IMPLANT THAT CONTAINS INHIBITING CALCIUM CARBONATE

Abstract

The invention relates to the use of inhibiting calcium carbonate as an additive for a composition used in an implant, the composition containing at least one polymer different from cellulose, and the inhibiting calcium carbonate being obtainable by a method in which calcium carbonate particles are coated with a composition that contains, each relative to its total weight, a mixture of at least 0.1 wt.-% of at least one calcium complexing agent and/or at least one conjugated base which is an alkali metal salt or calcium salt of a weak acid, together with at least 0.1 wt.-% of at least one weak acid.

The invention further relates to an implant comprising a composition that contains at least one polymer different from cellulose and inhibiting calcium carbonate, said inhibiting calcium carbonate being obtainable by a method in which calcium carbonate particles are coated with a composition that contains, each relative to its total weight, a mixture of at least 0.1 wt.-% of at least one calcium complexing agent and/or at least one conjugated base which is an alkali metal salt or calcium salt of a weak acid, together with at least 0.1 wt.-% of at least one weak acid.

Claims

1. Use of inhibiting calcium carbonate as an additive for a composition containing at least one polymer different from cellulose in an implant, characterized in that the inhibiting calcium carbonate is obtained by a method in which calcium carbonate particles are coated with a composition that contains, each relative to its total weight, a mixture of at least 0.1 wt.-% of at least one calcium complexing agent and/or at least one conjugated base which is an alkali metal salt or calcium salt of a weak acid, together with at least 0.1 wt.-% of at least one weak acid.

2. The use according to claim 1 for increasing the thermal stability of the composition and/or for increasing the peak temperature of the composition and/or for improving the mechanical properties of the composition.

3. An implant comprising the composition that contains at least one polymer different from cellulose and inhibiting calcium carbonate, wherein the inhibiting calcium carbonate is obtainable by a method in which calcium carbonate particles are coated with a composition that contains, each relative to its total weight, a mixture of at least 0.1 wt.-% of at least one calcium complexing agent and/or at least one conjugated base which is an alkali metal salt or calcium salt of a weak acid, together with at least 0.1 wt.-% of at least one weak acid.

4. The implant according to claim 3, wherein the weak acid is selected from the group consisting of phosphoric acid, metaphosphoric acid, hexametaphosphoric acid, citric acid, boric acid, sulfurous acid, acetic acid and mixtures thereof, and/or in that the conjugated base is a sodium salt or calcium salt of a weak acid and/or in that the conjugated base is sodium hexametaphosphate and/or in that the conjugated base is sodium hexametaphosphate and the weak acid is phosphoric acid and/or in that the calcium complexing agent is selected from the group consisting of sodium hexametaphosphate and common multidentate chelate-forming ligands and preferably the common multidentate chelate-forming ligands are selected from the group consisting of ethylenediaminetetraacetic acid (EDTA), triethylenetetramine, diethylenetriamine, o-phenanthroline, oxalic acid and mixtures thereof.

5. The implant according to claim 3, wherein the content of the calcium complexing agent or of the conjugated base is within the range from 0.1 parts by weight to 25.0 parts by weight, based on 100 parts by weight of calcium carbonate particles, and the content of the weak acid is within the range from 0.1 parts by weight to 30.0 parts by weight, based on 100 parts by weight of calcium carbonate particles.

6. The implant according to claim 3, wherein the calcium carbonate particles have an aspect ratio of less than 5 and/or the calcium carbonate particles comprise spherical calcium carbonate particles.

7. The implant according to claim 3, wherein the composition comprises at least one thermoplastic polymer.

8. The implant according to claim 3, wherein the composition comprises at least one absorbable polymer.

9. The implant according to claim 8, wherein the absorbable polymer has an inherent viscosity, measured in chloroform at 25 C., 0.1% polymer concentration, within the range from 0.3 dl/g to 8.0 dl/g.

10. The implant according to claim 3, wherein the composition comprises poly-D, poly-L and/or poly-D,L-lactic acid.

11. The implant according to claim 3, wherein the composition comprises at least one absorbable polyester having a number average molecular weight ranging from 500 g/mol to 1,000,000 g/mol.

12. The implant according to claim 3, wherein the percentage by weight of the inhibiting calcium carbonate, based on the total weight of the composition, is at least 0.1 wt.-%.

13. The implant according to claim 3, wherein the composition, based on the total weight of the composition, comprises 40.0 wt.-% to 80.0 wt.-% of PLLA and 20.0 wt.-% to 60.0 wt.-% of inhibiting calcium carbonate.

14. The implant according to claim 3, wherein the composition consists of inhibiting calcium carbonate and at least one polymer.

Description

EXAMPLE 1

[0320] A CO.sub.2 gas mixture containing 20% of CO.sub.2 and 80% of N.sub.2 was introduced to 4 I of calcium hydroxide suspension having a concentration of 75 g/l CaO at an initial temperature of 10 C. The gas flow was 300 l/h. The reaction mixture was stirred at 350 rpm and the reaction heat was dissipated during reaction. Upon abrupt drop of the conductance (drop of more than 0.5 mS/cm/min and decrease of the conductance by more than 0.25 mS/cm within 30 seconds) 0.7% of amino tri(methylene phosphonic acid), based on CaO (as theoretical reference variable) is added to the suspension. The reaction into the spherical calcium carbonate particles was completed when the reaction mixture was carbonated quantitatively into spherical calcium carbonate particles, wherein the reaction mixture then showed a pH value between 7 and 9. In the present case, the reaction was completed after about 2 h and the reaction mixture had a pH value of 7 at the reaction end.

[0321] The resulting spherical calcium carbonate particles were separated and dried in a conventional way. They showed a mean particle diameter of 12 m. A typical SEM image is shown in FIG. 1.

EXAMPLE 2

[0322] 500 ml of VE (demineralized) water were provided in a 1000 ml beaker. 125 g of spherical calcium carbonate particles according to Example 1 were added under stirring and the resulting mixture was stirred for 5 min. 37.5 g of a 10% sodium metaphosphate (NaPO.sub.3).sub.n solution were slowly added and the resulting mixture was stirred for 10 min. 75.0 g of 10% phosphoric acid were slowly added and the resulting mixture was stirred for 20 h. The precipitation is separated and dried in the drying cabinet over night at 130 C. The resulting spherical calcium carbonate particles equally had a mean particle diameter of 12 m.

[0323] A SEM image of the spherical calcium carbonate particles is shown in FIG. 2. On the surface of the spherical calcium carbonate particles a thin phosphate layer is visible.

EXAMPLE 3

[0324] A composite powder of spherical calcium carbonate particles and a polylactide (PLLA) was prepared in accordance with the method described in JP 62083029 A using the NHS-1 apparatus. It was cooled with water at 12 C. A polylactide granulate 1 was used as mother particles and the spherical calcium carbonate particles of Example 1 were used as the baby particles (filler).

[0325] 39.5 g of polylactide granulate were mixed with 26.3 g CaCO.sub.3 powder and filled at 6.400 rpm. The rotor speed of the unit was set to 6.400 rpm (80 m/s) and the metered materials were processed for 10 min. The maximum temperature reached in the grinding chamber of NHS-1 was 35 C. A total of 7 repetitions were carried out with equal material quantities and machine settings. A total of 449 g of composite powder was obtained. The composite powder obtained was manually sieved to dry through a 250 m sieve. The sieve residue (fraction >250 m) was 0.4%.

[0326] A SEM image of the composite powder obtained is shown in FIG. 3a.

EXAMPLES 4 to 7

[0327] Further composite powders were prepared analogously to Example 3, wherein in Example 5 cooling took place at about 20 C. In each case 30 g of polylactide granulate were mixed with 20 g of CaCO.sub.3 powder. The maximum temperature reached within the grinding chamber of NHS-1 was 33 C. for Example 4, 58 C. for Example 5, 35 C. for Example 6 and 35 C. for Example 7. The products were sieved to remove the course fraction >250 m where possible (manual dry sieving through 250 m sieve). In the Examples 4, 6 and 7, additionally the fraction <20 m was classified by flow where possible (by means of air separation) or by sieving (by means of air jet sieving machine). The materials used, the implementation of preparation with or without sieving/air separation as well as the properties of the composite powders obtained are listed in the following Table 3.

[0328] FIG. 3a, FIG. 3b and FIG. 3c illustrate a SEM image of Example 3 and images of plural doctor blade applications (12.5 mm/s) of Example 3 (FIG. 3b: 200 m doctor blade; FIG. 3c: 500 m doctor blade).

[0329] The SEM image of the composite powder obtained is shown in FIG. 3a. In contrast to the edgy irregular particulate form which is typical of the cryogenically ground powders, the particles of the composite powder obtained take a round particulate form and, resp., high sphericity very advantageous to SLM methods. The PLLA surface is sparsely occupied with spherical calcium carbonate particles and fragments thereof. The sample has a definitely smaller particle size distribution having increased fine fraction.

[0330] The powder is flowable to a restricted extent (FIGS. 3b and 3c). A powder heap is pushed along in front of the doctor blade. The restricted flow behavior, probably caused by a higher fraction of fine particles, causes only very thin layers to be formed by both doctor blades.

[0331] FIG. 4a, FIG. 4b and FIG. 4c illustrate a SEM image of Example 4 as well as images of plural doctor blade applications (12.5 mm/s) of Example 4 (FIG. 4b: 200 m doctor blade; FIG. 4c: 500 m doctor blade).

[0332] The SEM image of the composite powder obtained is shown in FIG. 4a. In contrast to the edgy irregular particulate form which is typical of the cryogenically ground powders, the particles of the composite powder obtained take a round particulate form and, resp., high sphericity very advantageous to SLM methods. The PLLA surface is sparsely occupied with spherical calcium carbonate particles and fragments thereof. The sample has a definitely smaller particle size distribution having a small fine fraction.

[0333] The powder is properly flowable and applicable (FIGS. 4b and 4c). The thin layers (200 m), too, can be applied and are largely free from doctor streaks (tracking grooves). The powder layer applied with 500 m is homogeneous, densely packed, smooth and free from doctor streaks.

[0334] FIG. 5a, FIG. 5b and FIG. 5c illustrate a SEM image of Example 5 as well as images of several applications (12.5 mm/s) of Example 5 (FIG. 5b: 200 m doctor blade; FIG. 5c: 500 m doctor blade). The powder is flowable to a restricted extent. A powder heap is pushed along by the doctor blade. Due to the restricted flow behavior, probably caused by a higher fraction of fine particles, only very thin layers are formed by both doctor blades.

[0335] FIG. 6a, FIG. 6b and FIG. 6c illustrate a SEM image of Example 6 as well as images of plural applications (12.5 mm/s) of Example 6 (FIG. 6b: 200 m doctor blade; FIG. 6c: 500 m doctor blade). The powder is properly flowable and applicable. The thin layers (200 m), too, can be applied. Individual doctor streaks caused by probably too coarse powder particles are visible. The powder layer applied by 500 m is not quite densely packed but is free from doctor streaks.

[0336] FIG. 7a, FIG. 7b and FIG. 7c illustrate a SEM image of Example 7 as well as images of plural applications (12.5 mm/s) of Example 7 (FIG. 7b: 200 m doctor blade; FIG. 7c: 500 m doctor blade). The powder is flowable and applicable. The thin layers (200 m), too, can be applied. They are not homogeneous and increasingly interspersed with doctor streaks. Somewhat restricted flow behavior is probably caused by too coarse powder particles. The powder layer applied with 500 m is homogeneous and free from doctor streaks.

[0337] Comparison 1

[0338] Microstructured composite particles of spherical calcium carbonate particles of Example 1 and an amorphous polylactide (PDLLA) were prepared in accordance with the method described in JP 62083029 A using the NHS-1 apparatus. It was cooled with water at 12 C. A polylactide granulate 3 was used as mother particles and the spherical calcium carbonate particles of Example 1 were used as the baby particles.

[0339] 39.5 g of polylactide granulate were mixed with 10.5 g of CaCO.sub.3 powder and filled at 8,000 rpm. The rotor speed of the unit was set to 8,000 rpm (100 m/s) and the metered materials were processed for 1.5 min. The maximum temperature reached within the grinding chamber of the NHS-1 was 71 C. A total of 49 repetitions was carried out with equal material quantities and machine settings. A total of 2376 g of structured composite particles were obtained. The obtained structured composite particles were manually dry-sieved through an 800 m sieve for measuring the particle size distribution. The sieve residue (fraction >800 m) amounted to 47%.

[0340] The properties of the microstructured composite particles obtained are listed in the following Table 3.

[0341] FIG. 8a, FIG. 8b and FIG. 8c illustrate a SEM image of Comparison 1 as well as images of plural applications (12.5 mm/s) of Comparison 1 (FIG. 8b: 200 m doctor blade; FIG. 8c : 500 m doctor blade). The powder is poorly flowable and cannot be applied to form layer thicknesses of 200 and, resp., 500 m thickness. The too coarse irregular particles get jammed during application. Non-homogeneous layers having very frequent and distinct doctor streaks are formed.

[0342] The SEM analysis illustrates that the surfaces of the structured composite particles are sparsely occupied with spherical calcium carbonate particles and the fragments thereof. In comparison to the Examples 3 to 7, the particles show a more irregular particle geometry.

EXAMPLE 8

[0343] A composite powder of -tricalcium phosphate particles and a polylactide (PDLLA) was prepared in accordance with the method described in JP 62083029 A using the NHS-1 apparatus. It was cooled with water at 12 C. A polylactide granulate 3 was used as mother particles and -tricalcium phosphate ((-TCP; d.sub.20=30 m; d.sub.50=141 m; d.sub.90=544 m) was used as baby particles. The SEM image of the -TCP used is shown in FIG. 9a and FIG. 9b.

[0344] 30.0 g of polylactide granulate were mixed with 20.0 g of -TCP powder and were filled at 6,400 rpm. The rotor speed of the unit was set to 6,400 rpm (80 m/s) and the metered materials were processed for 10 min. A total of 5 repetitions with equal material quantities and machine settings was carried out. A total of 249 g of composite powder was obtained. The product was sieved to remove the coarse fraction >250 m where possible (manual dry-sieving through a 250 m sieve). Then the fine fraction <20 m was separated through a 20 m sieve by means of an air jet sieving machine.

EXAMPLE 9

[0345] A composite powder of rhombohedral calcium carbonate particles and a polylactide (PDLLA) was prepared in accordance with the method described in JP 62083029 A using the NHS-1 apparatus. It was cooled with water at 12 C. A polylactide granulate 3 was used as mother particles and rhombohedral calcium carbonate particles (d.sub.20=11 m; d.sub.50=16 m; d.sub.90=32 m) were used as baby particles.

[0346] 30.0 g of polylactide granulate were mixed with 20.0 g of the rhombohedral calcium carbonate particles and were filled at 6,400 rpm. The rotor speed of the unit was set to 6,400 rpm (80 m/s) and the metered materials were processed for 10 min. A total of 5 repetitions with equal material quantities and machine settings was carried out. A total of 232 g of composite powder was obtained. The product was sieved to remove the coarse fraction >250 m where possible (manual dry-sieving through a 250 m sieve). Then the fine fraction <20 m was separated through a 20 m sieve by means of an air jet sieving machine.

EXAMPLE 10

[0347] A composite powder of ground calcium carbonate particles and a polylactide (PDLLA) was prepared in accordance with the method described in JP 62083029 A using the NHS-1 apparatus. It was cooled with water at 12 C. A polylactide granulate 3 was used as mother particles and ground calcium carbonate (GCC; d.sub.20=15 m; d.sub.50=46 m; d.sub.90=146 m) were used as baby particles.

[0348] 30.0 g of polylactide granulate were mixed with 20.0 g of GCC and were filled at 6,400 rpm. The rotor speed of the unit was set to 6,400 rpm (80 m/s) and the metered materials were processed for 10 min. A total of 5 repetitions with equal material quantities and machine settings was carried out. A total of 247 g of composite powder was obtained. The product was sieved to remove the coarse fraction >250 m where possible (manual dry-sieving through a 250 m sieve). Then the fine fraction <20 m was separated through a 20 m sieve by means of an air jet sieving machine.

TABLE-US-00003 TABLE 3 Example 3 Example 4 Example 5 Example 6 Example 7 Comparison 1 Composition for the preparation of the composite powder with microstructured particles m(Example 1) [wt.-%] 40 40 0 40 40 20 m(Example 2) [wt.-%] 0 0 40 0 0 0 polylactide Granulate 1 Granulate 1 Granulate 1 Granulate 2 Granulate 3 Granulate 3 m(polylactide) [wt.-%] 60 60 60 60 60 80 Preparation of the composite powder with microstructured particles sieving <250 m <250 m <250 m <250 m <250 m <800 m <20 m <20 m <20 m (for measurement of (air separation) (air jet sieving) (air jet sieving) particle size distribution only) CaCO.sub.3 content [wt.-%].sup.1 41.1 22.4 35.0 19.5 22.3 22.4 (mean value from 5 measurements) T.sub.P [ C.].sup.1 291 310 341 304 286 319 (mean value from 5 measurements) d.sub.50 [m].sup.1 25 47 26 112 136 228 share <20 m 43.6 13.7 37.7 0.3 2.3 20.6 [vol %].sup.1 d.sub.20 [m].sup.1 9 26 14 69 80 d.sub.90 [m].sup.1 86 102 70 223 247 d.sub.20/d.sub.50 [%] 36 52 54 62 59 moisture [wt.-%].sup.1 0.8 0.6 0.5 0.9 0.9 0.3 inherent viscosity [dl/g] 1.0 1.0 0.9 1.9 1.9 1.9 three-point flexural 66 68 77 84 67 79 strength [MPa] E modulus [N/mm.sup.2] 4782 3901 4518 3530 3594 3420 flowability 4 1 4 2 3 5 cytotoxicity test non-cytotoxic non-cytotoxic non-cytotoxic non-cytotoxic non-cytotoxic Example 8 Example 9 Example 10 Composition for the preparation of the composite powder with microstructured particles m(filler) [wt.-%] 40 40 40 polylactide Granulate 3 Granulate 3 Granulate 3 m(polylactide) [wt.-%] 60 60 60 Preparation of the composite powder with microstructured particles sieving <250 m <250 m <250 m <20 m <20 m <20 m Air jet sieving Air jet sieving Air jet sieving filler content [wt.-%]* 24.9 24.2 26.6 T.sub.P [ C.] 341 C. 303 C. 303 C. d.sub.20 [m] 85 74 75 d.sub.50 [m] 131 128 120 d.sub.90 [m] 226 257 230 fraction <20 m 3.0 4.5 1.6 [vol %] moisture [wt.-%] 0.6 0.6 0.6 inherent viscosity [dl/g] 1.8 1.8 1.8 .sup.1at least double-determination