Strontium-apatite-cement-preparations and the use thereof

The present invention relates to a calcium-strontium-hydroxyphosphate (strontium-apatite) -cement formulation containing calcium and strontium, and its use. The present invention further relates to strontium-apatite-cement formed from the cement formulation and the methods used in its production. Strontium-apatite is well suited as a bone replacement material with special suitability for pharmaceutical purposes, especially for filling bone defects due to osteoporosis.

Human and animal hard tissues are basically formed from hydroxyapatite. In the hard tissue, hydroxyapatite, which is almost stoichiometric, is also absent, and there is an apatite structure in which salts of Na, K, Mg and strontium are incorporated. Within the hard tissue, carbonates are further incorporated in place of phosphates in the apatite structure.

Physiologically present apatite is a nanocrystalline structure, which is shown in the X-ray diffraction pattern in a linearly spreading shape in which no exact assignment of the apatite structure is possible. This is because the individual peaks are rather superimposed.

Calcium phosphate is biocompatible and osteosynthetic. That means that the newly formed bone tissue is placed directly there. Calcium phosphate is also resorbable because it is recognized as its own and can be degraded within the range of natural bone metabolism and specific bone resorption cells (osteoclasts). During the alteration process, calcium phosphate can be degraded and replaced with its own bone.

Since about 1970, calcium phosphate-ceramics have been on the market and are mainly incorporated into human and animal bodies in the form of mass-produced moldings or granules. These materials, which have been demonstrated in clinical use, were very rarely incorporated with friction (kraftschluessig) in defects that are almost irregular. However, incorporation with defective friction often results in particle outflow and connective tissue growth within the defect. This leads to the abandonment of augmentation.

Calcium phosphate-ceramic is mainly produced from hydroxyapatite, which is not absorbed by ceramic. Alternatively, the ceramic is formed from various proportions of calcium β-triphosphate (β-TCP) and hydroxyapatite, and the absorbability of the calcium β-triphosphate allows it to absorb at least partially, corresponding to a portion of the material. It is produced from two-phase calcium phosphate-ceramics that can be made.

Calcium phosphate-cement first appeared in the literature in 1985. Calcium Phosphate-Cement has the advantage over ceramics that it traps and incorporates forces into the body (WEBrown and LCChow, "A new calcium phosphate, watersetting cement", Chem.Res.Prog.1986,352-379; USA Patent No. 4,612,053; US Pat. No. 5,149,368; US Pat. No. 4,518,430; International Application 96/14265; European Patent Application Publication 0 835 668 A1).

This cement is indicated by a Ca / P ratio 1.5.

This ratio can be further increased by adding carbonate. Contradictory reports have been made regarding the absorbency of this cement. Because such cement is non-absorbable if the final reaction product is hydroxyapatite and is absorbed by osteoclasts if the final reaction product is calcium deficient-hydroxyapatite (CDHA). It can also be replaced by new bone by osteoclasts. Absorption rate is unpredictable as absorption depends on the recipient's cell activity, local blood circulation ratio, and location of injection.

Such cements have already been successfully marketed on the market (Bone Source, Norian SRS, Biobon, Calcibon). The main issue on the user side is, of course, absorbency. The market wants a product that guarantees high mechanical strength, yet is completely absorbed after a given time and should be replaced by its own bone. For this reason, many manufacturers use CaHPO as a bone substitute to increase absorption rates beyond passive solubility.₄, CaSO₄, CaCO₃Or, we are trying to add an inorganic substance such as β-TCP. However, this only solves some of the problems, as the main components are still difficult to absorb or remain unabsorbed.

Controlled cement absorption based on cellular phenomena follows Wolff's law. Wolff's law exhibits a constant mode of bone alteration, the core meaning of which is that bone remains only where it is needed from a biomechanical point of view. In this sense, it is concluded that the pressure strength of the artificial bone replacement raw material should be directed to the pressure strength of the columnar bone.

This means that no pressure strength higher than 40MPa is required. This is because otherwise the cement creates a so-called "pressure shield", which results from the high strength of the cement and relaxes the bone structure that borders the implant layer. As such, the site of weakest biomechanical strength shifts to the undesired external transplant layer due to cement.

The main use of bone replacement raw materials is in the filling of bone defects and vertebral bodies in the tubular bone growth area. This deficiency occurs primarily during the course of osteoporosis. Osteoporosis is a systemic disease of the whole body that essentially results from an imbalance in bone exchange. Here, the anabolic and catabolic bone alteration processes are reversed, and bone is destroyed by the vitality of osteoclasts rather than by the vitality of osteoblasts. Various systematically effective materials have been tested to address this imbalance in bone destruction with respect to bone formation. It includes, among other things, bisphosphate and hormonal agents, which impose a burden on the entire body. In this regard, not only pure bone replacement raw materials or fillers, but also bone replacement materials that act on surrounding bone cells to almost reverse the metabolic process are desired. As a result, excess osteoclast vitality is suppressed by the bone replacement raw material itself, and the vitality of osteoblasts (forming bone) is promoted. According to the criteria for such development purposes, the bone replacement material once provided for the symptoms of osteoporosis is destroyed by the increased osteoclast vitality and at the same time affected and suppressed by osteoporosis. Due to the vitality of the osteoblasts, it is avoided that new bone is not formed.

This problem cannot be solved by considering the prior art. International application 02/02478 A1 contains strontium ions in SrCO₃Calcium phosphate contained in the form of is disclosed. However, here, strontium carbonate is used only for the influence of the expansion properties of cement composed of magnesium-ammonium-phosphate as the main component. This strontium carbonate also rapidly dissolves from cement due to its potential solubility. As a result, no delay effect occurs and therefore bone metabolism cannot be affected.

<p> An object of the present invention is to provide an optimal material as a bone substitute material, particularly for osteoporotic bone.</p>

<p> This challenge is specifically addressed by the cement formulation according to claim 1 or 11, and by the use of this cement formulation according to claims 21 and 22, strontium-apatite-cement according to claim 23. And by the strontium-apatite formed from this cement formulation according to claim 26.</p><p> A preferred embodiment is reproduced in a sub-claim of the above claim.</p><p> Cement formulations according to the invention are superior due to the presence of calcium and strontium ions. The calcium and strontium ions can be provided in the formulation in the form of their phosphates or bicarbonates, and optionally also in the form of their carbonates. Preferably, magnesium ions are not provided or can be provided in very small amounts, approximately unavoidable small amounts.</p><p> Based on its composition, the cement formulations according to the invention, and the strontium-apatite formed and cured using it, have the ability to dissociate delayed strontium ions. As a result, bone material exchange inside the osteoporotic bone is positively stimulated, and especially inside the osteoporotic bone, anabolic vitality can be generated during the bone material exchange. There is a feasibility of. Therefore, especially inside the bone of osteoporosis, a constant stimulation of osteoblast activity is caused, accompanied by simultaneous suppression of osteoclast activity enhanced by osteoporosis.</p><p> Further, the present invention allows the free use of cement systems for positively filling bone defects (formschluessig). Here, the cement formulation can be cured not only at room temperature but also at body temperature, and can be processed for a sufficiently long time. The cement formulation according to the invention has suitable and high pressure strength in the human or animal body after its curing. Calcium-strontium-hydroxyphosphate (strontium-apatite) formed from cement formulations is nanocrystals that reach maximum strength within hours to days.</p><p> The cement formulations of the present invention can be biologically removed or absorbed into the body, depending on the biological context. Here, the material according to the present invention is excellent due to its good aggregating ability upon contact with body fluids. The material according to the invention has a higher aqueous solution than calcium deficient-hydroxyapatite. It has an advantage over alternatives through its own bones.</p><p> Therefore, according to the present invention, a material that not only closes a bone defect but also causes anabolic vitality in the bone and thereby positively contributes to bone formation is provided based on the constitution. To.</p>

The present invention and preferred embodiments thereof will be described in detail below.

The cement formulation defined in claim 1 according to the present invention has a molar Ca / P ratio and a molar Sr / P within the range of 1.00 &lt;Ca / P 1.50 and 0 &lt;Sr / P &lt;1.50 in the powder mixture. Have a ratio. The Sr / P ratio is preferably at least 0.2, more preferably at least 0.5.

The cement formulation defined in claim 11 according to the present invention is for forming strontium-apatite-cement by the chemical composition of the basic components, and as the minimum component in the powder mixture, α-TCP. And / or Ca that can exist as β-TCP₃(PO₄)₂Besides (TCP), SrHPO₄And / or Sr₃(PO₄)₂, And, if necessary, further SrCO₃including.

The following description relates to the two objects of the present invention.

Alkaline or ammonium salts of orthophosphoric acid can be present as the basis material of the formulation, separated from the powder mixture and water and / or aqueous solution. Preferably, the salt is present in the form of an aqueous solution that is mixed with a dry powder mixture as a mixture for forming cement. Additional alkaline or ammonium salts in the dry state may be present in the powder mixture to control the reaction rate. Here, the powder mixture is preferably further NaH.₂PO₄And / or Na₂HPO₄, KH₂PO₄And / or K₂HPO₄, Or a combination of the listed Na and K salts of orthophosphoric acid.

Suitable alkaline salts for the aqueous solution of the mixture are, in particular, Na and / or K salts of orthophosphoric acid, in particular primary and secondary salts, especially mixtures thereof. Preferably, the alkaline salt of orthophosphoric acid is the following component, the primary potassium salt of orthophosphoric acid (KH).₂PO₄), Dipotassium salt of orthophosphoric acid (K₂HPO₄), And their mixture, the monosodium salt of orthophosphoric acid (NaH)₂PO₄), Disodium salt of orthophosphoric acid (Na₂HPO₄), And mixtures thereof, and combinations of the listed potassium and sodium salts, selected from the group. As the ammonium salt for the aqueous solution of the mixture, especially (NH₄)₂HPO₄Is suitable.

Strontium is favorably incorporated into the powder mixture, advantageously strontium phosphate (Sr), so that strontium ions are favorably incorporated into the strontium apatite structure.₃(PO₄)₂), Or strontium hydrogen phosphate (SrHPO)₄), Or a mixture thereof. SrHPO in powder mixture₄And / or Sr₃(PO₄)₂The amount of is preferably greater than 10% by weight and up to 60% by weight. More preferably, it is contained in an amount of more than 15% by weight, and particularly more than 20% by weight. SrCO provided more selectively in the powder mixture₃Can be present in quantities ranging from 0.01% to 10% by weight.

The powder mixture is a more suitable material, such as metal carbonate, Ca sulphate, Mg sulphate, Sr sulphate, Na sulphate, K sulphate, Ca sulphate, Na sulphate, K sulphate, It may further contain Ca acid hydrogen salt, Na phosphate hydrogen salt, K acid hydrogen salt, and their oxides and / or hydroxides, if desired.

To produce strontium-apatite-cement, the powder component is mixed with the aqueous component (of the mixture) and the mixture is subsequently cured. As a result, strontium-apatite is formed as the final reaction product. Here, (NH₄)₂HPO₄, K₂HPO₄, And / or Na₂HPO₄Alkaline solution containing, and NaH₂PO₄And / or KH₂PO₄The powder mixture is cured with an acidic solution containing the above, or with a mixture of the first orthophosphate and the second orthophosphate. The aqueous solution preferably has a pH value in the range of 5-12. After mixing, a paste is usually formed. This paste can be filled in one mold. Thereby, after the paste of the mold is cured, a subsequently defined mold can be produced as a base material. Here, the viscosity and firmness of the mixture is set so that the mixture can be injected as well as provided to the defect using the instrument as a paste.

The cement formulations or strontium-apatite-cements according to the invention are particularly suitable as carrier materials for working materials of pharmacological and biological origin. As such, the formulations are contained in powder and / or aqueous components, as well as pharmacologically and / or biologically effective substances such as antibiotics, cell growth inhibitors, analgesics, disinfectants, growth. Includes factors, proteins or biopharmacology, or combinations of the above-mentioned active materials. In particular, the input of one agent selected from the group consisting of gentamicin, or tobramycin, clindamycin, vancomycin, TGF-β series substances, or BMP series substances, or a combination of the above agents is particularly effective. Suitable.

A further preferred embodiment is a formulation comprising a granular particulate material that dissolves in the powder component and further in the aqueous liquid component, such as salts, sugars, synthetic hydrolyzable polymers. The granular particles are provided, for example, in a crystal size of 10-300 μm and produce a pore system during the curing process after mixing. As a result, the surface area is increased and the absorption performance is promoted.

The present invention will be described in detail below based on, but not limited to, examples.

In the examples, the following abbreviations are used.

P = powder mixture L = liquid Liquid / powder mixture ratio in units of L / P = ml / g t_i = Initial curing time (according to ASTM C266-89) t_f = Final cure time (according to ASTM C266-89) C_gAfter x hours / y days in 0.9% aqueous salt solution at (xh / yd) = 37 ° C Compression strength in Mpa units Mpa = Mega Pascal Manufacture of strontium-apatite-cement formulation and the cement formed thereby As shown in Examples 1-7 below, after measuring all the constituents, the powder component P is homogeneously ground in a spherical grinder, followed by the aqueous solution L to the indicated ratio. Mixed. After the lapse of a predetermined curing time, the compressive strength was determined respectively.

Example 1: P = 65g Ca₃(PO₄)₂ + 16g Sr₃(PO₄)₂L = 3.5M (NH₄)₂HPO₄L / P = 0.40 C_g(48h) = 30 MPa C_g(10d) = 43.8 MPa Example 2: P = 65g Ca₃(PO₄)₂ + 16g Sr₃(PO₄)₂L = 4% Na₂HPO₄L / P = 0.35 t_i = 13'30'' (13 minutes 30 seconds) Example 3: P = 65g Ca₃(PO₄)₂ + 16g Sr₃(PO₄)₂ + 3g SrCO₃L = 3.5M (NH₄)₂HPO₄L / P = 0.40 C_g(10d) = 46.4 MPa Example 4: P = 60g Ca₃(PO₄)₂ + 10g Sr₃(PO₄)₂ + 10g SrHPO₄ + 3g SrCO₃L = 3M K₂HPO₄/ 1M KH₂PO₄L / P = 0.40 C_g(2h) = 3.8 MPa C_g(18h) = 26.4 MPa Example 5: P = 65g Ca₃(PO₄)₂ + 16g SrHPO₄ + 3g SrCO₃L = 3.5MK₂HPO₄/ 1M KH₂PO₄L / P = 0.30 C_g(5h) = 18.4 MPa Example 6: P = 65g Ca₃(PO₄)₂ + 12g Sr₃(PO₄)₂ + 14g SrHPO₄ + 3g SrCO₃L = 3.2M (NH₄)₂HPO₄L / P = 0.35 C_g(5h) = 13.0 MPa Example 7: P = 30g Ca₃(PO₄)₂ + 10g Sr₃(PO₄)₂ + 10g SrHPO₄ + 5g SrCO₃ + 10g K₂HPO₄L = 3M K₂HPO₄/ 1M KH₂PO₄L / P = 0.22 C_g(72h) = 40 MPa