Nucleotide hemi-sulfate salt for the treatment of hepatitis c virus
Inventors
Moussa, Adel • Sommadossi, Jean-Pierre
Assignees
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Publication Number
US-12006340-B2
Publication Date
2024-06-11
Expiration Date
Abstract
A hemi-sulfate salt of the structure: to treat a host infected with hepatitis C, as well as pharmaceutical compositions and dosage forms, including solid dosage forms, thereof.
Core Innovation
The document describes preparing Compound 2 as a hemisulfate salt using Compound 1. A process is provided in which Compound 1 is dissolved in an organic solvent, followed by adding an H2SO4/solvent mixture to the solution of Compound 1 to form a hemisulfate salt (Compound 2). The mixture is stirred until Compound 2 precipitates, and the resulting precipitate is recovered by filtering and washing with an organic solvent or a mixture of organic solvents.
Compound 2 is described as a nucleotide hemi-sulfate salt formed from free base Compound 1, with enhanced bioavailability, improved liver-selective distribution over heart, potent pan-genotypic antiviral activity, and superior physical properties suitable for solid dosage forms. The document states that Compound 2 is a stable white solid, non-hygroscopic, and substantially higher in solubility versus Compound 1.
The document further states improved stability versus other salts, including a mono-sulfate salt identified as Compound 3, and includes alternative forms such as amorphous and crystalline forms, and stereochemical/isotopic variants. Experimental content also addresses solid-state forms of Compound 1, oxalate (Compound 4), amorphous counter-ion salts, and crystallization screening with analytical readouts including XRPD/HPLC.
Claims Coverage
The independent claim content covers a process for preparing Compound 2 as a hemisulfate salt from Compound 1 through dissolution, hemisulfate-salt formation using an H2SO4/solvent mixture, precipitation by stirring, and recovery by filtration and organic-solvent washing.
Hemisulfate salt formation from Compound 1 using an H2SO4/solvent mixture
Dissolving Compound 1 in an organic solvent, adding a sufficient amount of H2SO4/solvent mixture to form a hemisulfate salt (Compound 2), and stirring until Compound 2 precipitates.
Precipitate recovery by filtering and organic-solvent washing
Filtering the Compound 2 precipitate and washing with an organic solvent or a mixture of organic solvents.
Across the independent claim, the core coverage is the formation of Compound 2 as a hemisulfate salt by reacting Compound 1 in an organic solvent with an H2SO4/solvent mixture, followed by stirring to precipitation and isolation by filtration and organic-solvent washing.
Stated Advantages
Enhanced bioavailability, indicated by higher plasma AUC via surrogate metabolite 1-7.
Improved liver-selective distribution over heart, indicated by higher liver/heart partitioning.
Potent pan-genotypic antiviral activity, indicated by steady-state trough levels exceeding in vitro EC95 across HCV genotypes.
Superior physical properties for solid dosage, including stable white solid and non-hygroscopic behavior.
Substantially higher solubility versus Compound 1.
Improved stability versus other salts such as mono-sulfate Compound 3.
Documented Applications
Hepatitis C treatment using Compound 2 (a nucleotide hemi-sulfate salt derived from free base Compound 1).
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