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 method for treating ocular inflammation, comprising:
administering to an eye of a subject in need of treatment for ocular inflammation an effective amount of a 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 topical pharmaceutical composition comprises loteprednol etabonate at about 1% w/v in total;
wherein the 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 pharmaceutical composition is about 2:1.
2. The method of claim 1 , wherein the method treats post-surgical inflammation or post-surgical pain in the subject.
3. The method of claim 1 , wherein the pharmaceutical composition is administered to the subject twice a day.
4. The method of claim 1 , wherein the triblock copolymer is poloxamer 407.
5. The method of claim 1 , wherein the loteprednol etabonate comprises at least 90 wt % of the core particle.
6. The method of claim 5 , wherein the core particle is substantially free of a polymeric component.
7. The method of claim 6 , wherein the coated nanoparticles have an average size of about 50 nm to about 700 nm.
8. The method of claim 7 , wherein the average size is measured by dynamic light scattering.
9. The method of claim 8 , wherein the average size is as measured in Z-average diameter by dynamic light scattering.
10. The method of claim 7 , wherein the polydispersity index of the pharmaceutical composition is less than or equal to about 0.5.
11. The method of claim 7 , wherein the polydispersity index of the pharmaceutical composition is less than or equal to about 0.4.
12. The method of claim 11 , wherein the polydispersity index is measured by dynamic light scattering.
13. The method of claim 5 , wherein the coated nanoparticles have the triblock copolymer adsorbed to the core particle at an average density of at least 0.1 molecules/nm 2 and less than 1 molecule/nm 2 .
14. The method of claim 5 , wherein the coated nanoparticles have a relative velocity of greater than 0.5 and less than 6.0 in human cervicovaginal mucus.
15. The method of claim 5 , wherein the pharmaceutical composition further comprises less than or equal to 0.5 wt % 17α-[(ethoxycarbonyl)oxy]-11β-hydroxy-3-oxoandrosta-4-ene-17-carboxylic acid chloromethyl ester relative to the weight of the loteprednol etabonate in the pharmaceutical composition.
16. The method of claim 15 , wherein the pharmaceutical composition is made sterile by a sterilization proves comprising gamma irradiation, and wherein the 17α-[(ethoxycarbonyl)oxy]-11β-hydroxy-3-oxoandrosta-4-ene-17-carboxylic acid chloromethyl ester is at less than or equal to 0.5 wt % relative to the weight of the loteprednol etabonate in the pharmaceutical composition after the gamma irradiation.
17. A method for treating ocular inflammation, comprising:
administering to an eye of a subject in need of treatment for ocular inflammation 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 pharmaceutical composition comprises about 1% w/v loteprednol etabonate in total and about 0.5% w/v poloxamer 407 in total.
18. The method of claim 17 , wherein the method treats post-surgical inflammation in the subject.
19. The method of claim 17 , wherein the pharmaceutical composition is administered to the subject twice a day.
20. The method of claim 17 , wherein the core particle is substantially free of a polymeric component.
21. The method of claim 17 , wherein the pharmaceutical composition comprises an ionic tonicity agent.
22. The method of claim 21 , wherein the ionic tonicity agent is sodium chloride.
23. The method of claim 22 , wherein the pharmaceutical composition comprises about 0.1 to about 1% w/v sodium chloride.
24. The method of claim 22 , wherein the pharmaceutical composition further comprises about 0.5 to about 3% w/v glycerin.
25. The method of claim 17 , wherein the coated nanoparticles have a relative velocity of greater than 0.5 and less than 6.0 in human cervicovaginal mucus.
26. The method of claim 17 , 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 .
27. The method of claim 26 , wherein the average density is at least 0.1 molecules/nm 2 and less than 1 molecule/nm 2 .
28. The method of claim 21 , wherein the coated nanoparticles have an average size of about 50 nm to about 700 nm.
29. The method of claim 28 , wherein the average size is measured by dynamic light scattering.
30. The method of claim 29 , wherein the average size is as measured in Z-average diameter by dynamic light scattering.
31. The method of claim 28 , wherein the polydispersity index of the pharmaceutical composition is less than or equal to 0.5.
32. The method of claim 28 , wherein the polydispersity index of the pharmaceutical composition is less than or equal to 0.4.
33. The method of claim 32 , wherein the polydispersity index is measured by dynamic light scattering.
34. The method of claim 24 , wherein the pharmaceutical composition comprises less than or equal to 0.5 wt % 17α-[(ethoxycarbonyl)oxy]-11β-hydroxy-3-oxoandrosta-4-ene-17-carboxylic acid chloromethyl ester relative to the weight of the loteprednol etabonate in the pharmaceutical composition.
35. The method of claim 34 , wherein the pharmaceutical composition is made sterile by a sterilization process comprising gamma irradiation, and wherein the 17α-[(ethoxycarbonyl)oxy]-11β-hydroxy-3-oxoandrosta-4-ene-17-carboxylic acid chloromethyl ester is at less than or equal to 0.5 wt % relative to the weight of the loteprednol etabonate in the pharmaceutical composition after the gamma irradiation.
36. The method of claim 1 , wherein the loteprednol etabonate constitutes at least 95% of the core particle by weight.
37. The method of claim 36 , wherein the loteprednol etabonate constitutes at least 99% of the core particle by weight.
38. The method of claim 17 , wherein the loteprednol etabonate constitutes at least 95% of the core particle by weight.
39. The method of claim 38 , wherein the loteprednol etabonate constitutes at least 99% of the core particle by weight.