COMPOSITIONS AND METHODS FOR OPHTHALMIC AND/OR OTHER APPLICATIONS

• US 20150125539A1
• Filed: 11/02/2013
• Published: 05/07/2015
• Est. Priority Date: 05/03/2012
• Status: Active Grant

• Current Assignee: Kala Pharmaceuticals, Inc.
• Original Assignee: Kala Pharmaceuticals, Inc.
• Inventors: Popov, Alexey, Enlow, Elizabeth M., Chen, Hongming, Bourassa, James
• Granted Patent: US 9,827,191 B2
• Time in Patent Office: Days
• US Class Current: 424/497
• 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

1-27. -27. (canceled)

28. A pharmaceutical composition suitable for administration to an eye, comprising:

a plurality of coated particles, comprising;

a core particle comprising loteprednol etabonate; and

a coating comprising a surface-altering agent surrounding the core particle, wherein the surface-altering agent comprises a (poly(ethylene oxide))-(poly(propylene oxide))-(poly(ethylene oxide)) triblock copolymer, wherein the hydrophobic block has a molecular weight of about 3600 Da, and the hydrophilic 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 pharmaceutical composition in an amount between about 0.1% to about 2% loteprednol etabonate by weight; and

,

wherein the one or more surface altering agents is present in the pharmaceutical composition in an amount of between about 0.01% to about 2% by weight.

31. The pharmaceutical composition of claim 28, 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.

33. The pharmaceutical composition of claim 31, wherein the one or more ophthalmically acceptable carriers, additives, and/or diluents further comprises sodium citrate, citric acid, and water.

35. The pharmaceutical composition of claim 28, wherein the ratio of the weight of the loteprednol etabonate to the weight of the surface-altering agent present in the pharmaceutical composition is greater than or equal to about 1:

1, and less than or equal to about 3;

1.

39. The pharmaceutical composition of claim 28, wherein the surface-altering agent is non-covalently adsorbed to the core particles.

41. The pharmaceutical composition of claim 28, wherein the surface-altering agent is Pluronic®

F127.

43. The pharmaceutical composition of claim 28, wherein the plurality of coated particles have an average smallest cross-sectional dimension of about 200 nm to about 500 nm.

44. The pharmaceutical composition of claim 28, wherein the plurality of coated particles have an average smallest cross-sectional dimension of about 200 nm to about 300 nm.

29. 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 pharmaceutical composition comprising;

a plurality of coated particles, comprising;

a core particle comprising loteprednol etabonate; and

a coating comprising a surface-altering agent surrounding the core particle, wherein the surface-altering agent comprises a (poly(ethylene oxide))-(poly(propylene oxide))-(poly(ethylene oxide)) triblock copolymer, wherein the hydrophobic block has a molecular weight of about 3600 Da, and the hydrophilic 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 pharmaceutical composition in an amount between about 0.1% to about 2% loteprednol etabonate by weight; and

,

wherein the one or more surface altering agents is present in the pharmaceutical composition in an amount of between about 0.01% to about 2% by weight.

32. The method of claim 29, 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.

34. The method of claim 32, wherein the one or more ophthalmically acceptable carriers, additives, and/or diluents further comprises sodium citrate, citric acid, and water.

36. The method of claim 29, wherein the ratio of the weight of the loteprednol etabonate to the weight of the surface-altering agent present in the pharmaceutical composition is greater than or equal to about 1:

1, and less than or equal to about 3;

1.

37. The method of claim 29, comprising delivering the pharmaceutical agent to a tissue in the front of the eye of the subject.

38. The method of claim 29, comprising delivering the pharmaceutical agent to a tissue in the back of the eye of the subject.

40. The method of claim 29, wherein the surface-altering agent is non-covalently adsorbed to the core particles.

42. The method of claim 29, wherein the surface-altering agent is Pluronic®

F127.

45. The method of claim 29, wherein the plurality of coated particles have an average smallest cross-sectional dimension of about 200 nm to about 500 nm.

46. The method of claim 29, wherein the plurality of coated particles have an average smallest cross-sectional dimension of about 200 nm to about 300 nm.

30. A method of making a composition comprising

a plurality of coated particles comprising:

a core particle comprising loteprednol etabonate; and

a coating comprising a surface-altering agent surrounding the core particle, wherein the surface-altering agent comprises a (poly(ethylene oxide))-(poly(propylene oxide))-(poly(ethylene oxide)) triblock copolymer, wherein the hydrophobic block has a molecular weight of about 3600 Da, and the hydrophilic 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 pharmaceutical composition in an amount between about 0.1% to about 2% loteprednol etabonate by weight;

wherein the one or more surface altering agents is present in the pharmaceutical composition in an amount of between about 0.01% to 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,

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 a (poly(ethylene oxide))-(poly(propylene oxide))-(poly(ethylene oxide)) triblock copolymer, wherein the hydrophobic block has a molecular weight of about 3600 Da, and the hydrophilic blocks constitute about 70 wt % of the 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.

53. The method of claim 30, 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.

47. A pharmaceutical composition suitable for administration to an eye, comprising:

a plurality of coated particles, comprising;

a core particle comprising loteprednol etabonate; and

a coating comprising a surface-altering agent surrounding the core particle, wherein the surface-altering agent comprises a (poly(ethylene oxide))-(poly(propylene oxide))-(poly(ethylene oxide)) triblock copolymer, wherein the hydrophobic block has a molecular weight of about 3600 Da, and the hydrophilic 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 pharmaceutical composition in an amount between about 0.1% to about 1% loteprednol etabonate by weight; and

wherein the ratio of the weight of the loteprednol etabonate to the weight of the surface-altering agent is about 2;

1.

48. The pharmaceutical composition of claim 47, further comprising sodium citrate, citric acid, and water.

49. The pharmaceutical composition of claim 48, wherein the loteprednol etabonate is present in the pharmaceutical composition in an amount about 0.25% loteprednol etabonate by weight.

50. The pharmaceutical composition of claim 48, wherein the loteprednol etabonate is present in the pharmaceutical composition in an amount about 1% loteprednol etabonate by weight.

51. The pharmaceutical composition of claim 49, wherein the glycerin is present in an amount of about 0.6%.

52. The pharmaceutical composition of claim 50, wherein the glycerin is present in an amount of about 0.6%.

54-56. -56. (canceled)