Compositions comprising enzyme-cleavable phenol-modified tapentadol prodrug

Inventors

Jenkins, Thomas E. • Seroogy, Julie D. • Wray, Jonathan W.

Assignees

Signature Therapeutics Inc

Abstract

A method of providing a patient with controlled release of tapentadol using a prodrug capable, upon enzymatic activation and intramolecular cyclization, of releasing tapentadol is disclosed. The disclosure also provides such prodrug compounds and pharmaceutical compositions comprising such compounds. Such pharmaceutical compositions can optionally include an enzyme inhibitor that interacts with the enzyme(s) to mediate the enzymatically-controlled release of tapentadol from the prodrug so as to modify enzymatic cleavage of the prodrug. Also included are methods to use such compounds and pharmaceutical compositions.

Core Innovation

The disclosure describes phenol-modified tapentadol prodrugs and trypsin-cleavable prodrug moieties defined by structural variability using substituent definitions including R1, R2, R5, and n. The prodrugs include formula embodiments TC-(I), TC-(II), and TC-(III), as well as TP-1, TP-3, and TP-4, and are designed for enzymatically controlled, post-administration release of tapentadol. The trypsin-cleavable moiety R4 is described as able to mimic charged substrates, including amino acid side chains such as L-lysine and L-arginine, to enable oriented trypsin cleavage at a defined scissile bond.

The disclosure further states that TC-(III) specifies a trypsin-cleavable moiety as the enzyme-sensitive trigger, consistent with biological exposure to GI enzyme or trypsin and controlled conversion of the prodrug to tapentadol after administration. The patent includes example compound structures identified as TP-1, TP-3, and TP-4, and describes a progression of scheme-based syntheses leading to phenol-modified tapentadol prodrugs. Conversion assay content and figure descriptions support the described conversion behavior and PK/time-course effects.

For pharmaceutical use, the patent provides compositions that include a trypsin inhibitor to attenuate enzymatic cleavage and release in the gastrointestinal tract after oral administration. It also describes use of a corresponding trypsin inhibitor co-formulated in a dose unit with the prodrug to modulate tapentadol Cmax, Tmax, and exposure, while maintaining compatibility with oral administration. The disclosure includes pharmaceutical compositions and dose-unit or container concepts alongside methods of use including PK-modulated dosing strategies.

Claims Coverage

The claim coverage includes multiple independent compound claims for TP-1, TP-3, TP-4, and TC-(I), with dependent claims extending to pain-treatment or prevention, pharmaceutical compositions, and co-formulation with a trypsin inhibitor selected from named inhibitors. Across the family, there are four principal inventive features in the independent compound definitions and related dependent composition and use claims.

Overall, the claims are directed to specific, enumerated compound formula definitions, with dependent coverage for pain-treatment or prevention and for pharmaceutical compositions with a pharmaceutically acceptable carrier. Further dependents add a trypsin inhibitor selected from an enumerated group and, in the disclosure, the inhibitor is used to modulate enzymatic cleavage and release.

Stated Advantages

Documented Applications