JP4080572B2 - Manufacturing method of bone filler - Google Patents

Description

[0001]
BACKGROUND OF THE INVENTION
The present invention relates to the field of bioceramics such as medical or dental bone filler or bone cement, and the field of spherical ceramics such as various adsorption carriers.
[0002]
[Prior art and its problems]
Spherical particles have applications in a wide range of fields such as powder processing fields, catalyst carriers, etc., so that spherical particles that can be supplied to the field can be manufactured with variable particle sizes according to orders, It is particularly preferable and desirable that various particles can be functionally supported on the particles themselves.
In the medical field, with the development of a so-called drug delivery system in which a drug is carried on a particle and the drug is effectively released at a target location in the body, the characteristics of the particle itself have been attracting attention.
Furthermore, the following points can be pointed out in biomaterials.
[0003]
As a ceramic having excellent biocompatibility, calcium phosphate has been widely applied in the fields of bone filler and bone cement. Most of the shapes when applied are crushing irregular shapes, block bodies, porous bodies, self-curing cements and the like. In particular, some of the bone fillers are in the form of fractured irregular shapes and block shapes. Japanese Patent Application Laid-Open Nos. 3-131580 and 1-314572 disclose a method for producing a porous block of calcium phosphate ceramics. In these methods, it is necessary to process the block during surgery in accordance with the shape of the bone defect. In addition, the embedded block body is often dissipated or discharged out of the body before bone-adhering to the new bone. To overcome this drawback, i.e., in order to fix the granules to each other, JP 60-256460, the same 60-256461 JP attempts have been made to use a full Iburin glue as sizing agent. However, full Iburin glue, because it is produced from human blood, there is a risk of infection hepatitis, AIDS and the like. JP-A-59-88351 and 59-182263 disclose a method for producing a bone repair cement mainly composed of α-tricalcium phosphate or tetracalcium phosphate. In these methods, since the bone defect portion is hardened after being hardened, living tissues such as osteoblasts and cells do not enter the filling material unlike the porous block. Therefore, the calcium phosphate porous block is superior in bone replacement ability.
[0004]
[Problems to be solved by the invention]
When a conventional granular bone filler or porous calcium phosphate block is embedded in a bone defect, it is often dissipated before bone adhesion with new bone. Moreover, since bone cement adheres densely after hardening, the bone replacement ability is inferior to that of porous calcium phosphate bone filler. Therefore, a granular bone filler or a porous calcium phosphate block that can prevent anchoring or dissipation in a bone defect is preferable, and a bone filler having both functions of a bone filler and a bone cement has not been put to practical use. .
[0005]
[Means for Solving the Problems]
In view of the above matters, the present invention is intended to easily and easily produce a spherical ceramic having a functional composite layer having a physical property different from that of the inside and the outer periphery being porous. The present invention provides a bone filler and a method for producing the same, in which a new bone and bone adhesion or bone replacement action are rapidly expressed in a natural manner without being dissipated when the bone defect is filled. The specific method is known synthetic methods, preferably a high-purity calcium phosphate powder obtained by wet synthesis and dry synthesis is preferably obtained by mixing hydroxyapatite, tricalcium phosphate, a binder tetracalcium phosphate The slurry is dropped into a cryogenic refrigerant such as liquid nitrogen to form a spherical body, which is then fired at a temperature of 800-1500 ° C.
Moreover, it is possible to make the ceramics porous after firing by mixing a burnable substance into the binder.
[0006]
Put the obtained porous or dense calcium phosphate ceramics and appropriate amount of ion-exchanged water in a heat-resistant sterilization bottle, and heat at 80 to 150 ° C, preferably 100 to 120 ° C for 30 minutes or more, preferably 12 to 24 hours in a sealed atmosphere By doing so, high purity calcium phosphate crystals are deposited on the surface of the spherical ceramic particles . Hereinafter, this method is referred to as hydrothermal treatment. This crystal is formed by reprecipitation of phosphoric acid and calcium eluted from the surface of the sintered body on the ceramic surface. Therefore, extremely high purity calcium phosphate crystals are deposited on the entire ceramic surface. Ceramics grow grains when fired, and the specific surface area rapidly decreases. However, it is possible to recover the specific surface area to some extent again by precipitating crystals on the surface by the above method. By increasing the specific surface area, it is possible to obtain an anchoring effect in vivo even if it is used as a bone filler in this state.
[0007]
In the hydrothermal treatment in the present invention, it is possible to precipitate crystals under water vapor using an autoclave other than the above method. More specifically, high-purity calcium phosphate crystals are precipitated on the ceramic surface by heating at 80 to 150 ° C., preferably 100 to 120 ° C. for 30 minutes or more, preferably 12 to 24 hours in a sealed water vapor atmosphere in the autoclave. . In addition, by using an aqueous solution in which ceramics are immersed in a method using a heat-resistant sterilization bottle and a method using an autoclave and an aqueous solution containing ions such as calcium and phosphorus in a water vapor atmosphere, the hydrothermal treatment time is shortened and the deposited layer is controlled. Is possible.
In the hydrothermal treatment, the width of the deposited layer is controlled by the processing time, pressurization amount, pressurization temperature, processing atmosphere, etc., specifically, bone filler, DDS carrier, dental root canal filler , Ceramic adsorbent, packing material for column chromatography and the like.
In order to further increase the anchoring effect, a method of coating the bone cement on the surface of the bone filler without impairing the hardening function will be described below. Calcium phosphate ceramics with crystals precipitated on the surface are mixed with water or a hardening cement by kneading with a hardening liquid. The bone cement is preferably α-tricalcium phosphate, tetracalcium phosphate, octacalcium phosphate, calcium sulfate, or a cement arbitrarily mixed with these substances.
[0008]
Furthermore, the present invention is not limited to biomaterials, and is particularly preferably fine particles having the composite layer, particularly porous fine particles, in which various substances are supported 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 in an ultra low temperature atmosphere before the cement is completely cured. Bone cement has a large specific surface area, and when moisture adheres to the cement surface, crystal growth starts by a hydrolysis reaction. The grown crystals are entangled with each other to be hardened as bone cement. It is possible to stop crystal growth for hardening by instantly freezing the bone cement taken into the gaps between the crystals deposited on the ceramic surface by mixing and kneading with the cement material. Then, the bone cement and bone filler that have been frozen at this moment are freeze-dried. Freeze-drying can completely remove moisture while retaining the specific surface area of the cement to some extent. Therefore, after the obtained dried product is classified into a bone filler and cement, it can function again as cement.
[0009]
Bone cement is taken into the gap between the crystals re-deposited on the surface of the bone filler. The incorporated bone cement has a specific surface area required for hardening by freeze-drying. Therefore, the bone filler according to the present invention is a bone filler whose surface is coated with a curable bone cement. When the bone filler is embedded in a bone defect portion, when it comes into contact with moisture, the bone filler is bonded to each other by the surface hardening action. It is possible to effectively prevent the filler from escaping. Moreover, by making the ceramic as the core porous, it has a bone replacement ability equivalent to that of the granular porous bone filler. As described above, a wide variety of drugs are used as the drug to be supported, and the dissolution rate in the body is adjusted as a result of the reprecipitation treatment, so that its functionality becomes extremely remarkable. As described above, good sustained-release products can be obtained by carrying various drugs, but due to excellent long-term sustained release properties, for example, penicillin antibiotics, tetracycline antibiotics, anticancer agents Five Syu, carboplatin, Drugs such as cisplatin, aclarubicin hydrochloride, daunorubicin hydrochloride, neocartinostatin, actinomycin D, pepromycin sulfate, pirarubicin hydrochloride, doxorubicin hydrochloride, bleomycin hydrochloride, bleomycin sulfate, mitomycin are preferably used .
[0010]
【Example】
Example 1
After mixing 1 g of calcium phosphate fine powder (# 400 mesh or less) of Ca / P = 1.48 synthesized by a known wet synthesis method into 3 g of a polyvinyl alcohol 10 wt% aqueous solution, 0.5 g of ion-exchanged water was added and further mixed and stirred. The obtained slurry was filled in a Terumo syringe 10 ml and dropped onto liquid nitrogen using an injection needle 24G (inner diameter 0.47 mm). The obtained frozen product was dried using a vacuum freeze dryer and then sintered at 1400 ° C. for 5 hours to obtain 0.9 g of spherical ceramics. The obtained spherical ceramics had a diameter of 0.8 to 1.2 mm. (Fig. 1 (a), (b))
0.9 g of the obtained spherical ceramics was placed in a heat-resistant sterilization bottle, and 50.times. Ion-exchanged water was added and the stopper was plugged. This was placed in an incubator at 120 ° C. for 1 hour to precipitate calcium phosphate crystals on the spherical ceramic surface. When the surface state was observed with a scanning electron microscope after drying in an incubator, it was confirmed that 10-20 μm calcium phosphate crystals were distributed over the entire circumference. (Fig. 2 (a), (b))
[0011]
Example 2
Spherical ceramics on which calcium phosphate crystals were deposited on the surface produced in Experimental Example 1 and calcium sulfate powder were mixed, and an appropriate amount of ion-exchanged water was added to form a cement. Then, after kneading for 1 minute, this cement was put into an eggplant-shaped flask and immersed in liquid nitrogen to freeze the cement instantaneously. Thereafter, it was quickly dried using a freeze dryer. The dried sample was screened using a rated sieve # 100 to remove excess calcium sulfate, and a bone filler having a surface coated with calcium sulfate cement was obtained. (Fig. 3 (a), (b))
[0012]
Example 3
In order to examine the hardening state of the bone filler prepared in Example 3, a hole having a diameter of about 4 mm was drilled in a rib of an edible pig, and the hole was filled with the bone filler. About 1 hour after filling, the bone filler was completely hardened, and it was impossible to remove the bone filler from the drilled hole. From this experiment, it was confirmed that when the bone defect part was filled with the bone filler, the possibility of deviating from the affected part was extremely low.
[0013]
【The invention's effect】
In this manufacturing method, ceramic cement is coated on the surface of the ceramic sintered granule with excellent biocompatibility, so that when cemented into the bone defect, the cement is hardened by a hydrolysis reaction, and the ceramic sintered granule is transformed into the bone defect. Anchor to Therefore, the conventional granular bone filler has a problem of being dissipated from the bone defect, but the present invention solves this problem.
[Brief description of the drawings]
FIG. 1 is a scanning electron micrograph after immersion in a refrigerant in the production process of a spherical ceramic of the present invention.
FIG. 2 is a scanning electron micrograph after hydrothermal treatment in the production process of the spherical ceramic of the present invention.
FIG. 3 is a scanning electron micrograph after cement coating in the production process of the spherical ceramic of the present invention.

Claims (4)

A slurry containing calcium phosphate fine powder is dripped into an ultra-low temperature refrigerant to form a frozen material, freeze-dried and fired, and then subjected to hydrothermal treatment to precipitate calcium phosphate crystals on the surface, and the surface is further hydroset bone cement. A method for producing a bone filler, which is prepared by freezing an ultra-low temperature refrigerant coated with lyophilized and then freeze-dried. The method for producing a bone filler according to claim 1, wherein the calcium phosphate fine powder is # 400 mesh or less. The bone filler manufacturing method according to claim 1, wherein the spherical calcium phosphate ceramics are porous. The method for producing a bone filler according to claim 1, wherein the calcium phosphate fine powder is synthesized by a wet method.

Images