Pharmaceutical compositions containing 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide

Abstract

The present invention relates to pharmaceutical compositions comprising 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide (Lalmitalont), processes for its preparation and its use in medical treatment.

Description

[Technical Field]

[0001] The present invention relates to pharmaceutical compositions comprising 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide (Formula I), methods for their preparation and their use in medical treatment. [Background technology]

[0002] WO2017157873, the entire contents of which are incorporated herein by reference, discloses the TAAR1 agonist 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide (Formula I), which is useful for the treatment of certain diseases and disorders of the central nervous system. [ka]

[0003] The compound of formula I is also known as INN Larmitaronto (WHO Drug Information, Vol. 33, No. 2, 2019, p. 323).

[0004] For some medical indications for larmitront, such as schizophrenia, miniature tablets are needed to improve patient compliance. Miniature tablets require the provision of API-excipient blends with high drug loadings, e.g., 30% wt / wt API. WO 2017157873 discloses tablet and capsule formulations containing high loadings of larmitront. However, it has been found that larmitront is cohesive, and API-excipient blends containing it, especially those containing high amounts, do not flow well, making tablet manufacturing difficult. Furthermore, this compound contains a secondary amine, and manufacturing processes under high humidity conditions, such as wet granulation as disclosed in WO 2017157873, increase the risk of nitrosamine formation.

[0005] Furthermore, it is desirable to manufacture Lalmitalonto tablets in a continuous manner rather than the traditional batch procedure. Continuous manufacturing has commercial manufacturing advantages such as improved process control, reduced product handling, and real-time release efficiency. The overall result is a more robust, controllable, and scalable process that requires fewer process checks. However, the blends disclosed in WO2017157873 have been found to be less suitable for tablet production in a continuous manufacturing procedure.

[0006] In summary, there is a high unmet need for new formulations containing larmitalonto. Summary of the Invention

[0007] The present invention provides new formulation blends containing high loadings of ralmitaront that avoid the wet granulation process described in WO2017157873. Some of the new blends are suitable for roller compaction, while others are suitable for continuous direct compression, particularly continuous minibatch direct compression. The present invention also provides new methods for producing tablets containing ralmitaront, as well as the use of such tablets in medical therapy. [Brief explanation of the drawings]

[0008] [Figure 1] FIG. 1 shows a flow chart of the continuous mini-batch direct compression process according to the present invention as described in Example 1. [Figure 2] FIG. 2 shows a flow chart of roller compaction according to the present invention as described in Example 2. [Figure 3]3 shows the effect of formulations represented by Examples 5, 6, and 7 on tablet tensile strength and Srel% (standard relative deviation of tablet weight) during the compression process in a rotary press. "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 tag associated with the batch number indicates which tablet sample the variable was measured on, i.e., "Start" means that the tablet sample was collected at the beginning of tabletting, "Middle" means that the tablet sample was collected toward the middle of tabletting, "End" means that the tablet sample was collected at the end of tabletting, and the "Mix" tablet sample consists of a mixture of tablets toward the middle and end of tabletting. DETAILED DESCRIPTION OF THE INVENTION

[0009] definition It should be understood that any feature, integer, characteristic, compound, chemical moiety, or group described in connection with a particular aspect, embodiment, or example of the invention is applicable to any other aspect, embodiment, or example described herein, except where inconsistent therewith. All features disclosed herein (including any accompanying claims, abstract, and drawings), and / or all methods or method steps so disclosed, may be combined in any combination, except combinations in which at least some of such features and / or steps are mutually exclusive. The invention is not limited to the details of any of the foregoing embodiments. The invention extends to any novel one or any novel combination of features disclosed herein (including any accompanying claims, abstract, and drawings), or any novel one or any novel combination of methods or method steps so disclosed.

[0010] As used herein, the term "dose strength" relates to the absolute amount, expressed in milligrams (mg), of the compound of formula I in free base form contained in a tablet formulation according to the invention. Thus, when the compound of formula I is used in the form of a pharmaceutically acceptable salt, the term "dose" relates to the respective free base equivalent.

[0011] As used herein, the term "larmitalont" refers to 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide (Formula I), and pharmaceutically acceptable salts thereof, particularly the monohydrochloride salt.

[0012] 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. Pharmaceutically acceptable fillers are described in Remington's Pharmaceutical Sciences and listed in Handbook of Pharmaceutical Excipients, Sheskey et al., 2017. Non-limiting examples of fillers include 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.

[0013] As used herein, the term "disintegrant" refers to a substance added to a pharmaceutical composition to help break down (disintegrate) and release an active ingredient, such as, for example, Form B described herein, after administration. Pharmaceutically acceptable 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 croscarmellose sodium. A preferred, but non-limiting, example of a disintegrant is croscarmellose sodium.

[0014] The terms "glidant" and "lubricant" are used interchangeably herein and refer to substances added to pharmaceutical compositions to help reduce adhesion of powder granules to equipment surfaces. Pharmaceutically acceptable 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.

[0015] As used herein, the term "flow agent" refers to a substance added to a pharmaceutical composition to promote product flow by reducing interparticle friction. Pharmaceutically acceptable 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 silicon dioxide Aerosil® 200, talc, etc. A preferred, but non-limiting example, is silica, colloidal anhydrous.

[0016] The term "MicroceLac®" refers to an additive containing 75% alpha-lactose monohydrate and 25% microcrystalline cellulose, which are co-processed by spray drying.

[0017] The term "SMCC90" refers to an additive containing 98% microcrystalline cellulose and 2% colloidal silicon dioxide, where the microcrystalline cellulose and colloidal silicon dioxide are co-processed by spray drying.

[0018] The term "Ludipress®" refers to an excipient comprising 93% lactose monohydrate, 3.5% povidone with a K value of 30 ("Kollidon® 30"), and 3.5% crospovidone with a bulk density of 0.30-0.40 g / mL ("Kollidon® CL").

[0019] The term "HPMC" refers to hydroxypropyl methylcellulose. As used herein, the term "treating" means the total or partial alleviation of a disorder, disease or condition, or of one or more symptoms associated with a disorder, disease or condition, or the slowing or halting of further progression or worsening of those symptoms, or the alleviation or eradication of the cause(s) of the disorder, disease or condition itself.

[0020] As used herein, the term "preventing" includes preventing or delaying the appearance of clinical symptoms of a condition, disorder or condition that occurs in a mammal, particularly a human who is afflicted with or susceptible to the condition, disorder or condition, but who has not yet experienced or exhibited clinical or asymptomatic symptoms of the condition, disorder or condition.

[0021] As used herein, the term "patient" refers to a human.

[0022] A new tablet formulation of Larmitalonto In a first aspect, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis, comprising: (i) a nucleus; (ii) a coating, The core is the active ingredient 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide (Formula I) [ka] or a pharmaceutically acceptable salt thereof. In one embodiment, a tablet according to the invention comprises the compound of formula I in the form of its monohydrochloride salt.

[0023] In one embodiment, the dosage of the tablet according to the present invention is between 40 mg and 160 mg, preferably between 45 mg and 150 mg, more preferably 45 mg or 150 mg.

[0024] In a preferred embodiment, the dosage of the tablet according to the invention is 45 mg.

[0025] In a preferred embodiment, the dosage of the tablet according to the invention is 150 mg.

[0026] In one embodiment, the coating of the tablet according to the invention comprises: (i) HPMC; (ii) lactose monohydrate; and (iii) titanium dioxide; (iv) macrogol. In one embodiment, (i) HPMC represents 34% ± 1% of the total weight of the coating; (ii) lactose monohydrate represents 28% ± 1% of the total weight of the coating; (iii) titanium dioxide represents 26% ± 1% of the total weight of the coating; (iv) Macrogol represents 12% ± 1% of the total weight of the coating.

[0027] In one embodiment, the coating of a tablet according to the invention is Opadry II White.

[0028] Continuous minibatch direct compression formulations Formulation A In one embodiment of the tablet according to the invention, the core comprises the following excipients: (i) a filler; (ii) a disintegrant; and (iii) a glidant.

[0029] In one embodiment, (i) the filler is selected from MicroceLac® 100 and SMCC 90; (ii) the disintegrant is croscarmellose sodium; (iii) The glidant is sodium stearyl fumarate.

[0030] In one embodiment, (i) the filler is MicroceLac® 100; (ii) the disintegrant is croscarmellose sodium; (iii) The glidant is sodium stearyl fumarate.

[0031] In one embodiment, (i) the filler is SMCC90, (ii) the disintegrant is croscarmellose sodium; (iii) The glidant is sodium stearyl fumarate.

[0032] In one embodiment, (i) the weight of said filler is equivalent to 58% ± 1% of the total weight of the core; (ii) the weight of the disintegrant is equivalent to 5%±1% of the total weight of the core; (iii) the weight of the glidant is equivalent to 4%±1% of the total weight of the core; (iv) The weight of the compound of formula I or a pharmaceutically acceptable salt thereof represents 33%±1% of the total weight of the core.

[0033] Formulation B In one embodiment of the tablet according to the invention, the core comprises the following excipients: (i) a first filler; (ii) a second filler; and (iii) a lubricant.

[0034] In one embodiment, (i) the first filler is Ludipress®; (ii) the second filler is microcrystalline cellulose; (iii) The lubricant is sodium stearyl fumarate.

[0035] In one embodiment, (i) the weight of the first filler is equivalent to 43%±1% of the total weight of the core; (ii) the weight of the second filler is equal to 20%±1% of the total weight of the core; (iii) the weight of said lubricant is equal to 4% ± 1% of the total weight of the core; (iv) The weight of the compound of formula I or a pharmaceutically acceptable salt thereof represents 33%±1% of the total weight of the core.

[0036] Continuous mini-batch direct compression In one aspect, the present invention provides a continuous process for manufacturing tablets based on Formulation A or Formulation B described herein, comprising: (i) feeding the API and components (i)-(iii) into a blender through four individual screw feeders; (ii) blending the mixture of step (i); (iii) compressing the blend from step (ii) into tablet cores; (iv) spraying the film coating suspension onto the tablet cores from step (iii).

[0037] Roller-compacted formulations Formulation C In one embodiment of the tablet according to the invention, the core comprises the following excipients: (i) a first filler; (ii) a second filler; and (iii) a disintegrant; and (iv) a glidant; and (v) a flow agent.

[0038] In one embodiment, (i) the first filler is microcrystalline cellulose; (ii) the second filler is lactose monohydrate; (iii) the disintegrant is croscarmellose sodium; (iv) the glidant is sodium stearyl fumarate; (v) The flow agent is colloidal silicon dioxide.

[0039] In one embodiment, (i) the weight of the first filler is equivalent to 33%±1% of the total weight of the core; (ii) the weight of the second filler is equal to 23%±1% of the total weight of the core; (iii) the weight of the disintegrant is equivalent to 5%±1% of the total weight of the core; (iv) the weight of the glidant is equivalent to 4%±1% of the total weight of the core; (v) the weight of said flow agent is equivalent to 2% ± 1% of the total weight of the core; (vi) The weight of the compound of formula I or a pharmaceutically acceptable salt thereof represents 33%±1% of the total weight of the core.

[0040] Roller compaction In one aspect, the present invention provides a roller compaction process for producing tablets based on Formulation C described herein, comprising: (i) blending an API, a first filler, a second filler, a disintegrant, and a glidant; (ii) screening the blend obtained from step (i); (iii) screening a 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) screening 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; (vii) spraying the film coating suspension onto the tablet cores from step (vi).

[0041] use In one aspect, the present invention provides a tablet as described herein for use as a pharmaceutical.

[0042] In one aspect, the present 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.

[0043] In one aspect, the invention provides a tablet as described herein for use in a method of treating or preventing a TAAR1(4) mediated disease in a patient.

[0044] In one aspect, the invention provides the use of a tablet as described herein in a method of treating or preventing a TAAR1(4) mediated disease in a patient.

[0045] In one embodiment, the TAAR1(4) mediated disease is selected from depression, anxiety disorders, 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, disorders of energy expenditure and assimilation, disorders and dysfunction of temperature homeostasis, disorders of sleep and circadian rhythm, and cardiovascular disorders.

[0046] In a preferred embodiment, said TAAR1(4) mediated disease is selected from schizophrenia, substance abuse, and addiction.

[0047] In a particularly preferred embodiment, said TAAR1(4) mediated disease is schizophrenia.

[0048] In a particularly preferred embodiment, said TAAR1(4)-mediated disease is drug abuse.

[0049] In a particularly preferred embodiment, said TAAR1(4) mediated disease is addiction. [Example]

[0050] The following examples are given to illustrate the present invention and should not be considered as limiting the scope of the invention, but merely as representative thereof.

[0051] Example 1 - Tablet formation from a continuous mini-batch direct compression process

[0052] [Table 1]

[0053] process 1. A large feeder supplies additive (i) and three small feeders supply API, additive (ii) and additive (iii) to the mini-batch blender. 2. Blend a mini batch in a mini batch blender. 3. Discharge into tablets and press the mini-batches prepared in steps 1 and 2. 4. Press the tablet cores. Perform IPC on the tablet cores for individual tablet weight, hardness, thickness, friability and disintegration time. 5. Repeat steps 1-4 as necessary to produce the desired final batch. 6. Prepare film coating suspension and spray film coat onto the tablet cores obtained from step 4. Perform IPC for average weight, thickness and disintegration time of film coated tablets.

[0054] In one embodiment, the API is larmitalont monohydrochloride, excipient (i) is a filler selected from MicroceLac® 100 and SMCC90, excipient (ii) is a disintegrant which is croscarmellose sodium, and excipient (iii) is a lubricant which is sodium stearyl fumarate (see Examples 5, 7, and 9).

[0055] In one embodiment, the API is larmitalont monohydrochloride, additive (i) is a first filler that is Ludipress®, additive (ii) is a second filler that is microcrystalline cellulose, and additive (iii) is a lubricant that is sodium stearyl fumarate (see Example 6).

[0056] A schematic of this process is shown in Figure 1.

[0057] Example 2 - Tablet formation from a roller compaction process

[0058] [Table 2]

[0059] process 1. Weigh and blend the API, microcrystalline cellulose, lactose monohydrate, croscarmellose, and colloidal silicon dioxide. 2. Screen the blend from step 1. 3. Screen 50% of the total amount of sodium stearyl fumarate and add it to the powder blend from step 2 and blend. 4. The blend is subjected to roller compaction. 5. Screen 50% of the total amount of sodium stearyl fumarate and add it to the granules from step 4 and blend. 6. Tablet manufacturing is carried out using the final blend from step 5. Perform IPC for individual tablet weight, hardness, thickness, friability and disintegration time of the tablet cores. 7. Prepare film coating suspension and spray film coat onto the tablet cores obtained from step 6. Perform IPC for average weight, thickness and disintegration time of film coated tablets.

[0060] A schematic of this process is shown in Figure 2.

[0061] Example 3 - Comparison of different fillers for continuous minibatch direct compression Comparison of the three formulations in Examples 5, 6, and 7 surprisingly showed that the blend containing the filler SMCC90 (Example 7) provided stronger tablets than comparable blends containing MicroceLac® 100 (Example 5) or Ludipress® (Example 6). Furthermore, the standard relative deviation ("Srel") of the main compression force during tablet compression was lower when SMCC90 was used in the blend compared to when MicroceLac® 100 or Ludipress® were used. In other words, the blend described in Example 7 containing SMCC90 as a filler provided 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 is shown in Figure 3.

[0062] Example 4 - 150 mg Tablet Formulation

[0063] [Table 3]

[0064] All excipients used in the formulation are of compendial (European Pharmacopoeia and / or United States Pharmacopoeia / National Formulary (USP / NF)) grade.

[0065] Tablets can be manufactured according to the process described in Example 2.

[0066] Example 5 - Alternative 150 mg Tablet Formulation

[0067] [Table 4]

[0068] a) MicroceLac® 100 is a commercially available additive consisting of co-processed microcrystalline cellulose and alpha-lactose monohydrate.

[0069] All excipients used in the formulation are of compendial (European Pharmacopoeia and / or United States Pharmacopoeia / National Formulary (USP / NF)) grade.

[0070] Tablets can be manufactured according to the continuous process described in Example 1.

[0071] Example 6 - Alternative 150 mg Tablet Formulation

[0072] [Table 5]

[0073] a) Ludipress® is a commercially available excipient consisting of co-processed lactose monohydrate, povidone, and crospovidone.

[0074] All excipients used in the formulation are of compendial (European Pharmacopoeia and / or United States Pharmacopoeia / National Formulary (USP / NF)) grade.

[0075] Tablets can be manufactured according to the continuous process described in Example 1.

[0076] Example 7 - Alternative 150 mg Tablet Formulation

[0077] [Table 6]

[0078] a) SMCC90 is a commercially available additive consisting of silicified microcrystalline cellulose.

[0079] All excipients used in the formulation are of compendial (European Pharmacopoeia and / or United States Pharmacopoeia / National Formulary (USP / NF)) grade.

[0080] Tablets can be manufactured according to the continuous process described in Example 1.

[0081] Example 8 - 45 mg Tablet Formulation

[0082] [Table 7]

[0083] All excipients used in the formulation are of compendial (European Pharmacopoeia and / or United States Pharmacopoeia / National Formulary (USP / NF)) grade.

[0084] Tablets can be manufactured according to the process described in Example 2.

[0085] Example 9 - Alternative 45 mg tablet formulation

[0086] [Table 8]

[0087] a MicroceLac® 100 is a commercially available additive consisting of co-processed microcrystalline cellulose and alpha-lactose monohydrate.

[0088] All excipients used in the formulation are of compendial (European Pharmacopoeia and / or United States Pharmacopoeia / National Formulary (USP / NF)) grade.

[0089] Tablets can be manufactured according to the continuous process described in Example 1.

[0090] Example 10 - Alternative 45 mg tablet formulation

[0091] [Table 9]

[0092] a) Ludipress® is a commercially available excipient consisting of co-processed lactose monohydrate, povidone, and crospovidone.

[0093] All excipients used in the formulation are of compendial (European Pharmacopoeia and / or United States Pharmacopoeia / National Formulary (USP / NF)) grade.

[0094] Tablets can be manufactured according to the continuous process described in Example 1.

[0095] Example 11 - Alternative 45 mg tablet formulation

[0096] [Table 10]

[0097] a) SMCC90 is a commercially available additive consisting of silicified microcrystalline cellulose.

[0098] All excipients used in the formulation are of compendial (European Pharmacopoeia and / or United States Pharmacopoeia / National Formulary (USP / NF)) grade.

[0099] Tablets can be manufactured according to the continuous process described in Example 1.

Claims

1. (i) the nucleus, (ii) A tablet comprising a coating, The aforementioned nucleus is the active ingredient 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide (Formula I) 【Chemistry 1】 or comprising a pharmaceutically acceptable salt thereof, wherein the nucleus further contains the following additives: (i) A first filler which is microcrystalline cellulose, (ii) A second filler which is lactose monohydrate, (iii) Croscarmellose sodium is a disintegrant, (iv) Sodium stearyl fumarate, a fluidity enhancer, (v) A tablet comprising a fluid agent which is colloidal silicon dioxide.

2. (i) The weight of the first filler corresponds to 33% ± 1% of the total weight of the nucleus, (ii) The weight of the second filler corresponds to 23% ± 1% of the total weight of the nucleus, (iii) The weight of the disintegrant is equivalent to 5% ± 1% of the total weight of the nucleus, (iv) The weight of the flow promoter is equivalent to 4% ± 1% of the total weight of the nucleus, (v) The weight of the fluid is equivalent to 2% ± 1% of the total weight of the nucleus, (vi) The tablet according to claim 1, wherein the weight of the compound of formula I or a pharmaceutically acceptable salt thereof corresponds to 33% ± 1% of the total weight of the nucleus.

3. (i) the nucleus, (ii) A tablet comprising a coating, The aforementioned nucleus is the active ingredient 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide (Formula I) 【Chemistry 2】 or comprising a pharmaceutically acceptable salt thereof, wherein the nucleus further contains the following additives: (i)(a) Excipient comprising 75% α-lactose monohydrate and 25% microcrystalline cellulose, wherein the α-lactose monohydrate and microcrystalline cellulose are co-treated by spray drying. and (b) SMCC90 A filler selected from, (ii) Croscarmellose sodium is a disintegrant, (iii) A tablet containing a fluidity enhancer, which is sodium stearyl fumarate.

4. The filler is an excipient comprising 75% α-lactose monohydrate and 25% microcrystalline cellulose, wherein the α-lactose monohydrate and microcrystalline cellulose are co-treated by spray drying. The tablet according to claim 3.

5. The tablet according to claim 3, wherein the filler is SMCC90.

6. (i) The weight of the filler corresponds to 58% ± 1% of the total weight of the nucleus, (ii) The weight of the disintegrant is equivalent to 5% ± 1% of the total weight of the nucleus, (iii) The weight of the flow promoter corresponds to 4% ± 1% of the total weight of the nucleus, (iv) The tablet according to any one of claims 3 to 5, wherein the weight of the compound of formula I or a pharmaceutically acceptable salt thereof corresponds to 33% ± 1% of the total weight of the nucleus.

7. (i) the nucleus, (ii) A tablet comprising a coating, The aforementioned nucleus is the active ingredient 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide (Formula I) 【Transformation 3】 or comprising a pharmaceutically acceptable salt thereof, wherein the nucleus further contains the following additives: (i) A first filler which is an excipient comprising 93% lactose monohydrate, 3.5% povidone having a K-value of 30, and 3.5% crospovidone having a bulk density of 0.30–0.40 g / mL, (ii) A second filler which is microcrystalline cellulose, (iii) A tablet containing a lubricant, sodium stearyl fumarate.

8. (i) The weight of the first filler corresponds to 43% ± 1% of the total weight of the nucleus, (ii) The weight of the second filler corresponds to 20% ± 1% of the total weight of the nucleus, (iii) The weight of the lubricant is equivalent to 4% ± 1% of the total weight of the nucleus, (iv) The tablet according to claim 7, wherein the weight of the compound of formula I or a pharmaceutically acceptable salt thereof corresponds to 33% ± 1% of the total weight of the nucleus.

9. A tablet according to any one of claims 1 to 5, 7, and 8, comprising the compound of formula I in the form of its monohydrochloride salt.

10. A tablet according to any one of claims 1 to 5, 7 and 8, wherein the content is 40 mg to 160 mg, preferably 45 mg to 150 mg, more preferably 45 mg or 150 mg.

11. A process for manufacturing the tablets described in claim 1 or 2, (i) A step of blending API, a first filler, a second filler, a disintegrant, and a flow promoter, (ii) A step of screening the blend obtained from step (i), (iii) A step of screening a first portion of the lubricant and adding it to the blend from step (ii), (iv) A step of rolling the blend from step (iii) to form granules, (v) A step of screening the second portion of the lubricant and adding it to the granules from step (iv), (vi) A step of compressing the blend from step (v) to form a tablet core, A process comprising (vii) spraying a film coating suspension onto the tablet nuclei from step (vi).

12. A continuous process for manufacturing tablets according to any one of claims 3 to 5, 7 and 8, (i) A step of supplying the API and components (i) to (iii) from four individual screw feeders to the blender, (ii) A step of blending the mixture from step (i), (iii) A step of compressing the blend from step (iii) to form a tablet core, A continuous process comprising (iv) spraying a film coating suspension onto the tablet nuclei from step (iii).

13. The aforementioned coating (i) HPMC and, (ii) Lactose monohydrate and (iii) Titanium dioxide and (iv) A tablet according to any one of claims 1 to 5, 7 and 8, comprising macrogol.

14. (i) HPMC is equivalent to 34% ± 1% of the total weight of the coating, (ii) Lactose monohydrate is equivalent to 28% ± 1% of the total weight of the coating, (iii) Titanium dioxide accounts for 26% ± 1% of the total weight of the coating, (iv) The tablet according to claim 13, wherein macrogol is equivalent to 12% ± 1% of the total weight of the coating.

15. For treating or preventing depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder (ADHD), stress-related disorders, schizophrenia, Parkinson's disease, Alzheimer's disease, epilepsy, migraine, hypertension, drug abuse, intoxication, eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy expenditure and assimilation, disorders and dysfunctions of thermoregulation, disorders of sleep and circadian rhythms, and / or cardiovascular disorders, A pharmaceutical composition comprising a tablet according to any one of claims 1 to 5, 7, and 8.

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