PHARMACEUTICAL COMPOSITION CONTAINING REGORAFENIB AND A STABILIZING AGENT

Abstract

The present invention relates to an enteric coated pharmaceutical composition comprising a solid dispersion comprising regorafenib and at least one stabilizing agent outside of the solid dispersion, its process of preparation and its use for treating disorders.

Claims

1. A pharmaceutical composition comprising a solid dispersion comprising regorafenib and at least one pharmaceutically acceptable excipient inside of the solid dispersion, and at least one stabilizing agent wherein the stabilizing agent is outside of the solid dispersion and the pharmaceutical composition is enteric coated.

2. The composition of claim 1 where in the stabilizing agent is selected from the group consisting of methyl cellulose, ethyl cellulose, hydroxyethyl methyl cellulose (HPMC), hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and its acetate, succinate, proprionate, butyrate, adipate, suberate, sebacate and phthalate ester derivatives like carboxy methyl cellulose, cellulose acetate, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate acetate succinate, hydroxypropyl methyl cellulose acetate succinate and carmellose sodium and mixtures thereof.

3. The composition of claim 1 wherein the stabilizing agent is selected from the group consisting of hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose acetate succinate (HPMCAS), hydroxypropylmethylcellulose phthalate, hydroxycarboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, croscarmellose sodium and mixtures thereof.

4. The composition of claim 1 wherein the stabilizing agent is selected from the group consisting of hydroxypropyl methyl cellulose acetate succinate (HPMCAS), hydroxypropyl methyl cellulose (HPMC) or mixtures thereof.

5. The composition of claim 1 which is a tablet.

6. The composition of claim 5 wherein the tablet is an immediate release tablet.

7. The composition of claim 1 wherein the solid dispersion comprising regorafenib is in amorphous form.

8. The composition of claim 1 wherein the solid dispersion comprises a solid dispersion matrix agent selected from the group consisting of polyvinylpyrrolidone, vinylpyrrolidone/vinylacetate copolymer, polyalkylene glycol, hydroxyalkyl, hydroxyalkyl methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, ethyl cellulose, polymethacrylates, polyvinyl alcohol, polyvinyl acetate, vinyl alcohol/vinyl acetate copolymer, polyglycolized glycerides, xanthan gum, carrageenan, chitosan, chitin, polydextrin, dextrin, starch, proteins, sucrose, lactose, fructose, maltose, raffinose, sorbitol, lactitol, mannitol, maltitol, erythritol, inositol, trehalose, isomalt, inulin, maltodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin or sulfobutyl ether cyclodextrin or a mixture thereof.

9. The composition of claim 8 wherein the solid dispersion comprises a solid dispersion matrix agent selected from the group consisting of polyvinylpyrrolidone, copovidone, polyethylene glycol, polyethylene oxide or a mixture thereof.

10. The composition of claim 8 comprising regorafenib and the solid dispersion matrix agent in a weight ratio of 1:0.5 to 1:20.

11. The composition of claim 8 wherein the solid dispersion matrix agent is polyvinylpyrrolidone, croscarmellose sodium and/or microcrystalline cellulose.

12. The composition of claim 8 wherein the pharmaceutically acceptable matrix agent is polyvinylpyrrolidone.

13. The composition of any of claim 12 comprising the regorafenib and the solid dispersion matrix agent in a weight ratio of 1:1 to 1:5.

14. The composition of claim 1 wherein the weight amount of the stabilizing agent in the pharmaceutical composition outside of the solid is at least 2% based on the total weight of regorafenib in the pharmaceutical composition.

15. The composition of claim 14 wherein the weight amount of the stabilizing agent in the pharmaceutical composition outside of the solid is at least 5% based on the total weight of regorafenib in the pharmaceutical composition.

16. The composition of claim 1 wherein the at least one stabilizing agent is present only in the enteric coating.

17. The pharmaceutical composition of claim 1 for use as medicament for treating hyper-proliferative disorders.

18. The pharmaceutical composition of claim 1 for use as medicament wherein the hyper-proliferative disorders are selected from the group consisting of cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases.

19. (canceled)

20. A method of treating hyper-proliferative disorders in a subject in need thereof comprising administering an effective amount of the pharmaceutical composition of claim 1.

21. The method of claim 20 wherein the hyper-proliferative disorder is glioblastoma, colorectal cancer, hepatocellular cancer, lung cancer or gastric cancer.

22. A pharmaceutical composition comprising a solid dispersion comprising regorafenib wherein the amount of regorafenib is 30 mg.

23. The method of claim 20 wherein the hyper-proliferative disorder is colorectal cancer or hepatocellular cancer.

24. The method of claim 21 wherein the lung cancer is NSLC.

Description

[0169] FIG. 1: Dissolution in transfer model using gastric (FaSSGF) to intestinal (FaSSIF) transfer for RGF ASDs. Single dissolution curves are shown.

[0170] FIG. 2: Stabilization of RGF supersaturation of RGF_PVP by addition of HPMCAS in presence of RGF crystal seeds.

[0171] FIG. 3: RGF plasma profile in rats after application of RGF_PVP ASD with(out) stabilizer HPMCAS.

[0172] FIG. 4: Biorelevant dissolution using transfer model, mimicking rat conditions for RGF_PVP ASD with(out) stabilizer HPMCAS.

EXAMPLES

Abbreviations:

[0173] ASD—amorphous solid dispersion (containing the active ingredient in amorphous form) [0174] HPMC—hydroxypropyl methyl cellulose [0175] HPMCAS—hydroxypropyl methyl cellulose acetate succinate [0176] PVA—polyvinylalcohol [0177] PVP—polyvinylpyrrolidone [0178] PK—phramakokinetic [0179] RGF—regorafenib [0180] RGF MH—regorafenib monohydrate crystalline [0181] RGF_PVP—ASD of regorafenib and PVP [0182] RGFx_HPMCASy_PVPz—ASD of x parts of regorafenib, y parts of PVP and z parts of HPMCAS [0183] RGF_PVP+X % HPMCAS—ASD of RGF_PVP ASD and co-administration of X % by weight of HPMCAS in powder form related to the PVP amount in the matrix [0184] RGF HPMCAS—ASD of regorafenib and HPMCAS

[0185] High Performance Liquid Chromatography (HPLC/UV): A Dionex P580 system was used, consisting of an ASI-100T autosampler and UVD-340U UV detector with a YMC-Pack Pro C18 RS column. The oven temperature was set to 40° C. and the injection volume was 100.0 μL. UV absorption was measured at 262 nm. Methanol and water with 0.2% trifluoroacetic acid (TFA) were used as mobile phase in a gradient from 65:35 to 95:5 (v:v) and the flow rate was set to 1 mL/min.

[0186] Biorelevant dissolution studies were performed in a USP apparatus 2 dissolution vessel at 37±0.5° C. and 75 rpm. To obtain biorelevant conditions, fasted state simulated gastric fluid (FaSSGF) and fasted state simulated intestinal fluid (FaSSIF) were used as dissolution media. For transfer dissolution experiments, a dose of 200 mg of the amorphous solid dispersion (ASD) formulations were dissolved in FaSSGF for 120 min prior to FaSSIF equilibration with 500 mL concentrated FaSSIF. For one-compartment dissolution studies, only mimicking dissolution at intestinal conditions, the ASD formulations were dissolved in FaSSIF. All samples were filtrated through a 0.2 μm syringe polypropylene filter, considering the API filter adsorption and diluted with methanol for HPLC/UV analysis.

[0187] Biorelevant supersaturation stabilization studies were performed with an equivalent ratio of ASD dose to FaSSIF media, deviating from the biorelevant dissolution studies method above in total volume of 50-60 mL and in hydrodynamic conditions (ca. 300-400 rpm). The dissolution studies were performed with or without regorafenib monohydrate seeding. For seeding experiments, the same amount of crystalline regorafenib monohydrate was added to the dissolution system as incorporated in the ASD. All samples were filtrated through a 0.2 μm syringe filter and diluted with methanol for HPLC/UV analysis.

[0188] Unless otherwise stated, all mean values are calculated from 3 experimental runs. The relative standard deviations (RSD) are calculated from the absolute standard deviations (sd) as RSD=sd/mean*100%.

Example 1: ASD Containing Amorphous Regorafenib and PVP and/or HPMCAS and In-Vitro Dissolution Profiles and Supersaturation Robustness Investigations of Regorafenib Amorphous Solid Dispersions

[0189] a) Solid Dispersion (ASD)

[0190] A solution of 6.224 g regorafenib monohydrate (RGF MH, mass calculated to regorafenib) and 24.0 g of PVP (type K25) and/or 24.0 g of HPMCAS (type 716G) in organic solvents was prepared. For an ASD consisting of regorafenib and PVP, a mixture of 85/15 butanone/ethanol (v/v) and for an ASD consisting of regorafenib and HPMCAS, pure acetone was used as solvents. For ASDs consisting of regorafenib, PVP and HPMCAS, methanol was used as solvent. A Rotavapor RII rotary evaporator (Büchi, Essen, Germany) and Variopro PC3001 vacuum pump (Vacuubrand, Wertheim a. M., Germany) were used for solvent evaporation at 60° C. The resulting ASD was dried for at least 24 h at vacuum and room temperature conditions. The ASD formulations containing PVP as single matrix polymer and the formulations containing both HPMCAS and PVP as matrix polymers were manually ground and sieved to <125 μm mesh size. For ASDs containing HPMCAS as single matrix polymer, grinding was not performed. The investigated formulations are listed in Table 1a.

TABLE-US-00001 TABLE 1a Formulation composition of regorafenib amorphous solid dispersion (ASD) in [%] (by weight). Formulation code Regorafenib (RGF) PVP HPMCAS RGF_PVP 20 80 — RGF_HPMCAS 20 — 80

Test Results:

[0191] 1) Biorelevant Dissolution Seeding Assay

[0192] b) HPMCAS as Stabilizer

TABLE-US-00002 TABLE 1.1a.1 Biorelevant supersaturation stabilization study: Impact of co-administration of HPMCAS RGF_PVP + RGF_PVP + 100% HPMCAS + RGF_PVP RGF MH seeding RGF MH seeding dissolution Mean RSD Mean RSD Mean RSD time [min] [μg/mL] % [μg/mL] % [μg/mL] % 90 32.66 10.62 23.24 8.81 25.22 1.95 210 25.81 63.34 5.73 12.15 28.79 2.19 1440 3.84 35.98 1.07 7.61 6.73 17.42 RGF_PVP + 100% HPMCAS Dissolution Mean RSD time [min] [μg/mL] [%] 90 28.92 5.58 231 32.56 6.96 1440 3.77 31.84

[0193] Biorelevant supersaturation stabilization studies with RGF MH seeding were performed as described above.

[0194] In Table 1.1a.1, the results demonstrate the impact of regorafenib monohydrate (RGF MH) seeding regarding supersaturation achieved from RGF_PVP formulation and the stabilization properties of co-administered HPMCAS. RGF_PVP leads to fast API release with high supersaturation at 90 min, but is decreased after 210 min. For RGF_PVP+100% HPMCAS, the API release is followed by a more stable supersaturation than in the case of RGF_PVP. Seeding of RGF MH at RGF_PVP dissolution leads to lower dissolved RGF concentrations at these time points. The co-administration of HPMCAS at RGF MH seeding conditions still allows for rapid drug release after 90 min and supersaturation stabilization. HPMCAS co-administration was investigated in a range from X=5-100% by weight related to the amount of PVP. The results in Table 1.1a.2 show the independence of RGF supersaturation stabilization from the investigated HPMCAS co-administration amounts.

TABLE-US-00003 TABLE 1.1a.2 Biorelevant supersaturation stabilization study: Impact of amount of co-administration of HPMCAS RGF_PVP + 100% HPMCAS + RGF_PVP + 66% HPMCAS + RGF_PVP + 33% HPMCAS + RGF MH seeding RGF MH seeding RGF MH seeding Dissolution Mean RSD Mean RSD Mean RSD time [min] [μg/mL] [%] [μg/mL] [%] [μg/mL] [%] 90 28.16 3.52 26.46 5.25 28.82 4.75 258 32.48 1.83 31.38 5.83 28.21 18.50 1440 0.00 0.00 0.10 173.21 0.62 173.21 RGF_PVP + 20% HPMCAS + RGF_PVP + 10% HPMCAS + RGF_PVP + 5% HPMCAS + RGF MH seeding RGF MH seeding RGF MH seeding Dissolution Mean RSD Mean RSD Mean RSD time [min] [μg/mL] [%] [μg/mL] [%] [μg/mL] [%] 90 21.95 3.87 25.32 8.34 27.99 3.20 258 33.79 3.54 32.40 6.72 28.84 10.73 1440 4.72 5.11 5.56 35.23 4.55 14.31

[0195] b) HPMC as Stabilizer

[0196] Biorelevant supersaturation stabilization studies with RGF MH seeding were performed as described above.

[0197] Besides HPMCAS, also HPMC can act as supersaturation stabilizing agent. Methocel E3 Premium LV HP MC (DuPont, Luzern, Switzerland) was used. After 90 min, high RGF supersaturation is achieved, which is stabilized for at least 258 min under seeding conditions, as can be seen in Table 1.1b.

TABLE-US-00004 TABLE 1.1b Biorelevant dissolution results of the impact of co-administration of HPMC RGF_PVP + 10% HPMC + RGF MH seeding dissolution Mean RSD time [min] [μg/mL] [%] 90 28.68 4.37 258 26.05 26.34 1440 5.22 26.03

[0198] c) Biorelevant Dissolution: Impact of Gastric Transit

[0199] Biorelevant one-compartment dissolution studies were performed for RGF_PVP and RGF_HPMCAS as described above. In Table 1.2.1, our results show the rapid drug release of RGF_PVP, leading to a high supersaturation at 90 min, that is stable for at least 5 h. In contrast, for RGF_HPMCAS less RGF is dissolved for 6 h but the supersaturation obtained is stable for more than 24 h.

[0200] Biorelevant transfer dissolution studies were performed for RGF_PVP and RGF_HPMCAS as described above. As shown in Table 1.2.2, RGF_HPMCAS shows slow dissolution to high supersaturation, which is stable for more than 24 h. In contrast, RGF_PVP shows fast dissolution to a reduced supersaturation level, which is reached at 90 min.

[0201] These results show the necessity of protection of RGF_PVP from acidic gastric conditions, to allow for both, fast RGF release and prolonged supersaturation.

TABLE-US-00005 TABLE 1.2.1 Biorelevant one-compartment dissolution studies RGF_PVP RGF_HPMCAS Dissolution Mean RSD Mean RSD time [min] [μg/mL] [%] [μg/mL] [%] 0 0.00 0.0 0.00 0 30 19.44 10.17 3.22 4.97 60 28.47 4.26 7.23 7.47 90 33.38 3.24 11.33 5.57 120 32.64 1.07 14.36 6.28 150 33.93 2.21 17.49 7.73 180 34.76 1.93 20.09 5.14 210 32.61 2.01 23.23 8.67 240 34.90 6.31 23.25 4.23 300 32.53 3.13 26.22 4.35 360 27.26 14.00 28.22 1.79 1440 4.14 14.51 37.53 4.35 2880 1.54 16.92 3.98 3.41

TABLE-US-00006 TABLE 1.2.2 Biorelevant transfer dissolution studies, including transfer from FaSSGF to FaSSIF conditions after 120 min at FaSSGF conditions Dissolution time RGF_PVP RGF_HPMCAS [min] after Mean RSD Mean RSD FaSSIF transfer [μg/mL] [%] [μg/mL] [%] 0 5.46 55.31 0.00 0.00 30 6.25 32.26 2.61 9.40 60 7.00 21.51 6.27 3.32 90 7.38 14.81 9.67 5.83 120 7.55 10.55 13.24 4.80 150 7.70 6.09 15.96 5.46 180 7.69 5.05 18.75 4.74 210 7.66 6.03 20.94 5.69 240 7.73 2.01 23.21 4.40 270 7.77 3.75 24.77 6.42 300 7.76 2.00 26.84 4.85 330 7.79 1.76 28.16 3.85 360 7.91 4.93 29.39 2.54 1440 7.32 7.84 41.50 1.44 2880 0.00 0.00 0.01 173.21

[0202] d) Ternary ASDs RGF_PVP_HPMCAS Dissolution Under Biorelevant Conditions

[0203] a. Biorelevant Dissolution at Intestinal Conditions

[0204] To prevent RGF from early precipitation at gastric conditions before entering the small intestine, one approach was embedding RGF in an ASD matrix consisting of two polymers, HPMCAS and PVP, forming ternary ASDs.

[0205] Biorelevant supersaturation stabilization without seeding studies were performed as described above, the results are listed in Table 1.3a. For all investigated ternary ASDs, the RGF release rate was decreased in presence of HPMCAS in the ASD matrix.

TABLE-US-00007 TABLE 1.3a Dissolution of ternary ASDs RGFx_HPMCASy_PVPz in FaSSIF RGF20_HPMCAS40_PVP40 RGF10_HPMCAS45_PVP45 RGF20_HPMCAS5_PVP75 dissolution Mean RSD Mean RSD Mean RSD time [min] [μg/mL] % [μg/mL] % [μg/mL] % 90 7.47 6.31 14.46 44.68 12.46 8.17 258 26.78 28.92 36.83 1.69 24.91 11.47 1440 3.48 39.44 3.25 12.21 4.35 13.56

[0206] b. Biorelevant Dissolution at Intestinal Conditions, Including Simulated Gastric Transit

[0207] Biorelevant supersaturation stabilization studies without seeding were performed. Deviating from the method described above, a dissolution media transfer was implemented. The ASDs were dissolved in FaSSGF for 120 min. By addition of concentrated FaSSIF media, the conditions were changed to FaSSIF conditions. Results are shown in Table 1.3b.

[0208] All investigated ternary ASD formulations showed reduced RGF release after FaSSIF media change, compared to RGF_PVP dissolution at subsection 2. Incorporation of HPMCAS into the ASD matrix does not lead to a rapid RGFG release and long lasting supersaturation.

TABLE-US-00008 TABLE 1.3b Biorelevant supersaturation stabilization studies of ternary ASDs RGFx_HPMCASy_PVPz in FaSSIF, after 120 min exposure to FaSSGF conditions RGF20_HPMCAS40_PVP40 RGF10_HPMCAS45_PVP45 RGF20_HPMCAS5_PVP75 dissolution Mean RSD Mean RSD Mean RSD time [min] [μg/mL] % [μg/mL] % [μg/mL] % 30 7.94 4.78 14.94 8.12 2.57 8.50 210 14.87 9.04 21.19 8.27 5.27 10.13 258 11.18 13.99 13.62 21.61 6.86 7.08 1440 5.44 2.01 6.11 16.29 4.48 2.95

[0209] c. Biorelevant Dissolution at Intestinal Conditions, Impact of RGF MH Seeding

[0210] Biorelevant supersaturation stabilization studies with RGF MH seeding were performed as described above. The results from these experiments are given in Table 1.3c. Comparing these results to biorelevant supersaturation stabilization studies without RGF MH seeding, see Table 1.3a, all investigated ternary ASDs lead to robust supersaturation.

TABLE-US-00009 TABLE 1.3c Biorelevant seeding dissolution of ternary ASD formulations RGF20_HPMCAS40_PVP40 + RGF10_HPMCAS45_PVP45 + RGF20_HPMCAS5_PVP75 + RGF MH seeding RGF MH seeding RGF MH seeding dissolution Mean RSD Mean RSD Mean RSD time [min] [μg/mL] % [μg/mL] % [μg/mL] % 90 8.30 43.82 12.03 33.68 8.68 18.58 258 28.98 12.11 33.63 4.73 17.69 18.70 1440 3.98 6.13 3.21 21.83 4.16 16.52

[0211] e) Biorelevant Dissolution Mimicking Rat Conditions

[0212] A biorelevant dissolution at rat conditions was performed. The obtained results are in accordance with in-vivo PK data, which are shown in Example 2.

[0213] Biorelevant transfer dissolution studies were performed for RGF_PVP and RGF_PVP plus HPMCAS as described above. To mimic the physiological conditions in rats, the pH of FaSSGF was adjusted to 3.2, the pH of FaSSIF was adjusted to 5.0 and transfer time from FaSSGF to FaSSIF was decreased to 15 min.

TABLE-US-00010 TABLE 4.1 Biorelevant transfer dissolution at simulated rat conditions Dissolution time RGF_PVP RGF_PVP + 10% HPMCAS [min] after Mean RSD Mean RSD FaSSIF transfer [μg/mL] % [μg/mL] % 5 0.00 0.00 0.00 0.00 15 12.53 11.39 11.04 6.53 30 24.78 12.76 17.41 13.66 60 32.33 8.92 26.66 29.41 120 33.64 4.53 24.49 8.93 180 32.64 3.87 25.28 9.22 300 24.39 16.48 27.48 5.34 420 13.62 35.77 28.73 5.06 1440 1.72 11.66 29.83 7.20 2880 0.00 0.00 0.00 0.00 Co-administration of HPMCAS leads to pronounced RGF supersaturation at 420 min and 24 h, as can be seen in Table 4.1.

Example 2: In-Vivo Pharmacokinetic (PK) Study in Rats

[0214] ASDs were prepared as described above.

[0215] The pharmacokinetic parameters of the compounds according to the invention are determined in male Wistar rats. Oral administration of the drug substance is performed via gavage and the administration volume for rats is 5 ml/kg. The applied dose was calculated to 50 mg RGF/kg rat. After application of the in water pre-suspended ASDs, blood samples were drawn over 48 h and analyzed by LC/MS. The pharmacokinetic parameters are calculated by non-compartmental analysis (NCA). The algorithms for calculating the parameters are defined in an internal process description and are based on rules published in general textbooks of pharmacokinetics.

Sampling from Rat PK Study:

[0216] Blood samples are removed from the test animals into sodium EDTA (or other anticoagulant)-containing tubes. For sample preparation, 50 μl of plasma are mixed with 250 μl of acetonitrile (the precipitating agent acetonitrile also contains the internal standard ISTD for later analytical determination) and then allowed to stand at room temperature for 5 minutes. The mixture is then centrifuged for up to 8 minutes. The supernatant is taken off, and 500 μl of a buffer suitable for the mobile phase are added. The samples are then examined by LC-MS/MS analysis (e.g. liquid chromatography using a Gemini C18 50 mm×3 mm column from Phenomenex; by mass spectrometry using an API 6500; SCIEX) to determine the concentration of the test substance in the individual samples.

TABLE-US-00011 TABLE 2.1 Plasma concentration of regorafenib in rats RGF_PVP RGF_PVP + 10% HPMCAS PK study Mean RSD Mean RSD time [min] [μg/L] % [μg/L] % 0 0 0 0 0 5 31 37 93 70 15 432 80 1542 86 30 2968 42 5047 59 60 6665 36 9765 52 120 11695 28 14259 49 180 11754 41 14550 51 300 9851 45 12133 53 420 8262 45 10630 44 1440 2201 50 3660 69 1500 1915 51 3272 68 2880 269 64 608 67

TABLE-US-00012 TABLE 2.2 Summary: PK study of regorafenib ASDs in rats RGF_PVP + PK study parameter RGF_PVP 10% HPMCAS AUC [kg*h/L]norm, total 3.0 ± 41% 4.1 ± 54% t½ [h] mean 7.7 ± 20% 9.2 ± 21% cmax [μg/L] mean 12346.8 ± 34%   14817.3 ± 49%   AUC = Area under the curve; t½ = RGF plasma elimination half time; cmax = maximal observed RGF plasma concentration

[0217] Both ASD formulations show plasma variability in rats, results are shown in Table 2.1. For RGF_PVP+10% HPMCAS, AUC, t1/2 and cmax showed superior results as shown in Table 2.2. Biorelevant dissolution experiments mimicking rat conditions predicted a prolonged supersaturation after 420 min (see Example 1, subsection 4), which can be confirmed by the PK data.

Example 3: Tablet Comprising Regorafenib and Coated with HPMCAS

[0218] Coated tablets containing regorafenib were prepared according to the method described in WO 2006/026500. Said tablets were additionally coated with HPMCAS 716G (HPMCAS, Affinisol 716G, Dow Chemical (now DuPont)), as shown in Table 3.1.

a) Solid Dispersion

[0219] A solution of 0.415 kg of regorafenib monohydrate (corresponding to 0.40 kg regorafenib) and 1.60 kg of polyvinyl pyrrolidone (PVP 25) in a mixture of 4.80 kg acetone and 1.20 kg ethanol was prepared. Using a fluidized bed vacuum granulator this solution was sprayed onto a powder bed of 1.00 kg croscarmellose sodium and 1.00 kg microcrystalline cellulose at a temperature of 60-70° C.

b) Tableting

[0220] The granulate of step a) was roller compacted and screened 3.15 mm and 1.0 mm. Subsequently the compacted granulate was blended with 0.54 kg croscarmellose sodium, 0.0240 kg colloidal anhydrous silica and 0.0360 kg magnesium stearate. This ready-to-press blend was compressed on a rotary tablet press into tablets containing 20 mg and 40 mg of regorafenib.

c) PVA Film Coating

[0221] For coating of the 20 mg tablets 0.160 kg of Opadry™ II 85G35294 pink was homogeneously dispersed in 0.640 kg water. For coating of the 40 mg tablets 0.120 kg of Opadry™ II 85G35294 pink was homogeneously dispersed in 0.480 kg water. These coating suspensions were sprayed onto the 20 mg respectively 40 mg tablets of step b) in a perforated drum coater at an outlet air temperature of 35° C. The coating process resulted in evenly coated tablets with a smooth surface. Coating defects could not be observed. Commercially available Opadry™ II 85G35294 pink contains polyvinyl alcohol (partially hydrolyzed) [44% by weight of the total mixture], polyethylenglycol (PEG 3350) [12.4% by weight of the total mixture], lecithin (soya), ferric oxides, titanium dioxide and talc.

d) HPMCAS Film Coating

[0222] For the HPMCAS coating of the PVA coated tablets, HPMCAS was dissolved in acetone to a concentration of 6.0% (m/m). The coating solution was sprayed onto the tablets. A BFC 5 drum coater (Bohle, Ennigerloh, Germany) was used for the coating process, the parameters are given in Table 3.2. Before spraying, the tablets were heated up to an outlet air temperature of 35° C. After coating, the tablets were dried for 72 h at room temperature to remove residual solvent. The coating process resulted in evenly coated tablets with a smooth surface. Coating defects could not be observed. A total of 20.1 mg of HPMCAS was coated on each tablet.

TABLE-US-00013 TABLE 3.1 Composition of tablets containing regorafenib mass Substance [mg/tablet] Regorafenib 40.00 Polyvinylpyrrolidone (PVP 25) 160.00 Croscarmellose sodium 154.00 Microcrystalline cellulose 100.00 Magnesium stearate 3.60 Silica colloidal anhydrous 2.40 HPMCAS 20.1 Opadry lacquer 12 Sum 492.1 Tablet format oval Dimensions of the tablet Length: 16 mm, width: 7 mm

TABLE-US-00014 TABLE 3.2 Process parameters for HPMCAS coating Parameter Value Drum speed 17-19 rpm Air flow 140-160 Nm.sup.3/h Air temperature 40° C. Atomizer pressure 0.3 bar Forming pressure 0.5 bar Spray rate 32 (initially) - 12 g/min

Test Results:

[0223] The impact of an additional HPMCAS coating on PVA coated regorafenib tablets was investigated by biorelevant dissolution transfer studies as described above. The results obtained are listed in Table 3.3, from each formulation 6 tablets were investigated separately.

TABLE-US-00015 TABLE 3.3 Biorelevant dissolution transfer studies of Stivarga ™ original (Example 3 a)-c)) and HPMCAS coated Stivarga ™ tablets (Example 3 a)-d)) dissolution time Stivarga ™ HPMCAS coated [min] after original RSD Stivarga RSD FaSSIF transfer [μg/mL] % [μg/mL] % 0 28.52 15.31 0.09 244.95 30 29.73 19.66 12.00 11.19 60 27.36 22.85 23.54 4.20 90 25.66 28.05 28.92 4.35 120 23.29 34.77 31.33 4.29 150 21.45 38.10 33.51 6.40 180 19.94 41.20 33.89 2.74 210 18.50 41.26 35.56 2.52 240 17.37 43.05 36.03 2.36 270 16.29 41.65 36.46 1.99 300 15.40 41.13 36.77 3.36 330 14.63 36.88 36.98 2.34 360 14.14 36.33 37.77 2.94 1440 7.50 13.81 11.50 17.45 2880 2.12 113.73 4.25 82.23

[0224] Stivarga™ original tablets shows supersaturation already directly after media change to FaSSIF conditions, whereas HPMCAS coated Stivarga™ tablets lead to higher RGF supersaturation from 90 min to 1440 min.

[0225] To achieve improved bioavailability from poorly soluble regorafenib, the robustness of supersaturation at intestinal conditions is of high importance. This supersaturated state of regorafenib can be stabilized by the polymer. So far, one or more polymers for supersaturation stabilization are incorporated into the ASD matrix. The results demonstrate the superiority of embedding regorafenib in an ASD matrix to be co-administered with the stabilizing polymer HPMCAS or HPMC externally added as supersaturation stabilizing polymers.