STABLE PHARMACEUTICAL FORMULATION

Abstract

The present invention relates to a pharmaceutical composition of (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine, a process for the preparation thereof and its use in the treatment of diseases.

Claims

1. A pharmaceutical composition comprising a compound of formula I, ##STR00002## or a pharmaceutically acceptable salt thereof, a complexing agent and an antioxidant.

2. The pharmaceutical composition according to claim 1, comprising the dihydrochloride salt of the compound of formula I, a complexing agent and an antioxidant.

3. The pharmaceutical composition according to any one of claim 1 or 2, wherein the complexing agent is disodium edetate, and the antioxidant is ascorbic acid.

4. The pharmaceutical composition according to any one of claims 1-3, wherein the pharmaceutical composition is a solid dosage form for oral administration.

5. The pharmaceutical composition according to any one of claims 1-4, wherein the pharmaceutical composition is a solid dosage form comprising a kernel and a film coating system.

6. The pharmaceutical composition according to any one of claims 1-5, comprising the compound of formula I or a pharmaceutically acceptable salt thereof in a kernel.

7. The pharmaceutical composition according to any one of claims 1-6, comprising the dihydrochloride salt of the compound of formula I in a kernel.

8. The pharmaceutical composition according to any one of claims 1-7, comprising the complexing agent and the antioxidant in a kernel, and further comprising at least one of the following compounds in the kernel: i) filler, ii) binder, and iii) lubricant.

9. The pharmaceutical composition according to claim 7 or 8, comprising the following compounds in the kernel: i) filler, preferably 85%±2% filler, ii) binder, preferably 10%±1% binder, iii) complexing agent, preferably 0.4%±0.1% complexing agent, iv) antioxidant, preferably 2%±0.5% antioxidant, and v) lubricant, preferably 2% t 0.5% lubricant.

10. The pharmaceutical composition according to claim 9, wherein i) the fillers are mannitol and microcrystalline cellulose, preferably 64%±2% mannitol and 21%±1% microcrystalline cellulose, ii) the binder is maltodextrin, preferably 10%±1% maltodextrin, iii) the complexing agent is disodium edetate, preferably 0.4%±0.1% disodium edetate, iv) the antioxidant is ascorbic acid, preferably 2%±0.5% ascorbic acid, and v) the lubricant is polyethylene glycol 6000, preferably 2%±0.5% polyethylene glycol 6000.

11. The pharmaceutical composition according to any one of claims 1-10, comprising a film coating system, preferably a film coating system comprising: i) a coating agent, ii) a plasticizer, iii) an anti-caking agent, and iv) a colorant.

12. The pharmaceutical composition according to any one of claims 1-11, comprising a film coating system comprising: i) 2±0.5 mg/tablet coating agent, ii) 1±0.25 mg/tablet plasticizer, iii) 0.75±0.25 mg/tablet anti-caking agent, and iv) 1.25±0.25 mg/tablet colorant.

13. The pharmaceutical composition according to claim 11 or 12, wherein i) the coating agent is polyvinyl alcohol, ii) the plasticizer is polyethylene glycol 3350, iii) the anti-caking agent is tale, and iv) the colorant is titanium dioxide.

14. The pharmaceutical composition according to any one of claims 1-13, wherein the kernel according to any one of claims 5-10 is film coated with 5% of a film coating system according to any one of claims 11-13 based on the kernel weight.

15. A process to produce the pharmaceutical composition as described in any one of claims 1-14, comprising: a) mixing a filler and optionally one or more portions of a binder to form a mixture, b) wet granulating the mixture from step a) with a solution comprising the compound of formula I or a pharmaceutically acceptable salt thereof, a complexing agent, an antioxidant, one or more portions of a binder and a solvent, followed by drying and optionally sieving the resulting granulate, c) mixing the granulate obtained from step b) with a lubricant to form a mixture, d) compressing the mixture obtained in step c) to form a tablet, and e) optionally, coating the tablet with a film coating system.

16. The pharmaceutical composition as described in any one of claims 1-14 for use as medicament.

17. The pharmaceutical composition as described in any one of claims 1-14 for use in the treatment of a disease associated with LSD1.

18. The pharmaceutical composition as described in any one of claims 1-14 for use in the treatment of cancer.

19. A method of treating a disease associated with LSD1, comprising administering to a patient in need thereof a pharmaceutical composition as described in any one of claims 1-14.

20. A method of treating cancer, comprising administering to a patient in need thereof a pharmaceutical composition as described in any one of claims 1-14.

21. The pharmaceutical composition for use of claim 18 or the method of claim 20, wherein the cancer is small cell lung cancer or leukemia.

22. An immediate release tablet comprising a pharmaceutical composition as described in any one of claims 1-14.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0184] FIG. 1: A manufacturing process of a pharmaceutical composition as described herein.

[0185] FIG. 2: All tablet compositions without antioxidant and complex former (complexing agent) showed significant decrease of (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine content over time stored at 25° C./60% relative humidity. See Example 3 for more details.

[0186] FIGS. 3A and 3B: Granulates stored at 25° C./ambient humidity containing antioxidant and complex former exhibited highly improved stability compared to unprotected composition without antioxidant and complex former, which showed strong (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine decrease over time. FIG. 3A: composition 7 vs 8; FIG. 3B: composition 5 vs 6. See Example 3 for more details.

[0187] FIGS. 4A and 4B: Granulates stored at 50° C./ambient humidity containing antioxidant and complex former exhibited highly improved stability compared to unprotected composition without antioxidant and complex former, which showed strong (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine decrease over time. FIG. 4A: composition 7 vs 8; FIG. 4B: composition 5 vs 6. See Example 3 for more details.

[0188] FIG. 5: Tablets containing antioxidant and complex former described in examples 1 and 2 were stable at 25° C./60% relative humidity over a test period of 18 months and at 40° C./75% relative humidity over a test period of 6 months.

EXPERIMENTAL PART

Example 1: 100 μg Tablet

[0189]

TABLE-US-00003 mg Kernel a dihydrochloride salt of a compound 0.132 of formula I Mannitol 64.098 Microcrystalline Cellulose 21.37 Maltodextrin 10 Disodium Edetate 0.4 Ascorbic Acid 2 Polyethylene Glycol 6000 2 Film Coating System Polyvinyl Alcohol 2 Polyethylene Glycol 3350 1.01 Talc 0.74 Titanium Dioxide 1.25

Example 2: 300 μg Tablet

[0190]

TABLE-US-00004 mg Kernel a dihydrochloride salt of a compound 0.132 of formula I Mannitol 63.965 Microcrystalline Cellulose 21.24 Maltodextrin 10 Disodium Edetate 0.4 Ascorbic Acid 2 Polyethylene Glycol 6000 2 Film Coating System Polyvinyl Alcohol 2 Polyethylene Glycol 3350 1.01 Talc 0.74 Titanium Dioxide 1.25

Example 3: Stability

[0191] Excipient selection/composition development was conducted in order to stabilize (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine in the final drug product to prevent its chemical degradation. (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine is very unstable in presence of excipients which are used to form a tablet composition. This is reflected by a decrease of the (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine content (assay) over time upon storage. The effect is more pronounced at elevated storage temperature.

[0192] Tablets containing 0.1 and 0.3% (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine respectively were developed and stability assessment performed. The other excipients were Mannitol (filler), maize starch (filler), microcrystalline cellulose (filler), corn starch (filler), Maltodextrin or Hydroxypropyl methylcellulose (binder), crospovidone (disintegrant), sodium stearylfumarate (glidant) and commercially available Opadry® white (coating agent). Their composition is indicated in the table below:

TABLE-US-00005 Comp. 1 Comp. 2 Comp. 3 Comp. 4 mg mg mg mg Kernel a dihydrochloride salt of a 0.132 0.396 0.132 0.132 comound of formula I Mannitol 27.87 27.60 38.74 39.5 Microcrystalline Cellulose 25.00 25.00 15.00 15.00 Maltodextrin 4.34 Starch 1500 15.00 15.00 15.00 15.00 Corn Starch 20.00 20.00 20.00 20.00 Copovidone (Kollidon VA 5.13 64) Crospovidone 4.00 4.00 4.00 4.00 Sodium Stearyl Fumarate 2.00 2.00 2.00 2.00 Hydroxypropyl 6.00 6.00 methylcelullose Film Coating System Polyvinyl Alcohol 2 2 2 2 Polyethylene Glycol 3350 1.01 1.01 1.01 1.01 Talc 0.74 0.74 0.74 0.74 Titanium Dioxide 1.25 1.25 1.25 1.25

[0193] All tablet compositions showed significant decrease of (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine content overtime stored at 25° C./60% relative humidity (FIG. 2).

[0194] Decrease of (trans)-N1-(1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine content was potentially caused by metal-ion induced oxidative degradation. Therefore metal-complexing excipients as well as antioxidants were introduced to the composition that prevent degradation. These components are here not part of liquid or semi-solid compositions. A number of granulates with different compositions were manufactured with and without antioxidant (ascorbic acid) and complexing agent (disodium edetate) and stability assessment was performed Their composition is indicated in the table below:

TABLE-US-00006 Comp. 5 Comp. 6 Comp. 7 Comp. 8 Granulate mg mg mg mg a dihydrochloride salt of a 0.396 0.396 0.396 0.396 compound of formula I Isomalt GalenIQ801 72.28 70.36 MCC Vivapur 101 17.32 16.84 Croscarmellose Sodium 3.00 3.00 Aerosi1200 2.00 2.00 Mannitol 27.60 25.07 Microcrystalline Cellulose 25.0 25.0 Starch 1500 15.00 15.00 Corn Starch 20.00 20.00 HPMC 2910 3cp 6.00 6.00 Disodium Edetate 0.4 0.42 Ascorbic Acid 2.00 2.11

[0195] Granulates stored at 25° C./60% relative humidity containing ascorbic acid as antioxidant and disodium edetate as complexing agent (compositions 6 and 8) exhibited good stability, whereas unprotected compositions (compositions 5 and 7) showed strong (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine decrease over time (FIG. 3A: comparison of stability of composition 7 vs 8, and FIG. 3B: comparison of stability of composition 5 vs 6). The effect was even more pronounced at elevated temperature (50° C.) (FIG. 4A: composition 7 vs 8; FIG. 4B: composition 5 vs 6).

[0196] As shown by the data in FIGS. 3 and 4, the combination of antioxidant and complexing agent clearly improved the API stability independently from the underlying formulation composition.

[0197] The benefit of antioxidant and complexing agent is clearly shown and therefore applied for examples 1 and 2, which were prepared using ascorbic acid as antioxidant and disodium edetate as complexing agent. Stability was confirmed and assay within specification over a test period of 18 months at every test storage condition. As a way of example, results of stability testing for the tablets of Examples 1 and 2 at 25° C./60% relative humidity over a test period of 18 months and at 40° C./75% relative humidity over a test period of 6 months are provided in FIG. 5, showing these tablets containing antioxidant (ascorbic acid) and complexing agent (disodium edetate) are stable.

Example 4: Process

[0198] Examples 1 and 2 are manufactured using a fluid bed granulation process. Standard fluid bed granulation is performed with a powder blend containing API and excipients which is granulated with a binder solution.

[0199] As target drug load for (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine was only 0.1 (example 1) and 0.3% (example 2) respectively, the process was adapted in order to achieve desired drug uniformity in the final drug product. (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine, ascorbic acid and disodium edetate were dissolved in the maltodextrin solution and carefully sprayed upon the moving powder bed containing mannitol and microcrystalline cellulose. Content uniformity was achieved.

[0200] Alternatively, in order to prevent the ascorbic acid causing precipitation of disodium edetate due to pH-shift, the granulation liquid was divided into two phases; one containing maltodextrin and Na.sub.2-EDTA and the other maltodextrin and ascorbic acid. The two solutions were fed separately to the fluid bed drier and united via Y-fitting after passing the peristaltic pump shortly before entering the bi-fluid nozzle.

[0201] Stability results of batches with the composition of examples 1 and 2 manufactured with two separated granulation liquids and single granulation liquid exhibited assay within specification over a test period of 12 months at 25° C./60% relative humidity and over a test period of 6 months at 40° C./75% relative humidity.