JP2017093987A - Production method of medical-use ceramic hollow particle, and production method of medical-use ceramic porous body - Google Patents

Abstract

PROBLEM TO BE SOLVED: To control easily the size of pores.SOLUTION: A production method of ceramic hollow particles includes a coating step SA1 for coating the surface of core particles with a mixture of a ceramic raw material and fine particles having a smaller particle size than the core particles, a transpiration step SA2 for obtaining hollow spherical particles comprising the mixture by transpiring the core particles and the fine particles by heating the core particles coated with the mixture, and a particle firing step SA3 for firing the hollow spherical particles.SELECTED DRAWING: Figure 1

Description

  The present invention relates to a method for producing medical ceramic hollow particles and a method for producing a medical ceramic porous body.

  Conventionally, porous particles made of ceramics have been used as a drug sustained release material (see, for example, Patent Document 1). In Patent Document 1, a spherical frozen material is generated by dropping an aqueous solution containing a ceramic powder and a binder into liquid nitrogen, and ceramic particles having a large number of pores are generated by drying the frozen material. By impregnating such ceramic particles with the drug, the drug can be released gradually.

Japanese Patent No. 4143705

In Patent Document 1, pores are formed by drying the binder. This method has a problem that it is difficult to control the size of the pores.
The present invention has been made in view of the above-described circumstances, and provides a method for manufacturing hollow ceramic particles for medical use and a method for manufacturing porous ceramic materials for medical use that can easily control the size of pores. With the goal.

In order to achieve the above object, the present invention provides the following means.
One embodiment of the present invention includes a coating step of coating the surface of the core particles with a mixture of a ceramic raw material and fine particles having a particle size smaller than the core particles, and heating the core particles coated with the mixture to This is a method for producing ceramic hollow particles, comprising a transpiration step of evaporating core particles and the fine particles to obtain hollow spherical particles made of the mixture, and a particle firing step of firing the hollow spherical particles.

  According to this aspect, the hollow spherical particles made of the ceramic raw material are obtained by evaporating the core particles coated with the mixture of the ceramic raw material and the fine particles by the coating step by the transpiration step. The hollow spherical particles are fired by a particle firing step to produce medical ceramic hollow particles.

  A spherical cavity is formed inside the medical ceramic hollow particle by the evaporation of the core particle. In addition, the ceramic layer constituting the medical ceramic hollow particle is connected to a spherical microcavity generated by the evaporation of the fine particles, thereby forming a communication hole that connects the inside and the outside of the ceramic layer. Therefore, the chemical | medical agent hold | maintained at the cavity of the medical ceramic hollow particle can be gradually released through a communicating hole.

  In this case, the cavity diameter can be easily controlled by the particle diameter of the core particles. Further, the hole diameter of the communication hole can be easily controlled by the particle diameter of the fine particles. Furthermore, the thickness of the ceramic layer can be easily controlled by the thickness of the ceramic raw material layer formed on the core particles in the coating step.

In the above aspect, the main component of the ceramic raw material may be a calcium phosphate compound.
By doing in this way, the medical ceramic hollow particle suitable as a material of an artificial bone can be manufactured. The main component of the ceramic raw material is β-type tricalcium phosphate (β-TCP), α-type tricalcium phosphate (α-TCP), hydroxyapatite (HAP), fluoroapatite, tetracalcium phosphate, calcium phosphooctanoate. (OCP), calcium carbonate, calcium hydrogen phosphate anhydrate, calcium hydrogen phosphate dihydrate, TTCP, calcium diphosphate, calcium metaphosphate, and carbonate-substituted hydroxyapatite (CHA) Is preferred.

Moreover, in the said aspect, you may form the layer of the said mixture which has a thickness of 10 micrometers or more in the said covering step.
By doing so, a ceramic layer having a thickness of about 10 μm or more is formed. Thereby, the medical ceramic hollow particle which has the intensity | strength which can be processed can be manufactured. Furthermore, the sustained release rate of the drug depends on the thickness of the ceramic layer. By setting the thickness of the ceramic layer to about 10 μm or more, the sustained release rate of the drug can be suppressed.

Moreover, in the said aspect, 1: 10-10: 1 may be sufficient as the mixing ratio of the said ceramic raw material and the said microparticles | fine-particles.
By doing in this way, the intensity | strength and communication property of a medical ceramic hollow particle can be made compatible.

Moreover, in the said aspect, before the said covering | coating step, the calcination step which heats the said ceramic raw material at the temperature lower than the calcination temperature in the said particle | grain baking step may be included. The shrinkage of the ceramic raw material in the firing step can be suppressed, and the cavity diameter and the hole diameter of the communication hole can be controlled more accurately.

  Another aspect of the present invention includes a mixing step of mixing ceramic hollow particles manufactured by any one of the above-described methods for manufacturing ceramic hollow particles and a ceramic raw material to obtain a mixture, and a mixture obtained by the mixing step It is a manufacturing method of a porous ceramic body for medical use, which includes a forming step of forming a molded body to obtain a molded body and a molded body firing step of firing the molded body.

According to this aspect, the medical ceramic porous body containing the medical ceramic hollow particles can be produced by molding the mixture of the medical ceramic hollow particles and the ceramic raw material and firing the obtained molded body. it can.
In this case, the sustained release rate of the drug in the medical ceramic porous body can be controlled by using the medical ceramic hollow particles in which the cavity diameter and the hole diameter of the communication hole are controlled.

  According to the present invention, there is an effect that the size of the pores can be easily controlled.

It is a flowchart which shows the manufacturing method of the ceramic ceramic hollow particle which concerns on one Embodiment of this invention. It is explanatory drawing which shows the manufacturing process of the ceramic ceramic hollow particle. It is a flowchart which shows the manufacturing method of the medical ceramic porous body which concerns on one Embodiment of this invention. It is a block diagram of the system used for manufacture of a medical ceramic porous body. It is a SEM photograph of the PMMA bead used in the example. It is a SEM photograph of PS beads used in an example. It is a SEM photograph of PS beads coated with a mixture of HAP powder and PMMA beads. It is a graph which shows the temperature program in a particle baking step. It is a SEM photograph of HAP hollow particles. FIG. 10 is an SEM image obtained by enlarging a cross section of the HAP hollow particle in FIG.

Below, the manufacturing method of the medical ceramic hollow particle which concerns on one Embodiment of this invention is demonstrated with reference to FIG. 1 and FIG.
As shown in FIG. 1, the method for producing medical ceramic hollow particles according to the present embodiment includes a coating step SA1 in which core particles are coated with a mixture of ceramic raw materials and fine particles, and the core particles and fine particles are evaporated by heating. The transpiration step SA2 for obtaining hollow spherical particles made of ceramic raw material and the particle firing step SA3 for firing hollow spherical particles to obtain medical ceramic hollow particles are included.

  The core particles are made of an organic material that burns at a temperature lower than the firing temperature in the particle firing step SA3. As the core particle, for example, polystyrene beads are suitable. Other core particles include polyolefins such as polyethylene, polypropylene, and polyacetal, vinyl polymers such as polyvinyl chloride and polyvinyl acetate, polyamides such as nylon, polyesters such as polyethylene terephthalate and polybutylene terephthalate, polysulfone, polyethersulfone, and polyether. Engineering plastics such as ether ketone, thermoplastic polyimide and polyamideimide, synthetic rubber such as isoprene rubber, butadiene rubber, styrene-butadiene rubber, chloroprene rubber, nitrile rubber, polyisobutylene, ethylene propylene rubber and acrylic rubber, natural rubber such as latex , Cellulose, starch, gelatin, natural polymers such as chitosan, acrylic resin (PMMA), polyurethane, AB Any material can be used as long as it evaporates at a temperature lower than the sintering temperature of the ceramic raw material to be coated, such as S resin, polycarbonate, and silicone resin.

  The particle diameter (outer diameter) of the core particles is appropriately selected according to the use of the medical ceramic hollow particles. As will be described later, when medical ceramic hollow particles are used as a material for artificial bone, the particle size of the core particles can promote the penetration of osteoblasts into the medical ceramic hollow particles. It is preferably 10 μm or more and 1000 μm or less, and more preferably 100 μm or more and 400 μm or less.

  The ceramic raw material contains a calcium phosphate compound as a main component. Calcium phosphate compounds include β-type tricalcium phosphate (β-TCP), α-type tricalcium phosphate (α-TCP), hydroxyapatite (HAP), calcium-deficient hydroxyapatite, fluoroapatite, tetracalcium phosphate, and phosphoric acid. Any of octacalcium (OCP), calcium carbonate, calcium hydrogen phosphate anhydrate, calcium hydrogen phosphate dihydrate, TTCP, calcium diphosphate, calcium metaphosphate, and carbonate-substituted hydroxyapatite (CHA) Preferably there is.

  The fine particles have a smaller particle size (for example, several tens of μm) than the core particles. Similar to the core particles, the fine particles are also made of an organic material that burns at a temperature lower than the firing temperature in the particle firing step SA3. As the fine particles, for example, beads made of polymethyl methacrylate are suitable. As fine particles, organic polymers such as nylon, polypropylene, polyvinyl chloride, ABS resin, acrylic resin, cellulose, or carbon beads may be used.

  In the coating step SA1, as shown in FIGS. 2 (a) and 2 (b), the mixture is sprayed onto the core particle 2 to form the mixture layer 3 that covers the entire outer surface of the core particle 2. . Spraying of the mixture is performed, for example, by using a tumbling fluidized coating apparatus and spraying the slurry containing the mixture toward the core particles 2 while stirring the powdered core particles 2 in the air by an air flow. The slurry may contain a binder (binder). By using the rolling fluidized coating apparatus, the individual core particles 2 can be uniformly coated with the mixture while preventing aggregation of the core particles 2.

  The thickness of the mixture layer 3 depends on the amount of the mixture sprayed onto the core particles 2 and is preferably 10 μm or more. By setting the thickness of the mixture layer 3 to 10 μm or more, it is possible to give the medical ceramic hollow particles high strength that can withstand the processing in the manufacturing process of the medical ceramic porous body. Furthermore, the medical ceramic hollow particle 1 without a defect can be manufactured by setting the thickness of the mixture layer 3 to 10 μm or more. When the thickness of the mixture layer 3 is less than 10 μm, a part of the medical ceramic hollow particles 1 tends to be deficient.

The mixing ratio of the ceramic raw material and the fine particles in the mixture (the weight of the ceramic raw material: the weight of the fine particles) is preferably 1:10 to 10: 1.
By doing in this way, the intensity | strength of a medical ceramic hollow particle and formation of the communicating hole 5 can be made compatible. When the weight of the ceramic raw material is less than 10% of the weight of the fine particles, the strength of the medical ceramic hollow particles is lowered. On the other hand, when the weight of the fine particles is less than 10% of the weight of the ceramic raw material, the communication holes 5 are hardly formed.
In the coating step SA1, ceramics may be coated using other methods. For example, ceramics may be coated while incorporating other particles on the surface of the particles by a fluid mixing type composite device or a surface modification device.

  Next, in the transpiration step SA2, the core particle 2 on which the mixture layer 3 is formed is heated to a temperature lower than the calcination temperature in the particle calcination step SA3 and the organic material composing the core particle 2 and the fine particles 4 is combusted. To do. Thereby, as shown in FIG. 2C, the core particles 2 are removed by transpiration, and cavities (pores) are formed inside the mixture layer 3. The diameter of this cavity is equal to the particle size of the core particle 2. Further, the fine particles 4 are removed by evaporation in the mixture layer 3, and a microcavity (pore) is formed in the mixture layer 3. The pore size of the microcavity is equal to the particle size of the fine particles 4.

  Next, in the particle firing step SA3, the hollow spherical mixture layer 3 is heated to the firing temperature of the ceramic raw material to fire the mixture layer 3. Thereby, as shown in FIG. 2D, hollow spherical medical ceramic hollow particles 1 made of ceramics are manufactured. In the ceramic layer constituting the medical ceramic hollow particle 1, a communication hole 5 is formed in which spherical microcavities having a diameter substantially equal to the particle diameter of the fine particles 4 are connected. At this time, the maximum firing temperature is desirably 500 ° C. to 1500 ° C., but 800 ° C. to 1300 ° C. is more preferable for the shape retention of the hollow particles and the stability of the composition. Note that the evaporation step SA2 for hollowing and the particle firing step SA3 for forming the communication holes 5 may be performed simultaneously in a single step.

  When the drug is held in the cavity of the medical ceramic hollow particle 1, the drug is gradually released from the inside to the outside of the medical ceramic hollow particle 1 through the communication hole 5. The sustained release rate of the drug at this time depends on the thickness of the ceramic layer and the hole diameter of the communication hole 5.

  According to this embodiment, the thickness of the ceramic layer is determined according to the amount of the mixture sprayed onto the core particle 2 in the coating step SA1. Therefore, the thickness of the ceramic layer can be accurately and easily controlled by adjusting the spray amount of the mixture. Furthermore, the hole diameter of the communication hole 5 is determined according to the particle diameter of the fine particles 4. Therefore, the hole diameter of the communication hole 5 can be accurately and easily controlled by the particle diameter of the fine particles 4 to be used. Thereby, there exists an advantage that the medical ceramic hollow particle 1 which exhibits the desired sustained release rate of a chemical | medical agent can be manufactured easily.

  Further, the hollow diameter of the medical ceramic hollow particle 1 is substantially equal to the particle diameter of the core particle 2. Therefore, the cavity diameter formed in the medical ceramic hollow particle 1 can be easily controlled by the particle diameter of the core particle 2 to be used, and the medical ceramic hollow particle 1 having an arbitrary cavity diameter can be manufactured. There is an advantage that you can. Furthermore, the amount of drug that can be held by the medical ceramic hollow particles 1 is determined according to the cavity diameter. Therefore, there exists an advantage that the quantity of the chemical | medical agent which the medical ceramic hollow particle 1 hold | maintains can be controlled.

In this embodiment, it is preferable to further include a calcining step of firing (calcining) the ceramic raw material at a temperature lower than the firing (main firing) temperature in the particle firing step SA3 before the coating step SA1.
The ceramic raw material contained in the mixture layer 3 shrinks during the firing process. By using the calcined ceramic raw material, shrinkage of the mixture layer 3 in the main firing is reduced. Thereby, the cavity diameter, communicating hole diameter, thickness, and particle diameter of the medical ceramic hollow particles 1 can be controlled more accurately.

Next, the manufacturing method of the medical ceramic porous body which concerns on this embodiment using the medical ceramic hollow particle 1 is demonstrated with reference to FIG.
As shown in FIG. 3, the method for producing a medical ceramic porous body according to the present embodiment is a mixing step in which the medical ceramic hollow particles 1 produced in steps SA1 to SA3 are mixed with a main material to obtain a mixture. SB1, a molding step SB2 for obtaining a molded body by pressure molding the mixture obtained in the mixing step SB1, and a molded body firing step SB3 for firing the molded body.

  The main raw material is a powder containing a ceramic raw material. The ceramic raw material in the main raw material may be the same as or different from the ceramic raw material of the medical ceramic hollow particle 1. When a material having higher strength than the ceramic raw material of the medical ceramic hollow particle 1 is used as the main ceramic raw material, the strength of the medical ceramic porous body can be improved.

In the mixing step SB1, the medical ceramic hollow particles 1 and the main raw material are mixed.
Next, in the molding step SB2, the mixture is filled in a mold and uniaxial pressure molding is performed. Thereafter, the obtained molded body may be further pressurized by a cold isostatic press (CIP).
Next, a ceramic body for medical use is manufactured by firing the compact in the compact firing step SB3.

  In the ceramic porous body, medical ceramic hollow particles 1 are dispersed and contained. Therefore, pores composed of cavities of the medical ceramic hollow particles 1 are formed in the medical ceramic porous body. When such a medical ceramic porous body is transplanted into the body, osteoblasts enter into the pores, and bone formation is performed using the medical ceramic porous body as a scaffold. Thereby, the bone can be regenerated.

In this case, by using the medical ceramic hollow particles 1 whose cavity diameter, communication hole diameter, particle diameter and thickness are accurately controlled, the pore diameter, porosity, strength and artificial bone of the medical ceramic porous body There is an advantage that the function can be accurately controlled.
Further, β-TCP or HAP constituting the medical ceramic hollow particle 1 has a characteristic that bone replacement is performed by the action of osteoclasts and osteoblasts, but the mechanical strength is small. Therefore, by using a material having higher strength than β-TCP or HAP as the main raw material, a medical ceramic porous body having high strength and high bone forming ability can be produced.

Next, the Example of the manufacturing method of a medical ceramic hollow particle is demonstrated.
FIG. 4 shows the system used in this embodiment. As shown in FIG. 4, the present system includes a container 20 for storing the HAP slurry 10, a weigh scale 30 for measuring the weight of the container 20, and a tumbling fluidized coating apparatus (MP-01, manufactured by POWREC Co., Ltd.). ) 40 and a pump 50 for feeding the slurry 10 from the container 20 to the rolling fluid coating apparatus 40. The weigh scale 30 is for measuring the supply amount of the slurry 10 to the rolling fluidized coating apparatus 40.

As the fine particles, polymethyl methacrylate (PMMA) beads having a particle diameter of 20 μm were used. FIG. 5 shows a scanning electron microscope (SEM) photograph of the PMMA beads.
As the core particles, polystyrene (PS) beads having a particle size of 100 μm to 400 μm were used. FIG. 6 shows an SEM photograph of PS beads.

  The slurry was prepared by mixing a mixture of HAP powder and PS beads at a weight ratio of 1: 1 with purified water and HPC-L (8% aqueous solution). HPC-L (hydroxypropylcellulose) is a binder. HAP used was pre-calcined at 880 ° C.

(Coating step)
PS beads were introduced into a tumbling fluidized coating apparatus. Next, the slurry was supplied into a tumbling fluidized coating apparatus, and the slurry was sprayed on PS beads at 80 ° C. FIG. 7 shows a scanning microscope (SEM) photograph of PS beads coated with the mixture.

(Transpiration step / Particle firing step)
Next, PS beads and PMMA beads were evaporated and the HAP layer was baked by heating the PS beads coated with the mixture at a high temperature. Specifically, as shown in FIG. 8, PS beads and PMMA beads are evaporated by heating for a total of 42 hours while increasing the temperature from room temperature to 250 ° C., 300 ° C., 450 ° C., and a hollow spherical HAP layer Was generated. Next, the generated HAP layer was cooled to room temperature, then heated from room temperature to 1150 ° C., and the HAP layer was baked at 1150 ° C. for 1 hour. Thereby, HAP hollow particles were obtained.

FIG. 9 shows an SEM photograph of the obtained HAP hollow particles. As shown in FIG. 9, a large number of micropores were confirmed on the surface of the HAP hollow particles.
FIG. 10 shows a cross section of the HAP hollow particles taken by destroying the HAP hollow particles of FIG. As can be seen from FIG. 10, the HAP layer in the HAP hollow particles was confirmed to have communication holes formed by continuous microcavities having a pore diameter substantially equal to the particle diameter of the PMMA beads.

DESCRIPTION OF SYMBOLS 1 Medical ceramic hollow particle 2 Core particle 3 Mixture layer 4 Fine particle SA1 Coating step SA2 Evaporation step SA3 Particle baking step SB1 Mixing step SB2 Molding step SB3 Molded body baking step

Claims (7)

A coating step of coating the surface of the core particles with a mixture of ceramic raw material and fine particles having a particle size smaller than the core particles;
A transpiration step of heating the core particles coated with the mixture to evaporate the core particles and the fine particles to obtain hollow spherical particles made of the mixture;
A method for producing hollow ceramic particles for medical use, comprising a particle firing step for firing the hollow spherical particles.   The method for producing medical ceramic hollow particles according to claim 1, wherein a main component of the ceramic raw material is a calcium phosphate compound.   The main component of the ceramic raw material is β-type tricalcium phosphate (β-TCP), α-type tricalcium phosphate (α-TCP), hydroxyapatite (HAP), calcium-deficient hydroxyapatite, fluoroapatite, and tetraphosphate. Of calcium, calcium phosphooctanoate (OCP), calcium carbonate, calcium hydrogen phosphate anhydrate, calcium hydrogen phosphate dihydrate, TTCP, calcium diphosphate, calcium metaphosphate, and carbonate-substituted hydroxyapatite (CHA) The method for producing hollow ceramic ceramic particles according to claim 2.   The method for producing medical ceramic hollow particles according to any one of claims 1 to 3, wherein a layer of the mixture having a thickness of 10 µm or more is formed in the covering step.   The method for producing hollow medical ceramic particles according to any one of claims 1 to 4, wherein a mixing ratio of the ceramic raw material and the fine particles is 1:10 to 10: 1.   The medical ceramic hollow particle according to any one of claims 1 to 5, further comprising a calcination step of heating the ceramic raw material at a temperature lower than a firing temperature in the particle firing step before the coating step. Production method. A mixing step of mixing medical ceramic hollow particles produced by the method for producing medical ceramic hollow particles according to any one of claims 1 to 6 and a ceramic raw material to obtain a mixture;
A molding step of molding the mixture obtained by the mixing step to obtain a molded body;
A method for producing a porous ceramic body for medical use, comprising a molded body firing step for firing the molded body.