Topical treatment for prevention of ocular infections
View Patent ↗Azalide antibiotics such as azithromycin are useful in the treatment and prevention of infections by bacteria and other parasites. Stabilized aqueous compositions containing azithromycin suitable for administration without reconstitution are provided for. Also provided for are aqueous formulations suitable for ocular administration in a employing a convenient dosing formulation suitable for administration in depot formats.
1. A composition comprising water, a polymeric suspending agent and an azalide antibiotic, wherein said composition has a pH of about 6.0 to 6.6.
2. The composition of claim 1 , wherein said composition is an ophthalmic composition.
3. The composition of claim 2 , wherein said polymeric suspending agent is a water-swellable water-insoluble crosslinked carboxy-vinyl polymer.
4. The composition of claim 3 , wherein said polymer comprises at least 90% acrylic acid monomers and about 0.1% to about 5.0% of a difunctional crosslinking agent, wherein said polymeric suspending agent is contained in an amount of about 0.5% to about 1.2%.
5. The composition of claim 1 , wherein said composition is incorporated into a formulation administerable in a depot format.
6. The composition of claim 5 , wherein said depot contains sufficient azalide antibiotic to maintain the azalide antibiotic above the MIC 50 for at least about 12 hours after administration.
7. The composition of claim 1 , wherein said azalide antibiotic is azithromycin.
8. The composition of claim 1 , wherein said azalide antibiotic has a formula of:
wherein R 1 and R 2 each independently represent a hydrogen atom or a methyl group.
9. The composition of claim 1 , wherein said azalide antibiotic is present at a concentration of about 0.1% to about 10.0%.
10. The composition of claim 1 , wherein said composition has a pH of about 6.0 to about 6.5.
11. The composition of claim 1 , wherein said composition has a pH of about 6.2 to about 6.4.
12. The composition of claim 1 , wherein said composition has a pH of about 6.3.
13. A composition comprising water, an azalide antibiotic, and one or more agents selected from the group consisting of: a buffering agent, an osmolarity adjusting agent, disodium EDTA, a polymeric suspending agent, a water-swellable water-insoluble crosslinked carboxy-vinyl polymer that comprises at least 90% acrylic acid monomers and about 0.1% to about 5.0% crosslinking agent, and an additional medicament selected from the group consisting of an antibiotic, an antiviral, an antifungal, an anesthetic, an anti-inflammatory agent, and an anti-allergic agent, wherein said composition has a pH of about 6.0 to 6.6.
14. The composition of claim 13 , wherein the additional medicament is selected from the group consisting of amikacin, gentamycin, tobramycin, streptomycin, netilmycin, kanamycin, ciprofloxacin, norfloxacin, ofloxacin, trovafloxacin, lomefloxacin, levofloxacin, enoxacin, sulfonamides, polymyxin, chloramphenicol, neomycin, paramomomycin, colistimethate, bacitracin, vancomycin, tetracyclines, rifampins, cycloserine, beta-lactams, cephalosporins, amphotericins, fluconazole, flucytosine, natamycin, miconazole, ketoconazole, corticosteroids, diclofenac, flurbiprofen, ketorolac, suprofen, comolyn, lodoxamide, levocabastin, naphazoling, antazoline, and pheniramimane.
15. A solid, semi-solid, powdered, or lyophilized composition comprising an azalide antibiotic and a polymeric suspending agent, which upon addition of water produces an aqueous formulation having a pH from about 6.0 to about 6.6.
16. The composition according to claim 15 , wherein said polymeric suspending agent is a lightly crosslinked carboxy vinyl polymer.
17. A method of preparing a stable azalide antibiotic composition for medicinal use, comprising the steps of:
(a) dispersing or solubilizing an azalide antibiotic and a polymeric suspending agent in an aqueous medium having a pH less than about 5.0;
(b) adding a base to the composition formed in step (a);
(c) adding water to the solution formed in step (b); and
(d) adjusting the solution formed in step (c) to a pH of about 6.0 to about 6.6.
18. The method as in claim 17 , wherein the aqueous medium employed in step (a) is a citric acid buffer or solution, and the base in step (b) is sodium citrate.
19. The method of claim 17 , wherein said pH is adjusted by adding sodium hydroxide in step (b) or step (d).
20. The method of claim 17 , wherein said composition has been formulated for ocular administration and said polymeric suspending agent is a water-swellable water-insoluble crosslinked carboxy-vinyl polymer; wherein said polymer comprises at least 90% acrylic acid monomers and about 0.1% to about 5.0% of a difunctional crosslinking agent and said pH in step (d) is from about 6.2 to about 6.4; said composition having an initial viscosity which increases when the pH of the composition rises to at least about 7.0 upon administration to a target tissue.
21. The method of claim 17 , wherein said composition is a ocular composition to be is administered as a depot, and wherein said composition contains sufficient azalide antibiotic to provide a sustained release of the administration of the antibiotic to the target tissue for least about 12 hours.
22. The method of claim 17 , further comprising the step of(e) adding an agent to adjust osmolarity.
23. A method of treating a patient infected with a bacterial infection comprising administering a composition comprising an azalide antibiotic formulation and a polymeric suspending agent to a subject in need thereof in an antibacterial effective amount, wherein said composition has a pH from about 6.0 to about 6.6.
24. The method of claim 23 , wherein said pH is from about 6.0 to about 6.5.
25. The method of claim 23 , wherein said pH is from about 6.2 to about 6.4.
26. The method of claim 23 , wherein said pH is about 6.3.
27. A method of treating a patient infected with a bacterial infection comprising administering a composition comprising an azalide antibiotic formulation to an eye of a subject in need thereof in an antibacterial effective amount, wherein said composition has a pH from about 6.0 to about 6.6.
28. The method of 27 , wherein said composition is injected into the eye.
29. The method of 23 , wherein said composition is topically applied to the eye.
30. The method of claim 29 , wherein said polymeric suspending agent is a water-swellable water-insoluble crosslinked carboxy-vinyl polymer, and wherein said carboxy-vinyl polymer comprises at least 90% acrylic acid monomers and about 0.1% to about 5% crosslinking agent and a difunctional crosslinking agent.
31. The method of claim 27 , wherein said composition is to be administered as a depot, and wherein said composition contains sufficient azalide antibiotic to provide a sustained release of the administration of the antibiotic to the target tissue for at least about 12 hours.
32. The method of claim 27 , wherein said azalide antibiotic is azithromycin.
33. The method of claim 27 , wherein said azalide antibiotic has a formula of:
wherein R 1 and R 2 each independently represent a hydrogen atom or a methyl group.
34. The method of claim 23 , wherein said composition further comprises an agent to adjust osmolarity.
35. The method of claim 23 , wherein said composition further comprises one or more additional medicaments.
36. The composition of claim 2 , wherein said polymer comprises at least 90% acrylic acid monomers and about 0.1% to about 5.0% of a difunctional crosslinking agent, wherein said polymeric suspending agent is contained in an amount of about 0.5% to about 1.2%.
37. The composition of claim 1 , further comprising one or more agents selected from the group consisting of: a solubilizing agent, a buffering agent, an osmolarity adjusting agent, a chelating agent, disodium EDTA, a polymeric suspending agent, a water-swellable water-insoluble crosslinked carboxy-vinyl polymer that comprises at least 90% acrylic acid monomers and about 0.1% to about 5.0% crosslinking agent, and an additional medicament selected from the group consisting of an antibiotic, an antiviral, an antifungal, an anesthetic, an anti-inflammatory agent, and an anti-allergic agents.
38. The composition of claim 1 , wherein said azalide antibiotic is present at a concentration of about 0.1% to about 0.5%.
39. The method of treating a patient of claim 23 , wherein said administering is one or two doses of said composition per day for one to three days.
40. The method of treating a patient of claim 23 , wherein said administering is one or two doses of said composition per day for at least six days.
41. The method of treating a patient of claim 23 , wherein said administering is one or two doses of said composition per day for six to fourteen days.
42. The method of treating a patient of claim 27 , wherein said administering is one or two doses of said composition per day for one to three days.
43. The method of treating a patient of claim 27 , wherein said administering is one or two doses of said composition per day for at least six days.
44. The method of treating a patient of claim 27 , wherein said administering is one or two doses of said composition per day for six to fourteen days.