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US-20260125373-A1 - Pharmaceutical Formulations and Methods for the Treatment of Gastrointestinal Disorders

US20260125373A1US 20260125373 A1US20260125373 A1US 20260125373A1US-20260125373-A1

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.

Inventors

  • Pascal Jean Druzgala
  • Peter Milner
  • Jien Heh Tien

Assignees

  • RENEXXION, LLC

Dates

Publication Date
20260507
Application Date
20250814

Claims (8)

  1. 1 . A bulk 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, which has the following formula: and at least one container.
  2. 2 - 5 . (canceled)
  3. 6 . 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, which has the following formula: and a pharmaceutically acceptable excipient.
  4. 7 - 10 . (canceled)
  5. 11 . A method of treating a gastrointestinal disorder in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 6 .
  6. 12 - 24 . (canceled)
  7. 25 . A method of improving gastrointestinal motility in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 6 .
  8. 26 - 30 . (canceled)

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation application of U.S. application Ser. No. 18/801,407, filed Aug. 12, 2024, which is a continuation application of U.S. application Ser. No. 18/363,600, filed Aug. 1, 2023, now U.S. Pat. No. 12,098,149, which is a continuation application of U.S. application Ser. No. 18/157,783, filed Jan. 20, 2023, now U.S. Pat. No. 11,827,631, which is a divisional application of U.S. application Ser. No. 17/887,325, filed Aug. 12, 2022, now U.S. Pat. No. 11,643,409, which is a continuation application of U.S. application Ser. No. 16/734,961, filed Jan. 6, 2020, now U.S. Pat. No. 11,498,918, which is a divisional application of U.S. application Ser. No. 16/181,177, filed Nov. 5, 2018, now U.S. Pat. No. 10,570,127, each of which is hereby incorporated by reference in its entirety. FIELD The present disclosure relates to bulk compositions and pharmaceutical compositions 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, and methods of treating gastrointestinal disorders with this form. BACKGROUND Benzamide derivatives and pharmaceutically acceptable salts thereof can act as stimulators of gastrointestinal motility. Many of these compounds are also antagonists of the dopamine D2 receptor, which also plays an important role in the gastrointestinal system. Dopaminergic effects in the gastrointestinal system may include nausea and vomiting. Thus, some of these benzamides are effective anti-emetic agents and they may be used to control vomiting during cancer chemotherapy or radiotherapy, especially when highly emetogenic compounds such as cisplatin are used. This anti-emetic action is believed to be the result of the ability of the benzamides to block the actions of serotonin (5HT) at specific sites of action, called the 5HT3-receptor. A second prominent action of some benzamide derivatives is in augmenting gastrointestinal smooth muscle activity from the esophagus through the proximal small bowel, thus accelerating esophageal and small intestinal transit as well as facilitating gastric emptying and increasing lower esophageal sphincter tone. It is currently believed that the primary smooth muscle effects of some benzamide derivatives are the result of an agonist action upon a class of serotonin receptors referred to as 5HT4 receptors, which are located on interneurons in the myenteric plexus of the gut wall. The benzamide Cisapride, a potent 5-HT4 agonist, was introduced more than 20 years ago and it has been used primarily to treat gastroesophageal reflux disease (GERD). Other 5-HT4 agonists of the benzamide class were subsequently introduced to patients. Because of their activity as prokinetic agents, some 5-HT4 agonists also appear to be useful to treat dyspepsia, gastroparesis, constipation, post-operative ileus, and intestinal pseudo-obstruction. However, many of these compounds, including Cisapride, are associated with serious cardiac arrhythmias, such as ventricular tachycardia, ventricular fibrillation, torsades de pointer, and QT prolongation. The safety of 5HT4 receptor agonists may also be limited by adverse drug interactions due to hepatic cytochrome P-450 metabolism. Thus, what is needed in the art are benzamide 5-HT4 agonists that have a lower incidence of cardiac arrhythmias, which may be used to treat gastrointestinal disorders. Naronapride ((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) is an orally bioavailable selective serotonin 5-HT4 receptor agonist that has been shown in animals and in humans to be safe for use in treating gastrointestinal disorders, and has a low incidence of adverse cardiovascular effects. See U.S. Pat. Nos. 7,176,218; 7,282,509; 7,326,787; 7,629,466; 8,138,204; and 8,524,736, incorporated herein by reference in their entireties. What is needed in the art are improved forms of naronapride for clinical use, and methods of producing bulk compositions thereof. BRIEF SUMMARY In some aspects, provided herein is a bulk 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, which has the following formula: and at least one container. In other aspects, provided herein is 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, which has the following formula: and a pharmaceutically acceptable excipient. In certain aspects, provided herein is a dosage form that includes the pharmaceutical composition. Also provided herein is a method of treating a gastrointestinal disorde