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-11173135-B2
Publication Date
2021-11-16
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 a pharmaceutical composition in unit dosage form comprising 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 document also describes isolated compound claims for cysteamine-N-acetyl-L-cysteine disulfide and pantetheine-N-acetyl-L-cysteine disulfide or salts thereof.
The invention further addresses treating disease by administering a therapeutically-effective amount of one of the specified disulfide compounds or salts. The document describes methods for treating neurodegenerative diseases including Huntington’s disease and Parkinson’s disease, and methods for treating cysteamine sensitive disorders selected from cystinosis; sickle cell disease; chronic obstructive pulmonary disease (COPD); cystic fibrosis (CF); non-alcoholic steatohepatitis (NASH); alcoholic steatohepatitis; and non-alcoholic fatty liver disease (NAFLD).
The described strategies are presented in the context of oral drug delivery using cysteamine precursors, including gastroretentive, sustained/enteric/colon-targeted, and mixed release formulations. The disclosed approach also links controlled pharmacokinetic goals to extending exposure, reducing peaks, reducing Cmax-related toxicity, and sustaining therapeutic cysteamine plasma levels.
Claims Coverage
The independent claims cover a unit-dosage pharmaceutical composition and therapeutic methods using a selected list of cysteamine precursor disulfides and salts. The inventive features center on the specific compound selection and the treatment of defined disease scopes, with isolated compound coverage for two disulfides.
Unit dosage form composition of selected cysteamine disulfides
A pharmaceutical composition in unit dosage form comprising 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.
Isolated cysteamine-N-acetyl-L-cysteine disulfide compound
The compound cysteamine-N-acetyl-L-cysteine disulfide or a salt thereof.
Isolated pantetheine-N-acetyl-L-cysteine disulfide compound
The compound pantetheine-N-acetyl-L-cysteine disulfide or a salt thereof.
Treating Huntington’s disease or Parkinson’s disease with selected cysteamine disulfides
A method for treating a neurodegenerative disease in a subject comprising administering to the subject 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, wherein said neurodegenerative disease is Huntington's disease or Parkinson's disease.
Treating cysteamine sensitive disorders with selected cysteamine disulfides
A method for treating a cysteamine sensitive disorder in a subject comprising administering to the subject 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, wherein said cysteamine sensitive disorder is selected from cystinosis; sickle cell disease; chronic obstructive pulmonary disease (COPD); cystic fibrosis (CF); non-alcoholic steatohepatitis (NASH); alcoholic steatohepatitis; and non-alcoholic fatty liver disease (NAFLD).
Overall claim coverage centers on administering or formulating selected cysteamine precursor disulfides and salts in a unit dosage form or in a therapeutically-effective amount, with disease scope restricted to neurodegenerative diseases or cysteamine sensitive disorders.
Stated Advantages
Extend exposure.
Reduce Cmax-related toxicity.
Improve dosing convenience.
Sustain therapeutic cysteamine plasma levels.
Reduce peaks and side effects.
Constrain Cmax.
Address halitosis/body odor associated with cysteamine exposure.
Documented Applications
Treating Huntington's disease or Parkinson's disease in a subject.
Treating cysteamine sensitive disorders selected from cystinosis, sickle cell disease, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and non-alcoholic fatty liver disease (NAFLD).
Oral pharmaceutical composition strategies including gastroretentive, sustained/enteric/colon-targeted delivery and mixed release formulations for extending exposure and reducing Cmax-related toxicity.
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