A2-73 crystalline polymorph compositions of matter and methods of use thereof
Inventors
Missling, Christopher U. • Selvey, Alani
Assignees
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Publication Number
US-12180174-B2
Publication Date
2024-12-31
Expiration Date
Abstract
The present disclosure provides crystalline forms of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine (A2-73), in freebase or salt forms. Also described are pharmaceutical formulations and dosage forms comprising the disclosed crystal forms, and methods of using crystalline A2-73 in dosage forms for neuroprotection including treatment of neurodegenerative and other diseases.
Core Innovation
The invention relates to crystalline polymorphs of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine (A2-73; Anavex2-73; AV2-73) in freebase or pharmaceutically acceptable salt forms. Crystalline forms are described for hydrochloride, freebase, sulfate, mesylate, oxalate, dihydrogen phosphate, edisylate, and fumarate/hydrogen fumarate forms, with solid-state characterization including XRPD and PLM and associated particle shape information.
The disclosure further addresses hydration tendencies, variable hydrate and dehydration behavior, melting and thermal behavior using DSC, and solubility behavior including pH-dependent solubility considerations and freebase solubility in water. Crystal chirality is discussed in terms of racemic versus homochiral conglomerate, and these physical properties are connected to stability considerations for the specified crystalline A2-73 forms.
Pharmaceutical formulations and dosage forms are disclosed containing therapeutically effective amounts of the specified crystalline A2-73 forms. Dosage embodiments include extended-release transdermal patches, enteric-coated oral formulations, and subcutaneous/injectable forms, and the transdermal patch embodiment is described with a stated blood level target range for A2-73.
The disclosure also provides in vitro and in vivo evidence that ANAVEX2-73, described as a Sig-1R agonist and mixed muscarinic ligand, induces autophagic flux and improves proteostasis. The evidence includes effects associated with LC3-II and markers used in autophagy/proteostasis pathways and reports reduced protein aggregation/paralysis phenotypes in C. elegans models.
Claims Coverage
The independent claim defines one specific crystalline form and its solid-state identification, characterized by an XRPD pattern. Dependent claims further add particle-shape characterization and downstream pharmaceutical embodiments, including dosage form types and a quantitative blood-level range for a transdermal patch, together with a pharmaceutical composition defined by a therapeutically effective amount plus pharmaceutically acceptable excipients.
Dihydrogen phosphate XRPD-characterized crystalline form of A2-73
A crystalline form of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine (A2-73) in which the crystalline form is a dihydrogen phosphate salt characterized by the XRPD pattern shown in FIG. 25.
Particle-shape characterization for the A2-73 dihydrogen phosphate crystalline form
The crystalline form of the dihydrogen phosphate salt is further characterized by the particle shapes depicted in FIG. 24.
Transdermal patch with defined A2-73 blood levels
A transdermal patch dosage form maintains A2-73 blood levels ranging from about 5 ng/ml to about 15 ng/ml.
Transdermal patch dosage form embodiment
The dosage form is a transdermal patch.
Enteric-coated oral dosage form embodiment
The dosage form is an enteric coated oral dosage form.
Pharmaceutical composition with A2-73 dihydrogen phosphate and excipients
A pharmaceutical composition for delivery of A2-73 comprising a therapeutically effective amount of the crystalline form of A2-73 dihydrogen phosphate salt and one or more pharmaceutically acceptable excipients.
Overall, the claim set anchors protection in a specific XRPD-characterized crystalline dihydrogen phosphate salt of A2-73, adds particle-shape characterization, and extends coverage to pharmaceutical compositions and dosage form embodiments, including an extended blood-level constraint for a transdermal patch and narrowed dosage forms for transdermal and enteric-coated oral formulations.
Stated Advantages
Induces autophagic flux and improves proteostasis, with reduction of protein aggregation/paralysis phenotypes described in C. elegans models.
Documented Applications
Therapeutic/neuroprotective use of A2-73 in neurodegenerative diseases including Alzheimer’s, Parkinson’s, and progressive dementia.
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