Methods for the treatment of gastro-intestinal disorders

Inventors

Druzgala, Pascal Jean • Milner, Peter

Assignees

Renexxion LLC

Abstract

Provided herein is a bulk composition comprising the trihydrate form of (3S, 4R, 3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoic acid 1-azabicyclo[2.2.2]oct-3′-yl ester di-hydrochloride salt. Provided are also pharmaceutical compositions and dosage forms comprising the trihydrate form, and methods and uses for treating a gastrointestinal disorder in a subject with the trihydrate form. In some embodiments, the gastrointestinal disorder is gastroesophageal reflux disease (GERD), dyspepsia (such as functional dyspepsia or functional motility disorder), gastroparesis, paralytic ileus, post-operative ileus, emesis, nausea, heartburn, intestinal pseudo-obstruction, irritable bowel syndrome (IBS), constipation, enteral feeding intolerance (EFI), or esophagitis. In some embodiments, the gastrointestinal disorder is post-operative ileus, chronic grass sickness, constipation, megacolon, gastritis, gastrointestinal stasis, or abomasal emptying defect.

Core Innovation

The patent describes a crystalline form of (3S, 4R, 3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoic acid 1-azabicyclo[2.2.2]oct-3′-yl ester di-hydrochloride salt, referred to as Compound 1, as a trihydrate form. The crystalline identity is characterized using XRPD 2θ peaks, including principal peaks at 7.74±0.5° and 20.95±0.5° and an XRPD pattern shown in FIG. 3 top trace.

The patent addresses the problem of providing a crystalline form suitable for pharmaceutical use, including improved stability and handling compared with an anhydrous form, as indicated by the storage tolerance and stability/weight change information. The crystalline form is further associated with analytical characterization tools described in the document, including XRPD, FTIR, water vapor sorption isotherms, NMR, and thermographic analysis.

The invention is implemented in methods of improving gastrointestinal motility and treating gastrointestinal disorders in subjects in need thereof by administering a therapeutically effective amount of the characterized crystalline di-hydrochloride salt. Pharmaceutical compositions and dosage forms, as well as kits and containerized bulk packaging, are described as using the compound.

Claims Coverage

The independent claims are directed to four inventive features centered on using a specific crystalline ester di-hydrochloride salt defined by XRPD peak characteristics or an XRPD pattern shown in FIG. 3 top trace, in some embodiments as a trihydrate crystalline form.

Across the independent claims, the coverage centers on using a specific crystalline di-hydrochloride salt defined by XRPD 2θ peaks at 7.74±0.5° and 20.95±0.5° or by the FIG. 3 top trace XRPD pattern to improve gastrointestinal motility or to treat a selected gastrointestinal disorder. Dependent claims further narrow the crystalline form characterization with additional XRPD peak constraints and, in some embodiments, specify the trihydrate form (2HCl·3H2O).

Stated Advantages

Documented Applications