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. Implant material on the basis of a hydraulic cement of at least one component in the form of a paste, suspension or dispersion, containing at least one powdery solid containing calcium and/or magnesium compounds, that, upon mixing with an aqueous liquid or after introduction into an aqueous liquid, cures to a solid body, wherein the at least one component contains a solid and a carrier liquid that is substantially free of water and in the chemical sense is not miscible with water, and wherein the paste, suspension or dispersion under normal conditions does not surpass the consistency of a kneedable mass.

2. Implant material according to claim 1, characterized in that the solids are suspended/dispersed as a fine powder and in that at least 10% of the solids have a particle size <10 m and in that at least 10% of the solids have a particle size of >50 m.

3. Implant material according to claim 1 or 2, 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. Implant material according to one of the claims 1 to 3, characterized in that the solids to >75% are comprised of calcium and/or magnesium salts and/or oxides and/or hydroxides of calcium and/or magnesium.

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

6. Implant material according to claim 3 or 4, 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), -tricalcium phosphate (-TCP), -tricalcium phosphate (-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.40.5H.sub.2O), calcium sulfate dihydrate (CaSO.sub.42 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.

7. Implant material according to claim 3 or 4, 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.

8. Implant material according to claim 3 or 4, characterized in that the solids to >25% contain - or -tricalcium phosphate, tetracalcium phosphate, dicalcium phosphate anhydrite or amorphous calcium phosphate.

9. Implant material according to one of claims 3 to 7, characterized in that the solids moreover contain ammonium salts that with one of the magnesium compounds cure to a magnesium ammonium phosphate solid material.

10. Implant material according to one of claims 3 to 7, characterized in that the solids contain to >5% calcium or magnesium hydrogen phosphate as hydrate or anhydrous substance.

11. Implant material according to one of the claims 3 to 7, characterized in that the solids to >10% contain calcium sulfate and in particular to >10% calcium sulfate hemihydrate.

12. Implant material according to one of claims 1-11, 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.

13. Implant material according to one of the claims 1-11, 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.

14. Implant material according to one of the claims 1-13, characterized in that the solids are partially or completely dispersed in the carrier liquid and that the carrier liquid itself is soluble to less than 25% in water.

15. Implant material according to one of the claims 1-14, characterized in that the carrier liquid contains dissolved, suspended or dispersed solids or liquids that in water are soluble to more than 1% (W/W), are greatly swellable in water, or in the chemical sense are miscible with water.

16. Implant material according to one of the claims 1-15, characterized in that the carrier liquid is miscible with water and/or aqueous solutions in the physical sense and/or in that the carrier liquid contains substances that assist the formation of physical mixtures with water or aqueous solutions (emulsions) and stabilize it.

17. Implant material according to one of the claims 1-16, characterized in that the carrier liquid is comprised of at least 2 substances that at normal conditions are liquid and wherein each of the substances to at least 0.1% is contained in the carrier liquid.

18. Implant material according to one of the claims 1-17, characterized in that the carrier liquid to >50% is comprised of aliphatic hydrocarbons, esters, ethers, organic acids or mono-valent or multi-valent alcohols with a molecular weight of <2,500 or their mixtures.

19. Implant material according to one of the claims 1-18, characterized in that the carrier liquid to >50% is comprised of esters of mono-valent and/or multi-valent alcohols with fatty acids.

20. Implant material according to one of the claims 1-18, characterized in that the carrier liquid to >50% is comprised of esters or oligoesters of mono-valent or multi-valent alcohols with hydroxy acids, in particular of lactic acid, glycol acids, hydroxy butanoic acid or caprolactone or their mixtures, co-oligomers and/or stereoisomers.

21. Implant material according to one of the claims 1-18, characterized in that the carrier liquid to >1% is comprised of oligomers or polymers and/or co-oligomers or copolymers of ethylene glycol and/or propylene glycol with one another and/or other building blocks, wherein the ethylene glycol and propylene glycol units together make up more than 50% by weight of the corresponding compound and wherein the compounds at normal conditions are liquid.

22. Implant material according to one of the claims 1 to 21, characterized in that the dispersed solids are contained to 25% by weight up to 75% by weight in the paste, suspension or dispersion comprised of liquid and solids.

23. Implant material according to one of the claims 1-21, characterized in that the dispersed solids are contained to >70% by weight in the paste, suspension or dispersion comprised of liquid and solids.

24. Implant material according to one of the claims 1-23, characterized in that the paste, suspension or dispersion contains one or several surface-active agents in addition to suspended/dispersed solids and carrier liquid.

25. Implant material according to one of the claims 1-24 characterized in that the paste, suspension or dispersion contains iron oxides, clay minerals, silicon dioxide, barium sulfate or glycerine stearate as further highly dispersed solids that enhance the formation and stability of physical mixtures (emulsions).

26. Implant material according to claim 24 or 25, characterized in that the paste, suspension or dispersion contains, in addition to suspended/dispersed solids carrier liquid, one or several surface-active agents and/or highly dispersed solids, dissolved or suspended polymers with a molecular weight of >2,500.

27. Implant material according to one of the claims 1-26, characterized in that the paste, suspension or dispersion contains one or several dissolved or suspended pharmacological active ingredients.

28. Implant material according to one of the claims 1-27, characterized in that it contains as a further component an aqueous solution or pure water.

29. Implant material according to claim 28, characterized in that the aqueous solution contains substances that participate in the curing reaction and/or affect its reaction kinetics.

30. Implant material according to claim 28 or 29, characterized in that the aqueous solution contains substances that increase the viscosity of the aqueous solution, in particular water-soluble and/or water-swellable polymers and/or highly dispersed solids.

31. Implant material according to one of the claims 28-30, characterized in that non-reactive components of the mineral cement solids are contained partially or completely in the aqueous solution.

32. Implant material according to one of the claims 28-31, characterized in that the aqueous solution contains substances that affect the crystal structure of the solid phases that are formed in the curing reaction, in particular anionic surface-active agents, magnesium salts, silicates, collagen, gelatin, hyaluronic acid, chondroitin sulfate, amino acids, its phosphorylated derivatives, vitamins and their derivatives, starch and its derivatives, chitosan and its derivatives, cellulose and its derivatives, polyacrylic acid and its derivatives or salts, and generally water-soluble and/or water-swellable polymers whose isoelectric point is <7.

33. Implant material according to one of the claims 28-32, characterized in that the aqueous solution contains suspended and/or dissolved pharmacological active ingredients and/or excipients that affect the stability and/or the release kinetics of the active ingredients.

34. Multi-component application system with a mixing device, comprising implant material according to one of the claims 1 to 33.

35. Single component application system containing implant material according to one of the claims 1 to 27 wherein it contains all substances required for triggering a curing reaction with the exception of water and upon introduction into an aqueous medium and/or contact with water-containing surfaces a curing reaction is spontaneous triggered.

36. Use of implant materials according to one of the claims 1 to 33 for producing bone cements, bone replacement materials, bone adhesives, tooth filling materials and/or implantable active ingredient carriers.

37. Use of an implant material according to one of the claims 1 to 33 in combination with application systems for augmenting osteoporotic or other pathologically modified bone areas and for filling bone defects of all kinds.

Description

EXAMPLES

[0143] Based on the following examples the invention will be explained in more detail:

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

First Component

[0144] The employed CPC is comprised of 60% by weight -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.

[0145] 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 315 min. (30 min. interruption, respectively) at a speed of 500 rpm. The result is a homogenous viscous paste with the consistency of peanut butter.

2nd Component

[0146] As a water-containing carrier liquid 6% hydroxy ethyl starch, 5 Tween 80 and 4% Na.sub.2HPO.sub.4 are combined in water.

[0147] With the two components the following tests are performed: [0148] 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. [0149] 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. [0150] c) 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. [0151] 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.

[0152] 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 decisivewhich is the case in most situations.

Example 2: Calcium Phosphate Cement as Single Component System

[0153] 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) 315 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

[0154] 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 662 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.

TABLE-US-00004 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 m. 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.

[0155] As an oil Miglyol 812 was used.

[0156] 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

[0157] Two component cements according to the following formulation have been formulated and tested in accordance with example 1b.

TABLE-US-00005 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.

[0158] 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.

[0159] 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

[0160] ACP amorphous calcium phosphate
CdHA calcium-deficient hydroxyl apatite
CP calcium phosphate
CPC calcium phosphate cement
DCPA dicalcium phosphate anhydrite
DCPD dicalcium phosphate dihydrate
HA hydroxyl apatite
Miglyol 812 saturated triglyceride with fatty acids of the chain lengths of 8-12
MCPA monocalcium phosphate anhydrite
MCPM monocalcium phosphate monohydrate
OCP octacalcium phosphate
SDS sodium dodecyl sulphate
TCP tricalcium phosphate
TTCP tetracalcium phosphate