Phospholipid depot
The present invention provides a clear depot comprising at least one hydrophilic water-soluble pharmaceutically active agent selected from the group consisting of vancomycin, gentamicin, a pharmaceutically acceptable salt thereof and a mixture thereof, water, a phospholipid, an oil, optionally a pH adjusting agent, and a viscosity modifying agent selected from the group consisting of ethanol, isopropanol, and a mixture thereof, wherein the water present in the depot is no more than about 4 wt % relative to the total weight of the depot and the depot has a pH of between about 3 and about 6, method of making and administering same.
1. A method for making a depot comprising:
(a) forming an oil-in-water emulsion including a phospholipid, an oil, at least one hydrophilic water-soluble pharmaceutically active agent selected from the group consisting of vancomycin, gentamicin, a pharmaceutically acceptable salt thereof and a mixture thereof and water;
(b) converting the emulsion to a monophasic solution having a pH of between about 3 to about 6;
(c) lyophilizing the monophasic solution to obtain a dry paste,
(d) adding a viscosity modifying agent to the dry paste in an amount sufficient to obtain a viscosity modified solution,
(e) removing at least some of the viscosity modifying agent to obtain a depot, and
(f) sterilizing the depot, wherein the water present in the depot is no more than about 4 wt % relative to the total weight of the depot.
2. The method of claim 1 , wherein the depot is clear.
3. The method of claim 1 , wherein the depot is ultra clear.
4. The method of claim 1 , wherein said step of forming the oil-in-water emulsion comprises: dissolving the at least one hydrophilic water-soluble pharmaceutically active agent selected from the group consisting of vancomycin, gentamicin, a pharmaceutically acceptable salt thereof and a mixture thereof in the water to obtain an aqueous solution; and mixing the aqueous solution with the phospholipid and the oil.
5. The method of claim 1 , wherein the amount of the viscosity modifying agent in the depot is from about 2 wt % to about 18 wt % relative to the total weight of the depot.
6. The method of claim 1 , wherein the at least one hydrophilic water-soluble pharmaceutically active agent is vancomycin hydrochloride and gentamicin sulfate.
7. The method of claim 1 , wherein the viscosity modifying agent is ethanol.
8. A depot produced in accordance with a method comprising:
(a) forming an oil-in-water emulsion including a phospholipid, an oil, at least one hydrophilic water-soluble pharmaceutically active agent selected from the group consisting of vancomycin, gentamicin, a pharmaceutically acceptable salt thereof and a mixture thereof and water;
(b) converting the emulsion to a monophasic solution having a pH of between about 3 to about 6;
(c) lyophilizing the monophasic solution to obtain a dry paste;
(d) adding a viscosity modifying agent to the dry paste in an amount sufficient to obtain a viscosity modified solution;
(e) removing at least some of the viscosity modifying agent to obtain a depot; and
(f) sterilizing the depot, wherein the water present in the depot is no more than about 4 wt % relative to the total weight of the depot.
9. The depot of claim 8 , wherein the depot is clear.
10. The depot of claim 8 , wherein the depot is ultra clear.
11. The depot of claim 8 , wherein said step of forming the oil-in-water emulsion comprises: dissolving the at least one hydrophilic water-soluble pharmaceutically active agent selected from the group consisting of vancomycin, gentamicin, a pharmaceutically acceptable salt thereof and a mixture thereof in the water to obtain an aqueous solution; and mixing the aqueous solution with the phospholipid and the oil.
12. The depot of claim 8 , wherein the amount of the viscosity modifying agent in the depot is from about 2 wt % to about 18 wt % relative to the total weight of the depot.
13. The depot of claim 8 , wherein the at least one hydrophilic water-soluble pharmaceutically active agent is vancomycin hydrochloride and gentamicin sulfate.
14. The depot of claim 8 , wherein the viscosity modifying agent is selected from the group consisting of ethanol, isopropanol, and a mixture thereof.
15. A depot comprising a hydrophilic water-soluble pharmaceutically active agent selected from the group consisting of vancomycin, gentamicin, a pharmaceutically acceptable salt thereof, and a mixture thereof water; a phospholipid; an oil; and a viscosity modifying agent; wherein the water present in the depot is no more than about 4 wt % relative to the total weight of the depot and the viscosity of the depot is from about 100 centipoise to about 5000 centipoise.
16. The depot of claim 15 , wherein the amount of the viscosity modifying agent present in the depot is from about 1 wt % to about 20 wt % relative to the total weight of the depot.
17. The depot of claim 15 , wherein the viscosity modifying agent is selected from the group consisting of ethanol, isopropanol, and a mixture thereof.
18. The depot of claim 15 , wherein the depot is clear.
19. The method of claim 15 , wherein the depot is ultra clear.
20. A method of administering the depot of claim 15 to a patient in need thereof via intradermal, intraincisional, intramuscular, subcutaneous, instillation or topically wherein the depot is sufficient to release the pharmaceutically active agent for a period of about at least one day with a dosing volume from about 0.1 mL to about 100 mL.
21. A method of treating surgical site infection by introducing the depot of claim 15 wherein the depot is sufficient to release the pharmaceutically active agent for a period of about at least one day with a dosing volume from about 0.1 mL to about 100 mL.
22. A depot comprising at least one hydrophilic water-soluble pharmaceutical active agent selected from the group comprising vancomycin, gentamicin, a pharmaceutically acceptable salt thereof, or mixtures thereof; water; a phospholipid; an oil; optionally pH adjusting agent; and a viscosity modifying agent; wherein the depot is administered via intradermal, intraincisional, intramuscular, subcutaneous, instillation or topically and provides high local tissue concentrations and low systemic concentrations of vancomycin and/or gentamicin.
23. The depot of claim 22 , wherein the depot is administered for preventing and/or treating infection.
24. The depot of claim 22 , wherein the depot is administered for preventing and/or treating surgical site infection.
25. The depot of claim 22 , wherein the depot is rendering localized tissue unable to sustain pathogenic microorganisms at wound.
26. The depot of claim 22 , wherein the depot comprising gentamicin and provides systemic concentration of gentamicin less than about 10 mg/l.
27. The depot of claim 22 , wherein the depot does not cause toxicity to kidney and/or other organs.
28. The depot of claim 22 , wherein the amount of the viscosity modifying agent present in the depot is from about 1 wt % to about 20 wt % relative to the total weight of the depot.
29. The depot of claim 22 , wherein the viscosity modifying agent is selected from the group consisting of ethanol, isopropanol, and a mixture thereof.
30. A method of treating surgical site infection by introducing the depot of claim 22 wherein the depot is sufficient to release the pharmaceutically active agent for a period of about at least one day with a dosing volume from about 0.1 mL to about 100 mL.
31. A method of treating a wound infection comprising administering to said wound the depot of claim 15 .
32. A method of treating a wound infection comprising administering to said wound the depot of claim 22 .
33. The method of claim 32 , wherein the method renders localized tissue unable to sustain pathogenic microorganisms by administering a depot of the present invention to the wound.
34. The method of claim 33 , wherein the wound infection is surgical site infection.
35. The method of claim 32 , wherein the method provides sufficiently high tissue concentration to treat and/or prevent infections at a local site.
36. The method of claim 32 , wherein the method does not cause toxicity to kidney and/or other organs.
37. The method of claim 32 , wherein the depot is sufficient to release the pharmaceutically active agent for a period of about at least one day with a dosing volume from about 0.1 mL to about 100 mL.
38. The method of claim 32 , wherein the depot comprising gentamicin, provides systemic concentration of gentamicin less than about 10 mg/l.
39. A method of treating a wound infection comprising administering to said wound a depot comprising: at least one hydrophilic water-soluble pharmaceutically active agent selected from group consisting of vancomycin, gentamicin, and pharmaceutically acceptable salts thereof; water; a phospholipid; an oil; and a viscosity modifying agent; wherein the water present in the depot is no more than about 4 wt % relative to the total weight of the depot.
40. The method of claim 39 , wherein the method renders localized tissue unable to sustain pathogenic microorganisms by administering a depot of the present invention to the wound.
41. The method of claim 40 , wherein the wound infection is surgical site infection.
42. The method of claim 39 , wherein the method provides sufficiently high tissue concentration to treat and/or prevent infections at a local site.
43. The method of claim 39 , wherein the method does not cause toxicity to kidney and/or other organs.
44. The method of claim 39 , wherein the depot is sufficient to release the pharmaceutically active agent for a period of about at least one day with a dosing volume from about 0.1 mL to about 100 mL.
45. The method of claim 39 , wherein the depot comprising gentamicin, provides systemic concentration of gentamicin less than about 10 mg/l.