JPH1129374A - Composite sphere ceramic - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a bone filler that can develop bone adhesion to or bone substitution with neonatal bones, when the bone defective part is filled with the ceramic balls without dissipation, by dropping the powdery starting material to an ultra-low temperature medium to form spherical ceramics and subjecting the resultant spherical ceramics to hydrothermal treatment to form a composite lamination. SOLUTION: The powdery starting material, preferably calcium phosphate prepared by the wet process is mixed with, for example, water and polyvinyl alcohol under agitation to form a slurry. Then, the slurry is dripped into ultra low temperature medium and the resultant frozen product is dried in a vacuum freeze-drier, then sintered at, for example, 1,400 deg.C to form spherical ceramic particles. Then, the ceramic particles are charged in a heat-resistant sterilized bottle with a suitable amount of ion-exchanged water and they are treated with heat at 120 deg.C in a tightly sealed atmosphere. By the hydrothermal treatment, calcium phosphate, preferably of high purity are precipitated in crystal forms on the surface of the spherical ceramics thereby forming the objective composite layer.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to the field of bioceramics such as bone filler or bone cement for medical or dental use and the field of spherical ceramics such as various adsorbent carriers.

[0002]

2. Description of the Related Art Spherical particles have applications in a wide range of fields such as the field of powder processing, catalyst carriers, etc.
As the spherical particles that can be supplied to the field, it is particularly preferable that the particles can be manufactured so that the particle size can be varied according to an order, and various substances can be functionally supported on the particles themselves, and It is what is desired. In the medical field,
With the development of a so-called drug delivery system in which a drug is carried on particles and a drug is effectively released at a target site in the body, the characteristics of the particles themselves have come to attract attention. Further, the following can be pointed out for biomaterials.

[0003] Calcium phosphate has been widely applied in the fields of bone fillers and bone cement as a ceramic having excellent biocompatibility. As the shape to be applied, a crushable irregular shape, a block body, a porous body, a self-hardening cement and the like occupy the majority. In particular, some of the bone filling materials have a crushable irregular shape or a block shape, and some of them have been commercialized. JP-A-3-131580 and JP-A-1-314572 disclose a method for producing a porous block of calcium phosphate ceramics. In these methods, it is necessary to process the block at the time of surgery according to the shape of the bone defect. In addition, the implanted block is often dissipated or discharged outside the body before the block adheres to the new bone. In order to overcome this disadvantage, that is, to fix the granules to each other,
In JP-A-60-256460 and JP-A-60-256461, an attempt is made to use hibrin glue as a sizing agent. However, since hiblin glue is produced from human blood, there is a risk of infection with hepatitis, AIDS and the like. Also, JP-A-59-88351
Nos. 59 and 182263 disclose a method for producing a bone repair cement containing α-tricalcium phosphate or tetracalcium phosphate as a main component. In these methods, after hardening at the bone defect site, they are firmly fixed, so that living tissues and cells such as osteoblasts do not enter the inside of the filling material unlike the porous block. Accordingly, the bone replacement ability of the calcium phosphate porous block is superior.

[0004]

When a conventional granular bone filler or a porous calcium phosphate block is implanted in a bone defect, it is often dissipated before the bone is fused with the new bone. In addition, since bone cement is firmly fixed after hardening, the bone replacement ability is inferior to that of a porous calcium phosphate bone filler. Therefore, a granular bone filler or a porous calcium phosphate block capable of preventing anchoring or dissipation in a bone defect is preferable, and a bone filler having both actions of a bone filler and a bone cement has not been put to practical use. .

[0005]

SUMMARY OF THE INVENTION In view of the above, the present invention provides a simple and easy method for producing a spherical ceramic having a functional composite layer having physical properties different from those of the inside with the inside being porous and the outside being inside. And, more specifically, a bone filling material capable of rapidly expressing a new bone and an osseous adhesion or bone replacement action in a natural form without dissipating when filled into a bone defect, and a method for producing the same. I will provide a. The specific method is a known synthetic method, preferably high-purity calcium phosphate powder obtained by wet synthesis and dry synthesis, preferably hydroxyapatite, tricalcium phosphate,
After mixing the binder into tetracalcium phosphate, the mixture is molded by any method and fired at a temperature of 800 to 1500 ° C. to obtain a calcium phosphate ceramic having excellent biocompatibility. The molding can be easily performed by using a uniaxial pressing press, a rubber press or the like. In addition, it is possible to make the ceramic porous after firing by mixing a burnable substance into the binder. When the porous ceramic is embedded in a bone defect, an in-vivo tissue such as an osteoblast can easily enter, and the bone regeneration ability can be more suitably exhibited. However, its mechanical strength is poor, so care must be taken when using it.

[0006] The obtained porous or dense calcium phosphate ceramics and an appropriate amount of ion-exchanged water are put into a heat-resistant sterilization bottle, and kept at 80 to 150 ° C, preferably 100 to 120 ° C in a closed atmosphere.
For 30 minutes or more, preferably for 12 to 24 hours, to precipitate high-purity calcium phosphate crystals on the ceramic surface. Hereinafter, this method is referred to as hydrothermal treatment. These crystals are phosphoric acid and calcium eluted from the surface of the sintered body and reprecipitated on the ceramic surface. Therefore, extremely high-purity calcium phosphate crystals are deposited on the entire ceramic surface. Ceramics grow grains by firing, and the specific surface area rapidly decreases. However, it is possible to recover the specific surface area to some extent again by depositing crystals on the surface by the above method. Due to the increase in specific surface area, an anchoring effect can be obtained in vivo even when used as a bone filler in this state.

In the hydrothermal treatment according to the present invention, it is possible to precipitate crystals under steam using an autoclave in addition to the above method. More specifically, 80 to 150 ° C., preferably 100 to 150 ° C. in a closed steam atmosphere in an autoclave.
By heating at 120 ° C. for 30 minutes or more, preferably for 12 to 24 hours, high-purity calcium phosphate crystals are precipitated on the ceramic surface. In addition, in the method using a heat-resistant sterilization bottle and the method using an autoclave, the use of an aqueous solution in which ceramics are immersed and an aqueous solution containing ions such as calcium and phosphorus in a steam atmosphere shorten the hydrothermal treatment time and control the deposited layer. It is possible to do. In the hydrothermal treatment, the width of the deposited layer is controlled by the treatment time, the amount of pressurization, the pressurized temperature, the treatment atmosphere, and the like,
Specifically, bone filler, DDS carrier, dental root canal filler,
It can be appropriately selected depending on the use such as a ceramic adsorbent and a packing material for column chromatography. In order to further increase the anchoring effect, a method of coating bone cement on the surface of the bone filler without impairing the hardening function will be described below. A calcium phosphate ceramic having crystals precipitated on its surface is mixed with water or a hardening liquid and mixed with a bone cement which hardens. As the bone cement, α-tricalcium phosphate, tetracalcium phosphate, octacalcium phosphate, calcium sulfate, a cement in which these substances are arbitrarily mixed, and the like are preferable.

Further, the present invention is not limited to biomaterials, and it is particularly preferable that the fine particles having the composite layer, particularly porous fine particles, carry various substances on the porous portion. . After mixing, add an appropriate amount of ion-exchanged water and knead quickly. Then, the cement is instantly frozen in an ultra-low temperature medium such as liquid nitrogen or liquid helium or an ultra-low temperature atmosphere while the cement is not completely hardened. Bone cement has a large specific surface area, and when moisture adheres to the cement surface, crystal growth starts by a hydrolysis reaction. When the grown crystals are entangled with each other, they harden as bone cement. By mixing and kneading with the cement material, the bone cement taken into the gaps between the crystals precipitated on the ceramic surface can be instantaneously frozen, thereby stopping the crystal growth for hardening. Then, the bone cement and the bone filler which have been instantaneously frozen are freeze-dried. Freeze-drying can completely remove moisture while maintaining the specific surface area of the cement to some extent. Therefore, it is possible to classify the obtained dried product into a bone filler and cement, and then to function as a cement again.

[0009] Bone cement is taken into the gaps between the crystals reprecipitated on the surface of the bone filler. The incorporated bone cement is freeze-dried to secure a specific surface area required for hardening. Therefore, the bone filler according to the present invention is a bone filler having a surface coated with a hardenable bone cement,
When implanted in a bone defect, when it comes into contact with moisture, it is bonded to each other by the hardening action of the surface, and it is possible to effectively prevent the filler from dissipating after implantation. In addition, by making the core ceramics porous, it has the same bone replacement ability as the granular porous bone filler. As described above, a wide variety of agents are used as the agents to be carried, and the function of the surface is extremely remarkable because the re-deposition treatment adjusts the dissolution rate in the body. As described above, a good sustained-release product can be obtained by carrying various drugs.However, due to excellent long-term sustained-release properties, for example, penicillin antibiotics, tetracycline antibiotics, anticancer drugs FSU, carboplatin, Drugs such as sisplatin, aclarubicin hydrochloride, daunorubicin hydrochloride, neocarzinostatin, actinomycin D, peplomycin sulfate, pirarubicin hydrochloride, doxorubicin hydrochloride, bleomycin hydrochloride, bleomycin sulfate, and mitomycin are preferably used. The invention of the present application, in addition to the above, orally administered drugs, processed foods, beverages, various adsorption column materials, cosmetics,
Toothpastes, deodorants, deodorants, bath salts, facial cleansers, shampoos and other toiletries, textiles or paper materials with functionalities such as adsorption, etc. It can be used as a main material or a base material for various things such as a field to be used.

[0010]

【Example】

Example 1 1 g of calcium phosphate fine powder (# 400 mesh or less) having a Ca / P of 1.48 synthesized by a known wet synthesis method was mixed with 3 g of a 10 wt% aqueous solution of polyvinyl alcohol, and 0.5 g of ion-exchanged water was added. Stirred. The obtained slurry was filled in a 10 ml thermosyringe, and a 24G injection needle was used.
(With an inner diameter of 0.47 mm). After drying the obtained frozen material using a vacuum freeze dryer, 1400
Sintering was conducted at 5 ° C. for 5 hours to obtain 0.9 g of spherical ceramics. The resulting spherical ceramic had a diameter of 0.8 to 1.2 mm.
(Fig. 1 (a), (b)) Obtained spherical ceramic 0.9
g was placed in a heat-resistant sterilized bottle, and 50 g of ion-exchanged water was added thereto, followed by stoppering. Put this in a 120 ° C incubator for 1 hour,
Calcium phosphate crystals were deposited on the spherical ceramic surface. After drying in an incubator, the surface state was observed with a scanning electron microscope, and it was confirmed that calcium phosphate crystals of 10 to 20 μm were distributed over the entire circumference. (FIGS. 2A and 2B)

Example 2 A spherical ceramic having calcium phosphate crystals precipitated on the surface prepared in Experimental Example 1 was mixed with calcium sulfate powder, and an appropriate amount of ion-exchanged water was added to form a cement. After kneading for 1 minute, the cement was put into an eggplant-shaped flask and immersed in liquid nitrogen to instantaneously freeze the cement. Then, it was immediately dried using a freeze dryer. By using a rated sieve # 100 to remove excess calcium sulfate from the dried sample, a bone filler having calcium sulfate cement coated on its surface was obtained. (FIGS. 3A and 3B)

Example 3 In order to examine the hardened state of the bone filler prepared in Example 3, a hole having a diameter of about 4 mm was formed in a rib of an edible pork, and the hole was filled with the bone filler. About 1 hour after filling, the bone filler was completely cured, and it was impossible to remove the bone filler from the drilled hole. This experiment confirmed that the possibility of deviating from the affected area was extremely low when the bone defect was filled with the product of the present invention.

[0013]

According to the present production method, ceramic cement is coated on the surface of ceramic sintered granules having excellent biocompatibility, so that when implanted in a bone defect, the cement is hardened by a hydrolysis reaction and the ceramic sintering is performed. The granules are anchored in the bone defect. Therefore, the conventional granular bone filler has a problem that it is scattered from the bone defect, but the present invention solves this problem.

[Brief description of the drawings]

FIG. 1 is a scanning electron microscope photograph of a spherical ceramic of the present invention after immersion in a cooling medium in a manufacturing process.

FIG. 2 is a scanning electron microscope photograph after a hydrothermal treatment in the production process of the spherical ceramic of the present invention.

FIG. 3 is a scanning electron microscope photograph after cement coating in the production process of the spherical ceramic of the present invention.

Claims (5)

[Claims] 1. A composite spherical ceramic having a composite layer obtained by subjecting a starting material powder to dropping in an ultra-low temperature medium and subjecting the spherical ceramic to a hydrothermal treatment. 2. A composite spherical ceramic having a cement layer further coated with cement on the surface of the composite layer. 3. A material which can be used as a bone filler or other biorepair material, and which is subjected to hydrothermal treatment at a high temperature and a high pressure on a spherical ceramic obtained by dropping into an ultra-low temperature medium to precipitate crystals on its surface. And a method for producing a bone filler that exhibits an anchoring effect when implanted in an affected part. 4. The method for producing a bone filling material according to claim 3, wherein the bone filling material has an anchoring effect when implanted in an affected part by coating the surface with a bone cement. 5. The method of coating a bone filling material according to claim 4, wherein the cement hardened by crystal growth is flash frozen before crystal growth and freeze-dried to obtain a cement effect on the bone filler surface. A method for producing a bone filler, which provides uniform coating without any loss.