Methods and compositions for inhibiting or preventing adverse effects of oral antibiotics
This invention provides, in part, various compositions and methods for protecting the gastrointestinal microbiome from antibiotic disruption.
1. A pH-dependent modified-release formulation comprising a beta-lactamase, wherein the formulation releases the beta-lactamase in the gastrointestinal (GI) tract, and wherein the formulation comprises at least one pH-dependent modified-release pellet with each pellet comprising:
about 10-20% by weight beta-lactamase;
about 15-25% by weight sucrose sphere;
about 25-35% by weight hydroxypropylcellulose;
about 20-30% by weight a first enteric polymer;
about 1-10% by weight a second enteric polymer;
about 1-10% by weight triethyl citrate; and
about 1-2% by weight buffer salt; and
wherein the formulation releases the beta-lactamase at a pH of greater than 6.2.
2. The pH-dependent modified-release formulation of claim 1 , wherein the first enteric polymer is EUDRAGIT L100 (poly(methacrylic acid, methylmethacrylate)).
3. The pH-dependent modified-release formulation of claim 1 , wherein the second enteric polymer is EUDRAGIT S100 (poly(methacrylic acid, methylmethacrylate)).
4. A method of preventing an antibiotic-associated adverse effect in a subject in need thereof, comprising administering the pH-dependent modified-release formulation of claim 1 ,
wherein the antibiotic is an oral antibiotic, the oral antibiotic being a substrate for the beta-lactamase; and
wherein the subject is undergoing treatment with the oral antibiotic.
5. The method of claim 4 , wherein the antibiotic-associated adverse effect is Clostridium difficile infection.
6. The method of claim 4 , wherein the antibiotic-associated adverse effect is antibiotic associated diarrhea.
7. The method of claim 4 , wherein the beta-lactamase comprises an amino acid sequence of SEQ ID NO: 1, having asparagine (N) replacing aspartic acid (D) at position 276, according to Ambler classification.
8. The pH-dependent modified-release formulation of claim 1 , wherein the beta-lactamase comprises an amino acid sequence of SEQ ID NO: 1, having asparagine (N) replacing aspartic acid (D) at position 276 , according to Ambler classification.
9. The pH-dependent modified-release formulation of claim 1 , wherein the formulation comprises at least one pH-dependent modified-release pellet with each pellet comprising:
about 14% by weight beta-lactamase, the beta-lactamase comprising an amino acid sequence of SEQ ID NO: 1 and having an asparagine (N) replacing aspartic acid (D) at position 276 , according to Ambler classification;
about 21% by weight sucrose sphere;
about 31% by weight hydroxypropylcellulose;
about 24% by weight EUDRAGIT L100 (poly(methacrylic acid, methylmethacrylate));
about 6% by weight EUDRAGIT S100 (poly(methacrylic acid, methylmethacrylate));
about 3% by weight triethyl citrate; and
about 1% by weight buffer salt; and
wherein the formulation releases the beta-lactamase at a pH of greater than 6.2.
10. A method of preventing an antibiotic-associated adverse effect in a subject in need thereof, comprising administering the pH-dependent modified-release formulation of claim 9 ,
wherein the antibiotic is an oral antibiotic, the oral antibiotic being a substrate for the beta-lactamase; and
wherein the subject is undergoing treatment with the oral antibiotic.
11. The method of claim 10 , wherein the antibiotic-associated adverse effect is Clostridium difficile infection.
12. The method of claim 10 , wherein the antibiotic-associated adverse effect is antibiotic associated diarrhea.