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 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 loteprednol etabonate is present in the pharmaceutical composition in an amount between about 0.01% and about 2% by weight in total; and
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 greater than or equal to about 1:1 and less than or equal to about 3:1,
wherein the coated nanoparticles are mucus-penetrating.
2. The topical pharmaceutical composition of claim 1 , wherein the loteprednol etabonate is present in the topical pharmaceutical composition in an amount between about 0.1% and about 2% by weight in total.
3. The topical pharmaceutical composition of claim 1 , wherein the mucus penetration enhancing coating is present in the topical pharmaceutical composition in an amount between about 0.01% and about 2% by weight in total.
4. 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 .
5. The topical pharmaceutical composition of claim 4 , wherein the average density is at least 0.1 molecules/nm 2 and less than 1 molecule/nm 2 .
6. 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.
7. 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.
8. The topical pharmaceutical composition of claim 1 , further comprising about 0.01% w/v to about 1% w/v disodium ethylenediaminetetraacetic acid.
9. The topical pharmaceutical composition of claim 1 , wherein the triblock copolymer is poloxamer 407.
10. The topical pharmaceutical composition of claim 1 , wherein the coated nanoparticles have an average size of about 50 nm to about 700 nm.
11. The topical pharmaceutical composition of claim 10 , wherein the polydispersity index of the composition is less than or equal to about 0.5.
12. The topical pharmaceutical composition of claim 11 , wherein the polydispersity index is less than or equal to about 0.4.
13. The topical pharmaceutical composition of claim 12 , wherein the core particle is substantially free of a polymeric component.
14. The topical pharmaceutical composition of claim 13 , wherein the coated nanoparticles have an average size of about 50 nm to about 700 nm.
15. The topical pharmaceutical composition of claim 14 , wherein the average size of the coated nanoparticles is measured by dynamic light scattering.
16. The topical pharmaceutical composition of claim 14 , wherein the average size of the coated nanoparticles is as measured in Z-average diameter by dynamic light scattering.
17. The topical pharmaceutical composition of claim 14 , wherein the polydispersity index of the composition is less than or equal to about 0.5.
18. The topical pharmaceutical composition of claim 17 , wherein the polydispersity index is measured by dynamic light scattering.
19. The topical pharmaceutical composition of claim 13 , 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 .
20. The topical pharmaceutical composition of claim 13 , wherein the coated nanoparticles have a relative velocity of greater than 0.5 and less than 6.0 in human cervicovaginal mucus.
21. 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.
22. 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.
23. 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.
24. 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.
25. The topical pharmaceutical composition of claim 24 , wherein the composition is made sterile via a sterilization process comprising gamma irradiation.
26. The topical pharmaceutical composition of claim 25 , 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.
27. The topical pharmaceutical composition of claim 25 , wherein the coated nanoparticles have an average size of about 50 nm to about 700 nm.
28. The topical pharmaceutical composition of claim 27 , wherein the average size of the coated nanoparticles is measured by dynamic light scattering.
29. The topical pharmaceutical composition of claim 28 , wherein the average size of the coated nanoparticles is as measured in Z-average diameter by dynamic light scattering.
30. The topical pharmaceutical composition of claim 27 , wherein the polydispersity index of the composition is less than or equal to about 0.5.
31. The topical pharmaceutical composition of claim 30 , wherein the polydispersity index is measured by dynamic light scattering.
32. The topical pharmaceutical composition of claim 25 , 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 .
33. The topical pharmaceutical composition of claim 25 , wherein the polydispersity index of the composition is less than or equal to about 0.5.
34. 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 loteprednol etabonate is present in the pharmaceutical composition in an amount between about 0.01% and about 2% by weight 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.
35. The pharmaceutical composition of claim 34 , wherein the loteprednol etabonate is present in the pharmaceutical composition in an amount between about 0.1% and about 2% by weight in total.
36. The pharmaceutical composition of claim 35 , wherein the ionic tonicity agent is sodium chloride.
37. The pharmaceutical composition of claim 36 , wherein the composition comprises about 0.1% w/v to about 1% w/v sodium chloride.
38. The pharmaceutical composition of claim 37 , further comprising about 0.01% w/v to about 1% w/v disodium ethylenediaminetetraacetic acid.
39. The pharmaceutical composition of claim 38 , further comprising about 0.001 to about 0.05% w/v benzalkonium chloride.
40. The pharmaceutical composition of claim 39 , further comprising sodium citrate, citric acid, and water.
41. The pharmaceutical composition of claim 34 , wherein the nanoparticles of loteprednol etabonate coated with poloxamer 407 have an average smallest cross-sectional dimension of about 200 nm to about 500 nm.
42. The pharmaceutical composition of claim 34 , wherein the nanoparticles 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.
43. The pharmaceutical composition of claim 34 , 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 .
44. The pharmaceutical composition of claim 43 , wherein the average density is at least 0.1 molecules/nm 2 and less than 1 molecule/nm2.
45. The pharmaceutical composition of claim 34 , wherein the nanoparticles of loteprednol etabonate coated with poloxamer 407 have an average size of about 200 nm to about 700 nm.
46. The pharmaceutical composition of claim 45 , wherein the average size of the coated nanoparticles is measured by dynamic light scattering.
47. The pharmaceutical composition of claim 45 , wherein the average size of the coated nanoparticles is as measured in Z-average diameter by dynamic light scattering.
48. The pharmaceutical composition of claim 45 , wherein the polydispersity index of the composition is less than or equal to about 0.5.
49. The pharmaceutical composition of claim 45 , wherein the polydispersity index of the composition is less than or equal to about 0.4.
50. The pharmaceutical composition of claim 49 , wherein the polydispersity index is measured by dynamic light scattering.
51. The pharmaceutical composition of claim 34 , wherein the poloxamer 407 non-covalently coated on the loteprednol etabonate particles is in equilibrium with free poloxamer 407 in the pharmaceutical composition.
52. The pharmaceutical composition of claim 34 , 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.
53. The pharmaceutical composition of claim 34 , 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.
54. The pharmaceutical composition of claim 34 , 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.
55. The pharmaceutical composition of claim 54 , wherein the composition is made sterile via a sterilization process comprising gamma irradiation.
56. The pharmaceutical composition of claim 55 , 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.
57. The pharmaceutical composition of claim 56 , wherein the nanoparticles of loteprednol etabonate coated with poloxamer 407 have an average size of about 50 nm to about 700 nm.
58. The pharmaceutical composition of claim 57 , wherein the average size of the coated nanoparticles is measured by dynamic light scattering.
59. The pharmaceutical composition of claim 58 wherein the average size of the coated nanoparticles is as measured in Z-average diameter by dynamic light scattering.
60. The pharmaceutical composition of claim 57 , wherein the polydispersity index of the composition is less than or equal to about 0.5.
61. The pharmaceutical composition of claim 60 , wherein the polydispersity index is measured by dynamic light scattering.
62. The pharmaceutical composition of claim 55 , 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 .
63. The pharmaceutical composition of claim 55 , wherein the nanoparticles 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.
64. 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 0.01% to 2% w/v loteprednol etabonate in total 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,
wherein the coated nanoparticles are mucus-penetrating.
65. The pharmaceutical composition of claim 64 , wherein the core particle is substantially free of a polymeric component.
66. The pharmaceutical composition of claim 64 , wherein the composition further comprises an ionic tonicity agent.
67. The pharmaceutical composition of claim 66 , wherein the ionic tonicity agent is sodium chloride.
68. The pharmaceutical composition of claim 67 , wherein the composition comprises about 0.1 to about 1% w/v sodium chloride.
69. The pharmaceutical composition of claim 64 , wherein the coated nanoparticles have an average smallest cross-sectional dimension of about 200 nm to about 500 nm.
70. The pharmaceutical composition of claim 64 , wherein the coated nanoparticles have a relative velocity of greater than 0.5 and less than 6.0 in human cervicovaginal mucus.
71. The pharmaceutical composition of claim 65 , 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 .
72. The pharmaceutical composition of claim 71 , wherein the average density is at least 0.1 molecules/nm 2 and less than 1 molecule/nm 2 .
73. The pharmaceutical composition of claim 64 , wherein the particles of loteprednol etabonate coated with poloxamer 407 have an average size of about 200 nm to about 700 nm.
74. The pharmaceutical composition of claim 73 , wherein the average size of the coated nanoparticles is measured by dynamic light scattering.
75. The pharmaceutical composition of claim 74 , wherein the average size of the coated nanoparticles is as measured in Z-average diameter by dynamic light scattering.
76. The pharmaceutical composition of claim 73 , wherein the polydispersity index of the composition is less than or equal to about 0.5.
77. The pharmaceutical composition of claim 73 , wherein the polydispersity index of the composition is less than or equal to about 0.4.
78. The pharmaceutical composition of claim 77 , wherein the polydispersity index is measured by dynamic light scattering.
79. The pharmaceutical composition of claim 67 , wherein the composition further comprises about 0.5 to about 3% w/v glycerin.
80. The pharmaceutical composition of claim 79 , 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.
81. The pharmaceutical composition of claim 79 , 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.
82. The pharmaceutical composition of claim 79 , 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.
83. The pharmaceutical composition of claim 82 , wherein the composition is made sterile via a sterilization process comprising gamma irradiation.
84. The pharmaceutical composition of claim 83 , 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.
85. The pharmaceutical composition of claim 84 , wherein the coated nanoparticles have an average size of about 50 nm to about 700 nm.
86. The pharmaceutical composition of claim 85 , wherein the average size of the coated nanoparticles is measured by dynamic light scattering.
87. The pharmaceutical composition of claim 85 , wherein the average size of the coated nanoparticles is as measured in Z-average diameter by dynamic light scattering.
88. The pharmaceutical composition of claim 85 , wherein the polydispersity index of the composition is less than or equal to about 0.5.
89. The pharmaceutical composition of claim 88 , wherein the polydispersity index is measured by dynamic light scattering.
90. The pharmaceutical composition of claim 83 , wherein the coated nanoparticles have a relative velocity of greater than 0.5 and less than 6.0 in human cervicovaginal mucus.
91. The pharmaceutical composition of claim 83 , 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 .