CA2325740A1 - Bio-cements having improved properties - Google Patents

Abstract

The invention relates to biologically degradable calcium phosphate cement, especially mixtures of powders which contain calcium phosphate and which are of a different stoichiometric composition, exhibiting improved properties. The inventive mixtures all contain tricalcium phosphate (TCP) and one or more other compounds which contain phosphate and which are of a different composition, whereby the TCP portion is available in a well-defined range of particle sizes.

Description

Hio-cements having improved properties The invention relates to biodegradable calcium phosphate cements, in particular mixtures of calcium phosphate-containing powders of different stoichio-metric composition having improved properties. The mixtures according to the invention all comprise tricalcium phosphate (TCP) and one or more other phosphate-containing inorganic compounds of different composition, the TCP content being present in a well defined particle size range.
Naturally occurring bone material consists of calcium phosphate having the hydroxylapatite structure.
However, the composition of bone minerals does not correspond to the ideal stoichiometric composition of crystalline hydroxylapatite (Calo(P04)6(0H)2) but as a rule has a nonstoichiometric composition which is due to the incorporation of other anions, such as carbonate or hydrogen phosphate, instead of orthophosphate, but also of other cations, such as sodium, potassium or magnesium, instead of calcium.
Biodegradable calcium phosphate cements (CaP) are attracting more and more interest in traumatology and orthopaedics owing to the limited availability of autogenous bone and the problem of the bioburden with allogenic bone. A disadvantage of many available synthetic bone substitutes based on calcium and phosphorus is essentially that they are not degradable.
For some years it has been possible to prepare synthetic bone material which is based on hydroxyl apatite-like calcium phosphate compounds and, owing to its qualitative and structural similarity, is very similar to natural bone. It is thus possible to avoid the known disadvantages which may arise through the acquisition of natural autogenous or heterogeneous bone. Furthermore, these materials have the advantage that they withstand mechanical loads virtually just as well as natural bones, which suggests their use in the case of more major bone defects or bone fractures.

The main components of these materials are, for example, tricalcium phosphate (TCP), dicalcium phosphate (DCP) and tetracalcium phosphate (TTCP), which, in the presence of water, react to give hydroxylapatite, the end product of the cement formation reaction. Since hydroxylapatite formed in this manner has formed in an aqueous environment, it resembles the biological apatites far more than the hydroxylapatite which is produced at high temperatures.
Such cements are therefore osteotransductive and hence very suitable for the repair and reconstruction of bones. They are rapidly integrated into bone structures and then converted into new bone tissue by the cellular activity of the osteoblasts.
Depending on the condition, essentially the following solids can occur in the system Ca(OH)z - H3P04 - H20:
Ca (HzP04 ) z ~ Hz0 (MCPM) CaHP04 (DCP) CaHP04 ~ 2Hz0 (DCPD) Ca8(HP04)z(P04)4~5H20 (OCP) Ca9 (HP04) (P04) sOH (CDA) Calo (P04) 6 (OH) z (PHA) 2 5 Ca3 ( P04 ) z ~ H20 (ACP ) Ca3 (P04) z (a, ~i-TCP) Such cements are disclosed, for example, in US 4,518,430, US 4,612,053, US 4,678,355, US 4,880,610, US 5,053,212, US 5,152,836, US 5,605,713, EP 0 416 761, EP 0 543 765, EP 0 664 133 or WO 96/36562.
The prior art furthermore discloses a cement consisting of a-TCP and ~i-TCP and a small amount, serving as a crystallization nucleus, of precipitated hydroxylapatite (PHA) whose setting behaviour has been investigated (Jansen et al., J Mat Sc: Mat Med 6 (1995) 653-657). The following is a general equation for the reaction of a-TCP with water:

3a-Ca3 ( P04 ) 2 + Hz0 ~ Ca9 (HP04 ) ( P04 ) sOH
and the following for the reaction with dicalcium phosphate (DCP) 2CaHP04 + 2a-Ca3 ( P04 ) z + 5 H20 -~ Cae (HP04 ) 2 ( P04 ) 4 ~ 5H20 .
The hardening of the initially pasty mixture takes place by the intermeshing of the calcium-deficient hydroxylapatite crystals precipitated during the setting process.
The properties of the known hydroxylapatites or calcium phosphate cements, in particular their physio logical acceptance, acquired bioabsorbability and the ability to be replaced by newly generated natural bone tissue or stimulation of the growth thereof, and some of their physical properties, such as, for example, compressive strength and hardening times, depend on the more or less pronounced crystallinity, on the particle size and on the porosity which can be achieved during the preparation.
Thus, different biocements were obtained, for example, by adding CaHP04 or CaC03 or CaHP04 together with CaC03 to a mixture of a-TCP and (3-TCP (Khairoun et al., Biomaterials, 10 (1997) 1535-1539). The compres-sive strength of certain compositions which was obtained after hardening was in the region of 30 MPa and hence in the region of trabecular human bone (Driessens et al., Bioceramics 10 (1997) 279-282), but the achievement of these high compressive strength values took 15 to 30 hours in spite of the use of customary hardening accelerators, which however is too long for use in traumatology and orthopaedics for the purpose of early stability and load bearing. In these cases, the a,(3-TCP mixture had been milled in such a way that about 60% to 705 of the powder had a particle size of less than 8 ~m and the remainder of the particles had a size of less than about 35 Vim.

Thus, there is still interest in the development of bone cements which have various properties to meet the different requirements. The present invention provides such cements having particular properties. The problem on which the invention was based was specifically whether novel cements having improved properties can be obtained by variation of the milling of the particle size of a TCP
mixture together with admixtures of other inorganic phosphate compounds.
The present invention thus relates to a mixture of powders which are suitable for the preparation of absorbable calcium phosphate cements and, in addition to tricalcium phosphate (TCP), comprise at least one further other phosphate-containing inorganic compound, which is characterized in that the TCP particles have the following particle size distribution:
30-90%: 0.1-40 ~m and 10-70%: 40-300 Vim.
That a certain proportion of fine particles (about 1-40 Vim) and very fine particles (0.1-1 Vim) must be present in addition to a certain proportion of coarse particles (40-300 Vim) is to be regarded as essential to the invention.
The mixtures according to the invention must always contain TCP. TCP occurs mainly in two different crystal modifications, a and ~3. According to the invention, the mixtures comprise a-TCP, it being possible to admix up to 60% of ~3-TCP. The invention thus relates to a mixture in which 40 to 100% of the TCP present is in the a-form (a-TCP) and 0 to 60% is in the (3-form (~i-TCP) . Where the term TCP is used above or below, this mixture of a- and ~3-TCP is, by definition, always meant.
The invention relates in particular to those mixtures in which 30 to 70% of the TCP particles have a particle size of 0.1 to 7 Vim. The invention furthermore relates to those mixtures in which 10 to 60% of the TCP
particles have a particle size of 40 to 100 Vim.
Corresponding mixtures which have the following particle size distribution of the TCP particles are particularly preferred:
30-50%: 1-7 ~,m 20-40% : 7-40 ~tm and 10-50%: 40-100 Vim.
It was found that not only does the particle size of the TCP particles or their particle size distribution have an advantageous effect but that the size and property of the remaining phosphate-containing compounds in the mixture also play a role. According to the invention, at least 50% of these non-TCP particles should have a size between 10 and 100 ~.m. In general, these particles, too, may not be milled either too fine or too coarse. The proportion of these non-TCP
compounds in the mixtures according to the invention is 1-85%, preferably 5 to 60%.
Suitable compounds which can be mixed with TCP
are in general all inorganic compounds which comprise calcium and phosphate. Particularly suitable compounds are disclosed in EP 543 765. The compounds which are selected from the following group are preferred:
Ca (HzP04 ) z ' HzO, CaHP04 , CaHP04 ' 2HZ0, Ca8 (HP04 ) z ( P04 ) 4 ' SHzO, Ca9 (HP04) (P04) SOH, Calo (P04) 6 (OH) z, carbonate-containing apatite, CaC03, Ca (OH) z, MgHP04' 3H20, Mg3 (P04) z, CaNaP04, CallNa ( P04 ) z , CaKP04 , Caz P04C1, CazNaK ( P04 ) z , Calo ( P04 ) 6C1 z , ZnHP04 ' 4H20 and Zn3 ( P04 ) z in particular from the group:
Cae(HP04)z(P04)4'SHzO, Calo(P04)6(OH)z, CaHP04 and CaC03.
In summary, the mixtures having the following composition are particularly suitable:

(i) TCP: 90-99% Calo (P04) s (OH) z: 1-10%;

(ii) TCP: 90-99% Ca8 (HP04) z (P04) 4' 5H20:
1-10%;

(iii) TCP: 70-99% Calo(P04)s(OH)z: 1-10%, CaC03: 10-20%;

(iv) TCP: 70-99% Cae (HP04) z (P04) 4' SH20:1-10%, CaC03: 10-20%;

(v) TCP: 40-99% Calo(P04)s(OH)z: 1-10%, CaHP04: 1-50%;

(vi) TCP: 40-99% Cae (HP04) z (P04) 4' SHzO:
1-10%, CaHP04: 1-50%;
(vi) TCP: 20-99% Calo (PO4) s (OH) z : 1-10%, CaHP04: 1-50%, CaC03: 1-20%;
(vii) TCP: 20-99% Cae (HP04) z (P04) 4' 5H20: 1-10%, CaHP04: 1-50%, CaC03: 1-20%.
The mixtures according to the present invention can, if desired, also contain known hardening accelerators. Disodium hydrogen phosphate is preferred here.
Furthermore, it was found that the TCP-containing bio-cements of the present invention are particularly advantageous if the content of magnesium in the starting materials is not more than about 0.13%
and the content of sodium not more than about 0.2%.
The implantation of biomaterials in the human or animal body always involves the risk of populating these inanimate materials with germs, because these materials initially have no vascular supply and therefore cannot be protected by the immune system. It is therefore desirable to add antibiotics, for example from the aminoglycosides, such as gentamicin, or cefazolin, clindamycin palmitate, in particular clindamycin phosphate, or disinfectants to the biomaterials for their own temporary protection from population with germs, to avoid population with germs during the implantation. This gives rise to the next object, to demonstrate that antibiotics and/or disinfectants are not only mixed into the cements but are also eluted therefrom. Furthermore, mixing in _ 7 _ antibiotics and/or disinfectants should not adversely affect the mechanical properties or the processing properties of the cements, for example with respect to the hardening times, in accordance with the intended use. Suitable disinfectants are acridines, in particular biguanides, such as chlorhexidine and, here in turn, in particular polyhexanidum (Lavasept~).
Furthermore, by the mixing in and progressive release of antibiotics and/or disinfectants from absorbable calcium phosphate cements, this biomaterial can, after surgical debridement, be implanted in areas with a risk of infection. Moreover, the treatment of osteomyelitis, which is characterized by chronic infection and osteonecrosis, is facilitated because it may be possible to remedy the osteomyelitis by a single operation.
Furthermore, it is desirable to mix with absorbable biocements further pharmaceutical active ingredients which have a very wide range of actions, for example increase the cellular activity of the bone surrounding the cement, to achieve increased absorption of the cement and replacement thereof by endogenous bone or formation of a composite of endogenous bone and unabsorbed portions of the cement, or active ingredients in the sense of chemotherapeutics which prevent the loosening of a stabilizing cement filling after tumour resection by tumour cells remaining in the vicinity.
Examples of such suitable pharmaceutical active ingredients are growth factors, such as FGF (Fibroblast Growth Factor), BMP (Bone Morphogenetic Protein) or TGF-~ (Tissue Growth Factor), or other active ingredients, such as prostaglandins or substances which influence the prostaglandin metabolism, active ingredients which interact with the metabolism of the thyroid glands or pithyroid glands, or even chemotherapeutics, such as, for example, methotrexate.
It has now been found that admixing such substances leads to corresponding hardened biocements which, owing _ g _ to their structure, are capable of releasing these active ingredients into the environment within a few or several days after implantation.
The invention thus also relates to mixtures which additionally contain one or more pharmaceutical active ingredients or one or more disinfectants.
For implantation or injection, the mixtures according to the invention must be mixed with an aqueous liquid so that setting or formation of apatite structures or apatite-like materials occurs according to the equation mentioned at the outset. As a result, advantageous properties are obtained after the powder mixtures are mixed with the aqueous liquids. These properties are characterized in that the paste obtained after the mixing of solid and liquid phase permit, in a temperature-dependent manner, certain processing possi-bilities, such as modelling and injectability, at certain time intervals. Suitable aqueous liquids are, for example, physiological saline solution, body fluids, such as blood or serum, or aqueous buffers.
In principle, the additives, such as pharmacological active ingredients or hardening accelerators, can not only be mixed with the TCP powder but also added in aqueous solution to the biocement to be stirred. This is then present as a creamy suspension or paste that can easily be introduced into the intended sites or defective bone structures.
Thus, the invention also relates to a corresponding mixture in the form of an aqueous solution, paste or suspension and its use for the preparation of biodegradable implantable synthetic bone materials.
The stirred and setting mixtures according to the invention are distinguished in particular by a desired compressive strength of 30 MPa or more, which, depending on the composition of the mixture according to the invention, is reached after only very short hardening times between two and ten, preferably between three and six, hours, whereas in the prior art, in the _ g _ case of mixtures having a slightly changed composition, hardening times of 15 to 30 hours as a rule and the strength is only slightly above 30 MPa. Within these longer hardening times, compressive strengths as high as 40 to 50 MPa can be achieved in the case of the mixtures according to the invention.
The figures are explained briefly below.
Fig. 1: Antibiotic elution from biocement D
Batches:
I. 1 g of cement + 0.7 ml of Refobacin 120; 0.7 g thereof / 20 ml of buffer (= 20 mg) II. 1 ml of Med. 5-agar + 0.7 ml of Refobacin 120/20 ml of buffer III. 1 g of cement + 0.7 ml of cefazolin 60 mg/ml, 1.04 g thereof / 20 ml of buffer (= 25.7 mg) IV. 1 g of cement + 0.7 ml of netilmycin 60 mg/ml, 1.15 g/20 inl of buffer (= 28.4 mg) V. 1 g of cement + 0.7 ml of clindamycin phosphate 60 mg/ml, 0.99 g / 20 ml of buffer (= 24.5 mg) Elution in 1/15 M phosphate buffer, pH 7.4, 37°C
Paragraphs [sic] I to V correspond to the identically denoted curves in the figure.
Fig. 2: Gentamicin release from H-, B-, F- and D-cement Release in ~g Mixture 1 2 3 4 Cement H B F D

Buffer 20 20 20 20 Gentamicin in 4.2 4.2 4.2 4.2 %

Additive NazHP04 Na2HP04 Na2HP04 NazHP04 Day 1 249.13 308.28 238.91 302.06 Day 2 18.93 21.35 29.55 22.16 Day 3 7.05 8.96 12.30 14.02 Day 4 6.63 7.20 9.05 12.64 Day 5 3.91 4.14 6.44 9.44 Day 6 4.05 4.07 5.15 7.95 Day 7 2.53 3.57 5.13 6.71 Day 8 1.83 2.96 2.55 3.74 Day 9 1.39 3.75 2.96 4.55 Day 10 1.86 3.20 2.75 3.99 Total 290.37 367.47 314.78 387.27 The numbers of the mixtures correspond to the identically denoted curves.
Example 1:
a-TCP was prepared by a calcination process at 1350°C
for 4 hours, and subsequent cooling in room air, of a 2:1 molar mixture of CaHP04 and CaC03: The reaction product obtained contained less than 10% of ~i-TCP.
The a-TCP was milled, sieved and mixed in such a way that about 50% had a particle size between 0.1 and 7 Vim, about 25% between 7 and 25 ~m and a further 25% between 25 and 80 Vim. The OCP was prepared by the 1S method of LeGeros (Calzif. Tiss. Int. 37 (1985) 194-197) .
The properties of the following cement mixtures were demonstrated by way of example:
Below, the meanings are as follows:
Hiocement H: Mixture of a-TCP and PHA
Hiocement F: Mixture of a-TCP, DCP and PHA

Biocement D: Mixture of a-TCP, DCP, CaC03 and PHA

Biocement H-OCP: Mixture of a-TCP OCP
and Biocement F-OCP: Mixture of a-TCP, OCP
DCP and Hiocement D-OCP: Mixture of a-TCP, DCP, CaC03 and OCP

Hiocement a-TCP DCP CaC03 PHA OCP

a-TCP 20 - - - -H 20 - - 0.40 -H-OCP 20 - - - 1.00 F 14 6.0 - 0.40 -F-OCP 14 6.0 - - 1.00 D 14 6.0 2.0 0.40 -D-OCP 14 6.0 2.0 - 1.00 The numerical data of the mixing ratios are in grammes. The liquid used for mixing the powders is a 4~
solution of NaZHP04 in water. The liquid/powder ratio is 0.30 ml/g of powder.
The initial hardening (ti) and the time until reaching the final hardness (tf) were determined at room temperature (20~1°C) and at 37~1°C according to ASTM standard by means of Gilmoore needles.
The compressor strength was determined using a Lloyd type LR50K material tester after immersion for 1, 2, 4, 18 and 65 hours in Ringer's solution. The reaction product was determined by means of X-ray diff ractometry.
For the preparation of the bio-cements F, F-OCP, D and D-OCP, whose common feature is the admixing of DCP, a particularly preferred DCP is one whose Ca/P ratio is > 1.45.
Example 2:
Antibiotics/disinfectants in liquid formulation and as solid were mixed into the cements obtained, and the release behaviour was determined. The elution solution used was a phosphate buffer according to Sorensen, pH

7.4 at 37°C.
The hardening properties of mixtures of cements with antibiotics/disinfectants were determined according to ASTM standards.
X-ray diffractometry showed that CaHP04 in the cements F-OCP and D-OCP did not react and, in spite of the additional OCP as a crystallization nucleus, formed a calcium-deficient hydroxylapatite.
Setting times (min.) as ti and tf at 20°C and 37°C
(standard deviation) Hiocement ti (20C) ti tf (20C) tf (37C) (37C) a-TCP 31 (1) 4.5 (0.25) 51 (1) 7 (0.5) H 19 (1) 3.25 (0.25) 40 (1) 6 (0.5) H-OCP 17.5 (1) 3.25 (0.25) 35 (1) 6 (0.5) F 5.75 (0.25) 3.25 (0.25) 16 (1) 9 (0.5) F-OCP 10 (0.5) 3.5 (0.25) 16.5 4.5 (0.25) (1) D 9.75 (0.5) 3.5 (0.25) 19 (1) 8.25 (0.5) D-OCP 11.5 (0.5) 3 .25) 22 (1) 6.5 (0.5) (0 Compressor strength after 1, 2, 4, 18 and 65 hours Biocement 1 2 4 h 18 h 65 h h h a-TCP 10 (1) 18 (1) 31 (2) - 32 (3) H 11 (1) 20 (1) 38 (2) 40 (4) 41 (5) H-OCP 13 (1) 18 (2) 37 (3) 40 (5) -F 11 (1) 18 (3) 28 (3) 31 (4) 39 (2) F-OCP 11 (1) 2 (1) 32 (2) 42 (3) 41 (2) D 10 (2) 16 (1) 26 (2) 45 (5) 47 (2) D-OCP 10 (1) 16 (2) 23 (1) 45 (3) 4 (6) The results show that the object of the invention has been achieved. The initial and final hardening time is shortened in comparison with a-TCP
(with 10% ~3-TCP content) by adding OCP and PHA. The shift of the kinetics of hardening towards shorter times is particularly pronounced at low temperature, whereas at body temperature the effect is only very slight. This is particularly advantageous for the processing properties of the cement obtained because sufficiently long processing time is ensured at room temperature whereas the hardening at body temperature is not too short and hence the cement introduced can still be modelled. The data on the compressor strength of the biocements demonstrated here by way of example show that the final strength is generally reached after 6 hours and that the biocement D and D-OCP achieve strengths of up to 50 MPa.
Example 3:
The next of object of the invention, namely the mixing in and progressive release of active ingredients from the cements, for example of an antibiotic for implant protection or for fighting infection, is also shown below to have been achieved.
The kinetics of release of the biocement D chosen by way of example and containing various antibiotics as well as the kinetics of release of various biocements containing gentamicin are shown in Figures 1 and 2.
By mixing in antibiotics/disinfectants, the kinetics of hardening or the strength is not adversely affected in relation to the desired effect of the release of antibiotics. The results of using biocement H, F and D
with gentamicin sulphate powder in a liquid/powder ratio of 0.30 with the use of NaZHP04 or gentamicin sulphate solution as liquid at 37°C are shown as an example. The stated strength values were determined after 20 hours. The values ti and tf are measured in minutes and relate to the measurements using the Gilmoore needle. The cohesion time (CT) was measured at room temperature and is stated in minutes.

Measured values determined using gentamicin sulphate owder 120 mg / 5 g of cement Biocamant ti tt CT F (MPa) ti tt CT F (MPa) without gentamicin with gentamicin H 3.5 6 6 404 8 14 1.5 373 F 3.5 5 3.5 314 7.5 9.5 1.5 393 D 4 5.5 1.5 455 5 8 1.5 41+1 Measured values determined using gentamicin sulphate as solution (Refobacin 120~) without the use of NazHP04 and only with Na2HP04 Biocement ti tf CT F (MPa) ti tt CT F
(MPa) Refobacin120~ Na2HP04 H 7 12 < 2 484 3.5 6 6 40+4 F 3.5 5 3.5 314 7.5 9.5 1.5 39+3 D 4 5.5 1.5 455 5 8 1.5 411 Example 4:
Preparation of TCP with starting materials In the preparation of TCP, the percentage content of a/~3 TCP is substantially influenced by the percentages by weight of Mg and Na in the starting substances but also by the relative Ca/P ratio. The following table gives an overview of the effect of Mg and Na on the phase composition of TCP:
%Mg %Na %~i-TCP

0.11 0.12 5 0.39 0.10 70 0.25 0.022 35 0.23 0.025 25 <0.0005 0.0024 <5 <0.0005 0.0029 <5 <0.0005 0.0013 <5 0.062 0.0081 <5 0.11 0.72 100 0.0024 0.20 <5 0.13 0.20 <5

Claims (17)

Claims:

1. Mixture of powders suitable for the preparation of absorbable calcium phosphate cements, comprising tricalcium phosphate (TCP) and at least one further other phosphate-containing inorganic compound, characterized in that the TCP particles have the following particle size distribution:
30-90%: 0.1-40 µm and 10-70%: 40-300 µm.

2. Mixture according to Claim 1, characterized in that 30-70% of the TCP particles have a particle size of between 0.1 and 7 µm.

3. Mixture according to Claim 1, characterized in that at least 10-60% of the TCP particles have a particle size of between 40 and 100 µm.

4. Mixture according to Claim 1, characterized in that the TCP particles have the following particle size distribution:
30-50%: 1-7 µm 20-40%: 7-40 µm and 10-50%: 40-100 µm.

5. Mixture according to any of Claims 1 to 4, characterized in that at least 50% of the remaining particles have a particle size of between 10 and 100 µm.

6. Mixture according to any of Claims 1 to 5, characterized in that 40 to 100% of the TCP is present in the .alpha.-form (.alpha.-TCP) and 0 to 60% in the .beta. form (.beta.-TCP).

7. Mixture according to any of Claims 1 to 6, characterized in that the proportion of said other phosphate-containing compounds is 1 to 85% of the total mixture.

8. Mixture according to any of Claims 1 to 7, characterized in that at least one other phosphate-containing compound was selected from the group:
Ca(H2PO4)2~H20, CaHPO4, CaHPO4~2H2O, Ca8(HPO4)2(PO4)4~5H2O, Ca9(HPO4)(PO4)5OH, Ca10(PO4)6(OH)2, carbonate-containing apatite, CaCO3, Ca(OH)2, MgHPO4 ~ 3H2O, Mg3(PO4)2, CaNaPO4, Ca11Na(PO4)2, CaKPO4, Ca2PO4Cl, Ca2NaK(PO4)2, Ca10(PO4)6Cl2.
ZnHPO4 ~ 4H2O and Zn3(PO4)2.

9. Mixture according to Claim 8, characterized in that at least one other phosphate-containing compound was selected from the group:
Ca8(HPO4)2(PO4)4 ~ 5H2O, Ca10(PO4)6(OH)2, CaHPO4 and CaCO3.

10. Mixture according to Claim 9 in a total composition selected from the following group:
(i) TCP: 90-99% Ca10(PO4)6(OH)2: 1-10%;
(ii) TCP: 90-99% Ca8(HPO4)2(P04)4 ~ 5H2O: 1-10%;
(iii) TCP: 70-99% Ca10(PO4)6(OH)2: 1-10%, CaCO3: 10-20%;
(iv) TCP: 70-99% Ca8(HPO4)2(PO4)4 ~ 5H2O: 1-10%, CaCO3: 10-20%;
(v) TCP: 40-99% Ca10(PO4)6(OH)2: 1-10%, CaHPO4: 1-50%;
(vi) TCP: 40-99% Ca8(HPO4)2(PO4)4~5H2O: 1-10%, CaHPO4: 1-50%;
(vi) TCP: 20-99% Ca10(PO4)6(OH)2: 1-10%, CaHPO4: 1-50%, CaCO3: 1-20%;
(vii) TCP: 20-99% Ca8(HPO4)2(P04)4 ~ 5H2O: 1-10%, CaHPO4: 1-50%, CaCO3: 1-20%.

11. Mixture according to any of Claims 1 to 10, characterized in that the percentage content of magnesium and sodium in the starting components does not exceed a value of 0.13 (Mg) and 0.2 (Na), respectively.

12. Mixture according to any of Claims 1 to 11, characterized in that it additionally comprises a setting accelerator.

13. Mixture according to any of Claims 1 to 12, characterized in that it additionally comprises a pharmaceutical active ingredient.

14. Mixture according to Claim 13, characterized in that it comprises an antibiotic or disinfectant.

15. Mixture according to any of Claims 1 to 14, characterized in that it is present in the form of an aqueous solution, suspension or paste.

16. Biodegradable implant, produced from a hardened mixture according to Claim 15.

17. The use of a mixture according to Claim 15 for the preparation of biodegradable implantable synthetic bone materials.