Gastro-resistant formulation containing posaconazole

Abstract

The present invention relates to a gastro-resistant pharmaceutical composition comprising a solid solution prepared by hot-melt extrusion, whereby the solid solution contains posaconazole, an enteric polymer and a non-enteric polymer. The composition is preferably a granulate material that can be filled into a capsule or compressed into a tablet.

Claims

1. A gastro-resistant pharmaceutical composition comprising posaconazole, wherein the posaconazole is molecularly dispersed in a mixture containing an enteric polymer and a non-enteric polymer, the mixture is prepared by hot-melt extrusion, wherein the enteric polymer and non-enteric polymer are present in a ratio of 6:1 to 1:1 and the gastro-resistant pharmaceutical composition releases posaconazole in the intestine and releases≤10% of the posaconazole after two hours in 0.01M HCl and releases at least 80% of the posaconazole after the two hours in 0.01 M HCl followed by 45 minutes at pH 6.8.

2. The composition according to claim 1, wherein the enteric polymer is selected from hypromellose derivatives, cellulose derivatives, polyvinylacetate derivatives and polymethacrylic acid derivatives.

3. The composition according to claim 2, wherein the enteric polymer is a polymethacrylic acid derivative selected from poly(methacrylic acid/methyl methacrylate) and poly(methacrylic acid/ethyl acrylate).

4. The composition according to claim 1, wherein the non-enteric polymer is selected from polyvinylpyrrolidone, poly(vinylpyrrolidone/vinyl acetate), polyvinylcaprolactam/polyvinylacetate/polyethylene glycol graft copolymer, polyethylene glycol/polyvinyl alcohol graft copolymer, poly(ethyl ene oxide/propylene oxide), macrogolglycerol hydroxystearate, polyethylene glycol, hypromellose, hydroxypropyl cellulose, hydroxyethyl cellulose and maltodextrins.

5. The composition according to claim 4, wherein the enteric polymer is poly(methacrylic acid/ethyl acrylate) and the non-enteric polymer is selected from poly(vinyl-pyrrolidone/vinylacetate), polyethylene glycol, hydroxypropyl cellulose and polyvinylpyrrolidone.

6. The composition according to claim 1, wherein the composition contains an antioxidant.

7. The composition according to claim 6, wherein the antioxidant is contained in the mixture.

8. The composition according to claim 6, wherein the antioxidant is selected from butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), sodium metabisulfite or potassium metabisulfite, sodium bisulfite, sodium sulfite, sodium thiosulfate, cysteine, acetyl cysteine, methionine, glutathione, sodium formaldehyde sulfoxylate, ascorbic acid and ascorbic derivatives, ascorbyl palmitate, tocopherol and tocopherol derivatives, tocopheryl succinate, tocopheryl polyethylene glycol succinate (TPGS) and propyl gallate.

9. The composition according to claim 1, wherein the mixture contains a monomeric plasticizer.

10. The composition according to claim 9, wherein the monomeric plasticizer is selected from triethyl citrate, triacetin, dibutyl sebacate, diethyl phthalate, glycerylmonostearate, glycerine and propylene glycol.

11. The composition according to claim 1, wherein the mixture contains a sugar alcohol.

12. The composition according to claim 1, wherein the sugar alcohol is selected from xylitol, sorbitol, mannitol and maltitol.

13. The composition according to claim 1, wherein the composition is a granulate material.

14. The composition according to claim 13, wherein the granules are coated with an enteric polymer.

15. The composition according to claim 13, wherein the granules are filled into a capsule or compressed into a tablet.

16. A gastro-resistant pharmaceutical composition comprising posaconazole, wherein the posaconazole is molecularly dispersed in a mixture containing an enteric polymer and a non-enteric polymer, the mixture is prepared by hot-melt extrusion, wherein the enteric polymer and non-enteric polymer are present in a ratio of 6:1 to 1:1 and the gastro-resistant pharmaceutical composition releases≤10% of the posaconazole in the stomach and at least 80% of the posaconazole is released in stomach and intestine combined.

17. The composition according to claim 16, wherein the enteric polymer is selected from hypromellose derivatives, cellulose derivatives, polyvinylacetate derivatives and polymethacrylic acid derivatives.

18. The composition according to claim 17, wherein the enteric polymer is a polymethacrylic acid derivative selected from poly(methacrylic acid/methyl methacrylate) and poly(methacrylic acid/ethyl acrylate).

19. The composition according to claim 16, wherein the non-enteric polymer is selected from polyvinylpyrrolidone, poly(vinylpyrrolidone/vinyl acetate), polyvinylcaprolactam/polyvinylacetate/polyethyl ene glycol graft copolymer, polyethylene glycol/polyvinyl alcohol graft copolymer, poly(ethylene oxide/propylene oxide), macrogolglycerol hydroxystearate, polyethylene glycol, hypromellose, hydroxypropyl cellulose, hydroxyethyl cellulose and maltodextrins.

20. The composition according to claim 19, wherein the enteric polymer is poly(methacrylic acid/ethyl acrylate) and the non-enteric polymer is selected from poly(vinyl-pyrrolidone/vinylacetate), polyethylene glycol, hydroxypropyl cellulose and polyvinylpyrrolidone.

21. The composition according to claim 16, wherein the composition contains an antioxidant.

22. The composition according to claim 21, wherein the antioxidant is contained in the mixture.

23. The composition according to claim 21, wherein the antioxidant is selected from butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), sodium metabisulfite or potassium metabisulfite, sodium bisulfite, sodium sulfite, sodium thiosulfate, cysteine, acetyl cysteine, methionine, glutathione, sodium formaldehyde sulfoxylate, ascorbic acid and ascorbic derivatives, ascorbyl palmitate, tocopherol and tocopherol derivatives, tocopheryl succinate, tocopheryl polyethylene glycol succinate (TPGS) and propyl gallate.

24. The composition according to claim 16, wherein the mixture contains a monomeric plasticizer.

25. The composition according to claim 24, wherein the monomeric plasticizer is selected from triethyl citrate, triacetin, dibutyl sebacate, diethyl phthalate, glycerylmonostearate, glycerine and propylene glycol.

26. The composition according to claim 16, wherein the mixture contains a sugar alcohol.

27. The composition according to claim 26, wherein the sugar alcohol is selected from xylitol, sorbitol, mannitol and maltitol.

28. The composition according to claim 16, wherein the composition is a granulate material.

29. The composition according to claim 28, wherein the granules are coated with an enteric polymer.

30. The composition according to claim 28, wherein the granules are filled into a capsule or compressed into a tablet.

Description

EXAMPLES

(1) Hot melt extrusion was performed with a Pharma 11 Twin-screw hot melt extruder from Thermo Fisher Scientific Inc. The used film coating system Opadry II® 85F520152 yellow comprises polyvinyl alcohol, titanium dioxide, polyethylene glycol/macrogol, talc and yellow iron oxide.

Example 1

(2) TABLE-US-00001 Ingredients mg Stage-A: (Hot-melt extrusion) Posaconazole (Form I) 100 Methacrylic acid/ethyl acrylate copolymer 150 (1:1), Type B (Kollicoat ® MAE 100P) Polyethylene glycol 1450 (Macrogol 1450) 30 Copovidone (Kollidon ® VA 64) 25 Sorbitol (Neosorb ® P 100 T) 20 Total weight after HME 325 Stage-B: (Blending and Lubrication) Posaconazole HME granules 325 Low-substituted Hydroxypropylcellulose 60 (L-HPC LH-11) Microcrystalline cellulose (Comprecel ® M 102D+) 165 Colloidal silicon dioxide (Aerosil ® 200 pharma) 4 Croscarmellose sodium 42 Sodium stearyl fumarate (Pruv ®) 4 Core tablet weight 600 Stage-C: (Coating) Opadry II ® 85F520152 yellow 18 Water, purified q.s. Coated tablet weight 618

(3) Process:

(4) Posaconazole and the excipients of stage A were sifted and blended. The mixture was subjected to hot melt extrusion and the obtained extrudate was milled. Low-substituted hydroxypropylcellulose, microcrystalline cellulose, silicon dioxide, croscarmellose sodium, and sodium stearyl fumarate were sifted and blended with the extrudate. The mixture was subjected to compression to obtain a tablet, which was finally film-coated.

Example 2

(5) TABLE-US-00002 Ingredients mg Stage-A: (Hot-melt extrusion) Posaconazole (Form I) 100 Methacrylic acid/ethyl acrylate copolymer 150 (1:1), Type B (Kollicoat ® MAE 100P) Polyethylene glycol 1450 (Macrogol 1450) 30 Copovidone (Kollidon ® VA 64) 25 Sorbitol (Neosorb ® P 100 T) 20 Total weight after HME 325 Stage-B: (Enteric coating by top-spray granulation) Kollicoat MAE 100P 10 Polyethylene glycol 400 2 Water, purified q.s Total weight of granules 337 Stage-C: (Blending and Lubrication) Posaconazole HME granules 337 Low-substituted Hydroxypropylcellulose 60 (L-HPC 11) Microcrystalline cellulose (Comprecel M 102D+) 153 Colloidal silicon dioxide (Aerosil 200 pharma) 4 Croscarmellose sodium 42 Sodium stearyl fumarate 4 Core tablet weight 600 Stage-D: (Coating) Opadry II ® 85F520152 yellow 18 Water, purified q.s. Coated tablet weight 618

(6) Process:

(7) Posaconazole and the excipients of stage A were sifted and blended, and then subjected to hot melt extrusion. The extrudate was milled and coated with the material of stage B by top-spray granulation. Low-substituted hydroxypropyl cellulose, microcrystalline cellulose, silicon dioxide, croscarmellose sodium, and sodium stearylfumarate of stage C were sifted and blended with the enteric-coated extrudate. The mixture was subjected to compression to obtain a tablet, which was finally film-coated.

Example 3

(8) TABLE-US-00003 Ingredients mg Stage-A: (Hot-melt extrusion) Posaconazole (Form I) 100 Methacrylic acid/ethyl acrylate copolymer 150 (1:1), Type B (Kollicoat ® MAE 100P) Polyethylene glycol 4000 (Macrogol 4000) 30 Copovidone (Kollidon ® VA 64) 25 Total weight after HME 305 Stage-B: (Lubrication and compression) Posaconazole HME granules 305 Low-substituted Hydroxypropylcellulose 103 (L-HPC LH-11) Microcrystalline cellulose (Comprecel ® M 102D+) 105.5 Colloidal silicon dioxide (Aerosil ® 200 pharma) 24 Croscarmellose sodium 60 Magnesium Stearate 2.5 Core tablet weight 600 Stage-C: (Film Coating) Opadry ® II 85F520152 yellow 18 Water, purified q.s. Coated tablet weight 618

(9) Process:

(10) Posaconazole and the excipients of stage A were sifted and blended. The mixture was subjected to hot melt extrusion and the obtained extrudate was milled. Low-substituted hydroxypropylcellulose, microcrystalline cellulose, silicon dioxide, croscarmellose sodium, and magnesium stearate of stage B were sifted and blended with the extrudate. The mixture was subjected to compression to obtain a tablet, which was finally film-coated.

Example 4

(11) TABLE-US-00004 Ingredients mg Stage-A: (Hot-melt extrusion) Posaconazole (Form I) 100 Methacrylic acid/ethyl acrylate copolymer 162 (1:1), Type B (Kollicoat ® MAE 100P) Polyethylene glycol (Macrogol 1450) 30 Copovidone (Kollidon ® VA 64) 50 Xylitol (Xylisorb ® 90) 20 Total weight after HME 362 Stage-B: (Lubrication and compression) Posaconazole HME granules 362 Low-substituted Hydroxypropylcellulose 60 (L-HPC LH-11) Microcrystalline cellulose (Comprecel ® M 102D+) 128 Colloidal silicon dioxide (Aerosil ® 200 pharma) 4 Croscarmellose sodium 42 Stage-C: (Lubrication) Sodium stearyl fumarate (Pruv ®) 4 Core tablet weight 600 Stage-D: (Film Coating) Opadry ® II 85F520152 yellow 18 Water, purified q.s. Coated tablet weight 618

(12) Process:

(13) Posaconazole and the excipients of stage A were sifted and blended. The mixture was subjected to hot melt extrusion and the obtained extrudate was milled. Low-substituted hydroxypropylcellulose, microcrystalline cellulose, silicon dioxide, and croscarmellose sodium of stage B were sifted and blended with the extrudate. The mixture was lubricated with sodium stearyl fumarate and then subjected to compression to obtain a tablet, which was finally film-coated.

Example 5

(14) TABLE-US-00005 Ingredients mg Stage-A: (Hot-melt extrusion) Posaconazole (Form I) 100 Methacrylic acid/ethyl acrylate copolymer 162 (1:1), Type B (Kollicoat ® MAE 100P) Polyethylene glycol (Carbowax ™ Sentry ™) 30 Copovidone (Kollidon ® VA 64) 50 Xylitol (Xylisorb ® 90) 20 Total weight after HME 362 Stage-B: (Lubrication and compression) Posaconazole HME granules 362 Hydroxypropyl cellulose (Klucel EXF Pharma) 75 Microcrystalline cellulose (Comprecel ® M 102D+) 113 Colloidal silicon dioxide (Aerosil ® 200 pharma) 4 Croscarmellose sodium 42 Stage-C: (Lubrication) Sodium stearyl fumarate (Pruv ®) 4 Core tablet weight 600 Stage-D: (Film Coating) Opadry ® II 85F520152 yellow 18 Water, purified q.s. Coated tablet weight 618

(15) Process:

(16) Posaconazole and the excipients of stage A were sifted and blended. The mixture was subjected to hot melt extrusion and the obtained extrudate was milled. Hydroxypropyl cellulose, microcrystalline cellulose, silicon dioxide, and croscarmellose sodium of stage B were sifted and blended with the extrudate. The mixture was lubricated with sodium stearyl fumarate and then subjected to compression to obtain a tablet, which was finally film-coated.

Example 6

(17) TABLE-US-00006 Ingredients mg Stage-A: (Hot-melt extrusion) Posaconazole (Form I) 100 Methacrylic acid/ethyl acrylate copolymer 162 (1:1), Type B (Kollicoat ® MAE 100P) Polyethylene glycol (Carbowax ™ Sentry ™) 30 Copovidone (Kollidon ® VA 64) 50 Xylitol (Xylisorb ® 90) 20 Propyl gallate 2 Total weight after HME 364 Stage-B: (Lubrication and compression) Posaconazole HME granules 364 Hydroxypropyl cellulose (Klucel EXF Pharma) 75 Microcrystalline cellulose (Comprecel ® M 102D+) 111 Colloidal silicon dioxide (Aerosil ® 200 pharma) 4 Croscarmellose sodium 42 Stage-C: (Lubrication) Sodium stearyl fumarate (Pruv ®) 4 Core tablet weight 600 Stage-D: (Film Coating) Opadry ® II 85F520152 yellow 18 Water, purified q.s. Coated tablet weight 618

(18) Process:

(19) Posaconazole and the excipients of stage A were sifted and blended. The mixture was subjected to hot melt extrusion and the obtained extrudate was milled. Hydroxypropyl cellulose, microcrystalline cellulose, silicon dioxide, and croscarmellose sodium of stage B were sifted and blended with the extrudate. The mixture was lubricated with sodium stearyl fumarate and then subjected to compression to obtain a tablet, which was finally film-coated.

Examples 7a and 7b

(20) TABLE-US-00007 Ex. 7a Ex. 7b Ingredients mg mg Stage-A: (Granulation) Methacrylic acid/ethyl acrylate copolymer 162 162 (1:1), Type B (Kollicoat ® MAE 100P) Copovidone (Kollidon ® VA 64) 50 50 Triethyl citrate 30 30 Total weight after granulation 242 242 Stage-B: (Hot-melt extrusion) Granules 242 242 Posaconazole (Form I) 100 — Posaconazole (amorphous) — 100 Xylitol (Xylisorb ® 90) 20 20 Propyl gallate 2 2 Total weight after HME 364 364 Stage-C: (Blending) Posaconazole HME granules 364 364 Hydroxypropyl cellulose (Klucel EXF Pharma) 75 75 Microcrystalline cellulose (Comprecel ® M 102D+) 111 111 Colloidal silicon dioxide (Aerosil ® 200 pharma) 4 4 Croscarmellose sodium 42 42 Stage-D: (Lubrication) Sodium stearyl fumarate (Pruv ®) 4 4 Core tablet weight 600 600 Stage-E: (Film Coating) Opadry ® II 85F520152 yellow 18 18 Water, purified q.s. q.s. Coated tablet weight 618 618

(21) Process:

(22) The excipients of stage A were sifted and granulated. Posaconazole and the excipients of stage B were sifted and blended with the granules of stage A. The mixture was subjected to hot melt extrusion and the obtained extrudate was milled. Hydroxypropyl cellulose, microcrystalline cellulose, silicon dioxide, and croscarmellose sodium of stage C were sifted and blended with the extrudate. The mixture was lubricated with sodium stearyl fumarate and then subjected to compression to obtain a tablet, which was finally film-coated.

Example 8

(23) TABLE-US-00008 Ingredients mg Stage-A: (Granulation) Methacrylic acid/ethyl acrylate copolymer 162 (1:1), Type B (Kollicoat ® MAE 100P) Triethyl citrate 30 Total weight after granulation 192 Stage-B: (Hot-melt extrusion) Granules 192 Posaconazole (Form I) 100 Povidone K 30 25 Xylitol (Xylisorb ® 90) 40 Propyl gallate 2 Total weight after HME 359 Stage-C: (Blending) Posaconazole HME granules 359 Hydroxypropyl cellulose (Klucel EXF Pharma) 75 Microcrystalline cellulose (Comprecel ® M 102D+) 116 Colloidal silicon dioxide (Aerosil ® 200 pharma) 4 Croscarmellose sodium 42 Stage-D: (Lubrication) Sodium stearyl fumarate (Pruv ®) 4 Core tablet weight 600 Stage-E: (Film Coating) Opadry ® II 85F520152 yellow 18 Water, purified q.s. Coated tablet weight 618

(24) Process:

(25) The excipients of stage A were sifted and granulated. Posaconazole and the excipients of stage B were sifted and blended with the granules of stage A. The mixture was subjected to hot melt extrusion and the obtained extrudate was milled. Hydroxypropyl cellulose, microcrystalline cellulose, silicon dioxide, and croscarmellose sodium of stage C were sifted and blended with the extrudate. The mixture was lubricated with sodium stearyl fumarate and then subjected to compression to obtain a tablet, which was finally film-coated.

Examples 9a and 9b

(26) TABLE-US-00009 Ex. 9a Ex. 9b Ingredients mg mg Stage-A: (Granulation) Methacrylic acid/ethyl acrylate copolymer 250 250 (1:1), Type B (Kollicoat ® MAE 100P) Triethyl citrate 30 10 Total weight after granulation 280 260 Stage-B: (Hot-melt extrusion) Granules 280 260 Posaconazole (Form I) 100 100 Hydroxypropyl cellulose 75 75 (Klucel EXF Pharma) Xylitol (Xylisorb ® 90) 28 28 Propyl gallate 2 1 Total weight after HME 485 464 Stage-C: (Blending) Posaconazole HME granules 485 464 Hydroxypropyl cellulose 30 30 (Klucel EXF Pharma) Microcrystalline cellulose 180 64 Colloidal silicon dioxide 3 3 (Aerosil ® 200 pharma) Croscarmellose sodium 35 35 Stage-D: (Lubrication) Sodium stearyl fumarate (Pruv ®) 4 4 Core tablet weight 737 600 Stage-E: (Film Coating) Opadry ® II 85F520152 yellow 22 24 Water, purified q.s. q.s. Coated tablet weight 759 624

(27) Process:

(28) The excipients of stage A were sifted and granulated. Posaconazole and the excipients of stage B were sifted and blended with the granules of stage A. The mixture was subjected to hot melt extrusion and the obtained extrudate was milled. Hydroxypropyl cellulose, microcrystalline cellulose, silicon dioxide, and croscarmellose sodium of stage C were sifted and blended with the extrudate. The mixture was lubricated with sodium stearyl fumarate and then subjected to compression to obtain a tablet, which was finally film-coated.

Examples 10a and 10b

(29) TABLE-US-00010 Ex. 10a Ex. 10b Ingredients mg mg Stage-A: (Hot-melt extrusion) Posaconazole (Form I) 100 100 Methacrylic acid/ethyl acrylate copolymer 162 162 (1:1), Type B (Kollicoat ® MAE 100P) Polyethylene glycol (Carbowax ™ Sentry ™) 30 30 Copovidone (Kollidon ® VA 64) 50 50 Xylitol (Xylisorb ® 90) 20 20 Total weight after HME 362 362 Stage-B: (Lubrication and compression) Posaconazole HME granules 362 362 Hydroxypropyl cellulose (Klucel ELF Pharma) 125 125 Microcrystalline cellulose (Comprecel ® M 102D+) 63 63 Colloidal silicon dioxide (Aerosil ® 200 pharma) 4 4 Croscarmellose sodium 42 42 Propyl gallate — 0.65 Stage-C: (Lubrication) Sodium stearyl fumarate (Pruv ®) 4 4 Core tablet weight 600 600.65 Stage-D: (Film Coating) Opadry ® II 85F520152 yellow 18 18 Water, purified q.s. q.s. Coated tablet weight 618 618.65

(30) Process:

(31) Posaconazole and the excipients of stage A were sifted and blended. The mixture was subjected to hot melt extrusion and the obtained extrudate was milled. Hydroxypropyl cellulose, microcrystalline cellulose, silicon dioxide, croscarmellose sodium and optionally propyl gallate of stage B were sifted and blended with the extrudate. The mixture was lubricated with sodium stearyl fumarate and then subjected to compression to obtain a tablet, which was finally film-coated.

Example 11

(32) TABLE-US-00011 Ingredients mg Stage-A: (Granulation) Methacrylic acid/ethyl acrylate copolymer 162 (1:1), Type B (Kollicoat ® MAE 100P) Copovidone (Kollidon ® VA 64) 50 Triethyl citrate 30 Total weight after granulation 242 Stage-B: (Hot-melt extrusion) Granules 242 Posaconazole (Form I) 100 Xylitol (Xylisorb ® 90) 20 Propyl gallate 2 Total weight after HME 364 Stage-C: (Blending) Posaconazole HME granules 364 Hydroxypropyl cellulose (Klucel EXF Pharma) 75 Microcrystalline cellulose (Comprecel ® M 102D+) 111 Colloidal silicon dioxide (Aerosil ® 200 pharma) 4 Croscarmellose sodium 42 Stage-D: (Lubrication) Sodium stearyl fumarate (Pruv ®) 4 Core tablet weight 600 Stage-E: (Film Coating) Opadry ® II 85F520152 yellow 18 Water, purified q.s. Coated tablet weight 618

(33) Process:

(34) The excipients of stage A were sifted and granulated. Posaconazole and the excipients of stage B were sifted and blended with the granules of stage A. The mixture was subjected to hot melt extrusion and the obtained extrudate was milled. Hydroxypropyl cellulose, microcrystalline cellulose, silicon dioxide, and croscarmellose sodium of stage C were sifted and blended with the extrudate. The mixture was lubricated with sodium stearyl fumarate and then subjected to compression to obtain a tablet, which was finally film-coated.

Example 12

(35) TABLE-US-00012 Ingredients mg Stage-A: (Hot-melt extrusion) Posaconazole (Form I) 100 Methacrylic acid/ethyl acrylate copolymer 250 (1:1), Type B (Kollicoat ® MAE 100P) Hydroxypropyl cellulose (Klucel EXF Pharma) 75 Xylitol (Xylisorb ® 90) 58 Propyl gallate 2 Total weight after HME 485 Stage-B: (Blending) Microcrystalline cellulose (Comprecel ® M 102D+) 73 Colloidal silicon dioxide (Aerosil ® 200 pharma) 3 Croscarmellose sodium 35 Sodium stearyl fumarate (Pruv ®) 4 Core tablet weight 600 Stage-C: (Film Coating) Opadry ® II 85F520152 Yellow 24 Water, purified q.s. Coated tablet weight 624

(36) Process:

(37) Posaconazole and the excipients of stage A were sifted and blended. The mixture was subjected to hot melt extrusion and the obtained extrudate was milled. Microcrystalline cellulose, silicon dioxide, croscarmellose sodium, and sodium stearyl fumarate were sifted and blended with the extrudate. The mixture was subjected to compression to obtain a tablet, which was finally film-coated.

Example 13— Stability Tests

(38) Stability testing was conducted according to guideline Q 1 A (R2) of International Conference on Harmonization (ICH). The film-coated tablets were stored either for 48 hours at 80° C. and 40% relative humidity (80° C./40% RH) or for 3 and 6 months at accelerated conditions (40° C. and 75% relative humidity, 40° C./75% RH). The film-coated tablets stored for 48 hours at 80° C. and 40% RH were not packed, whereas the film-coated tablets tested under accelerated conditions (40° C./75% RH for 3 and 6 months) were packed in alu-alu blisters.

(39) TABLE-US-00013 TABLE 1 Total impurities (%) 48 hr at 80° Sample Initial C./40% RH Example 10a 0.51 1.43 Example 10b 0.46 1.26 Example 6 0.11 0.28 Example 11 0.19 0.39

(40) TABLE-US-00014 TABLE 2 Total impurities (%) 3 months at 40° 6 M at 40° Sample Initial C./75% RH C./75% RH Example 10a 0.51 — 1.02 Example 10b 0.46 — 1.07 Example 6 0.11 — — Example 11 0.19 0.16 0.41

Example 14a-g

(41) Stability testing was conducted according to guideline Q 1 A (R2) of International Conference on Harmonization (ICH). The granulate was stored either for 48 hours at 80° C. and 40% relative humidity (80° C./40% RH) or for 3 months at accelerated conditions (40° C. and 75% relative humidity, 40° C./75% RH).

(42) TABLE-US-00015 Ex. 14a Ex. 14b Ex. 14c Ex. 14d Ex. 14e Ex. 14f Ex. 14g Ingredients mg mg mg mg mg mg mg Hot-melt extrusion Posaconazole (Form-I) 100 100 100 100 100 100 100 Kollicoat ® MAE 100P 162 162 162 162 162 162 162 Povidone K 30 — — 25 25 25 25 25 (Plasdone ® K 29/32) Polyethylene glycol 50 50 30 30 30 30 50 (PEG 1450) Propyl gallate — 2 — — 2 — — Butyl hydroxy toluene 0.13 — — 0.13 — — — (BHT) Sodium metabisulfite — — — — — 2.5 — Kolliphor ® TPGS — — — — — — 1 Total weight 312.13 314 317 317.13 319 319.5 338

(43) TABLE-US-00016 Total impurities (%) Initial 0.45 0.18 0.39 0.49 0.25 0.29 0.24 80° C./40% RH - 48 h 0.80 0.24 1.74 1.27 0.24 1.46 1.13 (open) 40° C./75% RH - 3 M 0.68 0.32 1.31 0.85 0.34 0.54 0.79 (open)

(44) Process:

(45) Posaconazole and the excipients were sifted and blended. The mixture was subjected to hot melt extrusion and the obtained extrudate was milled. The granules were subjected to the stability testing.