Pharmaceutical compositions comprising 5-ethyl-4-methyl-n-[4-[(2s) morpholin-2-yl] phenyl]-1h-pyrazol-3-carboxamide

Abstract

The present invention relates to a pharmaceutical composition comprising 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl] phenyl]-1H-pyrazol-3-carboxamide (ramitratron), to a process for the preparation thereof, and to the use thereof in medical treatment. The invention also relates to a pharmaceutical composition comprising 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl] phenyl]-1H-pyrazol-3-carboxamide.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition comprising 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide (Formula I), a method for preparing the same and its use in medical treatment. Background Art

[0002] WO2017157873, the entire contents of which are incorporated herein by reference, discloses a TAAR1 agonist 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide (Formula I) that can be used to treat certain central nervous system diseases and disorders.

[0003]

[0004] The compound of formula I is also known under INN ralmitaront (WHO Drug Information, Vol. 33, No. 2, 2019, p. 323).

[0005] For some medical indications of ralmitaront, such as schizophrenia, small-sized tablets are needed to improve patient compliance. Small-sized tablets require API-excipient blends that provide high drug loads, such as 30% wt / wt API drug loads. WO2017157873 discloses tablet and capsule preparations with high-load ralmitaront. However, studies have found that ralmitaront is sticky and API excipient blends containing it (especially in large quantities) have poor fluidity, making tablet production challenging. In addition, the compound includes secondary amines, and manufacturing methods under high humidity conditions (such as wet granulation disclosed in WO2017157873) increase the risk of nitrosamine formation.

[0006] In addition, it is desirable to manufacture ralmitaront tablets in a continuous manner rather than in a conventional batch setting. Continuous manufacturing has commercial manufacturing advantages, such as improved process control, reduced product handling, and real-time market entry efficiency. The overall result is a more robust, controllable, and scalable process that requires less process inspection. However, it was found that the blend disclosed in WO2017157873 is not well suited for producing tablets in a continuous manufacturing setting.

[0007] In conclusion, there is a high unmet need for new formulations comprising ralmitaront. Summary of the invention

[0008] The present invention provides novel formulation blends containing high-load ralmitaront, which avoids the wet granulation described in WO2017157873. Some novel blends are suitable for roller compaction, while others are suitable for continuous direct compression, especially continuous small batch direct compression. The present invention also provides a novel method for manufacturing tablets containing ralmitaront, and the use of the tablets in medical therapy. BRIEF DESCRIPTION OF THE DRAWINGS

[0009] Figure 1 A flow chart of the continuous mini-batch direct compression method according to the present invention described in Example 1 is depicted.

[0010] Figure 2 A flow chart of the roller pressing according to the present invention described in Example 2 is depicted.

[0011] Figure 3 The effects of the formulations represented by Examples 5, 6, and 7 on tablet tensile strength and Srel% (standard relative deviation of tablet weight) during the compaction process in a rotary press are depicted. "Batch 1" refers to the formulation of Example 5, "Batch 2" refers to the formulation of Example 6, and "Batch 3" refers to the formulation of Example 7. The label accompanying the batch number indicates on which tablet sample the variable measurement was performed: "Start" means the tablet sample was collected at the beginning of tableting, "Middle" means the tablet sample was collected during the middle of tableting, "End" means the tablet sample was collected during the end of tableting, and the "Mixed" tablet sample consists of a mixture of tablets at the middle and end of tableting. DETAILED DESCRIPTION

[0012] definition

[0013] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All features disclosed in this specification (including any accompanying claims, abstract and drawings) and / or all steps of any method or process disclosed thereby may be combined in any combination, except for combinations in which at least some of these features and / or steps are mutually exclusive. The invention is not limited to the details of any foregoing embodiments. The invention extends to any novel feature or any novel combination of features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel step or any novel combination of steps of any method or process disclosed thereby.

[0014] As used herein, the term "dosage strength" relates to the absolute amount of the free base form of the compound of formula I contained in the tablet formulation according to the invention, expressed in milligrams (mg). Thus, if the compound of formula I is used in the form of a pharmaceutically acceptable salt, the term "dosage strength" relates to the corresponding free base equivalent.

[0015] As used herein, the term "ralmitaront" relates to 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide (Formula I) and its pharmaceutically acceptable salts, in particular the monohydrochloride salt.

[0016] As used herein, the term "filler" refers to a substance added to a pharmaceutical composition to increase the weight and / or size of the pharmaceutical composition. Pharmaceutical fillers are described in Remington's Pharmaceutical Sciences and listed in Handbook of Pharmaceutical Excipients, Sheskey et al., 2017. Non-limiting examples of fillers are starch (e.g., pregelatinized starch), cellulose (e.g., microcrystalline cellulose), and lactose (e.g., lactose monohydrate). Preferred but non-limiting examples of fillers are cellulose and lactose.

[0017] As used herein, the term "disintegrant" refers to a substance added to a pharmaceutical composition to help break down (disintegrate) (e.g., after administration) and release the active ingredient (such as Form B described herein). Pharmaceutical disintegrants are described in Remington's Pharmaceutical Sciences and listed in Handbook of Pharmaceutical Excipients, Sheskey et al., 2017. Non-limiting examples of disintegrants are low-substituted hydroxypropyl cellulose and cross-linked sodium carboxymethyl cellulose. A preferred but non-limiting example of a disintegrant is cross-linked sodium carboxymethyl cellulose.

[0018] The terms "glidant" and "lubricant" are used interchangeably herein and refer to substances added to pharmaceutical compositions to help reduce the adhesion of particles of the powder to the surface of the equipment. Pharmaceutical glidants are described in Remington's Pharmaceutical Sciences and listed in Handbook of Pharmaceutical Excipients, Sheskey et al., 2017. Non-limiting examples of glidants are sodium stearyl fumarate and magnesium stearate. A preferred but non-limiting example of a glidant is sodium stearyl fumarate.

[0019] As used herein, the term "flow agent" refers to a substance added to a pharmaceutical composition to enhance product flow by reducing interparticle friction. Pharmaceutical flow agents are described in Remington's Pharmaceutical Sciences and listed in Handbook of Pharmaceutical Excipients, Sheskey et al., 2017. Non-limiting examples of flow agents include silicon dioxide (colloidal), polyethylene glycol PEG 6000, fumed silica, 200, talc, etc. A preferred but non-limiting example is anhydrous colloidal silica.

[0020] the term Refers to an excipient comprising 75% α-lactose monohydrate and 25% microcrystalline cellulose, wherein the α-lactose monohydrate and microcrystalline cellulose have been co-processed by spray drying.

[0021] The term "SMCC90" refers to an excipient comprising 98% microcrystalline cellulose and 2% colloidal silicon dioxide, wherein the microcrystalline cellulose and colloidal silicon dioxide have been co-processed by spray drying.

[0022] the term It refers to 93% lactose monohydrate, 3.5% povidone with a K value of 30 and 3.5% crospovidone with a volume density of 0.30-0.40 g / mL of excipients.

[0023] The term "HPMC" refers to hydroxypropyl methylcellulose.

[0024] As used herein, the term "treat," ...

[0025] As used herein, the term "preventing" includes preventing or delaying the onset of clinical symptoms of a disease, disorder or condition in a mammal, especially a human, who may be suffering from or susceptible to a disease, disorder or condition but has not yet experienced or displayed clinical or subclinical symptoms of the disease, disorder or condition.

[0026] As used herein, the term "patient" refers to a human.

[0027] Novel tablet formulation of Ralmitaront

[0028] In a first aspect, the present invention provides a tablet comprising:

[0029] (i) the kernel; and

[0030] (ii) coating;

[0031] The core contains the active ingredient 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide (Formula I) or a pharmaceutically acceptable salt thereof,

[0032]

[0033] In one embodiment, a tablet according to the invention comprises the compound of formula I in the form of its monohydrochloride salt.

[0034] In one embodiment, the dosage strength of the tablet according to the invention is 40 mg to 160 mg, preferably 45 mg to 150 mg, more preferably 45 mg or 150 mg.

[0035] In a preferred embodiment, the dosage strength of the tablet according to the invention is 45 mg.

[0036] In a preferred embodiment, the dosage strength of the tablet according to the invention is 150 mg.

[0037] In one embodiment, the coating of the tablet according to the present invention comprises:

[0038] (i) HPMC;

[0039] (ii) lactose monohydrate;

[0040] (iii) titanium dioxide; and

[0041] (iv) Polyethylene glycol (macrogol).

[0042] In one embodiment:

[0043] (i) HPMC accounts for 34% ± 1% of the total weight of the coating;

[0044] (ii) lactose monohydrate accounts for 28% ± 1% of the total weight of the coating;

[0045] (iii) titanium dioxide constitutes 26% ± 1% of the total weight of the coating; and

[0046] (iv) Polyethylene glycol accounts for 12% ± 1% of the total weight of the coating.

[0047] In one embodiment, the coating of the tablet according to the present invention is Opadry II White.

[0048] Formulations for direct compression in small continuous batches

[0049] Preparation A

[0050] In one embodiment of the tablet according to the present invention, the core further comprises the following excipients:

[0051] (i) fillers;

[0052] (ii) a disintegrant; and

[0053] (iii) Glidants.

[0054] In one embodiment:

[0055] (i) the filler is selected from 100 and SMCC90;

[0056] (ii) the disintegrant is cross-linked carboxymethyl cellulose sodium; and

[0057] (iii) The glidant is sodium stearyl fumarate.

[0058] In one embodiment:

[0059] (i) The filler is 100;

[0060] (ii) the disintegrant is cross-linked carboxymethyl cellulose sodium; and

[0061] (iii) The glidant is sodium stearyl fumarate.

[0062] In one embodiment:

[0063] (i) the filler is SMCC90;

[0064] (ii) the disintegrant is cross-linked carboxymethyl cellulose sodium; and

[0065] (iii) The glidant is sodium stearyl fumarate.

[0066] In one embodiment:

[0067] (i) the weight of the filler accounts for 58% ± 1% of the total weight of the inner core;

[0068] (ii) the weight of the disintegrant accounts for 5%±1% of the total weight of the core;

[0069] (iii) the weight of the glidant accounts for 4%±1% of the total weight of the inner core; and

[0070] (iv) the weight of the compound of formula I or a pharmaceutically acceptable salt thereof accounts for 33%±1% of the total weight of the inner core.

[0071] Preparation B

[0072] In one embodiment of the tablet according to the present invention, the core further comprises the following excipients:

[0073] (i) a first filler;

[0074] (ii) a second filler; and

[0075] (iii) Lubricants.

[0076] In one embodiment:

[0077] (i) the first filler is

[0078] (ii) the second filler is microcrystalline cellulose; and

[0079] (iii) The lubricant is sodium stearyl fumarate.

[0080] In one embodiment:

[0081] (i) the weight of the first filler accounts for 43%±1% of the total weight of the inner core;

[0082] (ii) the weight of the second filler accounts for 20%±1% of the total weight of the core;

[0083] (iii) the weight of the lubricant accounts for 4% ± 1% of the total weight of the core;

[0084] (iv) the weight of the compound of formula I or a pharmaceutically acceptable salt thereof accounts for 33%±1% of the total weight of the inner core.

[0086] Continuous small batch direct compression

[0087] In one aspect, the present invention provides a continuous process for manufacturing tablets based on formulation A or B described herein, the process comprising:

[0088] (i) feeding the API and components (i) to (iii) from four separate screw feeders into a blender;

[0089] (ii) blending the mixture of step (i);

[0090] (iii) compressing the blend from step (ii) into tablet cores; and

[0091] (iv) Spraying the film coating suspension onto the tablet cores from step (iii).

[0092] Roller Pressed Preparation

[0093] Preparation C

[0094] In one embodiment of the tablet according to the present invention, the core further comprises the following excipients:

[0095] (i) a first filler;

[0096] (ii) a second filler;

[0097] (iii) disintegrants;

[0098] (iv) a glidant; and

[0099] (v) Flowing agent.

[0100] In one embodiment:

[0101] (i) the first filler is microcrystalline cellulose;

[0102] (ii) the second filler is lactose monohydrate;

[0103] (iii) the disintegrant is croscarmellose sodium;

[0104] (iv) the glidant is sodium stearyl fumarate; and

[0105] (v) The flow agent is colloidal silicon dioxide.

[0106] In one embodiment:

[0107] (i) the weight of the first filler accounts for 33%±1% of the total weight of the inner core;

[0108] (ii) the weight of the second filler accounts for 23%±1% of the total weight of the core;

[0109] (iii) the weight of the disintegrant accounts for 5%±1% of the total weight of the inner core;

[0110] (iv) the weight of the glidant accounts for 4%±1% of the total weight of the inner core;

[0111] (v) the weight of the flow agent accounts for 2% ± 1% of the total weight of the inner core; and

[0112] (vi) The weight of the compound of formula I or a pharmaceutically acceptable salt thereof accounts for 33%±1% of the total weight of the inner core.

[0114] Roller Pressing

[0115] In one aspect, the present invention provides a roller compaction method for making a tablet based on Formulation C described herein, the method comprising:

[0116] (i) blending the API, a first filler, a second filler, a disintegrant and a glidant;

[0117] (ii) sieving the blend obtained from step (i);

[0118] (iii) sieving the first portion of the lubricant and adding it to the blend from step (ii);

[0119] (iv) roller compacting the blend from step (iii) to form granules;

[0120] (v) sieving a second portion of the lubricant and adding it to the granules from step (iv);

[0121] (vi) compressing the blend from step (v) into tablet cores; and

[0122] (vii) Spraying the film coating suspension onto the tablet cores from step (vi).

[0123] use

[0124] In one aspect, the invention provides a tablet as described herein for use as a medicament.

[0125] In one aspect, the invention provides a method for treating or preventing a TAAR1(4)-mediated disease in a patient, the method comprising administering to the patient one or more tablets described herein.

[0126] In one aspect, the present invention provides a tablet as described herein for use in a method of treating or preventing a TAAR1 (4) mediated disease in a patient.

[0127] In one aspect, the present invention provides for use of a tablet as described herein in a method for treating or preventing a TAAR1(4)-mediated disease in a patient.

[0128] In one embodiment, the TAAR1(4)-mediated disease is selected from depression, anxiety, bipolar disorder, attention deficit hyperactivity disorder (ADHD), stress-related disorders, schizophrenia, Parkinson's disease, Alzheimer's disease, epilepsy, migraine, hypertension, substance abuse, addiction, eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, energy expenditure and assimilation disorders, body temperature homeostasis disorders and dysfunctions, sleep and circadian rhythm disorders and cardiovascular disorders.

[0129] In a preferred embodiment, the TAAR1(4)-mediated disease is selected from schizophrenia, substance abuse and addiction.

[0130] In a particularly preferred embodiment, the TAAR1(4)-mediated disease is schizophrenia.

[0131] In a particularly preferred embodiment, the TAAR1(4)-mediated disease is substance abuse.

[0132] In a particularly preferred embodiment, the TAAR1(4)-mediated disease is addiction.

[0133] Examples

[0134] The following examples are provided to illustrate the present invention. They should not be considered as limiting the scope of the present invention, but merely as representative thereof.

[0135] Example 1 - Tablet Formation by Continuous Small Batch Direct Compression Process

[0136] equipment

[0137]

[0138] method

[0139] 1. Feed excipient (i) from a large feeder; and API, excipient (ii) and excipient (iii) from three small feeders into a small batch blender.

[0140] 2. Blend small batches in a small batch blender.

[0141] 3. Pour the small batch of material prepared in steps 1 and 2 into the tablet press.

[0142] 4. Tablet cores. IPC is performed on individual tablet weight, hardness, thickness, friability and disintegration time of the tablet cores.

[0143] 5. Repeat steps 1 through 4 as necessary to make the desired final batch.

[0144] 6. Prepare film coating suspension and spray the film coating onto the cores obtained from step 4. Perform IPC on the average weight, thickness and disintegration time of the film coated tablets.

[0145] In one embodiment, the API is ralmitaront monohydrochloride, and the excipient (i) is selected from The fillers are SMCC 100 and SMCC 90; the excipient (ii) is a disintegrant which is croscarmellose sodium; and the excipient (iii) is a lubricant which is sodium stearyl fumarate (see Examples 5, 7 and 9).

[0146] In one embodiment, the API is ralmitaront monohydrochloride, and the excipient (i) is a first filler, which is Excipient (ii) is a second filler which is microcrystalline cellulose; and excipient (iii) is a lubricant which is sodium stearyl fumarate (see Example 6).

[0147] A schematic overview of the method is provided in Figure 1 middle.

[0148] Example 2 - Tablet Formation by Roller Compaction

[0149] equipment

[0150]

[0151] method

[0152] 1. Weigh API, microcrystalline cellulose, lactose monohydrate, croscarmellose and colloidal silicon dioxide and blend.

[0153] 2. Sieve the blend obtained from step 1.

[0154] 3. Screen 50% of the total amount of Sodium Stearyl Fumarate, add it to the powder blend of step 2 and blend.

[0155] 4. Roll the blend.

[0156] 5. Sieve the remaining 50% of the total amount of sodium stearyl fumarate, add it to the granules of step 4 and blend.

[0157] 6. Tablet manufacturing was performed using the final blend obtained from step 5. IPC was performed on individual tablet weight, hardness, thickness, friability and disintegration time of the tablet cores.

[0158] 7. Prepare film coating suspension and spray the film coating onto the cores obtained from step 6. Perform IPC on the average weight, thickness and disintegration time of the film coated tablets.

[0159] A schematic overview of the method is provided in Figure 2 middle.

[0160] Example 3 – Comparison of different fillers for continuous small batch direct compression

[0161] Comparison of the three formulations of Examples 5, 6 and 7 surprisingly shows that the blend containing filler SMCC90 (Example 7) provides better results than the blend containing 100 (Example 5) or (Example 6) compared to the blends of the same firm tablet. 100 or The standard relative deviation ("Srel") of the main compression force during tablet compression was lower when SMCC90 was used in the blend than when SMCC90 was used in the blend. In other words, the blend described in Example 7 comprising SMCC90 as a filler produced higher quality tablets, i.e., stronger tablets, and made the tableting process more stable, i.e., reduced Srel, compared to the blends described in Examples 5 and 6. This Figure 3 shown.

[0162] Example 4 - 150 mg tablet formulation

[0163]

[0164] All excipients used in the formulations were of pharmacopoeial (Ph. Eur. and / or USP / NF) grade.

[0165] Tablets can be manufactured according to the method described in Example 2.

[0166] Example 5 - 150 mg tablet formulation

[0167]

[0168] a) ACTIVE(R) 100 is a commercially available excipient consisting of co-processed microcrystalline cellulose and α-lactose monohydrate.

[0169] All excipients used in the formulations were of pharmacopoeial (Ph. Eur. and / or USP / NF) grade.

[0170] Tablets can be manufactured according to the continuous process described in Example 1.

[0171] Example 6 - 150 mg tablet formulation

[0172]

[0173] a) is a commercially available excipient consisting of co-processed lactose monohydrate, povidone and crospovidone.

[0174] All excipients used in the formulations were of pharmacopoeial (Ph. Eur. and / or USP / NF) grade. Tablets can be manufactured according to the continuous process described in Example 1.

[0175] Example 7 - 150 mg tablet formulation

[0176]

[0177] a) SMCC90 is a commercially available excipient consisting of silicified microcrystalline cellulose. All excipients used in the formulation are of pharmacopoeia (Ph.Eur. and / or USP / NF) grade. Tablets can be manufactured according to the continuous process described in Example 1.

[0178] Example 8 - 45 mg tablet formulation

[0179]

[0180] All excipients used in the formulations were of pharmacopoeial (Ph. Eur. and / or USP / NF) grade.

[0181] Tablets can be manufactured according to the method described in Example 2.

[0182] Example 9 - 45 mg tablet formulation

[0183]

[0184] a ACTIVE(R) 100 is a commercially available excipient consisting of co-processed microcrystalline cellulose and α-lactose monohydrate.

[0185] All excipients used in the formulations were of pharmacopoeial (Ph. Eur. and / or USP / NF) grade.

[0186] Tablets can be manufactured according to the continuous process described in Example 1.

[0187] Example 10 - 45 mg tablet formulation

[0188]

[0189] a) is a commercially available excipient consisting of co-processed lactose monohydrate, povidone and crospovidone.

[0190] All excipients used in the formulations were of pharmacopoeial (Ph. Eur. and / or USP / NF) grade.

[0191] Tablets can be manufactured according to the continuous process described in Example 1.

[0192] Example 11 - 45 mg tablet formulation

[0193]

[0194] a) SMCC90 is a commercially available excipient composed of silicified microcrystalline cellulose.

[0195] All excipients used in the formulations were of pharmacopoeial (Ph. Eur. and / or USP / NF) grade.

[0196] Tablets can be manufactured according to the continuous process described in Example 1.

Claims

1. A tablet comprising: (i) the kernel; and (ii) coating; The inner core comprises the active ingredient 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide (Formula I) or a pharmaceutically acceptable salt thereof, And wherein the core further comprises the following excipients: (i) a first filler; (ii) a second filler; (iii) disintegrants; (iv) a glidant; and (v) Flowing agent.

2. The tablet according to claim 1, wherein: (i) the first filler is microcrystalline cellulose; (ii) the second filler is lactose monohydrate; (iii) the disintegrant is cross-linked carboxymethyl cellulose sodium; (iv) the glidant is sodium stearyl fumarate; and (v) The flow agent is colloidal silicon dioxide.

3. The tablet according to claim 1 or 2, wherein: (i) the weight of the first filler accounts for 33%±1% of the total weight of the inner core; (ii) the weight of the second filler accounts for 23%±1% of the total weight of the inner core; (iii) the weight of the disintegrant accounts for 5%±1% of the total weight of the inner core; (iv) the weight of the glidant accounts for 4%±1% of the total weight of the inner core; (v) the weight of the flow agent accounts for 2% ± 1% of the total weight of the inner core; and (vi) The weight of the compound of formula I or a pharmaceutically acceptable salt thereof accounts for 33%±1% of the total weight of the inner core.

4. A tablet comprising: (i) the kernel; and (ii) coating; The inner core comprises the active ingredient 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide (Formula I) or a pharmaceutically acceptable salt thereof, And wherein the core further comprises the following excipients: (i) fillers; (ii) a disintegrant; and (iii) Glidants.

5. The tablet according to claim 4, wherein: (i) the filler is selected from 100 and SMCC90; (ii) the disintegrant is cross-linked carboxymethyl cellulose sodium; and (iii) The glidant is sodium stearyl fumarate.

6. The tablet according to claim 4 or 5, wherein: (i) the weight of the filler accounts for 58%±1% of the total weight of the inner core; (ii) the weight of the disintegrant accounts for 5%±1% of the total weight of the inner core; (iii) the weight of the glidant accounts for 4%±1% of the total weight of the inner core; and (iv) the weight of the compound of formula I or a pharmaceutically acceptable salt thereof accounts for 33%±1% of the total weight of the inner core.

7. A tablet comprising: (i) the kernel; and (ii) coating; The inner core comprises the active ingredient 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide (Formula I) or a pharmaceutically acceptable salt thereof, And wherein the core further comprises the following excipients: (i) a first filler; (ii) a second filler; and (iii) Lubricants.

8. The tablet according to claim 7, wherein: (i) the first filler is (ii) the second filler is microcrystalline cellulose; and (iii) The lubricant is sodium stearyl fumarate.

9. The tablet according to claim 7 or 8, wherein: (i) the weight of the first filler accounts for 43%±1% of the total weight of the inner core; (ii) the weight of the second filler accounts for 20%±1% of the total weight of the inner core; (iii) the weight of the lubricant accounts for 4%±1% of the total weight of the core; (iv) the weight of the compound of formula I or a pharmaceutically acceptable salt thereof accounts for 33%±1% of the total weight of the inner core.

10. A tablet according to any one of claims 1 to 9 comprising the compound of formula I in the form of its monohydrochloride salt.

11. The tablet according to any one of claims 1 to 10, wherein the dosage strength is 40 mg to 160 mg, preferably 45 mg to 150 mg, more preferably 45 mg or 150 mg.

12. A method for producing a tablet according to any one of claims 1, 3, 10 and 11, the method comprising: (i) blending the API, a first filler, a second filler, a disintegrant and a glidant; (ii) sieving the blend obtained from step (i); (iii) sieving the first portion of the lubricant and adding it to the blend from step (ii); (iv) roller compacting the blend from step (iii) to form granules; (v) sieving a second portion of the lubricant and adding it to the granules from step (iv); (vi) compressing the blend from step (v) into tablet cores; and (vii) Spraying the film coating suspension onto the tablet cores from step (vi).

13. A continuous process for producing a tablet according to any one of claims 4 to 11, the process comprising: (i) feeding the API and components (i) to (iii) from four separate screw feeders into a blender; (ii) blending the mixture of step (i); (iii) compressing the blend from step (ii) into tablet cores; and (iv) spraying the film coating suspension onto the tablet cores from step (iii).

14. A tablet according to any one of claims 1 to 11, wherein the coating comprises: (i) HPMC; (ii) lactose monohydrate; (iii) titanium dioxide; and (iv) Polyethylene glycol.

15. The tablet according to claim 14, wherein: (i) HPMC accounts for 34% ± 1% of the total weight of the coating; (ii) lactose monohydrate accounts for 28% ± 1% of the total weight of the coating; (iii) titanium dioxide accounts for 26% ± 1% of the total weight of the coating; and (iv) Polyethylene glycol accounts for 12% ± 1% of the total weight of the coating.

16. A tablet according to any one of claims 1 to 11, 14 and 15 for use as a medicament.

17. A method for treating or preventing depression, anxiety, bipolar disorder, attention deficit hyperactivity disorder (ADHD), stress-related disorders, schizophrenia, Parkinson's disease, Alzheimer's disease, epilepsy, migraine, hypertension, substance abuse, addiction, eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, energy expenditure and assimilation disorders, body temperature homeostasis disorders and dysfunctions, sleep and circadian rhythm disorders and / or cardiovascular diseases in a patient, the method comprising administering to the patient one or more tablets according to any one of claims 1 to 11, 14 and 15.

18. A tablet according to any one of claims 1 to 11, 14 and 15 for use in a method according to claim 17.

19. Use of a tablet according to any one of claims 1 to 11, 14 and 15 in a method according to claim 17.

20. The invention as hereinbefore described.

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