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:
(1) 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 or a mixture thereof and water;
(2) homogenizing the emulsion to obtain a primary emulsion;
(3) microfluidizing the primary emulsion to obtain a monophasic solution;
(4) ensuring the pH of the primary emulsion and/or the monophasic solution is between about 3 to about 6 by adjusting the pH as necessary,
(5) lyophilizing the monophasic solution of desired pH to obtain a dry paste,
(6) adding a viscosity modifying agent to the dry paste in an amount of about 25 wt % or more of the total weight of a resulting viscosity modified solution,
(7) removing at least some of the viscosity modifying agent to obtain a depot having from about 1 wt % to about 20 wt % of the viscosity modifying agent relative to the total weight of the depot, and
(8) 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 5 , wherein the amount of the viscosity modifying agent is from about 5 wt % to about 6.5% relative to the total weight of the depot.
7. The method of claim 1 , wherein the pharmaceutically acceptable salt of vancomycin and/or gentamicin is selected from the group consisting of acetate, hydrochloride, hydrobromide, citrate, formate, lactate, succinate, and sulfate.
8. The method of claim 1 , wherein the at least one hydrophilic water-soluble pharmaceutically active agent is vancomycin hydrochloride and gentamicin sulfate.
9. The method of claim 8 , wherein initial drug concentration of the vancomycin hydrochloride in water is from about 1 mg/ml to about 50 mg/ml.
10. The method of claim 9 , wherein the initial drug concentration of vancomycin hydrochloride in water is from about 5 mg/ml to about 20 mg/ml.
11. The method of claim 8 , wherein initial drug concentration of the gentamicin sulfate in water is from about 1 mg/ml to about 75 mg/ml.
12. The method of claim 11 , wherein the initial drug concentration of the gentamicin sulfate in water is from about 5 mg/ml to about 20 mg/ml.
13. The method of claim 1 , further comprising a step of optionally adding a stabilizing agent and/or a pH adjusting agent to the emulsion, the primary emulsion and/or the monophasic solution.
14. The method of claim 13 , wherein the stabilizing agent is selected from the group consisting of EDTA disodium, glycine, L-histidine, citric acid, methionine, ascorbic acid, L-cysteine, alpha-tocopherol, and mixtures thereof.
15. The method of claim 1 , wherein the amount of the water in the emulsion prior to creating the primary emulsion is from about 60 wt % to about 80 wt % relative to the total weight of the emulsion.
16. The method of claim 1 , wherein the droplets of the monophasic solution have an average diameter of less than about 120 nm.
17. The method of claim 1 , wherein the pH of the monophasic solution is adjusted to from about 3 to about 5.
18. The method of claim 1 , wherein the viscosity modifying agent is selected from the group consisting of ethanol, isopropanol, and a mixture thereof.
19. The method of claim 18 , wherein the viscosity modifying agent is ethanol.
20. The method of claim 19 , wherein the ethanol is absolute ethanol.
21. The method of claim 1 , wherein the amount of the viscosity modifying agent added is about 25 wt % or more relative to the total weight of the viscosity modified solution.
22. The method of claim 1 , wherein the viscosity of the viscosity modified solution is from about 10 to about 200 centipoise.
23. The method of claim 22 , wherein the viscosity of the viscosity modified solution is about 20 to about 50 centipoise.
24. The method of claim 1 , wherein the viscosity of the depot is from about 100 centipoise to about 5000 centipoise.
25. The method of claim 24 , wherein the viscosity of the depot is from about 200 centipoise to about 2000 centipoise.
26. The method of claim 25 , wherein the viscosity of the depot is from about 300 centipoise to about 1500 centipoise.
27. The method of claim 1 , wherein the pH of the depot is from about 3 to about 6.
28. The method of claim 1 , wherein the amount of the water present in the depot is no more than about 2 wt % relative to the total weight of the depot.
29. The method of claim 28 , wherein the amount of the water present in the depot is no more than about 1 wt % relative to the total weight of the depot.
30. The method of claim 29 , wherein the amount of the water present in the depot is no more than about 0.5 wt % relative to the total weight of the depot.
31. The method of claim 1 , further comprising the step of pre-filtering of the viscosity modified solution to obtain a filtered solution prior to the step of removing at least some of the viscosity modifying agent.
32. The method of claim 1 , further comprising a step of aseptically filling the depot in a syringe, a vial any other appropriate device of storing and/or delivering the depot to the treatment site or wound.
33. A method for making a depot comprising:
(1) 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;
(2) converting the emulsion to a monophasic solution having a pH of between about 3 to about 6;
(3) lyophilizing the monophasic solution to obtain a dry paste,
(4) adding a viscosity modifying agent to the dry paste in an amount sufficient to obtain a viscosity modified solution,
(5) removing at least some of the viscosity modifying agent to obtain a depot, and
(6) sterilizing the depot, wherein the depot is clear.
34. The method of claim 33 , wherein the viscosity modifying agent is ethanol.
35. The method of claim 33 , wherein the amount of the water present in the depot is no more than about 4 wt % relative to the total weight of the depot.
36. The method of claim 33 , wherein the amount of the viscosity modifying agent added to obtain a viscosity modified solution is about 25 wt % or more relative to the total weight of the viscosity modified solution.
37. The method of claim 33 , 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.
38. A depot produced in accordance with a method comprising:
(1) 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 or a mixture thereof and water:
(2) homogenizing the emulsion to obtain a primary emulsion;
(3) microfluidizing the primary emulsion to obtain a monophasic solution;
(4) ensuring the pH of the primary emulsion and/or the monophasic solution is between about 3 to about 6 by adjusting the pH as necessary,
(5) lyophilizing the monophasic solution of desired pH to obtain a dry paste,
(6) adding a viscosity modifying agent to the dry paste in an amount of about 25 wt % or more of the total weight of a resulting viscosity modified solution,
(7) removing at least some of the viscosity modifying agent to obtain a depot having from about 1 wt % to about 20 wt % of the viscosity modifying agent relative to the total weight of the depot, and
(8) 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.
39. The depot of claim 38 , 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.
40. The depot of claim 38 , wherein the viscosity of the depot is from about 100 centipoise to about 5000 centipoise.
41. A method of administering the depot of claim 38 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.
42. A 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; 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 and viscosity modifying agent present in the final depot from about 2 wt % to about 18 wt % relative to the total weight of the depot.
43. The depot of claim 42 , wherein the viscosity of the depot is from about 100 centipoise to about 5000 centipoise.
44. A method of administering the depot of claim 42 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.
45. The depot of claim 42 , wherein the phospholipid present in the depot from about 5 wt % to about 95 wt %.
46. The depot of claim 42 , wherein the phospholipid present in the depot from about 25 wt % to about 75 wt %.
47. The depot of claim 42 , wherein the phospholipid present in the depot from about 35 wt % to about 60 wt %.
48. The depot of claim 42 , wherein the depot is administered via intradermal, intramuscular, intraincisional, subcutaneous, instillation or topically.
49. The depot of claim 42 , wherein the depot provides 2-Theta Structure in small angle X-ray diffraction.
50. The depot of claim 42 , wherein the oil present in the depot is from about 5 wt % to about 95 wt %.
51. The depot of claim 42 , wherein the oil present in the depot is from about 25 wt % to about 75 wt %.
52. The depot of claim 42 , wherein the oil present in the depot is from about 35 wt % to about 60 wt %.
53. The depot of claim 42 , wherein said depot is prepared by a multi-step process following the steps of: (1) emulsification, (2) homogenization/microfluidization, (3) lyophilization, (4) dilution, (5) pre-filtration, (6) viscosity modifying agent removal and (7) filtration.
54. The depot of claim 42 , wherein the depot is administered 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.
55. The depot of claim 42 , wherein the viscosity modifying agent is added after lyophilization.
56. A 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; wherein the depot exhibits 2-theta structure in Small Angle X-ray Diffraction, and wherein the depot is clear.
57. The depot of claim 56 , 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.
58. The depot of claim 56 , wherein the viscosity of the depot is from about 100 centipoise to about 5000 centipoise.
59. The depot of claim 56 , wherein the depot is administered via intradermal, intramuscular, intraincisional, subcutaneous, instillation or topically.
60. The depot of claim 56 , wherein said depot is prepared by a multi-step process following the steps of: (1) emulsification, (2) homogenization/microfluidization, (3) lyophilization, (4) dilution, (5) pre-filtration, (6) viscosity modifying agent removal and (7) filtration.
61. The depot of claim 56 , wherein the water present in the depot is no more than about 4 wt % relative to the total weight of the depot.
62. The depot of claim 42 , wherein the depot is clear.
63. A method of treating surgical site infection by introducing the depot of claim 38 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.
64. A method of treating surgical site infection by introducing the depot of claim 42 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.
65. A method of administering the depot of claim 56 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.
66. A method of treating surgical site infection by introducing the depot of claim 56 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.