Beta-lactamase formulations and uses thereof
The present invention provides, in part, formulations comprising a beta-lactamase. Particularly, modified-release formulations comprising a beta-lactamase are provided which release a substantial amount of the beta-lactamase in the intestines. Therapeutic uses of the beta-lactamase formulations are also provided.
1. A method of treating or preventing a Clostridium difficile infection (CDI) and/or a Clostridium difficile -associated disease in the gastrointestinal tract, comprising administering a modified-release formulation to a patient in need thereof, wherein the formulation comprises at least one modified-release pellet, and wherein each modified-release pellet comprises:
about 10-20% by weight of a beta-lactamase which comprises an amino acid sequence having at least 95% sequence identity to SEQ ID NO:1, 3 or 6;
about 20-30% by weight sucrose sphere;
about 30-40% by weight hydroxypropylcellulose;
about 15-25% by weight an enteric polymer;
about 1.5-2.5% by weight triethyl citrate;
about 0.5-15% by weight glyceryl monostearate;
about 0.1-10% by weight polysorbate-80; and
about 1-2% by weight of buffer salt.
2. The method of claim 1 , wherein each modified-release pellet comprises:
about 16% by weight of the beta-lactamase;
about 23% by weight sucrose sphere;
about 35% by weight hydroxypropylcellulose;
about 21% by weight an enteric polymer;
about 2% by weight triethyl citrate;
about 1% by weight glyceryl monostearate;
about 0.5% by weight polysorbate-80; and
about 2% by weight of buffer salt.
3. The method of claim 1 , wherein each modified-release pellet comprises:
about 15.8% by weight of the beta-lactamase;
about 23.3% by weight sucrose sphere;
about 35% by weight hydroxypropylcellulose;
about 20.8% by weight an enteric polymer;
about 2.1% by weight triethyl citrate;
about 1% by weight glyceryl monostearate;
about 0.4% by weight polysorbate-80; and
about 1.6% by weight of buffer salt.
4. The method of claim 1 , wherein the beta-lactamase comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 1.
5. The method of claim 4 , wherein the beta-lactamase comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 1 and an asparagine at Ambler position 276.
6. The method of claim 1 , wherein the beta-lactamase is released in the GI tract.
7. The method of claim 6 , wherein the beta-lactamase is released in the intestines.
8. The method of claim 1 , wherein the formulation is in the form of a capsule.
9. The method of claim 1 , wherein each modified-release pellet comprises a core particle and a base coat over the core particle,
wherein the base coat comprises the beta-lactamase.
10. The method of claim 1 , wherein the formulation comprises a plurality of modified-release pellets.
11. The method of claim 1 , wherein the formulation further comprises a modified-release coating that is stable in gastric fluid.
12. The method of claim 1 , wherein the formulation further comprises a modified-release coating having a solubility that is pH-dependent.
13. The method of claim 12 , wherein the modified-release coating comprises a poly(methacrylic acid, methylmethacrylate) compound.
14. The method of claim 1 , wherein the CDI or C. difficile -associated disease is one or more of: antibiotic-associated diarrhea, C. difficile diarrhea (CDD), a Clostridium difficile intestinal inflammatory disease, colitis, pseudomembranous colitis, fever, abdominal pain, dehydration and disturbances in electrolytes.
15. A method of treating or preventing a Clostridium difficile infection (CDI) and/or a Clostridium difficile -associated disease in the gastrointestinal tract, comprising administering a modified-release formulation to a patient in need thereof, wherein the formulation comprises at least one modified-release pellet, and wherein each modified-release pellet comprises:
about 16% by weight of a beta-lactamase;
about 23% by weight sucrose sphere;
about 35% by weight hydroxypropylcellulose;
about 21% by weight an enteric polymer;
about 2% by weight triethyl citrate;
about 1% by weight glyceryl monostearate;
about 0.5% by weight polysorbate-80; and
about 2% by weight of buffer salt;
wherein the beta-lactamase comprises an amino acid sequence having the sequence of SEQ ID NO: 1 with an asparagine at Ambler position 276.
16. The method of claim 15 , wherein the CDI or C. difficile -associated disease is one or more of: antibiotic-associated diarrhea, C. difficile diarrhea (CDD), a Clostridium difficile intestinal inflammatory disease, colitis, pseudomembranous colitis, fever, abdominal pain, dehydration and disturbances in electrolytes.