[go: up one dir, main page]

WO2025073002A1 - Formulation de comprimé - Google Patents

Formulation de comprimé Download PDF

Info

Publication number
WO2025073002A1
WO2025073002A1 PCT/AU2024/051042 AU2024051042W WO2025073002A1 WO 2025073002 A1 WO2025073002 A1 WO 2025073002A1 AU 2024051042 W AU2024051042 W AU 2024051042W WO 2025073002 A1 WO2025073002 A1 WO 2025073002A1
Authority
WO
WIPO (PCT)
Prior art keywords
immediate
release tablet
tablet formulation
amount
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/AU2024/051042
Other languages
English (en)
Inventor
Allen Lee LAWSON JR.
Fujun Li
Thomas Robert Malefyt
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.)
Actinogen Medical Ltd
Original Assignee
Actinogen Medical Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from AU2023903165A external-priority patent/AU2023903165A0/en
Application filed by Actinogen Medical Ltd filed Critical Actinogen Medical Ltd
Publication of WO2025073002A1 publication Critical patent/WO2025073002A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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

Definitions

  • the present disclosure generally relates to the formulation of pharmaceutical active agents and excipients, particularly as immediate-release tablet formulations.
  • Xanamem also known as UE2343, is an effective inhibitor of l ip- hydroxysteroid dehydrogenase type 1 (l ip-HSDl). Due to its inhibitory action, Xanamem has been proposed as a treatment of disorders that are ameliorated by the inhibition of 11 P-HSD1, such as metabolic syndrome, cardiovascular disorders, and CNS disorders.
  • the active ingredient is compatible with the co-formulated excipients, achieves a desired release profile, has a desired level of shelf stability by not undergoing any problematic degradation, and can be manufactured at scale and in a suitable dosage per unit formulation.
  • further challenges may need to be overcome. Such challenges include those of patient compliance, storage requirements, and manufacturing processes.
  • capsules and tablets may be a preferred option.
  • the compound of Formula I is a compound Formula la:
  • the compound of Formula I is a compound Formula lai:
  • the ratio (w/w) of lactose to microcrystalline cellulose is between about 80:20 and about 20:80.
  • a process for preparing the immediate -release tablet formulation comprising: preparing granules by blender mixing intragranular components and subsequent granulation using roller compaction and milling; blending the granules with extragranular components to provide a final blend; compressing the final blend using a rotary tablet press to yield a tablet core; and film-coating the tablet cores to provide the immediate -release film-coated tablets.
  • a method of treating a neurological condition in a subject in need thereof comprising administering the immediate-release tablet formulation.
  • composition of matter, group of steps or group of compositions of matter shall be taken to encompass one and a plurality (i.e. one or more) of those steps, compositions of matter, groups of steps or group of compositions of matter.
  • Figure 2 shows the dissolution of Xanamem prototype tablets Lot 22852-7 in 0.1 N HC1, USP type II apparatus.
  • Figure 4 shows the evaluation of dissolution medium volumes and paddle rotation speed using Xanamem prototype 20 mg tablets in 0.1 N HC1.
  • Figure 6 shows optical microscope images of Xanamem drug substance, batch CJ1456 under cross-polarised light (top: unmicronized; bottom: micronized).
  • Figure 8 shows particle size distribution of final blend from compaction study for 10 mg tablet formulation.
  • Figure 9 shows particle size distribution of final blend for clinical batches.
  • Figure 10 shows dissolution profiles of Xanamem tablets, 5 mg and 10 mg, in 900 mL of 0.1 N HC1, USP type II apparatus at 50 rpm.
  • the term “and/or”, e.g., “X and/or Y” shall be understood to mean either “X and Y" or "X or Y” and shall be taken to provide explicit support for both meanings or for either meaning, e.g. A and/or B includes the options i) A, ii) B or iii) A and B..
  • the term about refers to +/- 20%, typically +/- 10%, typically +/- 5%, of the designated value.
  • range format is included for convenience and should not be interpreted as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range, unless specifically indicated. For example, description of a range such as from 1 to 5 should be considered to have specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 5, from 3 to 5 etc., as well as individual and partial numbers within the recited range, for example, 1, 2, 3, 4, 5, 5.5 and 6, unless where integers are required or implicit from context. This applies regardless of the breadth of the disclosed range. Where specific values are required, these will be indicated in the specification.
  • treating includes a reduction, alleviation and/or elimination of one or more symptoms associated with a specific disorder or condition. Such symptoms may be correlated with a neurological disorder in subjects.
  • treating a neurological condition includes improving, reducing, alleviating and/or eliminating symptoms associated with a neurological condition, relative to the symptoms prior to treatment.
  • the term “preventing” includes prophylaxis of the specific disorder or condition.
  • the phrase “preventing a neurological condition” refers to preventing the onset or duration of the symptoms associated with a neurological condition in subjects.
  • the phrase “preventing a neurological condition” refers to slowing or halting the progression of a neurological condition.
  • the phrase “preventing a neurological condition” refers to delaying or preventing the onset of the symptoms of neurological condition. Prevention may be absolute (such that no symptoms of the neurological condition are observed), or may be effective only in some individuals, to some extent, or for a limited amount of time.
  • the term “subject” may be used interchangeably with the terms “patient” and “individual”.
  • the subject is a mammal.
  • the subject is a human.
  • halogen means fluorine, chlorine, bromine, or iodine.
  • alkyl encompasses both straight-chain (i.e., linear) and branched-chain hydrocarbon groups.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, i-butyl, sec-butyl, pentyl, and hexyl groups.
  • the alkyl group is of one to six carbon atoms (i.e. Ci- ealkyl).
  • alkoxy refers to the group -O-alkyl, where “alkyl” is as described above.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, and butoxy groups.
  • the alkoxy group is of one to six carbon atoms (i.e. -O-Ci-6alkyl).
  • alkenyl refers to both straight and branched chain unsaturated hydrocarbon groups with at least one carbon-carbon double bond.
  • alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl groups.
  • the alkenyl group is of two to six carbon atoms (i.e. C2-6alkenyl).
  • alkynyl refers to both straight and branched chain unsaturated hydrocarbon groups with at least one carbon-carbon triple bond.
  • alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl groups.
  • the alkynyl group is of two to six carbon atoms (i.e. C2-6alkynyl).
  • haloalkyl refers to an alkyl group having at least one halogen substituent, where “alkyl” and “halogen” are as described above.
  • haloalkyl means an alkyl group having two halogen substituents
  • trihaloalkyl means an alkyl group having three halogen substituents.
  • haloalkyl groups include fluoromethyl, chloromethyl, bromomethyl, iodomethyl, fluoropropyl, and fluorobutyl groups.
  • dihaloalkyl groups include difluoromethyl and difluoroethyl groups.
  • trihaloalkyl groups include trifluoromethyl and trifluoroethyl groups.
  • the haloalkyl group is of one to six carbon atoms (i.e. Cnehaloalkyl).
  • oxyhaloalkyl refers to the group -O-haloalkyl, where “haloalkyl” is as described above.
  • -O-haloalkoxy groups include -O- fluoromethyl, -O-chloromethyl, -O-bromomethyl, -O-iodomethyl, -O-fluoropropyl, and -Ofluorobutyl groups.
  • the oxyhaloalkyl group is of one to six carbon atoms (i.e. -O-Cnehaloalkyl).
  • carbocyclyl refers to an aromatic or non-aromatic cyclic group of carbon atoms.
  • a carbocyclyl group may, for example, be monocyclic or polycyclic (i.e. bicyclic, tricyclic).
  • a polycyclic carbocyclyl group may contain fused rings.
  • the carbocyclyl group is of three to ten carbon atoms (i.e. C3- locarbocyclyl).
  • the carbocyclyl group is of three to seven carbon atoms (i.e. C3-7carbocyclyl).
  • Examples of monocyclic non-aromatic carbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl groups.
  • Aromatic carbocyclyl groups include phenyl and napthalenyl.
  • heterocyclyl refers to an aromatic or non-aromatic cyclic group which is analogous to a carbocyclic group, but in which from one to three of the carbon atoms is/are replaced by one or more heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • a heterocyclyl group may, for example, be monocyclic or polycyclic (e.g. bicyclic).
  • a polycyclic heterocyclyl may for example contain fused rings.
  • a bicyclic heterocyclyl group there may be one or more heteroatoms in each ring, or heteroatoms only in one of the rings.
  • a heteroatom may be N, O, or S.
  • Heterocyclyl groups containing a suitable nitrogen atom include the corresponding N- oxides.
  • the heterocyclyl group is of three to ten atoms (i.e. 3-10- membered heterocyclyl).
  • the heterocyclyl group is of three to seven atoms (i.e. 3-7-membered heterocyclyl).
  • Examples of monocyclic non-aromatic heterocyclyl groups include aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl and azepanyl.
  • Examples of bicyclic heterocyclyl groups in which one of the rings is non-aromatic include dihydrobenzofuranyl, indanyl, indolinyl, isoindolinyl, tetrahydroisoquinolinyl, tetrahydroquinolyl, and benzoazepanyl.
  • monocyclic aromatic heterocyclyl groups include furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazyl, isothiazolyl, isoxazolyl, pyrazinyl, pyrazolyl, and pyrimidinyl.
  • bicyclic aromatic heterocyclyl groups include quinoxalinyl, quinazolinyl, pyridopyrazinyl, benzoxazolyl, benzothiophenyl, benzimidazolyl, naphthyridinyl, quinolinyl, benzofuranyl, indolyl, benzothiazolyl, oxazolyl[4,5-b]pyridyl, pyridopyrimidinyl, isoquinolinyl, and benzohydroxazole.
  • the subject matter of the present disclosure is predicated in part on the surprising discovery that a mixture of lactose and microcrystalline cellulose can be utilised to provide an immediate-release tablet formulation of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, as described herein, that may demonstrate advantageous properties.
  • an immediate -release tablet formulation comprising a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof:
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, Ci-ealkyl, -O-Ci-6alkyl, Ci-ehaloalkyl, -O-Ci-ehaloalkyl, Ci ealkenyl, Ci ealkynyl, 3-10-membered carbocyclyl, 3-10-membered heterocyclyl, -CN, -CF3, - OR 3 , -SR 3 , -NR 3 R 4 , -COR 3 , -CO2R 3 , -CONR 3 R 4 , -NR 3 COR 4 , -SO2R 3 , -SO 2 NR 3 R 4 , and -NR 3 SO 2 R 4 ; wherein R 3 and R 4 are each independently selected from the group consisting of hydrogen, Ci-ealkyl, 3-7-membered carbocyclyl and 3-7-membered heterocyclyl; wherein each 3-10-membere
  • Lactose is a disaccharide sugar having the molecular formula, D12H22O11, and the following chemical structure:
  • Lactose is derived from the condensation reaction of galactose and glucose, and can therefore be hydrolysed into galactose and glucose products. Lactose may be provided in many forms, including as lactose hydrous, lactose anhydrous, lactose monohydrate, or spray-dried lactose. In one example, lactose is lactose hydrous. In one example, lactose is lactose anhydrous. In one example, lactose is lactose monohydrate. In one example, lactose is spray-dried lactose.
  • Spray-dried lactose is available commercially as “Fast Flo 316”, which is a spray -dried mixture of crystalline and amorphous lactose.
  • lactose is Fast Flo 316.
  • Lactose has long been used as an excipient in pharmaceutical formulations, primarily as a diluent and/or filler, including in compression tableting. It is an ideal excipient in that it is chemically and physically inert to other excipients and active ingredients.
  • Microcrystalline cellulose is a term for refined wood pulp, which is a naturally occurring polymer comprised of glucose units connected by a 1-4 beta glycosidic bond.
  • the linear cellulose chains are bundled together as a microfibril, with each microfibril exhibiting a high degree of three-dimensional internal bonding resulting in a crystalline structure that is physically and chemically inert, and additionally insoluble in water. Due to these properties, microcrystalline cellulose has also been widely employed in the food industry, as an anti-caking agent, emulsifier, extender, and bulking agent. It is also utilised as an excipient in pharmaceutical formulations, primarily as a binder and/or filler.
  • lactose and microcrystalline cellulose is employed as a diluent.
  • “diluent” refers to a substance used to dilute an active ingredient. While the use of lactose and microcrystalline cellulose in tablet formulations has been previously reported, the combination of lactose, microcrystalline cellulose, and a compound of Formula I, as described herein, in the preparation of an immediate -release tablet formulation, has been surprisingly discovered to provide one or more advantageous properties to the immediate -release tablet formulation.
  • beneficial tableting properties may include, for example, one or more of compressibility, tablet hardness, and tablet friability.
  • a combination of a compound of Formula I, or pharmaceutically acceptable salt or solvate thereof, and microcrystalline cellulose (MCC) may provide some advantageous properties, and such dual combination may experience slow dissolution.
  • MMC microcrystalline cellulose
  • the inclusion of lactose unexpectedly increases this rate of dissolution, while maintaining the advantageous properties (e.g., compressibility, tablet hardness, and tablet friability).
  • an immediate -release tablet formulation comprising a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, as described herein; and lactose and microcrystalline cellulose.
  • an immediate -release tablet formulation comprising a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, as described herein; and lactose and microcrystalline cellulose in a ratio (w/w) of lactose to microcrystalline cellulose of between about 80:20 and about 20:80.
  • an immediate -release tablet formulation comprising a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, as described herein; and lactose and microcrystalline cellulose in a ratio (w/w) of lactose to microcrystalline cellulose of between about 70:30 and about 30:70.
  • an immediate- release tablet formulation comprising a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, as described herein; and lactose and microcrystalline cellulose in a ratio (w/w) of lactose to microcrystalline cellulose of between about 60:40 and about 40:60.
  • an immediate-release tablet formulation comprising a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, as described herein; and lactose and microcrystalline cellulose in a ratio (w/w) of lactose to microcrystalline cellulose of about 50:50.
  • the immediate-release tablet formulation comprises lactose and microcrystalline cellulose. In some embodiments, the immediate -release tablet formulation comprises lactose and microcrystalline cellulose in a ratio (w/w) of lactose to microcrystalline cellulose of between about 80:20 and about 20:80. In some embodiments, the immediate-release tablet formulation comprises lactose and microcrystalline cellulose in a ratio (w/w) of lactose to microcrystalline cellulose of between about 80:20 and about 20:80, between about 75:25 and about 25:75, between about 70:30 and about 30:70, between about 65:35 and about 35:65, between about 60:40 and about 40:60, between about 55:45 and about 45:55, or about 50:50.
  • the immediate -release tablet formulation comprises a compound of Formula I, or pharmaceutically acceptable salt or solvate thereof, and lactose in a ratio (w/w) of a compound of Formula I, or pharmaceutically acceptable salt or solvate thereof, to lactose of between about 10:90 and about 90: 10, between about 15:85 and about 80:20, between about 17:83 and about 70:30, between about 20:80 and about 60:40, or between about 30:70 to about 50:50.
  • the immediate- release tablet formulation comprises a compound of Formula I, or pharmaceutically acceptable salt or solvate thereof, and lactose in a ratio (w/w) of a compound of Formula I, or pharmaceutically acceptable salt or solvate thereof, to lactose is about 17:83.
  • the immediate-release tablet formulation comprises a compound of Formula I, or pharmaceutically acceptable salt or solvate thereof, and lactose in a ratio (w/w) of a compound of Formula I, or pharmaceutically acceptable salt or solvate thereof, to lactose is about 32:68.
  • the immediate -release tablet formulation comprises a compound of Formula I, or pharmaceutically acceptable salt or solvate thereof, and microcrystalline cellulose in a ratio (w/w) of a compound of Formula I, or pharmaceutically acceptable salt or solvate thereof, to microcrystalline cellulose of between about 10:90 and about 90: 10, between about 15:85 and about 80:20, between about 20:80 and about 70:30, between about 25:75 and about 60:40, between about 30:70 to about 55:45, or between about 40:60 and about 50:50.
  • the immediate- release tablet formulation comprises a compound of Formula I, or pharmaceutically acceptable salt or solvate thereof, and microcrystalline cellulose in a ratio (w/w) of a compound of Formula I, or pharmaceutically acceptable salt or solvate thereof, to microcrystalline cellulose is about 24:76.
  • the immediate-release tablet formulation comprises a compound of Formula I, or pharmaceutically acceptable salt or solvate thereof, and microcrystalline cellulose in a ratio (w/w) of a compound of Formula I, or pharmaceutically acceptable salt or solvate thereof, to lactose is about 41:59.
  • the immediate -release tablet formulation comprises a compound of Formula I, or pharmaceutically acceptable salt or solvate thereof, and microcrystalline cellulose, and lactose in a ratio (w/w/w) of a compound of Formula I, or pharmaceutically acceptable salt or solvate thereof, to microcrystalline cellulose, to lactose of about 10:50:40, about 11:53:36, about 20:50:30, or about 22:47:31.
  • the immediate-release tablet formulation comprises a compound of Formula I, or pharmaceutically acceptable salt or solvate thereof, and microcrystalline cellulose, and lactose in a ratio (w/w/w) of a compound of Formula I, or pharmaceutically acceptable salt or solvate thereof, to microcrystalline cellulose, to lactose of about 11:53:36.
  • the immediate-release tablet formulation comprises a compound of Formula I, or pharmaceutically acceptable salt or solvate thereof, and microcrystalline cellulose, and lactose in a ratio (w/w/w) of a compound of Formula I, or pharmaceutically acceptable salt or solvate thereof, to microcrystalline cellulose, to lactose of about 22:47:31.
  • the immediate-release tablet formulation comprises a compound of Formula lai, or pharmaceutically acceptable salt or solvate thereof, and lactose in a ratio (w/w) of a compound of Formula lai, or pharmaceutically acceptable salt or solvate thereof, to lactose of between about 10:90 and about 90: 10, between about 15:85 and about 80:20, between about 17:83 and about 70:30, between about 20:80 and about 60:40, or between about 30:70 to about 50:50.
  • the immediate- release tablet formulation comprises a compound of Formula lai, or pharmaceutically acceptable salt or solvate thereof, and lactose in a ratio (w/w) of a compound of Formula lai, or pharmaceutically acceptable salt or solvate thereof, to lactose is about 17:83.
  • the immediate-release tablet formulation comprises a compound of Formula lai, or pharmaceutically acceptable salt or solvate thereof, and lactose in a ratio (w/w) of a compound of Formula lai, or pharmaceutically acceptable salt or solvate thereof, to lactose is about 32:68.
  • the immediate -release tablet formulation comprises a compound of Formula lai, or pharmaceutically acceptable salt or solvate thereof, and microcrystalline cellulose in a ratio (w/w) of a compound of Formula lai, or pharmaceutically acceptable salt or solvate thereof, to microcrystalline cellulose of between about 10:90 and about 90: 10, between about 15:85 and about 80:20, between about 20:80 and about 70:30, between about 25:75 and about 60:40, between about 30:70 to about 55:45, or between about 40:60 and about 50:50.
  • the immediate- release tablet formulation comprises a compound of Formula lai, or pharmaceutically acceptable salt or solvate thereof, and microcrystalline cellulose in a ratio (w/w) of a compound of Formula lai, or pharmaceutically acceptable salt or solvate thereof, to microcrystalline cellulose is about 24:76.
  • the immediate-release tablet formulation comprises a compound of Formula lai, or pharmaceutically acceptable salt or solvate thereof, and microcrystalline cellulose in a ratio (w/w) of a compound of Formula lai, or pharmaceutically acceptable salt or solvate thereof, to lactose is about 41:59.
  • the immediate -release tablet formulation comprises a compound of Formula lai, or pharmaceutically acceptable salt or solvate thereof, and microcrystalline cellulose, and lactose in a ratio (w/w/w) of a compound of Formula lai, or pharmaceutically acceptable salt or solvate thereof, to microcrystalline cellulose, to lactose of about 10:50:40, about 11:53:36, about 20:50:30, or about 22:47:31.
  • the immediate-release tablet formulation comprises a compound of Formula lai, or pharmaceutically acceptable salt or solvate thereof, and microcrystalline cellulose, and lactose in a ratio (w/w/w) of a compound of Formula lai, or pharmaceutically acceptable salt or solvate thereof, to microcrystalline cellulose, to lactose of about 11:53:36.
  • the immediate-release tablet formulation comprises a compound of Formula lai, or pharmaceutically acceptable salt or solvate thereof, and microcrystalline cellulose, and lactose in a ratio (w/w/w) of a compound of Formula lai, or pharmaceutically acceptable salt or solvate thereof, to microcrystalline cellulose, to lactose of about 22:47:31.
  • the immediate -release tablet formulation may comprise any other suitable excipient that is useful in formulating the immediate -release tablet. This includes both intragranular and extragranular components. As used herein, the term “intragranular component” will be understood to be a component added to the formulation prior to the granulation process. Similarly, as used herein, the term “extragranular component” will be understood to be a component added to the formulation after the granulation process and prior to the compaction process. In one example, the immediate-release tablet formulation comprises an intragranular component. In one example, the immediate- release tablet formulation comprises an extragranular component. In one example, the immediate-release tablet formulation comprises both intragranular and extragranular components.
  • the immediate-release tablet formulation comprises between about 50% and about 99%, between about 60% and about 99%, between about 70% and about 99%, or between about 75% and about 99% of intragranular components. In one example, the immediate-release tablet formulation comprises between about 1% and about 50%, between about 10% and about 40%, between about 15% and about 35%, or between about 20% and about 30% of extragranular components.
  • a compound of Formula I, or pharmaceutically acceptable salt or solvate thereof is considered the active ingredient in the immediate-release tablet formulation. That is, the compound of Formula I, or pharmaceutically acceptable salt or solvate thereof, is the drug substance.
  • a compound of Formula I has the following chemical structure:
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, Ci-ealkyl, -O-Ci-6alkyl, Ci-ehaloalkyl, -O-Ci-ehaloalkyl, Ci ealkenyl, Ci ealkynyl, 3-10-membered carbocyclyl, 3-10-membered heterocyclyl, -CN, -CF3, - OR 3 , -SR 3 , -NR 3 R 4 , -COR 3 , -CO2R 3 , -CONR 3 R 4 , -NR 3 COR 4 , -SO2R 3 , -SO 2 NR 3 R 4 , and -NR 3 SO 2 R 4 .
  • R 1 is hydrogen. In some embodiments, R 1 is halogen. In some embodiments, R 1 is chlorine. In some embodiments, R 1 is fluorine. In some embodiments, R 1 is bromine. In some embodiments, R 1 is iodine. In some embodiments, R 1 is Ci-6alkyl. In some embodiments, R 1 is -O-Ci-6alkyl. In some embodiments, R 1 is Ci-ehaloalkyl. In some embodiments, R 1 is -O-Ci-ehaloalkyl. In some embodiments, R 1 is C2-6alkenyl. In some embodiments, R 1 is C2-6alkynyl.
  • R 1 is -COR 3 . In some embodiments, R 1 is -CO2R 3 . In some embodiments, R 1 is - CONR 3 R 4 . In some embodiments, R 1 is -NR 3 COR 4 . In some embodiments, R 1 is -SO2R 3 . In some embodiments, R 1 is -SO2NR 3 R 4 . In some embodiments, R 1 is -NR 3 SO2R 4 .
  • R 2 is hydrogen. In some embodiments, R 2 is halogen. In some embodiments, R 2 is chlorine. In some embodiments, R 2 is fluorine. In some embodiments, R 2 is bromine. In some embodiments, R 2 is iodine. In some embodiments, R 2 is Ci-6alkyl. In some embodiments, R 2 is -O-Ci-6alkyl. In some embodiments, R 2 is Ci-ehaloalkyl. In some embodiments, R 2 is -O-Ci-ehaloalkyl. In some embodiments, R 2 is C2-6alkenyl. In some embodiments, R 2 is C2-6alkynyl.
  • R 2 is 3- 10-membered carbocyclyl. In some embodiments, R 2 is a 6-membered carbocyclyl. In some embodiments, R 2 is a 5-membered carbocyclyl. In some embodiments, R 2 is 3-10- membered heterocyclyl. In some embodiments, R 2 is a 6-membered heterocyclyl. In some embodiments, R 2 is a 5-membered heterocyclyl. In some embodiments, R 2 is -CN. In some embodiments, R 2 is -CF3. In some embodiments, R 2 is -OR 3 . In some embodiments, R 2 is -SR 3 . In some embodiments, R 2 is -NR 3 R 4 .
  • R 2 is -COR 3 . In some embodiments, R 2 is -CO2R 3 . In some embodiments, R 2 is - CONR 3 R 4 . In some embodiments, R 2 is -NR 3 COR 4 . In some embodiments, R 2 is -SO2R 3 . In some embodiments, R 2 is -SO2NR 3 R 4 . In some embodiments, R 2 is -NR 3 SO2R 4 .
  • each 3-10-membered carbocyclyl and 3-10-membered heterocyclyl may be further substituted with one or more substituents selected from the group consisting of hydrogen, halogen, Ci-ealkyl, -O-Ci-6alkyl, Ci-ehaloalkyl, -O-Ci-ehaloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -CN, -CF3, -OR 5 , -SR 5 , -NR 5 R 6 , -COR 5 , -CO2R 5 , -CONR 5 R 6 , - NR 5 COR 6 , -SO2R 5 , -SO 2 NR 5 R 6 , and -NR 5 SO 2 R 6 .
  • substituents selected from the group consisting of hydrogen, halogen, Ci-ealkyl, -O-Ci-6alkyl, Ci-ehaloalkyl, -O-Ci-ehaloal
  • the 3-10-membered carbocyclyl is substituted with one or more halogen substituents. In some embodiments, the 3-10-membered carbocyclyl is substituted with one or more Ci-ealkyl substituents. In some embodiments, the 3-10- membered carbocyclyl is substituted with one or more -O-Ci-6alkyl substituents. In some embodiments, the 3-10-membered carbocyclyl is substituted with one or more Ci- ehaloalkyl substituents. In some embodiments, the 3-10-membered carbocyclyl is substituted with one or more -O-Ci-ehaloalkyl substituents.
  • the 3- 10-membered carbocyclyl is substituted with one or more Ci ealkcnyl substituents. In some embodiments, the 3-10-membered carbocyclyl is substituted with one or more C2- ealkynyl substituents. In some embodiments, the 3-10-membered carbocyclyl is substituted with one or more -CN substituents. In some embodiments, the 3-10- membered carbocyclyl is substituted with one or more -CF3 substituents. In some embodiments, the 3-10-membered carbocyclyl is substituted with one or more -OR 5 substituents.
  • the 3-10-membered carbocyclyl is substituted with one or more -SR 5 substituents. In some embodiments, the 3-10-membered carbocyclyl is substituted with one or more -COR 5 substituents. In some embodiments, the 3-10- membered carbocyclyl is substituted with one or more halogen substituents. In some embodiments, the 3-10-membered carbocyclyl is substituted with one or more -CO2R 5 substituents. In some embodiments, the 3-10-membered carbocyclyl is substituted with one or more -CONR 5 R 6 substituents.
  • the 3-10-membered carbocyclyl is substituted with one or more -NR 5 COR 6 substituents. In some embodiments, the 3-10-membered carbocyclyl is substituted with one or more -SO2R 5 substituents. In some embodiments, the 3-10-membered carbocyclyl is substituted with one or more -SO2NR 5 R 6 substituents. In some embodiments, the 3-10-membered carbocyclyl is substituted with one or more -NR 5 SO2R 6 substituents.
  • R 1 is a 6-membered carbocyclyl and is substituted with one or more substituents selected from the group consisting of hydrogen, halogen, Ci- ealkyl, -O-Ci-6alkyl, Ci-ehaloalkyl, -O-Ci-ehaloalkyl, C2-6alkenyl, C2-6alkynyl, -CN, -CF3, -OR 5 , -SR 5 , -NR 5 R 6 , -COR 5 , -CO2R 5 , -CONR 5 R 6 , -NR 5 COR 6 , -SO2R 5 , -SO 2 NR 5 R 6 , and -NR 5 SO2R 6 .
  • substituents selected from the group consisting of hydrogen, halogen, Ci- ealkyl, -O-Ci-6alkyl, Ci-ehaloalkyl, -O-Ci-ehaloalkyl, C2-6alkeny
  • R 1 is a 5-membered carbocyclyl and is substituted with one or more substituents selected from the group consisting of hydrogen, halogen, Ci-6alkyl, -O-Ci-6alkyl, Ci-ehaloalkyl, -O-Ci-ehaloalkyl, C2-6alkenyl, C2-6alkynyl, -CN, - CF 3 , -OR 5 , -SR 5 , -NR 5 R 6 , -COR 5 , -CO2R 5 , -CONR 5 R 6 , -NR 5 COR 6 , -SO2R 5 , -SO 2 NR 5 R 6 , and -NR 5 SO 2 R 6 .
  • substituents selected from the group consisting of hydrogen, halogen, Ci-6alkyl, -O-Ci-6alkyl, Ci-ehaloalkyl, -O-Ci-ehaloalkyl, C2-6alkenyl
  • the 3-10-membered heterocyclyl is substituted with one or more halogen substituents. In some embodiments, the 3-10-membered heterocyclyl is substituted with one or more Ci-ealkyl substituents. In some embodiments, the 3-10- membered heterocyclyl is substituted with one or more -O-Ci-6alkyl substituents. In some embodiments, the 3-10-membered heterocyclyl is substituted with one or more Ci- ehaloalkyl substituents. In some embodiments, the 3-10-membered heterocyclyl is substituted with one or more -O-Ci-ehaloalkyl substituents.
  • the 3- 10-membered heterocyclyl is substituted with one or more C2-6alkenyl substituents. In some embodiments, the 3-10-membered heterocyclyl is substituted with one or more C2- ealkynyl substituents. In some embodiments, the 3-10-membered heterocyclyl is substituted with one or more -CN substituents. In some embodiments, the 3-10- membered heterocyclyl is substituted with one or more -CF3 substituents. In some embodiments, the 3-10-membered heterocyclyl is substituted with one or more -OR 5 substituents. In some embodiments, the 3-10-membered heterocyclyl is substituted with one or more -SR 5 substituents.
  • the 3-10-membered heterocyclyl is substituted with one or more -COR 5 substituents. In some embodiments, the 3-10- membered heterocyclyl is substituted with one or more halogen substituents. In some embodiments, the 3-10-membered heterocyclyl is substituted with one or more -CO2R 5 substituents. In some embodiments, the 3-10-membered heterocyclyl is substituted with one or more -CONR 5 R 6 substituents. In some embodiments, the 3-10-membered heterocyclyl is substituted with one or more -NR 5 COR 6 substituents.
  • the 3-10-membered heterocyclyl is substituted with one or more -SO2R 5 substituents. In some embodiments, the 3-10-membered heterocyclyl is substituted with one or more -SO2NR 5 R 6 substituents. In some embodiments, the 3-10-membered heterocyclyl is substituted with one or more -NR 5 SO2R 6 substituents.
  • R 2 is a 6-membered carbocyclyl and is substituted with one or more substituents selected from the group consisting of hydrogen, halogen, Ci- ealkyl, -O-Ci-6alkyl, Ci-ehaloalkyl, -O-Ci-ehaloalkyl, C2-6alkenyl, C2-6alkynyl, -CN, -CF 3 , -OR 5 , -SR 5 , -NR 5 R 6 , -COR 5 , -CO2R 5 , -CONR 5 R 6 , -NR 5 COR 6 , -SO2R 5 , -SO 2 NR 5 R 6 , and -NR 5 SO2R 6 .
  • substituents selected from the group consisting of hydrogen, halogen, Ci- ealkyl, -O-Ci-6alkyl, Ci-ehaloalkyl, -O-Ci-ehaloalkyl, C2-6al
  • R 2 is a 5-membered carbocyclyl and is substituted with one or more substituents selected from the group consisting of hydrogen, halogen, Ci-6alkyl, -O-Ci-6alkyl, Ci-ehaloalkyl, -O-Ci-ehaloalkyl, C2-6alkenyl, C2-6alkynyl, -CN, - CF 3 , -OR 5 , -SR 5 , -NR 5 R 6 , -COR 5 , -CO2R 5 , -CONR 5 R 6 , -NR 5 COR 6 , -SO2R 5 , -SO 2 NR 5 R 6 , and -NR 5 SO 2 R 6 .
  • substituents selected from the group consisting of hydrogen, halogen, Ci-6alkyl, -O-Ci-6alkyl, Ci-ehaloalkyl, -O-Ci-ehaloalkyl, C2-6alkenyl
  • each R 3 and R 4 are independently selected from the group consisting of hydrogen, Ci-ealkyl, 3-7-membered carbocyclyl and 3-7-membered heterocyclyl.
  • R 3 is hydrogen. In some embodiments, R 3 is Ci-6alkyl. In some embodiments, R 3 is 3-7-membered carbocyclyl. In some embodiments, R 3 is 3-7- membered carbocyclyl. In some embodiments, R 3 is a 5-membered carbocyclyl. In some embodiments R 3 is a 6-membered carbocyclyl.
  • R 4 is hydrogen. In some embodiments, R 4 is Ci-ealkyl. In some embodiments, R 4 is 3-7-membered carbocyclyl. In some embodiments, R 4 is 3-7- membered carbocyclyl. In some embodiments, R 4 is a 5-membered carbocyclyl. In some embodiments R 4 is a 6-membered carbocyclyl.
  • each R 5 and R 6 are independently selected from the group consisting of hydrogen and Ci-ealkyl.
  • R 5 is hydrogen. In some embodiments, R 5 is Ci-6alkyl.
  • R 6 is hydrogen. In some embodiments, R 6 is Ci-6alkyl.
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, 3-10-membered carbocyclyl, 3-10-membered heterocyclyl, -OH, -CN, and -NH2. If present, each 3-10-membered carbocyclyl and 3- 10-membered heterocyclyl may be further substituted with one or more substituents selected from the group consisting of hydrogen, halogen, -OH, -CN, -CF3, -NH2, and Ci- ealkyl.
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, 6-membered carbocyclyl, 6-membered heterocyclyl, - OH, -CN, and -NH2. If present, each 6-membered carbocyclyl and 6-membered heterocyclyl may be further substituted with one or more substituents selected from the group consisting of hydrogen, halogen, -OH, -CN, -CF3, -NH2, and Ci-ealkyl.
  • R 1 is selected from the group consisting of hydrogen, halogen, -OH, -CN, -CF3, -NH2, and Ci-ealkyl
  • R 2 is independently selected from the group consisting of:
  • R 1 is hydrogen and R 2 is independently selected from the group consisting of: and
  • R 1 is halogen and R 2 is independently selected from the group consisting of:
  • R 1 is -OH and R 2 is independently selected from the group consisting of:
  • R 1 is -CN and R 2 is independently selected from the group consisting of:
  • R 1 is -CF3 and R 2 is independently selected from the group consisting of:
  • R 1 is -NH2 and R 2 is independently selected from the group consisting of:
  • R 1 is Ci-ealkyl and R 2 is independently selected from the group consisting of: In some embodiments, R 1 is chlorine and R 2 is independently selected from the group consisting of:
  • R 1 is bromine and R 2 is independently selected from the group consisting of: and
  • R 1 is fluorine and R 2 is independently selected from the group consisting of:
  • R 1 is iodine and R 2 is independently selected from the group consisting of:
  • R 2 is selected from the group consisting of hydrogen, halogen, -OH, -CN, -CF3, -NH2, and Ci-ealkyl
  • R 1 is independently selected from the group consisting of:
  • R 2 is hydrogen and R 1 is independently selected from the group consisting of: and
  • R 2 is halogen and R 1 is independently selected from the group consisting of:
  • R 2 is -OH and R 1 is independently selected from the group consisting of:
  • R 2 is -CN and R 1 is independently selected from the group consisting of:
  • R 2 is -CF3 and R 1 is independently selected from the group consisting of:
  • R 2 is -NH2 and R 1 is independently selected from the group consisting of:
  • R 2 is Ci-ealkyl and R 1 is independently selected from the group consisting of: In some embodiments, R 2 is chlorine and R 1 is independently selected from the group consisting of:
  • R 2 is bromine and R 1 is independently selected from the group consisting of: and
  • R 2 is fluorine and R 1 is independently selected from the group consisting of: In some embodiments, R 2 is iodine and R 1 is independently selected from the group consisting of:
  • R 1 and R 2 are each independently selected from the group consisting of: and
  • the compound of Formula I is:
  • the compound of Formula I is:
  • the compound of Formula I is:
  • the compound of Formula I is:
  • the compound of Formula I is:
  • the compound of Formula I is:
  • the compound of Formula I is:
  • the compound of Formulae s any stereoisomers of the depicted structure. That is, the compound of Formulaes a racemic mixture.
  • a compound of Formula la has the following chemical structure:
  • R 1 and R 2 are the same as those provided for a compound of Formula I. That is, the difference between a compound of Formula I and a compound of Formula la is that the stereochemistry in a compound of Formula la has been resolved.
  • the compound of Formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof, has the following chemical structure:
  • the compound of Formula lai when having such particular stereochemistry, is also referred to as “UE2343” or “Xanamem”, and has CAS No.: 1346013-80-6.
  • the chemical name (i.e., IUPAC name) of Formula lai is (5-(lH-Pyrazol-4-yl)thiophen-3- yl)(3-hydroxy-3-(pyrimidin-2-yl)-8-azabicyclo[3.2.1] octan-8-yl)methanone.
  • the compound of Formula I may be provided in the immediate-release tablet formulation in an suitable form (e.g., amorphous, crystalline).
  • the compound of Formula I is provided in the immediate-release tablet formulation as an amorphous solid.
  • the compound of Formula I is provided in the immediate-release tablet formulation as a crystalline solid.
  • the compound of Formula la is provided in the immediate-release tablet formulation as an amorphous solid.
  • the compound of Formula la is provided in the immediate-release tablet formulation as a crystalline solid.
  • the compound of Formula lai is provided in the immediate -release tablet formulation as an amorphous solid.
  • the compound of Formula lai is provided in the immediate-release tablet formulation as a crystalline solid.
  • the solid may be in the form of a powder.
  • the compound of Formula I is provided in the immediate- release tablet formulation as a crystalline powder.
  • the compound of Formula la is provided in the immediate-release tablet formulation as a crystalline powder.
  • the compound of Formula lai is provided in the immediate- release tablet formulation as a crystalline powder.
  • a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof may be prepared by any suitable method as would be understood by the person skilled in the art.
  • a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof may be prepared in accordance with the procedure described in WO2011135276, which is herein incorporated by reference thereto.
  • a corresponding salt of the compound such as, for example, a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salt refers to pharmaceutically acceptable organic or inorganic salts. Examples of pharmaceutically acceptable salts are discussed in Berge etal., 1977, “Pharmaceutically Acceptable Salts,” J. Pharm. Sci., vol. 66, pl-19.
  • a salt may be formed with a suitable cation.
  • suitable inorganic cations include, but are not limited to, alkali metal ions such as Na + and K + , alkaline earth cations such as Ca 2+ and Mg 2+ , and other cations such as Al 3+ .
  • suitable organic cations include, but are not limited to, ammonium ion (i.e., NH4 + ) and substituted ammonium ions (e.g., NH3R + , NH2R2 + , NHR3 + , NR 4 + ).
  • Suitable substituted ammonium ions include, but are not limited to, those derived from ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine.
  • An example of a common quaternary ammonium ion is N(CH3)4 + .
  • a salt may be formed with a suitable anion.
  • suitable inorganic cations include, but are not limited to, those derived from the inorganic acids including hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous.
  • Suitable organic anions include, but are not limited to, those derived from the organic acids including 2-acetyoxybenzoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucheptonic, gluconic, glutamic, glycolic, hydroxy maleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicyclic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, and valeric.
  • a pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counterion.
  • the counterion may be any organic or inorganic moiety that stabilises the charge on the parent compound.
  • a pharmaceutically acceptable salt may have more than one charged atom in its structure. Instances where multiple charged atoms are part of the pharmaceutically acceptable salt can have multiple counter ions. Hence, a pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counterion.
  • non-pharmaceutically acceptable salts also fall within the scope of the present disclosure since these may be useful as intermediates in the preparation of pharmaceutically acceptable salts or may be useful during storage or transport. Unless otherwise specified herein, reference to a particular compound also includes salts thereof.
  • solvates refers to such a complex of solute (e.g., a compound, salt of a compound) and solvent.
  • solvents that may form pharmaceutically acceptable solvates include, but are not limited to, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.
  • the solvate may be conventionally referred to as a “hydrate”.
  • the pharmaceutically acceptable solvate is a pharmaceutically acceptable hydrate.
  • the hydrate may be, for example, a mono-hydrate, a di-hydrate, a tri-hydrate, etc. Unless otherwise specified herein, reference to a particular compound also includes solvates thereof.
  • prodrug refers to compound which, when metabolised (e.g., in vivo), yields the desired active compound.
  • the prodrug is inactive, or less active that the desired active compound, but may provide advantageous handling, administration, or metabolic properties.
  • some prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound.
  • the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative.
  • the immediate-release tablet formulation comprises a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, in an amount (w/w) of between about 1% and about 50%, between about 5% and about 40%, between about 7.5% and about 30%, or between about 10% and about 20%.
  • the immediate -release tablet formulation comprises a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, in an amount (w/w) of at least about 1%, at least about 5%, at least about 7.5%, at least about 10%, at least about 15%, or at least about 20%.
  • the immediate -release tablet formulation comprises a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, in an amount (w/w) of less than about 50%, less than about 40%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, or less than about 10%.
  • the immediate-release tablet formulation comprises a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, in an amount (w/w) of about 5%, about 7.5%, about 10%, about 12.5%, about 15%, about 17.5%, about 20%, about 25%, or about 30%.
  • the immediate- release tablet formulation comprises a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, in an amount (w/w) of between about 10% and about 20%. In one example, the immediate-release tablet formulation comprises a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, in an amount (w/w) of about 10%. In one example, the immediate -release tablet formulation comprises a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, in an amount (w/w) of about 20%.
  • the immediate-release tablet formulation may comprise a diluent.
  • a “diluent” refers to a substance used to dilute an active ingredient.
  • the immediate -release tablet formulation comprises a diluent.
  • the diluent may be provided as either of an intragranular component or an extragranular component.
  • the diluent is an intragranular component.
  • the diluent is an extragranular component.
  • diluents include, but are not limited to, anhydrous lactose, lactose monohydrate, spray-dried lactose, dibasic calcium phosphate dehydrate, dibasic calcium phosphate anhydrous, starch (e.g., maize, potato, wheat, pea), pregelatinised starch, dextrose, dextrin, kaolin, calcium carbonate, calcium lactate, cellulose acetate, erythritol, ethylcellulose, fructose, isomalt, lactitol, polydextrose, semimethicone, trehalose, and sugar alcohols such as sorbitol, xylitol, and mannitol.
  • the diluent is lactose.
  • the diluent is lactose monohydrate.
  • the diluent is microcrystalline cellulose (MCC).
  • lactose may act as a diluent in the immediate-release tablet formulation.
  • the immediate-release tablet formulation comprises lactose as a diluent.
  • microcrystalline cellulose (MCC) may act as a diluent in the immediate -release tablet formulation.
  • the immediate -release tablet formulation comprises microcrystalline cellulose (MCC) as a diluent.
  • lactose is an intragranular component.
  • lactose is an extragranular component.
  • microcrystalline cellulose (MCC) is an intragranular component.
  • microcrystalline cellulose (MCC) is an extragranular component.
  • the immediate-release tablet formulation comprises total lactose in an amount (w/w) of between about 20% and about 70%, between about 30% and about 60%, between about 40% and about 50%, or between about 41% and about 49%. In some embodiments, the immediate-release tablet formulation comprises total lactose in an amount (w/w) of at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 42%, at least about 45%, or at least about 47%. In some embodiments, the immediate-release tablet formulation comprises total lactose in an amount (w/w) of less than about 90%, less than about 80%, less than about 70%, less than about 60%, or less than about 50%.
  • the immediate -release tablet formulation comprises total lactose in an amount (w/w) of about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, or about 50%. In one example, the immediate-release tablet formulation comprises total lactose in an amount (w/w) of between about 40% and about 50%. In one example, the immediate-release tablet formulation comprises total lactose in an amount (w/w) of about 48%. In one example, the immediate -release tablet formulation comprises total lactose in an amount (w/w) of about 42%. In one example, the immediate-release tablet formulation comprises total lactose in an amount (w/w) of about 48.5%. In one example, the immediate-release tablet formulation comprises total lactose in an amount (w/w) of about 42.5%.
  • the immediate -release tablet formulation comprises total microcrystalline cellulose in an amount (w/w) of between about 20% and about 50%, between about 25% and about 40%, between about 27.5% and about 35%, or between about 30% and about 32.5%. In some embodiments, the immediate -release tablet formulation comprises total microcrystalline cellulose in an amount (w/w) of at least about 10%, at least about 20%, at least about 25%, at least about 27.5%, at least about 30%, or at least about 32.5%. In some embodiments, the immediate-release tablet formulation comprises total microcrystalline cellulose in an amount (w/w) of less than about 70%, less than about 60%, less than about 50%, less than about 40%, or less than about 35%.
  • the immediate-release tablet formulation comprises total microcrystalline cellulose in an amount (w/w) of about 25%, about 27.5%, about 28%, about 28.5%, about 29%, about 30%, about 30.5%, about 31%, about 31.5%, about 32%, about 32.5%, or about 33%.
  • the immediate-release tablet formulation comprises total microcrystalline cellulose in an amount (w/w) of between about 27% and about 33%.
  • the immediate-release tablet formulation comprises total microcrystalline cellulose in an amount (w/w) of about 32%.
  • the immediate-release tablet formulation comprises total microcrystalline cellulose in an amount (w/w) of about 28%.
  • the immediate-release tablet formulation comprises total microcrystalline cellulose in an amount (w/w) of about 32.5%.
  • the immediate -release tablet formulation comprises total microcrystalline cellulose in an amount (w/w) of about 28.5%.
  • the immediate -release tablet formulation comprises total diluent in an amount (w/w) of between about 5% and about 90%, between about 10% and about 80%, between about 20% and about 80%, between about 30% and about 80%, or between about 40% and about 80%. In some embodiments, the immediate-release tablet formulation comprises total diluent in an amount (w/w) of at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, or at least about 80%.
  • the immediate- release tablet formulation comprises total diluent in an amount (w/w) of less than about 95%, less than about 90%, less than about 85%, less than about 80%, or less than about 75%. In some embodiments, the immediate-release tablet formulation comprises total diluent in an amount (w/w) of about 40%, about 50%, about 60%, about 70%, about 75%, about 80%, about 85%, or about 90%. In one example, the immediate-release tablet formulation comprises total diluent in an amount (w/w) of about 80%. In one example, the immediate-release tablet formulation comprises total diluent in an amount (w/w) of about 81%. In one example, the immediate -release tablet formulation comprises total diluent in an amount (w/w) of about 70%. In one example, the immediate-release tablet formulation comprises total diluent in an amount (w/w) of about 71%.
  • the immediate -release tablet formulation may comprise a disintegrant.
  • disintegrant refers to a substance added to a tablet to facilitate its disintegration into smaller units/fragments to allow for dissolution.
  • the disintegrant may be provided as either of an intragranular component or an extragranular component. In one example, the disintegrant is an intragranular component. In one example, the disintegrant is an extragranular component.
  • disintegrants examples include, but are not limited to, crospovidone, croscarmellose sodium (e.g., Ac-Di-Sol SD-711), sodium starch glycolate (e.g., Explotab), low-substituted hydroxypropyl cellulose, chitosan hydrochloride, corn starch, pregelatinised starch, calcium alginate, calcium sodium alginate, docusate sodium, microcrystalline cellulose, hydroxypropyl starch, magnesium aluminate silicate, methylcellulose, sodium alginate, starch, calcium carboxymethylcellulose, calcium cellulose glycolate, carmellose calcium, and powdered cellulose.
  • the disintegrant is sodium starch glycolate (e.g., Explotab).
  • the disintegrant is croscarmellose sodium (e.g., Ac-Di-Sol SD-711).
  • the immediate-release tablet formulation comprises total sodium starch glycolate in an amount (w/w) of between about 0.1% and about 10%, between about 0.5% and about 5%, or between about 1% and about 3%. In some embodiments, the immediate -release tablet formulation comprises total sodium starch glycolate in an amount (w/w) of at least about 0.1%, at least about 0.5%, at least about 1%, at least about 1.5%, or at least about 2%. In some embodiments, the immediate- release tablet formulation comprises total sodium starch glycolate in an amount (w/w) of less than about 10%, less than about 5%, less than about 4%, less than about 3%, or less than about 2%.
  • the immediate -release tablet formulation comprises total sodium starch glycolate in an amount (w/w) of about 0.5%, about 1%, about 1.5%, about 2%, about 2.5%, or about 3%. In one example, the immediate-release tablet formulation comprises total sodium starch glycolate in an amount (w/w) of about 2%.
  • the immediate -release tablet formulation comprises total croscarmellose sodium in an amount (w/w) of between about 0.1% and about 10%, between about 0.5% and about 5%, or between about 1% and about 3%. In some embodiments, the immediate-release tablet formulation comprises total croscarmellose sodium in an amount (w/w) of at least about 0.1%, at least about 0.5%, at least about 1%, at least about 1.5%, or at least about 2%. In some embodiments, the immediate -release tablet formulation comprises total croscarmellose sodium in an amount (w/w) of less than about 10%, less than about 5%, less than about 4%, less than about 3%, or less than about 2%.
  • the immediate-release tablet formulation comprises total croscarmellose sodium in an amount (w/w) of about 0.5%, about 1%, about 1.5%, about 2%, about 2.5%, or about 3%. In one example, the immediate -release tablet formulation comprises total croscarmellose sodium in an amount (w/w) of about 2%.
  • the immediate-release tablet formulation comprises total diluent in an amount (w/w) of about 0.1%, about 0.5%, about 1%, about 1.5%, about 2%, about 2.5%, or about 3%. In one example, the immediate -release tablet formulation comprises total disintegrant in an amount (w/w) of about 4%.
  • the immediate-release tablet formulation may comprise a glidant.
  • glidant refers to a substance added to a powder to improve its flowability, for example, to enhance the flow of a granular mixture.
  • the glidant is typically provided as an intragranular component.
  • the glidant is an intragranular component.
  • glidants include, but are not limited to, colloidal silicon dioxide, talc, tribasic calcium phosphate, calcium silicate, cellulose (powdered), magnesium oxide, sodium stearate, magnesium silicate, silica, magnesium trisilicate, and hydrophobic colloidal silica.
  • the glidant is colloidal silicon dioxide (Cab-O-Sil M5P).
  • the immediate -release tablet formulation comprises total colloidal silicon dioxide in an amount (w/w) of between about 0.1% and about 10%, between about 0.5% and about 5%, between about 1% and about 3%, or between about 1% and about 2%.
  • the immediate-release tablet formulation comprises total colloidal silicon dioxide in an amount (w/w) of at least about 0.1%, at least about 0.5%, at least about 1%, at least about 1.5%, at least about 2%, or at least about 2.5%. In some embodiments, the immediate-release tablet formulation comprises total colloidal silicon dioxide in an amount (w/w) of less than about 10%, less than about 7%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1%. In some embodiments, the immediate -release tablet formulation comprises total colloidal silicon dioxide in an amount (w/w) of about 0.1%, about 0.5%, about 1%, about 1.5%, about 2%, about 2.5%, or about 3%.
  • the immediate-release tablet formulation comprises total colloidal silicon dioxide in an amount (w/w) of between about 1% and about 2%. In one example, the immediate- release tablet formulation comprises total colloidal silicon dioxide in an amount (w/w) of about 1%. In one example, the immediate -release tablet formulation comprises total colloidal silicon dioxide in an amount (w/w) of about 2%.
  • the immediate -release tablet formulation comprises total glidant in an amount (w/w) of between about 0.1% and about 10%, between about 0.5% and about 5%, between about 1% and about 3%, or between about 1% and about 2%. In some embodiments, the immediate-release tablet formulation comprises total glidant in an amount (w/w) of at least about 0.1%, at least about 0.5%, at least about 1%, at least about 1.5%, at least about 2%, or at least about 2.5%.
  • the immediate-release tablet formulation comprises total glidant in an amount (w/w) of less than about 10%, less than about 7%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1%. In some embodiments, the immediate-release tablet formulation comprises total glidant in an amount (w/w) of about 0.1%, about 0.5%, about 1%, about 1.5%, about 2%, about 2.5%, or about 3%. In one example, the immediate-release tablet formulation comprises total glidant in an amount (w/w) of between about 1% and about 2%. In one example, the immediate-release tablet formulation comprises total glidant in an amount (w/w) of about 1%. In one example, the immediate-release tablet formulation comprises total glidant in an amount (w/w) of about 2%.
  • the immediate -release tablet formulation may comprise a lubricant.
  • lubricant refers to a substance added to the formulation to prevent adhesion of the formulation to the surfaces of the dies and/or punches utilised in the tablet manufacturing process.
  • a lubricant may also improve the flow properties of the powder blend and granules.
  • lubricants include, but are not limited to, magnesium stearate, magnesium silicate, calcium stearate, sodium lauryl sulfate, sodium stearyl fumarate, magnesium lauryl sulfate, stearic acid, calcium stearate, glyceryl behenate, lauric acid, glyceryl monostearate, glyceryl tristearate, myristic acid, palmitic acid, poloxamer, polyethylene glycol, polysorbate 20, polysorbate 40, potassium benzoate, sodium benzoate, sorbitan monolaurate, sorbitan monooleate, sodium stearate, zinc stearate, sorbitan trioleate, and talc.
  • the lubricant is magnesium stearate (Hyqual 2257).
  • the immediate -release tablet formulation comprises total magnesium stearate in an amount (w/w) of between about 0.1% and about 10%, between about 0.5% and about 5%, between about 1% and about 4%, or between about 1.5% and about 3%. In some embodiments, the immediate-release tablet formulation comprises total magnesium stearate in an amount (w/w) of at least about 0.1%, at least about 0.5%, at least about 1%, at least about 1.5%, at least about 2%, at least about 2.5%, or at least about 3%. In some embodiments, the immediate-release tablet formulation comprises total magnesium stearate in an amount (w/w) of less than about 10%, less than about 5%, less than about 4%, less than about 3%, or less than about 2%.
  • the immediate -release tablet formulation comprises total magnesium stearate in an amount (w/w) of about 0.5%, about 1%, about 1.5%, about 2%, about 2.5%, or about 3%. In one example, the immediate -release tablet formulation comprises magnesium stearate in an amount (w/w) of between about 1.5% and about 3%. In one example, the immediate-release tablet formulation comprises total magnesium stearate in an amount (w/w) of about 1.5%. In one example, the immediate-release tablet formulation comprises total magnesium stearate in an amount (w/w) of about 3%.
  • the immediate -release tablet formulation comprises total lubricant in an amount (w/w) of between about 0.1% and about 10%, between about 0.5% and about 5%, between about 1% and about 4%, or between about 1.5% and about 3%. In some embodiments, the immediate-release tablet formulation comprises total lubricant in an amount (w/w) of at least about 0.1%, at least about 0.5%, at least about 1%, at least about 1.5%, at least about 2%, at least about 2.5%, or at least about 3%. In some embodiments, the immediate-release tablet formulation comprises total lubricant in an amount (w/w) of less than about 10%, less than about 5%, less than about 4%, less than about 3%, or less than about 2%.
  • the immediate -release tablet formulation comprises total lubricant in an amount (w/w) of about 0.5%, about 1%, about 1.5%, about 2%, about 2.5%, or about 3%. In one example, the immediate-release tablet formulation comprises total lubricant in an amount (w/w) of between about 1.5% and about 3%. In one example, the immediate -release tablet formulation comprises total lubricant in an amount (w/w) of about 1.5%. In one example, the immediate-release tablet formulation comprises total lubricant in an amount (w/w) of about 3%.
  • the immediate -release tablet formulation may comprise a film coating.
  • film coating refers to a substance used to coat the tablet.
  • film coatings include, but are not limited to, solvents, plasticisers, colourants/pigments, and opaquant-extenders.
  • the film coating comprises a polymer, plasticiser, and colourant/pigment.
  • the film coating is Opdary TF (Opadry TF, Titanium- free, 276U180005, white).
  • the immediate -release tablet formulation comprises total Opadry TF in an amount (w/w) of between about 0.1% and about 10%, between about 0.5% and about 5%, between about 1% and about 4%, or between about 1.5% and about 3%. In some embodiments, the immediate-release tablet formulation comprises total Opadry TF in an amount (w/w) of at least about 0.1%, at least about 0.5%, at least about 1%, at least about 1.5%, at least about 2%, at least about 2.5%, or at least about 3%. In some embodiments, the immediate -release tablet formulation comprises total Opadry TF in an amount (w/w) of less than about 10%, less than about 5%, less than about 4%, less than about 3%, or less than about 2%.
  • the immediate -release tablet formulation comprises total Opadry TF in an amount (w/w) of about 0.5%, about 1%, about 1.5%, about 2%, about 2.5%, or about 3%. In one example, the immediate-release tablet formulation comprises total Opadry TF in an amount (w/w) of between about 1.5% and about 3%. In one example, the immediate -release tablet formulation comprises total Opadry TF in an amount (w/w) of about 1.5%. In one example, the immediate -release tablet formulation comprises total Opadry TF in an amount (w/w) of about 3%.
  • the immediate -release tablet formulation will comprise a net weight.
  • the net weight will be understood to mean the total weight of the intragranular and extragranular components of the tablet.
  • the net weight of the immediate -release tablet is about 5 mg, about 10 mg, about 25 mg, about 40 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 500 mg, about 750 mg, or about 1000 mg.
  • the net weight if the immediate -release tablet is greater than about 5 mg, about 10 mg, about 25 mg, about 40 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 500 mg, about 750 mg, or about 1000 mg.
  • the net weight of the immediate-release tablet is between about 5 mg and about 1000 mg, between about 10 mg and about 500 mg, between about 25 mg and about 200 mg, or between about 50 mg and about 100 mg. In one example, the net weight of the immediate -release tablet is about 50 mg. In one example, the net weight of the immediate-release tablet is about 100 mg.
  • the immediate-release tablet formulation will have a film coating applied.
  • the weight of the film-coating is about 0.2 mg, about 0.5 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, or about 5.0 mg.
  • the immediate -release tablet formulation will have a total weight (net weight plus film-coating weight).
  • the net weight of the immediate-release tablet formulation is about 50 mg, and the total weight of the immediate-release tablet is about 51.5 mg.
  • the net weight of the immediate-release tablet formulation is about 100 mg, and the total weight of the immediate-release formulation is about 103 mg.
  • the amount of the active ingredient may also be used to define the immediate-release tablet formulation.
  • a “10 mg dose tablet” will refer to the immediate-release tablet formulation comprising about 10 mg of active ingredient (i.e., a compound of Formula I, or pharmaceutically acceptable salt or solvate thereof). That is, about a 10 mg dose of the active ingredient is provided in each “10 mg dose tablet”.
  • a “5 mg dose tablet” will refer to the immediate- release tablet formulation comprising about 5 mg of active ingredient (i.e., a compound of Formula I, or pharmaceutically acceptable salt or solvate thereof). That is, about a 5 mg dose of the active ingredient is provided in each “5 mg dose tablet”.
  • the immediate-release tablet formulation is a “10 mg dose tablet”.
  • the immediate-release tablet formulation is a “5 mg dose tablet”.
  • an immediate-release tablet formulation comprising the compound of Formula I, or pharmaceutically acceptable salt or solvate thereof, in an amount (w/w) of about 10% to about 20%; lactose monohydrate in an amount (w/w) of about 40% to about 50%; microcrystalline cellulose in an amount (w/w) of about 25% to 35%; and one or more pharmaceutically acceptable excipients in an amount (w/w) up to 100%.
  • an immediate-release tablet formulation consisting of the compound of Formula I, or pharmaceutically acceptable salt or solvate thereof, in an amount (w/w) of about 10% to about 20%; lactose monohydrate in an amount (w/w) of about 40% to about 50%; microcrystalline cellulose in an amount (w/w) of about 25% to 35%; and optionally one or more pharmaceutically acceptable excipients in an amount (w/w) up to 100%.
  • an immediate-release tablet formulation comprising the compound of Formula I, or pharmaceutically acceptable salt or solvate thereof, in an amount (w/w) of about 10%; lactose monohydrate in an amount (w/w) of about 48.5%; microcrystalline cellulose in an amount (w/w) of about 32.5%; and one or more pharmaceutically acceptable excipients in an amount (w/w) up to 100%.
  • an immediate-release tablet formulation comprising the compound of Formula lai, or pharmaceutically acceptable salt or solvate thereof, in an amount (w/w) of about 10%; lactose monohydrate in an amount (w/w) of about 48.5%; microcrystalline cellulose in an amount (w/w) of about 32.5%; sodium starch glycolate in an amount (w/w) of about 2%; croscarmellose sodium in an amount (w/w) of about 2%; colloidal silicon dioxide in an amount (w/w) of about 2%; and magnesium stearate in an amount (w/w) of about 3%.
  • an immediate-release tablet formulation consisting of the compound of Formula lai, or pharmaceutically acceptable salt or solvate thereof, in an amount (w/w) of about 10%; lactose monohydrate in an amount (w/w) of about 48.5%; microcrystalline cellulose in an amount (w/w) of about 32.5%; sodium starch glycolate in an amount (w/w) of about 2%; croscarmellose sodium in an amount (w/w) of about 2%; colloidal silicon dioxide in an amount (w/w) of about 2%; and magnesium stearate in an amount (w/w) of about 3%.
  • an immediate-release tablet formulation comprising the compound of Formula I, or pharmaceutically acceptable salt or solvate thereof, in an amount (w/w) of about 20%; lactose monohydrate in an amount (w/w) of about 42.5%; microcrystalline cellulose in an amount (w/w) of about 28.5%; and one or more pharmaceutically acceptable excipients in an amount (w/w) up to 100%.
  • an immediate-release tablet formulation consisting of the compound of Formula I, or pharmaceutically acceptable salt or solvate thereof, in an amount (w/w) of about 20%; lactose monohydrate in an amount (w/w) of about 42.5%; microcrystalline cellulose in an amount (w/w) of about 28.5%; and optionally one or more pharmaceutically acceptable excipients in an amount (w/w) up to 100%.
  • an immediate-release tablet formulation comprising the compound of Formula lai, or pharmaceutically acceptable salt or solvate thereof, in an amount (w/w) of about 20%; lactose monohydrate in an amount (w/w) of about 42.5%; microcrystalline cellulose in an amount (w/w) of about 28.5%; sodium starch glycolate in an amount (w/w) of about 2%; croscarmellose sodium in an amount (w/w) of about 2%; colloidal silicon dioxide in an amount (w/w) of about 2%; and magnesium stearate in an amount (w/w) of about 3%.
  • an immediate-release tablet formulation consisting of the compound of Formula lai, or pharmaceutically acceptable salt or solvate thereof, in an amount (w/w) of about 20%; lactose monohydrate in an amount (w/w) of about 42.5%; microcrystalline cellulose in an amount (w/w) of about 28.5%; sodium starch glycolate in an amount (w/w) of about 2%; croscarmellose sodium in an amount (w/w) of about 2%; colloidal silicon dioxide in an amount (w/w) of about 2%; and magnesium stearate in an amount (w/w) of about 3%.
  • the immediate -release tablet formulation is a 10 mg dose tablet (i.e., each tablet comprises about 10 mg of the active ingredient).
  • a 10 mg dose tablet has a net weight of about 50 mg. That is, in a 10 mg dose tablet, with a net weight of about 50 mg, the immediate -release tablet formulation comprises about 40 mg of excipients.
  • a 10 mg dose tablet has a total weight of about 51.5 mg.
  • the immediate -release tablet formulation is a 10 mg dose tablet (i.e., each tablet comprises about 10 mg of the active ingredient), and further comprises a diluent, disintegrant, glidant, lubricant, and film-coating.
  • the immediate -release tablet formulation is a 10 mg dose tablet (i.e., each tablet comprises about 10 mg of the active ingredient), and further comprises lactose and microcrystalline cellulose.
  • the immediate -release tablet formulation is a 10 mg dose tablet (i.e., each tablet comprises about 10 mg of the active ingredient), and further comprises lactose and microcrystalline cellulose, and a disintegrant, a glidant, a lubricant, and a film-coating.
  • the immediate-release tablet formulation is a 10 mg dose tablet (i.e., each tablet comprises about 10 mg of the active ingredient), and further comprises between about 20 and about 30 mg lactose, between about 10 mg and about 15 mg microcrystalline cellulose, between about 0.5 mg and about 2 mg sodium starch glycolate, between about 0.5 mg and about 2 mg croscarmellose sodium, between about 0.5 mg and about 2 mg colloidal silicon dioxide, between about 1 mg and about 2 mg magnesium stearate, and between about 1 mg and about 2 mg Opadry TF.
  • the immediate-release tablet formulation is a 10 mg dose tablet (i.e., each tablet comprises about 10 mg of the active ingredient), and further comprises about 21.25 mg lactose, about 14.25 mg microcrystalline cellulose, about 1 mg sodium starch glycolate, about 1 mg croscarmellose sodium, about 1 mg colloidal silicon dioxide, about 1.5 mg magnesium stearate, and about 1.5 mg Opadry TF.
  • the immediate -release tablet formulation is a 10 mg dose tablet (i.e., each tablet comprises about 10 mg of the active ingredient), and further comprises between about 20 mg and about 30 mg lactose, and between about 10 mg and about 15 mg microcrystalline cellulose.
  • the immediate -release tablet formulation is a 10 mg dose tablet (i.e., each tablet comprises about 10 mg of the active ingredient), and further comprises about 21.25 mg lactose, and about 14.25 mg microcrystalline cellulose.
  • the immediate-release tablet formulation is a 10 mg dose tablet (i.e., each tablet comprises about 10 mg of the active ingredient) and has a net weight of about 50 mg. In one example, the immediate-release tablet formulation is a 10 mg dose tablet (i.e., each tablet comprises about 10 mg of the active ingredient) and has a total weight of about 51.5 mg.
  • the immediate-release tablet formulation is a 5 mg dose tablet (i.e., each tablet comprises about 5 mg of the active ingredient).
  • a 5 mg dose tablet has a net weight of about 50 mg. That is, in a 5 mg dose tablet, with a net weight of about 50 mg, the immediate -release tablet formulation comprises about 45 mg of excipients.
  • a 5 mg dose tablet has a total weight of about 51.5 mg.
  • the immediate-release tablet formulation is a 5 mg dose tablet (i.e., each tablet comprises about 5 mg of the active ingredient), and further comprises a diluent, disintegrant, glidant, lubricant, and film-coating.
  • the immediate-release tablet formulation is a 5 mg dose tablet (i.e., each tablet comprises about 5 mg of the active ingredient), and further comprises lactose and microcrystalline cellulose.
  • the immediate -release tablet formulation is a 5 mg dose tablet (i.e., each tablet comprises about 5 mg of the active ingredient), and further comprises lactose and microcrystalline cellulose, and a disintegrant, a glidant, a lubricant, and a film-coating.
  • the immediate-release tablet formulation is a 5 mg dose tablet (i.e., each tablet comprises about 5 mg of the active ingredient), and further comprises between about 20 and about 30 mg lactose, between about 15 mg and about 20 mg microcrystalline cellulose, between about 0.5 mg and about 2 mg sodium starch glycolate, between about 0.5 mg and about 2 mg croscarmellose sodium, between about 0.5 mg and about 2 mg colloidal silicon dioxide, between about 1 mg and about 2 mg magnesium stearate, and between about 1 mg and about 2 mg Opadry TF.
  • the immediate-release tablet formulation is a 5 mg dose tablet (i.e., each tablet comprises about 5 mg of the active ingredient), and further comprises about 24.25 mg lactose, about 16.25 mg microcrystalline cellulose, about 1 mg sodium starch glycolate, about 1 mg croscarmellose sodium, about 1 mg colloidal silicon dioxide, about 1.5 mg magnesium stearate, and about 1.5 mg Opadry TF.
  • the immediate-release tablet formulation is a 5 mg dose tablet (i.e., each tablet comprises about 5 mg of the active ingredient) and has a net weight of about 50 mg. In one example, the immediate-release tablet formulation is a 5 mg dose tablet (i.e., each tablet comprises about 5 mg of the active ingredient) and has a total weight of about 51.5 mg.
  • the immediate-release tablet formulation may be manufactured according to any suitable process as would be understood by the person skilled in the art. This may entail a dry granulation process or a wet granulation process. As would be understood by the person skilled in the art, while dry granulation typically uses mechanical compression or compaction to facilitate the agglomeration of dry powder particles, wet granulation typically uses granulation liquid (e.g., binder, solvent) to facilitate the agglomeration by formation of wet mass by adhesion. Accordingly, in one example, the immediate-release tablet formulation is manufactured using a dry granulation process. In one other example, the immediate-release tablet formulation is manufactured using a wet granulation process.
  • granulation liquid e.g., binder, solvent
  • intragranular component will be understood to be a component added to the formulation prior to the granulation process.
  • extragranular component will be understood to be a component added to the formulation after the granulation process and prior to the compression process.
  • intragranular components include, but are not limited to, an active ingredient, diluent, disintegrant, glidant, and lubricant.
  • the compound of Formula I, or pharmaceutically acceptable salt or solvate thereof is an intragranular component.
  • lactose is an intragranular component.
  • microcrystalline cellulose is an intragranular component.
  • extragranular components include, but are not limited to, a diluent, and lubricant.
  • microcrystalline cellulose is an extragranular component.
  • granules may be prepared by blender mixing of intragranular components, and then granulation using roller compaction and milling to produce the granules.
  • a blend is prepared by blender mixing of the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, lactose, and microcrystalline cellulose.
  • the process comprises blender mixing of further intragranular components, including, but not limited to, any one or more of a diluent, disintegrant, glidant, and lubricant.
  • a blend is prepared by blender mixing of the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, lactose, microcrystalline cellulose, a disintegrant, a glidant, and a lubricant.
  • a blend is prepared by blender mixing of the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, lactose, microcrystalline cellulose, sodium starch glycolate, Croscarmellose sodium, Colloidal silicon dioxide, and magnesium stearate. Subsequent granulation using roller compaction and milling results in the granules.
  • the granules are then blended with extragranular components to yield the final blend. Accordingly, in some embodiments, the granules are blended with extragranular components, including, but not limited to, any one or more of a diluent and lubricant. In one example, the granules are blended with microcrystalline cellulose. In one example, the granules are blended with microcrystalline cellulose and a lubricant. In one example, the granules are blended with microcrystalline cellulose and magnesium stearate.
  • the final blend is then compressed into tablet cores using a rotary tablet press.
  • the tablet cores are film-coated to provide the immediate -release film-coated tablets.
  • the tablet cores are film-coated with film-coating components, including, but not limited to, any one or more of a film-coating agent.
  • the tablet cores are film-coated with a film-coating agent.
  • the tablet cores are film- coated with Opadry FT, Titanium Free (276U180005).
  • the film-coating agent may be provided as a suspension, or otherwise as a solid for dissolution in a suitable solvent.
  • the immediate -release tablet formulation is manufactured by: blender mixing of the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, lactose, microcrystalline cellulose, and any further intragranular components, and then using roller compaction and milling to provide the granules; blending the granules with the microcrystalline cellulose and any further extragranular components to yield the final blend; compression of final blend to produce tablet cores; and film-coating the tablet cores with a film-coating solvent and/or film-coating material.
  • the immediate-release tablet formulation is manufactured by: blender mixing of the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, lactose, microcrystalline cellulose, sodium starch glycolate, Croscarmellose sodium, Colloidal silicon dioxide, and magnesium stearate and then granulation using roller compaction and milling to provide the granules; blending the granules with the microcrystalline cellulose and magnesium stearate to yield the final blend; compression of final blend to produce tablet cores; and film-coating the tablet cores with Opadry FT, Titanium Free (276U180005).
  • the compound of Formula I, or pharmaceutically acceptable salt or solvate thereof, lactose, and microcrystalline cellulose (MCC) are individually screened into a container. If present, other intragranular components are similarly individually screened into a container. In some embodiments, the components are transferred to a blender. In some embodiments, the intragranular components are blended at about 10 rpm, about 20 rpm, about 30 rpm, about 40 rpm, or about 50 rpm. In one example, the intragranular components are blended at about 30 rpm. The intragranular components may be blended for any suitable time so as to provide the suitable pre-blend.
  • the intragranular components are blended for at least about 5 minutes, about 10 minutes, about 11 minutes, about 12 minutes, about 13 minutes, about 14 minutes, about 15 minutes, or about 20 minutes. In one example, the intragranular components are blended for about 13 minutes. In one example, the intragranular components are blended at about 30 rpm for 13 minutes.
  • a lubricant e.g., magnesium stearate
  • a suitable speed e.g., blended at about 10, about 20, about 30, about 40, or about 50 rpm
  • a suitable time at least about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, or about 5 minutes.
  • the pre -blend, as described herein, is transferred to a hopper and roller compacted.
  • the roll gap is between about 0.1 mm and about 5 mm, between about 0.5 mm and about 4 mm, between about 1.0 mm and about 3 mm, or between about 1.5 mm and about 2.5 mm. In one example, the roll gap is between about 1.5 mm and about 2.5 mm.
  • the roll force is between about 1 kN/cm and about 30 kN/cm, between about 5kN/cm and about 20 kN/cm, or between about 6 kN/cm and about 12 kN/cm. In one example, the roll force is between about 6 kN/cm and about 12 kN/cm.
  • the roll speed is between about 0.5 rpm and about 20 rpm, between about 1 rpm and about 10 rpm, between about 1 rpm and about 5 rpm, or between about 1 rpm and about 3 rpm. In one example, the roll speed is between about 1 rpm and about 3 rpm.
  • the mill screen size is between about 0.1 mm and about 5 mm, between about 0.2 mm and about 3 mm, between about 0.3 mm and about 1 mm, or between about 0.5 mm and about 0.8 mm. In one example, the mill screen size is about 0.8 mm.
  • the extragranular components are individually screened. If present in the extragranular components, microcrystalline cellulose (MCC) may also be individually screened.
  • MCC microcrystalline cellulose
  • the extragranular components may be transferred to a blender.
  • the milled granules may be added to the blender.
  • the extragranular components and the milled granules are blended at about 10, about 20, about 30, about 40, or about 50 rpm. In one example, the extragranular components and milled granules are blended at about 30 rpm.
  • the extragranular components and milled granules may be blended for any suitable time so as to provide the suitable final blend.
  • the extragranular components and milled granules are blended for at least about 5 minutes, about 10 minutes, about 11 minutes, about 12 minutes, about 13 minutes, about 14 minutes, about 15 minutes, or about 20 minutes. In one example, the extragranular components and milled granules are blended for about 13 minutes. In one example, the extragranular components and milled granules are blended at about 30 rpm for 13 minutes.
  • any other extragranular components may then be added to the blender and blended at a suitable speed (e.g., blended at about 10, about 20, about 30, about 40, or about 50 rpm) for a suitable time (at least about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, or about 5 minutes).
  • a suitable speed e.g., blended at about 10, about 20, about 30, about 40, or about 50 rpm
  • a suitable time at least about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, or about 5 minutes.
  • Powder compression behaviour is understood to be governed by the physical and mechanical properties of the material, as well as aspects of the compression process such as pressure (i.e., stress), degree of deformation (i.e., strain), and rate of deformation (i.e., strain rate).
  • a tablet is formed by the densification of a loosely packed powder sample confined within a rigid die using two rigid punches that approach from above and below the vertical plane.
  • Various compression methods have been used to characterise the compression properties of pharmaceutical powders/tablets.
  • the compression profile of a tablet is understood to be a function of compactability, compressability, and tabletability.
  • the final blend is compressed on a rotary tablet press with round punches to provide the tablet cores.
  • the diameter of the round punches is between about 3 mm and about 10 mm, between about 3.5 mm and about 7 mm, or between about 4 mm and about 5 mm. In one example, the round punches are 4.76 mm diameter round punches.
  • the average immediate-release tablet core weight is between about 45 mg and about 55 mg, between about 46 mg and about 54 mg, between about 47 mg and about 53 mg, between about 48 mg and about 52 mg, or between about 48.5 mg and about 51.5 mg. In one example, the average immediate-release tablet core weight is between about 48.5 mg and about 51.5 mg. In one example, the average immediate-release tablet core weight is 50.0 mg (+ 3%).
  • the individual immediate-release tablet core weight is between about 40 mg and about 60 mg, between about 45 mg and about 55 mg, between about 46 mg and about 54 mg, or between about 46.5 mg and about 53.5 mg. In one example, the individual immediate-release tablet core weight is between about 46.5 mg and about 53.5 mg. In one example, the individual immediate-release tablet core weight is about 50.0 mg (+ 7%).
  • the average immediate-release tablet core thickness is between about 1.5 mm and about 3.5 mm, between about 2 mm and about 3 mm, or between about 2.4 mm and about 2.8 mm. In one example, the average immediate-release tablet core thickness is between about 2.4 mm and about 2.8 mm.
  • the bulk density (g/mL) of the immediate -release tablet formulation is assessed.
  • “bulk density” is the ratio of the mass of the powder to the volume occupied by the powder. The total volume includes particle volume, inter-particle void volume, and internal pore volume. Bulk density may be measured by any conventional means as known in the art.
  • the bulk density (g/mL) of the immediate-release tablet formulation is between about 0.1 g/mL and about 0.9 g/mL, between about 0.2 g/mL and about 0.8 g/mL, between about 0.3 g/mL and about 0.7 g/mL, or between about 0.4 g/mL and about 0.6 g/mL. In one example, the bulk density (g/mL) of the immediate -release tablet formulation is between about 0.4 g/mL and about 0.6 g/mL.
  • the tapped density (g/mL) of the immediate -release tablet formulation is assessed.
  • “tapped density” of a powder is the ratio of the mass of the powder to the volume occupied by the powder, after it has been tapped until the volume does not change (intervals of 100 taps).
  • the powder is tapped for 100 taps.
  • the powder is tapped for 200 taps.
  • the powder is tapped for 300 taps.
  • the powder is tapped for 400 taps.
  • the powder is tapped for 500 taps.
  • the powder is tapped for 600 taps.
  • the powder is tapped for 700 taps.
  • the powder is tapped for 800 taps. In one example, the powder is tapped for 900 taps. In one example, the powder is tapped for 1000 taps.
  • the tapped density (g/mL) of the immediate-release tablet formulation is between about 0.3 g/mL and about 1.0 g/mL, between about 0.4 g/mL and about 0.9 g/mL, between about 0.5 g/mL and about 0.85 g/mL, or between about 0.6 g/mL and about 0.8 g/mL. In one example, the tapped density (g/mL) of the immediate- release tablet formulation is between about 0.6 g/mL and about 0.8 g/mL.
  • the Carr index also referred to as Carr’s index or Carr’s compressibility index, of the immediate-release tablet formulation is assessed.
  • the Carr index is calculated as a function of both the bulk density and the tapped density of the powder, and therefore provides an indication as to the flowability and compressibility of the powder. In a free-flowing powder, the bulk density and tapped density would be similar in value, and therefore the Carr index would be small. On the other hand, in a poor-flowing powder, there would be a greater difference between the bulk density and the tapped density, and therefore the Carr index would be large.
  • the immediate-release tablet formulation has a Carr’s index (%) of less than about 35, about 30, about 25, about 20, or about 15. In one example, the immediate-release tablet formulation has a Carr’s index (%) of less than about 25. In one example, the immediate- release tablet formulation has a Carr’s index (%) of less than about 20.
  • the Hausner ratio of the immediate -release tablet formulation is assessed.
  • the Hausner ratio is calculated as a function of both the bulk density and the tapped density of the powder, and provides an indication as to the flowability and compressibility of the powder.
  • the immediate- release tablet formulation has a Hausner ratio of less than about 2.5, about 2.25, about 2.0, about 1.75, about 1.5, about 1.25, or about 1.0.
  • the immediate- release tablet formulation has a Hausner ratio of less than about 1.5.
  • the immediate-release tablet formulation has a Hausner ratio of less than about 1.25.
  • the flowability index of the immediate -release tablet formulation is assessed.
  • the flowability index of the immediate -release tablet formulation is assessed by using a Flodex tool.
  • the Flodex tool takes into account the numerous parameters that affect powder flowability, such as particle size and shape, “fines”, unit surface, actual and bulk density, porosity, settling, and electrostatic charge.
  • the flowability index of the immediate-release tablet formulation is less than about 25 mm, about 20 mm, about 15 mm, about 10 mm, or about 5 mm, when measured using the Flodex tool.
  • the flowability index of the immediate-release tablet formulation is between about 5 mm and about 20 mm, or between about 10 mm and about 20 mm, when measured using the Flodex tool. In one example, the flowability index of the immediate-release tablet formulation is between about 10 mm and about 20 mm, when measured using the Flodex tool.
  • the hardness of a tablet which is often referred to as “breaking force”, is understood to be the Force (in Newtons, N), required to cause tablet mechanical failure.
  • the average immediate-release tablet hardness of the cores is between about 0.1 kp and about 20 kp, between about 0.5 kp and about 15 kp, between about 1 kp and about 10 kp, between about 2 kp and about 7 kp, or between about 2.5 kp and about 6.5 kp. In one example, the average immediate-release tablet hardness is between about 2.5 kp and about 6.5 kp.
  • the average immediate- release tablet hardness of the cores is at least about 0.5 kp, about 1.0 kp, about 1.5 kp, about 2.0 kp, about 2.5 kp, about 3.0 kp, about 3.5 kp, about 4.0 kp, about 4.5 kp, about 5.0 kp, about 5.5 kp, about 6.0 kp, or about 6.5 kp.
  • tablet hardness is a measure of the breaking point and structural integrity of the tablet.
  • Hardness may be measured by any suitable technique known in the art, including, but not limited to, the Monsanto tester, the Strong-Cobb tester, the Pfizer tester, the Erweka tester, the Dr. Schleuniger Pharmatron tester, and the Kraemer Elektronik’s tablet testing system. Tablet hardness may also be referred to as crushing strength.
  • the immediate-release tablet friability of the cores is not more than about 0.1%, about 0.2%, about 0.3%, about 0.4%, or about 0.5%. In one example, the immediate-release tablet friability of the cores is not more than about 0.5%. In some embodiments, the immediate-release tablet friability of the cores is less than about 1.0%, less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, or less than about 0.1%. As will be understood by the person skilled in the art, tablet friability is a measure of the tendency of the tablet to break into smaller pieces under duress or contact (e.g., rubbing).
  • tablet friability is defined as the percentage weight loss of powder from the surface of a tablet due to mechanical action.
  • tablet friability testing involves weighing the sample of tablet cores, and then placing them into a rotating drum. The weight loss is calculated as a percentage.
  • the immediate-release tablet (either formulation core or film-coated tablet) disintegration is not more than about 5 minutes, about 8 minutes, about 10 minutes, about 11 minutes, about 12 minutes, about 13 minutes, about 14 minutes, about 15 minutes, or about 20 minutes. In one example, the immediate -release tablet disintegration is not more than about 15 minutes.
  • disintegration refers to the mechanical break-up of a compressed tablet into small granules upon ingestion. It is therefore characterised by the breakdown of the interparticulate bonds that were forget during the compaction of the tablet.
  • the final immediate-release tablet may be prepared by film-coating of the tablet core.
  • the film-coating suspension is prepared in purified water in a mixing tank.
  • the film-coating suspension is sprayed onto the tablet cores that are subjected to hot air flow.
  • the film-coating process is continued until the target weight gain of about 3% is achieved.
  • the film- coated tablets are dried and cooled prior to discharging into a storage container.
  • At least about 50%, about 60%, about 70%, about 80% or about 90% of the compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof is released within about 10 minutes (as measured in 900 mL dissolution medium, 0.1 N HC1, using USP type II apparatus at 50 rpm paddle rotation speed). In some embodiments, at least about 50%, about 60%, about 70%, about 80% or about 90% of the compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, is released within about 15 minutes (as measured in 900 mL dissolution medium, 0.1 N HC1, using USP type II apparatus at 50 rpm paddle rotation speed).
  • At least about 50%, about 60%, about 70%, about 80% or about 90% of the compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof is released within about 20 minutes (as measured in 900 mL dissolution medium, 0.1 N HC1, using USP type II apparatus at 50 rpm paddle rotation speed). In some embodiments, at least about 50%, about 60%, about 70%, about 80% or about 90% of the compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, is released within about 30 minutes (as measured in 900 mL dissolution medium, 0.1 N HC1, using USP type II apparatus at 50 rpm paddle rotation speed).
  • At least about 50%, about 60%, about 70%, about 80% or about 90% of the compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof is released within about 60 minutes (as measured in 900 mL dissolution medium, 0.1 N HC1, using USP type II apparatus at 50 rpm paddle rotation speed). In some embodiments, at least about 85% of the compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, is released within about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 45 minutes, or about 60 minutes (as measured in 900 mL dissolution medium, 0.1 N HC1, using USP type II apparatus at 50 rpm paddle rotation speed).
  • At least about 85% of the compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof is released within about 60 minutes (as measured in 900 mL dissolution medium, 0.1 N HC1, using USP type II apparatus at 50 rpm paddle rotation speed). In one example, at least about 90% of the compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, is released within about 60 minutes (as measured in 900 mL dissolution medium, 0.1 N HC1, using USP type II apparatus at 50 rpm paddle rotation speed).
  • At least about 95% of the compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof is released within about 60 minutes (as measured in 900 mL dissolution medium, 0.1 N HC1, using USP type II apparatus at 50 rpm paddle rotation speed).
  • the immediate-release tablet formulation provides for complete release of the active ingredient (i.e., the compound of Formula I, or pharmaceutically acceptable salt or solvate thereof).
  • complete dissolution of the compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof is achieved in less than about 60 minutes, about 45 minutes, about 30 minutes, about 20 minutes, or about 15 minutes.
  • complete dissolution of the compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof is achieved in less than about 60 minutes (when measured in 900 mL of 0.1 N HC1 using USP type II apparatus at 50 rpm).
  • complete dissolution of the compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof is achieved in less than about 30 minutes (when measured in 900 mL of 0.1 N HC1 using USP type II apparatus at 50 rpm).
  • the present disclosure provides for a method of treating or preventing a neurological disease in a subject.
  • the methods can comprise administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof.
  • the methods can comprise administering to the subject a therapeutically effective amount of an immediate -release tablet formulation, as described herein.
  • the present disclosure provides an immediate-release tablet formulation for preventing or treating a condition associated with 11 P-HSD1 activity. Accordingly, in one example, there is provided an immediate -release tablet formulation for preventing or treating a disorder that is ameliorated through inhibition of 11 P-HSD1.
  • the immediate-release tablet formulation for use in the treatment of metabolic syndrome.
  • the immediate-release tablet formulation for use in the treatment of a cardiovascular disorder.
  • the immediate-release tablet formulation for use in the treatment of a central nervous system (CNS) disorder.
  • the immediate-release tablet formulation for use in the treatment of a neurological disease.
  • a method of treating or preventing a neurological disease in a subject comprising administering to the subject the immediate -release tablet formulation, as described herein.
  • the use of the immediate-release tablet formulation, as described herein, in the manufacture of a medicament for the treatment or prevention of a neurological disease comprising administering to the subject the immediate -release tablet formulation, as described herein.
  • neurological diseases include, but are not limited to, Alzheimer’s disease and depression. In one example, the neurological disease is Alzheimer’s disease. In one example, the neurological disease is depression.
  • “therapeutically effective amount” refers to a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, being administered in an amount sufficient to alleviate or prevent to some extent one or more of the symptoms of the disorder or condition being treated, typically without undue adverse side effects or to achieve a desired pharmacological effect or therapeutic improvement with a reduced side effect profile.
  • the results can be the reduction and/or alleviation of the signs, symptoms, or causes of a disease or condition, or any other desired alteration of a biological system.
  • the term “therapeutically effective amount” refers to a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, being administered in an amount sufficient to result in a reduction of symptoms associated with a neurological disease.
  • Therapeutically effective amounts may, for example, be determined by routine experimentation, including but not limited to a dose escalation clinical trial.
  • the phrase “therapeutically effective amount” includes, for example, a prophylactically effective amount.
  • a prophylactically effective amount is an amount sufficient to prevent a neurological disease.
  • an effective amount or “a therapeutically effective amount” can vary from subject to subject, due to variation in metabolism of the compound and any of age, weight, general condition of the subject, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician.
  • An appropriate an effective amount” or “a therapeutically effective amount” in any individual case may be determined by one of ordinary skill in the art using routine experimentation.
  • the amount of a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, that will be effective in the treatment and/or prevention of a particular disorder or condition disclosed herein will depend on the nature of the disorder or condition, and can be determined by standard clinical techniques.
  • in vitro or in vivo assays may optionally be employed to help identify optimal dosage ranges. Such techniques are known to the person skilled in the art.
  • suitable dosage ranges for oral administration are generally from about 0.001 milligram to 1000 milligrams of the compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof per kilogram body weight.
  • the compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof is administered in an amount so as to deliver a total daily dosage (in mg) of at least about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 75, 100, 150, or 200.
  • the compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof is administered in an amount so as to deliver a total daily dosage (in mg) of less than about 200, 150, 100, 75, 60, 50, 45, 40, 35, 30, 25, 20, 15, 10, 5, or 1.
  • the total daily dosage may be provided in a range between at any two of these upper and/or lower amounts.
  • a total daily dosage may be provided in an amount of between about 1 and 100 mg, about 5 and 75 mg, about 10 and 50 mg, about 15 and 45 mg, or about 20 and 40 mg.
  • the immediate-release tablet formulation described herein is suitable for an active ingredient (i.e., a compound of Formula I, or pharmaceutically acceptable salt or solvate thereof) load of between about 2 mg and about 20 mg, between about 4 mg and about 15 mg, or between about 5 mg and about 10 mg.
  • the immediate -release tablet formulation described herein is suitable for an active ingredient (i.e., a compound of Formula I, or pharmaceutically acceptable salt or solvate thereof) load of between about 5 mg and about 10 mg.
  • the immediate-release tablet formulation described herein is suitable for an active ingredient (i.e., a compound of Formula I, or pharmaceutically acceptable salt or solvate thereof) load of about 5 mg.
  • the immediate -release tablet formulation described herein is suitable for an active ingredient (i.e., a compound of Formula I, or pharmaceutically acceptable salt or solvate thereof) load of about 10 mg.
  • the immediate-release tablet formulation described herein is suitable for an active ingredient (i.e., a compound of Formula I, or pharmaceutically acceptable salt or solvate thereof) load in an amount (w/w) of between about 1% and about 60%, between about 2% and about 50%, or between about 4% and about 40%, based on the weight of the core tablet (i.e., prior to tablet coating).
  • the immediate-release tablet formulation described herein is suitable for an active ingredient (i.e., a compound of Formula I, or pharmaceutically acceptable salt or solvate thereof) load in an amount of between about 4% and about 40%.
  • a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof is administered to the subject at a predetermined frequency.
  • a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof is administered to the subject according to a dosage regimen in which a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof is administered once daily, twice daily, three times daily, or four times daily.
  • the a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof is administered to the subject according to a dosage regimen in which a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof is administered once daily.
  • a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof is administered to the subject according to a dosage regimen in which a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof is administered twice daily.
  • a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof is administered to the subject according to a dosage regimen in which a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof is administered three times daily.
  • a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof is administered to the subject according to a dosage regimen in which a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof is administered four times daily.
  • a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof is administered to the subject according to a dosage regimen in which a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof is administered multiple times daily.
  • a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof is administered as a once daily dose of between about 10 mg and 30 mg, for example at about 20 mg.
  • a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof is administered as a twice daily dose of between about 5 mg and 20 mg per dose, for example at about 10 mg per dose.
  • a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof is administered as a three- times daily dose of between about 5 mg and 15 mg per dose, for example at about 10 mg per dose.
  • a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof is administered to the subject at a predetermined frequency and/or duration.
  • administration according to any embodiments (e.g. frequency) as described herein may be for a duration of about, or at least about, 1 day, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 12 months, 2 years, or 5 years.
  • Administration of the therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof may be ongoing so long as a therapeutic effect is received by the subject.
  • the term "administer” and “administering” are used to mean introducing the compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, into a subject.
  • the compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof is provided at, or after the onset of, a symptom of a neurological disease.
  • the therapeutic administration of this substance serves to attenuate any symptom, or prevent additional symptoms from arising.
  • administration is for the purposes of preventing or reducing the likelihood of developing a neurological disease
  • the compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof is provided in advance of any visible or detectable symptom.
  • the prophylactic administration of the compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof serves to attenuate subsequently arising symptoms or prevent or reduce the likelihood of the symptoms from arising altogether.
  • a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof may be administered by any suitable route. Examples include, but are not limited to, oral, topical, transdermal, intranasal, vaginal, rectal, intraarterial, intramuscular, intraosseous, intraperitoneal, epidural and intrathecal.
  • a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof is administered orally.
  • the immediate-release tablet formulation is administered orally.
  • a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof may be administered to the subject with respect to the subject’s fasted state, as would be understood by the person skilled in the art.
  • the subject may be administered a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof before, with, or after a meal.
  • a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof is administered to the subject before a meal (i.e., the subject being in a fasted state).
  • a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof is administered to the subject with a meal.
  • a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof is administered at a certain interval (i.e., 30 mins, 1 hour, 2 hours, 3 hours, etc.) following a meal.
  • a certain interval i.e., 30 mins, 1 hour, 2 hours, 3 hours, etc.
  • a tablet formulation was developed. The objective was to develop an immediate-release tablet formulation that is suitable for a drug load between 2 mg and 20 mg.
  • the core tablet weight was targeted at 50 mg for ease of swallowing in elderly patients.
  • the formulations were designed to have the same tablet weight and different drug load ranging from 4% to 40%.
  • the granular material was prepared by blender mixing intragranular components using a 4 Qt V-shell blender and then granulated using a Vector roller compactor. The granules were blended with extragranular components to yield the final blend. The final blend was then compressed into tablet cores using a Globe Pharma mini-press with 4.76 mm round punches to obtain a target tablet core weight of 50 mg. The batch sizes were between 100 g and 500 g. Selected tablet core batches were film coated using Opadry TF 276U180005, white. The prototype formulations are presented in the below table. Table. Composition of Prototype Tablet Formulations.
  • Coating solution is prepared at 12% (w/w) total solids in purified water
  • Formulations 22852-3 to 22852-5 have the same composition, but different drug (Xanamem) load. There was no processing issue for formulation 22852-3 with 4% drug load. However, both formulations 22852-4 and 22852-5 had sticking issues to the lower punch. Additional lubricant was required. To overcome sticking issues, the formulation was adjusted to increase magnesium stearate to 2.5% in extragranular formulation and decrease it to 0.5% in intragranular formulation. Furthermore, sodium starch glycolate was decreased to 1.0% in both intragranular and extragranular formulation.
  • Dissolution test was performed on selected prototype formulations in 0.1 N HC1 with USP type II apparatus.
  • 500 mL dissolution medium at 50 rpm paddle rotation speed complete drug release was achieved for the 2 mg tablet strength, while only approximately 60% drug release was achieved in 60 min for the 10 mg and 20 mg tablet strengths as shown in Figure 1.
  • the drug release reached over 90%.
  • Additional dissolution tests were performed at 75 rpm paddle rotation speed and in 900 mL dissolution medium for the 20 mg tablet strength. As shown in Figure 2, complete drug release was only reached in 900 mL dissolution medium at 75 rpm, whereas dissolution was incomplete in 60 min with either 500 mL at 75 rpm or 900 mL at 50 rpm.
  • Formulation 22852-8 with lactose monohydrate had a good flow property, however the individual tablet weight control was poor and the formulation had poor uniformity compared to the formulation 22852-7 with MCC.
  • the acceptable tablet hardness range is narrow (1.1 - 2.8 kp) compared to formulation 22852-7 (1.7 - 5.7 kp).
  • complete dissolution was achieved in 30 min in 900 mL of 0.1 N HC1 using USP II at 50 rpm, as shown in Figure 3.
  • Formulation 22852-9 with mannitol was not compressible and could not achieve the tablet hardness higher than 3 kp. It had poor tablet weight control and high friability. Thus, this formulation was not considered.
  • formulation 22852-10 was prepared with the 10 mg tablet strength.
  • the formulation composition and physical characterization results are provided in the above tables.
  • the final blend showed acceptable flow property and the process went well without any issues.
  • the tablets had acceptable weight control, hardness, friability, and content uniformity.
  • the dissolution profile is presented in Figure 3. The dissolution was comparable to the formulation 22852-8 with lactose and reached completion in 30 min, which was faster than the formulation 22852-7 with MCC alone.
  • dissolution method development was to select a suitable in vitro dissolution method for Xanamem drug product to ensure batch-to-batch consistency.
  • the solubility of Xanamem is pH-dependent. It has a solubility of over 2 mg/mL at pH 1 and pKa of 1.5. Thus, the sink condition is easily achieved in 0.1 N HC1 dissolution medium.
  • the dissolution method with 900 mL of 0.1 N HC1 dissolution medium and paddle rotation speed of 100 rpm was used for dissolution test of the capsule formulations (capsule placed in a sinker). The goal was to achieve over 80% drug release in 45 minutes.
  • the rank order of dissolution conditions for % drug dissolved of 20 mg tablet with microcrystalline cellulose formulation is: 900 mL with 75 rpm > 500 mL with 75 rpm > 900 mL with 50 rpm > 500 mL with 50 rpm. Only dissolution condition using 900 mL and paddle speed of 75 rpm reached complete dissolution in 30 min and 45 min.
  • the sink condition was confirmed by dissolving five 20 mg tablets in 500 mL of 0.1 N HC1 at 37°C.
  • the resulting concentration was 0.19 mg/mL, which is much higher than the required dissolution sink condition (> 0.12 mg/mL calculated using 20 mg x 3 /500 mL or > 0.067 mg/mL calculated using 20 mg x 3 /900 mL).
  • dissolution condition with 900 mL of 0.1 N HC1 and USP apparatus II at 50 rpm was selected for dissolution test of tablet formulations.
  • the dissolution profiles presented in Figure 3 demonstrated discriminatory power of the method towards formulation changes using different diluents in the tablet formulation.
  • Xanamem is a white to off-white crystalline powder. Only one crystalline form has been identified.
  • the drug substance consists of angular plate-like particles with a broad size distribution (range from ⁇ 10 pm to 250 pm).
  • the drug substance was micronized to achieve a Dv90 below 30 pm.
  • Figure 5 shows the particle size distribution of the micronized drug substance batch CJ1465 determined by laser diffraction using heptane with 0.1% Span 80 as dispersant.
  • optical microscope images are presented in Figure 6 for unmicronized (with 100X magnification) and micronized (with 200X magnification) drug substance. Both materials are birefringent under cross -polarized light, suggesting high crystallinity.
  • the solubility of Xanamem is pH dependent.
  • the drug substance has higher solubility in acidic condition (> 2 mg/mL at pH 1) and lower solubility in neutral condition (0.1 mg/mL).
  • the 10 mg dose strength can completely dissolve in 250 mL of aqueous media at intestinal pH. Therefore, the drug substance is considered as having high solubility according to the Biopharmaceutics Classification System (BCS).
  • BCS Biopharmaceutics Classification System
  • the permeability of Xanamem was determined using Caco-2 cell monolayers.
  • the average apparent permeability (Papp A-B) is 20.9 x 10’ 6 cm/sec at 1 pM in Caco-2 cells with an efflux ratio of 1.3, suggesting that Xanamem is a highly permeable compound.
  • Xanamem is classified as a class 1 compound according to the BCS, published by CDER from Food and Drug Administration in December 2017 (Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System).
  • the drug substance compatibility with selected excipients was evaluated to determine compatible excipients to be used in the drug product formulations to ensure that the quality of the finished product meets the desired expectation.
  • the drug substance (approximately 10 mg) and appropriate amount of each excipient were mixed well in a 4 mL amber glass vial with PTFE lined screw cap and then stored at 25°C and 50°C.
  • Three sample formulations were also prepared using a combination of excipients and 1% drug substance. The samples were pulled after 2 and 4 weeks and analyzed by HPLC for assay and impurities. The assay results are provided in the below Table, and the chromatograms with impurity profiles are shown in Figure 7. Table. Compatibility of Xanamem with Excipients.
  • the Xanamem drug substance has poor flowability.
  • the bulk density is around 0.3 g/mL for unmicronized drug substance and 0.2 g/mL for micronized drug substance. Due to a broad particle size distribution of Xanamem drug substance (range from ⁇ 10 pm to 250 pm by microscopy), it was decided to reduce the particle size by jet milling to ensure the content uniformity of the tablet formulation with a low drug load. Direct compression process was not considered due to poor flow properties of the drug substance and low dose strength. Therefore, dry granulation by roller compaction was selected as an appropriate granulation method to increase drug substance density and flowability, as well as improve the content uniformity of the tablets. Furthermore, roller compaction process is a continuous process that lends itself to scale-up.
  • Gerteis Minipactor is used for roller compaction.
  • the final blends were characterized and compressed to tablet cores using a Korsch XL 100 tablet press with a round 4.76 mm tooling.
  • Ribbon thickness (mm) 1.2-2.1 1.2-1.4 1.0-1.4
  • Disintegration (mm: ss) 00:20 00:21 00:10 a. NA: not applicable.
  • Gravity feeder was used At higher roll force (5 and 8 kN/cm), the envelope density is higher compared to that at lower roll force (2 kN/cm). The flowability is significantly better at roll force of 8 kN/cm, which is consistent with more larger particles at roll force of 8 kN/cm compared to those at 2 and 5 kN/cm roll forces.
  • the tablets produced from these final blends have acceptable tablet weight, hardness, friability, and disintegration time. Therefore, 8 kN/cm roll force was selected for manufacture of clinical batches.
  • Atomizing air pressure 15.0-15.1 14.1-15.2
  • PSD particle size distribution
  • the Xanamem tablets are manufactured using a dry granulation process, as depicted in the below Figure.
  • FIG. 1 Flow Diagram for the Manufacturing Process of Xanamem tablets.
  • a pre-blend of intragranular components is prepared by blender mixing and then granulated using roller compaction and milling to produce granules.
  • the granules are blended with extragranular components to yield the final blend.
  • the final blend is then compressed into tablet cores using a rotary tablet press.
  • the Xanamem tablet cores are film coated using a white ready-to-use coating material to obtain the final tablets.
  • Microcrystalline cellulose, Xanamem drug substance, sodium starch glycolate, croscarmellose sodium, colloidal silicon dioxide, and lactose monohydrate are individually screened into a container. The materials are transferred to a blender and blended at 30 rpm for about 13 min or equivalent. Then magnesium stearate is screened and added to the blender and blended for about additional 4 min or equivalent.
  • the pre-blend is transferred to a hopper and roller compacted using the following recommended settings:
  • Extragranular components microcrystalline cellulose and magnesium stearate are screened separately.
  • the microcrystalline cellulose and the compacted milled granules are added to the blender and blended at 30 rpm for about 13 min or equivalent.
  • magnesium stearate is added to the blender and blended for about additional 4 min or equivalent.
  • the final blend is compressed on a rotary tablet press with 4.76 mm round punches.
  • the compression parameters can be adjusted during the run to achieve the desired tablet weight and hardness. In-process tests are performed as outlined in the below Table.
  • the film-coating suspension is prepared in purified water in a mixing tank. In a coating pan, the film-coating suspension is sprayed onto the cores subjected to a hot air flow. In-process samples are taken periodically to measure and record the weight gain. The coating process is continued until the target weight gain of 3% is achieved. The film- coated tablets are dried and cooled before discharging into storage container.
  • the finished product is bulk packaged into HDPE containers that are lined with 2 polyethylene bags.
  • the Xanamem tablets are packaged in the primary packaging intended for clinical use.
  • Xanamem tablets are supplied as 5 mg and 10 mg immediate release film-coated tablets for oral administration. Both 5 mg and 10 mg tablet strengths are white, round tablets with the same tablet size and weight.
  • the composition of the Xanamem tablets is provided in the below Table, along with the function of each component.
  • the tablets are packaged into 40 cc white HDPE bottles with CRC induction- sealed caps (33 mm finish screw cap).

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Inorganic Chemistry (AREA)
  • Biochemistry (AREA)
  • Emergency Medicine (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

Le Xanamem, également connu sous le nom d'UE2343, est un inhibiteur efficace de la 11β-hydroxystéroïde déshydrogénase de type 1 (11β-HSD1). Du fait de son action inhibitrice, le Xanamem a été proposé en tant que traitement de troubles qui sont améliorés par l'inhibition de 11 β-HSD1, tels que le syndrome métabolique, les troubles cardiovasculaires et les troubles du SNC. La présente divulgation concerne la formulation de Xanamem et d'excipients, en particulier du lactose et de la cellulose microcristalline, en tant que formulations de comprimés à libération immédiate.
PCT/AU2024/051042 2023-10-03 2024-10-03 Formulation de comprimé Pending WO2025073002A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AU2023903165A AU2023903165A0 (en) 2023-10-03 Tablet formulation
AU2023903165 2023-10-03

Publications (1)

Publication Number Publication Date
WO2025073002A1 true WO2025073002A1 (fr) 2025-04-10

Family

ID=95284043

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/AU2024/051042 Pending WO2025073002A1 (fr) 2023-10-03 2024-10-03 Formulation de comprimé

Country Status (1)

Country Link
WO (1) WO2025073002A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011135276A1 (fr) * 2010-04-29 2011-11-03 The University Of Edinburgh (8-aza-bicyclo[3.2.1]oct-8-yl)-[5-(1h-pyrazol-4-yl]-méthanones 3,3-disubstituées en tant qu'inhibiteurs de 11-(bêta)-hsd1
WO2019186171A1 (fr) * 2018-03-28 2019-10-03 Benevolentai Bio Limited Traitement des maladies sarcopéniques
WO2021062472A1 (fr) * 2019-09-30 2021-04-08 Actinogen Medical Limited Traitements cognitifs médicinaux
AU2021374232A1 (en) * 2020-11-06 2023-06-08 Actinogen Medical Limited Process for preparing heterocyclic methanone compounds and aza-bicyclo intermediates thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011135276A1 (fr) * 2010-04-29 2011-11-03 The University Of Edinburgh (8-aza-bicyclo[3.2.1]oct-8-yl)-[5-(1h-pyrazol-4-yl]-méthanones 3,3-disubstituées en tant qu'inhibiteurs de 11-(bêta)-hsd1
WO2019186171A1 (fr) * 2018-03-28 2019-10-03 Benevolentai Bio Limited Traitement des maladies sarcopéniques
WO2021062472A1 (fr) * 2019-09-30 2021-04-08 Actinogen Medical Limited Traitements cognitifs médicinaux
AU2021374232A1 (en) * 2020-11-06 2023-06-08 Actinogen Medical Limited Process for preparing heterocyclic methanone compounds and aza-bicyclo intermediates thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ACTINOGEN MEDICAL: "A Phase II Study to Assess the Safety, Tolerability and Efficacy of Xanamem™ in Subjects With Mild Dementia Due to AD (XanADu) (XanADu) - NCT02727699", CLINICAL TRIALS, CLINICALTRIALS.GOV, 30 March 2016 (2016-03-30), XP093301432, Retrieved from the Internet <URL:https://clinicaltrials.gov/study/NCT02727699?term=NCT.02727699&rank=1> *
WEBSTER, SP. ET AL.: "Selection and early clinical evaluation of the brain-penetrant 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) inhibitor UE2343 (Xanamem?", BR J P HARMACOL, vol. 174, no. 5, pages 396 - 408, XP055812172, DOI: 10.1111/bph.13699 *

Similar Documents

Publication Publication Date Title
US20220339111A1 (en) Immediate-release tablets containing a drug and processes for forming the tablets
US11883399B2 (en) Bromocriptine formulations
CN101939003A (zh) 生物利用度改善的恩他卡朋、左旋多巴与卡比多巴的药物组合物
TWI794214B (zh) 包含5-氯-n4-[2-(二甲基磷醯基)苯基]-n2-{2-甲氧基-4-[4-(4-甲基哌嗪-1-基)哌啶-1-基]苯基}嘧啶-2,4-二胺之醫藥調配物
CN107810005B (zh) 阿格列汀制剂
CN112603900A (zh) 含[(4-羟基-1-甲基-7-苯氧基-异喹啉-3-羰基)-氨基]-乙酸的固体制剂
CN108174596A (zh) 包含8-[(3r)-3-氨基-1-哌啶基]-7-(2-丁炔-1-基)-3,7-二氢-3-甲基-1-[4-甲基-2-喹唑啉基)甲基]-1h-嘌呤-2,6-二酮或其药学上可接受的盐的药物组合物
WO2025073002A1 (fr) Formulation de comprimé
JP6453858B2 (ja) 共結晶形態でアゴメラチンを含むアゴメラチン製剤
HK40061820A (en) Immediate-release tablets containing a drug and processes for forming the tablets
HK40069271A (en) Immediate-release tablets containing a drug and processes for forming the tablets
WO2025226228A1 (fr) Nouvelle formulation pour comprimé de palbociclib
JP2023536341A (ja) カルバメート化合物を含む経口用固形製剤及びその製造方法
KR20250041176A (ko) 나포라페닙을 포함하는 무정형 고체 분산물
HK1254389B (en) Immediate-release tablets containing a drug and processes for forming the tablets
HK1213783A1 (zh) 布洛芬钠片剂和制备包含布洛芬钠的药物组合物的方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24873911

Country of ref document: EP

Kind code of ref document: A1