Pharmaceutical formulations for the treatment of gastrointestinal disorders
Inventors
Druzgala, Pascal Jean • Tien, Jien Heh
Assignees
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Publication Number
US-12098149-B2
Publication Date
2024-09-24
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 relates to a pharmaceutical composition comprising a crystalline form of a defined (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, together with a pharmaceutically acceptable excipient. The crystalline form is characterized by XRPD 2θ peaks at about 7.74°±0.5 and 15.0°±0.2.
Specific embodiments further define the crystalline form as a trihydrate, with the XRPD profile constrained by additional XRPD 2θ peaks and by selected peak sets drawn from a defined list. The embodiments impose relative intensity constraints on XRPD peaks and require an additional set of XRPD peaks.
Further embodiments address production-related constraints for the trihydrate dihydrochloride salt, including limitations on organic solvent content and selection of organic solvents, with emphasis on C1–C8 alcohols such as ethanol, n-propanol, and isopropanol. The document associates the trihydrate dihydrochloride salt with treatment of gastrointestinal disorders.
Claims Coverage
The document contains one independent claim, which covers a pharmaceutical composition containing a crystalline form of the defined ester di-hydrochloride salt characterized by specified XRPD 2θ peaks, and a pharmaceutically acceptable excipient. Dependent claims further refine the crystalline form by hydration state and by additional XRPD peak and intensity constraints using selected peak sets and single additional peak positions.
Crystalline xrpd-defined di-hydrochloride pharmaceutical composition
A pharmaceutical composition comprising 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, wherein the crystalline form is characterized by XRPD 2θ peaks at 7.74°±0.5 and 15.0°±0.2, and a pharmaceutically acceptable excipient.
Trihydrate crystalline form
A crystalline form wherein the crystalline form is a trihydrate of the di-hydrochloride salt (2HCl·3H2O) as defined in the dependent claim.
Selected xrpd peak set definition
A crystalline form characterized by one or more specified XRPD 2θ peak values selected from a listed set.
Requirement for multiple specified xrpd peaks from the list
A crystalline form that has two or more specified XRPD 2θ peaks at the listed angle values (±0.2° tolerance).
Additional single xrpd peak constraint at 20.95°
A crystalline form characterized by an XRPD 2θ peak at 20.95°±0.5°.
Additional single xrpd peak constraint at 21.3°
A crystalline form defined by an XRPD 2θ peak at 21.3°±0.2°.
Overall claim coverage focuses on a pharmaceutical composition containing a crystalline ester di-hydrochloride salt defined by specific XRPD 2θ peaks, with dependent claims narrowing the crystalline form by specifying a trihydrate hydration state and by imposing additional XRPD peak constraints through selected peak sets, minimum peak counts, and specific single additional peak positions.
Stated Advantages
The crystalline trihydrate is intended for bulk compositions and pharmaceutical compositions/dosage forms that include a pharmaceutically acceptable excipient.
The document emphasizes XRPD-based characterization for reliable identification of the crystalline form.
The crystalline trihydrate is presented with improved stability under storage and solvent-related constraints.
The document discloses low residual organic solvent constraints.
Documented Applications
Gastrointestinal disorders including GERD, dyspepsia/FD, gastroparesis, paralytic/post-operative ileus, emesis/nausea/heartburn, intestinal pseudo-obstruction, IBS, constipation, and enteral feeding intolerance (EFI).
Esophagitis, including PPI-resistant GERD, erosive esophagitis (EE), and eosinophilic esophagitis (EoE).
Opioid-induced constipation (OIC), chronic idiopathic constipation (CIC), and IBS-C (IBSc).
Various veterinary/animal indications.
Use of the trihydrate dihydrochloride in treating gastrointestinal disorders including PPI-resistant GERD and constipation subtypes.
Use of the trihydrate dihydrochloride in treating gastrointestinal disorders including gastroparesis and ileus.
Use of the trihydrate dihydrochloride in treating gastrointestinal disorders including intestinal pseudo-obstruction and IBS-C.
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