Method for producing an implant using a calcium carbonate-containing composite powder comprising microstructured particles

Abstract

The invention relates to a method for producing an implant which contains a composite powder comprising microstructured particles, obtainable by a method in which large polymer particles are bonded to small spherical calcium carbonate particles. Said calcium carbonate particles can be obtained by a method with the following steps: a) providing a calcium hydroxide suspension, b) introducing carbon dioxide or a carbon dioxide-containing gas mixture into the suspension from step a), and c) separating the calcium carbonate particles formed, while adding 0.3 wt.-% to 0.7 wt.-% of at least one amino trialkylene phosphonic acid.

Claims

1. A method for producing an implant using a composite powder having microstructured particles, the method comprising: bonding large particles to small particles, wherein the large particles comprise at least one polymer and have an average particle diameter in the range from 0.1 μm to 10 mm, wherein the small particles: are arranged on the surface of the large particles or are distributed non-homogeneously within the large particles, and comprise spherical precipitated calcium carbonate particles having an average diameter in the range from 0.05 μm to 50.0 μm, wherein the spherical precipitated calcium carbonate particles are obtained by: providing a calcium hydroxide suspension, introducing carbon dioxide or a gas mixture containing carbon dioxide into the calcium hydroxide suspension, separating the spherical precipitated calcium carbonate particles formed, and adding 0.3% by weight to 0.7% by weight of at least one aminotrialkylene phosphonic acid; and forming the implant by selective laser sintering of a composition comprising the composite powder, wherein the microstructured particles of the composite powder have an average particle size of d.sub.50 within the range from 10 μm to less than 200 μm.

2. The method according to claim 1, further comprising adding at least one of: aminotrimethylene phosphonic acid, aminotriethylene phosphonic acid, aminotripropylene phosphonic acid or aminotributylene phosphonic acid obtain the spherical precipitated calcium carbonate particles.

3. The method according to claim 1, wherein introducing the carbon dioxide or the gas mixture containing carbon dioxide is performed until the reaction mixture has a pH value of less than 9.

4. The method according to claim 1, wherein the reaction of the calcium hydroxide suspension with the carbon dioxide or the gas mixture containing carbon dioxide is carried out at a temperature of less than 25° C.

5. The method according to claim 1, wherein at least one of: the carbon dioxide or the gas mixture containing carbon dioxide is introduced into the calcium hydroxide suspension with a gas flow rate in the range from 0.02 l CO.sub.2/(h*g Ca(OH).sub.2) to 2.0 l CO.sub.2/(h*g Ca(OH).sub.2), the spherical calcium carbonate particles have a mean diameter greater than 3.0 μm, the spherical calcium carbonate particles have an average diameter of less than 30.0 μm, the spherical calcium carbonate particles have a size distribution in which at least 90.0% by weight of all calcium carbonate particles have a particle diameter in the range from mean particle diameter −30% to mean particle diameter+30%, or the spherical calcium carbonate particles have a form factor of greater than 0.90, defined as the quotient of minimum particle diameter and maximum particle diameter.

6. The method according to claim 1, wherein the large particles comprise at least one thermoplastic polymer.

7. The method according to claim 1, wherein the large particles comprise at least one resorbable polymer.

8. The method according to claim 7, wherein the resorbable polymer has an inherent viscosity, measured in chloroform at 25° C. with 0.1% polymer concentration, in the range from 0.3 dl/g to 8.0 dl/g.

9. The method according to claim 1, wherein at least one of: the large particles comprise poly-D-, poly-L- or poly-D,L-lactic acid, the large particles comprise at least one resorbable polyester having a number average molecular weight in the range from 500 g/mol to 1,000,000 g/mol, the large particles comprise at least one polyimide, the large particles comprise at least one polyurethane, the proportion by weight of the spherical precipitated calcium carbonate particles, based on the total weight of the composite powder, is at least 0.1% by weight, or the composite powder, based on the total weight of the composite powder, comprises 40.0 wt. % to 80.0 wt. % PLLA and 20.0 wt. % to 60.0 wt. % of the spherical precipitated calcium carbonate particles.

10. A method for forming an implant having spherical calcium carbonate particles, the method comprising: providing a calcium hydroxide suspension; introducing carbon dioxide or a gas mixture containing carbon dioxide into the calcium hydroxide suspension; separating the spherical calcium carbonate particles formed; adding 0.3% by weight to 0.7% by weight of at least one aminotrialkylene phosphonic acid; and forming the implant by selective laser sintering of a composition comprising the spherical calcium carbonate particles, wherein the spherical calcium carbonate particles of the composition have an average particle size d.sub.50 within the range from 10 μm to less than 200 μm.

11. The method according to claim 10, wherein the spherical calcium carbonate particles are used as an additive for the implant which implant is prepared for in medical technology.

12. The method according to claim 2, wherein introducing the carbon dioxide or the gas mixture containing carbon dioxide is performed until the reaction mixture has a pH value of less than 9.

13. The method according to claim 2, wherein the reaction of the calcium hydroxide suspension with the carbon dioxide or the gas mixture containing carbon dioxide is carried out at a temperature of less than 25° C.

14. The method according to claim 3, wherein the reaction of the calcium hydroxide suspension with the carbon dioxide or the gas mixture containing carbon dioxide is carried out at a temperature of less than 25° C.

15. The method according to claim 2, wherein at least one of: the carbon dioxide or the gas mixture containing carbon dioxide is introduced into the calcium hydroxide suspension with a gas flow rate in the range from 0.02 l CO.sub.2/(h*g Ca(OH).sub.2) to 2.0 l CO.sub.2/(h*g Ca(OH).sub.2), the spherical calcium carbonate particles have a mean diameter greater than 3.0 μm, the spherical calcium carbonate particles have an average diameter of less than 30.0 μm, the spherical calcium carbonate particles have a size distribution in which at least 90.0% by weight of all calcium carbonate particles have a particle diameter in the range from mean particle diameter −30% to mean particle diameter+30%, or the spherical calcium carbonate particles have a form factor of greater than 0.90, defined as the quotient of minimum particle diameter and maximum particle diameter.

16. The method according to claim 3, wherein at least one of: the carbon dioxide or the gas mixture containing carbon dioxide is introduced into the calcium hydroxide suspension with a gas flow rate in the range from 0.02 l CO.sub.2/(h*g Ca(OH).sub.2) to 2.0 l CO.sub.2/(h*g Ca(OH).sub.2), the spherical calcium carbonate particles have a mean diameter greater than 3.0 μm, the spherical calcium carbonate particles have an average diameter of less than 30.0 μm, the spherical calcium carbonate particles have a size distribution in which at least 90.0% by weight of all calcium carbonate particles have a particle diameter in the range from mean particle diameter −30% to mean particle diameter+30%, or the spherical calcium carbonate particles have a form factor of greater than 0.90, defined as the quotient of minimum particle diameter and maximum particle diameter.

17. The method according to claim 4, wherein at least one of: the carbon dioxide or the gas mixture containing carbon dioxide is introduced into the calcium hydroxide suspension with a gas flow rate in the range from 0.02 l CO.sub.2/(h*g Ca(OH).sub.2) to 2.0 l CO.sub.2/(h*g Ca(OH).sub.2), the spherical calcium carbonate particles have a mean diameter greater than 3.0 μm, the spherical calcium carbonate particles have an average diameter of less than 30.0 μm, in particular less than 20.0 μm, the spherical calcium carbonate particles have a size distribution in which at least 90.0% by weight of all calcium carbonate particles have a particle diameter in the range from mean particle diameter −30% to mean particle diameter+30%, or the spherical calcium carbonate particles have a form factor of greater than 0.90, defined as the quotient of minimum particle diameter and maximum particle diameter.

18. The method according to claim 2, wherein the large particles comprise at least one thermoplastic polymer.

19. The method according to claim 3, wherein the large particles comprise at least one thermoplastic polymer.

20. A method for producing an implant using a composite powder having microstructured particles, the method comprising: bonding large particles to small particles, wherein the small particles: are arranged on the surface of the large particles or are distributed non-homogeneously within the large particles, and comprise spherical precipitated calcium carbonate particles having an average diameter in the range from 0.05 μm to 50.0 μm; wherein the spherical precipitated calcium carbonate particles are obtained by: providing a calcium hydroxide suspension, introducing carbon dioxide or a gas mixture containing carbon dioxide into the calcium hydroxide suspension, separating the spherical precipitated calcium carbonate particles formed, and adding 0.3% by weight to 0.7% by weight of at least one aminotrialkylene phosphonic acid; and forming the implant by selective laser sintering of a composition comprising the composite powder, wherein the microstructured particles of the composite powder have an average particle size d.sub.50 within the range from 10 μm to less than 200 μm.

Description

EXAMPLE 1

(1) A CO.sub.2 gas mixture containing 20% of CO.sub.2 and 80% of N.sub.2 was introduced into 41 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 value), is added to the suspension. The conversion to the spherical calcium carbonate particles was completed when the reaction mixture was carbonated quantitatively in relation to the 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.

(2) The resulting spherical calcium carbonate particles were separated and dried in a conventional way. They showed a mean particle diameter of 12 μm. A typical SEM image is shown in FIG. 1.

EXAMPLE 2

(3) 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 μm.

(4) An 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

(5) 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).

(6) 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 amount of 449 g of composite powder was obtained. The composite powder obtained was manually dry-sieved through a 250 μm sieve. The sieve residue (fraction >250 μm) was 0.4%.

(7) An SEM image of the composite powder obtained is shown in FIG. 3a.

EXAMPLES 4 TO 7

(8) 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 μm where possible (manual dry sieving through 250 μm sieve). In the Examples 4, 6 and 7, additionally the fraction <20 μm 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 the preparation with or without sieving/air separation as well as the properties of the composite powders obtained are listed in the following Table 3.

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

(10) 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 show a round particulate form and also high sphericity, with both attributes being very advantageous to SLM methods. The PLLA surface is sparsely occupied with spherical calcium carbonate particles and fragments thereof. The sample has a wide particle size distribution having increased fine-grain fraction.

(11) 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.

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

(13) 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 show a round particulate form and also high sphericity, with both attributes being very advantageous to SLM methods. The PLLA surface is sparsely occupied with spherical calcium carbonate particles and fragments thereof. The sample exhibits a considerably smaller particle size distribution having a small fine-grain fraction.

(14) The powder has a very good flowability and can be applied very well by doctor blades (FIGS. 4b and 4c). The thin layers (200 μm), too, can be applied by doctor blades and are largely free from doctor streaks (tracking grooves). The powder layer applied with a doctor blade with 500 μm is homogeneous, densely packed, smooth and free from doctor streaks.

(15) FIG. 5a, FIG. 5b and FIG. 5c illustrate an SEM image of Example 5 as well as images of several applications (12.5 mm/s) of Example 5 (FIG. 5b: 200 μm doctor blade; FIG. 5c: 500 μm 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.

(16) FIG. 6a, FIG. 6b and FIG. 6c illustrate an SEM image of Example 6 as well as images of plural applications (12.5 mm/s) of Example 6 (FIG. 6b: 200 μm doctor blade; FIG. 6c: 500 μm doctor blade). The powder has a good flowability and can be applied well by doctor blades. The thin layers (200 μm), too, can be applied. Individual doctor streaks caused by probably too coarse powder particles are visible. The powder layer applied with 500 μm is not quite densely packed but is free from doctor streaks.

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

(18) Comparison 1

(19) 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.

(20) 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 amount of 2376 g of structured composite particles were obtained. The obtained structured composite particles were manually dry-sieved through an 800 μm sieve for measuring the particle size distribution. The sieve residue (fraction >800 μm) amounted to 47%.

(21) The properties of the microstructured composite particles obtained are listed in the following Table 3.

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

(23) The SEM analysis shows that the surfaces of the structured composite particles are sparsely occupied with spherical calcium carbonate particles and the fragments thereof. As compared to the Examples 3 to 7, the particles show a more irregular particle geometry.

EXAMPLE 8

(24) A composite powder of β-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 β-tricalcium phosphate (β-TCP; d.sub.20=30 μm; d.sub.50141 μm; d.sub.90=544 μm) was used as baby particles. The SEM image of the β-TCP used is shown in FIG. 9a and FIG. 9b.

(25) 30.0 g of polylactide granulate were mixed with 20.0 g of β-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 amount of 249 g of composite powder was obtained. The product was sieved to remove the coarse fraction >250 μm where possible (manual dry-sieving through a 250 μm sieve). Then, the fine-grain fraction <20 μm was separated through a 20 μm sieve by means of an air jet sieving machine.

EXAMPLE 9

(26) 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 μm; d.sub.50=16 μm; d.sub.90=32 μm) were used as baby particles.

(27) 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 amount of 232 g of composite powder was obtained. The product was sieved to remove the coarse fraction >250 μm where possible (manual dry-sieving through a 250 μm sieve). Then the fine-grain fraction <20 μm was separated through a 20 μm sieve by means of an air jet sieving machine.

EXAMPLE 10

(28) 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 μm; d.sub.50=46 μm; d.sub.90=146 μm) were used as baby particles.

(29) 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 amount of 247 g of composite powder was obtained. The product was sieved to remove the coarse fraction >250 μm where possible (manual dry-sieving through a 250 μm sieve). Then, the fine-grain fraction <20 μm was separated through a 20 μm sieve by means of an air jet sieving machine.

(30) 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) [Gew.-%] 40 40 0 40 40 20 m(Example 2) [Gew.-%] 0 0 40 0 0 0 Polylactide Granulate 1 Granulate 1 Granulate 1 Granulate 2 Granulate 3 Granulate 3 m(Polylactide) [Gew.-%] 60 60 60 60 60 80 Preparation of the composite powder with microstructured particles Sieving <250 μm <250 μm <250 μm <250 μm <250 μm <800 μm (for  <20 μm  <20 μm  <20 μm measurement (air separation) (air jet (air jet of the particle sieving) sieving) size distribution) CaCO.sub.3 content [Gew.-%].sup.1 41.0 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 [μm].sup.1 25 47 26 112 136 228 Share <20 μm [Vol.-%].sup.1 43.6 13.7 37.7 0.3 2.3 20.6 d.sub.20 [μm].sup.1 9 26 14 69 80 d.sub.90 [μm].sup.1 86 102 70 223 247 d.sub.20/d.sub.50 [%] 36 52 54 62 59 Moisture [Gew.-%].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- non- non- — non- non- cytotoxic cytotoxic cytotoxic cytotoxic cytotoxic Example 8 Example 9 Example 10 Composition for the preparation of the composite powder with microstructured particles m(Filler) [Gew.-%] 40 40 40 Polylactide Granulate 3 Granulate 3 Granulate 3 m(Polylactide) [Gew.-%] 60 60 60 Preparation of the composite powder with microstructured particles Sieving <250 μm <250 μm <250 μm  <20 μm  <20 μm  <20 μm Air jet sieving Air jet sieving Air jet sieving Filler content [Gew.-%]* 24.9 24.2 26.6 T.sub.P [° C.] 341° C. 303° C. 303° C. d.sub.20 [μm] 85 74 75 d.sub.50 [μm] 131 128 120 d.sub.90 [μm] 226 257 230 Share <20 μm [Vol.-%] 3.0 4.5 1.6 Moisture [Gew.-%] 0.6 0.6 0.6 Inherent viscosity [dl/g] 1.8 1.8 1.9 .sup.1At least double determination