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Publication Number
US-9808467-B2
Publication Date
2017-11-07
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 treatment of an enteric nervous system disorder in a human subject by administering an effective dose of a compound of formula III, or a pharmaceutically acceptable salt, solvate, or metabolite thereof. The administering occurs for over 5 days, and the disclosed therapeutic scope includes functional and motility gastrointestinal disorders.
The background problem addressed is functional and motility gastrointestinal disorders associated with an enteric nervous system disorder, including IBS/abdominal pain, functional dyspepsia, gastroparesis, cyclic vomiting syndrome, chemotherapy-induced nausea and vomiting, and related symptoms such as nausea, vomiting, abdominal pain, constipation, diarrhea, gas, bloating, and reduced appetite. The patent text associates treatment with management of these gastrointestinal symptoms and related delayed gastric emptying and other disorder manifestations.
The document further describes peripherally restricted compounds that do not effectively cross the blood-brain barrier or are limited in blood-brain barrier crossing, together with safety and exposure limitations that do not increase adverse cardiac side effect probability and adverse extrapyramidal side effect probability. Chemical embodiments include formula sets I–XI, explicit example structures, prodrugs of metopimazine and metopimazine acid, and exclusion language including that the compound is not domperidone and not Formula (Y) in certain embodiments.
Claims Coverage
The independent claim coverage centers on a method of treating an enteric nervous system disorder by administering an effective dose of a compound of formula III, or a pharmaceutically acceptable salt, solvate, or metabolite thereof, for over 5 days. The claim set also refines duration, daily dose, selected additional therapeutic agent classes, routes of administration, and limitations concerning blood-brain barrier crossing.
Treating enteric nervous system disorder with a formula III compound for over 5 days
A method of treating an enteric nervous system disorder in a human subject in need thereof, comprising administering to the subject an effective dose of a compound of formula III or a pharmaceutically acceptable salt, solvate, or metabolite thereof, wherein the administering occurs for over 5 days.
Extended treatment duration
The method is administered for a duration of more than 12 weeks.
High daily effective dose
The method is performed with an effective dose of more than 30 mg of the compound per day.
Co-administration with selected therapeutic agent classes
An additional therapeutic agent is selected from serotonin agonists, serotonin antagonists, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, anticonvulsants, opioid receptor agonists, bradykinin receptor antagonists, NK receptor antagonists, adrenergic receptor agonists, benzodiazepines, gonadotropin-releasing hormone analogues, calcium channel blockers, somatostatin analogs, antihistamines, anticholinergics, steroids, anti-emetics, insulin, dopaminergic agents, MAOIs, COMT inhibitors, beta blockers, proton pump inhibitors, H2 receptor antagonists, immunosuppressants, steroid receptor antagonists, antioxidants, and molecular chaperones.
Selected routes of administration
The method is administered via one of oral, parenteral, enteral, intraperitoneal, topical, transdermal, ophthalmical, intranasal, local, by spray, subcutaneous, intravenous, intratonsillal, intramuscular, buccal, sublingual, rectal, intra-arterial, by infusion, or intrathecal.
Limiting blood-brain barrier crossing
The method is applied such that the compound does not effectively cross a blood brain barrier.
The claim coverage is a chronic treatment method for an enteric nervous system disorder using a formula III compound, or its pharmaceutically acceptable salt, solvate, or metabolite, administered for more than 5 days. The inventive features further include longer administration, higher daily dose, optional co-administration with selected therapeutic agent classes, selected routes of administration, and a limitation that the compound does not effectively cross a blood brain barrier.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treatment of an enteric nervous system disorder in a human subject, including functional and motility gastrointestinal disorders.
Treatment of gastroparesis and gastric motility.
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