Note: Descriptions are shown in the official language in which they were submitted.
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CALCIUM PHOSPHATE CEMENT, USE
AND PF'.EPARATION THEREOF
FIELD OF THE Il~'~El~TIOT~
[0001] The present invention relates generally to a calcium phosphate cement,
and
particularly to a fast-setting calcium phosphate cement, for use in dental and
bone
prosthesis.
BACKGROUND OF THE INVENTION
[0002] A calcium phosphate cement (abbreviated as CPC) has been widely used as
an
implant or filling material in dental and bone prostheses, and details of its
technical
description can be found in many patents, for example, U.S. Patent Nos.
4,959,104;
5,092,888; 5,180,426; 5,262,166; 5,336,264; S,S2S,148; S,OS3,212; 5,149,368;
5,342,441;
S,S03,164; 5,542,973; S,S4S,2S4; S,69S,729 and 5,814,681. Tn general, the
prior art
calcium phosphate cements suffer one or more drawbacks as follows: 1)
requiring
additives with a relatively poor bioactivity; 2) a complicated preparation
process; 3) an
undesired setting time or working time for the CPC that is difficult to
adjust; 4) being
incapable of setting to a desired shape in water, blood or body fluid; and S)
having poor
initial strength after setting of the CPC.
SUM1VIARY OF THE INVENTION
[0003] The present invention is based on the discovery that monophasic
particles of
tetracalcium phosphate (TTCP) having whiskers or fme crystals on surfaces of
the
particles can be prepared and used to make a calcium phosphate cement suitable
for
preparation of bone and tooth prosthesis.
[0004] In one embodiment, the invention provides calcium phosphate cement
particles
comprising monophasic tetracalcium phosphate (TTCP) particles, wherein said
TTCP
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particles on their surfaces have whiskers or fme crystals with a width ranging
from 2 to
500 nm and a length ranging from 5 to 5000 nm.
[OOOS] In another embodiment, the invention provides methods for preparing a
paste for
use in treating a defect in a bone or a tooth in a patient by introducing said
paste into a
bone defect or bone cavity of said patient or shaping said paste and
implanting the
resulting shaped paste into a bone defect or a bone cavity of said patient,
said method
comprising mixing invention TTCP particles and a hardening aqueous solution
sufficient
to form a paste.
[0006] In still another embodiment, the invention provides methods for
preparing TTCP
particles comprising mixing a powder or small pieces of invention TTCP
particles with a
wetting agent, and controlling growth of whiskers or fine crystals of TTCP on
surfaces of
said TTCP powder or small pieces of TTCP by a controlling treatment, to
provide
whiskers or fine crystals of TTCP having a width ranging from 1 nm to 100 nm
and a
length ranging from 1 nm to 5000 nm.
DETAILED DESCRIPTION OF THE INVENTION
[0007] The present invention provides a calcium phosphate cement comprising
monophasic TTCP particles having a diameter of 0.05 to 100 microns, wherein
said
TTCP particles on their surfaces have whiskers or fme crystals having a width
ranging
from 2 to 500 nm and a length ranging from 5 to 5000 nm, for example a width
ranging
from 2 to 100 nm and a length ranging from 5 to 1000 nm, or a width ranging
from 2 nm
to about 200 nm and a length ranging from 10 nm to about 2000 nm.
[0008] By adjusting the diameter of the TTCP particles, the width and/or the
length of the
whiskers or fine crystals, the working time and/or the setting time of the
calcium
phosphate cement of can be adjusted to conform to requirements for various
purposes.
I~Ioreover, the calcium phosphate cement of the present invention is fast-
setting, and is
non-dispersive in water or an aqueous solution.
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[0009] A suitable process for preparing the calcium phosphate cement of the
present
invention comprises mixing a TTCP powder or small pieces of monophasic TTCP
with a
wetting agent, and controlling growth of whiskers or fine crystals on surfaces
of said
TTCP powder or small pieces of TTCP by an controlling treatment. The shape of
the
monophasic small pieces of TTCP or grains of TTCP powder are not limited, and
can
include spherical or irregular shapes; and the crystal structure thereof can
be single
crystal, polycrystal, mixed crystals, semi-crystal, or amorphous.
[0010] Suitable wetting agents used to wet the powder or small pieces of TTCP
include
any aqueous solution comprising alkaline ions (for example, sodium(Na) or
potassium(K) ions);alkaline earth ions (for example, magnesium(Mg) or
calcium(Ca)
ions); fluorine(F) ion; chlorine (Cl)'1 ion; carbonate (C03)'2 ion, nitrate
(N03)'1 ion,
acetate (CH3C00) '1 ion; phosphate (P04)-3 ion; ammonium ion (NH4) +, hydrogen
(H) +
ion, or hydroxyl (OH)' ion. Preferably, however, the wetting agent used is a
diluted
aqueous solution containing phosphoric acid or phosphate.
[0011] The amount of the wetting agent mixed with the monophasic TTCP powder
or
small pieces, in general, should be enough to substantially wet all the TTCP
powder or
small pieces of TTCP. However, it is not necessarily the case when the
controlling
treatment is the organic solvent treatment, where a water miscible organic
solvent is
added to the mixture of said wetting agent and the TTCP powder or small pieces
of TTCP
to form a paste for a subsequent processing step. For example, a dilute
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
can be
mixed with the monophasic TTCP particles or powder prior to the controlling
treatment.
[0012] The controlling treatment is selected from a vacuuming treatment, an
organic
solvent treatment, a microwave treatment, a heating treatment, or any other
treatments
that can control growth of whiskers or fine crystals on surfaces of monophasic
TTCP
powder or small pieces. I~ue to its simplicity and effectiveness, the most
frequently used
controlling treatment is heating to about 50 °C for 1 day.
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[0013] The process for preparing the calcium phosphate cement can further
comprise
grinding the resulting product from the controlling treatment to fonn TTCP
particles
having a diameter of 0.05 to 100 microns, wherein said whiskers or one
crystals of TTCP
have a width ranging from 1 to 100 nm and a length ranging from 1 to 1000 nm.
[0014] Preferably, the process for preparing the calcium phosphate cement of
the present
invention comprises soaking said TTCP powder or said small pieces of TTCP with
a
diluted aqueous solution containing more than 100 ppm of phosphoric acid or
phosphate,
and carrying out (a) a heating treatment comprising drying the resulting
soaked TTCP
powder or soaked small pieces of TTCP at a temperature in the range from about
50°C to
about ; (b) a vacuuming treatment comprising drying the resulting soaked TTCP
powder
or soaked small pieces of TTCP under vacuum; or (c) a microwave treatment
comprising
drying the resulting soaked-TTCP powder or soaked small pieces of TTCP by
microwave
heating. More preferably, the resulting soaked TTCP powder or soaked small
pieces of
TTCP are well mixed to form a uniform mixture prior to being subjected to
treatment (a),
(b) or (c).
[0015] Alternatively, the process for preparing the calcium phosphate cement
of the
present invention comprises mixing the TTCP powder or the small pieces of TTCP
with
the diluted aqueous solution containing more than 100 ppm of phosphoric acid
or
phosphate, and carrying out the organic solvent treatment comprising mixing
the mixture
of the wetting agent and the TTCP powder or small pieces of TTCP with a water
miscible
organic solvent, and drying the resulting mixture under vacuum. Preferably,
the organic
solvent treatment is carried out while stirring, and more preferably, the
mixture of the
diluted aqueous solution containing more than 100 ppm of phosphoric acid or
phosphate
and the TTCP powder or small pieces of TTCP is well mixed prior to being
subjected to
the organic solvent treatment.
[0016] Preferably, the TTCP particles of the calcium phosphate cement of the
present
invention have a diameter of 0.2 to ~0 microns, and more preferably 0.5 to 50
microns.
[0017] As used herein, 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
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value of the first 30% of the diameters of the fine crystal, which are shorter
than the other
70% thereof. As used herein, 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.
[001] Preferably, the whiskers or fine crystals of TTCP have a width ranging
from 2 to
70 nm and a length ranging from S to 800 nm, and more preferably a length
ranging from
to 700 nm.
[0019] Preferably, the TTCP 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.
[0020] The calcium phosphate cement of the present invention is biocompatible
and a
paste made therefrom is non-dispersive in water. The paste 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 prostheses, where the paste must
contact
water, blood or body fluid when implanted. In one embodiment, the paste made
from the
calcium phosphate cement of the invention is suitable for direct injection
into a bone
defect or cavity as an implant or filling material.
[0021] The present invention also discloses a method of treating a defect in
bone or a
tooth in a patient, by mixing the calcium phosphate cement of the present
invention with a
hardening -promoter-containing aqueous solution to form a paste, and a)
injecting the
paste into a bone defect or cavity of said patient or b) shaping the paste and
implanting
the resulting shaped paste into a bone defect or cavity of the patient.
[0022] In one embodiment of the invention methods, the calcium phosphate
cement may
further comprise an agent that promotes bone growth, such as a growth factor,
a bone
morphology protein or a pharmaceutical carrier, or the hardening-promoter-
containing
aqueous solution can further comprises such an agent, for example, a growth
factor, a
bone morphology protein or a pharmaceutical carrier.
[0023] The hardening-promoter-containing aqueous solution can further comprise
any
known compound or composition that promotes the solidification of calcium
phosphate,
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for example phosphates, calcium salts, and fluorides. For example, the
hardening-
promoter-containing aqueous solution may be an aqueous solution comprising
phosphate
ions, calcium ions, fluorine ions, or phosphate ions together with additional
fluorine ions
as a hardening promoter.
[0024] The amount of the hardening promoter in the hardening-promoter-
containing
aqueous solution has no special limitation, but preferably the concentration
of the
hardening promoter therein ranges from 0.1 1VI to 81VI, and more preferably
from 1 M to 6
1VI.
[0025] The mixing ratio of the calcium phosphate cement of the present
invention and the
hardening-promoter-containing aqueous solution is not restricted to any
particular ranges;
however, the amount of said hardening-promoter-containing aqueous solution in
the
mixture 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. Furthermore, the amount of the hardening promoter in the hardening-
promoter-
containing aqueous solution should be adjusted to a higher level when a lesser
amount of
said hardening-promoter-containing aqueous solution is used in the mixture.
[0026] A "subject" as the term is used herein is any mammal, including zoo,
farm and
domestic animals and humans.
[0027] An "effective amount" of the injectable calcium-phosphate-based bone
substitute
as the term is used herein is an amount effective to accomplish fusion of
vertebrae
adjacent to the interbody site in the subject.
[0028] "Setting time" as the term is used herein is the time after which a 1
mm diameter
pin with a load of 1/4 pound can be inserted only 1 mm deep into the surface
of a CPC
paste, as determined using ISO 1566, a method commonly used for measuring the
setting
time of dental zinc phosphate cements as well as CPC
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[0029] "Working time" as the term is used herein means the time after which a
CPC paste
becomes too viscous to be stirred. Caenerally working time is a few minutes
shorter than
setting time.
[0030] After setting for about 30 minutes, the CPC paste made by the invention
methods
has a minimum compressive strength of about 10 MPa and a minimum compressive
strength of 25 MPa is obtained within 24~ hours after exposure to
physiological conditions.
The compressive strength herein is as determined using ASTM F451-99, a method,
that is
commonly used for the compressive strength measurement of CPC.
[0031] An injectable formulation of the invention CPC paste can be introduced
into a
defect in a bone or tooth using any method known in the art and will have
working and
setting times of about 5 to about 30 minutes. About 30 minutes after
introduction into the
defect or after exposure to biological conditions, the invention CPC paste
will form a
substance with a minimum compressive strength of about 10 MPa, or a minimum of
25
MPa compressive strength within 24 hours. Additionally, when solidified, the
bone
substitute produced from the invention CPC paste can have a porosity of about
20% to
about 50% by volume as measured using ASTM C~30-00 water saturation technique.
[0032] The CPC paste having these characteristics can consist essentially of
calcium
phosphate, for example being a substantially monophasic TTCP, and is made from
invention particles of monophasic TTCP having surface whiskers or fine needles
of
calcium phosphate, said whiskers having a length ranging from 1 to about 1000
nm and a
width ranging from 1 to about 100 nm as described herein.
[0033] The following examples are meant to illustrate an embodiment of the
invention
and not to limit the scope of the invention.
EXAMPLE 1
[0034] The most-frequently used wetting agent used in preparation of the
invention
TTCP monophasic particles is (NH4)2HP~4 with a concentration range 0.1 - ~M,
preferably 1 - 6M. The length of exposure to the wetting agent will also
affect the
composition of the particles. For example, when TTCP monophasic particles are
treated
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by exposure to (NH4)2HP04 for 10 min, the whiskers formed are of monophasic
TTCP.
However, when the same TTCP monophasic particles are treated by exposure to
(~IHø)2HPOq for 24 hours the whiskers become pure hydroxyapatite.
[003] The working and setl:ing times for the CPC cement derived from TTCP
particles
being treated in (NH4)2HPO4 for 5-10 min (maximum strength obtained) are about
7 and
9 min, respectively. The water solubility for such CPC paste is only about
0.65°1° in
weight after immersing the hardened cement in 37 °C deionized water for
568 hours.
EXAMPLE 2
[0036] The following tables demonstrate the relationship between compressive
strength
of CPC paste subjected to physiological conditions (exposure to Hank's
solution for one
day) when the TTCP particles used to make the CPC paste are treated for growth
of
whiskers for varying amounts of time resulting in whiskers of various size.
Compressive strength (CS) of CPC derived from TTCP particles
whisker-treated in HCl solution
Whisker- lOmin lh 4h 12h 24h
treating
time
CS (MPa) 21.12.6 22.72.8 33.13.3 484.3 294.1
Compressive strength of CPC derived from TTCP particles
whisker-treated in (NHa)zHPOa solution
Smin lOm 30min 24hr _
in
CS(MPa) 416.2 _ 26.83.2 6.31.6
43.95.6
The CPC was immersed in Hanks' solution for one day before being tested for
compressive strength. These studies show the compressive strength of CPC
prepared
from the whisker-treated TTCP powder increases with treating time until a
maximum
strength is obtained. When treated further, the strength declines due to
"overgrowing" of
the whiskers.
[0037] Although the invention has been described with respect to specific
embodiments, it will be understood that modifications and variations are
encompassed
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within the spirit and scope of the invention. Accordingly, the invention is
limited only by
the following claims.
