Material for the treatment of gastro-intestinal disorders
Inventors
Druzgala, Pascal Jean • Tien, Jien Heh
Assignees
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Publication Number
US-11643409-B2
Publication Date
2023-05-09
Expiration Date
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 invention defines 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, including a trihydrate form and XRPD-based identity criteria. The crystalline identity is supported by XRPD, FTIR, thermographic analysis, water vapor sorption isotherm, NMR, and corresponding relative intensity criteria, with specified XRPD 2θ peak positions and an XRPD pattern shown in FIG. 3 top trace.
Residual organic solvent limits are described as part of the solid-state characterization, including C1-C8 alcohol solvents such as ethanol, n-propanol, and isopropanol. The document addresses stability of anhydrous and trihydrate forms, water content, mass change behavior, and residual solvent considerations relevant to pharmaceutical formulation and storage.
The crystalline form is described in bulk compositions, pharmaceutical compositions, dosage forms, and kits using pharmaceutically acceptable excipient materials, including hydrated/hygroscopic excipients. Methods of treating gastrointestinal disorders are described using the trihydrate form, and veterinary gastrointestinal use cases are also described.
Claims Coverage
The document includes two independent claims. Both independent claims focus on defining the specified di-hydrochloride salt by XRPD characterization, with one claim defined by specific XRPD 2θ peaks and the other by an XRPD pattern shown in a figure trace. Additional claim features narrow the coverage by trihydrate specification, further XRPD requirements, and pharmaceutical composition context.
Crystalline form defined by XRPD 2θ peaks
A crystalline form of the specified (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, characterized by XRPD 2θ peaks at 7.74°±0.5° and 20.95°±0.5° or at 7.6°±0.2° and 20.7°±0.2°.
Crystalline form defined by XRPD pattern in FIG. 3 top trace
A crystalline form of the specified di-hydrochloride salt characterized by an XRPD pattern as shown in FIG. 3 top trace.
Trihydrate crystalline form
The crystalline form is specified as a trihydrate form, including 2HCl·3H2O.
Pharmaceutical composition context
Pharmaceutical compositions comprising the crystalline form with pharmaceutically acceptable excipients are included in the claim set.
The inventive coverage is grounded in XRPD-defined crystalline identity, with one definition requiring specified XRPD peak positions and the other requiring the XRPD pattern shown in FIG. 3 top trace. Dependent features further narrow coverage by trihydrate characterization and pharmaceutical composition context.
Stated Advantages
Improved storage tolerance of the trihydrate form over the anhydrous form.
Formulation compatibility with hydrated/hygroscopic excipients.
Considerations of mass/water content aligned with stability, including water content and mass change behavior.
Reliable identification and specification of the crystalline trihydrate form by XRPD and supporting analytical features.
Documented Applications
Bulk compositions comprising the trihydrate form of Compound 1.
Pharmaceutical compositions and dosage forms comprising the crystalline trihydrate form with pharmaceutically acceptable excipient(s).
Kits comprising the trihydrate form.
Treatment of gastrointestinal disorders including GERD, dyspepsia, gastroparesis, paralytic ileus, post-operative ileus, emesis, nausea, IBS, constipation, enteral feeding intolerance (EFI), and esophagitis.
Treatment of proton pump inhibitor (PPI)-resistant GERD.
Additional gastrointestinal disorders including heartburn, intestinal pseudo-obstruction, erosive esophagitis (EE), eosinophilic esophagitis (EoE), IBS constipation type (IBSc), opiate-induced constipation (OIC), chronic idiopathic constipation (CIC), and chronic grass sickness.
Veterinary use cases including treatment in ruminant, equine, cat, dog, rabbit, and guinea pig, and references to neonatal calves and passive immunity transfer to colostrum-fed calf.
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