Compositions and methods for treating disorders ameliorated by muscarinic receptor activation
Inventors
BETANCOURT, Aimesther • Rehlaender, Bruce • Thibert, Roch
Assignees
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Publication Number
US-11452692-B2
Publication Date
2022-09-27
Expiration Date
Abstract
Provided herein is an oral pharmaceutical composition, comprising a plurality of xanomeline beads having a core comprising xanomeline or a salt thereof; and a plurality of trospium beads having a core comprising a salt of trospium.
Core Innovation
The disclosure describes an oral pharmaceutical composition and methods of treating a disorder ameliorated by activating muscarinic receptors. The method administers xanomeline and/or a salt thereof together with trospium salt to a patient in need thereof, with dosing twice daily within specified ranges. The composition includes a plurality of xanomeline beads and a plurality of trospium beads, each bead type having a core comprising the respective active ingredient and optionally a coating, and the bead-containing composition is provided as a capsule containing the plurality of xanomeline beads and the plurality of trospium beads.
The disclosure further supports separating the muscarinic-receptor activator and the anticholinergic component into different bead populations within the same oral capsule. Xanomeline and trospium are administered as bead-based formulations with independent bead cores and optional coatings. The capsule formulation and bead structure are associated with dissolution behavior and pharmacokinetic characterization of the combined formulation.
The document identifies treatment targets including disorders ameliorated by activating muscarinic receptors, and provides an example focused on schizophrenia. It also describes pharmacokinetic markers for xanomeline and trospium after twice-daily dosing and reports exposure metrics and accumulation observations across regimens.
Claims Coverage
The independent claim coverage includes 2 independent claims. Across the claims, the inventive features focus on twice-daily oral dosing of xanomeline (or a xanomeline salt) and trospium salt, using separate plurality bead populations in a capsule formulation with optional bead coatings and defined active bead core compositions; one independent claim is directed specifically to schizophrenia.
Twice-daily oral bead-capsule coadministration of xanomeline and trospium salt
Administering between 100 mg and 125 mg xanomeline and/or a salt thereof and between 20 mg and 30 mg trospium salt to a patient twice daily, wherein the xanomeline and/or a salt thereof and trospium salt are administered as a pharmaceutical composition comprising a plurality of xanomeline beads having a core comprising the xanomeline or a salt thereof and optionally a coating, and a plurality of trospium beads having a core comprising the trospium salt and optionally a coating, and wherein the pharmaceutical composition is a capsule containing the plurality of xanomeline beads and the plurality of trospium beads.
Twice-daily oral bead-capsule treatment of schizophrenia using xanomeline tartrate and trospium chloride
Orally administering between 100 mg and 125 mg xanomeline tartrate and between 20 mg and 30 mg trospium chloride to a patient twice daily, wherein the xanomeline and/or a salt thereof and trospium salt are administered as a pharmaceutical composition comprising a plurality of xanomeline beads having a core comprising the xanomeline or a salt thereof and optionally a coating, and a plurality of trospium beads having a core comprising the trospium salt and optionally a coating.
Both independent claims require a twice-daily oral treatment approach that combines xanomeline (or its salt) with trospium salt, delivered as separate bead populations in a capsule, with optional coatings and specified active dose ranges; one claim additionally specifies schizophrenia and the particular salts xanomeline tartrate and trospium chloride.
Stated Advantages
Provides enhanced blood levels in the KarXT formulation.
Reports no new safety signals.
Improved tolerability versus xanomeline alone by co-administering trospium chloride to reduce peripheral cholinergic adverse events.
Enhanced pharmacokinetic exposures for the combined formulation.
Storage stability and purity considerations, including impurity A limits.
Documented Applications
Pharmacokinetic characterization of xanomeline and trospium after twice-daily dosing of KarXT dose cohorts, including Day 7 with comparisons to Day 3 and Day 1, using metrics such as Cmax, Tmax, half-life, and AUC.
Characterization of cholinergic TEAEs, including salivary hypersecretion and hyperhidrosis, and diarrhea, nausea, vomiting, for a related study arm.
Application to treating a disorder ameliorated by activating muscarinic receptors, including treatment of schizophrenia.
Treating a disorder ameliorated by activating muscarinic receptors by administering an oral bead-based capsule containing xanomeline (or salt) beads and trospium salt beads.
Treating schizophrenia by orally administering xanomeline tartrate and trospium chloride twice daily using the described bead-based pharmaceutical composition.
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