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Publication Number
US-11147820-B2
Publication Date
2021-10-19
Expiration Date
Abstract
Provided herein are methods, compositions, and kits for the treatment of an enteric nervous system disorder. Such methods may comprise administering to a subject an effective amount of a phenothiazine compound, a peripherally restricted dopamine decarboxylase inhibitor, and/or a peripherally restricted dopamine D2 receptor antagonist that does not substantially inhibit hERG channels.
Core Innovation
The invention relates to methods of treating gastroparesis in a subject in need thereof by administering a pharmaceutical composition comprising a pharmaceutically acceptable salt of metopimazine and a pharmaceutically acceptable carrier. The treatment is directed to modulating gastrointestinal function associated with enteric nervous system disorder states and to disorders associated with delayed gastric emptying.
The disclosed approach links the treatment to nausea and vomiting, and to symptom sets including constipation, diarrhea, abdominal pain, gas, bloating, gastroesophageal reflux, reduced appetite, and delayed gastric emptying. The pharmaceutical composition is used to improve gastric emptying and address associated gastrointestinal symptoms.
The disclosure further characterizes metopimazine and metopimazine acid as potent, selective D2 antagonists that are peripherally restricted and weak hERG inhibitors. It also describes peripherally restricted properties through assays that assess lack of intact blood brain barrier crossing and reports improving gastric motility/emptying in canines and rodents, with no significant QTc increase in dogs at test doses.
Claims Coverage
The independent claim is directed to a method of treating gastroparesis using a pharmaceutical composition comprising a pharmaceutically acceptable salt of metopimazine and a pharmaceutically acceptable carrier. Six inventive features are identified across the claims coverage, with dependent claims further refining symptom scope, administration timing, dosing frequency, treatment duration, and a daily dose threshold.
Metopimazine salt pharmaceutical composition for gastroparesis treatment
Administering to a subject a pharmaceutical composition comprising a pharmaceutically acceptable salt of metopimazine and a pharmaceutically acceptable carrier for treating gastroparesis.
Gastroparesis defined with included symptom selection
The gastroparesis includes a symptom selected from nausea, vomiting, delayed gastric emptying, diarrhea, abdominal pain, gas, bloating, gastroesophageal reflux, reduced appetite, or constipation.
Acute administration characterization
The pharmaceutical composition is administered acutely.
Minimum chronic treatment duration
Administering the pharmaceutical composition for at least 12 weeks.
Administration frequency range
Administering the pharmaceutical composition one to four times per day.
Daily dose threshold for metopimazine salt
Administering more than 20 mg per day of a pharmaceutically acceptable salt of metopimazine.
Across the independent method and its refinements, the claimed inventive elements focus on administering a pharmaceutically acceptable salt of metopimazine with a pharmaceutically acceptable carrier to treat gastroparesis, with symptom selection and further characterization by acute or at least 12 weeks of treatment, one to four times per day, and more than 20 mg per day.
Stated Advantages
Improving gastric motility/emptying in canines and rodents.
No significant QTc increase in dogs at test doses.
Potent, selective D2 antagonism together with peripherally restricted behavior and weak hERG inhibition.
Documented Applications
Treatment of gastroparesis in a subject in need thereof.
Improving gastric motility/emptying, as demonstrated in canines and rodents.
Assessment of peripherally restricted D2 antagonism and hERG inhibition through assays and blood brain barrier crossing assays [procedural detail omitted for safety].
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