Compositions and methods for ophthalmic and/or other applications
Particles, compositions, and methods that aid particle transport in mucus are provided. The particles, compositions, and methods may be used, in some instances, for ophthalmic and/or other applications. In some embodiments, the compositions and methods may involve modifying the surface coatings of particles, such as particles of pharmaceutical agents that have a low aqueous solubility. Such compositions and methods can be used to achieve efficient transport of particles of pharmaceutical agents though mucus barriers in the body for a wide spectrum of applications, including drug delivery, imaging, and diagnostic applications. In certain embodiments, a pharmaceutical composition including such particles is well-suited for ophthalmic applications, and may be used for delivering pharmaceutical agents to the front of the eye and/or the back of the eye.
1. A topical pharmaceutical composition comprising:
(a) a plurality of coated nanoparticles, each coated nanoparticle comprising:
(i) a core particle comprising a loteprednol etabonate, wherein the loteprednol etabonate constitutes at least 80% of the core particle by weight, and
(ii) a mucus penetration-enhancing coating comprising a (poly(ethylene oxide))-(poly(propylene oxide))-(poly(ethylene oxide)) triblock copolymer, wherein the poly(propylene oxide) block has a molecular weight of about 3600 Da and the poly(ethylene oxide) blocks constitute about 70 wt % of the triblock copolymer, and wherein the triblock copolymer is non-covalently adsorbed to the core particle;
(b) about 0.5% w/v to about 3% w/v glycerin; and
(c) about 0.1% w/v to about 1% w/v sodium chloride
wherein the topical pharmaceutical composition comprises loteprednol etabonate at about 0.25% w/v in total;
wherein the topical pharmaceutical composition is a topical suspension, and wherein the ratio of the total weight of loteprednol etabonate to the total weight of triblock copolymer comprised in the topical suspension is about 2:1; and
wherein the coated nanoparticles are mucus-penetrating.
2. The topical pharmaceutical composition of claim 1 , wherein the coated nanoparticles have the triblock copolymer adsorbed to the core particle at an average density of at least 0.01 molecules/nm 2 and less than 1 molecule/nm 2 .
3. The topical pharmaceutical composition of claim 2 , wherein the average density is at least 0.1 molecules/nm 2 and less than 1 molecule/nm 2 .
4. The topical pharmaceutical composition of claim 1 , wherein the coated nanoparticles have an average smallest cross-sectional dimension of about 200 nm to about 500 nm.
5. The topical pharmaceutical composition of claim 1 , wherein the coated nanoparticles have a relative velocity of greater than 0.5 and less than 6.0 in human cervicovaginal mucus.
6. The topical pharmaceutical composition of claim 1 , further comprising about 0.01% w/v to about 1% w/v disodium ethylenediaminetetraacetic acid.
7. The topical pharmaceutical composition of claim 1 , wherein the triblock copolymer is poloxamer 407.
8. The topical pharmaceutical composition of claim 1 , wherein the coated nanoparticles have an average size of about 50 nm to about 700 nm.
9. The topical pharmaceutical composition of claim 8 , wherein the polydispersity index of the composition is less than or equal to about 0.5.
10. The topical pharmaceutical composition of claim 9 , wherein the polydispersity index is less than or equal to about 0.4.
11. The topical pharmaceutical composition of claim 1 , wherein the core particle is substantially free of a polymeric component.
12. The topical pharmaceutical composition of claim 11 , wherein the coated nanoparticles have an average size of about 50 nm to about 700 nm.
13. The topical pharmaceutical composition of claim 12 , wherein the average size of the coated nanoparticles is measured by dynamic light scattering.
14. The topical pharmaceutical composition of claim 12 , wherein the average size of the coated nanoparticles is as measured in Z-average diameter by dynamic light scattering.
15. The topical pharmaceutical composition of claim 12 , wherein the polydispersity index of the composition is less than or equal to about 0.5.
16. The topical pharmaceutical composition of claim 15 , wherein the polydispersity index is measured by dynamic light scattering.
17. The topical pharmaceutical composition of claim 11 , wherein the triblock copolymer adsorbed to the core particle is at an average density of at least 0.1 molecules/nm 2 and less than 1 molecule/nm 2 .
18. The topical pharmaceutical composition of claim 11 , wherein the coated nanoparticles have a relative velocity of greater than 0.5 and less than 6.0 in human cervicovaginal mucus.
19. The topical pharmaceutical composition of claim 1 , wherein the triblock copolymer adsorbed to the core particle is in equilibrium with non-adsorbed triblock copolymer in the pharmaceutical composition.
20. The topical pharmaceutical composition of claim 1 , further comprising one or more degradants of the loteprednol etabonate, and wherein the concentration of each degradant is less than or equal to about 1 wt % relative to the weight of the loteprednol etabonate.
21. The topical pharmaceutical composition of claim 1 , further comprising one or more degradants of the loteprednol etabonate at less than or equal to about 3 wt % in total relative to the weight of the loteprednol etabonate.
22. The topical pharmaceutical composition of claim 1 , further comprising one or more degradants of the loteprednol etabonate, wherein the one or more degradants of the loteprednol etabonate includes 17α-[(ethoxycarbonyl)oxy]-11β-hydroxy-3-oxoandrosta-4-ene-17-carboxylic acid chloromethyl ester at less than or equal to about 0.5 wt % relative to the weight of the loteprednol etabonate.
23. The topical pharmaceutical composition of claim 22 , wherein the composition is made sterile via a sterilization process comprising gamma irradiation.
24. The topical pharmaceutical composition of claim 23 , wherein the 17α-[(ethoxycarbonyl)oxy]-11β-hydroxy-3-oxoandrosta-4-ene-17-carboxylic acid chloromethyl ester is at less than or equal to about 0.5 wt % relative to the weight of the loteprednol etabonate four weeks after the gamma irradiation.
25. The topical pharmaceutical composition of claim 24 , wherein the coated nanoparticles have an average size of about 50 nm to about 700 nm.
26. The topical pharmaceutical composition of claim 25 , wherein the average size of the coated nanoparticles is measured by dynamic light scattering.
27. The topical pharmaceutical composition of claim 26 , wherein the average size of the coated nanoparticles is as measured in Z-average diameter by dynamic light scattering.
28. The topical pharmaceutical composition of claim 25 , wherein the polydispersity index of the composition is less than or equal to about 0.5.
29. The topical pharmaceutical composition of claim 28 , wherein the polydispersity index is measured by dynamic light scattering.
30. The topical pharmaceutical composition of claim 24 , wherein the triblock copolymer adsorbed to the core particle is at an average density of at least 0.1 molecules/nm 2 and less than 1 molecule/nm 2 .
31. The topical pharmaceutical composition of claim 24 , wherein the polydispersity index of the composition is less than or equal to about 0.5.
32. A pharmaceutical composition comprising:
(a) a plurality of particles of loteprednol etabonate;
(b) about 0.5% w/v to about 3% w/v glycerin;
(c) an ionic tonicity agent; and
(d) poloxamer 407;
wherein the particles of loteprednol etabonate are non-covalently coated with the poloxamer 407 to form coated nanoparticles, and wherein the coated nanoparticles are mucus-penetrating;
wherein the pharmaceutical composition comprises loteprednol etabonate at about 0.25% w/v in total; and
wherein the pharmaceutical composition is a topical suspension, and wherein the ratio of the total weight of the loteprednol etabonate to the total weight of the poloxamer 407 comprised in the topical suspension is about 2:1.
33. The pharmaceutical composition of claim 32 , wherein the ionic tonicity agent is at about 0.1% w/v to about 1% w/v.
34. The pharmaceutical composition of claim 33 , wherein the ionic tonicity agent is sodium chloride.
35. The pharmaceutical composition of claim 33 , further comprising about 0.01% w/v to about 1% w/v disodium ethylenediaminetetraacetic acid.
36. The pharmaceutical composition of claim 35 , further comprising about 0.001% w/v to about 0.05% w/v benzalkonium chloride.
37. The pharmaceutical composition of claim 36 , further comprising sodium citrate, citric acid, and water.
38. The pharmaceutical composition of claim 32 , wherein the particles of loteprednol etabonate coated with poloxamer 407 have an average smallest cross-sectional dimension of about 200 nm to about 500 nm.
39. The pharmaceutical composition of claim 32 , wherein the particles of loteprednol etabonate coated with poloxamer 407 have a relative velocity of greater than 0.5 and less than 6.0 in human cervicovaginal mucus.
40. The pharmaceutical composition of claim 32 , wherein the poloxamer 407 coating on the particles of loteprednol etabonate is at an average density of at least 0.01 molecules/nm 2 and less than 1 molecule/nm 2 .
41. The pharmaceutical composition of claim 40 , wherein the average density is at least 0.1 molecules/nm 2 and less than 1 molecule/nm 2 .
42. The pharmaceutical composition of claim 33 , wherein the particles of loteprednol etabonate coated with poloxamer 407 have an average size of about 200 nm to about 700 nm.
43. The pharmaceutical composition of claim 42 , wherein the average size of the coated nanoparticles is measured by dynamic light scattering.
44. The pharmaceutical composition of claim 42 , wherein the average size of the coated nanoparticles is as measured in Z-average diameter by dynamic light scattering.
45. The pharmaceutical composition of claim 42 , wherein the polydispersity index of the composition is less than or equal to about 0.5.
46. The pharmaceutical composition of claim 42 , wherein the polydispersity index of the composition is less than or equal to about 0.4.
47. The pharmaceutical composition of claim 46 , wherein the polydispersity index is measured by dynamic light scattering.
48. The pharmaceutical composition of claim 32 , wherein the poloxamer 407 non-covalently coated on the loteprednol etabonate particles is in equilibrium with free poloxamer 407 in the pharmaceutical composition.
49. The pharmaceutical composition of claim 32 , further comprising one or more degradants of the loteprednol etabonate, and wherein the concentration of each degradant is less than or equal to about 1 wt % relative to the weight of the loteprednol etabonate.
50. The pharmaceutical composition of claim 32 , further comprising one or more degradants of the loteprednol etabonate at less than or equal to about 3 wt % in total relative to the weight of the loteprednol etabonate.
51. The pharmaceutical composition of claim 32 , further comprising one or more degradants of the loteprednol etabonate, wherein the one or more degradants of the loteprednol etabonate includes 17α-[(ethoxycarbonyl)oxy]-11β-hydroxy-3-oxoandrosta-4-ene-17-carboxylic acid chloromethyl ester at less than or equal to about 0.5 wt % relative to the weight of the loteprednol etabonate.
52. The pharmaceutical composition of claim 51 , wherein the composition is made sterile via a sterilization process comprising gamma irradiation.
53. The pharmaceutical composition of claim 52 , wherein the 17α-[(ethoxycarbonyl)oxy]-11β-hydroxy-3-oxoandrosta-4-ene-17-carboxylic acid chloromethyl ester is at less than or equal to about 0.5 wt % relative to the weight of the loteprednol etabonate four weeks after the gamma irradiation.
54. The pharmaceutical composition of claim 32 , wherein the particles of loteprednol etabonate coated with poloxamer 407 have an average size of about 50 nm to about 700 nm.
55. The pharmaceutical composition of claim 54 , wherein the average size of the coated nanoparticles is measured by dynamic light scattering.
56. The pharmaceutical composition of claim 55 , wherein the average size of the coated nanoparticles is as measured in Z-average diameter by dynamic light scattering.
57. The pharmaceutical composition of claim 54 , wherein the polydispersity index of the composition is less than or equal to about 0.5.
58. The pharmaceutical composition of claim 57 , wherein the polydispersity index is measured by dynamic light scattering.
59. The pharmaceutical composition of claim 53 , wherein the poloxamer 407 coating on the particles of loteprednol etabonate is at an average density of at least 0.1 molecules/nm 2 and less than 1 molecule/nm 2 .
60. The pharmaceutical composition of claim 53 , wherein the particles of loteprednol etabonate coated with poloxamer 407 have a relative velocity of greater than 0.5 and less than 6.0 in human cervicovaginal mucus.
61. A pharmaceutical composition, comprising:
(a) a plurality of coated nanoparticles, each of the coated nanoparticles comprising:
(i) a core particle comprising a single pharmaceutical agent, wherein the single pharmaceutical agent is loteprednol etabonate, and wherein the loteprednol etabonate comprises at least 90 wt % of the core particle; and
(ii) a coating on the core particle, the coating comprising poloxamer 407 non-covalently adsorbed to the core particle; and
(b) one or more ophthalmically acceptable carriers, additives, and/or diluents;
wherein the pharmaceutical composition is a topical suspension, and wherein the topical suspension comprises about 0.25% w/v loteprednol etabonate in total and about 0.125% w/v poloxamer 407 in total; and
wherein the coated nanoparticles are mucus-penetrating.
62. The pharmaceutical composition of claim 61 , wherein the core particle is substantially free of a polymeric component.
63. The pharmaceutical composition of claim 61 , wherein the composition further comprises an ionic tonicity agent.
64. The pharmaceutical composition of claim 63 , wherein the ionic tonicity agent is sodium chloride.
65. The pharmaceutical composition of claim 64 , wherein the composition comprises about 0.1 w/v to about 1% w/v sodium chloride.
66. The pharmaceutical composition of claim 61 , wherein the coated nanoparticles have an average smallest cross-sectional dimension of about 200 nm to about 500 nm.
67. The pharmaceutical composition of claim 61 , wherein the coated nanoparticles have a relative velocity of greater than 0.5 and less than 6.0 in human cervicovaginal mucus.
68. The pharmaceutical composition of claim 61 , wherein the coated nanoparticles have poloxamer 407 adsorbed to the core particle at an average density of at least 0.01 molecules/nm 2 and less than 1 molecule/nm 2 .
69. The pharmaceutical composition of claim 68 , wherein the average density is at least 0.1 molecules/nm 2 and less than 1 molecule/nm 2 .
70. The pharmaceutical composition of claim 61 , wherein the coated nanoparticles have an average size of about 200 nm to about 700 nm.
71. The pharmaceutical composition of claim 70 , wherein the average size of the coated nanoparticles is measured by dynamic light scattering.
72. The pharmaceutical composition of claim 71 , wherein the average size of the coated nanoparticles is as measured in Z-average diameter by dynamic light scattering.
73. The pharmaceutical composition of claim 70 , wherein the polydispersity index of the composition is less than or equal to about 0.5.
74. The pharmaceutical composition of claim 70 , wherein the polydispersity index of the composition is less than or equal to about 0.4.
75. The pharmaceutical composition of claim 74 , wherein the polydispersity index is measured by dynamic light scattering.
76. The pharmaceutical composition of claim 64 , wherein the composition further comprises about 0.5 w/v to about 3% w/v glycerin.
77. The pharmaceutical composition of claim 76 , further comprising one or more degradants of the loteprednol etabonate, and wherein the concentration of each degradant is less than or equal to about 1 wt % relative to the weight of the loteprednol etabonate.
78. The pharmaceutical composition of claim 76 , further comprising one or more degradants of the loteprednol etabonate at less than or equal to about 3 wt % in total relative to the weight of the loteprednol etabonate.
79. The pharmaceutical composition of claim 76 , further comprising one or more degradants of the loteprednol etabonate, wherein the one or more degradants of the loteprednol etabonate includes 17α-[(ethoxycarbonyl)oxy]-11β-hydroxy-3-oxoandrosta-4-ene-17-carboxylic acid chloromethyl ester at less than or equal to about 0.5 wt % relative to the weight of the loteprednol etabonate.
80. The pharmaceutical composition of claim 79 , wherein the composition is made sterile via a sterilization process comprising gamma irradiation.
81. The pharmaceutical composition of claim 80 , wherein the 17α-[(ethoxycarbonyl)oxy]-11β-hydroxy-3-oxoandrosta-4-ene-17-carboxylic acid chloromethyl ester is at less than or equal to about 0.5 wt % relative to the weight of the loteprednol etabonate four weeks after the gamma irradiation.
82. The pharmaceutical composition of claim 61 , wherein the coated nanoparticles have an average size of about 50 nm to about 700 nm.
83. The pharmaceutical composition of claim 82 , wherein the average size of the coated nanoparticles is measured by dynamic light scattering.
84. The pharmaceutical composition of claim 82 , wherein the average size of the coated nanoparticles is as measured in Z-average diameter by dynamic light scattering.
85. The pharmaceutical composition of claim 82 , wherein the polydispersity index of the composition is less than or equal to about 0.5.
86. The pharmaceutical composition of claim 85 , wherein the polydispersity index is measured by dynamic light scattering.
87. The pharmaceutical composition of claim 81 , wherein the coated nanoparticles have a relative velocity of greater than 0.5 and less than 6.0 in human cervicovaginal mucus.
88. The pharmaceutical composition of claim 81 , wherein the coated nanoparticles have poloxamer 407 adsorbed to the core particle at an average density of at least 0.1 molecules/nm 2 and less than 1 molecule/nm 2 .
89. A method for treating inflammation or pain in an eye of a patient in need thereof, comprising administering to an eye of a subject in need thereof an effective amount of the pharmaceutical composition of any one of claim 1 , 32 , or 61 .
90. The method of claim 89 , wherein the composition is in the form of eye drops.
91. The method of claim 89 , wherein the composition is administered to the subject once a day.
92. The method of claim 89 , wherein the composition is administered to the subject more than once a day.