TWI623492B - Method for preparing tetracalcium phosphate - Google Patents

Abstract

The invention provides a method for preparing tetracalcium phosphate, which comprises: (1) heat-treating a fish scale and grinding the fish scale into a powder to obtain a fish scale powder; (2) adding a raw material to the fish scale powder to change The mineral components in the fish scale powder are used to obtain a raw meal powder; and (3) the raw meal powder is sintered at a high temperature to obtain a mixture containing tetracalcium phosphate.

Description

Method for preparing tetracalcium phosphate

The invention relates to a method for preparing tetracalcium phosphate, which is characterized in that fish scale is used as a raw material to transform into tetracalcium phosphate.

The research and development of human tissue repair materials is a topic of global concern. Calcium Phosphate Cement (CPC) is a non-ceramic hydroxyapatite artificial bone material with self-setting properties. It is made by mixing solid phase powder and solidified liquid in a certain ratio, where solid phase powder is composed of one or more calcium phosphate salts, and solidified liquid is composed of water, phosphate solution, dilute phosphoric acid, physiological saline, and blood. composition. The solid-phase powder is mixed with the solidifying liquid to form an easy-to-shape slurry, which is cured on its own in a short time and at an appropriate temperature (room temperature or close to the temperature of the human body) to form apatite similar to the inorganic components and crystal structure of the bone tissue. It has good biocompatibility, osteoconductivity, degradability, plasticity, self-curing under the physiological environment of the human body, and the curing reaction does not produce heat. It is widely used in the field of bone implantation and repair. The current process of calcium phosphate cement cannot achieve mass production. In the currently published literature on calcium phosphate cement, the source of experimental materials mostly stays in the laboratory's own preparation stage. Taking the commonly used series of tetracalcium phosphate and dibasic calcium phosphate (TTCP + DCPD) as an example: dicalcium phosphate dehydrate (DCPD) powder is based on reagent grade calcium nitrate (Ca (NO ₃ ) ₂ ) The solution and diammonium hydrogen phosphate ((NH ₄ ) ₂ HPO ₄ ) solution are formed by liquid-phase precipitation under acidic conditions; and tetracalcium phosphate (TTCP) powder is obtained by combining DCPD with DCPD and Calcium carbonate (CaCO ₃ ) was prepared by sintering at 1550 ° C for about 10 hours. Therefore, it is important to improve the production method to increase the production capacity.

Fish scales are derivatives of the skin of fish, which have the function of protecting the fish body, preventing microorganisms from invading the body, resisting diseases and avoiding infection. According to the structural characteristics of scales, fish scales can be divided into bone scales, ganoid scales and placoid scales. Among them, bone scales can be divided into cycloid scales and ctenoid scales. scale), the bone scale is the most common fish scale of teleost fish. The main ingredients of fish scales contain 45% collagen and 55% hydroxyapatite (HAp). Among them, hydroxyapatite is a calcium phosphate compound, which is also human or animal bones and teeth. The main inorganic component of sulphonate is about 60 ~ 70% in bones. Due to the grain characteristics of the hydroxyl apatite and the tiny pores formed between these grains, the hydroxyl apatite can have a good biological affinity for bones and a function of recalcification of teeth. In addition, Because of its good biological activity, it has been widely used in clinical orthopedic and dental biomedical materials, such as artificial bones, artificial teeth, hard bone repair, artificial joints, etc.

U.S. Patent Publication Nos. 2009/0036656 and 2005/0191226 and U.S. Patent Publication No. 7838038 point out that fish scales are used as raw materials, either through mechanical grinding and sieving, or after high temperature 700 ° C thermal pretreatment before After sintering at 1500 ° C, biomedical tissue repair materials can be prepared. However, this type of phosphate-based tissue repair materials still has disadvantages such as low preparation efficiency, high temperature heat treatment, and low purity.

Therefore, if fish scales are used for the preparation of biological materials, if the manufacturing process can be improved, such as simplifying the preparation steps or increasing the purity, the added value of fish scales will be further enhanced.

The present invention uses fish scales to prepare high-purity tetracalcium phosphate powder; after heat treatment at 380 ° C, the fish scales will destroy the organic matter of the fish scales, and then they will be crushed and ground into a powder. The powder is used for a No. 30 mesh The sieving rate can reach 100%; after that, calcium carbonate and 0%, 10%, 15%, 20%, and 25% added proportions are mixed with the powder to obtain a mixture, and the mixture is sintered at 1350 ° C. 6 After hours and rapid cooling, a mixture containing tetracalcium monophosphate can be obtained. The X-ray diffraction (XRD) test results of the mixture containing tetracalcium phosphate monophosphate showed that the fish scales without calcium carbonate were still hydroxyapatite (HAp) after high temperature sintering. With the increase of the calcium carbonate addition ratio, the more tetracalcium phosphate mineral phase is generated, however, when the addition ratio is greater than 25%, there is excess free lime (f-CaO) in the tetracalcium phosphate powder, which cannot fully react; the mixture The ratio of internal calcium oxide to phosphorus pentoxide (CaO / P ₂ O ₅ ) is preferably 1.45, and the purity of tetracalcium phosphate obtained with CaO / P ₂ O ₅ as 1.45 is greater than 90%. Therefore, the fish scale is heat-treated at a certain temperature by using fish scales, and then matched with calcium oxide precursors (limestone or oyster shells, etc.), using a process similar to portland cement, through raw material grinding, high temperature sintering and rapid chilling. It can prepare more than 90% high-purity tetracalcium phosphate and meet the heavy metal content standard in medical grade tetracalcium phosphate specifications; therefore, the method of the present invention is a simple and rapid method for preparing tetracalcium phosphate.

The terms "a" or "an" are used herein to describe the elements and ingredients of the invention. This term is used merely for convenience of description and to give the basic idea of the present invention. This narrative should be understood To include one or at least one, and unless explicitly indicated otherwise, the singular also includes the plural. When used with the term "comprising" in the scope of a patent application, the term "a" may mean one or more than one.

The term "or" in this text means "and / or".

The invention provides a method for preparing tetracalcium phosphate, which comprises: (1) heat-treating a fish scale and grinding the fish scale into a powder to obtain a fish scale powder; (2) adding a raw material to the fish scale powder to obtain A raw meal powder, wherein the raw material is selected from the group consisting of calcium monoxide, a precursor of calcium monoxide, a phosphorus pentaoxide and a phosphorus pentaoxide precursor; and (3) sintering the raw meal powder at high temperature The molar ratio of calcium oxide to phosphorus pentoxide (CaO / P ₂ O ₅ ) in the raw meal powder is in the range of 1.2 to 1.7, and a tetracalcium monotetraphosphate (tetracalcium) is obtained after high temperature sintering is completed. phosphate; TTCP).

In a specific embodiment, the types of fish scales include a bone scale, a ganoid scale, and a placoid scale. In a specific embodiment, the fish scale includes a hydroxyapatite (HAp), calcium monoxide (CaO), and phosphorus pentoxide (CaO / P ₂ O ₅ ).

In order to make the fish scales uniformly mixed with the raw material powder (such as calcium carbonate) to prepare tetracalcium phosphate, the fish scales must be crushed and ground into powder. However, because the fish scale is a combination of organic collagen and inorganic hydroxide phosphate stone, it has certain toughness characteristics; therefore, the fish scale can effectively destroy the internal organic structure of the fish scale after heat treatment (for example, greater than 380 ° C), so that Fish scales can be efficiently ground and ground. In a specific embodiment, the temperature of the heat treatment is greater than 300 ° C. In a preferred embodiment, the temperature of the heat treatment is greater than 350 ° C. In a more specific embodiment, the temperature of the heat treatment is greater than 380 ° C. In another embodiment, the heat treatment time is greater than 30 minutes. In a preferred embodiment, the heat treatment time is greater than 1 hour. In a more specific embodiment, the heat treatment time is greater than 2 hours.

The "grinding" herein may be a conventional grinding method without limitation, and ball milling is preferred. In a specific embodiment, the particle size of the fish scale powder ranges from 20 μm to 800 μm. In a preferred embodiment, the particle size of the fish scale powder ranges from 50 μm to 700 μm. In a more specific embodiment, the particle size of the fish scale powder ranges from 75 μm to 600 μm.

In order to make the raw meal powder sintered at high temperature, the molar ratio of calcium oxide to phosphorus pentoxide (CaO / P ₂ O ₅ ) in the raw meal powder should be in a specific range to sinter the tetraphosphoric acid powder. Minerals of calcium. Therefore, depending on the weight percentage of the original calcium oxide and phosphorus pentoxide of the fish scale powder itself, in order to determine the type and amount of the raw material, for example, the calcium oxide precursor (or calcium oxide) or the five Phosphorus oxide precursor (or phosphorus pentoxide), or both the calcium oxide precursor (or calcium oxide) and the phosphorus pentoxide precursor (or phosphorus pentoxide), so that the raw material and the fish scale meal During the sintering process of the raw meal powder obtained by the bulk mixing, the molar ratio of calcium oxide to phosphorus pentoxide (CaO / P ₂ O ₅ ) reaches a specific range. In a specific embodiment, the shape of the raw material is a powder. In a preferred embodiment, the raw material is a raw material powder.

Therefore, the purpose of the present invention is to make the raw meal powder sintered at a high temperature, and the molar ratio of calcium oxide to phosphorus pentoxide (CaO / P ₂ O ₅ ) in the raw meal powder should be in a specific range. . Therefore, the present invention can adopt the following two methods: (1) directly adding calcium oxide or phosphorus pentoxide to the fish scale powder, or both calcium oxide and phosphorus pentoxide, so that the raw meal powder The molar ratio of calcium oxide to phosphorus pentoxide (CaO / P ₂ O ₅ ) reaches a specific range before sintering; or (2) adding calcium oxide precursors (such as calcium carbonate) or dipentoxide to the fish scale powder Phosphorus precursors, or both calcium oxide precursors and phosphorus pentoxide precursors are added; therefore, during the sintering process, the calcium oxide precursors can be heated to produce calcium oxide and the phosphorus pentoxide precursors can be heated. The production of phosphorus pentoxide can also change the proportion of calcium oxide and phosphorus pentoxide in the raw meal powder, so that the molar ratio of calcium oxide to phosphorus pentoxide (CaO / P ₂ O ₅ ) It can also reach a specific range during the sintering process.

The term "calcium oxide precursor" as used herein includes, but is not limited to, a substance that can react to produce calcium oxide. In a specific embodiment, the calcium oxide precursor includes calcium carbonate, calcium gluconate, and calcium citrate. In a preferred embodiment, the calcium oxide precursor comprises calcium carbonate.

The term "phosphorus pentoxide precursor" as used herein includes, but is not limited to, a substance capable of producing phosphorus pentoxide through reaction. In a specific embodiment, the phosphorous pentoxide precursor includes an apatite, a monohydroxyapatite, calcium hydrogen phosphate dihydrate, and a fish scale.

When sintering at high temperature, the molar ratio of calcium oxide to phosphorus pentoxide (CaO / P ₂ O ₅ ) in the raw meal powder must be within a specific range to produce a mineral of tetracalcium phosphate. In a preferred embodiment, the molar ratio of calcium oxide to phosphorus pentoxide (CaO / P ₂ O ₅ ) in the raw meal powder ranges from 1.35 to 1.67. In a more specific embodiment, the molar ratio of calcium oxide to phosphorus pentoxide (CaO / P ₂ O ₅ ) in the raw meal powder ranges from 1.4 to 1.6.

The raw meal powder of the present invention must be sintered at high temperature so that the calcium oxide (CaO) in the raw meal powder reacts with the hydroxide apatite (HAp) to gradually grow the tetracalcium phosphate. Mineral phase. The term "high temperature sintering" herein includes sintering using a high temperature furnace, which includes an electric kiln, a gas kiln, and a material kiln. In a specific embodiment, the temperature of the high-temperature sintering is greater than 1000 ° C. In a preferred embodiment, the high-temperature sintering temperature is greater than 1200 ° C. In a more specific embodiment, the high-temperature sintering temperature is greater than 1350 ° C. In another embodiment, the high-temperature sintering time is greater than 0.5 hours. In a preferred embodiment, the high-temperature sintering time is greater than 2 hours. In a more specific embodiment, the high-temperature sintering time is greater than 6 hours.

In addition, in order to maintain the mineral phase activity of the raw powder when the high temperature sintering is completed, the tetracalcium phosphate content in the mixture containing the tetracalcium phosphate is maintained. Therefore, the present invention further includes a step (4), which is subsequent to the step (3), and comprises cooling the mixture containing the tetracalcium phosphate. "Cooling" in this article includes but is not limited to rapid cooling, that is, cooling is performed immediately after sintering is completed. In a specific embodiment, the cooling is performed by using a temperature difference method. In another embodiment, the temperature difference mode is that the cooling temperature is lower than the high temperature sintering temperature by 800 ° C or more. In a preferred embodiment, the temperature difference mode is that the cooling temperature is lower than the high-temperature sintering temperature by more than 1000 ° C. In a more specific embodiment, the temperature difference mode is that the cooling temperature is lower than the high temperature sintering temperature by more than 1200 ° C. Therefore, the mixture containing the tetracalcium phosphate produced after high-temperature sintering (eg, above 1350 ° C) is directly cooled at room temperature (about 25 ° C), and the instantaneous temperature difference is extremely large, and the effect of rapid cooling can be achieved. In a specific embodiment, the cooling the mixture containing the tetracalcium phosphate is cooling the mixture containing the tetracalcium phosphate at room temperature. The purpose of this "cooling" step is to maintain the mineral composition of the mixture containing the tetracalcium phosphate just after sintering. The preferred cooling in the furnace may cause the mineral composition of the mixture containing the tetracalcium phosphate to change, that is, the content of the tetracalcium phosphate will be reduced; therefore, the rapid cooling step can keep the freshly sintered The mineral component of the mixture containing the tetracalcium phosphate results in a product containing higher purity tetracalcium phosphate.

In addition, in order to cooperate with the application product of tetracalcium phosphate, the mixture containing the tetracalcium phosphate is further ground and sieved, so that the mixture containing the tetracalcium phosphate is formed into a product with a certain particle size to facilitate subsequent applications. Therefore, the method of the present invention further includes step (5), which is followed by step (4), which comprises grinding the mixture containing the tetracalcium phosphate into a powder to obtain a tetracalcium phosphate powder. In a specific embodiment, the particle size of the tetracalcium phosphate powder is less than 150 μm. In a preferred embodiment, the particle size of the tetracalcium phosphate powder is less than 100 μm. In a more specific embodiment, the particle size of the tetracalcium phosphate powder is less than 75 μm. In another specific embodiment, the particle size of the tetracalcium phosphate powder is less than 50 μm.

The mixture containing the tetracalcium phosphate includes the tetracalcium phosphate and a monohydroxyapatite (HAp). In a specific embodiment, the weight percentage of the tetracalcium phosphate to the mixture containing the tetracalcium phosphate is more than 60%. In a preferred embodiment, the weight percentage of the tetracalcium phosphate to the mixture containing the tetracalcium phosphate is more than 80%. In a more specific embodiment, the weight percentage of the tetracalcium phosphate in the mixture containing the tetracalcium phosphate is more than 90%. In another specific embodiment, the weight percentage of the hydroxylapatite to the mixture containing the tetracalcium phosphate is 40% or less. In a preferred embodiment, the weight percentage of the hydroxylapatite to the mixture containing the tetracalcium phosphate is less than 20%. In a more specific embodiment, the weight percentage of the hydroxide apatite to the mixture containing the tetracalcium phosphate is 10% or less.

The tetracalcium phosphate powder of the present invention can be used in biological materials, such as bone cement, as an artificial bone and dental root canal sealing material, and as a raw material for synthesizing calcium lactate phosphate. In addition, if the calcium phosphate powder is improved in liquid The degree of phase dissociation (calcium ions and phosphate ions) can be used as human calcium supplements and dental health repair materials.

The invention provides a bone cement having a spherical structure, wherein the material of the bone cement is a phosphate.

In a specific embodiment, the phosphate comprises tetracalcium phosphate and a hydroxide apatite. In a preferred embodiment, the shape of the tetracalcium phosphate is a monoclinic crystal. In another specific embodiment, the shape of the hydroxylapatite is a hexagonal crystal.

In a specific embodiment, the diameter of the spherical structure is less than 150 μm. In a preferred embodiment, the diameter of the spherical structure is less than 100 μm. In a more specific embodiment, the diameter of the spherical structure is less than 75 μm.

In a specific embodiment, the weight percentage of the tetracalcium phosphate to the phosphate is more than 60%. In a preferred embodiment, the weight percentage of the tetracalcium phosphate to the phosphate is more than 80%. In a more specific embodiment, the weight percentage of the tetracalcium phosphate to the phosphate is more than 90%. In another embodiment, the weight percentage of the hydroxide apatite to the phosphate is 40% or less. In a preferred embodiment, the weight percentage of the hydroxide apatite to the phosphate is less than 20%. In a more specific embodiment, the weight percentage of the hydroxide apatite to the phosphate is less than 10%.

Compared with other conventional technologies, the method for preparing tetracalcium phosphate provided by the present invention has the following advantages: (1) Generally speaking, fish scales are biological wastes of the non-edible part of fish, unless specially processed. Treatment, otherwise the fish scales have no use value. Therefore, the process of the present invention can prepare tetracalcium phosphate from fish scales, so that the fish scales have additional application value; therefore, the process of the present invention can reach "zero waste", "recycling of resources" and "improving the added value of reused products". Efficacy, so the present invention is of practical value; and (2) the process of the present invention is simpler and faster than the traditional method of preparing tetracalcium phosphate, thus improving the efficiency of the process; at the same time, the temperature used in the process of the present invention is also Compared with the traditional manufacturing process, the present invention can effectively reduce heat consumption and reduce environmental impact caused by high temperature. In addition, as long as the ratio of calcium oxide to phosphorus pentoxide (CaO / P ₂ O ₅ ) in the raw meal powder is appropriate at high temperature sintering, high-purity (more than 90%) tetracalcium phosphate can be prepared, which can greatly improve Production capacity.

10‧‧‧ bone cement

100‧‧‧ spherical structure

200‧‧‧tetracalcium phosphate

300‧‧‧ Hydroxyapatite

FIG. 1 is a process for preparing tetracalcium phosphate according to the present invention.

Figure 2 shows the grinding results of fish scales after different heat treatments. Figure 2 (A) shows the fish scales being crushed and ground without heat treatment. Figure 2 (B) shows the fish scales being crushed and ground by heat treatment at 90 ° C. Figure 2 (C) shows the fish scales being crushed and ground by heat treatment at 380 ° C. Figure 2 (D) shows the sieving rate of the fish scales after being crushed and ground (using a 30 mesh screen) after different heat treatment temperatures (unheated, 90 ° C and 380 ° C).

Figure 3 shows the X-rays caused by adding different amounts of calcium carbonate to fish scale powder. Change of mineral phase in diffraction analysis (XRD). Figure 3 (A) shows the results of the mineral phase of XRD without calcium carbonate. FIG. 3 (B) shows the result of mineral phase of XRD with 10% calcium carbonate added by weight. Fig. 3 (C) shows the result of mineral phase of XRD with 15% by weight of calcium carbonate added. Fig. 3 (D) shows the result of the mineral phase of XRD in which 20% by weight of calcium carbonate was added. FIG. 3 (E) shows the result of the mineral phase of XRD in which 25% by weight of calcium carbonate was added. The triangle is tetracalcium phosphate (TTCP).

Figure 4 is a comparative example of various minerals in a mixture containing tetracalcium phosphate obtained by sintering a raw meal powder with CaO / P ₂ O ₅ of 1.45 identified by Rietveld-X-ray diffraction analysis (Rietveld XRD) test results. The blue line is the XRD standard spectrum of the mineral crystal phase of the mixture containing tetracalcium phosphate obtained from the sintering of the raw meal powder with CaO / P ₂ O ₅ of 1.45; the red line is the one of the Rietwald-X-ray diffraction analysis method. The calculated spectrum is simulated; and the black line is the error result. After the blue line and the red line are compared with each other, it can be known that the composition of tetracalcium phosphate in the mixture containing tetracalcium phosphate reaches about 92%, and the rest is hydroxyl apatite (HAp), which is about 8%.

Figure 5 shows the structure of the bone cement of the present invention.

The present invention includes, but is not limited to, the above and below descriptions. The implementation is shown in the following example.

1. Materials and methods

(a) Thermal analysis and thermal pretreatment test of fish scales

The present invention uses general fish scales as a method for preparing tetracalcium phosphate. Phosphate (TTCP) powder is used as a raw material, so in order to understand the characteristics of heat-treated fish scales that can be broken into powder by grinding equipment, the present invention uses a thermogravimetric / thermal difference analyzer (TG / DTA, Hitachi TG7200) to explore the thermal cracking characteristics of fish scales. , The temperature rise condition of the sample is from 25 ° C to 600 ° C; the temperature increase rate is 10 ° C / min. The heat-treated fish scales were ground for 5 minutes with a crushing and grinding equipment and sieved with a No. 30 mesh (ASTM No. 30 mesh) to investigate the effect of fish scales treated at different temperatures on the crushing and screening rate.

(b) Proportion control of calcium oxide to phosphorus pentoxide (CaO / P ₂ O ₅ ) in fish scales

In the invention, after the fish scales are washed with water to remove surface contaminants, they are dried and calcined at a temperature of 380 ° C using a high-temperature furnace, and the fish scales after the thermal pretreatment are ground into a fish scale powder by a grinding device, and a No. 30 sieve powder The powder is sieved; the chemical composition of the fish scale powder (after calcination at 380 ° C) and the calcium carbonate powder is shown in Table 1. In the present invention, calcium carbonate powders (0%, 10%, 15%, 20%, and 25% by weight) of different proportions are added to the fish scale powder, so that the fish scale powder is formulated to make the fish scale powder at high temperature. During sintering, the molar ratios of calcium oxide to phosphorus pentoxide (CaO / P ₂ O ₅ ) are controlled to be 1.15, 1.28, 1.36, 1.45, and 1.55, respectively.

(c) High temperature thermal sintering test and XRD test

In the present invention, the raw meal powder obtained by mixing the fish scale powder calcined at 380 ° C with calcium carbonate powder is sintered at a high temperature using a high-temperature furnace, and the calcium oxide and phosphorus pentoxide (CaO / P) contained in the raw meal powder are discussed. _{The effect} of different molar ratios of ₂ O ₅ ) on the formation status of tetracalcium phosphate mineral phase. In order to increase the reaction rate of the raw meal powder at high temperature, the raw meal powder was subjected to ingot treatment using a 25-ton ingot press. The ingot-treated tetracalcium phosphate raw material was sintered at 1350 ° C and held at the temperature for 6 hours to simulate the tetracalcium phosphate raw material Sintering; at the same time, in order to maintain the mineral phase activity after sintering, it is subjected to rapid chilling treatment after being held at a high temperature of 1350 ° C for 6 hours. The sintered raw meal powder is rapidly ground and sieved again after being rapidly chilled. The ground powder (particle size less than 75 μm) is X-ray diffraction (XRD) (XRD model D2 phaser, Bruker) was used for mineral phase analysis. The scanning angle (2θ) of the sample was 10-75 °; the scanning rate was 0.015 ° / s; the scanning time was 0.35 seconds for XRD pattern scanning analysis.

Therefore, the process for preparing tetracalcium phosphate according to the present invention is shown in Figure 1. The process of the present invention is: (1) heat treatment and grinding: heat treatment of the fish scales (treatment at 380 ° C for 1 hour), so as to destroy the organic structure of the fish scales and be smooth. Grind into fish scale powder; (2) Add raw materials: Add raw materials and mix with the fish scale powder to obtain a raw meal powder, the purpose of which is to adjust the raw meal powder in the sintering process. Ratio of calcium oxide to phosphorus pentoxide contained in the raw material is selected from the group consisting of calcium oxide, calcium oxide precursor, phosphorus pentoxide, and phosphorus pentoxide precursor; (3) high temperature sintering : Using a high-temperature furnace to sinter the raw meal powder at a high temperature of 1350 ° C to change the mineral phase in the raw meal powder to produce tetracalcium phosphate; and (4) rapid cooling: in order to maintain the freshly-sintered powder The mineral composition of the raw material powder, that is, the high-purity tetracalcium phosphate, requires the raw material powder that has just been sintered to be quickly placed at room temperature to achieve a great temperature difference and achieve rapid cooling effect. High-purity tetracalcium phosphate was obtained. In addition, the obtained high-purity tetracalcium phosphate can be further ground and sieved according to product requirements, for example, the ground tetracalcium phosphate can form a tetracalcium phosphate powder with a particle size of less than 75 μm.

2. Results

(a) Thermal analysis and pretreatment of fish scales

In the present invention, fish scales are used as a raw material of tetracalcium phosphate. Therefore, in order to enable the fish scales to be uniformly mixed with the calcium carbonate powder, the fish scales must be crushed and ground into powder. However, because the fish scale is a combination of organic collagen and inorganic hydroxide phosphate stone, the fish scale has certain toughness characteristics; therefore, the present invention first uses mechanical grinding of the fish scale, and finds that the fish scale is mechanically ground into a sheet-like cement (such as As shown in Figure 2 (A)), the organic matter and the inorganic matter in the fish scale cannot be effectively separated, and the sieving rate is only about 29% by sieving with a No. 30 mesh.

Therefore, in order to effectively destroy the organic structure of fish scales, the present invention uses a thermogravimetric / thermal difference analyzer to analyze the thermal cracking temperature of the fish scales, and the results of the thermogravimetric / thermal difference analysis of the fish scales show that the temperatures at 56 ° C and 343 ° C, respectively Thermogravimetric loss rate with maximum rate 13.1% and 26.7% (data not shown), respectively, indicating water volatilization on the surface of the fish scale and structural cracking of the fish scale. Therefore, the fish scales were heat-treated at a temperature of 90 ° C. and 380 ° C., ground with a grinder for 5 minutes, and then sieved through a No. 30 sieve. The fish scales after heat treatment at 90 ° C are still crushed and ground, and still show a cotton wool structure (as shown in Figure 2 (B)). They cannot be completely ground and crushed to a powder state. There is not much difference in the sieving rate of broken fish scales. However, after heat treatment at 380 ° C, the fish scales were completely crushed and ground to a powder state (as shown in Figure 2 (C)), and the sieving rate was increased to 100%, which greatly improved the grinding efficiency of the fish scales. Figure 2 (D) shows the sieving rate of the fish scales after being crushed and ground (using No. 30 sieve) after different heat treatment temperatures (unheated, 90 ° C and 380 ° C heat treatment). The organic matter structure inside the fish scale enables the fish scale to be efficiently processed into a powder state.

(b) XRD mineral phase analysis

Fish scales which have been calcined and heat-treated at 380 ° C are ground into fish scale powder. Firstly, they are sieved with a No. 30 mesh (ASTM No. 30 mesh), and then they are sieved with a smaller size (ASTM No. 200 mesh). Fish scale powder. Add different weight percentages of 0%, 10%, 15%, 20%, and 25% calcium carbonate powder to the fish scale powder, so that the fish scale powder and calcium carbonate powder are evenly mixed to obtain a raw meal powder. After being sintered at 1350 ° C for 6 hours, the mixture is quenched to obtain a mixture containing tetracalcium phosphate (TTCP), which is a white powder. Figures 3 (A) to 3 (E) are the effects of different calcium carbonate addition ratios on the mineral phase growth in the raw meal powder. The test results show that when the calcium carbonate addition ratio is 0%, CaO / P ₂ O _{When the} ratio of ₅ is 1.15, the main structure is still the existing hydroxyapatite (HAp) structure of the fish scale. However, as the proportion of calcium carbonate is increased, the structure of XRD spectrum shows a tetracalcium phosphate structure, indicating that calcium oxide (CaO) reacts with fish scale's hydroxide apatite (HAp), and a tetracalcium phosphate structure gradually grows. However, when the calcium carbonate addition ratio was increased to 25% and the CaO / P ₂ O ₅ ratio was 1.55, the excess calcium oxide could not undergo a sintering reaction with the hydroxyapatite (HAp), so that more than four calcium phosphate powders existed. Free lime (free-CaO; f-CaO) may cause the volume stability of tetracalcium phosphate (TTCP). Therefore, as shown in the map of FIG. 3, the preferred calcium carbonate addition ratio is 20%, that is, when the CaO / P ₂ O ₅ content of the raw material powder composition is 1.45, it has a more appropriate tetracalcium phosphate (TTCP )generate.

In order to understand the formation ratio of tetracalcium phosphate, the present invention uses Rietveld-X-ray diffraction analysis (Rietveld XRD) to identify and quantify the proportion of tetracalcium phosphate in the sintered mixture containing tetracalcium phosphate. The Rietwald-X-ray diffraction analysis method needs to set a standard spectrum as a reference value when performing simulation calculations. Therefore, the sintered raw meal powder with CaO / P ₂ O ₅ of 1.45 contains tetraphosphoric acid. The calcium mixture passes through the set detection conditions again to obtain a standard spectrum of the mineral crystal phase (as shown by the blue line in Figure 4), and then calculates the spectrum with the simulation of Rietwald-X-ray diffraction analysis (see Figure 4). The middle red line) compares with each other. FIG. 4 shows the results of a comparative example of various minerals in a mixture containing tetracalcium phosphate obtained by sintering a raw meal powder having CaO / P ₂ O ₅ of 1.45 as quantified by Rietveld XRD. The test results show that the formation rate of tetracalcium phosphate is about 92%, and the rest is a hydroxide apatite (HAp) structure, which is about 8%. The results show that the use of fish scales to prepare tetracalcium phosphate powder can obtain more than 90% high-purity tetracalcium phosphate after a certain sintering temperature treatment, which is significantly different from the traditional chemical preparation method of tetracalcium phosphate.

In addition, Table 2 is a heavy metal composition specification table for medical grade tetracalcium phosphate powder, in which the content of lead (Pb), mercury (Hg), arsenic (As), and cadmium (Cd) needs to be less than 30, 5, 3, and 5 ppm, respectively. The present invention uses a mixed raw material of fish scale powder and calcium carbonate with CaO / P ₂ O ₅ of 1.45 to obtain tetracalcium phosphate powder after sintering. The chemical composition is analyzed by X-Ray Fluorescence (XRF). According to analysis, the analysis result of the chemical composition is shown in Table 3. The chemical main components of the tetracalcium phosphate (TTCP) powder of the present invention are calcium and phosphorus elements, and the content of heavy metals is small, and only a small amount of chromium (Cr), manganese ( Mn) and other heavy metal elements, which meet the specifications of medical grade tetracalcium phosphate powder.

ND: Undetectable

Therefore, the tetracalcium phosphate produced by the present invention is used as a bone filling material, that is, bone cement. FIG. 5 is a structure 10 of the bone cement of the present invention, which has a spherical structure 100, and the material thereof is a phosphate. The phosphate contains tetracalcium phosphate 200 and a hydroxide apatite 300. The shape of the tetracalcium phosphate 200 is a monoclinic crystal, and the shape of the hydroxide apatite 300 is a hexagonal crystal. .

Appropriate descriptions of the invention may be implemented with elements or limitations not specifically disclosed herein. Terms that have been used for description are not restrictive. There is no difference in the expression and description of these terms and any equivalents other than this, but it should be recognized that the rights within the present invention are possible to modify. Therefore, although the present invention has described embodiments and other circumstances, the contents disclosed herein can be modified and changed by those skilled in the art, and such modifications and changes are considered to be within the scope of the rights of the present invention.

Claims (10)

A method for preparing tetracalcium phosphate, comprising: (1) heat-treating a fish scale and grinding the fish scale into a powder to obtain a fish scale powder; (2) adding a raw material to the fish scale powder to obtain a raw meal powder The raw material is selected from the group consisting of calcium monoxide, calcium monoxide precursor, phosphorus pentoxide and phosphorus pentoxide precursor; and (3) sintering the raw meal powder at high temperature, so that The molar ratio of calcium oxide to phosphorus pentoxide (CaO / P ₂ O ₅ ) in the raw meal powder ranges from 1.2 to 1.7, and a mixture containing tetracalcium phosphate monophosphate is obtained after high temperature sintering is completed. The method according to item 1 of the scope of patent application, wherein the temperature of the heat treatment is greater than 300 ° C. The method according to item 1 of the patent application range, wherein the particle size of the fish scale powder ranges from 20 μm to 800 μm. The method of claim 1, wherein the calcium oxide precursor comprises calcium carbonate, calcium gluconate, and calcium citrate. The method according to item 1 of the scope of the patent application, wherein the phosphorus pentoxide precursor comprises apatite, monohydroxyapatite, calcium hydrogen phosphate dihydrate, and a fish scale. The method according to item 1 of the scope of patent application, wherein the temperature of the high-temperature sintering is greater than 1000 ° C. The method according to item 1 of the scope of patent application, further comprising a step (4), which is subsequent to the step (3) and comprises cooling the mixture containing the tetracalcium phosphate. The method according to item 7 of the scope of patent application, wherein the cooling the mixture containing the tetracalcium phosphate is cooling the mixture containing the tetracalcium phosphate at room temperature. The method according to item 7 of the patent application scope, further comprising step (5), which is followed by step (4), which comprises grinding the mixture containing the tetracalcium phosphate into a powder to obtain a tetracalcium phosphate powder body. The method according to item 9 of the scope of patent application, wherein the particle diameter of the tetracalcium phosphate powder is less than 150 μm.