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Publication Number
US-12280048-B2
Publication Date
2025-04-22
Expiration Date
Abstract
The disclosure provides new, stable, pharmaceutically acceptable amorphous solid dispersions of 1-(4-fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido [3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-l-one, together with methods of making and using them, and pharmaceutical compositions comprising them.
Core Innovation
The patent discloses stable amorphous solid dispersions comprising ITI-007 free base, formulated with pharmaceutically acceptable excipients including cellulose acetate, cellulose acetate phthalate, and HPMC-P. The amorphous solid dispersion is formed by dissolving ITI-007 and the excipient and removing the solvent.
The amorphous solid dispersions are characterized using XRPD, mDSC, TGA, and HPLC to establish physical and chemical stability. The X-ray diffraction pattern is free of peaks characteristic of the excipient, the amorphous solid dispersion shows a single glass transition temperature greater than 75°C, and limited weight loss is observed up to 100°C.
The document reports that the only combinations meeting the required physical and chemical stability include specific excipient screens using cellulose acetate, cellulose acetate phthalate, and HPMC-P at defined ratios, and that corresponding ITI-007 tosylate dispersions fail. The failure includes physical instability and/or high decomposition and is described as unexpected, while the ITI-007 free base dispersions show high chemical stability with more than 90% ITI-007 remaining.
The patent further describes use of the amorphous solid dispersions in galenic pharmaceutical compositions, including oral tablet/capsule and depot LAI formulations. Therapeutic targeting is described through signaling involving 5-HT2A, SERT, and/or dopamine D1/D2 receptors for a disease set including schizophrenia and other listed disorders.
Claims Coverage
The independent claims cover methods of treating a human for a list of diseases or disorders by administering therapeutically effective amounts of an amorphous solid dispersion of ITI-007 free base combined with a pharmaceutically acceptable diluent or carrier. Three inventive features are identified, each tied to a specific excipient and defined ITI-007 free base:excipient weight ratio, with one feature also including an XRPD limitation.
Cellulose acetate carrier with excipient-free XRPD
Administering a therapeutically effective amount of an amorphous solid dispersion comprising ITI-007 free base with a pharmaceutically acceptable diluent or carrier comprising cellulose acetate in a weight ratio of 5:95 to 50:50 ITI-007 free base to cellulose acetate, wherein the X-ray diffraction pattern of the amorphous solid dispersion is free of peaks characteristic of the excipient.
Cellulose acetate phthalate carrier within a defined weight ratio
Administering a therapeutically effective amount of an amorphous solid dispersion comprising ITI-007 free base with a pharmaceutically acceptable diluent or carrier comprising cellulose acetate phthalate in a weight ratio of 25:75 to 75:25 ITI-007 free base to cellulose acetate phthalate.
HPMC-P carrier within a defined weight ratio
Administering a therapeutically effective amount of an amorphous solid dispersion comprising ITI-007 free base with a pharmaceutically acceptable diluent or carrier comprising HPMC-P in a weight ratio of 25:75 to 75:25 ITI-007 free base to HPMC-P.
Across the independent claims, the inventive coverage is directed to treatment methods using ITI-007 free base amorphous solid dispersions where the pharmaceutically acceptable carrier is constrained to specific excipients at defined ITI-007 free base:excipient weight ratios. One independent claim additionally requires that the XRPD pattern of the dispersion is free of peaks characteristic of the excipient.
Stated Advantages
High chemical stability, with more than 90% ITI-007 remaining.
Physical stability characterized by no texture or appearance change after 7 days at 75% RH/40°C.
An X-ray diffraction pattern free of peaks characteristic of the excipient.
A single glass transition temperature greater than 75°C.
Limited weight loss up to 100°C.
Documented Applications
Galenic pharmaceutical compositions, including oral tablet/capsule and depot LAI formulations, comprising the disclosed amorphous solid dispersions.
Therapeutic use via signaling involving 5-HT2A, SERT, and/or dopamine D1/D2 receptors for treating schizophrenia and the other disorders listed in the disease set.
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