Compositions and methods of treatment with prodrugs of tizoxanide, an analogue or salt thereof

Inventors

Rossignol, Jean-Francois • Stachulski, Andrew

Assignees

Romark Laboratories LC

Abstract

Prodrugs of tizoxanide, an analog or salt thereof are disclosed. The prodrugs have an ester moiety comprising an amino acid moiety, and increase the bioavailability of the tizoxanide, an analog or salt thereof. Compositions and methods of treating an intracellular protozoan infection, a viral infection or a cancer are also disclosed.

Core Innovation

The invention relates to prodrugs of tizoxanide, and to analogues and salts thereof, defined by a chemical structure (Formula I). The compounds incorporate an ester prodrug moiety that includes an amino acid moiety, with amino-acid/ester variants defined by Formula A. The structural definition specifies substituent relationships on a phenyl group (R1–R5) and on a thiazole group (R6/R9), together with defined amino-acid/ester fragments within the prodrug.

The invention addresses the problem of increasing bioavailability for tizoxanide by providing ester prodrugs containing an amino acid moiety. The disclosure includes pharmaceutical compositions in solid oral controlled release and solid oral immediate release forms, as well as injectable formulations including intravenous suitability, where the prodrug compounds or pharmaceutically acceptable salts are combined with pharmaceutical excipients.

The disclosure further supports therapeutic use for treating intracellular protozoan infections, including Cryptosporidium, Leishmania, Toxoplasma gondii, and Trypanosoma cruzi, and for treating viral infections including influenza and hepatitis B. The disclosure also states methods for treating cancers including leukemia, melanoma, non-Hodgkin lymphoma, and renal cell carcinoma.

A pharmacokinetic comparison is provided for RM-5061 in rats, showing higher Cmax and AUC for tizoxanide and tizoxanide glucuronide after oral dosing versus nitazoxanide, together with reduced variability. The document links these bioperformance results to increased bioavailability and improved absorption of the active moieties derived from the ester amino-acid prodrug approach.

Claims Coverage

The document provides one independent claim directed to a compound defined by a chemical formula, or a pharmaceutically acceptable salt thereof, with dependent claims refining salt identity and claiming pharmaceutical composition embodiments including injectable and intravenous-suitable dosage forms. The independent claim therefore covers the core chemical-structure scope, while the dependent claims add specific salt and formulation features.

Overall claim coverage centers on a compound defined by a specific chemical formula, or its pharmaceutically acceptable salt, with dependent coverage for hydrochloric salt and pharmaceutical compositions, including injectable formulations and embodiments suitable for intravenous administration.

Stated Advantages

Documented Applications