NK1-antagonist combination and method for treating synucleinopathies
Inventors
Chase, Thomas N. • Clarence-Smith, Kathleen E.
Assignees
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Publication Number
US-11160809-B2
Publication Date
2021-11-02
Expiration Date
Abstract
The present invention describes the use of a NK1-antagonist, in combination with 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine, to facilitate the treatment of a patient suffering from a synucleinopathy by enabling a therapeutically effective 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine daily dose to act without the typical adverse effects caused by pramipexole dihydrochloride monohydrate when administered alone.
Core Innovation
The disclosed invention relates to treating a synucleinopathy in a patient by administering an effective daily dose of an NK1-antagonist together with an effective daily dose of 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine. The document describes the combination as expanding pramipexole tolerable dosing and reducing adverse effects, particularly gastro-intestinal side effects. The NK1-antagonist is exemplified by agents including aprepitant, fosaprepitant, rolapitant, and netupitant.
The invention further relates to using this combination to normalize plasma exosomal monomeric/oligomeric alpha-synuclein ratios, thereby targeting alpha-synuclein oligomerization and aggregation. The document states that the combination enables higher-than-typical pramipexole doses for neuroprotection and disease modification. Plasma is described in terms of exosomal monomeric/oligomeric alpha-synuclein ratio changes associated with the treatment approach.
In addition, the disclosed approach includes pharmaceutical dosing and formulation aspects, including acceptable salt and solvate forms and unit dosage forms. The description includes example Phase I human studies showing that an aprepitant regimen attenuates dose-limiting gastro-intestinal intolerance with supra-therapeutic pramipexole doses. The disclosed treatment scope includes synucleinopathies such as Parkinson’s disease, Lewy body dementia, Lewy body variant of Alzheimer’s disease, and multiple system atrophy, including forms associated with glucocerebrosidase (GBA) mutations.
Claims Coverage
The partial content provides two independent claims. Across these, the inventive subject matter covers both a method of treating a synucleinopathy using an NK1-antagonist plus a 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine and a corresponding dosage-unit pharmaceutical composition containing the same components, with specified amount ranges and optional enantiomer/salt/solvate selections for the benzothiazole amine.
Treating a synucleinopathy with NK1-antagonist and benzothiazole amine
Administering to a patient in need of treatment an effective daily dose of an NK1-antagonist in combination with an effective daily dose of 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine.
Dosage-unit pharmaceutical composition of NK1-antagonist and benzothiazole amine
Providing a pharmaceutical composition in dosage unit form comprising a NK1-antagonist, in an amount per unit form of from 1 μg to 600 mg, and a 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine selected from the racemate or a pharmaceutically acceptable salt thereof, pramipexole or a pharmaceutically acceptable salt thereof, and a (R)/(S)-mixture, in an amount per unit form equivalent to from 0.25 mg to 90 mg of pramipexole dihydrochloride monohydrate, in admixture with a pharmaceutical carrier or vehicle.
The claim coverage centers on administering or formulating an NK1-antagonist together with a benzothiazole amine, including pramipexole and related forms, for treating synucleinopathies, with dosage-unit compositions defined by specified component amount ranges and optional selections of racemate, pramipexole, or (R)/(S)-mixture.
Stated Advantages
Expands pramipexole tolerable dosing.
Reduces gastro-intestinal adverse effects.
Normalizes plasma exosomal monomeric/oligomeric alpha-synuclein ratios.
Enables higher-than-typical pramipexole doses for neuroprotection and disease modification.
Attenuates dose-limiting gastro-intestinal intolerance with supra-therapeutic pramipexole doses.
Documented Applications
Treating synucleinopathies in patients, including Parkinson’s disease, Lewy body dementia, Alzheimer’s disease (Lewy body variant), multiple system atrophy, and parkinsonian disorders associated with glucocerebrosidase (GBA) mutations.
Example Phase I human studies evaluating aprepitant’s attenuation of dose-limiting gastro-intestinal intolerance with supra-therapeutic pramipexole doses.
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