U.S. patent application number 09/944999 was filed with the patent office on 2002-01-17 for process for producing ceramics.
This patent application is currently assigned to KABUSHIKI KAISHA ADVANCE. Invention is credited to Arai, Takehiko, Umezu, Yoshikazu.
Application Number | 20020006427 09/944999 |
Document ID | / |
Family ID | 26512541 |
Filed Date | 2002-01-17 |
United States Patent
Application |
20020006427 |
Kind Code |
A1 |
Umezu, Yoshikazu ; et
al. |
January 17, 2002 |
Process for producing ceramics
Abstract
Spherical-shape ceramics obtained by dropping starting ceramics
into a low temperature medium or composite spherical-shape ceramics
having a composite layer obtained by applying a hydrothermal
treatment thereto.
Inventors: |
Umezu, Yoshikazu;
(Tokorozawa-shi, JP) ; Arai, Takehiko; (Tokyo,
JP) |
Correspondence
Address: |
CHRISTIE, PARKER & HALE, LLP
350 WEST COLORADO BOULEVARD
SUITE 500
PASADENA
CA
91105
US
|
Assignee: |
KABUSHIKI KAISHA ADVANCE
|
Family ID: |
26512541 |
Appl. No.: |
09/944999 |
Filed: |
August 31, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09944999 |
Aug 31, 2001 |
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09308607 |
May 20, 1999 |
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09308607 |
May 20, 1999 |
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PCT/JP97/04288 |
Nov 25, 1997 |
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Current U.S.
Class: |
424/423 ;
264/653 |
Current CPC
Class: |
A61L 27/10 20130101;
A61L 27/12 20130101; A61L 27/54 20130101; C04B 38/009 20130101;
A61K 9/1611 20130101; A61L 27/12 20130101; C04B 2111/00836
20130101; A61L 27/54 20130101; A61L 27/10 20130101; C04B 35/447
20130101; A61L 27/54 20130101; C04B 38/009 20130101; C04B 40/0078
20130101 |
Class at
Publication: |
424/423 ;
264/653 |
International
Class: |
A61F 002/00; C04B
033/30 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 25, 1996 |
JP |
8-328012 |
Jul 11, 1997 |
JP |
9-201033 |
Claims
1. A process for producing ceramics comprising dropping a starting
ceramics into a low temperature medium, followed by freeze drying
and then sintering the same.
2. A process for producing ceramics as claimed in claim 1, wherein
the ceramics is calcium phosphate, tricalcium phosphate, calcium
dihydrogenphosphate, tetracalcium phosphate, octacalcium phosphate,
and a mixture of these calcium phosphates.
3. A sustained drug release product obtained by forming the
ceramics obtained according to claim 1 or 2 into a porous product,
followed by impregnating the pores with a drug.
4. A sustained drug release product as claimed in claim 3, wherein
after the drug is impregnated into the porous ceramics, the
impregnated parts are plugged by said ceramics, whereby the
sustained release time of the drug is controlled.
5. A process for producing ceramics, wherein a ceramics solution is
brought into contact with a low temperature medium.
6. A composite spherical ceramics having a composite layer obtained
by dropping a powder of a starting material into a low temperature
medium and applying a hydrothermal treatment to the spherical-shape
ceramics obtained.
7. A composite spherical-shape ceramics having a composite layer as
claimed in claim 6, further having a cement layer obtained by
coating the surface of the composite layer with a cement.
8. A process for producing a bone filler, comprising dropping a
material capable of using, as a bone filler or other biorepair
material, into a low temperature medium and applying a hydrothermal
treatment to the spherical-shape ceramics thus obtained under a
high temperature and high pressure so as to precipitate crystal on
the surface, whereby an anchoring effect can be obtained at the
time of implantation in a diseased portion.
9. A process for producing a bone filler as claimed in claim 8,
wherein the surface is coated with a bone cement so as to give the
anchoring effect when implanting the filler into a diseased
portion.
10. A process for producing a bone filler as claimed in claim 9,
wherein the coating method of the bone filler comprises
instantaneously freezing a cement to be settable by crystal growth,
before the crystal growth, followed by freeze drying to thereby
homogeneously coat the surface of the bone filler without impairing
the effect of the cement.
Description
TECHNICAL FIELD
[0001] The present invention relates to a process for producing
ceramics, more specifically relates to a process for producing
porous ceramics suitable for use as a bone filler or a DDS carrier.
The present invention further relates to composite spherical-shape
ceramics suitable for use as a medical or dental bone filler or
bone cement or other bioceramic material or various resorbable
carriers etc.
BACKGROUND ART
[0002] In the past, as ceramics having superior biocompatibility,
in the field of bone fillers and bone cement, calcium phosphate has
been broadly used. The forms at the time of use have mostly been
splinter-powder (break to powder), blocks, porous substances,
self-setting cements, etc. In particular, in bone fillers, some
splinter-powder (break to powder) and blocks have been
commercialized.
[0003] As an example of application of calcium phosphate, recently
attention has been made to the use for DDS carriers. For example,
Japanese Unexamined Patent Publication (Kokai) No. 60-106459
discloses a process for producing a sustained drug release type
carrier comprising coating combustible beads with calcium phosphate
and then sintering them to cause the combustible beads to burn away
and leave hollow beads of calcium phosphate, then filling a drug
into the hollow portions. Further, Japanese Unexamined Patent
Publication (Kokai) No. 59-101145 discloses a process for producing
a carrier having a similar effect by impregnating a drug into
porous calcium phosphate having open pores.
[0004] However, in the above processes, the production steps, such
as the injection of the drug into the hollow beads, becomes
complicated. Further, it is difficult to control the rate of
sustained release of the drug. In the latter process as well,
similarly there is a concern over problems such as the complexity
of the production steps and the difficulty of control of the rate
of sustained release.
[0005] On the other hand, spherical-shape calcium phosphate is used
as a column filler for liquid chromatography. The general
production process is a spray drying granulation method. The spray
drying granulation method is generally used for the production of
particles having a particle size of 100 .mu.m or less. An extremely
large-sized apparatus is required when producing larger particles.
Further, as a process for producing spherical-shape calcium
phosphate having a size of 100 .mu.m or more, Japanese Unexamined
Patent Publication (Kokai) No. 64-75030 discloses a process
comprising injecting a ceramics slurry into an oil phase to form a
water-in-oil emulsion, then injecting this again into a water phase
to solidify the oil phase, followed by sintering to burn off the
oil phase, whereby spherical-shape calcium phosphate is
obtained.
[0006] However, for use as a bone filler, particles having a size
of 100 .mu.m or more are desirable. Capital investment is required
for producing this by the spray drying granulation method, and
therefore, the costs are increased. Further, in the process
disclosed in Japanese Unexamined Patent Publication (Kokai) No.
64-75030, production-steps for adjusting the oil phase etc. become
necessary, and therefore, there are again concerns of increased
cost.
[0007] An application for DDS requires a superior drug carrying
property, biocompatibility, sustained drug release, and
biodegrarative. Calcium phosphate is superior in biocompatibility
and resorption in the living body or organism. In the past,
considerable research went into its application for DDS, but
nothing has been commercialized yet. One of the reasons is that,
since it is ceramics, it is hard to process. Porosity has to be
imparted in order to carry a drug, but it is difficult to change
conditions such as the size, strength, distribution of pores, etc.
Further, from the viewpoint of the rate of filling in the diseased
location or operability, it is desirable that DDS carriers and bone
fillers be spherical. Since it is extremely difficult to process
ceramics into spheres, this has not yet been commercialized.
[0008] Spherical-shape particles have applications in a broad range
of fields such as processing powders and carrying catalysts, so
that the spherical-shape particles which can be supplied to these
fields, it is particularly preferable or sought to produce them in
a manner enabling the particle size to be changed in depending upon
the order and to enable the particles themselves to functionally
carry various substances.
[0009] In the medical field, the properties of the particles
themselves have come under focus along with the development of drug
delivery systems which use particles to carry a drug and
effectively release the drug at the desired location in the
organism.
[0010] Further, in biomaterials as well, calcium phosphate is being
broadly used in the fields of bone fillers and bone cement as
ceramics superior in biocompatibility. The shapes at the time of
use are mostly splinter-powder (break to power), blocks, porous
substances, self-setting cement, etc. In particular, in bone
fillers, some splinter-powder (break to powder) or blocks have been
commercialized.
[0011] Japanese Unexamined Patent Publication (Kokai) Nos. 3-131580
and 1-314572 disclose processes of preparation of a porous block of
calcium phosphate ceramics. In these processes, it is necessary to
shape the block at the time of surgery to match the shape of the
bone loss. Further, the implanted block member is often scattered
or ejected from the organism before the fusion with the newly grown
bone.
[0012] To overcome this problem, that is, to cause the granules to
fix with each other, Japanese Unexamined Patent Publication (Kokai)
Nos. 60-256460 and 60-256461 attempt to use a fibrin paste as a
glue. However, a fibrin paste is produced from human blood,
therefore had the risk of infection by hepatitis, AIDS, etc.
[0013] Further, Japanese Unexamined Patent Publication (Kokai) No.
59-88351 and No. 59-182263 disclose processes for producing a bone
repair cement having .alpha.-tricalcium phosphate or tetracalcium
phosphate as its main ingredient. In these processes, the cement
cures at the bone loss portion, then fixes to it densely, so
osteoblasts and other tissue and cells will not enter the inside of
the filler such as with a porous block. Therefore, the bone
substitution ability of a calcium phosphate porous block is
superior.
[0014] The conventional granular bone filler or porous calcium
phosphate block often scatters before fusion with the newly grown
bone when implanted in a bone loss portion. Further, the bone
cement is inferior in bone substitution capability compared with a
porous calcium phosphate bone filler due to the fact that it fixes
densely after curing. Therefore, a granular bone filler or porous
calcium phosphate block capable of achieving anchoring or
preventing scattering at the bone loss portion is preferred. No
bone filler having both the functions of a bone filler and bone
cement has yet been commercialized.
DISCLOSURE OF THE INVENTION
[0015] Accordingly, an object of the present invention is to
provide a technique for easily processing a hard-to-process calcium
phosphate ceramics into a spherical shape, whereby an effective
means of treatment of cancer or bone tumors by impregnation of a
drug and administration to the diseased portion is provided, since
the spherical-shape ceramics has pores and a resorption in the
organism optimal for DDS.
[0016] Another object of the present invention is to enable the
simple and easy production of spherical-shape ceramics having a
functional composite layer having a porous inside and having an
outer periphery with different physical properties from the inside,
more particularly, to provide a bone filler which enables fusion
with newly grown bone or bone substitution action quickly in a
natural manner, without scattering, when filled in a bone loss
portion and a process of production of the same.
[0017] In accordance with the present invention, there is provided
a process for producing ceramics by dropping starting ceramics into
a low temperature medium, followed by freeze drying and, then
sintering.
[0018] In accordance with the present invention, there is further
provided composite spherical-shape ceramics having a composite
layer obtained by dropping a starting material powder into a low
temperature medium applying a hydrothermal treatment to the
resultant spherical-shape ceramics.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] The present invention will now be explained in detail with
reference to the drawings.
[0020] FIGS. 1(a) and 1(b) are scanning-type electron micrographs
of the surface of porous ceramics powder shown in Example I-2
(100.times. and 1000.times., respectively).
[0021] FIGS. 2(a) and 2(b) are scanning-type electron micrographs
of the sliced cross-section of porous ceramics powder shown in
Example I-2 (100.times. and 1000.times., respectively).
[0022] FIGS. 3(a), 3(b), 3(c), 3(d), 3(e), 3(f), 3(g), 3(h), 3(i),
and 3(j) are scanning-type electron micrographs showing the mode of
dissolution along with time of the porous ceramics shown in Example
I-4 in ion exchange water.
[0023] FIGS. 4(a) and 4(b) are scanning-type electron micrographs
of the frozen sliced cross-section of porous ceramics shown in
Example I-5 (1000.times. and 3000.times., respectively).
[0024] FIG. 5 is a graph of the results of Example I-6.
[0025] FIGS. 6(a) and 6(b) are scanning-type electron micrographs
after immersion in a refrigerant in the production process of the
spherical-shape ceramics of the present invention (150.times. and
1000.times., respectively).
[0026] FIGS. 7(a) and 7(b) are scanning-type electron micrographs
after the hydrothermal treatment in the process of production of
the spherical-shape ceramics of the present invention (150.times.
and 1000.times., respectively).
[0027] FIGS. 8(a) and 8(b) are scanning-type electron micrographs
after cement coating in the process of production of the
spherical-shape ceramics of the present invention (150.times. and
1000.times., respectively).
BEST MODE FOR CARRYING OUT THE INVENTION
[0028] A first embodiment of the present invention will now be
explained.
[0029] Calcium phosphate synthesized by a known synthesis method,
preferably wet synthesis or dry synthesis, preferably
hydroxyapatite, tricalcium phosphate, calcium dihydrogenphosphate,
tetracalcium phosphate, octacalcium phosphate, calcium phosphate
glass, or mixtures thereof calcium phosphates, more preferably
tricalcium phosphate, is made into a powder, preferably not more
than 100 microns, using a pulverizer or spray dryer etc. Into this
powder is added, stirred, and mixed a binder slurry, preferably, an
aqueous solution of one or more of a water-soluble cellulose
derivative, polyvinyl alcohol, polyacrylic acid, polyacrylamide,
polyvinyl pyrrolidone, polyethylene glycol, and starch, more
preferably a 3 to 15% by weight aqueous solution of polyvinyl
alcohol or polyethylene glycol in an amount of 1 to 5 times,
preferably 2 to 4 times, of the weight of the powder. At this time,
a similar result can be obtained even if using a 10 to 50% by
weight slurry of calcium phosphate other than the powder.
[0030] As the ceramics in the present invention, in addition to the
above-mentioned calcium phosphate ceramics, alumina, zirconia,
carbon, etc. may be mentioned.
[0031] The above-mentioned binders are merely examples. In
addition, additives may sometimes be added depending upon the mode
of use etc., for example, a glycol may be added as a stabilizing
agent. Further, if not a porous state, the binder may not be
necessary.
[0032] The calcium phosphate slurry obtained containing a binder is
filled into a cylinder and is dropped from a thin tube attached to
the front end of the cylinder, preferably having an inner diameter
of 0.3 to 2 mm, into a low temperature refrigerant solution
prepared in advance and having a temperature of about -10.degree.
C. or less, preferably, liquid nitrogen, liquid helium, acetone+dry
ice, methanol+dry ice, or ethyl ether+dry ice.
[0033] The dropped calcium phosphate slurry containing the binder
becomes spherical shape during its fall and at the surface of the
liquid nitrogen and can be frozen, while maintaining the spherical
shape.
[0034] The frozen slurry obtained is freeze-dried so as not to thaw
and to completely remove the moisture. The spherical-shape calcium
phosphate thus obtained is sintered using an electric furnace at
800.degree. C. to 1500.degree. C., preferably 1000.degree. C. to
1400.degree. C., to obtain the spherical-shape ceramics.
[0035] The diameter of the ceramics powder obtained by this
production process is 0.01 to 10 mm, but can be adjusted in various
ways by the mode of contact such as the dropping conditions.
[0036] In the present invention, it is sufficient to bring the
ceramics solution into contact with a low temperature refrigerant.
Various modes of contact are possible, but other than the dropping,
spraying by an atomizer such as a spray dryer, pressurized spraying
by a spray, contact with a container in by injection, pouring, and
other means of introduction into a container, etc. may be
mentioned.
[0037] The spherical-shape ceramics has fine pores formed at the
time of evaporation of the binder over the spheres as a whole. A
drug etc. may be impregnated into the ceramics from these pores.
Further, the diameter of the pores may be varied by the content of
the binder. Further, since the pores can be plugged by a known
calcium phosphate cement or other synthetic resin etc., control of
the rate of sustained release is possible.
[0038] Due to the uniform porosity, the sustainability of the
sustained release in the orgnism is, for example, units of several
days or several weeks in the body fluids, more specifically for one
week to three weeks. A similar sustainability can be obtained in
the body tissue as well.
[0039] Therefore, by filling this spherical-shape ceramics into a
portion of bone loss, since the pores, one of the features of this
spherical-shape ceramics, do not block the flow of blood, it is
possible to quickly regenerate the bone. Further, the effect can be
enhanced further by impregnating the pores with bone-growth
factors, collagen, antibiotics, and other drugs.
[0040] The present invention, in addition to the above, may be used
as a main material or additive etc. for various products such as
orally administered drugs, processed foods, beverages, various
adsorption column materials, cosmetics, dentifrices, fumigants, air
fresheners and deodorizing agents, bath additives, facial
cleansers, shampoos, and other toiletries, fibers having adsorption
or other functions or paper materials and other fields requiring
adsorption and sustained release of the carried substances.
[0041] In this above way, a good sustained release drug can be
obtained by carrying various drugs. Due to the superior sustained
release, for example, penicillin type antibiotics, tetracycline
type antibiotics, the anticancer drugs 5FU, carboplatin, cisplatin,
etc. are preferably used.
[0042] The specific production process of composite spherical-shape
ceramics according to the second aspect of the present invention
comprises mixing a binder into a high purity calcium phosphate
powder obtained by a known synthetic method, preferably wet
synthesis and dry synthesis, preferably a hydroxyapatite,
tricalcium phosphate, or tetracalcium phosphate, then shape the
mixture by any method and sinter it at a temperature of 800 to
1500.degree. C. to obtain a calcium phosphate ceramics superior in
biocompatibility. As the method of shaping, a monoaxial press,
rubber press, etc. may be used for easy shaping. Further, by mixing
a burn-off substance in the binder, it is possible to make the
ceramics porous after sintering. Porous ceramics facilitate the
entry of osteoblasts and other tissue in the organism and a bone
regenerating capability to be exhibited more suitably, when
implanted in a bone loss portion. However, since the dynamic
strength is poor, it is necessary to pay close attention at the
time of use.
[0043] The porous or dense calcium phosphate ceramics obtained, and
a suitable amount of ion exchange water are placed in a heat
resistant sterile bottle and heated in a sealed atmosphere at
80.degree. C. to 150.degree. C., preferably 100.degree. C. to
120.degree. C., for at least 30 minutes, preferably 12 to 24 hours
to cause high purity calcium phosphate crystal to precipitate on
the surface of the ceramics (hereinafter this technique is called
"hydrothermal treatment"). The crystal is comprised of the
phosphoric acid and calcium eluted from the surface of the sintered
product reprecipitating on the surface of the ceramics. Therefore,
an extremely high purity calcium phosphate crystal precipitates
over the entire surface of the ceramics. The particles of ceramics
grow by the sintering and the specific surface area rapidly drops.
However, by using the above process to cause crystals to
precipitate on the surface, the specific surface area can be
restored to a certain extent again. By increasing the specific
surface area, it is possible to obtain an anchoring effect in the
organism even if used as a bone filler in this state.
[0044] The hydrothermal treatment in the present invention may be
performed by causing crystal to precipitate in steam using an
autoclave in addition to the above technique. More specifically,
this consists of heating the mixture under a sealed steam
atmosphere in an autoclave at 80.degree. C. to 150.degree. C.,
preferably 100.degree. C. to 120.degree. C., for at least 30
minutes, preferably 12 to 24 hours so as to cause high purity
calcium phosphate crystal to precipitate on the surface of the
ceramics. Further, in the process using a heat resistant sterilize
bottle or the process using an autoclave, it is possible to reduce
the hydrothermal treatment time and control the precipitated layer
by using an aqueous solution for impregnated with the ceramics and
an aqueous solution containing calcium, phosphate, or other ions in
a steam atmosphere.
[0045] In this hydrothermal treatment, the width of the
precipitated layer is controlled by the treatment time, amount of
pressure, pressurizing temperature, treatment atmosphere, etc.
Specifically, it may be suitably selected depending upon the
application such as the bone filler, DDS carrier, dental root canal
filler, ceramics adsorbent, column chromatography filler, or other
application.
[0046] The coating method of a cement on the surface of a bone
filler, without impairing, the setting (or curing) function, to
enhance the anchoring effect is explained below. The calcium
phosphate ceramics with crystal precipitated on the surface thereof
is mixed with a bone cement which cures by kneading with water and
a setting (or curing) solution. As the bone cement,
.alpha.-tricalcium phosphate, tetracalcium phosphate, octacalcium
phosphate, calcium sulfate, or any mixture thereof is preferable as
the cement.
[0047] Further, the present invention is not limited in
biomaterials. Any fine particles having the composite layer, in
particular porous fine particles, which can be made to carry
various substances in the porous portions are particularly
preferred.
[0048] After mixing, a suitable amount of ion exchange water is
added and quickly kneaded. The cement is instantaneously frozen in
liquid nitrogen, liquid helium, or another super-low temperature
medium or super-low temperature atmosphere before the cement
completely sets (or cures). A bone cement has a large specific
surface area. The crystal growth starts by a hydrolysis reaction
when moisture adheres to the cement surface. By mixing and kneading
this with a cement material, the bone cement in the intervals of
the crystals precipitated on the surface of the ceramics can stop
the crystal growth due to the setting by the instantaneous
freezing. The instantaneously frozen bone cement and bone filler
are then freeze-dried. The freeze-drying can completely remove the
moisture while maintaining the specific surface area of the cement
to a certain extent. Therefore, it is possible to separate the
dried product obtained into the bone filler and cement, then cause
it to function as cement again.
[0049] Bone cement is taken into the intervals of the crystal
reprecipitated on the surface of the bone filler. The bone cement
taken in secures the specific surface area required for setting due
to the freeze-drying. Therefore, the bone filler according to the
present invention is a bone filler coated on the surface thereof
with a setting type bone cement. When implanted in a bone loss
portion, it can bond with the portion by the setting action of the
surface and effectively prevent the bone filler from scattering
after implantation. Further, by making the core ceramics porous,
there is the same bone substitution ability as a granular porous
filler.
[0050] As explained above, as the drug carried, a broad range of
drugs can be used. Further, since the surface is treated by
reprecipitation, the rate of dissolution in the organism is
adjusted, therefore the function becomes extremely marked.
[0051] A good sustained release drug is obtained by carrying
various drugs. Due to the superior sustained release, for example,
penicillin type antibiotics, tetracycline type antibiotics, the
anticancer drugs 5FU, carboplatin, cisplatin, acrarubicin
hydrochloride, daunorubicin hydrochloride, neocartinostatin,
acutinomycin D, pepromycin sulfate, piralbicin hydrochloride,
doxorubicin hydrochloride, bleomycin hydrochloride, bleomycin
sulfate, mitomycin, and other drugs may be suitably used.
[0052] In the second embodiment of the present invention as well,
in addition to the above, the present invention may be used as a
main material or substrate etc. for various products such as orally
administered drugs, processed foods, beverages, various adsorption
column materials, cosmetics, dentifrices, fumigants, air fresheners
and deodorizing agents, bath additives, facial cleansers, shampoos,
and other toiletries, fibers having adsorption or other functions
or paper materials and other fields requiring adsorption and
sustained release of the carried substances.
EXAMPLES
[0053] The present invention will be explained in more detail with
reference to Examples, but the present invention is of course not
limited to these Examples in scope.
Example I-1
[0054] 1 g of calcium phosphate powder (#400 mesh or less) having
Ca/P=1.48 synthesized by a known wet synthesis method was mixed
into 3 g of a 10% by weight aqueous solution of polyvinyl alcohol,
then 0.5 g of ion exchange water was added and the mixture further
mixed and stirred. 10 ml of the slurry obtained was filled into a
thermosyringe and a 24G needle (inner diameter 0.47 mm) was used to
drop it into liquid nitrogen. The frozen product obtained was dried
using a vacuum freeze dryer, then was sintered at 1400.degree. C.
for 5 hours to obtain 0.9 g of spherical-shape ceramics. The
spherical-shape ceramics obtained had a diameter of 0.8 to 1.2 mm.
Powder X-ray measurement confirmed that the spherical-shape
ceramics was a single phase of .alpha.-tricalcium phosphate.
Example I-2
[0055] The spherical ceramics prepared in Example I-1 was observed
by a scanning-type electron microscope (SEM). The sample was
observed by two types of methods: the surface of the sample and the
sliced section of the sample. As a result, the surface of the
sample was observed to have pores of 1 to 4 .mu.m distributed over
its entire surface. Further, the SEM image of the sliced section
showed that there were pores of 100 to 200 .mu.m inside the
spherical-shape ceramics. It was confirmed that there was a mozaic
structure of calcium phosphate around it. (See FIGS. 1(a) and 1(b)
and FIGS. 2(a) and 2(b).)
Example I-3
[0056] The spherical ceramics prepared in Example I-1 was immersed
in red ink, then deaerated under vacuum for about 10 minutes. This
was returned to ordinary pressure, then the excess ink was wiped
off and the sample dried by freeze-drying in vacuum. The sample was
sliced at its center portion, whereupon it was confirmed that the
red ink had penetrated to the inside of the ceramics. Therefore, it
is possible to easily impregnate a drug by just a short period of
vacuum deaeration.
Example I-4
[0057] The spherical-shape porous ceramics prepared in Example I-1
was immersed in 50 ml of ion exchange water for 1 hour, 1 day, 3
days, 7 days, and 14 days and the form of dissolution was observed
over time by a scanning-type electron microscope. The obtained
electron micrographs are shown in FIG. 3(a) (1 hour, 500.times.),
3(b) (1 hour, 1000.times.), 3(c) (1 day, 500.times.), 3(d) (1 day,
1000.times.), 3(e) (3 days, 500.times.), 3(f) (3 days,
1000.times.), 3(g) (7 days, 500.times.), 3(h) (7 days,
1000.times.), 3(i) (14 days, 500.times.), and 3(j) (14 days,
1000.times.). The sample was a spherical-shape porous ceramics for
a drug carrier superior in resorption in the body.
[0058] As a result, it was confirmed that the spherical-shape
porous ceramics quickly dissolved and the state of dissolution
occurred with units of clump of grain peeling off in a plate shape.
A similar trend may be seen in the body as well. This material was
shown to be a material which is finally completely resorbed while
releasing the drug.
Example I-5
[0059] The spherical-shape porous ceramics prepared in Example I-1
was immersed in a dispersion of fine hydroxyapatite particles and
subjected to ultrasonic waves, while being vacuum deaerated. Then,
the sample was frozen and sliced and observed under a scanning-type
electron microscope.
[0060] As a result, fine hydroxyapatite particles were filled in
the fine pores of spherical-shape porous ceramics. Hydroxyapatite
has a superior absorbing action. It is possible to have the fine
hydroxyapatite particles impregnated and absorb a drug. If the fine
hydroxyapatite particles are administered into the body in this
state, the absorbed drug becomes immediately released and there is
no sustained drug release effect. Therefore, by filling the fine
pores of the spherical-shape porous ceramics with fine
hydroxyapatite particles impregnated with and absorbing the drug,
it is possible to obtain a sustained release effect. (See FIGS.
4(a) and 4(b).)
Example I-6
[0061] As a simulation experiment for confirming the sustained drug
release effect, 10% by weight of fine hydroxyapatite particles was
mixed into a 10 mM aqueous Methyl Orange solution and stirred well.
This was filled into the fine pores of the spherical-shape porous
ceramics by the method shown in Example I-5. 0.2 g of the sample
filled in the fine pores was introduced into 200 ml of ion exchange
water, then the immersion solution was taken after a predetermined
time and the amount of elution of Methyl Orange was compared by the
absorbance by an ultraviolet spectrophotometer. As a control,
spherical-shape porous ceramics without the fine pores filled
immersed in a 10 mM aqueous Methyl Orange solution was used.
[0062] As a result, it was found that the sample having the filled
fine pores carried about three times the amount of Methyl Orange
compared with a sample not filled. Further, as a result of the
sustained release, the Methyl Orange could be released over an
approximately 10 times longer period. The possibility of obtaining
excellent therapeutic effects by replacing the Methyl Orange with
various types of antibiotics or antitumor preparations was
suggested (see FIG. 5).
Example II-1
[0063] 1 g of calcium phosphate powder (#400 mesh or less) having a
Ca/P=1.48 synthesized by a known wet synthesis method was mixed
into 3 g of a 10% by weight aqueous solution of polyvinyl alcohol,
then 0.5 g of ion exchange water was added and the mixture further
mixed and stirred. 10 ml of the slurry obtained was filled into a
thermosyringe and a 24G needle (inner diameter 0.47 mm) was used to
drop it into liquid nitrogen. The frozen product obtained was dried
using a vacuum freeze dryer, then this was sintered at 1400.degree.
C. for 5 hours to obtain 0.9 g of spherical-shape ceramics. The
spherical-shape ceramics obtained had a diameter of 0.8 to 1.2 mm.
(See FIGS. 6(a) and 6(b).)
[0064] 0.9 g of the spherical-shape ceramics obtained was inserted
into a heat resistant sterile bottle, then 50 ml of ion exchange
water was added and the bottle corked. This was placed in a
120.degree. C. incubator for 1 hour to make calcium phosphate
crystal precipitate on the surface of the spherical-shape ceramics.
This was dried in the incubator, then the surface condition was
observed by a scanning-type electron microscope, whereupon it was
confirmed that 10 to 20 .mu.m calcium phosphate crystals were
distributed over the entire surface. (See FIG. 7(a) and 7(b).)
Example II-2
[0065] Spherical-shape ceramics on the surface of which calcium
phosphate crystal was precipitated, prepared in Example II-1, and
calcium sulfate powder were mixed and then a suitable quantity of
ion exchange water was added to create a cement-like state. This
was kneaded for 1 minute, then the cement was filled into an
eggplant-shaped flask which was then immersed in liquid nitrogen to
instantaneously freeze the cement. Then, this was quickly dried
using a freeze dryer. The dried sample was passed through a rated
sieve #100 to remove the surplus deposited calcium sulfate to coat
calcium sulfate cement on the surface and obtain a bone filler.
(See FIGS. 8(a) and 8(b).)
Example II-3
[0066] To investigate the state of curing of the bone filler
prepared in Example II-2, a hole of a diameter of about 4 mm was
bored into the rib of a hog and the bone filler was filled in the
hole. After about 1 hour after filling, the bone filler completely
set and it became impossible to withdraw the bone filler from the
hole. This experiment confirmed the low possibility of the product
of the present invention detaching from the diseased portion when
filled in a portion of bone loss.
INDUSTRIAL APPLICABILITY
[0067] As explained above, according to the present invention, it
is possible to produce ceramics freely controlled in particle size
and pore size simply and in a short time. Therefore, when used as a
bone filler, there is the effect of promoting bone regeneration,
without blocking the flow of blood in the bone. Further, by
impregnating a drug in the resorbable ceramics, an ideal sustained
drug release carrier is obtained.
[0068] According to the present invention, by coating a ceramic
cement on the surface of ceramics with a superior biocompatibility,
the cement sets by a hydrolysis reaction when implanted at the bone
loss portion and anchors the ceramics sintered granules in the bone
loss portion. Therefore, while past granular bone fillers had
suffered from the problem of scattering from the bone loss portion,
this problem has been solved by the present invention.
* * * * *