Methods for metabolizing metopimazine and its salts

Abstract

Provided herein is a method for preparing metopimazine acid by reacting metopimazine or a pharmaceutically acceptable salt thereof with human microsomal liver amidase.Similarly, provided herein is a method for treating gastroparesis in a human subject in need thereof with metopimazine or a pharmaceutically acceptable salt thereof in combination with an additional therapeutic agent that is not metabolized by human microsomal liver amidase and / or human liver cytosolic aldehyde oxidase.

Description

[Technical field]

[0001] Related Applications This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 131,419, filed December 29, 2020, and U.S. Provisional Patent Application No. 63 / 219,047, filed July 7, 2021, which are incorporated by reference in their entireties herein. [Background technology]

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

[0003] Disorders of the gastrointestinal (GI) tract affect many humans. Irritable bowel syndrome (IBS), a disorder in which the intestines do not function normally due to dysfunction of the muscles or nerves of the GI tract, affects 10-15% of the adult population. Symptoms of IBS include constipation, diarrhea, and abdominal pain. Functional dyspepsia (indigestion caused by dysfunction of the muscles or nerves associated with the upper GI tract) affects 10-20% of the adult population. Gastrointestinal reflux, a disorder that causes improper mashing of food by the stomach and delayed gastric emptying, affects up to 10% of the total population. In the United States, gastroesophageal reflux disorder (GERD), a chronic digestive disorder that occurs when stomach acid and / or bile reflux into the esophagus, is estimated to affect up to 35% of infants in the first few months of life and more than half of the total population.

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

[0005] ENS dysfunction has been implicated in several of the disorders listed above, for example, impaired or dysfunctional ENS neuronal signaling has been strongly implicated as a causative factor in gastroparesis.

[0006] There are currently no adequate treatments for these disorders. For example, lubiprostone for the treatment of IBS is used to treat constipation and mimic infectious diarrhea. However, these drugs do not repair the underlying ENS dysfunction and are not universally effective. Domperidone and metoclopramide, dopamine D2 receptor antagonists, were previously indicated for the treatment of nausea and vomiting, but are not recommended for use, especially long-term, due to serious safety issues. Two serious safety concerns relate to (1) undesirable cardiac side effects, caused, for example, by the interaction of these drugs with ion channels involved in cardiac action potentials, and (2) undesirable motor dysfunction caused by the action of dopamine antagonists crossing the blood-brain barrier and entering the brain. For example, it has been demonstrated that a number of dopamine receptor antagonists inhibit the hERG channel (a type of potassium channel) and cause drug-induced long QT syndrome, a cardiac condition characterized by abnormalities in cardiac action potential rhythms. Long QT syndrome may increase the risk of cardiac arrhythmias, which may result in sudden cardiac death. In fact, domperidone, a dopamine D2 antagonist, has been shown to inhibit hERG activity, increasing the risk of long QT syndrome and sudden cardiac death. This has led to the FDA banning its use in the United States and the European Medicines Agency initiating a safety review of its use. Metoclopramide cannot be taken for more than 12 weeks and carries a black box warning due to CNS-related side effects such as tardive dyskinesia, a refractory and often incurable disorder characterized by involuntary, repetitive body movements.

[0007] Metopimazine (MPZ) is a drug approved in France under the trade name Vogalene® (metopimazine, free base) that has been used for 40 years for the short-term treatment of nausea and vomiting. A new salt formulation of MPZ is in clinical development in the United States to treat gastroparesis, a chronic disorder of the stomach characterized by delayed gastric emptying without evidence of mechanical obstruction (Camilleri et al. (2013) "Clinical Guideline: Management of Gastroparesis" Am. J. Gastroenterol, 108:18-38; Stein et al. (2015) "Gastroparesis A Review of Current Diagnosis and Treatment Options" J. Clin. Gastroenterol. 49:550-558; NCT04303195). MPZ is a phenothiazine (1) that undergoes extensive first-pass metabolism in humans (Herrstedt et al., (1990) "The effect of food on serum concentrations of metopimazine" Br. J. Clin. Pharmacol. 30:237-43; Mallet, et al., (2015) "Pharmacokinetic study of metopimainze by oral route in children" Pharma. Res. Per., 3(3):1-7). MPZ is a potent D2 / D3 selective dopamine receptor antagonist that does not cross the blood-brain barrier (De Colle et al., (2016) "A Potent and Selective Dopamine D2 Receptor Antagonist as a Potential Alternative to Metoclopramide and Domperidone for the Treatment of Gastroparesis" AGA Abstracts Volume 150, Issue 4, Supplement 1, S214).Although much is known about MPZ, the metabolism of this drug is not fully understood. MPZ is deaminated to form metopimazine acid (MPZA) (2), the major circulating metabolite, which is present at significantly higher plasma concentrations than its parent (Herrstedt et al., 1990). MPZA retains some pharmacological activity but is approximately 200-fold less potent at human D2 receptors than its parent (De Colle et al., 2016). Given the renewed interest in exploring the potential of MPZ for new clinical indications, identifying the enzymes responsible for the biotransformation of this drug to its primary metabolites is important for understanding any potential impact of metabolic variability on efficacy and safety risks, as well as for evaluating potential drug-drug interactions. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Camilleri et al. (2013) "Clinical Guideline: Management of Gastroparesis" Am. J. Gastroenterol, 108:18-38 [Non-Patent Document 2] Stein et al. (2015) "Gastroparesis A Review of Current Diagnosis and Treatment Options" J. Clin. Gastroenterol. 49:550-558 [Non-Patent Document 3] Herrstedt et al., (1990) "The effect of food on serum concentrations of metopimazine" Br. J. Clin. Pharmacol. 30:237-43 [Non-Patent Document 4] Mallet, et al., (2015) "Pharmacokinetic study of metopimainze by oral route in children" Pharma. Res. Per., 3(3):1-7 [Non-Patent Document 5] De Colle et al., (2016) "A Potent and Selective Dopamine D2 Receptor Antagonist as a Potential Alternative to Metoclopramide and Domperidone for the Treatment of Gastroparesis" AGA Abstracts Volume 150, Issue 4, Supplement 1, S214 Summary of the Invention [Means for solving the problem]

[0009] SUMMARY OF THE APPLICATION The present application relates to an acidic form of metopimazine. [ka] A method for preparing metopimazine [ka] or a pharmaceutically acceptable salt thereof with human microsomal liver amidase. The present application further provides a method for preparing an acid of metopimazine, comprising contacting metopimazine or a pharmaceutically acceptable salt thereof with human liver cytosolic aldehyde oxidase. In certain embodiments of the above-described method, metopimazine or a pharmaceutically acceptable salt thereof is metopimazine mesylate. [ka] It is.

[0010] The present application provides a method of treating gastroparesis in a subject, comprising administering to a human subject in need thereof metopimazine or a pharma- ceutically acceptable salt thereof in combination with an additional therapeutic agent, wherein the additional therapeutic agent is not metabolized by human microsomal hepatic amidase. The present application further provides a method of treating gastroparesis in a subject, comprising administering to a human subject in need thereof metopimazine or a pharma- ceutically acceptable salt thereof in combination with an additional therapeutic agent, wherein the additional therapeutic agent is not metabolized by human hepatic cytosolic aldehyde oxidase. In certain embodiments of the above-mentioned method, the gastroparesis is diabetic gastroparesis. In certain other embodiments of the above-mentioned method, the gastroparesis is idiopathic gastroparesis. In certain embodiments, the gastroparesis comprises a symptom selected from the group consisting of early satiety, post-prandial fullness, abdominal fullness, nausea, vomiting, delayed gastric emptying, diarrhea, abdominal pain, gas, bloating, gastroesophageal reflux, loss of appetite, and constipation. In certain such embodiments, the gastroparesis comprises a symptom of nausea. In other such embodiments, the gastroparesis comprises a symptom of vomiting.

[0011] The present application provides a method of treating nausea associated with gastroparesis in a subject, comprising administering to a human subject in need thereof metopimazine or a pharma- ceutically acceptable salt thereof in combination with an additional therapeutic agent, wherein the additional therapeutic agent is not metabolized by human microsomal hepatic amidase. The present application further provides a method of treating nausea associated with gastroparesis in a subject, comprising administering to a human subject in need thereof metopimazine or a pharma- ceutically acceptable salt thereof in combination with an additional therapeutic agent, wherein the additional therapeutic agent is not metabolized by human hepatic cytosolic aldehyde oxidase.

[0012] The present application provides a method of treating emesis associated with gastroparesis in a subject, comprising administering to a human subject in need thereof metopimazine or a pharma- ceutically acceptable salt thereof in combination with an additional therapeutic agent, wherein the additional therapeutic agent is not metabolized by human microsomal hepatic amidase. The present application further provides a method of treating emesis associated with gastroparesis in a subject, comprising administering to a human subject in need thereof metopimazine or a pharma- ceutically acceptable salt thereof in combination with an additional therapeutic agent, wherein the additional therapeutic agent is not metabolized by human hepatic cytosolic aldehyde oxidase.

[0013] The present application provides a method of improving gastric emptying in a subject, comprising administering to a human subject in need thereof metopimazine or a pharma- ceutically acceptable salt thereof in combination with an additional therapeutic agent, wherein the additional therapeutic agent is not metabolized by human microsomal liver amidase. The present application further provides a method of improving gastric emptying in a subject, comprising administering to a human subject in need thereof metopimazine or a pharma- ceutically acceptable salt thereof in combination with an additional therapeutic agent, wherein the additional therapeutic agent is not metabolized by human liver cytosolic aldehyde oxidase.

[0014] The present application provides a method of treating GI tract dysfunction and motility disorders in a subject, comprising administering to a human subject in need thereof metopimazine or a pharma- ceutically acceptable salt thereof in combination with an additional therapeutic agent, wherein the additional therapeutic agent is not metabolized by human microsomal liver amidase. The present application further provides a method of treating GI tract dysfunction and motility disorders in a subject, comprising administering to a human subject in need thereof metopimazine or a pharma- ceutically acceptable salt thereof in combination with an additional therapeutic agent, wherein the additional therapeutic agent is not metabolized by human liver cytosolic aldehyde oxidase.

[0015] The present application provides a method for treating an enteric nervous system disorder in a subject, comprising administering to a human subject in need thereof metopimazine or a pharma- ceutically acceptable salt thereof in combination with an additional therapeutic agent, wherein the additional therapeutic agent is not metabolized by human microsomal liver amidase. The present application further provides a method for treating an enteric nervous system disorder in a subject, comprising administering to a human subject in need thereof metopimazine or a pharma- ceutically acceptable salt thereof in combination with an additional therapeutic agent, wherein the additional therapeutic agent is not metabolized by human liver cytosolic aldehyde oxidase. 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, ganglioneuroma, multiple endocrine neoplasia type 2B (MEN2B), gastrointestinal neuropathy, functional dyspepsia, gastroesophageal reflux disease (GERD) and intestinal neuronal dysplasia. In certain embodiments, the enteric nervous system disorder comprises a symptom selected from the group consisting of early satiety, postprandial fullness, abdominal bloating, nausea, vomiting, delayed gastric emptying, diarrhea, abdominal pain, gas, bloating, gastroesophageal reflux, loss of appetite and constipation. In certain such embodiments, the enteric nervous system disorder comprises a symptom of nausea. In other such embodiments, the enteric nervous system disorder comprises a symptom of vomiting.

[0016] In certain embodiments of any of the methods described above, metopimazine or a pharma- ceutically acceptable salt thereof is administered chronically to the subject. In certain other embodiments of any of the methods described above, metopimazine or a pharma- ceutically acceptable salt thereof is administered acutely to the subject.

[0017] In certain embodiments of any of the aforementioned methods, metopimazine or a pharma- ceutically acceptable salt thereof is administered to the subject for at least 6 days, at least 7 days, at least 4 weeks, or at least 12 weeks.

[0018] In certain embodiments of any of the aforementioned methods, metopimazine or a pharma- ceutically acceptable salt thereof is administered to the subject once daily, twice daily, three times daily, or four times daily.

[0019] In certain embodiments of any of the above methods, between about 5 mg and about 160 mg of metopimazine or a pharma- ceutically acceptable salt thereof is administered to the subject per day.In certain such embodiments, greater than 20 mg of metopimazine or a pharma- ceutically acceptable salt thereof is administered to the subject per day.

[0020] In certain embodiments of any of the above methods, metopimazine or a pharma- ceutically acceptable salt thereof and the additional therapeutic agent are administered simultaneously in separate compositions. In certain other embodiments of any of the above methods, metopimazine or a pharma- ceutically acceptable salt thereof and the additional therapeutic agent are administered at different times in separate compositions. In certain other embodiments of any of the above methods, metopimazine or a pharma- ceutically acceptable salt thereof and the additional therapeutic agent are administered in a composition in which both agents are present.

[0021] In certain embodiments of any of the above methods, metopimazine or a pharma- ceutically acceptable salt thereof is suitable for administration orally, intraduodenal, intracolonic, intraintestinal, topical, intranasal, parenteral, buccal, sublingual, by inhalation or rectally, such as orally, intraduodenal, intracolonic, parenteral, intraintestinal, intraperitoneal, topical, transdermal, ocular, intranasal, local, parenteral, by spray, subcutaneously, intravenously, intratonsillar, intramuscular, buccal, sublingual, intraarterial, intrathecal, by injection, by inhalation or rectally. In certain such embodiments, metopimazine or a pharma-ceutically acceptable salt thereof is suitable for administration orally. In certain other embodiments, metopimazine or a pharma-ceutically acceptable salt thereof is suitable for administration sublingually.

[0022] In certain embodiments of any of the above methods, metopimazine or a pharma- ceutically acceptable salt thereof is formulated as a tablet, capsule, paste, powder, suspension, suppository, extended release formulation, or modified release formulation, such as formulated as a tablet, capsule, paste, powder, suspension, syrup, enema, suppository, emulsion, liquid, extended release formulation, or modified release formulation. In certain such embodiments, metopimazine or a pharma- ceutically acceptable salt thereof is formulated as an extended release formulation. In certain other embodiments, metopimazine or a pharma- ceutically acceptable salt thereof is formulated as a capsule.

[0023] In certain embodiments of any of the aforementioned methods, the metopimazine or a pharma- ceutically acceptable salt thereof is metopimazine mesylate.

[0024] The present application further provides a pharmaceutical composition comprising metopimazine or a pharma- ceutically acceptable salt thereof in combination with an additional therapeutic agent, wherein the additional therapeutic agent is not metabolized by human microsomal hepatic amidase. The present application further provides a pharmaceutical composition comprising metopimazine or a pharma- ceutically acceptable salt thereof in combination with an additional therapeutic agent, wherein the additional therapeutic agent is not metabolized by human hepatic cytosolic aldehyde oxidase. In certain embodiments of the above-mentioned pharmaceutical composition, the metopimazine or a pharma- ceutically acceptable salt thereof is a pharma- ceutically acceptable salt of metopimazine. In certain such embodiments, the pharma- ceutically acceptable salt of metopimazine is mesylate.

[0025] The present application further provides a method of treating gastroparesis in a subject, comprising administering to a human subject in need thereof a pharmaceutical composition comprising metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) in combination with an additional therapeutic agent, wherein the additional therapeutic agent is not metabolized by human microsomal hepatic amidase and / or is not metabolized by human hepatic cytosolic aldehyde oxidase. In certain embodiments, the gastroparesis is diabetic gastroparesis. In other embodiments, the gastroparesis is idiopathic gastroparesis. In certain embodiments of the above, the gastroparesis comprises a symptom selected from the group consisting of early satiety, postprandial fullness, abdominal distension, nausea, vomiting, delayed gastric emptying, diarrhea, abdominal pain, gas, bloating, gastroesophageal reflux, decreased appetite, and constipation. In certain such embodiments, the gastroparesis comprises a symptom of nausea. In other such embodiments, the gastroparesis comprises the symptom of vomiting.

[0026] A method of treating nausea associated with gastrointestinal paralysis in a human subject in need thereof, comprising administering to a subject a pharmaceutical composition comprising metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate), in combination with an additional therapeutic agent, wherein the additional therapeutic agent is not metabolized by human microsomal hepatic amidase and / or is not metabolized by human hepatic cytosolic aldehyde oxidase.

[0027] A method of treating emesis associated with gastrointestinal paralysis in a subject, comprising administering to a human subject in need thereof a pharmaceutical composition comprising metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate), in combination with an additional therapeutic agent, wherein the additional therapeutic agent is not metabolized by human microsomal hepatic amidase and / or is not metabolized by human hepatic cytosolic aldehyde oxidase.

[0028] A method of improving gastric emptying in a subject comprising administering to a human subject in need thereof a pharmaceutical composition comprising metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) in combination with an additional therapeutic agent, wherein the additional therapeutic agent is not metabolized by human microsomal hepatic amidase and / or is not metabolized by human hepatic cytosolic aldehyde oxidase.

[0029] A method for treating GI tract dysfunction and motility disorders in a human subject in need thereof, comprising administering to a human subject a pharmaceutical composition comprising metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate), in combination with an additional therapeutic agent, wherein the additional therapeutic agent is not metabolized by human microsomal hepatic amidase and / or is not metabolized by human hepatic cytosolic aldehyde oxidase.

[0030] A method of treating an enteric nervous system disorder in a subject, comprising administering to a human subject in need thereof a pharmaceutical composition comprising metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) in combination with an additional therapeutic agent, wherein the additional therapeutic agent is not metabolized by human microsomal hepatic amidase and / or is not metabolized by human hepatic cytosolic aldehyde oxidase. 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 of the above, 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 neurodysplasia. In certain embodiments, the enteric nervous system disorder comprises a symptom selected from the group consisting of early satiety, postprandial fullness, abdominal bloating, nausea, vomiting, delayed gastric emptying, diarrhea, abdominal pain, gas, bloating, gastroesophageal reflux, loss of appetite and constipation.In certain such embodiments, the enteric nervous system disorder comprises a symptom of nausea.In other such embodiments, the enteric nervous system disorder comprises a symptom of vomiting.

[0031] In certain embodiments of any of the methods described above, the pharmaceutical composition is administered chronically to the subject. In certain other embodiments of any of the methods described above, the pharmaceutical composition is administered acutely to the subject.

[0032] In certain embodiments of any of the aforementioned methods, the pharmaceutical composition is administered to the subject for at least 6 days, at least 7 days, at least 4 weeks, or at least 12 weeks.

[0033] In certain embodiments of any of the aforementioned methods, the pharmaceutical composition is administered to the subject once per day, twice per day, three times per day, or four times per day.

[0034] In certain embodiments of any of the above methods, between about 5 mg and about 160 mg of metopimazine or a pharma- ceutically acceptable salt thereof is administered to the subject per day.In certain such embodiments, greater than 20 mg of metopimazine or a pharma- ceutically acceptable salt thereof is administered to the subject per day.

[0035] In certain embodiments of any of the above methods, the pharmaceutical composition is suitable for administration orally, intraduodenal, intracolonic, intraintestinal, topical, intranasal, parenteral, buccal, sublingual, by inhalation or rectally, such as orally, intraduodenal, intracolonic, parenteral, intraintestinal, intraperitoneal, topical, transdermal, ocular, intranasal, local, parenteral, by spray, subcutaneously, intravenously, intratonsillar, intramuscular, buccal, sublingual, intraarterial, intrathecal, by injection, by inhalation or rectally. In certain such embodiments, the pharmaceutical composition is suitable for administration orally. In certain other embodiments, the pharmaceutical composition is suitable for administration sublingually.

[0036] In certain embodiments of any of the above-mentioned methods, the pharmaceutical composition is formulated as a tablet, capsule oil, capsule, gel, paste, powder, suspension, suppository, extended release formulation or modified release formulation, such as formulated as a tablet, capsule, paste, powder, suspension, syrup, enema, suppository, emulsion, liquid, extended release formulation or modified release formulation.In certain such embodiments, the pharmaceutical composition is formulated as an extended release formulation.In certain other embodiments, the pharmaceutical composition is formulated as a capsule. [Brief description of the drawings]

[0037] [Figure 1]1 illustrates the mean (±standard deviation) concentrations of MPZ, MPZA, and MPZS after incubation with 10 μM metopimazine in pooled human liver microsomes, with NADPH and without inhibitor, with NADPH in the presence of the pan-cytochrome P450 inhibitor 1-ABT, and with neither NADPH nor inhibitor. MPZA is unaffected by ABT or by the absence of NADPH, while MPZS is strongly inhibited by ABT and does not form in the absence of NADPH. [Diagram 2] Figure 2 illustrates the peak area ratios of MPZ, MPZA, MPZS and MPZH from the same sample. MPZA is not affected by CYP inhibition or by the absence of NADPH, while MPZH and MPZS are inhibited in the presence of ABT and are not produced in the absence of NADPH. [Diagram 3] Figure 3 illustrates the mean (± standard deviation) concentrations of MPZ, MPZA, and MPZS following a 60-minute incubation of 1 μM MPZ with HLM with inhibitors specific for seven common cytochrome P450 enzymes, respectively. MPZS formation was inhibited by the presence of the CYP3A4 / 5 inhibitor itraconazole. [Figure 4] Figure 4 illustrates the PAR of metopimazine and its metabolites upon incubation of 1 μM metopimazine with certain recombinant CYP enzymes, where H means that MPZH was produced by CYP2D6 and S indicates that MPZS was produced by CYP3A4. [Diagram 5] Figure 5 illustrates the mean (± standard deviation) concentrations of metopimazine, MPZA, and MPZS following incubation of 1 μM metopimazine with specific recombinant CYP isoforms for 60 min. MPZS was produced primarily by CYP3A4, but not by CYP3A5. [Figure 6]Figure 6 illustrates the mean (± standard deviation) concentrations of metopimazine, MPZA and MPZS after incubation of 1 μM metopimazine in mixed pooled HKM in the presence of NADPH in triplicate at pH 8.4. Heat inactivation (5 min, 50°C) and the presence and absence of the FMO inhibitor methimazole were all tested. No metabolites were formed under any condition. [Figure 7] FIG. 7 illustrates the mean (±standard deviation) concentrations of MPZ, MPZA and MPZS following incubation with recombinant FMO enzymes at 1 μM MPZ. [Figure 8] FIG. 8 illustrates the formation of MPZA (in nM (mean ± standard deviation)) following incubation of 10 μM metopimazine in HLM for 60 minutes in the absence and presence of 2 μM and 16 μM of the known amidase inhibitor BNPP at pH 7.4, 8.4, and 9.4. MPZA production occurs at all pHs and is increased at higher than physiological pH, including pH 9.4. The amidase inhibitor BNPP effectively inhibits MPZA formation under all conditions. [Figure 9] Figure 9 illustrates the metabolism of metopimazine in humans, showing the formation of the major metabolite MPZA in vivo, which is formed primarily by hepatic amidase and to a lesser extent by cytosolic aldehyde oxidase. A minor amount of the CYP-mediated metabolite MPZS was also present in human samples. [Figure 10] Figure 10 illustrates representative total ion chromatograms of MPZS quantified by monitoring the transition 462.3→98.1 m / z. Unidentified isobaric peaks were observed in some samples (marked with arrows). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0038] Detailed Description of the Application The present application relates to an acidic form of metopimazine. [ka] A method for preparing metopimazine [ka] or a pharmaceutically acceptable salt thereof with human microsomal liver amidase. The present application further provides a method for preparing an acid of metopimazine, comprising contacting metopimazine or a pharmaceutically acceptable salt thereof with human liver cytosolic aldehyde oxidase. In certain embodiments of the above-described method, metopimazine or a pharmaceutically acceptable salt thereof is metopimazine mesylate. [ka] It is.

[0039] The present application provides a method for preparing an acid of metopimazine, comprising contacting a pharmaceutically acceptable salt of metopimazine with human microsomal liver amidase. The present application further provides a method for preparing an acid of metopimazine, comprising contacting a pharmaceutically acceptable salt of metopimazine with human liver cytosolic aldehyde oxidase. In certain embodiments of the above-mentioned method, the pharmaceutically acceptable salt of metopimazine is mesylate.

[0040] The present application provides a method of treating gastroparesis in a subject, comprising administering to a human subject in need thereof metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) in combination with an additional therapeutic agent, wherein the additional therapeutic agent is not metabolized by human microsomal liver amidase. The present application further provides a method of treating gastroparesis in a subject, comprising administering to a human subject in need thereof metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) in combination with an additional therapeutic agent, wherein the additional therapeutic agent is not metabolized by human hepatic cytosolic aldehyde oxidase. In certain embodiments, the additional therapeutic agent is not metabolized by human microsomal liver amidase and is not metabolized by human hepatic cytosolic aldehyde oxidase. In certain embodiments of the above-mentioned methods of treating gastroparesis, the gastroparesis is diabetic gastroparesis. In certain other embodiments of the above-mentioned method of treating gastroparesis, gastroparesis is idiopathic gastroparesis.In certain embodiments, gastroparesis comprises symptoms selected from the group consisting of early satiety, postprandial fullness, abdominal distension, nausea, vomiting, delayed gastric emptying, diarrhea, abdominal pain, gas, bloating, gastroesophageal reflux, loss of appetite and constipation.In certain such embodiments, gastroparesis comprises symptoms of nausea.In other such embodiments, gastroparesis comprises symptoms of vomiting.In certain embodiments of the above-mentioned method of treating gastroparesis, the additional therapeutic agent is an additional agent useful for treating gastroparesis, such as motilin agonist, ghrelin agonist, 5HT3 antagonist, D2 antagonist or 5HT4 agonist. In other embodiments of the above-described methods of treating gastroparesis, the additional therapeutic agent is an agent useful for treating a co-occurring condition, such as an agent useful for treating GERD, IBS, IBD, constipation, diarrhea, or pain.

[0041] The present application provides a method of treating nausea associated with gastroparesis in a subject, comprising administering to a human subject in need thereof metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) in combination with an additional therapeutic agent, where the additional therapeutic agent is not metabolized by human microsomal hepatic amidase. The present application further provides a method of treating nausea associated with gastroparesis in a subject, comprising administering to a human subject in need thereof metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) in combination with an additional therapeutic agent, where the additional therapeutic agent is not metabolized by human hepatic cytosolic aldehyde oxidase.

[0042] The present application provides a method of treating emesis associated with gastroparesis in a subject, comprising administering to a human subject in need thereof metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) in combination with an additional therapeutic agent, where the additional therapeutic agent is not metabolized by human microsomal hepatic amidase. The present application further provides a method of treating emesis associated with gastroparesis in a subject, comprising administering to a human subject in need thereof metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) in combination with an additional therapeutic agent, where the additional therapeutic agent is not metabolized by human hepatic cytosolic aldehyde oxidase.

[0043] The present application provides a method of improving gastric emptying in a subject, comprising administering to a human subject in need thereof metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) in combination with an additional therapeutic agent, where the additional therapeutic agent is not metabolized by human microsomal hepatic amidase. The present application further provides a method of improving gastric emptying in a subject, comprising administering to a human subject in need thereof metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) in combination with an additional therapeutic agent, where the additional therapeutic agent is not metabolized by human hepatic cytosolic aldehyde oxidase.

[0044] The present application provides a method of treating GI tract dysfunction and motility disorders in a subject, comprising administering to a human subject in need thereof metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) in combination with an additional therapeutic agent, wherein the additional therapeutic agent is not metabolized by human microsomal hepatic amidase. The present application further provides a method of treating GI tract dysfunction and motility disorders in a subject, comprising administering to a human subject in need thereof metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) in combination with an additional therapeutic agent, wherein the additional therapeutic agent is not metabolized by human hepatic cytosolic aldehyde oxidase.

[0045] The present application provides a method of treating an enteric nervous system disorder in a subject, comprising administering to a human subject in need thereof metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) in combination with an additional therapeutic agent, wherein the additional therapeutic agent is not metabolized by human microsomal hepatic amidase. The present application further provides a method of treating an enteric nervous system disorder in a subject, comprising administering to a human subject in need thereof metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) in combination with an additional therapeutic agent, wherein the additional therapeutic agent is not metabolized by human hepatic cytosolic aldehyde oxidase. 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, ganglioneuroma, multiple endocrine neoplasia type 2B (MEN2B), gastrointestinal neuropathy, functional dyspepsia, gastroesophageal reflux disease (GERD) and enteric neurodysplasia.In certain embodiments, the enteric nervous system disorder comprises a symptom selected from the group consisting of early satiety, postprandial fullness, abdominal bloating, nausea, vomiting, delayed gastric emptying, diarrhea, abdominal pain, gas, bloating, gastroesophageal reflux, loss of appetite and constipation.In certain such embodiments, the enteric nervous system disorder comprises a symptom of nausea.In other such embodiments, the enteric nervous system disorder comprises a symptom of vomiting.

[0046] In certain embodiments of any of the methods disclosed herein, metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) is administered chronically to the subject. In certain other embodiments of any of the methods disclosed herein, metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) is administered acutely to the subject.

[0047] In certain embodiments of any of the methods disclosed herein, metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) is administered to the subject for at least 6 days. In certain embodiments of any of the methods disclosed herein, metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) is administered to the subject for at least 7 days. In certain embodiments of any of the methods disclosed herein, metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) is administered to the subject for at least 4 weeks. In certain embodiments of any of the methods disclosed herein, metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) is administered to the subject for at least 12 weeks.

[0048] In certain embodiments of any of the methods disclosed herein, metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) is administered to the subject once a day. In certain embodiments of any of the methods disclosed herein, metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) is administered to the subject twice a day. In certain embodiments of any of the methods disclosed herein, metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) is administered to the subject three times a day. In certain embodiments of any of the methods disclosed herein, metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) is administered to the subject four times a day.

[0049] In certain embodiments of any of the methods disclosed herein, between about 5 mg and about 160 mg of metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) is administered to the subject per day. In certain embodiments of any of the methods disclosed herein, more than 20 mg of metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) is administered to the subject per day. In certain embodiments of any of the methods disclosed herein, more than 30 mg of metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) is administered to the subject per day. In certain embodiments of any of the methods disclosed herein, between about 5 mg and about 240 mg of metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) is administered to the subject per day, such as about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 80 mg, about 90 mg, about 100 mg, about 120 mg, about 150 mg, about 160 mg, about 180 mg, about 200 mg, about 240 mg of metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) is administered to the subject per day. In certain embodiments of any of the methods disclosed herein, about 5 mg of metopimazine or a pharma- ceutically acceptable salt thereof (e.g., metopimazine mesylate, etc.) is administered to the subject once, twice, three times, or four times per day.In certain embodiments of any of the methods disclosed herein, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, or about 60 mg of metopimazine or a pharma- ceutically acceptable salt thereof (e.g., metopimazine mesylate, etc.) is administered to the subject once, twice, three times, or four times per day.In certain embodiments of any of the methods disclosed herein, about 40 mg of metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma-ceutically acceptable salt of metopimazine, such as metopimazine mesylate) is administered to the subject four times a day. In certain embodiments of any of the methods disclosed herein, about 60 mg of metopimazine or a pharma-ceutically acceptable salt thereof (e.g., a pharma-ceutically acceptable salt of metopimazine, such as metopimazine mesylate) is administered to the subject four times a day.

[0050] In certain embodiments of any of the methods disclosed herein, metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) and the additional therapeutic agent are administered simultaneously in separate compositions. In certain other embodiments of any of the methods disclosed herein, metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) and the additional therapeutic agent are administered at different times in separate compositions. In certain other embodiments of any of the methods disclosed herein, metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) and the additional therapeutic agent are administered in a composition in which both agents are present.

[0051] In certain embodiments of any of the methods disclosed herein, metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) is suitable for administration orally, intraduodenal, intracolonic, intraintestinal, topical, intranasal, parenteral, buccal, sublingual, by inhalation, or rectally, such as orally, intraduodenal, intracolonic, parenteral, intraintestinal, intraperitoneal, topical, transdermal, ocular, intranasal, local, parenteral, by spray, subcutaneously, intravenously, intratonsillar, intramuscular, buccal, sublingual, intraarterial, intrathecal, by injection, by inhalation, or rectally. In certain such embodiments, metopimazine or a pharma-ceutically acceptable salt thereof (e.g., a pharma-ceutically acceptable salt of metopimazine, such as metopimazine mesylate) is suitable for administration orally. In certain other embodiments, metopimazine or a pharma- ceutically acceptable salt thereof (eg, a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) is suitable for sublingual administration.

[0052] In certain embodiments of any of the methods disclosed herein, metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) is formulated as a tablet, capsule, paste, powder, suspension, suppository, extended release formulation, or modified release formulation, such as formulated as a tablet, capsule, paste, powder, suspension, syrup, enema, suppository, emulsion, liquid, extended release formulation, or modified release formulation. In certain such embodiments, metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) is formulated as an extended release formulation. In certain other embodiments, metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) is formulated as a capsule.

[0053] In certain embodiments of any of the methods disclosed herein, the metopimazine or a pharma- ceutically acceptable salt thereof is metopimazine mesylate.

[0054] The present application further provides a pharmaceutical composition comprising metopimazine or a pharma- ceutically acceptable salt thereof in combination with an additional therapeutic agent, wherein the additional therapeutic agent is not metabolized by human microsomal liver amidase. The present application further provides a pharmaceutical composition comprising metopimazine or a pharma- ceutically acceptable salt thereof in combination with an additional therapeutic agent, wherein the additional therapeutic agent is not metabolized by human hepatic cytosolic aldehyde oxidase. In certain embodiments, the additional therapeutic agent is not metabolized by human microsomal liver amidase and is not metabolized by human hepatic cytosolic aldehyde oxidase. In certain embodiments of the above-mentioned pharmaceutical composition, metopimazine or a pharma- ceutically acceptable salt thereof is a pharma- ceutically acceptable salt of metopimazine. In certain such embodiments, the pharma- ceutically acceptable salt of metopimazine is mesylate.

[0055] The present application further provides a method of treating gastroparesis in a subject, comprising administering to a human subject in need thereof a pharmaceutical composition comprising metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) in combination with an additional therapeutic agent, wherein the additional therapeutic agent is not metabolized by human microsomal hepatic amidase and / or is not metabolized by human hepatic cytosolic aldehyde oxidase. In certain embodiments, the gastroparesis is diabetic gastroparesis. In other embodiments, the gastroparesis is idiopathic gastroparesis. In certain embodiments of the above, the gastroparesis comprises a symptom selected from the group consisting of early satiety, postprandial fullness, abdominal distension, nausea, vomiting, delayed gastric emptying, diarrhea, abdominal pain, gas, bloating, gastroesophageal reflux, decreased appetite, and constipation. In certain such embodiments, the gastroparesis comprises a symptom of nausea. In other such embodiments, the gastroparesis comprises the symptom of vomiting.

[0056] A method of treating nausea associated with gastrointestinal paralysis in a human subject in need thereof, comprising administering to a subject a pharmaceutical composition comprising metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate), in combination with an additional therapeutic agent, wherein the additional therapeutic agent is not metabolized by human microsomal hepatic amidase and / or is not metabolized by human hepatic cytosolic aldehyde oxidase.

[0057] A method of treating emesis associated with gastrointestinal paralysis in a subject, comprising administering to a human subject in need thereof a pharmaceutical composition comprising metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate), in combination with an additional therapeutic agent, wherein the additional therapeutic agent is not metabolized by human microsomal hepatic amidase and / or is not metabolized by human hepatic cytosolic aldehyde oxidase.

[0058] A method of improving gastric emptying in a subject comprising administering to a human subject in need thereof a pharmaceutical composition comprising metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) in combination with an additional therapeutic agent, wherein the additional therapeutic agent is not metabolized by human microsomal hepatic amidase and / or is not metabolized by human hepatic cytosolic aldehyde oxidase.

[0059] A method for treating GI tract dysfunction and motility disorders in a human subject in need thereof, comprising administering to a human subject a pharmaceutical composition comprising metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate), in combination with an additional therapeutic agent, wherein the additional therapeutic agent is not metabolized by human microsomal hepatic amidase and / or is not metabolized by human hepatic cytosolic aldehyde oxidase.

[0060] A method of treating an enteric nervous system disorder in a subject, comprising administering to a human subject in need thereof a pharmaceutical composition comprising metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) in combination with an additional therapeutic agent, wherein the additional therapeutic agent is not metabolized by human microsomal hepatic amidase and / or is not metabolized by human hepatic cytosolic aldehyde oxidase. 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 of the above, 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 neurodysplasia. In certain embodiments, the enteric nervous system disorder comprises a symptom selected from the group consisting of early satiety, postprandial fullness, abdominal bloating, nausea, vomiting, delayed gastric emptying, diarrhea, abdominal pain, gas, bloating, gastroesophageal reflux, loss of appetite and constipation.In certain such embodiments, the enteric nervous system disorder comprises a symptom of nausea.In other such embodiments, the enteric nervous system disorder comprises a symptom of vomiting.

[0061] In certain embodiments of any of the methods described above, the pharmaceutical composition is administered chronically to the subject. In certain other embodiments of any of the methods described above, the pharmaceutical composition is administered acutely to the subject.

[0062] In certain embodiments of any of the methods disclosed herein, the pharmaceutical composition is administered to the subject for at least 6 days.In certain embodiments of any of the methods disclosed herein, the pharmaceutical composition is administered to the subject for at least 7 days.In certain embodiments of any of the methods disclosed herein, the pharmaceutical composition is administered to the subject for at least 4 weeks.In certain embodiments of any of the methods disclosed herein, the pharmaceutical composition is administered to the subject for at least 12 weeks.

[0063] In certain embodiments of any of the methods disclosed herein, the pharmaceutical composition is administered to the subject once a day.In certain embodiments of any of the methods disclosed herein, the pharmaceutical composition is administered to the subject twice a day.In certain embodiments of any of the methods disclosed herein, the pharmaceutical composition is administered to the subject three times a day.In certain embodiments of any of the methods disclosed herein, the pharmaceutical composition is administered to the subject four times a day.

[0064] In certain embodiments of any of the methods disclosed herein, between about 5 mg and about 160 mg of metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) is administered to the subject per day. In certain embodiments of any of the methods disclosed herein, more than 20 mg of metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) is administered to the subject per day. In certain embodiments of any of the methods disclosed herein, more than 30 mg of metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) is administered to the subject per day. In certain embodiments of any of the methods disclosed herein, between about 5 mg and about 240 mg of metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) is administered to the subject per day, such as about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 80 mg, about 90 mg, about 100 mg, about 120 mg, about 150 mg, about 160 mg, about 180 mg, about 200 mg, about 240 mg of metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) is administered to the subject per day. In certain embodiments of any of the methods disclosed herein, about 5 mg of metopimazine or a pharma- ceutically acceptable salt thereof (e.g., metopimazine mesylate, etc.) is administered to the subject once, twice, three times, or four times per day.In certain embodiments of any of the methods disclosed herein, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, or about 60 mg of metopimazine or a pharma- ceutically acceptable salt thereof (e.g., metopimazine mesylate, etc.) is administered to the subject once, twice, three times, or four times per day.In certain embodiments of any of the methods disclosed herein, about 40 mg of metopimazine or a pharma- ceutically acceptable salt thereof (e.g., metopimazine mesylate, etc.) is administered to the subject four times a day. In certain embodiments of any of the methods disclosed herein, about 60 mg of metopimazine or a pharma-ceutically acceptable salt thereof (e.g., metopimazine mesylate, etc.) is administered to the subject four times a day.

[0065] In certain embodiments of any of the above methods, the pharmaceutical composition is suitable for administration orally, intraduodenal, intracolonic, intraintestinal, topical, intranasal, parenteral, buccal, sublingual, by inhalation or rectally, such as orally, intraduodenal, intracolonic, parenteral, intraintestinal, intraperitoneal, topical, transdermal, ocular, intranasal, local, parenteral, by spray, subcutaneously, intravenously, intratonsillar, intramuscular, buccal, sublingual, intraarterial, intrathecal, by injection, by inhalation or rectally. In certain such embodiments, the pharmaceutical composition is suitable for administration orally. In certain other embodiments, the pharmaceutical composition is suitable for administration sublingually.

[0066] In certain embodiments of any of the above-mentioned methods, the pharmaceutical composition is formulated as a tablet, capsule oil, capsule, gel, paste, powder, suspension, suppository, extended release formulation or modified release formulation, such as formulated as a tablet, capsule, paste, powder, suspension, syrup, enema, suppository, emulsion, liquid, extended release formulation or modified release formulation.In certain such embodiments, the pharmaceutical composition is formulated as an extended release formulation.In certain other embodiments, the pharmaceutical composition is formulated as a capsule.

[0067] In certain embodiments of any of the above-mentioned methods, metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) is administered as a pharmaceutical composition comprising an effective amount of metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) and a pharma- cetically acceptable diluent or carrier. In certain such embodiments, the composition further comprises an additional therapeutic agent, wherein the additional therapeutic agent is not metabolized by human microsomal hepatic amidase. In other such embodiments, the composition further comprises an additional therapeutic agent, wherein the additional therapeutic agent is not metabolized by human hepatic cytosolic aldehyde oxidase.

[0068] definition As used in this specification and claims, the singular forms "a," "an," and "the" include plural references unless specifically and clearly dictates otherwise. For example, the term "a cell" includes a plurality of cells, including mixtures thereof.

[0069] 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. Agonists generally mimic the action of an endogenous ligand (such as, for example, dopamine) that binds to the same receptor.

[0070] The term "antagonist" as used herein refers to a molecule, such as a compound, that reduces, inhibits or prevents the cellular response to a receptor that is activated by an agonist. Antagonists can include, but are not limited to, competitive antagonists, non-competitive antagonists, uncompetitive antagonists, partial agonists and inverse agonists. Competitive antagonists can reversibly bind to a receptor at the same binding site (active site) as an endogenous ligand or agonist, without necessarily activating the receptor. Non-competitive antagonists (also known as allosteric antagonists) can bind to a binding site distinctly different from that of agonists and exert antagonistic effects on the receptor through the different binding site. Non-competitive antagonists generally do not compete with agonists for binding. The binding of a non-competitive antagonist to a receptor can reduce the affinity of an agonist to the receptor. Alternatively, the binding of a non-competitive antagonist to a receptor may prevent the conformational changes of the receptor required for agonist-mediated receptor activation. A non-competitive antagonist may require receptor activation by an agonist before it can bind to a separate allosteric binding site. A partial agonist may refer to a molecule that may elicit a difference in the magnitude of functional response at a given receptor after maximal receptor occupancy. Although a partial agonist is an agonist, it can act as a competitive antagonist when co-administered with a full agonist, as it competes with a full agonist for receptor occupancy, resulting in a net reduction in receptor activation observed with a full agonist alone. An inverse agonist can have an effect similar to an antagonist, but causes a series of distinct downstream biological responses. Constitutively active receptors that exhibit intrinsic or basal activity can have inverse agonists that not only block the action of bound agonists like conventional antagonists, but also inhibit the basal activity of the receptor.

[0071] As used herein, "gastrointestinal (GI) tract" refers to the portion of the digestive tract where significant absorption is observed. As one of ordinary skill in the art would readily appreciate, significant absorption is generally observed in the oral cavity, the small intestine (e.g., the duodenum, jejunum, and ileum), and the large intestine (e.g., the colon).

[0072] As used herein, "metopimazine mesylate" refers to 1-(3-(2-(methylsulfonyl)-10H-phenothiazin-10-yl)propyl)piperidine-4-carboxamide methanesulfonic acid.

[0073] As used herein, "oral cavity" refers generally to the mouth and includes the lips, cheeks and inner lining of the lips, tongue, upper and lower gums, floor of the mouth under the tongue, sublingual mucosa, upper mouth, and the area behind the wisdom teeth.

[0074] As used herein, "peripherally restricted" compound generally refers to a compound that does not substantially pass through the intact blood-brain barrier of a subject.This term also encompasses compounds that can pass through the intact blood-brain barrier, but when administered to a subject, are rapidly metabolized into a form that does not substantially pass through the intact blood-brain barrier of a subject.A compound can be considered to be "peripherally restricted" if, when administered to a subject, less than 50%, less than 45%, less than 40%, less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1% of the compound passes through the intact blood-brain barrier of a subject.

[0075] The term "solvate" refers to a crystalline solid adduct that contains either stoichiometric or non-stoichiometric amounts of a solvent incorporated into the crystal structure. Thus, the term "non-solvate" form, as used herein, refers to a salt crystal that does not contain or is substantially free of solvent molecules within the crystal structure of the present invention. Similarly, the term "non-hydrate form" refers to a salt crystal that does not contain or is substantially free of water molecules within the crystal structure of the present invention.

[0076] As used herein, the terms "treatment" or "treating" are used interchangeably herein. These terms refer to an approach to obtain beneficial or desired results, including, but not limited to, therapeutic benefit and / or preventive benefit. Therapeutic benefit can mean eradication or improvement of the underlying disorder being treated. Similarly, therapeutic benefit can be achieved by eradication or improvement of one or more of the physiological symptoms associated with the underlying disorder, such that the subject may still suffer from the underlying disorder, but improvement is observed in the subject. Preventive effects include delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, stopping or reversing the progression of a disease or condition, or any combination thereof. With regard to preventive benefit, the 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 diagnosis of this disease has not been made.

[0077] A "sub-therapeutic amount" of a drug is an amount less than the effective amount for that drug. When combined with an effective or sub-therapeutic amount of one or more additional drugs, the sub-therapeutic amount can produce a result desired by the physician, for example, due to synergy with the beneficial effect produced or the reduction of adverse effects.

[0078] A "synergistically effective" therapeutic amount or "synergistically effective" amount of a drug or treatment is an amount that, when combined with an effective or subtherapeutic amount of one or more additional drugs, produces a greater effect than any of these drugs used alone. In some embodiments, a synergistically effective therapeutic amount of a drug or treatment produces an effect when used in combination that is greater than the additive effect of any of the individual drugs used alone. The term "greater effect" encompasses not only the alleviation of symptoms of the disorder being treated, but also improved side effect profile, improved tolerability, improved patient compliance, improved efficacy, or any other improved clinical outcome.

[0079] The terms "co-administration," "administration in combination," and their grammatical equivalents, as used herein, encompass 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 administration at the same time in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.

[0080] The terms "determining," "measuring," "evaluating," "assessing," "assaying," and "analyzing" are used interchangeably herein and refer to any form of measurement, including determining whether an element is present or not. These terms include both quantitative and / or qualitative determinations. Evaluating may be relative or absolute. "Assessing the presence of" includes determining the amount of something present, as well as determining whether it is present or absent.

[0081] Example Subjects The pharmaceutical compositions and / or combinations disclosed herein can be used to treat disorders in subjects in need thereof. The subjects can be suffering from, diagnosed with, or showing symptoms of disorders, or suspected of having disorders. The disorders can be gastrointestinal disorders, enteric nervous system disorders, or other disorders. The disorders can be characterized by hypomotility of at least a portion of the gastrointestinal tract. For example, the disorders can be characterized by hypomotility of the stomach and / or intestine. Hypomotility can be caused by abnormal ENS neuronal signaling, for example, by abnormal dopamine signaling activity.

[0082] In some embodiments, the enteric nervous system disorder is gastroparesis. The terms "gastrotropia" and "delayed gastric emptying" are used interchangeably herein to refer to, for example, a disorder that slows or stops the movement of food from the stomach to the small intestine. Normally, the stomach muscles controlled by the vagus nerve are responsible for breaking down food and moving it to the gastrointestinal (GI) tract. Gastrotropia can occur, for example, when the vagus nerve is damaged by disease or injury, causing the stomach muscles to stop working normally. In subjects with gastroparesis, food can move slowly from the stomach to the small intestine or may stop moving altogether. Thus, subjects may suffer from gastroparesis, may be diagnosed with gastroparesis, may show symptoms of gastroparesis, or may be suspected of having gastroparesis.

[0083] If a subject shows or shows symptoms of gastroparesis, it may be suspected that the subject has gastroparesis. Symptoms of gastroparesis may include gastroesophageal reflux (GER), also called acid reflux or gastric reflux. Gastroesophageal reflux generally refers to the condition in which stomach contents flow backwards and back up into the esophagus. Other symptoms associated with gastroparesis include, but are not limited to, early satiety, postprandial fullness, abdominal distension, abdominal pain and / or burning sensation in the stomach area, abdominal bloating, loss of appetite, anorexia, malnutrition, nausea and vomiting. Symptoms of gastroparesis may be mild, moderate or severe, and may occur frequently or irregularly. Symptoms of gastroparesis may vary in severity over time in the same subject. Thus, the subject may exhibit or is exhibiting GER, early satiety, postprandial fullness, abdominal bloating, abdominal pain and / or burning in the stomach area, abdominal distension, loss of appetite, anorexia, malnutrition, nausea and / or vomiting.

[0084] A subject may be diagnosed with gastroparesis. Gastrotroparesis can be diagnosed by any means known to those skilled in the art or otherwise described herein. Gastrotroparesis can be diagnosed, for example, by physical examination, medical history, blood test, tests to exclude blockage or structural problems in the GI tract, gastric emptying assay, and assay of GI contractile activity. Tests may also identify nutritional disorders or underlying diseases. Tests useful for diagnosing gastroparesis include, but are not limited to, upper gastrointestinal (GI) endoscopy, upper GI imaging, ultrasound, gastric emptying scintigraphy, gastric emptying breath test, intraantral manometry, electrogastrography and / or electrogastroenterography.

[0085] Upper GI endoscopy can be used to exclude other conditions (e.g., physical obstruction, etc.) that may cause delayed gastric emptying. Upper GI endoscopy usually 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 show physical obstructions in the upper GI tract, such as large gastroliths (e.g., solid deposits of food, mucus, dietary fiber, hair, or other substances). In some embodiments, if a subject shows symptoms of gastroparesis and upper GI endoscopy does not reveal a physical obstruction that causes delayed gastric emptying, the subject is diagnosed with gastroparesis.

[0086] An upper GI scan can be performed to view the small intestine. This test may be performed in a hospital or outpatient facility by an X-ray technician, and the images may be interpreted by a radiologist. During the procedure, the subject may stand or sit in front of an X-ray machine and drink barium, a powdery liquid. The barium coats the small intestine, making signs of gastroparesis more visible on an X-ray. Gastrotropia may be indicated when an X-ray shows food in the stomach after fasting. In some embodiments, a subject is diagnosed with gastroparesis when an upper GI scan reveals food in the stomach after fasting.

[0087] Ultrasound can be useful in ruling out other syndromes that may share common symptoms with gastroparesis. Such other syndromes include gallbladder disease and pancreatitis. Ultrasound generally uses a device called a transducer that bounces safe, painless sound waves off organs to create images of their structures. The procedure can be performed in a health care provider's office, an outpatient facility, or a hospital by a specially trained technician. The ultrasound images can be interpreted by a radiologist. If a subject shows 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.

[0088] Gastric emptying scintigraphy can be used to diagnose gastroparesis in subjects. Gastric emptying scintigraphy can include the ingestion of a bland tasting meal, such as eggs or egg substitutes, containing a small amount of radioactive material. The radioactive material can be 99-M Technetium (TC) sulfur colloid, or other radioactive ligand. The test can be performed at a radiology facility or hospital. An external camera can be used to detect and / or measure radioactivity in the abdominal area. Radioactivity can be measured at time intervals, for example, 1, 2, 3, and 4 hours after a meal. Gastroparesis can be identified as positive in subjects who demonstrate 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 when 50% of the meal is emptied from the stomach. See, e.g., Thomforde, GM et al., Evaluation of an inexpensive screening scintigraphic test of gastric emptying, 36 J. Nucl. Med. 93 (1995), incorporated herein by reference. In some embodiments, a subject is diagnosed with gastroparesis by gastric emptying scintigraphy.

[0089] A breath test useful for assessing gastric emptying involves the administration of radioactively labeled food (e.g., C 13 1-octanoic acid) can be used. 13 Once it reaches the small intestine, it can be absorbed. 13 is then rapidly metabolized in the liver to 13 CO2 can be generated. 13 CO2 can be detected in the breath of a subject. The breath of a subject can be collected and sampled at regular intervals. 13 CO2 can be analyzed by any means known in the art. 13 The rate at which CO2 appears can be used to indicate the rate of gastric emptying. 13An exemplary method for performing an -octanoic acid breath test is described in Ghoos, YS, et al., 104 Gastroenterology 1640-1647 (1993), which is incorporated herein by reference. In some embodiments, a subject is diagnosed with gastroparesis by a breath test.

[0090] Manometry generally refers to the evaluation of pressure changes in the lumen. Intraantral manometry, which may also be referred to as antroduodenal manometry, generally refers to a technique for the evaluation of contractile activity in the distal stomach and duodenum. Intraluminal pressure in the stomach and / or duodenum can be measured by a pressure sensor introduced into the lumen by a catheter. Measurements can be recorded over time to evaluate changes in intraluminal pressure. Recordings may continue 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). Reduced postprandial contractile motility can indicate gastroparesis in a subject. Thus, a subject may exhibit reduced postprandial gastric motility as determined by manometry.

[0091] Electrogastrography generally refers to techniques and methods for recording electrical activity of the stomach. Similarly, electrogastrography refers to techniques and methods for recording electrical activity of the stomach and small intestine. Such electrical activity can be recorded from the gastrointestinal mucosa, serosa, or external skin surface (skin). 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. Recording can be performed during fasting and after ingestion of a meal (usually for 60 minutes). Deviations from the normal frequency of electrical activity can include slow waves and / or fast waves. Control subjects usually show increased electrical activity after a meal, indicating improved GI motility. Subjects with abnormal GI motility can show abnormal rhythms of activity and / or impaired improvement after a meal. The normal frequency of GI electrical activity can be, for example, 3 cycles per minute. Slow waves, which can be characterized as a frequency of GI electrical activity that is reduced from normal, for example, less than 2 cycles per minute for at least 1 minute, can indicate gastroparesis. In some embodiments, a subject can exhibit slow waves. Electrogastrography (EGG), which measures electrical activity using skin electrodes similar to those used in electrocardiograms, can also be used to diagnose gastroparesis. (Stern, RN et al. EGG: Common issues in validation and methodology, 24 Psychophysiology 55-64 (1987)), incorporated herein by reference. Thus, a subject can be diagnosed with gastroparesis as determined by electrogastrography.

[0092] The subject may suffer from, be diagnosed with, show symptoms of, or be suspected of having GERD. GERD may be a chronic condition that results in GERD. GERD symptoms include, for example, heartburn, chronic dry cough, wheezing, asthma, recurrent pneumonia, nausea, vomiting, sore throat, difficulty swallowing, chest or upper abdominal pain, dental erosion, halitosis, and spitting. GERD may be diagnosed with the aid of tests. Tests useful for diagnosing GERD include, for example, upper GI imaging, upper endoscopy, esophageal pH monitoring, and esophageal manometry, as described herein.

[0093] The subject may suffer from, be diagnosed with, exhibit symptoms of, or be suspected of having an enteric nervous system disorder associated with otovestibular disorders. The otovestibular disorder may be Ménétrier's disease. Ménétrier's disease may be characterized by the expansion of the ridges (also referred to herein as folds) along the inside of the stomach wall, forming giant folds in the stomach lining. Ménétrier's disease may also cause reduced stomach acid due to a reduction in acid-producing parietal cells. Symptoms of Ménétrier's disease include, by way of example only, severe stomach pain, nausea, frequent vomiting, and the like.

[0094] The subject may suffer from, be diagnosed with, show symptoms of, or be suspected of having Cyclic Vomiting Syndrome (CVS). Cyclic vomiting syndrome can be characterized by episodes or cycles of severe nausea and vomiting alternating with asymptomatic periods. Such episodes can last for hours or even days. Episodes can begin at the same time of day, last the same length of time, and occur with the same symptoms and intensity levels. Episodes can be so severe that a person must stay in bed for several days and cannot 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. Continuous 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 subjects who have experienced the following symptoms for at least three months: vomiting episodes lasting less than one week beginning with severe vomiting several times per hour, three or more separate vomiting episodes in the past year, and no nausea or vomiting between episodes.

[0095] A subject may suffer from, be diagnosed with, show symptoms of, or be suspected of having irritable bowel syndrome (IBS). IBS generally refers to a syndrome that includes multiple subtypes, in which a subject experiences recurrent or chronic gastrointestinal symptoms. IBS symptoms may include, for example, abdominal pain, abdominal discomfort, constipation, diarrhea, mucus in stool, abdominal bloating, or any combination of the above. IBS may be diagnosed when a person has abdominal pain or discomfort at least three times per month for the last three months, without other diseases or injuries that can explain the pain. IBS pain or discomfort may occur with changes in stool frequency or consistency, or may be relieved by defecation. IBS may be classified into four subtypes based on the subject's usual stool consistency. The four subtypes of IBS are: IBS with constipation (IBS-C), IBS with diarrhea (IBS-D), mixed IBS (IBS-M) and IBS unclassified (IBS-U). Subjects with IBS-C may have hard or stool-like stool at least 25% of the time, and may have loose or watery stool less than 25% of the time, or a combination of the two. Subjects with IBS-D may have loose or watery stool at least 25% of the time, and may have hard or stool-like stool less than 25% of the time, or a combination of the two. Subjects with IBS-M may have hard or stool-like stool at least 25% of the time, and may have loose or watery stool at least 25% of the time. The subject with IBS-U may have hard or rabbit feces less than 25% of the time, and may have loose or watery stool less than 25% of the time, or may have a combination of the two.The constipation associated with IBS may be due to slow or delayed gastric motility.In some embodiments, the subject with IBS experiences 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 medical provider.Healthcare provider can perform physical examination and obtain the medical history of the subject.IBS can be diagnosed when the subject shows one or more symptoms of IBS for at least 3, 4, 5 or 6 months, with one or more symptoms occurring at least 3 times per month in the past 3 months.Additional tests that can be useful for diagnosing IBS include, but are not limited to, stool test, lower GI series, flexible sigmoidoscopy or colonoscopy.

[0096] The subject may suffer from, be diagnosed with, or show symptoms of functional dyspepsia (e.g., digestive disorders), or may be suspected of having functional dyspepsia. Dyspepsia symptoms include, but are not limited to, chronic or recurrent pain in the upper abdomen, upper abdominal fullness, postprandial fullness, early satiety, bloating, eructation, nausea, vomiting, heartburn, and sour taste in the mouth. Functional dyspepsia (e.g., non-ulcer dyspepsia) generally refers to indigestion without evidence of organic disease that may explain the symptoms of dyspepsia. An example of functional dyspepsia is dyspepsia without ulcer. Functional dyspepsia is estimated to affect about 15% of the total population in Western countries. Other exemplary ENS disorders include, but are not limited to, intestinal motility disorders, ganglioneuroma, multiple endocrine neoplasia type 2B (MEN2B), gastrointestinal neuropathy, and enteric neurodysplasia.

[0097] The subject may suffer from, be diagnosed with, show symptoms of, or be suspected of having an enteric nervous system disorder caused by another underlying disease.For example, the enteric nervous system disorder may be Parkinson's disease-induced ENS disorder.Parkinson's disease-induced ENS disorder may be related to the degeneration of dopamine ENS neurons.Symptoms of Parkinson's disease-induced ENS disorder include, for example, constipation, nausea, vomiting, etc.In some embodiments, the subject treated by the method of the present application has been diagnosed with Parkinson's disease, suffers from, is suspected of having, and further shows symptoms of ENS disorder as described herein.

[0098] The subject may suffer from, be diagnosed with, exhibit symptoms of, or be suspected of having an enteric nervous system disorder that may be associated with scleroderma. Scleroderma can be characterized by hardening and tightness of the skin and connective tissue. In some embodiments, the subject may suffer from, be diagnosed with, exhibit symptoms of, or be suspected of having gastroparesis associated with scleroderma.

[0099] The subject may suffer from, be diagnosed with, show symptoms of, or be suspected of having diabetes-related enteric nervous system disorder.The diabetes-related enteric nervous system disorder may be diabetes-related gastroparesis.The subject may suffer from, be diagnosed with, show symptoms of, or be suspected of having enteric nervous system disorder associated with multiple sclerosis.

[0100] Other diseases and clinical conditions that can cause enteric nervous system disorders such as gastroparesis include, for example, cancer, hypothyroidism, hyperthyroidism, hyperparathyroidism, adrenal insufficiency (Addison's disease), gastric ulcers, gastritis, following gastric surgery such as total vagotomy (removal of the vagus nerve), antrectomy (removal of the 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), and fundoplication (a surgical procedure in which the upper part of the stomach is wrapped around the lower end of the esophagus), and polymyositis (which can cause muscle weakness). These conditions include chronic inflammatory muscle diseases with progressive muscle weakness, muscular dystrophies (diseases that can cause progressive muscle weakness), amyloidosis (characterized by the accumulation of amyloid in tissues or organs of a subject, such as in the gastrointestinal tract), ileus pseudo-obstruction (a condition that causes symptoms related to, but does not cause, an intestinal obstruction), 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), eating disorders such as anorexia and bulimia, depression, paraneoplastic syndromes, and high cervical cord lesions (e.g., lesions at or above spinal cord C4).

[0101] The subject may suffer from symptoms of enteric nervous system disorders. Exemplary symptoms are described herein. In some embodiments, the symptoms are nausea and / or vomiting. In some embodiments, the cause of the symptoms is unknown (e.g., unexplained nausea). In some embodiments, the symptoms are chronic or recurrent symptoms. The subject may, for example, experience symptoms 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 symptoms 1, 2, 3, 4, 5, 6, 7, 8, 8, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 or more than 31 times per month.

[0102] The subject may be, for example, a mouse, a rat, a hamster, a gerbil, a dog, a cat, a primate such as a monkey or a human. In some embodiments, the subject is a human. The subject may be an adult, a child or an infant. The subject may be of any age.

[0103] Use of the pharmaceutical compositions and / or combinations The pharmaceutical compositions and / or combinations described herein can be safely administered to subjects.The pharmaceutical compositions and / or combinations described herein can be administered without necessarily increasing the risk of developing adverse cardiac side effects.For example, the pharmaceutical compositions and / or combinations described herein may not increase the risk of modulating myocardial action potential, and / or may not increase the risk of inducing long QT syndrome, and / or may not increase the risk of cardiac arrest, and / or may not increase the risk of sudden death due to cardiac arrest.

[0104] A subject can be safely administered an effective amount of the pharmaceutical composition and / or combination described herein for an unlimited amount of time. A subject can be safely administered an effective amount of the pharmaceutical composition and / or combination acutely or chronically. For example, a subject can be safely administered an effective amount of the pharmaceutical composition and / or combination once per day, at least 2 days, at least 3 days, at least 4 days, 5 days, at least 5 days, at least 6 days, at least 7 days (1 week), at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months (1 year), at least 2 years, at least 5 years, or at least 10 years.

[0105] The administration of the pharmaceutical composition and / or combination described herein may result in an acceptable risk that the subject will develop undesirable cardiac side effects.The administration risk of the pharmaceutical composition and / or combination 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 and / or combination compared to the incidence of sudden death in a population of control subjects not administered the pharmaceutical composition and / or combination.The risk can be determined by tracking the number of subjects administered the pharmaceutical composition and / or combination who experience undesirable cardiac side effects and the number of subjects administered the pharmaceutical composition and / or combination who do not experience undesirable cardiac side effects. For example, if a=the number of subjects administered the pharmaceutical composition and / or combination that experienced an undesirable cardiac side effect, and b=the number of subjects administered the pharmaceutical composition and / or combination that did not experience an undesirable cardiac side effect, then the risk of experiencing an undesirable cardiac side effect resulting from administration of the pharmaceutical composition and / or combination can be calculated as a / (a+b). Relative risk (RR) can be used to compare the risk of developing an undesirable cardiac side effect resulting from administration of the pharmaceutical composition and / or combination to the risk of developing an undesirable cardiac side effect in a population of subjects not administered the pharmaceutical composition and / or combination.For example, if a=the number of subjects administered the pharmaceutical composition and / or combination who experienced an undesirable cardiac side effect, b=the number of subjects administered the pharmaceutical composition and / or combination who did not experience an undesirable cardiac side effect, c=the number of subjects not administered the pharmaceutical composition and / or combination who experienced an undesirable cardiac side effect, and d=the number of subjects not administered the pharmaceutical composition and / or combination who did not experience an undesirable cardiac side effect, then the RR resulting from administration of the pharmaceutical composition and / or combination can be calculated as a / (a+b) / (c / (c+d)). For other examples, the risk can be determined by calculating the odds ratio.

[0106] The RR of administration of a pharmaceutical composition and / or combination described herein with 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.

[0107] The odds ratio of administration of the pharmaceutical composition and / or combination described herein with sudden cardiac death can be an acceptable odds ratio. The term odds ratio (OR) generally refers to a measure of association between an exposure (e.g., exposure to a drug) and an outcome (e.g., sudden cardiac death). OR can represent the odds of an outcome occurring given a particular exposure, compared to the odds of the outcome occurring in the absence of that exposure. Odds ratios can be used in case-control studies, as well as cross-sectional and cohort design studies. For example, if a=the number of subjects administered the pharmaceutical composition and / or combination who experienced undesirable cardiac side effects, b=the number of subjects administered the pharmaceutical composition and / or combination who did not experience undesirable cardiac side effects, c=the number of subjects not administered the pharmaceutical composition and / or combination who experienced undesirable cardiac side effects, and d=the number of subjects not administered the pharmaceutical composition and / or combination who did not experience undesirable cardiac side effects, the OR resulting from administration of the pharmaceutical composition and / or combination can be calculated as ad / bc.

[0108] The OR of administration of a pharmaceutical composition and / or combination described herein with 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.

[0109] The pharmaceutical compositions and / or combinations described herein for use in treating ENS are peripherally restricted, unlike other drugs that modulate dopamine that have been previously indicated for treating ENS.Therefore, such pharmaceutical compositions and / or combinations can be safely administered to subjects without increasing the risk of subjects developing dysfunctions related to movement mediated by brain dopaminergic signaling.For example, such pharmaceutical compositions and / or combinations can be safely administered to subjects without increasing the risk of subjects developing extrapyramidal side effects.Exemplary extrapyramidal side effects include, for example, tardive dyskinesia (involuntary asymmetric movement of muscles), dystonia (characterized by sustained muscle contraction), akinesia (lack of movement), akathisia (sense of motor restlessness), bradykinesia (slow movement), stiffness and tremors, twisting and / or repetitive movements, abnormal postures, muscle spasms, such as neck muscle spasms (torticollis), eye muscle spasms (gaze seizures), tongue spasms, jaw spasms, etc. 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 for administration of the pharmaceutical compositions and / or combinations described herein for use in treating an enteric nervous system disorder with the occurrence 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.

[0110] The pharmaceutical composition and / or combination of the present application can promote gastric motility when administered to a subject. Such pharmaceutical composition and / or combination can promote gastric motility, for example, by reducing dopamine D2-receptor-mediated signaling in the subject's enteric neurons. For example, the pharmaceutical composition and / or combination can antagonize the dopamine D2 receptor in the subject's enteric neurons. For another example, the pharmaceutical composition and / or combination can reduce the dopaminergic neurotransmission of enteric neurons.

[0111] 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 intraantral manometry or by methods useful in the diagnosis of gastroparesis.Exemplary methods useful in the diagnosis of gastroparesis are described herein.

[0112] Administration of the pharmaceutical compositions and / or combinations described herein can improve gastric motility compared to a control subject and / or a control population. The control subject can be an individual who has not received the pharmaceutical compositions and / or combinations described herein. The control population can be a plurality of individuals who have not received the pharmaceutical compositions and / or combinations described herein. The control subject can be a subject who has, has been diagnosed with, is suspected of having, or exhibits symptoms of an ENS disorder, who has not received the pharmaceutical compositions and / or combinations described herein. The control subject does not necessarily have to be a different individual, but can be the same subject at a time point before receiving a dose of the pharmaceutical compositions and / or combinations described herein. The control subject can be the same subject at a time point after receiving a dose of the pharmaceutical compositions and / or combinations described herein after sufficient time has passed for the pharmaceutical compositions and / or combinations described herein to no longer have an effect in the subject. The control subject can be a different subject. In some embodiments, administration of the pharmaceutical compositions and / or combinations improves gastric motility by at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100% or greater than 100% compared to control subjects.

[0113] In some embodiments, administration of the pharmaceutical compositions and / or combinations described herein is effective to treat symptoms of enteric nervous system disorders in a subject. Exemplary symptoms are described herein. The symptoms may be selected from the group consisting of nausea, vomiting, delayed gastric emptying, diarrhea, abdominal pain, gas, bloating, gastroesophageal reflux, loss of appetite, weight loss, and constipation. In certain cases, administration of the pharmaceutical compositions and / or combinations described herein reduces nausea in a subject. Administration of the pharmaceutical compositions and / or combinations described herein can reduce the severity of any of the symptoms described herein. In some cases, administration of the pharmaceutical compositions and / or combinations 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 and / or combinations described herein reduces the severity of 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 greater.

[0114] Administration of the pharmaceutical compositions and / or combinations described herein may reduce the frequency of occurrence of the symptoms. In some cases, administration of the pharmaceutical compositions and / or combinations described herein reduces the frequency of occurrence 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 and / or combinations described herein reduces the frequency of occurrence 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%. In some cases, administration of the pharmaceutical compositions and / or combinations described herein reduces the frequency of occurrence of symptoms 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 every 12 months (yearly).

[0115] hERG channel inhibition can be determined by any means known in the art or otherwise described herein. hERG channel inhibition can be evaluated in vitro, for example, by utilizing cultured cells expressing hERG. Cultured cells expressing hERG for evaluating hERG channel inhibition are available from several commercial suppliers, for example, Life Technologies, Cyprotex, etc. hERG channel inhibition can be evaluated by various means known in the art, including, for example, voltage clamp studies, hERG binding assays, etc. Voltage clamp studies can use the use of commercially available high throughput systems. Exemplary high throughput systems are described, for example, in U.S. Pat. No. 8,329,009 and U.S. Patent Publication No. 20020164777, which are incorporated herein by reference. hERG binding assays can be performed by: 3H Dofetilide can be used to include competitive binding assay and / or saturation binding assay. 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 evaluating myocardial action potential.

[0116] Minimal hERG inhibition would be an IC of >0.1 μM, >0.2 μM, >0.3 μM, >0.4 μM, >0.5 μM, >0.6 μM, >0.7 μM, >0.8 μM, >0.9 μM, >1 μM, >2 μM, >3 μM, >4 μM, >5 μM, >6 μM, >7 μM, >8 μM, >9 μM, >10 μM, >15 μM, >20 μM, >30 μM, >40 μM, >50 μM, >60 μM, >70 μM, >80 μM, >90 μM or >100 μM. 50 It can be proved by:

[0117] Minimal hERG inhibition can also be demonstrated by measuring the % inhibition of hERG-mediated tail current at any given dose of drug. hERG-mediated tail current can be measured by voltage clamp study, for example, patch clamp study. For example, hERG-mediated tail current can be measured in cells expressing hERG before contacting the cells with a test agent. Then, hERG-mediated tail current can be measured in cells expressing hERG after contacting with a dose of a test agent. The difference between the hERG-mediated tail current before and after administration of the test agent can be used to determine the degree to which the test agent inhibits hERG-mediated tail current. Suitable agents for use in the disclosed methods are capable of inhibiting hERG-mediated tail currents 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 are capable of inhibiting hERG-mediated tail currents 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 at a dose of 3 μM can inhibit hERG-mediated tail currents 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%.In some embodiments, metopimazine acid at doses of 10 μM or higher can inhibit hERG-mediated tail currents 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%.

[0118] Exemplary Compounds When referring to metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate), it should be understood to include the solvent addition forms, or crystalline forms thereof, particularly solvates or polymorphs. Solvates contain either stoichiometric or non-stoichiometric solvents and may be formed during the process of crystallization with pharma- ceutical acceptable solvents, such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein may be conveniently prepared or formed during the methods described herein. In addition, the compounds provided herein can exist in unsolvated and solvated forms. In general, solvated forms are considered equivalent to unsolvated forms for the compounds and methods provided herein. Polymorphs include different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability and solubility. Various factors such as recrystallization solvent, crystallization rate and storage temperature may cause a single crystalline form to predominate.

[0119] In certain embodiments, metopimazine or a pharma- ceutically acceptable salt thereof is anhydrous metopimazine mesylate. In certain embodiments, metopimazine or a pharma- ceutically acceptable salt thereof is metopimazine mesylate hydrate. In certain such embodiments, metopimazine mesylate hydrate is metopimazine mesylate monohydrate. In certain such embodiments, metopimazine mesylate as described herein comprises a mixture of anhydrous metopimazine mesylate and metopimazine mesylate hydrate. In certain such embodiments, the mixture comprises about 10% metopimazine mesylate hydrate to about 100% metopimazine mesylate hydrate. For example, the mixture contains about 10% metopimazine mesylate hydrate, about 20% metopimazine mesylate hydrate, about 30% metopimazine mesylate hydrate, about 40% metopimazine mesylate hydrate, about 50% metopimazine mesylate hydrate, about 60% metopimazine mesylate hydrate, about 70% metopimazine mesylate hydrate, about 80% metopimazine mesylate hydrate, about 90% metopimazine mesylate hydrate or about 95% metopimazine mesylate hydrate.

[0120] Metopimazine mesylate described herein may be in various forms, including, but not limited to, amorphous, pulverized and nanoparticulate forms.Furthermore, metopimazine mesylate described herein includes crystalline forms, also known as polymorphs.Polymorphs include different crystal packing arrangements of the same elemental composition of a compound.Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability and solubility.Various factors, such as recrystallization solvent, crystallization rate and storage temperature, may cause a single crystalline form to predominate.

[0121] Exemplary Pharmaceutical Compositions The pharmaceutical composition utilized in the method of the present application may include a pharma- ceutically acceptable carrier. The pharma- ceutically acceptable carrier for the composition may include, but is not limited to, amino acids, peptides, biopolymers, non-biopolymers, simple sugars or starches, inorganic salts, and gums, which may be present alone or in combination. The peptides used in the acceptable carrier may include, for example, gelatin and / or albumin. Cellulose or its derivatives may be used in the pharma- ceutically acceptable carrier. The sugars used in the acceptable carrier may be lactose and / or glucose. Other useful sugars that may be utilized in the pharmaceutical composition include, but are not limited to, fructose, galactose, lacticol, maltitol, maltose, mannitol, melezitose, myo-inositol, palatinate, raffinose, stachyose, sucrose, trehalose, xylitol, hydrates thereof, and combinations thereof. A binder may be included in the pharma- ceutical acceptable carrier. Examples of binders include, but are not limited to, starch (e.g., corn starch or potato starch), gelatin; natural or synthetic gums such as acacia, sodium alginate, powdered tragacanth, guar gum, cellulose or cellulose derivatives (e.g., methycellulose, ethylcellulose, cellulose acetate); microcrystalline cellulose, polyvinylpyrrolidone, and mixtures thereof. The inorganic salt used in the acceptable carrier may be a magnesium salt, e.g., magnesium chloride or magnesium sulfate. Other inorganic salts, e.g., calcium salts, may also be used. Examples of calcium salts include, but are not limited to, calcium chloride, calcium sulfate.Other examples of materials that can be used in pharma- ceutically acceptable carriers include, but are not limited to, vegetable oils such as peanut oil, cottonseed oil, olive oil, corn oil, and the like; polyols such as glycerin, propylene glycol, polyethylene glycol, and the like; pyrogen-free water, isotonic saline, phosphate buffer solutions; emulsifiers such as Tweens®; wetting agents, lubricants, colorants, flavoring agents, and preservatives.

[0122] The term "wetting agent" can be used interchangeably with "surfactant" and refers to a substance that reduces the surface tension of a liquid, thereby allowing 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.

[0123] Suitable hydrophilic surfactants can generally have an HLB value of at least 10, while suitable lipophilic surfactants can generally have an HLB value of about 10 or less. A useful parameter that can be used to characterize the relative hydrophilicity and hydrophobicity of nonionic amphiphilic compounds is the hydrophilic-lipophilic balance ("HLB" value). Surfactants with lower HLB values ​​are more hydrophobic and more soluble in oil, while surfactants with higher HLB values ​​are more hydrophilic and more soluble in aqueous solutions. Hydrophilic surfactants are generally considered to be compounds with HLB values ​​higher than about 10, and anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable. Similarly, lipophilic (i.e., hydrophobic) surfactants are generally considered to be compounds with HLB values ​​of about 10 or less. However, the HLB value of a surfactant provides only a rough guideline that is generally used to enable the formulation of emulsions for industrial, pharmaceutical, and cosmetic applications.

[0124] Hydrophilic surfactants can be either ionic or non-ionic.Suitable ionic surfactants include, but are not limited to, alkyl ammonium salts, fatty acid derivatives of amino acids, glyceride derivatives of amino acids, fusidate salts, oligopeptides and polypeptides, oligopeptides and polypeptides, lecithin and hydrogenated lecithin, lysolecithin and hydrogenated lysolecithin, phospholipids and derivatives thereof, fatty acid salts, lysophospholipids and derivatives thereof, carnitine fatty acid ester salts, alkyl sulfate salts, docusate sodium, acylactylate, mono- and diacetylated tartaric acid esters of mono- and diglycerides, succinylated mono- and diglycerides, citric acid esters of mono- and diglycerides, and mixtures thereof.

[0125] Within the foregoing group, ionic surfactants include, but are not limited to, lecithin, lysolecithin, phospholipids, lysophospholipids and derivatives thereof, carnitine fatty acid ester salts, fatty acid salts, alkyl sulfates, docusate sodium, acylactylates, mono- and diacetylated tartaric acid esters of mono- and diglycerides, succinylated mono- and diglycerides, citrate esters of mono- and diglycerides, and mixtures thereof.

[0126] Ionic surfactants include lactate 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 lactate, glyceryl esters of ... The ionic forms of the acid may be acetylated, ...

[0127] Hydrophilic nonionic surfactants can include, but are not limited to, alkyl glucosides, alkyl thioglucosides, alkyl maltosides, lauryl macrogol glycerides, polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers, polyoxyalkylene alkylphenols such as polyethylene glycol alkylphenols, polyoxyalkylene alkylphenol fatty acid esters such as polyethylene glycol glycerol fatty acid esters, polyethylene glycol fatty acid monoesters and polyethylene glycol fatty acid diesters, polyglycerol fatty acid esters, polyoxyethylene-polyoxypropylene block copolymers and mixtures thereof, polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters, hydrophilic transesterification products of polyols with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols, polyoxyethylene sterols and derivatives or analogs thereof, polyoxyethylated vitamins and derivatives thereof, polyethylene glycol sorbitan fatty acid esters, and hydrophilic transesterification products of polyols with at least one member of the group consisting of triglycerides, vegetable oils and hydrogenated vegetable oils. The polyol can be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol or a saccharide.

[0128] 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 ...40 dilaurate, PEG-40 dilaurate, PEG-40 dilaurate, PEG-40 dilaurate PEG-20 Glyceryl Trioleate, PEG-25 Glyceryl Trioleate, PEG-32 Dioleate, PEG-20 Glyceryl Laurate, PEG-20 Trioleate, PEG-30 Glyceryl Laurate, PEG-20 Glyceryl Stearate, PEG-20 Glyceryl Oleate, PEG-30 Glyceryl Oleate, PEG-30 Glyceryl Laurate, PEG-40 Glyceryl Laurate, PEG-50 Hydrogenated Castor Oil, PEG-40 Castor Oil, PEG-35 Castor Oil, PEG-60 Castor Oil, PEG-4 0 Palm Kernel Oil, PEG-40 Hydrogenated Castor Oil, PEG-60 Hydrogenated Castor Oil, PEG-60 Corn Oil, PEG-6 Capric / Caprylic Glycerides, PEG-8 Capric / Caprylic Glycerides, Polyglyceryl-10 Laurate, PEG-30 Cholesterol, PEG-25 Phytosterols, PEG-30 Soy Sterols, PEG-40 Sorbitan Oleate, PEG-80 Sorbitan Laurate, Polysorbate 20, Polysorbate 80, POE-9 Lauryl Ether, POE-23 Lauryl Examples of suitable glyceryl ethers include sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonylphenol series, PEG 15-100 octylphenol series, and poloxamers.

[0129] Suitable lipophilic surfactants include, but are not limited to, fatty alcohols, glycerol fatty acid esters, acetylated glycerol fatty acid esters, lower alcohol fatty acid esters, propylene glycol fatty acid esters, sorbitan fatty acid esters, polyethylene glycol sorbitan fatty acid esters, sterols and sterol derivatives, polyoxyethylated sterols and sterol derivatives, polyethylene glycol alkyl ethers, sugar ethers, sugar esters, hydrophobic transesterification products of polyols with at least one member of the group consisting of 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 this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters and mixtures thereof, or hydrophobic transesterification products of polyols with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils and triglycerides.

[0130] Lubricants that can be used in the pharmaceutical composition 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 oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil), zinc stearate, ethyl oleate, ethylaureate, or mixtures thereof. Additional lubricants include, by way of example, syloid silica gel, coagulated aerosol of synthetic silica, or mixtures thereof. Lubricants can be added as needed in an amount of less than about 1% by weight of the pharmaceutical composition.

[0131] The composition may include one or more pharma- ceutically acceptable additives, including, but not limited to, detackifiers, antifoaming agents, buffering agents, antioxidants, polymers, preservatives, chelating agents, odorants, opacifying agents, suspending agents, fillers, plasticizers, and mixtures thereof.

[0132] In some embodiments, the pharma- ceutically 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% of the pharmaceutical composition on a w / w, w / v or v / v basis. , greater than 0.04%, greater than 0.03%, greater than 0.02%, greater than 0.01%, greater than 0.009%, greater than 0.008%, greater than 0.007%, greater than 0.006%, greater than 0.005%, greater than 0.004%, greater than 0.003%, greater than 0.002%, greater than 0.001%, greater than 0.0009%, greater than 0.0008%, greater than 0.0007%, greater than 0.0006%, greater than 0.0005%, greater than 0.0004%, greater than 0.0003%, greater than 0.0002% or greater than 0.0001%.

[0133] In some embodiments, the concentration of metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as 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% of the pharmaceutical composition on a w / w, w / v or v / v basis. 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%.

[0134] In some embodiments, the concentration of metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) is from about 0.0001% to about 50%, from about 0.001% to about 40%, from about 0.01% to about 20%, from about 0.02% to about 29%, from about 0.03% to about 28%, from about 0.04% to about 27%, from about The range is from about 0.05% to about 26%, from about 0.06% to about 25%, from about 0.07% to about 24%, from about 0.08% to about 23%, from about 0.09% to about 22%, from about 0.1% to about 21%, from about 0.2% to about 20%, from about 0.3% to about 19%, from about 0.4% to about 18%, from about 0.5% to about 17%, from about 0.6% to about 16%, from about 0.7% to about 15%, from about 0.8% to about 14%, from about 0.9% to about 12%, or from about 1% to about 10%.

[0135] In some embodiments, the concentration of metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as 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 on a w / w, w / v, or v / v basis.

[0136] Some non-limiting examples of pharmaceutical compositions are described below.

[0137] Pharmaceutical Composition for Oral Administration A pharmaceutical composition comprising an effective amount of metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) may be formulated for oral administration. In some embodiments, a pharmaceutical composition comprising an effective amount of metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) for oral administration is a solid pharmaceutical composition. In some embodiments, the solid pharmaceutical composition may be presented as a separate (e.g., unit) oral dosage form. Non-limiting examples of separate oral dosage forms include tablets, capsules, caplets, gelatin capsules, extended release formulations, lozenges, thin films, lollipops, and chewing gum. In some embodiments, the separate oral dosage form is an orally disintegrating oral dosage form, such as, for example, an orally disintegrating tablet.

[0138] Separate 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 sustained action. In some embodiments, metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) is mixed with one or more inert solid diluents, such as calcium carbonate or calcium phosphate. In some embodiments, metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) is presented as a soft gelatin capsule, in which metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) is mixed with, for example, water or with an oily medium, such as peanut oil or olive oil.

[0139] In some embodiments, the pharmaceutical composition for oral administration that contains an effective amount of metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) is a liquid pharmaceutical composition. Non-limiting examples of liquid compositions for oral administration include hydrophilic suspensions, emulsions, liquids, gels, syrups, slurries, solutions, elixirs, softgels, tinctures, and hydrogels. In some embodiments, the solid or liquid composition for oral administration that contains an effective amount of metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) contains various sweeteners or flavorings or colorings. Examples of colorings include grape skin extract, red beet powder, beta-carotene, annatto, carmine, turmeric, paprika, and other FD&C. colors and natural colorings. Derivatives, analogs and isomers of any of the above colored compounds may also be used.

[0140] Such dosage forms may be prepared by methods well known to those skilled in the art, for example, at a pharmacy, which includes the step of combining metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) with a pharma- ceutically acceptable carrier.

[0141] Because water may promote the decomposition of metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate), the present application further encompasses anhydrous pharmaceutical compositions and dosage forms comprising an effective amount of metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate). In some embodiments, the anhydrous pharmaceutical compositions and dosage forms of the present application are prepared using anhydrous or low moisture containing ingredients. In some embodiments, the anhydrous pharmaceutical compositions and dosage forms of the present application are prepared under low humidity or low moisture conditions. Pharmaceutical compositions of the present application containing lactose may be made anhydrous if substantial contact with moisture and / or humidity during manufacturing, packaging and / or storage is expected. Anhydrous pharmaceutical compositions comprising metopimazine or a pharma- ceutically acceptable salt thereof may be prepared and stored to maintain their anhydrous nature. For example, anhydrous compositions may be packaged using materials known to prevent exposure to water, including, but not limited to, hermetically sealed foils, plastics, unit dose containers, blister packs, and strip packs such that they can be included in suitable formulary kits.

[0142] Pharmaceutical Compositions for Injection or Parenteral Administration In some embodiments, the pharmaceutical composition is formulated for parenteral administration. "Parenteral administration" generally refers to a route of administration other than the gastrointestinal tract. Examples of parenteral administration include, but are not limited to, intravenous injection, intraarterial injection, intrathecal injection (into the spinal cord), intratonsillar injection, subcutaneous injection, intramuscular injection, injection or implantation. Injection may be intradermal, subcutaneous, or by transdermal implant. Exemplary pharmaceutical compositions for parenteral administration are disclosed in the following references, which are incorporated herein by reference: US Patent Application Publication No. 2006 / 0287221, US Patent Nos. 5,244,925, 4,309,421, 4,158,707, and 5,164,405.

[0143] Compositions formulated for parenteral administration may include aqueous solutions and / or buffers commonly used for injection and / or infusion. Commonly used aqueous buffers and / or solutions may include, but are not limited to, about 0.9% sodium chloride solution, phosphate buffer, lactated Ringer's solution, acetated Ringer's solution, phosphate buffered saline, citrate buffer, Tris buffer, histidine buffer, HEPES buffer, glycine buffer, N-glycylglycine buffer, etc. Other pharma- ceutically acceptable carriers for parenteral administration include ethanol, glycerol, propylene glycol, cyclodextrin and cyclodextrin derivatives, vegetable oils, etc.

[0144] In some embodiments, the pharmaceutical composition for injection and / or infusion contains a preservative present in an amount that effectively prevents or reduces microbial contamination or degradation.Various agents, such as phenol, m-cresol, benzyl alcohol, paraben, 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.

[0145] In some embodiments, sterile solution is prepared by incorporating the required amount of metopimazine or its pharmaceutically acceptable salt (e.g., metopimazine mesylate, etc., metopimazine pharmaceutically acceptable salt) in a suitable solvent together with various other components as described herein as necessary, and then sterilizing by filtration.Generally, dispersion is prepared by incorporating various sterilized active ingredients into a sterile vehicle that contains a basic dispersion medium and other components as required from those listed above.In the case of sterile powder for preparing sterile solution for injection, certain methods of preparation include, but are not limited to, vacuum drying and freeze-drying techniques, which obtain a powder of active ingredient and any additional desired ingredients from its solution that has been previously sterilized and filtered.

[0146] In some embodiments, the pharmaceutical composition is formulated for topical and / or transdermal delivery. The compositions of the present application can be formulated into liquid, semi-solid or solid form preparations suitable for local or topical administration. Examples of forms suitable for local or topical administration include, but are not limited to, gels, water-soluble jellies, creams, lotions, suspensions, foams, powders, slurries, ointments, oils, pastes, suppositories, liquids, sprays, emulsions, saline solutions, and dimethylsulfoxide (DMSO)-based solutions. In general, carriers with higher density can provide areas that are exposed to the active ingredient for a longer period of time. In contrast, solution formulations can provide more rapid exposure of the active ingredient to selected areas.

[0147] Pharmaceutical compositions may include suitable solid-phase or gel-phase carriers, which are compounds that can enhance the penetration or aid in the delivery of therapeutic molecules through the stratum corneum barrier of skin.There are many of these penetration-promoting molecules known to those skilled in the art of topical formulation.Examples of such carriers and excipients include, but are not limited to, alcohol (e.g., ethanol), fatty acid (e.g., oleic acid), humectants (e.g., urea), glycol (e.g., propylene glycol), surfactants (e.g., isopropyl myristate and sodium lauryl sulfate), glycerol monolaurate, sulfoxides, pyrrolidone, 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.

[0148] Another exemplary formulation for use in the method of the present application uses a transdermal delivery device ("patch"). Such a transdermal patch can be used to provide continuous or intermittent infusion of a controlled amount of metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) described herein, with or without an additional agent. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, for example, U.S. Patent Nos. 5,023,252; 4,992,445; and 5,001,139, which are incorporated herein by reference.

[0149] In some embodiments, the present application provides a pharmaceutical composition comprising an effective amount of metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) described herein for transdermal delivery, and a suitable pharmaceutical excipient for delivery by inhalation. Compositions for inhalation include solutions and suspensions in pharma- ceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. Liquid or solid compositions can contain suitable pharma- ceutically acceptable excipients as described herein. The compositions may be administered by oral or nasal respiratory routes for systemic action. In some embodiments, the compositions, preferably in pharma- ceutical acceptable solvents, may be nebulized by the use of inert gases. In some embodiments, the nebulized solutions 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 compositions may be administered, preferably orally or nasally, from a device that delivers the formulation in an appropriate manner.

[0150] Other Pharmaceutical Compositions The pharmaceutical compositions and / or combinations used in the present application may be formulated for intraocular (eye), rectal, sublingual, buccal or intranasal (e.g. pulmonary) administration. Formulations suitable for intraocular administration include eye drops in which the active ingredient is dissolved or suspended in a suitable carrier for the active ingredient, especially an aqueous solvent. The active ingredient is preferably present in such formulations in a concentration of 0.5-20% w / w, advantageously 0.5-10% w / w, in particular about 1.5% w / w. Formulations suitable for sublingual administration are usually formulated to dissolve rapidly when placed in the mouth, allowing the active ingredient to be absorbed via the blood vessels under the tongue. Exemplary sublingual formulations include, for example, lozenges, which contain active ingredients in a base that is usually flavored with sucrose and acacia or tragacanth; troches, which contain active ingredients in an inert base such as gelatin and glycerin, or sucrose and acacia; mouthwashes, which contain active ingredients in a suitable liquid carrier; disintegrating tablets, which can disintegrate in less than 90 seconds when placed in the mouth; and thin films. Such disintegration can be measured by in vitro dissolution tests. Formulations for oral administration can include, for example, oral tablets, bioadhesive particles, wafers, lozenges, medicated chewing gums, adhesive gels, patches, films, to name a few, which can be delivered as aqueous solutions, pastes, ointments or aerosols. Formulations for rectal administration can be presented as suppositories, which contain a suitable base, for example, including cocoa butter or salicylates. Formulations suitable for pulmonary or nasal administration may have a particle size ranging, for example, from 0.1 to 500 microns (including particle sizes ranging between 0.1 to 500 microns in micron increments such as 0.5, 1, 30 microns, 35 microns, etc.), administered by rapid inhalation through the nasal passages to reach the alveolar sacs, or by inhalation through the mouth. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered together with other therapeutic agents, such as compounds conventionally used to treat or prevent cancerous infections, as described below.The pharmacological formulation of the present application can be administered to a patient in an injectable formulation containing any compatible carrier, such as various vehicles, adjuvants, additives and diluents. Alternatively, the metopimazine mesylate utilized in the present application can be administered to a patient parenterally in the form of slow release subcutaneous implants or targeted delivery systems, such as monoclonal antibodies, vectored 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 known to those skilled in the art.

[0151] Formulations for such pharmaceutical compositions are described, for example, in Anderson, Philip O.; Knoben, James E.; Troutman, William 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 which are incorporated herein by reference in their entireties.

[0152] Exemplary Modes of Administration Administration of the pharmaceutical compositions and / or combinations described herein can be by any method that allows delivery of metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) to the site of action. The compositions and / or combinations can be administered orally, parenterally, enterally, intraperitoneally, topically, transdermally, ophthalmically, intranasally, locally, parenterally, by spray, subcutaneously, intravenously, intratonsillarly, intramuscularly, bucally, sublingually, rectally, intraarterially, by infusion, or intrathecally. In some embodiments, the compositions and / or combinations are administered orally. In some cases, oral administration can include administration of any of the oral dosage forms described herein. The effective amount of metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) administered will depend on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate), and the discretion of the prescribing physician.

[0153] A subject can be administered a daily dosage of metopimazine or a pharma- ceutical acceptable salt thereof (e.g., a pharma- ceutical acceptable salt of metopimazine, such as metopimazine mesylate) as described herein for the treatment of an enteric nervous system disorder. The daily dosage can be from about 0.01 mg to about 500 mg per kg of body weight per day.

[0154] In some embodiments, administration may include infusion. In some cases, infusion may include chronic constant administration. For example, devices for chronic constant administration by controlled pumps are known in the art (examples may be described in US7341577, US7351239, US8058251, which are incorporated herein by reference).

[0155] Administration of metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) may continue as long as necessary. In some embodiments, metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In certain embodiments, metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) is administered for more than 5 days. In some embodiments, metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) is administered for more than 12 weeks. In some embodiments, metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) is administered for more than one month, more than two months, more than four months, more than six months, more than one year, more than two years, or more than five years. In some embodiments, metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) is administered for less than five days.

[0156] Exemplary Combination Therapies In the methods disclosed herein that include co-administration of an additional agent, the additional agent can be a small molecule, a nutraceutical, 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 liposomal formulation, a nanoparticle formulation, a toxin, a therapeutic radioisotope, and the like.

[0157] In some embodiments, the methods of the present application include co-administration of a peripherally restricted dopamine decarboxylase inhibitor with a pharmaceutical composition described herein. For example, the methods of the present application can include co-administration of carbidopa with a pharmaceutical composition described herein.

[0158] The additional agent can be a drug for use in treating enteric nervous system disorders. In some embodiments, the additional agent is an additional antiemetic agent (e.g., for use in treating nausea and / or vomiting). The additional antiemetic agent can be, by way of non-limiting example only, a 5-HT3 receptor antagonist, a dopamine receptor antagonist, an NK1 receptor antagonist, an antihistamine, a cannabinoid, a benzodiazepine, an anticholinergic agent, a steroid, a phenothiazine or other antiemetic agent. 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, tradipitant or casopitant. Exemplary antihistamines include, for example, cyclizine, diphenhydramine (Benadryl), dimenhydrinate (Grabol, Dramamine), doxylamine, meclozine (Bonin, Antibate), promethazine (Pentazine, Phenergan, Promacot), and hydroxyzine (Bistaryl), cimetidine, famotidine, lafutidine, nizatidine, ranitidine, roxatidine, tiotidine. Exemplary cannabinoids include, for example, cannabis, Sativex, tetrahydrocannabinol, dronabinol, and synthetic cannabinoids such as nabilone. Exemplary benzodiazepines include, for example, midazolam or lorazepam. Exemplary anticholinergics include, for example, scopolamine. Other exemplary antiemetics include, for example, trimethobenzamide, ginger, emthrol, propofol, peppermint, erythromycin, muscimol, botulinum toxin A (e.g., injected into stomach to relax pylorus muscle) and ajwain.Exemplary phenothiazines include, for example, thiethylperazine (Trecan), prochlorperazine (Compro, Compazine), promethazine (Phenergan), thiethylperazine (Trecan). Other exemplary agents are gastrointestinal motility enhancers, such as bethanechol (Urecoline), cisapride (Proprusside), domperidone (Motilium), erythromycin (E-mycin), metoclopramide (Reglan, Metozorb), pyridostigmine bromide (Mestinon). The additional agent can be an agent for the treatment of another disease or clinical syndrome associated with gastroparesis. Exemplary other diseases and clinical syndromes are described herein.

[0159] The additional agent can be a gastrointestinal motility agent, such as a ghrelin agonist or a motilin agonist. Exemplary ghrelin agonists include, for example, reramorelin and urimorelin. Exemplary motilin agonists include, for example, erythromycin, azithromycin, or clarithromycin.

[0160] The additional agent can be a drug that treats diabetes.The exemplary drug that treats diabetes includes, for example, insulin.Other drugs for treating diabetes are described in, for example, U.S. Patent No. 6,274,549, U.S. Patent No. 8,349,818, U.S. Patent No. 6,184,209, U.S. Patent Application Publication No. US20070129307 and PCT Application Publication No. WO / 2004 / 082667A1, all of which are incorporated herein by reference.

[0161] The additional agent can be for treating upper and lower motor dysfunction disorders related to Parkinson's disease.The additional agent can be for treating Parkinson's disease.Exemplary agents for treating Parkinson's disease include, for example, dopaminergic agents, such as MAO-A or B inhibitors, such as selegiline, COMT inhibitors, such as entacapone, amantadine, stem cell transplants, and neuroprotective agents.Exemplary dopaminergic agents include, but are not limited to, levodopa, bromocriptine, pergolide, pramipexole, cabergoline, ropinorole, apomorphine, or combinations thereof.

[0162] The additional agent can be for treating pain, such as an analgesic. Exemplary analgesics include, for example, amitriptyline (Elavil), gabapentin (Neurontin), pregabalin (Lyrica), hydromorphone (Dilaudit), ibuprofen (Advil, Motrin), acetaminophen (Tylenol), ketorolac tromethamine (Toradol), mirtazapine (Remeron), morphine (MS Contin), naproxen (Aleve), nortriptyline (Pamelor), oxycodone (Oxycotin), oxycodone and paracetamol (Percocet), tapentadol (Nucinta), tramadol (Ultram, Ultracet).

[0163] The additional agent can be for treating hypothyroidism, hyperthyroidism, or hyperparathyroidism. Exemplary agents for treating such diseases include, for example, beta-adrenergic blockers ("beta-blockers"), levothyroxine calcium receptor agonists, estrogen, progesterone, bisphosphonates.

[0164] The additional agent can be for treating adrenal insufficiency. Exemplary agents for treating adrenal insufficiency include, for example, corticosteroid hormones (e.g., aldosterone, fludrocortisone, and cortisol).

[0165] The additional agent can be for treating gastroesophageal reflux. Exemplary agents for treating gastroesophageal reflux include antacids such as calcium carbonate or magnesium hydroxide, proton pump inhibitors such as omeprazole, H2 receptor antagonists such as ranitidine, famotidine, antacids, mosapride, sucralfate and baclofen, potassium-competitive acid blockers (P-CABs) such as vonoprazan, fexuprezan or tegoprazan.

[0166] The additional agent can be for treating scleroderma.For example, the additional agent can be an immunosuppressant, such as D-penicillamine, colchicine, PUVA, relaxin, cyclosporine and EPA (omega-3 oil derivative), such as methotrexate, cyclophosphamide, azathioprine and mycophenolate.The additional agent can be for treating polymyositis.For example, the additional agent can be a corticosteroid, such as prednisone, or can be an immunosuppressant.

[0167] The additional agent can be for treating muscular dystrophy.For example, the additional agent can be, for example, a glucocorticoid receptor antagonist.Exemplary glucocorticoid receptor antagonists include, but are not limited to, mifepristone, 11β-(4-dimethylaminoethoxyphenyl)-17α-propynyl-17β-hydroxy-4,9 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-benzodiox-5-yl)-17-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one.

[0168] The additional agent can be for treating amyloidosis. For example, the additional agent 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), peptidyl prolyl cis-trans-isomerase (PPI), trimethylamine N-oxide (TMAO), betaine, glycine betaine, glycero-phosphorylcholine, carbohydrates such as glycerol, sorbitol, arabitol, myo-inositol and trehalose, choline, 4-phenylbutyric acid and taurine-conjugated ursodeoxycholic acid.

[0169] The additional agent can be for treating chronic idiopathic intestinal pseudo-obstruction. For example, the additional agent can be prucalopride, pyridostigmine, metoclopramide, cisapride, linaclotide, octreotide, cannabinoids, and erythromycin.

[0170] The additional agent can be one for treating dermatomyositis. For example, the additional agent can be prednisolone, methotrexate, mycophenolate (Cellcept / Myfortic), intravenous immunoglobulin, azathioprine (Imuran), cyclophosphamide, rituximab, and Acthar gel.

[0171] The additional agent can be for treating systemic lupus erythematosus. For example, the additional agent can be a kidney transplant, a corticosteroid, an immunosuppressant, hydroxychloroquine, cyclophosphamide, mycophenolic acid, an immunosuppressant, analgesic, intravenous immunoglobin, etc.

[0172] The additional agent can be for treating anorexia and / or bulimia.For example, the additional agent 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, opiate antagonists such as naloxone and naltrexone, and topiramate.

[0173] The additional agent can be for treating depression. For example, the additional agent can be a selective serotonin reuptake inhibitor, a serotonin and norepinephrine reuptake inhibitor, bupropion, a tricyclic antidepressant, a monoamine oxidase inhibitor, etc. The additional agent can be for treating paraneoplastic syndromes. The additional agent can be for treating high cervical spinal cord lesions. For example, the additional agent can be a corticosteroid or other anti-inflammatory agent. The additional agent can be for treating multiple sclerosis. For example, the additional agent can be interferon beta-1b, interferon beta-1a, glatiramer acetate, mitoxantrone, natalizumab, fingolimod, teriflunomide, or cladribine.

[0174] The additional therapeutic agent may be selected from the group consisting of serotonin agonists, serotonin antagonists, selective serotonin reuptake inhibitors, anticonvulsants, opioid receptor agonists, bradykinin receptor antagonists, NK receptor antagonists, adrenoceptor agonists, benzodiazepines, gonadotropin releasing hormone analogues, calcium channel blockers and somatostatin analogues.

[0175] The dosage of the additional agent and metopimazine or a pharma- ceutically acceptable salt thereof (e.g., metopimazine mesylate, etc.) for use in treating enteric nervous system disorders may vary depending on the type of additional therapeutic agent used, the disease or condition being treated, etc. Subtherapeutic amounts of the additional agent and metopimazine or a pharma- ceutically acceptable salt thereof (e.g., metopimazine mesylate, etc.) or both may be used. Subtherapeutic amounts of the additional agent and metopimazine or a pharma- ceutically acceptable salt thereof (e.g., metopimazine mesylate, etc.) or both may be synergistically effective amounts. Therapeutic amounts of the additional agent and metopimazine or a pharma- ceutically acceptable salt thereof (e.g., metopimazine mesylate, etc.) or both may be used. The pharmaceutical compositions and additional agents described herein may be administered either simultaneously or sequentially. If administered sequentially, the attending physician or caregiver can determine the appropriate sequence of administering metopimazine or a pharma- ceutically acceptable salt thereof (e.g., a pharma- ceutically acceptable salt of metopimazine, such as metopimazine mesylate) and the additional therapeutic agent.

[0176] In some embodiments, the method comprising administering any of the pharmaceutical compositions and / or combinations described herein further comprises a 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 pacemakers can utilize electrical current to induce contractions of the stomach and / or duodenum, thereby promoting motility of the gastrointestinal tract. Such medical devices, and methods of using them, are disclosed in U.S. Patent No. 8,095,218, which is incorporated herein by reference.

[0177] The embodiments of the present application are further described in detail by referring to the following examples. These examples are presented for illustrative purposes only and are not intended to be limiting unless otherwise specified. Therefore, the present application should not be interpreted as being limited to the following examples in any way, but rather as embracing any and all variations that become evident as a result of the teachings presented herein. EXAMPLES

[0178] The following examples illustrate the present application but do not limit it.

[0179] Example 1 in vitro studies Test Articles, Metabolites and Reagents Metopimazine (MPZ), metopimazine acid (MPZA) and metopimazine sulfate (MPZS) were supplied by Pacific Pharmaceutical Services (Reno, NV). Bupropion, dextromethorphan, diclofenac, midazolam, paclitaxel, phenacetin, testosterone, itraconazole, montelukast, quinidine, sulfaphenazole, benzydamine, bis(4-nitrophenyl)phosphate (BNPP), 7-ethoxycoumarin (7-EC), menadione, methimazole, phthalazine and β-nicotinamide adenine dinucleotide phosphate (NADPH, tetrasodium salt) were purchased from Sigma-Aldrich (St. Louis, MO). Chlorzoxazone and 1-aminobenzotriazole (ABT) were purchased from Tokyo Chemical Industry Co., Ltd. (Portland, OR). Coumarin was purchased from Acros Organics (Waltham, MA). (S)-Mephenytoin, (+)-benzylnirvanol, and tranylcypromine were purchased from Toronto Research Chemicals (North York, Ontario, Canada). Furaphylline was purchased from Cayman Chemical (Ann Arbor, MI). Pooled human liver microsomes (HLM) and human kidney microsomes (HKM) were purchased from BioIVT (Westbury, NY). Pooled human liver S9 and human intestinal S9 fractions and pooled human liver cytosol (HLC) were purchased from Xenotech (Lenexa, KS). Supersomes™ CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A5, FMO1, FMO3 and FMO5 were purchased from Corning Inc. (Corning, NY). CTL P450 (Supersomes™ containing only P450 reductase and cytochrome b5) was also purchased from Corning, Inc. and used to normalize protein content in the CYP reactions. Upon receipt, all test systems were stored at ≦70° C. until use.

[0180] Preparation of reagents Potassium dihydrogen phosphate (1M) and dipotassium hydrogen phosphate (1M) stock solutions were diluted to 100 mM with water (Milli-Q®, Millipore). 100 mM potassium phosphate buffer was prepared by adding potassium dihydrogen phosphate solution (100 mM) to dipotassium hydrogen phosphate solution (100 mM) until the pH value was adjusted to 7.4, 8.4 or 9.4. The resulting 100 mM potassium phosphate buffer (KPi) was stored refrigerated (4° C.). Before use, NADPH solution (tetrasodium salt) was freshly prepared in KPi buffer and used in the reaction at a final concentration of 1 mM.

[0181] Preparation of stock solutions A stock solution of 20 mM MPZ (Lot No. AP237759063 076-01) was prepared in DMSO and stored at -20°C until use. Prior to incubation, MPZ was prepared at 1 μM or 10 μM (final concentration in incubation mixture). A primary stock solution (Stock A) of the positive control probe (7-EC) was prepared in ethanol and stored at -20°C until use. The concentration of Stock A was 100 mM. On the day of the experiment, a subsequent working solution of the positive control was prepared (from Stock A) at 100× incubation concentration using the appropriate buffer (Stock B).

[0182] Primary stock solutions (Stock A) of the positive control probes (benzydamine and phthalazine) were prepared in DMSO and stored at -20°C until use. The concentrations of Stock A were 100 mM (for benzydamine) and 1 mM (for phthalazine), respectively. On the day of the experiment, subsequent working solutions of the positive controls were prepared (from Stock A) in KPi buffer (Stock B).

[0183] Incubation of MPZ in human liver S9 Initial experiments were performed with S9 fractions from liver and intestine to evaluate the role of hepatic and intestinal enzymes in the metabolism of MPZ. The reaction mixture contained 2.5 μM MPZ, pooled human liver or intestinal S9 fractions (1 mg / mL S9 protein), and 100 mM KPi buffer (pH 7.4). The reaction mixture was preincubated for 3-5 min at 37 °C in a humidified incubator filled with 5% CO2, and then NADPH (1 mM) was added to initiate the reaction. The reactions were incubated for 0 and 60 min. The total percentage of organic solvents in the incubation mixture was ≤0.1%. The reaction was terminated by the addition of a sample mixture of acetonitrile and ethanol (90:10, v / v). The positive control substrate 7-EC was incubated in triplicate with the S9 fractions in an identical manner to MPZ.

[0184] Incubation with HLM To optimize protein concentration, 1 μM MPZ was incubated with various concentrations of HLM protein (0.1, 0.25, 0.5, and 1.0 mg / mL microsomal protein) in 100 mM KPi buffer (pH 7.4). After preincubation for 3–5 min at 37°C, reactions were initiated by the addition of NADPH (1 mM) in triplicate for 60 min.

[0185] To optimize incubation times, 1 μM MPZ was incubated with pooled HLM (0.5 mg / mL microsomal protein) and 100 mM KPi buffer (pH 7.4). After preincubation for 3–5 min at 37 °C, reactions were initiated by the addition of NADPH (1 mM) and incubated for 0, 10, 20, 40, 60, and 90 min to determine optimal incubation times (linear range). All metabolic reactions in this study were terminated by the addition of cold organic solvent (acetonitrile:ethanol 90:10, v / v) containing an internal standard, unless otherwise indicated.

[0186] Incubation of HLM with CYP inhibitors To determine the role of microsomal CYP enzymes in the metabolism of MPZ, MPZ was incubated in triplicate with pooled HLM at 1 μM and 10 μM to assess the disappearance of MPZ and the formation of known metabolites (MPZA, MPZS, and MPZH). First, two sets of incubations were performed with HLM (0.5 mg / mL microsomal protein), 1 μM and 10 μM MPZ, and 100 mM KPi buffer (pH 7.4), one set in the presence of 1 mM ABT, a nonspecific CYP inhibitor, for 60 min, and the other set in the absence of ABT for 60 min. This allowed the assessment of the overall contribution of CYPs to MPZ metabolism. Next, CYP-specific chemical inhibitors were used to assess the contribution of each major CYP isoform, where HLM was incubated with 1 μM or 10 μM MPZ in the presence and absence of each CYP-specific inhibitor for 60 min at 37°C. The following CYP isoform-specific chemical inhibitors were used: furafylline (10 μM), tranylcypromine (10 μM), montelucast (0.5 μM), sulfaphenazole (5 μM), (+) benzylnirubino (5 μM), quinidine (1 μM) and itraconazole (2.5 μM) for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 / 5. Parallel incubations with seven CYP-specific probe substrates were included as positive controls. For negative control reactions, MPZ was incubated in duplicate at 37° C. in reaction mixtures without NADPH. All other procedures were the same as previously described.

[0187] Incubation with recombinant CYP isoforms Recombinant CYP isoforms (Supersomes™) were used to determine the contribution of CYP isoforms in the metabolism of MPZ. 1.0 μM MPZ was incubated in triplicate with individual CYP Supersomes™ (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP3A5). The final P450 content in the incubation mixture was 50 pmol / mL. All protein concentrations of CYP isoforms were normalized to the recombinant CYP containing the highest protein concentration. Reaction mixtures containing MPZ or CYP substrates, KPi buffer (pH 7.4) and CYP enzymes were pre-incubated for 3-5 min at 37 °C. All other procedures were the same as previously described. Marker substrates (coumarin for CYP2A6, chlorzoxazone for CYP2E1, midazolam for CYP3A4 and CYP3A5, and probe substrates for other CYP isoforms as listed in Section 7.2.8) were incubated in parallel at 1.0 μM. Negative controls for the incubation reactions were incubated under identical conditions but in the absence of NADPH.

[0188] Incubation with HLM and HKM in case of FMO MPZ at 1.0 μM and 10.0 μM was incubated with HLM or HKM to determine the contribution of microsomal FMO to the metabolism of MPZ.

[0189] Reaction mixtures containing KPi buffer (pH 8.4), HLM or HKM (0.5 mg / mL protein) and MPZ (1.0 μM and 10.0 μM) were pre-incubated at 37 °C for 3-5 min. The reaction was started by adding NADPH to the reaction mixture. The reaction was carried out for 0 and 60 min. A positive control (benzydamine, 100 μM) was incubated in duplicate for 0 and 20 min. Parallel incubations were carried out by adding 1 mM methimazole, a non-specific FMO inhibitor, under the same conditions. Heat-inactivated microsomes (at least 5 min, 50 °C) were incubated under the same conditions as the negative control. All other procedures were the same as those already described.

[0190] Incubation with recombinant FMO 1.0 μM MPZ was incubated in triplicate with individual recombinant FMOs (Supersomes™ for FMO1, FMO3 and FMO5). All protein concentrations of rFMO isoforms were 0.05 mg / mL. Positive controls (benzydamine, 100 μM) were incubated for 20 min. Reaction mixtures containing MPZ or FMO substrates, KPi buffer (pH 8.4) and FMO Supersomes™ were preincubated for 3-5 min at 37°C. All other procedures were the same as previously described. Negative control reactions were incubated in the absence of NADPH.

[0191] Incubation with HLM for microsomal hydrolase / amidase activity Prior to reaction for amidase activity, the reaction mixture containing KPi buffer (pH 7.4, 8.4 or 9.4) and HLM was pre-incubated at 50°C for 5 min to inactivate CYP and FMO activity in HLM. The mixture was placed on ice and cooled. An aliquot was taken and considered as the t=0 min incubation. 10 μM MPZ was then added to the remaining mixture and incubated at 37°C for 60 min on an orbital shaker. A parallel set of incubations was performed with 10 μM MPZ in the presence of 2 μM and 16 μM BNPP (a known inhibitor of amidases). All reactions were in triplicate. The total percentage of organic solvent in the incubation mixture was ≦0.1%. The reaction was terminated by the addition of cold acetonitrile:methanol 90:10 (v / v). Samples were vortex mixed, stored at ≦-70°C and subjected to analysis by LC MS / MS.

[0192] Incubation with HLC fractions for AO activity The metabolism of MPZ was evaluated in human liver cytosol incubations. Metabolic incubations were performed with HLC (1 mg / mL protein) and 10 μM MPZ for 60 min at 37° C. on an orbital shaker. A parallel set of incubations was also performed with 10 μM MPZ in the presence of 100 μM menadione, a known inhibitor of human aldehyde oxidase. Another set of incubations was also performed under the same conditions with 1 μM phthalazine, a known substrate for aldehyde oxidase, as a positive control.

[0193] LC / MS / MS method LC separation conditions were developed for MPZ and its metabolites (MPZA and MPZS), 7-hydroxycoumarin, each metabolite of the CYP probe substrate, benzydamine N-oxide, and phthalazine. The LC-MS / MS system consisted of a Shimadzu Nexera X2 LC-30 UPLC system (Shimadzu Corporation, Kyoto, Japan) and an API4000 triple quadrupole mass spectrometer (SCIEX, Framingham, MA) were used for analysis. All analytes were analyzed using electrospray ionization (ESI) in positive ion mode, except for 7-EC, which was used in negative ion mode. The LC-MS / MS system was controlled by Analyst software (version 1.6.1, SCIEX, Framingham, MA).

[0194] For each analytical method, a calibration curve was generated to quantify MPZ and its two metabolites (MPZA and MPZS). Due to the lack of a reference standard, hydroxylated metopimazine (MPZH) was determined qualitatively based on the peak area ratio (PAR) of the putative hydroxylated analyte to IS. PAR was also used for all positive control compounds.

[0195] Data analysis The extent of disappearance of each analyte was assessed by comparing the analyte's PAR to the IS, or the concentrations at different sampling time points to the PAR at time 0 (t = 0, 100%). The % of parent remaining value was calculated according to the following formula: % Parent Remaining = (mean concentration or PAR at each sampling time point / mean concentration or PAR at time 0) x 100

[0196] All statistics (e.g., mean, standard deviation) presented in the data tables are based on "Precision displayed" numbers (MS Excel, version 2010). GraphPad Prism (version 8, San Diego, CA) was used for plotting.

[0197] result Metabolism in liver and intestinal S9 fractions and in microsomes When MPZ was incubated with HLM, three primary metabolites were observed in the full-scan LC-MS analysis. Based on peak area, the maximum signal was found at m / z 447.14, which corresponded to MPZA, the major in vivo metabolite in humans. Two other isobaric peaks were observed at m / z 462.15, corresponding to MPZH and MPZS metabolites (Table 1). [Table 1]

[0198] In human liver S9 fraction, nearly 30% of MPZ disappeared, and all three metabolites (MPZA, MPZH, and MPZS) were formed after 60 min of incubation. In contrast, human intestinal S9 fraction showed virtually no metabolism of MPZ, indicating low intestinal metabolic potential. Based on MPZ disappearance, HLM incubations were optimized for protein concentration and time, determined based on PAR. MPZ (1 μM) was incubated with the indicated HLM for 60 min. A HLM protein concentration of 0.5 mg / mL was selected for time-optimized incubation. MPZ was incubated in HLM at a protein concentration of 0.5 mg / mL for 90 min. The disappearance of MPZ was essentially linear over the incubation period, with 37.2% remaining at 60 min of incubation time, which was considered optimal for future incubations. Authentic standards of MPZ, MPZA and MPZS were available for quantification, whereas MPZH could only be semi-quantified using peak area ratios due to the lack of a synthetic standard.

[0199] Involvement of cytochrome P450 To determine the involvement of cytochrome P450 enzymes, MPZ was incubated in HLM at 1 μM and 10 μM in the presence and absence of 1-ABT, a known non-specific CYP inhibitor, with and without the addition of NADPH cofactor to the incubation mixture. As shown in Figure 1, the presence of 1-ABT in the incubation inhibited the formation of MPZS but did not affect MPZA. Furthermore, the absence of NADPH also did not reduce the formation of MPZA, but completely blocked the formation of MPZS. Qualitative observation of the peak area ratios (PAR) in Figure 2 indicates that the formation of MPZH as well as MPZS was inhibited by 1-ABT, a pan-CYP inhibitor, and that the formation of MPZH was also completely blocked in the absence of NADPH. This indicates that NADPH-dependent cytochrome P450 enzymes are involved in the generation of both MPZS and MPZH metabolites, but MPZA is not formed by cytochrome P450 enzymes or any NADPH-dependent metabolic process. To determine which CYP isoforms are involved in MPZ metabolism, separate HLM incubations were performed with specific inhibitors for each of the seven cytochrome P450 enzymes, and the amounts of MPZ, MPZA, and MPZS were quantified by mass spectrometry. MPZS formation was clearly inhibited by the presence of the CYP3A4-specific inhibitor itraconazole (Figure 3). MPZS formation was clearly inhibited by the presence of the CYP3A4-specific inhibitor itraconazole, whereas the CYP2D6-specific inhibitor quinidine inhibited the formation of MPZH. None of these inhibitors affected MPZA formation. Furthermore, recombinant CYP was incubated with MPZ for 60 min, and the formation of both metabolites was confirmed, as shown in Figures 4 and 5. In the recombinant CYP experiments, MPZS was mainly produced by CYP3A4, but also to a lesser extent by CYP2D6. Consistent with the inhibition experiments, MPZH was only produced with recombinant CYP2D6. None of the other CYP enzymes appeared to contribute significantly to MPZ metabolism.

[0200] Enzymes involved in the formation of MPZA As MPZA formation was not mediated by cytochrome P450, other enzymes, FMO and hydroxylases, were investigated. To determine the contribution of microsomal FMO to the metabolism of MPZ, incubations of MPZ were performed in triplicate in mixed pooled HLM or HKM at 1 μM and 10 μM in the presence of NADPH with and without an FMO inhibitor (methimazole) at pH 8.4 (a pH that should minimize CYP involvement). HLM controls were included where HLM was preincubated at 50°C for 5 min to inactivate CYP and FMO activity. Significant formation of MPZA was observed in all conditions in HLM at pH 8.4, and increased with increasing concentrations of MPZ.

[0201] Incubation of MPZ with HKM at pH 8.4 did not produce any metabolites (Figure 6). Taken together, these results indicate that liver metabolism is unaffected by pH, FMO inhibition, and even incubation at elevated temperature, while there is no evidence of metabolism by HKM. The absence of any metabolite formation at pH 8.4 upon incubation of HKM demonstrates that the formation of MPZA is not catalyzed by pH alone. Furthermore, MPZA formation was not inhibited by the known FMO inhibitor methimazole or heat (FMO inactivation), excluding the involvement of FMO enzymes in the formation of MPZA metabolites. Consistent with this, recombinant flavin monooxygenase enzymes (rhFMO1, rhFMO3, and rhFMO5) did not metabolize MPZ upon incubation (Figure 7).

[0202] To find out which hydrolase activity is responsible for the metabolism of MPZ to MPZA, HLM incubations were performed under the previous conditions, except that the pH was increased to 7.4, 8.4, and 9.4. MPZA formation was indeed faster at higher pH, including very strong formation at pH 9.4, consistent with amidase activity (Figure 8). In addition, the amidase inhibitor, bis-p-nitrophenyl phosphate (BNPP), was also added to some of the incubations. At 2 μM, at least 97% of all activity was inhibited in the presence of this amidase inhibitor, even at the highest and most active pH conditions. When the inhibitor concentration was increased to 16 μM, >99% of MPZA formation was inhibited at all three pH values. Taken together, these results are consistent with MPZA being formed by human microsomal liver amidase.

[0203] The formation of MPZA was also observed in human liver cytosol (HLC) upon incubation with 10 μM MPZ. HLC catalyzed some MPZA formation over a 60-minute incubation, which was inhibited (48%) when 100 μM menadione, a known inhibitor of human AO, was included in the incubation (Table 2). This finding suggests that human liver cytosolic aldehyde oxidase is a potential contributor to the MPZA pathway. [Table 2]

[0204] These results clearly demonstrate a plausible MPZ metabolic scheme in which the major in vivo metabolite, MPZA, is catalyzed by hepatic amidases with some potential contribution from aldehyde oxidase. Minor metabolites are catalyzed by CYP3A4 and CYP2D6. However, the contribution of CYP enzymes was much smaller than that of microsomal hydrolases / amidases in MPZ metabolism in vitro (Figure 9).

[0205] MPZ has been shown to undergo hydrolysis in human liver microsomes to form MPZA. This conversion of MPZ to MPZA is not inhibited by any of the individual CYP inhibitors, including ABT, a nonspecific inhibitor of CYP. This activity is not dependent on NADPH and is increased under conditions above physiological pH. Amidases / hydrolases such as fatty acid amide hydrolase (FAAH) are known to have optimal activity in the pH range of 8.5-10 (Ueda, N, Yamanaka, K, and Yamamoto, S (2001) Purification and Characterization of an Acid Amidase Selective for N-Palmitoylethanolamine, a Putative Endogenous Anti-inflammatory Substance J. Biol. Chem. 276: 35552-35557; Bisogno, T, Maurelli, S, Melck, D, De Petrocellis, L, and Di Marzo, V (1997) Biosynthesis, Uptake, and Degradation of Anandamide and Palmitoyl ethanolamide in Leukocytes J. Biol. Chem. 272: 3315-3323; Asano, Y, Achibana, MT, and Ani, YT, Yamada, H (1982) Purification and Characterization of Amidase which Participates in Nitrile Degradation. Agric. Biol. Chem., 46 (5): 1175-1181). In HLM, microsomal conversion of MPZ to MPZA was greatest at pH 9.4, the highest pH tested. These characteristics clearly indicate that hepatic amidase is the enzyme responsible for MPZA formation.Consistent with these findings, addition of the known amidase inhibitor BNPP (Shih, T, Pai, C, Yang, P, Chang, W, Wang, N, and Hu, OY (2013) A Novel Mechanism Underlies the Hepatotoxicity of Pyrazinamide. Antimicrob. Agents Chemother.57: 1685-1690; Sarich TC, Adams, SP, Petricca, G. and Wright, JM (1999) Inhibition of Isoniazid-Induced Hepatotoxicity in Rabbits by Pretreatment with an Amidase Inhibitor. J. Pharmacol. Exp. Ther. 289: 695-702) dramatically inhibited MPZA formation in HLM.

[0206] While hepatic amidase conversion appears to be the main biotransformation enzyme involved in MPZ metabolism, another enzyme that may contribute to the formation of MPZA is the cytosolic enzyme AO. We observed the conversion of MPZ to MPZA in HLC, but to a much lesser extent than in HLM. This activity was moderately inhibited by menadione, a known inhibitor of AO, suggesting the possible contribution of AO to MPZ metabolism. AO is a metalloenzyme that contains a molybdenum cofactor and normally exhibits hydroxylase activity (Mendel RR (2009) Cell biology of molybdenum. Biofactors 35: 429-434). AO is most extensively expressed in the liver, but also in the GI tract, as well as the kidneys, lungs and skin (Abbasi A, Paragas EM, Joswig-Jones CA, Rodgers JT, Jones JP (2019) Time Course of Aldehyde Oxidase and Why It Is Nonlinear. Drug Metab Dispos 47: 473-483). AO catalyzes the oxidation of a wide range of aldehydes to their corresponding carboxylic acids. AO is involved in the metabolism of several clinically important drugs, such as famciclovir, zaleplon, zonisamide and ziprasidone. A link between AO and the pathophysiology of several clinical disorders such as amyotrophic lateral sclerosis and alcohol-induced liver injury has been suggested (Kitamura, S, Sugihara, K and Ohta, S (2006) Drug Metabolizing Ability of Molybdenum Hydrolases. Drug Metab. Pharmacokinet. 21 (2): 83-98).

[0207] Example 2 in vivo studies Test articles, metabolites and reagents; preparation of reagents and stock solutions Supply and preparation of test articles, reagents and solutions was as in Example 1 above.

[0208] clinical research The clinical study was conducted at Biotrial Rennes (Rennes, France) in accordance with the Declaration of Helsinki. The study (NG100-101) was a double-blind, placebo-controlled, ascending single- and multiple-dose study of the safety, tolerability, and pharmacokinetics of metopimazine administered orally to healthy adult subjects. The study protocol, informed consent form, and appropriate related documentation were approved by the Institutional Review Board, and all subjects provided written informed consent prior to participation in this study.

[0209] In this study, sequential ascending single doses were administered to four cohorts of eight participants (6 active and 2 placebo per cohort after 6:2 randomization in cohorts 1, 2 and 3, and 1:1 randomization to two sentinel participants in cohort 4). Eight healthy adult subjects (male or female, aged 18-45 years) received metopimazine (or matching placebo) orally in the morning after an overnight fast of at least 10 hours. Cohorts 1-4 received matching placebo or ascending doses of Vogalene (metopimazine) capsules at doses of 15 mg, 30 mg, 45 mg or 60 mg, respectively. Blood samples were collected at the following time points: pre-dose and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 12, 18 and 24 hours post-dose. Plasma samples were obtained by centrifugation of blood samples. Comprehensive safety and pharmacokinetic analyses of each cohort for the SAD and MAD parts of the study will be performed and presented elsewhere. Four subjects from the highest single-dose cohort were analyzed for the presence of metabolites using targeted discovery methods. Plasma concentrations of metopimazine, metopimazine acid, and metopimazine sulfoxide were quantified using LC-MS / MS methods.

[0210] Rat PK study The pharmacokinetics of metopimazine (parent) and metopimazine acid (metabolite) were evaluated in male and female Sprague-Dawley rats after a single oral dose of 45 mg / kg metopimazine (free base). Three animals per sex in each dose group were sampled at each time point after dosing (0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours). Rats (rattus norvegicus) were obtained from Envigo RMS, Inc. (Indianapolis, IN) and were 2 months old. Animals were weighed prior to each dose administration for dose calculations. Total venous blood samples of approximately 0.5 mL were collected from a peripheral vein of the animals to determine exposure to metopimazine and metopimazine acid. Three animals per sex were sampled at each time point. Samples were collected into tubes containing K2EDTA with protease inhibitor cocktail (Sigma, #P8340, 1:100 ratio) and kept on ice until processed for plasma by centrifugation at 3000 rpm for at least 10 min under refrigeration. After centrifugation, the supernatant was removed and stored frozen in a -70°C freezer until analyzed by LC-MS / MS.

[0211] PK study in dogs The pharmacokinetics of metopimazine (parent) and metopimazine acid (metabolite) were evaluated in three male beagle dogs following a single oral dose of 10 mg / kg metopimazine (free base). Dogs were obtained from Marshall BioResources (North Rose, NY). Animals were weighed prior to each dose administration for dose calculation. Metopimazine was administered in size 13 gelatin capsules. Total venous blood samples of approximately 1.0 mL were collected from a peripheral vein in all animals for the determination of metopimazine and metopimazine acid. Samples were collected at the following time points: 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours after administration of the test article. All animals were sampled at each time point. Samples were collected into tubes containing K2EDTA and placed on ice until processed for plasma by centrifugation at 3000 rpm for at least 10 minutes under refrigeration. After centrifugation, the supernatant was removed and stored frozen in a −70° C. freezer until analysis by LC-MS / MS.

[0212] Preparation of human plasma samples Venous blood samples (6 mL) for determining plasma concentrations of MPZ and metabolites (MPZA and MPZS) were drawn by direct venipuncture or via an intravenous catheter into K2EDTA Vacutainer® tubes. It was important to avoid hemolysis during blood collection. Within 60 minutes of collection, blood samples were centrifuged at 3000 revolutions per minute for 10 minutes at 5°C. The resulting plasma was separated into two equal 1000 μL aliquots (aliquots A and B) transferred to polypropylene tubes, which were labeled and frozen within 120 minutes of blood collection and stored at -70°C until required for biological analysis. Immediately prior to biological analysis, samples were thawed, 200 μL aliquots were removed, and analytes were extracted using acetonitrile protein precipitation. Extracted samples were reanalyzed twice, once for quantification of MPZ and MPZA, and again for quantification of MPZS as described below.

[0213] LC / MS / MS method for metopimazine and metopimazine acid in rat, dog, and human plasma samples. An MRM LC-MS / MS method was developed for MPZ and metopimazine acid (MPZA) in rat, dog and human plasma. The method was performed in reversed phase in positive ion mode. LC separation conditions were achieved for MPZ and MPZA using a Supelco Discovery HS F5 50x4.0mm 3μm column (Sigma-Aldrich, St. Louis, MO) using an LC-MS / MS system consisting of a Shimadzu Nexera X2 LC-30UPLC system (Shimadzu, Kyoto, Japan) and an API4000 triple quadrupole mass spectrometer (SCIEX, Framingham, MA) running Analyst software 1.4. D6 isotope-labeled internal standards were used for each analyte. The following m / z transitions were monitored: metopimazine 446.3→141.1 and metopimazine acid 447.2→142.1. Calibration curves were generated for the quantification of MPZ and MPZA.

[0214] LC / MS / MS method for metopimazine sulfoxide in human plasma An MRM LC-MS / MS method was developed to monitor metopimazine sulfoxide (MPZS) in human plasma. The method was performed in reversed phase in positive ion mode. The system was identical to that described above, except for a slightly longer column, a Supelco Discovery HS F5 100x4.0mm (3μM) column (Sigma-Aldrich, St. Louis, MO). A D6 isotope-labeled internal standard was used for MPS, and the m / z transition monitored was 462.3→98.1. A calibration curve was generated for quantification of MPZS in human plasma.

[0215] Data analysis The extent of disappearance of each analyte was assessed by comparing the analyte's PAR to the IS, or the concentrations at different sampling time points to the PAR at time 0 (t = 0, 100%). The % of parent remaining value was calculated according to the following formula: % Parent Remaining = (mean concentration or PAR at each sampling time point / mean concentration or PAR at time 0) x 100

[0216] All statistics (e.g., mean, standard deviation) presented in the data tables are based on "Precision displayed" numbers (MS Excel, version 2010). GraphPad Prism (version 8, San Diego, CA) was used for plotting.

[0217] Noncompartmental pharmacokinetic analysis was performed using Phoenix64 Winnonlin version 8.1.

[0218] result Clinical Pharmacokinetics In vitro metabolism studies identified three possible metabolites: MPZA, MPZS, and MPZH. A bioanalytical method was developed to quantify MPZ, MPZA, and MPZS in human plasma. The MPZH metabolite is isobaric to MPZS and is sufficiently resolved from MPZS to be visible (qualitative only) by the same methods in the in vitro studies. To observe the presence of these metabolites in vivo, plasma was sampled over a 24-hour period from four subjects from the highest SAD cohort. Mean clinical exposure parameters following a single oral dose of 60 mg metopimazine are presented in Table 3. [Table 3]

[0219] As expected, the major circulating metabolite was MPZA, with Tmax ranging from 1.25 to 3 hours, and this analyte was present at all time points. MPZS was also found in all four subjects, but at much lower concentrations. MPZS appeared at 30-45 minutes and was not quantifiable by 12 hours. Representative chromatograms are shown in Figure 10. In some of the samples, there was a very small isobaric peak that eluted just after 2 minutes (see arrow in Figure 10). Presumably, this is likely an MPZH metabolite, although present in only trace amounts, and is unlikely to be quantifiable even if a standard could be made. A rough estimate of the percent circulating drug-related substances of confirmed in vivo metabolites based on AUClast is shown in Table 4. [Table 4]

[0220] On this basis, MPZA represents approximately 90% of the circulating material, while the parent represents less than 10%. Similarly, MPZS is a minor metabolite present at less than 1% of the total circulating drug-related material.

[0221] Preclinical Pharmacokinetics Considering that MPZA is the major circulating metabolite in humans, bioanalytical methods were developed to quantify both the parent and the major human metabolite. To determine the pharmacokinetic properties of metopimazine and its acid metabolite in rats and dogs, a single dose of metopimazine (free base) was administered orally to each species and plasma samples were collected and analyzed over time. Noncompartmental analysis of the bioanalytical data was performed to determine the pharmacokinetic parameters. Table 5 shows the mean PK exposure parameters in rats and dogs. [Table 5]

[0222] Interestingly, the ratio of MPZA metabolite to parent was significantly lower in dogs and, in particular, in rats than in humans, indicating that MPZA is produced disproportionately in humans.

[0223] While preferred embodiments of the present application have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are presented by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the present application. It should be understood that various alternatives to the embodiments of the application described herein may be used in practicing the present application. It is intended that the following claims define the scope of the present application, and that methods and structures within the scope of these claims, and their equivalents, be covered thereby.

[0224] Incorporation by Reference All references cited in this application, and all references therein, are hereby incorporated by reference in their entirety, where appropriate, for teachings of additional or alternative details, features and / or technical background.

Claims

1. A composition for treating gastroparesis in a human subject in need of such treatment, comprising metopimazine or a pharma- ceutically acceptable salt thereof, the composition being administered in combination with an additional therapeutic agent, the additional therapeutic agent not being metabolized by human microsomal hepatic amidase.

2. 2. The composition of claim 1, wherein the gastroparesis comprises symptoms selected from the group consisting of early satiety, postprandial fullness, abdominal bloating, nausea, vomiting, delayed gastric emptying, diarrhea, abdominal pain, gas, bloating, gastroesophageal reflux, loss of appetite and constipation.

3. A composition for treating nausea associated with gastroparesis in a human subject in need of such treatment, comprising metopimazine or a pharma- ceutically acceptable salt thereof, the composition being administered in combination with an additional therapeutic agent, the additional therapeutic agent not being metabolized by human microsomal hepatic amidase.

4. The composition of claim 1 or 3, wherein the composition is administered chronically to the subject.

5. The composition of claim 1 or 3, wherein the composition is administered acutely to the subject.

6. 4. The composition of claim 1 or 3, wherein the composition is administered to the subject for at least 6 days.

7. 7. The composition of claim 6, wherein the composition is administered to the subject for at least 7 days.

8. 7. The composition of claim 6, wherein the composition is administered to the subject for at least 4 weeks.

9. 7. The composition of claim 6, wherein the composition is administered to the subject for at least 12 weeks.

10. 4. The composition of claim 1 or 3, wherein the composition is administered to the subject twice daily.

11. The composition described in claim 1 or 3, characterized in that the composition is administered to the subject in an amount of between about 5 mg and about 160 mg of metopimazine or a pharma- ceutically acceptable salt thereof per day.

12. The composition of claim 1 or 3, wherein the composition is formulated as a capsule.

13. The composition of claim 1 or 3, wherein the metopimazine or a pharma- ceutically acceptable salt thereof is metopimazine mesylate.

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