SURGICAL CEMENTS

CIMENTS CHIRURGICAUX

English Abstract

There is described a surgical cement comprising a bulking agent, a polymerisable monomer and an activator characterised in that the
polymerisable monomer is an acrylate; methods for its preparation and its use.

French Abstract

L'invention concerne un ciment chirurgical comprenant un agent de gonflement, un monomère polymérisable ainsi qu'un activateur, caractérisé en ce que le monomère polymérisable est un acrylate; l'invention concerne également les procédés de préparation et d'utilisation dudit ciment.

Claims

CLAIMS
1. A surgical cement comprising a bulking agent, a polymerisable
monomer and an activator characterised in that the polymerisable
monomer is a compound of formula I,
<IMG> I
in which n is an integer from 1 to 6, and
X is halogen, or (trialkylsiloxy) silyl.
2. A surgical cement according to claim 1 wherein X is chloro.
3. A surgical cement according to claim 1 wherein the compound
of formula I is 2-chloroethyl methacrylate.
4. A surgical cement according to claim 1 wherein the compound
of formula I is tris(trimethylsiloxy)-3-silylpropyl methacrylate.
5. A surgical cement according to any one of the previous claims
comprising a solid and a liquid component system.
6. A surgical cement according to claim 5 wherein the solid
component comprises a bulking agent.
7. A surgical cement according to claim 5 wherein the bulking
agent contains a compound of formula I in polymerised form.
8. A surgical cement according to claim 5 wherein the liquid
component comprises a polymerisable monomer and an activator.
9. A surgical cement according to claim 1 which is radio-opaque.
10. A surgical cement according to claim 1 comprising from 0.5 to
50% w/w of a compound of formula I.

11. The use of a compound of formula I,
<IMG> I
in which n is an integer from 1 to 6, and
X is halogen, or (trialkylsiloxy) silyl,
in the manufacture of a surgical cement.
12. A method of fixing a prosthesis into a patient which comprises
the application of a surgical cement according to claim 1 to an
implantable prosthesis prior or during implant.
13. A method according to claim 12 wherein the implant is an
orthopaedic implant.

Description

- 2 1 7 1~ 9 ~ c ~r ~r c ~ r ~
r
CEMENTS
The present invention re!ates to cements and, in particular
surgical cements such as bone cements and dental cements
Bone cements are frequently used in the fixation of prostheses
to living bone. Such cements are typically polymeric materials. It is
known to use acrylic monomers in the preparation of such polymeric
cements, however, they suffer from the disadvantage that residual
low molecular weight acrylates may be present in the cements and
the cements may suffer from fatigue fractures. In addition,
excessive heat may be generated on curing known cPments.
Improved bone cements are known from European Patent
Application No.218471. Bone cements described therein comprise
a solid powder phase, eg. a bulking agent, comprising n-butyl
methacrylate.
It is also known to use polyacrylates as, eg. film coatings in the
area of woundcare, for example, British Patent No.G81278572
describes the use of monomers such as methoxyethyl methacrylate
in the preparation of woundcare films.
Orthopaedic cements are also known from US Patent
No.4404327 which describes cements prepared from a mixture of
methacrylate monomers and a polymer in powder form, formed from
an ester or esters of acrylic or methacrylic acid. However, there is
no discfosure in US Patent No.4404327 of the use haloalkyl
methacrylates or (trialkylsiloxy)silyl methacrylates.
JP-A-49057054 describes dental adhesives comprising (meth)
acryloxyalkylenetris(dialkyl-siloxy)silane however there is no
disclosure of the use of trialkyl siloxy silyl moieties.
We have now surprisingly found that certain monomeric
acrylates are useful as polymerisable monomers in the preparation
of surgical cements.
A~lENo~o SHEE7

2171429
.
According to the invention we provide a surgical cement
comprising a bulking agent, a polymerisable monomer and an
activator characterised in that the polymerisable monomer is a
5 compound of formula 1,
CH
Il 2
CH3CC02(CH 2) nX
in which n is an integer from 1 to 6, and
X is halogen or (trialkylsiloxy)silyl.
~- When X is halogen it may be bromo, fluoro, iodo but preferably
chloro. When X is (trialkylsiloxy)silyl, the alkyl group defined therein
15 may be alkyl C1 to 6, preferably alkyl C1 to 4 and especially methyl.
It is not essential, but preferable, that the three alkyl groups in the
trialkylsiloxy moiety are the same.
The integer n is preferably from 1 to 4. When X is halogen, n
20 is preferably 1 to 3 and especially 2. When X is (trialkylsiloxy)silyl,
n is preferably 2 to 4 and especially 3.
Thus, the most preferred silyl methacrylate is tris
(trimethylsiloxy)-3-silylpropyl methacrylate (TRIS) which is available
25 from Fluorochem in the UK. The most preferred haloalkyl
methacrylate is 2-chloroethyl methacrylate (CEMA) which is
available from Lancaster Synthesis in the UK.
The surgical cement according to the invention may comprise
30 a solid and a liquid component system. The solid component may
comprise a bulking agent whilst the liquid component comprises a
polymerisable monomer as hereinbefore defined and an activator.
The bulking agent usually comprises a powdered methacrylate
35 polymer, eg. a methacrylate such as polymethyl methacrylate
..
~ ~,.

2171429
.
2a
(PMMA). Alternatively, the bulking agent may contain a compound
or a mixture of compounds of formula I in polymerised form.
Any conventionally known activators may be used, but
preferred activators are toluidines and especially N-alkyl C1 to 6
toluidines, eg. N,N-dialkyl toluidines such as N,N-dimethyl toluidine.
A polymerisation initiator will be required for the cement to
cure. The initiator may be included in the solid component. Such
initiators include radical initiators, such as peroxides, eg. benzoyl
.,

WO 95/07107 ~ 1 7 1 ~ ~ 9 PCT/GBg4/01970
peroxide, thus polymerisation of the monomer, leading to cement
setting or curing may start SpG nld~leously when the solid and liquid
components are mixed.
..
Allen~ali~/ely, redox initiators may be used. A redox initiator
may be included in the solid or liquid component. Curing can be
initiated in the presence of a redox initiator by the addition of water.
Preferred oxidising or reducing agents of redox catalysts are those
described in European Patent No.94222. One such prere
initiator may be sodium metabisulphite/Cu (Il).
The solid and liquid con~ponents may be supplied as a
premixed cen~ei ll. Polymerisation of the premixed cen,ent may be
inilialed either by the addition of a radical initiator, or aller"ali./ely a
redox initiator may be included in the premixed cement such that the
illilidliull may be co"""el1ced by the addition of water.
In order to avoid premature setting it is essential that the
initiator and the activator be in separate components of the system.
In the case of radical activated cemer"s the activator, is preferaL ly
in the liquid co",po"ent and thus the initiator is preferably in the
solid component, or alternatively the initiator may be added
separately, eg. to the premixed cement. It is a particular advantage
of the redox catalysed system that the initiation reaction is catalysed
by the addition of water which may be added separately.
The cement accGrdil)g to the invention may optionally
coi"~,ise a radio-opaque material. Such radio-opaque materials are
preferably incorporated into the solid component phase. Any
conventional radio-opaque materials may be used, but prerer, ed
materials include salts, such as zirconium and/or barium salts, eg.
zirconium dioxide and/or barium sulphate.
By the inclusion of monomers such as compounds of formula I
in either the polymerised form or as monomeric components, an
improved surgical cement can be formulated which benefits from
having one or more of the following properties:

WO 95/07107 PCT/GB94/01970
2~ 71~29 4
(i) a lower glass transition temperature material such as
TRIS which has a crack blunting function and as such improves the
fatigue properties of the surgical cement,
(ii) red~ ~ced odour; and
(iii) radio-opacity.
In addition, if incorporating a compound of formula I in the
10 polymerised form in the liquid component or a premixed cement this
red(lces the conce, Ill aLion of polymerisable double bonds prior to
set and hence reduces the amount of heat generated for a specific
quantity of cement.
A readily activatable cement can be prod~ ~ced which, eg. on
~xposl ~re to a water-activated polymerisation catalyst, produces a
cement of good strength.
The present invention in a still further aspect provides the use
of a co""~ound of formula I in the manufacture of a surgical cement
or a col"ponent of a surgical cement as hereinbefore described.
Generally the compound of formula I accounts for 0.5 to 50%
w/w of the solid and liquid component system or of the premixed
cement.
The present invention is a still further aspect provides the use
of a compound of formula I in the manufacture of a surgical cement
or a component of a surgical cement as hereinbefore described.
A water curable composition accordi, lg to the invention may
include those water-activatable vinyl polymerisation catalysts
described in European Patent No.94222.
Suitable vinyl polymerisation catalysts of this type are well
known in the literature.

~ = =
WO 9S/07107 2 17 1 ~ 2 9 PCT/GB94/01970
Where the catalyst is a redox catalyst the premixed cer"ei1l
may be in association with the oxidising agent or reducing agent or
preferably both.
The amount of catalyst used in the polymerisation process eg.
in ~ssoci-lion with the premixed ce",e"t is suitably 0.1 to 10% by
weight and prererably 0.2 a~.p, oxi,Y~ately 3% eg. 0.2 to 2% by
weight of the prepolymer.
Desirably in surgical cei"ents of the present invention those
compollel 11~ containing polymerisable material may be in
~.ssoci~tion with a polymerisation inhibitor to prevent premature
poiymerisation during its p,epa,dlion and storage.
Suitable poly",e,isalion inhibitors include polymerisation
inhibitors of the art. A favoured inhibitor for preventing premature
polymerisation of such polymerisable materials during storage is
p-methoxyphenol.
In use curing of the cements may be brought about by either
mixing of the solid and liquid co",ponents or adding a suitable
initiator or water to the premixed cement.
By the term surgical cement we mean bone cements and/or
dental cel"el,ls although bone cements are preferred.
Accor.ling to the invention we also provide a method of fixing a
prosthesis into a patient which comprises the application of a
surgical cement accordi"g to the invention to an implantable
prosthesis prior or during implant.
By the term prosthesis we include surgical ie. orthopaedic or
dental ie. orthodontic prostheses.
The invention will now be illustrated but in no way limited by
the following Examples.

WO 95/07107 PCT/GB94/01970
2 9 6
Example 1
The liquid component for a 4 bone cement formulations are
shown in Table 1. Formulation 1 was the control. For each
5 formulation each of the ingredients was measured into a small
beaker and mixed thoroughly.
~,
TABLE I
Forrnulation No. 1 2 3 4
Methyl r"ell ,aa ylate Oml 1 9ml 1 8ml 1 6ml
NN dimethyl toluidine .4ml .4ml .4ml .4ml
TRIS - 1 ml 2ml 4ml
For each of the above formulations 33.69 medium MW
polymethylmethacrylate powder was mixed with 5.99 zirconium
dioxide and 0.49 benzoyl peroxide. To this the required liquid
c~,l"~o"ent was added and stirred in for 1 minute ev~Gu~ted for 1.5
15 minutes and then poured into dumbell moulds. After 30 minutes
curing was complete and the dumbells were removed from their
moulds.
The dumbells were tested for ulli",ate tensile strength.
The results are illustrated in Table ll.
TABLE ll
Forrnulation No. Mean Tensile Strength (M/Pa)
23.3
2 24.5
3 25.5
4 16.5

WO 95/07107 PCT/GB94/01970
2~7~29
ExamPle 2
The liquid cor",vo"ent for 3 bone ce",enl formulations are
shown in Table 1. Formulation 2 was the negative control and 3 the
5 positive control. For each formulation each of the ingredients was
measured into a small beaker and mixed thoroughly.
TABLE I
Formulation No. 1 2 3
Methyl metl,ac,~late - 20ml 20ml
Chloroethyl ~ Lha~ylate 20ml
NN dimethyltoluidine 0.4ml 0.4ml 0.4ml
TABLE ll
Formulation No. 1 2 3
Medium MW poly methyl 36.3g 36.39 36.39
Illell ,ac, ylate
Zirconium dioxide - - 5.99
Benzoyl peroxide 0.4g 0.49 0.49
Each of the powder components were made up by mixing the
15 dry ingredients in a 4OZ bottle. To each the required liquid
component was added and stirred in for 1 minute evAc~ ted for 1.5
minutes and then poured into dumbell moulds. After 30 minutes
curing was complete and the dumbells were removed from their
moulds.
The dumbells were x-rayed to det~r",ine relative film
exposures.