Compositions and methods for treating synucleinopathies
Inventors
Chase, Thomas N. • Clarence-Smith, Kathleen E.
Assignees
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Publication Number
US-11547700-B2
Publication Date
2023-01-10
Expiration Date
Abstract
The present invention describes the use of a 5HT3-antagonist, in combination with a 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine, to reduce adverse effects and to facilitate the neuroprotective treatment of a patient suffering from a synucleinopathic disorder to enable a therapeutically effective 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine daily dose without the dose-limiting adverse effects caused by pramipexole when administered alone.
Core Innovation
The invention provides a pharmaceutical composition in dosage unit form for treating synucleinopathies, where a 5HT3-antagonist is combined with a 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine. The composition is formulated as an admixture with a pharmaceutical carrier or vehicle, and the disclosed framework includes racemate, pramipexole, and (R)/(S)-mixtures with an (S)-enantiomer, together with pharmaceutically acceptable salts and solvates.
The background problem addressed is the occurrence of gastro-intestinal adverse effects associated with pramipexole use, described as nausea, vomiting, and retching that limit dosing. The invention states that 5HT3 antagonism, particularly using ondansetron and/or ondansetron hydrochloride dihydrate, reduces GI dose-limiting adverse effects from pramipexole co-administration and enables higher, more tolerated pramipexole dosing for synucleinopathy treatment.
The disclosed therapeutic framework links treatment to abnormal monomeric and oligomeric alpha-synuclein ratios in CNS-derived plasma exosomes, with a described aim of normalization of those ratios. Immediate release and extended release unit forms, fixed-dose combination versus separate administration, and transdermal therapeutic systems, including transdermal patches, are also described as formulation options.
Claims Coverage
The provided claims center on one independent claim defining a unit dosage pharmaceutical composition that combines a 5HT3-antagonist in a specified per-unit amount range with a 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine selected from racemate, pramipexole, or an (R)/(S)-mixture, together with a pharmaceutical carrier or vehicle. Dependent claims narrow the 5HT3-antagonist identity and refine pramipexole-equivalent dosing windows, including IR-unit-form and ER-unit-form contexts.
5HT3-antagonist with unit-dose amount range plus pramipexole-equivalent benzothiazole-2-amine
A pharmaceutical composition in dosage unit form comprising a 5HT3-antagonist in an amount per unit form of from 1 μg to 300 mg and a 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine selected from the group consisting of the racemate or a pharmaceutically acceptable salt thereof, pramipexole or a pharmaceutically acceptable salt thereof, and an (R)/(S)-mixture including an (S)-enantiomer or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutical carrier or vehicle.
The claim scope is anchored by the independent unit-dose composition combining a 5HT3-antagonist with a specified 6-propylamino benzothiazole amine, using pramipexole-dihydrochloride-monohydrate-equivalent ranges and a pharmaceutical carrier or vehicle. The dependent claims further specify the 5HT3-antagonist identity, including ondansetron hydrochloride dihydrate, and refine dosing and unit-form contexts.
Stated Advantages
Attenuation of pramipexole-associated gastro-intestinal adverse effects when a 5HT3-antagonist is co-administered.
Increase in maximum tolerated dose and first intolerable dose outcomes as described for humans in a Phase I study.
Enabling an increase in tolerated pramipexole dose by more than 2-fold in humans.
Normalization of abnormal monomeric and oligomeric alpha-synuclein ratios in CNS-derived plasma exosomes.
Documented Applications
Treatment of synucleinopathies involving alpha-synuclein, including normalization of abnormal monomeric and oligomeric alpha-synuclein ratios in CNS-derived plasma exosomes.
A Phase I single-blind dose-escalation study context to assess co-administration effects on pramipexole-associated gastro-intestinal adverse events.
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