Methods for the treatment of gastro-intestinal disorders
Inventors
Druzgala, Pascal Jean • Milner, Peter
Assignees
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Publication Number
US-11498918-B2
Publication Date
2022-11-15
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 crystalline 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. The solid state form is characterized by XRPD 2θ peaks at 7.74±0.5° and 20.95±0.5°, with additional selectable XRPD peak sets described. The trihydrate is linked to water content behavior, stability, and phase and impurity constraints relative to an anhydrous form.
The invention further provides pharmaceutical compositions and dosage forms comprising the crystalline trihydrate form and a pharmaceutically acceptable excipient. The compositions include solid-state quality attributes, including limits on total organic solvent content, restrictions on alcohol solvent types, water content targets and endpoints, and trihydrate:anhydrous ratios. Bulk and pharmaceutical compositions and dosage forms such as tablets, capsules, and kits or containers are described.
A trihydrate preparation method is described that forms the di-hydrochloride trihydrate crystalline form from the free base, including acidification with HCl, precipitation, isolation, and reduced-pressure drying to reach defined water content. The resulting product is characterized with XRPD peak lists and additional analytical characterization including TGA dehydration behavior and water vapor sorption isotherm, and stability data compare anhydrous versus trihydrate forms under controlled humidity.
Claims Coverage
The independent claims center on two inventive features built around the same XRPD-defined crystalline trihydrate form, with the claims differing in therapeutic use. Dependent and related claim content further refines disorder scope, subject types, and solid-state or formulation constraints including additional XRPD peak subsets, water and organic solvent limits, optional anhydrous phase content, and dosage-form selection.
XRPD-defined crystalline trihydrate di-hydrochloride salt in a pharmaceutical composition
A therapeutically effective amount of a pharmaceutical composition comprising a 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, wherein the trihydrate form is in a crystalline form characterized by XRPD 2θ peaks at 7.74±0.5° and 20.95±0.5°, and a pharmaceutically acceptable excipient.
Treating a gastrointestinal disorder with crystalline trihydrate XRPD-defined solid form
A method of treating a gastrointestinal disorder in a subject in need thereof by administering a therapeutically effective amount of a pharmaceutical composition comprising a crystalline 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 with a pharmaceutically acceptable excipient, wherein the trihydrate is characterized by XRPD 2θ peaks at 7.74±0.5° and 20.95±0.5°, and wherein the gastrointestinal disorder is selected from GERD, functional dyspepsia, functional motility disorder, gastroparesis, paralytic ileus, post-operative ileus, intestinal pseudo-obstruction, IBS, constipation, enteral feeding intolerance, esophagitis, megacolon, gastritis, gastrointestinal stasis, and abomasal emptying defect.
Improving gastrointestinal motility with crystalline trihydrate XRPD-defined solid form
A method of improving gastrointestinal motility in a subject in need thereof by administering a therapeutically effective amount of a pharmaceutical composition comprising a crystalline 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 with a pharmaceutically acceptable excipient, wherein the trihydrate is characterized by XRPD 2θ peaks at 7.74±0.5° and 20.95±0.5°.
Across the independent claims, the inventive coverage centers on administering a therapeutically effective amount of a pharmaceutical composition containing an XRPD-defined crystalline trihydrate of the specified di-hydrochloride ester compound. The claimed scope includes treating a defined group of gastrointestinal disorders and improving gastrointestinal motility.
Stated Advantages
Broader storage tolerance compared with anhydrous form.
Enables formulation with hydrated and/or hygroscopic excipients.
Reduced dosing/formulation deficit risk compared with anhydrous form.
Improved stability, reflected by reduced mass change over months under defined RH/temperature conditions.
Documented Applications
Treatment of gastrointestinal disorders including GERD, functional dyspepsia, functional motility disorder, gastroparesis, paralytic ileus, post-operative ileus, intestinal pseudo-obstruction, irritable bowel syndrome, constipation, enteral feeding intolerance, esophagitis, megacolon, gastritis, gastrointestinal stasis, and abomasal emptying defect.
Improving gastrointestinal motility.
Veterinary or non-human use including chronic grass sickness, megacolon, gastritis, gastrointestinal stasis, and abomasal emptying defect.
Bulk and pharmaceutical compositions and dosage forms such as tablets, capsules, and kits or containers for administering the pharmaceutical composition.
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