Compositions and methods for ophthalmic and/or other applications

• US 9,827,191 B2
• Filed: 11/02/2013
• Issued: 11/28/2017
• Est. Priority Date: 05/03/2012
• Status: Active Grant

• Current Assignee: Alcon Incorporated
• Original Assignee: Johns Hopkins University
• Inventors: Popov, Alexey, Enlow, Elizabeth M., Chen, Hongming, Bourassa, James
• Primary Examiner(s): Wax, Robert A
• Assistant Examiner(s): NIELSEN, THOR B
• Application Number:
  US14/070,506
• Publication Number:
  US 20150125539A1
• Time in Patent Office: 1,487 Days
• CPC Class Codes: A61K 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• CPC Class Codes: A61K 9/0048 Eye, e.g. artificial tears
• CPC Class Codes: A61K 9/5031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/5123 Organic compounds, e.g. fats, sugars
• CPC Class Codes: A61K 9/5138 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/5146 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
• CPC Class Codes: A61P 27/02 Ophthalmic agents

Abstract

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.

Claims

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/nm².

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.

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.

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.

11. The topical pharmaceutical composition of claim 1, 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.

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.

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/nm².

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.

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.

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.

12. The method of claim 2, wherein the mucus penetration-enhancing coating is non-covalently adsorbed to the core particles.

14. The method of claim 2, wherein the mucus penetration-enhancing coating is poloxamer 407.

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.

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/nm²;

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.

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.

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/nm².

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%.