JPH10158075A - Production of ceramics - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a ceramics capable of freely controlling its particle size or pore diameter, excellent in carrying property for a medicine, affinity to a live body, sustained release property for a medicine and absorption property for live body and useful as a bone filler and a sustained release carrier for medicine by dropping a ceramic material onto a low temp. medium to freeze-dry the material and then sintering. SOLUTION: The ceramics consisting preferably of calcium phosphate, more preferably of hydroxyapatite, tricalcium phosphate, calcium secondary phosphate, tetracalcium phosphate, octacalcium phosphate or the mixture thereof is pulverized, for example, preferably to <=100μm particle size. Then the ceramic material is mixed with a binder slurry (such as PVA soln.) and dropped onto a low temp. medium (such as liquid nitrogen) to freeze while its spherical shape is maintained. The frozen material is dried to remove the water content while preventing defrosting, and further sintered at 800 to 1,500 deg.C, preferably 1,000 to 1,400 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing ceramics, and more particularly to a field of porous ceramics for use as a bone filler or a DDS carrier.

[0002]

2. Description of the Related Art Conventionally, calcium phosphate has been widely applied as a ceramic having excellent biocompatibility in the fields of bone filler and bone cement. 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. As an application example of this calcium phosphate, its use for a DDS carrier has recently attracted attention. For example, JP-A-60-1
No. 06449 discloses a method in which flammable beads are coated with calcium phosphate, and the flammable beads are burned out to eliminate the flammable beads.
A method for producing a sustained-release drug carrier by filling the hollow portion with a drug is disclosed. Also, JP-A-59-101145
Japanese Patent Application Publication No. JP-A-2003-133873 discloses a method for producing a carrier having the same effect by impregnating a drug into porous calcium phosphate having open pores. However, the above-mentioned method complicates the manufacturing process, such as injecting a drug into the hollow beads. Also, it is difficult to appropriately control the sustained release rate of the drug. Similarly, in the method described later, there are concerns about problems such as complicated production steps and difficulty in controlling the sustained release rate. On the other hand, spherical calcium phosphate has been applied as a column packing material for liquid chromatography. As a production method, a spray drying granulation method is generally used. The spray drying granulation method is generally used for producing particles having a particle diameter of 100 μm or less, and when producing particles having a particle diameter larger than this, a huge apparatus is required. Also, 100μ
As a method for producing a spherical calcium phosphate having a diameter of m or more, a ceramic slurry is injected into an oil phase in JP-A-64-75030, and a W / O emulsion is formed. A method is disclosed in which the oil phase is eliminated by firing to produce spherical calcium phosphate. However, for use as a bone filler, 100μ
m or more is preferable. In order to produce the particles by the spray drying granulation method, capital investment is required and the cost increases. Also,
The method disclosed in JP-A-64-75030 requires a production step such as adjustment of an oil phase, and there is a concern about an increase in cost.

[0003]

In order to be applied to DDS, it is necessary to have excellent drug carrying properties, biocompatibility, sustained drug release properties, and bioabsorbability. Calcium phosphate has excellent biocompatibility and bioabsorbability, and has been actively studied for application to DDS, but has not yet been put to practical use. One of the reasons is that it is difficult to process because it is a ceramic. In order to carry the drug, it is necessary to make it porous, but it is difficult to change conditions such as size, strength and pore distribution. Further, from the viewpoint of improving the filling rate and operability in the affected part, it is preferable that the DDS carrier and the bone filler are spherical, but they have not yet been put to practical use because processing into a spherical shape is extremely difficult.

[0004]

SUMMARY OF THE INVENTION In view of the above, the present invention provides a technique for easily processing a calcium phosphate ceramic which is difficult to process into a spherical shape. In addition, this spherical ceramic has the optimal pores and bioabsorbability for DDS, and can be one of effective treatments for cancer and bone tumors by impregnating the drug and administering it to the affected area .

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION A detailed description of the present invention will be given below. Known synthesis methods, preferably wet or dry synthesis,
Calcium phosphate, preferably hydroxyapatite, tricalcium phosphate, dicalcium phosphate, tetracalcium phosphate, octacalcium phosphate,
Calcium phosphate glass A mixture of these calcium phosphates, more preferably tricalcium phosphate, is made into a powder, preferably 100 microns or less, using a crusher or a spray dryer. A binder slurry to this powder, preferably a water-soluble cellulose derivative, polyvinyl alcohol,
Polyacrylic acid, polyacrylamide, polyvinylpyrrolidone, polyethylene glycol, one or more aqueous solutions of starch, etc., more preferably polyvinyl alcohol, 3 to 15 wt% aqueous solution of polyethylene glycol, 1 to 5 times the weight of the powder, preferably Is stirred and mixed after adding 2 to 4 times. At this time, the same result can be obtained by using a 10 to 50 wt% calcium phosphate slurry other than the powder. Examples of the ceramic in the present invention include alumina, zirconia, carbon, and the like, in addition to the above-described calcium phosphate ceramics.

The above-mentioned binder is merely an example, and other additives such as glycols may be added as a stabilizer depending on the use mode. If the binder is not porous, the binder may not necessarily be required. The obtained binder-containing calcium phosphate slurry is filled in a cylinder, and a capillary tube attached to the end of the cylinder, preferably an inner diameter of 0.3 to 2 mm, a low-temperature refrigerant solution of about -10 ° C. or less prepared in advance, preferably liquid nitrogen , Liquid helium, acetone + dry ice, methanol + dry ice, ethyl ether + dry ice. The dropped binder-containing calcium phosphate slurry becomes spherical during the drop and on the liquid nitrogen liquid level, and can be frozen while maintaining the spherical shape. The obtained frozen product is freeze-dried so as not to be thawed, and water is completely removed. The spherical calcium phosphate thus obtained is heated to 800 to 1500 ° C. using an electric furnace, preferably 1000 to 140 ° C.
Sintering at 0 ° C. gives spherical ceramics. The diameter of the ceramic powder obtained by the production method is 0.1 to 10 mm, but can be variously adjusted depending on the contact mode such as the dripping condition. In the present invention, the ceramic solution may be brought into contact with the low-temperature refrigerant, and the contact mode is as follows.
Various types, other than dripping, spraying with an atomizer typified by a spray dryer, pressurized spraying by spraying, pouring, flowing, and contacting the whole container when introduced into another container, etc. Is exemplified.

[0007] In this spherical ceramics, fine pores formed when the binder evaporates are formed in the entire spherical shape.
It is possible to impregnate the inside of the ceramics with a chemical or the like from these small holes. Also, the diameter of the small holes can be changed by the content of the binder. Further, since the pores can be closed with a known calcium phosphate cement or other synthetic resin, it is possible to control the sustained release rate. The sustainability of the sustained release in the body can be sustained in a body fluid, for example, in a unit of several days or weeks, more specifically, in one week to three weeks due to its uniform porosity. Similar persistence is obtained. And
By filling the spherical ceramic into the bone defect portion, the ostium, which is one of the features of the spherical ceramic, does not block the blood flow, so that the bone can be regenerated at an early stage. It is more effective to impregnate these pores with drugs such as bone morphogenetic factors, collagen, and antibiotics. In addition to the above, the invention of the present application has functions of orally administered drugs, processed foods, beverages, various adsorption column materials, cosmetics, dentifrices, deodorants, deodorants, bath salts, face wash agents, shampoos and other toiletry articles, adsorption and the like. Fiber or paper materials, etc.
It can be used as a main material or a base material of various things such as a field that requires sustained release of a loaded material. As described above, a good sustained-release product can be obtained by carrying various drugs, but with an excellent long-term sustained-release property, for example, penicillin antibiotics, tetracycline antibiotics, anticancer drugs Five S, carboplatin, Drugs such as sisplatin are preferably used.

[0008]

【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.

Example 2 The spherical ceramic produced in Experimental Example 1 was observed with a scanning electron microscope (SEM). Two types of observation methods were used: the sample surface and the sample cross section. As a result, it was confirmed that small holes of 1 to 4 micrometers were distributed on the entire surface of the sample. And from the cross section SEM observation image, there is a hole of 100 to 200 micrometers inside the spherical ceramic,
It was confirmed that the surrounding area was occupied by mosaic calcium phosphate. (Fig. 1 ・ a, b and Fig.2 ・ a, b)

Example 3 After the spherical ceramic produced in Example 1 was immersed in red ink, it was evacuated for about 10 minutes. After returning to vapor pressure,
Excess ink was wiped off and dried with a vacuum freeze dryer. When this sample was cut at the center, it was confirmed that the red ink had penetrated into the ceramic. Therefore, it is possible to easily impregnate the drug by only vacuum degassing for a short time.

[0011]

According to the present manufacturing method, ceramics having a freely controlled particle size and pore size can be manufactured in a simple and short time. Therefore, when used as a bone filler, it has the effect of promoting bone regeneration without blocking blood flow in the bone. Further, by impregnating a bioabsorbable ceramic with a drug, it becomes an ideal drug sustained release carrier.

[Brief description of the drawings]

FIG. 1 is a scanning electron micrograph of the surface of a porous ceramic powder shown in Examples.

FIG. 2 is a scanning electron micrograph of a cross section of the porous ceramic powder shown in the examples.

Continued on the front page (51) Int.Cl. ⁶ Identification code FI F26B 5/06 F26B 5/06

Claims (5)

[Claims] 1. A method for producing a ceramic obtained by dropping a ceramic on a low-temperature refrigerant, freeze-drying and sintering. 2. The method for producing ceramics according to claim 1, wherein said ceramics is calcium phosphate, preferably hydroxyapatite, tricalcium phosphate, dicalcium phosphate, tetracalcium phosphate, octacalcium phosphate, or a mixture of these calcium phosphates. . 3. A drug sustained-release body obtained by making the ceramics porous and impregnating the pores with a drug. 4. The drug sustained-release body according to claim 3, wherein after the porous ceramic is impregnated with a drug, the drug sustained release time obtained by closing the impregnated portion with the ceramic can be controlled. 5. A method for producing ceramics, comprising bringing a ceramic solution into contact with a low-temperature refrigerant.