Methods of treatment of tuberous sclerosis complex
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Publication Number
US-11998535-B2
Publication Date
2024-06-04
Expiration Date
Abstract
Provided herein are methods of treating tuberous sclerosis complex in a subject in need thereof by administering to the subject compositions comprising an mGlu5 negative allosteric modulator (NAM), having the structure of Formula I:
Core Innovation
The invention relates to a method of treating a medical condition associated with tuberous sclerosis complex (TSC) by administering to a subject in need thereof a composition comprising a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of Formula I. The compound of Formula I is 2-chloro-4-[1-(4-fluorophenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]pyridine, and the pharmaceutically acceptable salt comprises a crystalline anhydrate form (Form A) of a monosulfate salt of the compound of Formula I. The Form A is characterized by X-ray powder diffraction peaks obtained with Cu Kα radiation at specific 2θ values selected from a defined set.
The crystalline anhydrate monosulfate Form A is specified using solid-state characterization constraints, including the requirement of at least three peaks selected from the defined Cu Kα X-ray powder diffraction peak set. Related solid-state forms described include a crystalline monohydrate form (Form B) and a crystalline hemisalftate form (Form C), each associated with corresponding X-ray powder diffraction and thermal behavior. The composition can further include solid-state purity constraints where the crystalline anhydrate Form A constitutes at least 90% by weight of the salt present in the composition.
The document also describes solid pharmaceutical formulation approaches for the described Form A monosulfate salt, including modified release tablets/matrix pellets and capsule matrix pellet formulations. The formulation description includes matrix pellet compositions with excipients such as microcrystalline cellulose, methacrylic acid copolymer, hypromellose, and talc. Therapeutic efficacy is framed around clinical outcomes including reduction in seizures, and patient/caregiver functional or cognitive measures such as Caregiver Global Impression of Change (CGIC) and Sheehan Disability Scale, consistent with use as adjunctive therapy in TSC patients with seizures.
Claims Coverage
The document provides one independent claim, directed to a treating method for a medical condition associated with TSC using a therapeutically effective amount of a pharmaceutically acceptable salt of a Formula I compound. The inventive features are centered on the specific solid-state identification of a crystalline anhydrate monosulfate Form A and its administration for treatment of TSC-associated conditions. Dependent claims further refine the Form A characterization, particle size, melting temperature, and fraction, and narrow an efficacy determination threshold for seizures.
Crystalline anhydrate monosulfate Form A defined by Cu Kα XRD peaks
Administering a therapeutically effective amount of a pharmaceutically acceptable salt of a Formula I compound, where the salt comprises a crystalline anhydrate form (Form A) of a monosulfate salt characterized by at least three Cu Kα X-ray powder diffraction peaks at 2θ values selected from 9.8±10.2°, 13.4±10.2°, 14.2±10.2°, 18.1±10.2°, 18.9±10.2°, 19.6±10.2°, 22.6±10.2°, 22.9±10.2°, 25.7±10.2°, 27.1±10.2°, and 29.9±10.2°.
Crystalline anhydrate Form A monosulfate with particle size constraint
The pharmaceutically acceptable salt being the crystalline anhydrate form (Form A) of a monosulfate salt of the Formula I compound having a median particle size (Dv50) of less than or equal to about 100 μm.
Crystalline anhydrate Form A monosulfate with DSC melting temperature range
The pharmaceutically acceptable salt being the crystalline anhydrate form (Form A) of a monosulfate salt of the Formula I compound having a melting temperature (Tm) of about 180–190°C as measured by differential scanning calorimetry.
High Form A fraction of the monosulfate salt
The pharmaceutically acceptable salt being at least 90% by weight of the crystalline anhydrate form (Form A) relative to the total weight of the salt present in the composition.
Seizure reduction efficacy threshold within four weeks
Therapeutic efficacy defined as a reduction in seizures of at least 25% from baseline within four weeks.
Claim coverage centers on treating a medical condition associated with TSC using a pharmaceutically acceptable salt of a Formula I compound, specifically requiring a crystalline anhydrate monosulfate Form A identified by a defined Cu Kα XRD peak set. Additional dependent claim features refine Form A characterization using particle size and DSC melting temperature, impose a minimum Form A fraction by weight, and narrow efficacy to at least a 25% seizure reduction from baseline within four weeks.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Adjunctive therapy for tuberous sclerosis complex (TSC) patients with seizures, including efficacy endpoints such as seizure frequency reduction and caregiver/patient measures (CGIC, Sheehan Disability Scale).
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