IE57251B1 - Use of difunctional acrylic and methacrylic esters for making hardenable bone cements - Google Patents

Abstract

1. Use of difunctional acrylic or methacrylic esters of the general formula see diagramm : EP0123323,P6,F2 in which a has the value 1 or 2, b the value 1 or 2, m the value 0, 1 or 2, n the value 0, 1 or 2, R**1 denotes H or CH3 , R**2 denotes H, CH3 or C2 H5 and R**3 denotes H or CH3 in hardenable bone cements for cementing bones.

Description

This invention relates to the use of special difunctional acrylic and methacrylic esters in hardenable bone cements for cementing bonels. Bone cements usually consist of two components to be mixed and can be used for securing artificial joints, filling bone defects or adhering bone parts to each other.

Hitherto as bone cements compositions were generally used which were obtained by mixing a powder with a liquid and subsequent swelling. The powders are polymers or .copolymers of acrylic esters or methacrylic esters, preferably copolymers of methyl metliacr y I at e and methyl .Ruyl.ite in the form of fine beads with a typical particle size of about 50 μπι. To this polymer X-ray · contrast agents, for example barium sulfate or zirconium dioxide are added and usually an antibiotic as well.

In addition the powder contains a peroxide as polymerization initiator.

As liquid methyl methacrylate is generally used which in most cases is mixed with a dye and contains as polymerization accelerator an aromatic amine, for example N,N-dimethyl-p-toluidine. Such a bone cement is described for example in DE-OS 2,511,122.

A disadvantage of these bone cements is their high temperature development in curing and the relatively high toxicity of the methyl methacrylate which passes into the circulatory system and in some cases produces a dramatic reduction in the blood pressure. The high temperatures can damage the surrounding tissue which can result in loosening of the connection between cement and bone. The combined toxic and thermal action has sometimes led to fat embolisms. The strength of these bone cements was also inadequate for many applications, for example securing artificial hips, which resulted in loosening of the implants.

Numerous attempts have been made to obviate the disadvantages outlined above of conventional bone cements havinq a methyl methacrylate base.

According to DE-OS 2,552,070 to avoid the temperature increase the monomeric methyl methacrylate is used in an aqueous emulsion. However, this cement provides no improvement as regards strength and toxicity.

As described in DE-OS 2,724,814, to improve the mechanical properties inorganic fillers have been additionally added to the polymeric methacrylates. However, in the hardening of these cements the difficulties as regards the heat development and toxicity remain unchanged. The admixing of apatite or carbon fibres described in EP-A 0 006 414 also i lends to similar'results. The reinforcement wi£h sponge-like elements according to DE-OS 3,042,003 leads only to an Improvement in the mechanical strength without overcoming the other difficulties referred to.

According to DE-PS 2,229,702 an attempt was made to replace part of the monomeric methyl methacrylate by monomeric Isobutyl methacrylate. However, this •resulted only in a reduction of the temperature peak without solving the toxicological and mechanical problems satisfactorily.

The so called low viscosity bone cements of DE-OS 3,106,4S2 also produce only an improvement of the anchoring of the bone cement in the irregularities of the bone. The teaching of this publication does not overcome the problems due to the heat development and the toxic action. Finally, EP-A 0 037 759 describes the use of epoxides together with the polybutadienes containing hydroxyl groups as hardenable component for a bone cement. However, this cement is not practical in use because it must be mixed together from four components. Moreover, the curing of these cements takes a relatively long time although mercapto-2ethanol is used as accelerator.

Another serious disadvantage is the offensive odour of mercapto-2-methanol· According to the invention it has been found that bone cements meeting the above requirements can be obtained if as polymerizable component of these bone cements difunctional acrylic or methacrylic esters of the following general formula The problem underlying the invention is to provide an easily workable bone cement which in the curing results in a small temperature rise, is distinguished by low toxicity and high strength of the polymers and hardens rapidly. β J are used i: n which a is 1 or 2, b is 1 or 2, m is 0, 1 or 2, n is 0, 1 or 2, 2 is H or ch3, R is H, C H3 or C2H R3 is H or ch3.

Compounds of this type and their use in dentistry V are described in DE«-PS 1,921,869 and DE-AS 2,656,847.

However, in view of the completely different problems involved compared with dentistry it could not have been expected that of the multitude of acrylic and methacrylic esters which have been used in dentistry precisely the substances according to the invention would give suitable bone cements. Among other things, in the field of bone cements the following factors play a part which are of only secondary significance for compositions to be used in dentistry. In bone cements the toxicity of the individual constituents· plays a particularly important part because it is to be expected that the cements will be absorbed directly into the surrounding tissue and the circulatory system whereas in the case of dental compositions an absorption of the constituents is to be expected only in exceptional cases and can be suppressed by using a so called underfilling. Moreover, in the filling of teeth the heat development of the compositions during curing is only of minor significance because the amounts used are relatively small and the tooth material is relatively temperature resistant and ensures a good and rapid heat dissipation. Of course, in the case of bones, which are covered all round, a substantially slower temperature equalization is to be expected and furthermore the amounts used are relatively large; there is also a danger that by elevated temperatures surrounding tissue is damaged and proteins and the like are denatured.

Finally, teeth and bones differ as regards their structure, their mechanical properties and their regular mechanical stressing to such an extent that it was not possible to draw from the suitability of certain materials as dental filling materials conclusions as to whether such substances are also suitable as bone cements. This is also confirmed by the fact that of the compositions hitherto used for dental purposes none of the products has proved to be a satisfactory bone cement. The methacrylic esters and dimethacrylic esters used according to the invention can be made by the methods described in DE-PS 1,921,869 and DE-AS 2,656,847.

Crystalline representatives of the substance classes used according to the invention, if they have melting points below about 40°C, can be brought by hea.ting into a fluid form suitable for application , Preferably, however, they are dissolved in a liquid representative of the substance class according to the invention or in another liquid physiologically neutral medium and used in this form.

Generally, the substances used according to the invention can be employed with other physiologically neutral acrylic esters or methacrylic esters.

Preferred are higher molecular, in particular difunctional, acrylic or methacrylic esters such as decane di(meth)acrylate or bis-hydroxymethyl-tricyclo [5.2,1,0^'B]decane di(meth)acrylate. Such additives may for example be desired as thinners.

Preferably, however, the said substances are used alone, in particular the compounds present in liquid form. Due to their low toxicity, in particular V methacrylates are preferred. A particularly preferred product is 2,2-bis-|p-(jp-hydroxypropoxy)phenylj-propane dimethacrylate, which Is liquid at room temperature.

This compound can be made according to example 10 of DE-PS 1,921,869.

The acrylic and methacrylic esters used according to the invention can contain the usual antioxidants, stabilizers, plasticizers, and/or pigments.

The hardening can be effected with all usual polymerization initiators. Of course, for bone cements only the techniques of cold setting are suitable. The initiator system peroxide/aromatic amine is preferred. Suitable peroxides are for example dibenzoyl peroxide, bis-(p-chlorobenzoyl) peroxide or bis-(p-tert.-butylbenzoyl) peroxide. Suitable amines are for example N,N-dimethylp-toluidine or the tert.buty1-subsituted anilines described in DE-OS 2,658,538.

Further suitable initiator systems are the combinations of barbituric acid/peroxide/copper compound /halide ion which are described in DE-AS 1,495,520 and the combinations malonyl sulfamide/peroxide/halide ion/ copper -compound explained in DE-OS 3,107,577. In particular, the use of malonyl sulfamides as polymerization initiator leads to particularly low temperature peaks during the curing operation.

The initiator constituents are used in the usual concentrations which must be chosen so that the physician has sufficient working time to bring the I bone cement into the desired situation. On the other hand a relatively rapid hardening must be ensured to permit the shortest possible duration of the surgical operation.

To increase the mechanical strength, to reduce the polymerization shrinkage, to further reduce the temperature peak and to obtain a consistency favourable for working, the bone cement according to the invention is generally used together with a filler.

The filler quantity may be 10 to 80 and preferably 20 to 70 % by weight.

All the usual organic fillers may be employed, such as poly (me th) acrylates or polyamides. Poly (methyl methacrylate) and copolymers of methyl .methacrylate and methyl acrylate have proved very suitable.

Inorganic fillers have also proved suitable. Suitable in part--i mil ar are silicic acid , silicate glasses, ceramic, quartz and minerals, such as, for example, apatite and calcium fluoride. Carbon fibres and other physiologically neutral fibrous reinforcing fillers can also be employed. When silicate fillers are used it is expedient to subject them to a surface treatment for binding, into the acrylate or methacrylate matrix. Suitable is in particular the known treatment with silanes, preferably with ^-methacroyloxypropyl trimethoxy silane.

To impart X-ray opacity to the bone cement at least partially X-ray visible fillers or additives are used. Suitable X-ray opaque substances are barium, strontium t'J or lanthanum-containing glasses, but also barium sulfate, lanthanum oxide, bismuth phosphate , calcium tungstenate or other known X-ray positive additives. Fundamentally, the x-ray opacity can also be achieved by introducing heavy atoms, for example bromine or iodine atoms, into one of the polymerizable monomers ς or into a polymeric additive.

To control the viscosity and prevent the settling of the fillers it has been found suitable to add to the bone cement according to the invention microfine silicic acid which can likewise be surface treated with silane. Microfine silicic acid may however also be used in a larger amount directly as a filler.

To control the viscosity and to influence the elasticity behaviour of the cured bone cement it may furthermore be advantageous to add soluble polymers to the monomers.

Usually, the bone cements according to the invention are offered in two components amongst which the active components of the initiator system are so distributed that a good storability of the separate constituents is obtained.

Thus, for example, the peroxide may be admixed with the filler whilst the amine may be dissolved in the monomer mixture containing the polymerizable monomers according to the invention. The bone cement is prepared by mixing liquid with solid shortly before * application.

Advantageously, in particular when using inorganic fillers, the bone cement may also be made available in the form of two pastes. The first paste consists of a mixture of peroxide dissolved in monomer with filler and other usual additives whilst the second paste is made from a monomer/amine solution and filler and further additives. In this manner, intensive kneading and/or evacuation by the maker a particularly good wetting of the filler by the * monomer liquid can take place, and this contributes to increasing the mechanical strength of the cured cement. The bone cement is made in simple manner by mixing equivalent parts of the two pastes shortly before application and can be applied immediately.

It is however also possible to dissolve the amine in the total monomer part and work it with the total filler to form a paste into which shortly before application the solution or suspension of the peroxide in a plasticizer is worked.

When using barbituric acid or malonyl suIfamide initiator systems in favourable manner the copper compound and the halide ion donator are dissolved in the liquid monomer phase. This solution can now be mixed with the filler whilst barbituric acid or malonyl sulfamide on the one hand and peroxide on the other together with a plasticizer are stored separately and mixed together shortly before application. It is however alternatively possible to mix barbituric acid or malonyl sulfamide and peroxide in solid form into the filler and to mix with the copper and halidej containing monomer solution immediately prior to application.

It is also possible in a manner known per se to add to the bone cement medicaments, e.g. antibiotics for preventing inflammations. As antibiotic gentamycin has proved particularly suitable.

The components of the bone cement must be prepared for use in sterile form. Insofar as the individual components are not per se sterile they can be sterilized by methods known per se, for example by ionizing radiation, by heating, by sterile filtration or by treatment for example with ethylene oxide. It v should be ensured that the active initiator components, for example the peroxide, are not destroyed.

To control the mixing with two-paste systems and for better contrast in the operation situation it is expedient to add pigments and/or dyes to the bone cement. Particularly suitable are physiologically completely neutral colouring constituents, for example chlorophyll or ultramarine blue.

The examples explain the invention.

Example 1 A solution of 1.4 g p-chlorobenzoyl peroxide in 142.5 g 2,2-bis-fp- (-hy dr oxy p r opoxy) pheny lj propane dimethacrylate is carefully kneaded under vacuum with 20.0 g pyrogenic -silicic acid and 213 g silanized quartz to form a homogenous paste (paste A).

A solution of 0.32 g N,N-bis-hydroxyethyl-3,5-di-tert.butyl aniline in 142.5 g 2,2-bis-[p-(f-hydroxypropoxy)phenyl/ propane dimethacrylate is carefully kneaded in vacuo with .0 g pyrogenic silicic acid, 140.0 g barium sulfate for X-ray purposes and 97 g finely divided silanized > quartz, and 160 mg chlorophyll to form a homogeneous paste (paste B).

Equal parts by weight of paste A and paste B are ia homogeneously mixed. A plastically deformable bone cement Is obtained which can be worked for about 5 minutes at room temperature and after about 10 minutes has solidified to form a hard mass. w 5 The compressive strength of the cement is 170 MPa and the bending strength 85 MPa. ύ Implantation of the bone cement in animal bones The upper half of the caput femuris was sawn off a pig's bone and a hole drilled in the medullary space. The interior of the medullary space was scraped out with a curette and thereafter flushed with Ringer's solution. A fresh mixture of paste A and paste B (1:1) was introduced into the medullary space. After the hardening of the cement the femur shaft was sawn open on the longitudinal side and inspected visually.

The cement bonded well to the spongiosa and to the Inner wall of the bone. It could not be broken out without destruction.

Dynamic investigation on the test simulator A used hip joint socket (increased friction) was embedded with a 1:1 mixture of the pastes A and B in a plastic block. After 200,000 cycles under a load of about 350 kp and in each case a tilting, movement through 45° by the corresponding joint ball in a J test simulator no signs of loosening or crack formation Ί at all were detected.

Example 2 73.5 g peroxide solution of example 1 is kneaded in vacuo with 10.0 g pyrogenic silicic acid and 55.7 g granulated silicic acid (silanized) according to WO 81/01366 to form a homogeneous paste (paste C).

Furthermore, 71.5 g of the amine solution of example 1 is kneaded under vacuum with 10.0 g pyrogenic silicic acid, 70.0 g barium sulfate, v 7.0 g granulated silicic acid (see above) and 400 mg chlorophyll to form a homogeneous paste ft (paste D).

By mixing equal parts by weight of pastes C and D a bone cement is obtained which can be worked for .50 minutes and has set after 8.50 minutes. The compressive strength is 168 MPa and the bending strength 78 MPa.

Comparative tests In the following table the physical data of two commercially usual bone cements on the basis of methyl methacrylate /poly (methyl methacrylate/jnethyl acrylate) are compared with the data of the bone cements according to the invention in accordance With examples 1 and 2.

Table Cement Max, temperature rise on polymerization (e C) Compressive . strength (MPa) Surface hardness (MPa) Water absorption (%) According to example 1 12 170 189 0.1 According to example 2 15 168 191 0.2 Commercial product 1 (Palacos, Kulzer) 32 94 130 1 .6 Commercial product 2 (ΆΚΖ, Howmedica) 31 108 - -

Claims (3)

1. Use of a difunctional acrylic or methacrylic ester of the general formula in which a is 1 or 2, b is 1 or 2, m is 0, 1 or 2, n is 0, 1 or 2, R 1 is H or ch 3 . 1, R 3 is H, CH 3 or C 2 H 5 and is H or ch 3 i in hardenable bone cements for cementing bones. 10

2. Use according to claim 1, wherein 2,2-bis[p(jf-hydr oxy propoxy) pheny lj propane dimethacrylate is used as a difunctional methacrylic ester.

3. Use accoring to claim 1, substantially as hereinbefore described and exemplified.