PARTICLES, COMPOSITIONS, AND METHODS FOR OPHTHALMIC AND/OR OTHER APPLICATIONS
This disclosure relates to particles, compositions, and methods that aid particle transport in mucus. The particles, compositions, and methods may be used, in some instances, for ophthalmic and/or other applications.
1 . A pharmaceutical composition, comprising:
a plurality of mucus-penetrating coated particles, each coated particle comprising:
a core particle comprising loteprednol etabonate crystalline form I or form II, and a mucus penetration-enhancing coating comprising a surface-altering agent surrounding the core particle,
wherein the surface-altering agent comprises one or more of the following components:
a) a triblock copolymer comprising a hydrophilic block—hydrophobic block—hydrophilic block configuration, wherein the hydrophobic block has a molecular weight of at least about 2 kDa, and the hydrophilic blocks constitute at least about 15 wt % of the triblock copolymer, wherein the hydrophobic block associates with the surface of the core particle, and wherein the hydrophilic block is present at the surface of the coated particle and renders the coated particle hydrophilic,
b) a synthetic polymer having pendant hydroxyl groups on the backbone of the polymer, the polymer having a molecular weight of at least about 1 kDa and less than or equal to about 1000 kDa, wherein the polymer has a degree of hydrolysis of at least about 30% and less than about 95%, or
c) a polysorbate, and
at least one pharmaceutically acceptable carrier, additive, or diluent;
wherein the surface-altering agent is present on the outer surface of the core particle at a density of at least 0.01 molecules/nm 2 ,
wherein the surface-altering agent is present in the pharmaceutical composition in an amount of between about 0.001% to about 5% by weight in total.
2 . The pharmaceutical composition of claim 1 , wherein the crystalline form I of loteprednol etabonate has X-ray powder diffraction (XRPD) peaks at about 5.6, 7.7, 11.9, 14.1, 17.0 and 18.8±0.2° 2θ; and wherein the crystalline form II of loteprednol etabonate has X-ray powder diffraction (XRPD) peaks at about 15.0°, 18.1°, and 19.8°±0.2° 2θ.
3 . The pharmaceutical composition of claim 2 , wherein the crystalline form I of loteprednol etabonate has further XRPD peaks at about 16.0, 21.0 and 22.0±0.2° 2θ; and wherein the crystalline form II of loteprednol etabonate has further XRPD peaks at about 9.8°, 15.6°, 16.6°, 17.2°, 23.0°, 24.8°, and 26.3°±0.2° 2θ.
4 . The pharmaceutical composition of claim 1 , wherein the surface-altering agent is present on the surfaces of the coated particles at a density of at least about 0.1 molecules per nanometer squared.
5 . The pharmaceutical composition of claim 1 , wherein the surface-altering agent is non-covalently adsorbed to the core particles.
6 . The pharmaceutical composition of claim 1 , wherein the surface-altering agent comprises the triblock copolymer.
7 . The pharmaceutical composition of claim 6 , wherein the triblock copolymer is poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide).
8 . The pharmaceutical composition of claim 1 , wherein the surface altering agent is poly(vinyl alcohol).
9 . The pharmaceutical composition of claim 1 , wherein the crystalline form I or form II of loteprednol etabonate comprises at least about 80 wt % of the core particle.
10 . The pharmaceutical composition of claim 1 , wherein the coated particles have an average size of about 10 nm to about 1 μm.
11 . The pharmaceutical composition of claim 1 , wherein the polydispersity index of the composition is less than or equal to about 0.5.
12 . The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is suitable for topical administration to the eye.
13 . The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is suitable for direct injection into the eye.
14 . The pharmaceutical composition of claim 1 , wherein the pharmaceutically acceptable carrier, additive, or diluent comprises glycerin.
15 . The pharmaceutical composition of claim 1 , wherein the composition comprises about 0.1 to about 1% w/v sodium chloride.
16 . A method of treating, diagnosing, preventing, or managing an ocular condition in a subject, the method comprising: administering a pharmaceutical composition of claim 1 to an eye of a subject and thereby delivering the loteprednol etabonate, to a tissue in the eye of the subject.
17 . The method of claim 16 , comprising sustaining an ophthalmically efficacious level of the loteprednol etabonate, in a palpebral conjunctiva, a fornix conjunctiva, a bulbar conjunctiva, or a cornea for at least 12 hours after administration.
18 . The method of claim 16 , comprising delivering the loteprednol etabonate, to a tissue in the front of the eye of the subject or to tissue in the back of the eye of the subject.
19 . The method of claim 16 , wherein the ocular condition is inflammation, pain, macular degeneration, macular edema, uveitis, or dry eye.
20 . A method of sustaining an ophthalmically efficacious level of loteprednol etabonate in an eye tissue in a subject in need thereof, comprising administering a pharmaceutical composition of claim 1 to the eye tissue of the subject, wherein the level of loteprednol etabonate is sustained for at least 12 hours after administration.