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 for administration to an eye comprising a plurality of coated particles, each particle comprising:
a core comprising a single pharmaceutical agent, wherein the pharmaceutical agent consists of loteprednol etabonate in an amount that is effective for treatment of a condition affecting an ocular surface, wherein the core is coated with 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
one or more ophthalmically acceptable carriers, additives, and/or diluents;
wherein the loteprednol etabonate is present in the topical pharmaceutical composition in an amount between about 0.1% and about 2% loteprednol etabonate by weight;
wherein the mucus penetration-enhancing coating is present in the topical pharmaceutical composition in an amount of between about 0.01% and about 2% by weight; and
wherein the mucus penetration-enhancing coating is present on the surface of the loteprednol etabonate at a density of at least about 0.01 molecules/nm 2 .
2. A method for treating inflammation, macular degeneration, macular edema, uveitis, dry eye, blepharitis, cystoid macular edema, and/or other disorder in an eye of a patient, comprising:
administering to an eye of the patient, a topical pharmaceutical composition comprising a plurality of coated particles, each particle comprising a core comprising a single pharmaceutical agent, wherein the pharmaceutical agent consists of an amount of loteprednol etabonate effective to treat a condition affecting an ocular surface, wherein the core is coated with 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
one or more ophthalmically acceptable carriers, additives, and/or diluents;
wherein the loteprednol etabonate is present in the topical pharmaceutical composition in an amount between about 0.1% and about 2% loteprednol etabonate by weight; and,
wherein the mucus penetration-enhancing coating is present in the topical pharmaceutical composition in an amount of between about 0.01% and about 2% by weight; and
wherein the mucus penetration-enhancing coating is present on the surface of the loteprednol etabonate at a density of at least about 0.01 molecules/nm 2 .
3. A method of making a composition for topical administration to the eye comprising a single pharmaceutical agent, wherein the pharmaceutical agent consists of loteprednol etabonate wherein the pharmaceutical agent is coated with 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 forming a plurality of coated particles; and
one or more ophthalmically acceptable carriers, additives, and/or diluents,
wherein the loteprednol etabonate is present in the topical pharmaceutical composition in an amount between about 0.1% and about 2% loteprednol etabonate by weight;
wherein the mucus penetration-enhancing coating is present in the pharmaceutical composition in an amount of between about 0.01% and about 2% by weight,
wherein the plurality of coated particles have an average smallest cross-sectional dimension of about 0.2 microns to about 0.3 microns; and
wherein the mucus penetration-enhancing coating is present on the surface of the loteprednol etabonate at a density of at least about 0.01 molecules/nm 2 ;
the method comprising:
milling a coarse aqueous suspension containing about 2-20% loteprednol etabonate in the form of coarse or micronized crystals, about 0.2-20% of the (poly(ethylene oxide))-(poly(propylene oxide))-(poly(ethylene oxide)) triblock copolymer, about 0.5-3% glycerin, about 0.1-1% sodium chloride, and about 0.001-0.1% EDTA in the presence of milling media to produce a nanosuspension of loteprednol etabonate particles sized in the range of about 200 nm to about 300 nm;
separating the nanosuspension of loteprednol etabonate particles from the milling media; and
mixing the nanosuspension of loteprednol etabonate particles with diluent.
4. The topical pharmaceutical composition of claim 1 , wherein the one or more ophthalmically acceptable carriers, additives, and/or diluents comprises about 0.5-3% glycerin, about 0.1-1% sodium chloride, about 0.001-0.1% disodium ethylenediaminetetraacetic acid, and about 0.001-0.05% benzalkonium chloride.
5. The method of claim 2 , wherein the one or more ophthalmically acceptable carriers, additives, and/or diluents comprises about 0.5-3% glycerin, about 0.1-1% sodium chloride, about 0.001-0.1% disodium ethylenediaminetetraacetic acid, and about 0.001-0.05% benzalkonium chloride.
6. The topical pharmaceutical composition of claim 4 , wherein the one or more ophthalmically acceptable carriers, additives, and/or diluents further comprises sodium citrate, citric acid, and water.
7. The method of claim 5 , wherein the one or more ophthalmically acceptable carriers, additives, and/or diluents further comprises sodium citrate, citric acid, and water.
8. The topical pharmaceutical composition of claim 1 , wherein the ratio of the weight of the loteprednol etabonate to the weight of the mucus penetration-enhancing coating in the topical pharmaceutical composition is greater than or equal to about 1:1, and less than or equal to about 3:1.
9. The method of claim 2 , wherein the ratio of the weight of the loteprednol etabonate to the weight of the mucus penetration-enhancing coating in the topical pharmaceutical composition is greater than or equal to about 1:1, and less than or equal to about 3:1.
10. The method of claim 2 , comprising delivering the pharmaceutical agent to a tissue in the front of the eye of the subject.
11. The topical pharmaceutical composition of claim 1 , wherein the mucus penetration-enhancing coating is non-covalently adsorbed to the core particles.
12. The method of claim 2 , wherein the mucus penetration-enhancing coating is non-covalently adsorbed to the core particles.
13. The topical pharmaceutical composition of claim 1 , wherein the mucus penetration-enhancing coating is poloxamer 407.
14. The method of claim 2 , wherein the mucus penetration-enhancing coating is poloxamer 407.
15. The topical pharmaceutical composition of claim 1 , wherein the plurality of coated particles have an average smallest cross-sectional dimension of about 200 nm to about 500 nm.
16. The topical pharmaceutical composition of claim 1 , wherein the plurality of coated particles have an average smallest cross-sectional dimension of about 200 nm to about 300 nm.
17. The method of claim 2 , wherein the plurality of coated particles have an average smallest cross-sectional dimension of about 200 nm to about 500 nm.
18. The method of claim 2 , wherein the plurality of coated particles have an average smallest cross-sectional dimension of about 200 nm to about 300 nm.
19. A topical pharmaceutical composition for administration to an eye comprising a plurality of coated particles, each particle comprising:
a core comprising a single pharmaceutical agent, wherein the pharmaceutical agent consists of loteprednol etabonate in an amount that is effective for treatment of a condition affecting an ocular surface, wherein the core is coated with 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;
about 0.5% to about 1% glycerin;
about 0.1% to about 1% sodium chloride;
about 0.01% to about 0.1% disodium ethylenediaminetetraacetic acid; and
about 0.01% to about 0.03% benzalkonium chloride;
wherein the loteprednol etabonate is present in the topical pharmaceutical composition in an amount between about 0.1% and about 1% loteprednol etabonate by weight; and
wherein the ratio of the weight of the loteprednol etabonate to the weight of the mucus penetration-enhancing coating is about 2:1; and
wherein the mucus penetration-enhancing coating is present on the surface of the loteprednol etabonate at a density of at least about 0.01 molecules/nm 2 .
20. The topical pharmaceutical composition of claim 19 , further comprising sodium citrate, citric acid, and water.
21. The topical pharmaceutical composition of claim 20 , wherein the loteprednol etabonate is present in the topical pharmaceutical composition in an amount about 0.25% loteprednol etabonate by weight.
22. The topical pharmaceutical composition of claim 20 , wherein the loteprednol etabonate is present in the topical pharmaceutical composition in an amount about 1% loteprednol etabonate by weight.
23. The topical pharmaceutical composition of claim 21 , wherein the glycerin is present in an amount of about 0.6%.
24. The topical pharmaceutical composition of claim 22 , wherein the glycerin is present in an amount of about 0.6%.
25. The method of claim 3 , wherein the diluent comprises about 0.5-3% glycerin, about 0.1-1% sodium chloride, about 0.001-0.1% disodium ethylenediaminetetraacetic acid, and about 0.001-0.05% benzalkonium chloride.