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Assignees
Member
Icahn School of Medicine at Mount SinaiThe Icahn School of Medicine at Mount Sinai, located in New York City, is an international leader in biomedical education, research, and patient care. As the academic partner of the Mount Sinai Health System, the school is renowned for its innovative education, groundbreaking research, and commitment to health equity. With over 7,000 faculty, 1,200 students, and 2,500 residents and fellows, the institution fosters a culture of bold thinking, multidisciplinary teamwork, and a willingness to challenge conventional wisdom. Its mission is to radically advance the art and science of medical care through collaborative learning, scholarly inquiry, and a deep respect for diversity, preparing the next generation of healthcare leaders to revolutionize medicine and biomedical science.
The Icahn School of Medicine at Mount Sinai, located in New York City, is an international leader in biomedical education, research, and patient care. As the academic partner of the Mount Sinai Health System, the school is renowned for its innovative education, groundbreaking research, and commitment to health equity. With over 7,000 faculty, 1,200 students, and 2,500 residents and fellows, the institution fosters a culture of bold thinking, multidisciplinary teamwork, and a willingness to challenge conventional wisdom. Its mission is to radically advance the art and science of medical care through collaborative learning, scholarly inquiry, and a deep respect for diversity, preparing the next generation of healthcare leaders to revolutionize medicine and biomedical science.
Publication Number
US-12023324-B2
Publication Date
2024-07-02
Expiration Date
2040-09-19
Abstract
Disclosed herein are controlled release compositions comprising riluzole and the uses thereof.
Core Innovation
This invention relates to controlled release formulations comprising riluzole or pharmaceutically acceptable derivatives thereof that provide improved pharmacokinetic profiles for the treatment of neurological and neuropsychiatric disorders. The disclosed formulations aim to achieve once daily dosing while maintaining plasma riluzole concentrations within therapeutic ranges, minimizing peak to trough fluctuations, and potentially mitigating liver toxicity associated with the drug.
The problem addressed is the clinical limitations of riluzole's currently available immediate release formulations, which require twice daily dosing and must be taken at least 1 hour before or 2 hours after meals due to a significant negative food effect. Additionally, riluzole suffers from high variability in hepatic metabolism, dose-dependent liver effects, low water solubility, poor oral palatability, and pH-dependent stability which together limit its clinical use and patient compliance. The invention proposes controlled release compositions, including gastroretentive or multiparticulate formulations, that mitigate these concerns by providing a plasma riluzole concentration of at least about 0.04 mcg/mL for 24 hours or more, with a Cmax below about 0.3 mcg/mL, thus enabling once daily administration potentially with or without food.
Claims Coverage
The patent discloses multiple independent claims focused on pharmaceutical compositions of riluzole derivatives with specific controlled release pharmacokinetic parameters and methods of treatment using these compositions. The main inventive features encompass dosage ranges, pharmacokinetic targets, administration regimens, reduced liver toxicity, and specific therapeutic applications.
Pharmaceutical composition with specified riluzole derivatives and dosage range
A pharmaceutical composition comprising from about 75 mg up to about 300 mg of specific riluzole prodrug derivatives.
Steady-state maximum plasma concentration control
The composition provides a Cmax at steady state of less than about 0.3 mcg/mL for at least about 24 hours.
Steady-state minimum plasma concentration maintenance
The composition provides a Cmin at steady state of at least about 0.04 mcg/mL for at least about 24 hours.
Area under the curve exposure range at steady state
The composition provides an AUC at steady state from about 1.5 mcg*h/mL to about 4 mcg*h/mL for at least about 24 hours, optionally about 2.5 mcg*h/mL.
Once daily administration formulation
The pharmaceutical composition is formulated to be administered once a day.
Formulation suitable for administration without food
The pharmaceutical composition is formulated to be taken without regard to food.
Formulation reducing liver toxicity relative to immediate release riluzole
The pharmaceutical composition is formulated to reduce liver toxicity compared to 50 mg of immediate release riluzole given twice daily.
Methods of treating neurological and neuropsychiatric disorders
Methods of treating Alzheimer's disease, amyotrophic lateral sclerosis, obsessive compulsive disorder, or spinocerebellar ataxia by administering the described pharmaceutical compositions to subjects in need thereof.
The independent claims cover pharmaceutical compositions of specific riluzole derivatives with controlled release properties achieving defined plasma concentration parameters, enabling once daily dosing optionally without food, reducing liver toxicity, and their use in treating specified neurodegenerative and neuropsychiatric disorders.
Stated Advantages
Improved patient compliance through once daily dosing compared to twice daily immediate release riluzole.
Maintaining higher trough concentrations to improve therapeutic efficacy.
Minimizing side effects, including liver toxicity, by avoiding high peak plasma concentrations.
Reducing inter-subject pharmacokinetic variability.
Potentially enabling riluzole administration without regard to meals, mitigating negative food effects.
Documented Applications
Treatment of neurodegenerative diseases including Alzheimer's disease and amyotrophic lateral sclerosis (ALS).
Treatment of neuropsychiatric disorders such as obsessive compulsive disorder and generalized anxiety disorder.
Treatment of spinocerebellar ataxia.
Treatment of a central nervous system (CNS) state.
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