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-11471413-B2
Publication Date
2022-10-18
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 concerns an oral dosage form and a method of administering the dosage form to a patient in need thereof, where the dosage form comprises xanomeline and/or a salt thereof and trospium salt within specified dose ranges. The dosage form releases the xanomeline and/or salt thereof and the trospium salt at comparable rates so that an in-vivo plasma profile is achieved with a defined median Tmax for xanomeline and a defined median Tmax for trospium.
In one aspect, the median Tmax for xanomeline is 2 hours and the median Tmax for trospium is 1 hour. In another aspect, the dissolution rate is defined so that at least 80% of the xanomeline or a salt thereof and the trospium salt is released within 20 minutes in pH 6.8 buffer solution.
The invention further includes xanomeline tartrate and trospium chloride. Across the disclosure, the matched release profile is used to modulate tolerability by balancing muscarinic activation with trospium's antagonistic action, and pharmacokinetic targets include mean dose-normalized Cmax and mean dose-normalized AUC0-12 ranges in the in-vivo plasma profile.
Claims Coverage
Two independent methods are identified. Each independent claim centers on administering an oral dosage form containing specified ranges of xanomeline and/or a salt thereof and trospium salt, with comparable release characteristics, and each ties the release behavior to target in-vivo plasma profile outcomes or dissolution-release performance. The independent claims collectively emphasize timed plasma appearance (median Tmax) and a dissolution-release criterion (≥80% released within 20 minutes in pH 6.8 buffer), with dependent-claim refinements to quantitative exposure ranges and salt forms.
Comparable release to reach median Tmax targets
A method administering a dosage form comprising between 50 mg and 125 mg xanomeline and/or a salt thereof and between 20 mg and 30 mg trospium salt, wherein the dosage form releases the xanomeline and/or salt thereof and the trospium salt at comparable rates such that the method achieves an in-vivo plasma profile comprising a median Tmax for xanomeline of 2 hours and a median Tmax for trospium of 1 hour.
Comparable release to reach pH 6.8 dissolution release criterion
A method administering a dosage form comprising between 50 mg and 125 mg xanomeline and/or a salt thereof and between 20 mg and 30 mg trospium salt, wherein the dosage form releases the xanomeline and/or salt thereof and the trospium salt at comparable rates such that the dosage form has a dissolution rate such that at least 80% of the xanomeline or a salt thereof and the trospium salt is released within 20 minutes in pH 6.8 buffer solution.
The claim set centers on administering an oral xanomeline or salt and trospium-salt dosage form with comparable release of both components, where one claim is anchored on median Tmax targets for xanomeline and trospium and the other is anchored on a defined in-buffer dissolution release threshold.
Stated Advantages
Achieves an in-vivo plasma profile with a median Tmax of 2 hours for xanomeline and a median Tmax of 1 hour for trospium.
Achieves a dissolution rate such that at least 80% of xanomeline or a salt thereof and trospium salt is released within 20 minutes in pH 6.8 buffer solution.
All reported cholinergic TEAEs are mild/moderate, with no SAEs/deaths and no new safety signals.
Reduces incidence of cholinergic adverse events with xanomeline plus trospium as described in the partial disclosure.
Provides enhanced PK exposure with the disclosed formulation as described in the partial disclosure.
Documented Applications
Oral BID dosing of KarXT in multiple dose cohorts with reported pharmacokinetic outcomes for xanomeline (Day 3 and Day 7) and trospium (Day 1, Day 3, and Day 7), including accumulation ratios and comparative exposure findings versus KAR-001.
Assessment of cholinergic TEAEs and safety conclusions following oral BID dosing, including reporting of salivary hypersecretion, hyperhidrosis, and diarrhea as cholinergic preferred terms within the stated safety population.
Treating muscarinic receptor-ameliorated disorders including schizophrenia, Alzheimer's disease, Parkinson's disease, depression, movement disorders, pain, drug addiction, tauopathies, and synucleinopathies via muscarinic receptor activation using the disclosed composition.
Muscarinic receptor activation using the disclosed composition with optional combination with other therapies as described in the partial disclosure.
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