Hydraulic cement-based implant material and use thereof

Abstract

The invention relates to implant materials that are based on hydraulic cements in the form of one or more pastes, suspensions or dispersions that contain mineral and/or organic and/or organomineral solids and that react, when combined or when reacted with an aqueous liquid, to a solid in a cement-type initiation reaction. The invention also relates to the use of these materials as technical, medical-technical and/or pharmaceutical products, especially as bone cements, bone replacement materials, bone glues, dental filling materials and implantable active ingredient carriers. The implant materials according to the invention in the form of one or more pastes, suspensions or dispersions that contain mineral and/or organic and/or organomineral solids are formulated in an excipient liquid in such a manner that the pastes, suspensions or dispersions are stable in storage at normal conditions over a prolonged period of time and that they react, when combined with an aqueous liquid or when added to an aqueous liquid, in a cement-type initiation reaction and set to a solid. The excipient liquid of the mineral paste, suspension or dispersion is substantially water-free, and water immiscible or insoluble or hardly soluble in water in the chemical sense.

Claims

1. Paste, suspension or dispersion for producing an implant material on the basis of a hydraulic cement, the paste, suspension or dispersion containing a powdery solid containing calcium and/or magnesium compounds, wherein the solids to >75% are comprised of calcium and/or magnesium salts and/or oxides and/or hydroxides of calcium and/or magnesium, that, upon mixing with an aqueous liquid or after introduction into an aqueous liquid, cures to a solid body, wherein the paste, suspension or dispersion further contains a hydrophobic carrier liquid in a quantity of 10% by weight to 50% by weight of a total weight of the paste, suspension or dispersion, wherein the hydrophobic carrier liquid is characterized by not being soluble in water or by being only soluble in water to less than 25% by volume and characterized by water not being soluble or by being only soluble to less than 25% by volume in the carrier liquid, said hydrophobic carrier liquid being medium-chain triglycerides, wherein the paste, suspension or dispersion contains a surface active agent comprising cetyl phosphate, and wherein the paste, suspension or dispersion under normal conditions of 25 degrees Celsius and 101.3 kPa has a liquid to pasty consistency and is free of water.

2. Paste, suspension or dispersion according to claim 1, characterized in that the powdery solid is suspended/dispersed as a fine powder and in that at least 10% of the powdery solid has a particle size <10 μm and in that at least 10% of the powdery solid has a particle size of >50 μm.

3. Paste, suspension or dispersion according to claim 1, characterized in that the solids to >30% are comprised of salts of silicic acid or its condensates and/or salts of phosphoric acid or its condensates and/or salts of the glycerine phosphoric acid and/or salts of sulfuric acid and/or salts of carbonic acid.

4. Paste, suspension or dispersion according to claim 3, characterized in that the solids are comprised to >50% of calcium and/or magnesium phosphates.

5. Paste, suspension or dispersion according to claim 3, characterized in that the calcium compounds are selected from monocalcium phosphate monohydrate (MCPM), monocalcium phosphate anhydrite (MCPA), dicalcium phosphate anhydrite (DCPA), dicalcium phosphate dihydrate (DCPD), octacalcium phosphate (OCP), α-tricalcium phosphate (α-TCP), β-tricalcium phosphate (β-TCP), amorphous calcium phosphate (ACP), hydroxyl apatite (HA), calcium-deficient hydroxyl apatite (CdHA), substituted hydroxyl apatite, non-stoichiometric hydroxyl apatite, nano hydroxyl apatite, tetracalcium phosphate (TTCP), calcium sulfate (CaSO.sub.4), calcium sulfate hemihydrate (CaSO.sub.4×0.5 H.sub.2O), calcium sulfate dihydrate (CaSO.sub.4×2 H.sub.2O), calciumoxide (CaO), calcium hydroxide (Ca(OH).sub.2), calcium carbonate (CaCO.sub.3), calcium glycerophosphate, calcium citrate, calcium lactate, calcium acetate, calcium tartrate, calcium chloride (CaCl.sub.2), calcium silicates and their mixtures with one another.

6. Paste, suspension or dispersion according to claim 3, characterized in that the magnesium compounds are selected from magnesium hydrogen phosphate (MgHPO.sub.4) in the form of the hydrates and as anhydrous substance, trimagnesium phosphate (Mg.sub.3(PO.sub.4).sub.2), magnesium dihydrogen phosphate (Mg(H.sub.2PO.sub.4).sub.2) in the form of the hydrates and as anhydrous substance, magnesium chloride (MgCl.sub.2) in the form of the hydrates and as anhydrous substance, magnesium glycerophosphate, magnesium hydroxide (Mg(OH).sub.2), magnesium hydroxide carbonate, magnesium oxide (MgO), magnesium citrate, calcium magnesium carbonate (CaMg(CO.sub.3).sub.2, dolomite) and their mixtures with one another.

7. Paste, suspension or dispersion according to claim 3, characterized in that the solids to >25% contain α- or β-tricalcium phosphate, tetracalcium phosphate, dicalcium phosphate anhydrite or amorphous calcium phosphate.

8. Paste, suspension or dispersion according to claim 3, characterized in that the solids moreover contain ammonium salts that with one of the magnesium compounds cure to a magnesium ammonium phosphate solid material.

9. Paste, suspension or dispersion according to claim 3, characterized in that the solids contain to >5% calcium or magnesium hydrogen phosphate as hydrate or anhydrous substance.

10. Paste, suspension or dispersion according to claim 3, characterized in that the solids contain >10% calcium sulfate.

11. Paste, suspension or dispersion according to claim 1, characterized in that the at least one component contains a mineral powder mixture that in combination with the aqueous solution has a molar calcium/phosphate ratio of >1.35.

12. Paste, suspension or dispersion according to claim 1, characterized in that the at least one component contains a mineral powder mixture that in combination with the aqueous solution has a molar calcium/phosphate ratio of 0.9-1.35.

13. Paste, suspension or dispersion according to claim 1, characterized in that the powdery solid is either partially or completely dispersed in the carrier liquid and that the carrier liquid itself is soluble to less than 25% in water.

14. Paste, suspension or dispersion according to claim 1, characterized in that the carrier liquid contains dissolved, suspended or dispersed solids or one or more liquids that have a solubility in water of more than 1% (w/w), wherein the carrier liquid is swellable or miscible with water.

15. Paste, suspension or dispersion according to claim 1, characterized in that the carrier liquid is miscible with water or the carrier liquid is miscible with aqueous solutions that are stabilized by an emulsifier.

16. Paste, suspension or dispersion according to claim 1, characterized in that the carrier liquid comprises two or more substances wherein each of the substances are present in the carrier liquid in at least 0.1%.

17. Paste, suspension or dispersion according to claim 1, characterized in that from about 25% to about 75% by weight of the paste, suspension or dispersion comprises dispersed solids.

18. Paste, suspension or dispersion according to claim 1, characterized in that the paste, suspension or dispersion contains >70% of dispersed solids.

19. Paste, suspension or dispersion according to claim 1, characterized in that the paste, suspension or dispersion contains, in addition to suspended/dispersed solids and the carrier liquid, said one or several surface-active agents and/or highly dispersed solids, dissolved or suspended polymers with a molecular weight of >2,500.

20. Paste, suspension or dispersion according to claim 1, characterized in that the paste, suspension or dispersion further contains one or more dissolved or suspended pharmacological active ingredients.

21. Multi-component application system with a mixing device, comprising the paste, suspension or dispersion according to claim 1.

22. Single component application system containing the paste, suspension or dispersion according to claim 1, wherein the paste, suspension or dispersion contains all substances required for triggering a curing reaction with the exception of water and upon introduction of the paste, suspension or dispersion into an aqueous medium and/or contact with water-containing surfaces a curing reaction of the paste, suspension or dispersion is spontaneously triggered.

23. Paste, suspension or dispersion according to claim 1 in the form of bone cements, bone replacement materials, bone adhesives, tooth filling materials and/or implantable active ingredient carriers.

24. Paste, suspension or dispersion according to claim 1 in combination with application systems for augmenting osteoporotic or other pathologically modified bone areas and for filling bone defects of all kinds.

25. Paste, suspension or dispersion according to claim 1, characterized in that the powdery solid contains 60% by weight of tricalcium phosphate, 26% by weight CaHPO.sub.4, 10% by weight CaCO.sub.3, and 4% by weight precipitated hydroxyl apatite.

Description

DESCRIPTION OF PREFERRED EMBODIMENTS

Examples

(1) Based on the following examples the invention will be explained in more detail:

Example 1: Calcium Phosphate Cement CPC as Two-Component System

(2) First Component

(3) The employed CPC is comprised of 60% by weight α-TCP, 26% by weight CaHPO4, 10% by weight CaCO3 and 4% by weight precipitated hydroxyl apatite. The powders that have been comminuted beforehand are mixed in a ball mill and intensively ground.

(4) 100 g of the powder component of the CPC are mixed with 20 ml Miglyol 812 in a planetary ball mill (Fritsch Pulverisette 6) in a 500 ml beaker with 50 balls (10 mm diameter, each made of zirconium dioxide) for 3×15 min. (30 min. interruption, respectively) at a speed of 500 rpm. The result is a homogenous viscous paste with the consistency of peanut butter.

(5) 2nd Component

(6) As a water-containing carrier liquid 6% hydroxy ethyl starch, 5% Tween 80 and 4% Na.sub.2HPO.sub.4 are combined in water.

(7) With the two components the following tests are performed: a) As a cement mixture according to the invention 10 g of the paste with 2 ml of the aqueous solution are placed into a beaker and mixed with a spatula. Paste and aqueous liquid can be levigated homogeneously within a short period of time wherein the viscosity of the mixture increases slowly. Approximately 3 min after start of the mixing action, the paste begins to solidify and reaches an initial strength. After 6 hours the formulation according to the invention has a compression strength of approximately 12 MPa, after 3 days the compression strength is 15 MPa. b) The test under a) is repeated after storage of the paste for 6 months under normal conditions. The paste was stored for this purpose in a simple screw-lid glass without further measures. The mixing behavior shows no recognizable differences to the tests under a). The compression strength after 6 hours is 12 MPa, after 3 days 15 MPa. The test under a) is repeated with 10 g of the paste and 2.5 ml of the aqueous solution With the greater quantity of aqueous solution it takes somewhat longer until paste and solution are distributed homogeneously. Otherwise no recognizable differences between the two versions is noted. The initial strength is also reached after 3 min. The compression strength after 6 hours is 10 MPa, after 3 days 14 MPa. d) The test under c) is repeated with a conventional double chamber syringe of the company Mixpac (volume: 10 ml; ratio of cartridges: 4:1). After a minimal inhomogeneity at the beginning of the dispensing action the further dispensed strand is homogeneous and cures as in the manually mixed sample in appr. 3 min.

(8) In example 1 with respect to use of the cement in a two-chamber injection syringe (Mixpac) a very short curing time was selected because in this case the cement can be applied directly to the implant location. For an open mixing action in a mixing beaker the initial curing time can be adjusted to a value of appr. 5-7 min in that the concentration of Na2HPO4 solution is reduced to 1.0%. Surprisingly and notably in this connection is also the fact that the calcium phosphate cement according to example 1 cures faster than the corresponding conventional calcium phosphate cement. The results thus show that with the novel formulation cements are obtained that react to a solid material. The obtained strength values of the solid materials are approximately 30-40% lower than in conventional counterparts made from powder and mixing liquid. However, upon further optimization significantly higher strength values are to be expected (the conventional base cement is also the result of extensive optimization work) and, moreover, the measured values are at or above the level of spongious bone and therefore the tested formulations are already suitable for clinical use in many indications, in particular in those in which the mechanical properties of the bone replacement material are not decisive—which is the case in most situations.

Example 2: Calcium Phosphate Cement as Single Component System

(9) 20 g CPC cement powder according to example 1 are manually premixed with 4 ml Miglyol 812, 300 mg Na.sub.2HPO.sub.4, 500 mg Tween 80, and 200 mg Amphisol A and subsequently mixed in a 100 ml beaker with 10 balls of 10 mm diameter (zirconium dioxide embodiment) 3×15 min with 30 min interruption inbetween at 500 rpm. The result is a homogeneous viscous paste. The paste is filled into a 10 ml syringe and subsequently injected into a beaker with simulated body fluid (SBF) (without cannula). The extruded strand remains completely intact even when lightly shaken and cures in less than 60 min to such an extent that it can be removed from the liquid without falling apart. The liquid remains completely clear which indicates that no cement particles are washed out. The final strength is reached as in conventionally mixed powder+liquid after appr. 24 hours.

Example 3, Single Component Cements

(10) Single component cements according to the following formulation have been formulated in accordance with example 2 and tested in that the obtained respective pastes are filled into a 6×6×2 mm mold and introduced into simulated body fluid for curing. The compression strength was determined in a universal testing machine after 100 hours of incubation time. The determination of the curing time was done according to ASTM 266C. The consistency of the paste was adjusted to a value comparable to that of peanut butter at room temperature.

(11) TABLE-US-00005 Single component cements cement accelerator/ compression curing type powder oil Tween Amphisol reactant strength time CPC 80% 15%   3% 1%  1% 14 MPa 5 min Na2HPO4 MgPC *) 74% 13% 0.8% 2% 10% 13 MPa 5 min (NH4)2HPO4 CPC: calcium phosphate cement according to example 1 MgPC: magnesium phosphate cement; the manufacture of the MgPC cement powder was carried out by sintering at 1,100° C. for 3 hours from MgHPO.sub.4, and Mg(OH).sub.2 in a ratio (2:1), leading to a molar composition of Mg.sub.3(PO.sub.4).sub.2. After sintering, the cement powder was ground in a ball mill for 4 hours to an average particle size of <25 μm. Amphisol: surface-active agent. +) magnesium phosphate cement cures by reaction with ammonium salts; in this example with diammonium hydrogen phosphate ((NH.sub.4)2HPO.sub.4), 10% (NH.sub.4)2HPO.sub.4 are therefore to be added to the cement powder so that a total powder quantity of 84% results.

(12) As an oil Miglyol 812 was used.

(13) The list of cement formulations shows that the inventive principle of use of anhydrous liquids that in the chemical sense are not miscible with water as carrier liquids for mineral hydraulic bone cements is very versatile, universally applicable and profitable.

Example 4, Additional Two-Component Cements

(14) Two component cements according to the following formulation have been formulated and tested in accordance with example 1b.

(15) TABLE-US-00006 Two-paste cements (2-component cements) cement accelerator/ compression curing type powder oil Tween Amphisol paste 2 strength time CPC 80% 17% 2% 1% 100% water  14 MPa 8 min MgPC *) 75% 13% 0.8%   0.8%   10%  23 MPa 5 min (NH4)2HPO4 in paste 1; paste 2: 28% (NH4)2HPO4, 3% CMS, 1% Span, 68% water brushite 81% 17% 1% 1% paste 2: 4% 4.5 MPa 6 min cement Na2HPO4, 3% CMS, 1% Span, 92% water HA 81% 17% 1% 1% paste 2: 4% 6.4 MPa 12 min  cement Na2HPO4, 3% CMS, 1% Span, 92% water CMS: carboxymethyl starch Span: surface-active agent *) the total quantity of cement powder is in this embodiment 85% because the anhydrous paste contains 10% (NH.sub.4)2HPO.sub.4 as a solid and additionally a portion of this ammonium salt is dissolved in the aqueous mixing solution. Brushite cement: cement powder according to Pittet C, Lemaitre J. Mechanical characterization of brushite cements: A Mohr circles' approach, J Biomed Mater Res 2000; 53 (6) 769-780 HA cement: cement powder according to Brown W E, Chow L C. A new calcium phosphate water setting cement. In: Brown P W, editor. Cements research progress. Westerville, OH: American Ceramic Society; 1986. p. 352-79.

(16) All solids-containing pastes (paste 1, respectively) were adjusted by appropriate adjustment of the quantity ratios of powder and oil to a consistency of peanut butter at room temperature.

(17) The illustrated results are measured values of applicability tests. It is to be assumed that with all tested cement types upon further optimization work significant increases in the strength values will be achieved. The tested MgCaP cements exhibit excellent mechanical properties already after initial experiments. The curing times for the carried-out experiments are already within the range of known corresponding powder-liquid variants.

ABBREVIATIONS

(18) ACP amorphous calcium phosphate

(19) CdHA calcium-deficient hydroxyl apatite

(20) CP calcium phosphate

(21) CPC calcium phosphate cement

(22) DCPA dicalcium phosphate anhydrite

(23) DCPD dicalcium phosphate dihydrate

(24) HA hydroxyl apatite

(25) Miglyol 812 saturated triglyceride with fatty acids of the chain lengths of 8-12

(26) MCPA monocalcium phosphate anhydrite

(27) MCPM monocalcium phosphate monohydrate

(28) OCP octacalcium phosphate

(29) SDS sodium dodecyl sulphate

(30) TCP tricalcium phosphate

(31) TTCP tetracalcium phosphate