaining on the surface of PNIPAm / SiO ₂ -CaP microspheres at 100 ° C or less was observed, and weight loss of 45 Wt% was caused by PNIPAm to 300-400 ° C. It was confirmed that PNIPAm was synthesized on the surface of the spherical particles of the calcium phosphate compound coated with silicon.

< Experimental Example  1-10> Particle Size Analysis and Particle Size Comparison

The particle size and particle size of the PNIPAm / SiO ₂ -CaP microspheres prepared in Example 1-4 were analyzed and the results are shown in FIG.

In FIG. 12, the average sizes of CaP microparticles, SiO ₂ -CaP microparticles and PNIPAm / SiO ₂ -CaP microparticles were 459.7 μm, 499.0 μm and 593.3 μm, respectively. Since SiO ₂ has been -CaP PNIPAm the polymerization to the micro particle surface PNIPAm / SiO ₂ is great and the size of the microparticles -CaP, SiO ₂ And PNIPAm, it was confirmed that the particle size increases as microparticles are coated.

< Example  2> DOX  end Supported PNIPAm / SiO ₂ - CaP  Preparation of micro spherical particles

The surface-modified silicon dioxide-coated calcium phosphate microparticles synthesized in Example 1-3 were loaded with DOX, which is an anticancer agent.

1 mg of DOX was dissolved in 1 ml of the second solution, and the surface-modified silicon dioxide-coated calcium phosphate microparticles synthesized in Example 1-3 were immersed for 12 hours and then vacuum-dried at room temperature.

Thereafter, NIPAm was polymerized on the surface in the same manner as in Example 1-4 to prepare PNIPAm / SiO ₂ -CaP microparticles carrying DOX.

& Lt; Comparative Example & gt; SiO ₂ - CaP microspheres synthesis

The silicon dioxide-coated calcium phosphate microparticles synthesized up to the above Example 1-2 were used as a comparative example.

< Experimental Example  > Identify drug release patterns

The emission patterns of the PNIPAm / SiO ₂ -CaP microparticles carrying the DOX prepared in Example 2 and the SiO ₂ -CaP microparticles prepared in the above Comparative Example were confirmed.

The buffer was replaced with fresh phosphate buffer (5 mL) at a constant rate of 160 rpm at 37 ° C and 25 ° C in 5 mL phosphate buffer (pH 7.4, 10 mM) The absorbance was measured at 25 ^° C and 37 ^° C at constant intervals.

Fig. 13 shows the results of the release experiments of the SiO ₂ -CaP microparticles carrying the DOX and the PNIPAm / SiO ₂ -CaP microparticles in the 10 mM PBS buffer solution at 25 ° C and 37 ° C, respectively.

Experimental results show that the release of DOX from SiO ₂ -CaP microparticles is faster at 37 ° C (a) than at 25 ° C (b). On the other hand, in the case of PNIPAm / SiO ₂ -CaP microparticles, it was confirmed that the DOX release occurred much slower than in the case of SiO ₂ -CaP microparticles, and the drug release continued for 216 h or longer. During the initial 12 h, burst release of the drug occurred. After the initial burst release, the PNIPAm / SiO ₂ -CaP microparticles no longer released DOX at 25 ° C, but at 37 ° C, the drug was continuously released for a long time.

< Example  3> DOX  And IMC  end Supported PNIPAm / SiO ₂ - CaP  Preparation of micro spherical particles

Indomethacin (IMC) was further supported on the DOX-loaded PNIPAm / SiO ₂ -CaP microparticles synthesized in Example 2 above. The IMC was dissolved in 1 ml of ethanol and the DOX and IMC were carried by immersing the DOX-loaded PNIPAm / SiO ₂ -CaP microparticles synthesized in Example 2. Then, NIPAm was immersed in the surface Lt; / RTI &gt;

< Experimental Example  > Identify drug release patterns

The emission patterns of the PNIPAm / SiO ₂ -CaP microparticles carrying the DOX prepared in Example 3 and the SiO ₂ -CaP microparticles prepared in the above Comparative Example were confirmed.

Figure 14 shows the drug release experiment results of the two drugs, DOX (A) and IMC (B), in PNIPAm / SiO ₂ -CaP microparticles. As shown in Fig. 14, in the case of PNIPAm-coated microparticles, A burst release of both drugs occurred. PNIPAm / SiO ₂ -CaP microparticles containing both DOX and IMC showed a decrease in initial burst release at 37 ° C, and the drug was slowly and continuously released during 300 h.

FIG. 15 shows the results of drug release experiment by changing the temperature of the PNIPAm / SiO ₂ -CaP microparticles containing DOX and IMC at constant time intervals.

The temperature was changed to 25 ° C and 37 ° C every 24 hours, and the amount of DOX and IMC released by the temperature change was confirmed. As a result, it was confirmed that the amount of DOX and IMC was reduced at 25 ° C, followed by the on-off mode where the drug was released again at 37 ° C. At low temperatures, the polymer swells and prevents the drug inside the polymer from escaping. When the temperature rises above the LCST of PNIPAm, the polymer shrinks and squeezes out of the polymer pores. A change in hydration / dehydration occurs around 37 ° C, which is the LCST of PNIPAm / SiO ₂ -CaP microparticles, resulting in faster release of the drug at 37 ° C than 25 ° C.

Claims (12)

A hydroxyapatite spherical particle core portion;
A silica shell part formed on the surface of said hydroxyapatite spherical particle core part; And
A temperature-sensitive polymer shell part formed on the surface of the silica shell part; Lt; / RTI &gt;
The temperature-sensitive polymer may be selected from the group consisting of poly (N-isopropylacrylamide) (PNIPAm), polymethacrylic acid, poly (2-hydro methacrylic acid) Fumaric acid,
Wherein the silica shell part forms a C = C double bond on the surface.
delete delete The method according to claim 1,
Wherein the organic / inorganic hybrid drug delivery vehicle has a particle diameter of 550 to 650 占 퐉.
The method according to claim 1,
Wherein the drug is selected from the group consisting of proteins, peptides, synthetic compounds, extracts and nucleic acids.
The method according to claim 1,
Wherein the drug is selected from the group consisting of osteoporosis treating agents, antibiotics, anticancer agents, antiinflammatory agents, antiviral agents, antibacterial agents and hormones.
Preparing hydroxyapatite spherical particles;
Forming a silica shell part on the hydroxyapatite spherical particle surface; And
Polymerizing the temperature-sensitive polymer at the silica shell surface; Lt; / RTI &gt;
The temperature-sensitive polymer may be selected from the group consisting of poly (N-isopropylacrylamide) (PNIPAm), polymethacrylic acid, poly (2-hydro methacrylic acid) &Lt; / RTI &gt; fumaric acid and fumaric acid.
8. The method of claim 7,
The step of polymerizing the temperature-sensitive polymer on the silica shell surface
Modifying the surface of the silica shell portion;
Polymerizing the temperature-responsive polymer in the modified silica shell part. &Lt; RTI ID = 0.0 &gt; 21. &lt; / RTI &gt;
9. The method of claim 8,
Wherein the step of modifying the surface of the silica shell part comprises forming a C = C double bond on the surface of the silica shell part by using a silane coupling agent having a double bond.
10. The method of claim 9,
Wherein the silane coupling agent is 3- (trimethoxysilyl) propyl methacrylate. 2. The method of claim 1, wherein the silane coupling agent is 3- (trimethoxysilyl) propyl methacrylate.
8. The method of claim 7,
In the step of polymerizing the temperature-sensitive polymer on the surface of the silica shell part, N, N'-methylenebisacrylamide is used as a crosslinking agent, and potassium persulfate is used as an initiator. Wherein the temperature-responsive polymer is polymerized. &Lt; RTI ID = 0.0 &gt; 11. &lt; / RTI &gt;
8. The method of claim 7,
The method of claim 1, further comprising the step of supporting the drug on the prepared drug delivery system.

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