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 an eye disorder in a patient in need thereof comprising:
administering into an eye of the patient an ophthalmic suspension comprising:
(a) a plurality of coated nanoparticles, wherein each of the coated nanoparticles comprises:
(i) a core particle comprising loteprednol etabonate, wherein the loteprednol etabonate comprises at least 95 wt % of the core particle; and
(ii) poloxamer 407 non-covalently adsorbed to the core particle;
(b) sodium chloride;
(c) glycerin;
(d) disodium ethylenediaminetetraacetic acid;
(e) sodium citrate;
(f) citric acid; and
(g) water;
wherein the ophthalmic suspension comprises about 1% w/v loteprednol etabonate;
wherein the pH of the ophthalmic suspension is about 5 to about 7;
wherein the eye disorder treated is post-operative inflammation;
wherein the ophthalmic suspension is formulated as an eye drop; and
wherein the administration of the ophthalmic suspension occurs two times daily.
2. The method of claim 1 , wherein the ophthalmic suspension further comprises benzalkonium chloride.
3. The method of claim 2 , wherein:
the poloxamer 407 is present in the ophthalmic suspension in an amount of about 0.01% w/v to about 2% w/v;
the sodium chloride is present in the ophthalmic suspension in an amount of about 0.1% w/v to about 1% w/v;
the glycerin is present in the ophthalmic suspension in an amount of about 0.5% w/v to about 3% w/v;
the disodium ethylenediaminetetraacetic acid is present in the ophthalmic suspension in an amount of about 0.001% w/v to about 0.1% w/v; and
the benzalkonium chloride is present in the ophthalmic suspension in an amount of about 0.001% w/v to about 0.05% w/v.
4. The method of claim 3 , wherein the ratio of the weight of the loteprednol etabonate present in the ophthalmic suspension to the weight of the poloxamer 407 present in the ophthalmic suspension is greater than or equal to about 1:1, and less than or equal to about 3:1.
5. The method of claim 3 , wherein the poloxamer 407 is present in the ophthalmic suspension in an amount of about 0.5% w/v.
6. The method of claim 5 , wherein:
the sodium chloride is present in the ophthalmic suspension in an amount of about 0.45% w/v to about 0.9% w/v;
the glycerin is present in the ophthalmic suspension in an amount of about 0.6% w/v; and
the disodium ethylenediaminetetraacetic acid is present in the ophthalmic suspension in an amount of about 0.01% w/v to 0.1% w/v.
7. The method of claim 6 , wherein the ophthalmic suspension has an osmolarity of about 200 mOsm/L to about 450 mOsm/L.
8. The method of claim 6 , wherein administration of the ophthalmic suspension comprises instillation of one to two drops of the ophthalmic suspension into the eye of the patient.
9. The method of claim 6 , wherein the ophthalmic suspension comprises less than or equal to about 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 ophthalmic suspension.
10. The method of claim 6 , wherein administration of the ophthalmic suspension reduces post-surgical pain.
11. The method of claim 1 , wherein the core particle is substantially free of a polymeric component.
12. The method of claim 1 , wherein:
the osmolality of the ophthalmic suspension is about 300 mOsm/kg; and
administration of the ophthalmic suspension comprises instillation of one to two drops into the eye of the patient.
13. The method of claim 1 , wherein the coated nanoparticles have an average particle size of about 200 nm to about 600 nm, and wherein the average size is as measured in Z-average diameter by dynamic light scattering.
14. The method of claim 6 , wherein the poloxamer 407 is present on the loteprednol etabonate nanoparticles at an average density of at least 0.05 molecules/nm 2 and less than 10 molecule/nm 2 .
15. The method of claim 6 , wherein the loteprednol etabonate comprises at least 99 wt % of the core particle.
16. A method for administering an ophthalmic suspension for treatment of an eye disorder to a patient in need thereof comprising:
topically instilling the ophthalmic suspension into an eye of the patient, wherein the ophthalmic suspension comprises:
(a) a plurality of coated particles, wherein each of the coated particles comprises:
(i) a core particle comprising loteprednol etabonate, wherein the loteprednol etabonate comprises at least 95 wt % of the core particle; and
(ii) poloxamer 407 non-covalently adsorbed to the core particle;
(b) sodium chloride;
(c) glycerin;
(d) disodium ethylenediaminetetraacetic acid;
(e) sodium citrate;
(f) citric acid; and
(g) water;
wherein the ophthalmic suspension comprises about 1% w/v loteprednol etabonate;
wherein the pH of the ophthalmic suspension is about 5 to about 7;
wherein the eye disorder treated is post operative inflammation;
wherein the ophthalmic suspension is formulated as an eye drop; and
wherein the administration of the ophthalmic suspension occurs two times daily.
17. The method of claim 16 , wherein the ophthalmic suspension further comprises benzalkonium chloride.
18. The method of claim 17 , wherein:
the poloxamer 407 is present in the ophthalmic suspension in an amount of about 0.01% w/v to about 2% w/v;
the sodium chloride is present in the ophthalmic suspension in an amount of about 0.1% w/v to about 1% w/v;
the glycerin is present in the ophthalmic suspension in an amount of about 0.5% w/v to about 3% w/v;
the disodium ethylenediaminetetraacetic acid is present in the ophthalmic suspension in an amount of about 0.001% w/v to about 0.1% w/v; and
the benzalkonium chloride is present in the ophthalmic suspension in an amount of about 0.001% w/v to about 0.05% w/v.
19. The method of claim 18 , wherein the ratio of the weight of the loteprednol etabonate present in the ophthalmic suspension to the weight of the poloxamer 407 present in the ophthalmic suspension is greater than or equal to about 1:1, and less than or equal to about 3:1.
20. The method of claim 18 , wherein the poloxamer 407 is present in the ophthalmic suspension in an amount of about 0.5% w/v.
21. The method of claim 20 , wherein:
the sodium chloride is present in the ophthalmic suspension in an amount of about 0.45% w/v to about 0.9% w/v;
the glycerin is present in the ophthalmic suspension in an amount of about 0.6% w/v; and
the disodium ethylenediaminetetraacetic acid is present in the ophthalmic suspension in an amount of about 0.01% w/v to 0.1% w/v.
22. The method of claim 21 , wherein the ophthalmic suspension has an osmolarity of about 200 mOsm/L to about 450 mOsm/L.
23. The method of claim 22 , wherein the administration of the ophthalmic suspension comprises instillation of one to two drops of the ophthalmic suspension into the eye of the patient.
24. The method of claim 21 , wherein the ophthalmic suspension comprises less than or equal to about 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 ophthalmic suspension.
25. The method of claim 21 , wherein the administration of the ophthalmic suspension reduces post-surgical pain.
26. The method of claim 16 , wherein the core particle is substantially free of a polymeric component.
27. The method of claim 16 , wherein:
the osmolality of the ophthalmic suspension is about 300 mOsm/kg; and
administration of the ophthalmic suspension comprises instillation of one to two drops into each eye of the patient.
28. The method of claim 16 , wherein the coated nanoparticles have an average particle size of about 200 nm to about 600 nm, and wherein the average size is as measured in Z-average diameter by dynamic light scattering.
29. The method of claim 21 , wherein the poloxamer 407 is present on the loteprednol etabonate nanoparticles at an average density of at least 0.05 molecules/nm 2 and less than 10 molecule/nm 2 .
30. The method of claim 21 , wherein the loteprednol etabonate comprises at least 99 wt % of the core particle.