WO2024033459A1 - Pharmaceutical compositions comprising 5-ethyl-4-methyl- n-[4-[(2 s) morpholin-2-yl]phenyl]-1h-pyrazole-3-carboxamide - Google Patents
Pharmaceutical compositions comprising 5-ethyl-4-methyl- n-[4-[(2 s) morpholin-2-yl]phenyl]-1h-pyrazole-3-carboxamide Download PDFInfo
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- WO2024033459A1 WO2024033459A1 PCT/EP2023/072132 EP2023072132W WO2024033459A1 WO 2024033459 A1 WO2024033459 A1 WO 2024033459A1 EP 2023072132 W EP2023072132 W EP 2023072132W WO 2024033459 A1 WO2024033459 A1 WO 2024033459A1
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- XHHXGKRFUPEPFM-OAHLLOKOSA-N 5-ethyl-4-methyl-N-[4-[(2S)-morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide Chemical compound C(C)C1=C(C(=NN1)C(=O)NC1=CC=C(C=C1)[C@H]1CNCCO1)C XHHXGKRFUPEPFM-OAHLLOKOSA-N 0.000 title claims abstract description 19
- 239000008194 pharmaceutical composition Substances 0.000 title abstract description 9
- 238000000034 method Methods 0.000 claims abstract description 27
- 239000000203 mixture Substances 0.000 claims description 52
- 239000000945 filler Substances 0.000 claims description 46
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 38
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 25
- 239000007884 disintegrant Substances 0.000 claims description 21
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical group O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 claims description 15
- 239000011248 coating agent Substances 0.000 claims description 15
- 238000000576 coating method Methods 0.000 claims description 15
- 208000035475 disorder Diseases 0.000 claims description 14
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical group CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 14
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 14
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 13
- 150000001875 compounds Chemical class 0.000 claims description 13
- 239000000314 lubricant Substances 0.000 claims description 13
- 238000004519 manufacturing process Methods 0.000 claims description 13
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 13
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 13
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 12
- 229960001021 lactose monohydrate Drugs 0.000 claims description 11
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 10
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical group [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 9
- 239000008186 active pharmaceutical agent Substances 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 9
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 9
- 238000009490 roller compaction Methods 0.000 claims description 9
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims description 8
- 238000010924 continuous production Methods 0.000 claims description 8
- 239000007888 film coating Substances 0.000 claims description 6
- 238000009501 film coating Methods 0.000 claims description 6
- 239000008187 granular material Substances 0.000 claims description 6
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 6
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 6
- 238000012216 screening Methods 0.000 claims description 6
- 239000000725 suspension Substances 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 claims description 5
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 5
- 201000000980 schizophrenia Diseases 0.000 claims description 5
- 208000011117 substance-related disease Diseases 0.000 claims description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 4
- 229960003511 macrogol Drugs 0.000 claims description 4
- 238000005507 spraying Methods 0.000 claims description 4
- 201000009032 substance abuse Diseases 0.000 claims description 4
- 231100000736 substance abuse Toxicity 0.000 claims description 4
- 239000004408 titanium dioxide Substances 0.000 claims description 4
- 206010012335 Dependence Diseases 0.000 claims description 3
- 208000024827 Alzheimer disease Diseases 0.000 claims description 2
- 208000019901 Anxiety disease Diseases 0.000 claims description 2
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 claims description 2
- 208000020925 Bipolar disease Diseases 0.000 claims description 2
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 2
- 208000002249 Diabetes Complications Diseases 0.000 claims description 2
- 206010012655 Diabetic complications Diseases 0.000 claims description 2
- 208000032928 Dyslipidaemia Diseases 0.000 claims description 2
- 208000030814 Eating disease Diseases 0.000 claims description 2
- 208000019454 Feeding and Eating disease Diseases 0.000 claims description 2
- 206010020772 Hypertension Diseases 0.000 claims description 2
- 208000017170 Lipid metabolism disease Diseases 0.000 claims description 2
- 208000019695 Migraine disease Diseases 0.000 claims description 2
- 208000008589 Obesity Diseases 0.000 claims description 2
- 208000018737 Parkinson disease Diseases 0.000 claims description 2
- 230000036760 body temperature Effects 0.000 claims description 2
- 230000027288 circadian rhythm Effects 0.000 claims description 2
- 206010012601 diabetes mellitus Diseases 0.000 claims description 2
- 235000014632 disordered eating Nutrition 0.000 claims description 2
- 238000005265 energy consumption Methods 0.000 claims description 2
- 206010015037 epilepsy Diseases 0.000 claims description 2
- 230000013632 homeostatic process Effects 0.000 claims description 2
- 230000007257 malfunction Effects 0.000 claims description 2
- 206010027599 migraine Diseases 0.000 claims description 2
- 235000020824 obesity Nutrition 0.000 claims description 2
- 230000007958 sleep Effects 0.000 claims description 2
- 229940017792 ralmitaront Drugs 0.000 abstract description 12
- 238000002360 preparation method Methods 0.000 abstract description 2
- 239000003826 tablet Substances 0.000 description 58
- 238000009472 formulation Methods 0.000 description 22
- 201000010099 disease Diseases 0.000 description 11
- 239000007916 tablet composition Substances 0.000 description 11
- 101000890887 Homo sapiens Trace amine-associated receptor 1 Proteins 0.000 description 9
- 102100040114 Trace amine-associated receptor 1 Human genes 0.000 description 9
- 230000001404 mediated effect Effects 0.000 description 8
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 6
- 238000007907 direct compression Methods 0.000 description 6
- 239000000126 substance Chemical group 0.000 description 5
- 229940124531 pharmaceutical excipient Drugs 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000007906 compression Methods 0.000 description 3
- 230000006835 compression Effects 0.000 description 3
- 229960000913 crospovidone Drugs 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 3
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 229940069328 povidone Drugs 0.000 description 3
- GUBGYTABKSRVRQ-UHFFFAOYSA-N 2-(hydroxymethyl)-6-[4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxane-3,4,5-triol Chemical compound OCC1OC(OC2C(O)C(O)C(O)OC2CO)C(O)C(O)C1O GUBGYTABKSRVRQ-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 239000007941 film coated tablet Substances 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 229960001375 lactose Drugs 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 125000004312 morpholin-2-yl group Chemical group [H]N1C([H])([H])C([H])([H])OC([H])(*)C1([H])[H] 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 238000001694 spray drying Methods 0.000 description 2
- 238000005550 wet granulation Methods 0.000 description 2
- 229910002016 Aerosil® 200 Inorganic materials 0.000 description 1
- 208000017164 Chronobiology disease Diseases 0.000 description 1
- 229920003085 Kollidon® CL Polymers 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 239000008118 PEG 6000 Substances 0.000 description 1
- 229920002584 Polyethylene Glycol 6000 Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920003081 Povidone K 30 Polymers 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 description 1
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 239000007963 capsule composition Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000012777 commercial manufacturing Methods 0.000 description 1
- 238000005056 compaction Methods 0.000 description 1
- 229960005168 croscarmellose Drugs 0.000 description 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- 208000037765 diseases and disorders Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000013160 medical therapy Methods 0.000 description 1
- XKLJHFLUAHKGGU-UHFFFAOYSA-N nitrous amide Chemical compound ON=N XKLJHFLUAHKGGU-UHFFFAOYSA-N 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 238000004886 process control Methods 0.000 description 1
- 238000010963 scalable process Methods 0.000 description 1
- -1 schizophrenia Chemical compound 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/282—Organic compounds, e.g. fats
- A61K9/2826—Sugars or sugar alcohols, e.g. sucrose; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Definitions
- the present invention relates to pharmaceutical compositions comprising 5-ethyl-4- methyl-7V-[4-[(25) morpholin-2-yl]phenyl]-lH-pyrazole-3-carboxamide (Formula I), to processes for their preparation and their use in medical treatment.
- WO2017157873 discloses the TAAR1 agonist 5-ethyl-4-methyl-N-[4-[(2S) morpholin-2-yl]phenyl]-lH-pyrazole- 3-carboxamide (Formula I), which is useful for the treatment of certain diseases and disorders of the central nervous system.
- the compound of Formula I is also known under the INN ralmitaront (WHO Drug Information, Vol. 33, No. 2, 2019, p. 323).
- ralmitaront For some of the medical indications of ralmitaront, such as schizophrenia, small sized tablets are required to improve patient compliance. Small sized tablets require the provision of API-excipient blends with a high drug load, for example, a drug load of 30% wt/wt API.
- WO2017157873 discloses tablet and capsule formulations with high loads of ralmitaront. However, it was found that ralmitaront is cohesive and API-excipient blends containing it, especially in high amounts, do not flow well, making tablet production challenging. Additionally, the compound includes a secondary amine and a manufacturing process under high humidity conditions, such as wet granulation disclosed in WO2017157873 would increase the risk of nitrosamine formation.
- the present invention provides new formulation blends comprising a high load of ralmitaront that avoid the wet granulation described in WO2017157873. Some of the new blends are suitable for roller compaction, while others are suitable for continuous direct compression, in particular for continuous mini-batch direct compression. The present invention also provides new processes for manufacturing tablets comprising ralmitaront, as well as the use of said tablets in medical therapy.
- Figure 1 depicts a flow chart of the continuous mini-batch direct compression process according to the invention described in Example 1.
- Figure 2 depicts a flow chart of the roller compaction according to the invention described in Example 2.
- Figure 3 depicts the effect of the formulations represented by examples 5, 6 and 7, on the tablet tensile strength and Srel% (standard relative deviation of tablet weight) during the compaction process in the rotary press.
- Batch 1 refers to the formulation of Example 5
- batch 2 refers to the formulation of Example 6
- batch 3 refers to the formulation of Example 7.
- the tag that accompanies the batch number indicates on what tablet sample the measurement of the variables was made: “Start” means the tablet sample was collected at the start 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, “Mixed” the tablet sample is constituted by a mixture of tablets in the middle and end of tableting.
- dose strength relates to the absolute amount of the compound of Formula I in its free base form contained in a tablet formulation according to the invention, expressed in milligrams (mg). Consequently, if the compound of formula I is used in the form of a pharmaceutically acceptable salt, the term “dose strength” relates to the respective free base equivalent.
- ralmitaronf relates to 5-ethyl-4-methyl-A-[4-[(25) morpholin-2- yl]phenyl]-lH-pyrazole-3-carboxamide (Formula I), and pharmaceutically acceptable salts thereof, in particular the mono hydrochloric acid salt.
- 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, yet non-limiting examples of fillers are cellulose and lactose.
- disintegrant refers to a substance added to a pharmaceutical composition to help break apart (disintegrate), e.g., after administration, and release 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 croscarmellose sodium. A preferred, yet non-limiting example of a disintegrant is croscarmellose sodium.
- glidanf and “lubricant” are used herein interchangeably and refer to a substance added to a pharmaceutical composition to help reduce the adherence of a granule of powder 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, yet non-limiting example of a glidant is sodium stearyl fumarate.
- flow agent refers to a substance added to a pharmaceutical composition to enhance product flow by reducing interparticulate 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 and the like.
- a preferred, yet non-limiting example is silica, colloidal anhydrous.
- MicroceLac® refers to an excipient comprising 75% alpha-lactose monohydrate and 25 % microcrystalline cellulose, wherein said alpha-lactose monohydrate and microcrystalline cellulose have been co-processed by spray drying.
- SCC90 refers to an excipient comprising 98% microcrystalline cellulose and 2% colloidal silicon dioxide, wherein said microcrystalline cellulose and colloidal silicon dioxide have been co-processed by spray drying.
- Lupress® refers to an excipient comprising 93% lactose monohydrate, 3.5% povidone having a K- value of 30 (“Kollidon® 30”) and 3.5% crospovidone having a bulk density of 0.30 - 0.40 g/mL (“Kollidon® CL”).
- HPMC refers to hydroxypropylmethylcellulose.
- treating means an alleviation, in whole or in part, of a disorder, disease or condition, or one or more of the symptoms associated with a disorder, disease, or condition, or slowing or halting of further progression or worsening of those symptoms, or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself.
- the term “preventing” includes: preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a mammal and especially a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition.
- the term “patient” refers to a human.
- the present invention provides a tablet comprising:
- the tablet according to the invention comprises the compound of
- the dose 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.
- the dose strength of the tablet according to the invention is In a preferred embodiment, the dose strength of the tablet according to the invention is 150 mg.
- the coating of the tablet according to the invention comprises:
- HPMC represents 34% ⁇ 1% of the total weight of the coating
- lactose monohydrate represents 28% ⁇ 1% of the total weight of the coating
- titanium dioxide represents 26% ⁇ 1% of the total weight of the coating
- (iv) macrogol represents 12% ⁇ 1% of the total weight of the coating.
- the coating of the tablet according to the invention is Opadry II White.
- the kernel further comprises the following excipients:
- said filler is selected from MicroceLac® 100 and SMCC90;
- said disintegrant is croscarmellose sodium
- said glidant is sodium stearyl fumarate.
- said filler is MicroceLac® 100;
- said disintegrant is croscarmellose sodium
- said glidant is sodium stearyl fumarate.
- said disintegrant is croscarmellose sodium
- said glidant is sodium stearyl fumarate.
- the weight of said filler represents 58% ⁇ 1% of the total weight of the kernel
- the weight of said disintegrant represents 5% ⁇ 1% of the total weight of the kernel
- the weight of said glidant represents 4% ⁇ 1% of the total weight of the kernel
- the weight of said compound of Formula I, or a pharmaceutically acceptable salt thereof represents 33% ⁇ 1% of the total weight of the kernel.
- the kernel further comprises the following excipients:
- said first filler is Ludipress®
- said second filler is microcrystalline cellulose
- said lubricant is sodium stearyl fumarate.
- the weight of said first filler represents 43% ⁇ 1% of the total weight of the kernel
- the weight of said second filler represents 20% ⁇ 1% of the total weight of the kernel
- the weight of said lubricant represents 4% ⁇ 1% of the total weight of the kernel
- the weight of said compound of Formula I, or a pharmaceutically acceptable salt thereof represents 33% ⁇ 1% of the total weight of the kernel.
- the present invention provides a continuous process for manufacturing a tablet based on Formulation A or B described herein, comprising: (i) feeding the API and components (i)-(iii) from four individual screw feeders into a blender;
- step (ii) blending the mixture of step (i);
- step (iv) spraying a film coating suspension onto the tablet kernels from step (iii).
- the kernel further comprises the following excipients:
- said first filler is microcrystalline cellulose
- said second filler is lactose monohydrate
- said disintegrant is croscarmellose sodium
- said glidant is sodium stearyl fumarate
- said flow agent is colloidal silicon dioxide.
- the weight of said first filler represents 33% ⁇ 1% of the total weight of the kernel
- the weight of said second filler represents 23% ⁇ 1% of the total weight of the kernel
- the weight of said disintegrant represents 5% ⁇ 1% of the total weight of the kernel
- the weight of said glidant represents 4% ⁇ 1% of the total weight of the kernel
- the present invention provides a roller compaction process for manufacturing a tablet based on Formulation C described herein, comprising:
- step (iii) screening a 1 st portion of the lubricant and adding it to the blend from step (ii);
- step (iv) performing a roller compaction with the blend from step (iii) to form granules
- step (v) screening a 2 nd portion of the lubricant and adding it to the granules from step (iv);
- step (vi) compressing the blend from step (v) into tablet kernels
- step (vii) spraying a film coating suspension onto the tablet kernels from step (vi).
- the present invention provides a tablet as described herein, for use as a medicament.
- the present invention provides a method for treating or preventing a TAAR1(4) mediated disease in a patient, comprising administering one or more tablets described herein to the patient.
- the present invention provides a tablet described herein, for use in a method of treating or preventing a TAAR1(4) mediated disease in a patient.
- the present invention provides the use of a tablet described herein in a method of treating or preventing a TAAR1(4) mediated disease in a patient.
- said 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 consumption and assimilation, disorders and malfunction of body temperature homeostasis, disorders of sleep and circadian rhythm, and cardiovascular disorders.
- ADHD attention deficit hyperactivity disorder
- said TAAR1(4) mediated disease is selected from schizophrenia, substance abuse, and addiction. In a particularly preferred embodiment, said TAAR1(4) mediated disease is schizophrenia.
- said TAAR1(4) mediated disease is substance abuse.
- said TAAR1(4) mediated disease is addiction.
- Example 1 Tablet Formation from a Continuous Mini-Batch Direct Compression Process Equipment
- step 6. Prepare film coating suspension and spray film coat onto tablet cores obtained from step 4. Perform IPC on the average weight, thickness and disintegration time of film-coated tablets.
- the API is ralmitaront mono hydrochloride
- excipient (i) is a filler selected from MicroceLac® 100 and SMCC90
- excipient (ii) is a disintegrant being croscarmellose sodium
- excipient (iii) is a lubricant being sodium stearyl fumarate (see Examples 5, 7 and 9).
- the API is ralmitaront mono hydrochloride
- excipient (i) is a first filler being Ludipress®
- excipient (ii) is a second filler being microcrystalline cellulose
- excipient (iii) is a lubricant being sodium stearyl fumarate (see Example 6).
- Example 2 Tablet Formation from a Roller Compaction Process
- step 6. Perform tablet manufacturing with final blend obtained from step 5. Perform IPC on the individual tablet weight, hardness, thickness, friability and disintegration time for tablet cores.
- step 7. Prepare film coating suspension and spray film coat onto tablet cores obtained from step 6. Perform IPC on the average weight, thickness and disintegration time of film-coated tablets.
- MicroceLac® 100 is a commercially available excipient consisting of co-processed microcrystalline cellulose and alpha-lactose monohydrate. All excipients used in the formulation are compendial (Ph. Eur. and/or USP/NF) grade.
- the tablets may be manufactured according to the continuous process described in Example 1.
- Ludipress® is a commercially available excipient consisting of co-processed lactose monohydrate, povidone and crospovidone.
- the tablets may be manufactured according to the continuous process described in Example 1.
- SMCC90 is a commercially available excipient consisting of silicified microcrystalline cellulose.
- All excipients used in the formulation are compendial (Ph. Eur. and/or USP/NF) grade.
- the tablets may be manufactured according to the continuous process described in
- the tablets may be manufactured according to the process described in Example 2.
- MicroceLac® 100 is a commercially available excipient consisting of co-processed microcrystalline cellulose and alpha-lactose monohydrate.
- All excipients used in the formulation are compendial (Ph. Eur. and/or USP/NF) grade.
- the tablets may be manufactured according to the continuous process described in Example 1.
- Ludipress® is a commercially available excipient consisting of co-processed lactose monohydrate, povidone and crospovidone.
- All excipients used in the formulation are compendial (Ph. Eur. and/or USP/NF) grade.
- the tablets may be manufactured according to the continuous process described in
- SMCC90 is a commercially available excipient consisting of silicified microcrystalline cellulose.
- All excipients used in the formulation are compendial (Ph. Eur. and/or USP/NF) grade.
- the tablets may be manufactured according to the continuous process described in
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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 COMPOSITIONS COMPRISING 5-ETHYL-4-METHYL4V- [44(25) MORPHOLIN-2-YL]PHENYL]-lH-PYRAZOLE-3-CARBOXAMIDE
Field of the invention
The present invention relates to pharmaceutical compositions comprising 5-ethyl-4- methyl-7V-[4-[(25) morpholin-2-yl]phenyl]-lH-pyrazole-3-carboxamide (Formula I), to processes for their preparation and their use in medical treatment.
Background of the invention
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]-lH-pyrazole- 3-carboxamide (Formula I), which is useful for the treatment of certain diseases and disorders of the central nervous system.
The compound of Formula I is also known under the INN ralmitaront (WHO Drug Information, Vol. 33, No. 2, 2019, p. 323).
For some of the medical indications of ralmitaront, such as schizophrenia, small sized tablets are required to improve patient compliance. Small sized tablets require the provision of API-excipient blends with a high drug load, for example, a drug load of 30% wt/wt API. WO2017157873 discloses tablet and capsule formulations with high loads of ralmitaront. However, it was found that ralmitaront is cohesive and API-excipient blends containing it, especially in high amounts, do not flow well, making tablet production challenging. Additionally, the compound includes a secondary amine and a manufacturing process under high humidity conditions, such as wet granulation disclosed in WO2017157873 would increase the risk of nitrosamine formation.
Furthermore, it would be desirable to manufacture ralmitaront tablets in a continuous fashion, rather than in a conventional batch setup. Continuous manufacturing has commercial
manufacturing advantages, such as improved process control, reduced product handling, and real time release efficiencies. The overall result is a more robust, controllable, and scalable process that requires fewer process checks. However, it was found that the blends disclosed in WO2017157873 are not well suited for tablet production in a continuous manufacturing setup.
In summary, there is a high unmet need for new formulations comprising ralmitaront.
Summary of the invention
The present invention provides new formulation blends comprising a high load of ralmitaront that avoid the wet granulation described in WO2017157873. Some of the new blends are suitable for roller compaction, while others are suitable for continuous direct compression, in particular for continuous mini-batch direct compression. The present invention also provides new processes for manufacturing tablets comprising ralmitaront, as well as the use of said tablets in medical therapy.
Brief Description of the Figures
Figure 1 depicts a flow chart of the continuous mini-batch direct compression process according to the invention described in Example 1.
Figure 2 depicts a flow chart of the roller compaction according to the invention described in Example 2.
Figure 3 depicts the effect of the formulations represented by examples 5, 6 and 7, on the tablet tensile strength and Srel% (standard relative deviation of tablet weight) during the compaction process in the 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 that accompanies the batch number indicates on what tablet sample the measurement of the variables was made: “Start” means the tablet sample was collected at the start 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, “Mixed” the tablet sample is constituted by a mixture of tablets in the middle and end of tableting.
Detailed description of the invention
Definitions
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 of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the 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 its free base form contained in a tablet formulation according to the invention, expressed in milligrams (mg). Consequently, if the compound of formula I is used in the form of a pharmaceutically acceptable salt, the term “dose strength” relates to the respective free base equivalent.
As used herein, the term “ralmitaronf ’ relates to 5-ethyl-4-methyl-A-[4-[(25) morpholin-2- yl]phenyl]-lH-pyrazole-3-carboxamide (Formula I), and pharmaceutically acceptable salts thereof, in particular the mono hydrochloric acid salt.
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, yet 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 help break apart (disintegrate), e.g., after administration, and release 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 croscarmellose sodium. A preferred, yet non-limiting example of a disintegrant is croscarmellose sodium.
The terms “glidanf ’ and “lubricant” are used herein interchangeably and refer to a substance added to a pharmaceutical composition to help reduce the adherence of a granule of powder 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, yet non-limiting example of a glidant is sodium stearyl fumarate.
As used herein, the term “flow agent” refers to a substance added to a pharmaceutical composition to enhance product flow by reducing interparticulate 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 and the like. A preferred, yet non-limiting example is silica, colloidal anhydrous.
The term “MicroceLac®” refers to an excipient comprising 75% alpha-lactose monohydrate and 25 % microcrystalline cellulose, wherein said alpha-lactose monohydrate and microcrystalline cellulose have been co-processed by spray drying.
The term “SMCC90” refers to an excipient comprising 98% microcrystalline cellulose and 2% colloidal silicon dioxide, wherein said microcrystalline cellulose and colloidal silicon dioxide have been co-processed by spray drying.
The term “Ludipress®” refers to an excipient comprising 93% lactose monohydrate, 3.5% povidone having a K- value of 30 (“Kollidon® 30”) and 3.5% crospovidone having a bulk density of 0.30 - 0.40 g/mL (“Kollidon® CL”).
The term “HPMC” refers to hydroxypropylmethylcellulose.
As used herein, the term “treating” means an alleviation, in whole or in part, of a disorder, disease or condition, or one or more of the symptoms associated with a disorder, disease, or condition, or slowing or halting of further progression or worsening of those symptoms, or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself.
As used herein, the term “preventing” includes: preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a mammal and especially a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition.
As used herein, the term “patient” refers to a human.
Novel Tablet Formulation of Ralmitaront
In a first aspect, the present invention provides a tablet comprising:
(i) a kernel; and
(ii) a coating; wherein the kernel comprises the active ingredient 5-ethyl-4-methyl-N-[4-[(2S) morpholin- 2-yl]phenyl]-lH-pyrazole-3-carboxamide (Formula I), or a pharmaceutically acceptable salt thereof,
In one embodiment, the tablet according to the invention comprises the compound of
Formula I in the form of its mono hydrochloric acid salt.
In one embodiment, the dose 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.
In a preferred embodiment, the dose strength of the tablet according to the invention is
In a preferred embodiment, the dose strength of the tablet according to the invention is 150 mg.
In one embodiment, the coating of the tablet according to the invention comprises:
(i) HPMC;
(ii) lactose monohydrate;
(iii) titanium dioxide; and
(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; and
(iv) macrogol represents 12% ± 1% of the total weight of the coating.
In one embodiment, the coating of the tablet according to the invention is Opadry II White.
Formulation for Continuous Mini-Batch Direct Compression
Formulation A
In one embodiment of the tablet according to the invention, the kernel further comprises the following excipients:
(i) a filler;
(ii) a disintegrant; and
(iii) a glidant.
In one embodiment:
(i) said filler is selected from MicroceLac® 100 and SMCC90;
(ii) said disintegrant is croscarmellose sodium; and
(iii) said glidant is sodium stearyl fumarate.
In one embodiment:
(i) said filler is MicroceLac® 100;
(ii) said disintegrant is croscarmellose sodium; and
(iii) said glidant is sodium stearyl fumarate.
In one embodiment:
(i) said filler is SMCC90;
(ii) said disintegrant is croscarmellose sodium; and
(iii) said glidant is sodium stearyl fumarate.
In one embodiment:
(i) the weight of said filler represents 58% ± 1% of the total weight of the kernel;
(ii) the weight of said disintegrant represents 5% ± 1% of the total weight of the kernel;
(iii) the weight of said glidant represents 4% ± 1% of the total weight of the kernel; and
(iv) the weight of said compound of Formula I, or a pharmaceutically acceptable salt thereof, represents 33% ± 1% of the total weight of the kernel.
Formulation B
In one embodiment of the tablet according to the invention, the kernel further comprises the following excipients:
(i) a first filler;
(ii) a second filler; and
(iii) a lubricant.
In one embodiment:
(i) said first filler is Ludipress®;
(ii) said second filler is microcrystalline cellulose; and
(iii) said lubricant is sodium stearyl fumarate.
In one embodiment:
(i) the weight of said first filler represents 43% ± 1% of the total weight of the kernel;
(ii) the weight of said second filler represents 20% ± 1% of the total weight of the kernel;
(iii) the weight of said lubricant represents 4% ± 1% of the total weight of the kernel;
(iv) the weight of said compound of Formula I, or a pharmaceutically acceptable salt thereof, represents 33% ± 1% of the total weight of the kernel.
Continuous Mini-Batch Direct Compression
In one aspect, the present invention provides a continuous process for manufacturing a tablet based on Formulation A or B described herein, comprising:
(i) feeding the API and components (i)-(iii) from four individual screw feeders into a blender;
(ii) blending the mixture of step (i);
(iii) compressing the blend from step (ii) into tablet kernels; and
(iv) spraying a film coating suspension onto the tablet kernels from step (iii).
Formulation for Roller Compaction
Formulation C
In one embodiment of the tablet according to the invention, the kernel further comprises the following excipients:
(i) a first filler;
(ii) a second filler;
(iii) a disintegrant;
(iv) a glidant; and
(v) a flow agent.
In one embodiment:
(i) said first filler is microcrystalline cellulose;
(ii) said second filler is lactose monohydrate;
(iii) said disintegrant is croscarmellose sodium;
(iv) said glidant is sodium stearyl fumarate; and
(v) said flow agent is colloidal silicon dioxide.
In one embodiment:
(i) the weight of said first filler represents 33% ± 1% of the total weight of the kernel;
(ii) the weight of said second filler represents 23% ± 1% of the total weight of the kernel;
(iii) the weight of said disintegrant represents 5% ± 1% of the total weight of the kernel;
(iv) the weight of said glidant represents 4% ± 1% of the total weight of the kernel;
(v) the weight of said flow agent represents 2% ± 1% of the total weight of the kernel; and
(vi) the weight of said compound of Formula I, or a pharmaceutically acceptable salt thereof, represents 33% ± 1% of the total weight of the kernel.
Roller Compaction
In one aspect, the present invention provides a roller compaction process for manufacturing a tablet based on Formulation C described herein, comprising:
(i) blending the API, first filler, second filler, disintegrant, and glidant;
(ii) screening the blend obtained from step (i);
(iii) screening a 1st portion of the lubricant and adding it to the blend from step (ii);
(iv) performing a roller compaction with the blend from step (iii) to form granules;
(v) screening a 2nd portion of the lubricant and adding it to the granules from step (iv);
(vi) compressing the blend from step (v) into tablet kernels; and
(vii) spraying a film coating suspension onto the tablet kernels from step (vi).
Uses
In one aspect, the present invention provides a tablet as described herein, for use as a medicament.
In one aspect, the present invention provides a method for treating or preventing a TAAR1(4) mediated disease in a patient, comprising administering one or more tablets described herein to the patient.
In one aspect, the present invention provides a tablet 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 the use of a tablet described herein in a method of treating or preventing a TAAR1(4) mediated disease in a patient.
In one embodiment, said 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 consumption and assimilation, disorders and malfunction of body temperature homeostasis, disorders of sleep and circadian rhythm, and cardiovascular disorders.
In a preferred embodiment, said TAAR1(4) mediated disease is selected from schizophrenia, substance abuse, and addiction.
In a particularly preferred embodiment, said TAAR1(4) mediated disease is schizophrenia.
In a particularly preferred embodiment, said TAAR1(4) mediated disease is substance abuse.
In a particularly preferred embodiment, said TAAR1(4) mediated disease is addiction. Examples
The following examples are provided for illustration of the invention. They should not be considered as limiting the scope of the invention, but merely as being representative thereof.
Example 1 — Tablet Formation from a Continuous Mini-Batch Direct Compression Process Equipment
Process
1. Feeding of excipient (i) from the large feeder; and API, excipient (ii), and excipient (iii) from the three small feeders into the mini-batch blender.
2. Blending of the mini-batch in the mini-batch blender.
3. Discharge into the tablet press the mini-batch prepared in steps 1 and 2.
4. Press tablet cores. Perform IPC on the individual tablet weight, hardness, thickness, friability and disintegration time for tablet cores.
5. Repeat steps 1 to 4 as needed to manufacture the desired final batch.
6. Prepare film coating suspension and spray film coat onto tablet cores obtained from step 4. Perform IPC on the average weight, thickness and disintegration time of film-coated tablets.
In one embodiment, the API is ralmitaront mono hydrochloride, excipient (i) is a filler selected from MicroceLac® 100 and SMCC90; excipient (ii) is a disintegrant being croscarmellose sodium; and excipient (iii) is a lubricant being sodium stearyl fumarate (see Examples 5, 7 and 9).
In one embodiment, the API is ralmitaront mono hydrochloride, excipient (i) is a first filler being Ludipress®; excipient (ii) is a second filler being microcrystalline cellulose; and excipient (iii) is a lubricant being sodium stearyl fumarate (see Example 6).
A schematic overview of this process is provided in Figure 1.
Example 2 — Tablet Formation from a Roller Compaction Process
Equipment
Process
1. Weigh API, Microcrystalline Cellulose, Lactose Monohydrate, Croscarmellose and Colloidal Silicon Dioxide and blend.
2. Screen the obtained blend from step 1.
3. Screen 50% of total amount of Sodium Stearyl Fumarate, add it to the powder blend from step 2 and blend.
4. Perform a roller compaction with the blend.
5. Screen remaining 50% of total amount of Sodium Stearyl Fumarate, add it to the granule from step 4 and blend.
6. Perform tablet manufacturing with final blend obtained from step 5. Perform IPC on the individual tablet weight, hardness, thickness, friability and disintegration time for tablet cores.
7. Prepare film coating suspension and spray film coat onto tablet cores obtained from step 6. Perform IPC on the average weight, thickness and disintegration time of film-coated tablets.
A schematic overview of this process is provided in Figure 2.
Example 3 — Comparison of Different Fillers for Continuous Mini-Batch Direct
Compression
Comparison of the three formulations of examples 5, 6 and 7 surprisingly showed that a blend comprising the filler SMCC90 (Example 7) afforded stronger tablets than comparable blends comprising MicroceLac® 100 (Example 5) or Ludipress® (Example 6). In addition, the standard relative deviation of main compression force (“Srel”) during the tablet compression was lower when using SMCC90 in the blend, compared to when using MicroceLac® 100 or Ludipress®. In other words, the blend described in Example 7, comprising SMCC90 as a filler, yields tablets of higher quality, i.e. stronger tablets, and makes the tabletting process more stable, i.e., reduces the Srel, compared to the blends described in Examples 5 and 6. This is illustrated in Figure 3.
Example 4 — 150 mg Tablet Formulation
All excipients used in the formulation are compendial (Ph. Eur. and/or USP/NF) grade.
The tablets may be manufactured according to the process described in Example 2. Example 5 — Alternative 150 mg Tablet Formulation
a) MicroceLac® 100 is a commercially available excipient consisting of co-processed microcrystalline cellulose and alpha-lactose monohydrate.
All excipients used in the formulation are compendial (Ph. Eur. and/or USP/NF) grade.
The tablets may be manufactured according to the continuous process described in Example 1.
Example 6 — Alternative 150 mg Tablet Formulation
a) Ludipress® is a commercially available excipient consisting of co-processed lactose monohydrate, povidone and crospovidone.
All excipients used in the formulation are compendial (Ph. Eur. and/or USP/NF) grade.
The tablets may be manufactured according to the continuous process described in Example 1.
Example 7 — Alternative 150 mg Tablet Formulation
a) SMCC90 is a commercially available excipient consisting of silicified microcrystalline cellulose.
All excipients used in the formulation are compendial (Ph. Eur. and/or USP/NF) grade. The tablets may be manufactured according to the continuous process described in
Example 1.
Example 8 — 45 mg Tablet Formulation
All excipients used in the formulation are compendial (Ph. Eur. and/or USP/NF) grade.
The tablets may be manufactured according to the process described in Example 2.
Example 9 - Alternative 45 mg Tablet Formulation
a MicroceLac® 100 is a commercially available excipient consisting of co-processed microcrystalline cellulose and alpha-lactose monohydrate.
All excipients used in the formulation are compendial (Ph. Eur. and/or USP/NF) grade. The tablets may be manufactured according to the continuous process described in Example 1.
Example 10 — Alternative 45 mg Tablet Formulation
a) Ludipress® is a commercially available excipient consisting of co-processed lactose monohydrate, povidone and crospovidone.
All excipients used in the formulation are compendial (Ph. Eur. and/or USP/NF) grade. The tablets may be manufactured according to the continuous process described in
Example 1.
Example 11 — Alternative 45 mg Tablet Formulation
a) SMCC90 is a commercially available excipient consisting of silicified microcrystalline cellulose.
All excipients used in the formulation are compendial (Ph. Eur. and/or USP/NF) grade. The tablets may be manufactured according to the continuous process described in
Example 1.
Claims
Claims
1. A tablet comprising:
(i) a kernel; and
(ii) a coating; wherein the kernel comprises the active ingredient 5-ethyl-4-methyl-N-[4-[(2S) morpholin-
2-yl]phenyl]-lH-pyrazole-3-carboxamide (Formula I), or a pharmaceutically acceptable salt thereof,
and wherein the kernel further comprises the following excipients:
(i) a first filler;
(ii) a second filler;
(iii) a disintegrant;
(iv) a glidant; and
(v) a flow agent.
2. The tablet according to claim 1, wherein:
(i) said first filler is microcrystalline cellulose;
(ii) said second filler is lactose monohydrate;
(iii) said disintegrant is croscarmellose sodium;
(iv) said glidant is sodium stearyl fumarate; and
(v) said flow agent is colloidal silicon dioxide.
3. The tablet according to claim 1 or 2, wherein:
(i) the weight of said first filler represents 33% ± 1% of the total weight of the kernel;
(ii) the weight of said second filler represents 23% ± 1% of the total weight of the kernel;
(iii) the weight of said disintegrant represents 5% ± 1% of the total weight of the kernel;
(iv) the weight of said glidant represents 4% ± 1% of the total weight of the kernel;
(v) the weight of said flow agent represents 2% ± 1% of the total weight of the kernel; and
(vi) the weight of said compound of Formula I, or a pharmaceutically acceptable salt thereof, represents 33% ± 1% of the total weight of the kernel. A tablet comprising:
(i) a kernel; and
(ii) a coating; wherein the kernel comprises the active ingredient 5-ethyl-4-methyl-N-[4-[(2S) morpholin- 2-yl]phenyl]-lH-pyrazole-3-carboxamide (Formula I), or a pharmaceutically acceptable salt thereof,
and wherein the kernel further comprises the following excipients:
(i) a filler;
(ii) a disintegrant; and
(iii) a glidant. The tablet according to claim 4, wherein:
(i) said filler is selected from MicroceLac® 100 and SMCC90;
(ii) said disintegrant is croscarmellose sodium; and
(iii) said glidant is sodium stearyl fumarate. The tablet according to claim 4 or 5, wherein:
(i) the weight of said filler represents 58% ± 1% of the total weight of the kernel;
(ii) the weight of said disintegrant represents 5% ± 1% of the total weight of the kernel;
(iii) the weight of said glidant represents 4% ± 1% of the total weight of the kernel; and
(iv) the weight of said compound of Formula I, or a pharmaceutically acceptable salt thereof, represents 33% ± 1% of the total weight of the kernel. A tablet comprising:
(i) a kernel; and
(ii) a coating; wherein the kernel comprises the active ingredient 5-ethyl-4-methyl-N-[4-[(2S) morpholin- 2-yl]phenyl]-lH-pyrazole-3-carboxamide (Formula I), or a pharmaceutically acceptable salt thereof,
and wherein the kernel further comprises the following excipients:
(i) a first filler;
(ii) a second filler; and
(iii) a lubricant. The tablet according to claim 7, wherein:
(i) said first filler is Ludipress®;
(ii) said second filler is microcrystalline cellulose; and
(iii) said lubricant is sodium stearyl fumarate. The tablet according to claim 7 or 8, wherein:
(i) the weight of said first filler represents 43% ± 1% of the total weight of the kernel;
(ii) the weight of said second filler represents 20% ± 1% of the total weight of the kernel;
(iii) the weight of said lubricant represents 4% ± 1% of the total weight of the kernel;
(iv) the weight of said compound of Formula I, or a pharmaceutically acceptable salt thereof, represents 33% ± 1% of the total weight of the kernel.
10. The tablet according to any one of claims 1 to 9, comprising the compound of Formula I in the form of its mono hydrochloric acid salt.
11. The tablet according to any one of claims 1 to 10, wherein the dose strength is 40 mg to 160 mg, preferably 45 mg to 150 mg, more preferably 45 mg or 150 mg.
12. A process for manufacturing a tablet according to any one of claims 1, 3, 10 and 11, comprising:
(i) blending the API, first filler, second filler, disintegrant, and glidant;
(ii) screening the blend obtained from step (i);
(iii) screening a 1st portion of the lubricant and adding it to the blend from step (ii);
(iv) performing a roller compaction with the blend from step (iii) to form granules;
(v) screening a 2nd portion of the lubricant and adding it to the granules from step (iv);
(vi) compressing the blend from step (v) into tablet kernels; and
(vii) spraying a film coating suspension onto the tablet kernels from step (vi).
13. A continuous process for manufacturing a tablet according to any one of claims 4 to 11, comprising:
(i) feeding the API and components (i)-(iii) from four individual screw feeders into a blender;
(ii) blending the mixture of step (i);
(iii) compressing the blend from step (ii) into tablet kernels; and
(iv) spraying a film coating suspension onto the tablet kernels from step (iii).
14. The tablet according to any one of claims 1 to 11, wherein the coating comprises:
(i) HPMC;
(ii) lactose monohydrate;
(iii) titanium dioxide; and
(iv) macrogol.
15. The tablet according to claim 14, wherein:
(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; and
(iv) macrogol represents 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 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 consumption and assimilation, disorders and malfunction of body temperature homeostasis, disorders of sleep and circadian rhythm, and/or cardiovascular disorders in a patient, comprising administering one or more tablets according to any one of claims 1 to 11, 14 and 15, to the patient. 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. 0. The invention as described hereinbefore.
***
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP22190194 | 2022-08-12 | ||
| EP22190194.5 | 2022-08-12 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2024033459A1 true WO2024033459A1 (en) | 2024-02-15 |
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ID=82932411
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP2023/072132 WO2024033459A1 (en) | 2022-08-12 | 2023-08-10 | Pharmaceutical compositions comprising 5-ethyl-4-methyl- n-[4-[(2 s) morpholin-2-yl]phenyl]-1h-pyrazole-3-carboxamide |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2024033459A1 (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012168260A1 (en) * | 2011-06-09 | 2012-12-13 | F. Hoffmann-La Roche Ag | Pyrazole derivatives |
| WO2017157873A1 (en) | 2016-03-17 | 2017-09-21 | F. Hoffmann-La Roche Ag | 5-ethyl-4-methyl-pyrazole-3-carboxamide derivative having activity as agonist of taar |
| WO2021185878A1 (en) * | 2020-03-19 | 2021-09-23 | F. Hoffmann-La Roche Ag | Salts and crystalline forms of a taar1 agonist |
-
2023
- 2023-08-10 WO PCT/EP2023/072132 patent/WO2024033459A1/en unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012168260A1 (en) * | 2011-06-09 | 2012-12-13 | F. Hoffmann-La Roche Ag | Pyrazole derivatives |
| WO2017157873A1 (en) | 2016-03-17 | 2017-09-21 | F. Hoffmann-La Roche Ag | 5-ethyl-4-methyl-pyrazole-3-carboxamide derivative having activity as agonist of taar |
| WO2021185878A1 (en) * | 2020-03-19 | 2021-09-23 | F. Hoffmann-La Roche Ag | Salts and crystalline forms of a taar1 agonist |
Non-Patent Citations (2)
| Title |
|---|
| SHESKEY ET AL.: "Handbook of Pharmaceutical Excipients", 2017, article "Remington's Pharmaceutical Sciences" |
| WHO DRUG INFORMATION, vol. 33, no. 2, 2019, pages 323 |
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