Novel polymorphic forms of metopimazine

Abstract

Provided herein are novel polymorphic forms of metopimazine mesylate. These polymorphic forms are useful in methods, compositions, and kits for the treatment of an enteric nervous system disorder.

1 . A crystalline form of metopimazine mesylate, 
       
         
           
           
               
               
           
         
       
     
     
         2 . The crystalline form of  claim 1 , wherein the crystalline form comprises less than 10 wt. % of amorphous forms. 
     
     
         3 . The crystalline form of  claim 1  or  2 , wherein the crystalline form is in non-solvate form. 
     
     
         4 . The crystalline form of  claim 3 , wherein the crystalline form comprises less than 10 wt. % of solvate forms. 
     
     
         5 . The crystalline form of any preceding claim, wherein the crystalline form comprises metopimazine mesylate Crystal Form A. 
     
     
         6 . A crystalline form of metopimazine mesylate characterized by an X-ray powder diffraction (XRPD) pattern comprising two or more of the following 2θ values: 9.37°, 9.87°, 14.33°, 15.26°, 15.91°, 16.55°, 17.52°, 17.75°, 18.75°, 19.09°, 19.72°, 20.80°, 21.22°, 21.77°, 23.29°, 23.91°, 24.44°, 25.37°, 26.39°, 26.92°, 27.96°, 28.23°, 28.78°, 29.27°, 29.64°, 30.67°, 31.29°, 31.84°, 32.09°, 32.99°, 33.40°, 33.99°, 35.91°, 36.80°, 37.41°, 37.92°, and 39.27°±0.2°. 
     
     
         7 . The crystalline form of  claim 6 , characterized by an XRPD pattern comprising two or more of the following 2θ values: 9.37°, 9.87°, 14.33°, 15.26°, 15.91°, 16.55°, 17.52°, 17.75°, 18.75°, 19.09°, 19.72°, 20.80°, 21.22°, 21.77°, 23.29°, 23.91°, 24.44°, and 25.37°±0.2°. 
     
     
         8 . The crystalline form of  claim 6 , characterized by an XRPD pattern comprising three or more of the following 2θ values: 9.37°, 9.87°, 14.33°, 15.26°, 15.91°, 16.55°, 17.52°, 17.75°, 18.75°, 19.09°, 19.72°, 20.80°, 21.22°, 21.77°, 23.29°, 23.91°, 24.44°, and 25.37°±0.2°. 
     
     
         9 . The crystalline form of  claim 6 , characterized by an XRPD pattern comprising four or more of the following 2θ values: 9.37°, 9.87°, 14.33°, 15.26°, 15.91°, 16.55°, 17.52°, 17.75°, 18.75°, 19.09°, 19.72°, 20.80°, 21.22°, 21.77°, 23.29°, 23.91°, 24.44°, and 25.37°±0.2°. 
     
     
         10 . The crystalline form of  claim 6 , characterized by an XRPD pattern comprising peaks at the following 2θ values: 15.91° and 18.75°±0.2°. 
     
     
         11 . The crystalline form of  claim 6 , characterized by an XRPD pattern comprising peaks at the following 2θ values: 15.91°, 18.75°, and 24.44°±0.2°. 
     
     
         12 . A crystalline form of metopimazine mesylate characterized by an XRPD pattern comprising one or more of the following 2θ values: 9.37°, 15.26°, 15.91°, 18.75°, 19.09°, 20.80°, 21.22°, 21.77°, and 24.44°±0.2°. 
     
     
         13 . The crystalline form of  claim 12 , characterized by an XRPD pattern comprising two or more of the following 2θ values: 9.37°, 15.26°, 15.91°, 18.75°, 19.09°, 20.80°, 21.22°, 21.77°, and 24.44°±0.2°. 
     
     
         14 . The crystalline form of  claim 12 , characterized by an XRPD pattern comprising three or more of the following 2θ values: 9.37°, 15.26°, 15.91°, 18.75°, 19.09°, 20.80°, 21.22°, 21.77°, and 24.44°±0.2°. 
     
     
         15 . A crystalline form of metopimazine mesylate characterized by a  13 C solid state Nuclear Magnetic Resonance (ssNMR) spectrum comprising at least one peak, expressed as chemical shift in ppm, selected from the following: 176.8, 176.4, 142.2, 141.7, 140.9, 140.0, 128.3, 127.0, 126.2, 125.1, 121.1, 119.9, 114.7, 110.9, 57.0, 55.7, 50.6, 47.1, 45.6, 42.1, 40.2, 27.4, and 21.3±0.20 ppm. 
     
     
         16 . The crystalline form of  claim 15 , characterized by a  13 C ssNMR spectrum comprising at least three peaks, expressed as chemical shift in ppm, selected from the following: 176.8, 176.4, 142.2, 141.7, 140.9, 140.0, 128.3, 127.0, 126.2, 125.1, 121.1, 119.9, 114.7, 110.9, 57.0, 55.7, 50.6, 47.1, 45.6, 42.1, 40.2, 27.4, and 21.3±0.20 ppm. 
     
     
         17 . The crystalline form of  claim 15 , characterized by a  13 C ssNMR spectrum comprising at least four peaks, expressed as chemical shift in ppm, selected from the following: 176.8, 176.4, 142.2, 141.7, 140.9, 140.0, 128.3, 127.0, 126.2, 125.1, 121.1, 119.9, 114.7, 110.9, 57.0, 55.7, 50.6, 47.1, 45.6, 42.1, 40.2, 27.4, and 21.3±0.20 ppm. 
     
     
         18 . The crystalline form of  claim 15 , characterized by a  13 C ssNMR spectrum comprising at least six peaks, expressed as chemical shift in ppm, selected from the following: 176.8, 176.4, 142.2, 141.7, 140.9, 140.0, 128.3, 127.0, 126.2, 125.1, 121.1, 119.9, 114.7, 110.9, 57.0, 55.7, 50.6, 47.1, 45.6, 42.1, 40.2, 27.4, and 21.3±0.20 ppm. 
     
     
         19 . The crystalline form of  claim 15 , characterized by a  13 C ssNMR spectrum comprising at least one peak, expressed as chemical shifts in ppm, selected from the following: 21.3, 27.4, 42.1, 50.6, 57.0, 114.7, 119.9, 121.1, 176.4 and 176.8±0.20 ppm. 
     
     
         20 . The crystalline form of  claim 15 , characterized by a  13 C ssNMR spectrum comprising at least three peaks, expressed as chemical shifts in ppm, selected from the following: 21.3, 27.4, 42.1, 50.6, 57.0, 114.7, 119.9, 121.1, 176.4 and 176.8±0.20 ppm. 
     
     
         21 . The crystalline form of  claim 15 , characterized by a  13 C ssNMR spectrum comprising at least six peaks, expressed as chemical shifts in ppm, selected from the following: 21.3, 27.4, 42.1, 50.6, 57.0, 114.7, 119.9, 121.1, 176.4 and 176.8±0.20 ppm. 
     
     
         22 . A crystalline form of metopimazine mesylate characterized by a differential scanning calorimetry pattern comprising a single endotherm comprising an onset temperature range of 208° C. to 212° C. 
     
     
         23 . The crystalline form of  claim 22 , wherein the single endotherm comprises an onset temperature range of 208° C. to 211° C. 
     
     
         24 . The crystalline form of  claim 22 , wherein the single endotherm comprises an onset temperature range of 209° C. to 210° C. 
     
     
         25 . The crystalline form of any one of  claims 22 - 24 , wherein the single endotherm comprises a peak temperature range of 213° C. to 214° C. 
     
     
         26 . The crystalline form of any one of  claims 22 - 25 , wherein the single endotherm comprises an enthalpy of transition of 95-100 J/g. 
     
     
         27 . The crystalline form of  claim 26 , wherein the single endotherm comprises an enthalpy of transition of 96-98 J/g. 
     
     
         28 . The crystalline form of  claim 26 , wherein the single endotherm comprises an enthalpy of transition of 97-98 J/g. 
     
     
         29 . A crystalline form of metopimazine mesylate characterized by a thermogravimetric analysis profile comprising a total weight loss of 0.4% up to 150.0° C. 
     
     
         30 . A composition comprising the crystalline form of any one of  claims 6 - 29 , wherein the composition comprises less than 10 wt. % of other crystalline forms of metopimazine mesylate. 
     
     
         31 . The composition of  claim 30 , wherein the composition comprises less than 1 wt. % of other crystalline forms of metopimazine mesylate. 
     
     
         32 . The composition of  claim 30  or  31 , wherein the composition comprises less than 10 wt. % of amorphous forms of metopimazine mesylate. 
     
     
         33 . The composition of  claim 32 , wherein the composition comprises less than 1 wt. % of amorphous forms of metopimazine mesylate. 
     
     
         34 . A pharmaceutical composition comprising the crystalline form of any one of  claims 1 - 33  and a pharmaceutically acceptable excipient. 
     
     
         35 . The pharmaceutical composition of  claim 34 , wherein the pharmaceutical composition is suitable for administering administering orally, intraduodenally, intracolonically, enterally, topically, intranasally, non-orally, buccally, sublingually, by inhalation, or rectally. 
     
     
         36 . The pharmaceutical composition of  claim 35 , wherein the composition is suitable for administering orally. 
     
     
         37 . The pharmaceutical composition of  claim 35 , wherein the composition is suitable for administering sublingually. 
     
     
         38 . The pharmaceutical composition of any one of  claims 34 - 37 , wherein the pharmaceutical composition is formulated as a tablet, a capsule, a paste, a powder, a suspension, a suppository, an extended-release formulation, or a modified-release formulation. 
     
     
         39 . The pharmaceutical composition of  claim 38 , wherein the composition is formulated as an extended release formulation. 
     
     
         40 . The pharmaceutical formulation of  claim 38 , wherein the composition is formulated as a capsule. 
     
     
         41 . The pharmaceutical composition of any one of  claims 34 - 40 , wherein the composition comprises 5 mg of the crystalline form of metopimazine mesylate. 
     
     
         42 . The pharmaceutical composition of any one of  claims 34 - 40 , wherein the composition comprises 10 mg of the crystalline form of metopimazine mesylate. 
     
     
         43 . The pharmaceutical composition of any one of  claims 34 - 40 , wherein the composition comprises 20 mg of the crystalline form of metopimazine mesylate. 
     
     
         44 . The pharmaceutical composition of any one of  claims 34 - 43 , wherein the composition is suitable for administration one time per day. 
     
     
         45 . The pharmaceutical composition of any one of  claims 34 - 43 , wherein the composition is suitable for administration two times per day. 
     
     
         46 . The pharmaceutical composition of any one of  claims 34 - 43 , wherein the composition is suitable for administration three times per day. 
     
     
         47 . The pharmaceutical composition of any one of  claims 34 - 43 , wherein the composition is suitable for administration four times per day. 
     
     
         48 . The pharmaceutical composition of any one of  claims 34 - 47 , wherein between about 5 mg and about 160 mg of the crystalline form of metopimazine mesylate is administered per day. 
     
     
         49 . The pharmaceutical composition of any one of  claims 34 - 47 , wherein the composition is suitable for administration of more than 20 mg of the crystalline form of metopimazine mesylate per day. 
     
     
         50 . A method of treating an enteric nervous system disorder in a human subject in need thereof, comprising administering to the subject a pharmaceutical composition of any one of  claims 34 - 49 . 
     
     
         51 . The method of  claim 50 , wherein the enteric nervous system disorder is a chronic disorder. 
     
     
         52 . The method of  claim 50 , wherein the enteric nervous system disorder is an acute disorder. 
     
     
         53 . The method of  claim 50 , wherein the enteric nervous system disorder is selected from the group consisting of gastroparesis, Irritable Bowel Syndrome, lysosomal storage disorders, intestinal dysmotility, ganglioneuroma, multiple endocrine neoplasia type 2B (MEN2B), gastrointestinal neuropathy, functional dyspepsia, gastroesophageal reflux disease (GERD), and intestinal neuronal dysplasia. 
     
     
         54 . The method of any of  claims 50 - 53 , wherein the enteric nervous system disorder 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, reduced appetite, and constipation. 
     
     
         55 . The method of  claim 54 , wherein the enteric nervous system disorder symptom comprises nausea. 
     
     
         56 . The method of  claim 54 , wherein the enteric nervous system disorder symptom comprises vomiting. 
     
     
         57 . A method of treating gastroparesis in a human subject in need thereof, comprising administering to the subject a pharmaceutical composition of any one of  claims 34 - 49 . 
     
     
         58 . The method of  claim 57 , wherein gastroparesis is diabetic gastroparesis. 
     
     
         59 . The method of  claim 57 , wherein the gastroparesis is idiopathic gastroparesis. 
     
     
         60 . The method of any of  claims 57 - 59 , wherein 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, reduced appetite, and constipation. 
     
     
         61 . The method of  claim 60 , wherein the gastroparesis symptom comprises nausea. 
     
     
         62 . The method of  claim 60 , wherein the gastroparesis symptom comprises vomiting. 
     
     
         63 . A method of treating nausea associated with gastroparesis in a human subject in need thereof, comprising administering to the subject a pharmaceutical composition of any one of  claims 34 - 49 . 
     
     
         64 . A method of treating vomiting associated with gastroparesis in a human subject in need thereof, comprising administering to the subject a pharmaceutical composition of any one of  claims 34 - 49 . 
     
     
         65 . A method of improving gastric emptying in a human subject in need thereof, comprising administering to the subject a pharmaceutical composition of any one of  claims 34 - 49 . 
     
     
         66 . A method of treating functional and motility disorders of the GI tract in a human subject in need thereof, comprising administering to the subject a pharmaceutical composition of any one of  claims 34 - 49 . 
     
     
         67 . The method of any one of  claims 50 - 66 , wherein the pharmaceutical composition is administered to the subject chronically. 
     
     
         68 . The method of any one of  claims 50 - 66 , wherein the pharmaceutical composition is administered to the subject acutely. 
     
     
         69 . The method of any one of  claims 50 - 66 , wherein the pharmaceutical composition is administered to the subject for at least 6 days. 
     
     
         70 . The method of  claim 69 , wherein the pharmaceutical composition is administered to the subject for at least 7 days. 
     
     
         71 . The method of  claim 69 , wherein the pharmaceutical composition is administered to the subject for at least four weeks. 
     
     
         72 . The method of  claim 69 , wherein the pharmaceutical composition is administered to the subject for at least 12 weeks. 
     
     
         73 . The method of any one of  claims 50 - 72 , wherein the pharmaceutical composition is administered to the subject one time per day. 
     
     
         74 . The method of any one of  claims 50 - 72 , wherein the pharmaceutical composition is administered to the subject two times per day. 
     
     
         75 . The method of any one of  claims 50 - 72 , wherein the pharmaceutical composition is administered to the subject three times per day. 
     
     
         76 . The method of any one of  claims 50 - 72 , wherein the pharmaceutical composition is administered to the subject four times per day. 
     
     
         77 . The method of any one of  claims 50 - 76 , wherein between about 5 mg and about 160 mg of the metopimazine mesylate is administered to the subject per day. 
     
     
         78 . The method of any one of  claims 50 - 76 , wherein more than 20 mg of metopimazine mesylate is administered to the subject per day.