Tricalcium phosphate for use as implants

The invention relates to an absorbable porous tricalcium phosphate which is suitable as an additive to implant materials based on polyacrylates and / or polymethacrylates, its pores are filled with a biocompatible, resorbable filler.

It is known eg from DE-OS 29 05 878., implant materials, in particular bone cements based on polyacrylates and / or polymethacrylates, admix a resorbable in the body tricalcium phosphate, in order to achieve a good bony adhesion of the implant to the surrounding bone tissue. Also in DE-OS 29 05 878, the problem has already been mentioned that the pores of a porous tricalcium phosphate must be closed by a suitable filler, to the absorption of liquid acrylate or during mixing of the cement. Methacrylate monomers into the pore system, and thereby avoid the disadvantages caused. Fillers are mentioned there glycerine, water or aqueous salt or buffer solutions, ethylene glycol, low molecular weight polyethylene glycols and lower alcohols such as ethanol, n-propanol and isopropanol.

In addition, further additives are tricalcium phosphate for implantation such materials proposed or actually used, such as X-ray contrast agents, active ingredients, such as antibiotics in particular, for the control of infections or fibers to improve mechanical properties of the implant.

Although in itself of each of these additives exerts a positive influence, there is a danger that the mechanical stability and mixing properties of the bone cement is negatively influenced by the variety of the additives.

It was therefore the task of finding an improved bone cement in this regard.

It has now been found that a significant improvement can be achieved if as an additive a tricalcium phosphate is used, the pores are filled with a mixture of an antibiotic and another filler.

The invention is, therefore, an absorbable porous tricalcium phosphate which is suitable as an additive to implant materials based on polyacrylate and / or polymethacrylate and whose pores are filled with a biocompatible, resorbable filler, which is characterized in that the filler consists of at least two composed ingredients and removing one component is an antibiotic.

The invention also provides a process for the preparation of a resorbable, porous tricalcium phosphate which is suitable as an additive to implant materials based on polyacrylates and / or polymethacrylates, its pores are filled with a biocompatible, resorbable filler, which is characterized in that a porous tricalcium is brought into contact with the solution of an antibiotic and another filler and the solvent is then removed.

Similarly, the invention provides a precursor for the preparation of a bone cement and the implant materials produced therefrom, which are characterized by a content of tricalcium phosphate according to the invention.

Main advantage of the invention is that both the mixing properties of the bone cement as well as the mechanical properties of the hardened implant be substantially improved by the reduced number of additives. Furthermore, it was surprisingly found that the release of the antibiotic or of an implant according to the invention is significantly improved.

The term tricalcium phosphate, which is used in the present application is to be understood as a generic term for a number of different, primarily by the chemical formula Ca₃ (PO₄) ₂ to descriptive materials, the ratio of calcium: is 2: Phosphor approximately. 3 In addition to pure tricalcium phosphates, such as α- or β-Whitlockit should however only approximately by the formula Ca₃ (PO₄) ₂ to descriptive materials such as apatites or phosphorite, to be included. Definitely the tricalcium phosphate in the body is to be absorbable.

These materials are known per se and can be prepared by known methods. Essentially, this precipitation method or sintering method or a combination of such methods. Precipitated or sintering process for the preparation of the calcium phosphates are the Gmelin described in the standard works of inorganic chemistry, for example,. The starting materials are used in a rule soluble calcium salts and soluble phosphates or for the sintering process such as CaO, Ca (OH) ₂, CaCO₃ and CaHPO₄ which are sintered together with P₂O₅ or among themselves.

Tricalcium phosphate obtained by precipitation processes are particularly preferred in the present invention used. These are relatively soft and generally have a large pore volume which is in the order of about 0.3-0.5 ml / g. The absorption of these materials obtained by precipitation is better than that of sintered materials generally.

According to the invention, the pores of these tricalcium phosphates are sealed with a mixture of an antibiotic and another filler. As antibiotics to preferred aminoglycoside and particularly gentamicin are used. Also preferred are clindamycin and lincomycin and combinations of antibiotics such as gentamicin with clindamycin.

Another filler in principle all physiologically compatible, resorbable by the body and is not miscible with the Acrylatmonomoren substances into consideration. For example the already mentioned in the DE-OS 29 05 878 alcohols such as glycerol, ethylene glycol and low molecular weight polyethylene glycols, may be used or sugars such as glucose or sucrose, sugar alcohols such as mannitol or sorbitol, proteins and their degradation products, such as for example collagen, gelatin or elastin, and in particular also amino acids, such as valine, histidine, leucine, isoleucine, threonine, arginine, lysine and alanine. Particularly preferably threonine and arginine are used.

Although the pore volume of a selected tricalcium phosphate is fixed, but the amount of the fillers can be varied within relatively wide limits, without causing the mixing of the bone cement to a pickup of monomers in the void system of the tricalcium phosphate. This shows that obviously not the total pore volume of the tricalcium phosphate must be filled with the fillers, but it apparently is sufficient to seal the pores externally by the fillers.

Thus, when using a precipitated tricalcium phosphate, which has a relatively high pore volume, about 2-20, especially about 5-15, .-% by weight of antibiotic and about 0.5-5, especially about 0.8 to 3.2, wt .-% of another filler used. Only with the use of a liquid filler, such as glycerol, can be used up to about 30 wt .-% thereof.

These fillers are applied to the tricalcium phosphate by methods known per se. Thus, for example tricalcium phosphate are impregnated with a solution of the fillers and the solvent is then evaporated. In order to achieve an intensive penetration of the solution into the pore system of the tricalcium phosphate, for example, can either be carried out under elevated pressure or the tricalcium phosphate to be evacuated before addition of the fill solution. Suitable solvents for the fillers, both organic solvents and in particular water or aqueous buffer solutions with a physiological pH suitable.

A particularly advantageous product is obtained by spray drying. Since the tricalcium phosphate is preferably used has a very small particle size in the range of about 2-300 microns, more preferably about 20-200 microns possesses, suspensions of the tricalcium phosphate can be spray-dried in a solution of the fillers according to conventional methods. The case applicable conditions such as concentration of the suspension, the temperature and pressure are known to the expert and can, if necessary, in a tribute in textbooks such as "Pharmaceutical Technology", Georg Thieme Verlag, Stuttgart, 1978 described in Sucker, Fuchs and Speiser, methods are optimized by a few exploratory experiments with respect to the components actually used.

The tricalcium phosphate particles obtained by one of these methods as a free flowing powder can be used in the preparation of bone cements directly or after sterilization, for example by irradiation or by ethylene oxide gas. The known bone cements are formulated to containing about two parts of a finely divided, a polymerization catalyst (eg dibenzoyl) prepolymer, in particular polymethyl methacrylate or a copolymer of methyl acrylate and methyl methacrylate, with about one part of the liquid monomer, such as acrylic acid or methyl methacrylate or mixtures thereof, the an accelerator (for example, dimethyl-p-toluidine) which are mixed to form a moldable mass, which is implanted in the body where it cures. Such bone cements are for example under the trademark Palacos® commercially.

Tricalcium phosphate bone cements with the invention are prepared in an analogous manner so that either a mixture of the three constituents prepolymer, tricalcium phosphate and the monomer is carried out or in that tricalcium phosphate is added in advance to one of the other two constituents.

Preferably they shall bring the bone cement as in the trade that although the solid and liquid components separately but be in proportionate quantities in a ready to use package. Here preferably a ratio of about 40 g solid is adhered to 20 ml liquid monomer. The proportion of tricalcium phosphate according to the invention of the solid component is as a rule about 5-30, more preferably about 8-20, weight .-%.

In addition to the tricalcium phosphate according to the invention of the solid component, other additives may be added. Thus, for example in amounts of 0-20 wt .-%, a further Tricalciumphosphatanteil without fillers, such as a substantially pore-free sintered apatite, or a X-ray contrast agents, such as zirconium dioxide, can be admixed. In the latter part may be dispensed with, as even cause Tricalciumphosphatkomponenten a sufficient X-ray contrast. To improve the mechanical properties of the implant can also be in amounts of about 0-30 wt .-% component fibers, such as carbon or glass fibers or plastic fibers, such as those are attached from polymethyl methacrylate or aramid. In addition, other materials such as bioactive glass-ceramics, in particular, be included in amounts of 0-50 wt .-%. In any case the solid component is, however, such that the ratio of 40 g solid is adhered to 20ml monomer substantially, ie with increasing amount of other additives, the proportion of the prepolymer is reduced.

It has already been mentioned that, compared with an implant material to which a powdered antibiotic was added, the release of the antibiotic from an implant material according to the invention is significantly improved. In fact, it is a release which is improved by a factor of 5-10. This is a very valuable and beneficial new Tricalciumphosphatkomponente for the preparation of bone cements available.

example 1

In an adjusted to pH 7.4 solution of 0.8 g of L-arginine and 1.6 g gentamicin sulfate 97.6 g of tricalcium phosphate (Fa. E. Merck, Darmstadt, Item No. 2194) are a particle size below 63 microns and the suspension is in a spray system sprays (spray pressure: 2 bar; air flow 380 m³ / h; temperature input: 200 ° C; temperature output: 65 ° C).

example 2

It is analogous to Example 1, but 1.6 g of L-arginine and 96.8 g of tricalcium phosphate are employed.

example 3

It is analogous to Example 1, except that 1.6 g of L-arginine, 4.0 g gentamicin and 94.4 g of tricalcium phosphate are employed.

example 4

It is analogous to Example 1, except that 1.6 g of L-arginine, 8.0 g gentamicin and 90.4 g of tricalcium phosphate are employed.

example 5

It is analogous to Example 1, except that 1.6 g of L-arginine, 16.0 g gentamicin and 82.4 g of tricalcium phosphate are employed.

example 6

It is analogous to Example 1, except that 5.0 g of L-arginine, 8.0 g gentamicin and 87 g tricalcium phosphate are employed.

Examples 7-12

The procedure is analogous to Examples 1-6, but is being used instead of L-arginine L-threonine.