KR102744364B1 - Manufacturing method of octacalcium phosphate bone cement and octacalcium phosphate bone cement manufactured by the same - Google Patents

Abstract

The present invention aims to provide a method for producing octacalcium phosphate (OCP) bone cement having a short hardening reaction time at body temperature by adding distilled water or saline water to starting materials having a simple composition necessary for producing octacalcium phosphate cement, and octacalcium phosphate bone cement produced thereby. The present invention provides a method for producing octacalcium phosphate (OCP) bone cement, comprising the steps of: preparing α-tricalcium phosphate (α-TCP) powder; preparing a hardening agent powder including a monovalent cation hydrogen phosphate compound having the chemical formula of M _x H _y PO ₄ (M = monovalent alkali ion or ammonium ion, and x = 1 and y = 2; or x = 2 and y = 1); mixing the α-tricalcium phosphate powder and the hardening agent powder to prepare a liquid mixture; and hardening the liquid mixture by a hydration reaction.

Description

Method for manufacturing octacalcium phosphate bone cement and octacalcium phosphate bone cement manufactured thereby {MANUFACTURING METHOD OF OCTACALCIUM PHOSPHATE BONE CEMENT AND OCTACALCIUM PHOSPHATE BONE CEMENT MANUFACTURED BY THE SAME}

The present invention relates to a method for producing octacalcium phosphate bone cement and octacalcium phosphate bone cement produced thereby, and more specifically, to a method for producing octacalcium phosphate (OCP) bone cement having a short curing reaction time at body temperature by using a monovalent cation hydrogen phosphate compound having the chemical formula M _x H _y PO ₄ (wherein M = monovalent alkali ion or ammonium ion) as a hardener in tricalcium phosphate (α-TCP) powder, and to octacalcium phosphate bone cement produced thereby.

The human body is composed of soft tissues that form the skin and various organs, and hard tissues that form various types of bones and teeth. The bones of the human body, which support the body and protect various important organs, are composite materials composed of calcium phosphate-based inorganic substances (approximately 70%), organic substances mainly composed of collagen (approximately 20%), and water (approximately 10%). Autologous bone, allograft bone, xenograft bone, and synthetic bone (or artificial bone) are used as biomaterials used to treat bone loss or defects. However, autologous bone, which is the most preferred method, is not available in sufficient quantities and requires multiple surgical procedures, while allograft or xenograft bone carries the risk of disease infection or immune rejection, so the development of synthetic bone that can be artificially mass-produced is urgently needed.

The types of synthetic bones currently under development or in clinical use can be largely divided into two types: shaped bone and unshaped bone. The types of orthopedic synthetic bones include powder, granule, and block types, and the types of unshaped synthetic bones include cement, putty, and injectable types in addition to the cement type. Before insertion into the human body, orthopedic synthetic bones should be chemically, physically, and structurally similar to human bones, and the manufacturing, sterilization, and manipulation processes should be easy.

Bone cement for manufacturing synthetic bone is mainly used for complex fracture restoration, artificial joint surgery, and restoration of tooth dentin. IUPAC defines bone cement as an organic or inorganic substance that is self-setting (in situ self-curing) or photo-curing, and is used to fill the lost space of human tissue or for mechanical fixation of prosthetics. Bone cement currently used clinically consists of main raw material powder and hardening solution, and a third component may be added as needed. When a liquid solution is mixed with these compositions, it becomes a paste state with viscosity and fluidity, which has the advantage of being easily applied to the treatment area. After applying these bone cements to the human body, PMMA-based cements harden over time by neutralization reaction, and calcium phosphate-based cements harden by hydration reaction or acid-base reaction. Here, the characteristics that this cement composition must have are that the hardening reaction of the manufactured cement paste must be controllable at a desired speed, that fluidity (injectability) must be appropriate for clinical application, and that adhesion to surrounding bone tissue must be excellent. In addition, it must have sufficient mechanical strength after hardening, excellent biocompatibility so that there is no inflammatory reaction in the surrounding tissue due to heat, components, or by-products after the procedure, and in some cases, it must have the property of being biodegradable in the human body.

The most widely used bone cement to date is an acrylic cement called PMMA (polymethyl metacrylate) cement, which is made by mixing PMMA powder and MMA (methyl methacrylate) monomer liquid and then hardening it inside the human body. The mixed paste can secure a working time of about 4 minutes to be molded into a desired shape, and exhibits a high compressive strength of up to 90 MPa after hardening. Therefore, PMMA cement is generally used as a filler for damaged bone tissue in orthopedic surgery, or when bonding and fixing a prosthesis to the surrounding bone tissue. PMMA cement has excellent initial adhesion to the surrounding bone tissue, but due to mechanical bonding rather than chemical bonding with the surrounding bone, and large shrinkage due to polycondensation, a thick fibrous tissue film is formed around the cement, and it has been reported that this film becomes lower than the initial bonding strength over time, eventually causing the prosthesis to detach. In addition, PMMA has several problems, including non-absorbent properties, toxicity and inflammatory reactions due to unreacted monomers remaining during the curing reaction, and necrosis of surrounding tissues due to high heat generation of up to 80℃ at the surgical site during curing.

In order to solve the problems of the above-described bone cement, various calcium phosphate ceramic bone cements are being released as products. Calcium phosphate bone cement, like PMMA cement, is composed of a powdered solid and a solid/liquid hardener. When actually performing the procedure, the two components are mixed to make a viscous paste, which is then applied to the bone defect area using a syringe or by hand. Currently, calcium phosphate bone cements include apatite (HA) or brushite (DCPD). Apatite calcium phosphate bone cement is the most widely used because it has excellent biocompatibility after hardening in the human body. Initially, water was used for hydration or acid-base hardening reaction of HA cement compositions, but in this case, a long time was required for hardening, and heating at a high temperature of 80℃ or higher was required to obtain high strength. After that, a method of using organic acids instead of water as hardeners was developed to shorten the hardening time and improve mechanical strength. Calcium phosphate-based bone cement compositions containing organic acid curing agents can be manufactured in various compositions to have the desired curing time and fluidity. Calcium phosphate-based cements have excellent biocompatibility with surrounding bone tissues and do not generate much heat during curing, so they are being attempted as an alternative to PMMA-based cements. However, the weak mechanical strength, low handling, and relatively long reaction time of calcium phosphate-based cements are problems that must be solved for clinical application.

Currently commercialized calcium phosphate bone cements are classified into apatite (HA) and brushite (DCPD) types based on the final product after hardening in the human body. Representative starting powders of apatite cements include amorphous calcium phosphate (ACP), dicalcium phosphate anhydrous (DCPA), tetracalcium phosphate (TTCP), α-tricalcium phosphate (α-TCP), or β-tricalcium phosphate (β-TCP). Various calcium phosphate or phosphoric acid aqueous solutions, sodium succinate, sodium chondroitin sulfate, etc. are added as hardening agents to control hardening time, injectability, and adhesiveness. Meanwhile, the representative starting powders of brucite cement are β-tricalcium phosphate (β-TCP) and monocalcium phosphate (monocalcium phosphate monohydrate, MCPM), and sodium hyaluronate, phosphoric acid (H ₃ PO ₄ ), and sulfuric acid (H ₂ SO ₄ ) liquids are used as hardening agents. The hardening of brucite cement is relatively fast, less than 10 minutes, and its biodegradation rate is much higher than that of apatite cement and it is known to induce the formation of new bone (Materials 2009, 2, 221-291). The components and characteristics of conventionally used apatite cement and brucite cement are as shown in Fig. 1.

As mentioned above, the chemical composition of existing calcium phosphate bone cements is designed so that the final material after hydration and hardening in the human body is apatite (HA) or brushite (DCPD). Recently, in addition to the above two types of cements, octacalcium phosphate (OCP) bone cement has been attempted as another type of calcium phosphate bone cement.

However, OCP bone cement cannot be used as a bone cement that requires hardening within a few minutes to 30 minutes at the most because the hardening reaction time takes from several hours to more than a day, and the long hardening reaction time results in the temporary presence of a thermodynamically unstable OCP phase, which ultimately becomes the same as an apatite (HA)-based cement in which the HA phase becomes the main material.

Looking at the compositions of the currently known OCP cements and the research on hydration reactions, most of them were manufactured by mixing calcium phosphate-based materials to the Ca/P ratio of OCP of 1.33 and performing a hydration reaction or by immersing calcium phosphate-based materials in a calcium phosphate-based aqueous solution for a long time. With these methods, it was impossible to obtain a high-purity OCP phase at human body temperature, and the curing time was too long to be used as OCP cement. For these reasons, OCP products manufactured by the existing methods could not be used as bone cements, but could only be used as bone grafting materials or scaffolds for tissue engineering.

In consideration of the above circumstances, the present invention aims to provide a method for manufacturing octacalcium phosphate (OCP) bone cement having a short curing reaction time at body temperature using a mixture of a simple composition required for manufacturing octacalcium phosphate cement, and an octacalcium phosphate bone cement manufactured thereby.

One embodiment of the present invention can provide a method for manufacturing octacalcium phosphate (OCP) bone cement, including the steps of: preparing α-tricalcium phosphate (α-TCP) powder; preparing a hardening agent powder including a monovalent cationic hydrogen phosphate compound having a chemical formula of M _x H _y PO ₄ (M = monovalent alkali ion or ammonium ion, and x = 1 and y = 2; or x = 2 and y = 1); mixing the α-tricalcium phosphate powder and the hardening agent and then adding distilled water or saline solution to prepare a liquid mixture; and hardening the liquid mixture by a hydration reaction.

The above monovalent cation hydrogen phosphate compound is M ₁ H ₂ PO ₄ (M = monovalent alkali ion or ammonium ion), and the step of preparing the liquid mixture may include a step of mixing the hardening agent powder with the α-calcium phosphate powder and then adding distilled water or saline solution; or a step of adding distilled water or saline solution to the hardening agent powder and then mixing it with the α-calcium phosphate powder.

The above monovalent cation hydrogen phosphate compound is M ₂ HPO ₄ (M = monovalent alkali ion or ammonium ion), and the step of preparing the liquid mixture may include a step of preparing a liquid hardener by adding distilled water or saline solution to the hardener powder; a step of adjusting the pH to 4.0 to 6.0 by adding at least one strong acid selected from the group consisting of hydrochloric acid (HCl), acetic acid (CH ₃ COOH), sulfuric acid (H ₂ SO ₄ ), and nitric acid (HNO ₃ ) to the liquid hardener; and a step of mixing the α-calcium phosphate triphosphate powder into the liquid hardener of which the pH is adjusted to create a liquid mixture.

The step of preparing the above-mentioned hardener powder may use 0 to 100 parts by weight of a monovalent cationic hydrogen phosphate compound having the chemical formula of M ₁ H ₂ PO ₄ and 100 to 0 parts by weight of a monovalent cationic hydrogen phosphate compound having the chemical formula of M ₂ HPO ₄ as a hardener.

The step of mixing the above α-calcium phosphate tricalcium powder and the above curing agent may be performed by mixing the above α-calcium phosphate tricalcium powder and the above curing agent such that the atomic ratio of calcium and phosphorus (Ca/P ratio) is 1.00≤Ca/P≤1.33.

The step of mixing the above α-calcium phosphate tricalcium powder and the above curing agent may use 60 to 80 parts by weight of the above α-calcium phosphate tricalcium powder and 40 to 20 parts by weight of the above curing agent.

When the mixing ratio (P/L ratio) of the calcium phosphate-based mixed powder (P) and liquid (L) present in the above-mentioned bone cement is 1.0 to 2.5 g/ml, the curing time can be 5 to 120 minutes in a constant temperature and humidity chamber (37°C, RH 95%).

When the mixing ratio (P/L ratio) of the calcium phosphate-based mixed powder (P) and liquid (L) present in the above bone cement is 1.0 to 2.5 g/ml, the compressive strength of the bone cement hardened in a constant temperature and humidity chamber (37°C, RH 95%) can be 10 to 30 MPa.

When the mixing ratio (P/L ratio) of the calcium phosphate-based mixed powder (P) and liquid (L) present in the above bone cement is 1.0 to 2.5 g/ml, the OCP fraction of the bone cement hardened in a constant temperature and humidity chamber (37°C, RH 95%) can be 70% or more.

One embodiment of the present invention can also provide a bone cement manufactured by the above manufacturing method.

The method for manufacturing octacalcium phosphate bone cement of the present invention, unlike conventional methods, does not use other binder additives but simply adds distilled water or saline solution to a mixture containing calcium and phosphorus, and manufactures octacalcium phosphate bone cement by a hydration and hardening reaction at room temperature or body temperature without performing high-temperature heat treatment, thereby being environmentally friendly, having excellent biocompatibility, being relatively simple to use clinically, and also having excellent operability.

Figure 1 is a diagram showing the flow of a method for manufacturing octa-calcium phosphate bone cement according to one embodiment of the present invention.
Figure 2 is a diagram showing the flow of a method for manufacturing octa-calcium phosphate bone cement of embodiment 1 of the present invention.
Figure 3 is a diagram showing the flow of a method for manufacturing octa-calcium phosphate bone cement of embodiment 2 of the present invention.
Figure 4 is a diagram showing the change in average curing time and compressive strength according to the weight ratio of calcium phosphate-based mixed powder (P) and liquid (L) of the OCP cement composition.

The present invention provides a method for manufacturing octacalcium phosphate (OCP) bone cement, comprising the steps of: preparing α-tricalcium phosphate (α-TCP) powder; preparing a hardening agent powder including a monovalent cationic hydrogen phosphate compound having the chemical formula M _x H _y PO ₄ (M = monovalent alkali ion or ammonium ion, and x = 1 and y = 2; or x = 2 and y = 1); mixing the α-tricalcium phosphate powder and the hardening agent powder to prepare a liquid mixture; and hardening the liquid mixture by a hydration reaction.

The term “bone cement” as used herein refers to a cement that is a composition containing a calcium phosphate-based mixed powder and a hardener, which is prepared into a paste by mixing it with water or saline solution at room temperature and then applied to a bone defect, and which can act as a bone substitute by self-hardening in the human body.

Below, each step of the above manufacturing method is described in detail.

Steps for preparing α-tricalcium phosphate (α-TCP) powder

The method for manufacturing octacalcium phosphate (OCP) bone cement of the present invention includes a step of preparing α-tricalcium phosphate (α-TCP) powder.

In the present invention, α-calcium phosphate is classified as a monoclinic crystal in the space group of P21/a with lattice constants of a = 12.887 Å, b = 27.280 Å, c = 15.219 Å, and β = 126.20°.

The above α-calcium phosphate dihydrate can be purchased as a commercially available product, or can be manufactured and used as follows. As starting materials, DCPD (dicalcium phosphate dihydrate, CaHPO ₄ .2H ₂ O) and calcium carbonate (CaCO ₃ ) are mixed in a 2:1 molar ratio for 2 hours using a ball mill, the obtained powder is heat-treated at 1300° C. for 2 hours, and then rapidly cooled to room temperature to prepare a high-purity α-TCP powder, and the rapidly cooled powder is pulverized for 6 hours using a dry ball mill method using 6 mm diameter ZrO ₂ balls, and the pulverized powder is then sieved through a 10 mesh standard sieve to separate the balls and the powder. The α-calcium phosphate powder used in the present invention has a size of 50 μm or less.

M _x H _y PO ₄ A step of preparing a curing agent powder comprising a monovalent cationic hydrogen phosphate compound having the chemical formula

The method for manufacturing octacalcium phosphate (OCP) bone cement of the present invention comprises a step of preparing a hardening agent powder including a monovalent cationic hydrogen phosphate compound having a chemical formula of M _x H _y PO ₄ (M = monovalent alkali ion or ammonium ion, and x = 1 and y = 2; or x = 2 and y = 1).

The above-mentioned alkaline monovalent ion is at least one of Li ⁺ , Na ⁺ , K ⁺ , Rb ⁺ , and Cs ^+, and preferably at least one of Li ⁺ , Na ⁺ , and K ⁺ .

The above hardener may be a commercially available hardener.

The curing agent powder may contain 0 to 100 parts by weight of a monovalent cationic hydrogen phosphate compound having the chemical formula of MH ₂ PO ₄ and 100 parts by weight to 0 parts by weight of a monovalent cationic hydrogen phosphate compound having the chemical formula of M ₂ HPO ₄ . Preferably, it may contain more than 0 but less than 100 parts by weight of a monovalent cationic hydrogen phosphate compound having the chemical formula of MH ₂ PO ₄ and less than 100 parts by weight but more than 0 parts by weight of a monovalent cationic hydrogen phosphate compound having the chemical formula of M ₂ HPO ₄ . When two curing agents are mixed, the curing reaction speed can be controlled, and the phase fraction of the finally produced OCP can be improved.

Step of preparing a liquid mixture by mixing α-calcium phosphate powder and hardener powder

The method for manufacturing octacalcium phosphate (OCP) bone cement of the present invention includes a step of preparing a liquid mixture by mixing α-tricalcium phosphate powder and hardener powder.

The step of preparing a liquid mixture includes a step of mixing the curing agent powder with the α-calcium phosphate powder and then adding distilled water or saline solution; or a step of adding distilled water or saline solution to the curing agent powder and then mixing it with the α-calcium phosphate powder.

The step of mixing the above α-calcium phosphate tricalcium powder and the above hardening agent powder is performed by adding the α-calcium phosphate tricalcium powder and the above hardening agent powder such that the atomic ratio of calcium and phosphorus (Ca/P ratio) is in the range of 1.00≤Ca/P≤1.33. When the atomic ratio of calcium and phosphorus is less than 1.0, the DCPD fraction may be relatively high, and when it exceeds 1.33, the HA fraction may be relatively high.

Depending on the type of the monovalent cationic hydrogen phosphate compound having the chemical formula of M _x H _y PO ₄ as the curing agent, either embodiment 1 or 2 below can be carried out.

Implementation Example 1

Embodiment 1 is a case where a curing agent having a chemical formula of M ₁ H ₂ PO ₄ is used as a curing agent. The step of preparing a liquid mixture includes a step of mixing the curing agent powder with the α-calcium phosphate powder and then adding distilled water or saline solution; or a step of adding distilled water or saline solution to the curing agent powder and then mixing it with the α-calcium phosphate powder.

As a curing agent having the chemical formula M ₁ H ₂ PO ₄ , at least one of NaH ₂ PO ₄ , KH ₂ PO ₄ , and (NH ₄ )H ₂ PO ₄ can be used. The curing agent having the chemical formula M ₁ H ₂ PO ₄ has higher solubility in distilled water than other curing agents, and since the pH of its aqueous solution is 4 to 6, it can be used in a method for manufacturing octacalcium phosphate (OCP) bone cement without pH adjustment. If necessary, the pH can be adjusted by a method such as Embodiment 2 below before mixing with α-tricalcium phosphate (α-TCP) powder.

Implementation Example 2

Embodiment 2 is a case where a curing agent having a chemical formula of M ₂ HPO ₄ is used as a curing agent. The step of preparing the liquid mixture includes the step of preparing a liquid curing agent by adding distilled water or saline solution to the curing agent powder; and the step of adjusting the pH to 4.0 to 6.0 using at least one strong acid selected from the group consisting of hydrochloric acid (HCl), acetic acid (CH ₃ COOH), sulfuric acid (H ₂ SO ₄ ), and nitric acid (HNO ₃ ).

As a hardener having the above M ₂ HPO ₄ chemical formula, at least one of Na ₂ HPO ₄ , K ₂ HPO ₄ , and (NH ₄ ) ₂ HPO ₄ can be used. Since these hardeners have a pH of 7 to 9, additional pH adjustment is required for the OCP cement reaction.

A step of curing by hydrating the liquid mixture

The method for manufacturing octacalcium phosphate (OCP) bone cement of the present invention includes a step of hardening a liquid mixture by hydration reaction.

The solvent used in the above hydration reaction is distilled water or saline solution.

The above-mentioned hardening step is carried out at 25 to 40°C, preferably 37°C, which is body temperature, and is carried out for 3 minutes to 2 hours, preferably 10 to 30 minutes. If it hardens within 3 minutes, the hardening time is too short, so it hardens before oral treatment and cannot be performed. If it hardens for more than 2 hours, the hardening time is too long, so there is a high possibility that the shape will be deformed after oral treatment.

Example 1: M ₁ H ₂ PO ₄ If a hardener is used

α-TCP powder manufacturing

For the synthesis of α-TCP, DCPD (dicalcium phosphate dihydrate, CaHPO ₄ 2H ₂ O, Junsei Co. Ltd., Japan, 98.0%) and calcium carbonate (CaCO ₃ , Junsei Co. Ltd., Japan, 99.5%) were used as starting materials in a 2:1 molar ratio, and ball milled for 2 hours. The obtained powder was heat-treated at 1300°C for 2 hours and then rapidly cooled to room temperature to prepare high-purity α-TCP powder. The powder was pulverized and mixed using a dry ball mill method for 6 hours using 6 mm diameter ZrO ₂ balls. The mixed powder was sieved through a 10 mesh standard sieve to separate the balls and powder. The α-calcium phosphate trihydrate used in this example has a powder size of 50 μm or less.

OCP Bone Cement Manufacturing

NaH ₂ PO ₄ (Daejung Co. Ltd., Korea, 99.0%) powder was added as a curing agent to the above-mentioned manufactured α-TCP powder. The amount of the curing agent powder added is such that the atomic ratio of calcium and phosphorus (Ca/P ratio) of the final mixed powder is in the range of 1.00≤Ca/P≤1.33.

Distilled water is added to the uniformly mixed powder and stirred for 3 minutes to prepare a liquid mixture (paste). At this time, distilled water is added so that the powder to liquid ratio (P/L ratio) becomes 2.0 g/ml. When the obtained liquid mixture (paste) is hardened for 30 minutes in a constant temperature and humidity chamber (TH-ME-100, Jeiotech, Korea) at a temperature of 37℃ and a relative humidity of 100%, the following OCP cement reaction occurs.

Below, the hydrolysis reaction formula and the OCP crystallization reaction formula using the curing agent and distilled water shown in Example 1 are shown.

2NaH ₂ PO ₄ + (5+n)H ₂ O → 2H ₂ PO ₄ ^- + 2NaOH + H ₂ + (5+(n-2))H ₂ O

8Ca ₃ (PO ₄ ) ₂ + 2H ₂ PO ₄ ^- + H ₂ + (5+(n-2))H ₂ O → 3Ca ₈ H ₂ (PO ₄ ) ₆ ·5H ₂ O + (n-2)H ₂ O

The H ₂ PO ₄ ^- ions produced by hydrolysis serve as a template for OCP crystals, thereby promoting OCP crystallization.

Example 2: M ₂ HPO ₄ If a hardener is used

Distilled water with a pH of 7 is added to Na ₂ HPO ₄ powder as a hardener. The pH is adjusted to 4.8 by adding hydrochloric acid (HCl). The pH-adjusted liquid hardener is added to the α-TCP powder manufactured in Example 1. The amount of the hardener is added so that the atomic ratio of calcium and phosphorus (Ca/P ratio) of the final mixed powder is in the range of 1.00≤Ca/P≤1.33.

A liquid mixture (paste) is prepared by adding distilled water to the pH-adjusted mixture and stirring for 3 minutes. At this time, distilled water is added so that the powder to liquid ratio (P/L ratio) becomes 2.0 g/ml. When the obtained liquid mixture (paste) is cured for 30 minutes in a constant temperature and humidity chamber (TH-ME-100, Jeiotech, Korea) at a temperature of 37℃ and a relative humidity of 100%, the following OCP cement reaction occurs.

Below, the hydrolysis reaction formula and the OCP crystallization reaction formula using the curing agent, hydrochloric acid, and distilled water shown in Example 2 are shown.

2Na ₂ HPO ₄ + (5+n)H ₂ O → 2HPO ₄ ^- + 4NaOH + 2H ₂ + (5+(n-4))H ₂ O

2HPO ₄ ^- + 4NaOH + (5+(n-4))H ₂ O + 4HCl → 2HPO ₄ ^2- + 4NaCl + 4H ₂ O + (5+(n))H ₂ O

8Ca ₃ (PO ₄ ) ₂ + 2HPO ₄ ^2- + (5+(n))H ₂ O → 3Ca ₈ H ₂ (PO ₄ ) ₆ ·5H ₂ O + (n)H ₂ O

The HPO ₄ ^2- ion generated by hydrolysis acts as a template for OCP crystals, thereby promoting OCP crystallization.

Example 3: M ₁ H ₂ PO ₄ Hardener and M ₂ HPO ₄ When using mixed hardeners

Distilled water is added to the powder mixed with NaH ₂ PO ₄ powder and Na ₂ HPO ₄ powder as curing agents in the α-TCP powder manufactured in the above Example 1. Hydrochloric acid (HCl) is added to adjust the pH to 4.8. The liquid curing agent whose pH has been adjusted is added to the α-TCP powder manufactured in the above Example 1. The amount of the curing agent powder added is such that the atomic ratio of calcium and phosphorus (Ca/P ratio) of the final mixed powder is in the range of 1.00≤Ca/P≤1.33.

A liquid mixture (paste) is prepared by adding distilled water to the pH-adjusted mixture and stirring for 3 minutes. At this time, distilled water is added so that the powder to liquid ratio (P/L ratio) becomes 2.0 g/ml. When the obtained liquid mixture (paste) is hardened for 30 minutes in a constant temperature and humidity chamber (TH-ME-100, Jeiotech, Korea) at a temperature of 37℃ and a relative humidity of 100%, the following OCP cement reaction occurs.

Below, the hydrolysis reaction formula and the OCP crystallization reaction formula using the curing agent and distilled water shown in Example 3 are shown.

NaH ₂ PO ₄ + Na ₂ HPO ₄ + (5+n)H ₂ O → H ₂ PO ₄ ^- + HPO ₄ ^2- + 3NaOH + 1.5H ₂ + (5+(n-3))H ₂ O

H ₂ PO ₄ ^- + HPO ₄ ^2- + 3NaOH + 1.5H ₂ + (5+(n-3))H ₂ O + 3HCl → H ₂ PO ₄ ^- + HPO ₄ ^2- + 3NaCl + 3H ₂ O + 1.5 H ₂ + (5+(n-3))H ₂ O

8Ca ₃ (PO ₄ ) ₂ + HPO ₄ ^2- + H ₂ PO ₄ ^- + 1.5H ₂ + (5+(n))H ₂ O → 3Ca ₈ H ₂ (PO ₄ ) ₆ ·5H ₂ O + (n )H ₂ O

The HPO ₄ ^2- and H ₂ PO ₄ ^- ions produced by hydrolysis serve as templates for OCP crystals, thereby promoting OCP crystallization.

Comparative Example 1: M ₃ PO ₄ If a hardener is used

As a curing agent, Na ₃ PO ₄ or H ₃ PO ₄ powder was added to the α-TCP powder manufactured in Example 1. The amount of the curing agent added was such that the atomic ratio of calcium and phosphorus (Ca/P ratio) of the final mixed powder was in the range of 1.00≤Ca/P≤1.33.

Distilled water is added to the uniformly mixed powder and stirred for 3 minutes to prepare a liquid mixture. At this time, distilled water is added so that the powder to liquid ratio (P/L ratio) becomes 2.0 g/ml. When the obtained liquid mixture (paste) is hardened for 30 minutes in a constant temperature and humidity chamber (TH-ME-100, Jeiotech, Korea) at a temperature of 37℃ and a relative humidity of 100%, the following DCPD (brushite) cement reaction occurs instead of the OCP cement reaction.

Ca ₃ (PO ₄ ) ₂ + H ₃ PO ₄ + (2+n)H₂O → CaHPO₄·2H₂O + nH₂O

Here, the M ₃ PO ₄ compound refers to H ₃ PO 4, Li ₃ PO 4, Na ₃ PO 4, K ₃ PO 4, (NH ₄ ) ₃ PO 4, etc. Since the H ₃ PO ₄ aqueous solution used as a hardener is a very strong acid, the addition of a pH adjuster (e.g., NaOH) is required to cause the OCP cement reaction in the pH range of 4.0-6.0. That is, if there is no pH adjustment, DCPD (CaHPO 4 2H 2 O) is generated as in the reaction above, and if the pH is adjusted, time is required to generate ions that act as templates for OCP, and an additional chemical reaction is required. In conclusion, since an additional chemical reaction is required for the OCP cement reaction, the hardening reaction and OCP generation are delayed, so the OCP cement cannot function.

Experimental example

Below, the XRD (X-RAY Diffraction) pattern of the OCP bone cement manufactured in the above example is shown. It was confirmed by an X-ray diffraction analyzer (X’Pert MPD-PRO, PANalytical, Netherland). When measuring XRD, the acceleration voltage was 40 kV, the output was 30 mA, and 2θ was measured at a rate of 5° per minute from 3 to 60° with a Cu Ka line with a wavelength of 1.5419 Å. The measured diffraction pattern was analyzed using the X’pert Highscore program, and the inorganic crystal structure database (ICSD) was utilized as a reference.

As shown in the table above, in the examples of the present invention, when MH ₂ PO ₄ curing agent or M ₂ HPO ₄ curing agent was used, it could be confirmed that the OCP generation rate within 2 hours was much higher than when M ₃ PO ₄ curing agent was used.

The present invention is composed of a relatively simple composition compared to existing calcium phosphate cements because it reacts only with hydrogen phosphate containing alkali metal ions or ammonium ions that have high solubility and promote hydration reactions, and has excellent economic efficiency and simple and easy preparation manipulation for clinical use. In addition, high mechanical strength can be obtained through a rapid hydration reaction compared to the manufacturing process of other OCP cements. In all OCP crystallization reactions, initial or intermediate hydrogen phosphate ions (H ₂ PO ₄ ^- or HPO ₄ ^2- ) must be present, and it is thought that these ions serve as templates for rapid OCP crystallization during cement reaction.

Above, specific parts of the present invention have been described in detail. It will be obvious to those skilled in the art that such specific description is only a preferred embodiment and that the scope of the present invention is not limited thereby. Accordingly, it will be said that the actual scope of the present invention is defined by the appended claims and their equivalents.

Claims (10)

Step of preparing α-tricalcium phosphate (α-TCP) powder;
A step of preparing a curing agent powder comprising a monovalent cationic hydrogen phosphate compound having a chemical formula of MxHyPO4 (M = monovalent alkali ion or ammonium ion, and x = 1 and y = 2; or x = 2 and y = 1);
A step of preparing a liquid mixture by mixing the above α-calcium phosphate tricalcium powder and the above hardener and then adding distilled water or saline solution; and
Comprising a step of curing the above liquid mixture by hydration reaction,
The step of mixing the above α-calcium phosphate tricalcium powder and the above curing agent is to mix the above α-calcium phosphate tricalcium powder and the above curing agent so that the atomic ratio of calcium and phosphorus (Ca/P ratio) is 1.00≤Ca/P<1.33.
A method for manufacturing octacalcium phosphate (OCP) bone cement, characterized in that the step of mixing the above α-calcium phosphate tricalcium powder and the above hardening agent is to mix only the above α-calcium phosphate tricalcium powder and the above hardening agent. In the first paragraph,
The above monovalent cation hydrogen phosphate compound is M ₁ H ₂ PO ₄ (M = monovalent alkali ion or ammonium ion),
A method for producing octacalcium phosphate (OCP) bone cement, wherein the step of preparing the liquid mixture comprises: a step of mixing the hardening agent powder with the α-calcium phosphate powder and then adding distilled water or saline solution; or a step of adding distilled water or saline solution to the hardening agent powder and then mixing it with the α-calcium phosphate powder. In the first paragraph,
The above monovalent cation hydrogen phosphate compound is M ₂ HPO ₄ (M = monovalent alkali ion or ammonium ion),
A method for manufacturing octacalcium phosphate (OCP) bone cement, comprising: a step of preparing a liquid mixture, comprising: a step of preparing a liquid hardener by adding distilled _water or saline solution to the hardener powder; a step of adjusting the pH to 4.0 to 6.0 by adding at least one strong acid selected from the group consisting of hydrochloric acid (HCl), acetic acid (CH 3 COOH), sulfuric acid ( _{H 2} SO ₄ ), and nitric acid (HNO ₃ ) to the liquid hardener; and a step of mixing the α-calcium phosphate tricalcium powder into the pH-adjusted liquid hardener to create a liquid mixture. In the first paragraph,
A method for producing octacalcium phosphate (OCP) bone cement, wherein the step of preparing the above hardener powder uses 0 to 100 parts by weight of a monovalent cationic hydrogen phosphate compound having the chemical formula of M ₁ H ₂ PO ₄ and 100 to 0 parts by weight of a monovalent cationic hydrogen phosphate compound having the chemical formula of M ₂ HPO ₄ as a hardener. delete In the second or third paragraph,
A method for producing octacalcium phosphate (OCP) bone cement, wherein the step of mixing the above-mentioned α-calcium phosphate tricalcium powder and the above-mentioned hardening agent uses 60 to 80 parts by weight of the above-mentioned α-calcium phosphate tricalcium powder and 40 to 20 parts by weight of the above-mentioned hardening agent. In the second or third paragraph,
A method for manufacturing octacalcium phosphate (OCP) bone cement, characterized in that the curing time is 5 to 120 minutes in a constant temperature and humidity chamber (37°C, RH 95%) when the mixing ratio (P/L ratio) of the calcium phosphate-based mixed powder (P) and liquid (L) present in the bone cement is 1.0 to 2.5 g/ml. In the second or third paragraph,
A method for manufacturing octacalcium phosphate (OCP) bone cement, characterized in that the compressive strength of the bone cement hardened in a constant temperature and humidity chamber (37°C, RH 95%) is 10 to 30 MPa when the mixing ratio (P/L ratio) of the calcium phosphate-based mixed powder (P) and liquid (L) present in the bone cement is 1.0 to 2.5 g/ml. In the second or third paragraph,
A method for manufacturing octacalcium phosphate (OCP) bone cement, characterized in that the OCP phase fraction of the bone cement hardened in a constant temperature and humidity chamber (37°C, RH 95%) is 70% or more when the mixing ratio (P/L ratio) of the calcium phosphate-based mixed powder (P) and liquid (L) present in the bone cement is 1.0 to 2.5 g/ml. Bone cement manufactured by the manufacturing method of claim 1.