Novel polymorphic forms of metopimazine

Abstract

To provide novel polymorphic forms of metopimazine mesylate.SOLUTION: These polymorphic forms are useful in methods, compositions, and kits for the treatment of an enteric nervous system disorder. In certain embodiments, the crystalline form comprises less than 10 wt.% of amorphous forms. In certain embodiments, the crystalline form is in non-solvate forms. In certain such embodiments, the crystalline form comprises less than 10 wt.% of solvate forms. In certain embodiments of the foregoing, the present application provides a crystalline form of metopimazine mesylate where the crystalline form comprises metopimazine mesylate Crystal Form A.SELECTED DRAWING: None

Description

Technical Field

[0001] Related Applications This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 003,998, filed Apr. 2, 2020, and U.S. Application No. 16 / 838,402, filed Apr. 2, 2020, now U.S. Patent No. 10,836,757, the entireties of which are incorporated herein by reference.

Background Art

[0002] Background The enteric nervous system (ENS) contains approximately 100 million neurons embedded in the lining of the gastrointestinal tract. The ENS innervates the gastrointestinal tract, including the esophagus, stomach (e.g., the gastric region), and intestine. The motor neurons of the ENS control contractions of the stomach muscles, peristalsis, and agitation of the intestinal contents. It has been estimated that approximately 50% of the body's dopamine is found in the ENS.

[0003] A large number of humans suffer from disorders of the gastrointestinal (GI) tract. Due to muscle or nerve dysfunction in the GI tract, irritable bowel syndrome (IBS), a disorder in which the intestine does not function properly, affects 10-15% of the adult population. Symptoms of IBS include constipation, diarrhea, and abdominal pain. Functional dyspepsia (indigestion caused by muscle or nerve dysfunction related to the upper GI tract) affects 10-20% of the adult population. Gastroparesis, a disorder that causes inappropriate grinding of food by the stomach and delayed gastric emptying, affects up to 10% of the total population. In the United States, it is estimated that gastroesophageal reflux disorder (GERD), a chronic digestive disease that occurs when stomach acid and / or bile reflux into the esophagus, affects up to 35% of infants in the first few months of life and more than half of the total population.

[0004] Furthermore, gastrointestinal disorders can be associated with several other diseases. For example, some of the earliest symptoms of Parkinson's disease, which is a disorder characterized by the neurodegeneration of dopaminergic neurons, likely include constipation and other gastrointestinal symptoms due to the degeneration or dysfunction of ENS dopaminergic neurons. Another example is diabetes, which is one of the most common causes of gastroparesis, as chronic hyperglycemia can damage the vagus nerve that modulates the enteric nervous system. Multiple sclerosis is another disease associated with ENS disorders, such as gastroparesis. Migraine headaches are commonly associated with gastric stasis. Chemotherapy-induced nausea and / or vomiting is estimated to affect 85% of cancer patients receiving chemotherapy and can lead to treatment discontinuation. If chemotherapy-induced nausea and / or vomiting is not properly managed, it can cause dehydration and poor quality of life and may lead to the discontinuation of chemotherapy.

[0005] ENS dysfunction is involved in some of the above disorders. For example, impairment or dysfunction of signal transmission in ENS neurons is strongly involved as a causative factor in gastroparesis.

[0006] Appropriate treatments for these disorders do not currently exist. For example, lubiprostone and linaclotide for IBS treatment are used to treat constipation and to mimic infectious diarrhea. However, these drugs do not repair the underlying ENS dysfunction and are only marginally effective. Dopamine D 2The receptor antagonists domperidone and metoclopramide were previously indicated for the treatment of nausea and vomiting, but due to serious safety issues, their use, especially for long periods, is not recommended. Two serious safety concerns are: (1) unwanted cardiac side effects caused, for example, by the interaction of these agents with ion channels involved in myocardial action potentials, and (2) unwanted motor dysfunction associated with the action of dopamine antagonists that cross the blood-brain barrier and enter the brain. For example, numerous dopamine receptor antagonists have been shown to inhibit the hERG channel (a type of potassium channel), causing drug-induced QT prolongation syndrome, a cardiac condition characterized by abnormal myocardial action potential rhythms. QT prolongation syndrome can increase the risk of cardiac arrhythmias, which can lead to sudden cardiac death. Indeed, domperidone, a dopamine D 2 antagonist, has been shown to inhibit hERG activity, increasing the risk of QT prolongation syndrome and an increased risk of sudden cardiac death. As a result, in the United States, the FDA prohibited the use of domperidone, and the European Medicines Agency initiated a reexamination of the safety of domperidone use. Metoclopramide has a black box warning due to CNS-related side effects such as tardive dyskinesia, a refractory and often incurable disorder characterized by involuntary and repetitive body movements, and cannot be taken for more than 12 weeks. SUMMARY OF THE INVENTION MEANS FOR SOLVING THE PROBLEM

[0007] SUMMARY OF THE APPLICATION This application relates to the crystalline form of metopimazine mesylate

Chemical formula

[0008] This application provides a crystalline form of metopimazine mesylate, characterized by an X-ray powder diffraction (XRPD) pattern that includes 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 metopimazine mesylate is characterized by an XRPD pattern that includes 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 metopimazine mesylate is characterized by an XRPD pattern that includes 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 metopimazine mesylate is characterized by an XRPD pattern that includes 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°.

[0009] This application provides a crystalline form of metopimazine mesylate characterized by an XRPD pattern comprising peaks at the following 2θ values: 15.91° and 18.75° ± 0.2°. This application further provides a crystalline form of metopimazine mesylate characterized by an XRPD pattern comprising peaks at the following 2θ values: 15.91°, 18.75° and 24.44° ± 0.2°.

[0010] This application provides a crystalline form of metopimazine mesylate characterized by an XRPD pattern comprising a peak at the following 2θ value: 18.75°. In certain embodiments, the crystalline form of metopimazine 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 metopimazine mesylate is characterized by an XRPD pattern comprising peaks at the following 2θ values: 15.91°, 18.75° and 24.44°.

[0011] This application provides a crystalline form of metopimazine 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 metopimazine 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 metopimazine 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 metopimazine 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°.

[0012] This application provides a crystalline form of metopimazine mesylate, characterized by a 13C solid-state nuclear magnetic resonance (ssNMR) spectrum that includes at least one peak selected from the following chemical shifts 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 This application provides a crystalline form of metopimazine mesylate, characterized by a 13C solid-state nuclear magnetic resonance (ssNMR) spectrum that includes at least three peaks selected from the following chemical shifts 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 This application provides a crystalline form of metopimazine mesylate, characterized by a 13C solid-state nuclear magnetic resonance (ssNMR) spectrum that includes at least four peaks selected from the following chemical shifts 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 This application provides a crystalline form of metopimazine mesylate, characterized by a 13C solid-state nuclear magnetic resonance (ssNMR) spectrum that includes at least six peaks selected from the following chemical shifts 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. 13It is characterized by a C ssNMR spectrum. In certain embodiments, the crystalline form of metopimazine mesylate comprises at least one peak selected from the following chemical shifts in ppm: 21.3, 27.4, 42.1, 50.6, 57.0, 114.7, 119.9, 121.1, 176.4, and 176.8 ± 0.20 ppm. 13 It is characterized by a C ssNMR spectrum. In certain embodiments, the crystalline form of metopimazine mesylate comprises at least three peaks selected from the following chemical shifts in ppm: 21.3, 27.4, 42.1, 50.6, 57.0, 114.7, 119.9, 121.1, 176.4, and 176.8 ± 0.20 ppm. 13 It is characterized by a C ssNMR spectrum. In certain embodiments, the crystalline form of metopimazine mesylate comprises at least six peaks selected from the following chemical shifts in ppm: 21.3, 27.4, 42.1, 50.6, 57.0, 114.7, 119.9, 121.1, 176.4, and 176.8 ± 0.20 ppm. 13 It is characterized by a C ssNMR spectrum.

[0013] This application provides a crystalline form of metopimazine mesylate characterized by a differential scanning calorimetry pattern that includes a single endotherm with a starting temperature range of 208°C to 212°C. In certain embodiments, the single endotherm includes a starting temperature range of 208°C to 211°C. In certain embodiments, the single endotherm includes a starting temperature range of 209°C to 210°C. In certain embodiments of any of the above, the single endotherm includes a peak temperature range of 213°C to 214°C. In certain embodiments of any of the above, the single endotherm includes a transition enthalpy of 95 to 100 J / g. In certain such embodiments, the single endotherm includes a transition enthalpy of 96 to 98 J / g. In further embodiments, the single endotherm includes a transition enthalpy of 97 to 98 J / g.

[0014] The present application provides a crystalline form of metopimazine mesylate, characterized by a thermogravimetric analysis profile including a total weight loss of 0.4% up to 150.0 °C.

[0015] In certain specific embodiments of any of the above, the composition comprises less than 10% by weight of other crystalline forms. In certain such embodiments, the composition comprises less than 1% by weight of other crystalline forms. In certain specific embodiments of the above, the composition comprises less than 10% by weight of amorphous forms. In certain such embodiments, the composition comprises less than 1% by weight of amorphous forms.

[0016] The present application provides a pharmaceutical composition comprising any of the above crystalline forms and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition is suitable for administration orally, duodenally, intracolonically, enterally, topically, nasally, parenterally, buccally, sublingually, by inhalation or rectally. In certain embodiments, the composition is suitable for oral administration. In certain embodiments, the composition is suitable for sublingual administration. In certain specific embodiments of the above, the pharmaceutical composition is formulated as a tablet, capsule, paste, powder, suspension, suppository, sustained release formulation or release modulating formulation. In certain such embodiments, the composition is formulated as a sustained release formulation. In a further embodiment, the composition is formulated as a capsule.

[0017] In certain specific embodiments of any of the above pharmaceutical compositions, the composition comprises 5 mg of the crystalline form of metopimazine mesylate. In certain embodiments, the composition comprises 10 mg of the crystalline form of metopimazine mesylate. In certain embodiments, the composition comprises 15 mg of the crystalline form of metopimazine mesylate. In certain embodiments, the composition comprises 20 mg of the crystalline form of metopimazine mesylate.

[0018] In certain embodiments of any of the above pharmaceutical compositions, the composition is preferably administered once daily. In certain embodiments, the composition is preferably administered twice daily. In certain embodiments, the composition is preferably administered three times daily. In certain embodiments, the composition is preferably administered four times daily.

[0019] In certain embodiments of any of the above pharmaceutical compositions, a crystalline form of metopimazine mesylate between about 5 mg and about 160 mg per day is administered. In certain embodiments, the composition is suitable for administering a crystalline form of metopimazine mesylate in excess of 20 mg per day.

[0020] The present application provides a method for treating enteric nervous system disorders in a human subject in need thereof, the method comprising the step of administering to the subject any of the above pharmaceutical compositions. In certain embodiments, the enteric nervous system disorder is a chronic disorder. In other embodiments, the enteric nervous system disorder is an acute disorder. In certain embodiments, the enteric nervous system disorder is selected from the group consisting of gastroparesis, irritable bowel syndrome, lysosomal storage disease, intestinal motility disorder, gangliocytoma, multiple endocrine neoplasia type 2B (MEN2B), gastrointestinal neuropathy, functional dyspepsia, gastroesophageal reflux disease (GERD), and enteric neurogenic dysplasia. In certain embodiments as described above, the enteric nervous system disorder comprises symptoms selected from the group consisting of early satiety, postprandial fullness, abdominal distension, nausea, vomiting, delayed gastric emptying, diarrhea, abdominal pain, gas, abdominal bloating, gastroesophageal reflux, anorexia, and constipation. In certain embodiments, the symptoms of the enteric nervous system disorder include nausea. In other embodiments, the symptoms of the enteric nervous system disorder include vomiting.

[0021] The present application provides a method for treating gastroparesis in a human subject in need thereof, the method comprising the step of administering to the subject any of the above-described pharmaceutical compositions. In certain embodiments, the gastroparesis is diabetic gastroparesis. In other embodiments, the gastroparesis is idiopathic gastroparesis. In certain embodiments above, the gastroparesis includes symptoms selected from the group consisting of early satiety, postprandial fullness, abdominal fullness, nausea, vomiting, delayed gastric emptying, diarrhea, abdominal pain, gas, abdominal distension, gastroesophageal reflux, anorexia, and constipation. In certain such embodiments, the gastroparesis symptoms include nausea. In other embodiments, the gastroparesis symptoms include vomiting.

[0022] The present application provides a method for treating nausea associated with gastroparesis in a human subject in need thereof, the method comprising the step of administering to the subject any of the above-described pharmaceutical compositions.

[0023] The present application provides a method for treating vomiting associated with gastroparesis in a human subject in need thereof, the method comprising the step of administering to the subject any of the above-described pharmaceutical compositions.

[0024] The present application provides a method for improving gastric emptying in a human subject in need thereof, the method comprising the step of administering to the subject any of the above-described pharmaceutical compositions.

[0025] The present application provides a method for treating GI tract dysfunction and motility disorders in a human subject in need thereof, the method comprising the step of administering to the subject any of the above-described pharmaceutical compositions.

[0026] In certain embodiments of any of the above methods, the pharmaceutical composition is administered to the subject for a long period of time. In other embodiments of any of the above methods, the pharmaceutical composition is administered to the subject for a short period of time.

[0027] In certain specific embodiments of any of the above 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 for at least 4 weeks. In certain embodiments, the pharmaceutical composition is administered to the subject for at least 12 weeks.

[0028] In certain specific embodiments of any of the above 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.

[0029] In certain specific embodiments of any of the above methods, between about 5 mg and about 160 mg of metopimazine mesylate per day is administered to the subject. In certain such embodiments, more than 20 mg of metopimazine mesylate per day is administered to the subject. In embodiments of the present invention, for example, the following items are provided. (Item 1) The crystalline form of metopimazine mesylate. [Chemical formula] (Item 2) The crystalline form according to Item 1, wherein the crystalline form contains less than 10% by weight of the amorphous form. (Item 3) The crystalline form according to Item 1 or 2, wherein the crystalline form is an unsolvated form. (Item 4) The crystalline form according to Item 3, wherein the crystalline form contains less than 10% by weight of the solvated form. (Item 5) The crystalline form according to any of the above items, wherein the crystalline form contains crystalline form A of metopimazine mesylate. (Item 6) The crystalline form of metopimazine 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°. (Item 7) The crystalline form according to item 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°. (Item 8) The crystalline form according to item 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°. (Item 9) The crystalline form according to item 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°. (Item 10) The crystalline form according to item 6, characterized by an XRPD pattern comprising peaks at the following 2θ values: 15.91° and 18.75° ± 0.2°. (Item 11) The crystalline form according to item 6, characterized by an XRPD pattern comprising peaks at the following 2θ values: 15.91°, 18.75° and 24.44° ± 0.2°. (Item 12) The crystalline form of metopimazine 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°. (Item 13) The crystalline form according to item 12, 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° ± 0.2°. (Item 14) The crystalline form according to item 12, 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°. (Item 15) Comprising at least one peak selected from the following, represented as chemical shifts in ppm units: 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 The crystalline form of metopimazine mesylate, characterized by a 13C solid state nuclear magnetic resonance (ssNMR) spectrum. (Item 16) Characterized by chemical shifts in ppm units, as follows: at least three peaks selected from 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 The crystalline form according to item 15, characterized by a 13C ssNMR spectrum. (Item 17) Characterized by chemical shifts in ppm units, as follows: at least four peaks selected from 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 The crystalline form according to item 15, characterized by a 13C ssNMR spectrum. (Item 18) Characterized by chemical shifts in ppm units, as follows: at least six peaks selected from 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 The crystalline form according to item 15, characterized by a 13C ssNMR spectrum. (Item 19) Characterized by chemical shifts in ppm units, as follows: at least one peak selected from 21.3, 27.4, 42.1, 50.6, 57.0, 114.7, 119.9, 121.1, 176.4 and 176.8 ± 0.20 ppm, 13 The crystalline form according to item 15, characterized by a 13C ssNMR spectrum. (Item 20) At least three peaks selected from the following, represented as chemical shifts in ppm: 21.3, 27.4, 42.1, 50.6, 57.0, 114.7, 119.9, 121.1, 176.4 and 176.8 ± 0.20 ppm, 13 The crystalline form according to item 15, characterized by a 13 C ssNMR spectrum. (Item 21) At least six peaks selected from the following, represented as chemical shifts in ppm: 21.3, 27.4, 42.1, 50.6, 57.0, 114.7, 119.9, 121.1, 176.4 and 176.8 ± 0.20 ppm, 13 The crystalline form according to item 15, characterized by a 13 C ssNMR spectrum. (Item 22) The crystalline form of metopimazine mesylate, characterized by a differential scanning calorimetry pattern including a single endotherm with a starting temperature range of 208°C to 212°C. (Item 23) The crystalline form according to item 22, wherein the single endotherm includes a starting temperature range of 208°C to 211°C. (Item 24) The crystalline form according to item 22, wherein the single endotherm includes a starting temperature range of 209°C to 210°C. (Item 25) The crystalline form according to any one of items 22 to 24, wherein the single endotherm includes a peak temperature range of 213°C to 214°C. (Item 26) The crystalline form according to any one of items 22 to 25, wherein the single endotherm includes a transition enthalpy of 95 to 100 J / g. (Item 27) The crystalline form according to item 26, wherein the single endotherm includes a transition enthalpy of 96 to 98 J / g. (Item 28) The crystalline form according to item 26, wherein the single endotherm includes a transition enthalpy of 97 to 98 J / g. (Item 29) The crystalline form of metopimazine mesylate, characterized by a thermogravimetric analysis profile including a total weight loss of 0.4% up to 150.0°C. (Item 30) The composition according to any one of Items 6 to 29, which comprises less than 10% by weight of other crystal forms of metopimazine mesylate and contains the crystal form described therein. (Item 31) The composition according to Item 30, which comprises less than 1% by weight of other crystal forms of metopimazine mesylate. (Item 32) The composition according to Item 30 or 31, which comprises less than 10% by weight of the amorphous form of metopimazine mesylate. (Item 33) The composition according to Item 32, which comprises less than 1% by weight of the amorphous form of metopimazine mesylate. (Item 34) A pharmaceutical composition comprising the crystal form according to any one of Items 1 to 33 and a pharmaceutically acceptable excipient. (Item 35) The pharmaceutical composition according to Item 34, which is suitable for administration orally, intraduodenally, intracolonically, enterally, topically, nasally, parenterally, buccally, sublingually, by inhalation or rectally. (Item 36) The pharmaceutical composition according to Item 35, which is suitable for oral administration. (Item 37) The pharmaceutical composition according to Item 35, which is suitable for sublingual administration. (Item 38) The pharmaceutical composition according to any one of Items 34 to 37, which is formulated as a tablet, capsule, paste, powder, suspension, suppository, sustained release preparation or release control preparation. (Item 39) The pharmaceutical composition according to Item 38, which is formulated as a sustained release preparation. (Item 40) The pharmaceutical composition according to Item 38, which is formulated as a capsule. (Item 41) The pharmaceutical composition according to any one of items 34 to 40, wherein the composition contains 5 mg of the crystalline form of metopimazine mesylate. (Item 42) The pharmaceutical composition according to any one of items 34 to 40, wherein the composition contains 10 mg of the crystalline form of metopimazine mesylate. (Item 43) The pharmaceutical composition according to any one of items 34 to 40, wherein the composition contains 20 mg of the crystalline form of metopimazine mesylate. (Item 44) The pharmaceutical composition according to any one of items 34 to 43, wherein the composition is preferably administered once a day. (Item 45) The pharmaceutical composition according to any one of items 34 to 43, wherein the composition is preferably administered twice a day. (Item 46) The pharmaceutical composition according to any one of items 34 to 43, wherein the composition is preferably administered three times a day. (Item 47) The pharmaceutical composition according to any one of items 34 to 43, wherein the composition is preferably administered four times a day. (Item 48) The pharmaceutical composition according to any one of items 34 to 47, wherein the crystalline form of metopimazine mesylate between about 5 mg and about 160 mg per day is administered. (Item 49) The pharmaceutical composition according to any one of items 34 to 47, wherein the composition is suitable for administering a crystalline form of metopimazine mesylate exceeding 20 mg per day. (Item 50) A method for treating an enteric nervous system disorder in a human subject in need thereof, the method comprising the step of administering to the subject a pharmaceutical composition according to any one of items 34 to 49. (Item 51) The method according to item 50, wherein the enteric nervous system disorder is a chronic disorder. (Item 52) The method according to item 50, wherein the enteric nervous system disorder is an acute disorder. (Item 53) The method according to item 50, wherein the enteric nervous system disorder is selected from the group consisting of gastroparesis, irritable bowel syndrome, lysosomal storage disease, intestinal motility disorder, ganglioneuroma, multiple endocrine neoplasia type 2B (MEN2B), gastrointestinal neuropathy, functional dyspepsia, gastroesophageal reflux disease (GERD), and enteric neurogenic anomaly. (Item 54) The method according to any one of items 50 to 53, wherein the enteric nervous system disorder includes symptoms selected from the group consisting of early satiety, postprandial fullness, abdominal fullness, nausea, vomiting, delayed gastric emptying, diarrhea, abdominal pain, flatulence, abdominal distension, gastroesophageal reflux, anorexia, and constipation. (Item 55) The method according to item 54, wherein the symptom of the enteric nervous system disorder includes nausea. (Item 56) The method according to item 54, wherein the symptom of the enteric nervous system disorder includes vomiting. (Item 57) A method for treating gastroparesis in a human subject in need thereof, comprising the step of administering to the subject the pharmaceutical composition according to any one of items 34 to 49. (Item 58) The method according to item 57, wherein the gastroparesis is diabetic gastroparesis. (Item 59) The method according to item 57, wherein the gastroparesis is idiopathic gastroparesis. (Item 60) The method according to any one of items 57 to 59, wherein the gastroparesis includes symptoms selected from the group consisting of early satiety, postprandial fullness, abdominal fullness, nausea, vomiting, delayed gastric emptying, diarrhea, abdominal pain, flatulence, abdominal distension, gastroesophageal reflux, anorexia, and constipation. (Item 61) The method according to item 60, wherein the symptom of the gastroparesis includes nausea. (Item 62) The method according to item 60, wherein the symptom of the gastroparesis includes vomiting. (Item 63) A method for treating nausea associated with gastric paresis in a human subject in need thereof, the method comprising the step of administering to the subject a pharmaceutical composition according to any one of items 34 to 49. (Item 64) A method for treating vomiting associated with gastric paresis in a human subject in need thereof, the method comprising the step of administering to the subject a pharmaceutical composition according to any one of items 34 to 49. (Item 65) A method for improving gastric emptying in a human subject in need thereof, the method comprising the step of administering to the subject a pharmaceutical composition according to any one of items 34 to 49. (Item 66) A method for treating functional and motility disorders of the GI tract in a human subject in need thereof, the method comprising the step of administering to the subject a pharmaceutical composition according to any one of items 34 to 49. (Item 67) The method according to any one of items 50 to 66, wherein the pharmaceutical composition is administered to the subject for a long period of time. (Item 68) The method according to any one of items 50 to 66, wherein the pharmaceutical composition is administered to the subject for a short period of time. (Item 69) The method according to any one of items 50 to 66, wherein the pharmaceutical composition is administered to the subject for at least 6 days. (Item 70) The method according to item 69, wherein the pharmaceutical composition is administered to the subject for at least 7 days. (Item 71) The method according to item 69, wherein the pharmaceutical composition is administered to the subject for at least 4 weeks. (Item 72) The method according to item 69, wherein the pharmaceutical composition is administered to the subject for at least 12 weeks. (Item 73) The method according to any one of items 50 to 72, wherein the pharmaceutical composition is administered to the subject once a day. (Item 74) The method according to any one of items 50 to 72, wherein the pharmaceutical composition is administered to the subject twice a day. (Item 75) The method according to any one of items 50 to 72, wherein the pharmaceutical composition is administered to the subject three times a day. (Item 76) The method according to any one of items 50 to 72, wherein the pharmaceutical composition is administered to the subject four times a day. (Item 77) The method according to any one of items 50 to 76, wherein about 5 mg to about 160 mg of the metopimazine mesylate is administered to the subject per day. (Item 78) The method according to any one of items 50 to 76, wherein more than 20 mg of the metopimazine mesylate is administered to the subject per day.

Brief Description of the Drawings

[0030]

Figure 1

[0031]

Figure 2

[0032]

Figure 3

[0033]

Figure 4

[0034]

Figure 5

[0035]

Figure 6

[0036]

Figure 7

[0037]

Figure 8

[0038] Detailed description of the present application The present application provides **Chemical formula** crystalline forms of [chemical compound].

[0039] In certain embodiments of the present application, the crystalline form of metopimazine mesylate comprises less than 10% by weight of other crystalline forms, such as less than 5% by weight, less than 4% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.1% by weight or less than 0.01% by weight of other crystalline forms.

[0040] In certain embodiments of the present application, the crystalline form of metopimazine mesylate comprises less than 10% by weight of amorphous forms, such as less than 5% by weight, less than 4% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.1% by weight or less than 0.01% by weight of amorphous forms.

[0041] In certain embodiments of the present application, the crystalline form of metopimazine mesylate comprises less than 10% by weight of other forms (e.g., other crystalline forms of metopimazine mesylate or other amorphous forms of metopimazine mesylate), for example, less than 5% by weight, less than 4% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.1% by weight, or less than 0.01% by weight of other forms (e.g., other crystalline forms of metopimazine mesylate or other amorphous forms of metopimazine mesylate).

[0042] In certain embodiments of the present application, the crystalline form of metopimazine mesylate is in the non-solvate form. In certain such embodiments of the present application, the crystalline form of metopimazine mesylate comprises less than 10% by weight of the solvate form, for example, less than 5% by weight, less than 4% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.1% by weight, or less than 0.01% by weight of the solvate form.

[0043] In certain embodiments of the present application, the crystalline form of metopimazine mesylate is in the anhydrous form. In certain such embodiments, the crystalline form of metopimazine mesylate comprises from about 10% to about 100% of metopimazine mesylate anhydrate. For example, the crystalline form of metopimazine mesylate comprises about 10% of metopimazine mesylate anhydrate, about 20% of metopimazine mesylate anhydrate, about 30% of metopimazine mesylate anhydrate, about 40% of metopimazine mesylate anhydrate, about 50% of metopimazine mesylate anhydrate, about 60% of metopimazine mesylate anhydrate, about 70% of metopimazine mesylate anhydrate, about 80% of metopimazine mesylate anhydrate, about 90% of metopimazine mesylate anhydrate, or about 95% of metopimazine mesylate anhydrate. In certain such embodiments of the present application, the crystalline form of metopimazine mesylate comprises less than 10% by weight of the hydrate form, for example, less than 5% by weight, less than 4% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.1% by weight, or less than 0.01% by weight of the hydrate form.

[0044] In certain embodiments of the present application, the crystalline form of metopimazine mesylate is a solvate form such as a hydrate form (e.g., monohydrate form). In certain such embodiments, the crystalline form of metopimazine mesylate comprises from about 10% to about 100% of metopimazine mesylate monohydrate. For example, the crystalline form of metopimazine mesylate comprises about 10% of metopimazine mesylate monohydrate, about 20% of anhydrous metopimazine mesylate, about 30% of metopimazine mesylate monohydrate, about 40% of metopimazine mesylate monohydrate, about 50% of metopimazine mesylate monohydrate, about 60% of metopimazine mesylate monohydrate, about 70% of metopimazine mesylate monohydrate, about 80% of metopimazine mesylate monohydrate, about 90% of metopimazine mesylate monohydrate or about 95% of metopimazine mesylate monohydrate. In certain such embodiments of the present application, the crystalline form of metopimazine mesylate comprises less than 10 wt% of other solvate forms or non-solvate forms, e.g., 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 non-solvate forms.

[0045] The present application provides a crystalline form A of metopimazine mesylate, characterized by an X-ray powder diffraction (XRPD) pattern comprising one or more of the 2-theta (2θ) values presented in Table 1. The diffraction pattern was recorded using Cu, Kα irradiation. [Chemical formula] [Table 1-1] [Table 1-2]

[0046] In certain embodiments, crystalline Form A of metopimazine mesylate is characterized by an XRPD pattern comprising at least two 2θ values selected from those listed in Table 1. In certain embodiments, crystalline Form A of metopimazine mesylate 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 listed in Table 1. In certain embodiments, crystalline Form A of metopimazine mesylate is characterized by one or more 2θ values in the 2θ range of about 5 to about 25° in Table 1. In certain embodiments, crystalline Form A of metopimazine mesylate is characterized by at least two 2θ values in the 2θ range of about 5 to about 25° in Table 1. In certain embodiments, crystalline Form A of metopimazine mesylate 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 2θ range of about 5 to about 25° in Table 1. In certain embodiments, crystalline Form A of metopimazine mesylate is characterized by an XRPD pattern comprising 2θ values selected from those listed 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 for various reasons, including preferred orientation. It will also be understood by those skilled in the art that even smaller shifts in the measurement angle, and thus the d-spacing, can occur for various reasons, including variations in the sample surface level in the diffractometer. It is further understood by those skilled in the art that the 2θ degrees presented in Table 1 are generally reproducible within a range of about ±0.10 2θ degrees to about ±0.20 2θ degrees, with a preferred range of about ±0.10 2θ degrees. See, for example, U.S. Pharmacopeia XXV (2002), p. 2088-2089.

[0047] In certain embodiments, crystalline Form A of metopimazine 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°, 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, crystalline Form A of metopimazine 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, crystalline Form A of metopimazine 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, crystalline Form A of metopimazine 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° ± 0.1°.In certain embodiments, crystalline Form A of metopimazine 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°. In certain embodiments, crystalline Form A of metopimazine 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° ± 0.1°. In certain embodiments, crystalline Form A of metopimazine 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° ± 0.10 - 0.20(2θ). In certain embodiments, crystalline Form A of metopimazine mesylate 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, crystalline Form A of metopimazine 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° ± 0.10 - 0.20(2θ). In certain embodiments, crystalline Form A of metopimazine mesylate 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, crystalline Form A of metopimazine mesylate 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 to 0.20 (2θ).

[0048] In certain embodiments, crystalline Form A of metopimazine mesylate is characterized by an XRPD pattern comprising a peak at the following 2θ value 18.75° ± 0.10 to 0.20 (2θ). In certain embodiments, crystalline Form A of metopimazine mesylate is characterized by an XRPD pattern comprising peaks at the following 2θ values 15.91° and 18.75° ± 0.10 to 0.20 (2θ). In certain embodiments, crystalline Form A of metopimazine mesylate is characterized by an XRPD pattern comprising peaks at the following 2θ values 15.91°, 18.75°, and 24.44° ± 0.10 to 0.20 (2θ). In certain embodiments, crystalline Form A of metopimazine mesylate is characterized by an XRPD pattern comprising peaks at the following 2θ values 15.91°, 18.75°, 21.22°, and 24.44° ± 0.10 to 0.20 (2θ). In certain embodiments, crystalline Form A of metopimazine mesylate 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 to 0.20 (2θ). In certain embodiments, crystalline Form A of metopimazine mesylate 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 to 0.20 (2θ).

[0049] This application provides crystalline Form A of metopimazine mesylate, characterized by an XRPD pattern comprising at least two D-spacing values selected from those listed in Table 1. In certain embodiments, crystalline Form A of metopimazine mesylate is characterized by an XRPD pattern comprising at least three, at least four, at least five, or at least six D-spacing values selected from those listed in Table 1. In certain embodiments, crystalline Form A of metopimazine mesylate is characterized by an XRPD pattern comprising D-spacing values selected from those listed in Table 1.

[0050] In certain embodiments, crystalline Form A of metopimazine mesylate is characterized by the XRPD pattern listed in Table 1. In certain embodiments, crystalline Form A of metopimazine mesylate exhibits the XRPD pattern shown in Figure 1.

[0051] This application provides crystalline Form A of metopimazine mesylate, characterized by a 13C solid state nuclear magnetic resonance (ssNMR) spectrum comprising one or more peaks represented as chemical shifts in ppm as presented in Table 2. The spectrum 13 was obtained on a Bruker NEO spectrometer operating at 100.52 MHz for 13C and 13 399.71 MHz for 1H, or 1 at 100.46 MHz for 13C and 13 399.49 MHz for 1H. 1

Table 2

[0052] In certain embodiments, crystalline Form A of metopimazine mesylate comprises 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 selected from those listed in Table 2, represented as chemical shifts in ppm. 13Characterized by a C ssNMR spectrum. In certain embodiments, crystalline Form A of metopimazine mesylate comprises peaks selected from those set forth in Table 2, represented as chemical shifts in ppm units 13 Characterized by a C ssNMR spectrum. Including the appearance, intensity, and position of peaks in the spectrum 13 Those skilled in the art will understand that the C ssNMR spectrum can vary between different samples, different sample preparations, and different conditions for obtaining the spectrum. Accordingly, the peaks presented in Table 2, represented as chemical shifts in ppm units, are generally reproducible within a range of about ±0.10 ppm to about ±0.20 ppm, and a preferred range is about ±0.20 ppm as will be understood by those skilled in the art. In certain embodiments, crystalline Form A of metopimazine mesylate is as set forth in Table 2 13 Characterized by a C ssNMR spectrum. In certain embodiments, crystalline Form A of metopimazine mesylate having a purity of at least 90%, at least 95% or at least 99% is as set forth in Figure 6 13 Exhibits a C ssNMR spectrum

[0053] In certain embodiments, crystalline Form A of metopimazine mesylate comprises the following peaks, represented as chemical shifts in ppm units: 176.8 ± 0.10 to 0.20 ppm 13 Characterized by a C ssNMR spectrum. In certain embodiments, crystalline Form A of metopimazine mesylate comprises the following peaks, represented as chemical shifts in ppm units: 176.4 ± 0.10 to 0.20 ppm 13 Characterized by a C ssNMR spectrum. In certain embodiments, crystalline Form A of metopimazine mesylate comprises one or more of the following peaks, represented as chemical shifts in ppm units: 176.8 and 176.4 ± 0.10 to 0.20 ppm 13Characterized by a C ssNMR spectrum. In certain embodiments, crystalline Form A of metopimazine mesylate comprises the following peaks, expressed as chemical shifts in ppm: 176.8 and 176.4 ± 0.10 to 0.20 ppm 13 Characterized by a C ssNMR spectrum. In certain embodiments, crystalline Form A of metopimazine mesylate comprises the following peak, expressed as a chemical shift in ppm: 42.1 ± 0.10 to 0.20 ppm 13 Characterized by a C ssNMR spectrum. In certain embodiments, crystalline Form A of metopimazine mesylate comprises one or more, or two or more, or the following peaks, expressed as chemical shifts in ppm: 42.1, 176.4, and 176.8 ± 0.10 to 0.20 ppm 13 Characterized by a C ssNMR spectrum. In certain embodiments, crystalline Form A of metopimazine mesylate comprises the following peaks, expressed as chemical shifts in ppm: 42.1, 176.4, and 176.8 ± 0.10 to 0.20 ppm 13 Characterized by a C ssNMR spectrum. In certain embodiments, crystalline Form A of metopimazine mesylate comprises the following peak, expressed as a chemical shift in ppm: 57.0 ± 0.10 to 0.20 ppm 13 Characterized by a C ssNMR spectrum. In certain embodiments, crystalline Form A of metopimazine mesylate comprises one or more, two or more, or three or more of the following peaks, expressed as chemical shifts in ppm: 42.1, 57.0, 176.4, and 176.8 ± 0.10 to 0.20 ppm 13 Characterized by a C ssNMR spectrum. In certain embodiments, crystalline Form A of metopimazine mesylate comprises the following peaks, expressed as chemical shifts in ppm: 42.1, 57.0, 176.4, and 176.8 ± 0.10 to 0.20 ppm 13Characterized by a C ssNMR spectrum. In certain embodiments, crystalline Form A of metopimazine mesylate comprises the following peaks, expressed as chemical shifts in ppm: 27.4 ± 0.10 to 0.20 ppm 13 Characterized by a C ssNMR spectrum. In certain embodiments, crystalline Form A of metopimazine mesylate comprises one or more, two or more, three or more, or four or more of the following peaks, expressed as chemical shifts in ppm: 27.4, 42.1, 57.0, 176.4, and 176.8 ± 0.10 to 0.20 ppm 13 Characterized by a C ssNMR spectrum. In certain embodiments, crystalline Form A of metopimazine mesylate comprises the following peaks, expressed as chemical shifts in ppm: 27.4, 42.1, 57.0, 176.4, and 176.8 ± 0.10 to 0.20 ppm 13 Characterized by a C ssNMR spectrum. In certain embodiments, crystalline Form A of metopimazine mesylate comprises the following peak, expressed as a chemical shift in ppm: 121.1 ± 0.10 to 0.20 ppm 13 Characterized by a C ssNMR spectrum. In certain embodiments, crystalline Form A of metopimazine mesylate comprises one or more, two or more, three or more, four or more, or five or more of the following peaks, expressed as chemical shifts in ppm: 27.4, 42.1, 57.0, 121.1, 176.4, and 176.8 ± 0.10 to 0.20 ppm 13 Characterized by a C ssNMR spectrum. In certain embodiments, crystalline Form A of metopimazine mesylate comprises the following peaks, expressed as chemical shifts in ppm: 27.4, 42.1, 57.0, 121.1, 176.4, and 176.8 ± 0.10 to 0.20 ppm 13 Characterized by a C ssNMR spectrum. In certain embodiments, crystalline Form A of metopimazine mesylate comprises the following peak, expressed as a chemical shift in ppm: 21.3 ± 0.10 to 0.20 ppm 13Characterized by a C ssNMR spectrum. In certain embodiments, crystalline Form A of metopimazine mesylate comprises one or more, two or more, three or more, four or more, five or more, or six or more of the following peaks, expressed as chemical shifts in ppm: 21.3, 27.4, 42.1, 57.0, 121.1, 176.4, and 176.8 ± 0.10 to 0.20 ppm 13 Characterized by a C ssNMR spectrum. In certain embodiments, crystalline Form A of metopimazine mesylate comprises the following peaks, expressed as chemical shifts in ppm: 21.3, 27.4, 42.1, 57.0, 121.1, 176.4, and 176.8 ± 0.10 to 0.20 ppm 13 Characterized by a C ssNMR spectrum. In certain embodiments, crystalline Form A of metopimazine mesylate comprises the following peak, expressed as a chemical shift in ppm: 50.6 ± 0.10 to 0.20 ppm 13 Characterized by a C ssNMR spectrum. In certain embodiments, crystalline Form A of metopimazine mesylate comprises one or more, two or more, three or more, four or more, five or more, six or more, or seven or more of the following peaks, expressed as chemical shifts in ppm: 21.3, 27.4, 42.1, 50.6, 57.0, 121.1, 176.4, and 176.8 ± 0.10 to 0.20 ppm 13 Characterized by a C ssNMR spectrum. In certain embodiments, crystalline Form A of metopimazine mesylate comprises the following peaks, expressed as chemical shifts in ppm: 21.3, 27.4, 42.1, 50.6, 57.0, 121.1, 176.4, and 176.8 ± 0.10 to 0.20 ppm 13 C Characterized by an ssNMR spectrum. In certain embodiments, crystalline Form A of metopimazine mesylate comprises the following peak, expressed as a chemical shift in ppm: 114.7 ± 0.10 to 0.20 ppm 13Characterized by a C ssNMR spectrum. In certain embodiments, crystalline Form A of metopimazine mesylate comprises 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 of the following peaks, expressed as chemical shifts in ppm: 21.3, 27.4, 42.1, 50.6, 57.0, 114.7, 121.1, 176.4, and 176.8 ± 0.10 to 0.20 ppm 13 Characterized by a C ssNMR spectrum. In certain embodiments, crystalline Form A of metopimazine mesylate comprises the following peaks, expressed as chemical shifts in ppm: 21.3, 27.4, 42.1, 50.6, 57.0, 114.7, 121.1, 176.4, and 176.8 ± 0.10 to 0.20 ppm 13 Characterized by a C ssNMR spectrum. In certain embodiments, crystalline Form A of metopimazine mesylate comprises the following peak, expressed as a chemical shift in ppm: 119.9 ± 0.10 to 0.20 ppm 13 Characterized by a C ssNMR spectrum. In certain embodiments, crystalline Form A of metopimazine mesylate comprises 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 of the following peaks, expressed as chemical shifts in ppm: 21.3, 27.4, 42.1, 50.6, 57.0, 114.7, 119.9, 121.1, 176.4, and 176.8 ± 0.10 to 0.20 ppm 13 Characterized by a C ssNMR spectrum. In certain embodiments, crystalline Form A of metopimazine mesylate comprises the following peaks, expressed as chemical shifts in ppm: 21.3, 27.4, 42.1, 50.6, 57.0, 114.7, 119.9, 121.1, 176.4, and 176.8 ± 0.10 to 0.20 ppm 13 Characterized by a C ssNMR spectrum.

[0054] In certain embodiments, crystalline Form A of metopimazine mesylate is characterized by a differential scanning calorimetry (DSC) pattern that includes a single endotherm in a starting temperature range of 208°C to 212°C or 208°C to 211°C, such as 209°C to 210°C (e.g., 209.9°C). In certain embodiments, crystalline Form A of metopimazine mesylate is characterized by a DSC pattern that includes a single endotherm in a peak temperature range of 213°C to 214°C (e.g., 213.1°C). It will be understood by those skilled in the art that the endotherms described above and shown in Figure 3 are typically reproducible within a range of ±0.5 to 3°C, such as ±2°C, ±1°C or ±0.5°C. In certain embodiments, crystalline Form A of metopimazine mesylate is characterized by a DSC pattern that includes a single endotherm with a transition enthalpy of 95 to 100 J / g (e.g., 97.47 J / g), such as 96 to 98 J / g, 97 to 98 J / g or 97.5 J / g. In certain embodiments, crystalline Form A of metopimazine mesylate is characterized by the DSC pattern described in Figure 3.

[0055] In certain embodiments, crystalline Form A of metopimazine mesylate is characterized by a thermogravimetric analysis (TGA) profile with a total weight loss of 0.4% (e.g., 0.42%) up to 150.0°C. In certain embodiments, crystalline Form A of metopimazine mesylate is characterized by the TGA profile described in Figure 2.

[0056] In certain embodiments of the present application, crystalline Form A of metopimazine mesylate comprises less than 10 wt% of other crystalline forms (e.g., crystalline Form B of metopimazine mesylate hydrate), 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., crystalline Form B of metopimazine mesylate hydrate).

[0057] In certain embodiments of the present application, crystalline Form A of metopimazine mesylate comprises less than 10% by weight of the amorphous form, for example, less than 5% by weight, less than 4% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.1% by weight or less than 0.01% by weight of the amorphous form.

[0058] In certain embodiments of the present application, crystalline Form A of metopimazine mesylate comprises less than 10% by weight of other forms (e.g., other crystalline forms of metopimazine mesylate such as crystalline Form B of metopimazine mesylate or other amorphous forms of metopimazine mesylate), for example, less than 5% by weight, less than 4% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.1% by weight or less than 0.01% by weight of other forms (e.g., other crystalline forms of metopimazine mesylate such as crystalline Form B of metopimazine mesylate or other amorphous forms of metopimazine mesylate).

[0059] In certain embodiments of the present application, crystalline Form A of metopimazine mesylate is in the non-solvate form. In certain such embodiments of the present application, crystalline Form A of metopimazine mesylate comprises less than 10% by weight of the solvate, for example, less than 5% by weight, less than 4% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.1% by weight or less than 0.01% by weight of the solvate.

[0060] In certain embodiments of the present application, crystalline Form A of metopimazine mesylate is in the non-hydrate form. In certain such embodiments of the present application, crystalline Form A of metopimazine mesylate comprises less than 10% by weight of the hydrate form, for example, less than 5% by weight, less than 4% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.1% by weight or less than 0.01% by weight of the hydrate form.

[0061] The present application features crystalline Form B of metopimazine mesylate hydrate having an XRPD pattern comprising one or more 2θ values selected from those listed in Table 3

Chemical formula

[0062] In certain embodiments, crystalline Form B of metopimazine mesylate is characterized by an XRPD pattern comprising at least two 2θ values selected from those listed in Table 3. In certain embodiments, crystalline Form B of metopimazine mesylate 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 listed in Table 3. In certain embodiments, crystalline Form B of metopimazine mesylate is characterized by one or more 2θ values in the 2θ range of about 5 to about 25° in Table 3. In certain embodiments, crystalline Form B of metopimazine mesylate is characterized by at least two 2θ values in the 2θ range of about 5 to about 25° in Table 3. In certain embodiments, crystalline Form B of metopimazine mesylate 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 2θ range of about 5 to about 25° in Table 3. In certain embodiments, crystalline Form B of metopimazine mesylate hydrate is characterized by an XRPD pattern comprising 2θ values selected from those listed in Table 3. It is further understood by those skilled in the art that the 2θ degrees presented in Table 3 are generally reproducible within a range of about ±0.10 2θ degrees to about ±0.20 2θ degrees, and the preferred range is about ±0.10 2θ degrees. See, for example, United States Pharmacopoeia XXV (2002), p. 2088-2089.

[0063] In certain embodiments, crystalline Form B of metopimazine mesylate is characterized by an XRPD pattern that includes 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 to 0.20 (2θ). In certain embodiments, crystalline Form B of metopimazine mesylate is characterized by an XRPD pattern that includes 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 to 0.20 (2θ). In certain embodiments, crystalline Form B of metopimazine mesylate is characterized by an XRPD pattern that includes 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 to 0.20 (2θ). In certain embodiments, crystalline Form B of metopimazine mesylate is characterized by an XRPD pattern that includes 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 to 0.20 (2θ). In certain embodiments, crystalline Form B of metopimazine mesylate is characterized by an XRPD pattern that includes 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 to 0.20 (2θ).

[0064] In certain embodiments, crystalline Form B of metopimazine mesylate is characterized by an XRPD pattern that includes peaks at the following 2θ values: 16.90° ± 0.10 to 0.20 (2θ). In certain embodiments, crystalline Form B of metopimazine mesylate is characterized by an XRPD pattern that includes peaks at the following 2θ values: 16.90° and 20.00° ± 0.10 to 0.20 (2θ). In certain embodiments, crystalline Form B of metopimazine mesylate is characterized by an XRPD pattern that includes peaks at the following 2θ values: 16.30°, 16.90° and 20.00° ± 0.10 to 0.20 (2θ). In certain embodiments, crystalline Form B of metopimazine mesylate is characterized by an XRPD pattern that includes peaks at the following 2θ values: 11.12°, 16.30°, 16.90° and 20.00° ± 0.10 to 0.20 (2θ). In certain embodiments, crystalline Form B of metopimazine mesylate is characterized by an XRPD pattern that includes peaks at the following 2θ values: 10.71°, 16.30°, 16.90° and 20.00° ± 0.10 to 0.20 (2θ). In certain embodiments, crystalline Form B of metopimazine mesylate is characterized by an XRPD pattern that includes peaks at the following 2θ values: 16.30°, 16.90°, 17.89° and 20.00° ± 0.10 to 0.20 (2θ). In certain embodiments, crystalline Form B of metopimazine mesylate is characterized by an XRPD pattern that includes peaks at the following 2θ values: 16.30°, 16.90°, 20.00° and 27.12° ± 0.10 to 0.20 (2θ). In certain embodiments, crystalline Form B of metopimazine mesylate is characterized by an XRPD pattern that includes peaks at the following 2θ values: 10.71°, 11.12°, 16.30°, 16.90° and 20.00° ± 0.10 to 0.20 (2θ). In certain embodiments, crystalline Form B of metopimazine mesylate is characterized by an XRPD pattern that includes peaks at the following 2θ values: 10.71°, 11.12°, 16.30°, 16.90°, 17.89°, 20.00° and 27.12° ± 0.10 to 0.20 (2θ).

[0065] This application provides crystalline Form B of metopimazine mesylate hydrate, characterized by an XRPD pattern comprising at least two D-spacing values selected from those listed in Table 3. In certain embodiments, crystalline Form B of metopimazine mesylate hydrate is characterized by an XRPD pattern comprising at least three, at least four, at least five, or at least six D-spacing values selected from those listed in Table 3. In certain embodiments, crystalline Form B of metopimazine mesylate hydrate is characterized by an XRPD pattern comprising D-spacing values selected from those listed in Table 3.

[0066] In certain embodiments, crystalline Form B of metopimazine mesylate hydrate is characterized by the XRPD pattern listed in Table 3.

[0067] This application provides crystalline Form B of metopimazine mesylate, characterized by a 13C solid state NMR (ssNMR) spectrum comprising one or more peaks expressed as chemical shifts in ppm as presented in Table 4. The spectrum was obtained 13 using a Bruker NEO spectrometer operating at 100.52 MHz for 13C and 13 399.71 MHz for 1H, or 1 100.46 MHz for 13C and 13 399.49 MHz for 1H. 1 The spectrum was obtained using a Bruker NEO spectrometer operating at 100.46 MHz for 13C and 399.49 MHz for 1H. [Table 4-1] [Table 4-2]

[0068] In certain embodiments, crystalline Form B of metopimazine mesylate is characterized by a 13C solid state NMR (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 selected from those listed in Table 4 and expressed as chemical shifts in ppm.13 It is characterized by a C ssNMR spectrum. In certain embodiments, crystalline Form B of metopimazine mesylate comprises peaks selected from those set forth in Table 4, represented as chemical shifts in ppm units 13 It is characterized by a C ssNMR spectrum. Including the appearance, intensity and position of peaks in the spectrum 13 Those skilled in the art will understand that the C ssNMR spectrum can vary between different samples, different sample preparations, and different conditions for obtaining the spectrum. Thus, the peaks presented in Table 4, represented as chemical shifts in ppm units, are generally reproducible within a range of about ±0.10 ppm to about ±0.20 ppm, and the preferred range is understood by those skilled in the art to be about ±0.20 ppm. In certain embodiments, crystalline Form B of metopimazine mesylate is as described in Table 4 13 It is characterized by a C ssNMR spectrum. In certain embodiments, crystalline Form B of metopimazine mesylate is as described in FIG. 7 or FIG. 8 13 It shows a C ssNMR spectrum. In certain embodiments, crystalline Form B of metopimazine mesylate having a purity of at least 90%, at least 95% or at least 99% is as described in FIG. 8 13 It shows a C ssNMR spectrum

[0069] In certain embodiments, crystalline Form B of metopimazine mesylate comprises the following peaks, represented as chemical shifts in ppm units: 180.2 ± 0.10 to 0.20 ppm 13 It is characterized by a C ssNMR spectrum. In certain embodiments, crystalline Form B of metopimazine mesylate comprises the following peaks, represented as chemical shifts in ppm units: 177.7 ± 0.10 to 0.20 ppm 13 It is characterized by a C ssNMR spectrum. In certain embodiments, crystalline Form B of metopimazine mesylate comprises one or more of the following peaks, represented as chemical shifts in ppm units: 177.7 and 180.2 ± 0.10 to 0.20 ppm 13Characterized by a C ssNMR spectrum. In certain embodiments, crystalline Form B of metopimazine mesylate comprises the following peaks, expressed as chemical shifts in ppm: 177.7 and 180.2 ± 0.10 to 0.20 ppm 13 Characterized by a C ssNMR spectrum. In certain embodiments, crystalline Form B of metopimazine mesylate comprises the following peak, expressed as a chemical shift in ppm: 136.1 ± 0.10 to 0.20 ppm 13 Characterized by a C ssNMR spectrum. In certain embodiments, crystalline Form B of metopimazine mesylate comprises one or more, or two or more, of the following peaks, expressed as chemical shifts in ppm: 136.1, 177.7, and 180.2 ± 0.10 to 0.20 ppm 13 Characterized by a C ssNMR spectrum. In certain embodiments, crystalline Form B of metopimazine mesylate comprises the following peaks, expressed as chemical shifts in ppm: 136.1, 177.7, and 180.2 ± 0.10 to 0.20 ppm 13 Characterized by a C ssNMR spectrum. In certain embodiments, crystalline Form B of metopimazine mesylate comprises the following peak, expressed as a chemical shift in ppm: 149.0 ± 0.10 to 0.20 ppm 13 Characterized by a C ssNMR spectrum. In certain embodiments, crystalline Form B of metopimazine mesylate comprises one or more, two or more, or three or more of the following peaks, expressed as chemical shifts in ppm: 136.1, 149.0, 177.7, and 180.2 ± 0.10 to 0.20 ppm 13 Characterized by a C ssNMR spectrum. In certain embodiments, crystalline Form B of metopimazine mesylate comprises the following peaks, expressed as chemical shifts in ppm: 136.1, 149.0, 177.7, and 180.2 ± 0.10 to 0.20 ppm 13Characterized by 13C ssNMR spectrum. In certain embodiments, crystalline Form B of metopimazine mesylate comprises the following peaks, expressed as chemical shifts in ppm: 39.4 ± 0.10 to 0.20 ppm 13 Characterized by 13C ssNMR spectrum. In certain embodiments, crystalline Form B of metopimazine mesylate comprises one or more, two or more, three or more, or four or more of the following peaks, expressed as chemical shifts in ppm: 39.4, 136.1, 149.0, 177.7, and 180.2 ± 0.10 to 0.20 ppm 13 Characterized by 13C ssNMR spectrum. In certain embodiments, crystalline Form B of metopimazine mesylate comprises the following peaks, expressed as chemical shifts in ppm: 39.4, 136.1, 149.0, 177.7, and 180.2 ± 0.10 to 0.20 ppm 13 Characterized by 13C ssNMR spectrum. In certain embodiments, crystalline Form B of metopimazine mesylate comprises the following peaks, expressed as chemical shifts in ppm: 45.2 ± 0.10 to 0.20 ppm 13 Characterized by 13C ssNMR spectrum. In certain embodiments, crystalline Form B of metopimazine mesylate comprises one or more, two or more, three or more, four or more, or five or more of the following peaks, expressed as chemical shifts in ppm: 39.4, 45.2, 136.1, 149.0, 177.7, and 180.2 ± 0.10 to 0.20 ppm 13 Characterized by 13C ssNMR spectrum. In certain embodiments, crystalline Form B of metopimazine mesylate comprises the following peaks, expressed as chemical shifts in ppm: 39.4, 45.2, 136.1, 149.0, 177.7, and 180.2 ± 0.10 to 0.20 ppm 13 Characterized by 13C ssNMR spectrum. In certain embodiments, crystalline Form B of metopimazine mesylate comprises the following peaks, expressed as chemical shifts in ppm: 132.3 ± 0.10 to 0.20 ppm13 It is characterized by a C ssNMR spectrum. In certain embodiments, crystalline Form B of metopimazine mesylate comprises one or more, two or more, three or more, four or more, five or more, or six or more of the following peaks, expressed as chemical shifts in ppm: 39.4, 45.2, 132.3, 136.1, 149.0, 177.7, and 180.2 ± 0.10 to 0.20 ppm 13 It is characterized by a C ssNMR spectrum. In certain embodiments, crystalline Form B of metopimazine mesylate comprises the following peaks, expressed as chemical shifts in ppm: 39.4, 45.2, 132.3, 136.1, 149.0, 177.7, and 180.2 ± 0.10 to 0.20 ppm 13 It is characterized by a C ssNMR spectrum. In certain embodiments, crystalline Form B of metopimazine mesylate comprises the following peak, expressed as a chemical shift in ppm: 131.6 ± 0.10 to 0.20 ppm 13 It is characterized by a C ssNMR spectrum. In certain embodiments, crystalline Form B of metopimazine mesylate comprises one or more, two or more, three or more, four or more, five or more, six or more, or seven or more of the following peaks, expressed as chemical shifts in ppm: 39.4, 45.2, 131.6, 132.3, 136.1, 149.0, 177.7, and 180.2 ± 0.10 to 0.20 ppm 13 It is characterized by a C ssNMR spectrum. In certain embodiments, crystalline Form B of metopimazine mesylate comprises the following peaks, expressed as chemical shifts in ppm: 39.4, 45.2, 131.6, 132.3, 136.1, 149.0, 177.7, and 180.2 ± 0.10 to 0.20 ppm 13 It is characterized by a C ssNMR spectrum. In certain embodiments, crystalline Form B of metopimazine mesylate comprises the following peak, expressed as a chemical shift in ppm: 123.0 ± 0.10 to 0.20 ppm13 It is characterized by a C ssNMR spectrum. In certain embodiments, crystalline form B of metopimazine mesylate comprises 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 of the following peaks: 39.4, 45.2, 123.0, 131.6, 132.3, 136.1, 149.0, 177.7, and 180.2 ± 0.10 to 0.20 ppm, represented as chemical shifts in ppm units. 13 It is characterized by a C ssNMR spectrum. In certain embodiments, crystalline form B of metopimazine mesylate comprises the following peaks: 39.4, 45.2, 123.0, 131.6, 132.3, 136.1, 149.0, 177.7, and 180.2 ± 0.10 to 0.20 ppm, represented as chemical shifts in ppm units. 13 It is characterized by a C ssNMR spectrum. In certain embodiments, crystalline form B of metopimazine mesylate comprises the following peak: 130.2 ± 0.10 to 0.20 ppm, represented as a chemical shift in ppm units. 13 It is characterized by a C ssNMR spectrum. In certain embodiments, crystalline form B of metopimazine mesylate comprises 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 of the following peaks: 39.4, 45.2, 123.0, 130.2, 131.6, 132.3, 136.1, 149.0, 177.7, and 180.2 ± 0.10 to 0.20 ppm, represented as chemical shifts in ppm units. 13 It is characterized by a C ssNMR spectrum. In certain embodiments, crystalline form B of metopimazine mesylate comprises the following peaks: 39.4, 45.2, 123.0, 130.2, 131.6, 132.3, 136.1, 149.0, 177.7, and 180.2 ± 0.10 to 0.20 ppm, represented as chemical shifts in ppm units. 13It is characterized by a C ssNMR spectrum.

[0070] In certain embodiments, crystalline Form B of metopimazine mesylate is characterized by a DSC pattern that includes two endothermic peaks and a single exothermic peak. In certain such embodiments, crystalline Form B of metopimazine mesylate is characterized by a DSC pattern that includes a first endothermic peak having an onset temperature range of 122°C to 125°C or 123°C to 124°C (e.g., 123.5°C). In certain embodiments, crystalline Form B of metopimazine mesylate is characterized by a DSC pattern that includes a first endotherm having a peak temperature range of 125°C to 127°C such as 126°C to 127°C (e.g., 126.1°C). In certain such embodiments, crystalline Form B of metopimazine mesylate is characterized by a DSC pattern that includes a first endotherm with a transition enthalpy of 81 - 86 J / g (e.g., 83.47 J / g), such as 82 - 85 J / g, 83 - 84 J / g, or 83.5 J / g. In certain such embodiments, crystalline Form B of metopimazine mesylate is characterized by a DSC pattern that includes a second endothermic peak having an onset temperature range of 207°C to 210°C or 208°C to 209°C (e.g., 208.6°C). In certain embodiments, crystalline Form B of metopimazine mesylate is characterized by a DSC pattern that includes a second endotherm having a peak temperature range of 210°C to 212°C such as 211°C to 212°C (e.g., 211.2°C). In certain such embodiments, crystalline Form B of metopimazine mesylate is characterized by a DSC pattern that includes a second endotherm with a transition enthalpy of 82 - 87 J / g (e.g., 84.48 J / g), such as 83 - 86 J / g, 84 - 85 J / g, or 84.5 J / g. In certain such embodiments, crystalline Form B of metopimazine mesylate is characterized by a DSC pattern that includes a single exothermic peak having a peak temperature range of 143°C to 146°C such as 144°C to 145°C (e.g., 144.6°C). It will be understood by those skilled in the art that the endotherms and exotherms shown in FIGS. 4 and 5 are typically reproducible within a range of ±0.5 - 3°C, such as ±2°C, ±1°C, or ±0.5°C. In certain embodiments, crystalline Form B of metopimazine mesylate is characterized by the DSC pattern described in FIG. 5.

[0071] In certain embodiments, crystalline Form B of metopimazine mesylate is characterized by a TGA profile with a total weight loss of 5.5 - 6% (e.g., 5.8%) up to 180.0 °C. In certain embodiments, crystalline Form B of metopimazine mesylate is characterized by the TGA profile described in Figure 5.

[0072] In certain embodiments of the present application, crystalline Form B of metopimazine mesylate hydrate comprises less than 10 wt% of other crystalline forms (e.g., crystalline Form A 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 crystalline forms (e.g., crystalline Form A of metopimazine mesylate).

[0073] In certain embodiments of the present application, crystalline Form B of metopimazine mesylate hydrate comprises less than 10 wt% of an 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 an amorphous form.

[0074] In certain embodiments of the present application, crystalline Form B of metopimazine mesylate comprises less than 10 wt% of other forms (e.g., other crystalline forms of metopimazine mesylate such as crystalline Form A of metopimazine mesylate 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 crystalline Form A of metopimazine mesylate or other amorphous forms of metopimazine mesylate).

[0075] In certain embodiments of the present application, crystalline form B of metopimazine mesylate is a monohydrate form. In certain such embodiments of the present application, crystalline form B of metopimazine mesylate comprises less than 10% by weight of other solvate forms or non-solvate forms, such as less than 5% by weight, less than 4% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.1% by weight or less than 0.01% by weight of other solvate forms or non-solvate forms.

[0076] The present application provides a pharmaceutical composition comprising crystalline form A of metopimazine mesylate and a pharmaceutically acceptable carrier. In certain such embodiments, the pharmaceutical composition comprises from about 10% to about 100% by weight of crystalline form A of metopimazine mesylate. For example, the pharmaceutical composition comprises about 10% by weight of crystalline form A of metopimazine mesylate, about 20% by weight of crystalline form A of metopimazine mesylate, about 30% by weight of crystalline form A of metopimazine mesylate, about 40% by weight of crystalline form A of metopimazine mesylate, about 50% by weight of crystalline form A of metopimazine mesylate, about 60% by weight of crystalline form A of metopimazine mesylate, about 70% by weight of crystalline form A of metopimazine mesylate, about 80% by weight of crystalline form A of metopimazine mesylate, about 90% by weight of crystalline form A of metopimazine mesylate or about 95% by weight of crystalline form A of metopimazine mesylate.

[0077] In certain embodiments of the present application, a pharmaceutical composition comprising crystalline form A of metopimazine mesylate comprises less than 10% by weight of other forms of metopimazine mesylate (e.g., other crystalline forms of metopimazine mesylate such as crystalline form B of metopimazine mesylate or other amorphous forms of metopimazine mesylate), such as less than 5% by weight, less than 4% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.1% by weight or less than 0.01% by weight of other forms of metopimazine mesylate (e.g., other crystalline forms of metopimazine mesylate such as crystalline form B of metopimazine mesylate or other amorphous forms of metopimazine mesylate).

[0078] This application provides a pharmaceutical composition comprising crystalline form B of metopimazine mesylate and a pharmaceutically acceptable carrier. In certain such embodiments, the pharmaceutical composition comprises from about 10% to about 100% of crystalline form B of metopimazine mesylate. For example, the pharmaceutical composition may comprise about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% or about 95% of crystalline form B of metopimazine mesylate.

[0079] In certain embodiments of the present application, a pharmaceutical composition comprising crystalline form B of metopimazine mesylate comprises less than 10% by weight of other forms of metopimazine mesylate (e.g., other crystalline forms of metopimazine mesylate such as crystalline form A of metopimazine mesylate or other amorphous forms of metopimazine mesylate), for example, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.1% or less than 0.01% by weight of other forms of metopimazine mesylate (e.g., other crystalline forms of metopimazine mesylate such as crystalline form A of metopimazine mesylate or other amorphous forms of metopimazine mesylate).

[0080] In certain embodiments of any of the pharmaceutical compositions comprising the crystalline forms of metopimazine mesylate described herein (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate), the composition is suitable for administration orally, intraduodenally, intracolonically, parenterally, enterally, intraperitoneally, topically, transdermally, intravitreally, intranasally, locally, parenterally, by spray, subcutaneously, intravenously, intratonsillarly, intramuscularly, buccally, sublingually, rectally, intraarterially, by infusion or intrathecally. In certain embodiments, the composition is suitable for oral administration. In certain embodiments, the composition is suitable for sublingual administration.

[0081] In certain embodiments of any of the pharmaceutical compositions comprising the crystalline forms of metopimazine mesylate described herein (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate), the pharmaceutical composition is formulated as a tablet, capsule, cream, lotion, oil, ointment, gel, paste, powder, suspension, syrup, enema, suppository, emulsion or solution, sustained release formulation or release-modulated formulation. In certain embodiments, the composition is formulated as a sustained release formulation. In certain embodiments, the composition is formulated as a capsule.

[0082] In certain embodiments of any of the pharmaceutical compositions comprising a crystalline form of metopimazine mesylate as described herein (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate), the composition comprises 5 mg of metopimazine mesylate. In certain embodiments of any of the pharmaceutical compositions described above comprising a crystalline form of metopimazine mesylate (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate), the composition comprises 10 mg of a crystalline form of metopimazine mesylate (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate). In certain embodiments of any of the pharmaceutical compositions described above comprising a crystalline form of metopimazine mesylate (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate), the composition comprises 15 mg of a crystalline form of metopimazine mesylate (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate). In certain embodiments of any of the pharmaceutical compositions described above comprising a crystalline form of metopimazine mesylate (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate), the composition comprises 20 mg of a crystalline form of metopimazine mesylate (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate).

[0083] In certain embodiments of any of the pharmaceutical compositions comprising a crystalline form of metopimazine mesylate (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate) described herein, the composition is suitable for once-daily administration. In other embodiments of any of the above pharmaceutical compositions comprising a crystalline form of metopimazine mesylate (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate), the composition is suitable for twice-daily administration. In certain embodiments of any of the above pharmaceutical compositions comprising a crystalline form of metopimazine mesylate (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate), the composition is suitable for three-times-daily administration. In other embodiments of any of the above pharmaceutical compositions comprising a crystalline form of metopimazine mesylate (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate), the composition is suitable for four-times-daily administration.

[0084] In certain embodiments of any of the pharmaceutical compositions comprising a crystalline form of metopimazine mesylate as described herein (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate), a crystalline form of metopimazine mesylate (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate) between about 5 mg and about 160 mg is administered per day. In certain embodiments of any of the pharmaceutical compositions comprising a crystalline form of metopimazine mesylate as described herein (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate), a crystalline form of metopimazine mesylate (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate) between about 5 mg and about 240 mg is administered per day, for example, a crystalline form of metopimazine mesylate of 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 (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate) is administered per day. In certain embodiments of any of the pharmaceutical compositions comprising a crystalline form of metopimazine mesylate as described herein (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate), the composition is suitable for administering a crystalline form of metopimazine mesylate (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate) in excess of 20 mg per day. In certain embodiments of any of the pharmaceutical compositions comprising a crystalline form of metopimazine mesylate as described herein (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate), the composition is suitable for administering a crystalline form of metopimazine mesylate (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate) in excess of 30 mg per day.

[0085] 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 metopimazine mesylate (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate) as disclosed herein. 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 the group consisting of gastroparesis, irritable bowel syndrome, lysosomal storage disease, intestinal motility disorder, gangliocytoma, multiple endocrine neoplasia type 2B (MEN2B), gastrointestinal neuropathy, functional dyspepsia, gastroesophageal reflux disease (GERD), and enteric neurogenic abnormalities.

[0086] In certain embodiments, the enteric nervous system disorder comprises symptoms selected from the group consisting of early satiety, postprandial fullness, abdominal distension, nausea, vomiting, delayed gastric emptying, diarrhea, abdominal pain, gas, abdominal bloating, gastroesophageal reflux, anorexia, and constipation. In certain embodiments, the symptoms of the enteric nervous system disorder include nausea. In certain embodiments, the symptoms of the enteric nervous system disorder include vomiting.

[0087] 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 metopimazine mesylate (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate) as disclosed herein. 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 distension, nausea, vomiting, delayed gastric emptying, diarrhea, abdominal pain, gas, abdominal bloating, gastroesophageal reflux, anorexia, and constipation. In certain embodiments, the symptoms of the gastroparesis include nausea. In certain embodiments, the symptoms of the gastroparesis include vomiting.

[0088] The present application provides a method for treating nausea associated with gastric paresis in a human subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a crystalline form of metopimazine mesylate (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate) as disclosed herein.

[0089] The present application provides a method for treating vomiting associated with gastric paresis in a human subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a crystalline form of metopimazine mesylate (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate) as disclosed herein.

[0090] The present application provides a method for improving gastric emptying in a human subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a crystalline form of metopimazine mesylate (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate) as disclosed herein.

[0091] The present application provides a method for treating GI tract dysfunction and motility disorders in a human subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a crystalline form of metopimazine mesylate (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate) as disclosed herein.

[0092] In certain specific embodiments of any of the methods disclosed herein, the pharmaceutical composition is administered to the subject for a long period of time. In other embodiments of any of the methods disclosed herein, the pharmaceutical composition is administered to the subject for a short period of time. In certain specific embodiments of any of the methods disclosed herein, the pharmaceutical composition is administered to the subject for at least 6 days. In certain specific 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, the pharmaceutical composition is administered to the subject for at least 4 weeks. In certain further embodiments, the pharmaceutical composition is administered to the subject for at least 12 weeks.

[0093] In certain specific 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.

[0094] In certain embodiments of any of the methods disclosed herein, a crystalline form of metopimazine mesylate (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate) between about 5 mg and about 160 mg per day is administered to a subject. In certain embodiments of any of the methods disclosed herein, a crystalline form of metopimazine mesylate (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate) greater than 20 mg per day is administered to a subject. In certain embodiments of any of the methods disclosed herein, a crystalline form of metopimazine mesylate (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate) greater than 30 mg per day is administered to a subject. In certain embodiments of any of the methods described herein, a crystalline form of metopimazine mesylate (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate) between about 5 mg and about 240 mg per day is administered to a subject, for example, a crystalline form of metopimazine mesylate of 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 (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate) is administered to a subject. In certain embodiments of any of the methods disclosed herein, a crystalline form of metopimazine mesylate of about 5 mg (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate) is administered to a subject once, twice, three times, or four times per day. In certain embodiments of any of the methods disclosed herein, a crystalline form of metopimazine mesylate of about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, or about 60 mg (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate) is administered to a subject once, twice, three times, or four times per day.In certain embodiments of any of the methods disclosed herein, a crystalline form of about 40 mg of metopimazine mesylate (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate) is administered to a subject four times a day. In certain embodiments of any of the methods disclosed herein, a crystalline form of about 60 mg of metopimazine mesylate (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate) is administered to a subject four times a day. Definitions.

[0095] As used herein 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.

[0096] The term "agonist", as used herein, generally refers to a molecule such as a compound, drug, enzyme activator or hormone modulator that binds to a specific receptor in a cell and triggers a response. An agonist generally mimics the action of an endogenous ligand (e.g., dopamine) that binds to the same receptor.

[0097] The term "amorphous", as used herein, refers to a solid consisting of a disordered arrangement of molecules that does not have a distinguishable crystal lattice.

[0098] As used herein, the term "antagonist" refers to a molecule such as a compound that reduces, inhibits, or prevents a cellular response to a receptor activated by an agonist. Antagonists can include, but are not limited to, competitive antagonists, non-competitive antagonists, uncompetitive antagonists, partial agonists, and inverse agonists. A competitive antagonist can reversibly bind to a receptor at the same binding site (active site) as the endogenous ligand or agonist without necessarily activating the receptor. A non-competitive antagonist (also known as an allosteric antagonist) binds to a distinct binding site from the agonist and can exert its antagonistic effect on the receptor through another binding site. Non-competitive antagonists generally do not compete with agonists for binding. Binding of a non-competitive antagonist to a receptor may decrease the affinity of the agonist for that receptor. Alternatively, binding of a non-competitive antagonist to a receptor may prevent the conformational change of the receptor required for agonist-mediated receptor activation. An uncompetitive antagonist may require receptor activation by an agonist before it can bind to an individual allosteric binding site. A partial agonist can refer to a molecule that can cause a difference in the magnitude of the functional response induced after maximal receptor occupancy at a given receptor. A partial agonist is an agonist, but since it competes with a full agonist for receptor occupancy and causes a net decrease in receptor activation observed with the full agonist alone, a partial agonist can act as a competitive antagonist when co-administered with a full agonist. An inverse agonist can have an action similar to an antagonist but causes a distinct set of downstream biological responses. A constitutively active receptor that exhibits intrinsic or basal activity can have an inverse agonist, which not only blocks the action of the bound agonist like a conventional antagonist but also inhibits the basal activity of the receptor.

[0099] As used herein, the term "crystal (singular)" or "crystals (plural)" or "crystalline" or "crystalinic" 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 single crystal form. Thus, the salt crystals of the present invention may be in a crystal form of triclinic system, monoclinic system, orthorhombic system, tetragonal system, rhombohedral system, hexagonal system or cubic system or a mixture thereof. In particular, the salt crystals of the present invention are in a dry crystal form.

[0100] As used herein, "gastrointestinal (GI) tract" refers to the part of the digestive tract where significant absorption is observed. As will be readily understood by those skilled in the art, significant absorption is generally observed in the oral cavity, small intestine (e.g., duodenum, jejunum and ileum) and large intestine (e.g., colon).

[0101] As used herein, "metopimazine mesylate" refers to 1-(3-(2-(methylsulfonyl)-10H-phenothiazin-10-yl)propyl)piperidine-4-carboxamide methanesulfonic acid.

[0102] As used herein, "oral cavity" generally refers to the mouth and includes the lips, cheeks and the lining inside the lips, tongue, upper and lower gums, the floor of the mouth under the tongue, sublingual mucosa, the upper part of the oral cavity, and the area behind the uvula.

[0103] 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. This term also encompasses compounds that can cross the intact blood-brain barrier but are rapidly metabolized into a form that does not substantially cross the intact blood-brain barrier of the subject upon administration to the subject. A compound is considered "peripherally restricted" if 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 the subject when administered to the subject.

[0104] The term "solvate" refers to a crystalline solid adduct that contains either a stoichiometric or non-stoichiometric amount of solvent incorporated within the crystal structure. Thus, the term "non-solvated" form refers herein to a salt crystal that does not contain, or substantially does not contain, solvent molecules within the crystal structure of the present invention. Similarly, the term "anhydrous form" refers herein to a salt crystal that does not contain, or substantially does not contain, water molecules within the crystal structure of the present invention.

[0105] As used herein, the terms "treatment" or "treating" are used interchangeably. These terms refer to a method for obtaining a beneficial or desired result, including, but not limited to, a therapeutic benefit and / or a prophylactic benefit. A therapeutic benefit can mean eradication or amelioration of the underlying disorder being treated. Similarly, a therapeutic benefit can be achieved by eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that improvement is observed in the subject, even if the subject may still be afflicted with 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, halting or reversing the progression of a disease or condition, or any combination thereof. With respect to a prophylactic benefit, a composition may be administered to a subject at risk of developing a particular disease, or a subject reporting one or more of the physiological symptoms of a disease, even if the disease has not yet been diagnosed in the subject.

[0106] "Less than a therapeutic amount" of an agent means an amount less than the effective amount for that agent. When combined with one or more additional agents that are less than an effective or therapeutic amount, less than a therapeutic amount can produce a desired result by a physician, for example, due to a synergistic effect with respect to reducing the resulting effective effect or adverse effect.

[0107] A "synergistically effective" therapeutic amount or "synergistically effective" amount of an agent or treatment means an amount that, when combined with one or more additional agents that are less than an effective or therapeutic amount, produces a greater effect than when any of these agents are used alone. In some embodiments, a synergistically effective therapeutic amount of an agent or treatment produces a greater effect than the additive effect of any of the individual agents when used alone when used in combination. The term "greater effect" includes not only reduction of the symptoms of the disorder being treated, but also improvement of the side effect profile, improvement of tolerance, improvement of patient compliance with medication, improvement of efficacy, or improvement of any other clinical outcome.

[0108] As used herein, the terms "co - administration", "combination administration" and their grammatical equivalents include the administration of two or more agents to an animal such that both agents and / or their metabolites are present in the subject at the same time. Co - administration includes administering the individual compositions simultaneously, administering the individual compositions at different times, or administering in a composition in which both agents are present.

[0109] The terms "determining", "measuring", "evaluating", "assessing", "assaying" and "analyzing" are used interchangeably herein and refer to any form of measurement and include determining whether an element is present or not. These terms include both quantitative and / or qualitative determinations. An assessment may be relative or absolute. "Assessing the presence of" includes determining the amount of what is present and determining whether it is present or not present. Exemplary subject

[0110] The pharmaceutical compositions disclosed herein can be used for the treatment of disorders in a subject in need thereof. The subject may have suffered from a disorder, may have been diagnosed with a disorder, may have shown symptoms of a disorder, or may be suspected of having a disorder. The disorder can be a gastrointestinal disorder, an enteric nervous system disorder or other disorder. The disorder can be characterized by hypomotility of at least a portion of the gastrointestinal tract. For example, the disorder can be characterized by hypomotility of the stomach and / or intestine. Hypomotility can be caused, for example, by abnormal dopamine signaling activity or abnormal signaling of ENS neurons.

[0111] In some embodiments, the enteric nervous system disorder is gastroparesis. The terms “gastroparesis” and “gastric emptying delay” are used interchangeably herein and refer to a disorder that 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, are responsible for breaking down food and moving it into the gastrointestinal (GI) tract. Gastroparesis can occur, for example, when the vagus nerve is damaged by disease or injury, stopping the normal function of the stomach muscles. In subjects with gastroparesis, food may move slowly from the stomach to the small intestine or the movement may stop completely. Thus, a subject may have had, been diagnosed with, shown symptoms of, or be suspected of having gastroparesis.

[0112] If a subject shows or has shown symptoms of gastroparesis, they may be suspected of having gastroparesis. The symptoms of gastroparesis can include gastroesophageal reflux (GER), also known as so-called acid reflux or gastric acid reflux. Gastroesophageal reflux generally refers to a condition where the contents of the stomach flow backward and return to the esophagus. Other symptoms associated with gastroparesis include, but are not limited to, early satiety, postprandial fullness, abdominal distension, abdominal pain and / or a burning sensation in the stomach area, abdominal bloating, anorexia, loss of appetite, malnutrition, nausea, and vomiting. The symptoms of gastroparesis can be mild, moderate, or severe and can occur frequently or intermittently. The symptoms of gastroparesis can vary in severity over time in the same subject. Thus, a subject may show or have shown GER, early satiety, postprandial fullness, abdominal distension, abdominal pain and / or a burning sensation in the stomach area, abdominal bloating, anorexia, loss of appetite, malnutrition, nausea, and / or vomiting.

[0113] The subject may be diagnosed with gastroparesis. Gastroparesis can be diagnosed by any means known to those skilled in the art or otherwise described herein. Gastroparesis can be diagnosed, for example, by physical examination, medical history, blood tests, tests to rule out obstructions or structural problems in the GI tract, gastric emptying assays, and assays of GI contractile activity. The tests may also identify malnutrition or underlying diseases. Tests useful for diagnosing gastroparesis include, but are not limited to, upper gastrointestinal (GI) endoscopy, upper GI barium study, ultrasound, gastric emptying scintigraphy, gastric emptying breath test, intraluminal manometry, electrogastrogram, and / or electrogastroenterogram.

[0114] Upper GI endoscopy can be used to rule out other conditions (such as physical obstructions) that may cause delayed gastric emptying. Upper GI endoscopy typically involves the use of an endoscope (e.g., a small flexible tube with a light) to visualize the upper GI tract, including, for example, the esophagus, stomach, and duodenum (the first part of the small intestine). The endoscope is generally used to image the stomach and / or duodenum. A small camera attached to the endoscope can transmit video images to a monitor, allowing for a detailed examination of the intestinal lining. Upper GI endoscopy may reveal physical obstructions in the upper GI tract, such as large bezoars (e.g., solid deposits of food, mucus, food fibers, hair, or other substances). In some embodiments, if a subject exhibits symptoms of gastroparesis and upper GI endoscopy does not reveal a physical obstruction causing delayed gastric emptying, the subject is diagnosed with gastroparesis.

[0115] An upper GI series can be performed to view the small intestine. This examination may be performed in a hospital or outpatient facility by an X-ray technician, and the images can be interpreted by a radiologist. During the procedure, the subject may stand or sit in front of an X-ray machine and drink a powdery liquid called barium. The barium coats the small intestine, making signs of gastroparesis more clearly visible on X-ray. Gastroparesis can be indicated when X-rays show food in the stomach after fasting. In some embodiments, a subject is diagnosed with gastroparesis by upper GI series if it is revealed that there is food in the stomach after fasting.

[0116] Ultrasound can be useful in ruling out other syndromes that may share symptoms common to gastroparesis. Such other syndromes include gallbladder disease and pancreatitis. Ultrasound generally uses a device called a transducer that reflects safe, painless sound waves off of organs to create an image of their structure. This procedure can be performed by a specially trained technician in a healthcare provider's office, outpatient facility, or hospital. The ultrasound images can be interpreted by a radiologist. If a subject exhibits symptoms of gastroparesis and other syndromes, such as gallbladder disease, pancreatitis, etc., are ruled out, for example, by ultrasound, the subject can be diagnosed with gastroparesis.

[0117] In a subject, gastric emptying scintigraphy can be used to diagnose gastroparesis. Gastric emptying scintigraphy can involve ingestion of a bland-tasting meal, such as an egg or egg substitute, containing a small amount of a radioactive substance. The radioactive substance can be 99m-Tc sulfur colloid, or another radioactive ligand. The test may be performed in a radiation facility or a hospital. An external camera may be used to detect and / or measure radioactivity in the abdominal region. Radioactivity can be measured, for example, at time intervals of 1, 2, 3, and 4 hours after eating. Gastroparesis can be identified as positive in a subject showing more than 10 percent of the meal in the stomach at 4 hours. Other measures of gastric emptying include, but are not limited to, the time at which 50% of the meal has emptied from the stomach. See, for example, Thomforde, G. M. et al., Evaluation of an inexpensive screening scintigraphic test of gastric emptying, 36J. Nucl. Med. 93 (1995), which is incorporated herein by reference. In some embodiments, a subject is diagnosed with gastroparesis by gastric emptying scintigraphy.

[0118] A breath test useful for assessing gastric emptying can utilize a radioactively labeled food (e.g., labeled with C 13 -octanoic acid). C 13 derived from the food can be absorbed when it reaches the small intestine. The absorbed C 13 is then rapidly metabolized in the liver to 13 generate CO 2 . The generated 13 CO 2 can then be detected in the subject's breath. The subject's breath can be collected and sampled at regular intervals. The 13 CO 2 in the sample can be analyzed by any means known in the art. The rate of gastric emptying can be indicated using the ratio at which 13 CO 2 appears in the breath. C 13An exemplary method of performing an octanoic acid breath test is described in Ghoos, Y. S., et al., 104 Gastroenterology 1640-1647 (1993), which is incorporated herein by reference. In some embodiments, the subject is diagnosed with gastroparesis by a breath test.

[0119] Manometry generally refers to the assessment of pressure changes in a lumen. Intraluminal manometry, which may also be referred to as pyloroduodenal manometry, generally refers to a technique for the evaluation of contractile activity in 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 by a catheter. The measurements can be recorded over time to assess changes in intraluminal pressure. The recording may be continued for any amount of time. Changes in intraluminal pressure can be used to indicate contraction patterns in the stomach and / or duodenum. Changes in intraluminal pressure can be measured in the fasting state and / or after ingestion of a meal (postprandial). Postprandial hypomotility may indicate gastroparesis in a subject. Thus, a subject may show a decrease in postprandial gastric motility when determined by manometry.

[0120] The electrogastrogram examination method generally refers to techniques and methods for recording the electrical activity of the stomach. Similarly, the electrogastroenterogram examination method refers to techniques and methods for recording the electrical activity of the stomach and small intestine. Such electrical activity can be recorded from the gastrointestinal mucosa, serosa, or the outer skin surface (skin). The gastrointestinal mucosa can refer to the mucosal layer of the GI tract. The serosa of the gastrointestinal tract can include a thin layer of cells that secrete serous fluid and a thin epithelial layer. The recording can be performed during the fasting state and after food intake (usually for 60 minutes). Deviations from the normal frequency of electrical activity can include slow waves and / or fast waves. Control subjects usually show an increase in electrical activity indicating an improvement in GI motility after eating. Subjects with abnormal GI motility may show abnormal rhythms of activity and / or a reduction in the postprandial improvement. The normal frequency of GI electrical activity can be, for example, 3 cycles per minute. Slow waves, which can be characterized by a frequency of GI electrical activity that has decreased from the normal value, for example, less than 2 cycles per minute for at least 1 minute, can indicate gastric paresis. In some embodiments, a subject may show slow waves. Gastric paresis can also be diagnosed using the electrogastrogram (EGG) examination method, which measures electrical activity using skin electrodes similar to those used in electrocardiograms. (Stern, R. N. et al. EGG: Common issues in validation and methodology, 24 Psychophysiology 55-64 (1987)), which is incorporated herein by reference. Thus, a subject can be diagnosed with gastric paresis as determined by the electrogastrogram examination method.

[0121] The subject may have suffered from gastroesophageal reflux disease (GERD), been diagnosed with gastroesophageal reflux disease (GERD), shown symptoms of gastroesophageal reflux disease (GERD), or been suspected of having gastroesophageal reflux disease (GERD). GERD can be a chronic condition that results in gastroesophageal reflux. Symptoms of GERD include, for example, heartburn, chronic dry cough, wheezing, asthma, recurrent pneumonia, nausea, vomiting, sore throat, dysphagia, chest or upper abdominal pain, dental erosion, bad breath, and excessive salivation. GERD may be diagnosed with the aid of tests. Tests useful for the diagnosis of GERD include, for example, upper GI imaging, upper endoscopy, esophageal pH monitoring, and esophageal manometry as described herein.

[0122] The subject may have suffered from, been diagnosed with, shown symptoms of, or been suspected of having an enteric nervous system disorder associated with a vestibular disorder of the ear. The vestibular disorder of the ear can be Menetrier's disease. Menetrier's disease can be characterized by the dilation of the rugae (also referred to herein as folds) along the inner side of the stomach wall, forming giant folds in the lining of the stomach. Menetrier's disease may also cause a decrease in gastric acid, due to a decrease in acid-producing parietal cells. Symptoms of Menetrier's disease include, by way of example only, severe stomach pain, nausea, and frequent vomiting.

[0123] The subject has or has been diagnosed with cyclic vomiting syndrome (CVS), has exhibited symptoms of cyclic vomiting syndrome (CVS), or has been suspected of having cyclic vomiting syndrome (CVS). Cyclic vomiting syndrome can be characterized by episodes or cycles of severe nausea and vomiting that alternate with asymptomatic periods. Such episodes can last for hours or even days. The episodes may start at the same time of day, may last the same length of time, and may occur at the same level of symptoms and intensity. The episodes can be severe enough that a person has to stay in bed for several days and is unable to go to school or work. Other symptoms of cyclic vomiting syndrome include, for example, abdominal pain, diarrhea, fever, dizziness, and sensitivity to light during vomiting episodes. Persistent vomiting can cause severe dehydration, which can be life-threatening. Symptoms of dehydration include thirst and weight loss. Cyclic vomiting syndrome can be diagnosed in a subject who has experienced the following symptoms for at least three months: starting with severe vomiting several times per hour, vomiting episodes lasting less than one week, three or more separate vomiting episodes in the past year, and no nausea or vomiting between episodes.

[0124] The subject has, has been diagnosed with, has shown symptoms of, or has been suspected of having irritable bowel syndrome (IBS). IBS generally refers to a syndrome in which the subject experiences recurrent or chronic gastrointestinal symptoms. The symptoms of IBS can include, for example, abdominal pain, abdominal discomfort, constipation, diarrhea, mucus in the stool, abdominal distension, or any combination of the above. IBS may be diagnosed when there is no other disease or injury that can explain the pain and a human has had abdominal pain or discomfort at least three times per month for the last three months. The pain or discomfort of IBS may occur with changes in bowel frequency or consistency, or may be relieved by defecation. IBS can be classified into four subtypes based on the normal stool consistency of the subject. The four subtypes of IBS are as follows: IBS with constipation (IBS-C), IBS with diarrhea (IBS-D), mixed IBS (IBS-M), and IBS that cannot be classified into a subtype (IBS-U). Subjects with IBS-C may have hard or pellet-like stools at least 25% of the time, may have soft or watery stools less than 25% of the time, or may have a combination of the two. Subjects with IBS-D may have soft or watery stools at least 25% of the time, may have hard or pellet-like stools less than 25% of the time, or may have a combination of the two. Subjects with IBS-M may have hard or pellet-like stools at least 25% of the time and may have soft or watery stools at least 25% of the time. Subjects with IBS-U may have hard or pellet-like stools less than 25% of the time, may have soft or watery stools less than 25% of the time, or may have a combination of the two. Constipation associated with IBS can be due to slow or sluggish gastric motility. In some embodiments, the subject with IBS is experiencing constipation. IBS can be diagnosed in a subject by any means known in the art or otherwise described herein. For example, IBS can be diagnosed by a healthcare provider.A healthcare provider can perform a physical examination and obtain the subject's medical history. IBS may be diagnosed when the subject has one or more symptoms that occur at least three times per month for the past three months and shows one or more symptoms of IBS for at least three, four, five, or six months. Additional tests that may be useful for the diagnosis of IBS include, but are not limited to, fecal tests, lower GI imaging, flexible sigmoidoscopy, or colonoscopy.

[0125] The subject may have, be diagnosed with, show symptoms of, or be suspected of having functional dyspepsia (e.g., indigestion). Symptoms of dyspepsia include, but are not limited to, for example, chronic or recurrent pain in the upper abdomen, a feeling of fullness in the upper abdomen, a feeling of fullness after eating, early satiety, abdominal distension, belching, nausea, vomiting, heartburn, and a sour taste in the mouth. Functional dyspepsia (e.g., non-ulcer dyspepsia) generally refers to dyspepsia without evidence of an organic disease that could explain the symptoms of dyspepsia. An example of functional dyspepsia is dyspepsia without ulcers. Functional dyspepsia is estimated to affect approximately 15% of the general population in Western countries. Other exemplary ENS disorders include, but are not limited to, for example, intestinal motility disorders, gangliocytoma, multiple endocrine neoplasia type 2B (MEN2B), gastrointestinal neuropathy, and intestinal neurogenic abnormalities.

[0126] The subject may have, be diagnosed with, exhibit symptoms of, or be suspected of having an enteric nervous system disorder caused by a fundamentally different disease. For example, the enteric nervous system disorder can be Parkinson's disease-induced ENS disorder. Parkinson's disease-induced ENS disorder may be related to the degeneration of dopaminergic ENS neurons. Symptoms of Parkinson's disease-induced ENS disorder include, for example, constipation, nausea, vomiting, etc. In some embodiments, the subject to be treated by the method of the present application has been diagnosed with Parkinson's disease, suffers from this symptom, is suspected of having this, and further exhibits the symptoms of the ENS disorder described herein.

[0127] The subject may have, be diagnosed with, exhibit symptoms of, or be suspected of having an enteric nervous system disorder associated with scleroderma. Scleroderma can be characterized by hardening and tightening of the skin and connective tissues. In some embodiments, the subject may have, be diagnosed with, exhibit symptoms of, or be suspected of having gastroparesis associated with scleroderma.

[0128] The subject may have, be diagnosed with, exhibit symptoms of, or be suspected of having a diabetes-related enteric nervous system disorder. A diabetes-related enteric nervous system disorder can be a gastroparesis associated with diabetes. The subject may have, be diagnosed with, exhibit symptoms of, or be suspected of having an enteric nervous system disorder associated with multiple sclerosis.

[0129] Other diseases and clinical conditions that can cause enteric nervous system disorders such as gastric paresis include, for example, cancer, hypothyroidism, hyperthyroidism, hyperparathyroidism, adrenal insufficiency (Addison's disease), gastric ulcer, gastritis, for example, after gastric surgery such as total vagotomy (removal of the vagus nerve), pyloroplasty (removal of a part of the stomach distal to the gastric antrum), subtotal gastrectomy (removal of a gastric tumor), gastrojejunostomy (a surgical procedure that connects two lumens of the GI tract such as the proximal part of the stomach and a part of the small intestine), cardioplasty (a surgical procedure that wraps the upper part of the stomach around the lower end of the esophagus), polymyositis (a persistent inflammatory muscle disease that may cause muscle weakness), muscular dystrophy (a disease that may cause progressive muscle weakness), amyloidosis (characterized by the accumulation of amyloid in the target tissue or organ such as in the gastrointestinal tract), pseudo-obstruction (a condition that causes symptoms related to intestinal obstruction but no intestinal obstruction is seen), dermatomyositis (a disease characterized by muscle inflammation), systemic lupus erythematosus (a systemic autoimmune disease that can affect various tissues of the body including the nervous system), for example, eating disorders such as anorexia and bulimia, depression, tumor-associated syndromes, and high cervical spinal cord lesions (for example, lesions at spinal cord C4 or above).

[0130] Subjects may be affected by symptoms of enteric nervous system disorders. 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 (e.g., unexplained nausea). In some embodiments, the symptom is a chronic or recurrent symptom. Subjects may experience the symptom for 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. Subjects may experience the symptom 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 per month.

[0131] Subjects can be, for example, mice, rats, hamsters, gerbils, dogs, cats, primates such as monkeys or humans. In some embodiments, the subject is a human. The subject can be an adult, a child or an infant. The subject can be of any age. Use of Pharmaceutical Compositions

[0132] 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 developing harmful side effects on the heart. For example, the pharmaceutical compositions described herein may not increase the risk of modulating myocardial action potentials and / or may not increase the risk of inducing QT prolongation 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.

[0133] To a subject, an effective amount of the pharmaceutical composition described herein can be safely administered for a non-limiting amount of time. To a subject, an effective amount of the pharmaceutical composition can be safely administered for a short or long period of time. For example, to a subject, once a day, at least for 2 days, at least for 3 days, at least for 4 days, 5 days, at least for 5 days, at least for 6 days, at least for 7 days (1 week), at least for 2 weeks, at least for 3 weeks, at least for 4 weeks, at least for 5 weeks, at least for 6 weeks, at least for 7 weeks, at least for 8 weeks, at least for 9 weeks, at least for 10 weeks, at least for 11 weeks, at least for 12 weeks, at least for 3 months, at least for 4 months, at least for 5 months, at least for 6 months, at least for 7 months, at least for 8 months, at least for 9 months, at least for 10 months, at least for 11 months, at least for 12 months (1 year), at least for 2 years, at least for 5 years or at least for 10 years, an effective amount of the pharmaceutical composition can be safely administered.

[0134] Administration of the pharmaceutical compositions described herein may pose an acceptable risk that the subject will develop undesirable cardiac side effects. The risk of administration of the pharmaceutical composition with respect to the development of such undesirable cardiac side effects can be determined by any means known in the art or described herein. For example, the risk can be determined by comparing the incidence of sudden death in a population of subjects administered the pharmaceutical composition to the incidence of sudden death in a control population not administered the pharmaceutical composition. The risk can be determined by tracking the number of subjects who have received administration of the pharmaceutical composition and experienced an undesirable cardiac side effect and the number of subjects who have received administration of the pharmaceutical composition and not experienced an undesirable cardiac side effect. For example, if a = the number of subjects who have received administration of the pharmaceutical composition and experienced an undesirable cardiac side effect and b = the number of subjects who have received administration of the pharmaceutical composition and not experienced an undesirable cardiac side effect, the risk of experiencing an undesirable cardiac side effect resulting from receiving administration of the pharmaceutical composition can be calculated as a / (a + b). The relative risk (RR) can be used to compare the risk of developing an undesirable cardiac side effect resulting from administration of the pharmaceutical composition to the risk of developing an undesirable cardiac side effect in a population of subjects not receiving administration of the pharmaceutical composition. For example, if a = the number of subjects who have received administration of the pharmaceutical composition and experienced an undesirable cardiac side effect, b = the number of subjects who have received administration of the pharmaceutical composition and not experienced an undesirable cardiac side effect, c = the number of subjects not receiving administration of the pharmaceutical composition who have experienced an undesirable cardiac side effect, and d = the number of subjects not receiving administration of the pharmaceutical composition who have not experienced an undesirable cardiac side effect, the RR resulting from administration of the pharmaceutical composition can be calculated as a / (a + b) / (c / (c + d)). With regard to other examples, the risk can be determined by calculating the odds ratio.

[0135] The RR of administration of the pharmaceutical composition described herein in cases of sudden cardiac death can 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.

[0136] The odds ratio of administration of the pharmaceutical composition described herein in cases of sudden cardiac death can be an acceptable odds ratio. The term odds ratio (OR) generally refers to a measure of the association between an exposure (e.g., exposure to a drug) and an outcome (e.g., sudden cardiac death). The OR can represent the odds of an outcome occurring when a particular exposure is given, compared to the odds of the outcome occurring in the absence of that exposure. The odds ratio can be used in case-control studies, as well as in cross-sectional and cohort study designs. For example, if a = the number of subjects who received administration of the pharmaceutical composition and experienced an undesirable cardiac side effect, b = the number of subjects who received administration of the pharmaceutical composition and did not experience an undesirable cardiac side effect, c = the number of subjects who did not receive administration of the pharmaceutical composition and experienced an undesirable cardiac side effect, and d = the number of subjects who did not receive administration of the pharmaceutical composition and did not experience an undesirable cardiac side effect, the OR resulting from administration of the pharmaceutical composition can be calculated as ad / bc.

[0137] The OR of administration of the pharmaceutical composition described herein in cases of sudden cardiac death can 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.

[0138] The pharmaceutical compositions described herein for use in the treatment of ENS are peripherally restricted, unlike other drugs that modulate dopamine previously adapted for the treatment of ENS. Thus, such pharmaceutical compositions can be safely administered to a subject without increasing the risk of developing dysfunctions associated with movement mediated by brain dopaminergic signaling. For example, such pharmaceutical compositions can be safely administered to a subject without increasing the risk of developing extrapyramidal side effects. Exemplary extrapyramidal side effects include, for example, tardive dyskinesia (involuntary asymmetrical movements of muscles), dystonia (characterized by sustained muscle contractions), akinesia (absence of movement), restlessness (a feeling of unease and inability to sit still), bradykinesia (slow movement), rigidity and tremors, torsion and / or repetitive movements, abnormal postures, muscle spasms, such as neck muscle spasms (torticollis), eye muscle spasms (oculogyric crisis), tongue spasms, jaw spasms, and the like. Extrapyramidal symptoms can be assessed by any means known in the art or otherwise described 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 odds ratio of administration of the pharmaceutical compositions described herein for use in treating enteric nervous system disorders with the appearance 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.

[0139] The pharmaceutical compositions of the present application can promote gastric motility upon administration to a subject. Such pharmaceutical compositions can, for example, affect dopamine D in the enteric neurons of the subject 2- By reducing receptor-mediated signal transduction, gastric motility can be promoted. For example, a pharmaceutical composition can antagonize dopamine D 2 receptors in the enteric neurons of a subject. Regarding other examples, a pharmaceutical composition may reduce dopaminergic neurotransmission in enteric neurons.

[0140] Gastric motility can be assessed by any means known to those skilled in the art or otherwise described herein. For example, gastric motility can be assessed by intraluminal manometry or by methods useful in the diagnosis of gastroparesis. Exemplary methods useful in the diagnosis of gastroparesis are described herein.

[0141] Administration of the pharmaceutical composition described herein can improve gastric motility compared to a control subject and / or control population. The control subject can be an individual who has not received administration of the pharmaceutical composition described herein. The control population can be a plurality of individuals who have not received administration of the pharmaceutical composition described herein. The control subject can be a subject who has not received administration of the pharmaceutical composition described herein and who has, is diagnosed with, is suspected of having, or exhibits symptoms of an ENS disorder. The control subject does not necessarily have to be a different individual and can be the same subject at a time point prior to taking a certain dose of the pharmaceutical composition described herein. The control subject can be the same subject at a time point after a sufficient amount of time has elapsed such that the pharmaceutical composition no longer acts in the subject and after taking a certain dose of the pharmaceutical composition described herein. The control subject can be a different subject. In some embodiments, administration of the pharmaceutical composition results in an improvement in gastric motility of at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100% or more than 100% compared to the control subject.

[0142] In some embodiments, administration of the pharmaceutical compositions described herein is effective to treat symptoms of enteric nervous system disorders in a subject. Exemplary symptoms are described herein. The symptoms can be selected from the group consisting of nausea, vomiting, delayed gastric emptying, diarrhea, abdominal pain, gas, abdominal distension, gastroesophageal reflux, anorexia, weight loss, and constipation. In certain cases, administration of the pharmaceutical compositions described herein reduces nausea in a subject. Administration of the pharmaceutical compositions described herein can reduce the severity of any of the symptoms described herein. In some cases, administration of the pharmaceutical compositions described herein reduces the severity of the symptoms 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 the pharmaceutical compositions described herein reduces the severity of the symptoms 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%.

[0143] By administering the pharmaceutical composition described herein, the frequency of occurrence of symptoms can be reduced. In some cases, by administering the pharmaceutical composition described herein, the frequency of occurrence of symptoms is reduced by 1-5%, 2-10%, 5-20%, 10-30%, 20-50%, 40-70%, 50-80%, 70-90%, 80-95%, 90-100%. In some cases, by administering the pharmaceutical composition described herein, the frequency of occurrence of symptoms is reduced 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, by administering the pharmaceutical composition described herein, the frequency of occurrence of symptoms is reduced to less than 1 episode per day, less than 1 episode per week, less than 2 episodes per month, less than 1 episode per month, less than 1 episode every 2 months, less than 1 episode every 3 months, less than 1 episode every 4 months, less than 1 episode every 5 months, less than 1 episode every 6 months, less than 1 episode every 7 months, less than 1 episode every 8 months, less than 1 episode every 9 months, less than 1 episode every 10 months, less than 1 episode every 11 months, or less than 1 episode per 12 months (1 year).

[0144] hERG channel inhibition can be determined by any means known in the art or otherwise described herein. hERG channel inhibition can be assessed in vitro, for example, by using cultured cells expressing hERG. Cultured cells expressing hERG for assessing hERG channel inhibition are available from several commercial suppliers, such as Life Technologies, Cyprotex, etc. hERG channel inhibition can be assessed by various means known in the art, including, for example, voltage clamp studies, hERG binding assays, etc. Voltage clamp studies can utilize the use of 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 incorporated herein by reference. hERG binding assays can 3H include competitive binding assays and / or saturation binding assays using dofetilide. Such assays are described in J Pharmacol Toxicol Methods. 2004 Nov-Dec;50(3):187-99, which is incorporated herein by reference. hERG channel inhibition can be determined by in vivo studies in large animal models, such as dogs, for example, by assessment of myocardial action potentials.

[0145] Minimal hERG inhibition can be demonstrated by an IC 50 that is 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.

[0146] Minimal hERG inhibition can also be demonstrated by measuring the % inhibition of hERG-mediated tail current at any given dose of the drug. The hERG-mediated tail current can be measured by voltage clamp studies, for example, by patch clamp studies. For example, the hERG-mediated tail current can be measured in cells expressing hERG prior to contacting the cells with the test agent. Next, the hERG-mediated tail current can be measured in cells expressing hERG after contacting with a dose of the test agent. The difference between the hERG-mediated tail current before and after administration of the test agent can be used to determine the extent to which the test agent inhibits the hERG-mediated tail current. Suitable agents for use in the disclosed methods can inhibit the 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 the 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, metopimazine can inhibit the 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, the acid of metopimazine 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 higher. Exemplary pharmaceutical composition

[0147] The pharmaceutical composition used in the method of the present application can include a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers for the present composition can include, but are not limited to, amino acids, peptides, biopolymers, non-biopolymers, monosaccharides or starches, inorganic salts, and gums, which can be present alone or in combination. Peptides used in acceptable carriers can include, for example, gelatin and / or albumin. Cellulose or its derivatives may be used in pharmaceutically acceptable carriers. Sugars used in acceptable carriers may be lactose and / or glucose. Other useful sugars that can be utilized in pharmaceutical compositions include, but are not limited to, fructose, galactose, lactitol, maltitol, maltose, mannitol, melezitose, myo-inositol, palatinate, raffinose, stachyose, sucrose, trehalose, xylitol, their hydrates, and combinations thereof. Binders may be included in pharmaceutically acceptable carriers. Examples of binders include, but are not limited to, starches (e.g., corn starch or potato starch), gelatin; natural or synthetic gums such as acacia, sodium alginate, tragacanth powder, guar gum, cellulose or cellulose derivatives (e.g., methylcellulose, ethylcellulose, cellulose acetate); microcrystalline cellulose, polyvinylpyrrolidone, and mixtures thereof. Inorganic salts used in acceptable carriers may be magnesium salts, for example, magnesium chloride or magnesium sulfate. Other inorganic salts, such as calcium salts, may be used. Examples of calcium salts include, but are not limited to, calcium chloride, calcium sulfate. Other examples of substances that can be used in pharmaceutically acceptable carriers include, but are not limited to, vegetable oils such as peanut oil, cottonseed oil, olive oil, corn oil; polyols such as glycerin, propylene glycol, polyethylene glycol; pyrogen-free water, isotonic physiological saline, phosphate buffer solutions; emulsifiers such as Tweens (registered trademark); wetting agents, lubricants, coloring agents, flavoring agents, preservatives.

[0148] The term "wetting agent" can be used interchangeably with "surfactant" and refers to a substance that reduces the surface tension of a liquid, thereby enabling the liquid to spread more easily. 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 may be used, a mixture of lipophilic surfactants may be used, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be used.

[0149] 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 (the "HLB" value). The lower the HLB value of a surfactant, the higher its hydrophobicity and the higher its solubility in oil, while the higher the HLB value of a surfactant, the higher its hydrophilicity and the higher its solubility in aqueous solution. Hydrophilic surfactants are generally considered to be compounds having an HLB value higher than about 10, and 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 having an HLB value of about 10 or less. However, the HLB value of a surfactant only provides a mere rough guideline that is generally used to enable the formulation of industrial, pharmaceutical, and cosmetic emulsions.

[0150] The hydrophilic surfactant can be either ionic or non-ionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts, fatty acid derivatives of amino acids, glyceride derivatives of amino acids, fusidate salts, oligopeptides and polypeptides, oligopeptides and polypeptides, lecithin and hydrogenated lecithin, lysophosphatidylcholine and hydrogenated lysophosphatidylcholine, phospholipids and their derivatives, fatty acid salts, lysophospholipids and their derivatives, carnitine fatty acid ester salts, alkyl sulfates, sodium docusate, acylactylate, mono- and diacetyl tartrate esters of monoglycerides and diglycerides, succinylated monoglycerides and diglycerides, citrate esters of monoglycerides and diglycerides, and mixtures thereof.

[0151] Within the scope of the aforementioned group, ionic surfactants include, but are not limited to, lecithin, lysophosphatidylcholine, phospholipids, lysophospholipids and their derivatives, carnitine fatty acid ester salts, fatty acid salts, alkyl sulfates, sodium docusate, acylactylate, mono- and diacetyl tartrate esters of monoglycerides and diglycerides, succinylated monoglycerides and diglycerides, citrate esters of monoglycerides and diglycerides, and mixtures thereof.

[0152] Ionic surfactants may be in the ionized form of lactic acid esters of fatty acids, lecithin, lysolecithin, phosphatidylethanolamine, phosphatidylcholine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylserine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglyceride, mono / diacetylated tartaric acid esters of mono / diglycerides, citric acid esters of mono / diglycerides, cholylsarcosine, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, oleic acid, linoleic acid, linolenic acid, stearic acid, ricinoleic acid, lauryl sulfate, teracyl sulfate, docusate, lauroyl carnitine, palmitoyl carnitine, myristoyl carnitine, and salts and mixtures thereof.

[0153] The hydrophilic nonionic surfactant can include, but is not limited to, polyoxyalkylene alkyl ethers such as alkyl glucoside, alkyl thioglucoside, alkyl maltoside, lauryl macrogol glyceride, and polyethylene glycol alkyl ether; polyoxyalkylene alkyl phenols such as polyethylene glycol alkyl phenol; polyoxyalkylene alkyl phenol fatty acid esters such as polyethylene glycol glycerol fatty acid ester, polyethylene glycol fatty acid monoester, and polyethylene glycol fatty acid diester; polyglycerol fatty acid ester; polyoxyethylene - polyoxypropylene block copolymer and mixtures thereof; polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid ester; a hydrophilic transesterification product of a polyol and at least one member of the group consisting of glyceride, vegetable oil, hydrogenated vegetable oil, fatty acid, and sterol, polyoxyethylene sterol and their derivatives or analogs; polyoxyethylated vitamin and its derivatives; polyethylene glycol sorbitan fatty acid ester; and a hydrophilic transesterification product of a polyol and at least one member of the group consisting of triglyceride, vegetable oil, and hydrogenated vegetable oil. The polyol can be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or saccharide.

[0154] 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, glyceryl PEG-25 trioleate, PEG-32 dioleate, glyceryl PEG-20 laurate, PEG-20 trioleate, glyceryl PEG-30 laurate, glyceryl PEG-20 stearate, glyceryl PEG-20 oleate, glyceryl PEG-30 oleate, glyceryl PEG-30 laurate, glyceryl PEG-40 laurate, 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 caprylic / capric glyceride, PEG-8 caprylic / capric glyceride, polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phytosterol, PEG-30 soybean sterol, PEG-40 sorbitan oleate, 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 succinate PEG-100, PEG-24 cholesterol, polyglyceryl-10 oleate, Tween® 40, Tween® 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG10-100 nonylphenol series, PEG15-100 octylphenol series, and poloxamer.

[0155] 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 at least one member of the group consisting of polyols and glycerides, 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 the scope of this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters and mixtures thereof, or are hydrophobic transesterification products of at least one member of the group consisting of polyols and vegetable oils, hydrogenated vegetable oils and triglycerides.

[0156] Lubricants that can be used in pharmaceutical compositions include, but are not limited to, agar, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil), zinc stearate, ethyl oleate, ethyl laurate (ethylaureate), or mixtures thereof. Further lubricants include, by way of example, syloid silica gel, coagulated aerosol of synthetic silica, or mixtures thereof. The lubricant can be added as needed in an amount of less than about 1% by weight of the pharmaceutical composition.

[0157] The composition can include one or more pharmaceutically acceptable additives, which can include, but are not limited to, demolding agents, defoaming agents, buffering agents, antioxidants, polymers, preservatives, chelating agents, odorants, opacifying agents, suspending agents, fillers, plasticizers, and mixtures thereof.

[0158] 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 0.04%, more than 0.03%, more than 0.02%, more than 0.01%, more than 0.009%, 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 the pharmaceutical composition on a w / w, w / v or v / v basis.

[0159] In some embodiments, the concentration of the crystalline form of metopimazine mesylate (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate) in the composition is 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 0.07%, 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% on a w / w, w / v or v / v basis of the pharmaceutical composition.

[0160] In some embodiments, the concentration of the crystalline form of metopimazine mesylate (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate) in the composition is in the range of 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% on a w / w, w / v or v / v basis of the pharmaceutical composition.

[0161] In some embodiments, the concentration of the crystalline form of metopimazine mesylate (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate) is in the range of 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, based on w / w, w / v or v / v.

[0162] Some non-limiting examples of the pharmaceutical composition are described below. Pharmaceutical composition for oral administration

[0163] A pharmaceutical composition comprising an effective amount of the crystalline form of metopimazine mesylate (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate) can be formulated for oral administration. In some embodiments, a pharmaceutical composition for oral administration comprising an effective amount of the crystalline form of metopimazine mesylate (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate) is a solid pharmaceutical composition. In some embodiments, the solid pharmaceutical composition may be provided as individual (e.g., unit) oral dosage forms. Non-limiting examples of individual oral dosage forms include tablets, capsules, caplets, gelatin capsules, sustained release formulations, lozenges, thin layer films, lollipops, chewable gums. In some embodiments, the individual oral dosage form is an orally disintegrating dosage form, such as an orally disintegrating tablet.

[0164] Individual oral dosage forms such as tablets can be coated by known techniques to delay or extend absorption in the gastrointestinal tract, thus providing a longer duration of action. In some embodiments, the crystalline forms of metopimazine mesylate (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate) are mixed with one or more inert solid diluents such as calcium carbonate or calcium phosphate. In some embodiments, the crystalline forms of metopimazine mesylate (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate) are provided as soft gelatin capsules, in which case the crystalline forms of metopimazine mesylate (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate) are mixed with, for example, water or an oily medium such as peanut oil or olive oil.

[0165] In some embodiments, a pharmaceutical composition comprising an effective amount of a crystalline form of metopimazine mesylate (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine 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, slurries, solutions, elixirs, soft gels, tinctures and hydrogels. In some embodiments, a solid composition or a liquid composition comprising an effective amount of a crystalline form of metopimazine mesylate (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate) for oral administration comprises various sweetening agents or flavoring agents or coloring agents. Examples of coloring agents include food-suitable dyes such as grape skin extract, beet red powder, beta-carotene, annatto, carmine, turmeric, paprika, etc., F.D.&C. dyes and those known as natural coloring agents. Derivatives, analogs and isomers of any of the above colored compounds may also be used.

[0166] Such dosage forms may be prepared by methods well known to those skilled in the art, for example, in a pharmacy. Such methods include the step of combining a crystalline form of metopimazine mesylate (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate) with a pharmaceutically acceptable carrier.

[0167] Since water may promote the decomposition of the crystalline form of metopimazine mesylate (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate), the present application further encompasses anhydrous pharmaceutical compositions and dosage forms comprising an effective amount of the crystalline form of metopimazine mesylate (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate). In some embodiments, the anhydrous pharmaceutical compositions and dosage forms of the present application are prepared using anhydrous or low-moisture-containing components. In some embodiments, the anhydrous pharmaceutical compositions and dosage forms of the present application are prepared under low humidity or low moisture conditions. The pharmaceutical compositions of the present application containing lactose may be made anhydrous when significant contact with moisture and / or humidity during manufacture, packaging, and / or storage is anticipated. An anhydrous pharmaceutical composition comprising an effective amount of the crystalline form of metopimazine mesylate (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate) can be prepared and stored to maintain its anhydrous nature. For example, the anhydrous composition may be packaged using materials known to prevent exposure to water so that it can be included in a suitable prescription kit. Examples of these include, but are not limited to, airtight foils, plastics, etc., unit dose containers, blister packs, and strip packs. Pharmaceutical composition for injection or parenteral administration

[0168] In some embodiments, the pharmaceutical composition is formulated for parenteral administration. "Parenteral administration" generally refers to an administration route other than the gastrointestinal tract. Examples of parenteral administration include, but are not limited to, intravenous injection, intra-arterial injection, intrathecal injection (into the spinal cord), intratonsillar injection, subcutaneous injection, intramuscular injection, infusion or implantation. The infusion may be by intradermal, or subcutaneous, or transdermal implant. Exemplary pharmaceutical compositions for parenteral administration are disclosed in the following references, which are hereby incorporated by reference in their entirety: U.S. Patent Application Publication No. 2006 / 0287221, U.S. Patent Nos. 5,244,925, 4,309,421, 4,158,707 and 5,164,405, all of which are hereby incorporated by reference in their entirety.

[0169] Compositions formulated for parenteral administration may include aqueous solutions and / or buffered solutions commonly used for injection and / or infusion. Commonly used aqueous buffers and / or solutions can 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 can include ethanol, glycerol, propylene glycol, cyclodextrin and cyclodextrin derivatives, vegetable oils, and the like.

[0170] In some embodiments, the pharmaceutical composition for injection and / or infusion contains a preservative present in an amount effective to prevent or reduce microbial contamination or degradation. Various agents, such as phenol, m-cresol, benzyl alcohol, parabens, chlorobutanol, methotrexate, sorbic acid, thimerosol, ethyl hydroxybenzoate, bismuth tribromophenate, methyl hydroxybenzoate, bacitracin, propyl hydroxybenzoate, erythromycin, 5-fluorouracil, doxorubicin, mitoxantrone, rifamycin, chlorocresol, benzalkonium chloride can be used to prevent or reduce contamination.

[0171] In some embodiments, the sterile solution is prepared by incorporating the required amount of the crystalline form of metopimazine mesylate (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate) in a suitable solvent, together with various other ingredients described herein as required, and then filtering and sterilizing. Generally, the dispersion is prepared by formulating various sterilized active ingredients in a sterile vehicle containing a base dispersion medium and other ingredients required from those listed above. In the case of sterile powders for preparing sterile solutions for injection, certain methods of preparation include, but are not limited to, vacuum drying techniques and lyophilization techniques in which the powder of the active ingredient and any further desired ingredients are obtained from its pre-sterilized solution.

[0172] In some embodiments, the pharmaceutical composition is formulated for topical and / or transdermal delivery. The compositions of the present application can be formulated into preparations in liquid, semi-solid or solid forms suitable for topical or local administration. Examples of forms suitable for topical or local administration include, but are not limited to, gels, water-soluble jelly, creams, lotions, suspensions, foams, powders, slurries, ointments, oils, pastes, suppositories, solutions, sprays, emulsions, physiological saline solutions, and dimethyl sulfoxide (DMSO)-based solutions. Generally, carriers with higher density can provide regions with long-term exposure to the active ingredient. In contrast, solution formulations can provide more rapid exposure of the active ingredient to the selected region.

[0173] The pharmaceutical composition may include a suitable solid-phase carrier or gel-phase carrier, which are compounds that enable the enhancement of the penetration or the facilitation of the delivery of therapeutic molecules through the stratum corneum barrier of the skin. There are numerous such penetration-enhancing molecules known to those skilled in the art of topical formulations. Examples of such carriers and excipients include, but are not limited to, alcohols (e.g., ethanol), fatty acids (e.g., oleic acid), humectants (e.g., urea), glycols (e.g., propylene glycol), surfactants (e.g., isopropyl myristate and sodium lauryl sulfate), glyceryl monolaurate, sulfoxides, pyrrolidones, terpenes (e.g., menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycol.

[0174] Another exemplary formulation for use in the methods of the present application uses a transdermal delivery device (“patch”). Such transdermal patches can be used to provide a continuous or intermittent infusion of a controlled amount of the crystalline forms of metopimazine mesylate described herein (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate), either with or without the use of an additive. The construction and use of transdermal patches for the delivery of pharmaceutical agents are well known in the art. See, e.g., U.S. Patent Nos. 5,023,252; 4,992,445; and 5,001,139, which are incorporated herein by reference.

[0175] In some embodiments, the present application provides a pharmaceutical composition for transdermal delivery comprising an effective amount of the crystalline forms of metopimazine mesylate described herein (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate), and a pharmaceutical excipient suitable for delivery by inhalation. Compositions for inhalation include solutions and suspensions, and powders, in a pharmaceutically acceptable aqueous or organic solvent, or mixtures thereof. The liquid or solid composition can contain suitable pharmaceutically acceptable excipients as described herein. The composition can be administered by oral or nasal airway routes for systemic effect. In some embodiments, the composition, preferably in a pharmaceutically acceptable solvent, may be nebulized by the use of an inert gas. In some embodiments, the nebulized solution may be inhaled directly from the nebulizing device. In other embodiments, the nebulizing device may be attached to a face mask-type tent or to an intermittent positive pressure breathing apparatus. The solution, suspension or powder composition may be preferably administered orally or nasally from a device that delivers the formulation in a suitable manner. Other pharmaceutical compositions

[0176] The pharmaceutical compositions used in this application can be formulated for intraocular (eye), rectal, sublingual, buccal or intranasal (e.g., intrapulmonary) administration. Formulations suitable for intraocular administration include eye drops in which the active ingredient is dissolved or suspended in a suitable carrier for the active ingredient, especially an aqueous solvent. The active ingredient is preferably present in such formulations at a concentration of 0.5 - 20% w / w, preferably 0.5 - 10% w / w, especially about 1.5% w / w. Formulations suitable for sublingual administration are usually formulated so as to dissolve rapidly when placed in the mouth and enable the active ingredient to be absorbed via the blood vessels under the tongue. Exemplary sublingual formulations include, for example, lozenges containing the active ingredient in a base flavored with sucrose and acacia or tragacanth; troches containing the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia; mouthwashes containing the active ingredient in a suitable liquid carrier; orally disintegrating tablets, for example, that can disintegrate in less than 90 seconds when placed in the mouth; and thin layer films. Such disintegration can be measured by an in vitro dissolution test. Formulations for buccal administration can include, by way of example, buccal tablets, bioadhesive particles, wafers, lozenges, medicated chewing gums, adhesive gels, patches, film agents, which can be delivered as aqueous solutions, pastes, ointments or aerosols. Formulations for rectal administration can be supplied, for example, as suppositories with a suitable base containing cocoa butter or salicylate. Formulations suitable for intrapulmonary or nasal administration are administered by rapid inhalation from the nasal passages or by inhalation from the mouth so as to reach the alveolar sacs and can have a particle size in the range of, for example, 0.1 - 500 microns (including particle sizes in the range between 0.1 and 500 microns in micron increments such as 0.5, 1, 30 microns, 35 microns, etc.). Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration can be prepared according to conventional methods and may be delivered together with other therapeutic agents such as compounds conventionally used for the treatment or prevention of cancerous infections, as described below.The pharmacological formulations of the present application are injectable formulations containing any suitable carrier, such as various vehicles, adjuvants, additives, and diluents, and can be administered to patients. Alternatively, the metopimazine mesylate utilized in the present application can be parenterally administered to patients in the form of sustained-release subcutaneous implants or targeted delivery systems, such as monoclonal antibodies, vectorized delivery, iontophoresis, polymer matrices, liposomes, and microspheres. Examples of delivery systems useful in the present application include 5,225,182; 5,169,383; 5,167,616; 4,959,217; 4,925,678; 4,487,603; 4,486,194; 4,447,233; 4,447,224; 4,439,196; and 4,475,196. Many other such implants, delivery systems, and modules are well known to those skilled in the art.

[0177] Preparations related to such pharmaceutical compositions are described, for example, in Anderson, Philip O.; Knoben, James E.; Troutman, William Described in G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 20037ybg; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remingtons Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999). All of those are incorporated herein by reference in their entirety. Exemplary Modes of Administration

[0178] Administration of the pharmaceutical composition described herein can be carried out by any method that enables delivery of the crystalline form of metopimazine mesylate (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate) to the site of action. The composition can be administered orally, parenterally, enterally, intraperitoneally, topically, transdermally, intravitreally, nasally, locally, parenterally, by spray, subcutaneously, intravenously, intratonsillarly, intramuscularly, intraorally, sublingually, rectally, intraarterially, by infusion or intrathecally. In some embodiments, the composition is administered orally. In some cases, oral administration can include administration of any of the oral dosage forms described herein. The effective amount of the crystalline form of metopimazine mesylate (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate) to be administered will depend on the subject being treated, the severity of the disorder or condition, the rate of administration, the nature of the crystalline form of metopimazine mesylate (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate), and the discretion of the prescribing physician.

[0179] For the treatment of enteric nervous system disorders, a subject can be administered the crystalline form of metopimazine mesylate (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate) in a daily dosage as described herein. The daily dosage can be from about 0.01 mg to about 500 mg per kg of body weight per day.

[0180] In some embodiments, administration can include infusion. In some cases, infusion can include long-term steady-state administration. For example, devices for long-term steady-state administration by a controlled pump are known in the art (e.g., as described in US7341577, US7351239, US8058251, which are incorporated herein by reference).

[0181] Administration of the crystalline form of metopimazine mesylate (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate) may be continued for as long as necessary. In some embodiments, the crystalline form of metopimazine mesylate (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate) is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In certain embodiments, the crystalline form of metopimazine mesylate (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate) is administered for more than 5 days. In some embodiments, the crystalline form of metopimazine mesylate (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate) is administered for more than 12 weeks. In some embodiments, the crystalline form of metopimazine mesylate (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate) 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 metopimazine mesylate (e.g., crystalline form A of metopimazine mesylate or crystalline form B of metopimazine mesylate) is administered for less than 5 days. Exemplary combination therapies

[0182] In some embodiments, the method includes co - administration of an additive. The additive can be a small molecule, a dietary supplement, a vitamin such as vitamin D, a drug, a prodrug, a biologic, a peptide, a peptidomimetic, an antibody, an antibody fragment, a cell or tissue graft, 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 may 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, etc.

[0183] In some embodiments, the methods of the present application include co - administration of a peripherally - restricted dopamine decarboxylase inhibitor and the pharmaceutical composition described herein. For example, the methods of the present application can include co - administration of carbidopa and the pharmaceutical composition described herein.

[0184] The additive can be a drug for use in treating enteric nervous system disorders. In some embodiments, the additive is an additional antiemetic (e.g., for use in treating nausea and / or vomiting). Exemplary additional antiemetics can be, by way of non-limiting example only, 5-HT3 receptor antagonists, dopamine receptor antagonists, NK1 receptor antagonists, antihistamines, cannabinoids, benzodiazepines, anticholinergic agents, steroids or other antiemetics. Exemplary 5-HT3 receptor antagonists include, but are not limited to, ondansetron, tropisetron, granisetron, palonosetron, dolasetron. Exemplary dopamine receptor antagonists include, for example, metoclopramide (Reglan), domperidone (Motilium), olanzapine (Zyprexa), droperidol, haloperidol, chlorpromazine, promethazine, prochlorperazine, alizapride, prochlorperazine, sulpiride. Exemplary NK1 receptor antagonists include, for example, aprepitant, trazipitant or casopitant. Exemplary antihistamines include, for example, cyclizine, diphenhydramine (Benadryl), dimenhydrinate (Gravol, Dramamine), doxylamine, meclizine (Bonine, Antivert), promethazine (Phenergan, Phenadoz, Promacot), and hydroxyzine (Vistaril), cimetidine, famotidine, rafinitidine, nizatidine, ranitidine, roxatidine, tiotidine. Exemplary cannabinoids include, for example, marijuana, Sativex, tetrahydrocannabinol, dronabinol, and synthetic cannabinoids such as nabiximols. Exemplary benzodiazepines include, for example, midazolam or lorazepam. Exemplary anticholinergic agents include, for example, scopolamine. Other exemplary antiemetics include, for example, trimethobenzamide, ginger, Emetrol, propofol, peppermint, erythromycin, muscimol, botulinum toxin A (e.g., injected into the stomach to relax the pyloric sphincter) and ajowan.

[0185] The additive can be a drug for treating another disease or clinical syndrome associated with gastric paresis. Exemplary other diseases and clinical syndromes are described herein. The additive can be a drug for treating diabetes. Exemplary drugs for treating diabetes include, for example, insulin. Other drugs for treating diabetes are described, for example, in U.S. Patent Nos. 6274549, 8349818, 6184209, U.S. Patent Application Publication No. US20070129307, and PCT Application Publication No. WO / 2004 / 082667A1, all of which are incorporated herein by reference.

[0186] The additive can be for treating upper and lower body dyskinesia disorders associated with Parkinson's disease. The additive can be for treating Parkinson's disease. Exemplary drugs for treating Parkinson's disease include, for example, dopamine agonists, such as MAO-A or B inhibitors like selegiline, COMT inhibitors like entacapone, amantadine, stem cell grafts, and neuroprotective agents. Exemplary dopamine agonists include, but are not limited to, levodopa, bromocriptine, pergolide, pramipexole, cabergoline, ropinorole, apomorphine, or combinations thereof.

[0187] The additive can be for treating hypothyroidism, hyperthyroidism, or hyperparathyroidism. Exemplary drugs for treating such diseases include, for example, beta-adrenergic blockers ("beta blockers"), levothyroxine calcium receptor agonists, estrogen, progesterone, bisphosphonates.

[0188] The additive can be for treating adrenal insufficiency. Exemplary drugs for treating adrenal insufficiency include, for example, corticosteroid hormones (e.g., aldosterone, fludrocortisone, and cortisol).

[0189] The additive can be for treating gastroesophageal reflux. Exemplary agents for treating gastroesophageal reflux include, for example, antacids such as proton pump inhibitors such as omeprazole, H2 receptor antagonists such as ranitidine, antacids, mosapride, sucralfate and baclofen.

[0190] The additive can be for treating scleroderma. For example, the additive can be D-penicillamine, colchicine, PUVA, relaxin, cyclosporine and EPA (omega-3 oil derivatives), such as immunosuppressive agents such as methotrexate, cyclophosphamide, azathioprine and mycophenolate. The additive can be for treating polymyositis. For example, the additive can be a corticosteroid, such as prednisone, or an immunosuppressive agent.

[0191] The additive can be for treating muscular dystrophy. For example, the additive 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 estradien-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-diol and 4α(S)-benzyl-2(R)-chloroethynyl-1,2,3,4,4α,9,10,10α(R)-octahydro-phenanthrene-2,7-diol and (11β,17β)-11-(1,3-benzodioxo-5-yl)-17-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one.

[0192] The additive can be for treating amyloidosis. For example, the additive can be an amyloid beta sheet mimic, 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), peptidylprolyl cis-trans-isomerase (PPI), trimethylamine N-oxide (TMAO), betaine, glycine betaine, glycerophosphorylcholine, carbohydrates such as, for example, glycerol, sorbitol, arabitol, myo-inositol and trehalose, choline, 4-phenylbutyric acid and taurine-conjugated ursodeoxycholic acid.

[0193] The additive can be for treating chronic idiopathic pseudo-obstruction. For example, the additive can be prucalopride, pyridostigmine, metoclopramide, cisapride, linaclotide, octreotide, cannabinoid and erythromycin.

[0194] The additive can be for treating dermatomyositis. For example, the additive can be prednisone, methotrexate, mycophenolate (CellCept / Myfortic), intravenous immunoglobulin, azathioprine (Imuran), cyclophosphamide, rituximab and Acthar gel.

[0195] The additive can be for treating systemic erytematosus. For example, the additive can be a kidney graft, corticosteroid, immunosuppressant, hydroxychloroquine, cyclophosphamide, mycophenolic acid, immunosuppressant, analgesic, intravenous immunoglobin, etc.

[0196] The additive can be used for treating anorexia and / or bulimia. For example, the additive can be olanzapine, tricyclic antidepressants, MAO inhibitors, mianserin, selective serotonin reuptake inhibitors such as fluoxetine, lithium carbonate, trazodone and bupropion, phenytoin, carbamazepine, and valproic acid, opioid antagonists such as naloxone and naltrexone, and topiramate.

[0197] The additive can be used for treating depression. For example, the additive can be selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, bupropion, tricyclic antidepressants, monoamine oxidase inhibitors, etc. The additive can be used for treating paraneoplastic syndrome. The additive can be used for treating high cervical spinal cord lesions. For example, the additive can be corticosteroids or other anti-inflammatory drugs. The additive can be used for treating multiple sclerosis. For example, the additive can be interferon beta-1b, interferon beta-1a, glatiramer acetate, mitoxantrone, natalizumab, fingolimod, teriflunomide or cladribine.

[0198] The additional therapeutic agent can be selected from the group consisting of serotonin agonists, serotonin antagonists, selective serotonin reuptake inhibitors, antispasmodics, opioid receptor agonists, bradykinin receptor antagonists, NK receptor antagonists, adrenergic receptor agonists, benzodiazepines, gonadotropin-releasing hormone analogs, calcium channel blockers and somatostatin analogs.

[0199] The dosages of the additives and pharmaceutical compositions described herein for use in treating enteric nervous system disorders can vary depending on the type of additional therapeutic agent used, the disease or condition being treated, and the like. One or both of the additives and pharmaceutical compositions described herein in less than a therapeutic amount can be used. One or both of the additives and pharmaceutical compositions described herein in less than a therapeutic amount can be a synergistically effective amount. One or both of the additives and pharmaceutical compositions described herein in a therapeutically effective amount can be used. The pharmaceutical compositions and additives described herein can be administered either simultaneously or sequentially. When administered sequentially, the attending physician or caregiver can determine the appropriate order for administering the pharmaceutical compositions and additional therapeutic agents described herein.

[0200] In some embodiments, a method comprising the step of administering any of the pharmaceutical compositions described herein further comprises combination therapy with an additional treatment regimen. The additional treatment regimen can include implantation of a medical device. The medical device can be implanted in the stomach and / or abdomen, for example, the duodenum. The medical device can be an electrical device. The medical device can be a pacemaker. Such a pacemaker can utilize an electric current to induce contractions of the stomach and / or duodenum, thereby promoting gastrointestinal motility. Such medical devices, and methods of using them, are disclosed in U.S. Patent No. 8,095,218, which is incorporated herein by reference.

[0201] Embodiments of the present application are further described in detail by reference to the following examples. These examples are presented for illustrative purposes only and are not intended to be limiting unless otherwise specified. Accordingly, the present application should in no way be construed as being limited to the following examples, but rather should be construed as encompassing any and all variations that become apparent as a result of the teachings presented herein.

Examples

[0202] The following examples illustrate the present application but do not limit it. (Example 1) Synthesis of crystalline form A of metopimazine mesylate

[0203] Those skilled in the art will recognize that the following synthetic reactions and schemes can be modified by the selection of suitable conditions and reagents to obtain metopimazine mesylate, i.e., 1-(3-(2-(methylsulfonyl)-10H-phenothiazin-10-yl)propyl)piperidine-4-carboxamide methanesulfonic acid, from metopimazine, 1-(3-(2-(methylsulfonyl)-10H-phenothiazin-10-yl)propyl)piperidine-4-carboxamide. Metopimazine, and methods for making metopimazine, are described in DE1092476, which is incorporated herein by reference. Metopimazine can be obtained from various commercial sources (CAS registration number 0014008-44-7). By way of example only, metopimazine can be obtained from ABI Chemicals (#AC2A05HFH), AKos (#AKOS005065914), Biochempartner (#BCP9000716), Molport (#MolPort-003-808-703), Santa Cruz Biotechnology (#sc-211901), and Tractus Company Limited (#TX-013443). Scheme 1: Preparation of crystalline form A of metopimazine mesylate from metopimazine [Chemical formula]

[0204] To metopimazine (50 g), dimethyl sulfoxide (DMSO) (150 mL) was added, and then methanesulfonic acid (MsOH) (11.3 g) was added over 10 minutes at 20 - 25 °C to obtain a clear solution. Next, acetone (50 mL) was added, and the solution was filtered through filter paper. The filtrate was warmed to 68 °C, and acetone (175 mL) was added over 15 minutes at 68 °C. Next, the solution was cooled to 60 °C over 30 minutes, and then stirred at 60 °C for 1 hour. At this 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 reslurried with acetone (200 mL) for 30 minutes. The solid was collected by filtration, and the residual filter cake was reslurried again with acetone (200 mL) for 30 minutes. The solid was collected again by filtration. The filter cake was dried under vacuum at 50 °C for 6 hours to obtain crystalline form A of metopimazine mesylate as a yellow solid (40 g, 66% yield).

[0205] Similarly, large-scale preparation was carried out as follows. To metopimazine (1500 g), DMSO (4.5 L) was added, and then MsOH (341 g) was added over 30 minutes at 20 - 25 °C to obtain a clear solution. Next, acetone (1.5 L) was added, and the solution was filtered through filter paper. The filtrate was warmed to 68 °C, and acetone (5.25 L) was added over 30 minutes at 68 °C. Seed crystals (15 g) were added to the solution. Next, the turbid solution was stirred at 68 °C for 1 hour. The slurry was cooled to 0 °C over 6 hours, and the mixture was stirred at 0 °C for 14 hours. The solid was collected by filtration, and the filter cake was washed with acetone (4.5 L). The filter cake was stirred with acetone (6 L) for 30 minutes. The solid was collected by filtration, and the filter cake was stirred with acetone (6 L) for 30 minutes. The solid was collected by filtration. The filter cake was dried under vacuum at 50 °C for 7 hours to obtain crystalline form A of metopimazine mesylate as a yellow solid (1558 g, 85% yield).

[0206] The structure of metopimazine mesylate was determined by high-resolution mass spectrometry ([M + H]+ = 446.16), 11H NMR (Table 5) and 13 confirmed by 13C NMR (Table 6).

Table 5

Table 6-1

Table 6-2

[0207] The structure of the single crystal was successfully determined. The crystal system was monoclinic and the space group was Pn. The unit cell dimensions of the structure were as follows: a = 11.90502(6) Å, b = 5.57773(3) Å, c = 19.47543(12) Å, α = 90°, β = 103.5908(6)°, γ = 90°, V = 1257.014(13) Å3. The asymmetric unit was found to contain one metopimazine cation and one mesylate anion, indicating that Form A is the anhydrate. The final refinement parameters are listed in Table 7 below.

Table 7-1

Table 7-2

[0208] The peak list of the calculated XRPD of the single crystal of crystal form A of metopimazine mesylate is presented in Table 8.

Table 8-1

Table 8-2

[0209] For XRPD analysis, a PANalytical X-ray powder diffractometer was used. The sample was prepared by placing a layer of the sample (about 5 mg) in the center of a silicon wafer. The XRPD parameters used are listed in Table 9. The XRPD pattern is presented in Figure 1, and the peaks are presented in Table 1 above. [Table 9]

[0210] TGA data was collected using a TA Q5500 TGA from TA Instruments, and DSC was performed using a TA Q2500 DSC from TA Instruments. The details of the parameters used are listed in Table 10. The sample (about 2 mg) was prepared by adding it to a pan. The TGA plot is presented in Figure 2. The crystalline form A of metopimazine mesylate showed a minimal weight loss by TGA (0.4% up to 150.0 °C). The DSC plot is presented in Figure 3. The crystalline form A of metopimazine mesylate showed a distinct melting starting at 209.9 °C (melting = 213.1 °C; enthalpy = 97.47 J / g). [Table 10]

[0211] (Example 2) Synthesis of crystalline form B of metopimazine mesylate Scheme 2: Preparation of crystalline form B of metopimazine mesylate from crystalline form A of metopimazine mesylate [Chemical formula]

[0212] A glass beaker containing a thin layer of crystalline form A of metopimazine mesylate (10 g) was placed at room temperature and a relative humidity of 100% for approximately 3 - 5 days, and crystalline form B of metopimazine mesylate was obtained as an off-white solid. The structure of crystalline form B of metopimazine mesylate is 1Confirmed by \(^1\)H NMR (Table 11). [Table 11-1] [Table 11-2]

[0213] For XRPD analysis, a PANalytical X-ray powder diffractometer was used. The sample was prepared by placing a layer of the sample (about 5 mg) in the center of a silicon wafer. The XRPD parameters used are listed in Table 8 above. The XRPD pattern is presented in Figure 4, and the peaks are presented in Table 3 above.

[0214] TGA data were collected using a TA Q5500 TGA manufactured by TA Instruments, and DSC was performed using a TG Q2000 DSC manufactured by TA Instruments. Details of the parameters used are listed in Table 9 above. The sample (about 2 mg) was prepared by adding it to a pan. The TGA / DSC plot is presented in Figure 5. A weight loss of 5.8% was observed up to 180 °C, and two endothermic peaks (dissolution = 126.1 °C and 211.2 °C; enthalpy = 83.47 J / g and 84.48 J / g, respectively) and one exothermic peak at 144.6 °C (peak temperature) were observed at 123.5 °C and 208.6 °C (onset temperature). (Example 3) Pharmacokinetic analysis of crystalline form A of metopimazine mesylate

[0215] To understand the pharmacokinetic profile of crystalline form A of metopimazine mesylate in comparison with the free base of metopimazine, a clinical comparative pharmacokinetic study was conducted. This investigation was designed as a three-period crossover with three administrations of a single dose: an oral formulation of crystalline form A of metopimazine mesylate in the fasting state, an oral formulation of crystalline form A of metopimazine mesylate after a high-fat breakfast, and an oral formulation of free base of metopimazine in the fasting state, with a 48-hour washout period between each administration. Fifteen subjects were enrolled and received each of the three treatments. Various pharmacokinetic parameters of plasma samples from each subject were analyzed. A mixed model repeated measures (MMRM) analysis was performed for each sample. Comparison between form A of metopimazine mesylate and the free base of metopimazine showed that the T max values had statistically significantly lower variability than those of the free base of metopimazine. The results are shown in Table 12 below.

Table 12

[0216] The above results demonstrate that crystalline form A of metopimazine mesylate results in a more predictable onset of action compared to the free base of metopimazine. Since the population of subjects suffering from gastric atony requires a treatment that can be taken before meal times to alleviate symptoms that are always exacerbated by food intake, the smaller variability of the T max of crystalline form A of metopimazine mesylate provides an important benefit to that population.

[0217] The second objective of this investigation was to compare the pharmacokinetics of crystalline form A of metopimazine mesylate administered orally as a single 15 mg dose to 15 human subjects either in the fasting state or after a high-fat breakfast. Various pharmacokinetic parameters of plasma samples from each subject were analyzed. The geometric mean difference in C max was slight but significantly lower, while there was no statistical difference in the geometric mean of AUC. C maxBoth Cmax and AUC were well within the 90% confidence intervals. These results are shown in Table 13 below.

[0218] When crystalline form A of metopimazine mesylate was administered with food, a slight decrease in Cmax of approximately 15% was observed, but there was no significant difference in AUC (well within the range of the 90% upper and lower intervals defined as bioequivalence). max Such a slight difference in Cmax was not clinically significant (FDA Guidance for the industry: Food-Effect Bioavailability max and Fed Bioequivalence Studies). These results are in contrast to previously published data (Herrstedt et al., 1990) showing the food effect on free metopimazine base, which resulted in a 58% decrease in Cmax and a 23% decrease in AUC after administration of free metopimazine base before and after a high-fat breakfast. and Fed Bioequivalence Studies). These results are in contrast to previously published data (Herrstedt et al., 1990) showing the food effect on free metopimazine base, which resulted in a 58% decrease in Cmax and a 23% decrease in AUC after administration of free metopimazine base before and after a high-fat breakfast. max The population of subjects suffering from gastric stasis shows delayed gastric emptying and long-term residual of gastric food contents, which may exacerbate the PK variability of drugs highly sensitive to food such as free metopimazine base. Therefore, the lack of food effect on crystalline form A of metopimazine mesylate benefits such a population. [Table 13]

[0219] The population of subjects suffering from gastric stasis shows delayed gastric emptying and long-term residual of gastric food contents, which may exacerbate the PK variability of drugs highly sensitive to food such as free metopimazine base. Therefore, the lack of food effect on crystalline form A of metopimazine mesylate benefits such a population. (Example 4) 13C ssNMR Characterization of Crystalline Form A and Crystalline Form B of Metopimazine Mesylate 13 13C ssNMR Characterization of Crystalline Form A and Crystalline Form B of Metopimazine Mesylate Relaxation Parameters

[0220] Relaxation parameters for forms A and B of metopimazine mesylate, 1 1H T1 1 and 1 1H T2 1rhowere collected. The results are shown in Table 14. The parameters 1 HT 1 and 1 HT 1rho are helpful for determining the optimal acquisition parameters for ssNMR data collection.

[0221]

Table 14

[0222] The solid-state NMR (SSNMR) experiments were performed on a Bruker NEO spectrometer (Bruker, Billerica, MA) operating at 100.52 MHz for 13 C and 399.71 MHz for 1 H, or 100.46 MHz for 13 C and 399.49 MHz for 1 H. Data were acquired using a Chemagnetics APEX HX probe (Revolution NMR, Fort Collins, CO) re-equipped with a 7 mm magic-angle spinning module. Samples were packed into 7 mm rotors with Kel-F spacers for 13 C work. The magic-angle spinning rate was 5 kHz. For reference, 3-methylglutaric acid was used for the setting and optimization of the cross-polarization (CP) experiment. 13 13C chemical shifts were reported with an accuracy of ±0.4 ppm relative to the methyl peak of MGA at 18.84 ppm.

[0223] Data collection was performed at an apparent temperature of approximately 18.5 °C. Data collection was 13 performed using 13C cross-polarization and then acquired using SPINAL64 1 1H decoupling. 3960 points were acquired (acquisition time of approximately 50 ms). As discussed below, 4.4 μs H90, and SPINAL64 (RF field of approximately 56.8 kHz), 1.5 ms contact time (P15), with appropriate pulse delays 1H decoupling was used. The pulse delay was either 7.2 seconds or 8.2 seconds for crystalline form A of metopimazine mesylate and crystalline form B of metopimazine mesylate, respectively. 1 H T 1 For the experiment, 1 a saturation period (15 μs delay, 20 loops) was applied to H, followed by data acquisition using H90, cross-polarization (CP), and total sideband suppression (TOSS). 1 H T 1 The values were determined using the Bruker t1guide in the Topspin software package. 1 H T 1rho For, a spin-lock time of 0.5 - 32 ms (64 ms and 128 ms were also added if selected), followed by a standard CPTOSS sequence. T 1 The appropriate pulse delay determined from the results was used for data acquisition. High-quality 13 For the C spectrum, T 1 the appropriate pulse delay from the results was used. The pulse delay and the number of acquisitions were adjusted according to the sample. The data were collected for 2 - 18 hours according to the sample. Data processing

[0224] The initial data processing was performed using the Topspin 4.0.8 (copyright) software package from Bruker Biospin. The data were Fourier-transformed using the full FID (3960 points), and a line broadening of 0 Hz (KAS0221001 and KAS0221002) or 10 Hz (KAS0221003 and KAS0221004), phase adjustment (apk), and baseline correction (abs). Manual phase adjustment was performed if necessary. Sample preparation

[0225] The powder sample was packed into a 7 mm rotor without modification. The sample was pre-spun outside before being mounted on the NMR probe. 13 C ssNMR spectrum

[0226] Regarding crystalline forms A and B of metopimazine mesylate, 13 The 13C ssNMR spectra are presented in Figures 6 and 7, respectively. These two forms were found to have distinct spectra, while form B was found to contain trace amounts of form A. Therefore, in order to obtain the spectrum of pure form B, form A was subtracted from form B using the Topspin 4.0.8 (copyright) software package. The resulting spectrum is presented in Figure 8.

[0227] Preferred embodiments of the present application are shown and described herein, but it will be apparent to those skilled in the art that such embodiments are presented by way of example only. Without departing from the present application, numerous variations, modifications and substitutions will now occur to those skilled in the art. It should be understood that various alternatives to the embodiments of the application described herein can be used in the practice of the present application. The following claims are intended to define the scope of the present application and to include within those claims methods and structures and their equivalents that are embraced thereby. Incorporation by reference

[0228] All of the reference documents cited in the present application, and those references, are hereby incorporated by reference in their entirety herein, where appropriate, for additional or alternative details, features and / or teachings of the technical background.

Claims

[Claim 1] The invention described in this specification.

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