Novel polymorphic forms of metopimazine

Abstract

Provided herein are novel polymorphic forms of metopimazine methanesulfonate. These polymorphic forms are useful in methods, compositions, and kits for treating enteric nervous system disorders.

Description

[0001] This invention application is a divisional application based on a patent application with an application date of April 1, 2021, application number 202180037189.X, and invention name “New polymorphic form of metoprazine”.

[0002] Related applications

[0003] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 003,998, filed April 2, 2020, and U.S. Application No. 16 / 838,402, filed April 2, 2020 (now U.S. Patent No. 10,836,757), the disclosures of which are hereby incorporated by reference in their entireties. Background Art

[0004] The enteric nervous system (ENS) consists of approximately 100 million neurons embedded in the lining of the gastrointestinal system. The ENS innervates the gastrointestinal system, including the esophagus, stomach (e.g., gastric region), and intestines. Motor neurons in the ENS control stomach muscle contractions, peristalsis, and the movement of intestinal contents. It is estimated that approximately 50% of the body's dopamine production is found in the ENS.

[0005] Gastrointestinal (GI) tract disorders affect many people. Irritable bowel syndrome (IBS) is a disorder in which the intestines function abnormally due to abnormal function of the muscles or nerves of the gastrointestinal tract, which affects 10% to 15% of the adult population. Symptoms of IBS include constipation, diarrhea and abdominal pain. Functional dyspepsia (indigestion caused by abnormal function of the muscles or nerves associated with the upper gastrointestinal tract) affects 10% to 20% of the adult population. Gastroparesis is a condition that causes the stomach to under-grind food and delays stomach emptying, which affects up to 10% of the general population. Gastroesophageal reflux disorder (GERD) is a chronic digestive system disease that occurs when stomach acid and / or bile back up into the esophagus. In the United States, it is estimated that up to 35% of infants are affected in the first few months of life and more than half of the general population are affected.

[0006] Furthermore, gastrointestinal disorders can be associated with many other diseases. For example, some early symptoms of Parkinson's disease, a disorder characterized by neurodegeneration of dopamine neurons, include, for example, constipation and other gastrointestinal symptoms, which can be due to degeneration or dysfunction of ENS dopamine neurons. Another example is diabetes, which is one of the most common causes of gastroparesis because long-term high blood sugar damages the vagus nerve that regulates the enteric nervous system. Multiple sclerosis is another disease associated with ENS disorders such as, for example, gastroparesis. Migraine is often associated with gastric stasis. Chemotherapy-induced nausea and / or vomiting is estimated to affect 85% of cancer patients who undergo chemotherapy and can lead to treatment discontinuation. If chemotherapy-induced nausea and / or vomiting is not properly managed, it can lead to dehydration and decreased quality of life and can result in discontinuation of chemotherapy.

[0007] Dysfunction of the ENS is associated with several of the disorders described above. For example, impaired or dysfunctional ENS neuronal signaling is strongly implicated as a causative factor in gastroparesis.

[0008] There are currently insufficient treatments for these disorders. For example, IBS treatments lubiprostone and linaclotide are used to mimic infectious diarrhea in order to treat constipation; however, these agents do not correct underlying ENS dysfunction and have minimal efficacy. The dopamine D2 receptor antagonists metoclopramide and domperidone have previously been indicated for the treatment of nausea and vomiting, however, their use is discouraged, particularly for long-term use, due to serious safety concerns. Two important safety concerns involve: (1) unwanted cardiac side effects caused by the agents' interaction with ion channels involved in cardiac action potentials, and (2) motor dysfunction caused by the action of the dopamine antagonists crossing the blood-brain barrier into the brain. For example, it has been demonstrated that many dopamine receptor antagonists inhibit the hERG channel, a class of potassium channels, leading to drug-induced long QT syndrome, a cardiac condition characterized by abnormal rhythm of cardiac action potentials. Long QT syndrome increases the risk of arrhythmias, which can lead to sudden cardiac death. Indeed, the dopamine D2 antagonist metoclopramide has been shown to inhibit hERG activity, increasing the risk of long QT syndrome and thus sudden cardiac death. This has led to a ban on the use of metoclopramide by the US FDA and a review of the safety of metoclopramide by the European Medicines Agency. Domperidone cannot be taken for more than 12 weeks and has a black box warning for CNS-related side effects such as tardive dyskinesia, a difficult-to-treat and often incurable disorder characterized by involuntary, repetitive body movements. SUMMARY

[0009] The present application provides a crystalline form of metopimazine methanesulfonate salt, In certain embodiments, the crystalline form comprises less than 10 wt.% of an amorphous form. In certain embodiments, the crystalline form is in an unsolvated form. In certain such embodiments, the crystalline form comprises less than 10 wt.% of a solvated form. In certain of the foregoing embodiments, the present application provides a crystalline form of metopiramate mesylate, wherein the crystalline form comprises metopiramate mesylate Form A.

[0010] The present application provides a crystalline form of metoprazine mesylate characterized by an X-ray powder diffraction (XRPD) pattern comprising two or more of the following 2θ values: 9.37°, 9.87°, 14.33°, 15.26°, 15.91°, 16.55°, 17.52°, 17.75°, 18.75°, 19.09°, 19.72°, 20.80°, 21.22°, 21.77°, 23.29° , 23.91°, 24.44°, 25.37°, 26.39°, 26.92°, 27.96°, 28.23°, 28.78°, 29.27°, 29.64°, 30.67°, 31.29°, 31.84°, 32.09°, 32.99°, 33.40°, 33.99°, 35.91°, 36.80°, 37.41°, 37.92° and 39.27° ± 0.2°. In certain embodiments, the crystalline form of metoprazine mesylate is characterized by an XRPD pattern comprising two or more of the following 2θ values: 9.37°, 9.87°, 14.33°, 15.26°, 15.91°, 16.55°, 17.52°, 17.75°, 18.75°, 19.09°, 19.72°, 20.80°, 21.22°, 21.77°, 23.29°, 23.91°, 24.44°, and 25.37° ± 0.2°. In certain embodiments, the crystalline form of metoprazine mesylate is characterized by an XRPD pattern comprising three or more of the following 2θ values: 9.37°, 9.87°, 14.33°, 15.26°, 15.91°, 16.55°, 17.52°, 17.75°, 18.75°, 19.09°, 19.72°, 20.80°, 21.22°, 21.77°, 23.29°, 23.91°, 24.44°, and 25.37° ± 0.2°. In certain embodiments, the crystalline form of metoprazine mesylate is characterized by an XRPD pattern comprising four or more of the following 2θ values: 9.37°, 9.87°, 14.33°, 15.26°, 15.91°, 16.55°, 17.52°, 17.75°, 18.75°, 19.09°, 19.72°, 20.80°, 21.22°, 21.77°, 23.29°, 23.91°, 24.44°, and 25.37° ± 0.2°.

[0011] The present application provides a crystalline form of metopiramate mesylate characterized by an XRPD pattern comprising peaks at the following 2θ values: 15.91° and 18.75°±0.2°. The present application further provides a crystalline form of metopiramate mesylate characterized by an XRPD pattern comprising peaks at the following 2θ values: 15.91°, 18.75°, and 24.44°±0.2°.

[0012] The present application provides a crystalline form of metopiramate mesylate characterized by an XRPD pattern comprising peaks at the following 2θ values: 18.75°. In certain embodiments, the crystalline form of metopiramate mesylate is characterized by an XRPD pattern comprising peaks at the following 2θ values: 15.91° and 18.75°. In certain embodiments, the crystalline form of metopiramate mesylate is characterized by an XRPD pattern comprising peaks at the following 2θ values: 15.91°, 18.75°, and 24.44°.

[0013] The present application provides a crystalline form of metoprazine mesylate, characterized by an XRPD pattern comprising one or more of the following 2θ values: 9.37°, 15.26°, 15.91°, 18.75°, 19.09°, 20.80°, 21.22°, 21.77°, and 24.44° ± 0.2°. In certain embodiments, the crystalline form of metoprazine mesylate is characterized by an XRPD pattern comprising one or more of the following 2θ values: 9.37°, 15.26°, 15.91°, 18.75°, 19.09°, 20.80°, 21.22°, 21.77°, and 24.44°. In certain embodiments, the crystalline form of metopimazine mesylate is characterized by an X-ray powder diffraction pattern comprising two or more of the following 2θ values: 9.37°, 15.26°, 15.91°, 18.75°, 19.09°, 20.80°, 21.22°, 21.77°, and 24.44° ± 0.2°. In certain such embodiments, the crystalline form of metopimazine mesylate is characterized by an X-ray powder diffraction pattern comprising two or more of the following 2θ values: 9.37°, 15.26°, 15.91°, 18.75°, 19.09°, 20.80°, 21.22°, 21.77°, and 24.44°. In certain embodiments, the crystalline form of metopiramate mesylate is characterized by an XRPD pattern comprising three or more of the following 2θ values: 9.37°, 15.26°, 15.91°, 18.75°, 19.09°, 20.80°, 21.22°, 21.77°, and 24.44° ± 0.2°. In certain such embodiments, the crystalline form of metopiramate mesylate is characterized by an XRPD pattern comprising three or more of the following 2θ values: 9.37°, 15.26°, 15.91°, 18.75°, 19.09°, 20.80°, 21.22°, 21.77°, and 24.44°.

[0014] The present application provides a crystalline form of metoprazine mesylate, characterized in that it comprises at least one peak selected from the group consisting of: 13C solid state nuclear magnetic resonance (ssNMR) spectrum: 176.8, 176.4, 142.2, 141.7, 140.9, 140.0, 128.3, 127.0, 126.2, 125.1, 121.1, 119.9, 114.7, 110.9, 57.0, 55.7, 50.6, 47.1, 45.6, 42.1, 40.2, 27.4, and 21.3 ± 0.20 ppm. In certain embodiments, the crystalline form of metoprazine mesylate is characterized by comprising at least three peaks expressed as chemical shifts in ppm selected from the group consisting of 13 C ssNMR spectrum: 176.8, 176.4, 142.2, 141.7, 140.9, 140.0, 128.3, 127.0, 126.2, 125.1, 121.1, 119.9, 114.7, 110.9, 57.0, 55.7, 50.6, 47.1, 45.6, 42.1, 40.2, 27.4, and 21.3 ± 0.20 ppm. In certain embodiments, the crystalline form of metoprazine mesylate is characterized by comprising at least four peaks expressed as chemical shifts in ppm selected from the group consisting of 13 CssNMR spectrum: 176.8, 176.4, 142.2, 141.7, 140.9, 140.0, 128.3, 127.0, 126.2, 125.1, 121.1, 119.9, 114.7, 110.9, 57.0, 55.7, 50.6, 47.1, 45.6, 42.1, 40.2, 27.4, and 21.3 ± 0.20 ppm. In certain embodiments, the crystalline form of metoprazine mesylate is characterized by comprising at least six peaks expressed as chemical shifts in ppm selected from the group consisting of 13 C ssNMR spectrum: 176.8, 176.4, 142.2, 141.7, 140.9, 140.0, 128.3, 127.0, 126.2, 125.1, 121.1, 119.9, 114.7, 110.9, 57.0, 55.7, 50.6, 47.1, 45.6, 42.1, 40.2, 27.4, and 21.3 ± 0.20 ppm. In certain embodiments, the crystalline form of metoprazine mesylate is characterized by comprising at least one peak expressed as a chemical shift in ppm selected from the group consisting of 13C ssNMR spectrum: 21.3, 27.4, 42.1, 50.6, 57.0, 114.7, 119.9, 121.1, 176.4 and 176.8 ± 0.20 ppm. In certain embodiments, the crystalline form of metoprazine mesylate is characterized by comprising at least three peaks expressed as chemical shifts in ppm selected from the group consisting of 13 C ssNMR spectrum: 21.3, 27.4, 42.1, 50.6, 57.0, 114.7, 119.9, 121.1, 176.4 and 176.8 ± 0.20 ppm. In certain embodiments, the crystalline form of metoprazine mesylate is characterized by comprising at least six peaks expressed as chemical shifts in ppm selected from the group consisting of 13 CssNMR spectrum: 21.3, 27.4, 42.1, 50.6, 57.0, 114.7, 119.9, 121.1, 176.4 and 176.8 ± 0.20 ppm.

[0015] The present application provides a crystalline form of metoprazine mesylate, characterized by comprising a differential scanning calorimetry pattern comprising a single endotherm with an onset temperature range of 208°C to 212°C. In certain embodiments, the single endotherm comprises an onset temperature range of 208°C to 211°C. In certain embodiments, the single endotherm comprises an onset temperature range of 209°C to 210°C. In certain embodiments of any of the foregoing, the single endotherm comprises a peak temperature range of 213°C to 214°C. In certain embodiments of any of the foregoing, the single endotherm comprises a transition enthalpy of 95-100 J / g. In certain such embodiments, the single endotherm comprises a transition enthalpy of 96-98 J / g. In further embodiments, the single endotherm comprises a transition enthalpy of 97-98 J / g.

[0016] The present disclosure provides a crystalline form of metoprazine mesylate characterized by comprising a thermogravimetric analysis profile of 0.4% total weight loss up to 150.0°C.

[0017] In certain embodiments of any of the foregoing, the composition comprises less than 10 wt.% of other crystalline forms. In certain such embodiments, the composition comprises less than 1 wt.% of other crystalline forms. In certain embodiments of the foregoing, the composition comprises less than 10 wt.% of an amorphous form. In certain such embodiments, the composition comprises less than 1 wt.% of an amorphous form.

[0018] The application provides a kind of pharmaceutical composition, described pharmaceutical composition comprises any one of the aforementioned crystalline forms and pharmaceutically acceptable excipients.In certain embodiments, described pharmaceutical composition is suitable for oral, intraduodenal, intracolonic, enteral, external, intranasal, parenteral, buccal, sublingual, by inhalation or rectal administration.In certain embodiments, described composition is suitable for oral administration.In certain embodiments, described composition is suitable for sublingual administration.In certain embodiments of the aforementioned, described pharmaceutical composition is formulated as tablet, capsule, paste, powder, suspension, suppository, extended release formulation or modified release formulation.In some such embodiments, described composition is formulated as extended release formulation.In further embodiment, described composition is formulated as capsule.

[0019] In certain embodiments of any of the foregoing pharmaceutical compositions, the composition comprises 5 mg of a crystalline form of metopiramate mesylate. In certain embodiments, the composition comprises 10 mg of a crystalline form of metopiramate mesylate. In certain embodiments, the composition comprises 15 mg of a crystalline form of metopiramate mesylate. In certain embodiments, the composition comprises 20 mg of a crystalline form of metopiramate mesylate.

[0020] In certain embodiments of any of the foregoing pharmaceutical compositions, the composition is suitable for administration once a day. In certain embodiments, the composition is suitable for administration twice a day. In certain embodiments, the composition is suitable for administration three times a day. In certain embodiments, the composition is suitable for administration four times a day.

[0021] In certain embodiments of any of the foregoing pharmaceutical compositions, between about 5 mg and about 160 mg of the crystalline form of metopiramate mesylate is administered daily. In certain embodiments, the composition is suitable for administering more than 20 mg of the crystalline form of metopiramate mesylate daily.

[0022] The present application provides a method for treating an intestinal nervous system disorder of a human subject in need thereof, the method comprising administering any of the aforementioned pharmaceutical compositions to the subject. In certain embodiments, the intestinal nervous system disorder is a chronic disorder. In other embodiments, the intestinal nervous system disorder is an acute disorder. In certain embodiments, the intestinal nervous system disorder is selected from gastroparesis, irritable bowel syndrome, lysosomal storage disorders, intestinal motility disorders, ganglioneuroma, multiple endocrine neoplasia type 2B (MEN2B), gastrointestinal neuropathy, functional dyspepsia, gastroesophageal reflux disease (GERD) and intestinal neuroplasia. In certain of the aforementioned embodiments, the intestinal nervous system disorder includes symptoms selected from the following: early satiety, postprandial fullness, abdominal fullness, nausea, vomiting, delayed gastric emptying, diarrhea, abdominal pain, flatulence, bloating, gastroesophageal reflux, anorexia and constipation. In certain embodiments, the intestinal nervous system disorder symptoms include nausea. In other embodiments, the intestinal nervous system disorder symptoms include vomiting.

[0023] The present application provides a method for treating gastroparesis in a human subject in need thereof, the method comprising administering to the subject any one of the aforementioned pharmaceutical compositions. In certain embodiments, the gastroparesis is diabetic gastroparesis. In other embodiments, the gastroparesis is idiopathic gastroparesis. In certain of the aforementioned embodiments, the gastroparesis comprises symptoms selected from the group consisting of early satiety, postprandial fullness, abdominal fullness, nausea, vomiting, delayed gastric emptying, diarrhea, abdominal pain, flatulence, bloating, gastroesophageal reflux, loss of appetite, and constipation. In certain such embodiments, the gastroparesis symptom comprises nausea. In other embodiments, the gastroparesis symptom comprises vomiting.

[0024] The present application provides a method of treating nausea associated with gastroparesis in a human subject in need thereof, the method comprising administering to the subject any one of the aforementioned pharmaceutical compositions.

[0025] The present application provides a method of treating vomiting associated with gastroparesis in a human subject in need thereof, the method comprising administering to the subject any one of the aforementioned pharmaceutical compositions.

[0026] The present application provides a method of improving gastric emptying in a human subject in need thereof, comprising administering to the subject any one of the aforementioned pharmaceutical compositions.

[0027] The present application provides a method for treating gastrointestinal function and motility disorders in a human subject in need thereof, the method comprising administering any one of the aforementioned pharmaceutical compositions to the subject.

[0028] In certain embodiments of any of the foregoing methods, the pharmaceutical composition is administered chronically to the subject. In other embodiments of any of the foregoing methods, the pharmaceutical composition is administered acutely to the subject.

[0029] In certain embodiments of any of the foregoing methods, the pharmaceutical composition is administered to the subject for at least 6 days. In certain such embodiments, the pharmaceutical composition is administered to the subject for at least 7 days. In certain embodiments, the subject is administered for at least four weeks. In certain embodiments, the pharmaceutical composition is administered to the subject for at least 12 weeks.

[0030] In certain embodiments of any of the foregoing methods, the pharmaceutical composition is administered to the subject once a day. In certain embodiments, the pharmaceutical composition is administered to the subject twice a day. In certain embodiments, the pharmaceutical composition is administered to the subject three times a day. In certain embodiments, the pharmaceutical composition is administered to the subject four times a day.

[0031] In certain embodiments of any of the foregoing methods, between about 5 mg and about 160 mg of metopiramate mesylate is administered to the subject daily. In certain such embodiments, more than 20 mg of metopiramate mesylate is administered to the subject daily.

[0032] The present invention comprises:

[0033] 1. A crystalline form of metoprazine mesylate,

[0034] 2. The crystalline form of claim 1 , wherein the crystalline form comprises less than 10 wt.% of an amorphous form.

[0035] 3. The crystalline form according to item 1 or 2, wherein the crystalline form is in an unsolvated form.

[0036] 4. A crystalline form according to claim 3, wherein the crystalline form comprises less than 10 wt.% of solvate forms.

[0037] 5. The crystalline form according to the preceding item, wherein the crystalline form comprises metopiramate mesylate form A.

[0038] 6. A crystalline form of metopimazine mesylate, the crystalline form of metopimazine mesylate being characterized by an X-ray powder diffraction (XRPD) pattern comprising two or more of the following 2θ values: 9.37°, 9.87°, 14.33°, 15.26°, 15.91°, 16.55°, 17.52°, 17.75°, 18.75°, 19.09°, 19.72°, 20.80°, 21.22°, 21.77°, 23. .29°, 23.91°, 24.44°, 25.37°, 26.39°, 26.92°, 27.96°, 28.23°, 28.78°, 29.27°, 29.64°, 30.67°, 31.29°, 31.84°, 32.09°, 32.99°, 33.40°, 33.99°, 35.91°, 36.80°, 37.41°, 37.92° and 39.27° ± 0.2°.

[0039] 7. The crystalline form of claim 6, characterized by an XRPD pattern comprising two or more of the following 2θ values: 9.37°, 9.87°, 14.33°, 15.26°, 15.91°, 16.55°, 17.52°, 17.75°, 18.75°, 19.09°, 19.72°, 20.80°, 21.22°, 21.77°, 23.29°, 23.91°, 24.44°, and 25.37°±0.2°.

[0040] 8. The crystalline form of claim 6, characterized by an XRPD pattern comprising three or more of the following 2θ values: 9.37°, 9.87°, 14.33°, 15.26°, 15.91°, 16.55°, 17.52°, 17.75°, 18.75°, 19.09°, 19.72°, 20.80°, 21.22°, 21.77°, 23.29°, 23.91°, 24.44°, and 25.37°±0.2°.

[0041] 9. The crystalline form of claim 6, characterized by an XRPD pattern comprising four or more of the following 2θ values: 9.37°, 9.87°, 14.33°, 15.26°, 15.91°, 16.55°, 17.52°, 17.75°, 18.75°, 19.09°, 19.72°, 20.80°, 21.22°, 21.77°, 23.29°, 23.91°, 24.44°, and 25.37°±0.2°.

[0042] 10. The crystalline form of item 6, characterized by an XRPD pattern comprising peaks at the following 2-theta values: 15.91° and 18.75° ± 0.2°.

[0043] 11. The crystalline form of item 6, characterized by an XRPD pattern comprising peaks at the following 2-theta values: 15.91°, 18.75° and 24.44° ± 0.2°.

[0044] 12. A crystalline form of metopimazine mesylate characterized by an XRPD pattern comprising one or more of the following 2-theta values: 9.37°, 15.26°, 15.91°, 18.75°, 19.09°, 20.80°, 21.22°, 21.77° and 24.44° ± 0.2°.

[0045] 13. The crystalline form of item 12, characterized by an XRPD pattern comprising two or more of the following 2-theta values: 9.37°, 15.26°, 15.91°, 18.75°, 19.09°, 20.80°, 21.22°, 21.77° and 24.44° ± 0.2°.

[0046] 14. The crystalline form of item 12, characterized by an XRPD pattern comprising three or more of the following 2-theta values: 9.37°, 15.26°, 15.91°, 18.75°, 19.09°, 20.80°, 21.22°, 21.77° and 24.44° ± 0.2°.

[0047] 15. A crystalline form of metopimazine mesylate characterized by a solid state nuclear magnetic resonance (ssNMR) spectrum comprising at least one peak selected from the following expressed as chemical shift in ppm: 176.8, 176.4, 142.2, 141.7, 140.9, 140.0, 128.3, 127.0, 126.2, 125.1, 121.1, 119.9, 114.7, 110.9, 57.0, 55.7, 50.6, 47.1, 45.6, 42.1, 40.2, 27.4 and 21.3 ± 0.20 ppm. 13 C solid state nuclear magnetic resonance (ssNMR) spectrum: 176.8, 176.4, 142.2, 141.7, 140.9, 140.0, 128.3, 127.0, 126.2, 125.1, 121.1, 119.9, 114.7, 110.9, 57.0, 55.7, 50.6, 47.1, 45.6, 42.1, 40.2, 27.4 and 21.3 ± 0.20 ppm.

[0048] 16. The crystalline form of item 15, characterized by a solid state nuclear magnetic resonance (ssNMR) spectrum comprising at least three peaks selected from the following expressed as chemical shift in ppm: 176.8, 176.4, 142.2, 141.7, 140.9, 140.0, 128.3, 127.0, 126.2, 125.1, 121.1, 119.9, 114.7, 110.9, 57.0, 55.7, 50.6, 47.1, 45.6, 42.1, 40.2, 27.4 and 21.3 ± 0.20 ppm. 13C ssNMR spectrum: 176.8, 176.4, 142.2, 141.7, 140.9, 140.0, 128.3, 127.0, 126.2, 125.1, 121.1, 119.9, 114.7, 110.9, 57.0, 55.7, 50.6, 47.1, 45.6, 42.1, 40.2, 27.4, and 21.3 ± 0.20 ppm.

[0049] 17. The crystalline form of claim 15, characterized in that it comprises at least four peaks expressed as chemical shifts in ppm selected from the group consisting of 13 C ssNMR spectrum: 176.8, 176.4, 142.2, 141.7, 140.9, 140.0, 128.3, 127.0, 126.2, 125.1, 121.1, 119.9, 114.7, 110.9, 57.0, 55.7, 50.6, 47.1, 45.6, 42.1, 40.2, 27.4, and 21.3 ± 0.20 ppm.

[0050] 18. The crystalline form of claim 15, characterized in that it comprises at least six peaks expressed as chemical shifts in ppm selected from the group consisting of 13 C ssNMR spectrum: 176.8, 176.4, 142.2, 141.7, 140.9, 140.0, 128.3, 127.0, 126.2, 125.1, 121.1, 119.9, 114.7, 110.9, 57.0, 55.7, 50.6, 47.1, 45.6, 42.1, 40.2, 27.4, and 21.3 ± 0.20 ppm.

[0051] 19. The crystalline form of claim 15, characterized in that it comprises at least one peak selected from the group consisting of: 13 C ssNMR spectrum: 21.3, 27.4, 42.1, 50.6, 57.0, 114.7, 119.9, 121.1, 176.4 and 176.8 ± 0.20 ppm.

[0052] 20. The crystalline form of claim 15, characterized in that it comprises at least three peaks expressed as chemical shifts in ppm selected from the group consisting of 13 C ssNMR spectrum: 21.3, 27.4, 42.1, 50.6, 57.0, 114.7, 119.9, 121.1, 176.4 and 176.8 ± 0.20 ppm.

[0053] 21. The crystalline form of claim 15, characterized in that it comprises at least six peaks expressed as chemical shifts in ppm selected from the group consisting of 13 C ssNMR spectrum: 21.3, 27.4, 42.1, 50.6, 57.0, 114.7, 119.9, 121.1, 176.4 and 176.8 ± 0.20 ppm.

[0054] 22. A crystalline form of metopiramate mesylate characterized by comprising a differential scanning calorimetry pattern comprising a single endotherm with an onset temperature ranging from 208°C to 212°C.

[0055] 23. The crystalline form of clause 22, wherein the single endotherm comprises an onset temperature range of 208°C to 211°C.

[0056] 24. The crystalline form of item 22, wherein the single endotherm comprises an onset temperature range of 209°C to 210°C.

[0057] 25. The crystalline form of any one of items 22-24, wherein the single endotherm comprises a peak temperature range of 213°C to 214°C.

[0058] 26. The crystalline form of any one of items 22-25, wherein the single endotherm comprises a transition enthalpy of 95-100 J / g.

[0059] 27. The crystalline form of clause 26, wherein the single endotherm comprises a transition enthalpy of 96-98 J / g.

[0060] 28. The crystalline form of clause 26, wherein the single endotherm comprises a transition enthalpy of 97-98 J / g.

[0061] 29. A crystalline form of metopiramate mesylate characterized by a thermogravimetric analysis profile comprising a total weight loss of 0.4% up to 150.0°C.

[0062] 30. A composition comprising the crystalline form according to any one of items 6 to 29, wherein the composition comprises less than 10 wt.% of other crystalline forms of metopiramate mesylate.

[0063] 31. A composition according to item 30, wherein the composition comprises less than 1 wt.% of other crystalline forms of metopiramate mesylate.

[0064] 32. The composition of item 30 or 31, wherein the composition comprises less than 10 wt.% of metoprazine mesylate in amorphous form.

[0065] 33. A composition according to claim 32, wherein the composition comprises less than 1 wt.% of metoprazine mesylate in amorphous form.

[0066] 34. A pharmaceutical composition comprising the crystalline form according to any one of items 1 to 33 and a pharmaceutically acceptable excipient.

[0067] 35. The pharmaceutical composition according to item 34, wherein the pharmaceutical composition is suitable for oral, intraduodenal, intracolonic, enteral, topical, intranasal, parenteral, buccal, sublingual, by inhalation or rectal administration.

[0068] 36. A pharmaceutical composition according to item 35, wherein the composition is suitable for oral administration.

[0069] 37. A pharmaceutical composition according to item 35, wherein the composition is suitable for sublingual administration.

[0070] 38. The pharmaceutical composition according to any one of items 34-37, wherein the pharmaceutical composition is formulated as a tablet, a capsule, a paste, a powder, a suspension, a suppository, an extended release formulation or a modified release formulation.

[0071] 39. The pharmaceutical composition of claim 38, wherein the composition is formulated as an extended release formulation.

[0072] 40. The pharmaceutical formulation according to item 38, wherein the composition is formulated as a capsule.

[0073] 41. A pharmaceutical composition according to any one of items 34-40, wherein the composition comprises 5 mg of the crystalline form of metopiramate mesylate.

[0074] 42. A pharmaceutical composition according to any one of items 34-40, wherein the composition comprises 10 mg of the crystalline form of metopiramate mesylate.

[0075] 43. A pharmaceutical composition according to any one of items 34-40, wherein the composition comprises 20 mg of the crystalline form of metopiramate mesylate.

[0076] 44. A pharmaceutical composition according to any one of items 34-43, wherein the composition is suitable for once-daily administration.

[0077] 45. A pharmaceutical composition according to any one of items 34-43, wherein the composition is suitable for administration twice a day.

[0078] 46. ​​A pharmaceutical composition according to any one of items 34-43, wherein the composition is suitable for administration three times a day.

[0079] 47. A pharmaceutical composition according to any one of items 34-43, wherein the composition is suitable for administration four times a day.

[0080] 48. The pharmaceutical composition of any one of items 34-47, wherein between about 5 mg and about 160 mg of the crystalline form of metopiramate mesylate is administered per day.

[0081] 49. A pharmaceutical composition according to any one of items 34-47, wherein the composition is suitable for daily administration of more than 20 mg of the crystalline form of metopiramate mesylate.

[0082] 50. A method of treating an enteric nervous system disorder in a human subject, the method comprising administering to the subject a pharmaceutical composition according to any one of items 34-49.

[0083] 51. A method according to claim 50, wherein the enteric nervous system disorder is a chronic disorder.

[0084] 52. A method according to claim 50, wherein the enteric nervous system disorder is an acute disorder.

[0085] 53. A method according to claim 50, wherein the enteric nervous system disorder is selected from gastroparesis, irritable bowel syndrome, lysosomal storage disorders, intestinal motility disorders, ganglioneuroma, multiple endocrine neoplasia type 2B (MEN2B), gastrointestinal neuropathy, functional dyspepsia, gastroesophageal reflux disease (GERD) and intestinal neurodysplasia.

[0086] 54. A method according to any one of items 50-53, wherein the enteric nervous system disorder comprises symptoms selected from the group consisting of early satiety, postprandial fullness, abdominal fullness, nausea, vomiting, delayed gastric emptying, diarrhea, abdominal pain, flatulence, bloating, gastroesophageal reflux, loss of appetite and constipation.

[0087] 55. A method according to claim 54, wherein the symptoms of enteric nervous system disorders include nausea.

[0088] 56. A method according to claim 54, wherein the symptoms of enteric nervous system disorders include vomiting.

[0089] 57. A method of treating gastroparesis in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of any one of items 34-49.

[0090] 58. The method of claim 57, wherein the gastroparesis is diabetic gastroparesis.

[0091] 59. The method of claim 57, wherein the gastroparesis is idiopathic gastroparesis.

[0092] 60. The method of any one of items 57-59, wherein the gastroparesis comprises symptoms selected from the group consisting of early satiety, postprandial fullness, abdominal fullness, nausea, vomiting, delayed gastric emptying, diarrhea, abdominal pain, flatulence, bloating, gastroesophageal reflux, loss of appetite, and constipation.

[0093] 61. The method of claim 60, wherein the gastroparesis symptoms include nausea.

[0094] 62. The method of claim 60, wherein the gastroparesis symptom comprises vomiting.

[0095] 63. A method of treating nausea associated with gastroparesis in a human subject in need thereof, the method comprising administering to the subject a pharmaceutical composition according to any one of items 34-49.

[0096] 64. A method of treating vomiting associated with gastroparesis in a human subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of any one of items 34-49.

[0097] 65. A method of treating gastric emptying in a human subject in need thereof, the method comprising administering to the subject a pharmaceutical composition according to any one of items 34-49.

[0098] 66. A method of treating gastrointestinal function and motility disorders in a human subject in need thereof, the method comprising administering to the subject a pharmaceutical composition according to any one of items 34-49.

[0099] 67. The method of any one of items 50-66, wherein the pharmaceutical composition is administered to the subject chronically.

[0100] 68. The method of any one of items 50-66, wherein the pharmaceutical composition is acutely administered to the subject.

[0101] 69. The method of any one of items 50-66, wherein the pharmaceutical composition is administered to the subject for at least 6 days.

[0102] 70. The method of claim 69, wherein the pharmaceutical composition is administered to the subject for at least 7 days.

[0103] 71. The method of claim 69, wherein the pharmaceutical composition is administered to the subject for at least four weeks.

[0104] 72. The method of claim 69, wherein the pharmaceutical composition is administered to the subject for at least 12 weeks.

[0105] 73. The method of any one of items 50-72, wherein the pharmaceutical composition is administered to the subject once daily.

[0106] 74. The method of any one of items 50-72, wherein the pharmaceutical composition is administered to the subject twice daily.

[0107] 75. The method of any one of items 50-72, wherein the pharmaceutical composition is administered to the subject three times a day.

[0108] 76. The method of any one of items 50-72, wherein the pharmaceutical composition is administered to the subject four times a day.

[0109] 77. The method of any one of items 50-76, wherein between about 5 mg and about 160 mg of the metoprazine mesylate is administered to the subject daily.

[0110] 78. The method of any one of items 50-76, wherein more than 20 mg of metoprazine mesylate is administered to the subject per day. BRIEF DESCRIPTION OF THE DRAWINGS

[0111] Figure 1 Depicted is the X-ray powder diffraction pattern (XRPD) of metopiramate mesylate Form A.

[0112] Figure 2 Depicted is a thermogravimetric analysis (TGA) profile of metoprazine mesylate Form A.

[0113] Figure 3 Depicted is a differential scanning calorimetry (DSC) graph of metoprazine mesylate Form A.

[0114] Figure 4 Depicted is the X-ray powder diffraction pattern (XRPD) of metopiramate mesylate Form B.

[0115] Figure 5 Depicted are the TGA and DSC patterns of metoprazine mesylate Form B.

[0116] Figure 6 Depicted is the metoprazine mesylate form A (200 ppm to 0 ppm) 13 C ssNMR spectrum.

[0117] Figure 7 Depicted is the metoprazine mesylate form B (200 ppm to 0 ppm) 13 C ssNMR spectrum.

[0118] Figure 8 Depicted is the metoprazine mesylate Form B minus Form A (200 ppm to 0 ppm). 13 C ssNMR spectrum. DETAILED DESCRIPTION

[0119] The present application provides a crystalline form of metoprazine mesylate,

[0120] In certain embodiments of the present application, the crystalline form of metoprazine mesylate contains less than 10 wt.% of other crystalline forms, such as less than 5 wt.%, less than 4 wt.%, less than 3 wt.%, less than 2 wt.%, less than 1 wt.%, less than 0.1 wt.% or less than 0.01 wt.% of other crystalline forms.

[0121] In certain embodiments of the present application, the crystalline form of metoprazine mesylate contains less than 10 wt.% of amorphous form, such as less than 5 wt.%, less than 4 wt.%, less than 3 wt.%, less than 2 wt.%, less than 1 wt.%, less than 0.1 wt.% or less than 0.01 wt.% of amorphous form.

[0122] In certain embodiments of the present application, the crystalline form of metopiramate mesylate contains less than 10 wt.% of other forms (e.g., other crystalline forms of metopiramate mesylate or other amorphous forms of metopiramate mesylate), such as less than 5 wt.%, less than 4 wt.%, less than 3 wt.%, less than 2 wt.%, less than 1 wt.%, less than 0.1 wt.% or less than 0.01 wt.% of other forms (e.g., other crystalline forms of metopiramate mesylate or other amorphous forms of metopiramate mesylate).

[0123] In certain embodiments of the application, the crystalline form of metopimazine mesylate is in a non-solvate form. In certain such embodiments of the application, the crystalline form of metopimazine mesylate comprises less than 10 wt.% of solvate forms, such as less than 5 wt.%, less than 4 wt.%, less than 3 wt.%, less than 2 wt.%, less than 1 wt.%, less than 0.1 wt.% or less than 0.01 wt.% of solvate forms.

[0124] In certain embodiments of the application, the crystalline form of metopimazine mesylate is in a non-hydrate form. In certain such embodiments, the crystalline form of metopimazine mesylate comprises between about 10% metopimazine mesylate non-hydrate and about 100% metopimazine mesylate non-hydrate. For example, the crystalline form of metopimazine mesylate comprises about 10% metopimazine mesylate non-hydrate, about 20% metopimazine mesylate non-hydrate, about 30% metopimazine mesylate non-hydrate, about 40% metopimazine mesylate non-hydrate, about 50% metopimazine mesylate non-hydrate, about 60% metopimazine mesylate non-hydrate, about 70% metopimazine mesylate non-hydrate, about 80% metopimazine mesylate non-hydrate, about 90% metopimazine mesylate non-hydrate, or about 95% metopimazine mesylate non-hydrate. In certain such embodiments of the application, the crystalline form of metopimazine mesylate comprises less than 10 wt.% of hydrate forms, such as less than 5 wt.%, less than 4 wt.%, less than 3 wt.%, less than 2 wt.%, less than 1 wt.%, less than 0.1 wt.% or less than 0.01 wt.% of hydrate forms.

[0125] In certain embodiments of the present application, the crystalline form of metopiramate mesylate is in the form of a solvate, such as a hydrate (e.g., a monohydrate). In certain such embodiments, the crystalline form of metopiramate mesylate comprises between about 10% metopiramate mesylate monohydrate and about 100% metopiramate mesylate monohydrate. For example, the crystalline form of metopimaprozine mesylate comprises about 10% metopimaprozine mesylate monohydrate, about 20% metopimaprozine mesylate anhydrate, about 30% metopimaprozine mesylate monohydrate, about 40% metopimaprozine mesylate monohydrate, about 50% metopimaprozine mesylate monohydrate, about 60% metopimaprozine mesylate monohydrate, about 70% metopimaprozine mesylate monohydrate, about 80% metopimaprozine mesylate monohydrate, about 90% metopimaprozine mesylate monohydrate, or about 95% metopimaprozine mesylate monohydrate. In certain such embodiments of the present application, the crystalline form of metoprazine mesylate contains less than 10 wt.% of other solvate forms or unsolvate forms, such as less than 5 wt.%, less than 4 wt.%, less than 3 wt.%, less than 2 wt.%, less than 1 wt.%, less than 0.1 wt.% or less than 0.01 wt.% of other solvate forms or unsolvate forms.

[0126] The present application provides metoprazine mesylate crystalline form A, Characterized by an X-ray powder diffraction (XRPD) pattern comprising one or more of the 2-theta (2θ) values ​​provided in Table 1. The diffraction pattern was recorded using Cu, Kα radiation.

[0127] Table 1: Peaks identified on XRPD of metoprazine mesylate form A

[0128]

[0129]

[0130] In certain embodiments, metopimaprozine mesylate crystalline Form A is characterized by an XRPD pattern comprising at least two 2θ values ​​selected from those shown in Table 1. In certain embodiments, metopimaprozine mesylate crystalline Form A is characterized by an XRPD pattern comprising at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine 2θ values ​​selected from those shown in Table 1. In certain embodiments, metopimaprozine mesylate crystalline Form A is characterized by one or more 2θ values ​​in Table 1 ranging from about 5 to about 25 degrees 2θ. In certain embodiments, metopimaprozine mesylate crystalline Form A is characterized by at least two 2θ values ​​in Table 1 ranging from about 5 to about 25 degrees 2θ. In certain embodiments, metopimaprozine mesylate crystalline Form A is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine 2θ values ​​in Table 1 ranging from about 5 to about 25 degrees 2θ. In certain embodiments, metoprazine mesylate crystalline form A is characterized by an XRPD pattern comprising 2θ values ​​selected from those shown in Table 1. It will be understood by those skilled in the art that XRPD intensities may vary between different samples and different sample preparations due to various reasons including preferred orientation. It will also be appreciated by those skilled in the art that due to various reasons including changes in the sample surface level in the diffractometer, the angles measured and therefore the interplanar spacings may be less offset. It will be further understood by those skilled in the art that the 2θ degrees provided in Table 1 can generally be reproduced within a range of from about ± 0.10 2θ degrees to about ± 0.20 2θ (preferably in a range of about ± 0.10 2θ degrees). See, for example, United States Pharmacopoeia XXV (2002), pp. 2088-2089.

[0131] In certain embodiments, metoprazine mesylate crystalline Form A is characterized by an XRPD pattern comprising two or more of the following 2θ values: 9.37°, 9.87°, 14.33°, 15.26°, 15.91°, 16.55°, 17.52°, 17.75°, 18.75°, 19.09°, 19.72°, 20.80°, 21.22°, 21.77°, 23.29°, 23. .91°, 24.44°, 25.37°, 26.39°, 26.92°, 27.96°, 28.23°, 28.78°, 29.27°, 29.64°, 30.67°, 31.29°, 31.84°, 32.09°, 32.99°, 33.40°, 33.99°, 35.91°, 36.80°, 37.41°, 37.92° and 39.27°. In certain embodiments, metoprazine mesylate Form A is characterized by an XRPD pattern comprising two or more of the following 2θ values: 9.37°, 9.87°, 14.33°, 15.26°, 15.91°, 16.55°, 17.52°, 17.75°, 18.75°, 19.09°, 19.72°, 20.80°, 21.22°, 21.77°, 23.29°, 23.91°, 24.44°, and 25.37° ± 0.2°. In certain embodiments, metoprazine mesylate Form A is characterized by an XRPD pattern comprising three or more of the following 2θ values: 9.37°, 9.87°, 14.33°, 15.26°, 15.91°, 16.55°, 17.52°, 17.75°, 18.75°, 19.09°, 19.72°, 20.80°, 21.22°, 21.77°, 23.29°, 23.91°, 24.44°, and 25.37° ± 0.2°. In certain embodiments, metoprazine mesylate Form A is characterized by an XRPD pattern comprising three or more of the following 2θ values: 9.37°, 9.87°, 14.33°, 15.26°, 15.91°, 16.55°, 17.52°, 17.75°, 18.75°, 19.09°, 19.72°, 20.80°, 21.22°, 21.77°, 23.29°, 23.91°, 24.44°, and 25.37° ± 0.1°.In certain embodiments, metoprazine mesylate crystalline Form A is characterized by an XRPD pattern comprising four or more of the following 2θ values: 9.37°, 9.87°, 14.33°, 15.26°, 15.91°, 16.55°, 17.52°, 17.75°, 18.75°, 19.09°, 19.72°, 20.80°, 21.22°, 21.77°, 23.29°, 23.91°, 24.44°, and 25.37° ± 0.2°. In certain embodiments, metoprazine mesylate Form A is characterized by an XRPD pattern comprising four or more of the following 2θ values: 9.37°, 9.87°, 14.33°, 15.26°, 15.91°, 16.55°, 17.52°, 17.75°, 18.75°, 19.09°, 19.72°, 20.80°, 21.22°, 21.77°, 23.29°, 23.91°, 24.44°, and 25.37° ± 0.1°. In certain embodiments, metopimazine mesylate crystalline Form A is characterized by an XRPD pattern comprising one or more of the following 2θ values: 9.37°, 15.26°, 15.91°, 18.75°, 19.09°, 20.80°, 21.22°, 21.77°, and 24.44° ± 0.10-0.20 2θ. In certain embodiments, metopimazine mesylate crystalline Form A is characterized by an XRPD pattern comprising two or more of the following 2θ values: 9.37°, 15.26°, 15.91°, 18.75°, 19.09°, 20.80°, 21.22°, 21.77°, and 24.44° ± 0.10-0.20 2θ. In certain embodiments, metopimazine mesylate crystalline Form A is characterized by an XRPD pattern comprising three or more of the following 2θ values: 9.37°, 15.26°, 15.91°, 18.75°, 19.09°, 20.80°, 21.22°, 21.77°, and 24.44° ± 0.10-0.20 2θ. In certain embodiments, metopimazine mesylate crystalline Form A is characterized by an XRPD pattern comprising four or more of the following 2θ values: 9.37°, 15.26°, 15.91°, 18.75°, 19.09°, 20.80°, 21.22°, 21.77°, and 24.44° ± 0.10-0.20 2θ. In certain embodiments, metoprazine mesylate Form A is characterized by an XRPD pattern comprising five or more of the following 2θ values: 9.37°, 15.26°, 15.91°, 18.75°, 19.09°, 20.80°, 21.22°, 21.77°, and 24.44° ± 0.10-0.20 2θ.

[0132] In certain embodiments, metopimarazine mesylate crystalline Form A is characterized by an XRPD pattern comprising peaks at the following 2θ values: 18.75° ± 0.10-0.20 2θ. In certain embodiments, metopimarazine mesylate crystalline Form A is characterized by an XRPD pattern comprising peaks at the following 2θ values: 15.91° and 18.75° ± 0.10-0.20 2θ. In certain embodiments, metopimarazine mesylate crystalline Form A is characterized by an XRPD pattern comprising peaks at the following 2θ values: 15.91°, 18.75°, and 24.44° ± 0.10-0.20 2θ. In certain embodiments, metopimarazine mesylate crystalline Form A is characterized by an XRPD pattern comprising peaks at the following 2θ values: 15.91°, 18.75°, 21.22°, and 24.44° ± 0.10-0.20 2θ. In certain embodiments, metopimazine mesylate crystalline Form A is characterized by an XRPD pattern comprising peaks at the following 2θ values: 9.37°, 15.91°, 18.75°, 21.22°, and 24.44° ± 0.10-0.20 2θ. In certain embodiments, metopimazine mesylate crystalline Form A is characterized by an XRPD pattern comprising peaks at the following 2θ values: 9.37°, 15.26°, 15.91°, 18.75°, 21.22°, and 24.44° ± 0.10-0.20 2θ.

[0133] The present application provides metopimazine mesylate crystalline Form A, characterized by an XRPD pattern comprising at least two interplanar spacing values ​​selected from those shown in Table 1. In certain embodiments, metopimazine mesylate crystalline Form A is characterized by an XRPD pattern comprising at least three, at least four, at least five, or at least six interplanar spacing values ​​selected from those shown in Table 1. In certain embodiments, metopimazine mesylate crystalline Form A is characterized by an XRPD pattern comprising interplanar spacing values ​​selected from those shown in Table 1.

[0134] In certain embodiments, metopiramate mesylate crystalline Form A is characterized by the XRPD pattern shown in Table 1. In certain embodiments, metopiramate mesylate crystalline Form A exhibits Figure 1 The XRPD pattern shown.

[0135] The present application provides metoprazine mesylate crystalline form A, characterized by comprising one or more peaks provided in Table 2 expressed as chemical shifts in ppm. 13 C solid-state nuclear magnetic resonance (ssNMR) spectra. The spectra were obtained on a Bruker NEO spectrometer, where 13 C runs at 100.52MHz and for 1 H runs at 399.71MHz or for 13C was run at 100.46 MHz and is referenced to 1 H was run at 399.49 MHz.

[0136] Table 2: Metopimazine mesylate Form A is characterized by a13C ssNMR spectrum comprising at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten peaks expressed in chemical shifts in ppm selected from those shown in Table 2. 13 C ssNMR spectrum

[0137]

[0138]

[0139] In certain embodiments, metopimazine mesylate Form A is characterized by a13C ssNMR spectrum comprising at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten peaks expressed in chemical shifts in ppm selected from those shown in Table 2. 13 C ssNMR spectrum. In certain embodiments, metopimazine mesylate Form A is characterized by a13C ssNMR spectrum comprising peaks expressed in chemical shifts in ppm selected from those shown in Table 2. 13 C ssNMR spectrum. Those skilled in the art will appreciate that 13 The13C ssNMR spectrum (including the appearance, intensity, and position of peaks in the spectrum) can vary between different samples, different sample preparations, and different conditions under which the spectrum is obtained. Accordingly, those skilled in the art will appreciate that the peaks expressed in chemical shifts in ppm provided in Table 2 can generally be reproduced within a range of from about ± 0.10 ppm to about ± 0.20 ppm (preferably a range of about ± 0.20 ppm). In certain embodiments, metopimazine mesylate Form A is characterized by a13C ssNMR spectrum as shown in Table 2. 13 CssNMR spectrum. In certain embodiments, metopimazine mesylate Form A having a purity of at least 90%, at least 95%, or at least 99% exhibits a13C ssNMR spectrum as shown in Table 2. Figure 6 13 C ssNMR spectrum.

[0140] In certain embodiments, metopimazine mesylate Form A is characterized by a13C ssNMR spectrum comprising peaks expressed in chemical shifts in ppm selected from those shown in Table 2. 13 C ssNMR spectrum: 176.8 ± 0.10-0.20 ppm. In certain embodiments, metopimazine mesylate Form A is characterized by a13C ssNMR spectrum comprising peaks expressed in chemical shifts in ppm selected from those shown in Table 2. 13 CssNMR spectrum: 176.4 ± 0.10-0.20 ppm. In certain embodiments, metopimazine mesylate Form A is characterized by a13C ssNMR spectrum comprising one or more peaks expressed in chemical shifts in ppm selected from those shown in Table 2. 13 ​C ssNMR spectrum: 176.8 and 176.4 ± 0.10-0.20 ppm. In certain embodiments, metoprazine mesylate crystalline form A is characterized by comprising the following peaks expressed as chemical shifts in ppm: 13 C ssNMR spectrum: 176.8 and 176.4 ± 0.10-0.20 ppm. In certain embodiments, metoprazine mesylate crystalline form A is characterized by comprising the following peaks expressed as chemical shifts in ppm: 13 C ssNMR spectrum: 42.1 ± 0.10-0.20 ppm. In certain embodiments, metoprazine mesylate crystalline form A is characterized by one or more or two or more peaks expressed as chemical shifts in ppm: 13 CssNMR spectrum: 42.1, 176.4 and 176.8 ± 0.10-0.20 ppm. In certain embodiments, metoprazine mesylate crystalline form A is characterized by comprising the following peaks expressed as chemical shifts in ppm: 13 C ssNMR spectrum: 42.1, 176.4 and 176.8 ± 0.10-0.20 ppm. In certain embodiments, metoprazine mesylate crystalline form A is characterized by comprising the following peaks expressed as chemical shifts in ppm: 13 C ssNMR spectrum: 57.0 ± 0.10-0.20 ppm. In certain embodiments, metoprazine mesylate crystalline form A is characterized by comprising one or more, two or more, or three or more peaks expressed as chemical shifts in ppm: 13 C ssNMR spectrum: 42.1, 57.0, 176.4 and 176.8 ± 0.10-0.20 ppm. In certain embodiments, metoprazine mesylate crystalline form A is characterized by comprising the following peaks expressed as chemical shifts in ppm: 13 C ssNMR spectrum: 42.1, 57.0, 176.4 and 176.8 ± 0.10-0.20 ppm. In certain embodiments, metoprazine mesylate crystalline form A is characterized by comprising the following peaks expressed as chemical shifts in ppm: 13 C ssNMR spectrum: 27.4 ± 0.10-0.20 ppm. In certain embodiments, metoprazine mesylate crystalline form A is characterized by comprising one or more, two or more, three or more, or four or more peaks expressed as chemical shifts in ppm: 13C ssNMR spectrum: 27.4, 42.1, 57.0, 176.4 and 176.8 ± 0.10-0.20 ppm. In certain embodiments, metoprazine mesylate crystalline form A is characterized by comprising the following peaks expressed as chemical shifts in ppm: 13 C ssNMR spectrum: 27.4, 42.1, 57.0, 176.4 and 176.8 ± 0.10-0.20 ppm. In certain embodiments, metoprazine mesylate crystalline form A is characterized by comprising the following peaks expressed as chemical shifts in ppm: 13 C ssNMR spectrum: 121.1 ± 0.10-0.20 ppm. In certain embodiments, metoprazine mesylate crystalline form A is characterized by comprising one or more, two or more, three or more, four or more, or five or more peaks expressed as chemical shifts in ppm: 13 CssNMR spectrum: 27.4, 42.1, 57.0, 121.1, 176.4 and 176.8 ± 0.10-0.20 ppm. In certain embodiments, metoprazine mesylate crystalline form A is characterized by comprising the following peaks expressed as chemical shifts in ppm: 13 CssNMR spectrum: 27.4, 42.1, 57.0, 121.1, 176.4 and 176.8 ± 0.10-0.20 ppm. In certain embodiments, metoprazine mesylate crystalline form A is characterized by comprising the following peaks expressed as chemical shifts in ppm: 13 CssNMR spectrum: 21.3 ± 0.10-0.20 ppm. In certain embodiments, metoprazine mesylate crystalline form A is characterized by comprising one or more, two or more, three or more, four or more, five or more, or six or more peaks expressed as chemical shifts in ppm: 13 C ssNMR spectrum: 21.3, 27.4, 42.1, 57.0, 121.1, 176.4 and 176.8 ± 0.10-0.20 ppm. In certain embodiments, metoprazine mesylate crystalline form A is characterized by comprising the following peaks expressed as chemical shifts in ppm: 13 C ssNMR spectrum: 21.3, 27.4, 42.1, 57.0, 121.1, 176.4 and 176.8 ± 0.10-0.20 ppm. In certain embodiments, metoprazine mesylate crystalline form A is characterized by comprising the following peaks expressed as chemical shifts in ppm: 13C ssNMR spectrum: 50.6 ± 0.10-0.20 ppm. In certain embodiments, metoprazine mesylate crystalline form A is characterized by comprising one or more, two or more, three or more, four or more, five or more, six or more, or seven or more peaks expressed as chemical shifts in ppm: 13 CssNMR spectrum: 21.3, 27.4, 42.1, 50.6, 57.0, 121.1, 176.4 and 176.8 ± 0.10-0.20 ppm. In certain embodiments, metoprazine mesylate crystalline form A is characterized by comprising the following peaks expressed as chemical shifts in ppm: 13 C ssNMR spectrum: 21.3, 27.4, 42.1, 50.6, 57.0, 121.1, 176.4 and 176.8 ± 0.10-0.20 ppm. In certain embodiments, metoprazine mesylate crystalline form A is characterized by comprising the following peaks expressed as chemical shifts in ppm: 13 C ssNMR spectrum: 114.7 ± 0.10-0.20 ppm. In certain embodiments, metoprazine mesylate crystalline form A is characterized by comprising one or more, two or more, three or more, four or more, five or more, six or more, seven or more, or eight or more peaks expressed as chemical shifts in ppm: 13 C ssNMR spectrum: 21.3, 27.4, 42.1, 50.6, 57.0, 114.7, 121.1, 176.4 and 176.8 ± 0.10-0.20 ppm. In certain embodiments, metoprazine mesylate crystalline form A is characterized by comprising the following peaks expressed as chemical shifts in ppm: 13 C ssNMR spectrum: 21.3, 27.4, 42.1, 50.6, 57.0, 114.7, 121.1, 176.4 and 176.8 ± 0.10-0.20 ppm. In certain embodiments, metoprazine mesylate crystalline form A is characterized by comprising the following peaks expressed as chemical shifts in ppm: 13 CssNMR spectrum: 119.9 ± 0.10-0.20 ppm. In certain embodiments, metoprazine mesylate crystalline form A is characterized by comprising one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, or nine or more peaks expressed as chemical shifts in ppm: 13C ssNMR spectrum: 21.3, 27.4, 42.1, 50.6, 57.0, 114.7, 119.9, 121.1, 176.4 and 176.8 ± 0.10-0.20 ppm. In certain embodiments, metoprazine mesylate crystalline form A is characterized by comprising the following peaks expressed as chemical shifts in ppm: 13 C ssNMR spectrum: 21.3, 27.4, 42.1, 50.6, 57.0, 114.7, 119.9, 121.1, 176.4 and 176.8 ± 0.10-0.20 ppm.

[0141] In certain embodiments, metopimazine mesylate crystalline Form A is characterized by a differential scanning calorimetry (DSC) pattern comprising a single endotherm with an onset temperature ranging from 208°C to 212°C or from 208°C to 211°C, such as from 209°C to 210°C (e.g., 209.9°C). In certain embodiments, metopimazine mesylate crystalline Form A is characterized by a DSC pattern comprising a single endotherm with a peak temperature ranging from 213°C to 214°C (e.g., 213.1°C). It will be understood by those skilled in the art that the above and Figure 3 A given endotherm will typically be reproduced within a range of from ±0.5 to 3°C, such as ±2°C, ±1°C, or ±0.5°C. In certain embodiments, metopiramate mesylate crystalline Form A is characterized by a DSC trace comprising a single endotherm having a transition enthalpy of 95-100 J / g, such as 96-98 J / g, 97-98 J / g, or 97.5 J / g (e.g., 97.47 J / g). In certain embodiments, metopiramate mesylate crystalline Form A is characterized by a DSC trace comprising a single endotherm having a transition enthalpy of 95-100 J / g, such as 96-98 J / g, 97-98 J / g, or 97.5 J / g (e.g., 97.47 J / g). Figure 3 The DSC graph shown.

[0142] In certain embodiments, metopiramate mesylate Form A is characterized by a thermogravimetric analysis (TGA) curve having a total weight loss of 0.4% (e.g., 0.42%) up to 150.0°C. In certain embodiments, metopiramate mesylate Form A is characterized by Figure 2 The TGA curve is shown.

[0143] In certain embodiments of the present application, metopiramate mesylate crystalline form A contains less than 10 wt.% of other crystalline forms (e.g., metopiramate mesylate hydrate crystalline form B), such as less than 5 wt.%, less than 4 wt.%, less than 3 wt.%, less than 2 wt.%, less than 1 wt.%, less than 0.1 wt.% or less than 0.01 wt.% of other crystalline forms (e.g., metopiramate mesylate hydrate crystalline form B).

[0144] In certain embodiments of the application, metopimazine mesylate Form A comprises less than 10 wt.% of amorphous form, such as less than 5 wt.%, less than 4 wt.%, less than 3 wt.%, less than 2 wt.%, less than 1 wt.%, less than 0.1 wt.% or less than 0.01 wt.% of amorphous form.

[0145] In certain embodiments of the application, metopimazine mesylate Form A comprises less than 10 wt.% of other forms (e.g., other crystalline forms of metopimazine mesylate, such as metopimazine mesylate Form B; or other amorphous forms of metopimazine mesylate), such as less than 5 wt.%, less than 4 wt.%, less than 3 wt.%, less than 2 wt.%, less than 1 wt.%, less than 0.1 wt.% or less than 0.01 wt.% of other forms (e.g., other crystalline forms of metopimazine mesylate, such as metopimazine mesylate Form B; or other amorphous forms of metopimazine mesylate).

[0146] In certain embodiments of the application, metopimazine mesylate Form A is in a non-solvate form. In certain such embodiments of the application, metopimazine mesylate Form A comprises less than 10 wt.% of solvate form, such as less than 5 wt.%, less than 4 wt.%, less than 3 wt.%, less than 2 wt.%, less than 1 wt.%, less than 0.1 wt.% or less than 0.01 wt.% of solvate form.

[0147] In certain embodiments of the application, metopimazine mesylate Form A is in a non-hydrate form. In certain such embodiments of the application, metopimazine mesylate Form A comprises less than 10 wt.% of hydrate form, such as less than 5 wt.%, less than 4 wt.%, less than 3 wt.%, less than 2 wt.%, less than 1 wt.%, less than 0.1 wt.% or less than 0.01 wt.% of hydrate form.

[0148] The application provides metopimazine mesylate hydrate Form B, characterized by an XRPD pattern comprising one or more 2Θ values selected from those shown in Table 3. The diffractogram is recorded with Cu, Kα radiation.

[0149] Table 3: Peaks identified on XRPD for metopimazine mesylate hydrate Form B

[0150]

[0151]

[0152] In certain embodiments, metopimazine mesylate Form B is characterized by an XRPD pattern comprising at least two 2Θ values selected from those set forth in Table 3. In certain embodiments, metopimazine mesylate Form B is characterized by an XRPD pattern comprising at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine 2Θ values selected from those set forth in Table 3. In certain embodiments, metopimazine mesylate Form B is characterized by one or more 2Θ values in the range of from about 5 to about 25 °2Θ in Table 3. In certain embodiments, metopimazine mesylate Form B is characterized by at least two 2Θ values in the range of from about 5 to about 25 °2Θ in Table 3. In certain embodiments, metopimazine mesylate Form B is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine 2Θ values in the range of from about 5 to about 25 °2Θ in Table 3. In certain embodiments, metopimazine mesylate hydrate Form B is characterized by an XRPD pattern comprising 2Θ values selected from those set forth in Table 3. It will be further understood by those skilled in the art that the 2Θ degrees provided in Table 3 can generally be reproduced within a range of from about ±0.10 2Θ degrees to about ±0.20 2Θ, preferably a range of about ±0.10 2Θ degrees. See, e.g., United States Pharmacopoeia XXV (2002), pp. 2088-2089.

[0153] In certain embodiments, metopimazine mesylate crystalline Form B is characterized by an XRPD pattern comprising one or more of the following 2θ values: 4.64°, 10.71°, 11.12°, 16.30°, 16.90°, 17.89°, 20.00°, and 27.12° ± 0.10-0.20 2θ. In certain embodiments, metopimazine mesylate crystalline Form B is characterized by an XRPD pattern comprising two or more of the following 2θ values: 4.64°, 10.71°, 11.12°, 16.30°, 16.90°, 17.89°, 20.00°, and 27.12° ± 0.10-0.20 2θ. In certain embodiments, metopimazine mesylate crystalline Form B is characterized by an XRPD pattern comprising three or more of the following 2θ values: 4.64°, 10.71°, 11.12°, 16.30°, 16.90°, 17.89°, 20.00°, and 27.12° ± 0.10-0.20 2θ. In certain embodiments, metopimazine mesylate crystalline Form B is characterized by an XRPD pattern comprising four or more of the following 2θ values: 4.64°, 10.71°, 11.12°, 16.30°, 16.90°, 17.89°, 20.00°, and 27.12° ± 0.10-0.20 2θ. In certain embodiments, metoprazine mesylate Form B is characterized by an XRPD pattern comprising five or more of the following 2Θ values: 4.64°, 10.71°, 11.12°, 16.30°, 16.90°, 17.89°, 20.00°, and 27.12° ± 0.10-0.20 2Θ.

[0154] In certain embodiments, metopimazine mesylate crystalline Form B is characterized by an XRPD pattern comprising peaks at the following 2θ values: 16.90° ± 0.10-0.20 2θ. In certain embodiments, metopimazine mesylate crystalline Form B is characterized by an XRPD pattern comprising peaks at the following 2θ values: 16.90° and 20.00° ± 0.10-0.20 2θ. In certain embodiments, metopimazine mesylate crystalline Form B is characterized by an XRPD pattern comprising peaks at the following 2θ values: 16.30°, 16.90°, and 20.00° ± 0.10-0.20 2θ. In certain embodiments, metopimazine mesylate crystalline Form B is characterized by an XRPD pattern comprising peaks at the following 2θ values: 11.12°, 16.30°, 16.90°, and 20.00° ± 0.10-0.20 2θ. In certain embodiments, metopimazine mesylate crystalline Form B is characterized by an XRPD pattern comprising peaks at the following 2θ values: 10.71°, 16.30°, 16.90°, and 20.00° ± 0.10-0.20 2θ. In certain embodiments, metopimazine mesylate crystalline Form B is characterized by an XRPD pattern comprising peaks at the following 2θ values: 16.30°, 16.90°, 17.89°, and 20.00° ± 0.10-0.20 2θ. In certain embodiments, metopimazine mesylate crystalline Form B is characterized by an XRPD pattern comprising peaks at the following 2θ values: 16.30°, 16.90°, 20.00°, and 27.12° ± 0.10-0.20 2θ. In certain embodiments, metopimazine mesylate crystalline Form B is characterized by an XRPD pattern comprising peaks at the following 2θ values: 10.71°, 11.12°, 16.30°, 16.90°, and 20.00° ± 0.10-0.20 2θ. In certain embodiments, metopimazine mesylate crystalline Form B is characterized by an XRPD pattern comprising peaks at the following 2θ values: 10.71°, 11.12°, 16.30°, 16.90°, 17.89°, 20.00°, and 27.12° ± 0.10-0.20 2θ.

[0155] The present application provides metopimazine mesylate hydrate crystalline Form B, characterized by an XRPD pattern comprising at least two interplanar spacing values ​​selected from those shown in Table 3. In certain embodiments, metopimazine mesylate hydrate crystalline Form B is characterized by an XRPD pattern comprising at least three, at least four, at least five, or at least six interplanar spacing values ​​selected from those shown in Table 3. In certain embodiments, metopimazine mesylate hydrate crystalline Form B is characterized by an XRPD pattern comprising interplanar spacing values ​​selected from those shown in Table 3.

[0156] In certain embodiments, metoprazine mesylate hydrate Form B is characterized by the XRPD pattern shown in Table 3.

[0157] The present application provides metoprazine mesylate crystalline form B, characterized by comprising one or more peaks provided in Table 4, expressed as chemical shifts in ppm. 13 C solid-state NMR (ssNMR) spectra. The spectra were obtained on a Bruker NEO spectrometer, where 13 C runs at 100.52MHz and for 1 H runs at 399.71MHz or for 13 C runs at 100.46MHz and for 1 H runs at 399.49MHz.

[0158] Table 4: Metoprazine mesylate crystal form B 13 Peaks identified on the C ssNMR spectrum

[0159]

[0160]

[0161] In certain embodiments, metoprazine mesylate crystalline Form B is characterized by comprising at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten peaks expressed as chemical shifts in ppm selected from those shown in Table 4. 13 C ssNMR spectrum. In certain embodiments, metoprazine mesylate crystalline Form B is characterized by comprising peaks expressed as chemical shifts in ppm selected from those shown in Table 4. 13 C ssNMR spectrum. Those skilled in the art will understand that 13 C ssNMR spectra (including the appearance, intensity, and position of peaks in the spectra) can vary between different samples, different sample preparations, and different conditions under which the spectra were obtained. Thus, one skilled in the art will appreciate that the peaks provided in Table 4, expressed as chemical shifts in ppm, can typically be reproduced within a range of from about ±0.10 ppm to about ±0.20 ppm (preferably within a range of about ±0.20 ppm). In certain embodiments, metoprazine mesylate crystalline Form B is characterized by the following: 13 In certain embodiments, metoprazine mesylate salt Form B exhibits Figure 7 or Figure 8 shown 13In certain embodiments, metoprazine mesylate crystalline Form B having a purity of at least 90%, at least 95%, or at least 99% exhibits the following: Figure 8 shown 13 CssNMR spectrum.

[0162] In certain embodiments, metoprazine mesylate crystalline Form B is characterized by comprising the following peaks expressed as chemical shifts in ppm: 13 C ssNMR spectrum: 180.2 ± 0.10-0.20 ppm. In certain embodiments, metoprazine mesylate crystalline form B is characterized by comprising the following peaks expressed as chemical shifts in ppm: 13 CssNMR spectrum: 177.7 ± 0.10-0.20 ppm. In certain embodiments, metoprazine mesylate crystalline form B is characterized by comprising one or more of the following peaks expressed as chemical shifts in ppm: 13 C ssNMR spectrum: 177.7 and 180.2 ± 0.10-0.20 ppm. In certain embodiments, metoprazine mesylate crystalline Form B is characterized by comprising the following peaks expressed as chemical shifts in ppm: 13 C ssNMR spectrum: 177.7 and 180.2 ± 0.10-0.20 ppm. In certain embodiments, metoprazine mesylate crystalline Form B is characterized by comprising the following peaks expressed as chemical shifts in ppm: 13 C ssNMR spectrum: 136.1 ± 0.10-0.20 ppm. In certain embodiments, metoprazine mesylate crystalline form B is characterized by the following peaks expressed in ppm: 13 C ssNMR spectrum: 136.1, 177.7 and 180.2 ± 0.10-0.20 ppm. In certain embodiments, metoprazine mesylate crystalline Form B is characterized by comprising the following peaks expressed as chemical shifts in ppm: 13 C ssNMR spectrum: 136.1, 177.7 and 180.2 ± 0.10-0.20 ppm. In certain embodiments, metoprazine mesylate crystalline Form B is characterized by comprising the following peaks expressed as chemical shifts in ppm: 13 CssNMR spectrum: 149.0±0.10-0.20 ppm. In certain embodiments, metoprazine mesylate crystalline form B is characterized by comprising one or more, two or more, or three or more peaks expressed as chemical shifts in ppm: 13C ssNMR spectrum: 136.1, 149.0, 177.7 and 180.2 ± 0.10-0.20 ppm. In certain embodiments, metoprazine mesylate crystalline Form B is characterized by comprising the following peaks expressed as chemical shifts in ppm: 13 C ssNMR spectrum: 136.1, 149.0, 177.7 and 180.2 ± 0.10-0.20 ppm. In certain embodiments, metoprazine mesylate crystalline Form B is characterized by comprising the following peaks expressed as chemical shifts in ppm: 13 C ssNMR spectrum: 39.4 ± 0.10-0.20 ppm. In certain embodiments, metoprazine mesylate crystalline form B is characterized by comprising one or more, two or more, three or more, or four or more peaks expressed as chemical shifts in ppm: 13 C ssNMR spectrum: 39.4, 136.1, 149.0, 177.7 and 180.2 ± 0.10-0.20 ppm. In certain embodiments, metoprazine mesylate crystalline Form B is characterized by comprising the following peaks expressed as chemical shifts in ppm: 13 C ssNMR spectrum: 39.4, 136.1, 149.0, 177.7 and 180.2 ± 0.10-0.20 ppm. In certain embodiments, metoprazine mesylate crystalline Form B is characterized by comprising the following peaks expressed as chemical shifts in ppm: 13 C ssNMR spectrum: 45.2 ± 0.10-0.20 ppm. In certain embodiments, metoprazine mesylate crystalline form B is characterized by comprising one or more, two or more, three or more, four or more, or five or more peaks expressed as chemical shifts in ppm: 13 CssNMR spectrum: 39.4, 45.2, 136.1, 149.0, 177.7 and 180.2 ± 0.10-0.20 ppm. In certain embodiments, metoprazine mesylate crystalline Form B is characterized by comprising the following peaks expressed as chemical shifts in ppm: 13 CssNMR spectrum: 39.4, 45.2, 136.1, 149.0, 177.7 and 180.2 ± 0.10-0.20 ppm. In certain embodiments, metoprazine mesylate crystalline Form B is characterized by comprising the following peaks expressed as chemical shifts in ppm: 13C ssNMR spectrum: 132.3 ± 0.10-0.20 ppm. In certain embodiments, metoprazine mesylate crystalline form B is characterized by comprising one or more, two or more, three or more, four or more, five or more, or six or more peaks expressed as chemical shifts in ppm: 13 C ssNMR spectrum: 39.4, 45.2, 132.3, 136.1, 149.0, 177.7 and 180.2 ± 0.10-0.20 ppm. In certain embodiments, metoprazine mesylate crystalline Form B is characterized by comprising the following peaks expressed as chemical shifts in ppm: 13 CssNMR spectrum: 39.4, 45.2, 132.3, 136.1, 149.0, 177.7 and 180.2 ± 0.10-0.20 ppm. In certain embodiments, metoprazine mesylate crystalline Form B is characterized by comprising the following peaks expressed as chemical shifts in ppm: 13 C ssNMR spectrum: 131.6 ± 0.10-0.20 ppm. In certain embodiments, metoprazine mesylate crystalline form B is characterized by comprising one or more, two or more, three or more, four or more, five or more, six or more, or seven or more peaks expressed as chemical shifts in ppm: 13 C ssNMR spectrum: 39.4, 45.2, 131.6, 132.3, 136.1, 149.0, 177.7 and 180.2 ± 0.10-0.20 ppm. In certain embodiments, metoprazine mesylate crystalline Form B is characterized by comprising the following peaks expressed as chemical shifts in ppm: 13 C ssNMR spectrum: 39.4, 45.2, 131.6, 132.3, 136.1, 149.0, 177.7 and 180.2 ± 0.10-0.20 ppm. In certain embodiments, metoprazine mesylate crystalline Form B is characterized by comprising the following peaks expressed as chemical shifts in ppm: 13 C ssNMR spectrum: 123.0 ± 0.10-0.20 ppm. In certain embodiments, metoprazine mesylate crystalline Form B is characterized by comprising one or more, two or more, three or more, four or more, five or more, six or more, seven or more, or eight or more peaks expressed as chemical shifts in ppm: 13Css NMR spectrum: 39.4, 45.2, 123.0, 131.6, 132.3, 136.1, 149.0, 177.7, and 180.2 ± 0.10-0.20 ppm. In certain embodiments, metopimazine mesylate Form B is characterized by a Css NMR spectrum comprising one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, or nine or more peaks expressed in terms of chemical shift in ppm of 13 Css NMR spectrum: 39.4, 45.2, 123.0, 131.6, 132.3, 136.1, 149.0, 177.7, and 180.2 ± 0.10-0.20 ppm. In certain embodiments, metopimazine mesylate Form B is characterized by a Css NMR spectrum comprising one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, or nine or more peaks expressed in terms of chemical shift in ppm of 13 Css NMR spectrum: 130.2 ± 0.10-0.20 ppm. In certain embodiments, metopimazine mesylate Form B is characterized by a Css NMR spectrum comprising one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, or nine or more peaks expressed in terms of chemical shift in ppm of 13 Css NMR spectrum: 39.4, 45.2, 123.0, 130.2, 131.6, 132.3, 136.1, 149.0, 177.7, and 180.2 ± 0.10-0.20 ppm. In certain embodiments, metopimazine mesylate Form B is characterized by a Css NMR spectrum comprising one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, or nine or more peaks expressed in terms of chemical shift in ppm of 13 Css NMR spectrum: 39.4, 45.2, 123.0, 130.2, 131.6, 132.3, 136.1, 149.0, 177.7, and 180.2 ± 0.10-0.20 ppm.

[0163] In certain embodiments, metopimazine mesylate crystalline Form B is characterized by a DSC pattern comprising two endothermic peaks and a single exothermic peak. In certain such embodiments, metopimazine mesylate crystalline Form B is characterized by a DSC pattern comprising a first endothermic peak with an onset temperature ranging from 122°C to 125°C or from 123°C to 124°C (e.g., 123.5°C). In certain embodiments, metopimazine mesylate crystalline Form B is characterized by a DSC pattern comprising a first endothermic peak with a peak temperature ranging from 125°C to 127°C, such as from 126°C to 127°C (e.g., 126.1°C). In certain such embodiments, metopimazine mesylate crystalline Form B is characterized by a DSC pattern comprising a first endothermic peak with a transition enthalpy of 81-86 J / g, such as from 82-85 J / g, 83-84 J / g, or 83.5 J / g (e.g., 83.47 J / g). In certain such embodiments, metopimarazine mesylate crystalline Form B is characterized by a DSC trace comprising a second endotherm with an onset temperature ranging from 207° C. to 210° C. or from 208° C. to 209° C. (e.g., 208.6° C.). In certain embodiments, metopimarazine mesylate crystalline Form B is characterized by a DSC trace comprising a second endotherm with a peak temperature ranging from 210° C. to 212° C., such as from 211° C. to 212° C. (e.g., 211.2° C.). In certain such embodiments, metopimarazine mesylate crystalline Form B is characterized by a DSC trace comprising a second endotherm with a transition enthalpy of 82-87 J / g, such as from 83-86 J / g, 84-85 J / g, or 84.5 J / g (e.g., 84.48 J / g). In certain such embodiments, metoprazine mesylate crystalline Form B is characterized by a DSC pattern comprising a single endothermic peak with a peak temperature ranging from 143°C to 146°C, such as 144°C to 145°C (e.g., 144.6°C). Figure 5 The given endotherms and exotherms will typically be reproduced within a range of from ±0.5 to 3°C, such as ±2°C, ±1°C or ±0.5°C. In certain embodiments, metoprazine mesylate crystalline Form B is characterized by Figure 5 The DSC graph shown.

[0164] In certain embodiments, metopiramate mesylate Form B is characterized by having a TGA curve with a total weight loss of 5.5% to 6% (e.g., 5.8%) up to 180.0°C. In certain embodiments, metopiramate mesylate Form B is characterized by having a total weight loss of 5.5% to 6% (e.g., 5.8%) up to 180.0°C. Figure 5 The TGA curve is shown.

[0165] In certain embodiments of the present application, metopiramate mesylate hydrate Form B comprises less than 10 wt.% of other crystalline forms (e.g., metopiramate mesylate Form A), such as less than 5 wt.%, less than 4 wt.%, less than 3 wt.%, less than 2 wt.%, less than 1 wt.%, less than 0.1 wt.% or less than 0.01 wt.% of other crystalline forms (e.g., metopiramate mesylate Form A).

[0166] In certain embodiments of the present application, metoprazine mesylate hydrate Form B comprises less than 10 wt.% of amorphous form, such as less than 5 wt.%, less than 4 wt.%, less than 3 wt.%, less than 2 wt.%, less than 1 wt.%, less than 0.1 wt.% or less than 0.01 wt.% of amorphous form.

[0167] In certain embodiments of the present application, metopimarazine mesylate Form B contains less than 10 wt.% of other forms (e.g., other crystalline forms of metopimarazine mesylate, such as metopimarazine mesylate Form A; or other amorphous forms of metopimarazine mesylate), such as less than 5 wt.%, less than 4 wt.%, less than 3 wt.%, less than 2 wt.%, less than 1 wt.%, less than 0.1 wt.% or less than 0.01 wt.% of other forms (e.g., other crystalline forms of metopimarazine mesylate, such as metopimarazine mesylate Form A; or other amorphous forms of metopimarazine mesylate).

[0168] In certain embodiments of the present application, metopiramate mesylate Form B is in the form of a monohydrate. In certain such embodiments of the present application, metopiramate mesylate Form B contains less than 10 wt.% of other solvates or anhydrous forms, such as less than 5 wt.%, less than 4 wt.%, less than 3 wt.%, less than 2 wt.%, less than 1 wt.%, less than 0.1 wt.%, or less than 0.01 wt.% of other solvates or anhydrous forms.

[0169] The present application provides a pharmaceutical composition comprising metopimazine mesylate crystalline Form A and a pharmaceutically acceptable carrier. In certain such embodiments, the pharmaceutical composition comprises between about 10% metopimazine mesylate crystalline Form A and about 100% metopimazine mesylate crystalline Form A, for example, the pharmaceutical composition comprises about 10% metopimazine mesylate crystalline Form A, about 20% metopimazine mesylate crystalline Form A, about 30% metopimazine mesylate crystalline Form A, about 40% metopimazine mesylate crystalline Form A, about 50% metopimazine mesylate crystalline Form A, about 60% metopimazine mesylate crystalline Form A, about 70% metopimazine mesylate crystalline Form A, about 80% metopimazine mesylate crystalline Form A, about 90% metopimazine mesylate crystalline Form A, or about 95% metopimazine mesylate crystalline Form A.

[0170] In certain embodiments of the present application, the pharmaceutical composition comprising metopimarazine mesylate crystalline form A contains less than 10 wt.% of other forms of metopimarazine mesylate (e.g., other crystalline forms of metopimarazine mesylate, such as metopimarazine mesylate crystalline form B; or other amorphous forms of metopimarazine mesylate), such as less than 5 wt.%, less than 4 wt.%, less than 3 wt.%, less than 2 wt.%, less than 1 wt.%, less than 0.1 wt.% or less than 0.01 wt.% of other forms of metopimarazine mesylate (e.g., other crystalline forms of metopimarazine mesylate, such as metopimarazine mesylate crystalline form B; or other amorphous forms of metopimarazine mesylate).

[0171] The present application provides a pharmaceutical composition comprising metopimazine mesylate crystalline Form B and a pharmaceutically acceptable carrier. In certain such embodiments, the pharmaceutical composition comprises between about 10% metopimazine mesylate crystalline Form B and about 100% metopimazine mesylate crystalline Form B, for example, the pharmaceutical composition comprises about 10% metopimazine mesylate crystalline Form B, about 20% metopimazine mesylate crystalline Form B, about 30% metopimazine mesylate crystalline Form B, about 40% metopimazine mesylate crystalline Form B, about 50% metopimazine mesylate crystalline Form B, about 60% metopimazine mesylate crystalline Form B, about 70% metopimazine mesylate crystalline Form B, about 80% metopimazine mesylate crystalline Form B, about 90% metopimazine mesylate crystalline Form B, or about 95% metopimazine mesylate crystalline Form B.

[0172] In certain embodiments of the present application, the pharmaceutical composition comprising metopimarazine mesylate crystalline form B contains less than 10 wt.% of other forms of metopimarazine mesylate (e.g., other crystalline forms of metopimarazine mesylate, such as metopimarazine mesylate crystalline form A; or other amorphous forms of metopimarazine mesylate), such as less than 5 wt.%, less than 4 wt.%, less than 3 wt.%, less than 2 wt.%, less than 1 wt.%, less than 0.1 wt.% or less than 0.01 wt.% of other forms of metopimarazine mesylate (e.g., other crystalline forms of metopimarazine mesylate, such as metopimarazine mesylate crystalline form A; or other amorphous forms of metopimarazine mesylate).

[0173] In certain embodiments of any of the pharmaceutical compositions comprising a crystalline form of metopimazine mesylate as described herein (e.g., metopimazine mesylate Form A or metopimazine mesylate Form B), the composition is suitable for oral, intraduodenal, intracolonic, parenteral, enteral, intraperitoneal, topical, transdermal, ocular, intranasal, topical, parenteral, via spray, subcutaneous, intravenous, intratonsillar, intramuscular, buccal, sublingual, rectal, intraarterial, by infusion, or intrathecal administration. In certain embodiments, the composition is suitable for oral administration. In certain embodiments, the composition is suitable for sublingual administration.

[0174] In certain embodiments of any pharmaceutical composition comprising a crystalline form of metopiramate mesylate as described herein (e.g., metopiramate mesylate Form A or metopiramate mesylate Form B), the pharmaceutical composition is formulated as a tablet, capsule, cream, lotion, oil, ointment, gel, paste, powder, suspension, syrup, enema, suppository, emulsion or solution, extended release formulation or modified release formulation. In certain embodiments, the composition is formulated as an extended release formulation. In certain embodiments, the composition is formulated as a capsule.

[0175] In certain embodiments of any of the pharmaceutical compositions comprising a crystalline form of metopimarazine mesylate as described herein (e.g., metopimarazine mesylate Form A or metopimarazine mesylate Form B), the composition comprises 5 mg of the metopimarazine mesylate. In certain embodiments of any of the foregoing pharmaceutical compositions comprising a crystalline form of metopimarazine mesylate as described herein (e.g., metopimarazine mesylate Form A or metopimarazine mesylate Form B), the composition comprises 10 mg of the crystalline form of metopimarazine mesylate (e.g., metopimarazine mesylate Form A or metopimarazine mesylate Form B). In certain embodiments of any of the foregoing pharmaceutical compositions comprising a crystalline form of metopimarazine mesylate as described herein (e.g., metopimarazine mesylate Form A or metopimarazine mesylate Form B), the composition comprises 15 mg of the crystalline form of metopimarazine mesylate (e.g., metopimarazine mesylate Form A or metopimarazine mesylate Form B). In certain embodiments of any of the foregoing pharmaceutical compositions comprising a crystalline form of metopimarazine mesylate as described herein (e.g., metopimarazine mesylate Form A or metopimarazine mesylate Form B), the composition comprises 20 mg of the crystalline form of metopimarazine mesylate (e.g., metopimarazine mesylate Form A or metopimarazine mesylate Form B).

[0176] In certain embodiments of any of the pharmaceutical compositions comprising a crystalline form of metopimarazine mesylate as described herein (e.g., metopimarazine mesylate crystalline form A or metopimarazine mesylate crystalline form B), the composition is suitable for administration once a day. In other embodiments of any of the aforementioned pharmaceutical compositions comprising a crystalline form of metopimarazine mesylate (e.g., metopimarazine mesylate crystalline form A or metopimarazine mesylate crystalline form B), the composition is suitable for administration twice a day. In certain embodiments of any of the aforementioned pharmaceutical compositions comprising a crystalline form of metopimarazine mesylate (e.g., metopimarazine mesylate crystalline form A or metopimarazine mesylate crystalline form B), the composition is suitable for administration three times a day. In other embodiments of any of the aforementioned pharmaceutical compositions comprising a crystalline form of metopimarazine mesylate (e.g., metopimarazine mesylate crystalline form A or metopimarazine mesylate crystalline form B), the composition is suitable for administration four times a day.

[0177] In certain embodiments of any of the pharmaceutical compositions comprising a crystalline form of metopiramate mesylate as described herein (e.g., metopiramate mesylate Form A or metopiramate mesylate Form B), between about 5 mg and about 160 mg of the crystalline form of metopiramate mesylate (e.g., metopiramate mesylate Form A or metopiramate mesylate Form B) is administered daily. In certain embodiments of any of the pharmaceutical compositions comprising a crystalline form of metopimarazine mesylate as described herein (e.g., metopimarazine mesylate Form A or metopimarazine mesylate Form B), between about 5 mg and about 240 mg of the crystalline form of metopimarazine mesylate (e.g., metopimarazine mesylate Form A or metopimarazine mesylate Form B) is administered daily, such as about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 80 mg, about 90 mg, about 100 mg, about 120 mg, about 150 mg, about 160 mg, about 180 mg, about 200 mg, about 240 mg of the crystalline form of metopimarazine mesylate (e.g., metopimarazine mesylate Form A or metopimarazine mesylate Form B) is administered daily. In certain embodiments of any of the pharmaceutical compositions comprising a crystalline form of metopimarazine mesylate as described herein (e.g., metopimarazine mesylate Form A or metopimarazine mesylate Form B), the composition is suitable for daily administration of more than 20 mg of the crystalline form of metopimarazine mesylate (e.g., metopimarazine mesylate Form A or metopimarazine mesylate Form B). In certain embodiments of any of the pharmaceutical compositions comprising a crystalline form of metopimarazine mesylate as described herein (e.g., metopimarazine mesylate Form A or metopimarazine mesylate Form B), the composition is suitable for daily administration of more than 30 mg of the crystalline form of metopimarazine mesylate (e.g., metopimarazine mesylate Form A or metopimarazine mesylate Form B).

[0178] The present application provides a method for treating an enteric nervous system disorder in a human subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a crystalline form of metopiramate mesylate as disclosed herein (e.g., metopiramate mesylate Form A or metopiramate mesylate Form B). In certain embodiments, the enteric nervous system disorder is a chronic disorder. In certain embodiments, the enteric nervous system disorder is an acute disorder. In certain embodiments, the enteric nervous system disorder is selected from gastroparesis, irritable bowel syndrome, lysosomal storage disorders, intestinal motility disorders, ganglioneuroma, multiple endocrine neoplasia type 2B (MEN2B), gastrointestinal neuropathy, functional dyspepsia, gastroesophageal reflux disease (GERD) and enteric neurodysplasia.

[0179] In certain embodiments, the enteric nervous system disorder comprises a symptom selected from the group consisting of early satiety, postprandial fullness, abdominal fullness, nausea, vomiting, delayed gastric emptying, diarrhea, abdominal pain, flatulence, bloating, gastroesophageal reflux, loss of appetite, and constipation. In certain embodiments, the enteric nervous system disorder symptom comprises nausea. In certain embodiments, the enteric nervous system disorder symptom comprises vomiting.

[0180] The present application provides a method for treating gastroparesis in a human subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a crystalline form of metopiramate mesylate as disclosed herein (e.g., metopiramate mesylate Form A or metopiramate mesylate Form B). In certain embodiments, the gastroparesis is diabetic gastroparesis. In certain embodiments, the gastroparesis is idiopathic gastroparesis. In certain embodiments, the gastroparesis comprises symptoms selected from the group consisting of early satiety, postprandial fullness, abdominal fullness, nausea, vomiting, delayed gastric emptying, diarrhea, abdominal pain, flatulence, bloating, gastroesophageal reflux, loss of appetite, and constipation. In certain embodiments, the gastroparesis symptoms comprise nausea. In certain embodiments, the gastroparesis symptoms comprise vomiting.

[0181] The present application provides a method of treating nausea associated with gastroparesis in a human subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a crystalline form of metopiramate mesylate as disclosed herein (e.g., metopiramate mesylate Form A or metopiramate mesylate Form B).

[0182] The present application provides a method of treating vomiting associated with gastroparesis in a human subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a crystalline form of metopiramate mesylate as disclosed herein (e.g., metopiramate mesylate Form A or metopiramate mesylate Form B).

[0183] The present application provides a method of improving gastric emptying in a human subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a crystalline form of metopiramate mesylate as disclosed herein (e.g., metopiramate mesylate Form A or metopiramate mesylate Form B).

[0184] The present application provides a method for treating gastrointestinal function and motility disorders in a human subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a crystalline form of metopiramate mesylate as disclosed herein (e.g., metopiramate mesylate Form A or metopiramate mesylate Form B).

[0185] In certain embodiments of any of the methods disclosed herein, the pharmaceutical composition is administered to the subject for a long term. In other embodiments of any of the methods disclosed herein, the pharmaceutical composition is administered to the subject acutely. In certain embodiments of any of the methods disclosed herein, the pharmaceutical composition is administered to the subject for at least 6 days. In certain embodiments of any of the methods disclosed herein, the pharmaceutical composition is administered to the subject for at least 7 days. In certain such embodiments, wherein the pharmaceutical composition is administered to the subject for at least four weeks. In certain further embodiments, wherein the pharmaceutical composition is administered to the subject for at least 12 weeks.

[0186] In certain embodiments of any of the methods disclosed herein, the pharmaceutical composition is administered to the subject once a day. In certain embodiments, the pharmaceutical composition is administered to the subject twice a day. In certain embodiments, the pharmaceutical composition is administered to the subject three times a day. In certain embodiments, the pharmaceutical composition is administered to the subject four times a day.

[0187] In certain embodiments of any of the methods disclosed herein, between about 5 mg and about 160 mg of the crystalline form of metopimarazine mesylate (e.g., metopimarazine mesylate Form A or metopimarazine mesylate Form B) is administered to the subject daily. In certain embodiments of any of the methods disclosed herein, more than 20 mg of the crystalline form of metopimarazine mesylate (e.g., metopimarazine mesylate Form A or metopimarazine mesylate Form B) is administered to the subject daily. In certain embodiments of any of the methods disclosed herein, more than 30 mg of the crystalline form of metopimarazine mesylate (e.g., metopimarazine mesylate Form A or metopimarazine mesylate Form B) is administered to the subject daily. In certain embodiments of any of the methods as disclosed herein, between about 5 mg and about 240 mg of the crystalline form of metopiramate mesylate (e.g., metopiramate mesylate Form A or metopiramate mesylate Form B) is administered to the subject daily, such as about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 80 mg, about 90 mg, about 100 mg, about 120 mg, about 150 mg, about 160 mg, about 180 mg, about 200 mg, about 240 mg of the crystalline form of metopiramate mesylate (e.g., metopiramate mesylate Form A or metopiramate mesylate Form B) is administered to the subject daily. In certain embodiments of any of the methods disclosed herein, about 5 mg of a crystalline form of the metopimazine mesylate (e.g., metopimazine mesylate Form A or metopimazine mesylate Form B) is administered to the subject once, twice, three times, or four times a day. In certain embodiments of any of the methods disclosed herein, about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, or about 60 mg of a crystalline form of the metopimazine mesylate (e.g., metopimazine mesylate Form A or metopimazine mesylate Form B) is administered to the subject once, twice, three times, or four times a day. In certain embodiments of any of the methods disclosed herein, about 40 mg of a crystalline form of the metopimazine mesylate (e.g., metopimazine mesylate Form A or metopimazine mesylate Form B) is administered to the subject four times a day. In certain embodiments of any of the methods disclosed herein, about 60 mg of a crystalline form of metopiramate mesylate (eg, metopiramate mesylate Form A or metopiramate mesylate Form B) is administered to the subject four times a day.

[0188] definition

[0189] As used in the specification and claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. For example, the term "a cell" includes a plurality of cells, including mixtures thereof.

[0190] As used herein, the term "agonist" generally refers to a molecule, such as a compound, drug, enzyme activator, or hormone modulator, that binds to a specific receptor and triggers a response in a cell. Agonists typically mimic the effects of an endogenous ligand (such as, for example, dopamine) that binds to the same receptor.

[0191] The term "amorphous" as used herein refers to a solid having a disordered arrangement of molecules without a distinguishable crystal lattice.

[0192] As used herein, the term "antagonist" refers to a molecule, such as a compound, that weakens, inhibits or prevents a cell from responding to a receptor activated by an agonist. Antagonists may include, but are not limited to, competitive antagonists, non-competitive antagonists, uncompetitive antagonists, partial agonists and inverse agonists. Competitive antagonists can reversibly bind to receptors at the same binding site (active site) as an endogenous ligand or agonist, without having to activate the receptor. Non-competitive antagonists (also referred to as allosteric antagonists) can bind to significantly different binding sites with agonists, thereby exerting a role on the receptor via another binding site. Non-competitive antagonists generally do not compete with agonists for binding. The binding of non-competitive antagonists to receptors can result in a reduction in the affinity of agonists for the receptor. Alternatively, the binding of non-competitive antagonists to receptors can prevent the receptor conformational changes required for agonist-mediated receptor activation. Uncompetitive antagonists may require agonist activation of the receptor to bind to a separate allosteric binding site. Partial agonists can refer to molecules that may vary in the strength of the functional response elicited after maximum receptor occupancy at a given receptor. Although they are agonists, if co-administered with a full agonist, a partial agonist can act as a competitive antagonist because it competes with the full agonist for receptor occupancy and produces a net reduction in receptor activation observed with the full agonist alone. Inverse agonists may have similar effects to antagonists, but can induce a range of different downstream biological responses. Constitutively active receptors that exhibit intrinsic or basal activity can have inverse agonists that not only block the effects of the bound agonist like a classical antagonist, but also inhibit the basal activity of the receptor.

[0193] As used herein, the term "crystal" or "crystals," "crystals," or "crystalline" refers to any solid having short-range or long-range order of molecules, atoms, or ions in a fixed lattice arrangement. The salt crystals of the present invention may be in a single crystalline form. Thus, the salt crystals of the present invention may be triclinic, monoclinic, orthorhombic, tetragonal, rhombohedral, hexagonal, or cubic, or mixtures thereof. In particular, the salt crystals of the present invention are in dry crystalline form.

[0194] As used herein, "gastrointestinal (GI) tract" refers to the portion of the digestive tract where a large amount of absorption is observed. As will be readily understood by those skilled in the art, a large amount of absorption is typically observed in the mouth, small intestine (e.g., duodenum, jejunum, and ileum), and large intestine (e.g., colon).

[0195] As used herein, "metoprazine mesylate" refers to 1-(3-(2-(methylsulfonyl)-10H-phenothiazin-10-yl)propyl)piperidine-4-carboxamide methanesulfonic acid.

[0196] As used herein, "oral cavity" generally refers to the mouth and includes the lips, lining of the cheeks and inside of the lips, tongue, upper and lower gums, floor of the mouth under the tongue, sublingual mucosa, roof of the mouth, and area behind wisdom teeth.

[0197] As used herein, a "peripherally restricted" compound generally refers to a compound that does not substantially cross the intact blood-brain barrier of a subject. The term also encompasses compounds that can cross the intact blood-brain barrier, but are rapidly metabolized to a form that does not substantially cross the intact blood-brain barrier of a subject after administration to a subject. A compound is considered "peripherally restricted" if, after administration to a subject, less than 50%, less than 45%, less than 40%, less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1% of the compound crosses the intact blood-brain barrier of a subject.

[0198] The term "solvate" refers to a crystalline solid adduct containing a stoichiometric or non-stoichiometric amount of a solvent in the crystal structure. Thus, the term "non-solvate" form herein refers to a salt crystal that contains no or substantially no solvent molecules in the crystal structure of the present invention. Similarly, the term "anhydrate" form herein refers to a salt crystal that contains no or substantially no water molecules in the crystal structure of the present invention.

[0199] As used herein, the terms "treatment" or "treating" are used interchangeably herein. These terms refer to methods for obtaining beneficial or desired results, including but not limited to therapeutic benefit and / or prophylactic benefit. Therapeutic benefit can mean eradication or improvement of the underlying disorder being treated. In addition, therapeutic benefit can be achieved by eradicating or improving one or more physiological symptoms associated with the underlying disorder, such that improvement is observed in the subject, although the subject may still be suffering from the underlying disorder. Prophylactic effects include delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, stopping or reversing the progression of a disease or condition, or any combination thereof. For prophylactic benefit, the composition can be administered to a subject at risk for developing a particular disease, or to a subject reporting one or more physiological symptoms of a disease, even though a diagnosis of the disease may not yet have been made.

[0200] A "subtherapeutic amount" of a pharmaceutical agent is an amount that is less than the effective amount of the pharmaceutical agent. When combined with an effective or subtherapeutic amount of one or more additional pharmaceutical agents, a subtherapeutic amount can produce the results desired by the physician due to, for example, synergy with the effective effect produced or reduced side effects.

[0201] A "synergistically effective" therapeutic amount or a "synergistically effective" amount of an agent or therapy is an amount that, when combined with an effective or subtherapeutic amount of one or more additional agents, produces a greater effect than when either agent is used alone. In some embodiments, a synergistically effective therapeutic amount of an agent or therapy, when used in combination, produces an effect that is greater than the additive effect of any individual agent when used alone. The term "greater effect" encompasses not only a reduction in symptoms of the disorder to be treated, but also includes an improvement in the side effect profile, an improvement in tolerability, an improvement in patient compliance, an improvement in efficacy, or an improvement in any other clinical outcome.

[0202] As used herein, the terms "co-administration," "administered in combination with," and grammatical equivalents thereof encompass the administration of two or more pharmaceutical agents to an animal such that both agents and / or their metabolites are present in the subject at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.

[0203] The terms "determine," "measure," "evaluate," "assess," "determine," and "analyze" are used interchangeably herein to refer to any form of measurement, and include determining whether an element is present. These terms encompass quantitative and / or qualitative measurements. Assessments can be relative or absolute. "Assessing the presence" includes determining the amount of something that is present, as well as determining whether it is present.

[0204] Exemplary Subjects

[0205] Pharmaceutical compositions as disclosed herein can be used to treat disorders in subjects in need thereof. The subject may have the disorder, may be diagnosed with the disorder, may exhibit symptoms of the disorder, or may be suspected of having the disorder. The disorder may be a gastrointestinal disorder, an enteric nervous system disorder, or other disorder. The disorder may be characterized by decreased motility in at least a portion of the gastrointestinal tract. For example, the disorder may be characterized by decreased motility in the stomach and / or intestines. The decreased motility may be caused by abnormal ENS neuronal signaling, for example, by abnormal dopamine signaling activity.

[0206] In some embodiments, the enteric nervous system disorder is gastroparesis. The terms "gastroparesis" and "delayed gastric emptying" are used interchangeably herein to refer to a disorder that, for example, slows or stops the movement of food from the stomach to the small intestine. Normally, the muscles of the stomach, which are controlled by the vagus nerve, contract to break down food and move it through the gastrointestinal (GI) tract. For example, gastroparesis may occur when the vagus nerve is damaged by disease or injury, causing the stomach muscles to stop working properly. In a subject with gastroparesis, food may move slowly from the stomach to the small intestine, or may stop moving altogether. Thus, the subject may have gastroparesis, may be diagnosed with gastroparesis, may exhibit symptoms of gastroparesis, or may be suspected of having gastroparesis.

[0207] A subject may be suspected of having gastroparesis if they exhibit or have exhibited symptoms of gastroparesis. Symptoms of gastroparesis may include gastroesophageal reflux (GER), also known as acid reflux or regurgitation. Gastroesophageal reflux generally refers to a condition in which stomach contents flow back into the esophagus. Other symptoms associated with gastroparesis include, but are not limited to, early satiety, postprandial fullness, abdominal fullness, abdominal pain and / or burning sensation in the stomach, bloating, loss of appetite, anorexia, malnutrition, nausea, and vomiting. Symptoms of gastroparesis can be mild, moderate, or severe, and can be frequent or rare. The severity of gastroparesis symptoms can vary over time in the same subject. Thus, a subject may exhibit or have exhibited GER, early satiety, postprandial fullness, abdominal fullness, abdominal pain and / or burning sensation in the stomach, bloating, loss of appetite, anorexia, malnutrition, nausea, and / or vomiting.

[0208] The subject may be diagnosed with gastroparesis. Gastroparesis can be diagnosed by any means known to those skilled in the art or described elsewhere herein. For example, gastroparesis can be diagnosed by physical examination, medical history, blood tests, tests to rule out gastrointestinal obstruction or structural problems, gastric emptying assays, and gastrointestinal contractile activity assays. Tests can also identify nutritional disorders or underlying diseases. Tests that can help diagnose gastroparesis include, but are not limited to, upper gastrointestinal (GI) endoscopy, upper GI series, ultrasound testing, gastric emptying scintigraphy, gastric emptying breath testing, antral manometry, electrogastrogram, and / or electrogastroenterography.

[0209] Upper gastrointestinal endoscopy can be used to rule out other conditions (such as physical obstruction) that may cause delayed gastric emptying. Upper gastrointestinal endoscopy typically involves using an endoscope (e.g., a small flexible tube with a light) to observe the upper gastrointestinal tract, including, for example, the esophagus, stomach, and duodenum (the first part of the small intestine). An endoscope is typically used to image the stomach and / or duodenum. A small camera mounted on the endoscope can transmit video images to a monitor, allowing close inspection of the intestinal lining. Upper gastrointestinal endoscopy may show physical obstruction of the upper gastrointestinal tract, such as large gastric stones (e.g., solid collections of food, mucus, plant fiber, hair, or other substances). In some embodiments, if a subject exhibits symptoms of gastroparesis and an upper gastrointestinal endoscopy does not show a physical obstruction that causes delayed gastric emptying, the subject is diagnosed with gastroparesis.

[0210] An upper gastrointestinal sequence may be performed to view the small intestine. The test may be performed by an x-ray technician in a hospital or outpatient center, and the images may be interpreted by a radiologist. During the procedure, the subject may stand or sit in front of an x-ray machine and drink barium (a powdered liquid). The barium may coat the small intestine, making signs of gastroparesis more visible on x-rays. In cases where an x-ray shows food in the stomach after a fast, gastroparesis may be indicated. In some embodiments, if an upper gastrointestinal sequence shows food in the stomach after a fast, the subject is diagnosed with gastroparesis.

[0211] Ultrasound can be used to rule out other syndromes that may share symptoms with gastroparesis. Such other syndromes include gallbladder disease and pancreatitis. Ultrasound typically uses a device called a transducer that reflects safe, painless sound waves off organs to create images of their structures. The procedure can be performed by specially trained technicians in a healthcare provider's office, outpatient center, or hospital. The ultrasound images can be interpreted by a radiologist. If a subject exhibits symptoms of gastroparesis and other syndromes (such as, for example, gallbladder disease, pancreatitis) are ruled out by ultrasound, the subject can be diagnosed with gastroparesis.

[0212] Gastric emptying scintigraphy can be used to diagnose gastroparesis in a subject. Gastric emptying scintigraphy can involve ingesting a bland meal containing a small amount of radioactive material, such as eggs or an egg substitute. The radioactive material can be 99-M technetium (TC) sulfur colloid or other radioligands. The test can be performed at a radiology center or hospital. An external camera can be used to detect and / or measure radioactivity in the abdominal area. Radioactivity can be measured at regular intervals (e.g., 1, 2, 3, and 4 hours after a meal). A subject who exhibits more than 10% of food in the stomach within 4 hours may be positively identified as having gastroparesis. Other measures of gastric emptying include, but are not limited to, the time it takes for 50% of food to be emptied from the stomach. See, for example, Thomforde, GM et al., Evaluation of an inexpensive screening scintigraphic test of gastric emptying, 36 J. Nucl. Med. 93 (1995), which is hereby incorporated by reference. In some embodiments, the subject is diagnosed with gastroparesis via gastric emptying scintigraphy.

[0213] Breath tests used to assess gastric emptying can use radiolabeled food (e.g., with C 13 When food reaches the small intestine, the C 13 may be absorbed. Then, the absorbed C 13 It can be rapidly metabolized in the liver to produce 13 The resulting CO2 can then be detected in the subject's breath 13 The subject's breath can be collected and sampled at regular intervals. The samples can be analyzed by any means known in the art. 13 CO2. In breathing 13 The rate of CO2 appearance can be used to indicate the rate of gastric emptying. 13 An exemplary method for the octanoate breath test is described in Ghoos, YS, et al., 104 Gastroenterology 1640-1647 (1993), which is hereby incorporated by reference. In some embodiments, the subject is diagnosed with gastroparesis via a breath test.

[0214] Manometry generally refers to the assessment of pressure changes within the lumen. Antral manometry, also known as antral-duodenal manometry, generally refers to a technique for evaluating contractile activity of the distal stomach and duodenum. The intraluminal pressure of the stomach and / or duodenum can be measured by a pressure sensor introduced into the lumen via a catheter. The measurements can be recorded over time to assess changes in intraluminal pressure. The recording can continue for any period of time. Changes in intraluminal pressure can be used to indicate the contraction pattern of the stomach and / or duodenum. Changes in intraluminal pressure can be measured in the fasting state and / or after eating (postprandial). A decrease in postprandial contractile motility can indicate that the subject has gastroparesis. Therefore, the subject may exhibit decreased postprandial gastric motility, as determined by manometry.

[0215] Electrogastrogram generally refers to the technology and method of recording gastric electrical activity. Similarly, electrogastroenterography refers to the technology and method of recording gastric and small intestinal electrical activity. This electrical activity can be recorded from the gastrointestinal mucosa, chorion or outer skin surface (skin). Gastrointestinal mucosa can refer to the mucosal layer of the gastrointestinal tract. The gastrointestinal chorion can include a thin layer of cells that secrete serous fluid and a thin epithelial layer. Recording can be performed during fasting and after eating (usually 60 minutes). Deviations from the normal frequency of electrical activity can include bradygastria and / or tachygastria. Control subjects typically show an increase in electrical activity after eating, which indicates increased gastrointestinal motility. Subjects with abnormal gastrointestinal motility can show abnormal activity rhythms and / or increased damage after meals. The normal frequency of gastrointestinal electrical activity can be, for example, 3 cycles per minute. Bradygastria, characterized in that the frequency of gastrointestinal electrical activity decreases from a normal value (e.g., less than 2 cycles per minute) for at least one minute, can indicate gastroparesis. In some embodiments, the subject may show bradygastria. Electrogastrogram (EGG) can also be used to diagnose gastroparesis, which measures electrical activity using skin electrodes similar to those used in electrocardiograms (Stern, RN et al., EGG: Common issues in validation and methodology, 24 Psychophysiology 55-64 (1987), which is hereby incorporated by reference). Thus, a subject may be diagnosed with gastroparesis as determined by electrogastrogram.

[0216] The experimenter may suffer from gastroesophageal reflux disease (GERD), may be diagnosed as suffering from gastroesophageal reflux disease, may show the symptoms of gastroesophageal reflux disease or may be suspected of suffering from gastroesophageal reflux disease. GERD may be a chronic condition causing gastroesophageal reflux. The symptoms of GERD include, for example, heartburn, dryness, chronic cough, wheezing, asthma, recurrent pneumonia, nausea, vomiting, sore throat, dysphagia, chest or upper abdominal pain, dental erosion, bad breath, reflux. GERD can be diagnosed with a test aid. Tests that can be used for diagnosing GERD include, for example, upper gastrointestinal series as described herein, upper endoscopy, esophageal pH monitoring and esophageal manometry.

[0217] The subject may have, be diagnosed with, exhibit symptoms of, or be suspected of having an enteric nervous system disorder that is associated with a vestibular disorder of the ear. A vestibular disorder of the ear may be a Ménetrier disease. Ménétrier disease may be characterized by bulges (also referred to herein as rugae) along the inside of the stomach wall, forming large folds in the lining of the stomach wall. Ménétrier disease may also result in a decrease in gastric acid caused by a decrease in acid-producing parietal cells. By way of example only, symptoms of Ménétrier disease include severe stomach pain, nausea, frequent vomiting, and the like.

[0218] A subject may have cyclic vomiting syndrome (CVS), may be diagnosed with CVS, may exhibit symptoms of CVS, or may be suspected of having CVS. CVS may be characterized by episodes or cycles of severe nausea and vomiting alternating with symptom-free intervals. Such episodes may last for hours, or even days. Episodes may begin at the same time of day, may last for the same length of time, and may occur with the same symptoms and intensity levels. Episodes may be so severe that a person has to stay in bed for days, unable to go to school or work. Other symptoms of CVS include, for example, abdominal pain, diarrhea, fever, dizziness, and sensitivity to light during vomiting episodes. Persistent vomiting may lead to severe dehydration that may be life-threatening. Symptoms of dehydration include thirst, loss of appetite, and weight gain. CVS can be diagnosed in subjects who have experienced the following symptoms for at least 3 months: episodes of vomiting that begin with severe vomiting several times per hour and last for less than 1 week, three or more separate episodes of vomiting in the past year, and no nausea or vomiting between episodes.

[0219] A subject may have irritable bowel syndrome (IBS), may be diagnosed with IBS, may exhibit symptoms of IBS, or may be suspected of having IBS. IBS generally refers to a syndrome in which a subject experiences recurrent or long-term gastrointestinal symptoms. Symptoms of IBS can include, for example, abdominal pain, abdominal discomfort, constipation, diarrhea, mucus in the stool, bloating, or a combination of any of the above. If a person has had abdominal pain or discomfort at least three times a month in the past three months and has no other illness or injury that could explain the pain, they may be diagnosed with IBS. The pain or discomfort of IBS may occur with changes in the frequency or consistency of bowel movements, or may be relieved by bowel movements. IBS can be divided into four subtypes based on the subject's usual stool consistency. The four subtypes of IBS are: constipation-predominant IBS (IBS-C), diarrhea-predominant IBS, mixed IBS, and unclassified IBS-U. Subjects with IBS-C may have hard or lumpy stools at least 25% of the time, loose or watery stools less than 25% of the time, or both. A subject with IBS-D may have loose or watery stools at least 25% of the time, hard or lumpy stools less than 25% of the time, or both. A subject with IBS-M may have hard or lumpy stools at least 25% of the time, loose or watery stools at least 25% of the time. A subject with IBS-U may have hard or lumpy stools less than 25% of the time, loose or watery stools less than 25% of the time, or both. Constipation associated with IBS may be due to slow or delayed gastric motility. In some embodiments, a subject with IBS experiences constipation. IBS can be diagnosed in a subject by any means known in the art or described elsewhere herein. For example, IBS may be diagnosed by a healthcare provider. The healthcare provider may perform a physical examination and may record the subject's medical history. IBS can be diagnosed if a subject exhibits one or more IBS symptoms for at least 3, 4, 5, or 6 months, and one or more of the symptoms occur at least three times per month within the first 3 months. Additional tests that may be used to diagnose IBS include, but are not limited to, stool examination, lower gastrointestinal series, flexible sigmoidoscopy, or colonoscopy.

[0220] The subject may suffer from functional dyspepsia (e.g., impaired digestion), may be diagnosed as suffering from functional dyspepsia, may exhibit the symptoms of functional dyspepsia or may be suspected of suffering from functional dyspepsia. The symptoms of dyspepsia include, but are not limited to, for example, long-term or recurrent pain in the upper abdomen, upper abdominal fullness, postprandial fullness, early satiety, abdominal distension, hiccups, nausea, vomiting, heartburn, acid in the mouth. Functional dyspepsia (e.g., non-ulcer dyspepsia) generally refers to the dyspepsia without the organic disease evidence that may explain the dyspepsia symptoms. The example of functional dyspepsia is the dyspepsia in the absence of ulcer. It is estimated that functional dyspepsia has affected approximately 15% of the general population in Western countries. Other exemplary ENS disorders include, but are not limited to, for example, intestinal motility disorder, ganglioneuroma, multiple endocrine neoplasia 2B type (MEN2B), gastrointestinal neuropathy and enteric neuroplasia.

[0221] The subject may suffer from enteric nervous system disorder, may be diagnosed as suffering from enteric nervous system disorder, may show the symptom of enteric nervous system disorder or may be suspected of suffering from enteric nervous system disorder, and the enteric nervous system disorder is caused by another potential disease.For example, enteric nervous system disorder can be the ENS disorder induced by Parkinson's disease. The ENS disorder induced by Parkinson's disease may be relevant with the degeneration of dopamine ENS neurons. The symptoms of the ENS disorder induced by Parkinson's disease include, for example, constipation, nausea, vomiting etc. In some embodiments, the subject to be treated according to the method of the application is diagnosed as suffering from Parkinson's disease, has Parkinson's disease symptom, is suspected of suffering from Parkinson's disease, and further shows the symptom of ENS disorder as described herein.

[0222] The subject may have, be diagnosed with, exhibit symptoms of, or be suspected of having an enteric nervous system disorder that may be associated with scleroderma. Scleroderma can be characterized by hardening and tightening of the skin and connective tissue. In some embodiments, the subject may have, be diagnosed with, exhibit symptoms of, or be suspected of having gastroparesis that may be associated with scleroderma.

[0223] The subject may have a disorder, may be diagnosed with a diabetes-related enteric nervous system disorder, may exhibit symptoms of a diabetes-related enteric nervous system disorder, or may be suspected of having a diabetes-related enteric nervous system disorder. The diabetes-related enteric nervous system disorder may be diabetes-related gastroparesis. The subject may have a disorder, may be diagnosed with a disorder, may exhibit symptoms of a disorder, or may be suspected of having a disorder associated with multiple sclerosis.

[0224] Other diseases and clinical conditions that can cause enteric nervous system disorders (such as gastroparesis) include, for example, cancer, hypothyroidism, hyperthyroidism, hyperparathyroidism, adrenal insufficiency (Addison's disease), gastric ulcers, gastritis, after stomach surgery (such as vagotomy (vagus nerve removal), antrectomy (removal of a portion of the stomach distal to the antrum), subtotal gastrectomy (removal of a stomach tumor), gastrojejunostomy (connection of two lumens of the gastrointestinal tract (such as the proximal stomach and the small intestine), fundoplication (surgical procedure in which the upper part of the stomach is wrapped around the lower esophagus)), polymyositis (which may cause persistent muscle weakness) Examples of the diseases listed include: acute myocardial ischemia (AMI), inflammatory muscle disease (a progressive muscle weakness), muscular dystrophy (a disease that may cause progressive muscle weakness), amyloidosis (a disease characterized by the accumulation of amyloid protein in a subject's tissues or organs, such as the gastrointestinal tract), intestinal pseudo-obstruction (a disease that causes symptoms associated with intestinal obstruction but in which no intestinal obstruction is found), dermatomyositis (a disease characterized by muscle inflammation), systemic lupus erythematosus (a systemic autoimmune disease that may affect various tissues of the body, including the nervous system), eating disorders (such as anorexia and bulimia), depression, paraneoplastic syndromes, and high cervical spinal cord lesions (e.g., lesions at spinal cord level C4 or higher).

[0225] The subject may have the symptom of enteric nervous system disorder.Exemplary symptoms are described herein.In some embodiments, the symptom is nausea and / or vomiting.In some embodiments, the cause of the symptom is unknown (for example, unexplained nausea).In some embodiments, the symptom is long-term or recurrent symptom.The subject can for example experience symptom at least 3 days, at least 5 days, at least 1 week, at least 2 weeks, at least 4 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months (1 year), at least 1.5 years, at least 2 years, at least 3 years, at least 4 years, at least 5 years, at least 6 years, at least 7 years, at least 8 years, at least 9 years or at least 10 years. The subject may experience symptoms 1, 2, 3, 4, 5, 6, 7, 8, 8, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 or more times a month.

[0226] The subject can be, for example, a mouse, rat, hamster, gerbil, dog, cat, primate, such as a monkey, or human. In some embodiments, the subject is human. The subject can be an adult, a child, or an infant. The subject can be of any age.

[0227] Uses of the pharmaceutical composition

[0228] The pharmaceutical compositions described herein can be safely administered to a subject. The pharmaceutical compositions described herein can be administered without necessarily increasing the risk of producing harmful cardiac side effects. For example, the pharmaceutical compositions described herein may not increase the risk of modulating cardiac action potentials, and / or may not increase the risk of inducing long QT syndrome, and / or may not increase the risk of cardiac arrest, and / or may not increase the risk of sudden death due to cardiac arrest.

[0229] The pharmaceutical composition as described herein of effective amount can be safely applied to the subject for an unlimited time.The pharmaceutical composition of effective amount can be acutely or safely applied to the subject for a long time.For example, the pharmaceutical composition of effective amount can be safely applied to the subject once a day, for at least 2 days, at least 3 days, at least four days, five days, at least five days, at least six days, at least seven days (1 week), at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months (1 year), at least 2 years, at least 5 years or at least 10 years.

[0230] The administration of a pharmaceutical composition as described herein can confer an acceptable risk of producing an undesirable cardiac side effect on a subject. The administration of a pharmaceutical composition can be determined by any means known in the art or as described herein for the risk of producing such an undesirable cardiac side effect. For example, the risk can be determined by comparing the incidence of sudden death in a subject population to which the pharmaceutical composition is administered with the incidence of sudden death in a control subject population to which the pharmaceutical composition is not administered. The risk can be determined by tracking the number of subjects who have administered the pharmaceutical composition and experienced undesirable cardiac side effects and the number of subjects who have administered the pharmaceutical composition and have not experienced undesirable cardiac side effects. For example, if a=the number of subjects who have administered the pharmaceutical composition and experienced undesirable cardiac side effects, and b=the number of subjects who have administered the pharmaceutical composition and have not experienced undesirable cardiac side effects, the risk of experiencing an undesirable cardiac side effect produced by administering the pharmaceutical composition can be calculated as a / (a+b). Relative risk (RR) can be used to compare the risk of an undesirable cardiac side effect produced by administering the pharmaceutical composition with the risk of an undesirable cardiac side effect occurring in a subject population to which the pharmaceutical composition is not administered. For example, if a=the number of subjects who were administered the pharmaceutical composition and experienced an undesirable cardiac side effect, b=the number of subjects who were administered the pharmaceutical composition and did not experience an undesirable cardiac side effect, c=the number of subjects who were not administered the pharmaceutical composition and experienced an undesirable cardiac side effect, and d=the number of subjects who were not administered the pharmaceutical composition and did not experience an undesirable cardiac side effect, the RR resulting from the administration of the pharmaceutical composition can be calculated as a / (a+b) / (c / (c+d). For other examples, the risk can be determined by calculating an odds ratio.

[0231] The RR of sudden cardiac death with administration of a pharmaceutical composition as described herein may be less than 3.8, less than 3.7, less than 3.6, less than 3.5, less than 3.4, less than 3.3, less than 3.2, less than 3.1, less than 3.0, less than 2.9, less than 2.8, less than 2.7, less than 2.6, less than 2.5, less than 2.4, less than 2.3, less than 2.2, less than 2.1, less than 2.0, less than 1.9, less than 1.8, less than 1.7, less than 1.6, less than 1.5, less than 1.4, less than 1.3, less than 1.2, less than 1.1, less than 1.05, about 1, or less than 1.

[0232] The odds ratio of administering a pharmaceutical composition as described herein to sudden cardiac death can be an acceptable odds ratio. The term odds ratio (OR) generally refers to a measure of the correlation between exposure (e.g., exposure to a drug) and an outcome (e.g., sudden cardiac death). OR can represent the probability of the outcome occurring under the exposure condition compared to the probability of the outcome occurring in the absence of a specific exposure condition. Odds ratios can be used for case-control studies as well as cross-sectional and cohort study design studies. For example, if a=the number of subjects who have administered the pharmaceutical composition and experienced undesirable cardiac side effects, b=the number of subjects who have administered the pharmaceutical composition and have not experienced undesirable cardiac side effects, c=the number of subjects who have not administered the pharmaceutical composition and have experienced undesirable cardiac side effects, and d=the number of subjects who have not administered the pharmaceutical composition and have not experienced undesirable cardiac side effects, the OR produced by administering the pharmaceutical composition can be calculated as ad / bc.

[0233] The OR for sudden cardiac death from administration of a pharmaceutical composition as described herein may be less than 3.8, less than 3.7, less than 3.6, less than 3.5, less than 3.4, less than 3.3, less than 3.2, less than 3.1, less than 3.0, less than 2.9, less than 2.8, less than 2.7, less than 2.6, less than 2.5, less than 2.4, less than 2.3, less than 2.2, less than 2.1, less than 2.0, less than 1.9, less than 1.8, less than 1.7, less than 1.6, less than 1.5, less than 1.4, less than 1.3, less than 1.2, less than 1.1, less than 1.05, about 1, or less than 1.

[0234] Unlike other dopamine-modulating drugs previously indicated for treating ENS, the pharmaceutical compositions described herein for treating ENS are peripherally restricted. Thus, such pharmaceutical compositions can be safely administered to a subject without increasing the risk of the subject developing motor-related functional abnormalities mediated by brain dopaminergic signaling. For example, such pharmaceutical compositions can be safely administered to a subject without increasing the risk of the subject developing extrapyramidal side effects. Exemplary extrapyramidal side effects include, for example, tardive dyskinesia (involuntary asymmetrical movements of muscles), dystonia (characterized by persistent muscle contractions), akinesia (lack of movement), akathisia (feeling of motor unrest), bradykinesia (slowed movement), rigidity and tremor, twisting and / or repetitive movements, postural abnormalities, muscle spasms (e.g., neck muscle spasms (torticollis), eye muscle spasms (oculomotor crisis), tongue spasms, jaw spasms, etc.). Extrapyramidal symptoms can be assessed by any means known in the art or described elsewhere herein. For example, extrapyramidal symptoms can be assessed using the Simpson-Angus Scale (SAS) and / or the Barnes Akathisia Rating Scale (BARS). In some embodiments, the ratio of the administration of a pharmaceutical composition described herein for treating an enteric nervous system disorder to the incidence of extrapyramidal side effects is less than 4, less than 3.9, less than 3.8, less than 3.7, less than 3.6, less than 3.5, less than 3.4, less than 3.3, less than 3.2, less than 3.1, less than 3.0, less than 2.9, less than 2.8, less than 2.7, less than 2.6, less than 2.5, less than 2.4, less than 2.3, less than 2.2, less than 2.1, less than 2.0, less than 1.9, less than 1.8, less than 1.7, less than 1.6, less than 1.5, less than 1.4, less than 1.3, less than 1.2, less than 1.1, less than 1.05, about 1, or less than 1.

[0235] The pharmaceutical compositions of the present application can promote gastric motility upon administration to a subject. Such pharmaceutical compositions can promote gastric motility, for example, by reducing dopamine D2 receptor-mediated signaling in enteric neurons of the subject. For example, the pharmaceutical compositions can antagonize dopamine D2 receptors in enteric neurons of the subject. For other examples, the pharmaceutical compositions can reduce dopaminergic neurotransmission of enteric neurons.

[0236] Gastric motility can be assessed by any means known to one of skill in the art or described elsewhere herein. For example, gastric motility can be assessed by antral manometry or by a method for diagnosing gastroparesis. Exemplary methods that can be used to diagnose gastroparesis are described herein.

[0237] Compared to control subjects and / or control groups, administering a pharmaceutical composition as described herein can improve gastric motility. A control subject can be an individual to which a pharmaceutical composition as described herein is not administered. A control group can be a plurality of individuals to which a pharmaceutical composition as described herein is not administered. A control subject can be a subject suffering from ENS disorder, diagnosed with ENS disorder, suspected of having ENS disorder, or exhibiting symptoms of ENS disorder and not administering a pharmaceutical composition as described herein. A control subject is not necessarily a different individual, but can be the same subject at a certain time point before receiving a dosage of a pharmaceutical composition as described herein. A control subject can be the same subject at a certain time point after receiving a dosage of a pharmaceutical composition as described herein (after sufficient time has passed so that the pharmaceutical composition no longer works on the subject). A control subject can be a different subject. In some embodiments, administering the pharmaceutical composition increases gastric motility by at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100% or more than 100% compared to a control subject.

[0238] In some embodiments, administration of a pharmaceutical composition as described herein is effective for treating the symptoms of an enteric nervous system disorder in a subject. Exemplary symptoms are described herein. The symptoms may be selected from nausea, vomiting, delayed gastric emptying, diarrhea, abdominal pain, flatulence, bloating, gastroesophageal reflux, loss of appetite, weight loss, and constipation. In certain cases, administration of a pharmaceutical composition as described herein reduces nausea in a subject. Administration of a pharmaceutical composition as described herein can reduce the severity of any symptom described herein. In some cases, administration of a pharmaceutical composition as described herein reduces symptom severity by 1%-5%, 2%-10%, 5%-20%, 10%-30%, 20%-50%, 40%-70%, 50%-80%, 70%-90%, 80%-95%, 90%-100%. In some cases, administration of a pharmaceutical composition as described herein reduces symptom severity by at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or greater than 90%.

[0239] Administration of a pharmaceutical composition as described herein can reduce the frequency of symptom onset. In some cases, administration of a pharmaceutical composition as described herein reduces the frequency of symptom onset by 1%-5%, 2%-10%, 5%-20%, 10%-30%, 20%-50%, 40%-70%, 50%-80%, 70%-90%, 80%-95%, 90%-100%. In some cases, administration of a pharmaceutical composition as described herein reduces the frequency of symptom onset by at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90% or more than 90%. In some cases, administration of a pharmaceutical composition as described herein reduces the frequency of symptom onset to less than 1 attack per day, less than 1 attack per week, less than 2 attacks per month, less than 1 attack per month, less than 1 attack per 2 months, less than 1 attack per 3 months, less than 1 attack per 4 months, less than 1 attack per 5 months, less than 1 attack per 6 months, less than 1 attack per 7 months, less than 1 attack per 8 months, less than 1 attack per 9 months, less than 1 attack per 10 months, less than 1 attack per 11 months, or less than 1 attack per 12 months (1 year).

[0240] hERG channel inhibition can be determined by any means known in the art or described elsewhere herein. hERG channel inhibition can be assessed in vitro, for example, by utilizing cultured cells expressing hERG. Cultured cells expressing hERG for assessing hERG channel inhibition can be obtained from many commercial suppliers (such as Life Technologies, Cyprotex, etc.). hERG channel inhibition can be assessed by a variety of means known in the art (including, for example, voltage clamp studies, hERG binding assays, etc.). Voltage clamp studies can use commercially available high-throughput systems. Exemplary high-throughput systems are described, for example, in U.S. Patent No. 8,329,009 and U.S. Patent Application Publication No. 20020164777, which are hereby incorporated by reference. hERG binding assays can include the use of 3H Competition and / or saturation binding assays for dofetilide. Such assays are described in J Pharmacol Toxicol Methods. 2004 Nov-Dec; 50(3): 187-99, which is hereby incorporated by reference. hERG channel inhibition can be determined by in vivo studies, for example, by evaluating cardiac action potentials in large animal models (e.g., canines).

[0241] Minimal hERG inhibition can be achieved by the following IC 50To demonstrate: greater than 0.1 μM, greater than 0.2 μM, greater than 0.3 μM, greater than 0.4 μM, greater than 0.5 μM, greater than 0.6 μM, greater than 0.7 μM, greater than 0.8 μM, greater than 0.9 μM, greater than 1 μM, greater than 2 μM, greater than 3 μM, greater than 4 μM, greater than 5 μM, greater than 6 μM, greater than 7 μM, greater than 8 μM, greater than 9 μM, greater than 10 μM, greater than 15 μM, greater than 20 μM, greater than 30 μM, greater than 40 μM, greater than 50 μM, greater than 60 μM, greater than 70 μM, greater than 80 μM, greater than 90 μM or greater than 100 μM.

[0242] Minimum hERG inhibition can also be demonstrated by measuring the inhibition % of the tail current mediated by hERG under any given dose of the drug. The tail current mediated by hERG can be measured by voltage clamp studies (e.g., by patch clamp studies). For example, the tail current mediated by hERG can be measured in cells expressing hERG before the cells are contacted with the test agent. The tail current mediated by hERG can then be measured in cells expressing hERG after contact with a certain dose of the test agent. The difference between the tail current mediated by hERG before and after the test agent is applied can be used to determine the extent to which the test agent inhibits the tail current mediated by hERG. Suitable agents for use in the disclosed methods can inhibit hERG-mediated tail current by less than 50%, less than 45%, less than 40%, less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.4%, less than 0.3%, less than 0.25%, less than 0.2%, less than 0.15% or less than 0.1% at a dose of 1 μM. Suitable agents for use in the disclosed methods can inhibit hERG-mediated tail current by less than 20%, less than 15%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.4%, less than 0.3%, less than 0.25%, less than 0.2%, less than 0.15% or less than 0.1% at a dose of 100 nM. In some embodiments, metoprazine can inhibit hERG-mediated tail current by less than 50%, less than 45%, less than 40%, less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.4%, less than 0.3%, less than 0.25%, less than 0.2%, less than 0.15% or less than 0.1% at a dose of 3 μM. In some embodiments, metoprazine can inhibit hERG-mediated tail current by less than 50%, less than 45%, less than 40%, less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.4%, less than 0.3%, less than 0.25%, less than 0.2%, less than 0.15% or less than 0.1% at a dose of 10 μM or more.

[0243] Exemplary pharmaceutical compositions

[0244] The pharmaceutical composition for the method of the present application may include a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier for the composition of the present invention may include but is not limited to amino acids, peptides, biopolymers, non-biological polymers, monosaccharides or starches, inorganic salts and gums, which may exist alone or in combination. The peptide used in the acceptable carrier may include, for example, gelatin and / or albumin. Cellulose or its derivatives may be used in a pharmaceutically acceptable carrier. The sugar used in the acceptable carrier may be lactose and / or glucose. Other useful sugars that can be used in the pharmaceutical composition include but are not limited to fructose, galactose, lactitol, maltitol, maltose, mannitol, melezitose, inositol, palatinose (palatinate), raffinose, stachyose, sucrose, trehalose, xylitol, its hydrates and combinations thereof. Adhesives may be included in a pharmaceutically acceptable carrier. Examples of binders include, but are not limited to, starch (e.g., corn starch or potato starch), gelatin; natural or synthetic gums such as gum arabic, sodium alginate, powdered tragacanth, guar gum, cellulose or cellulose derivatives (e.g., methylcellulose, ethylcellulose, cellulose acetate); microcrystalline cellulose, polyvinylpyrrolidone, and mixtures thereof. The inorganic salt used in the acceptable carrier may be a magnesium salt, such as magnesium chloride or magnesium sulfate. Other inorganic salts may be used, such as calcium salts. Examples of calcium salts include, but are not limited to, calcium chloride, calcium sulfate. Other examples of substances that may be used in a pharmaceutically acceptable carrier include, but are not limited to, vegetable oils, such as peanut oil, cottonseed oil, olive oil, corn oil; polyols, such as glycerol, propylene glycol, polyethylene glycol; pyrogen-free water, isotonic saline, phosphate buffer solution; emulsifiers, such as Wetting agent, lubricant, coloring agent, flavoring agent, preservative.

[0245] The term "wetting agent" can be used interchangeably with "surfactant" and refers to a substance that reduces the surface tension of a liquid, thereby making the liquid more easily spread. Surfactants that can be used to form the pharmaceutical compositions and dosage forms of the present application include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants can be used, a mixture of lipophilic surfactants can be used, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant can be used.

[0246] Suitable hydrophilic surfactants can generally have an HLB value of at least 10, while suitable lipophilic surfactants can generally have an HLB value of about 10 or less. A useful parameter that can be used to characterize the relative hydrophilicity and hydrophobicity of nonionic amphiphilic compounds is the hydrophilic-lipophilic balance ("HLB" value). Surfactants with lower HLB values ​​are more hydrophobic and have greater solubility in oils, while surfactants with higher HLB values ​​are more hydrophilic and have greater solubility in aqueous solutions. Hydrophilic surfactants are generally considered to be those compounds with an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is generally not applicable. Similarly, lipophilic (i.e., hydrophobic) surfactants are generally considered to be compounds with an HLB value equal to or less than about 10. However, the HLB value of a surfactant only provides a rough indication that can generally be used to formulate industrial, pharmaceutical, and cosmetic emulsions.

[0247] The hydrophilic surfactant can be ionic or nonionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts, fatty acid derivatives of amino acids, glyceride derivatives of amino acids, fusidates, oligopeptides and polypeptides, oligopeptides and polypeptides, lecithin and hydrogenated lecithin, lysolecithin and hydrogenated lysolecithin, phospholipids and derivatives thereof, fatty acid salts, lysolecithin and derivatives thereof, carnitine fatty acid ester salts, alkyl sulfates, sodium docusate, acyl lactylates, mono- and di-acetylated tartaric acid esters of mono- and di-glycerides, succinylated mono- and di-glycerides, citric acid esters of mono- and di-glycerides, and mixtures thereof.

[0248] In the above group, ionic surfactants include, but are not limited to, lecithin, lysolecithin, phospholipids, lysophospholipids and their derivatives, carnitine fatty acid ester salts, fatty acid salts, alkyl sulfates, sodium docusate, acyl lactylates, mono- and diacetylated tartaric acid esters of mono- and diglycerides, succinylated mono- and diglycerides, citric acid esters of mono- and diglycerides, and mixtures thereof.

[0249] Ionic surfactants can be in the form of ions of lactic acid esters, lecithin, lysolecithin, phosphatidylethanolamine, phosphatidylcholine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylserine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, PEG phosphatidylethanolamide, PVP-phosphatidylethanolamine, stearoyl-2-lactate, stearoyl lactylate, succinylated monoglycerides, mono / diacetylated tartaric acid esters of mono / diglycerides, citrate esters of mono / diglycerides, cholylsarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, linoleate, linolenate, stearate, ricinoleate, lauryl sulfate, tetraacetyl sulfate, docusate, laurylcarnitine, palmitoylcarnitine, myristoylcarnitine, and salts and mixtures thereof.

[0250] The hydrophilic nonionic surfactant may include, but is not limited to, alkyl glucosides, alkylthio glucosides, alkyl maltosides, lauryl polyethylene glycol glycerides, polyoxyalkylene ethers (such as polyethylene glycol alkyl ethers), polyoxyalkylene phenols (such as polyethylene glycol alkylphenols), polyethylene glycol glycerol fatty acid esters, polyoxyalkylene alkylphenol fatty acid esters (such as polyethylene glycol fatty acid monoesters and polyethylene glycol fatty acid diesters), polyglycerol fatty acid esters, polyoxyethylene-polyoxypropylene block copolymers and mixtures thereof, polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters, hydrophilic transesterification products of polyols with at least one member of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols, polyoxyethylene sterols and their derivatives or analogs, polyoxyethylated vitamins and their derivatives, polyethylene glycol sorbitan fatty acid esters, and hydrophilic transesterification products of polyols with at least one of triglycerides, vegetable oils and hydrogenated vegetable oils. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol or a sugar.

[0251] Other hydrophilic nonionic surfactants include, but are not limited to, PEG-10 laurate, PEG-12 laurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 laurate, PEG-32 dilaurate, PEG-32 laurate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25 triolein, PEG-32 dioleate, PEG-20 laurate, PEG-20 triolein, PEG-30 laurate, PEG-20 stearin, PEG-20 olein, PEG-30 olein, PEG-30 laurate, and PEG-400 oleate. EG-40 lauric acid glyceryl, PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 palm kernel oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6 glyceryl caprate / glyceryl caprylate, PEG-8 glyceryl caprate / glyceryl caprylate, polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-2 5 plant sterols, PEG-30 soy sterols, PEG-40 sorbitan monooleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglyceryl-10 oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonylphenol series, PEG 15-100 nonylphenol series and poloxamer.

[0252] Suitable lipophilic surfactants include, but are not limited to, fatty alcohols, glycerol fatty acid esters, acetylated glycerol fatty acid esters, lower alcohol fatty acid esters, propylene glycol fatty acid esters, sorbitan fatty acid esters, polyethylene glycol sorbitan fatty acid esters, sterols and sterol derivatives, polyoxyethylated sterols and sterol derivatives, polyethylene glycol alkyl ethers, sugar ethers, sugar esters, hydrophobic transesterification products of polyols with at least one of glycerol esters, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols, oil-soluble vitamins / vitamin derivatives, lactic acid derivatives of monoglycerides and diglycerides, and mixtures thereof. Within this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or hydrophobic transesterification products of polyols with at least one of vegetable oils, hydrogenated vegetable oils and triglycerides.

[0253] Lubricants that can be used for pharmaceutical compositions include but are not limited to agar, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerol, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (for example, peanut oil, cottonseed oil, sunflower seed oil, sesame oil, olive oil, corn oil and soybean oil), zinc stearate, ethyl oleate, ethyl laurate or its mixture. For example, other lubricants include silicate silica, the solidified aerosol of synthetic silicon dioxide or its mixture. Lubricant can optionally be added in an amount less than about 1 weight percent of the pharmaceutical composition.

[0254] The composition may include one or more pharmaceutically acceptable additives, which may include, but are not limited to, anti-adherents, anti-foaming agents, buffers, antioxidants, polymers, preservatives, chelating agents, flavoring agents, opacifiers, suspending agents, fillers, plasticizers, and mixtures thereof.

[0255] In some embodiments, the pharmaceutically acceptable carrier comprises more than 90%, more than 80%, more than 70%, more than 60%, more than 50%, more than 40%, more than 30%, more than 20%, more than 10%, more than 9%, more than 8%, more than 6%, more than 5%, more than 4%, more than 3%, more than 2%, more than 1%, more than 0.5%, more than 0.4%, more than 0.3%, more than 0.2%, more than 0.1%, more than 0.09%, more than 0.08%, more than 0.07%, more than 0.06%, more than 0.05%, more than 1%. More than 0.001%, more than 0.0009%, more than 0.008%, more than 0.007%, more than 0.006%, more than 0.005%, more than 0.004%, more than 0.003%, more than 0.002%, more than 0.001%, more than 0.0009%, more than 0.0008%, more than 0.0007%, more than 0.0006%, more than 0.0005%, more than 0.0004%, more than 0.0003%, more than 0.0002%, or more than 0.0001% of a pharmaceutical composition.

[0256] In some embodiments, the concentration of the crystalline form of metopiramate mesylate (e.g., metopiramate mesylate Form A or metopiramate mesylate Form B) in the composition constitutes less than 100%, less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 9%, less than 8%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.4%, less than 0.3%, less than 0.2%, less than 0.1%, less than 0.09%, less than 0.08%, less than 0.1% on a w / w, w / v, or v / v basis. Less than 0.07%, less than 0.06%, less than 0.05%, less than 0.04%, less than 0.03%, less than 0.02%, less than 0.01%, less than 0.009%, less than 0.008%, less than 0.007%, less than 0.006%, less than 0.005%, less than 0.004%, less than 0.003%, less than 0.002%, less than 0.001%, less than 0.0009%, less than 0.0008%, less than 0.0007%, less than 0.0006%, less than 0.0005%, less than 0.0004%, less than 0.0003%, less than 0.0002%, or less than 0.0001% of the pharmaceutical composition.

[0257] In some embodiments, the concentration of the crystalline form of metopimazine mesylate (e.g., metopimazine mesylate Form A or metopimazine mesylate Form B) ranges from about 0.0001% to about 50%, about 0.001% to about 40%, about 0.01% to about 20%, about 0.02% to about 29%, about 0.03% to about 28%, about 0.04% to about 27%, about 0.05% to about 26%, about 0.06% to about 25%, about 0.07% to about 24%, about 0.08% to about 23%, about 0.09% to about 22%, about 0.1% to about 21%, about 0.2% to about 20%, about 0.3% to about 19%, about 0.4% to about 18%, about 0.5% to about 17%, about 0.6% to about 16%, about 0.7% to about 15%, about 0.8% to about 14%, about 0.9% to about 12%, about 1% to about 10% of the pharmaceutical composition, on a w / w, w / v, or v / v basis.

[0258] In some embodiments, the concentration of the crystalline form of metopimazine mesylate (e.g., metopimazine mesylate Form A or metopimazine mesylate Form B) ranges from about 0.0001% to about 5%, about 0.001% to about 4%, about 0.01% to about 2%, about 0.02% to about 1%, or about 0.05% to about 0.5% of the pharmaceutical composition, on a w / w, w / v, or v / v basis.

[0259] Some non-limiting examples of pharmaceutical compositions are described below.

[0260] Pharmaceutical compositions for oral administration

[0261] Pharmaceutical compositions comprising an effective amount of a crystalline form of metopimazine mesylate (e.g., metopimazine mesylate Form A or metopimazine mesylate Form B) can be formulated for oral administration. In some embodiments, the pharmaceutical compositions comprising an effective amount of a crystalline form of metopimazine mesylate (e.g., metopimazine mesylate Form A or metopimazine mesylate Form B) for oral administration are solid pharmaceutical compositions. In some embodiments, the solid pharmaceutical compositions can be provided in discrete (e.g., unit) oral dosage forms. Non-limiting examples of discrete oral dosage forms include tablets, capsules, caplets, gelatin capsules, sustained release formulations, lozenges, films, lollipops, chewing gums. In some embodiments, the discrete oral dosage form is an orodispersible oral dosage form, such as, for example, an orodispersible tablet.

[0262] Discrete oral dosage forms (such as tablets) can be coated by known techniques to delay or prolong gastrointestinal absorption, thereby providing a longer lasting effect. In some embodiments, a crystalline form of metopimazine mesylate (e.g., metopimazine mesylate crystal form A or metopimazine mesylate crystal form B) is mixed with one or more inert solid diluents (such as calcium carbonate or calcium phosphate). In some embodiments, a crystalline form of metopimazine mesylate (e.g., metopimazine mesylate crystal form A or metopimazine mesylate crystal form B) is provided in a soft gelatin capsule wherein the crystalline form of metopimazine mesylate (e.g., metopimazine mesylate crystal form A or metopimazine mesylate crystal form B) is mixed with water or an oil medium (e.g., such as peanut oil or olive oil).

[0263] In some embodiments, the pharmaceutical composition of the crystalline form of metopimaprozine mesylate (e.g., metopimaprozine mesylate crystalline form A or metopimaprozine mesylate crystalline form B) comprising an effective amount of metopimaprozine mesylate for oral administration is a liquid pharmaceutical composition. Non-limiting examples of liquid compositions for oral administration include hydrophilic suspensions, emulsions, liquids, gels, syrups, pastes (slurries), solutions, elixirs, soft gels, tinctures, and hydrogels. In some embodiments, the solid or liquid composition of the crystalline form of metopimaprozine mesylate (e.g., metopimaprozine mesylate crystalline form A or metopimaprozine mesylate crystalline form B) comprising an effective amount of metopimaprozine mesylate for oral administration includes a variety of sweeteners or flavorings or coloring agents. The example of coloring agent includes dyes suitable for food, such as those known as FD&C. dyes and natural colorants (such as grape skin extract, beet red powder, beta-carotene, annatto extract, carmine, turmeric, pepper, etc.). Derivatives, analogs, and isomers of any of the above colored compounds may also be used.

[0264] Such dosage forms can be prepared by methods well known to those skilled in the art, for example, in a pharmacy. Such methods would include combining a crystalline form of metopiramate mesylate (e.g., metopiramate mesylate Form A or metopiramate mesylate Form B) with a pharmaceutically acceptable carrier.

[0265] The present application further encompasses anhydrous pharmaceutical compositions and dosage forms comprising an effective amount of a crystalline form of metopimazine mesylate (e.g., metopimazine mesylate crystalline form A or metopimazine mesylate crystalline form B), because water can promote the degradation of the crystalline form of metopimazine mesylate (e.g., metopimazine mesylate crystalline form A or metopimazine mesylate crystalline form B). In some embodiments, anhydrous pharmaceutical compositions and dosage forms of the present application are prepared using anhydrous or low-moisture ingredients. In some embodiments, anhydrous pharmaceutical compositions and dosage forms of the present application are prepared under low humidity or low moisture conditions. If it is expected that substantial contact with moisture and / or humidity will occur during manufacture, packaging, and / or storage, the pharmaceutical composition containing lactose of the present application can be made anhydrous. Anhydrous pharmaceutical compositions comprising an effective amount of a crystalline form of metopimazine mesylate (e.g., metopimazine mesylate crystalline form A or metopimazine mesylate crystalline form B) can be prepared and stored to maintain its anhydrous nature. For example, the anhydrous compositions may be packaged using materials known to prevent exposure to water such that they can be included in suitable sheet packs, examples of which include, but are not limited to, hermetically sealed foils, plastics and the like, unit dose containers, blister packs, and strip packs.

[0266] Pharmaceutical compositions for injection or parenteral administration

[0267] In some embodiments, the pharmaceutical composition is formulated for parenteral administration. "Parenteral" generally refers to a route of administration outside the gastrointestinal tract. Examples of parenteral administration include, but are not limited to, intravenous injection, intraarterial injection, intrathecal injection (into the spinal cord), intratonsillar injection, subcutaneous injection, intramuscular injection, infusion or implantation. Infusion can be intradermal or subcutaneous or by percutaneous implantation. Exemplary pharmaceutical compositions for parenteral administration are disclosed in the following references, which are hereby incorporated by reference: U.S. Patent Application Publication No. 2006 / 0287221, U.S. Patent Nos. 5244925, 4309421, 4158707 and 5164405, all of which are hereby incorporated by reference.

[0268] Pharmaceutical compositions formulated for parenteral administration may include aqueous solutions and / or buffers commonly used for injection and / or infusion. Commonly used aqueous buffers and / or solutions may include, but are not limited to, about 0.9% sodium chloride solution, phosphate buffer, lactated Ringer's solution, acetate Ringer's solution, phosphate-buffered saline, citrate buffer, Tris buffer, histidine buffer, HEPES buffer, glycine buffer, N-glycylglycine buffer, and the like. Other pharmaceutically acceptable carriers for parenteral administration may include ethanol, glycerol, propylene glycol, cyclodextrin and cyclodextrin derivatives, vegetable oils, and the like.

[0269] In some embodiments, the pharmaceutical composition for injection and / or infusion contains a preservative in an amount effective to prevent or reduce microbial contamination or degradation. Various agents, such as phenol, metacresol, benzyl alcohol, parahydroxybenzoates, chlorobutanol, methotrexate, sorbic acid, thimerosal, ethyl hydroxybenzoate, bismuth tribromophenate, methyl hydroxybenzoate, bacitracin, propyl hydroxybenzoate, erythromycin, 5-fluorouracil, doxorubicin, mitoxantrone, rifamycin, chlorocresol, and benzalkonium chloride can be used to prevent or reduce contamination.

[0270] In some embodiments, sterile solutions are prepared by the following method: the desired amount of a crystalline form of metopimazine mesylate (e.g., metopimazine mesylate Form A or metopimazine mesylate Form B) is incorporated into an appropriate solvent with various other ingredients as described herein as needed, followed by filtration sterilization. Typically, dispersions are prepared by the following method: the various sterile active ingredients are incorporated into a sterile vehicle containing a basic dispersion medium and the desired other ingredients from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, certain preparation methods include, but are not limited to, vacuum drying and freeze drying techniques that produce a powder of the active ingredient and any additional desired ingredients from a previously sterile-filtered solution.

[0271] In some embodiments, the pharmaceutical composition is formulated for external use and / or transdermal delivery. The composition of the present application can be formulated into a preparation in a liquid, semisolid or solid form suitable for topical or external use. The example of a form suitable for external use or local application includes but is not limited to gel, water-soluble gel, cream, lotion, suspensoid, foam, powder, ointment, ointment, oil, paste, suppository, solution, spray, emulsion, saline solution, dimethyl sulfoxide (DMSO) base solution. Typically, a carrier with higher density can provide a region exposed to active ingredients for a long time. By contrast, solution formulations can make active ingredients more directly exposed to selected regions.

[0272] Pharmaceutical composition can include suitable solid phase carrier or gel phase carrier, and it is to allow to increase the penetration of therapeutic molecules to the skin stratum corneum barrier or help to deliver the therapeutic molecules through the compound of skin stratum corneum barrier.There are many external preparations field known to those skilled in the art of these penetration enhancing molecules.The example of such carrier and excipient includes but is not limited to alcohol (such as ethanol), fatty acid (such as oleic acid), wetting agent (such as urea), glycol (such as propylene glycol), surfactant (such as isopropyl myristate and sodium lauryl sulfate), glyceryl monolaurate, sulfoxide, pyrrolidone, terpene (such as menthol), amine, amide, alkane, alkanol, water, calcium carbonate, calcium phosphate, various sugars, starch, cellulose derivatives, gelatin and polymer such as polyethylene glycol.

[0273] Another exemplary formulation for use in the present application methods employs a transdermal delivery device ("patch"). Such a transdermal patch can be used to provide a continuous or discontinuous infusion of a crystalline form of metopiramate mesylate as described herein (e.g., metopiramate mesylate Form A or metopiramate mesylate Form B) in controlled amounts with or without additional pharmaceutical agents. The construction and use of transdermal patches for delivering pharmaceutical agents are well known in the art. See, for example, U.S. Patent Nos. 5,023,252; 4,992,445; and 5,001,139, which are incorporated herein by reference.

[0274] In some embodiments, the present application provides a pharmaceutical composition comprising an effective amount of a crystalline form of metopiramate mesylate as described herein (e.g., metopiramate mesylate form A or metopiramate mesylate form B) for transdermal delivery, and a pharmaceutical excipient suitable for delivery by inhalation. Compositions for inhalation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents or mixtures thereof, and powders. The liquid or solid composition may contain a suitable pharmaceutically acceptable excipient as described herein. The composition may be administered via the oral or nasal respiratory route to obtain a systemic effect. In some embodiments, the composition in a preferably pharmaceutically acceptable solvent may be atomized using an inert gas. In some embodiments, the atomized solution may be inhaled directly from the atomizing device. In other embodiments, the atomizing device may be attached to a mask tent or intermittent positive pressure breathing machine. The solution, suspension, or powder composition may be administered in an appropriate manner from a device for delivering the formulation, preferably orally or nasally.

[0275] Other pharmaceutical compositions

[0276] The pharmaceutical compositions employed in the present application can be formulated for intraocular (ophthalmic), rectal, sublingual, buccal, or intranasal (e.g., pulmonary) administration. Formulations suitable for intraocular administration include eye drops, in which the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is preferably present in such formulations in a concentration of 0.5% to 20% (advantageously 0.5% to 10%, particularly about 1.5% w / w). Formulations suitable for sublingual administration are typically formulated to rapidly dissolve after placement in the mouth, allowing absorption of the active ingredient via sublingual blood vessels. Exemplary sublingual formulations include, for example, lozenges comprising the active ingredient in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; aqueous or oily solutions or suspensions comprising the active ingredient; oral dissolving tablets which, for example, can disintegrate in less than 90 seconds after placement in the mouth; and films. Such disintegration can be measured by in vitro dissolution testing. Formulations for buccal administration can include, for example, oral tablets, bioadhesive particles, wafers, lozenges, drug-containing chewing gum, adhesive gels, patches, films (which can be delivered as an aqueous solution), pastes, ointments, or aerosols, to name a few. Formulations for rectal administration can be provided as suppositories by mixing the active ingredient with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore, will melt in the rectum to release the active ingredient. Such materials include cocoa butter, beeswax and polyethylene glycols. Formulations suitable for pulmonary or nasal administration can have a particle size that is selected to optimize delivery to the lungs or to the nasal lining. Such particle sizes and delivery mechanisms are well known. Suitable formulations include aqueous or oily suspensions, solutions, dry powders, and aerosols.

[0277] Methods for the preparation of such pharmaceutical compositions are described, for example, in Anderson, Philip O.; Knoben, James E.; Troutman, William G, ed., Handbook of Clinical Drug Data, 10th ed., McGraw-Hill, 2002; Pratt and Taylor, ed., Principles of Drug Action, 3rd ed., Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, 9th ed., McGraw Hill, 20037ybg; Goodman and Gilman, ed., The Pharmacological Basis of Therapeutics, 10th ed., McGraw Hill, 2001; Remingtons Pharmaceutical Sciences, 20th ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, 32nd ed. (The Pharmaceutical Press, London, 1999); all of which are incorporated herein by reference in their entirety.

[0278] Exemplary Administration

[0279] The pharmaceutical composition as described herein can be administered by any method capable of delivering a crystalline form of the metopimazine mesylate (e.g., metopimazine mesylate crystalline form A or metopimazine mesylate crystalline form B) to the site of action. The composition can be administered orally, parenterally, enterally, intraperitoneally, topically, transdermally, ocularly, intranasally, topically, parenterally, via spray, subcutaneously, intravenously, intratonsillarally, intramuscularly, buccally, sublingually, rectally, intraarterially, by infusion or intrathecally. In some embodiments, the composition is administered orally. In some cases, oral administration can include administering any oral dosage form as described herein. The effective amount of the crystalline form of metopimazine mesylate (e.g., metopimazine mesylate Form A or metopimazine mesylate Form B) administered will depend on the subject being treated, the severity of the disorder or condition, the rate of administration, the handling of the crystalline form of metopimazine mesylate (e.g., metopimazine mesylate Form A or metopimazine mesylate Form B), and the discretion of the prescribing physician.

[0280] A subject can be administered a daily dose of a crystalline form of metopiramate mesylate as described herein (e.g., metopiramate mesylate Form A or metopiramate mesylate Form B) for the treatment of enteric nervous system disorders. The daily dose can be from about 0.01 mg / kg to about 500 mg / kg body weight / day.

[0281] In some embodiments, administration can include infusion. In some cases, infusion may involve long-term, stable administration. Devices for long-term stable administration (e.g., by controlled pumps) are known in the art (examples can be described in US 7341577, US 7351239, US 8058251, which are incorporated herein by reference).

[0282] If necessary, the crystalline form of metopimarazine mesylate (e.g., metopimarazine mesylate Form A or metopimarazine mesylate Form B) can be continued to be administered. In some embodiments, the crystalline form of metopimarazine mesylate (e.g., metopimarazine mesylate Form A or metopimarazine mesylate Form B) is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In specific embodiments, the crystalline form of metopimarazine mesylate (e.g., metopimarazine mesylate Form A or metopimarazine mesylate Form B) is administered for more than 5 days. In some embodiments, the crystalline form of metopimarazine mesylate (e.g., metopimarazine mesylate Form A or metopimarazine mesylate Form B) is administered for more than 12 weeks. In some embodiments, the crystalline form of metopimarazine mesylate (e.g., metopimarazine mesylate Form A or metopimarazine mesylate Form B) is administered for more than 1 month, more than 2 months, more than 4 months, more than 6 months, more than 1 year, more than 2 years, or more than 5 years. In some embodiments, the crystalline form of metopimarazine mesylate (e.g., metopimarazine mesylate Form A or metopimarazine mesylate Form B) is administered for less than five days.

[0283] Exemplary Combination Therapies

[0284] In some embodiments, the method includes co-administering an additional agent. The additional agent can be: a small molecule, a nutrient, a vitamin (e.g., vitamin D), a drug, a prodrug, a biologic, a peptide, a peptide mimetic, an antibody, an antibody fragment, a cell or tissue transplant, a vaccine, a polynucleotide, a DNA molecule, an RNA molecule (i.e., siRNA, miRNA), an antibody conjugated to a drug, a toxin, a fusion protein. The agent can be delivered by a vector including, but not limited to, a plasmid vector, a viral vector, a non-viral vector, a liposome formulation, a nanoparticle formulation, a toxin, a therapeutic radioisotope, and the like.

[0285] In some embodiments, the methods of the present application include co-administration of a peripherally restricted dopamine decarboxylase inhibitor and a pharmaceutical composition as described herein. For example, the methods of use can include co-administration of carbidopa and a pharmaceutical composition as described herein.

[0286] The additional agent can be an agent for treating an enteric nervous system disorder. In some embodiments, the additional agent is an additional antiemetic agent (e.g., for treating nausea and / or vomiting). By way of non-limiting example only, the additional antiemetic agent can be a 5-HT3 receptor antagonist, a dopamine receptor antagonist, an NK1 receptor antagonist, an antihistamine, a cannabinoid, a benzodiazepine, an anticholinergic, a steroid, or other antiemetic. Exemplary 5-HT3 receptor antagonists include, but are not limited to, ondansetron, tropisetron, granisetron, palonosetron, dolasetron. Exemplary dopamine receptor antagonists include, e.g., metoclopramide (Reglan), domperidone (Motilium), olanzapine (Zyprexa), droperidol, haloperidol, chlorpromazine, promethazine, prochlorperazine, alizapride, prochlorperazine, sulpiride. Exemplary NK1 receptor antagonists include, e.g., aprepitant, tradipitant, or casopitant. Exemplary antihistamines include, e.g., cyclizine, diphenhydramine (Benadryl), Dramamine (dimenhydrinate, Dramamine), doxylamine, meclizine (Bonine, Antivert), promethazine (Pentazine, Phenergan, Promacot), and hydroxyzine (Vistaril), cimetidine, famotidine, ranitidine, nizatidine, roxatidine, ramelteon. Exemplary cannabinoids include, e.g., Indian hemp, Sativex, tetrahydrocannabinol, nabilone, and synthetic cannabinoids such as dronabinol. Exemplary benzodiazepines include, e.g., midazolam or hydroxychlorpromethazine. Exemplary anticholinergics include, e.g., scopolamine. Other exemplary antiemetics include, e.g., trimethobenzamide, ginger, gingerols, propofol, peppermint, erythromycin, ibotenic acid, botulinum toxin A (e.g., injected into the stomach to relax the pyloric muscle), and Ajwain.

[0287] The additional agent can be an agent for treating another disease or clinical syndrome associated with gastroparesis. Exemplary additional diseases and clinical syndromes are described herein. The additional agent can be an agent for treating diabetes. Exemplary agents for treating diabetes include, e.g., insulin. Other agents for treating diabetes are described in, e.g., U.S. Patent Nos. 6,274,549, 8,349,818, 6,184,209, U.S. Patent Application Publication No. US 20070129307, and PCT Application Publication No. WO / 2004 / 082667 Al, all of which are hereby incorporated by reference in their entireties.

[0288] The additional agent can be used to treat the up-and-down movement disorder associated with Parkinson's disease. The additional agent can be used to treat Parkinson's disease. Exemplary agents for the treatment of Parkinson's disease include, for example, dopaminergic agents, MAO-A or B inhibitors, such as selegiline, COMT inhibitors such as entocapone, amantadine, stem cell transplantation, and neuroprotective agents. Exemplary dopaminergic agents include, but are not limited to, levodopa, bromocriptine, pergolide, pramipexole, cabergoline, ropinirole, apomorphine, or a combination thereof.

[0289] The additional agent can be used to treat hypothyroidism, hyperthyroidism or hyperparathyroidism. Exemplary agents for treating such diseases include, for example, beta-adrenergic blocking agents ("beta blockers"), levothyroxine calcimimetics, estrogens, progestins, bisphosphonates.

[0290] The additional agent can be used to treat adrenal insufficiency. Exemplary agents for treating adrenal insufficiency include, for example, corticosteroid hormones (eg, aldosterone, fludrocortisone, and Cortisol).

[0291] The additional agent can be used to treat gastroesophageal reflux. Exemplary agents for treating gastroesophageal reflux include, for example, antacids such as proton pump inhibitors (e.g., omeprazole), H2 receptor antagonists (e.g., ranitidine, antacids, mosapride, sucralfate, and baclofen).

[0292] The additional agent can be used to treat scleroderma. For example, the additional agent can be D-penicillamine, colchicine, PUVA, relaxin, cyclosporine and EPA (ω-3 oil derivatives), immunosuppressants (such as methotrexate, cyclophosphamide, azathioprine and mycophenolate mofetil). The additional agent can be used to treat polymyositis. For example, the additional agent can be a corticosteroid (such as prednisone), or can be an immunosuppressant.

[0293] The additional agent can be used to treat muscular dystrophy. For example, the additional agent can be, for example, a glucocorticoid receptor antagonist. Exemplary glucocorticoid receptor antagonists include, but are not limited to, mifepristone, 11β-(4-dimethylaminoethoxyphenyl)-17α-propynyl-17β-hydroxy-4,9-estradiol-3-one, 17β-hydroxy-17α-19-(4-methylphenyl)androsta-4,9(11)-dien-3-one, 4α(S)-benzyl-2(R)-prop-1-ynyl-1,2,3,4, 4α,9,10,10α(R)-octahydro-phenanthrene-2,7-dione and 4α(S)-benzyl-2(R)-chloroethynyl-1,2,3,4,4α,9,10,10α(R)-octahydro-phenanthrene-2,7-dione and (11β,17β)-11-(1,3-benzodioxol-5-yl)-17-hydroxy-17-(1-propynyl)estr-4,9-dien-3-one.

[0294] The additional agent can be used to treat amyloidosis. For example, the additional agent can be an amyloid beta-sheet mimetic, an antioxidant, a molecular chaperone or other agent. Exemplary agents for treating amyloidosis are described, for example, in WO / 2008 / 141074. Exemplary molecular chaperones include, for example, HSP60, HSP70, HSP90, HSP100, BiP, GRP94, GRP170, calnexin and calreticulin, protein disulfide isomerase (PDI), peptidyl prolyl cis-trans isomerase (PPI), trimethylamine N-oxide (TMAO), betaine, glycine betaine, glycerophosphocholine, carbohydrates (such as glycerol, sorbitol, arabitol, inositol and trehalose), choline, 4-phenylbutyric acid and taurine-conjugated ursodeoxycholic acid.

[0295] The additional agent can be used to treat chronic idiopathic pseudo-obstruction. For example, the additional agent can be prucalopride, pyridostigmine, metoclopramide, cisapride, linaclotide, octreotide, cannabinoids and erythromycin.

[0296] The additional agent can be used to treat dermatomyositis. For example, the additional agent can be prednisolone, methotrexate, mycophenolate mofetil (CellCept / Myfortic), intravenous immunoglobulin, azathioprine (Imuran), cyclophosphamide, rituximab and Acthar Gel.

[0297] The additional agent can be used to treat systemic lupus erythematosus. For example, the additional agent can be a kidney transplant, corticosteroids, immunosuppressants, hydroxychloroquine, cyclophosphamide, mycophenolic acid, immunosuppressants, analgesics, intravenous immunoglobulin, etc.

[0298] The additional agent can be used to treat anorexia and / or bulimia. For example, the additional agent can be olanzapine, tricyclic antidepressants, MAO inhibitors, mianserin, selective serotonin reuptake inhibitors (e.g., fluoxetine, lithium carbonate, trazodone, and bupropion), phenytoin, carbamazepine, and valproic acid, opioid antagonists (e.g., naloxone and naltrexone), and topiramate.

[0299] The additional agent can be used to treat depression. For example, the additional agent can be a selective serotonin reuptake inhibitor, a serotonin and norepinephrine reuptake inhibitor, bupropion, a tricyclic antidepressant, a monoamine oxidase inhibitor, or the like. The additional agent can be used to treat paraneoplastic syndromes. The additional agent can be used to treat high cervical spinal cord lesions. For example, the additional agent can be a corticosteroid or other anti-inflammatory drug. The additional agent can be used to treat multiple sclerosis. For example, the additional agent can be interferon beta-1b, interferon beta-1a, glatiramer acetate, mitoxantrone, natalizumab, fingolimod, teriflunomide, or cladribine.

[0300] The additional therapeutic agent may be selected from serotonin agonists, serotonin antagonists, selective serotonin reuptake inhibitors, anticonvulsants, opioid receptor agonists, bradykinin receptor antagonists, NK receptor antagonists, adrenergic receptor agonists, benzodiazepines, gonadotropin-releasing hormone analogs, calcium channel blockers and somatostatin analogs.

[0301] The dosage of the additional agents and pharmaceutical compositions described herein for treating enteric nervous system disorders can vary depending on the type of additional therapeutic agent employed, the disease or condition to be treated, and the like. Subtherapeutic amounts of one or both of the additional agents and pharmaceutical compositions described herein can be used. Subtherapeutic amounts of one or both of the additional agents and pharmaceutical compositions described herein can be synergistically effective amounts. Therapeutically effective amounts of one or both of the additional agents and pharmaceutical compositions described herein can be used. The pharmaceutical compositions described herein and the additional agents can be administered simultaneously or sequentially. If administered sequentially, the attending physician or caregiver can determine the appropriate sequence of administration of the pharmaceutical compositions described herein and the additional therapeutic agents.

[0302] In some embodiments, the method comprising administering any of the pharmaceutical compositions described herein further comprises a combination therapy with an additional treatment regimen. The additional treatment regimen may include implanting a medical device. The medical device may be implanted in the stomach and / or abdomen, such as the duodenum. The medical device may be an electrical device. The medical device may be a pacemaker. Such a pacemaker may utilize electrical current to induce contractions in the stomach and / or duodenum, thereby promoting gastrointestinal motility. Such a medical device and methods of use thereof are disclosed in U.S. Patent No. 8,095,218, which is hereby incorporated by reference.

[0303] The embodiments of the present application are further described in detail by reference to the following examples. Unless otherwise specified, these examples are for illustrative purposes only and are not intended to be restrictive. Therefore, the application should never be interpreted as being limited to the following examples, but should be understood to encompass any and all variations that become apparent due to the teachings provided herein.

[0304] Example

[0305] The following examples are provided to illustrate but not to limit the present application.

[0306] Example 1: Synthesis of Metoprazine Methanesulfonate Form A

[0307] Those skilled in the art will recognize that the following synthetic reactions and schemes can be modified by selecting appropriate conditions and reagents to obtain metopimazine methanesulfonate, i.e., 1-(3-(2-(methylsulfonyl)-10H-phenothiazin-10-yl)propyl)piperidine-4-carboxamide, from metopimazine, i.e., 1-(3-(2-(methylsulfonyl)-10H-phenothiazin-10-yl)propyl)piperidine-4-carboxamide methanesulfonic acid. Metopimazine and methods for making metopimazine are described in DE 1092476, which is hereby incorporated by reference. Metopimazine can be obtained from various commercial sources (CAS Reg. No. 0014008-44-7). By way of example only, metoprazine is available from ABI Chemicals (#AC2A05HFH), AKos (#AKOS005065914), Biochempartner (#BCP9000716), Molport (#MolPort-003-808-703), Santa Cruz Biotechnology (#sc-211901), and Tractus Company Limited (#TX-013443).

[0308] Scheme 1: Preparation of metoprazine mesylate form A from metoprazine

[0309]

[0310] To metoprazine (50 g), dimethyl sulfoxide (DMSO) (150 mL) was added, followed by methanesulfonic acid (MsOH) (11.3 g) at 20-25 ° C over 10 min to obtain a clear solution. Acetone (50 mL) was then added and the solution was filtered through filter paper. The filtrate was warmed to 68 ° C and acetone (175 mL) was added at 68 ° C over 15 min. The solution was then cooled to 60 ° C over 30 minutes and then stirred at 60 ° C for one hour, at which point the solution became turbid. The slurry was cooled to 0 ° C over 1.5 hours and then stirred at 0 ° C for 1 hour. The solid was collected by filtration and the filter cake was re-slurried with acetone (200 mL) for 30 minutes. The solid was collected by filtration and the remaining filter cake was slurried again with acetone (200 mL) for 30 minutes. The solid was collected by filtration again. The filter cake was dried at 50°C under vacuum for 6 hours to give a yellow solid, metoprazine mesylate Form A, 40 g, 66% yield.

[0311] Similarly, large-scale preparation is carried out as follows. DMSO (4.5 L) is added to metoprazine (1500 g) and then MsOH (341 g) is added at 20° C.-25° C. over 30 min to obtain a clear solution. Acetone (1.5 L) is then added and the solution is filtered through filter paper. The filtrate is warmed to 68° C. and acetone (5.25 L) is added at 68° C. over 30 min. Seed crystals (15 g) are added to the solution. The turbid solution is then stirred at 68° C. for one hour. The slurry is cooled to 0° C. over 6 hours and the mixture is stirred at 0° C. for 14 hours. The solid is collected by filtration and the filter cake is washed with acetone (4.5 L). The filter cake is stirred with acetone (6 L) for 30 minutes. The solid is collected by filtration and the filter cake is stirred with acetone (6 L) for 30 minutes. The solid is collected by filtration. The filter cake was dried at 50°C under vacuum for 7 hours to give a yellow solid, metoprazine mesylate Form A, 1558 g, 85% yield.

[0312] By high-resolution mass spectrometry ([M+H]+=446.16), 1 H NMR (Table 5) and 13 C NMR (Table 6) confirmed the structure of metoprazine mesylate.

[0313] Table 5: Metoprazine mesylate 1 H NMR; 400 MHz 1 HNMR; DMSO-d6

[0314] Chemical shift (ppm) integral Multiplicity Coupling constant (J, Hz) 9.15 1H s - 6.91-7.48 9H m - 4.06 2H t 6.6 3.46 2H d 11.2 3.41 3H s - 3.17 2H m - 2.88 2H dd 22.8,11.2 2.37 4H m - 2.08 2H m - 1.90 2H m - 1.72 2H dd 24.4,12.0

[0315] Table 6: Metoprazine mesylate 13 C NMR; 400 MHz13 CNMR; DMSO-d6

[0316] Chemical shift Multiplicity 174.80 s 145.41 s 143.38 s 140.28 s 131.31 s 128.26 s 127.85 s 127.56 s 123.68 s 122.99 s 121.12 s 116.74 s 113.59 s 53.80 s 51.41 s 43.93 s 43.49 s 38.53 s 25.86 s 21.26 s

[0317] The structure of a single crystal was successfully determined. The crystal system is monoclinic, and the space group is Pn. The unit cell dimensions of the structure are as follows: α=90°, β=103.5908(6)°, γ=90°, The asymmetric unit was found to contain a metoprazine cation and a mesylate anion, indicating that Form A is an anhydrous compound. The final refinement parameters are listed in Table 7 below.

[0318] Table 7: Crystallization data and refinement parameters

[0319]

[0320]

[0321] Table 8 provides the calculated XRPD peak list for a single crystal of metoprazine mesylate Form A.

[0322] Table 8: Calculated XRPD peak list for a single crystal

[0323] Position [°2θ] Height [cts] Position [°2θ] Height [cts] Position [°2θ] Height [cts] Position [°2θ] Height [cts] 7.957 82.639 21.845 4066.813 28.902 450.327 34.203 679.729 9.336 2364.303 22.129 340.111 29.408 292.149 34.451 214.356 9.841 143.466 22.579 215.487 29.648 385.100 34.883 276.078 14.310 238.385 23.364 493.197 29.823 152.139 35.141 264.082 15.301 4263.465 23.718 472.990 30.079 108.698 35.270 273.631 15.953 6407.846 24.028 2541.677 30.723 885.873 35.759 193.775 16.555 1744.832 24.469 10199.890 30.887 972.559 36.027 936.252 17.505 1459.676 24.637 3353.198 31.403 403.286 36.528 111.915 17.781 4685.051 25.447 680.649 31.892 742.574 36.896 648.189 18.451 865.592 26.412 1432.003 32.130 481.241 37.494 276.960 18.727 4592.584 26.645 695.484 32.422 283.382 37.994 541.559 19.119 6048.643 26.975 274.768 32.575 162.015 38.137 408.057 19.759 691.551 27.574 219.672 33.107 579.165 38.798 73.631 20.827 4974.073 28.004 986.973 33.470 655.390 39.461 393.184 21.251 7494.354 28.208 1092.305 33.617 368.145 39.779 580.681 21.433 4760.087 28.467 377.833 33.864 416.154 / /

[0324] For XRPD analysis, a PANalytical X-ray powder diffractometer was used. The samples were prepared by placing a layer of sample (approximately 5 mg) on ​​the center of a silicon wafer. Table 9 lists the XRPD parameters used. Figure 1 The XRPD pattern is provided and the peaks are provided in Table 1 above.

[0325] Table 9: XRPD test parameters

[0326]

[0327]

[0328] *Filter: Beta filter nickel

[0329] TGA data were collected using a TA Q5500 TGA from TA Instruments and DSC was performed using a TA Q2500 DSC from TA Instruments. Table 10 lists the detailed parameters used. The samples were prepared by adding sample (approximately 2 mg) to a pan. Figure 2 A TGA graph is provided. Metopiramate mesylate Form A exhibited minimal weight loss by TGA (up to 150.0°C, 0.4%). Figure 3A DSC graph is provided. Metoprazine mesylate Form A exhibits a clear melt starting at 209.9°C (melting point = 213.1°C; enthalpy = 97.47 J / g).

[0330] Table 10: Parameters of TGA and DSC tests

[0331]

[0332] Example 2: Synthesis of Metoprazine Methanesulfonate Form B

[0333] Scheme 2: Preparation of Metoprazine Mesylate Form B from Metoprazine Mesylate Form A

[0334]

[0335] A glass beaker containing a thin layer of metopiramate mesylate Form A (10 g) was allowed to stand at room temperature and 100% relative humidity for approximately 3-5 days to provide metopiramate mesylate Form B as an off-white solid. 1 H NMR (Table 11) confirmed the structure of metoprazine mesylate Form B.

[0336] Table 11: Metoprazine mesylate crystal form B 1 H NMR; 400 MHz 1 HNMR; DMSO-d6

[0337] Chemical shift (ppm) integral Multiplicity Coupling constant (J, Hz) 8.96 1H s - 6.91-7.52 9H m - 4.06 2H t 6.7 3.46 2H d 11.4 3.24 3H s - 3.15 2H m - 2.89 2H dd 10.6,22.9 2.33 4H m - 2.09 2H m - 1.89 2H m - 1.69 2H dd 14.6,27.4

[0338] For XRPD analysis, a PANalytical X-ray powder diffractometer was used. The samples were prepared by placing a layer of sample (approximately 5 mg) on ​​the center of a silicon wafer. Table 8 above lists the XRPD parameters used. Figure 4 The XRPD pattern is provided and the peaks are provided in Table 3 above.

[0339] TGA data were collected using a TA Q5500 TGA from TA Instruments and DSC was performed using a TG Q2000 DSC from TA Instruments. The detailed parameters used are listed in Table 9 above. The samples were prepared by adding sample (approximately 2 mg) to a pan. Figure 5 TGA / DSC graphs are provided. A weight loss of 5.8% was observed up to 180°C, and two endothermic peaks at 123.5°C and 208.6°C (onset temperatures) (melting points = 126.1°C and 211.2°C, respectively; enthalpy = 83.47 J / g and 84.48 J / g, respectively) and one exothermic peak at 144.6°C (peak temperature) were observed.

[0340] Example 3: Pharmacokinetic Analysis of Metoprazine Methanesulfonate Form A

[0341] A clinically comparable pharmacokinetic study was conducted to understand the pharmacokinetic profile of metopimazine mesylate Form A compared to metopimazine free base. This study was a 3-period crossover design with 3 single dose administrations: oral formulation of metopimazine mesylate Form A on an empty stomach, oral formulation of metopimazine mesylate Form A after a high-fat breakfast, and oral formulation of metopimazine free base on an empty stomach, with a 48-hour washout period between each administration. Fifteen subjects were recruited and received the 3 treatments. Plasma samples from each subject were analyzed for various pharmacokinetic parameters. Mixed model repeated measures (MMRM) analysis was performed on each sample. Comparison of metopimazine mesylate Form A to metopimazine free base showed that T of metopimazine mesylate Form A was significantly lower than that of metopimazine mesylate Form A. max The values ​​had statistically significantly lower variance than metoprazine free base. The results are shown in Table 12 below.

[0342] Table 12: T max analyze

[0343]

[0344] 1. p < 0.0001***

[0345] The above results indicate that metopiramate mesylate Form A provides a more predictable onset of action than metopiramate free base. max The lower variance provides an important benefit to a population of subjects with gastroparesis who require treatment prior to mealtimes to reduce symptoms that worsen with eating.

[0346] The secondary objective of this study was to compare the pharmacokinetics of metoprazine mesylate Form A administered as a single oral dose of 15 mg in 15 human subjects in the fasting state or after a high-fat breakfast. Plasma samples from each subject were analyzed for various pharmacokinetic parameters. max The geometric mean difference was slightly but significantly lower, while the geometric mean AUC was not statistically different. max Both the AUC and the ROC curve were well within the 90% confidence interval. The results are shown in Table 13 below.

[0347] When metoprazine mesylate Form A is administered with food, approximately 15% of the C max There was a slight decrease, but no significant change in AUC (well within the 90% upper and lower intervals defining bioequivalence). maxThis minor difference is not of clinical significance (FDA Guidance for the industry: Food-Effect Bioavailability and Fed Bioequivalence Studies). These results are in contrast to previously published data which indicated that the food effect for metoclopramide free base resulted in a 58% decrease in Cmax and a 23% decrease in AUC following administration of metoclopramide free base before or after a high fat breakfast (Herrstedt et al. 1990).

[0348] Table 13: C max and AUC analysis

[0349]

[0350] * Bioequivalence

[0351] The lack of food effect for metoclopramide mesylate Form A provides a benefit to the population of subjects with gastroparesis as this population exhibits delayed gastric emptying and residual gastric food content for longer periods of time which can exacerbate the PK variability of food sensitive drugs such as metoclopramide free base.

[0352] Example 4: Metopiramate mesylate crystalline form A and metopiramate mesylate crystalline form B 13 C ssNMR table Sign Relaxation parameters

[0353] Relaxation parameters were collected for metoclopramide mesylate Form A and Form B 1 H T1and 1 H T 1rho Table 14 shows the results. Parameters 1 H T1and 1 H T 1rho This will help to determine the optimal acquisition parameters for ssNMR data collection.

[0354] Table 14: Relaxation parameters for Form A and Form B.

[0355]

[0356] Instrument information and data collection

[0357] Solid state NMR (ssNMR) experiments were performed on a Bruker NEO spectrometer (Bruker, Billerica, MA) where for 13 C was run at 100.52 MHz and for 1 H was run at 399.71 MHz or for 13 C was run at 100.46 MHz and for 1H was operated at 399.49 MHz. A Chemagnetics APEX HX probe modified with a 7 mm magic angle spinning module (Revolution NMR, Fort Collins, CO) was used to acquire the data. The samples were loaded into a 7 mm rotor with a Kel-F shim for 13 The magic angle spinning rate was 5 kHz. 3-Methylglutaric acid was used for the setup and optimization of the cross-polarization (CP) experiment for reference. The MGA methyl peak at 18.84 ppm was reported. 13 The accuracy of the C chemical shift is ±0.4 ppm.

[0358] Data collection was performed at a nominal temperature of approximately 18.5°C. 13 C cross polarization and then use SPINAL64 1 H decoupling acquisition was performed to collect data. 3960 points were acquired (acquisition time was approximately 50ms). 4.4μs H90 and 1 H decoupled SPINAL64 (approximately 56.8 kHz RF field), 1.5 ms contact time (P15), and appropriate pulse delays as described below. The pulse delays for metoprazine mesylate Form A and metoprazine mesylate Form B were 7.2 seconds or 8.2 seconds, respectively. 1 H T1 experiment, 1 H was subjected to a saturation cycle (15 μs delay, 20 cycles), followed by H90, cross polarization (CP) and data acquisition with total sideband suppression (TOSS). The Bruker t1 guide in the Topsin software package was used to determine the 1 H T1 value. 1 HT 1rho , spin lock time of 0.5-32ms (in selected cases, 64ms and 128ms were also added), followed by a standard CPTOSS sequence. The pulse delay appropriate to the material, determined based on the T1 results, was used for data acquisition. For high quality 13 For C spectra, use an appropriate pulse delay based on the T1 result. Modify the pulse delay and acquisition times based on the sample. Collect data for 2-18 hours, depending on the sample.

[0359] Data processing

[0360] Using Bruker Biospin's Topspin Initial data processing was performed using a software package. Fourier transformation of the data was performed using a full FID (3960 points) with 0 Hz line broadening (KAS0221001 and KAS0221002) or 10 Hz line broadening (KAS0221003 and KAS0221004), phasing (apk), and baseline correction (abs). Manual phasing was performed as needed.

[0361] Sample preparation

[0362] The powder samples were packed into a 7 mm rotor without modification. The samples were pre-spun externally before loading into the NMR probe.

[0363] 13 C ssNMR spectroscopy

[0364] respectively Figure 6 and Figure 7 Provided are metoprazine mesylate crystalline forms A and B. 13 C ssNMR spectrum. Although the two forms were found to have unique spectra, Form B was found to contain trace amounts of Form A. Therefore, in order to obtain a pure Form B spectrum, Topsin The software package subtracts Form A from Form B. Figure 8 The resulting spectra are provided in .

[0365] Although the preferred embodiment of the application has been shown and described herein, it is clear to those skilled in the art that this type of embodiment is only provided by way of example. Without departing from the application, those skilled in the art will now expect many variations, changes and replacements. Should be understood that the various alternatives of the application's embodiment as herein described can be used to put the application into practice. It is expected that the following claims limit the scope of the application, and thus cover the method and structure within the scope of these claims and their equivalents.

[0366] Incorporated by Reference

[0367] All references cited in this application and their references are, where appropriate, incorporated herein by reference in their entirety for teachings of additional or alternative details, features and / or technical background.

Claims

1. A crystalline form of metopiramate mesylate, the crystalline form of metopiramate mesylate being characterized by an X-ray powder diffraction (XRPD) pattern comprising the following 2θ values: 9.37°±0.2°, 15.26°±0.2°, 15.91°±0.2°, 18.75°±0.2°, and 24.44°±0.2°.

2. The crystalline form of claim 1 , characterized by an XRPD pattern comprising two or more of the following 2θ values: 9.87°±0.2°, 14.33°±0.2°, 16.55°±0.2°, 17.52°±0.2°, 17.75°±0.2°, 19.09°±0.2°, 19.72°±0.2°, 20.80°±0.2°, 21.22°±0.2°, 21.77°±0.2°, 23.29°±0.2°, 23.91°±0.2°, and 25.37°±0.2°.

3. The crystalline form of claim 1 , characterized by an XRPD pattern comprising three or more of the following 2θ values: 9.87°±0.2°, 14.33°±0.2°, 16.55°±0.2°, 17.52°±0.2°, 17.75°±0.2°, 19.09°±0.2°, 19.72°±0.2°, 20.80°±0.2°, 21.22°±0.2°, 21.77°±0.2°, 23.29°±0.2°, 23.91°±0.2°, and 25.37°±0.2°.

4. The crystalline form of claim 1 , characterized by an XRPD pattern comprising four or more of the following 2θ values: 9.87°±0.2°, 14.33°±0.2°, 16.55°±0.2°, 17.52°±0.2°, 17.75°±0.2°, 19.09°±0.2°, 19.72°±0.2°, 20.80°±0.2°, 21.22°±0.2°, 21.77°±0.2°, 23.29°±0.2°, 23.91°±0.2°, and 25.37°±0.2°.

5. The crystalline form of claim 1 , characterized by an XRPD pattern further comprising peaks at one or more of the following 2θ values: 9.87°±0.2°, 14.33°±0.2°, 16.55°±0.2°, 17.52°±0.2°, 17.75°±0.2°, 19.09°±0.2°, 19.72°±0.2°, 20.80°±0.2°, 21.22°±0.2°, 21.77°±0.2°, 23.29°±0.2°, 23.91°±0.2°, 25.37°±0.2°, 26.39°±0.2°, °, 26.92°±0.2°, 27.96°±0.2°, 28.23°±0.2°, 28.78°±0.2°, 29.27°±0.2°, 29.64°±0.2°, 30.67°±0.2°, 31.29°±0.2°, 31.84°±0.2°, 32.09°±0.2°, 32.99°±0.2°, 33.40°±0.2°, 33.99°±0.2°, 35.91°±0.2°, 36.80°±0.2°, 37.41°±0.2°, 37.92°±0.2° and 39.27°±0.2°.

6. The crystalline form of claim 1 , characterized by an XRPD pattern further comprising peaks at two or more of the following 2-theta values: 9.87°±0.2°, 14.33°±0.2°, 16.55°±0.2°, 17.52°±0.2°, 17.75°±0.2°, 19.09°±0.2°, 19.72°±0.2°, 20.80°±0.2°, 21.22°±0.2°, 21.77°±0.2°, 23.29°±0.2°, 23.91°±0.2°, 25.37°±0.2°, 26.39°±0.2°. 2°, 26.92°±0.2°, 27.96°±0.2°, 28.23°±0.2°, 28.78°±0.2°, 29.27°±0.2°, 29.64°±0.2°, 30.67°±0.2°, 31.29°±0.2°, 31.84°±0.2°, 32.09°±0.2°, 32.99°±0.2°, 33.40°±0.2°, 33.99°±0.2°, 35.91°±0.2°, 36.80°±0.2°, 37.41°±0.2°, 37.92°±0.2° and 39.27°±0.2°.

7. The crystalline form of claim 1 , further characterized by comprising at least one peak expressed as a chemical shift in ppm selected from the group consisting of 13 C solid-state nuclear magnetic resonance (ssNMR) spectrum: 176.8±0.20ppm, 176.4±0.20ppm, 142.2±0.20ppm, 141.7±0.20ppm, 140.9±0.20ppm, 140.0±0.20ppm, 128.3±0.20ppm, 127.0±0.20ppm, 126.2±0.20ppm, 125.1±0.20ppm, 121.1±0. 20ppm, 119.9±0.20ppm, 114.7±0.20ppm, 110.9±0.20ppm, 57.0±0.20ppm, 55.7±0.20ppm, 50.6±0.2 0ppm, 47.1±0.20ppm, 45.6±0.20ppm, 42.1±0.20ppm, 40.2±0.20ppm, 27.4±0.20ppm and 21.3±0.20ppm.

8. The crystalline form of claim 7, characterized in that it comprises at least three peaks expressed as chemical shifts in ppm selected from the group consisting of 13 C ssNMR spectrum: 176.8±0.20ppm, 176.4±0.20ppm, 142.2±0.20ppm, 141.7±0.20ppm, 140.9±0.20ppm, 14 0.0±0.20ppm, 128.3±0.20ppm, 127.0±0.20ppm, 126.2±0.20ppm, 125.1±0.20ppm, 121.1±0.20pp m, 119.9±0.20ppm, 114.7±0.20ppm, 110.9±0.20ppm, 57.0±0.20ppm, 55.7±0.20ppm, 50.6±0.20p pm, 47.1±0.20ppm, 45.6±0.20ppm, 42.1±0.20ppm, 40.2±0.20ppm, 27.4±0.20ppm and 21.3±0.20ppm.

9. The crystalline form of claim 7, characterized in that it comprises at least four peaks expressed as chemical shifts in ppm selected from the group consisting of 13 C ssNMR spectrum: 176.8±0.20ppm, 176.4±0.20ppm, 142.2±0.20ppm, 141.7±0.20ppm, 140.9±0.20ppm, 14 0.0±0.20ppm, 128.3±0.20ppm, 127.0±0.20ppm, 126.2±0.20ppm, 125.1±0.20ppm, 121.1±0.20pp m, 119.9±0.20ppm, 114.7±0.20ppm, 110.9±0.20ppm, 57.0±0.20ppm, 55.7±0.20ppm, 50.6±0.20p pm, 47.1±0.20ppm, 45.6±0.20ppm, 42.1±0.20ppm, 40.2±0.20ppm, 27.4±0.20ppm and 21.3±0.20ppm.

10. The crystalline form of claim 7, characterized in that it comprises at least six peaks expressed as chemical shifts in ppm selected from the group consisting of 13 C ssNMR spectrum: 176.8±0.20ppm, 176.4±0.20ppm, 142.2±0.20ppm, 141.7±0.20ppm, 140.9±0.20ppm, 14 0.0±0.20ppm, 128.3±0.20ppm, 127.0±0.20ppm, 126.2±0.20ppm, 125.1±0.20ppm, 121.1±0.20pp m, 119.9±0.20ppm, 114.7±0.20ppm, 110.9±0.20ppm, 57.0±0.20ppm, 55.7±0.20ppm, 50.6±0.20p pm, 47.1±0.20ppm, 45.6±0.20ppm, 42.1±0.20ppm, 40.2±0.20ppm, 27.4±0.20ppm and 21.3±0.20ppm.

11. The crystalline form of claim 7, characterized in that it comprises at least one peak expressed as a chemical shift in ppm selected from the group consisting of 13 C ssNMR spectrum: 21.3±0.20ppm, 27.4±0.20ppm, 42.1±0.20ppm, 50.6±0.20ppm, 57.0±0.20pp m, 114.7±0.20ppm, 119.9±0.20ppm, 121.1±0.20ppm, 176.4±0.20ppm and 176.8±0.20ppm.

12. The crystalline form of claim 7, characterized in that it comprises at least three peaks expressed as chemical shifts in ppm selected from the group consisting of 13 C ssNMR spectrum: 21.3±0.20ppm, 27.4±0.20ppm, 42.1±0.20ppm, 50.6±0.20ppm, 57.0±0.20pp m, 114.7±0.20ppm, 119.9±0.20ppm, 121.1±0.20ppm, 176.4±0.20ppm and 176.8±0.20ppm.

13. The crystalline form of claim 7, characterized in that it comprises at least six peaks expressed as chemical shifts in ppm selected from the group consisting of 13 C ssNMR spectrum: 21.3±0.20ppm, 27.4±0.20ppm, 42.1±0.20ppm, 50.6±0.20ppm, 57.0±0.20pp m, 114.7±0.20ppm, 119.9±0.20ppm, 121.1±0.20ppm, 176.4±0.20ppm and 176.8±0.20ppm.

14. The crystalline form of claim 1, wherein the differential scanning calorimetry of the crystalline form has a single endotherm with an onset temperature ranging from 208°C to 212°C.

15. The crystalline form of claim 14, wherein the onset temperature of the single endotherm is in the range of 208°C to 211°C.

16. The crystalline form of claim 14, wherein the onset temperature of the single endotherm is in the range of 209°C to 210°C.

17. The crystalline form of any one of claims 14-16, wherein the peak temperature of the single endotherm ranges from 213°C to 214°C.

18. The crystalline form according to any one of claims 14 to 16, wherein the transition enthalpy of the single endotherm is 95 to 100 J / g.

19. The crystalline form of claim 18, wherein the transition enthalpy of the single endotherm is 96-98 J / g.

20. The crystalline form of claim 18, wherein the transition enthalpy of the single endotherm is 97-98 J / g.

21. The crystalline form of claim 1, wherein the crystalline form has a thermogravimetric analysis curve at 150.0°C with a total weight loss of 0.4%.

22. A composition comprising the crystalline form according to any one of claims 1 to 21, wherein the composition comprises less than 10 wt.% of other crystalline forms of metopiramate mesylate.

23. The composition of claim 22, wherein the composition comprises less than 1 wt.% of other crystalline forms of metopiramate mesylate.

24. The composition of claim 22 or 23, wherein the composition comprises less than 10 wt.% of metoprazine mesylate in amorphous form.

25. The composition of claim 24, wherein the composition comprises less than 1 wt.% of metoprazine mesylate in amorphous form.

26. A pharmaceutical composition comprising the crystalline form according to any one of claims 1 to 21 and a pharmaceutically acceptable excipient.

27. The pharmaceutical composition according to claim 26, wherein the pharmaceutical composition is suitable for enteral administration.

28. The pharmaceutical composition according to claim 26, wherein the pharmaceutical composition is suitable for non-oral administration.

29. The pharmaceutical composition of claim 26, wherein the pharmaceutical composition is suitable for rectal administration.

30. The pharmaceutical composition of claim 26, wherein the pharmaceutical composition is suitable for oral, intraduodenal, intracolonic, topical, intranasal, buccal, sublingual, or administration by inhalation.

31. The pharmaceutical composition of claim 30, wherein the composition is suitable for oral administration.

32. The pharmaceutical composition of claim 30, wherein the composition is suitable for sublingual administration.

33. The pharmaceutical composition of any one of claims 26-32, wherein the pharmaceutical composition is formulated as a tablet, capsule, paste, powder, suspension, or suppository.

34. The pharmaceutical composition of claim 33, wherein the composition is formulated as an extended release formulation.

35. The pharmaceutical composition of claim 33, wherein the composition is formulated as a capsule.

36. The pharmaceutical composition of any one of claims 26-32 and 34-35, wherein the composition comprises 5 mg of the crystalline form of metopiramate mesylate.

37. The pharmaceutical composition of any one of claims 26-32 and 34-35, wherein the composition comprises 10 mg of the crystalline form of metopiramate mesylate.

38. The pharmaceutical composition of any one of claims 26-32 and 34-35, wherein the composition comprises 20 mg of the crystalline form of metopiramate mesylate.

39. Use of the pharmaceutical composition according to any one of claims 26-38 in the preparation of a medicament for treating an enteric nervous system disorder in a human subject in need thereof, wherein the symptoms of the enteric nervous system disorder are selected from nausea or vomiting.

40. The use according to claim 39, wherein the enteric nervous system disorder is a chronic disorder.

41. The use according to claim 39, wherein the enteric nervous system disorder is an acute disorder.

42. The use according to claim 39, wherein the symptom of the enteric nervous system disorder is nausea.

43. The use according to claim 39, wherein the symptom of the enteric nervous system disorder is vomiting.

44. Use of the pharmaceutical composition of any one of claims 26-38 in the preparation of a medicament for treating gastroparesis in a subject in need thereof.

45. The use according to claim 44, wherein the gastroparesis is diabetic gastroparesis.

46. ​​The use according to claim 44, wherein the gastroparesis is idiopathic gastroparesis.

47. The use according to any one of claims 44 to 46, wherein the symptoms of gastroparesis are selected from the group consisting of nausea, vomiting, delayed gastric emptying, diarrhea, abdominal pain, flatulence, bloating, gastroesophageal reflux, loss of appetite and constipation.

48. The use according to any one of claims 44-46, wherein the symptom of gastroparesis is early satiety.

49. The use according to any one of claims 44 to 46, wherein the symptom of gastroparesis is postprandial fullness.

50. The use according to any one of claims 44-46, wherein the symptom of gastroparesis is abdominal fullness.

51. The use according to claim 47, wherein the symptom of gastroparesis is nausea.

52. The use according to claim 47, wherein the symptom of gastroparesis is vomiting.

53. Use of the pharmaceutical composition of any one of claims 26-38 in the preparation of a medicament for treating nausea associated with gastroparesis in a human subject in need thereof.

54. Use of the pharmaceutical composition of any one of claims 26-38 in the preparation of a medicament for treating vomiting associated with gastroparesis in a human subject in need thereof.

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