Microbiome protection from oral antibiotics
This invention provides, in part, various compositions and methods for protecting the gastrointestinal microbiome from antibiotic disruption from orally administered antibiotics.
1. A method of protecting a subject's gastrointestinal (GI) microbiome from an oral antibiotic, comprising administering a formulation comprising a beta-lactamase capable of deactivating the oral antibiotic to a subject who is undergoing treatment or has recently undergone treatment with the oral antibiotic, wherein:
the formulation comprises an enterically coated capsule comprising an enterically coated pellet, the pellet comprising, relative to a pellet's weight:
about 20% to 30% sucrose sphere;
about 30% to 40% binder excipient;
about 13% to 18% beta-lactamase;
about 1% to 2% buffer salts;
and
about 15% to 30% pellets coating, and
the capsule is coated with EUDRAGIT® (poly(methacrylic acid, methylmethacrylate) FS 30 D.
2. The method of claim 1 , wherein the pellets coating comprises EUDRAGIT® coating, wherein the EUDRAGIT® coating is selected from EUDRAGIT® FS 30 D and EUDRAGIT® S100.
3. The method of claim 1 , wherein:
the binder excipient is hydroxypropylcellulose (HPC); and/or
the beta-lactamase is selected from P1A, P2A, P3A, or P4A.
4. The method of claim 3 , wherein the beta-lactamase is P3A.
5. The method of claim 1 , wherein the capsule is coated with EUDRAGIT® FS 30 D at about 10% of the total capsule weight.
6. The method of claim 1 , wherein the capsule has a body capacity of less than about 15 μL and is coated with EUDRAGIT® FS 30 D.
7. The method of claim 6 , wherein one or more capsules having body capacities of less than about 15 μL are loaded into a larger capsule.
8. The method of claim 1 , wherein the protection of the subject's microbiome comprises treatment or prevention of a microbiome-mediated disorder.
9. The method of claim 8 , wherein the microbiome-mediated disorder is selected from antibiotic-induced adverse effect, C. difficile infection (CDI), C. difficile -associated disease, ulcerative colitis, Crohn's disease, and irritable bowel syndrome.
10. The method of claim 9 , wherein the microbiome-mediated disorder is one or more of an antibiotic-induced adverse effect, C. difficile infection (CDI), and a C. difficile -associated disease.
11. The method of claim 10 , wherein the antibiotic-induced adverse effect and/or CDI or C. difficile -associated disease is one or more of: antibiotic-associated diarrhea, C. difficile diarrhea (CDD), C. difficile intestinal inflammatory disease, colitis, pseudomembranous colitis, fever, abdominal pain, dehydration and disturbances in electrolytes, megacolon, peritonitis, and perforation and/or rupture of the colon.
12. The method of claim 1 , wherein the protection of the subject's microbiome comprises maintenance of a normal intestinal microbiota.
13. The method of claim 1 , wherein the method treats and/or prevents the overgrowth of one or more pathogenic microorganisms in the GI tract of a subject, and/or wherein the method treats or prevents a nosocomial infection and/or a secondary emergent infection.
14. The method of claim 1 , wherein the beta-lactamase does not substantially interfere with plasma levels of a systemically absorbed orally administered antibiotic.
15. The method of claim 1 , wherein the beta-lactamase deactivates residual oral antibiotic residue excreted into the GI tract, wherein the residual oral antibiotic is not absorbed from the GI tract after an oral dose or is returned in active form to the intestinal tract from the systemic circulation.
16. The method of claim 1 , wherein the beta-lactamase is formulated for release in a location in the GI tract in which it does not substantially interfere with the systemic activity of the orally administered antibiotic.
17. The method of claim 1 , wherein the beta-lactamase is formulated for release in a location in the GI tract that is distal to the release of the orally administered antibiotic.
18. The method of claim 1 , wherein the pellet further comprises about 0.5% to 3% plasticizer.
19. The method of claim 18 , wherein the plasticizer is triethyl citrate.
20. The method of claim 1 , wherein the pellet further comprises about 0.5% to about 1.5% KH 2 PO 4 and about 2.5% to 5% hydroxypropyl methylcellulose (HPMC) 603.