TW202416999A - Pharmaceutical compositions comprising 5-ethyl-4-methyl-n-[4-[(2s) morpholin-2-yl]phenyl]-1h-pyrazole-3-carboxamide - Google Patents

Abstract

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

Description

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

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 use thereof in medicine.

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. (I)

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

For some medical indications of ralmitaront, such as schizophrenia, small tablet sizes are required to improve patient compliance. Small tablet sizes are required to provide API-formulated agent blends with high drug loading, such as 30% wt/wt API loading. WO2017157873 discloses tablet and capsule formulations with high loading of ralmitaront. However, ralmitaront was found to be sticky and API-formulated agent blends containing it (especially in large quantities) have poor flow properties, 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.

Furthermore, it is desirable to manufacture ralmitaront tablets in a continuous manner rather than in a conventional batch setting. Continuous manufacturing offers commercial manufacturing advantages such as improved process control, reduced product handling and real-time market efficiency. The overall result is a more robust, controllable and scalable process requiring fewer process checks. However, it was found that the blends disclosed in WO2017157873 were not well suited for the production of tablets in a continuous manufacturing setting.

In summary, there is a high unmet need for new formulations containing ralmitaront.

The present invention provides novel formulation blends containing high loadings of ralmitaront, which avoid wet granulation as described in WO2017157873. Some of the novel blends are suitable for roller compaction, while others are suitable for continuous direct compression, in particular continuous small batch direct compression. The present invention also provides novel methods for the manufacture of tablets containing ralmitaront, and the use of such tablets in medical treatment.

Definition

Features, integers, properties, 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 so disclosed may be combined in any combination, except for at least some mutually exclusive combinations of such features and/or steps. The invention is not limited to the details of any foregoing embodiment. 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 so disclosed.

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

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.

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 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.

As used herein, the term "disintegrant" refers to a substance added to a pharmaceutical composition to aid in the breakdown (disintegration) (e.g., after administration) and release of the active ingredient (such as Form B described herein). 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 cross-linked carboxymethyl cellulose sodium. A preferred but non-limiting example of a disintegrant is cross-linked carboxymethyl cellulose sodium.

The terms "glidant" and "lubricant" are used interchangeably herein and refer to a substance added to a pharmaceutical composition to help reduce the adhesion of powder particles to the surface of the equipment. 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.

As used herein, the term "glidant" refers to a substance added to a pharmaceutical composition to enhance product flow by reducing interparticle friction. 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 include silica (colloid), polyethylene glycol PEG 6000, fumed silica Aerosil ^® 200, talc, etc. A preferred but non-limiting example is anhydrous colloidal silica.

The term "MicroceLac ^® " refers to a formulation comprising 75% α-lactose monohydrate and 25% microcrystalline cellulose, wherein the α-lactose monohydrate and microcrystalline cellulose have been co-processed by spray drying.

The term "SMCC90" refers to a plasticizer comprising 98% microcrystalline cellulose and 2% colloidal silica, wherein the microcrystalline cellulose and colloidal silica have been co-processed by spray drying.

The term "Ludipress ^® " refers to a formulation 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").

The term "HPMC" refers to hydroxypropyl methylcellulose.

As used herein, the term "treating" means the complete or partial relief of a disorder, disease or condition, or one or more symptoms associated with a disorder, disease or condition; or the slowing down or cessation of further progression or worsening of such symptoms; or the alleviation or elimination of the cause of the disorder, disease or condition itself.

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

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

Ralmitaront New tablet formulation

In a first aspect, the present invention provides a tablet comprising: (i) a core; and (ii) a coating; wherein the core comprises an 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, (I).

In one embodiment, the tablets according to the invention comprise the compound of formula I in the form of a monohydrochloride salt.

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

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

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

In one embodiment, the coating of the tablet according to the present invention comprises: (i)        HPMC; (ii)       lactose monohydrate; (iii)      titanium dioxide; and (iv)      polyethylene glycol (macrogol).

In one embodiment: (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.

In one embodiment, the coating of the tablets according to the present invention is Opadry II White.

Formulations for continuous small batch direct compression

Preparation A

In one embodiment of the tablet according to the present invention, the core further comprises the following excipients: (i)        filler; (ii)       disintegrant; and (iii)      glidant.

In one embodiment: (i) the filler is selected from ^MicroceLac® 100 and SMCC90; (ii) the disintegrant is sodium cross-linked carboxymethyl cellulose; and (iii) the glidant is sodium stearyl fumarate.

In one embodiment: (i) the filler is ^MicroceLac® 100; (ii) the disintegrant is cross-linked sodium carboxymethyl cellulose; and (iii) the glidant is sodium stearyl fumarate.

In one embodiment: (i)        the filler is SMCC90; (ii)       the disintegrant is sodium cross-linked carboxymethyl cellulose; and (iii)      the glidant is sodium stearyl fumarate.

In one embodiment: (i) the weight of the filler is 58% ± 1% of the total weight of the core; (ii) the weight of the disintegrant is 5% ± 1% of the total weight of the core; (iii) the weight of the glidant is 4% ± 1% of the total weight of the core; and (iv) the weight of the compound of formula I or a pharmaceutically acceptable salt thereof is 33% ± 1% of the total weight of the core.

Preparation B

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

In one embodiment: (i) the first filler is ^Ludipress® ; (ii) the second filler is microcrystalline cellulose; and (iii) the lubricant is sodium stearyl fumarate.

In one embodiment: (i)        the weight of the first filler is 43% ± 1% of the total weight of the core; (ii)       the weight of the second filler is 20% ± 1% of the total weight of the core; (iii)      the weight of the lubricant is 4% ± 1% of the total weight of the core; (iv)      the weight of the compound of formula I or its pharmaceutically acceptable salt is 33% ± 1% of the total weight of the core.

Continuous small batch direct compression

In one embodiment, the present invention provides a continuous method for manufacturing tablets based on formulations A or B described herein, comprising: (i)        feeding the API and ingredients (i) to (iii) from four individual screw feeders into a blender; (ii)       blending the mixture of step (i); (iii)      pressing the blend from step (ii) into tablet cores; and (iv)      spraying a film coating suspension on the tablet core from step (iii).

Rolling compound

Preparation C

In one embodiment of the tablet according to the present invention, the core further comprises the following excipients: (i)        a first filler; (ii)       a second filler; (iii)      a disintegrant; (iv)      a glidant; and (v)       a flow aid.

In one embodiment: (i)        the first filler is microcrystalline cellulose; (ii)       the second filler is lactose monohydrate; (iii)      the disintegrant is cross-linked sodium carboxymethyl cellulose; (iv)      the glidant is sodium stearyl fumarate; and (v)       the glidant is colloidal silicon dioxide.

In one embodiment: (i)        the weight of the first filler is 33% ± 1% of the total weight of the core; (ii)       the weight of the second filler is 23% ± 1% of the total weight of the core; (iii)      the weight of the disintegrant is 5% ± 1% of the total weight of the core; (iv)      the weight of the glidant is 4% ± 1% of the total weight of the core; (v)       the weight of the flow aid is 2% ± 1% of the total weight of the core; and (vi)      the weight of the compound of formula I or a pharmaceutically acceptable salt thereof is 33% ± 1% of the total weight of the core.

Rolling

In one embodiment, the present invention provides a milling method for manufacturing a tablet based on the formulation C described herein, comprising: (i)        blending the API, the first filler, the second filler, the disintegrant and the glidant; (ii)       screening the blend obtained from step (i); (iii)      screening the first part of the lubricant and adding it to the blend from step (ii); (iv)      milling the blend from step (iii) to form granules; (v)       screening the second part 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).

use

In one aspect, the present invention provides a tablet as described herein for use as a medicine.

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

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.

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

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 function disorders, sleep and circadian rhythm disorders and cardiovascular disorders.

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

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

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

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

Examples

The following examples are provided to illustrate the present invention. They should not be considered to limit the scope of the present invention, but are merely representative thereof.

Examples 1 - Tablets are formed by a continuous small batch direct compression process

equipment Process steps Types Subclass equipment Feed Screw feed machine - ThreeTec ZD 12 ("Small Feeder") and 22 FB ("Large Feeder") Blending High shear blender - Loedige Ploughshare Mixer 5L Tablet compression Tablet Press Power assist Korsch XL100 Wipcon Film coating Pot coating Perforated coating system GMPC I

Method 1. Feed excipient (i) from a large feeder; and API, excipient (ii) and excipient (iii) from three small feeders into a small batch blender. 2. Blend small batches in the small batch blender. 3. Pour the small batches prepared in steps 1 and 2 into the tablet press. 4. Compress the tablet cores. Perform IPC on the individual tablet weight, hardness, thickness, friability and disintegration time of the tablet cores. 5. Repeat steps 1 to 4 as needed to manufacture the desired final batch. 6. Prepare film coating suspension and spray the film coating onto the tablet cores obtained from step 4. Perform IPC on the average weight, thickness and disintegration time of the film-coated tablets.

In one embodiment, the API is ralmitaront monohydrochloride, the excipient (i) is a filler selected from MicroceLac® 100 and SMCC90; the excipient (ii) is a disintegrant, which is sodium cross-linked carboxymethyl cellulose; and the excipient (iii) is a lubricant, which is sodium stearyl fumarate (see Examples 5, 7 and 9).

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

A schematic overview of the method is provided in Figure 1.

Examples 2 - Tablets are formed by rolling process

equipment Process steps Types Subclass equipment Blending Diffusion mixer Box type blending machine Servo blending machine Granulation Dry granulator Rolling Gerteis small press Tablet compression Tablet Press Power assist Korsch XL100 Wipcon Film coating Pot coating Perforated coating system Glatt GC750

Method 1. Weigh API, microcrystalline cellulose, lactose monohydrate, cross-linked carboxymethyl cellulose and colloidal silicon dioxide and blend. 2. Screen the blend obtained from step 1. 3. Screen 50% of the total amount of sodium stearyl fumarate and add it to the powder blend of step 2 and blend. 4. Roller compact the blend. 5. Screen the remaining 50% of the total amount of sodium stearyl fumarate and add it to the granules of step 4 and blend. 6. Use the final blend obtained from step 5 for tablet manufacturing. IPC was performed on individual tablet weight, hardness, thickness, friability and disintegration time of the tablet core. 7. Prepare film coating suspension and spray the film coating onto the core tablets obtained from step 6. Perform IPC on the average weight, thickness and disintegration time of the film-coated tablets.

A schematic overview of the approach is provided in Figure 2.

Examples 3 – Comparison of different fillers in continuous small batch direct compression

Comparison of the three formulations of Examples 5, 6 and 7 surprisingly showed that the blend containing the filler SMCC90 (Example 7) provided stronger tablets than the comparable blends containing MicroceLac® 100 (Example 5) or Ludipress® (Example 6). In addition, the standard relative deviation of the main compression force ("Srel") during tablet compression was lower when SMCC90 was used in the blend than when MicroceLac® 100 or Ludipress® was used. In other words, the blends described in Example 7 containing SMCC90 as filler produced higher quality tablets, i.e. stronger tablets, and made the tableting process more stable, i.e. lower Srel, compared to the blends described in Examples 5 and 6. This is shown in Figure 3.

Examples 4 – 150 mg Tablet formulations Components Function Dosage (mg/tablet) Ralmitaront monohydrochloride Active ingredients 167.40 mg (equivalent to 150 mg of the free base) Microcrystalline cellulose Filler 163.25 mg Lactose monohydrate Filler 114.35 mg Cross-linked sodium carboxymethyl cellulose Disintegrants 25.00 mg Sodium stearyl fumarate Slip agent 20.00 mg Colloidal silica Flow aids 10.00 mg Opadei II White Coating 20.00 mg Total tablet weight    520.00 mg

All excipients used in formulations are of pharmacopoeial (Ph. Eur. and/or USP/NF) grade.

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

Examples 5 – 150 mg Tablet formulations Components Function Dosage (mg/tablet) Ralmitaront monohydrochloride Active ingredients 167.40 mg (equivalent to 150 mg of the free base) MicroceLac ^® 100 ^a) Filler 287.6 mg Cross-linked sodium carboxymethyl cellulose Disintegrants 25.00 mg Sodium stearyl fumarate Lubricant 20.00 mg Opadei II White Coating 20.00 mg Total tablet weight    520.00 mg

^a) MicroceLac ^® 100 is a commercially available formulation consisting of co-processed microcrystalline cellulose and α-lactose monohydrate.

All excipients used in formulations are of pharmacopoeial (Ph. Eur. and/or USP/NF) grade.

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

Examples 6 – 150 mg Tablet formulations Components Function Dosage (mg/tablet) Ralmitaront monohydrochloride Active ingredients 167.40 mg (equivalent to 150 mg of the free base) Ludipress ^{® a)} Filler 212.6 mg Microcrystalline cellulose Filler 100.0 mg Sodium stearyl fumarate Lubricant 20.00 mg Opadei II White Coating 20.00 mg Total tablet weight    520.00 mg

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

All excipients used in formulations are of pharmacopoeial (Ph. Eur. and/or USP/NF) grade.

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

Examples 7 – 150 mg Tablet formulations Components Function Dosage (mg/tablet) Ralmitaront monohydrochloride Active ingredients 167.40 mg (equivalent to 150 mg of the free base) SMCC90 ^a) Filler 287.6 mg Cross-linked sodium carboxymethyl cellulose Disintegrants 25.00 mg Sodium stearyl fumarate Lubricant 20.00 mg Opadei II White Coating 20.00 mg Total tablet weight    520.00 mg

^a) SMCC90 is a commercially available excipient composed of silicified microcrystalline cellulose.

All excipients used in formulations are of pharmacopoeial (Ph. Eur. and/or USP/NF) grade.

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

Examples 8 – 45 mg Tablet formulations Components Function Dosage (mg/tablet) Ralmitaront monohydrochloride Active ingredients 50.22 mg (equivalent to 45 mg of the free base) Microcrystalline cellulose Filler 48.98 mg Lactose monohydrate Filler 34.30 mg Cross-linked sodium carboxymethyl cellulose Disintegrants 7.50 mg Sodium stearyl fumarate Slip agent 6.00 mg Colloidal silica Flow aids 3.00 mg Opadei II White Coating 6.00 mg Total tablet weight    156.00 mg

All excipients used in formulations are of pharmacopoeial (Ph. Eur. and/or USP/NF) grade.

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

Examples 9 – 45 mg Tablet formulations Components Function Dosage (mg/tablet) Ralmitaront monohydrochloride Active ingredients 50.22 mg (equivalent to 45 mg of the free base) MicroceLac ^® 100 ^a Filler 86.28 mg Cross-linked sodium carboxymethyl cellulose Disintegrants 7.50 mg Sodium stearyl fumarate Slip agent 6.00 mg Opadei II White Coating 6.00 mg Total tablet weight    156.00 mg

^a MicroceLac ^® 100 is a commercially available formulation consisting of co-processed microcrystalline cellulose and alpha-lactose monohydrate.

All excipients used in formulations are of pharmacopoeial (Ph. Eur. and/or USP/NF) grade.

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

Examples 10 – 45 mg Tablet formulations Components Function Dosage (mg/tablet) Ralmitaront monohydrochloride Active ingredients 50.22 mg (equivalent to 45 mg of the free base) Ludipress ^{® a)} Filler 63.78 mg Microcrystalline cellulose Filler 30.0 mg Sodium stearyl fumarate Lubricant 6.00 mg Opadei II White Coating 6.00 mg Total tablet weight    156.00 mg

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

All excipients used in formulations are of pharmacopoeial (Ph. Eur. and/or USP/NF) grade.

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

Examples 11 – 45 mg Tablet formulations Components Function Dosage (mg/tablet) Ralmitaront monohydrochloride Active ingredients 50.22 mg (equivalent to 45 mg of the free base) SMCC90 Filler 86.28 mg Cross-linked sodium carboxymethyl cellulose Disintegrants 7.50 mg Sodium stearyl fumarate Slip agent 6.00 mg Opadei II White Coating 6.00 mg Total tablet weight    156.00 mg

^a) SMCC90 is a commercially available excipient composed of silicified microcrystalline cellulose.

All excipients used in formulations are of pharmacopoeial (Ph. Eur. and/or USP/NF) grade.

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

FIG. 1 depicts a flow chart of a continuous small batch direct compression method according to the present invention described in Example 1. FIG. 2 depicts a flow chart of roller compaction according to the present invention described in Example 2. FIG. 3 depicts the effect 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. "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 attached to 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 "Mixed" tablet samples consist of a mixture of tablets from the middle and end of tableting.

Claims (20)

A tablet comprising: (i) a core; and (ii) a coating; wherein the core comprises an 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, (I); and wherein the core further comprises the following excipients: (i) a first filler; (ii) a second filler; (iii) a disintegrant; (iv) a glidant; and (v) a flow aid. The tablet of claim 1, wherein: (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; and (v)    the glidant is colloidal silicon dioxide. Tablets as claimed in claim 1 or 2, wherein: (i)     the weight of the first filler is 33% ± 1% of the total weight of the core; (ii)    the weight of the second filler is 23% ± 1% of the total weight of the core; (iii)   the weight of the disintegrant is 5% ± 1% of the total weight of the core; (iv)   the weight of the glidant is 4% ± 1% of the total weight of the core; (v)   the weight of the flow aid is 2% ± 1% of the total weight of the core; and (vi)   the weight of the compound of formula I or a pharmaceutically acceptable salt thereof is 33% ± 1% of the total weight of the core. A tablet comprising: (i) a core; and (ii) a coating; wherein the core comprises an 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, (I); and wherein the core further comprises the following excipients: (i) a filler; (ii) a disintegrant; and (iii) a glidant. A tablet as claimed in claim 4, wherein: (i) the filler is selected from MicroceLac ^® 100 and SMCC90; (ii) the disintegrant is cross-linked sodium carboxymethyl cellulose; and (iii) the glidant is sodium stearyl fumarate. Tablets as claimed in claim 4 or 5, wherein: (i)     the weight of the filler is 58% ± 1% of the total weight of the core; (ii)    the weight of the disintegrant is 5% ± 1% of the total weight of the core; (iii)   the weight of the glidant is 4% ± 1% of the total weight of the core; and (iv)   the weight of the compound of formula I or a pharmaceutically acceptable salt thereof is 33% ± 1% of the total weight of the core. A tablet comprising: (i) an inner core; and (ii) a coating; wherein the inner core comprises an 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, (I); and wherein the core further comprises the following shaping agents: (i) a first filler; (ii) a second filler; and (iii) a lubricant. A tablet as claimed in claim 7, wherein: (i) the first filler is ^Ludipress® ; (ii) the second filler is microcrystalline cellulose; and (iii) the lubricant is sodium stearyl fumarate. Tablets as claimed in claim 7 or 8, wherein: (i)     the weight of the first filler is 43% ± 1% of the total weight of the core; (ii)   the weight of the second filler is 20% ± 1% of the total weight of the core; (iii)   the weight of the lubricant is 4% ± 1% of the total weight of the core; (iv)   the weight of the compound of formula I or a pharmaceutically acceptable salt thereof is 33% ± 1% of the total weight of the core. A tablet according to any one of claims 1 to 9, comprising the compound of formula I in the form of a monohydrochloride salt. A tablet as claimed in any one of items 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. A method for manufacturing a tablet as claimed in any one of claims 1, 3, 10 and 11, 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 the first part of the lubricant and adding it to the blend from step (ii); (iv)   subjecting the blend from step (iii) to roller compaction to form granules; (v)   screening the second part 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 a film coating suspension on the tablet cores from step (vi). A continuous method for manufacturing a tablet as claimed in any one of claims 4 to 11, comprising: (i)     feeding the API and ingredients (i) to (iii) from four individual screw feeders into a blender; (ii)   blending the mixture of step (i); (iii)   pressing the blend from step (ii) into tablet cores; and (iv)   spraying a film coating suspension on the tablet cores from step (iii). A tablet as claimed in any one of claims 1 to 11, wherein the coating comprises: (i)     HPMC; (ii)    lactose monohydrate; (iii)  titanium dioxide; and (iv)  polyethylene glycol (macrogol). The tablet of 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. Tablets as claimed in any one of items 1 to 11, 14 and 15 are used as medicines. 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 diurnal rhythm disorders and/or cardiovascular disorders in a patient, comprising administering to the patient one or more tablets of any one of claims 1 to 11, 14 and 15. A tablet as claimed in any one of claims 1 to 11, 14 and 15, for use in the method as claimed in claim 17. Use of the tablet according to any one of claims 1 to 11, 14 and 15 in the method according to claim 17. The present invention as described above.