U.S. patent application number 11/762370 was filed with the patent office on 2007-10-04 for heat generating biocompatible ceramic materials for drug delivery.
This patent application is currently assigned to CERBIO TECH AB. Invention is credited to Niklas AXEN, Leif HERMANSSON, Dan MARKUSSON, Tobias PERSSON.
Application Number | 20070232704 11/762370 |
Document ID | / |
Family ID | 20289141 |
Filed Date | 2007-10-04 |
United States Patent
Application |
20070232704 |
Kind Code |
A1 |
AXEN; Niklas ; et
al. |
October 4, 2007 |
HEAT GENERATING BIOCOMPATIBLE CERAMIC MATERIALS FOR DRUG
DELIVERY
Abstract
The present invention pertains to injectable heat generating
biocompatible ceramic compositions based on hydraulic calcium
aluminate, which can be used for therapeutic treatment in vivo,
such as tumour treatment, pain control, vascular treatment, drug
activation etc, when curing in situ, and which form a biocompatible
solid material that can be left in the body for prolonged periods
of time without causing negative health effects. The present
invention can also be used to restore the mechanical properties of
the skeleton after cancerous diseases.
Inventors: |
AXEN; Niklas; (Jarlasa,
SE) ; HERMANSSON; Leif; (Uppsala, SE) ;
MARKUSSON; Dan; (Vaxjo, SE) ; PERSSON; Tobias;
(Uppsala, SE) |
Correspondence
Address: |
YOUNG & THOMPSON
745 SOUTH 23RD STREET
2ND FLOOR
ARLINGTON
VA
22202
US
|
Assignee: |
CERBIO TECH AB
Axel Johanssons gata 4-6
Uppsala
SE
754 51
|
Family ID: |
20289141 |
Appl. No.: |
11/762370 |
Filed: |
June 13, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10673250 |
Sep 30, 2003 |
7244301 |
|
|
11762370 |
Jun 13, 2007 |
|
|
|
Current U.S.
Class: |
514/770 |
Current CPC
Class: |
A61P 25/02 20180101;
A61P 9/00 20180101; A61L 27/10 20130101; A61P 35/00 20180101 |
Class at
Publication: |
514/770 |
International
Class: |
A61K 47/02 20060101
A61K047/02 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 30, 2002 |
SE |
0202895-9 |
Claims
1. A drug carrier for drug delivery in a patient's body comprising:
a biocompatible ceramic composition, wherein, said biocompatible
ceramic composition comprises a calcium aluminate mixture of (i)
less than 50 vol. %, but greater than 0%, of CA.sub.2 (ii), more
than 50 vol. % of CA and C.sub.12A.sub.7, and less than 10 vol. %,
but greater than 0%, of C.sub.3A as a hydraulic ingredient, said
biocompatible ceramic composition generates heat so as to activate
drugs in a patient's body.
2. The drug carrier according to claim 1, wherein said calcium
aluminate mixture is at least 50 vol % of all hydraulic ingredients
of said biocompatible ceramic composition.
3. The drug carrier according to claim 1, wherein said
biocompatible ceramic composition generates temperatures of
30-150.degree. C. when cured.
4. The drug carrier according to claim 1, wherein said
biocompatible ceramic composition further comprises at least one of
calcium silicate and calcium sulfate in amount less than 50 vol. %
of all hydraulic ingredients of said biocompatible ceramic
composition.
5. The drug carrier according to claim 1, wherein said
biocompatible ceramic composition further comprises particles or a
powder of one or more biocompatible materials selected from the
group consisting of calcium carbonate, calcium phosphate, apatite,
fluoroapatite, carbonates-apatites, and hydroxyapatite in a total
amount less than 30 vol. % of the total volume of said
biocompatible ceramic composition.
6. The drug carrier according to claim 1, wherein said
biocompatible composition further comprises a component which is a
water reducing agent selected from the group consisting of
polycarboxylic acids, polyacrylic acids, and superplasticisers.
7. The drug carrier according to claim 1, wherein said
biocompatible composition further comprises expansion controlling
additives.
8. The drug carrier according to claim 1, wherein said
biocompatible composition further comprises a water-based curing
liquid.
9. The drug carrier according to claim 8, wherein, said curing
liquid further comprises an accelerator agent which accelerates
hardening of said biocompatible ceramic composition, and said
accelerator agent is selected from the group consisting of lithium
chloride, lithium hydroxide, lithium carbonate, lithium sulphate,
lithium nitrate, lithium citrate, calcium hydroxide, potassium
hydroxide, potassium carbonate, sodium hydroxide, sodium carbonate,
sodium sulphate and sulfuric acid.
10. The drug carrier according to claim 9, wherein said
accelerating agent is LiCl present in an amount of 10-500 mg in 100
g of said curing liquid.
11. The drug carrier according to claim 8, wherein, said curing
liquid further comprises a retarder agent which retards hardening
of said biocompatible ceramic composition, and said retarder agent
is selected from the group consisting of polysaccharide, glycerine,
sugars, starch, and cellulose-based thickeners.
12. The drug carrier according to claim 1, wherein said
biocompatible composition is cured.
Description
THE FIELD OF THE INVENTION
[0001] This invention refers to biocompatible ceramic compositions,
which before curing show a high degree of formability or
mouldability, as well as injectability, and which hardens or cures
in-situ under generation of elevated temperatures, the levels of
which can be controlled. The compositions according to the present
invention, and the elevated temperatures they generate, can e.g. be
used for therapeutic purposes in vivo, such as tumour treatment,
pain control, vascular treatment, etc.
BACKGROUND OF THE INVENTION
[0002] Malignant tumours are traditionally treated by either of
three techniques: surgery, radiation or chemotherapy. Often
combinations of these techniques are necessary. By surgery, larger
tumours of suitable locations may be removed. Surgery alone is
however often not enough, due to residues of cancerous tissues and
twin tumours. Radiation is used for smaller tumours, particularly
in difficult-to-reach locations. By using radiation techniques,
surgery may not be necessary. Chemotherapy suffers from other side
effects, including necrotic effects on non-cancerous cells.
[0003] A therapeutic procedure explored in some fields of surgery
is to generate heat in vivo at specific locations in the body, and
to benefit from the heat for therapeutic purposes, such as the
treatment of cancer cells. Local heat may be achieved by several
methods, e.g. with catheters equipped with elements generating heat
by electrical resistivity, which can be controlled to desired
locations via the vascular system.
[0004] An alternative technique to achieve heat in-vivo, is to
apply small volumes of slurries or pastes of heat generating
materials at the desired locations, e.g. by injection with needles.
The material cures injected into the body cures through exothermal
chemical reactions and thereby generates the desired temperatures.
As the temperature rises, local therapeutic effects are generated.
Ideally, when the reactions are completed, the cured substance
should form a biocompatible solid material, which can be left for
prolonged periods of time in the body without any negative health
effects. Only a few types of therapies benefiting from heat
generating materials are performed today; the heat generating
material being PMMA (polymethylmethacrylate) bone cement, despite
the lack of biocompatibility.
[0005] Treatment of malignant cancerous tumours, as well as
metastasis, myeloms, various cysts, etc, involving the local
application of heat generating materials in vivo is used to some
degree, although it is still a less frequent treatment technique.
The technique involves either local thermal necrosis or restriction
of the nutritional or blood feed, or oxygenation, to the tumours or
cells.
[0006] The use of injectable heat generating materials for cancer
treatment is particularly suitable for tumours in the skeleton. The
procedure may involve direct injection of a cell-destroying cement;
or alternatively the removal of the tumour by surgery, followed by
filling of the remaining cavity by an in-situ-curing material. The
former procedure offers at least two advantages: One being that
increased temperatures during curing reduce the activity of, or
kills, residual cancerous tissue. Another effect is that the cement
restores the mechanical properties of the skeleton, hence reducing
the risk of fractures due to weakened bone.
[0007] Injectable pastes are also used in combination with
radiation treatment, as when spine vertebrae are first filled with
PMMA bone cement injected into the trabecular interior through the
pedicles to provide mechanical stability, followed by radiation
treatment of the same vertebra.
[0008] Similarly, injectable pastes are used for the treatment of
collapsed osteoporotic vertebrae. The filling of collapsed
vertebrae with bone cement reduces the pain and the dimensions of
the vertebrae may be restored. Here the heat generation
contributes, in addition to the mechanical stabilization of the
vertebrae to the reduction of pain in the spine.
[0009] Locally generated heat can be used for the local destruction
of nerves to reduce pain, to destroy the function of blood vessels,
and to locally trigger the effect of drugs.
[0010] As of today, there is no commercialised biocompatible
cement, specifically developed for therapeutic purposes by heat
generation. Only standard bone cement based on polymethyl
methacrylate (PMMA) is used. This material may generate sufficient
temperatures, but does not show adequate biocompatibility. Due to
lack of better alternatives, PMMA bone cement is however well
established in surgery.
Disadvantages with Present Materials
[0011] Today's PMMA based bone cements are developed for
orthopaedic needs, primarily the fixation of hip and knee implants
in the skeleton. Despite many disadvantages, these materials are
today established in orthopaedics after several decades of use.
There is however an on-going search for better, more biocompatible
bone cements.
[0012] PMMA based bone cements are not biocompatible materials.
They have clear toxic effects caused by leakage of components, such
as solvents and non-polymerised monomer. These leakages become
particularly high for low viscosity formulations (being injectable)
with high amounts of solvents and monomers.
[0013] Ideally in cell therapy with heat generating pastes, the
volume of cured material left after therapy, shall trigger a
minimum of unwanted tissue reactions. This requires a high degree
of chemical stability and biocompatibility.
[0014] For treatment of cancerous bone, the cured material left in
the skeleton ideally possesses mechanical properties similar to
those of natural bone. In particular, an insufficient strength or
stiffness is disadvantageous for load bearing parts of the
skeleton. An orthopaedic cement shall preferably have an elastic
modulus of around 10-20 GPa. Today's PMMA bone cements show elastic
modulii around 3 GPa.
[0015] Today's PMMA bone cements cure while generating heat in
amounts considered excessive for normal orthopaedic use. For use in
vertebroplasty, some argue that a temperature rise may be
advantageous, since it may contribute to reduce pain. However,
today's bone cements offer no, or very limited, possibilities for
the surgeon to control the generated temperature.
[0016] Also cements generating low temperatures rises during curing
are of interest. A low temperature bone cement based on hydraulic
ceramics is described in the pending Swedish patent application
"Ceramic material and process for manufacturing" (SE-0104441-1),
filed 27 Dec. 2001. In said patent application the temperature rise
due to the hydration reactions is damped by addition of suitable
inert, non-hydraulic phases, which are also favourable for the
mechanical properties and biocompatibility. However, these ceramic
materials do not offer the means to control the heat generation
through well controlled phase compositions of the hydrating
ceramic, or controlling the temperature by accelerators and
retarders.
SUMMARY OF THE INVENTION
[0017] In view of the drawbacks associated with the prior art
injectable paste compositions, when used for cell therapy, pain
control, vascular treatments etc, there is a need for an in-situ
curing paste-like material, which can be injected through fine
needles into a position in the human body, and which cures during a
controlled time span under generation of a controlled amount of
heat, triggering various therapeutic effects on targeted tissues
and organs, and forming a stable, non-toxic and biocompatible solid
volume. For use in the skeleton, the cured material should
preferably have mechanical properties similar to those of bone.
[0018] To fulfil these needs, the present invention uses hydraulic
cements, particularly calcium aluminates, which cure exothermically
as a result of chemical reactions with water forming solid ceramic
materials of high biocompatibility and suitable mechanical
properties.
[0019] The objective of the present invention is to provide
injectable heat generating ceramic biocement compositions, based on
hydraulic oxide ceramics, primarily calcium aluminates, the curing
times and temperature increase of which can be controlled to suit
clinical needs. After curing, a biocompatible material is formed,
which left in the body for prolonged periods of time causes no
negative health effects.
[0020] A further object of the present invention is to provide
compositions which can function as load bearing bone graft
material, restoring the mechanical properties of the skeleton after
that tumours have been removed or treated by radiation, hence
reducing the risk of fractures due to the weakening of the
bone.
[0021] A further object of the present invention is to use the
biocompatible ceramic composition for therapeutic treatment by the
heat generated from said compositions.
[0022] More particularly, the injectable biocompatible cement
compositions according to the present invention can suitably be
used for therapeutic purposes in vivo, e.g. for cancer treatment,
pain relief, vascular treatment, bone restoration and activation of
drugs, by the heat they generate when they cure in situ in the
body.
[0023] The biocompatible cement compositions according to the
present invention can further be used to for manufacturing medical
implants, orthopaedic implants, dental implant or used as dental
filling material, or
[0024] The present invention can also be used for manufacturing of
drug carrier for drug delivery in a patient's body.
[0025] These biocompatible ceramic compositions are in a basic form
composed of a hydraulic powder raw material, predominantly
comprising calcium aluminate phases; less than 50 vol. %,
preferably less than 10 vol. %, of CA.sub.2, based on the total
volume of the calcium aluminate phases, more than 50 vol. %,
preferably more than 90 vol. % of CA and C.sub.12A.sub.7, based on
the total volume of the of calcium aluminate phases, and less than
10 vol. %, preferably less than 3 vol. % of C.sub.3A, based on the
total volume of the of calcium aluminate phases. The composition
according to the present invention may optionally contain suitable
additives. The sum of all components amounts to 100%, and the
CA-phases amounts to at least 50%, preferably at least 70%, most
preferably at least 90%.
[0026] The hydraulic powder raw material of the present invention
may further comprise the hydraulic powders calcium silicate and/or
calcium sulphate in an amount less than 50 vol. % of the total
volume of hydraulic ingredients.
[0027] The compositions according to the present invention may
further comprise a non-hydraulic filler comprising calcium titanate
or any other ternary oxide of perovskite structure according to the
formula ABO.sub.3, where O is oxygen and A and B are metals, or any
mixture of such ternary oxides. A in the perovskite structure is
selected from the group comprising Mg, Ca, Sr or Ba, and that the B
in the perovskite structure is selected from the group comprising
Ti, Zr, or Hf. The non-hydraulic filler should be present in an
amount of less than 30 vol. %, preferably less than 10 vol. % of
the total volume of the ceramic ingredients.
[0028] In order to increase the bioactivity of the compositions
according to the present invention it may further comprise
particles or powder of one or more biocompatible materials selected
from the group comprising calcium carbonate, calcium phosphate,
apatite, fluoroapatite, carbonates-apatites, and hydroxyapatite,
the total amount of which should be less than 30 vol. % of the
total volume of the ceramic ingredients.
[0029] The grain size of the powder/particle raw material used is
predominately less than 20 microns, preferably less than 10
microns, and most preferably less than 3 microns.
[0030] The curing of the compositions according to the present
invention can be performed in various ways, such as treating the
biocompatible ceramic composition with a curing agent, such as a
water-based curing liquid or vapour, or by preparing a slurry from
said curing liquid and the biocompatible ceramic composition.
[0031] The curing agent may comprise additives to enhance the
generation of heat by controlling the curing time. These additives
can be selected from water reducing agents (an agent that reduces
the amount of water necessary to keep a high flowability and to
control the viscosity or workability of the ceramic powder slurry,
without having to add excessive amounts of water), such as
polycarboxylic acids, polyacrylic acids, and superplasticisers,
such as Conpac 30.RTM.. The additives according to the present
invention can further be selected from accelerator agents, which
accelerate the hardening process, and are selected from the group
comprising lithium chloride, lithium hydroxide, lithium carbonate,
lithium sulphate, lithium nitrate, lithium citrate, calcium
hydroxide, potassium hydroxide, potassium carbonate, sodium
hydroxide, sodium carbonate, sodium sulphate and sulphuric acid. In
a preferred embodiment of the present invention the accelerator is
LiCl, and in a more preferred embodiment of the present invention
LiCl is present in an amount of 10-500 mg in 100 g of curing
liquid. Still further additives according to the present invention
are retarder agents, which retard the hardening process, and are
selected from the group comprising polysaccharide, glycerine,
sugars, starch, and cellulose-based thickeners.
[0032] When the compositions according to the present invention are
used, in particular, as dental material or implants, the
compositions may further comprise expansion controlling additives
such as fumed silica and/or calcium silicate. The expansion during
curing of the material is .ltoreq.0.8%.
[0033] When injected or otherwise introduced into a patient's body,
the compositions according to the present invention can generate
temperatures of 30-150.degree. C. while curing.
[0034] When cured, the compositions according to the present
invention has a compressive strength of at least 100 MPa.
[0035] The present invention further pertains to a cured
biocompatible ceramic composition according the above, and also to
a medical device comprising said cured biocompatible ceramic
composition.
[0036] The present invention further pertains to a method for
manufacturing the above-described chemically bonded biocompatible
ceramic composition, which method comprises preparing a calcium
aluminate/powder mixture of selected phase composition and grain
size, and curing said mixture by treating the biocompatible ceramic
composition with a curing agent, such as a water-based curing
liquid or vapour, or by preparing a slurry from said curing liquid
and the biocompatible ceramic composition. The method may also
comprise the step of removing any residual water or organic
contamination from the powder mixture before curing.
[0037] The present invention also pertains to a therapeutic method
comprising the steps of introducing a biocompatible ceramic
composition into a patient's body and curing said composition,
whereby heat is generated.
[0038] In a preferred embodiment, the method of generating heat in
vivo in a patient's body for therapeutical purposes (e.g. cancer
treatment, vascular treatment, pain relief, and activation of
drugs), comprises the following steps:
[0039] preparing a calcium aluminate powder mixture comprising less
than 50 vol. %, preferably less than 10 vol. %, of CA.sub.2, based
on the total volume of the calcium aluminate phases, more than 50
vol. %, preferably more than 90 vol. % of CA and C.sub.12A.sub.7,
based on the total volume of the of calcium aluminate phases, less
than 10 vol. %, preferably less than 3 vol. % of C.sub.3A, based on
the total volume of the of calcium aluminate phases, wherein the
CA-phases amounts to at least 50%, preferably at least 70%, most
preferably at least 90%, and optionally adding calcium silicate
and/or calcium sulphate in an amount less than 50 vol. % of the
total volume of hydraulic ingredients,
[0040] The preferred embodiment of the method according to the
present invention optionally comprises adding non-hydraulic filler
in an amount of less than 30 vol. %, preferably less than 10 vol. %
of the total volume of the ceramic ingredients, optionally adding
particles or powder of one or more biocompatible materials, the
total amount of which should be less than 30 vol. % of the total
volume of the ceramic ingredients, optionally comprises reducing
the size of the powder/particle material to less than 20 microns,
preferably less than 10 microns, and most preferably less than 3
microns, optionally removing any residual water or organic
contamination from the powder mixture, optionally adding viscosity
and workability controlling additives such as water reducing
agents, expansion controlling additives, curing accelerator and
retarder additives.
[0041] The preferred embodiment of the method according to the
present invention also comprises introducing the above-described
composition into the body at a specific location of therapeutic
treatment and curing the composition in situ in a patient's
body.
[0042] The step of curing in the above mentioned method may
comprise, prior to the introduction into a patient's body, mixing
the biocompatible ceramic composition with a curing agent, thereby
obtaining a slurry, and then introduce the slurry into the desired
location in said patient. The step of curing can also be performed
by introducing the biocompatible ceramic composition into a
patient's body and then, in situ at the desired location, treated
the composition with a curing agent, such as a water-based solution
or water vapour.
BRIEF DESCRIPTION OF THE DRAWINGS
[0043] The present invention will become more fully understood from
the detailed description given below and the accompanying drawings
which are given by way of illustration only, and thus are not
limitative of the present invention, and wherein:
[0044] FIG. 1 shows a graph showing the temperature over time
generated by a composition according to the present invention
having a concentration of 0.4 wt. % of LiCl in the hydrating
solution.
[0045] FIG. 2 shows a graph showing the temperature over time
generated by a composition according to the present invention
having a concentration of 0.05 wt. % of LiCl in the hydrating
solution.
DETAILED DESCRIPTION OF THE INVENTION
[0046] The present invention refers to materials, which cure
exothermically under generation of controllable amounts of heat,
leading to elevated temperatures. The heat-generating materials can
be used for therapeutic purposes, involving local heating of cells,
cell systems and organs. The material is applied in the form of
slurries, pastes or putties to the desired location e.g. by
injection, where it cures into a solid body, generating sufficient
temperatures to achieve the desired effects, for example for tumour
treatment, pain control or vascular treatments. Materials according
to the present invention form an alternative to the established
PMMA based bone cements.
[0047] The material of the invention cures as a result of hydration
reactions, between ceramic oxide powders and water. Through the
hydration a new, strong binding phase composed of hydrates is
formed. Ceramic materials curing through hydration are referred to
as hydraulic cements. Hydraulic materials include concretes based
on Portland cement as well as special ceramics used in dentistry
and orthopaedics. The amount of heat generated during hydration
depends on several factors, as is further described below.
[0048] The most relevant hydraulic cement of the present invention
is calcium aluminate. This material consists of phases from the
CaO--Al.sub.2O.sub.3 system. Several phases are described in the
literature, primarily C.sub.3A, C.sub.12A.sub.7, CA and CA.sub.2
(C=CaO, A=Al.sub.2O.sub.3), all of which are relevant to the
present invention. As an alternative embodiment, calcium silicate
may be used according to the invention.
[0049] There are several reasons for using calcium aluminates as
base substance for injectable bio-cements. In comparison to other
water binding systems, e.g. phosphates, carbonates and sulphates of
calcium, the aluminates are characterised by high chemical
resistance, high strength and controlled curing pace. However,
silicates have properties similar to those of aluminates and can
also be used according to the present invention. Also, the curing
chemistry based on water makes the process relatively unaffected by
water-based body fluids. Before hardening, the material has good
workability; it can be used both as slurry or paste. Also, the
temperature generation of calcium aluminates may be controlled by
the details of the phase composition.
[0050] Bio-cement compositions based on calcium aluminate which are
relevant for the present invention are described in the pending
Swedish patent application "Ceramic material and process for
manufacturing" (SE-0104441-1), filed 27 Dec. 2001, and in
PCT/SE99/01803, "Dimension stable binding agent systems", filed 8
Oct. 1999. All additives disclosed in these patent applications are
relevant to the present invention.
[0051] If a powder of calcium aluminate is mixed with water or a
water-based solution a process starts, which involves the steps of
dissolution of the calcium aluminates in the water, forming a
solution containing ions of calcium and aluminium. At sufficient
ion concentrations, a precipitation of calcium-aluminate hydrates
crystallites starts in the liquid. These hydrates build up a new
strong binding phase in the cured solid material.
[0052] The temperatures reached as the hydraulic cement cures
depend on several factors, the most important ones being: the phase
composition of the starting calcium aluminate powder, grain size of
the starting material powder, the dissolution rate, the hydration
rate as controlled by additions of accelerators or retarders, the
amount of inert, non-hydraulic phases in the composition, the total
volume of hydrating material, and the heat transfer to the
environment.
[0053] The hydration of calcium aluminates and calcium silicates is
a stepwise process. The initially formed hydrates are transformed,
in several steps, into more stable hydrate phases. At room
temperature the initial hydrate phase is
CaO.Al.sub.2O.sub.3.10H.sub.2O, abbreviated as CAH.sub.10 (C=CaO,
A=Al.sub.2O.sub.3, H=H.sub.2O). The most stable hydrate phase is
C.sub.3AH.sub.6. The following reactions have been identified for
hydration of CA: [0054] (1) CA+10H.fwdarw.CAH.sub.10 [0055] (2)
2CA+11H.fwdarw.C.sub.2AH.sub.8+AH.sub.3 [0056] (3)
3CA+12H.fwdarw.C.sub.3AH.sub.6+2AH.sub.3 [0057] (4)
2CAH.sub.10.fwdarw.C.sub.2AH.sub.8+AH.sub.3+9H [0058] (5)
3C.sub.2AH.sub.8.fwdarw.2C.sub.3AH.sub.6+AH.sub.3+9H
[0059] All reaction steps are exothermal and heat is developed. The
formation of CAH.sub.10 (step 1) produces 245.+-.5 J/g,
C.sub.2AH.sub.8 following step 2, 280.+-.5 J/g and C.sub.3AH.sub.6
(step 3) 120.+-.5 J/g. The total amount of heat generated by
standard calcium aluminate cement, consisting mainly of the phases
CA and CA.sub.2, is in the range 450 to 500 J/g, as the sum of
several hydration steps. The principles of hydration are similar
for calcium silicate cements.
[0060] The details of the hydration steps are dependent on
temperature. The higher the temperature, the more reaction steps
may occur within a certain period of time. At room temperature the
CAH.sub.10 hydrate forms fast, but the conversion to
C.sub.3AH.sub.6 arise very slowly, over a period of months. At body
temperature (37.degree. C.), C.sub.3AH.sub.6 is formed within a few
hours. At 60.degree. C., the stable hydrate forms within minutes.
If several reaction steps occur fast during the initial hydration,
the generated temperature is higher. A slower hydration generates
lower temperatures.
[0061] There are also other calcium aluminate phases, primarily
C.sub.3A, C.sub.12A.sub.7 and CA.sub.2, which hydrate as a result
of similar reactions. It has been found that the hydration rate
depends on the stoichiometry of the starting phase. The higher the
amount of Ca in the starting powder, the faster the hydration
proceeds. Thus, C.sub.3A and C.sub.12A.sub.7 cure faster than CA
and CA.sub.2. The most probable explanation to this phenomenon is
found in the hydration mechanisms, which first involve dissolution
of the calcium aluminate into water, followed by precipitation of
hydrates as the concentrations of Ca- and Al-ions in the solution
reach sufficient levels. For the precipitation of hydrates to be
initiated, a higher Ca- than Al-concentration is required.
[0062] Any calcium aluminate cement is a mixture of phases. In
general, commercially available cements are composed of CA and
CA.sub.2. The phases C.sub.3A, C.sub.12A.sub.7 are not used in
commercial cements. Higher amounts of these fast hydrating calcium
aluminate phases however trigger faster hydration and thereby
higher temperatures. Additions of these phases can be used to steer
the temperature generated in a calcium aluminate based hydraulic
ceramic.
[0063] The temperatures generated by the calcium aluminate-based
hydraulic cements according to the present invention can be
controlled approximately to the interval between 30 and 150.degree.
C. This entire interval is of relevance for therapeutic
applications. Cell necrosis occurs from about 45.degree. C.,
depending also on exposure time. The volume used for the treatment
of osteoporotic spine vertebrae is between 3 and 8 ml. For tumour
treatment in the spine typically 1-5 ml is needed. In vascular
treatment around 0.5-2 ml is typical.
Controlling the Temperature Rise During Curing
[0064] To generate high temperatures during curing of an injectable
bio-cement, at least the following factors need to be taken into
account: [0065] The choice of phase composition in the hydraulic
starting powder, and the hydrates that are formed during the
initial curing phase. Calcium aluminate phases rich on Ca hydrate
faster. For example, an increased amount of C.sub.3A increases the
hydration rate compared to pure CA, and thus higher temperatures.
Additions of CA.sub.2 to CA reduce the hydration rate. For heat
generating materials, compositions with C.sub.3A and
C.sub.12A.sub.7 in addition to CA and CA.sub.2 are of particular
interest for the present invention.
[0066] Of particular interest to the invention are powder
compositions with no or very small amounts of CA.sub.2 (which cure
very slowly). The amount of CA.sub.2 should be lower than 50 vol.
%, preferably less than 10 vol. %, based on the total of calcium
aluminate phases; the majority of the calcium aluminates being CA
and C.sub.12A.sub.7 (with intermediate curing rates), together
forming more than 50 vol. %, preferably more than 90 vol. %. In
addition a smaller part of C.sub.3A is desired, acting as
accelerator or trigger for the curing. The amount of C.sub.3A
should be less than 10 vol. %, preferably less than 3 vol. % of the
total amount of calcium aluminate phases. It is unique for the
present invention to control the temperature generation of relevant
volumes of material by choosing phase compositions within said
intervals. [0067] The grain size of the starting powder. Smaller
grains dissolve and hydrate faster, and thereby generate higher
temperatures. The grain size is controlled by pre-treatment of the
hydraulic cement powder with size reducing methods, e.g. milling.
The powder grain size is preferably less than 10 microns, more
preferably less than 3 microns. [0068] The hydration rate is
controlled by the addition of accelerator agents and/or retarder
agents. There are several accelerating additives known in the
field, e.g. Li-salts such as lithium chloride; as well as
retarders, e.g. sugar and various hydrocarbons. With combinations
of accelerators and retarders special curing effects may be
achieved, characterised by a period of no or very slow curing,
followed by a delayed stage of fast hydration; a curing cycle of
exponential character.
[0069] In the present invention, accelerators and retarders are not
primarily used to control curing time, as known within the field,
but rather to control the temperature generation.
[0070] Of particular interest are compositions cured with LiCl
solutions with about 10-500 mg of LiCl in 100 g of water; as well
as compositions cured with solutions containing combinations of
accelerators and retarders, e.g. LiCl and sugar, respectively.
[0071] Examples of other salts that may be used as accelerators
according to the present invention are: lithium hydroxide, lithium
carbonate, lithium sulphate, lithium nitrate, lithium citrate,
calcium hydroxide, potassium hydroxide, potassium carbonate, sodium
hydroxide, sodium carbonate, sodium sulphate and sulphuric
acid.
[0072] Examples of retarders that can be used according to the
present invention are glycerine, polysaccharide, sugars, starch,
and cellulose-based thickeners.
[0073] The ceramic compositions according to the present invention
further comprises a component which is a water reducing agent based
on a compound selected from the group comprising polycarboxylic
acids, polyacrylic acids, and superplasticisers, such as Conpac
30.RTM.. [0074] The amount of inert, non-hydraulic phases in the
cement composition. Non-hydraulic phases, e.g. non-hydrating
oxides, other ceramics or metals, may be added for purposes such as
increased mechanical strength and dimensional stability during
hydration. However, for increased temperature generation the amount
of non-hydraulic phases should be kept low. Non-hydraulic phase
concentrations of less than 30 vol. % are of relevance to the
invention, preferably the amount should be less than 10 vol. % of
the total of ceramic ingredients. In addition, non-hydraulic
additives may also affect the hydration rate. [0075] Also, the
total volume of hydrating material and the heat transfer to the
environment have an influence on the temperature that can be
obtained. The volume specific heat generation therefore needs to be
higher for smaller volumes of bio-cement, to reach the same
temperature. Or inversely, larger volumes of cement are beneficial
to generate high temperatures.
EXAMPLES
Example 1
[0076] This example describes the manufacturing procedure of a
ceramic cement consisting of hydrated calcium aluminate without
fillers, and serves to illustrate the effect of hydration rate on
the generated temperatures. Note that the achieved temperatures
also depend on other factors, such as volume of cured material and
heat transportation to the environment.
[0077] As raw material, the commercial product Ternal White.RTM.
from Lafarge Aluminates, is used. This is a calcium aluminate with
an Al.sub.2O.sub.3/CaO-ratio of about 70/3O.
[0078] The first preparation step was to reduce the grain size of
the powder. This was achieved by ball milling. The milling was
performed with a rotating cylindrical plastic container filled to
1/3 of its volume with Ternal White powder, and 1/3 with inert
silicon nitride milling spheres having a diameter of 10 mm. The
milling liquid was iso-propanol, and the total milling time 72 hrs.
This milling reduced the size of 90% of the grains to less than 10
.mu.m.
[0079] After milling, the milling spheres were removed by sieving
and the alcohol evaporated. Thereafter the milled powder was burnt
at 400.degree. C. for 4 hours, to remove any residual water and
organic contamination.
[0080] The second step was to prepare a hydration solution. The
solution consisted of de-ionised water, to which a water reducing
agent and an accelerator was added. The water reducing agent was
selected from a group of commercial so called superplasticisers,
Conpac 30.RTM. from Perstorp AB, known within the field, but any
other similar agent would also function. The superplasticiser was
added to a concentration of 1 wt. % in the water. The accelerator
LiCl was added in concentrations of 0.05, 0.08, 0.2 or 0.4 wt.
%
[0081] The prepared Ternal White powder and the water solutions
were mixed so that the ratio of the weight of water to the weight
of milled Ternal White.RTM. powder was 0.35. The powder-liquid
mixtures were cured in 10 ml plastic containers in air, and the
temperature development was recorded with a thermocouple introduced
into the centre of the cement volume.
[0082] The results are provided in FIGS. 1 and 2. FIG. 1 shows that
a concentration of 0.4 wt. % of LiCl in the hydrating solution
produces above 90.degree. C. during curing in a room temperature
environment, while FIG. 2 illustrates the much lower temperatures
achieved with a LiCl concentration of 0.05 wt. %, as well as the
slower hydration rate.
[0083] This example only serves to illustrate the curing rate
effect as achieved by additions of curing accelerators, in this
case LiCl, on the temperature.
Example 2
[0084] This example describes the different curing rates typical
for calcium aluminates of different phases of calcium
aluminate.
[0085] Three different calcium aluminate powders composed to 99% of
the pure phases CA, C.sub.12A.sub.7, CA.sub.3 are used as starting
materials.
[0086] Powder grain sizes of less than 10 .mu.m were achieved by
milling, as described in Example 1. The milled powders were also
burnt at 400.degree. C. for 4 hours, to remove any residuals.
De-ionised water without any additives was used as hydration
liquid.
[0087] The prepared powders were mixed with water keeping the ratio
of water to powder constant at 0.35, by weight. The powder-water
mixtures were cured in 10 ml plastic containers in air at room
temperature.
[0088] The hydration rates for the CA, C.sub.12A.sub.7, CA.sub.3
phases, measured as time to solidification, were measured to 4-6
hours, 5-10 minutes and 2-4 seconds, respectively.
* * * * *