Methods and compositions for treating conditions associated with an abnormal inflammatory response
Inventors
Glick, Gary D. • Franchi, Luigi
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11793777-B2
Publication Date
2023-10-24
Expiration Date
Abstract
This disclosure features chemical entities (e.g., a compound exhibiting activity as a mitochondrial uncoupling agent or a pharmaceutically acceptable salt and/or hydrate and/or cocrystal thereof; e.g., a compound, such as niclosamide or a pharmaceutically acceptable salt and/or hydrate and/or cocrystal thereof; e.g., a compound, such as a niclosamide analog, or a pharmaceutically acceptable salt and/or hydrate and/or cocrystal thereof) that are useful, e.g., for treating one or more symptoms of a pathology characterized by an abnormal inflammatory response (e.g., inflammatory bowel diseases) in a subject (e.g., a human). This disclosure also features compositions as well as other methods of using and making the same.
Core Innovation
The invention relates to crystalline niclosamide, or a pharmaceutically acceptable salt, hydrate, or co-crystal thereof, in a pharmaceutical composition that includes a component that chemically or structurally predisposes the composition for delivery of the niclosamide to the lower gastrointestinal tract. The composition is disclosed with enteric material as the predisposition component, including specific enteric polymers and combinations thereof, and with oral solid dosage forms such as capsules, tablets, pills, powders, and granules.
The disclosure provides chemical definitions and structural examples for niclosamide and niclosamide-analog chemical entities, including niclosamide ethanolamine, salts, hydrates, and cocrystals held together via non-covalent interactions, including hydrogen bonding. The disclosure also notes low water solubility and drug permeability, and frames the approach as supporting local concentration in the GI tract relative to the plasma compartment after administration.
The description characterizes niclosamide and niclosamide analogs as mitochondrial uncoupling agents in pathogenic T cells and states that this promotes T-cell death. It further provides supporting rationale for inflammatory-response mediated conditions, including inflammatory bowel disease, and describes downregulation of inflammatory cytokines in the disease context.
Claims Coverage
The document provides two independent claims. Across the independent claims, the inventive features center on crystalline niclosamide, including pharmaceutically acceptable salt, hydrate, and co-crystal forms, combined with a component that chemically or structurally predisposes the composition for delivery to the lower gastrointestinal tract, with oral administration as the corresponding method.
Crystalline niclosamide with a lower-gI delivery predisposition component
A pharmaceutical composition comprising crystalline niclosamide or a pharmaceutically acceptable salt, hydrate, or co-crystal thereof and a component that chemically or structurally predisposes the composition for delivery of the niclosamide to the lower gastrointestinal tract.
Oral administration for lower gastrointestinal delivery
A method of delivering niclosamide to the lower gastrointestinal tract comprising orally administering a pharmaceutical composition comprising crystalline niclosamide or a pharmaceutically acceptable salt, hydrate, or co-crystal thereof and a component that chemically or structurally predisposes the composition for delivery of the niclosamide to the lower gastrointestinal tract.
Enteric delivery-predisposing component
A pharmaceutical composition in which the predisposing component is an enteric material.
Enteric material selected from specific enteric polymers
A pharmaceutical composition in which the enteric material is selected from hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, methacrylic acid-methyl methacrylate copolymers, and combinations thereof.
Oral solid dosage form selection
A pharmaceutical composition formulated as an oral solid dosage form selected from a capsule, tablet, pill, powder, or granule.
Crystalline niclosamide includes niclosamide ethanolamine
A pharmaceutical composition in which crystalline niclosamide includes niclosamide ethanolamine.
Higher local GI concentration than plasma concentration after administration
A pharmaceutical composition such that, after administration, the local concentration of niclosamide in the GI tract is higher than the concentration of the chemical entity in the plasma compartment.
Overall claim coverage centers on crystalline niclosamide, including pharmaceutically acceptable salt, hydrate, and co-crystal forms, formulated with a chemically or structurally predisposed component for delivery to the lower gastrointestinal tract. Dependent refinements further specify enteric materials, specific enteric polymers, oral solid dosage forms, niclosamide ethanolamine, and an after-administration relationship where local GI concentration exceeds plasma concentration.
Stated Advantages
Local concentration of niclosamide in the gastrointestinal tract is higher than the concentration of the chemical entity in the plasma compartment.
The compositions are positioned to support lower gastrointestinal delivery of niclosamide.
The description links lower gastrointestinal delivery to local effects, including mitochondrial uncoupling and T-cell death.
Provides treating inflammatory-response mediated conditions, including inflammatory bowel disease, using niclosamide-based mitochondrial uncoupling in pathogenic T cells.
Promotes T-cell death via mitochondrial uncoupling agent activity in pathogenic T cells.
Supports rectal or local efficacy relative to systemic distribution, consistent with targeted lower gastrointestinal tract delivery.
Downregulates inflammatory cytokines associated with the disease context.
Limits systemic exposure by emphasizing low systemic bioavailability.
Documented Applications
Orally delivering niclosamide to the lower gastrointestinal tract.
Delivering niclosamide using oral solid dosage forms such as capsules, tablets, pills, powders, and granules.
Local GI exposure and associated biological effects in immune cells, including gut tropic T cells and relevant immune cell readouts.
Treating inflammatory-response mediated conditions, notably inflammatory bowel disease, including ulcerative colitis and Crohn’s disease.
Interested in licensing this patent?