Nucleotide hemi-sulfate salt for the treatment of hepatitis C virus
Inventors
Moussa, Adel • Sommadossi, Jean-Pierre
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-10906928-B2
Publication Date
2021-02-02
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 invention relates to hepatitis C virus (HCV) treatment using a compound of the formula and a hemisulfate salt form of the isopropyl phosphoramidate nucleotide. The disclosure discusses the relationship between the salt form and biological performance in vivo, including the measurable plasma surrogate metabolite and the active intracellular triphosphate.
The disclosure states that the hemisulfate salt unexpectedly improves in vivo pharmacokinetics and liver selectivity compared with the free base. It reports higher AUC for the plasma surrogate metabolite and higher liver/heart partitioning ratio for the active triphosphate, and indicates that predicted steady-state trough concentrations exceed EC95 across HCV genotypes, supporting pan-genotypic antiviral activity.
The disclosure also states improved physical properties for the hemisulfate salt, including that it is described as a stable white solid with high solubility and non-hygroscopic behavior, and with stability under humidity and temperature. It contrasts this with other salt forms such as the mono-sulfate, described as an unstable sticky gum, and further includes therapeutic and prophylactic uses for HCV-related conditions and genotypes, together with solid dosage forms and different amorphous/crystalline forms.
Claims Coverage
The provided independent claims cover compounds defined by a formula, pharmaceutical compositions and solid dosage forms containing effective amounts in pharmaceutically acceptable carriers, route and dosage-form refinements, and stereochemical purity requirements specifying at least 90% free of the opposite phosphorus S-enantiomer. The main inventive features are concentrated on compound/formulation concepts and stereochemical purity constraints.
Compound defined by formula
A compound of the formula is claimed.
Pharmaceutical composition with effective amount
A pharmaceutical composition comprising an effective amount of the compound of the formula in a pharmaceutically acceptable carrier is claimed.
Solid dosage form with effective therapeutic amount
A solid dosage form comprising an effective therapeutic amount of a compound of the formula in a pharmaceutically acceptable carrier is claimed.
Parenteral pharmaceutical composition
The pharmaceutical composition is in a parenteral formulation.
Oral pharmaceutical composition
The pharmaceutical composition is in an oral dosage form.
Solid oral dosage form
The oral dosage form is a solid dosage form.
Liquid dosage form
The liquid dosage form is a suspension or solution.
Oral-suitable carrier
A pharmaceutically acceptable carrier suitable for oral delivery is specified.
Tablet carrier
The pharmaceutically acceptable carrier is formulated as a tablet.
Intravenous pharmaceutical composition
The pharmaceutical composition is provided in an intravenous formulation.
Delivery of at least 300 mg
A solid dosage form delivering at least 300 mg of the compound is specified.
Delivery of at least 700 mg
A pharmaceutical composition delivering at least 700 mg of the compound is specified.
Phosphorus S-enantiomer purity
A compound of the formula is claimed wherein the compound is at least 90% free of the opposite phosphorus S-enantiomer.
Solid dosage form with phosphorus S-enantiomer purity
A solid dosage form comprising an effective amount of a compound of the formula in a pharmaceutically acceptable carrier is claimed wherein the compound is at least 90% free of the opposite phosphorus S-enantiomer.
Pharmaceutical composition with phosphorus S-enantiomer purity
A pharmaceutical composition comprising an effective therapeutic amount of a compound of the formula in a pharmaceutically acceptable carrier is claimed wherein the compound is at least 90% free of the opposite phosphorus S-enantiomer.
Across the independent claims provided, coverage centers on compounds defined by a formula, pharmaceutical compositions and solid dosage forms containing effective amounts in pharmaceutically acceptable carriers, route and dosage-form refinements, and stereochemical purity requirements at a phosphorus center of at least 90% free of the opposite phosphorus S-enantiomer. Quantitative delivery refinements are indicated for solid dosage forms delivering at least 300 mg and pharmaceutical compositions delivering at least 700 mg.
Stated Advantages
Unexpectedly improved in vivo pharmacokinetics versus the free base, including higher AUC for the plasma surrogate metabolite.
Improved liver selectivity versus the free base, including a higher liver/heart partitioning ratio for the active triphosphate.
Supports pan-genotypic antiviral activity via predicted steady-state trough concentrations exceeding EC95 across HCV genotypes.
Improved physical properties including stability as a stable white solid, high solubility, non-hygroscopic behavior, and stability under humidity and temperature.
Documented Applications
Treatment of hepatitis C virus (HCV) infection using the disclosed compounds and salt form.
Therapeutic use across HCV-related conditions and genotypes.
Prophylactic use across HCV-related conditions and genotypes.
Interested in licensing this patent?