KR20160122656A - A hydroxyapatite-calcium sulfate microsphere as a drug carrier for sustainable release - Google Patents

Abstract

The present invention relates to a sustained release drug delivery and a production method thereof. More specifically the present invention relates to a hydroxyapatite-calcium microsphere as a sustained release drug delivery. To this end, the sustained release drug delivery includes: a microsphere matrix in which a drug and hydroxyapatite having a first degradation speed are dispersed without phase separation; and calcium sulfate particles inserted in the microsphere matrix and having a second decomposition speed which is faster than the first decomposition speed.

Description

A hydroxyapatite-calcium sulfate microsphere as a drug carrier for sustainable release as a sustained-

The present invention relates to a hydroxyapatite having a first decomposition rate and a microsphere matrix in which the drug is dispersed without phase separation; And a calcium sulfate particle having a second decomposition rate that is faster than the first decomposition rate and inserted in the microsphere matrix, and a method for producing the sustained drug delivery system.

Hydroxyapatite is the most similar material to the mineral component of bone and is widely used as biomaterial. The hydroxyapatite is biodegradable. When implanted into an implant, the hydroxyapatite is decomposed and absorbed in the body over a period of several months to several years depending on the crystallinity. The calcium and phosphate ions, which are released at this time, promote bone growth as a constituent of the bone It is widely used as a bone graft material.

As described above, the hydroxyapatite having excellent properties as a biomaterial is produced in the form of microspheres, which has various advantages. Microspheres can be injected with excellent diffusivity and fluidity, thus enabling surgery to minimize invasion. In addition, regardless of the shape of the bone, the material can be uniformly filled in the damaged region, and the body fluid can flow smoothly into the space between the filled microspheres, which is advantageous for helping the cell or tissue to grow vigorously.

There are two methods for producing the hydroxyapatite microspheres, namely, a method using a binder and a method involving heat treatment, and a method using the present cement.

First, the hydroxyapatite powder is mixed with a polymer binder and formed into a microsphere form by spray drying, oil dispersion, or solvent evaporation method. Then, the binder is removed through a high-temperature treatment and the hydroxyapatite powder is bonded to each other, It is a way to keep the sphere shape. The disadvantage of this method is that since it involves a high temperature treatment process, the drug can be carried out only by coating the drug only on the surface of the microspheres after the high temperature treatment is completed, so that the drug is rapidly released in the early stage, it's difficult. Thus, for sustained release, it can be prepared in the form of porous hydroxyapatite, but it is inconvenient to use because of its low mechanical strength.

The second method is to obtain hydroxyapatite microspheres, which are formed by dispersing calcium phosphate-based cement in oil to obtain a microsphere shape and after a certain period of time a hydroxyapatite phase change. The calcium phosphate-based cement can be converted into hydroxyapatite through phase change, and since it does not emit heat in the course of the reaction, it does not cause denaturation even when the drug is mixed at the same time. However, hydroxyapatite microspheres lacking sufficient pores have poor release of the loaded drug.

In order to function as a drug delivery system, the concentration of the drug should be maintained at an appropriate level. For example, it may not be effective at too low a concentration, and too high a concentration may be harmful to the human body. Thus, the drug delivery system must be capable of continuously releasing the drug at an appropriate level of concentration. However, the hydroxyapatite microspheres prepared by the conventional method described above have a limitation in that the drug is released rapidly in the early stage or the drug contained in the deep inside can not be sufficiently released.

The inventors of the present invention have intensively studied to produce a hydroxyapatite microsphere capable of smoothly releasing a drug uniformly loaded on hydroxyapatite without phase separation. As a result, it has been found that calcium sulfate particles, which are decomposed more rapidly in vivo than hydroxyapatite, When inserted into the sphere, it is held in the hydroxyapatite framework until the damaged bone to be replaced is recovered, but is retained in the matrix through the pores formed by the calcium sulfate particles decomposing more rapidly It was confirmed that the drug can be efficiently and continuously released to the drug contained therein, thus completing the present invention.

In order to accomplish the object of the present invention, a first aspect of the present invention relates to a microsphere matrix in which hydroxyapatite having a first decomposition rate and a drug are dispersed without phase separation; And a calcium sulfate particle having a second decomposition rate higher than the first decomposition rate and inserted in the microsphere matrix.

In a second aspect of the present invention, there is provided a dough comprising: a first step of preparing a dough by mixing a calcium phosphate type main cement powder, a calcium sulfate powder, a drug powder and a curing liquid; A second step of dispersing the dough into oil to form an emulsion and curing the calcium phosphate-based cement to form microspheres; And a third step in which the calcium phosphate-based main cement component constituting the cured microspheres is phase-changed into hydroxyapatite. The sustained-release drug delivery system according to the first aspect of the present invention is also provided.

Hereinafter, the present invention will be described in detail.

The present invention is designed to overcome the difficulty of completely releasing a drug loaded on a drug, and difficulty in releasing a drug contained therein, unless the drug-bearing hydroxyapatite microspheres otherwise form pores. The sustained-release drug delivery system of the present invention is characterized in that the calcium sulfate particles are evenly inserted into the hydroxyapatite microsphere matrix in which the drug is uniformly dispersed without phase separation. The calcium sulfate decomposed rapidly in the body compared with hydroxyapatite is decomposed and disappeared It was first confirmed that pores are formed in the pores and that the pores allow release of the delayed drug and that the drug contained in the pores can be completely released.

The sustained-release drug delivery system according to the present invention comprises a hydroxyapatite having a first decomposition rate and a microsphere matrix in which the drug is dispersed without phase separation; And calcium sulfate particles having a second decomposition rate faster than the first decomposition rate and inserted into the microsphere matrix.

The sustained-release drug delivery system according to the present invention decomposes calcium sulfate particles having a relatively high rate of biodegradation by body fluids during transplantation to form pores in the microsphere matrix and release the drug loaded in the mattress through the pores .

The sustained-release drug delivery system according to the present invention may be for insertion of a bone but is not limited thereto. The sustained-release drug delivery system includes hydroxyapatite, which is decomposed into calcium and phosphate ions, which are similar to bone mineral components, and can be applied regardless of its shape on the bone defect region due to the size and morphological characteristics of microspheres. For example, it can be applied to a narrow gap such as a fracture.

Examples of the drug to be carried on the sustained-release drug delivery system include, but are not limited to, an immune response modifier, an antiproliferative agent, an antimitotic agent, an antiplatelet agent, a platinum coordination complex, a hormone, an anticoagulant, An antimicrobial agent, an antimicrobial agent, an antiviral agent, an anti-inflammatory agent, an anti-inflammatory agent, an immunosuppressive agent, an angiogenic drug, an angiotensin receptor blocker, a nitric oxide donor, an antisense oligonucleotide, a cell cycle inhibitor, a corticosteroid, a hemostatic steroid, , Anti-cancer agents, anti-inflammatory agents, and growth factors.

The growth factor may be selected from the group consisting of bone morphogenetic proteins (BMPs), epidermal growth factor (EGF), erythropoietin (EPO), fibroblast growth factor (FGF) (HGF), insulin-like growth factor (IGF), myostatin (GDF-8), nerve growth factor (NGF), neurotrophins ), Platelet-derived growth factor (PDGF), thrombopoietin (TPO), transforming growth factor (TGF-?), Vascular endothelial growth factor (VEGF) ), Placental growth factor (PlGF), adrenomedullin (AM), autocrine motility factor, granulocyte-colony stimulating factor (G-CSF), granulocyte Granulocyte-macrophage colony IL-1, IL-2, IL-3, IL-4, IL-5, IL-6 or IL-7.

The sustained release drug delivery system according to the present invention is characterized in that a dough prepared by mixing a calcium phosphate type main cement powder, a calcium sulfate powder, a drug powder and a curing liquid is dispersed in oil to form an emulsion and the calcium phosphate type cement is cured, And then phase-changing the calcium phosphate-based main cement component constituting the cured microspheres to hydroxyapatite.

The calcium phosphate-based main cement may be a material having a self-hardening property which reacts with moisture to be cured. For example, calcium-based phosphate wherein the cement is α- tricalcium phosphate (α-tricalcium phosphate; α- TCP; Ca 3 (PO 4) 2), tetra-calcium phosphate _{(tetracalcium phosphate; TTCP; Ca 4} (PO 4) 2 O ), Or a combination thereof.

The calcium phosphate-based cement may be a mixture of α-tricalcium phosphate and tetracalcium phosphate in a ratio of 0.7: 1.3 to 1.3: 0.7, but is not limited thereto.

On the other hand, the calcium sulfate may be a hydrate.

The curing solution is a solution of sodium monophosphate (NaH ₂ PO ₄ ), sodium diphosphate (Na ₂ HPO ₄ ), sodium triphosphate (Na ₃ PO ₄ ) solution, citric acid solution, phosphoric acid (H ₃ PO ₄ ) But is not limited thereto. For example, the sodium monophosphate solution, the sodium diphosphate solution or the sodium triphosphate solution may be independently used at a concentration of 0.5 to 1.5 M, the citric acid solution may be used at a concentration of 5 to 30 wt%, and the phosphate solution may be used at a concentration of 10 to 50 mM .

The oil may be, but is not limited to, olive oil, mineral oil, 2- [2,3-bis (2-hydroxyethoxy) propoxyl] ethanol, hexadecanoic acid, octadecanoic acid or mixtures thereof.

The third step for converting the calcium phosphate-based cement to the hydroxyapatite may be carried out at 20 캜 to 45 캜 for 12 to 60 hours, but the present invention is not limited thereto.

Since the entire process of the process for preparing a sustained-release drug delivery system according to the present invention is carried out at a relatively low temperature of 45 ° C or less and the heat release from the reaction is low, the drug is not denatured, It is possible to provide a drug delivery system in which the drug is evenly dispersed.

According to the present invention, hydroxyapatite having a first decomposition rate and a microsphere matrix in which the drug is dispersed without phase separation; And the calcium sulfate particles inserted into the microsphere matrix having a second decomposition rate faster than the first decomposition rate, the calcium sulfate particles inserted at the time of implantation into the body are first decomposed to form pores, It is possible to release the drug as well as releasing the drug contained therein. Therefore, the drug can be effectively used as a drug delivery system capable of sustained drug release.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a diagram schematically illustrating a method for producing hydroxyapatite-calcium sulfate biphasic microspheres according to an embodiment of the present invention; FIG.
2 is a scanning electron microscope image of a phase-change front cross-section of a microsphere containing (A) calcium sulfate, (B) 25 wt% or (C) 50 wt% calcium sulfate. The arrow indicates the calcium sulfate particles.
3 is a scanning electron microscope (SEM) image of the microspheres after phase change and before biodegradation containing calcium sulfate (A), (B) 25 wt% or (C) 50 wt% calcium sulfate. The arrow indicates the calcium sulfate particles.
4 shows a scanning electron microscope image of a cross section after 1 week of biodegradation of microspheres containing (A) no calcium sulfate, (B) 25 wt% or (C) 50 wt% calcium sulfate.
FIG. 5 shows the X-ray diffraction curves of the microspheres containing no calcium sulfate, 25% by weight or 50% by weight, measured before (A) phase change, (B) after phase change and after biodegradation and (1) Fig. 5 shows a diffraction pattern. Fig.
Figure 6 is a graph showing the bone morphogenetic activity of bone mor- phogenesis inhibitor protein on bone mor- phogenesis induced by microsphere-bearing bone mor- phogenesis proteins containing no calcium sulfate (HA; black squares), 25% by weight (HA-25CSD; red circle) (BMP-2) over time.
FIG. 7 is a graph schematically showing drug release tendency over time from hydroxyapatite-calcium sulfate two-phase microspheres according to one embodiment of the present invention.

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are for further illustrating the present invention, and the scope of the present invention is not limited by these examples.

Example  1: Manufacture of Sustained Drug Delivery Implant

FIG. 1 schematically shows a method of manufacturing a sustained drug delivery microsphere according to an embodiment of the present invention.

As shown in FIG. 1, briefly, the sustained-release drug delivery microspheres according to the present invention are prepared by a) mixing calcium phosphate cement and calcium sulfate dihydrate powder as bone morphogenetic protein 2 (BMP-2) B) dissolving the dough in an oil to form an emulsion and curing; c) allowing the formed microspheres to remain in the oil at 37 DEG C for several days, Phase change to apatite, d) washing with acetone and sieving to obtain a uniform microsphere of the appropriate size.

Hereinafter, each of the above steps will be described in detail.

1.1. Calcium phosphate containing drug With this cement Calcium sulfate  Step a to prepare a mixed dough of dihydrate

Step a is a step of mixing the present cement paste and calcium sulfate dihydrate crystals with a solution containing a therapeutic compound or a therapeutic agent to prepare a dough, thereby uniformly mixing the therapeutic compound or the therapeutic agent into the cement paste. This cement was selected from calcium phosphate type materials. In particular, hydroxyapatite was used as apatite type material because it has excellent characteristics as a bioactive implant material. At this time, by controlling the amount of the calcium sulfate dihydrate to be mixed, the ability to carry and release the therapeutic compound carried in the microspheres could be controlled. In the present invention, three kinds of microspheres were prepared so as to contain calcium sulfate dihydrate at 0 wt% (control group), 25 wt% and 50 wt% (experimental group), respectively. An example of a therapeutic agent is bone morphogenetic protein-2 (BMP-2). The BMP-2 was dissolved in PBS at a concentration of 0.3 mg / ml. 0.15 ml of the above BMP-2 solution was uniformly mixed with 1 g of the present cement and calcium sulfate mixture in 0.45 ml of a curing solution obtained by dissolving citric acid in 13.3% by weight in a 1.33 M sodium phosphate solution to prepare a mixed dough. In order to prepare hydroxyapatite microspheres containing no calcium sulfate, 0.4584 g of alpha tricalcium phosphate and 0.5416 g of tetracalcium phosphate were used, and the hydroxyapatite microspheres containing 25% by weight of calcium sulfate were alpha tricalcium phosphate 0.4538 0.4062 g of tetra calcium phosphate, 0.25 g of calcium sulfate dihydrate, and 0.2292 g of alpha tris calcium phosphate, 0.2708 g of tetra calcium phosphate, and 0.5 g of calcium sulfate dihydrate were added to the hydroxyapatite microspheres containing 50% by weight of calcium sulfate ≪ / RTI >

1.2. Calcium phosphate containing drug With this cement Calcium sulfate  The mixed dough of the dihydrate is dispersed in the oil Emulsion  Step b for forming and curing

The dough containing the present cement, calcium sulfate and BMP-2 as a therapeutic agent prepared in Example 1.1 was stirred in oil to form an emulsion, and the mixture was cured. As the oil, 10 ml of olive oil containing 4% by volume, 5,5% by volume and 7% by volume of Labrafil ( ^R ) were used in doughs containing 0% by weight, 25% by weight and 50% by weight of calcium sulfate, respectively. The agitation proceeded at 10O < 0 > C with 300 rpm, spherical particles formed in the oil and the formed particles self-cured within 10 minutes of emulsion formation due to the self curing nature of the present cement.

1.3. Within 37 ° C oil Microsphere  Of calcium phosphate Hydroxyapatite in Phase-changing  Step c

Calcium Phosphate Water is essentially required for the phase change of the present cement to hydroxyapatite. In the present invention, the water content of the curing liquid causes the calcium phosphate to be phase-changed to hydroxyapatite in the oil. Through this phase change, the part composed of calcium phosphate except calcium sulfate of microsphere was converted into hydroxyapatite with excellent biocompatibility. Since the phase change is carried out in the oil, the therapeutic agent is stably carried on the inside of the microspheres, and the treatment is performed at a low temperature (37 캜), so that the therapeutic agent does not cause deformation or denaturation.

The phase change lasts for about 3 days, and stable calcium apatite is precipitated in the process of dissolving calcium ions and phosphate ions inside microspice containing moisture of the hardening liquid and precipitating again, and the time required for the entire reaction is It was adjusted according to the type and composition of calcium phosphate cement.

1.4. After washing with acetone and sieving, Microsphere  Step d to obtain

When the phase change according to Example 1.3 was completed, the oil present in the vial was separated and removed as much as possible, and the remaining microspheres were washed in a 100 ml acetone bath with stirring for 2 minutes or less. The filter paper was used to separate the acetone solution from the oil and the microspheres. The microspheres were left in the air for about 10 minutes to evaporate the acetone to obtain the washed microspheres. At this time, since the obtained microspheres had a distribution of several μm to several hundreds of μm, only microspheres having a diameter of 250 to 500 μm were collected using a sieving method.

Experimental Example  One: Calcium sulfate  Not included or included Hydroxyapatite Microsphere  Shape analysis

The sections before and after the phase change of hydroxyapatite of microspheres containing no calcium sulfate prepared according to Example 1 or containing 25% by weight or 50% by weight were observed with a scanning electron microscope, Respectively.

The section of the microspheres before phase change showed that calcium sulfate was evenly distributed in the calcium phosphate. 2 (A) is a cross-sectional view of a microsphere consisting of alpha tricalcium phosphate and tetracalcium phosphate, and FIGS. 2 (B) and 2 (C) are microspheres containing calcium sulfate in an amount of 25% It can be seen from the cross section that the rod-like calcium sulfate particles are distributed in the calcium phosphate. As the content of calcium sulfate increases, the presence of calcium sulfate in the cross section is more easily confirmed.

After the phase change, the cross section of the microspheres was observed with a scanning electron microscope. The calcium sulfate particles were still present in the microspheres, and the pores formed as the calcium phosphate changed into hydroxyapatite were further observed. FIG. 3 (A) shows a cross section of microsphere without calcium sulfate, and the porous microstructure of hydroxyapatite was observed. 3 (B) and 3 (C) show that calcium sulfate particles are distributed in hydroxyapatite by microspheres containing 25% by weight and 50% by weight of calcium sulfate, respectively (see the red arrow in the drawing).

Experimental Example  2: Calcium sulfate  Not included or included Hydroxyapatite Microsphere  Biodegradation analysis

Hydroxyapatite microspheres containing no calcium sulfate prepared in Example 1 or containing 25% by weight or 50% by weight were immersed in a simulated body fluid (SBF) for 1 week to cause biodegradation, The cross-section of the particles remaining under the microscope was observed and the results are shown in Fig. Furthermore, the X-ray diffraction patterns of the microspheres before, after, and after biodegradation were analyzed, and the results are shown in FIG.

After biodegradation was initiated in the simulated fluid, cross sections of the microspheres were observed with a scanning electron microscope. As a result, all the calcium sulfate particles were dissolved, and long-shaped pores formed in the space occupied by the particles were observed as the calcium sulfate particles were dissolved. Fig. 4 (A) shows the microstructure of hydroxyapatite, similar to that before biodegradation, in cross section of microsphere containing no calcium sulfate. Figures 4 (B) and 4 (C) show microspheres containing 25% and 50% by weight of calcium sulfate, respectively It was confirmed that pores were formed in the form of calcium sulfate particles observed immediately after preparation.

The components were analyzed using an X-ray diffraction pattern of hydroxyapatite microspheres containing no, or 25 wt% or 50 wt%, calcium sulfate prepared according to Example 1 above. 5 (A) shows the composition of microspheres before phase change in oil. Microspheres containing calcium sulfate are composed of alpha tricalcium phosphate and tetracalcium phosphate phases, and microspheres containing calcium sulfate are composed of alpha tre Calcium phosphate, tetra calcium phosphate, and calcium sulfate dihydrate. FIG. 5 (B) shows the composition of microspheres after phase change in oil. In microspheres containing no calcium sulfate, most of the alpha-tricalcium phosphate and tetracalcium phosphate phases were phase-changed to hydroxyapatite, In the microspheres containing calcium sulfate, it was confirmed that most of the alpha tricalcium phosphate and tetracalcium phosphate phases were phase-changed to hydroxyapatite and composed of calcium sulfate and hydroxyapatite biphase. FIG. 5 (C) shows the composition of microspheres after biodegradation for 1 week in simulated body fluids. It was confirmed that the internal calcium sulfate was completely degraded within one week, leaving only pure hydroxyapatite phase in all microspheres.

Experimental Example  3: Calcium sulfate  Not included or included Hydroxyapatite MIC Drug release over time from Los Peer analysis

BMP release over time from the hydroxyapatite microspheres containing no calcium sulfate prepared according to Example 1 or containing 25 wt% or 50 wt% was confirmed. The procedure was carried out for a total of 63 days, and the results are shown in Fig. All experimental conditions were the same except that microspheres (HA) without calcium sulfate were used as a control. As shown in FIG. 6, the hydroxyapatite microspheres containing no calcium sulfate used as a control group released most of the drug within 2 days at the initial stage of biodegradation, and the cumulative drug release was rapidly increased. However, But remained almost constant without increasing cumulative emissions. On the other hand, the hydroxyapatite 2 phase microspheres containing 25 wt% calcium sulfate showed a steady increase in cumulative release over time, indicating that continuous drug release is possible. In particular, it indicates that the drug can be continuously released over a long period of 2 months. Furthermore, the hydroxyapatite 2 phase microspheres containing 50 wt% calcium sulfate increased more rapidly as time progressed, and remained constant after about 3 weeks without any noticeable increase in cumulative release Respectively.

FIG. 7 schematically shows the release profile of the therapeutic agent after sustained release, biodegradation, and biodegradation of the sustained release drug delivery microspheres according to one embodiment of the present invention with time.

As shown in FIG. 7, it was confirmed that not only a large amount of therapeutic agent was coated or supported on the surface of the microsphere immediately after preparation of the drug delivery microsphere, but also a large amount of therapeutic agent was carried in the pores inside. Thus, in the initial state, the therapeutic agent was released from the surface layer of the microspheres.

After a certain period of time, the calcium sulfate dihydrate inside the microspheres is biodegraded and pores are formed. As a result, the therapeutic agent trapped in the microspheres begins to be released. Eventually, the calcium sulfate dihydrate constituting the microsphere is biodegraded Therapeutic agents in the inner core began to be released.

That is, when the therapeutic agent is evenly loaded on the hydroxyapatite microspheres for drug delivery according to one embodiment of the present invention, the drug coated on the surface of the microspheres or supported on the side close to the surface of the microspheres The drug is released over a long period of time, for example, over a period of several months, since the calcium sulfide moiety constituting the microsphere is decomposed, The efficacy of a sustained-release microsphere was demonstrated.

Claims (13)

Hydroxyapatite having a first decomposition rate and a microsphere matrix in which the drug is dispersed without phase separation; And
Wherein the microsphere matrix comprises calcium sulfate particles having a second degradation rate that is faster than the first degradation rate.
The method according to claim 1,
Wherein when the calcium sulfate particles are decomposed by body fluids, pores in the microsphere matrix are formed to release the drug in the mattress.
The method according to claim 1,
Sustained-release drug delivery system for bone insertion.
The method according to claim 1,
The drug may be selected from the group consisting of an immune response modifying factor, an antiproliferative agent, an antimitotic agent, an antiplatelet agent, a platinum coordination complex, a hormone, an anticoagulant, a fibrin cleavage agent, an antisecretory agent, Selected from the group consisting of receptor blockers, nitric oxide donors, antisense oligonucleotides, cell cycle inhibitors, corticosteroids, hemostatic steroids, antiparasitics, anti-glaucoma drugs, antibiotics, differentiation regulators, antiviral agents, anti-cancer agents, anti-inflammatory agents, growth factors Wherein the drug is at least one drug selected from the group consisting of:
5. The method of claim 4,
The growth factor may be selected from the group consisting of bone morphogenetic proteins (BMPs), epidermal growth factor (EGF), erythropoietin (EPO), fibroblast growth factor (FGF) (HGF), insulin-like growth factor (IGF), myostatin (GDF-8), nerve growth factor (NGF), neurotrophins ), Platelet-derived growth factor (PDGF), thrombopoietin (TPO), transforming growth factor (TGF-?), Vascular endothelial growth factor (VEGF) ), Placental growth factor (PlGF), adrenomedullin (AM), autocrine motility factor, granulocyte-colony stimulating factor (G-CSF), granulocyte Granulocyte-macrophage colony IL-1, IL-2, IL-3, IL-4, IL-5, IL-6 and IL-7. ≪ / RTI >
A first step of preparing a dough by mixing the calcium phosphate type main cement powder, the calcium sulfate powder, the drug powder and the curing liquid;
A second step of dispersing the dough into oil to form an emulsion and curing the calcium phosphate-based cement to form microspheres; And
And a third step in which the calcium phosphate-based main cement component constituting the cured microspheres is phase-changed into hydroxyapatite.
A method for producing the sustained release drug delivery system according to any one of claims 1 to 5.
The method according to claim 6,
Wherein the calcium phosphate-based cement has a magnetic hardening property by reacting with moisture.
8. The method of claim 7,
Wherein the calcium phosphate-based cement is a-tricalcium phosphate (α-TCP), tetracalcium phosphate (TTCP), or a combination thereof.
9. The method of claim 8,
Wherein the calcium phosphate-based cement is a mixture of a sustained-release drug such as α-tricalcium phosphate (α-TCP) and tetracalcium phosphate (TTCP) in a ratio of 0.7: 1.3 to 1.3: ≪ / RTI >
The method according to claim 6,
Wherein the calcium sulfate is a hydrate.
The method according to claim 6,
The curing solution is a solution of sodium monophosphate (NaH ₂ PO ₄ ), sodium diphosphate (Na ₂ HPO ₄ ), sodium triphosphate (Na ₃ PO ₄ ) solution, citric acid solution, phosphoric acid (H ₃ PO ₄ ) Of the sustained release drug delivery system.
The method according to claim 6,
Wherein the oil is an olive oil, mineral oil, 2- [2,3-bis (2-hydroxyethoxy) propoxyl] ethanol, hexadecanoic acid, octadecanoic acid or a mixture thereof. Way.
The method according to claim 6,
Wherein the third step is carried out by allowing to stand at 20 캜 to 45 캜 for 12 to 60 hours.

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