Method and compositions for inhibiting or preventing adverse effects of oral antibiotics
Inventors
Kaleko, Michael • Connelly, Sheila • Wacher, Vincent John
Assignees
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Publication Number
US-11944669-B2
Publication Date
2024-04-02
Expiration Date
Abstract
This invention provides, in part, various compositions and methods for protecting the gastrointestinal microbiome from antibiotic disruption.
Core Innovation
The invention relates to beta-lactamase-based formulations for protecting the gastrointestinal (GI) microbiome from disruption by oral antibiotics by hydrolyzing residual or excess antibiotic in the GI tract while not substantially affecting systemic antibiotic absorption. The formulations are designed for GI-targeted activity and distal GI release behavior.
The invention provides formulations comprising a beta-lactamase together with specific excipients present in defined proportions, including particles or pellets comprising hydroxypropylmethylcellulose acetate succinate (HPMCAS), ethylcellulose dispersion, sodium stearyl fumarate, buffer, and water. The formulations are positioned to enable pH-dependent and acid-inhibited release behavior based on the stated formulation design.
The beta-lactamase is further defined by amino acid sequence constraints including at least 95% identity with SEQ ID NO: 1 and SEQ ID NO: 5, and by an asparagine (N) substitution for aspartic acid (D) at position 276. Optional inclusion of a beta-lactamase inhibitor and adjunctive therapies is also described.
The invention is directed to preventing antibiotic-associated adverse effects when administering the beta-lactamase formulation to subjects being treated with an oral antibiotic that is a beta-lactamase substrate, including C. difficile infection and antibiotic-associated diarrhea.
Claims Coverage
The consolidated claim coverage includes two independent claims and multiple dependent refinements, covering four main inventive feature areas.
Particle-based beta-lactamase formulation with defined excipient percentages
Each particle comprises about 0.5-2.5% beta-lactamase; about 0.1-1% hydroxypropylmethylcellulose acetate succinate (HPMCAS); about 5-15% ethylcellulose dispersion; about 0.1-1% sodium stearyl fumarate; about 0.1-1% buffer; and about 80-90% water.
Pellet-based beta-lactamase formulation with defined excipient weight percentages
Each pellet comprises about 2.3% by weight beta-lactamase; about 0.3% HPMCAS; about 10.0% ethylcellulose dispersion; about 0.1% sodium stearyl fumarate; about 0.1% buffer; and about 87.5% water.
Sequence-defined beta-lactamase with ≥95% identity
The beta-lactamase comprises an amino acid sequence having at least 95% identity with the amino acid sequence selected from SEQ ID NO: 1 and SEQ ID NO: 5.
Specific beta-lactamase amino-acid substitution at position 276
The beta-lactamase is defined by an amino acid sequence of SEQ ID NO: 1 with an asparagine (N) substitution for aspartic acid (D) at position 276, consistent with Ambler classification.
Preventing antibiotic-associated adverse effects during oral antibiotic treatment
The formulation is administered to a subject being treated with an oral beta-lactamase substrate antibiotic to prevent an antibiotic-associated adverse effect.
Overall, the claims center on beta-lactamase formulations where particles or pellets contain defined proportions of HPMCAS, ethylcellulose dispersion, sodium stearyl fumarate, buffer, and water, combined with beta-lactamase defined by amino-acid identity relative to SEQ ID NO: 1 and SEQ ID NO: 5 and, in a dependent refinement, by a specific asparagine-for-aspartic-acid substitution at position 276. The coverage also extends to use in preventing antibiotic-associated adverse effects during oral antibiotic treatment, including C. difficile infection and antibiotic-associated diarrhea.
Stated Advantages
Protects the gastrointestinal (GI) microbiome from disruption by oral antibiotics by hydrolyzing residual or excess antibiotic in the GI tract.
Prevents antibiotic-associated adverse effects during oral antibiotic treatment, including C. difficile infection and antibiotic-associated diarrhea.
Documented Applications
Using beta-lactamase formulations administered to subjects taking an oral beta-lactamase substrate antibiotic to prevent antibiotic-associated adverse effects.
Preventing Clostridium difficile infection in the context of oral antibiotic treatment with a beta-lactamase substrate antibiotic.
Preventing antibiotic-associated diarrhea in the context of oral antibiotic treatment with a beta-lactamase substrate antibiotic.
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