Compositions for controlled release of cysteamine and systemic treatment of cysteamine sensitive disorders
Inventors
Stanton, Jr., Vincent P. • RIOUX, Patrice P.
Assignees
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Publication Number
US-11786491-B2
Publication Date
2023-10-17
Expiration Date
Abstract
The invention features compositions, methods, and kits containing (i) one or more cysteamine precursor compounds convertible to cysteamine in vivo, and (ii) optionally agents to enhance that conversion, formulated to produce a spectrum of pharmacokinetic profiles of cysteamine that can be tailored to individual patients and diseases. The invention also features varying modes of administration of the therapeutic substances in the treatment of cystinosis and other cysteamine sensitive disorders. In particular, formulations combining active ingredient(s) with pharmaceutical excipients that permit sustained cysteamine plasma concentrations are featured.
Core Innovation
The invention relates to compositions and methods for treating a cysteamine sensitive disorder by administering therapeutically-effective amounts of cysteamine precursor compounds selected from pantetheine-N-acetyl-L-cysteine disulfide, pantetheine-N-acetylcysteamine disulfide, cysteamine-pantetheine disulfide, cysteamine-4-phosphopantetheine disulfide, cysteamine-gamma-L-glutamyl-L-cysteine disulfide, and cysteamine-N-acetyl-L-cysteine disulfide, and salts thereof. The approach is designed for controlled in vivo conversion to cysteamine in the gastrointestinal tract and for sustained time profiles of cysteamine generation.
The document describes gastroretentive, delayed-release, sustained-release, and colon-targeted formulations, including microparticle mixtures having different release profiles. The disclosed systems support delivery concepts to the gastrointestinal tract, including ileal/colonic targeted delivery using enteric-bacteria-digestible polymers and pH-sensitive coatings, as well as combined approaches.
Optional co-formulation or co-administration of enhancers is described, including reducing agents, pantetheinase inducers, uptake/enzyme modulators, and enhancers that promote disulfide reduction, pantetheinase induction, cysteamine transporter-mediated uptake via OCT1/2/3, or inhibit cysteamine catabolism. The compositions are further grounded in pharmacokinetic targets for maintaining cysteamine plasma concentration and avoiding undesired peaks while sustaining exposure for several hours.
Claims Coverage
The document provides two independent claims directed to treating a cysteamine sensitive disorder and increasing cysteamine plasma concentration. Across the independent claims, the main inventive subject matter is the administration of selected cysteamine precursor disulfides (or salts) in specified therapeutic or unit-dosage formats to achieve treatment or increased plasma cysteamine levels.
Treating a cysteamine sensitive disorder with selected disulfide precursors
A method of treating a cysteamine sensitive disorder in a subject by administering a therapeutically-effective amount of a compound selected from pantetheine-N-acetyl-L-cysteine disulfide, pantetheine-N-acetylcysteamine disulfide, cysteamine-pantetheine disulfide, cysteamine-4-phosphopantetheine disulfide, cysteamine-gamma-L-glutamyl-L-cysteine disulfide, and cysteamine-N-acetyl-L-cysteine disulfide, and salts thereof.
Increasing cysteamine plasma concentration with unit-dosed disulfide precursors
A method of increasing cysteamine plasma concentration in a subject by administering a unit dosage comprising from about 750 mg to about 10,000 mg of a compound selected from pantetheine-N-acetyl-L-cysteine disulfide, pantetheine-N-acetylcysteamine disulfide, cysteamine-pantetheine disulfide, cysteamine-4-phosphopantetheine disulfide, cysteamine-gamma-L-glutamyl-L-cysteine disulfide, and cysteamine-N-acetyl-L-cysteine disulfide, and salts thereof.
The independent claims cover treatment of cysteamine sensitive disorders and increase of cysteamine plasma concentration through administration of a specified set of cysteamine precursor disulfides (or salts).
Stated Advantages
Maintaining therapeutic cysteamine levels while reducing Cmax-associated toxicity.
Prolonged cysteamine production/absorption versus cysteamine HCl.
Maintaining or increasing cysteamine plasma concentration in a subject.
Treating a cysteamine sensitive disorder.
Documented Applications
Treating cysteamine sensitive disorders including Huntington's disease, Parkinson's disease, cystinosis, sickle cell disease, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis, non-alcoholic fatty liver disease (NAFLD), Rett syndrome, and mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes (MELAS).
Increasing cysteamine plasma concentration in a subject.
NAFLD/NASH pediatric trial context (RP103/CyNCh).
Neurodegenerative disorder contexts including Huntington's disease and Parkinson's disease; and kidney disease context via 4-phosphopantetheine delivery.
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