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Publication Number
US-11834445-B2
Publication Date
2023-12-05
Expiration Date
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.
Core Innovation
The document describes pharmaceutical administration of crystalline metopimazine mesylate, including Crystal Form A and Crystal Form B, for treating disorders associated with the enteric nervous system, including gastroparesis. It provides administration routes, dosing ranges, and treatment duration windows in which the crystalline metopimazine mesylate is administered to a patient in need thereof. The crystalline forms are characterized and distinguished using analytical data including XRPD, DSC, and TGA.
Crystal Form A and Crystal Form B are related and converted, with Crystal Form A being converted to Crystal Form B by exposure to a high relative humidity condition. Crystal Form A is characterized by XRPD peak information and thermal behavior, including a minimal TGA weight loss and a DSC melt onset. Crystal Form B is characterized by its own XRPD pattern and distinct thermal behavior, including TGA weight loss and DSC endotherms and exotherm.
The document also provides confirmation and structural characterization for Crystal Form A using high resolution mass spectrometry, 1H NMR and 13C NMR, and single-crystal XRD reporting a monoclinic space group and unit cell parameters. It reports XRPD peak lists and thermal transition behavior (TGA and DSC). A pharmacokinetic crossover study is presented comparing Crystal Form A to metopimazine free base, reporting lower variance in Tmax and a reduced food effect in terms of Cmax for gastroparesis patients.
Claims Coverage
The independent claims define metopimazine mesylate by three distinct analytical fingerprints: an XRPD-defined crystalline form, a DSC-defined crystalline form, and a TGA-defined crystalline form.
Xrpd-defined crystalline form by selected 2θ peaks
A crystalline form of metopimazine mesylate characterized by an X-ray powder diffraction pattern comprising two or more of the specified 2θ values, with ±0.2° in the claim.
Dsc-defined crystalline form with two endotherms and one exotherm
A crystalline form of metopimazine mesylate characterized by a differential scanning calorimetry pattern comprising a first endothermic peak with an onset temperature range of 122°C to 125°C, a second endothermic peak with an onset temperature range of 207°C to 210°C, and a single exothermic peak with a peak temperature range of 143°C to 146°C.
Tga-defined crystalline form by total weight loss
A crystalline form of metopimazine mesylate characterized by a thermogravimetric analysis profile comprising a total weight loss of between 5.5–6% up to 180.0°C.
Overall, the claim coverage is directed to crystalline forms of metopimazine mesylate that are uniquely characterized by specified XRPD 2θ peak sets, specified DSC thermal events, and specified TGA total weight-loss behavior up to 180°C. Additional dependent coverage narrows the XRPD peak sets and imposes quantitative wt.% limits on other crystalline and amorphous forms, and it enumerates multiple administration routes.
Stated Advantages
Improved safety via peripheral restriction.
Crystal Form A provides more predictable onset, as indicated by significantly lower variance in Tmax for gastroparesis patients.
Crystal Form A shows a reduced food effect, with about a 15% reduction in Cmax with food and no notable change in AUC reported in the described crossover comparison.
Documented Applications
Treating enteric nervous system (ENS) disorders including gastroparesis, including diabetic gastroparesis, and delayed gastric emptying.
Treating nausea and vomiting.
Treatment of disorders associated with the enteric nervous system, including gastroparesis, using pharmaceutical administration of crystalline metopimazine mesylate (Crystal Form A and Crystal Form B).
Use in combination therapy with a peripherally restricted dopamine decarboxylase inhibitor (carbidopa) and anti-emetics including 5-HT3 receptor antagonists, dopamine receptor antagonists, and NK1 receptor antagonists.
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