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-10933020-B2
Publication Date
2021-03-02
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 invention provides an oral pharmaceutical composition comprising a plurality of xanomeline beads and a plurality of trospium beads. The xanomeline beads have a core comprising xanomeline or a salt thereof, and the trospium beads have a core comprising a salt of trospium. The composition is characterized by the dual-bead format that combines xanomeline and trospium as bead cores within an oral dosage form.
The disclosed compositions are directed to disorders ameliorated by muscarinic receptor activation and to treating a muscarinic disorder in a patient in need thereof. The provided context uses pharmacokinetic performance to support defined in-vivo plasma profiles and exposure behavior for xanomeline and trospium across dosing days, including median T_max values and exposure metrics.
The document further describes dissolution performance in aqueous solution, capsule formats and coating concepts in the context of controlled or pseudo-extended release and predictable T_max behavior. It also addresses impurity control by specifying a threshold for 3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-5-hydroxyl-1-methylpyridin-1-ium, with stability and dissolution testing results and impurity concentration limits.
Claims Coverage
The independent claims cover three inventive features: a dual-bead oral pharmaceutical composition, an oral composition with defined median in-vivo T_max values, and an oral composition with a specified low impurity level.
Dual bead oral pharmaceutical composition
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.
Xanomeline and trospium chloride with defined median Tmax plasma profile
An oral pharmaceutical composition comprising xanomeline and/or a salt thereof and trospium chloride for treating a muscarinic disorder in a patient in need thereof, wherein when administered to the patient in need thereof, is sufficient to provide an in-vivo plasma profile comprising a median T_max for xanomeline of 2 hours and a median T_max for trospium of 1 hour.
Low impurity level of a specified compound
An oral pharmaceutical composition comprising xanomeline and/or a salt thereof and less than 0.5 wt. % 3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-5-hydroxyl-1-methylpyridin-1-ium.
Overall, the claim coverage centers on an oral formulation that combines xanomeline and trospium as bead cores, achieves a defined in-vivo plasma profile with median T_max values for xanomeline and trospium, and limits a specified impurity to below 0.5 wt.%.
Stated Advantages
Reduced cholinergic TEAE incidence with xanomeline+trospium versus xanomeline alone.
Provides an in-vivo plasma profile with specified median T_max for xanomeline and trospium.
Provides dissolution performance in aqueous solution meeting a defined dissolution rate threshold within a defined time window.
Controls impurities by limiting the concentration of 3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-5-hydroxyl-1-methylpyridin-1-ium to less than 0.5 wt.%.
Xanomeline shows minimal-to-moderate accumulation while trospium shows minimal accumulation from Day 3 to Day 7 under most regimens.
Documented Applications
Treating disorders ameliorated by muscarinic receptor activation.
Treating a muscarinic disorder in a patient in need thereof.
Clinical investigation in Phase I studies, including KAR-001 and KAR-003, for xanomeline+trospium regimens.
Muscarinic-related disorders including schizophrenia, Alzheimer’s disease, and Parkinson’s disease.
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