Calcium phosphate cement composition

Abstract

A calcium phosphate cement composition that includes the following two components: A) one or several calcium phosphate powders suspended in an aqueous solution including inhibitor cations inhibiting a reaction of the calcium phosphate powders with water, the inhibitor cations being selected from Mg.sup.2+, Sr.sup.2+ and Ba.sup.2+ at a concentration greater than 0.01 M; and B) an aqueous solution including Ca.sup.2+ cations at a concentration greater than 0.1 M. This calcium phosphate cement compositions can be safely stored for years yet still retain its full reactivity when mixed.

Claims

1. A precursor to a calcium phosphate cement composition, said precursor comprising two distinct components A and B that are kept separate from each other: wherein component A comprises one or more calcium phosphate powders suspended in an aqueous solution that includes inhibitor cations inhibiting a reaction of the calcium phosphate powders with water, the inhibitor cations being selected from the group consisting of Mg.sup.2+, Sr.sup.2+ and Ba.sup.2+ and being present in the aqueous solution of component A at a concentration greater than 0.01 M; wherein component B comprises a second aqueous solution comprising Ca.sup.2+ cations at a concentration greater than 0.1 M; and wherein a ratio of an amount of component A to component B is such that upon mixing components A and B together to form a mixture, a molar ratio of Ca.sup.2+ ions to inhibitor cations in the mixture is greater than 2.

2. The precursor according to claim 1, wherein the inhibitor cations are Mg.sup.2+ only.

3. The precursor according to claim 1, wherein the inhibitor cations are Sr.sup.2+ only.

4. The precursor according to claim 1, wherein the ratio of the amount of component A to component B is such that upon mixing components A and B together to form the mixture, the molar ratio of Ca.sup.2+ ions to inhibitor cations in the mixture is greater than 5.

5. The precursor according to claim 1, wherein the calcium phosphate powder is alpha-tricalcium phosphate.

6. The precursor according to claim 1, wherein the calcium phosphate powder is amorphous calcium phosphate.

7. The precursor according to claim 1, wherein the calcium phosphate powder is obtained by calcination at a temperature in a range of 400 C. to 700 C. for at least 10 minutes.

8. The precursor according to claim 1, wherein the molar concentration of the inhibitor cations in the aqueous solution of component A is equal to or greater than 0.05 M.

9. The precursor according to claim 1, wherein component B comprises calcium salts having a solubility greater than 0.5 M.

10. The precursor according to claim 1, wherein component B comprises one or more calcium salts selected from the group consisting of anhydrous calcium chloride, calcium chloride monohydrate, calcium chloride dihydrate, calcium chloride hexahydrate, dicalcium phosphate dihydrate, calcium sulphate dihydrate, calcium sulfate hemihydrate, calcium sulfate, calcium nitrate, anhydrous calcium acetate, calcium acetate monohydrate, calcium acetate dihydrate, calcium citrate, calcium fumarate, calcium glycerophosphate, calcium lactate, calcium dl-malate, calcium l-malate, calcium malate dihydrogen, calcium maleate, calcium malonate, calcium oxalate, calcium oxalate hydrate, calcium salicylate, calcium succinate, calcium d-tartrate, calcium dl-tartrate, calcium mesotartrate, and calcium valerate.

11. The precursor according to claim 1, wherein a volume ratio of component A to component B is equal to or larger than 4.

12. The precursor according to claim 1, wherein a volume ratio of component A to component B is lower than 12.

13. The precursor according to claim 1, wherein the concentration of Ca2+ ions in component B is greater than to 0.5 M.

14. The precursor according to claim 1, wherein the component B further comprises a calcium phosphate powder.

15. The precursor according to claim 14, wherein the calcium phosphate powder in component B comprises an apatite.

16. The precursor according to claim 14, wherein the quantity of calcium phosphate powder in component B is equal to or greater than 0.4 g/mL.

17. The precursor according to claim 14, wherein the calcium phosphate powder in component B is in the form of nanocrystals.

18. The precursor according to claim 1, wherein component A or component B or both component A and component B comprise a small amount of water soluble polymer.

19. The precursor according to claim 18, wherein the polymer is selected from the group consisting of: (i) hyaluronan; (ii) chondroitin sulfate; (iii) cellulose derivatives; (iv) polyvinylpyrrolidone; (v) N-methyl-2-pyrrolydone; (vi) dimethylsiloxane; (vii) alginate; (viii) chitosan; (ix) gelatin; and (x) collagen.

20. The precursor according to claim 18, wherein the polymer is present in an amount of at least 0.1 weight percent.

21. The precursor according to claim 18, wherein the polymer is present in an amount no greater than 3.0 weight percent.

22. The precursor according to claim 1, further comprising a radiopacifier selected from the the group consisting of: (i) iodine based solutions; (ii) metallic powders and (iii) ceramics.

23. The precursor according to claim 1, wherein a calcium phosphate-to-liquid weight ratio, upon mixing of components A and B, is equal to or greater than 2.

24. The precursor according to claim 1, wherein component B has a pH equal to or lower than 6.

25. The precursor according to claim 24, wherein the pH of component B is adjusted using a weak acid.

26. The precursor according to claim 25, wherein the weak acid in component B is present at a concentration equal to or greater than 0.1 M.

27. The precursor according to claim 1, wherein component A has a pH greater than 8.

28. The precursor according to claim 5, wherein the alpha-tricalcium phosphate has a purity of greater than 80%.

29. The precursor according to claim 28, wherein the alpha-tricalcium phosphate is contaminated with apatite.

30. The precursor according to claim 5, wherein the alpha-tricalcium phosphate has a specific surface area (SSA) greater than 0.5 m2/g.

Description

A BRIEF DESCRIPTION OF THE DRAWINGS

(1) Several embodiments of the invention will be described in the following by way of example and with reference to the accompanying drawings in which:

(2) FIG. 1 is a graph illustrating the crystalline composition of the solid phase in component A following increasing storage time as analyzed by x-ray diffraction;

(3) FIG. 2 is a graph illustrating typical heat release curves obtained by isothermal calorimetry with 2 g of -TCP particles in 0.8 ml 0.1M MgCl.sub.2 solution when 0.2 ml of aqueous solution containing various concentrations of CaCl.sub.2 are added;

(4) FIG. 3 is a graph illustrating typical heat release curves of the cumulated total heat obtained from the release curves in FIG. 2;

(5) FIG. 4 is a graph illustrating typical heat release curves obtained by isothermal calorimetry during the first 30 minutes of the experiment with 2 g of -TCP particles in 0.8 ml 0.1M MgCl.sub.2 solution when 0.2 ml of aqueous CaCl.sub.2 solution containing various concentrations of acetic acid and/or HA seed crystal are added;

(6) FIG. 5 is a graph illustrating typical heat release curves obtained by isothermal calorimetry after the first 30 minutes of the experiment with 2 g of -TCP particles in 0.8 ml 0.1M MgCl.sub.2 solution when 0.2 ml of aqueous CaCl.sub.2 solution containing various concentrations of acetic acid and/or HA seed crystal are added;

(7) FIG. 6 is a graph illustrating typical heat release curves of the cumulated total heat obtained from the release curves in FIGS. 4 and 5;

(8) FIG. 7 is a graph illustrating typical heat release curves obtained by isothermal calorimetry with 2 g of -TCP particles in 0.8 ml 0.1M SrCl.sub.2 solution when 0.2 ml of aqueous solution containing various concentrations of CaCl.sub.2 are added;

(9) FIG. 8 is a graph illustrating typical heat release curves of the cumulated total heat obtained from the release curves in FIG. 2;

(10) FIG. 9 is a graph illustrating typical heat release curves obtained by isothermal calorimetry with 2 g of -TCP particles in 0.8 ml BaCl.sub.2 solution when 0.2 ml of aqueous solution containing various concentrations of CaCl.sub.2 are added; and

(11) FIG. 10 is a graph illustrating typical heat release curves of the cumulated total heat obtained from the release curves in FIG. 9.

(12) The following examples clarify the invention further in more detail.

EXAMPLE 1

(13) This example describes the use of a calcium phosphate cement consisting of two components: (A) a mixture of 6.0 g of -tricalcium phosphate powder (-TCP; Ca.sub.3(PO).sub.4).sub.2; SSA value: 0.6 m.sup.2/g; >99% purity; calcined at 500 C. for 24 h prior to being dispersed in the MgCl.sub.2 solution) and 2.6 ml of 0.1 M magnesium chloride (MgCl.sub.2) solution and (B) 0.52 ml of 5 M calcium chloride (CaCl.sub.2) solution.

(14) Although -TCP is known to react with water to form calcium-deficient hydroxyapatite (CDHA; Ca.sub.9(PO.sub.4).sub.5(HPO.sub.4)OH; reaction 1), this reaction does not occur in component A because of two factors i) -TCP powder was calcined at 500 C. for 24 h prior to dispersing it in the aqueous medium. This treatment has been shown to passivate the -TCP particles and thus results in -TCP powder with low reactivity, and ii) the a-TCP powder is mixed with an aqueous solution containing an inhibitor for CDHA nucleation and crystal growth (=Mg.sup.2+ ion). The combination of both these features is important for obtaining a paste that maintains its stability over several years of storage.
3-Ca.sub.3(PO.sub.4).sub.2+H.sub.2O.fwdarw.Ca.sub.9(PO.sub.4).sub.5(HPO.sub.4)OH[1]

(15) The two components A and B are stored in separate chambers of a dual-chamber syringe with 10:1 volume ratio until the eventual application of the cement. To initiate the cement reaction and hence hardening, components A and B are mixed together. Component B contains calcium ions as an activator which displaces the CDHA nucleation and crystal growth inhibitors present on the particle surface (=Mg.sup.2+ ions), thus initiating the cement reaction in aqueous environment. The mixing of the two components can be achieved by injecting the two components through a static mixer attached to the syringe. Alternatively, the two components A and B may also be mixed with each other using other methods such as with bowl and spatula.

(16) In order to accelerate the initiation of the setting reaction, apatite crystals may be incorporated into component B, or alternatively, the pH of component B may be adjusted to lower pH values as will be further illustrated in Example 3.

EXAMPLE 2

(17) Several samples of calcium phosphate cement compositions according to the invention with various compositions were tested in an isothermal calorimeter at 37 C. using the parameters described in Table 1.

(18) TABLE-US-00001 TABLE 1 Composition of the cement samples tested in isothermal calorimeter Sample Component A Component B 1 2.0 g of calcined -TCP powder 1.0 ml demineralised H.sub.2O 2 2.0 g of calcined -TCP 0.2 ml 0.4M of CaCl.sub.2 powder mixed with 0.8 ml solution 0.1M MgCl.sub.2 solution 3 2.0 g of calcined -TCP 0.2 ml 2.0M of CaCl.sub.2 powder mixed with 0.8 ml solution 0.1M MgCl.sub.2 solution 4 2.0 g of calcined -TCP 0.2 ml 4.0M of CaCl.sub.2 powder mixed with 0.8 ml solution 0.1M MgCl.sub.2 solution 5 2.0 g of calcined -TCP 0.2 ml demineralised H.sub.2O powder mixed with 0.8 ml 0.1M MgCl.sub.2 solution

(19) The -TCP powder (the same as the one used in example 1) was placed in a glass vial compartment of the sealed mixing cell used for the calorimeter experiment, while the liquid component of A was placed in one of the two sealed injection compartments of the mixing cell. The other one of these liquid compartments contained component B. Immediately after placing the mixing cell thus containing both components A and B within the calorimeter, the liquid component, i.e. the MgCl.sub.2 solution, of component A was injected into the -TCP powder and the powder and liquid were mixed together to a cement paste using the mixing rod present in the mixing cell. Following a 2 h incubation time during which both components reached the temperature of 37 C. as indicated by a constant calorimetric signal, component B was injected into the mixing cell containing component A and the formed paste was mixed with the mixing rod. The calorimetric signal was measured until a constant null value was obtained, typically more than 48 h after the injection of component B.

(20) As shown in FIG. 1, the -TCP paste maintains its stability in the aqueous MgCl.sub.2 solution when stored at room temperature for extended periods of time. Similarly, no hydraulic cement reaction indicated by significant heat release was detected for the sample containing 0.1 M MgCl.sub.2 solution with no added activator component (sample 5) in isothermal calorimetry experiments at 37 C. during a 24 days testing period, after which time the experiment was terminated. In comparison, calcined -TCP containing no Mg.sup.2+ ions as nucleation and grain growth inhibitors (sample 1) reacted readily in aqueous environment with the setting reaction initiating less than 10 h after exposure to water (FIG. 2).

(21) Addition of increasing amount Ca.sup.2+ ions as activators into component B (samples 2-4) resulted in increasingly accelerated initiation of the setting reaction with the highest tested concentration resulting in a hydraulic reaction after approximately 12 h as illustrated in FIG. 2. Total amount of heat released during the setting reaction was somewhat lower at low Ca.sup.2+-to-Mg.sup.2+ ratios (FIG. 3). The results indicate that the Ca.sup.2+ ions have the capacity to anneal the effect of the reaction-inhibiting Mg.sup.2+ ions (probably by displacing them from the -TCP particle surface) and thus initiating the cement reaction.

EXAMPLE 3

(22) Several samples of calcium phosphate cement compositions according to the invention were tested in an isothermal calorimeter at 37 C. using the parameters described in Table 2.

(23) TABLE-US-00002 TABLE 2 Composition of the cement samples tested in isothermal calorimeter Sample Component A Component B 6 2.0 g of calcined -TCP 0.2 ml of a mixture of 4M powder mixed with 0.8 ml CaCl.sub.2 and 0.1M acetic 0.1M MgCl.sub.2 solution acid solutions 7 2.0 g of calcined -TCP 0.2 ml of a mixture of 4M powder mixed with 0.8 ml CaCl.sub.2 and 0.25M acetic 0.1M MgCl.sub.2 solution acid solutions 8 2.0 g of calcined -TCP 0.2 ml of a mixture of 4M powder mixed with 0.8 ml CaCl.sub.2 and 0.5M acetic 0.1M MgCl.sub.2 solution acid solutions 9 1.8 g of calcined -TCP 0.2 ml of a mixture of 4M powder and 0.2 g of HA CaCl.sub.2 and 0.5M acetic mixed with 0.8 ml 0.1M acid solutions MgCl.sub.2 solution 10 1.8 g of calcined -TCP 0.2 ml 4M CaCl.sub.2 solution powder and 0.2 g of HA mixed with 0.8 ml 0.1M MgCl.sub.2 solution

(24) The -TCP powder (the same as the one used in example 1) was placed in a glass vial compartment of the sealed mixing cell used for the calorimeter experiment, while the liquid component of A was placed in one of the two sealed injection compartments of the mixing cell. The other one of these liquid compartments contained component B (calcium chloride was dissolved in various concentrations of acetic acid in order to adjust the pH of the activator solution). For samples containing hydroxyapatite crystals (HA; Ca.sub.5(PO.sub.4).sub.3OH; TRI-CAFOS PF, Budenheim; mean particle size: 5.0 m; specific surface area of 70.1 m.sup.2/g) the two powder components were mixed together in advance. Immediately after placing the mixing cell thus containing both components A and B within the calorimeter, the liquid component, i.e. the MgCl.sub.2 solution, of component A was injected into the -TCP powder and the powder and liquid were mixed together to a cement paste using the mixing rod present in the mixing cell. Following a 2 h incubation time during which both components reached the temperature of 37 C. as indicated by a constant calorimetric signal, component B was injected into the mixing cell containing component A and the formed paste was mixed with the mixing rod. The calorimetric signal was measured until a constant null value was obtained, typically more than 48 h after the injection of component B.

(25) Addition of acetic acid into component B (samples 5-8) resulted in an initial setting reaction during the first few minutes after the injection of component B into the cement paste as illustrated in FIG. 4. This initial setting reaction caused by the slight acidity of component B was followed by the main cement reaction indicated by the slower release of heat occurring 1-40 h after the addition of component B into the cement paste as shown in FIG. 5. The setting reaction was further accelerated by the addition of HA seed crystals (sample 9). This acceleration of the hydraulic setting reaction was also detected in sample 10 containing no acetic acid. However, the total cumulated amount of released heat was somewhat lower for samples containing high concentration of acetic acid, seed crystals, or the combination of both as shown in FIG. 6.

(26) Preferably the seed crystals should be contained in component B and mixed with component A only upon the eventual application of the cement paste. However, the HA crystals were added to the component A in the present example (samples 9 and 10) due to the narrow diameter of the inbuilt injection system of the mixing cells used in the calorimeter. Nonetheless, this was not considered to cause significant difference with the detected heat release rate because of the relatively short incubation time prior to the addition of component B to component A comprising the HA seed crystals.

EXAMPLE 4

(27) Several cement samples with various compositions according to the invention were tested in an isothermal calorimeter at 37 C. using the parameters described in Table 1.

(28) TABLE-US-00003 TABLE 3 Composition of the cement samples tested in isothermal calorimeter Sample Component A Component B 11 2.0 g of calcined -TCP powder 1.0 ml demineralised H.sub.2O 12 2.0 g of calcined -TCP 0.2 ml 0.4M of CaCl.sub.2 powder mixed with 0.8 ml solution 0.1M SrCl.sub.2 solution 13 2.0 g of calcined -TCP 0.2 ml 2.0M of CaCl.sub.2 powder mixed with 0.8 ml solution 0.1M SrCl.sub.2 solution 14 2.0 g of calcined -TCP 0.2 ml 4.0M of CaCl.sub.2 powder mixed with 0.8 ml solution 0.1M SrCl.sub.2 solution 15 2.0 g of calcined -TCP powder mixed with 1.0 ml 0.1M SrCl.sub.2 solution

(29) The -TCP powder (the same powder as used in Example 1) was placed in a glass vial compartment of the sealed mixing cell used for the calorimeter experiment, while the liquid component of A was placed in one of the two sealed injection compartments of the mixing cell. The other one of these liquid compartments contained component B. Immediately after placing the mixing cell thus containing both components A and B within the calorimeter, the liquid component, i.e. the SrCl.sub.2 solution, of component A was injected into the -TCP powder and the powder and liquid were mixed together to a cement paste using the mixing rod present in the mixing cell. Following a 2 h incubation time during which both components reached the temperature of 37 C. as indicated by a constant calorimetric signal, component B was injected into the mixing cell containing component A and the formed paste was mixed with the mixing rod. The calorimetric signal was measured until a constant null value was obtained, typically more than 48 h after the injection of component B.

(30) The inhibitory effect of Sr.sup.2+ ions on the setting reaction was found to be similar to the effect of Mg.sup.2+ as presented in Example 2. No hydraulic cement reaction indicated by significant heat release was detected for the sample containing 0.1 M SrCl.sub.2 solution during a 7 days testing period (Sample 15). In comparison, calcined -TCP containing no Sr.sup.2+ ions as nucleation and grain growth inhibitors (sample 11) reacted readily in aqueous environment with the setting reaction initiating less than 10 h after exposure to water (FIG. 7).

(31) Similar to Example 2, the addition of increasing amount Ca.sup.2+ ions as activators into component B (samples 12-14) resulted in increasingly accelerated initiation of the setting reaction with the highest tested concentration resulting in a hydraulic reaction after approximately 12 h as illustrated in FIG. 7. However, with Ca.sup.2+-to-Sr.sup.2+ ratios lower than 5:1, the reversal of the reaction inhibition with Ca.sup.2+ ions appeared somewhat hampered as indicated by the altered heat release kinetics for sample 12 in comparison to sample 2 with corresponding Ca.sup.2+-to-Mg.sup.2+ ratio, whereas the total amount of heat released was no significantly affected (FIG. 8 vs. FIG. 3). Nonetheless, the total amount of heat released during the setting reaction was somewhat lower at low Ca.sup.2+-to-Sr.sup.2+ ratio, as was also shown to be the case with Mg.sup.2+-stabilized -TCP. These results indicate that, similar to Mg.sup.2+ ions, Sr.sup.2+ ions have a reversible inhibitory effect on the hydrolysis reaction of -TCP as the added Ca.sup.2+ ions have the capacity to displace the reaction inhibiting Sr.sup.2+ ions on the -TCP particle surface, thus initiating the cement reaction.

EXAMPLE 5

(32) Several cement samples with various compositions according to the invention were tested in an isothermal calorimeter at 37 C. using the parameters described in Table 3.

(33) TABLE-US-00004 TABLE 3 Composition of the cement samples tested in isothermal calorimeter Sample Component A Component B 16 2.0 g of calcined -TCP powder 1.0 ml demineralised H.sub.2O 17 2.0 g of calcined -TCP 0.2 ml 0.4M of CaCl.sub.2 powder mixed with 0.8 ml solution 0.01M BaCl.sub.2 solution 18 2.0 g of calcined -TCP 0.2 ml 2.0M of CaCl.sub.2 powder mixed with 0.8 ml solution 0.05M BaCl.sub.2 solution 19 2.0 g of calcined -TCP 0.2 ml 4.0M of CaCl.sub.2 powder mixed with 0.8 ml solution 0.1M BaCl.sub.2 solution 20 2.0 g of calcined -TCP powder mixed with 1.0 ml 0.01M BaCl.sub.2 solution

(34) The -TCP powder (the same powder as used in Example 1) was placed in a glass vial compartment of the sealed mixing cell used for the calorimeter experiment, while the liquid component of A was placed in one of the two sealed injection compartments of the mixing cell. The other one of these liquid compartments contained component B. Immediately after placing the mixing cell thus containing both components A and B within the calorimeter, the liquid component, i.e. the BaCl.sub.2 solution, of component A was injected into the -TCP powder and the powder and liquid were mixed together to a cement paste using the mixing rod present in the mixing cell. Following a 2 h incubation time during which both components reached the temperature of 37 C. as indicated by a constant calorimetric signal, component B was injected into the mixing cell containing component A and the formed paste was mixed with the mixing rod. The calorimetric signal was measured until a constant null value was obtained, typically more than 48 h after the injection of component B.

(35) Ba.sup.2+ ions were found to elicit a more potent inhibitory effect on the setting reaction of -TCP cement in comparison to that induced by Mg.sup.2+ and Sr.sup.2+ ions (Examples 2 and 4). This was manifested by the capacity of BaCl.sub.2 concentration as low as 0.01 M to fully repress the conversion of -TCP to hydroxyapatite in aqueous environment throughout a 4 days testing period (sample 20). In comparison, calcined -TCP containing no Ba.sup.2+ ions as nucleation and grain growth inhibitors (sample 16) reacted readily in aqueous environment with the setting reaction initiating less than 10 h after exposure to water (FIGS. 9 and 10).

(36) Similar to Examples 2 and 4, the addition of the component B, which contained Ca.sup.2+ ions in Ca.sup.2+-to-Ba.sup.2+ ratio of 10:1, to the cement paste resulted in the initiation of the hydraulic setting reaction in samples 17 and 18 with initial Ba.sup.2+ concentrations of 0.01 M and 0.05 M, respectively. These results indicate that, similar to Mg.sup.2+ and Sr.sup.2+ ions, Ba.sup.2+ ions have a reversible inhibitory effect on the hydrolysis reaction of -TCP as the added Ca.sup.2+ ions have the capacity to displace the reaction inhibiting Ba.sup.2+ ions on the -TCP particle surface, thus initiating the cement reaction. However, unlike in the case of Mg.sup.2+ and Sr.sup.2+ ions, this inhibitory effect is only reversible at low Ba.sup.2+ concentrations (<0.1 M) as no hydraulic reaction could be initiated at BaCl.sub.2 concentration of 0.1 M by the addition of Ca.sup.2+ ions at Ca.sup.2+-to-Ba.sup.2+ molar ratio of 10:1 (sample 19).

(37) Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims.

(38) It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements.