Pharmaceutical combination and its use for treating synucleinopathties
Inventors
Chase, Thomas N. • Clarence-Smith, Kathleen E.
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11318122-B2
Publication Date
2022-05-03
Expiration Date
Abstract
The present invention describes the combination of a 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine or of a pharmaceutically acceptable salt or solvate thereof with fluoxetine or a pharmaceutically acceptable salt or solvate thereof, for use for treating a synucleinopathy such as Parkinson's disease, Lewy body disease, mutations in the glucocerebrosidase gene, or multiple system atrophy.
Core Innovation
The invention provides a pharmaceutical combination for treating a patient suffering from a synucleinopathy. The method comprises treating the patient with fluoxetine, or a pharmaceutically acceptable salt or solvate thereof, in combination with 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine, or a pharmaceutically acceptable salt or solvate thereof. The synucleinopathy target includes Parkinson’s disease, Lewy body disease, dementia with Lewy bodies, glucocerebrosidase (GBA) mutations, and multiple system atrophy.
The combination is described in terms of co-administration of fluoxetine with pramipexole/dexpramipexole, including (S)-enantiomer forms. The objective is to normalize plasma and exosomal alpha-synuclein species by co-treating with the two actives, where alpha-synuclein species and their congener changes are associated with reduced toxic species formation as reflected by peripheral exosomal synuclein and congener changes.
The disclosure further describes an unexpected clinical observation from a Phase I-II trial, where co-administration at approved doses of the pramipexole and fluoxetine combination is associated with peripheral exosomal synuclein/congener changes. It also states that fluoxetine attenuates pramipexole gastrointestinal adverse effects, enabling higher or full neuroprotective pramipexole dosing windows. The disclosure additionally includes pramipexole (including (S)-enantiomer) equivalents expressed in pramipexole dihydrochloride monohydrate equivalents, with IR/ER and fixed-dose combination ranges for both actives.
Claims Coverage
The independent claim covers treating a patient with a synucleinopathy by combining fluoxetine or a pharmaceutically acceptable salt or solvate with 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine or a pharmaceutically acceptable salt or solvate. The claim set includes six inventive features, with dependent claims refining the target synucleinopathy scope, stereospecific selection, dosage-unit composition, ER formulation, and daily dosing ranges.
Combination treatment for synucleinopathy
A method for treating a patient suffering from a synucleinopathy comprising treating the patient with fluoxetine or a pharmaceutically acceptable salt or solvate thereof in combination with 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine or a pharmaceutically acceptable salt or solvate thereof.
Defined synucleinopathy subtypes
The method includes treating a synucleinopathy selected from Parkinson's disease, Lewy body disease, Alzheimer's disease, mutations in the glucocerebrosidase gene, or multiple system atrophy.
Stereospecific benzothiazole (S)-enantiomer salt/solvate
The method includes using (S)-6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine dihydrochloride monohydrate or a pharmaceutically acceptable salt or solvate of that compound.
Dosage-unit pharmaceutical composition with pramipexole dihydrochloride monohydrate equivalents
The method includes formulating fluoxetine and 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine together in dosage unit pharmaceutical compositions with specified per-unit amounts and (S)-enantiomer amount equivalents based on pramipexole dihydrochloride monohydrate equivalents.
ER fluoxetine dosage unit for once-weekly administration
The claim specifies fluoxetine or a pharmaceutically acceptable salt formulated in a dosage unit form as an ER formulation containing 90 mg for once-weekly administration.
Daily dosing ranges including (S)-enantiomer component
In the method, fluoxetine is administered daily at 4–40 mg fluoxetine base equivalent, and 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine is administered daily at 1.5–3000 mg pramipexole dihydrochloride monohydrate equivalent, including a (S)-enantiomer component of 1.5–6 mg equivalent daily.
Overall, the claim set provides a combination-treatment framework using fluoxetine plus 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine for synucleinopathies, with further narrowing by synucleinopathy subtype, (S)-enantiomer salt or solvate selection, and dosage-unit, formulation, and dosing constraints including ER and pramipexole dihydrochloride monohydrate-equivalent amounts.
Stated Advantages
Normalizes plasma and exosomal alpha-synuclein species by co-administration, including peripheral exosomal synuclein/congener changes consistent with reduced toxic species formation.
Attenuates pramipexole gastrointestinal adverse effects.
Enables higher or full neuroprotective pramipexole dosing windows.
Documented Applications
Treating synucleinopathies, including Parkinson’s disease, Lewy body disease, dementia with Lewy bodies, glucocerebrosidase (GBA) mutations, and multiple system atrophy.
Interested in licensing this patent?