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WO2025029809A1 - Compositions pharmaceutiques comprenant du tolinapant et conditionnement - Google Patents

Compositions pharmaceutiques comprenant du tolinapant et conditionnement Download PDF

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Publication number
WO2025029809A1
WO2025029809A1 PCT/US2024/040193 US2024040193W WO2025029809A1 WO 2025029809 A1 WO2025029809 A1 WO 2025029809A1 US 2024040193 W US2024040193 W US 2024040193W WO 2025029809 A1 WO2025029809 A1 WO 2025029809A1
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WO
WIPO (PCT)
Prior art keywords
tolinapant
pharmaceutical composition
cancer
oxygen
dosage form
Prior art date
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PCT/US2024/040193
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English (en)
Inventor
Nipun Davar
Jim Kou
Christopher Norbert Johnson
Jonathan Paul Murphy
Bozena Ewa ADAMCZYK
David Alexander Rawlins
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Otsuka Pharmaceutical Co Ltd
Tanner Lorna L
Original Assignee
Otsuka Pharmaceutical Co Ltd
Tanner Lorna L
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Publication of WO2025029809A1 publication Critical patent/WO2025029809A1/fr
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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
    • A61K9/2013—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
    • 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
    • A61K9/2054—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
    • A61K9/2004—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • IAPs Inhibitors of apoptosis proteins
  • Tolinapant also known as ASTX660, is a potent antagonist of IAPs. Tolinapant has a unique IAP antagonist molecular profile and has been shown to exert its activity through both IAP antagonism and via an immune-related mechanism.
  • Tolinapant has the potential to result in enhanced pro-apoptotic activity and tumor cell death, compared to other IAP antagonists.
  • SUMMARY [0005] It has now been discovered that tolinapant is oxygen sensitive. When exposed to ambient air, increase of a compound represented by Formula (II), an oxidative degradation product of tolinapant, was observed in drug substance and drug product formulations: [0006] Inventors of the excipients and/or the manufacturing/blending process affects the stability of tolinapant, and thus pharmaceutical excipients and blending process are selected for increased stability of tolinapant. [0007] Further, to keep the oxidative degradation at a low, acceptable level, protective packages are contemplated using components with oxygen barrier properties.
  • a pharmaceutical composition comprising tolinapant or a pharmaceutically acceptable salt thereof, wherein the composition comprises no more than 2% w/w of a compound of Formula (II) compared to tolinapant free base.
  • the pharmaceutical composition may comprise about 20-40% w/w of said tolinapant or a pharmaceutically acceptable salt thereof. Said tolinapant or a pharmaceutically acceptable salt thereof may be in an amount equivalent to about 25-35 % w/w of tolinapant free base.
  • the pharmaceutical composition may further comprise one or more excipients selected from microcrystalline cellulose, mannitol, lactose monohydrate, sodium starch glycolate, and magnesium stearate.
  • the pharmaceutical composition may comprise about 20-40 % w/w of mannitol or 20-40 % w/w of lactose monohydrate.
  • the pharmaceutical composition may comprise about 20-40 % w/w of mannitol.
  • the pharmaceutical composition may comprise tolinapant in the amount of about 25-35 % w/w of tolinapant free base, about 25-40% w/w of microcrystalline cellulose, about 20-40 % w/w of mannitol, about 1-10% w/w of sodium starch glycolate, and about 0.1-5% w/w of magnesium stearate.
  • Tolinapant may be provided as tolinapant (+)-L-lactate.
  • a pharmaceutical composition comprising: about 20- 45 % w/w of tolinapant or a pharmaceutically acceptable salt thereof; about 25-40 % w/w of microcrystalline cellulose; about 20-40 % w/w of mannitol; about 1-10% w/w of sodium starch glycolate; and about 1-5% w/w of magnesium stearate.
  • the pharmaceutical composition may comprise about 30-40 % w/w of tolinapant or a pharmaceutically acceptable salt thereof; about 30-35% w/w of microcrystalline cellulose; about 25-35 % w/w of mannitol; about 1-10% w/w of sodium starch glycolate; and about 1-5% w/w of magnesium stearate.
  • the tolinapant may be provided as a salt, and amount of the salt of tolinapant is equivalent to about 30% w/w of tolinapant free base.
  • the pharmaceutical composition may comprise no more than 2% w/w of a compound of Formula (II) compared to tolinapant free base.
  • Tolinapant may be provided as tolinapant (+)-L-lactate.
  • a dosage form comprising the pharmaceutical composition.
  • the dosage form may comprise about 30 mg or 90 mg of tolinapant free base.
  • the dosage form may be a tablet or a capsule.
  • the dosage form may comprise one or more additional anti-cancer agents.
  • the dosage form upon storage in air for 90 days at 25°C and 60% relative humidity, is configured to include no more than 2% w/w of the compound of Formula (II) compared to tolinapant free base.
  • Attorney Docket No.: 94BB-350572-WO [0013]
  • provided herein is the pharmaceutical composition or the dosage form, for use in the treatment of cancer in a patient in need thereof.
  • the pharmaceutical composition or dosage form may be administered orally.
  • the cancer may be a solid tumor.
  • the cancer may be selected from the group consisting of acute myelogenous leukemia (AML), T-cell lymphomas, peripheral T-cell lymphoma, B-cell lymphomas, diffuse large B-cell lymphoma (DLBCL), MALT lymphoma, head and neck cancer, pancreatic cancer, ovarian cancer, breast cancer, colorectal cancer, rectal cancer, and cervical cancer.
  • AML acute myelogenous leukemia
  • T-cell lymphomas T-cell lymphomas
  • peripheral T-cell lymphoma B-cell lymphomas
  • DLBCL diffuse large B-cell lymphoma
  • MALT lymphoma MALT lymphoma
  • head and neck cancer pancreatic cancer
  • ovarian cancer breast cancer
  • colorectal cancer rectal cancer
  • cervical cancer pancreatic cancer
  • ovarian cancer breast cancer
  • colorectal cancer rectal cancer
  • cervical cancer pancreatic cancer
  • ovarian cancer breast cancer
  • colorectal cancer rectal cancer
  • a packaging for a pharmaceutical composition comprising tolinapant comprises a sealed bottle comprising: a bottle container; a bottle cap; and an oxygen absorber.
  • the laminate film of the blister pack may comprise one or more material selected from the group consisting of polyvinyl chloride (PVC), polyvinylidene chloride (PVDC), polypropylene (PP), polyethylene terephthalate (PET), polycarbonate (PC), polyamide nylon (OPA), polyethylene (PE), and aluminum foil.
  • the lidding film of the blister pack may comprise one or more material selected from the group consisting of polyvinyl chloride (PVC), polyvinylidene chloride (PVDC), polypropylene (PP), polyethylene terephthalate (PET), polycarbonate (PC), polyamide nylon (OPA), polyethylene (PE), aluminum foil, and paper.
  • the laminate film may be a peel/push film.
  • the interior of each blister may be configured to maintain an atmosphere containing less than 5% by volume of oxygen for at least 60, 90, or 180 days at 25°C and 60% relative humidity.
  • the packaging may include the pharmaceutical composition or the dosage form discussed herein. [0018] In some embodiments, a kit comprising the pharmaceutical composition and the packaging is provided.
  • FIG.1 is a graph illustrating a ratio of aldehyde degradation product of tolinapant (i.e., the compound of Formula (II)) in 6 different batches of tolinapant (ASTX660) over six months.
  • FIG.2 is a graph illustrating a ratio of aldehyde degradation product (i.e., the compound of Formula (II)) in six different batches of compositions including tolinapant over six months.
  • DETAILED DESCRIPTION Definitions [0021] The following description sets forth exemplary embodiments of the present technology.
  • alkyl refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., C1-20 alkyl), 1 to 8 carbon atoms (i.e., C1-8 alkyl), 1 to 6 carbon atoms (i.e., C1-6 alkyl), or 1 to 4 carbon atoms (i.e., C1-4 alkyl).
  • alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2- hexyl, 3-hexyl, and 3-methylpentyl.
  • alkyl residue having a specific number of carbons is named by chemical name or identified by molecular formula, all positional isomers having that number of carbons may be encompassed; thus, for example, “butyl” includes n-butyl (i.e. -(CH2)3CH3), sec-butyl (i.e.
  • a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, a divalent heteroaryl group, etc.
  • a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, a divalent heteroaryl group, etc.
  • an “alkylene” group or an “alkylenyl” group for example, methylenyl, ethylenyl, and propylenyl
  • an “arylene” group or an “arylenyl” group for example, phenylenyl or napthylenyl, or quinolinyl for heteroarylene
  • Alkenyl refers to an alkyl group containing at least one carbon-carbon double bond and having from 2 to 20 carbon atoms (i.e., C 2-20 alkenyl), 2 to 8 carbon atoms (i.e., C 2-8 alkenyl), 2 to 6 carbon atoms (i.e., C 2-6 alkenyl), or 2 to 4 carbon atoms (i.e., C 2-4 alkenyl).
  • alkenyl groups include ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).
  • Alkynyl refers to an alkyl group containing at least one (e.g., 1-3, or 1) carbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e., C 2-20 alkynyl), 2 to 12 carbon atoms (i.e., C 2-12 alkynyl), 2 to 8 carbon atoms (i.e., C 2-8 alkynyl), 2 to 6 carbon atoms (i.e., C 2-6 alkynyl), or 2 to 4 carbon atoms (i.e., C2-4 alkynyl).
  • alkynyl also includes those groups having one triple bond and one double bond.
  • Alkoxy refers to the group “alkyl-O-”. Examples of alkoxy groups include, e.g., methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.
  • Alkoxyalkyl refers to the group “alkyl-O-alkyl”.
  • Alkylthio refers to the group “alkyl-S-”.
  • Alkylsulfinyl refers to the group “alkyl-S(O)-”.
  • Alkylsulfonyl refers to the group “alkyl-S(O)2-”. “Alkylsulfonylalkyl” refers to -alkyl-S(O)2-alkyl. [0031] “Acyl” refers to a group -C(O)R y , wherein R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • acyl examples include, e.g., formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.
  • “Amido” refers to both a “C-amido” group which refers to the group -C(O)NR y R z and an “N- amido” group which refers to the group -NR y C(O)R z , wherein R y and R z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein, or R y and R z are taken together to form a cycloalkyl or heterocyclyl; each of which may be optionally substituted, as defined herein.
  • Amino refers to the group -NR y R z wherein R y and R z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • Amino refers to -C(NR y )(NR z 2 ), wherein R y and R z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • Aryl refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic) including fused systems.
  • aryl has 6 to 20 ring carbon atoms (i.e., C 6-20 aryl), 6 to 12 carbon ring atoms (i.e., C 6-12 aryl), or 6 to 10 carbon ring atoms (i.e., C 6-10 aryl).
  • Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthryl.
  • Aryl does Attorney Docket No.: 94BB-350572-WO not encompass or overlap in any way with heteroaryl defined below. If one or more aryl groups are fused with a heteroaryl, the resulting ring system is heteroaryl. If one or more aryl groups are fused with a heterocyclyl, the resulting ring system is heterocyclyl. [0036] “Arylalkyl” or “Aralkyl” refers to the group “aryl-alkyl-”.
  • Carbamoyl refers to both an “O-carbamoyl” group which refers to the group -O-C(O)NR y R z and an “N-carbamoyl” group which refers to the group -NR y C(O)OR z , wherein R y and R z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • Carboxyl ester or “ester” refer to both -OC(O)R x and -C(O)OR x , wherein R x is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • Cyanoalkyl refers to refers to an alkyl group as defined above, wherein one or more (e.g., 1 or 2) hydrogen atoms are replaced by a cyano (-CN) group.
  • Cycloalkyl refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings including fused, bridged, and spiro ring systems.
  • the term “cycloalkyl” includes cycloalkenyl groups (i.e., the cyclic group having at least one double bond).
  • cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C3-6 cycloalkyl).
  • Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • Cycloalkylalkyl refers to the group “cycloalkyl-alkyl-”.
  • “Imino” refers to a group -C(NR y )R z , wherein R y and R z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • “Imido” refers to a group -C(O)NR y C(O)R z , wherein R y and R z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • “Halogen” or “halo” refers to atoms occupying group VIIA of the periodic table, such as fluoro, chloro, bromo, or iodo.
  • Haloalkyl refers to an unbranched or branched alkyl group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a halogen.
  • a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached.
  • Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be, but are not necessarily, the same halogen.
  • haloalkyl examples include, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.
  • Haloalkoxy refers to an alkoxy group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a halogen.
  • Haloalkoxyalkyl refers to an alkoxyalkyl group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a halogen.
  • Hydroalkyl refers to an alkyl group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a hydroxy group.
  • Heteroalkyl refers to an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms), excluding any terminal carbon atom(s), are each independently replaced with the same or different heteroatomic group, provided the point of attachment to the remainder of the molecule is through a carbon atom.
  • the term “heteroalkyl” includes unbranched or branched saturated chain having carbon and heteroatoms. By way of example, 1, 2 or 3 carbon atoms may be independently replaced with the same or different heteroatomic group.
  • Heteroatomic groups include, but are not limited to, -NR y -, -O-, -S-, -S(O)-, -S(O)2-, and the like, wherein R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • heteroalkyl groups include, e.g., ethers (e.g., -CH2OCH3, -CH(CH3)OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, etc.), thioethers (e.g., -CH2SCH3, -CH(CH3)SCH3, -CH2CH2SCH3,-CH2CH2SCH2CH2SCH3, etc.), sulfones (e.g., -CH2S(O)2CH3, -CH(CH3)S(O)2CH3, -CH2CH2S(O)2CH3, -CH2CH2S(O)2CH2OCH3, etc.), and amines (e.g., -CH2NR y CH3, -CH(CH3)NR y CH3, -CH2CH2NR y CH3, -CH2CH2NR y CH2CH2NR y CH3, etc., where R y is hydrogen, alkyl
  • heteroalkyl includes 2 to 10 carbon atoms, 2 to 8 carbon atoms, or 2 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.
  • “Heteroaryl” refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • heteroaryl includes 1 to 20 ring carbon atoms (i.e., C1-20 heteroaryl), 3 to 12 ring carbon atoms (i.e., C 3-12 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C 3-8 heteroaryl), and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur.
  • ring carbon atoms i.e., C1-20 heteroaryl
  • 3 to 12 ring carbon atoms i.e., C 3-12 heteroaryl
  • 3 to 8 carbon ring atoms i.e., C 3-8 heteroaryl
  • 1 to 5 ring heteroatoms 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur.
  • heteroaryl includes 5-10 membered ring systems, 5-7 membered ring systems, or 5-6 membered ring systems, each independently having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur.
  • heteroaryl groups include, e.g., acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, Attorney Docket No.: 94BB-350572-WO benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxidopyri
  • fused-heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, where the heteroaryl can be bound via either ring of the fused system. Any aromatic ring, having a single or multiple fused rings, containing at least one heteroatom, is considered a heteroaryl regardless of the attachment to the remainder of the molecule (i.e., through any one of the fused rings).
  • Heteroaryl does not encompass or overlap with aryl as defined above.
  • “Heteroarylalkyl” refers to the group “heteroaryl-alkyl-”.
  • Heterocyclyl refers to a saturated or partially unsaturated cyclic alkyl group, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • the term “heterocyclyl” includes heterocycloalkenyl groups (i.e., the heterocyclyl group having at least one double bond), bridged-heterocyclyl groups, fused-heterocyclyl groups, and spiro-heterocyclyl groups.
  • Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl, regardless of the attachment (i.e., can be bound through a carbon atom or a heteroatom).
  • the term heterocyclyl is intended to encompass any non- aromatic ring containing at least one heteroatom, which ring may be fused to a cycloalkyl, an aryl, or heteroaryl ring, regardless of the attachment to the remainder of the molecule.
  • heterocyclyl has 2 to 20 ring carbon atoms (i.e., C2-20 heterocyclyl), 2 to 12 ring carbon atoms (i.e., C2-12 heterocyclyl), 2 to 10 ring carbon atoms (i.e., C2-10 heterocyclyl), 2 to 8 ring carbon atoms (i.e., C2-8 heterocyclyl), 3 to 12 ring carbon atoms (i.e., C3-12 heterocyclyl), 3 to 8 ring carbon atoms (i.e., C3-8 heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C 3-6 heterocyclyl); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur, or oxygen.
  • heterocyclyl groups include, e.g., azetidinyl, azepinyl, benzodioxolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, Attorney Docke
  • heterocyclyl also includes “spiroheterocyclyl” when there are two positions for substitution on the same carbon atom.
  • spiro-heterocyclyl rings include, e.g., bicyclic and tricyclic ring systems, such as oxabicyclo[2.2.2]octanyl, 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1- azaspiro[3.3]heptanyl.
  • fused-heterocyclyl rings include, but are not limited to, 1,2,3,4- tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl, where the heterocyclyl can be bound via either ring of the fused system.
  • Heterocyclylalkyl refers to the group “heterocyclyl-alkyl-.”
  • “Sulfonyl” refers to the group -S(O)2R y , where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.
  • “Sulfinyl” refers to the group -S(O)R y , where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • Examples of sulfinyl are methylsulfinyl, ethylsulfinyl, phenylsulfinyl, and toluenesulfinyl.
  • “Sulfonamido” refers to the groups -SO2NR y R z and -NR y SO2R z , where R y and R z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • R y and R z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • the terms “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
  • the term “optionally substituted” refers to any one or more hydrogen atoms on the designated atom or group may or may not be replaced by a moiety other than hydrogen.
  • substituted used herein means any of the above groups (i.e., alkyl, alkenyl, alkynyl, alkylene, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, and/or heteroalkyl) wherein at least one (e.g., 1 to 5 or 1 to 3) hydrogen atom is replaced by a bond to a non-hydrogen atom such as, but not limited to alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino, aryl, aralkyl, azido, carbamoyl, carboxy
  • substituted includes any of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups in which one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are independently replaced with deuterium, halo, cyano, nitro, azido, oxo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR g R h , -NR g C(O)R h , -NR g C(O)NR g R h , -NR g C(O)OR h , -NR g S(O)1-2R h , -C(O)R g , -C(O)OR g , -OC(O)OR g , -
  • R g and R h are the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and/or heteroarylalkyl.
  • substituted also means any of the above groups in which one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are replaced by a bond to an amino, cyano, hydroxy, imino, nitro, oxo, thioxo, halo, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, and/or heteroarylalkyl, or two of R g and R h and R i are taken together with the atoms to which they are attached to form a heterocyclyl ring optionally substituted with oxo, halo, or alkyl optionally substituted with oxo, halo, amino, hydroxy, or alkoxy.
  • Tautomers are in equilibrium with one another.
  • amide containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown, and regardless of the nature of the equilibrium among tautomers, the compounds are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers. Thus, the amide containing compounds are understood to include their imidic acid tautomers. Likewise, the imidic acid containing compounds are understood to include their amide tautomers.
  • the compounds of this disclosure are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
  • pharmaceutically acceptable salt of a given compound refers to salts that retain the biological effectiveness and properties of the given compound, and which are not biologically or otherwise undesirable.
  • “Pharmaceutically acceptable salts” or “physiologically acceptable salts” include, for example, salts with inorganic acids and salts with an organic acid.
  • the free base can be obtained by basifying a solution of the acid salt.
  • an addition salt particularly a pharmaceutically acceptable addition salt
  • a suitable organic solvent may be used to prepare nontoxic pharmaceutically acceptable addition salts.
  • Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include lactic acid (e.g.
  • pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases.
  • Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium, and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines (i.e., NH2(alkyl)), dialkyl amines (i.e., HN(alkyl)2), trialkyl amines (i.e., N(alkyl)3), substituted alkyl amines (i.e., NH2(substituted alkyl)), di(substituted alkyl) amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl) amines (i.e., N(substituted alkyl)3), alkenyl amines (i.e., NH2(alkenyl)), dialkenyl
  • Suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, Attorney Docket No.: 94BB-350572-WO isotonic and absorption delaying agents and the like.
  • Beneficial or desired clinical results may include one or more of the following: a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and/or preventing or delaying the spread (e.g., metastasis) of the disease or condition); and/or c) relieving the disease, that is, causing the regression of clinical symptoms (e.g., ameliorating the disease state, providing partial or total remission of the disease or condition, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival.
  • a) inhibiting the disease or condition e.g., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease or condition
  • prevention means any treatment of a disease or condition that causes the clinical symptoms of the disease or condition not to develop.
  • Compounds may, in some embodiments, be administered to a subject (including a human) who is at risk or has a family history of the disease or condition.
  • Subject refers to an animal, such as a mammal (including a human), that has been or will be the object of treatment, observation, or experiment. The methods described herein may be useful in human therapy and/or veterinary applications.
  • the subject is a mammal.
  • the subject is a human.
  • terapéuticaally effective amount or “effective amount” of a compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof means an amount sufficient to effect treatment when administered to a subject, to provide a therapeutic benefit such as amelioration of symptoms or slowing of disease progression.
  • a therapeutically effective amount may be an amount sufficient to decrease a symptom of T-cell lymphoma.
  • the therapeutically effective amount may vary depending on the subject, and disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the manner of administering, which can readily be determined by one or ordinary skill in the art.
  • Tolinapant is described in U.S. Patent No.9,783,538 and has a structure represented by Formula (I): Attorney Docket No.: 94BB-350572-WO (I), and is named 1-(6-(4- 2,3-dihydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)ethan-1-one (or alternatively 1- ⁇ 6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2- b]pyridin-1-yl ⁇ -2-[(2R,5R)-5-methyl-2- ⁇ [(3R)-3-methylmorpholin-4-yl]methyl ⁇ piperazin-1-yl]ethan-1- one).
  • Formula (I) Attorney Docket No.: 94BB-350
  • Pharmaceutically acceptable salts of tolinapant include acid addition salts.
  • Acid addition salts may be formed with a wide variety of acids, both inorganic and organic.
  • Examples of acid addition salts include mono- or di-salts formed with an acid selected from the group consisting of acetic, 2,2-dichloroacetic, adipic, alginic, ascorbic (e.g.
  • D-glucuronic D-glucuronic
  • glutamic e.g. L-glutamic
  • ⁇ -oxoglutaric glycolic, hippuric
  • hydrohalic acids e.g. hydrobromic, hydrochloric, hydriodic
  • isethionic lactic (e.g.
  • pharmaceutically acceptable salts of tolinapant may be one or more acid addition salts formed from acids selected from the group consisting of acetic, hydrochloric, hydriodic, phosphoric, nitric, sulfuric, citric, lactic, succinic, maleic, malic, isethionic, fumaric, benzenesulfonic, toluenesulfonic, methanesulfonic (mesylate), ethanesulfonic, naphthalenesulfonic, valeric, acetic, propanoic, butanoic, malonic, glucuronic and lactobionic acids.
  • acids selected from the group consisting of acetic, hydrochloric, hydriodic, phosphoric, nitric, sulfuric, citric, lactic, succinic, maleic, malic, isethionic, fumaric, benzenesulfonic, toluenesulfonic, methanesulfonic (mes
  • pharmaceutically acceptable salts of tolinapant may be one or more acid addition salts formed from lactic (e.g. (+)-L-lactic, (-)-D-lactic, or ( ⁇ )-DL-lactic), sulfuric and methanesulfonic (mesylate) acids.
  • pharmaceutically acceptable salts of tolinapant may be lactate salts (e.g. (+)-L-lactate, (-)-D-lactate, or Attorney Docket No.: 94BB-350572-WO ( ⁇ )-DL-lactate) or sulfate salts.
  • the pharmaceutically acceptable salt of the compound of Formula (I) may be a lactate salt.
  • the pharmaceutically acceptable salt of the compound of Formula (I) may be a (+)-L-lactate salt.
  • the lactate salt may be a (+)-L-lactate salt, such as the 1:1 salt of the compound of Formula (I) and (+)-L-lactic acid, as represented by Formula (Ia):
  • the term “tolinapant free base” refers specifically to the compound of Formula (I) as an active ingredient.
  • tolinapant or pharmaceutically acceptable salt thereof includes no more than 0.1% a/a, 0.2% a/a, 0.3% a/a, 0.4% a/a, 0.5% a/a, 0.6% a/a, 0.7% a/a, 0.8% a/a, 0.9% a/a, 1% a/a, 1.5% a/a, 2% a/a, 2.5% a/a, or 3% a/a of the compound of Formula (II), compared to total tolinapant and derivatives thereof.
  • a pharmaceutical composition including tolinapant or its pharmaceutically acceptable salt thereof, including any pharmaceutical compositions Attorney Docket No.: 94BB-350572-WO described herein includes no more than 0.05% w/w, 0.1% w/w, 0.2% w/w, 0.3% w/w, 0.4% w/w, 0.5% w/w, 0.6% w/w, 0.7% w/w, 0.8% w/w, 0.9% w/w, 1% w/w, 1.5% w/w, or 2% w/w of the compound of Formula (II), compared to tolinapant (free base).
  • compositions [0076] Tolinapant and/or a pharmaceutically acceptable salt thereof as described herein are usually administered in the form of pharmaceutical compositions.
  • compositions that contain tolinapant or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
  • a pharmaceutical composition comprising tolinapant or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition may include about 10-80 % w/w, about 10-75% w/w, about 10-70% w/w, about 10-65% w/w, about 10-60% w/w, about 10-50% w/w, about 10-40% w/w, about 10-39% w/w, about 10-38% w/w, about 10-37% w/w, about 10-36% w/w about 10-35% w/w, about 10-34% w/w, about 10-33% w/w, about 10-32% w/w, about 10-31% w/w about 10-30 % w/w, about 15-80 % w/w, about 15-75% w/w, about 15-70% w/w, about 15- 65% w/w, about 15-60% w/w, about 15-50% w/w, about 15-40% w/w, about 15-39% w/w, about 15-38% w/w, about 15-37% w/w/w, about
  • a pharmaceutical composition may include about 10 % w/w, about 15 % w/w, about 20 % w/w, about 25 % w/w, about 30 % w/w, about 31 % w/w, about 32 % w/w, about 33 % w/w, about 34 % w/w, about 35 % w/w, about 36 % w/w, about 37 % w/w, about 38 % w/w, about 39 % w/w, about 40 % w/w, about 45 % w/w, about 50 % w/w, about 55 % w/w, about 60 % w/w, about 70 % w/w, or about 80 % w/w of tolinapant or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition may include a salt of tolinapant, and tolinapant content from the salt of tolinapant is equivalent to: about 10-50% w/w, about 10-40% w/w, about 10-35% w/w, about 20-50% w/w, about 20-45% w/w, about 20-40% w/w, about 20-35% w/w, about 25-50% w/w, about 25-45% w/w, about 25-40% w/w, or about 25-35% w/w of tolinapant free base.
  • a pharmaceutical composition may include a salt of tolinapant, and tolinapant content from the salt of tolinapant is equivalent to about 10 % w/w, about 15 % w/w, about 20 % w/w, about 25 % w/w, about 30 % w/w, about 35 % w/w, about 40 % w/w, or about 50 % w/w of tolinapant free base.
  • the principal active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof.
  • a pharmaceutical excipient such as a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof.
  • the active ingredient may be dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.
  • excipients include various organic and inorganic carrier substances conventionally used as formulation materials, as exemplified by excipients, binders, disintegrants, lubricants, antioxidants, coating agents and so on in solid formulations, or which may be incorporated as solvents, solubilizers, suspending agents, isotonizing agents, buffering agents, soothing agents, or the like in liquid formulations.
  • excipients include starches, sugars, polysaccharides, inorganic compounds and so on. Examples of starches include potato starch, corn starch, rice starch, partially pregelatinized starch, and so on.
  • sugars include monosaccharides, disaccharides, trisaccharides and sugar alcohols, as exemplified by lactose, sucrose, trehalose, D-mannitol, raffinose, xylitol, erythritol, etc.
  • polysaccharides include cellulose, dextran and so on, as exemplified by crystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, etc.
  • anti-oxidants examples include ascorbic acid, ascorbic acid derivatives, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), Attorney Docket No.: 94BB-350572-WO tocopherol, tocopherol derivatives, propyl gallate, sodium ascorbate, sodium metabisulfite, citric acid, lecithin, etc.
  • suitable and pharmaceutically acceptable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, sodium starch glycolate, lactose monohydrate, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
  • the pharmaceutical composition includes one or more excipients selected from microcrystalline cellulose, mannitol, lactose monohydrate, sodium starch glycolate, and magnesium stearate.
  • a pharmaceutical composition comprising tolinapant or a pharmaceutically acceptable salt thereof comprises no more than 5% w/w of a compound of Formula (II) compared to tolinapant free base.
  • the pharmaceutical composition may comprise about 20-40 % w/w, or 30%-40% w/w of tolinapant or a pharmaceutically acceptable salt thereof, and one or more excipients.
  • the pharmaceutically acceptable salt of tolinapant includes tolinapant in an amount equivalent to about 25-35 % w/w of tolinapant free base.
  • the one or more excipients may be selected from microcrystalline cellulose, mannitol, lactose monohydrate, sodium starch glycolate, and magnesium stearate.
  • the pharmaceutical composition may include about 20-40 % w/w of mannitol or 20-40 % w/w of lactose monohydrate.
  • the pharmaceutically acceptable salt of tolinapant may be tolinapant (+)-L-lactate.
  • the pharmaceutical composition may be provided in a capsule.
  • the pharmaceutical composition comprises tolinapant or a pharmaceutically acceptable salt in the amount equivalent to about 20-40 % w/w of tolinapant free base, about 25-40% w/w of microcrystalline cellulose, about 20-40 % w/w of mannitol, about 1-10% w/w of sodium starch glycolate, and about 0.1-5% of magnesium stearate.
  • the pharmaceutical composition comprises tolinapant or a pharmaceutically acceptable salt thereof in the amount equivalent to about 30 % w/w of tolinapant free base, about 32.75 % w/w of microcrystalline cellulose, about 31 % w/w of mannitol, about 5% w/w of sodium starch glycolate, and about 1.25 % of magnesium stearate.
  • the pharmaceutical composition may be provided in a capsule.
  • the pharmaceutical composition comprises no more than 5% w/w of a compound of Formula (II) compared to tolinapant free base.
  • the pharmaceutically acceptable salt of tolinapant may be tolinapant (+)-L-lactate.
  • the pharmaceutical composition may be provided in a capsule.
  • the pharmaceutical composition may comprise 30 mg or 90 mg of tolinapant free base.
  • the pharmaceutical composition comprises about 20-45 % w/w of tolinapant or a pharmaceutically acceptable salt thereof, about 25-40% w/w of microcrystalline cellulose, about 20-40 % w/w of mannitol, about 1-10% w/w of sodium starch glycolate; and about 1-5% w/w of magnesium stearate.
  • the pharmaceutical composition comprises about 30-40 % w/w of tolinapant or a pharmaceutically acceptable salt thereof, about 30-35% w/w of microcrystalline cellulose, about 25-35 % w/w of mannitol, about 1-10% w/w of sodium starch glycolate; and about 1-5% w/w of magnesium stearate.
  • the pharmaceutical composition comprises about 35 % w/w of tolinapant or a pharmaceutically acceptable salt thereof, about 32.75 % w/w of microcrystalline cellulose, about 26 % w/w of mannitol, about 5 % w/w of sodium starch glycolate; and about 1.25 % w/w of magnesium stearate.
  • the tolinapant is provided as a salt, and amount of the salt of tolinapant is equivalent to about 30% w/w of tolinapant free base.
  • the pharmaceutical composition comprises no more than 5% w/w of a compound of Formula (II) compared to tolinapant free base.
  • the pharmaceutically acceptable salt of tolinapant may be tolinapant (+)-L-lactate.
  • the pharmaceutical composition may be provided in a capsule.
  • the pharmaceutical composition may comprise 30 mg or 90 mg of tolinapant free base.
  • the pharmaceutical composition may be manufactured by any appropriate method known in the art. For example, the pharmaceutical composition may be manufactured by dry blend process or the roller compaction process.
  • compositions or the compounds described herein may be administered in either single or multiple doses.
  • the pharmaceutical composition or the compounds described herein may be administered by various methods including, for example, orally.
  • a dosage form for the oral administration may be, for example, capsule or tablets.
  • tolinapant is usually mixed with an excipient, and the compositions can be in the form of tablets, pills, powders, granules, or sterile packaged powders.
  • the compositions can be enclosed within a carrier, such as a capsule.
  • the tablets, pills, or capsules of the compounds described herein may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach.
  • the tablet or pill can include an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
  • the tolinapant is administered as individual tablets or capsules.
  • the tablet or capsule further comprises lactose monohydrate, hypromellose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate.
  • the tablet has a film coating comprising polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and iron oxide red.
  • the tablets or capsules may comprise any of the pharmaceutical composition described herein.
  • the tolinapant may be in a dosage form of capsules, such as a HPMC capsule.
  • the capsule may include any of the pharmaceutical composition described herein elsewhere.
  • each capsule may include 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, or 160 mg of tolinapant (free base).
  • the dosage forms of tolinapant may be formed and/or stored, such that upon storage in air for 30, 60, 90, or 180 days at 25°C and 60% relative humidity, said dosage form includes no more than 5% w/w of the compound of Formula (II) compared to tolinapant free base.
  • the pharmaceutical composition including tolinapant or a pharmaceutically acceptable salt thereof may be stored in low oxygen atmosphere.
  • the pharmaceutical composition may be stored under an atmosphere containing less than 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% by volume of oxygen.
  • tolinapant in the pharmaceutical composition upon storage in air for at least 90 days at 25°C and 60 % relative humidity (RH), no more than 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, or 2% w/w of tolinapant in the pharmaceutical composition may be converted to the oxidated aldehyde degradation product (i.e., the compound of Formula (II)).
  • RH relative humidity
  • tolinapant in the pharmaceutical composition upon storage in air for at least 30 days at 25°C and 60 % relative humidity (RH), no more than 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, or 2% w/w of tolinapant in the pharmaceutical composition may be converted to the oxidated aldehyde degradation product (i.e., the compound of Formula (II)).
  • RH relative humidity
  • tolinapant in the pharmaceutical composition upon storage in air for at least 60 days at 25°C Attorney Docket No.: 94BB-350572-WO and 60 % relative humidity (RH), no more than 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, or 2% w/w of tolinapant in the pharmaceutical composition may be converted to the oxidated aldehyde degradation product (i.e., the compound of Formula (II)).
  • the oxidated aldehyde degradation product i.e., the compound of Formula (II)
  • tolinapant in the pharmaceutical composition may be converted to the oxidated aldehyde degradation product (i.e., the compound of Formula (II)).
  • tolinapant in the pharmaceutical composition upon storage in air for at least 12 months at 25°C and 60 % relative humidity (RH), no more than 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, 2% w/w of tolinapant in the pharmaceutical composition may be converted to the oxidated aldehyde degradation product (i.e., the compound of Formula (II)).
  • RH relative humidity
  • tolinapant in the pharmaceutical composition upon storage in air for at least 18 months at 25°C and 60 % relative humidity (RH), no more than 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, or 2% w/w of tolinapant in the pharmaceutical composition may be converted to the oxidated aldehyde degradation product (i.e., the compound of Formula (II)).
  • RH relative humidity
  • tolinapant in the pharmaceutical composition upon storage in air for at least 24 months at 25°C and 60 % relative humidity (RH), no more than 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, or 2% w/w of tolinapant in the pharmaceutical composition may be converted to the oxidated aldehyde degradation product (i.e., the compound of Formula (II)).
  • RH relative humidity
  • the pharmaceutical composition including tolinapant may be stored in a sealed packaging which provides a low oxygen atmosphere therein.
  • the sealed packaging may be, for example, blister packs, sealed bottles, sachets, or sealed ampoules.
  • a capsule or tablet containing tolinapant may be individually packaged in blister packs, or capsules or tablets may be packaged in sealed bottles in bulk.
  • the packaging is sealed such that the interior of the packaging provides an atmosphere containing less than 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% by volume of oxygen.
  • the packaging may maintain the low oxygen atmosphere for a prolonged period.
  • the atmosphere inside the packaging may maintain less than 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, Attorney Docket No.: 94BB-350572-WO 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% by volume of oxygen.
  • the atmosphere inside the packaging may maintain less than 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% by volume of oxygen.
  • the atmosphere inside the packaging may maintain less than 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% by volume of oxygen.
  • the atmosphere inside the packaging may maintain less than 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% by volume of oxygen.
  • the atmosphere inside the packaging may maintain less than 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% by volume of oxygen.
  • the packaging may be formed from materials having a low oxygen transmission rate (OTR).
  • the packaging may be formed from materials having an oxygen transmission rate (OTR) of no more than 50 cm 3 m -2 , 100 cm 3 m -2 , 150 cm 3 m -2 200 cm 3 m -2 , 250 cm 3 m -2 , 300 cm 3 m -2 , 350 cm 3 m -2 , 400 cm 3 m -2 , or 500 cm 3 m -2 , as measured at 23°C and 0% relative humidity (RH).
  • the packaging may be formed from materials including polyethylene terephthalate (PET) or high-density polyethylene (HDPE) .
  • the packaging may include a material to absorb oxygen.
  • the packaging may include Pharmakeep ® canisters or packets, StabilOx ® oxygen absorbing packets, or Activ-BlisterTM.
  • the oxygen absorbent material may be provided in a form such as a film, a powder, a powder in a canister, a packet, or a sachet.
  • Blister Pack [0099]
  • the packaging may be a blister pack.
  • each tablet or capsule may be contained within an individually sealed space, such that a patient may take one or more tablets/capsules to consume while maintaining seal for the rest of dosage forms (e.g., tablets or capsules).
  • the blister pack may include a laminate film, a lidding film, and an oxygen absorbent film.
  • one or more layers of the blister pack may be multi- layered, comprising a laminate film, a lidding film and/or an oxygen absorbent film.
  • the laminate film and/or the lidding film of the blister pack may include the oxygen absorbent film and/or an oxygen scavenger.
  • the laminate film and the lidding film may together define blisters for storing tablets or capsules, and the laminate film and the lidding film may be sealed to each other around the blisters, such that each blister may be hermetically sealed.
  • the oxygen absorbent film may be positioned within the cavity of blister, such that it can absorb oxygen and maintain low oxygen atmosphere within the blister.
  • the oxygen absorbent film can be attached to the lidding film.
  • the laminate film may be formed to define cavities for blisters, and the cavities are sized to accommodate dosage forms (e.g., tablets or capsules).
  • the laminate film may be constructed from any suitable material, to have a low oxygen transmission rate.
  • the laminate film may include multiple layers to provide greater barrier protection.
  • the laminate film may include one or more layers of materials selected from the group consisting of: polyvinyl chloride (PVC), polypropylene (PP), cast polypropylene (CPP), polyvinylidene chloride (PVDC), polyethylene terephthalate (PET), polycarbonate (PC), polyamide nylon (OPA), polyethylene (PE), aluminum foil, and oxygen scavenger.
  • the laminate film may further include adhesives for attaching its layers together.
  • the laminate film includes a PVC layer, an oPA layer, an aluminum foil layer, and a PVC layer, which are held together with adhesive disposed therebetween.
  • the laminate film may have a barrier property sufficient to maintain low oxygen level within the blisters.
  • the laminate film may have an oxygen transmission rate (OTR) of no more than 50 cm 3 m- 2 , 100 cm 3 m- 2 , 150 cm 3 m- 2 200 cm 3 m- 2 , 250 cm 3 m- 2 , 300 cm 3 m- 2 , 350 cm 3 m- 2 , 400 cm 3 m- 2 , or 500 cm 3 m- 2 , as measured at 23°C and 0% relative humidity (RH) in 24 hours.
  • OTR oxygen transmission rate
  • the laminate film may have an oxygen transmission rate (OTR) of less than 0.005 cm 3 m- 2 day -1 , 0.010 cm 3 m- 2 day -1 , 0.020 cm 3 m- 2 day -1 , 0.030 cm 3 m- 2 day -1 , 0.040 cm 3 m- 2 day -1 , 0.050 cm 3 m- 2 day -1 , 0.070 cm 3 m- 2 day -1 , or 0.1 cm 3 m- 2 day -1 , as measured at 23°C and 50% relative humidity (RH).
  • OTR oxygen transmission rate
  • the lidding film may be any suitable blister lidding film, having a low oxygen transmission rate.
  • the lidding may be push-through, peel, or peel/push type film.
  • the lidding film may include multiple layers to provide greater barrier protection.
  • the lidding film may include one or more layers of materials selected from the group consisting of: polyvinyl chloride (PVC), polypropylene (PP), polyethylene terephthalate (PET), polycarbonate (PC), polyamide nylon (OPA), polyethylene (PE), high density polyethylene (HDPE), polystyrene (PS), aluminum foil, paper, and oxygen scavenger.
  • PVC polyvinyl chloride
  • PP polypropylene
  • PET polyethylene terephthalate
  • PC polycarbonate
  • OPA polyamide nylon
  • PE polyethylene
  • HDPE high density polyethylene
  • PS polystyrene
  • aluminum foil paper
  • oxygen scavenger oxygen scavenger.
  • the lidding film may further include adhesives for attaching its layers together.
  • the lidding film includes a paper layer, a PET layer, and an aluminum foil layer, which are held together with adhesive disposed therebetween.
  • the lidding film may have a barrier property sufficient to maintain low oxygen level within the blisters.
  • the lidding film may have an oxygen transmission rate (OTR) of no more than 50 cm 3 m- 2 , 100 cm 3 m- 2 , 150 cm 3 m- 2 200 cm 3 m- 2 , 250 cm 3 m- 2 , 300 cm 3 m- 2 , 350 cm 3 m- 2 , 400 cm 3 m- 2, or 500 cm 3 m- 2 , as measured at 23°C and 0% relative humidity (RH) in 24 hours.
  • OTR oxygen transmission rate
  • the lidding film may have an oxygen transmission rate (OTR) of less than 0.005 cm 3 m- 2 day -1 , 0.010 cm 3 m- 2 day -1 , 0.020 cm 3 m- 2 day -1 , 0.030 cm 3 m- 2 day -1 , 0.040 cm 3 m- 2 day -1 , 0.050 cm 3 m- 2 day -1 , 0.070 cm 3 m- 2 day -1 , or 0.1 cm 3 m- 2 day -1 , as measured at 23°C and 50% relative humidity (RH).
  • OTR oxygen transmission rate
  • the oxygen absorbent film may include oxygen scavenging material and/or oxygen absorbing materials and can reduce oxygen within the blister.
  • the oxygen absorbent film includes oxygen scavenger, such as an oxygen scavenging resin formulation.
  • the oxygen scavenger may include iron-based, sulfite-based, ascorbate-based, or enzyme-based oxygen scavenging material.
  • the oxygen absorbent film includes Activ Blisters TM . [0107] The oxygen absorbent film may have enough oxygen absorbing capacity, such that it can maintain sufficiently low oxygen level within the blisters, without taking up too much space.
  • the oxygen absorbent film may have oxygen absorbing capacity greater than 0.1 cm 3 m- 2 , 0.2 cm 3 m -2 , 0.3 cm 3 m -2 , 0.4 cm 3 m -2 , 0.5 cm 3 m -2 , 0.6 cm 3 m -2 , 0.7 cm 3 m -2 , 0.8 cm 3 m -2 , 0.9 cm 3 m -2 , 1.0 cm 3 m -2 , 2.0 cm 3 m -2 , 3.0 cm 3 m -2 , or 5.0 cm 3 m -2 .
  • the oxygen absorbent film may be sized according to the size of blister and dosage form (e.g., capsule or tablet), such that the oxygen absorbent film fits within the blister.
  • the oxygen absorbent film may have a length of 30 mm, 29 mm, 28 mm, 27 mm, 26 mm, 25 mm, 24 mm, 23 mm, 22 mm, 21 mm, or 20 mm.
  • the laminate film, the lidding film, and the oxygen absorbent film may be tightly sealed, such that the interior of the blisters provides an atmosphere containing less than 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% by volume of oxygen.
  • the blister pack may maintain the low oxygen atmosphere for a prolonged period.
  • the atmosphere inside the blister may maintain less than 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% by volume of oxygen.
  • the atmosphere inside the blister may maintain less than 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% by volume of oxygen.
  • the blister upon storage in air for at least 60 days at 25°C and 60 % relative humidity (RH), the atmosphere inside Attorney Docket No.: 94BB-350572-WO the blister may maintain less than 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% by volume of oxygen.
  • the atmosphere inside the blister may maintain less than 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% by volume of oxygen.
  • the atmosphere inside the blister may maintain less than 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% by volume of oxygen.
  • a pharmaceutical composition including tolinapant may be stored within the blister of the blister pack.
  • tolinapant may convert to the oxidated aldehyde degradation product (i.e., the compound of Formula (II)), such that the purity of tolinapant can be maintained within an acceptable level.
  • the oxidated aldehyde degradation product i.e., the compound of Formula (II)
  • RH relative humidity
  • no more than 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, or 2% w/w of tolinapant free base in the pharmaceutical composition may be converted to the oxidated aldehyde degradation product (i.e. the compound of Formula (II)).
  • tolinapant free base in the pharmaceutical composition upon storage within the blister pack in air for at least 30 days at 25°C and 60 % relative humidity (RH), no more than 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, or 2% w/w of tolinapant free base in the pharmaceutical composition may be converted to the oxidated aldehyde degradation product (i.e. the compound of Formula (II)).
  • RH relative humidity
  • tolinapant free base in the pharmaceutical composition upon storage within the blister pack in air for at least 60 days at 25°C and 60 % relative humidity (RH), no more than 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, or 2% w/w w/w of tolinapant free base in the pharmaceutical composition may be converted to the oxidated aldehyde degradation product (i.e. the compound of Formula (II)).
  • RH relative humidity
  • tolinapant free base in the pharmaceutical composition may be converted to the oxidated aldehyde degradation product (i.e. the compound of Formula (II)).
  • tolinapant free base in the pharmaceutical composition upon storage within the blister pack in air for at least 12 months at 25°C and 60 % relative humidity (RH), no more than 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, or 2% w/w of tolinapant free base in the pharmaceutical composition may be converted to the oxidated aldehyde degradation product (i.e. the compound of Formula (II)).
  • RH relative humidity
  • tolinapant free base in the pharmaceutical composition may be converted to the oxidated aldehyde degradation product (i.e. the compound of Formula (II)).
  • tolinapant free base in the pharmaceutical composition upon storage within the blister pack in air for at least 24 months at 25°C and 60 % relative humidity (RH), no more than 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, or 2% w/w of tolinapant free base in the pharmaceutical composition may be converted to the oxidated aldehyde degradation product (i.e. the compound of Formula (II)).
  • RH relative humidity
  • tolinapant free base in the pharmaceutical composition upon storage within the blister pack in air for at least 36 months at 25°C and 60 % relative humidity (RH), no more than 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, or 2% w/w of tolinapant free base in the pharmaceutical composition may be converted to the oxidated aldehyde degradation product (i.e. the compound of Formula (II)).
  • RH relative humidity
  • the blister pack may be sealed with sufficient durability, such that the blister pack can maintain the seal even after exposed to stressed conditions for a prolonged time.
  • the blister pack can maintain the seal after being exposed to the temperature of greater than 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C or 80°C, for a prolonged time, such as greater than 2 weeks, 1 month, 2 month, 3 month, 4 month, 5 month or 6 month, such that oxygen concentration in blister stays less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% by volume.
  • a blister pack includes a laminate film, a lidding film, and an oxygen absorbent film, the laminate film and the lidding film are sealed to each other and define blisters.
  • the oxygen absorbent film may be positioned within each of the blisters.
  • the blister pack may include, within the blisters, a pharmaceutical composition comprising tolinapant or a pharmaceutically acceptable salt thereof, such as the pharmaceutical compositions described herein.
  • the pharmaceutical composition comprises tolinapant or a pharmaceutically acceptable salt in the amount equivalent to about 20-40 % w/w of tolinapant free base, about 25-40% w/w of microcrystalline cellulose, about 20-40 % w/w of mannitol, about 1-10% w/w of sodium starch glycolate, and about 0.1-5% of magnesium stearate.
  • the pharmaceutical composition comprises tolinapant or a pharmaceutically acceptable salt thereof in the amount equivalent to about 30 % w/w of tolinapant free base, about 32.75 % w/w of microcrystalline cellulose, about 31 % w/w of mannitol, about 5% w/w of sodium starch glycolate, and about 1.25 % of magnesium stearate.
  • the pharmaceutical composition may be provided in a capsule.
  • the pharmaceutical composition comprises about 20-45 % w/w of tolinapant or a pharmaceutically acceptable salt thereof, about 25-40% w/w of microcrystalline cellulose, about 20-40 % w/w of mannitol, about 1-10% w/w of sodium starch glycolate; and about 1-5% w/w of magnesium stearate.
  • the pharmaceutical composition comprises about 30-40 % w/w of tolinapant or a pharmaceutically acceptable salt thereof, about 30-35% w/w of microcrystalline Attorney Docket No.: 94BB-350572-WO cellulose, about 25-35 % w/w of mannitol, about 1-10% w/w of sodium starch glycolate; and about 1-5% w/w of magnesium stearate.
  • the pharmaceutical composition comprises about 35 % w/w of tolinapant or a pharmaceutically acceptable salt thereof, about 32.75 % w/w of microcrystalline cellulose, about 26 % w/w of mannitol, about 5 % w/w of sodium starch glycolate; and about 1.25 % w/w of magnesium stearate.
  • the pharmaceutical composition contained within the blister pack may include no more than 1, 2, 3%, 4%, or 5% w/w of an aldehyde degradation product of tolinapant (i.e., the compound of Formula (II)) compared to tolinapant free base.
  • the pharmaceutical composition is provided in a capsule.
  • the packaging for storing capsules or tablets including a pharmaceutical composition including tolinapant may be a sealed bottle.
  • the sealed bottle may include a bottle container, a bottle cap, and an oxygen scavenger.
  • the bottle container and the bottle cap together define a space for storing tablets or capsules.
  • the mouth of the bottle container may be sealed, such that the space inside the bottle container is fully sealed.
  • the oxygen absorber may be positioned within the space inside the bottle container, such that it can absorb oxygen and maintain low oxygen atmosphere within the space inside the bottle container.
  • the oxygen absorber may be attached or otherwise fixed onto an inner surface of the bottle container.
  • the bottle container may be formed to define cavities for containing dosage forms (e.g., tablets or capsules), and may be sized to accommodate certain amount of dosage forms (e.g., tablets or capsules).
  • the bottle container may accommodate up to 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 dosage forms (e.g., tablets or capsules) of the pharmaceutical composition including tolinapant.
  • the bottle container may be constructed from any suitable material, to have a low oxygen transmission rate. In some embodiments, the bottle container may include multiple layers to provide greater barrier protection.
  • the bottle container may be include one or more materials selected from the group consisting of: polyvinyl chloride (PVC), polyvinylidene chloride (PVDC), polypropylene (PP), polyethylene terephthalate (PET), polycarbonate (PC), polyamide nylon (OPA), polyethylene (PE), and aluminum foil.
  • PVC polyvinyl chloride
  • PVDC polyvinylidene chloride
  • PP polypropylene
  • PET polyethylene terephthalate
  • PC polycarbonate
  • OPA polyamide nylon
  • PE polyethylene
  • aluminum foil aluminum foil
  • the bottle container may have an oxygen transmission rate (OTR) of no more than 50 cm 3 m -2 , 100 cm 3 m -2 , 150 cm 3 m -2 200 cm 3 m -2 , 250 cm 3 m -2 , 300 cm 3 m -2 , 350 cm 3 m -2 , 400 cm 3 m -2 , or 500 cm 3 m -2 , as measured at 23°C and 0% relative humidity (RH) in 24 hours.
  • OTR oxygen transmission rate
  • the bottle container may have an oxygen transmission rate (OTR) of less than 0.005 cm 3 m- 2 day -1 , 0.010 cm 3 m -2 day -1 , 0.020 cm 3 m -2 day -1 , 0.030 cm 3 m -2 day -1 , 0.040 cm 3 m -2 day -1 , 0.050 cm 3 m -2 day -1 , 0.070 cm 3 m -2 day -1 , or 0.1 cm 3 m -2 day -1 , as measured at 23°C and 50% relative humidity (RH).
  • OTR oxygen transmission rate
  • the bottle container may be sealed at its mouth, such that the pharmaceutical composition is better protected from oxygen before the bottle is opened.
  • the mouth of the bottle container may be sealed with a sealing film having an oxygen barrier property.
  • the sealing film may have an oxygen transmission rate (OTR) of no more than 50 cm 3 m -2 , 100 cm 3 m -2 , 150 cm 3 m -2 200 cm 3 m -2 , 250 cm 3 m -2 , 300 cm 3 m -2 , 350 cm 3 m -2 , 400 cm 3 m -2 , or 500 cm 3 m -2 , as measured at 23°C and 0% relative humidity (RH).
  • OTR oxygen transmission rate
  • the sealing film may have an oxygen transmission rate (OTR) of less than 0.005 cm 3 m -2 day -1 , 0.010 cm 3 m -2 day -1 , 0.020 cm 3 m -2 day -1 , 0.030 cm 3 m -2 day -1 , 0.040 cm 3 m -2 day -1 , 0.050 cm 3 m -2 day -1 , 0.070 cm 3 m -2 day -1 , or 0.1 cm 3 m -2 day -1 , as measured at 23°C and 50% relative humidity (RH).
  • the sealing film may be induction sealed to the storage bottle.
  • the sealing film may include multiple layers to provide greater barrier protection.
  • the sealing film may include one or more layers of materials selected from the group consisting of: polyvinyl chloride (PVC), polypropylene (PP), polyethylene terephthalate (PET), polyethylene terephthalate (PEN), cyclic polyolefin (COP), polycarbonate (PC), polyamide nylon (OPA), polyethylene (PE), high density polyethylene (HDPE), aluminum foil, and paper.
  • PVC polyvinyl chloride
  • PP polypropylene
  • PET polyethylene terephthalate
  • PEN polyethylene terephthalate
  • COP cyclic polyolefin
  • PC polycarbonate
  • OPA polyamide nylon
  • PE polyethylene
  • HDPE high density polyethylene
  • the bottle cap may also have a low oxygen transmission rate.
  • the bottle cap may include one or more materials selected from the group consisting of: polyvinyl chloride (PVC), polypropylene (PP), polyethylene terephthalate (PET), polyethylene terephthalate (PEN), cyclic polyolefin (COP), polycarbonate (PC), polyamide nylon (OPA), polyethylene (PE), high density polyethylene (HDPE), and aluminum foil.
  • PVC polyvinyl chloride
  • PP polypropylene
  • PET polyethylene terephthalate
  • PEN polyethylene terephthalate
  • COP cyclic polyolefin
  • PC polyamide nylon
  • OPA polyamide nylon
  • PE polyethylene
  • HDPE high density polyethylene
  • aluminum foil aluminum foil
  • the bottle cap may have an oxygen transmission rate (OTR) of no more than 50 cm 3 m -2 , 100 cm 3 m -2 , 150 cm 3 m -2 , 200 cm 3 m -2 , 250 cm 3 m -2 , 300 cm 3 m -2 , 350 cm 3 m -2 , 400 cm 3 m -2 , or 500 cm 3 m -2 , as measured at 23°C and 0% relative humidity (RH) in 24 hours.
  • OTR oxygen transmission rate
  • the bottle cap may have an oxygen transmission rate (OTR) of less than 0.005 cm 3 m -2 day -1 , 0.010 cm 3 m- 2 day -1 , 0.020 cm 3 m -2 day -1 , 0.030 cm 3 m -2 day -1 , 0.040 cm 3 m -2 day -1 , 0.050 cm 3 m -2 day -1 , 0.070 cm 3 m -2 day -1 , or 0.1 cm 3 m -2 day -1 , as measured at 23°C and 50% relative humidity (RH).
  • OTR oxygen transmission rate
  • the oxygen absorber may include oxygen absorbing material and may be provided in any suitable forms, such as a sachet, a packet, a canister, or a polymer film.
  • the oxygen absorber may be a canister including oxygen absorbing material.
  • the oxygen absorber may be Pharmakeep ® canisters or packets, StabilOx ® oxygen absorbing packets, or Activ BlisterTM.
  • the oxygen absorber may have enough oxygen absorbing capacity, such that it can maintain sufficiently low oxygen level within the bottle container, without taking up too much space.
  • the oxygen absorber may have oxygen absorbing capacity greater than 0.1 cm 3 m -2 , 0.2 cm 3 m -2 , 0.3 cm 3 m- 2, 0.4 cm 3 m -2 , 0.5 cm 3 m -2 , 0.6 cm 3 m -2 , 0.7 cm 3 m -2 , 0.8 cm 3 m -2 , 0.9 cm 3 m -2 , 1.0 cm 3 m -2 , 2.0 cm 3 m -2 , 3.0 cm 3 m -2 , or 5.0 cm 3 m -2 .
  • the interior space of the bottle may maintain an atmosphere containing less than 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% by volume of oxygen.
  • the bottle may maintain the low oxygen atmosphere for a prolonged period.
  • the atmosphere inside the bottle may maintain less than 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1% by volume of oxygen.
  • the atmosphere inside the bottle may maintain less than 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1% by volume of oxygen.
  • the atmosphere inside the bottle may maintain less than 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1% by volume of oxygen.
  • the atmosphere inside the bottle may maintain less than 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1% by volume of oxygen.
  • the atmosphere inside the bottle may maintain less than 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% by volume of oxygen.
  • a pharmaceutical composition including tolinapant may be stored within the bottle.
  • tolinapant may convert to the oxidated aldehyde form (i.e., Formula (II)), such that the purity of tolinapant can be maintained within an acceptable level.
  • Formula (II) oxidated aldehyde form
  • tolinapant free base in the pharmaceutical composition upon storage within the bottle in air for at least 30 days at 25°C and 60 % relative humidity (RH), no more than 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, or 2% w/w of tolinapant free base in the pharmaceutical composition may be converted Attorney Docket No.: 94BB-350572-WO to the compound of Formula (II).
  • tolinapant free base in the pharmaceutical composition upon storage within the bottle in air for at least 60 days at 25°C and 60 % relative humidity (RH), no more than 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, or 2% w/w of tolinapant free base in the pharmaceutical composition may be converted to the compound of Formula (II).
  • tolinapant free base in the pharmaceutical composition upon storage within the bottle in air for at least 180 days at 25°C and 60 % relative humidity (RH), no more than 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, or 2% w/w of tolinapant free base in the pharmaceutical composition may be converted to the compound of Formula (II).
  • tolinapant free base in the pharmaceutical composition upon storage within the bottle in air for at least 12 months at 25°C and 60 % relative humidity (RH), no more than 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, or 2% w/w of tolinapant free base in the pharmaceutical composition may be converted to the compound of Formula (II).
  • tolinapant free base in the pharmaceutical composition upon storage within the bottle in air for 18 months at 25°C and 60 % relative humidity (RH), no more than 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, or 2% w/w of tolinapant free base in the pharmaceutical composition may be converted to the compound of Formula (II).
  • tolinapant free base in the pharmaceutical composition upon storage within the bottle in air for 24 months at 25°C and 60 % relative humidity (RH), no more than 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, or 2% w/w of tolinapant free base in the pharmaceutical composition may be converted to the compound of Formula (II).
  • tolinapant free base in the pharmaceutical composition upon storage within the bottle in air for 36 months at 25°C and 60 % relative humidity (RH), no more than 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, or 2% w/w of tolinapant free base in the pharmaceutical composition may be converted to the compound of Formula (II).
  • RH relative humidity
  • the bottle may be sealed with sufficient durability, such that the bottle can maintain the seal even after exposed to stressed conditions for a prolonged time.
  • the bottle can maintain the seal after being exposed to the temperature of greater than 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C or 80°C, for a prolonged time, such as greater than 2 weeks, 1 month, 2 month, 3 month, 4 month, 5 month or 6 month, such that oxygen concentration in blister stays less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% by volume.
  • a sealed bottle includes: a bottle container; a bottle cap; and an oxygen absorber within the bottle.
  • the sealed bottle may include, a pharmaceutical composition comprising tolinapant or a pharmaceutically acceptable salt thereof, such as the pharmaceutical compositions described herein.
  • the pharmaceutical composition comprises tolinapant or a pharmaceutically acceptable salt in the amount equivalent to about 20-40 % w/w of tolinapant free base, about 25-40% w/w of microcrystalline cellulose, about 20-40 % w/w of mannitol, about 1-10% w/w of sodium starch glycolate, and about 0.1-5% w/w of magnesium stearate.
  • the Attorney Docket No.: 94BB-350572-WO pharmaceutical composition comprises tolinapant or a pharmaceutically acceptable salt thereof in the amount equivalent to about 30 % w/w of tolinapant free base, about 32.75 % w/w of microcrystalline cellulose, about 31 % w/w of mannitol, about 5% w/w of sodium starch glycolate, and about 1.25 % of magnesium stearate.
  • the pharmaceutical composition may be provided in a capsule.
  • the pharmaceutical composition comprises about 20-45 % w/w of tolinapant or a pharmaceutically acceptable salt thereof, about 25-40% w/w of microcrystalline cellulose, about 20-40 % w/w of mannitol, about 1-10 % w/w of sodium starch glycolate; and about 1-5% w/w of magnesium stearate.
  • the pharmaceutical composition comprises about 30-40 % w/w of tolinapant or a pharmaceutically acceptable salt thereof, about 30-35 % w/w of microcrystalline cellulose, about 25-35 % w/w of mannitol, about 1-10 % w/w of sodium starch glycolate; and about 1-5 % w/w of magnesium stearate.
  • the pharmaceutical composition comprises about 35 % w/w of tolinapant or a pharmaceutically acceptable salt thereof, about 32.75 % w/w of microcrystalline cellulose, about 26 % w/w of mannitol, about 5 % w/w of sodium starch glycolate; and about 1.25 % w/w of magnesium stearate.
  • the pharmaceutical composition contained within the sealed bottle may include no more than 1, 2, or 3% w/w of an aldehyde derivative of tolinapant (i.e., compound of Formula (II)) compared to tolinapant free base.
  • the pharmaceutical composition is provided in a capsule.
  • kits that include a pharmaceutical composition including tolinapant or a pharmaceutically acceptable salt, and a sealed packaging, such as any packaging described in this specification.
  • a kit further includes instructions for use, a label and/or instructions for use of the compounds in the treatment of the indications, including the diseases or conditions, described herein.
  • the kit may be used for the treatment of cancer for patients in need thereof.
  • a kit including the pharmaceutical composition including tolinapant or a pharmaceutically acceptable salt thereof, and a blister pack or a bottle, such as the blister packs or bottles described herein may be provided.
  • the pharmaceutical composition or its dosage form may be contained within the packaging, such as the blister packs or the sealed bottles.
  • a pharmaceutical composition including tolinapant or pharmaceutically acceptable salt thereof, or a kit including the pharmaceutical composition described herein may be used for the treatment of, or manufacture a medicament for the treatment of one or more diseases or conditions mediated by IAP, including cancers mediated by IAP. Also provided herein are also methods of treating one or more one or more diseases or conditions mediated by IAP, including cancers mediated by IAP.
  • Attorney Docket No.: 94BB-350572-WO Cancers that can be treated may be a solid tumor or leukemia.
  • Cancers that can be treated include, but are not limited to, acute myelogenous leukemia (AML), T-cell lymphomas, peripheral T-cell lymphoma, B-cell lymphomas, diffuse large B-cell lymphoma (DLBCL), MALT lymphoma, head and neck cancer, pancreatic cancer, ovarian cancer, breast cancer, colorectal cancer, rectal cancer, and cervical cancer.
  • AML acute myelogenous leukemia
  • T-cell lymphomas T-cell lymphomas
  • peripheral T-cell lymphoma B-cell lymphomas
  • DLBCL diffuse large B-cell lymphoma
  • MALT lymphoma MALT lymphoma
  • head and neck cancer pancreatic cancer, ovarian cancer, breast cancer, colorectal cancer, rectal cancer, and cervical cancer.
  • the cancer can be an advanced cancer, such as an advanced head and neck cancer, pancreatic cancer, ovarian cancer, colorectal cancer, rectal cancer, or cervical cancer.
  • the T-cell lymphoma may be progressive, or refractory and relapsed peripheral T-cell lymphoma (PTCL), or relapsed or refractory cutaneous T-cell lymphoma (CTCL).
  • PTCL peripheral T-cell lymphoma
  • CCL cutaneous T-cell lymphoma
  • tolinapant or a pharmaceutically acceptable salt, compositions, or dosage forms disclosed herein may be used/administered in combination with one or more additional therapeutic agents that are being used and/or developed to treat cancers or T-cell lymphomas.
  • a dosage form comprising tolinapant or a pharmaceutically acceptable salt or the pharmaceutical compositions disclosed herein may further include said additional therapeutic agents that are being used and/or developed to treat cancers or T-cell lymphomas.
  • the one or more additional therapeutic agents may be selected from cedazuridine, azacitidine, venetoclax, navitoclax, entinostat, cisplatin, dexamethasone, paclitaxel, bevacizumab, pembrolizumab, or capecitabine.
  • a dosage form comprising tolinapant or a pharmaceutically acceptable salt or the pharmaceutical compositions disclosed herein may further include said additional therapeutic agents that are being used and/or developed to treat cancers or T-cell lymphomas.
  • the one or more additional therapeutic agents may be an additional IAP inhibitor.
  • tolinapant or a pharmaceutically acceptable salt, compositions, or dosage forms disclosed herein are administered in combination with therapeutical procedure, such as bone marrow / stem cell transplant, CAR-T cell therapies, or radiation therapy.
  • the pharmaceutical composition or a dosage form described herein may include one or more anti-cancer agents in addition to tolinapant or pharmaceutically acceptable salt thereof.
  • Dosing [0134] The specific dose level of a compound of the present application for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease in the subject undergoing therapy.
  • a dosage may be expressed as a number of milligrams of tolinapant or a pharmaceutically Attorney Docket No.: 94BB-350572-WO acceptable salt thereof described herein per kilogram of the subject’s body weight (mg/kg). Dosages of between about 0.1 and 150 mg/kg may be appropriate. In some embodiments, about 0.1 and 100 mg/kg may be appropriate. In other embodiments, a dosage of between 0.5 and 60 mg/kg may be appropriate. Normalizing according to the subject’s body weight is particularly useful when adjusting dosages between subjects of widely disparate size, such as occurs when using the drug in both children and adult humans or when converting an effective dosage in a non-human subject such as dog to a dosage suitable for a human subject.
  • the daily dosage may also be described as a total amount of tolinapant or a pharmaceutically acceptable salt thereof described herein administered per dose or per day.
  • daily dosage of tolinapant (free base) may be between about 1 mg and 4,000 mg, between about 2,000 to 4,000 mg/day, between about 1 to 2,000 mg/day, between about 1 to 1,000 mg/day, between about 10 to 500 mg/day, between about 20 to 500 mg/day, between about 50 to 300 mg/day, between about 75 to 200 mg/day, or between about 15 to 150 mg/day.
  • the total daily dosage for a human subject may be between 1 mg and 1,000 mg, between about 1,000-2,000 mg/day, between about 10-500 mg/day, between about 50-300 mg/day, between about 100-200 mg/day, between about 75-200 mg/day, or between about 100-150 mg/day.
  • the total daily dosage for a human subject may be about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 mg/day.
  • the total daily dose for a human subject may be about 30, 60, 90, 120, 150, or 180 mg per day.
  • Tolinapant or the compositions thereof may be administered once, twice, three, or four times daily, using any suitable mode described above. Also, administration or treatment with tolinapant may be continued for a number of days; for example, commonly treatment would continue for at least 7 days, 14 days, or 28 days, for one cycle of treatment. Treatment cycles are well known in cancer chemotherapy, and are frequently alternated with resting periods of about 1 to 28 days, commonly about 7 days or about 14 days, between cycles. The treatment cycles, in other embodiments, may also be continuous. [0138] In a particular embodiment, the method comprises administering to the subject an initial daily dose of about 30 to 200 mg of tolinapant or a pharmaceutical salt thereof and increasing the dose by increments until clinical efficacy is achieved.
  • increments of about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, or 180 mg can be used to increase the dose.
  • increments of about 30, 60, or 90 mg can be used to increase the dose.
  • the dosage can be increased daily, every other day, twice per week, or once per week.
  • Example 1 A capsule including a pharmaceutical composition including tolinapant (as (+)-L-lactate salt) was formed.
  • the formulation was formed by the dry blend process. Specifically, the ingredients including microcrystalline cellulose, mannitol, and sodium starch glycolate were sieved and charged to the blender, and were blended at 6 rpm blender speed at 10 kg batch scale.
  • Example 2 [0141] A pharmaceutical formulation containing tolinapant of Table 1 was formed using the method similar to the process described in Example 1.
  • Table 1 30mg C % 180 mg Capsule t ll Attorney Docket No.: 94BB-350572-WO
  • Example 3 Two formulations of tolinapant as (+)-L-lactate salt, including lactose monohydrate as a filler, were manufactured.
  • the other formulation shown in Table 3, was manufactured by dry blend, using the method similar to the process described in Example 1. Each formulation was packaged in PET bottles with oxygen absorbing canisters for stability study at 40°C/75% RH, 25°C/60% RH, and 5°C. The stability study was conducted by determination of content of the aldehyde derivative of tolinapant (i.e., a compound of Formula (II)).
  • Table 2 Formulation with Lactose Monohydrate Manufactured by Components Roller Compaction Process Formulation with Lactose Manufactured by Dry Blend C m n nt Pr compound of Formula (II)) was HPLC on a reversed-phase column with UV detection at 321 nm.
  • the HPLC method used a Zorbax Bonus-RP amide-linked sterically-protected diisopropyl-C14 highly endcapped column, 150 x 4.6 mm, 3.5 ⁇ m.
  • the mobile phases A and B consisted of 0.1% trifluoroacetic Attorney Docket No.: 94BB-350572-WO acid in water:acetonitrile (90:10) (A) and 0.1% trifluoroacetic acid in water:acetonitrile (10:90) (B), delivered at a flow rate of 1 mL/min in a multi-step gradient profile described in Table 4 below.
  • Table 4 Time (minutes) A (%) B (%) 0 100 0 [0145] The column tempe ⁇ L.
  • Samples and standards were prepared as 1.0 mg/mL solut ions in water/acetonitrile (50:50). Identification was accomplished by comparing the retention time of the aldehyde peak in the sample to that of the reference standard. The % w/w aldehyde (i.e., the compound of Formula (II)) content was calculated versus tolinapant label claim by external standard analysis.
  • Example 4 [0148] Two formulations of tolinapant 30 mg capsule, including mannitol as a filler, were manufactured. One formulation, shown in Table 6, was manufactured by roller compaction, and the other formulation, shown in Table 7, was manufactured by dry blend, using the methods similar to the process described in Example 2. Each formulation was packaged in PET bottles with Pharmakeep® oxygen absorbing canisters (2 canisters of 1 g each). A stability study was conducted at the storage conditions of 60°C (2 weeks), 40°C/75% RH (6 months), 25°C/60% RH (24 months), and 5°C (24 months). The stability study was conducted using the similar method described in Example 3.
  • Table 6 Formulation with Mannitol Manufactured by Roller Components Compaction Process l.
  • Table 7 Formulation with Mannitol Manufactured by Dry Blend C m n nt Pr ree base equ va ent and t e d erence n adjustment s compensated w t adjusted to t e er mann tol.
  • the stability results, shown in Table 8, shows that the degradation of tolinapant to the compound of Formula (II) was more significant for the roller compaction formulation of tolinapant 30 mg capsule than the dry blend formulation.
  • Tolinapant formulations for 30 mg and 90 mg capsule were developed using the method described in Example 1.
  • the composition of the formulation is provided in Table 9.
  • the magnesium stearate level in the formulation was increased from 1.0% to 1.25% to enhance the lubricity during the encapsulation process.
  • Example 6 [0152] A blister package was formed with a foil laminate (Formpack 4 Ply 92555 supplied by Amcor Flexibles, 60 ⁇ foil layer) and a foil lidding (Foil 1935-PE supplied by Constantia Flexibles).
  • an oxygen absorbing film (Activ-Blister TM CSP film supplied by Aptar CSP Attorney Docket No.: 94BB-350572-WO technologies) was added inside the blister cavity, adhered to the lidding, while the other batch was without the oxygen absorbing film.
  • Tolinapant 180 mg (180 mg as free base) capsules of Example 2 were stored in the blister cavity of these blister packages under stressed conditions (50 °C/ambient humidity, 25 °C/60%RH, 25 °C/75%RH) for up to 6 months.
  • the stressed samples were tested for assay and aldehyde degradation product (i.e., compound of Formula (II)) using the HPLC as described with regards to Example 3. The result is shown in Table 10.
  • Example 7 [0154] A blister package was formed with a foil laminate (Formpack 4 Ply 92555 supplied by Amcor Flexibles, 60 ⁇ m foil layer) and a foil lidding (Foil 1935-PE supplied by Constantia Flexibles). An oxygen absorbing film (Activ-BlisterTM CSP film supplied by Aptar CSP technologies) was added inside the blister cavity, adhered to the lidding, while the other batch was without the oxygen absorbing film.
  • Activ-BlisterTM CSP film supplied by Aptar CSP technologies
  • Tolinapant 30 mg (as the free base) capsule of Example 5 was packaged with the blister package for stressed stability study.
  • the blister packages including the tolinapant capsules were stored under stressed conditions of 60°C, 40°C, and 25°C for up to 1 month.
  • the stressed samples were tested for assay and degradation products.
  • the blister seal integrity was confirmed by measuring the oxygen level in the sealed blister cavities and the oxygen absorbing capacity of the CSP film recovered from the blister cavity.
  • the results are shown in Table 11.
  • Tolinapant 30 mg Capsule Degradation Products 9 [0156] As shown in Table 11, the drug product was stable through the stressed storage period. There was no adverse trending in the degradation product profile.
  • Aldehyde degradation product i.e., the compound of Formula (II)
  • the oxygen concentration in the blister cavity remained low, i.e., 4.9 – 7.3% at T0 and 1.3-4.9% under all stress conditions for 1 month.
  • the oxygen level in the cavities remained low, relative to the atmospheric concentration in ambient air of 21%. The stressing did not cause the oxygen concentration to increase, supporting that the seal integrity was maintained.
  • the oxygen absorbing capacity of the oxygen absorbent films recovered from the blister cavities of the stressed samples showed that the oxygen absorbent film was retaining full capacity, supporting that the seal integrity was maintained.
  • Example 8 A blister package was formed with a foil laminate (Formpack 4 Ply 92555 supplied by Amcor Flexibles, 60 ⁇ foil layer) and a foil lidding (Peel/Push 1935-PE supplied by Constantia Flexibles). An oxygen absorbing film (Activ-Blister TM CSP film supplied by Aptar CSP technologies) was added inside the blister cavity, adhered to the lidding. [0160] Blister stability samples of tolinapant capsules, including 3 batches of 30 mg capsule and 3 batches of 90 mg capsule from Example 5 were packaged in the selected blister package. [0161] A stressed stability test, at 60°C for 2 weeks, was performed to assess the blister seal integrity of the packaged blisters. The results of the stressed stability test are provided in Table 12.
  • the blister packages were also tested under The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) conditions for primary stability study.
  • the aldehyde degradation product (i.e., compound of Formula (II)) levels of samples stored at 40°C and 75% RH for up to 6 months are provided in FIG.1, showing that the aldehyde degradation product (i.e., compound of Formula (II)) level was stable in the blister packs with no adverse growing trend observed.
  • Up to 18 months of primary stability data (data not shown here) of these batches stored at 25°C and 60% RH and 2-8 °C also show that the aldehyde degradation product (i.e., compound of Formula (II)) level was stable without any increase trending.
  • a bottle package for tolinapant capsules were prepared.
  • the bottle package included polyethylene terephthalate (PET) bottle (Amber color supplied by Drug Plastics) containing tolinapant 30 mg capsules and Pharmakeep CD-2.15 oxygen absorber canister (supplied by Airnov Healthcare Packaging).
  • PET polyethylene terephthalate
  • Pharmakeep CD-2.15 oxygen absorber canister supplied by Airnov Healthcare Packaging
  • Another bottle package for tolinapant capsules were prepared.
  • the bottle package included high density polyethylene (HDPE) bottle containing tolinapant 30 mg capsules of Example 2 and Pharmakeep CD-2.15 oxygen absorber canister (supplied by Airnov Healthcare Packaging).
  • HDPE high density polyethylene
  • the induction sealer used was AP7114.
  • the fixed process parameters include ionized air pressure: 40 psi ( ⁇ 5 psi), conveyor speed: 21 fpm, and induction seal coil height above cap: 1/8’’ ( ⁇ 1/16’’)
  • the process parameters studied in DOE design included capping torque force pre- and post- induction sealing as well as the induction sealer power.
  • the study design including parameter ranges is shown in Table 14.
  • the in-process seal integrity tests including visual inspection and dye ingress leak test were performed.
  • the packaged bottles were subjected to additional stressed test of seal integrity as follows. The packaged bottle samples were stored at 60°C stressed condition for 2 weeks and tested of oxygen concentration inside the bottles and the oxygen absorbing capacity of the Pharmakeep canister recovered. The results are shown in Table 15.
  • the oxygen absorbing capacity of Pharmakeep canister was maintained at 24.0 - 31.8 mL (except for 1 sample at 11.4 mL which is attributed to variability of measurement).
  • the data indicate a fully capacity, if greater than or equal with 20 mL, according to the supplier specification.
  • statistical analysis indicated that none of the process parameters studied has significant impacts on the oxygen level inside the sealed bottles nor on Pharmakeep capacity. Therefore, it was concluded that the process parameters studied, i.e., torque (pre- and post- induction sealing) range of 15 - 25 lb/in 2 and induction seal power range of 75 - 85%, were acceptable for bottle packaging for tolinapant.
  • Example 11 A simulation study was performed on a bottle container closure system to assess oxygen ingress into sealed bottles. Relevant assumptions included, - tolinapant 30 mg and 90 mg capsules are encapsulated in Size 3 and Size 1 capsules, respectively, - Each bottle contains 14 capsules, - Oxygen transmission through the bottle system is through the bottle surface and the foil seal is considered impermeable to oxygen.
  • Example 12 The performance of the selected bottle package was further confirmed in the primary stability study of the registration batches.
  • a bottle package for tolinapant capsules were prepared.
  • the bottle package included polyethylene terephthalate (PET) bottle container (50cc wide mouth pharmaceutical round, white polyethylene terephthalate bottle supplied by Drug Plastics), 33 mm child resistant ribbed side white cap with a seal liner (33mm SecurRx Ribbed Side Test Top white cap supplied by Drug Plastics), and Pharmakeep ® CD-2.15 oxygen absorber canister (supplied by Airnov Healthcare Packaging).
  • PET polyethylene terephthalate
  • 33 mm child resistant ribbed side white cap with a seal liner 33mm SecurRx Ribbed Side Test Top white cap supplied by Drug Plastics
  • Pharmakeep ® CD-2.15 oxygen absorber canister supplied by Airnov Healthcare Packaging.
  • the bottled batches were tested for the primary stability study.
  • the stability data generated up to date showed that the level of the aldehyde degradation product (i.e., compound of Formula (II)) is within acceptable range.
  • the performance of the bottle Attorney Docket No.: 94BB-350572-WO package stored under the stressed condition of 40°C/75% RH is illustrated in FIG.2.
  • the aldehyde degradation (i.e., compound of Formula (II)) was shown to remain stable without a growing trend. * * * [0188] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

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Abstract

La présente divulgation concerne de manière générale des compositions pharmaceutiques comprenant du tolinapant ou un sel pharmaceutiquement acceptable de celui-ci, des méthodes de traitement et de conditionnement de la forme galénique.
PCT/US2024/040193 2023-07-31 2024-07-30 Compositions pharmaceutiques comprenant du tolinapant et conditionnement Pending WO2025029809A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9783538B2 (en) 2013-12-20 2017-10-10 Astex Therapeutics Limited Bicyclic heterocycle compounds and their uses in therapy
WO2021225955A1 (fr) * 2020-05-04 2021-11-11 Astex Pharmaceuticals, Inc. Composés antagonistes d'iap et intermédiaires et leurs procédés de synthèse
WO2023022235A1 (fr) * 2021-08-20 2023-02-23 大塚製薬株式会社 Association médicamenteuse

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9783538B2 (en) 2013-12-20 2017-10-10 Astex Therapeutics Limited Bicyclic heterocycle compounds and their uses in therapy
WO2021225955A1 (fr) * 2020-05-04 2021-11-11 Astex Pharmaceuticals, Inc. Composés antagonistes d'iap et intermédiaires et leurs procédés de synthèse
WO2023022235A1 (fr) * 2021-08-20 2023-02-23 大塚製薬株式会社 Association médicamenteuse

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