Medical compositions

Cements for medical or industrial purposes contain watersoluble borate or phosphate glasses including multivalent ions e.g. zinc, aluminium or calcium and a poly (carboxylic acid) such as polyacrylic acid. As the glass dissolves ions or other reactive species crosslink the polymer.

This invention is concerned with improvements in and relating to curable 
compositions of the so-called "polycarboxylate cement" type and to the 
preparation thereof. Whilst it is especially directed to the production of 
splinting bandages loaded with such compositions, it has general utility 
in the field of cements for medical and nonmedical e.g. constructional 
uses. 
Compositions for the production of polycarboxylate cements, as described 
for example in British Pat. No. 1,316,129, generally comprise two 
principal components, namely a poly (carboxylic acid) or precursor 
therefor, and an ion-leachable glass, generally in powdered form. When the 
two components are brought into contact in the presence of water, ions are 
leached out from the glass and lead to the cross-linking of the polymer to 
form a polycarboxylate cement. 
It has now been found, in accordance with the present invention, that the 
ions used to cross link the poly (carboxylic acid) may be provided by 
certain glasses containing at least one multivalent metal (i.e. a metal of 
valency two or more) which glasses are wholly or substantially soluble in 
the presence of water and such polycarboxylic acid to form at least one 
reactive component capable of cross linking a poly (carboxylic acid). 
Glasses of this type, which can be used in the process and compositions of 
the present invention are described in British patent application Nos. 
23789/77 and 48193/77. 
The use of compositions containing such water-soluble glasses offers a 
number of advantages as compared to the use of compositions containing 
ion-leachable glasses. 
The most likely predominant mechanism appears to be that the small 
particles of glass are progressively dissolved or eroded to give metal 
ions in solution which link with the --COOH groups of suitably adjacent 
polymer chains to cause crosslinking. It is however conceivable that pH 
conditions are such that the metal reprecipitates as oxide or hydroxide 
once dissolved; in such a case the --COOH groups could link to a common 
precipitated particle to give a cross-linking effect. Also, it is possible 
that (especially as the original glass particles grow smaller) they 
themselves become similarly chemically bound and immobilised to various 
polymer chains, giving a different form of cross-linking. It is intended 
in the present invention to cover all these possibilities. 
In normal conditions it is expected that substantially all the multivalent 
metal ions in a water-soluble glass will be released on dissolution of the 
glass. With an ion-leachable glass as in the prior art only a proportion 
of such ions are released, and this proportion is not easily quantifiable. 
Accordingly it is now possible to calculate more accurately the amount of 
multivalent ions available for cross-linking the poly (carboxylic acid) in 
the case of the water-soluble glasses than in the case of ion-leachable 
glasses. In the latter case the rate and amount of multivalent ion release 
will depend upon various factors such as, for example, the composition of 
the glass, the concentration of carboxylic groups in the polymer and the 
state of subdivision of the glass. The present system provides release of 
ions which is irrespective of the amount of polymer at least until there 
are substantial changes of pH i.e. towards the end of the reaction, and 
therefore the setting reaction does not slow down until towards the very 
end of the process. Further, since the amount of multivalent ion release 
is independent of the carboxylic acid group content of the polymer it is 
possible using a water-soluble glass to cross-link polymers having a lower 
concentration of carboxylic acid groups than would be attainable using the 
ion-leachable glasses of the prior art. 
There is also the possibility of using a poly (carboxylic acid) which is 
already partly cross-linked and water-soluble; such a gelled material 
would not be mobile enough for use with the static ion-leachable glass 
particles. 
Accordingly, one aspect of the invention provides a method for the 
production of a cement which comprises bringing into contact (a) a 
phosphate or borate glass containing at least one multivalent metal, said 
glass being present in particulate and/or fibrous form and being wholly or 
substantially soluble in aqueous conditions to form at least one reactive 
component capable of cross-linking a poly (carboxylic acid) and (b) a poly 
(carboxylic acid) or precursor therefor or partially cross-linked form 
thereof and (c) an aqueous medium, preferably water. 
The man skilled in the art will realise that the particles or fibres can be 
free-flowing and separate or can possibly be part of a structure e.g. a 
woven or non-woven fabric or a foam or other matrix. 
The glasses used in accordance with the invention must be water-soluble 
preferably completely but in all cases substantially or almost completely. 
They should be soluble moreover at common ambient temperatures (e.g. 
5.degree.-30.degree. C.). While the applicants do not wish to be bound to 
this feature in the broad scope of their invention, they have found for 
most of the glasses utilised the composition and particle size in such 
that the glass dissolved, with constant agitation in excess water within 
10 minutes to one hour, e.g. in about 20 minutes, at ambient temperatures. 
It is conceivable that a small proportion of each glass particle will 
remain undissolved in practice of the invention and provide a reinforcing 
filler medium in the eventual cement, as discussed above. 
Secondly, the glasses must contain at least one multivalent metal, 
preferably calcium, aluminium or zinc, but possibly magnesium or barium 
and for non-medical uses possibly also iron, chromium, copper or vanadium. 
It appears that such metals are generally present in such a form that on 
dissolution in water the metals are released in ionic form. 
It is preferred for some purposes for the glasses according to the 
invention to be based on borate (measured as boric acid, B.sub.2 O.sub.3) 
since these give a cement which is water resistant after setting. Glasses 
based on phosphates (P.sub.2 O.sub.5 glass) give a water-softenable cement 
with a different range of uses. 
The multivalent metal, again measured in the glass as its oxide provides 
for cross-linking as the glass dissolves and also modifies the rate of 
dissolution of the glass. It is possible in either the borate or phosphate 
glass to use only a two-component glass e.g. B.sub.2 O.sub.3 /ZnO or 
P.sub.2 O.sub.5 /ZnO but it is preferred in each case to add a further 
oxide, preferably Al.sub.2 O.sub.3 but possibly CaO, in small amounts to 
reduce the rate of dissolution and thus alter the handling properties of 
the cement while wet. 
Up to 2% of silica and small amounts (up to 5%) of sodium can also be 
present in the glass to modify its rate of dissolution. Too much 
monovalent ion, however, affects the degree of cross-linking. 
In some applications part of the zinc oxide may be replaced by up to 10 
mole percent of magnesium oxide, the magnesium also providing a 
cross-linking inducing cation for a PAA cement. Suitable compositions for 
such glasses, which may have a zero alumina content are as follows, all 
percentages being mole percent. 
______________________________________ 
Boric Oxide Zinc Oxide Magnesium Oxide 
______________________________________ 
38.4 59.5 1.9 
38.6 55.7 5.7 
38.6 51.9 9.5 
______________________________________ 
In all these compositions the alumina and/or the magnesium oxide content 
determines the water solubility of the material. Increasing the content of 
one or both oxides decreases the water solubility. 
In further applications small quantities of other solubility determining 
oxides may be added to the composition. Thus, alkaline earth oxides and 
silica decrease the water solubility whereas alkali metal oxides increase 
the solubility. 
Such glasses will generally be prepared by fusing together the 
glass-forming components (e.g. on the one hand boric acid in the case of 
borate glasses or polyphosphoric acid or an alkali metal polyphosphate in 
the case of the phosphate glasses, and on the other hand the multivalent 
metal oxide or a precursor therefor) at an appropriate temperature usually 
800.degree.-1400.degree. C., and causing or allowing the final mixture to 
cool to form a glass. Such glasses are in fact easy to melt and prepare in 
particulate form. 
Broadly speaking from 10 to 65 mole percent multivalent metal oxide will be 
present in the glass, and not more than 15 mole percent of further oxide 
to modify rate of dissolution, but the amount will vary depending upon the 
nature of the composition in which the glass is to be used. 
A preferred specific composition is form 35-50 mole percent of B.sub.2 
O.sub.3, 0-15 mole percent (preferably 0-5) of Al.sub.2 O3 and 10-65 mole 
percent (preferably 35-65) of ZnO. 
For example the total amount of cation to be released expressed in terms of 
grams of metal oxide per gram of poly (acrylic acid) in the cement is 
shown below: 
______________________________________ 
Gram of metal oxide per gram of 
Cation poly (acrylic acid) 
______________________________________ 
Ca.sup.2+ 0.38 
Zn.sup.2+ 0.565 
A1.sup.3+ 0.472 
______________________________________ 
The cation content has been expressed in terms of the oxides since it 
appears important to neutralise the poly (acrylic acid) during the setting 
reaction. If a borate glass is used, it is unlikely that the borate union 
will interfere with tne neutralisation reaction, but the situation may be 
more complex in the case of a phosphate glass and additional metal oxide 
may be required. 
The ratio by weight of glass to poly (carboxylic acid) should usually lie 
in the range between 3:1 and 1:1. Assuming complete dissolution of the 
glass, the metal oxide content for each cation is shown in the table 
below: 
______________________________________ 
Metal Oxide Glass / Acid Ratio 
% in glass 1/1 2/1 
______________________________________ 
CaO 38% 19% 
ZnO 56% 28% 
A1.sub.2 O.sub.3 
47% 23% 
______________________________________ 
For convenience in handling and in order to ensure rapid dissolution the 
water-soluble glass will preferably be employed in finely divided 
particulate form, e.g. with a particle maximum dimension below 250 microns 
and preferably less than 75 or even 50 microns. 
Generally spherical particles are preferred and theoretically a close ratio 
of sizes is valuable for uniformity. In practice we have used four 
classified grades of glass particles, 0-75, 0-38, 10-75 and 10-38 microns. 
The poly (carboxylic acids) are usually based on unsaturated monocarboxylic 
acids, and their anhydrides and unsaturated dicarboxylic acids and their 
anhydrides being homopolymers of any one of these, copolymers between any 
two or more of these or copolymers between one or more of these and one or 
more further ethylenically unsaturated monomers. Specific compounds are 
acrylic, itaconic, mesaconic, citraconic, or maleic acid, or anhydrides 
thereof. 
Preferred homopolymers are acrylic acid or acrylic acid anhydride 
homopolymers. Copolymers with acids preferably utilise acrylic acid with 
acrylamide or acrylonitrile as the ethylenically unsaturated comonomer, or 
maleic acid with vinyl methyl ether. Copolymers with anhydrides preferably 
use ethylene, propylene, butene, or styrene for this purpose as the 
ethylenically unsaturated comonomer, e.g. maleic anhydride/ethylene 
copolymer. 
The number average molecular weight of the polymeric material may be from 
1,000 to 1,000,000, values of 50,000 to 5000,000 being preferred. 
However, as stated above, partially cross-linked gellable polymeric 
materials could also be used, such as the polyacrylic acid material 
partially cross-linked with diallyl sucrose known under the Registered 
Trade Mark of "CARBOPOL." 
The invention also provides a curable composition comprising (a) a 
water-soluble glass as described above and (b) the poly (carboxylic acid) 
or percursor therefor or partially cross-linked form thereof, optionally 
together with an inert reinforcing filler. 
The curable composition may be formulated in different ways. Thus in 
accordance with one embodiment the present invention envisages a two-part 
package of (a) particulate and/or fibrous glass and (b) the polymeric acid 
or partially cross-linked form thereof, preferably in the form of an 
aqueous solution. There is also the possibility of providing the acid or 
anhydride as dry powdered material separate from the particulate and/or 
fibrous glass, for mixing together and subsequent activation by adding 
water. Both of these possibilities find utility in the field of dental and 
surgical cements. 
It may be desirable to incorporate a reinforcing filler in the composition 
(e.g. in association with the water-soluble glass) and suitable fillers 
include finely divided inorganic material which is not water-soluble such 
as silicate glasses, quartz, alumina, titania, zircon and the like. 
Fillers are of course cheaper than the specialised glass component. 
Preferred filler particle sizes range up to 250 microns overall 
(particles) or 250 microns maximum diameter and 3 mm length (fibres) and 
most preferably below 75 microns e.g. from 5 to 50 microns. A filler with 
a suitable particle size distribution for close packing is particularly 
valuable. A possible weight range of filler is from 5 to 50 percent by 
total weight. Organic fillers, such as sawdust or milled polyvinylchloride 
scrap, are possible if the resultant shrinkage levels are acceptable. 
It is a major aspect of the invention to provide the curable composition as 
an intimate particulate mixture of the particulate and/or fibrous glass 
and particulate polymeric acid or anhydride, (or precursor therefor or 
partially cross-linked form thereof), optionally together with the 
particulate inert. The weight ratio (glass; polymer) is suitably from 
0.5:1 to 5:1, preferably from 1:1 to 3:1. The polymer preferably has a 
particulate size below 150 microns. 
It is also valuable if such a particulate mixture contains a minor 
proportion of a hydroxycarboxylic acid, specifically tartaric acid, to 
assist workability and increase eventual tensile strength. Up to 20% of 
such acid by weight, based on the weight of the poly (carboxylic acid) is 
envisaged, and from 5 to 15% is preferred. 
Another additive which can be incorporated is sodium chloride as an 
antishrinkage agent. Surprisingly, we have found that the inherent linear 
shrinkage of cements made according to the invention is only about 2.5% 
maximum compared to a shrinkage of about 10% in prior art materials of the 
ionleachable glass type, even though all of these latter still possess a 
substantial volume of substantially unchanged glass particles after 
setting. Thus, a small addition of sodium chloride, under 5% by total 
weight, is adequate to overcome shrinkage problems in the present 
invention, which is advantageous since too much sodium tends to compete 
with cross-linking ions. 
Such particulate mixtures can be presented for use as a two-part pack 
comprising (a) the mixture and (b) a suitable amount of water, but is most 
usefully presented in association with a substrate in the form of a 
flexible carrier which is porous or otherwise provided with interstices. 
The mixture may be located at the surface of the flexible carrier, or 
within the pores of interstices, or both. 
A major aspect of the invention is constituted by a splinting bandage 
wherein an intimate particulate mixture of the glass as described above 
and the polymeric material as described above possibly together with the 
filler as described above is carried on and/or intermingled with the 
fibres of a fibrous bandage substrate. 
The total coating weight of such a bandage can be from 200 to 500 
g/m.sup.2, i.e. of the order of ten times that of the bandage itself. 
The fabric of such a bandage is preferably a Leno weave cotton gauze, as 
conventional in this art. However, other woven or non-woven (stitched or 
netted) substrates based on multifilamentary or spun yarns comprising 
synthetic polymers e.g. polyamides, polyolefins and especially- polyesters 
are also envisaged. 
Such bandages may be formed by contacting the substrate with a slurry 
containing the particulate and/or fibrous glass and the polymer in an 
anhydrous liquid and allowing this liquid to evaporate. Contacting can be 
effected by dipping, brushing, spraying or like manipulative steps but is 
preferably done by spreading. The solids content of the slurry can be 
greater than 50% by weight. The anhydrous liquid is preferably a volatile 
organic medium e.g. methylene chloride. Usually an adhesive or binder will 
be present in the anhydrous medium, being soluble both in the said medium 
and in water serving to minimise loss of solids when the eventual bandage 
is dipped into the water prior to use. Up to 5% e.g. from 2.5 to 5% of the 
binder is preferable, (based on solids content of slurry) and hydroxyalkyl 
cellulose, specifically hydroxypropyl cellulose are valuable for this 
purpose. 
Such bandages are dipped in water applied while wet to the patient, 
smoothed and manipulated into the desired shape, and allowed to gel and 
set. Water uptake is usually about 50% of powder loading, although we have 
found that the system as described above tolerates operator variability in 
this regard. A method of treating a human patient, or an animal, utilising 
such a bandage in the above-specified manner constitutes an aspect of the 
invention, as does the hardened and set bandage.