U.S. patent application number 11/129066 was filed with the patent office on 2005-12-08 for injectable calcium phosphate cements and the preparation and use thereof.
This patent application is currently assigned to Calcitec, Inc.. Invention is credited to Chen, Wen-Cheng, Chern Lin, Jiin-Huey, Ju, Chien-Ping.
Application Number | 20050271742 11/129066 |
Document ID | / |
Family ID | 35446277 |
Filed Date | 2005-12-08 |
United States Patent
Application |
20050271742 |
Kind Code |
A1 |
Chern Lin, Jiin-Huey ; et
al. |
December 8, 2005 |
Injectable calcium phosphate cements and the preparation and use
thereof
Abstract
A calcium phosphate cement suitable for use in dental and bone
prosthesis is disclosed, which include calcium phosphate particles
having a diameter of 0.05 to 100 microns, wherein said calcium
phosphate particles on their surfaces have whiskers or fine
crystals having a width ranging from 1 to 100 nm and a length
ranging from 1 to 1000 nm.
Inventors: |
Chern Lin, Jiin-Huey;
(Winnetka, IL) ; Ju, Chien-Ping; (Carbondale,
IL) ; Chen, Wen-Cheng; (Tainan Hsien, TW) |
Correspondence
Address: |
MEYERTONS, HOOD, KIVLIN, KOWERT & GOETZEL, P.C.
P.O. BOX 398
AUSTIN
TX
78767-0398
US
|
Assignee: |
Calcitec, Inc.
|
Family ID: |
35446277 |
Appl. No.: |
11/129066 |
Filed: |
May 13, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11129066 |
May 13, 2005 |
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10414582 |
Apr 16, 2003 |
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10414582 |
Apr 16, 2003 |
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09615384 |
Jul 13, 2000 |
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10414582 |
Apr 16, 2003 |
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10328019 |
Dec 26, 2002 |
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6840995 |
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10328019 |
Dec 26, 2002 |
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09351912 |
Jul 14, 1999 |
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6379453 |
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Current U.S.
Class: |
424/602 ;
433/217.1 |
Current CPC
Class: |
A61P 19/00 20180101;
A61L 24/001 20130101; C04B 28/346 20130101; Y10T 428/2991 20150115;
A61K 33/42 20130101; A61K 6/17 20200101; C04B 12/02 20130101; C04B
28/34 20130101; C04B 28/344 20130101; A61K 6/891 20200101; Y10T
428/2993 20150115; A61K 6/864 20200101; C04B 14/366 20130101; C04B
22/064 20130101; C04B 22/064 20130101; C04B 40/0263 20130101; C04B
22/126 20130101; C08L 89/00 20130101; C04B 20/023 20130101; C04B
20/008 20130101; C04B 20/1014 20130101; C04B 20/008 20130101; C08L
89/00 20130101; C04B 40/0218 20130101; C04B 40/0272 20130101; C04B
20/023 20130101; C04B 20/1014 20130101; C04B 20/008 20130101; C04B
20/107 20130101; C04B 28/344 20130101; C04B 28/346 20130101; A61L
24/02 20130101; A61K 6/69 20200101; C04B 14/366 20130101; C04B
14/366 20130101; C04B 28/346 20130101; C04B 28/346 20130101; A61K
6/838 20200101; C04B 12/025 20130101; C04B 28/34 20130101; A61L
27/50 20130101; A61K 6/891 20200101; A61L 27/12 20130101; C04B
2111/00836 20130101; A61C 5/62 20170201; C04B 14/366 20130101 |
Class at
Publication: |
424/602 ;
433/217.1 |
International
Class: |
A61K 033/42; A61C
005/00 |
Claims
1-45. (canceled)
46. A system for repairing a defect in a tooth or in a bone of a
patient comprising: calcium phosphate cement particles that are
non-dispersive in an aqueous solution, wherein the diameter of the
calcium phosphate cement particles is from about 0.05 microns to
about 100 microns, wherein at least a portion of the calcium
phosphate cement particles have surface whiskers comprising basic
calcium phosphate crystals, and wherein the surface whiskers have a
width ranging from 1 to 100 nm and a length ranging from 1 to 1000
nm; an aqueous solution, the aqueous solution comprising a
hardening promoter; and an injector configured to inject a paste
formed by contacting the calcium phosphate cement particles with
the aqueous solution into the defect in the bone or in the
tooth.
47. The system of claim 46, wherein the calcium phosphate cement
particles comprise calcium dihydrogen phosphate, calcium dihydrogen
phosphate hydrate, acid calcium pyrophosphate, anhydrous calcium
hydrogen phosphate, tetracalcium phosphate, calcium hydrogen
phosphate hydrate, calcium pyrophosphate, calcium triphosphate,
calcium polyphosphate, calcium metaphosphate, anhydrous tricalcium
phosphate, tricalcium phosphate hydrate, apatite and
hydroxyapatite, or a mixture thereof.
48. The system of claim 46, wherein the calcium phosphate cement
particles comprise dicalcium phosphate anhydrous, tetracalcium
phosphate, tricalcium phosphate, or mixtures thereof.
49. The system of claim 46, wherein the aqueous solution further
comprises a growth factor, a bone morphology protein, a
pharmaceutical carrier, or mixtures thereof.
50. The system of claim 46, further comprising a growth factor, a
bone morphology protein, a pharmaceutical carrier, or mixtures
thereof.
51. The system of claim 46, wherein the hardening promoter
comprises phosphate ions, calcium ions, fluorine ions, or mixtures
thereof.
52. The system of claim 46, wherein hardening-promoter comprises
about 1 mM to about 3 M phosphate ions.
53. The system of claim 46, wherein the pH of the aqueous solution
is at least about 6.0.
54. The system of claim 46, wherein the calcium phosphate cement
particles have a diameter ranging from about 0.5 microns to about
50 microns, and wherein the whiskers or fine crystals have a length
ranging from 10 nm to about 700 nm.
55. The system of claim 46, wherein the calcium phosphate cement
particles have a calcium to phosphate molar ratio ranging from
about 0.5 to about 2.5.
56. The system of claim 46, wherein the calcium phosphate cement
particles have a calcium to phosphate molar ratio ranging from
about 0.8 to about 2.3.
57. The system of claim 46, wherein the calcium phosphate cement
particles have a calcium to phosphate molar ratio ranging from
about 1.0 to about 2.2.
58. A method of repairing a defect in a bone of a patient
comprising: contacting calcium phosphate cement particles with an
aqueous solution comprising a hardening-promoter to form a
non-dispersive, injectable paste; shaping the paste, wherein the
shaped paste is substantially complementary to the defect in the
bone; and implanting the shaped paste into the bone to repair the
defect; wherein the average diameter of the calcium phosphate
cement particles is from about 0.05 microns to about 100 microns,
wherein at least a portion of the calcium phosphate particles have
surface whiskers comprising basic calcium phosphate crystals, and
wherein the surface whiskers have a width ranging from 1 to 100 nm
and a length ranging from 1 to 1000 nm.
59. The method of claim 58, wherein the calcium phosphate cement
particles comprise calcium dihydrogen phosphate, calcium dihydrogen
phosphate hydrate, acid calcium pyrophosphate, anhydrous calcium
hydrogen phosphate, tetracalcium phosphate, calcium hydrogen
phosphate hydrate, calcium pyrophosphate, calcium triphosphate,
calcium polyphosphate, calcium metaphosphate, anhydrous tricalcium
phosphate, tricalcium phosphate hydrate, apatite and
hydroxyapatite, or mixtures thereof.
60. The method of claim 58, wherein the calcium phosphate cement
particles comprise dicalcium phosphate anhydrous, tetracalcium
phosphate, tricalcium phosphate, or mixtures thereof.
61. The method of claim 58, wherein the paste further comprises a
growth factor, a bone morphology protein, a pharmaceutical carrier,
or mixtures thereof.
62. The method of claim 58, wherein the hardening-promoter
comprises phosphate ions, calcium ions, fluorine ions, or mixtures
thereof.
63. The method of claim 58, wherein the aqueous solution comprises
about 1 mM to about 3 M of the hardening promoter.
64. The method of claim 58, wherein hardening-promoter comprises
phosphate ions.
65. The method of claim 58, wherein the pH of the aqueous solution
is at least about 6.0.
66. The method of claim 58, wherein the calcium phosphate cement
particles have a diameter ranging from about 0.5 microns to about
50 microns.
67. The method of claim 58, wherein the whiskers or fine crystals
have a length ranging from about 10 nm to about 700 nm.
68. The method of claim 58, wherein the calcium phosphate cement
particles have a calcium to phosphate molar ratio ranging from
about 0.5 to about 2.5.
69. The method of claim 58, wherein the calcium phosphate particles
have a calcium to phosphate molar ratio ranging from about 0.8 to
about 2.3.
70. The method of claim 58, wherein the calcium phosphate particles
have a calcium to phosphate molar ratio ranging from about 1.0 to
about 2.2.
71. The method of claim 58, wherein the setting time of the
injectable paste is adapted to be less than about 30 minutes.
72. The method of claim 58, wherein the working time of the
injectable paste is adapted to be less than about 25 minutes.
Description
RELATED APPLICATION
[0001] This application is a continuation-in-part and claims the
benefit of priority under 35 USC .sctn.120 of U.S. application Ser.
No. 09/615,384, filed Jul. 13, 2000. The disclosure of the prior
application is considered part of and is incorporated by reference
in the disclosure of this application.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention is related to a calcium phosphate
cement, and in particular a fast-setting calcium phosphate cement,
for use in dental and bone prosthesis.
[0004] 2. Description of the Related Art
[0005] A calcium phosphate cement (abbreviated as CPC) has been
widely used as an implant or filling material in dental and bone
prosthesis, and its technical details can be found in many patents,
for examples U.S. Pat. Nos. 4,959,104; 5,092,888; 5,180,426;
5,262,166; 5,336,264; 5,525,148; 5,053,212; 5,149,368; 5,342,441;
5,503,164; 5,542,973; 5,545,254; 5,695,729 and 5,814,681. In
general, the prior art calcium phosphate cements suffer one or more
drawbacks as follows: 1) additives having a relatively poor
bioactivity being required; 2) a complicated preparation process;
3) an undesired setting time or working time of CPC, which are
difficult to be adjusted; 4) not capable of being set to a desired
shape in water, blood or body fluid; and 5) poor initial strength
after setting of the CPC.
SUMMARY OF THE INVENTION
[0006] An object of the present invention is to provide a calcium
phosphate cement.
[0007] Another object of the present invention is to provide a
calcium phosphate cement comprising particles having whiskers or
fine crystals on surfaces of the particles. Still another object of
the present invention is to provide a process for preparing a
calcium phosphate cement.
[0008] A further object of the present invention is to provide a
method of treating a born or a tooth having a defect in a patient
by using a calcium phosphate cement.
[0009] In order to accomplish the above objects of the present
invention a calcium phosphate cement prepared in accordance with
the present invention comprises calcium phosphate particles having
a diameter of 0.05 to 100 microns, wherein said calcium phosphate
particles on their surfaces have whiskers or fine crystals having a
width ranging from 1 to 100 nm and a length ranging from 1 to 1000
nm. By adjusting the diameter of the calcium phosphate particles,
the width and/or the length of the whiskers or fine crystals, the
inventors of the present invention are able to adjust the working
time and/or the setting time of the calcium phosphate cement of the
present invention to conform to requirements for various purposes.
Moreover, the calcium phosphate cement of the present invention is
fast-setting, and is non-dispersive in water or an aqueous
solution.
BRIEF DESCRIPTION OF THE DRAWINGS
[0010] FIG. 1 is a normalized particle amount (%) versus particle
diameter (pm) plot showing a particle diameter distribution of a
calcium phosphate cement (CPC) prepared in accordance with the
following Example 6 of the present invention.
[0011] FIG. 2 is a scanning electron microscopy (SEM) micrograph of
the calcium phosphate cement prepared in accordance with Example 6
of the present invention.
[0012] FIGS. 3 and 4 show the distributions of the lengths and the
widths of the whiskers or fine crystals on surfaces of the calcium
phosphate particles prepared in the following Example 6 of the
present invention, respectively, which are determined directly from
transmission electron microscopy (TEM).
[0013] FIGS. 5a to 5c are photographs showing a conventional CPC
paste injected into water via a syringe at 3, 10 and 30 seconds
after the conventional CPC paste being formed.
[0014] FIGS. 6a to 6c are photographs showing a CPC paste of the
present invention injected into water via a syringe at 3, 10 and 30
seconds after the CPC paste being formed in accordance with the
following Example 7.
[0015] FIGS. 7a to 7c are photographs showing two cylinders
prepared by separately molding a conventional CPC paste and a CPC
paste of the present invention prepared in the following Example 7,
which were taken at 5, 20 and 60 seconds after the two cylinders
being immersed in the water.
[0016] FIG. 8 is a TEM micrograph showing the calcium phosphate
cement of the present invention prepared in the following Example
7.
[0017] FIG. 9 is a TEM micrograph showing the calcium phosphate
cement of the present invention prepared in the following Example
7.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0018] A suitable process for preparing the calcium phosphate
cement of the present invention comprises mixing a calcium
phosphate powder or small pieces of calcium phosphate with a
wetting agent, and controlling growth of whiskers or fine crystals
on surfaces of said calcium phosphate powder or small pieces of
calcium phosphate by an controlling treatment.
[0019] Suitable calcium phosphates for use as the calcium phosphate
powder or small pieces of calcium phosphate in the present
invention can be any known calcium phosphates such as calcium
dihydrogen phosphate, calcium dihydrogen phosphate hydrate, acid
calcium pyrophosphate, anhydrous calcium hydrogen phosphate,
calcium hydrogen phosphate hydrate, calcium pyrophosphate, calcium
triphosphate, calcium polyphosphate, calcium metaphosphate,
anhydrous tricalcium phosphate, tricalcium phosphate hydrate,
apatite, hydroxyapatite, a mixture thereof and an adduct thereof.
Moreover, the shape of the calcium phosphate powder and the shape
of the small pieces of calcium phosphate are not limited, which can
be spherical or irregular; and the crystal structure thereof can be
single crystal, polycrystal, mixed crystals, semi-crystal, or
amorphous.
[0020] The process for preparing the calcium phosphate cement
preferably further comprises grinding the resulting product from
the controlling treatment to form calcium phosphate particles
having a diameter of 0.05 to 100 microns, wherein said whiskers or
fine crystals have a width ranging from 1 to 100 nm and a length
ranging from 1 to 1000 nm.
[0021] Said controlling treatment is a vacuuming treatment, an
organic solvent treatment, a microwave treatment, a heating
treatment, or any other treatments which can control growth of
whiskers or fine crystals on surfaces of said calcium phosphate
powder or small pieces of calcium phosphate.
[0022] Said wetting agent is used to wet the calcium phosphate
powder or small pieces of calcium phosphate, and preferably is a
diluted aqueous solution containing phosphoric acid or phosphate.
The amount of said wetting agent mixed with the calcium phosphate
powder or small pieces of calcium phosphate, in general, should be
enough to wet substantially all the calcium phosphate powder or
small pieces of calcium phosphate. However, it is not necessarily
the case when said controlling treatment is the organic solvent
treatment, where a water miscible organic solvent is added to the
mixture of said wetting agent and said calcium phosphate powder or
small pieces of calcium phosphate to form a paste for a subsequent
processing step.
[0023] Preferably, said wetting agent is a diluted aqueous solution
containing more than 20 ppm of phosphoric acid or phosphate, more
preferably more than 50 ppm, and most preferably more than 100 ppm
of phosphoric acid or phosphate.
[0024] Preferably, the process for preparing the calcium phosphate
cement of the present invention comprises soaking said calcium
phosphate powder or said small pieces of calcium phosphate with
said diluted aqueous solution containing more than 100 ppm of
phosphoric acid or phosphate, and carrying out (a) said heating
treatment comprising drying the resulting soaked calcium phosphate
powder or soaked small pieces of calcium phosphate at a temperature
higher than 45.degree. C.; (b) said vacuuming treatment comprising
drying the resulting soaked calcium phosphate powder or soaked
small pieces of calcium phosphate under vacuum; or (c) said
microwave treatment comprising drying the resulting soaked calcium
phosphate powder or soaked small pieces of calcium phosphate by
microwave heating. More preferably, the resulting soaked calcium
phosphate powder or soaked small pieces of calcium phosphate is
well mixed to form a uniform mixture prior to being subjected to
treatment (a), (b) or (c).
[0025] Alternatively, the process for preparing the calcium
phosphate cement of the present invention comprises mixing said
calcium phosphate powder or said small pieces of calcium phosphate
with said diluted aqueous solution containing more than 100 ppm of
phosphoric acid or phosphate, and carrying out said organic solvent
treatment comprising mixing the mixture of said wetting agent and
said calcium phosphate powder or small pieces of calcium phosphate
with a water miscible organic solvent, and drying the resulting
mixture under vacuum. Preferably, said organic solvent treatment is
carried out while stirring, and more preferably, the mixture of
said diluted aqueous solution containing more than 100 ppm of
phosphoric acid or phosphate and said calcium phosphate powder or
small pieces of calcium phosphate is well mixed prior to being
subjected to said organic solvent treatment.
[0026] Preferably, said calcium phosphate particles of the calcium
phosphate cement of the present invention have a diameter of 0.2 to
80 microns, and more preferably 0.5 to 50 microns.
[0027] The width of a whisker means an average value of lateral
cross-sectional diameters of the whisker, and the width of a fine
crystal means an average value of the first 30% of the diameters of
the fine crystal, which are shorter than the other 70% thereof. The
length of a fine crystal means an average value of the last 30% of
the diameters of the fine crystal, which are longer than the other
70% thereof.
[0028] Preferably, said whiskers or fine crystals have a width
ranging from 2 to 70 nm and a length ranging from 5 to 800 nm, and
more preferably a length ranging from 10 to 700 nm.
[0029] Preferably, said calcium phosphate particles have a molar
ratio of calcium to phosphate ranging from 0.5 to 2.5, more
preferably 0.8 to 2.3, and most preferably 1.0 to 2.2.
[0030] The calcium phosphate cement of the present invention is
biocompatible and a paste made therefrom is non-dispersive in
water, which has a working time from several minutes to hours and a
setting time from a few minutes to hours. Consequently, the calcium
phosphate cement of the present invention is extremely suitable for
use as an implant or filling material in dental or bone prosthesis,
where the paste must contact water, blood or body fluid.
Particularly, the paste made from the calcium phosphate cement of
the present invention is able to be directly injected into a bone
defect or cavity as an implant or filling material.
[0031] The present invention also discloses a method of treating a
born or a tooth having a defect in a patient, comprising mixing the
calcium phosphate cement of the present invention and a
hardening-promoter-contai- ning aqueous solution to form a paste,
and a) injecting said paste into a bone defect or cavity of said
patient or b) shaping said paste and implanting the resulting
shaped paste into a bone defect or cavity of said patient.
[0032] In the method of the present invention, said calcium
phosphate cement may further comprise a growth factor, a bone
morphology protein or a pharmaceutical carrier, or said
hardening-promoter-containing aqueous solution further comprises a
growth factor, a bone morphology protein or a pharmaceutical
carrier.
[0033] Said hardening-promoter-containing aqueous solution can be
an aqueous solution comprising any known compounds or compositions
which enable the solidification of calcium phosphate, for examples
phosphates, calcium salts, and fluorides. That is said
hardening-promoter-containing aqueous solution may be an aqueous
solution comprising phosphate ions, calcium ions, fluorine ions, or
phosphate ions together with fluorine ions as a hardening
promoter.
[0034] The content of said hardening promoter in said
hardening-promoter-containing aqueous solution has no special
limitation, but preferably ranges from 1 mM to 3 M, and more
preferably from 10 mM to 1 M.
[0035] The mixing ratio of the calcium phosphate cement of the
present invention and said hardening-promoter-containing aqueous
solution is not restricted to any particular ranges; however, the
amount of said hardening-promoter-containing aqueous solution mixed
should be sufficient to provide substantial wetting of the calcium
phosphate cement of the present invention. It should be noted that
more water can be supplied in-situ from saliva or body fluid, when
the paste is injected or implanted into the bone defect or cavity.
Further, the content of said hardening promoter in said
hardening-promoter-containing aqueous solution should be adjusted
to a higher level corresponding to a less amount of said
hardening-promoter-containing aqueous solution being mixed.
EXAMPLE 1
Heating Treatment
[0036] 5 g of Ca(H.sub.2PO.sub.4).sub.2.H.sub.2O powder and 1.6 ml
of 25 mM phosphoric acid aqueous solution were mixed, and stirred
for one minute. The resulting mixture was placed into an oven at
50.degree. C. for 15 minutes, and the resulting dried mixture was
mechanically ground for 20 minutes to fine particles after being
removed from the oven. 1 g of the fine particles and 0.4 ml of
phosphate aqueous solution (1.0 M, pH=6.0) were mixed to form a
paste, which was tested every 30 seconds to determine the working
time and the setting time. The setting time is the time required
when a 1 mm diameter pin with a load of 1/4 pounds can be inserted
only 1 mm deep into the surface of the paste. The working time is
the time after which the paste is too viscous to be stirred. The
working time of the paste of this example is 30 minutes and the
setting time thereof is one hour.
[0037] The paste was placed in a relatively large amount of
deionized water immediately following the formation thereof, and it
was observed that the paste was non-dispersive in deionized
water.
EXAMPLE 2
Vacuuming Treatment
[0038] 5 g of CaHPO.sub.4 (DCPA) powder and 1.2 ml of 25 mM
phosphoric acid aqueous solution were mixed, and stirred for one
minute. The resulting mixture was placed in a vacuum environment of
-100 Pa for 30 minutes, and the resulting dried mixture was
mechanically ground for 20 minutes to fine particles. 1 g of the
fine particles and 0.4 ml of phosphate aqueous solution (1.0 M,
pH=6.0) were mixed to form a paste, which was tested every 30
seconds to determine the working time and the setting time. The
working time of the paste of this example is 20.5 minutes and the
setting time thereof is 24 minutes.
[0039] The paste was placed in a relatively large amount of
deionized water immediately following the formation thereof, and it
was observed that the paste was non-dispersive in deionized
water.
EXAMPLE 3
Organic Solvent Treatment
[0040] 5 g of CaHPO.sub.4 (DCPA) powder and 1.6 ml of 25 mM
phosphoric acid aqueous solution were mixed, and stirred for one
minute. To the resulting mixture 1.6 ml of acetone was added while
stirring to form a paste followed by placing in a vacuum
environment of -100 Pa for one hour, and the resulting dried
mixture was mechanically ground for 20 minutes to fine particles. 1
g of the fine particles and 0.4 ml of phosphate aqueous solution
(1.0 M, pH=6.0) were mixed to form a paste, which was tested every
30 seconds to determine the working time and the setting time. The
working time of the paste of this example is 20.0 minutes and the
setting time thereof is 22.0 minutes.
[0041] The paste was placed in a relatively large amount of
deionized water immediately following the formation thereof, and it
was observed that the paste was non-dispersive in deionized
water.
EXAMPLE 4
Microwave Treatment
[0042] 3 g of a mixed powder of CaHPO.sub.4 (DCPA) and
Ca.sub.4(PO.sub.4).sub.2O (TTCP) in 1:1 molar ratio was mixed with
2.0 ml of 25 mM phosphoric acid aqueous solution, and the mixture
was stirred for five minutes. The resulting mixture was placed in a
microwave oven where it was heated under low power for five
minutes. The resulting dried mixture was mechanically ground for 20
minutes to fine particles. 1 g of the fine particles and 0.42 ml of
phosphate aqueous solution (1.0 M, pH=6.0) were mixed to form a
paste, which was tested every 30 seconds to determine the working
time and the setting time. The working time of the paste of this
example is 2.0 minutes and the setting time thereof is 4.0
minutes.
[0043] The paste was placed in a relatively large amount of
deionized water immediately following the formation thereof, and it
was observed that the paste was non-dispersive in deionized
water.
EXAMPLE 5
Heating Treatment
[0044] 5 g of a mixed powder of DCPA and TTCP in 1:1 molar ratio
was mixed with 1.6 ml of 25 mM phosphoric acid aqueous solution,
and the mixture was stirred for one minute. The resulting mixture
was placed in a high temperature oven at 500.degree. C. for five
minutes. The resulting dried mixture was mechanically ground for 20
minutes to fine particles. 1 g of the fine particles and 0.4 ml of
phosphate aqueous solution (1.0 M, pH=6.0) were mixed to form a
paste, which was tested every 30 seconds to determine the working
time and the setting time. The working time of the paste of this
example is 1.5 minutes and the setting time thereof is 2.5
minutes.
[0045] The paste was placed in a relatively large amount of
deionized water immediately following the formation thereof, and it
was observed that the paste was non-dispersive in deionized
water.
EXAMPLE 6
Heating Treatment
[0046] 5 g of a mixed powder of DCPA and TTCP in 1:1 molar ratio
was mixed with 1.6 ml of 25 mM phosphoric acid aqueous solution,
and the mixture was stirred for one minute. The resulting mixture
was placed in a high temperature oven at 1000.degree. C. for one
minute. The resulting dried mixture was mechanically ground for 20
minutes to fine particles. 1 g of the fine particles and 0.4 ml of
phosphate aqueous solution (1.0 M, pH=6.0) were mixed to form a
paste, which was tested every 30 seconds to determine the working
time and the setting time. The working time of the paste of this
example is 31 minutes and the setting time thereof is 35
minutes.
EXAMPLES 7-11
[0047] The procedures of Example 1 were repeated except that the
Ca(H.sub.2PO.sub.4).sub.2. H.sub.2O powder was replaced by a mixed
powder of DCPA and TTCP in 1:1 molar ratio and the 25 mM phosphoric
acid aqueous solution was replaced by a diluted phosphoric acid
aqueous solution having a pH of 1.96. The heating treatments were
carried out with conditions listed in Table 1. The performance is
also listed in Table 1.
CONTROL EXAMPLE 1
[0048] 1 g of a mixed powder of DCPA and TTCP in 1:1 mole and 0.4
ml of a diluted phosphoric acid aqueous solution having a pH of
1.96 were mixed to form a paste, which was tested every 30 seconds
to determine the working time and the setting time. The paste of
this example can not set within hours. The performance is listed in
Table 1.
EXAMPLE 12
[0049] The procedures of Example 2 were repeated except that the
DCPA powder was replaced by a mixed powder of DCPA and TTCP in 1:1
molar ratio and the 25 mM phosphoric acid aqueous solution was
replaced by a diluted phosphoric acid aqueous solution having a pH
of 1.96. The performance is listed in Table 1.
EXAMPLE 13
[0050] The procedures of Example 3 were repeated except that the
DCPA powder was replaced by a mixed powder of DCPA and TTCP in 1:1
molar ratio and the 25 mM phosphoric acid aqueous solution was
replaced by a diluted phosphoric acid aqueous solution having a pH
of 1.96. The performance is listed in Table 1.
EXAMPLE 14
[0051] The procedures of Example 4 were repeated except that the 25
mM phosphoric acid aqueous solution was replaced by a diluted
phosphoric acid aqueous solution having a pH of 1.96. The
performance is listed in Table 1.
1 TABLE 1 Setting/working Dispersive Controlling treatment time
(min) in Water Control Ex. 1 -- -- Yes Ex. 7 Heating, 50.degree. C.
11.5/6.5 No Ex. 8 Heating, 100.degree. C. 13.5/8.0 No Ex. 9
Heating, 150.degree. C. 8.5/8.0 No Ex. 10 Heating, 500.degree. C.
2.5/1.5 No Ex. 11 Heating, 1000.degree. C. 35/31 No Ex. 12
Vacuuming 14.5/11.5 No Ex. 13 Organic solvent 17.5/16.5 No Ex. 14
Microwave 3.5/2.5 No
[0052] The pastes prepared in Control Example 1 and Example 7 were
injected into water via a syringe at 3, 10 and 30 seconds after the
paste being formed. The results are shown in FIGS. 5a to 5c and
FIGS. 6a to 6c, respectively. It can be seen from FIGS. 5a to 5b
that the paste prepared in Control Example 1 is dispersive in
water. On the contrary, the paste prepared in Example 7 is
non-dispersive as shown in FIGS. 6a to 6c.
[0053] Two cylinders were prepared by separately molding the pastes
prepared in Control Example 1 and Example 7, and were then placed
in water. FIGS. 7a to 7c show the pictures taken at 5, 20 and 60
seconds after the cylinders being immersed in the water, from which
it can be seen that the left cylinder made from the paste prepared
in Control Example 1 collapses, while the right cylinder made form
the paste prepared in Example 7 remains almost intact.
[0054] It can be concluded from the results shown in FIGS. 5a to 7c
that the paste prepared from the calcium phosphate cement of the
present invention can be directly injected or implanted after being
molded into a block into a cavity in a deformed tooth or bone.
[0055] Two samples of the calcium phosphate cement prepared in
Example 7 were observed by transmission electron microscopy (TEM),
and the two TEM pictures shown in FIGS. 8 and 9 indicate that there
are whiskers on surfaces of calcium phosphate particles having
different diameters of the calcium phosphate cement.
[0056] The calcium phosphate cement prepared in Example 6 has a
particle diameter distribution shown in FIG. 1, which was
determined by using particle size analyzer (Sald-2001, Shimadzu
Co., Japan). The curve in FIG. 1 indicates that the particle
diameters of the calcium phosphate cement prepared in Example 6
range from about 0.47 microns to 93.49 microns. FIG. 2 shows a
scanning electron microscopy (SEM) micrograph of the calcium
phosphate cement prepared in Example 6. Moreover, the lengths and
the widths of the whiskers or fine crystals on surfaces of the
calcium phosphate particles prepared in Example 6 were determined
directly from TEM (JXA-840, JEOL Co., Japan), and the results are
shown in FIGS. 3 and 4, respectively. As shown in FIGS. 3 and 4,
the lengths and widths of the of the whiskers or fine crystals on
surfaces of the calcium phosphate particles prepared in Example 6
range from 1 to 625 nm and 1 to 65 nm, respectively.
EXAMPLES 15-19
[0057] The procedures of Example 7 were repeated by using the
calcium phosphate powders and the wetting solutions listed in Table
2. The performance is also listed in Table 2.
2 TABLE 2 Setting/ Dis- Calcium Heating working persive phosphate
Wetting treat- time in powder* solution ment (min) water Ex. 15 TCP
Acetic acid Yes 10/6.5 No Control TCP -- No Yes Ex. 2 Ex. 16 TCP
Acetic acid Yes 12.5/8.5 No Control TCP -- No -- Yes Ex. 3 Ex. 17
TTCP + DCPA Phosphoric Yes 11/18 No acid Control TTCP + DCPA -- No
-- Yes Ex. 4 Ex. 18 TTCP + DCPA + Phosphoric Yes -- No TCP acid
Control TTCP + DCPA + -- No -- Yes Ex. 5 TCP Ex. 19 DCPA + TCP
Phosphoric Yes 29/24 No acid Control DCPA + TCP -- No -- Yes Ex. 6
*TCP is anhydrous tricalcium phosphate. TTCP + DCPA is a mixed
powder of TTCP and DCPA in 1:1 molar ratio. TTCP + DCPA + TCP is a
mixed powder of TTCP + DCPA and TCP in 1:1 weight ratio. DCPA + TCP
is a mixed powder of DCPA and TCP in 1:2 molar ratio. DCPA + TCP is
a mixed powder of DCPA and TCP in 1:2 molar ratio.
CONTROL EXAMPLES 2-6
[0058] The procedures of Control Example 1 were repeated by using
the calcium phosphate powders and the wetting solutions listed in
Table 2. The performance is also listed in Table 2.
EXAMPLES 20-31
[0059] The procedures of Example 7 were repeated by using the
wetting solutions having different pH values listed in Table 3. The
performance is also listed in Table 3.
CONTROL EXAMPLES 7-14
[0060] The procedures of Control Example 1 were repeated by using
the wetting solutions having different pH values listed in Table 3.
The performance is also listed in Table 3.
3 TABLE 3 Heating Dispersive Wetting solution pH treatment in water
Ex. 20 Phosphoric acid 0.56 Yes No Control Ex. 7 -- -- No Yes Ex.
21 Phosphoric acid 1.03 Yes No Ex. 22 Phosphoric acid 1.17 Yes No
Ex. 23 Phosphoric acid 1.22 Yes No Ex. 24 Phosphoric acid 1.32 Yes
No Ex. 25 Phosphoric acid 2.0 Yes No Control Ex. 8 -- -- No Yes Ex.
26 Acetic acid + sodium 7.0 Yes No carbonate Control Ex. 9 -- -- No
Yes Ex. 27 Sodium hydroxide 9.5 Yes No Control Ex. 10 -- -- No Yes
Ex. 28 Sodium hydroxide 12.55 Yes No Control Ex. 11 -- -- No Yes
Ex. 29 Acetic acid 1.96 Yes No Control Ex. 12 -- -- No Yes Ex. 30
Ethanol -- Yes No Control Ex. 13 -- -- No Yes Ex. 31 Deionized
water 7.0 Yes No Control Ex. 14 -- -- No Yes
* * * * *