NZ717137B2 - Solid dosage forms of (s)-ethyl 2-amino-3-(4-(2-amino-6-((r)-1-(4-chloro-2-(3-methyl-1h-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate - Google Patents
Solid dosage forms of (s)-ethyl 2-amino-3-(4-(2-amino-6-((r)-1-(4-chloro-2-(3-methyl-1h-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate Download PDFInfo
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- NZ717137B2 NZ717137B2 NZ717137A NZ71713712A NZ717137B2 NZ 717137 B2 NZ717137 B2 NZ 717137B2 NZ 717137 A NZ717137 A NZ 717137A NZ 71713712 A NZ71713712 A NZ 71713712A NZ 717137 B2 NZ717137 B2 NZ 717137B2
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- NZ
- New Zealand
- Prior art keywords
- tablet
- phenyl
- amino
- trifluoroethoxy
- tablets
- Prior art date
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- 239000007909 solid dosage form Substances 0.000 title description 6
- MDSQOJYHHZBZKA-GBXCKJPGSA-N ethyl (2S)-2-amino-3-[4-[2-amino-6-[(1R)-1-[4-chloro-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoroethoxy]pyrimidin-4-yl]phenyl]propanoate Chemical compound C1=CC(C[C@H](N)C(=O)OCC)=CC=C1C1=CC(O[C@H](C=2C(=CC(Cl)=CC=2)N2N=C(C)C=C2)C(F)(F)F)=NC(N)=N1 MDSQOJYHHZBZKA-GBXCKJPGSA-N 0.000 title description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims abstract description 43
- 229920002785 Croscarmellose sodium Polymers 0.000 claims abstract description 23
- 229960001681 Croscarmellose Sodium Drugs 0.000 claims abstract description 22
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims abstract description 22
- 235000019359 magnesium stearate Nutrition 0.000 claims abstract description 22
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 18
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound 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 GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims abstract description 17
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 claims abstract description 12
- QIAFMBKCNZACKA-UHFFFAOYSA-M N-benzoylglycinate Chemical class [O-]C(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-UHFFFAOYSA-M 0.000 claims abstract description 12
- 239000008101 lactose Substances 0.000 claims abstract description 12
- XBDQKXXYIPTUBI-UHFFFAOYSA-N propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229920002678 cellulose Polymers 0.000 claims abstract description 10
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims abstract description 10
- 239000001913 cellulose Substances 0.000 claims abstract description 9
- 235000010980 cellulose Nutrition 0.000 claims abstract description 9
- -1 hydroxyl propyl Chemical group 0.000 claims abstract description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 6
- FYYHWMGAXLPEAU-UHFFFAOYSA-N magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 5
- 239000011777 magnesium Substances 0.000 claims description 5
- 229910052749 magnesium Inorganic materials 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims 2
- 229940091250 Magnesium supplements Drugs 0.000 claims 1
- NCLGDOBQAWBXRA-PGRDOPGGSA-N (2S)-2-amino-3-[4-[2-amino-6-[(1R)-1-[4-chloro-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoroethoxy]pyrimidin-4-yl]phenyl]propanoic acid Chemical compound N1=C(C)C=CN1C1=CC(Cl)=CC=C1[C@H](C(F)(F)F)OC1=CC(C=2C=CC(C[C@H](N)C(O)=O)=CC=2)=NC(N)=N1 NCLGDOBQAWBXRA-PGRDOPGGSA-N 0.000 abstract description 29
- 229950002246 Telotristat Drugs 0.000 abstract description 28
- 229940057948 Magnesium stearate Drugs 0.000 abstract description 17
- 239000002552 dosage form Substances 0.000 abstract description 15
- 150000003839 salts Chemical class 0.000 abstract description 10
- 239000011780 sodium chloride Substances 0.000 abstract description 10
- 239000007787 solid Substances 0.000 abstract description 3
- 239000000203 mixture Substances 0.000 description 33
- 239000008186 active pharmaceutical agent Substances 0.000 description 21
- 238000005469 granulation Methods 0.000 description 17
- 230000003179 granulation Effects 0.000 description 17
- 239000004615 ingredient Substances 0.000 description 14
- 238000009472 formulation Methods 0.000 description 13
- 239000008187 granular material Substances 0.000 description 10
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 9
- XAPRFLSJBSXESP-UHFFFAOYSA-N Oxycinchophen Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=C(O)C=1C1=CC=CC=C1 XAPRFLSJBSXESP-UHFFFAOYSA-N 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 9
- 239000002274 desiccant Substances 0.000 description 9
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 9
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 9
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 9
- 238000000634 powder X-ray diffraction Methods 0.000 description 9
- XSFPZBUIBYMVEA-CELUQASASA-N 2-benzamidoacetic acid;ethyl (2S)-2-amino-3-[4-[2-amino-6-[(1R)-1-[4-chloro-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoroethoxy]pyrimidin-4-yl]phenyl]propanoate Chemical compound OC(=O)CNC(=O)C1=CC=CC=C1.C1=CC(C[C@H](N)C(=O)OCC)=CC=C1C1=CC(O[C@H](C=2C(=CC(Cl)=CC=2)N2N=C(C)C=C2)C(F)(F)F)=NC(N)=N1 XSFPZBUIBYMVEA-CELUQASASA-N 0.000 description 8
- 238000007906 compression Methods 0.000 description 8
- 229950011306 telotristat etiprate Drugs 0.000 description 8
- 229960004543 Anhydrous Citric Acid Drugs 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000009490 roller compaction Methods 0.000 description 6
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 6
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 5
- 238000004090 dissolution Methods 0.000 description 5
- 239000011888 foil Substances 0.000 description 5
- 235000019589 hardness Nutrition 0.000 description 5
- 238000006460 hydrolysis reaction Methods 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 229940016286 microcrystalline cellulose Drugs 0.000 description 5
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 5
- 239000008108 microcrystalline cellulose Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000007884 disintegrant Substances 0.000 description 4
- 239000012458 free base Substances 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 239000000377 silicon dioxide Substances 0.000 description 4
- 235000012239 silicon dioxide Nutrition 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 229960000913 Crospovidone Drugs 0.000 description 3
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinylpyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 3
- 238000004166 bioassay Methods 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 230000004059 degradation Effects 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 238000009507 drug disintegration testing Methods 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 3
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 3
- 235000019260 propionic acid Nutrition 0.000 description 3
- 229960001866 silicon dioxide Drugs 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 230000004584 weight gain Effects 0.000 description 3
- 235000019786 weight gain Nutrition 0.000 description 3
- 229920004439 Aclar® Polymers 0.000 description 2
- 229960001375 Lactose Drugs 0.000 description 2
- 229940076279 Serotonin Drugs 0.000 description 2
- 238000004140 cleaning Methods 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 230000003247 decreasing Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 238000005461 lubrication Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000005023 polychlorotrifluoroethylene (PCTFE) polymer Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 239000012086 standard solution Substances 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-M stearate Chemical compound CCCCCCCCCCCCCCCCCC([O-])=O QIQXTHQIDYTFRH-UHFFFAOYSA-M 0.000 description 2
- 229940114926 stearate Drugs 0.000 description 2
- 239000007916 tablet composition Substances 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 description 1
- 230000036912 Bioavailability Effects 0.000 description 1
- 206010007270 Carcinoid syndrome Diseases 0.000 description 1
- 229960005168 Croscarmellose Drugs 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 208000002551 Irritable Bowel Syndrome Diseases 0.000 description 1
- 230000035536 Oral bioavailability Effects 0.000 description 1
- XMVJITFPVVRMHC-UHFFFAOYSA-N Roxarsone Chemical compound OC1=CC=C([As](O)(O)=O)C=C1[N+]([O-])=O XMVJITFPVVRMHC-UHFFFAOYSA-N 0.000 description 1
- 102000005506 Tryptophan Hydroxylase Human genes 0.000 description 1
- 108010031944 Tryptophan Hydroxylase Proteins 0.000 description 1
- 240000006802 Vicia sativa Species 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000035514 bioavailability Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000007963 capsule composition Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- 238000010192 crystallographic characterization Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drugs Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229920001903 high density polyethylene Polymers 0.000 description 1
- 239000004700 high-density polyethylene Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N lactose group Chemical group OC1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O)[C@H](O2)CO)[C@H](O1)CO GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 230000036220 oral bioavailability Effects 0.000 description 1
- 239000005022 packaging material Substances 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 229940080313 sodium starch Drugs 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 230000001225 therapeutic Effects 0.000 description 1
- 125000003652 trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- 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
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- 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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
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- 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
- A61K9/2893—Tablet coating processes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
Provided are solid pharmaceutical dosage forms comprising (S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate (telotristat)or a pharmaceutically acceptable salt thereof. In a preferred embodiment the dosage form is a tablet made from intragranular and extragranular components, wherein the intragranular components consist of the hippurate salt of telotristat, lactose anhydrous, hydroxyl propyl cellulose, croscarmellose sodium, magnesium stearate, and the extragranular components consist of lactose anhydrous, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate. is a tablet made from intragranular and extragranular components, wherein the intragranular components consist of the hippurate salt of telotristat, lactose anhydrous, hydroxyl propyl cellulose, croscarmellose sodium, magnesium stearate, and the extragranular components consist of lactose anhydrous, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate.
Description
SOLID DOSAGE FORMS OF (S)—ETHYL O—3—(4—(2—AMINO—6—((R)—1—(4—
—2—(3—M ETHYL—1H—PYRAZOL—1—YL)PHENYL)—2,2,2—
TRIFLUOROETHOXY)PYRIM|DIN—4—YL)PHENYL)PROPANOATE
This application claims priority to US. provisional patent application no. 61/547,894,
filed October 17, 2011, the entirety of which is incorporated herein by reference.
1. FIELD OF THE INVENTION
This invention relates to solid pharmaceutical dosage forms of (S)—ethyl 2-amino—3—(4—
(2-amino-6—((R)—1—(4-chloro(3—methyl-1H-pyrazolyl)phenyl)—2,2,2-trifluoroethoxy)pyrimidin-
4-yl)phenyl)propanoate (telotristat).
2. BACKGROUND OF THE INVENTION
The compound (S)-ethyl 2-amino(4-(2-amino((R)-1—(4-chloro(3-methyl-1H-
lyl)phenyl)—2,2,2-trifluoroethoxy)pyrimidinyl)phenyl)propanoate (telotristat) is an
inhibitor of tryptophan hydroxylase, the enzyme responsible for the imiting step in
thesis of 5-hydroxytryptamine (serotonin). See, e.g., US. patent no. 493. The
compound is believed to be useful in the treatment of diseases and ers associated
with abnormal levels of serotonin, such as diarrhea-predominant irritable bowel me
and carcinoid syndrome. Unfortunately, telotristat’s physicochemical properties make its
incorporation into a commercially viable dosage form difficult.
Telotristat hydrolyzes when contacted with water. Dosage forms comprising it must,
2O therefore, limit this degradation as much as possible, and must be made using methods that
limit the compounds re to moisture. The poor flowability of telotristat’s crystalline
hippurate salt (telotristat etiprate) further complicates the manufacture of dosage forms
comprising it. Further adding to the problem is the desire to provide single unit dosage forms
that contain at least 100 mg of the compound, and that rapidly release it upon oral
administration.
In view of these factors, a need exists for solid dosage forms of telotristat that can be
stored at typical temperatures and humidity levels for a commercially viable period of time,
and for s of their manufacture. Preferred dosage forms should be capable of rapidly
delivering the compound upon oral administration. A particular need exists for a rapid
release tablet formulation of telotristat with good chemical stability, actory oral
bioavailability, good processability, and high drug loading.
3. SUMMARY OF THE INVENTION
This invention is directed to solid dosage forms of telotristat. Particular dosage forms
are tablets made with the hippurate salt of telotristat (telotristat etiprate).
One embodiment of the invention encompasses a tablet suitable for administration to
a patient comprising at least 100, 200, or 300 mg of an active pharmaceutical ingredient
(API), which tablet has a disintegration time of less than 10, 5.0, 2.3, 2.0, or 1.8 s in
water, wherein the API is telotristat or a pharmaceutically acceptable salt thereof.
Another embodiment encompasses a tablet suitable for stration to a patient
comprising at least 100, 200, or 300 mg of an API based on free base, which tablet
comprises acoating and has a disintegration time of less than 5.5, 4.5, or 4.0 s in
water, wherein the API is telotristat or a pharmaceutically acceptable salt thereof.
Another embodiment encompasses a tablet having a core consisting essentially of
telotristat hippurate, e, hyrdroxy propyl cellulose, rmellose sodium, magnesium
stearate, and silicon dioxide.
Another embodiment encompasses a tablet comprising telotristat or a
pharmaceutically acceptable salt thereof, which forms less than 1.0, 0.8 or 0.5 percent (S)-2—
amino-3—(4—(2—amino-6—((R)-1—(4-chloro(3—methyl-1H-pyrazol-l—yl)phenyl)—2,2,2—
trifluoroethoxy)pyrimidinyl)phenyl)propanoic acid when stored at about 40°C and about
75% relative humidity for six months.
r embodiment encompasses a tablet comprising telotristat or a
pharmaceutically acceptable salt thereof, which forms less than 0.5 or 0.4 percent (S)—2—
amino-3—(4—(2—amino-6—((R)-1—(4-chloro(3—methyl-1H-pyrazol-l—yl)phenyl)—2,2,2—
2O trifluoroethoxy)pyrimidinyl)phenyl)propanoic acid when stored at about 40°C and about
75% relative humidity for three months.
Another embodiment encompasses a granule sing telotristat etiprate, e,
hydroxyl propyl cellulose, croscarmellose , magnesium stearate, and silicon dioxide.
Another embodiment encompasses a method of making a , which comprises:
combining es comprising intragranular ingredients with at least one extragranular
ingredient, and compressing the granules to provide a tablet; wherein the ranular
ingredients comprise telotristat or a pharmaceutically acceptable salt thereof, magnesium
stearate, and lactose; and at least one extragranular ingredient is lactose.
4. BRIEF DESCRIPTION OF THE FIGURES
3O Certain aspects of the invention can be understood with reference to the appended
figures.
Figure 1 shows an X—ray powder diffraction (XRPD) pattern of a crystalline form of
telotristat. The diffractogram was obtained using a Rigaku ex diffractometer (copper
Kor radiation).
Figure 2 provides an XRPD pattern of a crystalline form of telotristat etiprate. The
diffractogram was ed using a Bruker D8 Advance (copper Kor radiation).
Figure 3 shows the effects of temperature, humidity and time on the formation of the
hydrolysis product (S)—2-amino—3-(4-(-2amino--((R)(-4c-h-loro2--(-3methyl-1H--p-yrazol1--
yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidinyl)phenyl)propanoic acid in different dosage forms
of telotristat.
. DETAILED DESCRIPTION OF THE INVENTION
This invention is directed to solid pharmaceutical dosage forms in which an active
pharmaceutical ingredient (API) is (S)—ethyl 2-amino(4-(2-amino---6((R)(c-hloro2--(3-
methyl-1H-pyrazolyl)phenyl)-2,2,2-trifluoroethoxy)pyrimidinyl)phenyl)propanoate
ristat):
/ /N
MONE
or a pharmaceutically acceptable salt thereof. The compound, its salts and lline forms
can be ed by methods known in the art. See, e.g., U.S. patent no. 7,709,493.
Particular dosage forms comprise crystalline telotristat freebase. One form of this
compound has a melting point of about 104°C as determined by differential scanning
metry (DSC) (onset temperature). As used in connection with DSC temperatures, the
term “about” means 13°C. This form es an X-ray powder diffraction (XRPD) n
that contains peaks at about 10.7, 12.2, 12.8, 17.7 and/or 22.0 degrees 29. As used in
connection with XPRD peaks, the term ” means 10.3 degrees 29. As those skilled in
the art are well aware, the relative intensities of peaks in an XRPD pattern of a crystalline
2O material can vary depending on how the sample is prepared and how the data is collected.
With this in mind, an example of an XRPD pattern of this crystalline form is provided in Figure
ular dosage forms comprise the hippurate salt of telotristat (telotristat
hippurate; telotristat etiprate). A particular crystalline form of this salt has a melting point of
about 142°C (DSC onset temperature, with a peak at about . A particular crystalline
form es an XRPD pattern that contains peaks at about 8.2, 9.5, 12.6, 16.9, 21.8, 22.0,
22.7, 24.3 and/or 29.1 degrees 29. An example of an XRPD pattern of this form is provided
in Figure 2.
When contacted with water, telotristat can hydrolyze to form (S)—2-amino(4-(2-
amino--((R)(4--c-hloro2--(3-methyl-1H--pyrazol-y-l)phenyl)2, 2, 2--trifluoroethoxy)pyrimidin-
yl)phenyl)propanoic acid. Preferred dosage forms of this invention minimize this degradation.
Figure 3 shows the difference between two s of the invention—formulations 6 and 8,
described in the examples below—and a capsule dosage form that was used in human Phase
1 and 2 clinical trials. The capsules contained a e of 250 mg telotristat and 2%
magnesium te. Both tablet formulations are clearly more stable than the capsule
formulation.
The bioavailability of an API can greatly depend on the formulation in which it is
delivered to a patient. Here, tablets that rapidly disintegrate when administered to a patient
are desired. Particular non-coated tablets of this invention have a disintegration time of less
than 2.3, 2.0, or 1.8 minutes in water, or less than 4.0, 3.0, or 2.7 minutes in 0.1 N HCI.
Particular -film coated s of the invention have a disintegration time of less than 5.5,
4.5, or 4.0 minutes in water, or less than 5.4, 5.0, or 4.8 minutes in 0.1 N HCI. As used
herein, the term “disintegration time" refers to disintegration time in 100 mL of purified water
or 0.1 N HCI as measured ing to test USP <701>. The disintegration of a tablet can be
affected by the disintegrants it contains. Examples of disintegrants include alginates,
celluloses, croscarmellose sodium, vidone, and sodium starch ate. A preferred
disintegrant is croscarmellose sodium.
The ability of a tablet to rapidly disintegrate or dissolve must be balanced, however,
with the necessity that the tablet not fall apart in its packaging. Thus, particular tablets of the
invention have a ss greater than 8, 9, or 10 kP, and a friability of less than 0.4, 0.3, or
2O 0.25 nt loss).
The hardness and stability of a tablet are ed by the excipients it contains. The
excipients can also affect the ease with which a tablet is made (e.g., by affecting how well the
ingredients from which it is made flow and compress). Particular s of the invention
comprise telotristat etiprate, cellulose, lactose, croscarmellose sodium, magnesium stearate,
and silicon dioxide
This invention encompasses methods of making solid dosage forms of telotristat and
salts thereof that limit the compounds exposure to water and address the poor flow
properties exhibited by many of its forms. In a particular embodiment, roller compaction is
used to prepare a granular material (“granulate”) made of up granules comprising the
3O compound, which is then combined with additional excipients and compressed to provide a
tablet core. The core is then optionally coated to increase the stability of the resulting tablet.
ulate granules comprise telotristat etiprate, hydroxypropyl cellulose, lactose,
croscarmellose sodium, magnesium stearate, and silicon dioxide. red ates flow
and compress well, allowing the ready manufacture of tablets possessing the d
hardness, ity, and disintegration properties described herein.
The solid dosage forms (e.g., tablets) of the invention can be packaged by methods
and using containers known in the art. The packaging material may form a plurality of
divided containers such as a divided bottle or a divided foil packet. The container can be in
any conventional shape or form as known in the art which is made of a pharmaceutically
acceptable material, for example a paper or ard box, a glass or plastic bottle orjar with
or without desiccant, a lable bag (for example, to hold a “refill” of tablets for placement
into a different container), or a blister pack (e.g., Aclar bilsters or foil/foil rs) with
individual doses for pressing out of the pack according to a therapeutic schedule. In a
red embodiment, s are stored in an ion-sealed HDPE bottle with a
desiccant pack.
6. EXAMPLES
6.1. Tablet and Ingredient Characterization
Disintegration testing was performed as per USP <701> using the test for uncoated
tables and plain coated tablets. The disintegration was performed in 1000 mL purified water
or 0.1 N HCI. Disintegration endpoint was determined visually.
Dissolution was determined in 900 mL of 0.1 N HCI at 37°C using USP Apparatus 2
(paddles) set at 50 rpm. Filtrates of the dissolution test solution were collected at specific
time intervals. The samples were analyzed by high mance liquid tography
(HPLC) usinga PhenomenexSynergi 4p Max-RP column and a mobile phase of 70/30/02
(v/v/v) methanol/water/phosphoric acid at a flow rate of 1.0 mL/min. The HPLC system
utilized ultraviolet (UV) detection at a wavelength of 237 nm.
2O Granulation particle size was determined using a sieve method, wherein the tare
weight of each of several sieves (mesh 25, 40, 60, 100, 140, 230, and Fines) was recorded,
the sieves were stacked in order of the coarsest sieve on top and the finest on bottom, and
approximately 5 grams of the granulate material was transferred to the top sieve. The
assembly was secured and placed in an ATM Sonic , the pulse amplitude and sift
amplitudes both set to 5. After 5 minutes, the assembly was removed and the individual
sieves weighed. Flow properties were determined using a J.R. Johanson Flow lndicizer.
6.2. General Tablet Preparation
Tablets comprising 300 mg (measured as free base) of the API istat in the
hippurate salt form were made in two general steps. First, granules comprising crystalline
telotristat te and selected excipients (intragranular ents) were prepared. The
al was compressed using a roller tor and milled. The intragranular material
was then combined with additional excipients (“extragranular components"), and the
resulting mixture was compressed to provide the tablets. In some cases, the tablets were
coated.
Batches were prepared by screening all intragranular materials except magnesium
stearate through a 20-mesh screen. Components were blended in an appropriately sized V-
blender for 10 minutes. lntragranular ium stearate was combined with a portion of
the blend and co-screened through a 20-mesh screen. The screened magnesium stearate
blend was then charged into the V-blender and d for an onal three minutes. The
blend was then roller compacted using a Vector TF-Mini roller compactor with a target ribbon
thickness of 1.5 mm. The s were milled by sequentially oscillating them through a 14-
mesh and 20-mesh . All extragranular components except magnesium stearate were
combined and screened through a 20-mesh screen. Approximately half of the granulation
was charged into the V-blender followed by the screened extragranular components. The
remaining half of the granulation was charged into the V-blender and blended for five
minutes. A small portion of the blend was removed and combined with the magnesium
stearate and passed through a 20-mesh screen. The magnesium stearate blend was
d into the V-blender and blended for an onal three minutes. The final blend was
compressed into 6 300-mg tablets. Some batches were film coated in a Strea 1 Fluid
Bed Coater with Opadry 2 Clear to a 4% weight gain.
6.3. ation 1
In this e, tablets were made from the ingredients listed below in Table 1:
Table 1
lntragranular Components (mg/tablet)
API 402.12*
Citric Acid, Anhydrous 83.79
Lactose, Anhydrous 90.77
Hydroxy Propyl Cellulose 34.91
Croscarmellose Sodium 20.95
Magnesium Stea rate 3.49
Extragranular Components (mg/tablet)
Lactose, Anhydrous 34.28
rmellose Sodium 20.95
Colloidal Silicon Dioxide 3.49
Core Tablet Total 700.0
*Equivalent to 300 mg telotristat free base
First, the intragranular ents were mixed and roller compacted with a roller
pressure of 70 kg/cm2. The ribbons were 0.99 — 1.42 mm in thickness. A bench-top ribbon
disintegration test was performed by placing a one inch section of ribbon in a beaker
containing approximately 500 mL of DI water and allowed to disintegrate. The ribbon
disintegrated in 12.5 minutes. Inspection of the roller compactor rollers indicated that some
sticking had ed. Ribbons were milled by ating sequentially through a 14-mesh
and 20-mesh screen. The granulation was blended with extragranular components and
physical tests were med. The granules flowed poorly, and the l tablets exhibited
weight variations and low average tablet weight. Striations and chipping were also ed
on the first tablets produced. lnitial tablets also failed a friability test loss limit of S 0.8%, yet
sticking prevented the compression forces from being increased to improve the friability.
These problems were addressed by increasing the extragranular magnesium te by
0.25%, and blended with the remaining blend (the amount of ium stearate shown in
Table 1 reflects this additional amount). The resulting final blend was compressed into
tablets (0.300" x 0.680" capsule shaped tooling). No further sticking was observed.
Characteristics of the granulation and tablets are shown below in Table 2:
Table 2
Approximate Ribbon egration Time (min) 12.5
Bulk Density (g/mL) 0.6644
Tapped Density (g/mL) 0.886
Average Flow Rate Index (kg/sec) 0.511
Core Hardness Range (kP) 8.1 — 12.0
Average Core Weight (g) 0.679
e Tablet Thickness (mm) 5.65
Tablet Friability (% loss) 0.3
The tablets’ dissolution properties are shown below in Table 3:
Table 3
6.4. Formulation 2
In this e, tablets were made from the ingredients listed below in Table 4:
Table 4
lntragranular Components blet)
API 403.13
Citric Acid, Anhydrous 84.00
Microcrystalline ose 89.25
Hydroxy Propyl Cellulose 35.00
rmellose Sodium 28.00
Magnesium te 5.25
Extragranular Components (mg/tablet)
Microcrystalline Cellulose 18.62
Croscarmellose Sodium 28.00
Colloidal Silicon Dioxide 3.50
Core Tablet Total 700.0
First, the intragranular components were mixed and roller compacted with a roller
pressure of 45 kg/cm2. The ribbon thicknesses ranged from 1.16 — 1.46 mm. Bench-top
ribbon disintegration test resulted in a disintegration time of 3 minutes. Some sticking was
noted during the roller compaction of the blend. The ribbons were milled by oscillating
tially h a 14-mesh and 20—mesh screen. The ribbons were hard and more
difficult to mill. imately 0.75% of the batch did not pass through the oscillator. The
granulation was blended with extragranular components and physical tests were performed.
Granulation exhibited poor flow characteristics, although the ssion was manageable.
Some sticking to tablet punches was observed initially during compression, which subsided
after the punches were cleaned. The tablets exhibited a dull appearance, which did not
improve when the compression force was increased.
6.5. Formulation 3
In this example, tablets were prepared using the ingredients listed below in Table 5:
Table 5
lntragranular Components (mg/tablet)
Citric Acid, Anhydrous
Microcrystalline Cellulose
Hydroxy Propyl Cellulose
Crospovidone 28.00
Magnesium Stearate 5.25
Extragranular Components (mg/tablet)
rystalline Cellulose 18.62
vidone 28.00
Colloidal Silicon Dioxide 3.50
Core Tablet Total 700.0
The e of intragranular components was roller compacted with a roller pressure
of 50 kg/cm2. The ribbon thicknesses ranged from 1.40 — 1.90 mm. Bench-top ribbon
disintegration test resulted in an rable disintegration time of 11 minutes. Some
sticking was observed during the roller compaction process. The ribbons were similar to
Formulation 2 and were difficult to mill. ation was blended with extragranular
ents and physical tests were performed. The granulation exhibited poorflow, and
some rat-holing was observed in the hopper during compression, which was overcome by
agitating the hopper. Tablet compression was completed with no observable problems.
However, tablet disintegration testing in water and 0.1N HCI resulted in disintegration times
significantly longer than those observed the other formulations, suggesting that in these
formulations, crospovidone is a less effective disintegrant than croscarmellose sodium.
6.6. Formulation 4
In this example, granules were prepared using the ingredients listed below in Table 6:
Table 6
lntragranular Components (mg/tablet)
Citric Acid, Anhydrous
Mannitol
Microcrystalline Cellulose
Hydroxy Propyl Cellulose
Crospovidone
Magnesium Stea rate
Because the egration tests run on the ribbons made from this mixture showed a
egration time of 11 minutes, further work on this formulation was not done.
6.7. Formulation 5
In this e, tablets were prepared using the ingredients listed below in Table 7:
Table 7
lntragranular Components blet)
API 403.13
Citric Acid, Anhydrous 84.00
Mannitol 44.45
Hydroxy Propyl Cellulose 35.00
Croscarmellose Sodium 28.00
ium te 5.25
Extragranular Components (mg/tablet)
rystalline Cellulose 18.62
Croscarmellose Sodium 28.00
Colloidal Silicon Dioxide 3.50
Core Tablet Total 700.0
The mixture of intragranular components was roller compacted with a roller pressure
of 50 kg/cm2. The ribbon thickness ranged from 1.37 — 1.83 mm. Bench-top ribbon
disintegration time was 1 minute. Minor ng was observed throughout the roller
compaction process. The granulation was blended with the extragranular components and
physical tests were med. The granulation exhibited poor flow, but tablet compression
was completed with no observable problems. The formulation was capable of achieving
hardnesses exceeding 18 kP. Tablet disintegration testing in water and 0.1N HCI resulted in
acceptable disintegration times for an immediate release tablet: 2.0 minutes in water, 4.0 —
.25 minutes in 0.1N HCI. However, assay and related nce testingindicated that an
unacceptable amount of what is believed to be a hydrolysis product of the API sed
significantly at the nth time point when stored at 40°C/75% RH without desiccant.
An additional batch of Formulation 5 was manufactured, and in this case, the
resulting tablets were coated with Opadry Clear. The granulation lot was roller compacted
with a roller pressure of 50 kg/cm2, affording a ribbon thickness ranging from 1.24 — 1.57
mm. Bench-top ribbon egration time was 3.25 minutes. Minor sticking to the rollers
was observed throughout the roller compaction process. Blend was also observed to be
sticking to the walls of the hopper and exhibited poor flow. The granulation was blended with
the extragranular components and physical tests were performed. Sticking was observed
after 5 minutes of tablet compression. The punches were cleaned and compression was
restarted, but tablet sticking resumed immediately, suggesting that the granulation may
require additional lubrication or sed lubrication time to me ng issues. The
resulting tablets were coated to a 4% weight gain. The dissolution profile of these tablets
was acceptable, although the disintegration times in water and 0.1 N HCI were icantly
longer than the uncoated tablets. Assay and related substance testingindicated that coating
the tablet to a theoretical weight gain of 4% decreases the level of degradation, a level which
is further decreased with the use of ant.
6.8. Formulation 6
In this example, tablets were prepared using the ingredients listed below in Table 8:
Table 8
lntragranular Components (mg/tablet)
API 403.13
Mannitol 86.45
Microcrystalline Cellulose 86.45
Hydroxy Propyl Cellulose 35.00
Croscarmellose Sodium 28.00
Magnesium Stearate 5.25
Extragranular Components (mg/tablet)
Microcrystalline Cellulose 18.97
Croscarmellose Sodium 28.00
Colloidal n Dioxide 3.50
Core Tablet Total 700.0
The mixture of intragranular components was roller compacted with a roller pressure
of 50 kg/cm2. The ribbon ess ranged from 1.11 — 1.52 mm. Bench-top ribbon
disintegration time was 1 minute. Very little sticking was observed throughout the roller
compaction process. Although the granulation exhibited poor flow, it was blended and
compressed into tablets, during which some sticking was observed. Tablets exhibited some
ng during friability testing. Dissolution and disintegration times were: 1.3 — 1.5
minutes in water; 1.5 — 2.8 minutes in 0.1 N HCI. These tablets particularly stable (0.23 area
percent after 1 month at 40°C/75 % relative humidity), and more so when stored with
desiccant (0.16 area percent after 1 month at 40°C/75 % relative humidity).
6.9. Formulation 7
In this example, tablets were prepared using the ingredients listed below in Table 9:
Table 9
lntragranular Components (mg/tablet)
API 403.13
Citric Acid, Anhydrous 84.00
Lactose, Anhydrous 80.50
Hydroxy Propyl Cellulose 35.00
Croscarmellose Sodium 28.00
Magnesium te 5.25
Extragranular Components (mg/tablet)
Lactose, Anhydrous 27.37
rmellose Sodium 28.00
Colloidal Silicon Dioxide 3.50
Core Tablet Total 700.0
The mixture of intragranular components was roller compacted with a roller pressure
of 50 kg/cm2. The ribbon thickness ranged from 1.45 — 1.63 mm. Bench-top ribbon
egration time was 3 minutes. Very little sticking was observed during roller tion.
Granulation, which exhibited poorflow, was blended and compressed into s. Sticking
was observed on the punch faces and die walls during tablet ssion. Chipping was
also noted during lity testing. Dissolution and disintegration times were acceptable,
although assay and related substance testing indicated a significant increase in apparent API
hydrolysis product when stored for one month under accelerated ions without
desiccant (1.01 area percent after 1 month at 40°C/75 % relative humidity). Desiccant
decreased the observed level of hydrolysis product to 0.16.
6.10. Formulation 8
In this example, tablets were prepared using the ingredients listed below in Table 10:
Table 10
lntragranular Components (mg/tablet)
Lactose, Anhydrous
Hydroxy Propyl Cellulose
Croscarmellose Sodium
Magnesium Stea rate
Extragranular Components blet)
Lactose, Anhydrous 27.37
Croscarmellose Sodium 21.00
Colloidal Silicon Dioxide 3.50
Core Tablet Total 700.0
The mixture of intragranular components was roller ted with a roller pressure
of 55 kg/cm2. The ribbon thickness ranged from 1.07 — 1.52 mm. The material processed
very well, yielding long ribbons. Bench-top ribbon disintegration time was 2.5 minutes.
Approximately 2% of the ribbons did not pass through the 20-mesh oscillating screen.
Granulation was blended and ssed into tablets. The blend compressed well and no
sticking was observed. Some minor g was observed.
Physical characteristics of the granulation and tablets are shown below in Table 11:
Table 11
Approximate Ribbon Disintegration Time (min)
Core Hardness Range (kP) 8.5 — 11.9
Average Core Weight (g) 0.711
e Tablet Thickness (mm)
Tablet lity (% loss)
The tablets’ disintegration profile was acceptable: uncoated s disintegrated in
1.8 — 2.3 minutes in water and 2.7 — 4.0 minutes in 0.1N HCI; coated tablets disintegrated in
3.1 — 5.5 minutes in water and 4.4 — 5.4 minutes in 0.1N HCI. The ution profile of the
tablets is shown below in Table 12:
Table 12
Mean % Label Claim
Time (min)
Uncoated Tablets Coated Tablets
93.6 84.6
98.3 94.7
99.5 96.0
45 99.8 96.0
This formulation performed well during the stability study, with little of the hydrolysis
product observed in the uncoated tablets without desiccant (0.39 area percent after 1 month
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at 40°C/75 % relative humidity), in uncoated tablets with desiccant (0.32 area percent after
1 month at 40°C/75 % relative humidity), in coated s with desiccant (0.31 area
percent after 1 month at 40°C/75 % relative humidity), in Aclar blisters (0.42 area percent
after 1 month at 40°C/75 % relative humidity), and in foil/foil blisters(0.39 area percent
after 1 month at 40°C/75 % relative humidity).
6.11. ity Determination
The stability of tablets was determined by a reverse-phase HPLC-based method
employing the following conditions:
Column: Waters XTerra MS C18 (4.6 X 150 mm, 3.5 pm
Particle Size)
Autosampler 5°C
Temperature:
Mobile Phase A: 0.05% TFA in Water
Mobile Phase B: 0.05% TFA in ACN
Flow Rate: 1.0 mL/minute
Detection 254 nm
Wavelength:
Data Acquisition 41 minutes
Time:
Data Output: Ensure Peak is on Scale
The pump program used was:
Time (min) % Mobile Phase A % Mobile Phase B
A standard solution was prepared by dissolving telotristat etiprate in THF with a
concentration of approximately 0.25 ug/mL.
Samples were prepared from 300 mg tablets as s: 1) at least 4 tablets were
d; 2) then crushed using a mortar and pestle; 3) an amount of lent to about 50
mg drug substance (i.e., about 117 mg) was weighed and erred to a 100-mL volumetric
flask; 4) then diluted to about 1/2 to 2/3 volume with diluent (THF); 5) the flask was then
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placed on a shaker for at least 20 minutes at low speed; 6) the volume was then further
diluted with t and mixed well; 7) an aliquot was centrifuged for about 5 minutes at
approximately 3000 RPM; 8) an aliquot of the supernate was then awn for injection; 9)
steps 3 through 8 were repeated for a total of two replicates for injection; 10) the average
retention time of the API peak was then determined for the first six ions of the standard
solution; and 2) the ratio of the retention time of any peaks in the sample preparation to the
average retention time of the API peak in the first six injections of the standard was then
calculated.
Potency was determined using the following equation:
API (mg) per tablet = (Asample 7" Wtota|)/ (RFstd 7" Wsample 7" Ntotal) *DFsample
where: Asample = API sample peak area; Wtotal = total weight of the tablets (mg); DFsample =
sample dilution volume in mL (100 mL for the 300-mg s); RFstd = standard e
response factor (1st 6 injections); Wsample = Individual sample weight (mg); and Ntotal = Number
of tablets used (at least 4). Individual impurities were determined as a percent of the total
integrated peak area.
All references cited herein (e.g., patents and patent applications) are incorporated
herein in their entireties.
Claims (16)
1. A tablet made from intragranular and extragranular components, wherein the intragranular components consist of (S)-ethyl 2-amino(4-(2-amino((R)(4-chloro(31H-pyrazolyl)phenyl)-2,2,2-trifluoroethoxy)pyrimidinyl)phenyl)propanoate hippurate, lactose anhydrous, hydroxyl propyl cellulose, croscarmellose sodium, magnesium stearate, and the extragranular components t of lactose anhydrous, croscarmellose sodium, colloidal silicon dioxide, and magnesium te.
2. The tablet of claim 1, wherein the (S)-ethyl 2-amino(4-(2-amino((R)(4- 10 chloro(3-methyl-1H-pyrazolyl)phenyl)-2,2,2-trifluoroethoxy)pyrimidinyl)phenyl)propanoate ate is crystalline.
3. The tablet of claim 1, which is cally coated.
4. The tablet of claim 1, which comprises at least 100 mg (S)-ethyl 2-amino(4-(2- amino((R)(4-chloro(3-methyl-1H-pyrazolyl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin 15 yl)phenyl)propanoate hippurate.
5. The tablet of claim 4, which comprises at least 200 mg (S)-ethyl 2-amino(4-(2- 6-((R)(4-chloro(3-methyl-1H-pyrazolyl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin yl)phenyl)propanoate hippurate.
6. The tablet of claim 1, wherein the intragranular components consist of 403.13 20 mg of hyl 2-amino(4-(2-amino((R)(4-chloro(3-methyl-1H-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)phenyl)propanoate hippurate, 164.50 mg of lactose anhydrous, 35.00 mg of hydroxyl propyl cellulose, 35.00 mg of croscarmellose sodium and 5.25 mg of magnesium stearate, and the extragranular components consist of 27.37 mg of lactose anhydrous, 21.00 mg of croscarmellose sodium, 3.50 mg of colloidal silicon dioxide and 5.25 mg 25 of magnesium stearate.
7. The tablet of claim 1, which has a disintegration time of less than 4.5 minutes in water.
8. The tablet of claim 7, which has a disintegration time of less than 4.0 minutes in water. 30 9. The tablet of claim 1, which has a disintegration time of less than 5.4 minutes in
0.1 N HCl.
10. The tablet of claim 9, which has a disintegration time of less than 5.0 minutes in 0.1 N HCl.
11. The tablet of claim 1, which has a hardness greater than 8 kP.
12. The tablet of claim 11, which has a hardness r than 9 kP.
13. The tablet of claim 12, which has a hardness greater than 10 kP.
14. The tablet of claim 1, which has a friability of less than 0.4.
15. The tablet of claim 14, which has a friability of less than 0.3. 5
16. The tablet of claim 15, which has a friability of less than 0.25.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161547894P | 2011-10-17 | 2011-10-17 | |
US61/547,894 | 2011-10-17 | ||
NZ623423A NZ623423B2 (en) | 2011-10-17 | 2012-10-16 | Solid dosage forms of (s)-ethyl 2-amino-3-(4-(2-amino-6-((r)-1-(4-chloro-2-(3-methyl-1h-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ717137A NZ717137A (en) | 2017-10-27 |
NZ717137B2 true NZ717137B2 (en) | 2018-01-30 |
Family
ID=
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