PARTICLES OF A MIXTURE OF IRON(III)-OXYHYDROXIDE, SUCROSE AND ONE OR MORE STARCHES, PREFERABLY OF SUCROFERRIC OXYHYDROXIDE

Abstract

The invention relates to particles of a mixture of iron(III)-oxyhydroxide, sucrose and one or more starches, preferably of sucroferric oxyhydroxide having a certain particle size distribution, a process for the manufacture thereof, the pharmaceutical composition comprising the same, in particular compressed tablets.

Claims

1. Particles, comprising iron(III)-oxyhydroxide, sucrose and one or more starches, wherein the fraction of particles with a particle size of above 90 μm is 25 weight % or more, preferably 35 weight % or more, more preferably 40 weight % or more, even more preferably 45 weight % or more, and most preferably 50 weight % or more, and wherein the fraction of particles with a particle size of above 125 μm is 25 weight % or more, preferably 30 weight % or more, and more preferably 35 weight % or more, each based on the total weight of the particles, as determined by sieve analysis.

2. Particles according to claim 1, wherein the fraction of particles with a particle size in the range of 90 μm to 125 μm is 3 weight % or more, preferably 4 weight % or more, more preferably 5 weight % or more, each based on the total weight of the particles, as determined by sieve analysis.

3. Particles according to claim 1 or 2, wherein the fraction of particles with a particle size in the range of 125 μm to 180 μm is 3 weight % or more, preferably 4 weight % or more, more preferably 5 weight % or more, each based on the total weight of the particles, as determined by sieve analysis.

4. Particles according to any of claims 1 to 3, wherein the fraction of particles with a particle size in the range of 180 μm to 250 μm is 3 weight % or more, preferably 4 weight % or more, more preferably 5 weight % or more, each based on the total weight of the particles, as determined by sieve analysis.

5. Particles according to any of claims 1 to 4, wherein the fraction of particles with a particle size in the range of 250 μm to 355 μm is 3 weight % or more, preferably 4 weight % or more, more preferably 5 weight % or more, each based on the total weight of the particles, as determined by sieve analysis.

6. Particles according to any of claims 1 to 5, wherein the fraction of particles with a particle size in the range of 355 μm to 500 μm is 3 weight % or more, preferably 5 weight % or more, more preferably 8 weight % or more, each based on the total weight of the particles, as determined by sieve analysis.

7. Particles according to any of claims 1 to 6, wherein the fraction of particles with a particle size in the range of 500 μm to 710 μm is 3 weight % or more, preferably 4 weight % or more, more preferably 5 weight % or more, each based on the total weight of the particles, as determined by sieve analysis.

8. Particles according to any of claims 1 to 7, wherein the fraction of particles with a particle size in the range of 90 to 710 μm is 30 weight % or more, preferably 35 weight % or more, more preferably 40 weight % or more, each based on the total weight of the particles, as determined by sieve analysis.

9. Particles according to any of claims 1 to 8, wherein the fraction of particles with a particle size in the range of 125 μm to 180 μm is 3 weight % or more, preferably 4 weight % or more, more preferably 5 weight % or more, and the fraction of particles with a particle size in the range of 180 μm to 250 μm is 3 weight % or more, preferably 4 weight % or more, more preferably 5 weight % or more, and the fraction of particles with a particle size in the range of 250 μm to 355 μm is 3 weight % or more, preferably 4 weight % or more, more preferably 5 weight % or more, and the fraction of particles with a particle size in the range of 355 μm to 500 μm is 3 weight % or more, preferably 5 weight % or more, more preferably 8 weight % or more, and and the fraction of particles with a particle size in the range of 500 μm to 710 μm is 3 weight % or more, preferably 4 weight % or more, more preferably 5 weight % or more, each based on the total weight of the particles, as determined by sieve analysis.

10. Particles according to any of claims 1 to 9, wherein the fraction of particles with a particle size in the range of 125 μm to 180 μm is at most 20 weight %, more preferably at most 15 weight %, still more preferably at most 12 weight %, and the fraction of particles with a particle size in the range of 180 μm to 250 μm is at most 20 weight %, more preferably at most 15 weight %, still more preferably at most 10 weight %, and the fraction of particles with a particle size in the range of 250 μm to 355 μm is at most 20 weight %, more preferably at most 16 weight %, still more preferably at most 13 weight %, and the fraction of particles with a particle size in the range of 355 μm to 500 μm is at most 20 weight %, more preferably at most 18 weight %, still more preferably at most 16 weight %, and the fraction of particles with a particle size in the range of 500 μm to 710 μm is at most 20 weight %, more preferably at most 16 weight %, still more preferably at most 13 weight %, each based on the total weight of the particles, as determined by sieve analysis.

11. Particles according to any of claims 1 to 10, wherein the fraction of particles with a particle size in the range of 125 μm to 180 μm is in the range of 3 weight % to 20 weight %, more preferably in the range of 4 weight % to 15 weight %, still more preferably in the range of 5 weight % to 12 weight %, and the fraction of particles with a particle size in the range of 180 μm to 250 μm is in the range of 3 weight % to 20 weight %, more preferably in the range of 4 weight % to 15 weight %, still more preferably in the range of 5 weight % to 10 weight %, and the fraction of particles with a particle size in the range of 250 μm to 355 μm is in the range of 3 weight % to 20 weight %, more preferably in the range of 4 weight % to 16 weight %, still more preferably in the range of 5 weight % to 13 weight %, and the fraction of particles with a particle size in the range of 355 μm to 500 μm is in the range of 3 weight % to 20 weight %, more preferably in the range of 5 weight % to 18 weight %, still more preferably in the range of 8 weight % to 16 weight %, and the fraction of particles with a particle size in the range of 500 μm to 710 μm is in the range of 3 weight % to 20 weight %, more preferably in the range of 4 weight % to 16 weight %, still more preferably in the range of 5 weight % to 13 weight %, each based on the total weight of the particles, as determined by sieve analysis.

12. Particles according to any of claims 1 to 11, wherein the fraction of particles having a particle size of >710 μm is less than 5 weight %, and preferably less than 3 weight %, based on the total weight of the particles, as determined by sieve analysis.

13. Particles according to any of the previous claims consisting of iron(III)-oxyhydroxide, sucrose, one or more starches and water.

14. A process for the manufacture of the particles according to any of the previous claims, wherein particles, comprising iron(III)-oxyhydroxide, sucrose and one or more starches, wherein the fraction of particles with a particle size of above 90 μm is less than 25 weight %, based on the total weight of the particles, as determined by sieve analysis, are subjected to granulation.

15. Use of particles, comprising iron(III)-oxyhydroxide, sucrose and one or more starches, wherein the fraction of particles with a particle size of above 90 μm is 25 weight % or more, preferably 35 weight % or more, more preferably 40 weight % or more, even more preferably 45 weight % or more, and most preferably 50 weight % or more, and wherein the fraction of particles with a particle size of above 125 μm is 25 weight % or more, preferably 30 weight % or more, and more preferably 35 weight % or more, each based on the total weight of the particles, as determined by sieve analysis, for the manufacture of a pharmaceutical composition.

16. A pharmaceutical composition, comprising particles, comprising iron(III)-oxyhydroxide, sucrose and one or more starches, wherein the fraction of particles with a particle size of above 90 μm is 25 weight % or more, preferably 35 weight % or more, more preferably 40 weight % or more, even more preferably 45 weight % or more, and most preferably 50 weight % or more, and wherein the fraction of particles with a particle size of above 125 μm is 25 weight % or more, preferably 30 weight % or more, and more preferably 35 weight % or more, each based on the total weight of the particles, as determined by sieve analysis.

17. A compressed pharmaceutical composition, obtainable by compressing a pharmaceutical composition, comprising particles, comprising iron(III)-oxyhydroxide, sucrose and one or more starches, wherein the fraction of particles with a particle size of above 90 μm is 25 weight % or more, preferably 35 weight % or more, more preferably 40 weight % or more, even more preferably 45 weight % or more, and most preferably 50 weight % or more, and wherein the fraction of particles with a particle size of above 125 μm is 25 weight % or more, preferably 30 weight % or more, and more preferably 35 weight % or more, each based on the total weight of the particles, as determined by sieve analysis.

18. A compressed pharmaceutical composition according to the previous claim 17, which is selected from a tablet, in particular, a mini- or micro-tablet.

19. A pharmaceutical composition according to any of the previous claims 16 to 18, comprising at least about 90 wt-%, preferably at least about 95 weight %, still more preferably at least about 97 weight % of the total of iron(III)-oxyhydroxide, sucrose and one or more starches, based on the total weight of the pharmaceutical composition.

20. A pharmaceutical composition, according to any of the previous claims 16 to 19, comprising: a) the particles as defined above, b) magnesium stearate c) talc, and d) optionally one or more flavours.

21. A pharmaceutical composition according to any of the previous claims 16 to 20, comprising about 0.75 to about 1.25 weight-% of magnesium stearate and about 1.0 to about 3.0 weight-% of talc, each based on the total weight of the pharmaceutical composition.

22. A pharmaceutical composition according to any of the previous claims 16 to 21, wherein the composition does not contain any further excipients than those indicated before.

23. A pharmaceutical composition according to any of the previous claims 16 to 22 for use in the prophylaxis and treatment of hyperphosphataemia conditions, in particular in patients with chronic renal insufficiency.

24. A process for the manufacture of a compressed pharmaceutical composition according to any of the previous claims 17 to 23, which comprises the step of compressing a non-compressed pharmaceutical composition as defined in any of the previous claims into a tablet, preferably a mini-tablet.

25. A compressed tablet, preferably a mini-tablet, as obtainable by the process according to claim 24, said mini-tablet having a mass of about 9.1 to about 15.9 mg, preferably about 10.2 to about 14.8 mg, even more preferably from about 11.4 to about 13.6 mg.

Description

EXAMPLES

Comparative Example 1

[0239] Sucroferric oxyhydroxide (a mixture of about 33 wt-% iron(III)oxy hydroxide, about 30 wt-% sucrose, about 28 wt-% starches, and water) was obtained by spray drying as described in WO2008/062993 and WO2015/078900. The sucroferric oxyhydroxide had a particle size where about at least 82 wt-% had a particle size of less than 90 μm as determined by sieve analysis as shown in FIG. 2, which shows the results of five batches. The volume-average particle size d50 as determined by laser diffraction was about 55-56 μm.

Example 1

[0240] Sucroferric oxyhydroxide as obtained in comparative example 1 was subjected to roller compaction with a roller compactor (model WP120 from Alexanderwerk) with the following process parameters:

TABLE-US-00001 Process parameter Settings Roller gap  3.0 mm Hydraulic pressure   60 bar Sieve size 2 0.63 mm

[0241] During roller compaction process, the drug substance goes through the roller compactor. The drug substance is compacted in ribbons which are broken with a chopper and then subsequently milled through a final mesh screens size of approx. 0.63 mm. This dry compaction step is implemented to have a coarser particle size distribution of the drug substance. Therefore, the resulting compacted sucroferric oxyhydroxide had a particle size where about 44 wt-% had a particle size of less than 90 μm as determined by sieve analysis as shown in FIG. 3, which shows the results of four batches.

Tabletinq Examples

[0242] Sucroferric oxyhydroxide particles of one batch of each of comparative example 1 and example 1 were each mixed with flavor, sieved talc and sieved magnesium stearate in the quantities shown in the following table (amounts are wt-parts):

TABLE-US-00002 Tableting example Invention Comparison Compacted sucroferric 2500 (equivalent — oxyhydroxide to 500 mg iron) (example 1) Non-compacted sucroferric — 2500 (equivalent to oxyhydroxide (comparative 500 mg iron) example 1) Wood berry flavour 40 40 Talc (flow aid/lubricant) 12.49 12.49 Magnesium stearate (lubricant) 25 25

[0243] Mixing step started with a manual blending of sieved talc with flavor to obtain the pre-blend 1. Then this pre-blend is mixed with one portion of sieved drug substance to obtain the pre-blend 2. The sieved magnesium stearate is added to pre-blend 2 to obtain the pre-blend 3 which was mixed during 5 minutes to obtain the final blend.

[0244] The tablet compositions as shown in the table were then each tableted with a rotary tablet press fitted with 16-tips punches, and the ejection force (Multi-tips punches) was recorded. Critical parameters of the tableting process as final compression force or turret speed were fixed in order to achieve the granules (micro-tablets) characteristics regarding hardness, weight, thickness, friability and disintegration time. Red-brown, cylinder shaped granules (micro-tablets) with approximately 2 mm diameter, and approximately 2.8 mm height (thickness) were obtained.

[0245] The results on the evolution of the ejection forces are shown in FIG. 1.

[0246] The results show a significant lower ejection force (around 300 N lower) for the tablet composition according the invention (compacted sucroferric oxyhydroxide) than for the comparative tablet composition (non-compacted sucroferric oxyhydroxide). Moreover for the tablet composition according the invention the ejection force remains quite stable in time whereas for the comparative tablet composition a slight increase in ejection force. The same trends are observed when the speed of the tableting is increased.

[0247] Corresponding to the higher ejection force of the comparative tablet composition tablets made therefrom show dark brown marks on the extremities of the micro-tablets due to heating linked to the higher ejection force, which are not observed with the inventive tablet composition.