Methods and compositions for the treatment of C. difficile
Inventors
FARQUHAR, RONALD • Murphy, Christopher K. • Hill, Colin • Ross, Paul • Rea, Mary • O'DONNELL, MICHELLE • Healy, Brian • CHESNEL, LAURENT
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11896628-B2
Publication Date
2024-02-13
Expiration Date
Abstract
Disclosed herein are compositions and methods for preventing, ameliorating, or treating Clostridium difficile infections and/or reducing the severity of one or more risk factors, signs, or symptoms associated with C. difficile infections. In particular, the technology of the present disclosure relates to methods for administering an effective amount of a composition comprising strains of Bacillus amyloliquefaciens bacteria identified as ART24, ART4, and ART 12, to a subject suffering from or at risk for C. difficile infections.
Core Innovation
The invention relates to therapeutic compositions comprising one or more bacterial strains selected from ART24 (NCIMB Accession No. 43088), ART4 (NCIMB Accession No. 43086), and ART12 (NCIMB Accession No. 43087), including spores and lyophilized forms, for preventing and/or treating Clostridium difficile infection and Clostridium difficile-associated disease. The compositions may further include standard-of-care antibiotics and/or anti-toxin B monoclonal antibody.
The invention also provides formulations that include bacterial strains combined with a preservative, and optionally cryoprotectants, pharmaceutically acceptable carriers, and routes of administration. The disclosed preservative/cryoprotectant components include sucrose and trehalose and additional enumerated substances such as sodium ascorbate and glutathione, along with listed nucleotide compounds, bases, sugars, polyols, and polysaccharides, in pharmaceutically acceptable carriers such as polysaccharides, locust bean gum, and pectin.
The invention further describes anti-C. difficile activity associated with the bacterial strains, including activity attributed to anti-C. difficile bioactive peptides and proteinase resistance, with inhibition of C. difficile clinical isolates and toxin cleavage effects. Additional antimicrobial profiles are described for activity against C. perfringens, L. monocytogenes, and V. parahaemolyticus, and the document reports survivability of spores under simulated gastric fluid and in vivo efficacy in a mouse model.
The background problem addressed is the need for therapeutic approaches to prevent or treat Clostridium difficile infection and Clostridium difficile-associated disease, including the need for effective compositions and formulations that maintain activity under relevant conditions and provide outcomes comparable with, or improved relative to, comparator treatments.
Claims Coverage
The provided claim material centers on preparing a therapeutic composition by combining specified ART strains with a preservative, with dependent refinements that narrow the bacterial form and preserve choices, and add gastric fluid tolerance and cryoprotectant selections.
Preparing a therapeutic composition with specified ART strains and a preservative
A method of preparing a therapeutic composition, comprising, combining one or more bacterial strains selected from the group consisting of ART24 (NCIMB Accession No. 43088), ART4 (NCIMB Accession No. 43086), and ART12 (NCIMB Accession No. 43087) with a preservative.
Combining specified ART strains with a preservative selected from sucrose, trehalose, sodium ascorbate, or glutathione
The method of preparing the therapeutic composition wherein the preservative is selected from the group consisting of sucrose, trehalose, sodium ascorbate, and glutathione.
Using one or more ART strains in spore form
The method of preparing the therapeutic composition wherein the one or more bacterial strains are in spore form.
Sporulating the ART strains using nutrient exhaustion media
The method of preparing the therapeutic composition wherein the one or more bacterial strains are sporulated using nutrient exhaustion media.
Using sporulated ART strains that exhibit gastric fluid tolerance
The method of preparing the therapeutic composition wherein the one or more sporulated bacterial strains exhibit gastric fluid tolerance.
Selecting cryoprotectant components from enumerated nucleotides, bases, sugars, polyols, and carbohydrates
The method of preparing the therapeutic composition wherein the cryoprotectant is selected from the group consisting of inosine-5′-monophosphate (IMP), guanosine-5′-monophosphate (GMP), adenosine-5′-monophosphate (AMP), uranosine-5′-monophosphate (UMP), cytidine-5′-monophosphate (CMP), adenine, guanine, uracil, cytosine, guanosine, uridine, cytidine, hypoxanthine, xanthine, orotidine, thymidine, inosine, trehalose, maltose, lactose, sucrose, sorbitol, mannitol, dextrin, inulin, sodium ascorbate, glutathione, and skim milk.
The claim coverage is anchored on preparing a therapeutic composition by combining ART24, ART4, or ART12 with a preservative, with dependent refinements specifying preservative and cryoprotectant selections, restricting the bacterial state to spores, and requiring gastric fluid tolerance for the sporulated strains.
Stated Advantages
Preventing and/or treating Clostridium difficile infection and Clostridium difficile-associated disease.
Therapeutic compositions maintain anti-C. difficile activity, including proteinase resistance, and show inhibition of C. difficile clinical isolates.
Provides toxin cleavage effects associated with anti-C. difficile activity.
Supports survivability of spores under simulated gastric fluid conditions.
Includes antimicrobial profiles against C. perfringens, L. monocytogenes, and V. parahaemolyticus.
In vivo efficacy in a mouse model with outcomes comparable to vancomycin.
Documented Applications
Preventing and/or treating Clostridium difficile infection (CDI) and Clostridium difficile-associated disease (CDAD).
Using formulations for anti-C. difficile activity associated with ART strains, including spores and lyophilized forms under simulated gastric fluid conditions.
Providing compositions with antimicrobial profiles against C. perfringens, L. monocytogenes, and V. parahaemolyticus.
Interested in licensing this patent?