U.S. patent application number 09/101375 was filed with the patent office on 2001-06-21 for macro-porous composite support for medicinal substance(s) that can be used as a bone reconstitution material and a method of producing it.
Invention is credited to CAREL, CLAUDE, GAUDE, JEAN-FRANCOIS, LUCAS, ANITA, MICHEL, JEAN-FRANCOIS.
Application Number | 20010004713 09/101375 |
Document ID | / |
Family ID | 9488239 |
Filed Date | 2001-06-21 |
United States Patent
Application |
20010004713 |
Kind Code |
A1 |
LUCAS, ANITA ; et
al. |
June 21, 2001 |
MACRO-POROUS COMPOSITE SUPPORT FOR MEDICINAL SUBSTANCE(S) THAT CAN
BE USED AS A BONE RECONSTITUTION MATERIAL AND A METHOD OF PRODUCING
IT
Abstract
The invention relates to a macro-porous composite that can be
used as a bone reconstitution material characterised in that it is
made up of a combination of synthetic aragonite and at least one
medicinal substance such as notably, an antibiotic. The invention
also relates to a method of producing a composite characterised in
that it consists of producing a mixture comprising grains of
synthetic aragonite and at least one porogenic agent, compacting
said mixture and heating the product obtained in such a way as to
eliminate said porogenic agent, at least one medicinal substance
being included before or after said step of eliminating of said
porogenic agent.
Inventors: |
LUCAS, ANITA; (RENNES,
FR) ; MICHEL, JEAN-FRANCOIS; (RENNES, FR) ;
GAUDE, JEAN-FRANCOIS; (ACIGNE, FR) ; CAREL,
CLAUDE; (RENNES, FR) |
Correspondence
Address: |
MERCHANT & GOULD
P O BOX 2903
MINNEAPOLIS
MN
55402-0903
US
|
Family ID: |
9488239 |
Appl. No.: |
09/101375 |
Filed: |
September 28, 1998 |
PCT Filed: |
January 2, 1997 |
PCT NO: |
PCT/FR97/00007 |
Current U.S.
Class: |
623/23.51 ;
623/23.56; 623/23.61 |
Current CPC
Class: |
A61L 2300/406 20130101;
A61L 27/025 20130101; A61L 27/54 20130101 |
Class at
Publication: |
623/23.51 ;
623/23.56; 623/23.61 |
International
Class: |
A61F 002/28 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 15, 1996 |
FR |
96/00560 |
Claims
1. A composite that can be used as a bone reconstitution material
characterised in that it is made up of a combination of synthetic
aragonite having pores and at least one medicinal substance.
2. A composite according to claim 1 characterised in that the
synthetic aragonite represents between 85% and 99.5% of the total
mass of said composite.
3. A composite according to one of claims 1 or 2 characterised in
that said medicinal substance is an antibiotic.
4. A composite according to claim 3 characterised in that said
antibiotic is metronidazole.
5. A method of producing a composite according to any one of claims
1 to 4 characterised in that it consists of producing a mixture
comprising grains of synthetic aragonite and at least one porogenic
agent, compacting said mixture and heating the product obtained in
a way that said porogenic agent is eliminated. At least one
medicinal substance being included before or after the step of
eliminating said porogenic agent.
6. A method according to claim 5 characterised in that said
porogenic agent is a solid compound in the form of a powder.
7. A method according to claim 6 characterised in that said powder
is made up of particles having a mean diameter of between 100 .mu.m
and 1000 .mu.m.
8. A method according to one of claims 6 or 7 characterised in that
said porogenic agent is naphthalene.
9. A method according to one of claims 5 to 8 characterised in that
said heating step is carried out at temperatures of the order of
110.degree. C. when said medicinal substance is introduced before
said step of eliminating said porogenic agent.
10. A method according to one of claims 5 to 8 characterised in
that said heating step is carried out at temperatures of the order
of 400.degree. C. or more when said medicinal substance is
introduced after said step of eliminating said porogenic agent.
11. A method according to one of claims 5 to 10 characterised in
that said compacting step is carried out by uniaxial pressing at
about 900 MPa (9 kbar).
12. A method of synthesising synthetic aragonite for the production
of a composite according to one of claims 1 to 4 characterised in
that it consists of bringing potassium hydrogencarbonate into
contact with calcium chloride at the rate of 2 moles of potassium
hydrogencarbonate to one mole of calcium chloride at boiling point
and at a pH of between 7 and 9.
Description
[0001] The invention relates to the field of bio-materials that can
be used to replace a part of the bone system.
[0002] The bio-materials are materials used to replace a part of
the living system or to function with it. They are made up of
materials that are foreign to the receiver, implanted in him in
order to restore the morphology and/or the function of tissues
damaged by trauma or by a disease. Therefore they all have the
novelty of having to work under biological constraints.
[0003] The bio-material must satisfy physico-chemical
characteristics appropriate to the site where it will be implanted
and to the function that it will have to fulfil. The chances of
success of a bio-material in an organism result from the product of
many factors which will all have to be controlled.
[0004] From the point of view of implants carried out with such
bio-materials, the bio-compatibility of them is defined as the
control of reactions of the organism with respect to them during
the entire duration of contact between the bio-material being
considered and the organism. Mechanical and biological properties
of such a product are therefore very closely linked.
[0005] The invention relates more precisely to bio-materials that
can be used as bone reconstitution materials.
[0006] In this field, coral has been proposed and has been widely
used for ten years or so. This natural material has a mineral
exoskeleton of open porosity formed, in the main, of aragonite.
Aragonite is an allotropic form of calcium carbonate, which
crystallises in an orthorhombic system with lattice parameters a
4.9623(3).ANG., b= 7.968(1).ANG., c= 5.7439.ANG. for Z= 4. Its
theoretical density is d= 2.93.
[0007] Within the state of the technology, it has been proposed to
use preparations based on coral as bone reconstitution materials
within the field of paradontology (paradontal diseases, bone
surgery correcting loss of substance). This material is used in
this context in the form of granules of size ranging from 300 to
450 .mu.m for the filling in of paradontal defects and from 600 to
1000 .mu.m for the filling of sockets after dental extractions.
Granules are preferred to blocks which lead to the exfoliation of
the coral fragment after its implantation, the size of the
particles recommended for the filling in of paradontal defects then
being from 300 to 500 .mu.m.
[0008] French patent application FR 2637502 describes a bone
reconstitution material made up of madreporous coral washed of any
original organic substances and containing an organic osteogenesis
accelerator in the form of a proteinic gel based on Type I
collagen.
[0009] International patent application WO 94/26322 discloses a
porous material made up of a coral skeleton (of the Porites,
Acropora, Goniopora, Lobophyllia, Simphyllia or Millipora type) and
a growth factor capable of being an osteo-inductive agent.
[0010] European patent application EP 398187 describes a
bio-material made up of coral coated with a layer of
hydroxyapatite.
[0011] Experience has shown that coral has a high bio-compatibility
that confirms that it is of interest as a material for bone
reconstitution.
[0012] However, such a material has the major disadvantage of high
cost brought about by its processing when it is to be used as an
implant material. In practice, coral gathered from nature must be
divided up, then washed and incubated for several days in products
such as sodium hypochlorite in order to remove all organic
substances from it. Such an incubation must be carried out in such
a way that the product used is able to penetrate into the entire
structure of the porous coral. Blocks of coral treated in this way
must then be broken up and sorted into granule size ranges, or
machined in order to be made geometrically suitable for the
implantation sites and then washed once again.
[0013] Furthermore, coral has a porosity that it is not possible to
control. In relation to the desired speed of resorption, it is
advisable to choose this or that type of coral in relation to its
natural porosity.
[0014] The main objective of this invention is to provide a
bio-material that can be used as a bone reconstitution material and
which permits this problem to be resolved.
[0015] Another objective of the invention is to disclose such a
material that can be produced in such a way that its properties,
notably its porosity properties, can be modulated as a function of
the use to which it is to be put.
[0016] Yet another objective is to provide such a material that is
able to include one or more medicinal substances with a view to
administering these substances with their release being to varying
extents.
[0017] These various objectives as well as others which will become
apparent in what follows have been achieved thanks to the invention
which relates to a macro-porous composite that can be used as a
bone reconstitution material, characterised in that it is made up
of a combination of synthetic aragonite and at least one medicinal
substance.
[0018] Such a composite has numerous advantages.
[0019] In the first place, it is a material based on aragonite and
it can be resorbed slowly in situ. The medicinal substance that it
includes will be able to be progressively released into the
organism and there can be a delay effect.
[0020] The fact that at least one medicinal substance is included
in the synthetic aragonite substrate offers additional interesting
potential therapeutic features through the local action of this
medicinal substance at a high concentration.
[0021] Furthermore and above all, since the aragonite used is
synthetic, it will be possible to modulate certain parameters at
the time it is synthesised. Hence it will be possible to provide an
aragonite substrate having pores of smaller or greater size, having
open or closed porosity, or a substrate that allows the production
of a material that is more or less dense or more or less rigid.
Furthermore one may modulate the nominal concentration of the
medicinal substance or substances in the composite. The use of
synthetic aragonite therefore offers a considerable advantage
compared with natural substrates, the pores of which obviously
cannot be varied in size or nature depending on the objective
sought and into which one cannot simply introduce foreign
substances in specific quantity.
[0022] Finally, it should be noted that the cost price of such a
composite will be much less than that of preparations based on
coral from the state of the technology. More precisely, one may
estimate that the cost price would be about 10 times less than that
for preparations based on coral.
[0023] The composite according to the invention will notably be
used in odontology, in particular in buccal surgery and in
paradontology and in surgical orthopaedics. However it should be
noted that the field of application of such composites is not
limited to this one domain of dentistry and that later extension to
bone surgery in general is totally conceivable.
[0024] Preferably, the synthetic aragonite will represent between
about 85% and 99.5% of the total mass of the said composite.
However depending on the use that will be made of the composite
produced, one may consider in certain cases going outside of such a
range.
[0025] According to a particularly interesting variant, said
medicinal substance is an antibiotic. The significance of
antibiotics is known and, as mentioned above, the composite
according to the invention allows the medicinal substance included
in the composite to be administered with a retard effect. This is
particularly of interest for antibiotics. Furthermore, one may
consider that such an antibiotic associated with an aragonite
substrate in this way could have a local action at high
concentration, with a quantity 100 to 1000 times less than that
required when administered through the normal route.
[0026] Advantageously said antibiotic is a broad spectrum
antibiotic such as metronidazole, the action of which on anaerobic
germs is much sought after in bone surgery.
[0027] The invention also relates to a method of manufacturing such
a macro-porous composite characterised in that it consists of
producing a mixture that includes grains of synthetic aragonite and
at least one porogenic agent, compacting said mixture and heating
the product obtained in such a way that said porogenic agent is
eliminated, at least one medicinal substance being included before
or after said step of eliminating said porogenic agent.
[0028] The medicinal substance or substances, if one or more
powders, can be added before heating, or if one or more fluid
substances after heating, by impregnation or by aspiration.
[0029] Preferably, said porogenic agent is a solid compound also
being in powder form. The size of the grains of powder making up
said porogenic agent will approximately correspond to the size of
the pore of the composite. According to an interesting variant, the
size of these grains will preferably be between 100 and 1000
.mu.m.
[0030] Also preferably, said porogenic agent is naphthalene
(C.sub.10H.sub.8). As will be explained in greater detail below, it
has been observed that the presence of naphthalene during the
compacting stage confers a multi-directional character onto the
orientation of the grains of aragonite that allows one to avoid
transverse breakage of the tablets obtained using the method
according to the invention. One could also consider using other
types of porogenic agents known from the state of the art.
[0031] In the preferred case where the porogenic agent used is
naphthalene, said heating step implemented in the context of the
method according to the invention is advantageously carried out at
a temperature of around 110.degree. C. leading to the sublimation
of the naphthalene. It will be understood that in the case where a
porogenic agent other than naphthalene is chosen, another heating
temperature may be used.
[0032] In a general manner, when said medicinal substance is
introduced before said step of elimination of the porogenic agent,
said heating step will advantageously be carried out at
temperatures of the order of 110.degree. C.
[0033] However, when according to a variant of the invention, said
medicinal substance is introduced after said step of eliminating
said porogenic agent, said heating step may be carried out at
temperatures of the order of 400.degree. C. or more.
[0034] Also preferentially, said compacting step is carried out by
uniaxial pressing. Such a pressing has the advantage of being able
to be easily implemented. One might be afraid that this type of
pressing would lead to preferential orientation of the crystals of
aragonite. However it turns out that the presence in the mixture of
grains of naphthalene and the sublimation of this porogenic agent
leads to the advantageous provision of crystals that are relatively
disoriented.
[0035] It is possible to consider the production of the aragonite
substrate via several synthesis routes known from the state of the
technology. Aragonite, under ambient conditions of temperature and
pressure is not the thermodynamically stable form of calcium
carbonate which makes obtaining it more difficult than obtaining
calcite which is the stable form.
[0036] One of the possible routes of access is to reproduce in the
laboratory the conditions of precipitation in an aqueous phase that
are present in nature, under ordinary temperatures and pressures.
Aragonite can thus be obtained from sea water, natural or
artificial, with a high concentration of Ca.sup.2-ions.
Precipitation can then occur after generation of carbonate ions
from a solution saturated with hydrogencarbonate, by removal of
CO.sub.2.
[0037] Another route consists of adding carbonate ions to the
solution of Ca.sup.2+ ions in the form of a soluble carbonate such
as Na.sub.2CO.sub.3. In this case, the addition of ions that favour
the precipitation of aragonite is essential.
[0038] The major disadvantage of these methods is slow kinetics
[0039] The carbonation of lime water, possibly containing
additives, or of a solution of calcium nitrate, in a basic
environment also permits aragonite to be obtained under certain
conditions.
[0040] Other methods are also known but they lead to low quantities
of aragonite and/or the presence of other forms (calcite,
vaterite).
[0041] The invention also relates to a method of synthesising
synthetic aragonite, that permits the provision of aragonite
possibly containing another form as an impurity, notably calcite,
under conditions that are economically interesting. Such a method
is characterised in that it consists of bringing potassium
hydrogencarbonate into contact with calcium chloride at the rate of
2 moles of potassium hydrogencarbonate to one mole of calcium
chloride, in a solution at boiling point and at a pH of between 7
and 9.
[0042] The invention will be more easily understood, with the help
of the description that will follow of a non-limitative embodiment
of the invention, making reference to the drawings in which:
[0043] FIG. 1 represents the X-ray diffraction diagram of the
aragonite obtained by synthesis in the context of this embodiment
example;
[0044] FIG. 2 represents a diagrammatic view of a tabletting mould
used for the compacting of a aragonite-metronidazole-naphthalene
mixture;
[0045] FIG. 3 represents the change in the geometric density of the
composites obtained as a function of the percentage by mass of
naphthalene used;
[0046] FIG. 4 represents the change in the porosity of the
composites obtained as a function of the percentage by mass of
naphthalene used;
Synthesis of the Aragonite
[0047] A solution of 0.1M calcium chloride was continuously added
to a 0.1M solution of potassium hydrogencarbonate having a pH of
8.6 at 20.degree. C., at the rate of 2 moles of potassium
hydrogencarbonate for 1 mole of calcium chloride. The addition was
carried out at temperature (between 90.degree. C. and 100.degree.
C.) with the help of a controlled addition device. The solution was
placed on a hot plate with a magnetic stirrer, the agitation being
provided by a magnetised bar turning at a speed of 500 rpm.
[0048] This addition lead to precipitation of calcium carbonate in
its aragonite form, in accordance with the reaction that can be
written as:
2KHCO.sub.3+ CaCl.sub.2.fwdarw.CO.sub.2+ H.sub.2O+ CaCO.sub.3+
2KCl
[0049] The precipitate obtained was filtered onto paper using a
Buchner funnel preheated to the drying temperature. Then the
precipitate was washed with boiling de-ionised water
(.apprxeq.100.degree. C.) and then dried in an oven held at
110.+-.2.degree. C.
[0050] Using X-ray diffraction, it was verified that such a
synthesis method allows one to obtain calcium carbonate CaCO.sub.3
in the form of aragonite with the absence of other phases.
[0051] More precisely, the X-ray diffraction diagram was recorded
at ambient temperature and pressure. This diagram is represented in
FIG. 1.
[0052] The granulometric analysis by volume of the product obtained
showed that all the grains had an equivalent diameter less than 62
.mu.m. The number distribution indicated that 99.8% of the
particles had an equivalent diameter less than 1.8 .mu.m.
Preparation of the Composite
[0053] Naphthalene with a purity greater than 99% (Scintillation
grade from the company Aldrich) was ground manually in a mortar and
sieved using a vertical vibration sieving machine for 15 minutes.
The openings in the sieves in the sieving machine were successively
250, 160 and then 100 .mu.m.
[0054] A specific fraction of naphthalene was recovered from the
sieve with the 100 .mu.m openings. Abstracting from the natural
tendency for particles of naphthalene to agglomerate, it could be
verified that the diameter of the particles recovered lay between
100 and 160 .mu.m.
[0055] In addition, metronidazole (1-(2-hydroxy-ethyl)
-2-methyl-5-imidazole) in the form of a 99.95% pure, very pale
yellow crystalline powder, supplied by the company Spcia (Rhne
Poulenc Group Rorer Spcia) was ground by hand and sieved using a
vertical vibration sieve machine for 15 minutes. The sieve openings
used in the sieving machine were 160 and 100 .mu.m.
[0056] The sieved metronidazole was then manually mixed, without
grinding with the aragonite powder obtained according to the method
described above and then with the particles of ground
naphthalene.
[0057] Three different mixes were produced, in which the ground
metronidazole was always 5% of the total mass of the said mixture,
the naphthalene being successively 28.6%, 21.1% and 14.6% of this
total mass.
[0058] A mass of 0.1 g of each of the mixtures of synthetic
aragonite, metronidazole and naphthalene produced was then placed
between the two metal cylinders 1,2 of a tabletting mould (SPECAC--
registered trademark--diameter 6 mm) as is represented in
diagrammatic form in FIG. 2. The compacting of the mixtures 3 was
carried out by application of a strong uniaxial pressure of 900 MPa
(9 kbar) using a piston 4. This pressure was maintained for 5
minutes and was then progressively reduced down to atmospheric
pressure.
[0059] The naphthalene was eliminated by heating the tablets in an
oven fitted with an electronic regulator at 90.degree. C., under a
primary vacuum, for six hours. Following this treatment, the
tablets were treated at 110.degree. C., under atmospheric pressure
for 16 to 17 hours, and then cooled in a dry atmosphere in a
desiccator.
[0060] A variant of the preparation of the tablets, after having
eliminated the porogene from the porogene/aragonite mixture at the
usual temperatures, consists of bringing the porous aragonite thus
obtained to temperatures of the order of 400.degree. C. or more,
possibly under carbon dioxide CO.sub.2 in order to cause sintering
that allows the strength of the tablet to be increased. After
cooling this can then be charged with medicinal substance(s) by
impregnation or aspiration.
Properties of the Tablets Obtained
[0061] The products obtained following the operation described
above are in the form of tablets free of naphthalene with a
thickness varying from 1.92 mm to 2.04 mm for a diameter of 6
mm.
[0062] The table below indicates the geometric density and the
porosity of the three tablets corresponding to the mixtures
above.
1 % (mass) naphthalene Geometric density Porosity (%) 28.6 1.28
.+-. 0.02 54.0 .+-. 1.3 21.1 1.47 .+-. 0.03 47.1 .+-. 1.6 14.6 1.64
.+-. 0.03 41.0 .+-. 1.6
[0063] As one can see in FIGS. 3 and 4 showing the data from the
table above, the geometric density of the composite obtained
decreases approximately linearly when the content of the porogenic
agent used increases and, conversely, the porosity of the composite
increases approximately linearly when the content of the porogenic
agent used increases.
[0064] Observation of samples under the electron microscope shows
the nature of the tablets and the keying of the metronidazole
crystals into the porous inorganic matrix at well differentiated
sites. The metronidazole crystals are either encapsulated or
positioned along a continuous line of porosity.
[0065] The use of naphthalene as the porogenic material lead to
egg-shaped macro-pores being provided the size of which is related
to the choice made for the size of naphthalene particles, being
between about 100 and about 160 .mu.m. Furthermore, it has already
been indicated that the presence of naphthalene during compacting
confers a multidirectional character on the orientation of the
aragonite particles that allows one to avoid transverse fracture of
the tablets.
[0066] The embodiment of the invention that has been described here
does not have the purpose of reducing the range of the invention.
Hence it is possible to consider the introduction of modifications
without departing from the scope of the invention as defined in the
appended claims. Notably, the use of a medicinal substance other
than an antibiotic such as metronidazole might be considered, from
the point where this substance may be incorporated before or after
the manufacture of said porous composite. Of course a porogenic
agent other than naphthalene could be considered although this
still remains the preferred porogenic agent.
* * * * *