WO2008039002A1

WO2008039002A1 - High-strength calcium phosphate cements

Info

Publication number: WO2008039002A1
Application number: PCT/KR2007/004716
Authority: WO
Inventors: Sung Soo Kim
Original assignee: Korea Reserach Institute Of Chemical Technology
Priority date: 2006-09-28
Filing date: 2007-09-27
Publication date: 2008-04-03
Also published as: KR100844136B1; KR20080029059A

Abstract

Disclosed herein is a high-strength calcium phosphate cement having a short settingsettingfor joining bone, which is produced by mixing calcium phosphate powder, such as dicalcium phosphate anhydrous (DCPA), tetracalcium phosphate (TTCP), α-tricalcium phosphate (α-TCP), or the like, with biodegradable and water-insoluble polymeric acid powder, such as polyaspartic acid (PAA), polyglutamic acid (PGA), alginic acid (AA), carrageenanic acid (CA), or the like.

Description

Description HIGH-STRENGTH CALCIUM PHOSPHATE CEMENTS

Technical Field

[1] The present invention relates to a calcium phosphate cement, and, more particularly, to a high- strength calcium phosphate cement having a short setting time for joining bone, which is produced by mixing calcium phosphate powder, such as dicalcium phosphate anhydrous (DCPA) powder, tetracalcium phosphate (TTCP) powder, α- tricalcium phosphate (α-TCP) powder, or the like, with biodegradable and water- insoluble polymeric acid powder. Background Art

[2] Generally, cement for joining bone has been widely used to set artificial joints, such as an artificial hip joint, an artificial knee joint, and the like, to fill missing bone portions after a brain operation, to provide a filler after a bone tumor operation, and to conduct bone fracture treatment, plastic surgery, dental treatment, and the like.

[3] Acrylic cement, which includes polymethylmethacrylate (PMMA) as a main component, has been chiefly used as this cement for joining bone. Although this acrylic cement has high mechanical strength, it is disadvantageous in that it cannot regenerate bone tissue because it is not biodegradable. Further, although this acrylic cement has been recently applied to vertebroplasty for osteoporosis patients, it has a problem in that it damages vertebral nerves because the reaction is highly exothermic, and thus patients may become paralyzed on one side.

[4] In 1983, Brown and Chow developed the first calcium phosphate cement in history by mixing TTCP, DCP, etc. with a phosphate aqueous solution (W.E. Brown and L.C. Chow, A New Calcium Phosphate Water-Setting Cement. In P.W. Brown, editor, Cements Research Progress, Westville, OH; American Ceramic Society, 352-379, 1986). This calcium phosphate cement is chiefly composed of calcium phosphate powder and an aqueous solution containing a setting accelerator. Neutral or basic calcium phosphates, such as tetracalcium phosphate (TTCP), α-tricalcium phosphate (α-TCP), and the like, and acidic calcium phosphates, such as dicalcium phosphate anhydrous (DCPA), monocalcium phosphate monohydrate (MCPM), dicalcium phosphate dihydrate (DCPD), and the like, are used as the calcium phosphate powder. Citric acid, maleic acid, etc., and salts thereof are used as the setting accelerator. When this calcium phosphate cement is applied to a clinical usage in which calcium phosphate is mixed with a phosphate aqueous solution, the calcium phosphate is partially ionized by water and thus gradually dissolved in water, and is then precipitated into a calcium compound, such as hydroxy apatite (HA), and simultaneously particles are coagulated to each other, thereby causing a setting reaction. In this case, acidic compounds are used to accelerate the ionization of calcium phosphate because neutral or basic calcium phosphates are slowly ionized. Compounds for accelerating a precipitation reaction and compounds for accelerating the ionization of calcium phosphate have been used as the setting accelerator.

[5] Since calcium phosphate cement was first developed in 1983, various cements with improved material properties have been developed. The various cements will be described below.

[6] It was disclosed in U.S. Patent No. 4880610 that a cement was produced by mixing α-TCP, monocalcium phosphate monohydrate (MCPM), calcium carbonate (CC) and the like with water. It was disclosed in U.S. Patent No. 5338356 that a cement was produced by mixing α-TCP, TTCP, DCPA, HA and the like with water. It was disclosed in U.S. Patent No. 4619655 that calcium sulfate hemihydrate (CSH) was introduced into a cement. It was disclosed in WO 2004-00374 Al that calcium sulfate dihydrate (CSD) was introduced into a cement. It was disclosed in Korean Patent Registration No. 10-0371559 that polyphosphate was introduced into a cement. It was disclosed in Japanese Patent No. 345551 that a cement having antibacterial action was produced by introducing fluorine ions into a cement setting solution. It was disclosed in 2002-32827 Al that calcium phosphate nanoparticles were introduced into a cement.

[7] K. Miyazaki (Polymeric Calcium Phosphate Cements: Analysis of Reaction Products and Properties, Dental Materials, vol 9, 41-45, 1993), et al developed a high- strength calcium phosphate cement (CPC) using polyacrylic acid. However, this cement has a problem in that it cannot be easily handled and in that the production of HA is low, because the setting rate thereof is excessively rapid. Yoko Matsuya (Biomaterials, 20, 691-697, 1999), et al developed a high-strength calcium phosphate cement having a compression strength of 45 ~ 50 MPa using poly(methyl vinyl ether-maleic acid) as a setting accelerator in TTCP. Further, M.P. Ginebra (Mechanical and Rheological Improvement of a Calcium Phosphate Cement by the Addition of a Polymeric Drug, J. Biomedical Materials and Research, vol 57, 113-118, 2001), et al developed a calcium phosphate cement (CPC) having improved mechanical properties using poly- methacrylamide derived from 4-aminosalicylic acid. However, since the polymers used in the CPCs are water-soluble and nonbiodegradable, the polymeric compounds separated from the cements accumulate in the body and thus cause harmful side effects in the human body. Accordingly, the above cements have a problem in that it is difficult to use them in orthopedic applications.

[8] In these calcium phosphate cements, since calcium phosphate particles include powder, which is a main component, and an aqueous solution containing a setting acceleration material, such as phosphate, when these calcium phosphate cements are used in a clinical usage, they are injected by appropriately mixing the powder with the aqueous solution prior to the use thereof, or are directly injected into the affected part of the body.

[9] However, calcium phosphate cement has low mechanical properties. That is, compact bone has a compression strength of 130 ~ 220 MPa and a tensile strength of 80 ~ 150 MPa, and acrylic cement has a compression strength of 100 ~ 110 MPa and a tensile strength of 32 ~ 34 MPa. In contrast, calcium phosphate cement at most has a compression strength of 10 ~ 55 MPa and a tensile strength of 2.1 MPa. Therefore, calcium phosphate cement has a problem in that it is limitedly used only in affected parts suffered with a low load and requiring low strength, such as the hands, arms, face, and the like, and it cannot be used in affected parts suffered with a high load and requiring high strength, such as the vertebrae, legs, and the like. Disclosure of Invention Technical Problem

[10] Accordingly, the present invention has been made to overcome the above problems occurring in the prior art, and an object of the present invention is to provide a high- strength calcium phosphate cement having a short setting time, which is produced by mixing calcium phosphate powder with a biodegradable and water- insoluble polymeric organic compound and using a polyvalent organic acid compound as a setting accelerator. Technical Solution

[11] In order to accomplish the above object, the present invention provides a high- strength calcium phosphate cement having a short setting time for joining bone, which is produced by mixing calcium phosphate powder, such as dicalcium phosphate anhydrous (DCPA), monocalcium phosphate monohydrate (MCPM), tetracalcium phosphate (TTCP), α-tricalcium phosphate (α-TCP), or the like, with biodegradable and water-insoluble polymeric acid powder, such as polyaspartic acid (PAA), polyglutamic acid (PGA), alginic acid (AA), carrageenanic acid (CA), or the like.

[12] The present invention provides a high-strength and biodegradable cement, including a water-insoluble and biodegradable polymeric acid compound.

Advantageous Effects

[13] The calcium phosphate cement according to the present invention is advantageous in that, since it has a short setting time and high strength, the range of application thereof can be expanded. Brief Description of the Drawings

[14] FIG. 1 shows the schematic of ionic crosslinks through ionic bonds between hydroxy apatite and acidic biodegradable polymers in the calcium phosphate cement: [15] FIG. 2 shows calcium phosphate cement (CPC) and a process of injecting the calcium phosphate cement((l)γ-PGA/α-TCP;(2) 10% citric acid;(3) The mixture of (1) and (2); (4) PBS);

[16] FIG. 3 is a graph showing the weight change in the CPC depending on the incubation time((a) Example 5 ;(b) Comparative example 5); and

[17] FIG. 4 is a graph comparing the compression strength of the CPC of the present invention with those of the commercial products. Best Mode for Carrying Out the Invention

[18] Hereinafter, the present invention will be described in detail.

[19] The present invention provides a calcium phosphate cement composition for joining bone, which is produced by mixing a calcium phosphate compound with one or more biodegradable and water-insoluble polymeric acids selected from among polyaspartic acid (PAA), polyglutamic acid (PGA), alginic acid (AA), and carrageenanic acid (CA).

[20] More particularly, the calcium phosphate cement of the present invention is produced by mixing the calcium phosphate cement composition, in which the powdered calcium phosphate compound and the powdered biodegradable polymeric acid compound are mixed and pulverized, with water. In this case, the amount of water in the mixture of the mixed and pulverized calcium phosphate compound and biodegradable polymeric acid compound may be in the range of 25 ~ 40 parts by weight. When the amount of water is below 25 parts by weight, there is a problem in that the viscosity of the cement is excessively high, and thus the cement is difficult to handle. In contrast, when the amount of water is above 40 parts by weight, there is a problem in that the viscosity of the cement is excessively low, and thus the cement runs. Further, when the cement is applied to a human body, there is a problem in that the cement may be lost in body fluids.

[21] In the present invention, if necessary, a setting accelerator or a setting adjuster may be selectively added to the calcium phosphate cement. It has been found that the setting time of the calcium phosphate cement is decreased to about 5 - 10 minutes using the setting accelerator or setting adjuster, and that the compression strength thereof is increased to 60 MPa or more. The present invention is accomplished based on these findings. When the setting time thereof is above 10 minutes, at the time of applying the cement to the human body, the cement is not cured at one joining part, partially washes out along with body fluids, and is thus lost, so that the cement can not act for joining bones and can be harmful to the human body.

[22] In the present invention, a biodegradable calcium phosphate cement having improved strength and a short setting time can be produced by introducing water- insoluble and biodegradable polymeric acid compounds thereinto. [23] In the present invention, the calcium phosphate compound may be one or more powdered calcium phosphate compounds selected from among dicalcium phosphate anhydrous (DCPA), tetracalcium phosphate (TTCP), and α-tricalcium phosphate (α-TCP).

[24] The dicalcium phosphate anhydrous (DCPA), tetracalcium phosphate (TTCP) and α- tricalcium phosphate (α-TCP), which are calcium phosphate compounds, form hydroxy apatite (HA) independently or in a mixture of two or more of them in the presence of water, and are set. However, since the formed HA particles are bonded by van der Waals force, the bonding strength thereof is low, thereby causing the strength of the calcium phosphate cement to be low.

[25] Therefore, in the present invention, the strength of the calcium phosphate cement is improved by adding a polymeric compound, which can increase the strength thereof by forming ionic crosslinks through ionic bonds, to the calcium phosphate cement. Since the polymeric compound has relatively high flexibility, the polymeric compound serves to improve the material properties of cement, which is weak and brittle. This method of improving the strength of the calcium phosphate cement by adding the polymeric compound is similar to a method of reinforcing an earthen brick by putting straw therein or a method of reinforcing a lime-plastered wall by adding algin, extracted from brown seaweed, thereto.

[26] In the TTCP-based cement of the present invention, the actions of the water-insoluble and biodegradable polymeric acid compound are as follows:

[27] R-COOH → R-COO + H⁺ (I)

[28] Ca (PO ) O + 2H+ → 4Ca²⁺ +2PO ³ + H O (2)

[29] 2R-C00H + Ca (PO ) O → R-COO-Ca-COO-R + Ca (PO ) + H O (3)

[30] Ca₄(PO^₂O + 2Ca₃(PO₄)₂ + H₂O → Ca (PO₄)₆(OH)₂ (4)

[31] The polymeric acid compound (R-COOH) has acidic functional groups, such as a carboxylic acid group, a sulfonic acid group, and the like. These acidic functional groups are ionized in water, and thus hydrogen ions are formed, as represented by Equation 1. These hydrogen ions accelerate the ionization of calcium phosphate, as represented by Equation 2. Further, this polymeric acid compound is reacted with calcium ions and thus ionic-bonded therewith, as represented by Equation 3. Since this polymeric acid compound has a large number of acidic functional groups in the molecule thereof, ionic crosslinks are formed through ionic bonds. These ionic crosslinks serve to improve the strength of the calcium phosphate cement and to improve the material properties of cement, which is weak and brittle. FIG. 1 shows the formation of ionic crosslinks through ionic bonds between hydroxyapatite and acidic biodegradable polymers in the calcium phosphate cement.

[32] The salts of the polymeric acid compound can also form ionic crosslinks. However, according to the experiment of the present invention, it was found that they accelerate the absorption of water into cement, thus decreasing the strength of the cement, contrary to expectations. The reason for this is determined to be that the cations and phosphate ions adhered on the salts of the polymeric acid compound are reacted with each other, thus forming water-soluble salts, and the functional groups of the salts of the organic acid, which are not bonded with calcium ions, accelerate the absorption of water.

[33] The polymeric acid compound of the present invention may include compounds which can be biodegraded in the body, such as polyaspartic acid, polyglutamic acid, alginic acid, carrageenanic acid, and the like. These compounds are characterized in that, since these compounds, which are kinds of amino acid polymers or polysaccharides, are hydrolyzed or decomposed by an enzyme in the body, they cause few side effects in the human body.

[34] In the present invention, the amount of the polymeric acid compound may be 1 ~ 50 parts by weight, and more preferably 5 - 30 parts by weight, based on 100 parts by weight of the calcium phosphate compound. When the amount of the polymeric acid compound is much more than that of the calcium phosphate compound, the number of hydrophilic functional groups, which are not bonded with calcium ions, is increased, so that the absorption of water is increased, thereby decreasing the strength of the cement. In contrast, when the amount of the polymeric acid compound is much less than that of the calcium phosphate compound, insufficient ionic crosslinks are formed, and thus the strength of the cement is not good.

[35] The setting accelerator of the present invention may include phosphate compounds, which accelerate the formation of hydroxy apatite (HA) by accelerating the precipitation reaction of calcium ions and phosphate ions, such as NaH PO , K HPO , NH

2 4 2 4

H PO , and the like, and hydroxy apatite (HA) particles, serving as cores for accelerating the crystal growth of the hydroxy apatite (HA). Further, organic acids, such as citric acid, maleic acid, propionic acid, and the like, may be added to the cement, so that the ionization of calcium phosphate is accelerated, thereby accelerating the setting of the cement. When the setting accelerator was used, it was found that a setting time of about 10 minutes was attained.

[36] The setting adjuster of the present invention, serving to control the setting rate of the cement, may be citrate, pyrophosphate, or the like.

[37] The calcium phosphate cement according to the present invention is advantageous in that, when it is injected into bone fracture portions or bone defect portions, it can join bone tissue because a setting reaction takes place, and can regenerate the bone tissue because it is biodegradable and thus slowly decomposes in the body. Mode for the Invention

[38] Hereinafter, the present invention will be described in more detail with reference to

Examples. However, the present invention is not limited to these Examples.

[39] (Compression strength)

[40] The compression strength of the calcium phosphate cement was measured using a universal testing machine (UTM 4482, manufactured by Instron Corp.) according to ASTM F451-86. Here, the crosshead rate in the compression strength test was 20 mm/ min, and cylindrical samples having a diameter of 6 mm and a length of 20 mm were used.

[41] (Diametral tensile strength (DTS))

[42] The DTS of the calcium phosphate cement was measured using a universal testing machine (UTM 4482, manufactured by Instron Corp.). In this case, the crosshead rate in the DTS test was 20 mm/min, and cylindrical samples having a diameter of 6 mm and a height of 3 mm were used.

[43] (setting time)

[44] The setting time of the calcium phosphate cement was measured using a Gilmore needle method.

[45] The cement was put into an incubator having a temperature of 37⁰C and a relative humidity of 100%. Subsequently, the cement was pressed with a Vicat needle having a diameter of 1 mm by applying a force of 400 gf to the Vicat needle. Then, the time period to the time at which any recognizable mark did not remain on the cement was defined as the setting time.

[46]

[47] [Example 1]

[48] lOOg of α-TCP particles having an average particle size of 8 D was mixed with 1Og of γ-PGA particles having a molecular weight of 2,000,000 g/mol, and then the mixture was stirred and pulverized using a ball mill at a rotational speed of 230 rpm for 24 hours to form the powder component of the cement. Subsequently, the calcium phosphate powder component and a 10% citric acid solution as a liquid component were mixed at a ratio of 2: 1 (the ratio of the weight (g) of the calcium phosphate powder to the volume (ml) of the citric acid solution), and then the mixed solution was put into a syringe. Subsequently, the cement was injected into a glass tube and then left in a PBS (phosphate-buffered saline) solution for 7 days.

[49] Subsequently, the sample was put in acetone for 1 hour, thus ceasing the dissociation-precipitation reaction in the cement, and was then dried. As a result, the compression strength of the calcium phosphate cement was 80.2+10.0 MPa, the DTS thereof was 22.6+2.6 MPa, and the setting time thereof was about 5 minutes. [50] FIG. 2 shows calcium phosphate cement (CPC) and a process of injecting the calcium phosphate cement.

[51]

[52] [Comparative Example 1]

[53] As a control group, α-TCP-citric acid cement was produced using the same method as in Example 1, except that PGA was not used. As the result of testing the α- TCP-citric acid cement, the compression strength of the α-TCP-citric acid cement was 12.7+1.2 MPa, the DTS thereof was 2.4+0.8 MPa, and the setting time thereof was about 12 minutes.

[54]

[55] [Example 2]

[56] lOOg of TTCP particles having an average particle size of 5 D was mixed with 2Og of alginic acid particles, and then the mixture was stirred and pulverized using a ball mill at a rotational speed of 230 rpm for 24 hours to form the powder component of the cement. Subsequently, the calcium phosphate powder componentand a 10% citric acid solution as a liquid component were mixed at a ratio of 2: 1 (the ratio of the weight (g) of the calcium phosphate powder to the volume (ml) of the citric acid solution), and then the mixed solution was put into a syringe. Subsequently, the cement was injected into a glass tube and then left in a PBS (phosphate -buffered saline) solution for 7 days.

[57] Subsequently, the sample was put in acetone for 1 hour, thus ceasing the dissociation-precipitation reaction in the cement, and was then dried. As a result, the compression strength of the calcium phosphate cement was 61.5+10.0 MPa, the DTS thereof was 18.9+1.8 MPa, and the setting time thereof was about 5 minutes.

[58]

[59] [Comparative Example 2]

[60] As a control group, TTCP-citric acid cement was produced using the same method as in Example 2, except that alginic acid was not used. As the result of testing the TTCP- citric acid cement, the compression strength of the TTCP-citric acid cement was 10.7+1.9 MPa, the DTS thereof was 2.1+0.5 MPa, and the setting time thereof was about 20 minutes.

[61]

[62] [Example 3]

[63] 30g of α-TCP particles having an average particle size of 5 D was mixed with 6Og of

DCPA (CaHPO 4 ) particles having an average particle size of 5 D, and then 1Og of polyaspartic acid particles, having a molecular weight of about 20,000 g/mol, was mixed therewith. Thereafter, the mixture was stirred and pulverized using a ball mill at a rotational speed of 230 rpm for 24 hours to form the powder component of the cement. Subsequently, the calcium phosphate powder componentand a 2.5% by weight Na HPO solution as a liquid component were mixed at a ratio of 2: 1 (the ratio of the weight (g) of the calcium phosphate powder to the volume (ml) of the Na HPO solution), and then the mixed solution was put into a syringe. Subsequently, the cement was injected into a glass tube and then left in a PBS (phosphate-buffered saline) solution for 7 days.

[64] Subsequently, the sample was put in acetone for 1 hour, thus ceasing the dissociation-precipitation reaction in the cement, and was then dried. As a result, the compression strength of the calcium phosphate cement was 52.5+6.2 MPa, the DTS thereof was 14.9+1.2 MPa, and the setting time thereof was about 10 minutes.

[65]

[66] [Comparative Example 3]

[67] As a control group, α-TCP-DCPA cement was produced using the same method as in

Example 3, except that polyaspartic acid was not used. As the result of testing the α- TCP-DCPA cement, the compression strength of the α-TCP-DCPA cement was 10.2+1.2 MPa MPa, the DTS thereof was 1.6+0.5 MPa, and the setting time thereof was about 30 minutes.

[68]

[69] [Example 4]

[70] 50g of TTCP particles having an average particle size of 5 D was mixed with 50g of

DCPA (CaHPO ) particles having an average particle size of 5 D, and then 1Og of car- rageenanic acid particles was mixed therewith. Thereafter, the mixture was stirred and pulverized using a ball mill at a rotational speed of 230 rpm for 24 hours to form the powder component of the cement. Subsequently, the calcium phosphate powder component and a 15% citric acid solution as a liquid component were mixed at a ratio of 2:1 (the ratio of the weight (g) of the calcium phosphate powder to the volume (ml) of the citric acid solution), and then the mixed solution was put into a syringe. Subsequently, the cement was injected into a glass tube and then left in a PBS (phosphate -buffered saline) solution for 7 days.

[71] Subsequently, the sample was put in acetone for 1 hour, thus ceasing the dissociation-precipitation reaction in the cement, and was then dried. As a result, the compression strength of the calcium phosphate cement was 55.7+5.3 MPa, the DTS thereof was 14.9+1.2 MPa, and the setting time thereof was about 6 minutes.

[72]

[73] [Comparative Example 4]

[74] As a control group, TTCP-DCPA cement was produced using the same method as in

Example 4, except that carrageenanic acid was not used. As the result of testing the TTCP-DCPA cement, the compression strength of the TTCP-DCPA cement was 6.2+1.2 MPa, the DTS thereof was 1.2+0.5 MPa, and the setting time thereof was about 25 minutes.

[75]

[76] [Example 5]

[77] PGA-TCP cements was produced using the same method as in Example 1, except that the mixed ratio of the γ-PGA-incorporatedα-TCP powder (weight(g)) to the citric acid solution (volume (ml)) was 5:2.

[78]

[79] [Comparative example 5]

[80] As a control group, TCP-citric acid cement was produced usign the same as in

Example 5 except that γ-PGA was not used.

[81]

[82] [Experimental Example 1]

[83] In order to examine the decomposition behavior of the calcium phosphate cement

(CPC) of the present invention, it was compared Example 5 and Comparative Example 5. In this case, a PBS (phosphate-buffered saline) solution was used for incubation, and incubation times were 0, 1, 2, and 3 months, respectively. The decomposition rate of the CPC was evaluated by measuring the weight of the CPC. The results are shwon in FIG 4.

[84] As shown in FIG 4, it was found that the CPC of the present invention had decomposition characteristics because it was determined that the weight of the CPC was decreased, as the Comparative Example 5.

[85] FIG. 3 is a graph showing the weight change in the CPC depending on the incubation time.

[86] [Experimental Example 2]

[87] The compression strength of the CPC of the present invention, in which Example 1 was used, was compared and analyzed with those of commercial products. Examples of the commercial products include Bone-Source, a-BSM, MIIG X3, Norian SRS, and the like. The commercial products were produced using the method described in each of the products. The compression strengths of the products were measured after samples were cultured in a PBS solution for 1 week and then dried. The results shown in FIG 5.

[88] As shown in FIG 5, it was found that the strength of the CPC of the present invention was 3 - 10 times those of the commercial products or more. FIG. 4 is a graph comparing the compression strength of the CPC of the present invention with those of the commercial products.

[89]

[90] As described in the above Examples and Comparative Examples, it can be seen that the strength of the calcium phosphate cement of the present invention is increased by adding biodegradable polymeric acid.

Claims

[1] A calcium phosphate cement composition for joining bone, produced by mixing a calcium phosphate compound with a biodegradable polymeric acid.

[2] The calcium phosphate cement composition according to claim 1, wherein the calcium phosphate compound is one or more powdered calcium phosphate compounds selected from among dicalcium phosphate anhydrous (DCPA), monocalcium phosphate monohydrate (MCPM), tetracalcium phosphate (TTCP), and α-tricalcium phosphate (α-TCP).

[3] The calcium phosphate cement composition according to claim 1, wherein the biodegradable polymeric acid is one or more selected from among polyaspartic acid, poly glutamic acid, alginic acid, and carrageenanic acid.

[4] The calcium phosphate cement composition according to claim 1, wherein an amount of the polymeric acid is 1 ~ 50 parts by weight, based on 100 parts by weight of the calcium phosphate compound.

[5] A calcium phosphate cement for joining bone, produced by mixing 25 ~ 40 parts by weight of water with the calcium phosphate cement composition according to any one of claims 1 to 4.

[6] The calcium phosphate cement according to claim 5, wherein the calcium phosphate has a setting time of 5 ~ 10 minutes and a compression strength of 60 MPa or more.

[7] The calcium phosphate cement according to claim 5, wherein the calcium phosphate cement further comprises a setting accelerator or a setting adjuster.

[8] The calcium phosphate cement according to claim 7, wherein the setting accelerator is one or more phosphate compounds selected from among NaH PO , K

HPO and NH H PO , a hydroxy apatite fine particle, or one or more organic acids selected from among citric acid, maleic acid and propionic acid.

[9] The calcium phosphate cement according to claim 7, wherein the setting adjuster is citrate or pyrophosphate.