Compositions for treatment of retinal edema and ocular inflammation

Abstract

Provided herein are ophthalmic pharmaceutical compositions, including compositions containing a fixed dose combination of active agents that are suitable for topical delivery to the eye(s) of a subject. In embodiments, the ophthalmic pharmaceutical compositions contain a glucocorticoid receptor agonist and an intraocular pressure lowering agent. Also provided are methods of manufacturing ophthalmic pharmaceutical compositions of the disclosure. Further provided are methods involving coadministration of a glucocorticoid receptor agonist and an intraocular pressure lowering agent, such as in the treatment of a patient suffering from an ocular condition.

Description

Atty. Docket No.: PLXB-001 / 03WOCOMPOSITIONS FOR TREATMENT OF RETINAL EDEMA AND OCULAR INFLAMMATIONCROSS-REFEFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U. S. Provisional Application No.63 / 735,755, filed December 18, 2024, U. S. Provisional Application No, 63 / 900,434, filed October 16, 2025, and U. S. Provisional Application No. 63 / 923,787, filed November 24, 2025, each of which is incorporated herein in their entirety for all purposes.BACKGROUND

[0002] Over 10 million intravitreal injections are administered annually in the United States alone to treat retinal diseases. Intravitreal injections have become the primary method for delivering treatments to the posterior segment of the eye for various retinal diseases, including macular edema following retinal vein occlusion (MEfRVO), diabetic retinopathy, uveitis, cystoid macular edema, and age-related macular degeneration. This treatment approach, while effective, presents significant challenges. In one example, injection treatment regimens are burdensome, requiring patients to travel to their clinician for injections once or twice a month. Treatment also comes with a high financial cost. While the average eye injection dose costs around $1,000, some treatments can cost up to $10,000 per injection. Additionally, patient apprehension associated with the invasiveness of the procedure undermines long-term patient adherence and treatment outcomes. In patients receiving intravitreal injections for retinal diseases, topical corticosteroids can be administered as adjunctive therapy to provide additional anti-inflammatory effects. However, the effectiveness of current topical formulations is undercut by disruptive side effects and frequent dosing requirements. Accordingly, there exists a need to provide improved ophthalmic formulations, such as pharmaceutical compositions suitable for topical delivery the eye.SUMMARY OF THE DISCLOSURE

[0003] The present disclosure provides compositions and methods for treating ocular disorders characterized by decreased vision, pain, inflammation, and swelling, such as retinal edema, macular edema following retinal vein occlusion (MEfRVO), diabetic retinopathy, uveitis, cystoid macular edema, central serous retinopathy, and macular degeneration.

[0004] In embodiments, the present disclosure provides a topical ophthalmic composition, comprising: a therapeutically effective amount of a corticosteroid and a therapeutically effective amount of an intraocular pressure lowering agent. In embodiments, the compositionAtty. Docket No.: PLXB-001 / 03WOcomprises micelles, nanomicelles, nanocrystals, a nanoemulsion, nanoliposomes, a nanosuspension, or lipid nanoparticles.

[0005] In embodiments, ophthalmic administration of the composition to a patient in need thereof provides a synergistic reduction in ocular tissue pH, intraocular pressure, retinal edema or ocular inflammation compared to the separate administration of the active agents.

[0006] In embodiments, ophthalmic administration of the composition to the patient in need thereof provides about 30 ng / mL to about 150 ng / mL of the corticosteroid and about 50 ng / mL to about 80 ng / mL of the intraocular-pressure lowering agent in the patient’s aqueous humor and / or retina. In embodiments, the ophthalmic administration of the composition to a patient in need thereof provides about 30 ng / mL to about 90 ng / mL of the corticosteroid and about 60 ng / mL to about 80 ng / mL of the intraocular-pressure lowering agent in the patient’s vitreous humor and / or retina.

[0007] In embodiments, once, twice or three times daily ophthalmic administration of the composition to a patient in need thereof provides a reduction in the patient’s intraocular pressure (IOP) of about 2 mmHg to about 30 mmHg.

[0008] In embodiments, the once, twice or three times daily ophthalmic administration of the composition to a patient in need thereof provides about a 15% to about 90% reduction in the frequency that the patient requires intravitreal injection of therapeutic agents compared to prior to the administration. In embodiments, the therapeutic agents comprise an injectable corticosteroid, anti-VEGF, anti-Ang2, anti-inflammasome, anti-complement, or tyrosine kinase inhibitor.

[0009] In embodiments, the viscosity of composition is about 2 cP to about 5 cP. In embodiments, the viscosity of the composition is about 400 cP to about 1500 cP.

[0010] In embodiments, the particle size of the nanoemulsion is about 90 nm to about 130 nm,

[0011] In embodiments, the corticosteroid comprises prednisolone, loteprednol, difluprednate, clobetasol, clobetasol propionate, or a mixture thereof. In embodiments, the composition comprises about 0,01 wt% to 0.20 wt% of difluprednate. In embodiments, the intraocular-pressure lowering agent is dorzolamide, brinzolamide or a combination thereof. In embodiments, the intraocular-pressure lowering agent is a salt of dorzolamide, brinzolamide or a combination thereof.

[0012] In embodiments, the composition comprises about 0.01 wt% to about 2.0 wt% of the intraocular-pressure lowering agent. In embodiments, the composition comprises about 0.05 wt% of difluprednate and about 1 wt% of brinzolamide.Atty. Docket No.: PLXB-001 / 03WO

[0013] In embodiments, the composition further comprises one or more of 0.001 wt% to 0.005 wt% of edetate disodium, 0.004 wt% to 0.008 wt% of benzalkonium chloride and a surfactant.

[0014] In embodiments, the composition comprises about 0.02% to 0.04% wt / vol of difluprednate, about 0.5 %- 1.5% wt / vol of brinzolamide or dorzolamide, about 0.0002%-0.08% wt / vol of a quaternary ammonium compound, about 1.5%-6% wt / vol of polyethoxylated castor oil and about 0, l%-5% of polyvinyl alcohol or a derivative thereof in water.

[0015] In embodiments, the composition further comprises a Apisolex™ Polymer (a poly¬ amino acid based amphiphilic polymer).

[0016] In embodiments, the present disclosure provides a method of treating or preventing one or more of decreased vision, ocular pain, retinal hemorrhage, retinal neovascularization, drusen, atrophy, retinal inflammation, subretinal fluid, and retinal edema in a patient in need thereof, the method comprising topically administering the composition of any one of claims 1-17 to the patient.

[0017] In embodiments, the composition is administered once per day. In embodiments, the method of claim 18, wherein the composition is administered twice per day. in embodiments, the composition is administered three times per day. In embodiments, the composition is administered four times per day. In embodiments, the administration provides about 30 ng / mL to about 150 ng / mL of the corticosteroid and about 50 to about 80 ng / ml of the intraocular pressure lowering agent in the patient’s aqueous humor and / or retina. In embodiments, the administration provides about 30 ng / ml, to about 90 ng / ml, of the corticosteroid and about 60 ng / mL to about 80 ng / mL intraocular pressure lowering agent in the patient’s vitreous humor and / or retina.

[0018] In embodiments, the administration provides a reduction in the patient’s IOP of about 2 mm Hg to about 30 mm Hg. In embodiments, the administration provides a reduction of about 15% to about 90% in the frequency that the patient requires intravitreal injections of a therapeutic agent compared to prior to the administration.

[0019] In embodiments, the present disclosure provides a method of acidifying ocular tissues with a carbonic anhydrase inhibitor in order to improve stability of the steroid molecule in ocular tissues, steroid receptor activation and steroid binding, preferential delivery of steroid to the retina, decreased washout of the steroid through tire aqueous humor, and reduced levels of steroid in the aqueous humor, to improve duration and efficacy of a steroid when given in combination with the carbonic anhydrase inhibitor, the method comprising administering a therapeutically effective amount of a composition of the present disclosure.Atty. Docket No.: PLXB-001 / 03WOBRIEF DESCRIPTION OF THE DRAWINGS

[0020] FIG. 1 shows retina scans of macular edema following retinal vein occlusion MEfRVO patients treated -with an exemplary' coadministration regimen involving a corticosteroid and a carbonic anhydrase inhibitor.

[0021] FIG. 2 shows brinzolamide plasma concentrations following administration of exemplary' formulations of the present disclosure.

[0022] FIG. 3 show s. brinzolamide aqueous humor concentrations following administration of exemplary formulations of the present disclosure.

[0023] FIG. 4 shows brinzolamide cornea concentrations following administration of exemplary formulations of the present disclosure.

[0024] FIG.5 show s brinzolamide bulbar conjunctiva concentrations following administration of exemplary formulations of the present disclosure.

[0025] FIG. 6 show's brinzolamide palpebral conjunctiva concentrations following administration exemplary formulations of the present disclosure.

[0026] FIG. 7 shows brinzolamide retina concentrations following administration of exemplary formulations of the present disclosure.

[0027] FIG. 8 shows 21-descacetyl difluprednate plasma concentrations following administration of exemplary formulations of the present disclosure.

[0028] FIG. 9 shoyvs 21-descacetyl difluprednate aqueous humor concentrations following administration of exemplary formulations of the present disclosure.

[0029] FIG. 10 show's 21-descacetyl difluprednate cornea concentrations following administration of exemplary formulations of the present disclosure.

[0030] FIG. 11 shows 21-descacetyl difluprednate bulbar conjunctiva concentrations folloyving administration of exemplar}' formulations of the present disclosure.

[0031] FIG. 12 shoyvs 21-descacetyl difluprednate palpebral conjunctiva concentrations following administration of exemplary formulations of the present disclosure.

[0032] FIG. 13 shows 21-descacetyl difluprednate retina concentrations following administration of exemplary formulations of the present disclosure.

[0033] FIG. 14 show s brinzolamide matrix concentrations for Group 1 from Example 5.

[0034] FIG. 15 show's brinzolamide matrix concentrations for Group 2 from Example 5.

[0035] FIG. 16 shows brinzolamide matrix concentrations for Group 3 from Example 5.

[0036] FIG. 17 shows brinzolamide matrix concentrations for Group 4 from Example 5.

[0037] FIG. 18 shows brinzolamide matrix concentrations for Group 5 from Example 5.Atty. Docket No.: PLXB-001 / 03WO

[0038] FIG. 19 shows 21 -desacetyl difluprednate matrix concentrations for Group 1 from Example 5.

[0039] FIG. 20 shows 21 -desacetyl difluprednate matrix concentrations for Group 2 from Example 5.

[0040] FIG. 21 shows 21 -desacetyl difluprednate matrix concentrations for Group 3 from Example 5.

[0041] FIG. 22 shows 21 -desacetyl difluprednate matrix concentrations for Group 4 from Example 5.

[0042] FIG. 23 shows 21 -desacetyl difluprednate matrix concentrations for Group 5 from Example 5.

[0043] FIG. 24A shows a fluorescein angiogram of the retina of a patient with nonproliferative diabetic retinopathy before and after treatment with formulations of the present disclosure, FIG. 24B shows an expanded view with boxes highlighting changes in microaneurysms (white dots) and areas of poor perfusion (dark blotches).

[0044] FIG. 25 shows a fluorescein angiogram of the retina of a patient with non-proliferative diabetic retinopathy before and after treatment with formulations of the present disclosure.

[0045] FIG. 26 show s a photograph of the retina of a patient with non-proliferative diabetic retinopathy before and after treatment with formulations of the present disclosure.

[0046] FIG. 27 shows a fluorescein angiogram of the retina of a patient with non-proliferative diabetic retinopathy before and after treatment with formulations of the present disclosure.

[0047] FIG. 28 show's a photograph of the retina of a patient w ith non-proliferative diabetic retinopathy before and after treatment w ith formulations of the present disclosure.

[0048] FIG 29A shows a fluorescein angiogram of the retina of a patient with proliferative diabetic retinopathy before and after treatment with formulations of the present disclosure. FIG. 29B shows an expanded view' with boxes highlighting changes in neovascularization and fluid leakage.

[0049] FIG. 30 shows a photograph of the retina of a patient with proliferative diabetic retinopathy before and after treatment with formulations of the present disclosure.

[0050] FIG. 31 shows a photograph of the retina of a patient with proliferative diabetic retinopathy before and after treatment with formulations of the present disclosure.

[0051] FIG. 32 shows a photograph of the retina of a patient with proliferative diabetic retinopathy before and after treatment with formulations of the present disclosure.Atty. Docket No.: PLXB-001 / 03WO

[0052] FIG. 33A shows a photograph of the retina of a patient with proliferative diabetic retinopathy before and after treatment with formulations of tire present disclosure. FIG. 33B shows an expanded view showing changes in neovascularization and fluid leakage.

[0053] FIG. 34 shows a photograph of the retina of a patient with proliferative diabetic retinopathy before and after treatment with formulations of the present disclosure.

[0054] FIG. 35 shows optical coherence tomography results for a patient with proliferative diabe tic retinopathy (PDR) and diabetic macular edema (DME), before and after treatmen t with formulations of the present disclosure.

[0055] FIG. 36 shows optical coherence tomography results for a patient with central serous retinopathy (CSR). before and after treatment with formulations of the present disclosure, and after stopping treatment with formulations of the present disclosure.

[0056] FIG. 37 shows optical coherence tomography results for a patient with epiretinal membrane (ERM) and diabetic macular edema (DME), before and after treatment with formulations of the present disclosure.

[0057] Fig. 38A and 38B shows optical coherence tomography results for a patient with diabetic macular edema (DME) and cystoid macular edema (CME).DETAILED DESCRIPTIONDefinitions

[0058] Throughout this disclosure, various patents, patent applications and publications (including non-patent publications) are referenced. The disclosures of these patents, patent applications and publications in their entireties are incorporated into this disclosure by reference for all purposes in order to more fully describe the state of the art as known to those skilled therein as of the date of this disclosure. This disclosure will govern in the instance that there is any inconsistency between the patents, patent applications and publications cited and this disclosure.

[0059] For convenience, certain terms employed in the specification, examples and claims are collected here. Unless defined otherwise, all technical and scientific terms used in this disclosure have the same meanings as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0060] Hie term “about” when immediately preceding a numerical value means a range (e.g., plus or minus 10% of that value). For example, “about 50” can mean 45 to 55, “about 25,000”Atty. Docket No.: PLXB-001 / 03WOcan mean 22,500 to 27,500, etc., unless the context of the disclosure indicates otherwise, or is inconsistent with such an interpretation. For example, in a list of numerical values such as “about 49, about 50, about 55,...”, “about 50” means a range extending to less than half the interval(s) between the preceding and subsequent values, e.g., more than 49.5 to less than 52.5. Furthermore, the phrases “less than about” a value or “greater than about” a value should be understood in view of the definition of the term “about” provided herein. Similarly, the term “about” when preceding a series of numerical values or a range of values (e.g., “about 10, 20, 30” or “about 10-30”) refers, respectively to all values in the series, or the endpoints of the range.

[0061] Tire term “effective amount” or “therapeutically effective amount” as used interchangeably in this disclosure and refer to an amount of a compound, or a salt thereof, (or pharmaceutical composition containing the compound or salt) that, when administered to a patient, is capable of performing the intended result,

[0062] The terms “treating” as used herein with regard to a patient, refers to improving at least one symptom of the patient's disorder. Treating can be improving, or at least partially ameliorating a disorder or an associated symptom of a disorder.Ophthalmic Pharmaceutical Compositions

[0063] In aspects, provided herein are pharmaceutical compositions, such as ophthalmic pharmaceutical compositions, comprising a combination of active agents. In embodiments, the compositions of the present disclosure comprise each agent in the combination in a therapeutically effective amount. Representative therapeutic aims of the combination include reductions in ocular tissue pH, intraocular pressure (1OP), retinal edema, ocular inflammation, and neovascularization. In embodiments, the pharmaceutical composition is a topical ophthalmic composition, such as a composition suitable for topical delivery to the surface of the eye of a subject, such as a patient in need thereof.

[0064] In embodiments, the mixture of active agents comprises an anti-inflammatory agent and an eye pressure lowering agent, such as an intraocular-pressure (TOP) lowering agent, In embodiments, the compositions of the present disclosure comprise a glucocorticoid receptor agonist (GRA) and an IOP lowering agent.Glucocorticoid Receptor Agonists (GRAs)

[0065] Ocular glucocorticoid receptor agonists are potent anti-inflammatory agents used to treat various ocular inflammatory conditions. They exert their effects by binding to and activating the glucocorticoid receptor (GR), leading to both transactivation and transrepression of genes involved in inflammation. See, e.g., Yorio et al., Expert Rev Ophthalmol. 2020 MayAtty. Docket No.: PLXB-001 / 03WO14; 15(3): 145-157 and Patel et al., Cells. 2023 Oct 14;12(20):2452. Methods for determining agonism at the glucocorticoid receptor are available to one of skill in the art, e.g., through use of reporter assays and translocation assays that assess nuclear translocation of the GR.

[0066] In embodiments, the GRA in the compositions of the present disclosure has a binding affinity (Kd) to the GR receptor of at least about 3.0 x 10'9mol / L, about 6.0 x 10‘9mol / L, about 9.0 x 10'9mol / L, about 3,0 x J0‘10mol / L, about 6.0 x l0"!umol / L, about 9.0 x 10'10mol / L, about 3.0 x 10"11mol / L, about 6.0 x 10’11mol / L, or about 9.0 x 1 O’11mol / L, including all ranges and subranges therebetween. Binding affinity is typically quantified using the equilibrium dissociation constant (Kd), where a lower Kd indicates higher affinity for the receptor. Various in vitro assays are established and widely recognized in the field for determining these binding affinities. For example, binding affinity can be determined with use of a ligand binding competition assay, which measures the ability of a test compound to compete with a known ligand for binding to the GR.

[0067] In embodiments, the glucocorticoid receptor agonist is a corticosteroid. Corticosteroids are anti-inflammatory agents that stabilize the blood-retinal barrier and inhibit inflammatory mediators that contribute to macular edema. See, e.g., Fung et al., Clin Exp Ophthalmol. 2020 Jan 22;48(3):366-401 and Gabros et al. Topical Corticosteroids. [Updated 2023 Jul 10], In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https: / / www.ncbi.nlm.nih.gov / books / NBK532940 / . In embodiments, the compositions of the present disclosure comprise clobetasol, dexamethasone, difluprednate, fluoromethoIone, loteprednol, prednisolone, or triamcinolone acetonide, or a mixture thereof. In embodiments, the compositions of the present disclosure comprise difluprednate.

[0068] In embodiments, the compositions of the present disclosure comprise a glucocorticoid receptor agonist, such as a corticosteroid, in an amount ranging from about 0,001% to about 0.01% (w / w), about 0.005% to about 0.05% (w / w), about 0.001% to about 0.1% (w / w), about 0.01% to about 0.2% (w / w), about 0.05% to about 0.1% (w / w), about 0.025% to about 0.075% (w / w), about 0.01% to about 0.08% (w / w), about 0.03% to about 0.09% (w / w), about 0.007% to about 1.35% (w / w), and about 0.045% to about 0.09% (w / w). In embodiments, the compositions of the present disclosure comprise about 0.01% to about 0.2% (w / w) difluprednate.

[0069] In embodiments, the compositions of the present disclosure comprise a glucocorticoid receptor agonist, such as a corticosteroid, in an amount of about 0.001% (w / w), about 0.002% (w / w), about 0.003% (w / w ), about 0.004% (w / w ), about 0.005% (w / w), about 0.006% (w / w), about 0.007% (w / w), about 0.008% (w / w), about 0.009% (w / w), about 0.01% (w / w), aboutAtty. Docket No.: PLXB-001 / 03WO0.015% (w / w), about 0.02% (w / w), about 0.025% (w / w), about 0.03% (w / w), about 0.035% (w / w), about 0.04% (w / w), about 0.045% (w / w), about 0.05% (w / w), about 0.055% (w / w), about 0.06% (w / w), about 0.065% (w / w), about 0.07% (w / w), about 0.075% (w / w), about 0.08% (w / w), about 0.085% (w / w), about 0.09% (w / w), about 0.095% (w / w), about 0.1% (w / w), about 0.15% (w / w), about 0.2% (w / w), about 0.25% (w / w), about 0.3% (w / w), about 0.35% (w / w), about 0,4% (w / w), about 0.45% (w / w), about 0.5% (w / w), about 0.55% (w / w), about 0.6% (w / w), about 0.65% (w / w ), about 0.7% (w / w), about 0.75% (w / w), about 0.8% (w / w), about 0.85% (w / w), about 0.9% (w / w), and about 0.95% (w / w) or about 1% (w / w), including all ranges and subranges therebetween.

[0070] In embodiments, the compositions of tire present disclosure comprise about 0.35% (w / w), about 0.4% (w / w), about 0.45% (w / w), about 0.5% (w / w), about 0.55% (w / w), about 0.6% (w / w), or about 0.65% (w / w) difluprednate.

[0071] Along with their therapeutic effects, corticosteroids can produce a number of adverse side effects, including cataract formation, increased susceptibility to microbial infection, delayed wound healing, and elevation of I0P. See, e.g., Sheppard et al., Adv Ther. 2016 Mar 17;33(4): 532— 552. In one illustrative example, the corticosteroid difluprednate can be used to manage inflammation in various ocular conditions. However, it carries a risk of increasing intraocular pressure (IOP), which can lead to significant complications. The mechanism behind this undesirable side effect involves the drug's action on the trabecular meshwork, where it may hinder aqueous humor outflow, resulting in elevated IOP, This elevation can be particularly concerning as sustained high IOP is a major risk factor for optic nerve damage, potentially leading to glaucoma and irreversible vision loss. See, e.g., Meehan et al., Optometry. 2010 Dec;81(12):658-62.

[0072] In embodiments, the compositions of the present disclosure provide the advantage of mitigating dose-related adverse effects of corticosteroids. For example, by combining an IOP lowering agent and a corticosteroid in the same composition or dosing regimen, it is possible to use a higher dose of the corticosteroid than would be possible with use of the corticosteroid alone.

[0073] Corticosteroids present several formulation challenges for ophthalmic delivery, including poor aqueous solubility, limited bioavailability, and rapid clearance. Many corticosteroids have low water solubility, requiring formulation as suspensions or use of solubility-enhancing techniques. See, e.g., Salinger et al., Am JManag Care. 2019 Jul;25(12 Suppl): S215-S226.Atty. Docket No.: PLXB-001 / 03WO

[0074] Certain carbonic anhydrase inhibitors also present formulation challenges. For example, brinzolamide is poorly soluble near physiological pH. Acidic pH improves brinzolamide solubility, but is improper for direct administration to most tissues without improved formulations.

[0075] In embodiments, the compositions of the present disclosure are formulated such that the corticosteroid agent is comprised as a suspension. In embodiments, the compositions of the present disclosure are formulated such that the corticosteroid agent is comprised as an emulsion, including but not limited to a nanoemulsion. Suspensions, dispersions of solid particles that are not soluble in a liquid medium, and emulsions, mixtures of two immiscible liquids with one liquid dispersed as droplets within the other, of corticosteroids, are described among other formulation strategies by, e.g., WO 1998 / 030221 Al, WO 2012 / 073856 Al, WO 2014 / 126267 Al, and WO 2021 / 224902 A2.

[0076] In embodiments, the glucocorticoid receptor agonist, such as a corticosteroid, is formulated in a solubility-enhancing excipient. In embodiments, the solubility-enhancing excipient comprises any of amphiphilic block copolymers, co-sol vents, cyclodextrin inclusion complexes, nanoparticle formulations, solid dispersions. Amphiphilic block copolymers are composed of hydrophilic and hydrophobic blocks that can spontaneously self-assemble in aqueous environments to form micelles. The hydrophobic segments aggregate to form the core, while the hydrophilic segments extend outward into the surrounding water, creating a stable structure that encapsulates poorly soluble drugs within the hydrophobic core.

[0077] In embodiments, the glucocorticoid receptor agonist is solubilized in a solubilityenhancing copolymer, such as an amphiphilic block copolymer. In embodiments, the block copolymer is a diblock copolymer designed to improve the solubility and bioavailability of poorly soluble active pharmaceutical ingredients (APIs). In embodiments, the block copolymer comprises a plurality of amino acid groups, which contribute to its biocompatibility and biodegradability. In embodiments, the block copolymer has two distinct blocks: a hydrophilic block and a hydrophobic block. In embodiments, the block copolymer comprises hydrophilic poly(sarcosine) functional groups, which provide enhanced solubility in aqueous environments and serve as a non-toxic, non-immunogenic alternative to traditional solubilizers such as polyethylene glycol (PEG). In embodiments, the block copolymer also comprises a hydrophobic D, L-mixed poly(amino acid) groups that form the hydrophobic core of the copolymer. Suitable solubility-enhancing copolymers are described, e.g., by US10836869B1, US20210214496A1, US20210213132A1, WO2021141603A1, WO2021141605A1, and US16 / 740,211, and US10918619B1.Atty. Docket No.: PLXB-001 / 03WOIntraocular-Pressure Lowering Agents (lOP-Lowering Agents)

[0078] lOP-lowering agents may also be known, recognized, or referred to in the art as antiglaucoma drugs, ocular antihypertensive agents, ocular hypotensive drugs, or ophthalmic pressure-reducing medications.

[0079] In embodiments, the IOP lowering agent is capa ble of reducing the intraocular pressure of a subject’s eye by at least or about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50%. In embodiments, the eye pressure lowering agent is capable of reducing the intraocular pressure of a subject’s eye by about 15% to about 20%, about 20% to about 25%, about 20% to about 30%, about 25 % to about 35%, or about 35% to about 55%, including all ranges and subranges therebetween.

[0080] The extent of a reduction in IOP is typically assessed using tonometry methods, such as Goldmann applanation tonometry (GAT). Pressure reduction can be determined by comparing the baseline IOP to the IOP achieved after treatment, often expressed as a percentage decrease from the initial measurement. See, e.g., Bader et al. Tonometry. [Updated 2023 Dec 12]. In: StatPearls [Internet], Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https: / / www.ncbi.nlm.nih.gov / books / NBK493225 / .

[0081] Non-limiting examples of IOP lowering agents include prostaglandin analogs, [3-adrenergic blocking agents, a-adrenergic agonists, miotic (parasympathomimetic) agents, carbonic anhydrase inhibitors, and rho-kinase inhibitors. Across therapeutic classes, each 1OP-lowering agent is capable of reducing intraocular pressure through distinct mechanisms. For example, carbonic anhydrase inhibitors, e.g., dorzolamide, brinzolamide, suppress aqueous humor production by inhibiting activity of the carbonic anhydrase enzyme, thereby reducing bicarbonate ion formation and fluid transport. See, e.g., Aslam & Gupta. Carbonic Anhydrase Inhibitors. [Updated 2023 Apr 17], In: StatPearls [Internet], Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https: / / www.ncbi.nlm.nih.gov / books / NBK557736 / .

[0082] Representative members of the prostaglandin analog class of IOP lowering agents include latanoprost, bimatoprost, travoprost, tafluprost, and unoprostone. TOP lowering [3-adrenergic blocking agents include timolol, betaxolol, levobunolol, carteolol, and metipranolol. Brimonidine and apraclonidine are alpha-adrenergic agonists used for lowering IOP. Miotic (parasympathomimetic) agents used as lOP-lowering medications include pilocarpine, echothiophate iodide, carbachol, acetylcholine. lOP-lowering carbonic anhydrase inhibitors include acetazolamide, brinzolamide, dichlorphenamide, dorzolamide, ethoxzolamide, and methazolamide. Examples of lOP-lowering rho-kinase inhibitors include netarsudil (AR-13324), ripasudil (K-115), AR-12286, SNJ-1656 (Y-39983), fasudil (HA-1077), H-1152,Atty. Docket No.: PLXB-001 / 03WOAMA-0076, in embodiments, the compositions of the present disclosure comprise brinzolamide. In embodiments, the compositions of the present disclosure comprise dorzolamide.

[0083] In embodiments, the compositions of the present disclosure comprise an IOP lowering agent in an amount ranging from about 0.01% to about 2% (w / w), about 0.02% to about 1% (w / w), about 0.03% to about 1.5% (w / w), about 0.02% to about 2% (w / w), about 0,5% to about 2% (w / w), about 0.5% to about 3% (w / w), about 0.75% to about 3.5% (w / w), about 0.8% to about 3.8% (w / w ). about 1% to about 5% (w / w), about 3.5% to about 5% (w / w ), about 3% to about 5% (w / w), about 0.5% to about 3.2% (w / w), about 1.2% to about 4.7% (w7w), about 0.8% to about 4.1% (w / w), about 1.7% to about 3.9% (w / w), or about 0.4% to about 4.5% (wAv).

[0084] In embodiments, the compositions of the present disclosure comprise about 0.5% to about 2% (w / w) brinzolamide. In embodiments, the compositions of the present disclosure comprise about 0.5% to about 2% (w / w ) dorzolamide.

[0085] In embodiments, the compositions of the present disclosure comprise an IOP low ering agent in an amount of about 0.01% (w / w), about 0.02% (w / w), about 0.03% (w / w), about 0.04% (w / w), about 0.05% (w / w), about 0,06% (w / w), about 0.07% (w / w), about 0,08% (w / w), about 0.09% (wAv), about 0,1% (w / w ). about 0.2% (w'Av), about 0.3% (wAv), about 0,4% (w7w), about 0.5% (w / w), about 0.6% (w / w), about 0.7% (w / w), about 0.8% (wAv), about 0.9% (w7w), about 1% (w7w), about 1.1% (wAv), about 1.2% (w / w), about 1.3% (w / w), about 1.4% (w / w I. about 1.5% (w / w), about 1.6% (w / w ). about 1.7% (w / w ). about 1.8% (w / w), about 1.9% (w / w ), about 2% (w / w), about 2.1% (w / w), about 2.2% (w / w), about 2.3% (wAv), about 2.4% (w / w), about 2.5% (w / w), about 2.6% (wAv), about 2.7% (w / w), about 2.8% (w / w), about 2.9% (w / w), about 3% (w / w), about 3.1% (w / w ). about 3,2% (w / w), about 3,3% (w7w), about 3.4% (w / w), about 3,5% (w / w ). about 3.6% (w / w), about 3.7% (w / w). about 3.8% (w / w ). about 3.9% (wAv), about 4% (wAv), about 4.1% (w / w), about 4.2% (w / w ). about 4.3% (w / w), about 4.4% (w,7w), about 4.5% (w / w), about 4.6% (w / w), about 4.7% (w / w), about 4.8% (w / w), and about 4.9% (w / w) or about 5% (w / w ). including all ranges and subranges therebetween.

[0086] In embodiments, the compositions of the present disclosure comprise about 0.5% (w / w), about 0.6% (w / w), about 0.7% (w / w), about 0.8% (w / w), about 0.9% (w / w), about 1% (w / w), about 1,1% (w / w), about 1.2% (w / w), about 1.3% (w7w), about 1.4% (w / w ). or about 1.5% (w / w ) brinzolamide. In embodiments, the compositions of the present disclosure comprise about 0.5% (w / w ). about 0.6% (w / w), about 0.7% (w / w), about 0.8% (w / w), aboutAtty. Docket No.: PLXB-001 / 03WO0.9% (w / w), about 1% (w / w), about 1.1% (w / w), about 1.2% (w / w), about 1.3% (w / w), about 1.4% (w / w), or about 1.5% (w / w) dorzolamide.

[0087] In embodiments, the compositions of the present disclosure comprise a glucocorticoid receptor agonist and any of a prostaglandin analog, a p-adrenergic blocking agent, an a-adrenergic agonist, a miotic (parasympathomimetic) agent, a carbonic anhydrase inhibitor, a rho-kinase inhibitor, or a combination thereof.

[0088] In embodiments, the compositions of the present disclosure comprise a corticosteroid and any of a prostaglandin analog, a p-adrenergic blocking agent, an a-adrenergic agonist, a miotic (parasympathomimetic) agent, a carbonic anhydrase inhibitor, a rho-kinase inhibitor, or a combination thereof.

[0089] In embodiments, compositions of the present disclosure comprise a glucocorticoid receptor agonist, such as a corticosteroid, and a carbonic anhydrase inhibitor. In embodiments, the corticosteroid comprises a derivative of prednisolone. In embodiments, the corticosteroid comprises a prodrug of 6a,9-difluoroprednisolone 17-butyrate (DFB). In embodiments, the corticosteroid comprises difluprednate. In embodiments, the corticosteroid comprises clobetasol or a derivative thereof. One representative derivative of clobetasol is clobetasol propionate, the 17-propionate ester of clobetasol,

[0090] In embodiments, the composition of the present disclosure comprises a glucocorticoid receptor agonist, such as a corticosteroid, and a carbonic anhydrase inhibitor, the carbonic anhydrase inhibitor can be a sulfonamide derivative. In embodiments, the sulfonamide derivative comprises dorzolamide. In other embodiments, the sulfonamide derivative comprises brinzolamide. In general, the current disclosure is not limited to specific agents but rather should be understood to include therapeutically relevant prodrugs and derivatives thereof. Prodrug strategies for ocular drug delivery’ are described, e.g., by Barot et al,, Afe Chem. 2012 Jul;8(4):753-768, with brinzolamide prodrugs described by Ikuta et al., Sci Rep.2017 Mar 14:7:44229 and WO2013088255A1.

[0091] In clinical practice, Applicant observed that standalone therapy with either a carbonic anhydrase inhibitor or a corticosteroid provided little to no benefit to patients suffering from macular edema. However, combining the two agents substantially and consistently reduced or even resolved the occurrence of edema, indicating a synergistic therapeutic effect.

[0092] Several factors influence the stability and efficacy of corticosteroids when applied topically to the eye, including pH susceptibility. Without dedication to any particular theory, by acidifying the tear film, the carbonic anhydrase inhibitor may facilitate an environment that favors corticosteroid stability, thereby enhancing therapeutic activity, such as antiAtty. Docket No.: PLXB-001 / 03WOinflammatory effects. Improved stability may enhance penetration of the corticosteroid past the cornea, through the vitreous and into the retina.

[0093] Tire use of a topical carbonic anhydrase inhibitor, e.g., dorzolamide or brinzolamide, as the 1OP lowering agent in compositions of the present disclosure has multiple advantages. First, Applicant unexpectedly observed an enhanced and synergistic combinatory effect of using a topical carbonic anhydrase inhibitor with a corticosteroid on the reduction of macular edema. Second, topical delivery' of a carbonic anhydrase inhibitor in combination with a corticosteroid maximizes reduction of macular edema while substantially lowering the risk of clinically significant IOP elevations. Third, in the combination of a corticosteroid with a carbonic anhydrase inhibitor, such as in a fixed dose combination, the carbonic anhydrase inhibitor enhances the efficacy of the corticosteroid by altering the pH and ionic environment, creating favorable conditions for steroid activity, such as by enhancing anti-inflammatory effects and increasing steroid stability.

[0094] Inhibition of carbonic anhydrase results in acidification within ocular tissues. Corticosteroids have been shown to work more effectively in slightly acidic environments due to increased resistance to breakdown of the steroid molecule itself, increased steroid receptor activation and changes in receptor conformation that favor steroid binding. Lowering the pH with a carbonic anhydrase inhibitor enhances corticosteroid receptor activation and signaling which improves steroid efficacy. Without dedication to any particular theory, decreasing the pH through carbonic anhydrase inhibition facilitates persistence of corticosteroid activity, allowing for prolonged and enhanced efficacy.

[0095] Furthermore, carbonic anhydrase inhibitors reduce immune cell activation, which causes inflammation and edema of the macula, by limiting cellular functions that are pH dependent, such as cell motility. By reducing bicarbonate and chloride ion transport, carbonic anhydrase inhibitors augment the anti-inflammatory effects of steroids by modifying immune cell sw elling, cellular migration and adhesion which slow s immune cell infiltration and reduces their activity, reducing inflammation and edema that accompany immune cell activity. These complementary mechanisms lead to a more profound and sustained anti-inflammatory response when carbonic anhydrase inhibitors are used in combination with steroids according to the compositions disclosed herein.Fixed-Dose Combination

[0096] In embodiments, compositions of the present disclosure comprise a glucocorticoid receptor agonist and an lOP-lowering agent in a fixed-dose combination (i.e., both activeAtty. Docket No.: PLXB-001 / 03WOingredients are present in the same composition). In embodiments, a fixed-dose combination of the present disclosure comprises the glucocorticoid receptor agonist and the lOP-lowering agent in a w / w ratio ranging from 50:1 to 1:50.

[0097] In embodiments, a fixed-dose combination of the present disclosure comprises the glucocorticoid receptor agonist and the lOP-lowering agent in a w / w ratio ranging from about 50: 1 to about 25:1, about 40:1 to about 20:1, about 50:1 to about 10:1, about 5:1 to about 1:5, about 3:1 to about 1:3, about 2:1 to about 1:2, about 1:25 to about 1:50, about 1:20 to about 1:40, about 1: 10 to about 1:50, about 15: 1 to about 1:15, about 30: 1 to about 1:10, about 8: 1 to about 1:25, about 20:1 to about 1:30, or about 1:1 to about 1:20.

[0098] In embodiments, a fixed-dose combination of the present disclosure comprises difluprednate and brinzolamide in a w / w ratio ranging from 25: 1 to 1:25. in embodiments, a fixed-dose combination of the present disclosure comprises difluprednate and dorzolamide in a w / w ratio ranging from 25: 1 to 1:25,

[0099] In embodiments, a fixed-dose combination of the present disclosure comprises a glucocorticoid receptor agonist and an lOP-lowering agent in a w / w ratio of about 50:1, about 45:1, about 40:1, about 35:1, about 30:1, about 25:1, about 20:1, about 15:1, about 10:1, or about 5:1. In embodiments, a fixed-dose combination of the present disclosure comprises a glucocorticoid receptor agonist and an lOP-lowering agent in a w / w ratio of about 1:5, about 1:10, about 1:15, about 1:20, about 1:25, about 1:30, about 1:35, about 1:40, about 1:45, or about 1:50.

[0100] In embodiments, a fixed-dose combination of the present disclosure comprises difluprednate and brinzolamide in a w / w ratio of about 1:15, about 1:20, about 1:25, or about 1:30. In embodiments, a fixed-dose combination of the present disclosure comprises difluprednate and dorzolamide in a w / w ratio of about 1: 15, about 1:20, about 1:25, or about 1:30.

[0101] In embodiments, a composition of the present disclosure is formulated to deliver about 30 ng / mL to about 150 ng / mL, about 30 ng / mL to about 90 ng / mL, about 30 ng / mL to about 50 ng / mL, about 30 ng / mL to about 60 ng / mL, about 40 ng / mL to about 70 ng / mL, about 50 ng / mL to about 90 ng / mL, about 60 ng / mL to about 100 ng / mL, about 70 ng / mL to about 110 ng / mL, about 90 ng / mL to about 150 ng / mL, about 100 ng / mL to about 140 ng / mL, or about 120 ng / mL to about 150 ng / mL of the corticosteroid to the patient’s aqueous humor and / or retina.

[0102] In embodiments, a composition of the present disclosure is formulated to deliver about 20 ng / mL to about 40 ng / mL, about 20 ng / mL to about 50 ng / mL, about 30 ng / mL to about 60Atty. Docket No.: PLXB-001 / 03WOng / mL, about 40 ng / mL to about 60 ng / mL, about 45 ng / mL to about 65 ng / mL, about 50 ng / mL to about 70 ng / mL, about 60 ng / mL to about 80 ng / mL, about 65 ng / mL to about 80 ng / mL, about 70 ng / mL to about 80 ng / mL, about 50 ng / mL to about 80 ng / mL, or about 60 ng / mL to about 80 ng / mL of the intraocular-pressure lowering agent to the patient’s aqueous humor and / or retina.

[0103] Administration of a composition of the present disclosure to a patient in need thereof, such as topical delivery to the eye of the subject, may provide several therapeutic advantages. Examples of such therapeutic advantages include but are not limited to a significant or a synergistic reduction in any of ocular surface pH, intraocular pressure, retinal edema, ocular inflammation, and neovascularization, including combinations thereof. In some examples, the significant or synergistic reduction is determined upon comparison to separate administration of the active agents, such as the corticosteroid and the IOP lowering agent.

[0104] In embodiments, compositions of the present disclosure comprise a pharmaceutically acceptable excipient, such as an ophthalmically acceptable carrier. Such excipients sen e any of a variety of functions, including, e.g., improving drug solubility, sustaining formulation stability, enhancing viscosity, maintaining pH, providing antimicrobial protection, and increasing ocular comfort,

[0105] Non-limiting examples of pharmaceutically acceptable excipients include antioxidants, astringents, buffers, chelating agents, co-solvents, crystal growth inhibitors, demulcents, diluents, dispersion media, emollients, emulsifiers, gelling agents, humectants, hypertonicity agents, isotonic agents, lubricants, mucoadhesive agents, nanoparticles, osmoprotectants, osmotic / tonicity-adjusting agents, pH regulators, polymers, preservatives, proteins, solubilizers, soothing agent, solvents, surfactants, suspension aids, surface active agents, thickening agents, and viscosity enhancers.

[0106] Additional pharmaceutically acceptable excipients include any of cellulose-derivatives, emollients, lubricants, waxes, fatty alcohols, silicone -based ingredients, and esters. Representative examples of suitable excipients include ascorbic acid, sodium metabisulfite, trehalose, erythritol, 1-camitine, glycerin, propylene glycol, cyclodextrins, polyethylene glycol, carboxymethylcellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, benzalkonium chloride (BAK), purite, polyvinyl alcohol, polyethoxylated castor oil, boric acid, sodium borate, sodium chloride, potassium chloride, polysorbate 20, polysorbate 80, white petrolatum, mineral oil, lanolin, quaternary ammonium compounds, beeswax, st-wax, cetyl alcohol, castor oil, oleic acid, jojoba seed oil, silky wax,Atty. Docket No.: PLXB-001 / 03WOcyclomethicone, caprylic / capric triglyceride, ethyl alcohol, olive oil, super-refined olive oil, and isopropyl myristate.

[0107] In embodiments, the cellulose-derivatives comprise hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, or hydroxypropyl methylcellulose.

[0108] Various carriers for formulating ophthalmic pharmaceutical compositions and techniques for preparing the composition described in the art. See, e.g,, Remington: The Science and Practice of Pharmacy, 22nd Edition, Edited by Allen, Loyd V., Jr, Pharmaceutical Press; incorporated herein by reference in its entirety.

[0109] In embodiments, the compositions of the present disclosure comprise a penetration enhancer. Penetration enhancing agents temporarily modify the tear film or corneal barrier to allow for enhanced drug absorption. In embodiments, the compositions of the present disclosure comprise cyclodextrins, chitosan, or a combination thereof.

[0110] In embodiments, the compositions of the present disclosure comprise a viscosity enhancer. Viscosity enhancing agents increase the thickness and stickiness of eye drops and thereby prolong their contact time with the eye, potentially improving absorption of the applied active agent. In embodiments, the compositions of the present disclosure comprise hyaluronic acid, cellulose derivatives, or a combination thereof.

[0111] In embodiments, the compositions of the present disclosure comprise one or more preservatives, such as a quaternary ammonium compound, e.g., benzalkonium chloride (BAK), benzododecinium bromide, cetrimide, cetrimonium bromide, or cetylpyridinium chloride, or a combination thereof, benzethonium chloride, benzyl alcohol, busan, chlorhexidine, chlorobutanol, mercurial preservatives, phenylmercuric nitrate, phenylmercuric acetate, thimerosal, phenylethyl alcohol, phenol, cresol, p-amino benzoic acid, BDSA, sorbitrate, sorbic acid, oxychloride compounds, polyhexamethylene biguanide, sodium perborate, and the like.

[0112] In embodiments, tire compositions of the present disclosure comprise about 0.004% to about 0.008% (wt / v%), about 0.003% to about 0.009% (wt / v%), about 0.0045% to about 0.0075% (wt / 'v%), about 0.002% to about 0.010% (wt / v%), about 0,0035% to about 0.0085% (wt / v%), about 0.0041% to about 0.0079% (wt / v%), about 0.0038% to about 0.0082% (wt / v%), about 0.0042% to about 0.0078% (wt / v%), about 0.0039% to about 0.0081% (wt / v%), about 0.0043% to about 0.0077% (wt / v%), or about 0.0036% to about 0.0084% (wt / v%) of a preservative,

[0113] In embodiments, the compositions of the present disclosure comprise about 0.004 to about 0.008% (wt / v%) of a quaternary ammonium compound. In embodiments, theAtty. Docket No.: PLXB-001 / 03WOcompositions of the present disclosure comprise about 0.004 to about 0.008% (wt / v%) benzalkonium chloride (BAK).

[0114] In embodiments, the compositions of the present disclosure are intended for long-term use in chronic conditions is formulated and packaged to minimize or eliminate the use of preservatives that may irritate the eye, such as a “preservative-free” composition. For example, the ophthalmic pharmaceutical composition may be packaged in a single-dose containers, or in a container utilizing alternative means for minimizing microbial contamination, such as membranes, valve mechanisms, or silver.

[0115] In embodiments, the compositions of the present disclosure comprise a chelating agent, a crystal growth inhibitor, an isotonic agent, a wetting agent, a buffer, a stabilizer, a solubilizer, a thickening agent, and / or a dispersing agent. These agents are available to those skilled in the ophthalmic art. See, e.g., WO 1998 / 030221 Al, W02013013143A1, WO 2014 / 126266 Al, WO 2021 / 034850 Al, WO 2021 / 224902 A2, and WO2023218472A1.

[0116] In embodiments, the compositions of the present disclosure comprise a chelating agent. The chelating agent can inhibit microbial growth, stabilize the formulation by binding to metal ions that could otherwise catalyze degradation reactions of active ingredients, enhance drug penetration, or protect against oxidative damage. In embodiments, the compositions of the present disclosure comprise ethylenediaminetetraacetic acid (EDTA), edetate disodium (disodium salt of EDTA) (e.g., Titriplex III), disodium edetate, sodium ED TA, or deferiprone, or a combination thereof.

[0117] In embodiments, the compositions of the present disclosure comprise about 0.001% to about 0.05% (w / v%), about 0.0005% to about 0.06% (w / v%), about 0.0003% to about 0.07% (w / v%), about 0.0002% to about 0.08% (w / v%), about 0.0001% to about 0.09% (w / v%), about 0.0006% to about 0.055% (w / v%), about 0.0004% to about 0,065% (w / v%), about 0.0002% to about 0.075% (w / v%), about 0.0007% to about 0.058% (w / v%), about 0.0003% to about 0.068% (w / v%), or about 0.0001% to about 0.085% (w / v%) of an anionic surfactant.

[0118] In embodiments, the compositions of the present disclosure comprise about 0,001% to about 0.05% (w / v%) of edetate disodium.

[0119] In embodiments, the compositions of the present disclosure comprise a crystal growth inhibitor. Crystal growth inhibitors can be included to enhance stability, e.g., by preventing the formation and growth of drug crystals during storage, maintain efficacy, improve API solubility, prevent irritation, or control particle size. In embodiments, tire compositions of the present disclosure comprise polyvinyl alcohol (PVA) and derivatives thereof, povidoneAtty. Docket No.: PLXB-001 / 03WO(polyvinylpyrrolidone), copovidone, and cellulose derivatives, e.g., hydroxypropyl methylcellulose (HPMC) or carboxymethylcellulose (CMC), or a mixture thereof.

[0120] In embodiments, the compositions of the present disclosure comprise about 0.1% to about 5.0% (w / v%), about 0.05% to about 6.0% (w / v%), about 0.02% to about 7.0% (w / v%), about 0.08% to about 5.5%about 0.01% to about 6.5% (w / v%), about 0.03% to about 5.8% (w / v%), about 0.06% to about 6,2% (w / v%), about 0.04% to about 5.7% (w / v%), about 0.07% to about 6.3% (w / v%), about 0.01% to about 7.5% (w / v%), or about 0.03% to about 6.8% (w / v%) of a crystal growth inhibitor.

[0121] In embodiments, the compositions of the present disclosure comprise about 0.1 to about 5.0% (w / v%) of polyvinyl alcohol (PVA) or a derivative thereof.

[0122] In embodiments, the compositions of the present disclosure comprise an osmotic / tonicity-adjusting agent. An agent of this kind may maintain isotonicity of the composition with respect to the ophthalmic fluids present in the human eye and adjust osmolarity to a suitable level, such as between 200 to 400 mOsmol / L. In embodiments, the compositions of the present disclosure comprise glycerin, mannitol, sorbitol, sodium chloride, potassium chloride, calcium chloride, sodium bromide, sodium phosphate sodium sulfate, mannitol, glycerol, sorbitol, propylene glycol, dextrose, sucrose, or polyethylene glycols (PEG, such as PEG 400 or PEG 8000), or a mixture thereof.

[0123] In embodiments, the compositions of the present disclosure comprise a wetting agent that reduces the surface tension of water or another liquid, causing the liquid to spread across or penetrate more easily the surface of a solid. In embodiments, compositions of the present disclosure comprise carboxymethylcellulose, hydroxypropyl methylcellulose, glycerin, mannitol, polyvinyl alcohol, or hydroxyethylcellulose, or a mixture thereof.

[0124] In embodiments, the compositions of the present disclosure compose a buffering agent. Buffering agents maintain the pH in the therapeutically useful range. Buffering agents used are those known to those skilled in the art, and, while not intending to be limiting, some examples are acetate, borate, carbonate, citrate, and phosphate buffers. In embodiments, the compositions comprise citrate buffer. In embodiments, the compositions comprise 5 mM to 20 mM citrate buffer, or 10 mM citrate buffer. In embodiments, the citrate buffer comprises sodium citrate and citric acid.

[0125] In embodiments, the compositions of the present disclosure have a pH suitable for deliver^' to the eye of a subject, such as a patient in need thereof. In embodiments, delivery of the composition to the patient involves topical delivery to the surface of the patient’s eye(s). In embodiments, the pH of the pharmaceutical composition ranges from about 6.5 to about 7.8,Atty. Docket No.: PLXB-001 / 03WOabout 6.5 to about 6.8, about 6.5 to about 7.0, about 6.7 to about 7.1, about 6.9 to about 7.3, about 7.0 to about 7.4, about 7.1 to about 7.5, about 7.3 to about 7.6, about 7.4 to about 7.7, or about 7.5 to about 7.8. In embodiments, the pH of the pharmaceutical composition is about pH 7, about pH 7.1, about pH 7.2, about pH 7.3, about pH 7.4, about pH 7.5, about pH 7.6, about pH 7.7, or about pH 7.8, including all ranges and subranges therebetween.

[0126] In embodiments, compositions of the present disclosure comprise a surfactant. In embodiments, the surfactant is anon-ionic surfactant. In embodiments, the compositions of the present disclosure comprise polysorbate 80, polysorbate 60, poloxamers polysorbate, 40, polysorbate 20 (Tween 20), polyethoxylated castor oil, e.g., Cremophors, tyloxapols, poloxamers (e.g., poloxamer 407 and / or poloxamer 188), P35 castor oil, benzalkonium chloride, benzethonium chloride, cetyl alcohol, carbomer, cholesterol, sodium deoxycholate, cocamidopropyl betaine, glyceryl monostearate, lanolin alcohols, lauralkonium chlorides, n lauroylsarcosine, nonoxynol 9, octoxynol 40, polyoxyl 35 castor oil (e.g., Koliiphor® EL), polyoxyl 40 hydrogenated castor oil, polyoxyl 40 stearate, sorbitan monolaurate, or sorbitan monooleate, egg lecithin (e.g., egg lecithin E80), phosphatidycholine, or a mixture thereof.

[0127] In embodiments, compositions of the present disclosure comprise about 1% to about 10%, about 1.5% to about 6.0% (w / v%), about 0.3% to about 7.2% (w / v%), about 0.4% to about 7.1% (w / v%), about 0.6% to about 6.9% (w / v%), about 0.2% to about 7.3% (w / v%), about 0.7% to about 6.8% (w / v%), about 0.1% to about 7.4% (w / v%), about 0.8% to about 6.7% (w / v%), about 0,9% to about 6.6% (w / v%), about 0.45% to about 7.05% (w / v%), or about 0.55% to about 6.95% (w / v%) of a non-ionic surfactant.

[0128] In embodiments, the compositions of the present disclosure comprise 1.5% to about 6.0% (w / v%) of poly ethoxylated castor oil.

[0129] In embodiments, the compositions of the present disclosure comprise an anionic surfactant or a salt thereof. In embodiments, the anionic surfactant comprises any of sarcosinates, lactylates, sulfates, sulfonates, or a combination thereof. In embodiments, the compositions of the present disclosure comprise sodium lauroyl sarcosinate, sodium oleoyl sarcosinate, sodium myristoyl sarcosinate, sodium cocoyl sarcosinate, sodium stearoyl sarcosinate, sodium pelargodoyl sarcosinate, sodium capryl lactylate, sodium lauryl sulfate, or sodium olefin sulfonates, or a mixture thereof.

[0130] In embodiments, the compositions of the present disclosure compri se about 0,03% to about 0.06% (w / v%), about 0.025% to about 0.065% (w / v%), about 0.028% to about 0.062% (w / v%), about 0.032% to about 0.058% (w / v%), about 0.027% to about 0.063% (w / v%), about 0.031% to about 0.059% (w / v%), about 0.029% to about 0.061% (w / v%), about 0.026% toAtty. Docket No.: PLXB-001 / 03WOabout 0.064% (w / v%), about 0.033% to about 0.057% (w / v%), or about 0.024% to about 0.066% (w / v%) of an anionic surfactant.

[0131] In embodiments, the compositions of the present disclosure comprise 0.03-0.06% (wt / v%) of a salt of M -lauroyl sarcosine.

[0132] In embodiments, the compositions of the present disclosure comprise a stabilizer. Representative stabilizers include sodium hydrogen sulphite, ethylenediaminetetraacetic acids, and the like. In embodiments, the compositions of the present disclosure comprise one or more solubilizers. Representative solubilizers include polysorbate (e.g., polysorbate 80), polyethylene glycol, propylene glycol, macrogol 4000, diethylene glycol monoethyl ether (Transcutol® P), PEG 400, PEG 8000, PVP-K30, PVP-K90, and the like. Additional examples of solubilizers include cyclodextrins. Cyclodextrins can be used enhance the solubility of poorly or insoluble drags. Representative cyclodextrins include hydroxypropyl-beta-cyclodextrin (HP-[3-CD), 2-hydroxypropyl-P-cyclodextrin, sulfobutylether-P-cyclodextrin (SBE-CD), -cyclodextrin, alpha cyclodextrin, and gamma cyclodextrin.

[0133] In embodiments, the compositions of the present disclosure comprise one or more thickeners that make the preparation of the present disclosure dense or viscous in consistency. Suitable thickeners include, for example, non-ionic water-soluble polymers, fatty alcohols, fatty acids, anionic polymers, and their alkali salts and mixtures thereof. In embodiments, the compositions of the present disclosure comprise one or more dispersing agents, e.g., poly(ethylene-glycol), polyethoxylated castor oil, alcohol having 12 to 20 carbon atoms, and their mixtures thereof.

[0134] In embodiments, the composition comprises a carbomer. In embodiments, the carbomer improves composition (e.g., emulsion or suspension) stability, and / or provides a preferred viscosity'. In embodiments, the carbomer is carboxypolymethylene. In embodiments, the carboxypolymethylene is highly cross-linked (e.g., Carbopol® 974P). In embodiments, the carboxypolymethylene is lightly cross-linked (e.g., Carbopol® 97 IP). The relative degree of cross-linking of a particular carboxypolymethylene may be determined by one skilled in the art. In embodiments, the carbomer comprises acrylic acid crosslinked with allyl sucrose or allyl pentaerythritol.

[0135] In embodiments, the composition comprises a polysaccharide. In embodiments, the polysaccharide is gellan gum, agar, or gellatin,

[0136] In embodiments, the composi tion has a viscosity of about 1 to about 25 cps, about 1 to about 50 cps, about 1 to about 75 cps, about 26 to about 75 cps, about 26 to about 100 cps, about 51 to about 100 cps, about 76 to about 100 cps, about 76 to about 125 cps, or about 101Atty. Docket No.: PLXB-001 / 03WOto about 125 cps. In embodiments, the pharmaceutical composition has a viscosity of about 1 cps, about 5 cps, about 10 cps, about 15 cps, about 20 cps, about 25 cps, about 30 cps, about 35 cps, about 40 cps, about 45 cps, about 50 cps, about 55 cps, about 60 cps, about 65 cps, about 70 cps, about 75 cps, about 80 cps, about 85 cps, about 90 cps, about 95 cps, about 100 cps, about 105 cps, about 110 cps, about 115 cps, about 120 cps, or about 125 cps, including all ranges and subranges therebetween.

[0137] In embodiments, the composition has a viscosity of about 200 to about 3000 cps, about 400 to about 3000 cps, about 600 to about 3000 cps, about 800 to about 3000 cps, about 1000 to about 3000 cps, about 1200 to about 3000 cps, about 500 to about 2600 cps, about 500 to about 2400 cps, about 500 to about 2000 cps, about 800 to about 1800 cps, about 1000 to about 1600 cps or about 1200 to about 1500 cps. In embodiments, the viscosity is measured at 20 rpm.

[0138] An ophthalmic composition according to this disclosure may be suitable for topical delivery to a subject's eye or tissue surrounding the eye. In embodiments, the ophthalmic composition improves bioavailability of at least one component, for example the IOP lowering agent, such as brinzolamide. A pharmaceutical composition according to this disclosure may be in the form of an eye drop formulation. Other forms of application to the eye may be possible. For example, an ophthalmic pharmaceutical according to this disclosure may be in the form of a suspension. In other examples, an ophthalmic pharmaceutical according to this disclosure may be in the form of an emulsion. In other examples, an ophthalmic pharmaceutical according to this disclosure may be in the form of a nanoemulsion. In embodiments, an ophthalmic pharmaceutical according to this disclosure may be in the form of a gel. In embodiments, an ophthalmic pharmaceutical according to this disclosure may be in the form of an in situ gel forming solution. In embodiments, an ophthalmic pharmaceutical according to this disclosure may be in the form of an eye ointment. In embodiments, an ophthalmic pharmaceutical according to this disclosure may be in the form of an injectable solution. In embodiments, an ophthalmic pharmaceutical according to this disclosure may be in the form of an eye spray.

[0139] In embodiments, the compositions of the present disclosure comprise a colloidal drug delivery system. Colloidal drug delivery systems involve encapsulating one or more active pharmaceutical ingredients (APIs) in nanoparticles or liposomes to improve stability and potentially enhance penetration through the cornea. In embodiments, delivering compositions of the present disclosure to a patient in need thereof comprises iontophoresis. Iontophoresis is a non-invasive technique that uses a low electrical current to deliver charged drags through theAtty. Docket No.: PLXB-001 / 03WOcornea. In embodiments, delivering compositions of the present disclosure to a patient in need thereof comprises a microneedle-based ocular drug delivery system. Such systems involve use of tiny microneedles that painlessly pierce the outer layer of the eye, thereby creating a pathway for drug delivery. See, e.g., Beilstein, J Nanotechnol. 2022 Oct 24; 13: 1167—1184.

[0140] In embodiments, the compositions of the present disclosure comprise a colloidal dispersion, such as a nanoemulsion. In embodiments, the nanoemulsion is characterized by the presence of finely dispersed droplets with a targeted particle size distribution. In embodiments, the particles within the nanoemulsion have an average diameter ranging from about 80 to about 120 nm, about 80 to about 140 nm, about 80 to about 160 nm, about 121 to about 160 nm, about 121 to about 180 nm, about 141 to about 180 nm, about 161 to about 200 nm, about 181 to about 200 nm, or about 160 to about 200 nm. in embodiments, the particles within the nanoemulsion have an average diameter of about 80 nm, about 85 nm, about 90 nm, about 95 nm, about 100 nm, about 105 nm, about 110 nm, about 115 nm, about 120 nm, about 125 nm, about 130 nm, about 135 nm, about 140 nm, about 145 nm, about 150 nm, about 155 nm, about 160 nm, about 165 nm, about 170 nm, about 175 nm, about 180 nm, about 185 nm, about 190 nm, about 195 nm, or about 200 nm, including all ranges and subranges therebetween.

[0141] In embodiments, the compositions of the present disclosure comprise a nanosuspension. In embodiments, at least one of the IOP lowering agent and the glucocorticoid receptor agonist is present as nanoparticles, tire nanoparticles with a targeted particle size distribution. In embodiments, the nanoparticles have an average diameter ranging from about 1 to about 1000 nm, about 10 to about 800 nm, about 50 to about 800 nm, about 100 to about 800 nm, about 200 to about 800 nm, about 400 to about 800 nm, about 10 to about 900 nm, about 10 to about 600 nm, or about 10 to about 400 nm, or about 10 to 300 nm, or about 100 to 300 nm, including all ranges and subranges therebetween. In embodiments, the nanoparticles have a monomodal particle size distribution. In embodiments, the nanoparticles have a bimodal particle size distribution.

[0142] In embodiments, the nanoparticles comprising the IOP lowering agent are present in a first particle size distribution, and nanoparticles comprising the glucocorticoid receptor agonist are present in a second particle size distribution.

[0143] In embodiments, the compositions of the present disclosure comprise microparticles. In embodiments, at least one of the IOP lowering agent and the glucocorticoid receptor agonist is present as microparticles. In embodiments, the IOP lowering agent is present as microparticles. In embodiments, the IOP lowering agent is present as microparticles and the and the glucocorticoid receptor agonist is present as nanoparticles.Atty. Docket No.: PLXB-001 / 03WO

[0144] In embodiments, the microparticles have a target particle size distribution. In embodiments, the microparticles have an average diameter ranging from about 1 to about 1000 pm, about 10 to about 800 µm, about 20 to about 800 pm, about 50 to about 800 pm, about 100 to about 800 pm, about 400 to about 800 pm, about 5 to about 600 pm, about 5 to about 400 pm, about 5 to about 200 pm, or about 5 to about 100 pm, including ail ranges and subranges therebetween. In embodiments, the microparticles have a monomodal particle size distribution.

[0145] In embodiments, the IOP lowering agent is present as particles with an average diameter ranging from about 500 nm to about 1.5 pm, or about 800 nm to about 1.5 pm, or about 800 nm to about 1.2 pm, including all ranges and subranges therebetween.

[0146]

[0147] One of skill in the art will understand that different methods of particle size assessments will yield different results based on their principles. For example, laser diffraction may be used to characterize larger particles (>1 pm), while DLS can be used in the characterization of nanoparticles (<1 pm).

[0148] In embodiments, the compositions of the present disclosure comprise:Component ConcentrationBrinzolamide About 0.5 wt% to about 1.5 wt%, or about 0.8 wt% to about 1.2 wt%, or about 1.0 wt%Difluprednate About 0.02 wt% to about 0.06 wt%, or about 0.03 wt% to about 0.05 wt%, or about 0.04 wt%, or about 0.05 wt% Castor oil About 3 wt% to about 7 wt%, or about 4 wt% to about 6 wt%, or about 5.0 wt%Transcutol P [diethylene About 3 wt% to about 7 wt%, or about 4 wt% to about 6 wt%, glycol monoethyl ether] or about 4.8 w t%Sodium Citrate Dihydrate About 0.2 wt% to about 3 wt%, or about 0.5 wt% to about 2 wt%, or about 1 wt%, or about 1.1wt%Citric acid anhydrous About 0.001 wt% to about 0.5 wt%, or about 0.005 wt% to about 0,1 wt%, or about 0.01 wt%Kolliphor EL [poly oxy 1 35 About 5 wt% to about 30 wt%, or about 10 wt% to about 25 castor oil] wt%, or about 20 wt%, or about 21.0%Poloxamer 407 About 0.2 wt% to about 2 wt%, or about 0.5 wt% to about 1.5 wt%, or about 1 wt%, or about 1.1 wt%Atty. Docket No.: PLXB-001 / 03WOTitriplex III About 0.001 vrt% to about 0.1 wt%, or about 0.005 wt% to [ ethylenedinitrilotetraacetic about 0.05 wt%, or about 0.01 wt%acid disodium saltdihydrate]Carbopol 97 IP About 0.1 wt% to about 0.5 wt%, or about 0.1 to about 0.25 wt%, or about 0.12 wt% to about 0.2 wt%, or about 0.15 wt%, or about 0.16 wt%Water Q. S.

[0149] In embodiments, the compositions of the present disclosure comprise nanoliposomes. In embodiments, the composition comprises phosphatidylcholine, cholesterol, super refined olive oil, (2-hydroxypropyl)-P-cyclodextrin, sodium citrate dihydrate, citric acid anhydrous, sodium chloride, ethyl alcohol, poloxamer 407, sodium deoxycholate, ethylenedinitrilotetraacetic acid disodium (EDTA, such as Titriplex III), a carbomer, and water.

[0150] In embodiments, the compositions of the present disclosure comprise:Component ConcentrationBrinzolamide About 0.5 wt% to about 1.5 w t%, or about 0.8 wt% to about 1.2 wt%, or about 1.0 wt%Difluprednate About 0.02 wt% to about 0.06 wt%, or about 0.03 wrt% to about 0.05 wt%, or about 0.04 wt%, or about 0.05 wt% Phosphatidylcholine (PC) About 1 wt% to about 8 wt%, or about 2 wt% to about 6 wt%, or about 4 wt%, or about 4.1 wt%Cholesterol About 0.2 wt% to about 3 wt%, or about 0.5 wt% to about 2 wt%, or about 1 wt%, or about 1.24 wt%Super Refined Olive Oil - About 2 wt% to about 12 wt%, or about 4 wt% to about 10 LQ - (MH) wt%, or about 8 wt%, or about 8.26 wt%(2-hydroxypropyl)-p- About 0.1 wt% to about 2 wt%, or about 0.2 wt% to about 1 cyclodextrin wt%, or about 0.4 wt%, or about 0.5 wt%Sodium Citrate Dihydrate About 0.1 wt% to about 2 wt%, or about 0.2 wt% to about 1 wt%, or about 0.4 or about 0,5 wt%Citric acid anhydrous About 0.001 wt% to about 0.5 wt%, or about 0.005 wt% to about 0.2 wt%, or about 0.015 wt%Atty. Docket No.: PLXB-001 / 03WOEthyl alcohol About 0.01 wt% to about 0.1 wt%, or about 0.02 wt% to about 0.05 wt%, or about 0.033 wt%Poloxamer 407 About 0.2 wt% to about 2 wt%, or about 0.5 wt% to about 1.5 wt%, or about 1 wt%, or about 1.1 wt%Sodium Deoxycholate About 0.01 wt% to about 0.5 wt%, or about 0.05 wt% to about 0.2 wt%, or about 0.1 wt%Titriplex III About 0.001 wt% to about 0.1 wt%, or about 0.005 wt% to [ethylenedinitrilotetraacetic about 0.05 wt%, or about 0.01 wt%acid di sodium saltdihydrate]Carbopol 971P About 0.1 wt% to about 0,5 wt%, or about 0.15 wt% to about 0.3 wt%, or about 0.2 wt%Water Q. S

[0151]

[0152] In embodiments, the compositions of the present disclosure comprise a nanosuspension. In embodiments, the composition comprises polysorbate 80, oleic acid, a carbomer (e.g., Carbopol 971P or Carbopol 974 P), a polyethylene glycol (e.g., PEG 400 or PEG 8000), mannitol, and water.

[0153] In embodiments, the compositions of the present disclosure comprise:Component ConcentrationBrinzolamide About 0.5 wt% to about 1.5 wt%, or about 0.8 wt% to about 1.2 wt%, or about 1.0 wt%Difluprednate About 0.02 wt% to about 0.06 wt%, or about 0.03 wt% to about 0.05 wt%, or about 0.04 wt%, or about 0.05 wt%Polysorbate 80 About 0.1 wt% to about 0.3 wt%, or about 0.15 wt% to about 0.25 wt%, or about 0.2 wt%Oleic Acid About 0.01 wt%, or about 0.04 wt%, or about 0.02 wt%, or about 0.03 wt%, or about 0.025 wt%Carbopol 97 IP About 0.01 wt% to about 0.2 wt%, or about 0.02 wt% to about 0.1 wt%, or about 0.05 wt%PEG 8000 About 0.5 wt% to about 1.5 wt%, or about 0.8 wt% to about 1.2 wt%, or about 1 wt%Atty. Docket No.: PLXB-001 / 03WOMannitol About 1 wt% to about 6 wt%, or about 2 wt% to about 5 wt%, or about 3 wt%Water Q. S.

[0154] In embodiments, the compositions of the present disclosure comprise:Component ConcentrationBrinzolamide About 0.5 wt%to about 1.5 wt%, or about 0.8 wt%to about 1.2 wt%, or about 1.0 wt%Difluprednate About 0.02 wt% to about 0.06 wt%, or about 0.03 wt% to about 0,05 wt%, or about 0.04 wt%, or about 0.05 wt%Polysorbate 80 About 0.1 wt% to about 0.3 wt%, or about 0.15 wt% to about 0,25 wt%, or about 0.2 wt%Oleic Acid About 0,01 wt% to about 0.04 wt%, or about 0.02 wt%, or about 0.03 wt%, or about 0.025 wt%Carbopol 974P About 0.1 wt% to about 0.25 wt%, or about 0.12 wt% to about 0.2 wt%, or about 0.16 wt%PEG 8000 About 0.5 wt% to about 1.5 wt%, or about 0.8 wt% to about 1.2 wt%, or about 1 wt%Mannitol About 1 wt% to about 6 wt%, or about 2 wt% to about 5 wt%, or about 4 wt%, or about 4.3 wt%Water Q. S.

[0155] In embodiments, the compositions of the present disclosure comprise nanoparticles. In embodiments, the composition comprises polysorbate 80, oleic acid, cholesterol, egg lecithin (e.g,, egg lecithin E80), (2-hydroxypropyl)-P-cyclodextrin, and citrate buffer.

[0156] In embodiments, the compositions of the present disclosure comprise:Component ConcentrationBrinzolamide About 0.5 to about 1, 5 wt%, or about 0.8 wt% to about 1.2 wt%, or about 1.0 wt%Difluprednate About 0.02 wt% to about 0.06 wt%, or about 0,03 wt% to about 0.05 wt%, or about 0.04 wt%, or about 0.05 wt%Polysorbate 80 About 0.1 wt% to about 0.3 wt%, or about 0.15 wt% to about 0.25 wt%, or about 0.2 wt%Atty. Docket No.: PLXB-001 / 03WOOleic Acid About 0.1 wt% to about 3 wt%, or about 0.5 wt% to about 2 wt%, or about 1 wt %Cholesterol About 1 wt% to about 10 wt%, or about 2 wt% to about 8 wt%, or about 5 wt%Egg Lecithin E80 About 0.5 wt% to about 5 wt%, or about 1 wt% to about 4 wt%, or about 2.5 wt%(2-hydroxypropyl)-β- About 5 wt% to about 60 wt%, or about 10 wt% to about 50 wt%, cyclodextrin or about 30 wt%, or about 45 wt%10 mM citrate buffer Q. S.

[0157] In embodiments, compositions of the present disclosure include an additional active agent. Non-limiting examples of additional active agents include anesthetics, anti-angiogenic agents, antibiotics, antifungals, antihistamines / decongestants, antimicrobials, antiinflammatory agents, antivirals, beta blockers, cholinergic agents, lubricants, mydriatics, NSAIDs, and pressure regulators, including combinations thereof.Kits

[0158] In embodiments, the present disclosure provides a kit comprising an ophthalmic pharmaceutical composition according to this disclosure, such as a composition comprising a glucocorticoid receptor agonist and an lOP-lowering agent. In embodiments, a kit of the present disclosure comprises: a) a container (e.g., a syringe, tube, vial, dropper) comprising an ophthalmic pharmaceutical composition as described herein; and b) instructions for use, which may include diagrams, drawings, or photographs, in addition to text. In embodiments, the instructions comprise information related to administration, e.g., dosing information, storage conditions, such as temperature ranges for storage, and what to expect from using the composition, such as measures of treatment efficacy. In embodiments, the kit comprises a multi-dose dropper. In embodiments, the multi-dose dropper is preservative free. Multi-dose droppers are less cumbersome for the patient because of they reduce the bulk of single use vials and the chore of twisting off the cap and throwing away the vial after each use.

[0159] In embodiments, the present disclosure provides a kit that comprises a first container comprising a glucocorticoid receptor agonist and a second container comprising an 1OP-lowering agent. In embodiments, the kit of the present disclosure further comprises instructions for combining the contents of the first and second containers, such as providing a mixture ofAtty. Docket No.: PLXB-001 / 03WOglucocorticoid receptor agonist and lOP-lowering agent. In embodiments, the mixture provides a fixed dose combination of a glucocorticoid receptor agonist and an lOP-lowering agent.

[0160] In embodiments, the kit allows for the preparation of a fresh fixed dose combination immediately prior to administration, which may improve stability and efficacy of the combined active agents. In embodiments, the first container comprises a relatively concentrated level of the glucocorticoid receptor agonist, such as in a solution. In embodiments, the second container comprises a relatively concentrated level of the lOP-lowering agent in solution. In embodiments, the instructions comprise directions related to instructing the user to mix volumes, such as equal or distinct volumes, from each container to achieve the desired fixed dose combination.

[0161] In embodiments, a kit of the present disclosure further comprises a third container suitable for mixing the contents of the first and second containers. This third container may be sterile and appropriately sized for the intended volumes to be mixed.

[0162] The kit may also include additional components, e.g., a dropper for administration, preservative-free single-use containers, or other accessories that facilitate proper mixing and administration of the combined formulation.

[0163] By providing the active agents in separate containers with instructions for mixing, this kit format can facilitate extended shelf-life of the individual components. Additionally, such kit formats are configured to enable on-demand preparation of the fixed dose combination, such as for immediate use.Methods of Manufacturing

[0164] In aspects, provided herein are methods of manufacturing the provided pharmaceutical compositions. In embodiments, the methods of manufacturing of the present disclosure comprise providing a suspension comprising a glucocorticoid receptor agonist and an IOP lowering agent. In embodiments, the methods of manufacturing of the present disclosure comprise providing a colloidal dispersion comprising a glucocorticoid receptor agonist and an IOP lowering agent.

[0165] In embodiments, the methods of manufacturing of the present disclosure comprise providing an emulsion comprising a glucocorticoid receptor agonist and an IOP low ering agent. In embodiments, the methods of manufacturing of the present disclosure comprise providing a Type Illb emulsion. Type ITIb emulsions are characterized as three-phase systems that includes a microemulsion phase in equilibrium with excess oil and excess water phases. The microemulsion phase stabilizes the system between the two immiscible liquids (oil and water). In embodiments, the methods of manufacturing of the present disclosure comprise providing aAtty. Docket No.: PLXB-001 / 03WOType IV emulsion. Type IV emulsions represent an expansion of the middle phase microemulsions found in Type Illb systems at high surfactant concentrations. In Type IV emulsions, all excess oil and excess water are incorporated into a single phase, creating a more homogeneous system. See, e.g., The Many faces of microemulsions: Converting challenges to step-change opportunities, part I. (2016, November 17). Cosmetics & Toiletries and Tauer, K. (n.d.). Emulsions. Max Planck Institute of Colloids and Interfaces. https: / / www.mpikg.mpg.de / 886807 / Emulsions__-l.pdf.

[0166] In embodiments, methods of manufacturing of the present disclosure comprise providing a nanoemulsion comprising a glucocorticoid receptor agonist and an IOP lowering agent. In embodiments, the methods of manufacturing of the present disclosure comprise forming a nanoemulsion by high-pressure homogenization, microfluidization, phase inversion temperature, spontaneous emulsification, emulsion inversion point, or high-energy stirring, or a combination thereof. In embodiments, the methods of manufacturing of the present disclosure comprise dialysis, ultrasonication, or a combination thereof, to provide a nanoemulsion.

[0167] In embodiments, the methods of manufacturing of the present disclosure comprise solubilizing the glucocorticoid receptor agonist, such as a corticosteroid, in organic solvent, and providing a nanoemulsion therefrom. In embodiments, the methods of manufacturing of the present disclosure comprise mixing the glucocorticoid receptor agonist with a solubility enhancer, e.g., amphiphilic block copolymer or cyclodextrin, to form the nanoemulsion.

[0168] In embodiments, the methods of manufacturing of the present disclosure comprise solubilizing the IOP lowering agent, such as in organic solvent, and producing a solution thereof. In embodiments, the methods of manufacturing of the present disclosure comprise combining solutions comprising the glucocorticoid receptor agonist and the IOP lowering agent, such as providing a mixture thereof. In embodiments, the methods of manufacturing of the present disclosure comprise filtering the mixture of glucocorticoid receptor agonist and the IOP lowering agent. In embodiments, the methods of manufacturing of the present disclosure comprise dispensing the mixture of glucocorticoid receptor agonist and the IOP lowering agent into an appropriate container.

[0169] In embodiments, the methods of manufacturing of the present disclosure provide a composition comprising the glucocorticoid receptor agonist and the IOP lowering agent at a final weight ratio of about 50:1 to about 25:1, about 40:1 to about 20:1, about 50:1 to about 10:1, about 5: 1 to about 1:5, about 3: 1 to about 1:3, about 2: 1 to about 1:2, about 1:25 to about 1:50, about 1:20 to about 1:40, about 1:10 to about 1:50, about 15:1 to about 1:15, about 30:1 to about 1:10, about 8: 1 to about 1:25, about 20: 1 to about 1:30, or about 1: 1 to about 1:20.Atty. Docket No.: PLXB-001 / 03WO

[0170] In embodiments, the methods of manufacturing of the present disclosure provide a composition comprising the glucocorticoid receptor agonist and the IOP lowering agent at a final weight ratio of about 50:1, about 45:1, about 40:1, about 35:1, about 30:1, about 25:1, about 20:1, about 15:1, about 10:1, or about 5:1, including all ranges and subranges therebetween. In embodiments, the methods of manufacturing of the present disclosure provide a composition comprising the glucocorticoid receptor agonist and the IOP lowering agent at a final weight ratio of about 1:5, about 1:10, about 1:15, about 1:20, about 1:25, about 1:30, about 1:35, about 1:40, about 1:45, or about 1:50, including all ranges and subranges therebetween.Method of Treatment

[0171] In aspects, provided herein are methods of treating ocular conditions involving abnormal blood vessel growth, inflammation, hemorrhage, or fluid accumulation in the retina, such as fluid accumulation in the subretina, preretina, and / or vitreous gel.

[0172] Such conditions include, but are not limited to, ocular pain, ocular inflammation, postoperative ocular pain, post-operative ocular inflammation, macular edema, macular edema following retinal vein occlusion (MEfRVO), diabetic retinopathy, diabetic macular edema, macular degeneration, retinal edema, retinal neovascularization, non-proliferative diabetic retinopathy, proliferative diabetic retinopathy, choroidal neovascularization, central retinal vein occlusion, branch retinal vein occlusion, myopic choroidal neovascularization, cystoid macular edema, uveitis, radiation retinopathy, neovascular glaucoma retinopathy of prematurity, retinal hemorrhage, preretinal hemorrhage, vitreous hemorrhage, and excess subretinal fluid. In embodiments, the methods as otherwise described herein result in a reduction in macular edema, and / or subretinal fluid resorption and resolution.

[0173] Also provided are methods of administering a composition of the present disclosure, such as a topical ophthalmic composition, to a patient in need thereof. Methods of the present disclosure have the advantage of reducing retinal edema, ocular inflammation, among other ocular ailments, while substantially reducing the risk of clinically significant elevations in intraocular pressure. In embodiments, a method of treatment of the present disclosure comprises simultaneous administration of a glucocorticoid receptor agonist and an IOP lowering agent. For example, by combining a corticosteroid, such as difluprednate, clobetasol, or clobetasol propionate, with an IOP lowering agent, it is possible to reduce retinal edema and / or ocular inflammation, while also diminishing or alleviating the risk of a clinically significant secondary increase in intraocular pressure. The combination of these active pharmaceutical ingredients (APIs) facilitates administration of both agents simultaneously, without causing dilution or other issues associated with the separate administration of multipleAtty. Docket No.: PLXB-001 / 03WOeye drops. Additionally, challenges related to non-topical administration routes, e.g., systemic toxicity, are avoided.

[0174] In embodiments, two separate compositions are administered. In embodiments, a first composition comprising brinzolamide is administered, and a second composition comprising difluprednate is administered. In embodiments, a single composition is administered. In embodiments, a single composition comprising brinzolamide and difluprednate is administered.

[0175] In embodiments, the present disclosure provides a method of treating macular edema following retinal vein occlusion (MEfRVO) in a patient in need thereof, the method comprising administering a therapeutically effective amount of a composition of the present disclosure to a patient in need thereof.

[0176] In embodiments, the present disclosure provides a method of treating diabetic retinopathy in a patient in need thereof, the method comprising administering a therapeutically effective amount of a composition of the present disclosure to a patient in need thereof.

[0177] In embodiments, the present disclosure provides a method of treating diabetic macular edema in a patient in need thereof, the method comprising administering a therapeutically effective amount of a composition of the present disclosure to a patient in need thereof.

[0178] In embodiments, the present disclosure provides a method of treating macular degeneration in a patient in need thereof, the method comprising administering a therapeutically effective amount of a composition of the present disclosure to a patient in need thereof.

[0179] In embodiments, the present disclosure provides a method of treating or preventing retinal hemorrhage in a patient in need thereof, the method comprising administering a therapeutically effective amount of a composition of the present disclosure to a patient in need thereof.

[0180] In embodiments, the present disclosure provides a method of treating or preventing preretinal hemorrhage in a patient in need thereof, the method comprising administering a therapeutically effective amount of a composition of the present disclosure to a patient in need thereof.

[0181] In embodiments, the present disclosure provides a method of treating or preventing vitreous hemorrhage in a patient in need thereof, the method comprising administering a therapeutically effective amount of a composition of the present disclosure to a patient in need thereof.Atty. Docket No.: PLXB-001 / 03WO

[0182] In embodiments, the present disclosure provides a method of treating or preventing hemorrhage in a patient in need thereof, wherein the hemorrhage is a combination of at least two of retinal, preretinal, or vitreous hemorrhage, the method comprising administering a therapeutically effective amount of a composition of the present disclosure to a patient in need thereof.

[0183] In embodiments, the present disclosure provides a method of treating excess subretinal fluid in a patient in need thereof, the method comprising administering a therapeutically effective amount of a composition of the present disclosure to a patient in need thereof. In embodiments, the treatment results in at least a portion of excess subretinal fluid resorbing and / or resolving.

[0184] In embodiments, the patient has an ocular or periocular infection. In embodiments, the patient has active intraocular inflammation.

[0185] In embodiments, a method of treatment of the present disclosure comprises administering a provided ophthalmic pharmaceutical composition to a subject, such as a patient suffering from an ocular condition, in one administration, such as a single administration. In embodiments, a method of treatment of the present disclosure comprises administering a provided ophthalmic pharmaceutical composition to a subject, such as a patient suffering from an ocular condition, in multiple administrations.

[0186] In embodiments, a method of treatment of the present disclosure comprises two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty administrations, or more in a single day. In embodiments, a method of treatment of the present disclosure comprises two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty administrations, or more in one week. In embodiments, a method of treatment of the present disclosure comprises two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty administrations, or more in one month.

[0187] In embodiments, any of the multiple administrations is separated from each other by a relatively short interval of time, e.g., up to about 5 minutes, about 15 minutes, or about 30 minutes, a medium interval of time, e.g., about 1 minutes to about 4 hour, about 1 hour to about 12 hours, or about 12 hours to about 24 hours, or a relatively longer interval of time, e.g., at least about 24 hours, at least about 48 hours, at least about 72 hours, or at least about 96 hours.

[0188] In embodiments, a method of treatment of the present disclosure comprises administering multiple doses to a subject in one day, such as two doses per day, three doses perAtty. Docket No.: PLXB-001 / 03WOday, four doses per day, five doses per day, six doses per day, seven doses per day, eight doses per day, nine doses per day, or ten doses per day.

[0189] The dose (including the amount and dose schedule) of the glucocorticoid receptor agonist and / or the IOP lowering agent may be adjusted during the period that the patient is administered therapy. For example, the dose or dose frequency of the glucocorticoid receptor agonist and / or the IOP lowering agent may be changed to manage tolerability, or to achieve a particular clinical effect.

[0190] The dose of the glucocorticoid receptor agonist and / or IOP lowering agent may be adjusted by, e.g., changing the concentration of active ingredient in the composition administered (e.g., 0.1 mg / mL, 1, mg / mL, etc.), the amount of the composition administered (e.g., 1 drop, 2 drops, etc.), or the frequency of the administration (e.g., 1 drop once per day, or 1 drop twice per day, etc.). In embodiments, the dose is changed by changing the frequency of administration. For example, in embodiments, the dose is increased by providing one additional administration per day, or the dose is decreased by providing one fewer administration per day. In embodiments, each administration comprises the administration of 1 drop to the eye, or two drops to the eye, or three drops to the eye.

[0191] In embodiments, the present disclosure also provides methods of administration wherein the glucocorticoid receptor agonist and IOP lowering agent are administered an equal number of times per day. In embodiments, the glucocorticoid receptor agonist and IOP lowering agent are administered an unequal number of times per day. In embodiments, the glucocorticoid receptor agonist is administered one time, two times, or three times more per day than the IOP lowering agent.

[0192] In embodiments, the present disclosure also provides methods of administration wherein the glucocorticoid receptor agonist is administered one time, two times, or three times per day, and the IOP lowering agent is administered four times per day.

[0193] In embodiments, the glucocorticoid receptor agonist is administered three times per day, and the IOP lowering agent is administered four times per day,

[0194] In embodiments, the glucocorticoid receptor agonist and the IOP lowering agent are each administered four times per day.

[0195] In embodiments, the glucocorticoid receptor agonist is administered four times, five times, or six times per day, and the IOP lowering agent is administered four times, five times, six times, seven times, or eight times per day.

[0196] In embodiments, the glucocorticoid receptor agonist is administered six times per day, and the IOP lowering agent is administered eight times per day.Atty. Docket No.: PLXB-001 / 03WO

[0197] In embodiments, the present disclosure also provides methods of administration wherein the glucocorticoid receptor agonist and IOP lowering agent are present in a fixed-dose composition, and wherein the fixed-dose composition is administered twice per day. In embodiments, the fixed-dose composition is administered once per day, or three times a day, or four times a day.

[0198] In embodiments, the present disclosure provides methods comprising an induction period and a maintenance period. In embodiments, the induction period comprises monitoring the intraocular pressure, and adjusting the dose of at least one of the glucocorticoid receptor agonist and IOP lowering agent to avoid excessive intraocular pressure. In embodiments, the dose of brinzolamide is decreased. In embodiments, excessive intraocular pressure is that in excess of 18 mmHg, or 19 mmHg, or 20 mmHg, or 21 mmHg.

[0199] In embodiments, the maintenance period dosing of at least one of the glucocorticoid receptor agonist and IOP lowering agent is less than the corresponding dosing during the induction period. In embodiments, the glucocorticoid receptor agonist is administered three or four times per day and the IOP lowering agent is administered four times per day during the induction period. In embodiments, the glucocorticoid receptor agonist is administered one, two, or three times per day and / or the IOP lowering agent is administered one, two, three, or four times per day during the maintenance period. In embodiments, the glucocorticoid receptor agonist is administered three times per day during the induction period, and twice per day during the maintenance period.

[0200] In embodiments, the induction period comprises administration of the fixed-dose composition as otherwise described herein, wherein the fixed-dose composition is administered two, three, or four times per day. In embodiments, the maintenance period comprises administration of the fixed-dose composition as otherwise described herein, wherein the fixed-dose composition is administered once or twice per day, or is administered every other day, or every third day, or twice per week, or once per week. In embodiments, the fixed-dose compositions is administered twice per day during the induction period, and then once per day, or every' other day, during the maintenance period.

[0201] In embodiments, the induction period comprises about 7 days to about 365 days (1 year), about five days to about 90 days, about seven days to about 90 days, about 14 days to about 90 days, about 21 days to about 90 days, about 28 days to about 90 days, about 35 days to about 90 days, about 42 days to about 90 days, about 49 days to about 90 days, about 56 days to about 90 days, about one day to 56 days, about one day to about 49 days, about one day to about 42 days, about one day to about 35 days, about one day to about 28 days, about oneAtty. Docket No.: PLXB-001 / 03WOday to about 21 days, about 7 days to about 56 days, about 7 days to about 49 days, about 7 days to about 42 days, about 7 days to about 35 days, about 7 days to about 28 days, about 14 days to about 42 days, about 21 days to about 42 days, about 28 days to about 42 days, or about 35 days, or about 70 days. In embodiments, the induction period comprises about 3 months to about 12 months, or about 3 months to about 9 months, or about 3 months to about 6 months, or about 6 months, or about 9 months, and all ranges and values therebetween.

[0202] In embodiments, the maintenance period comprises at least about 7 days, or at least about one month, or at least about 6 months in duration. In embodiments, the maintenance period continues indefinitely, or continues until at least one clinical endpoint is reached as otherwise described herein.

[0203] In embodiments, the present disclosure provides methods comprising an initial dose and a titrated dose. In embodiments, the titrated dose of at least one of the glucocorticoid receptor agonist and IOP lowering agent is greater than the initial dose (e.g., in embodiments, the ti trated dose has a greater dose frequency than the initial dose). In embodiments, the titrated dose of at least one of the glucocorticoid receptor agonist and IOP lowering agent is less than the initial dose. In embodiments, the titrated dose is increased until a pharmaceutical effect or clinical endpoint as otherwise described herein is reached.

[0204] In embodiments, the initial dose of the comprises the glucocorticoid receptor agonist being administered one, two, three or four times per day and the IOP lowering agent being administered one, two, three, or four times per day. In embodiments, the initial dose of the comprises the glucocorticoid receptor agonist being administered one time per day and the IOP lowering agent being administered four times per day. In embodiments, the initial dose of the comprises the glucocorticoid receptor agonist being administered three times per day and the IOP lowering agent being administered four times per day,

[0205] In embodiments, the titrated dose comprises the glucocorticoid receptor agonist being administered one, two, three, four, five, six, seven, or eight times per day and / or the IOP lowering agent is administered one, two, three, four, five, six, seven, or eight times per day. In embodiments, the titrated dose comprises the glucocorticoid receptor agonist being administered four times per day and / or the IOP lowering agent is administered four times per day. In embodiments, the titrated dose comprises the glucocorticoid receptor agonist being administered six times per day and / or the IOP lowering agent is administered eight times per day.

[0206] In embodiments, the initial dose comprises administration of the fixed-dose composition as otherwise described herein, wherein the fixed-dose composition is administeredAtty. Docket No.: PLXB-001 / 03WOevery other day, or one, two, three, or four times per day. in embodiments, the titrated dose comprises administration of the fixed-dose composition as otherwise described herein, wherein the fixed-dose composition is administered one, two, three, or four times per day, or is administered every other day, or every third day, or twice per week, or once per week. In embodiments, the initial dose comprises administration of the fixed-dose composition once per day, and the titrated dose comprises administration of the fixed-dose composition two or three times per day. In embodiments, the initial dose comprises administration of the fixed-dose composition one time or two times per day, and the titrated dose comprises administration of the fixed-dose composition every other day.

[0207] In additional aspects, the present disclosure also provides methods for sequential administration of a glucocorticoid receptor agonist and an IOP lowering agent. In embodiments, a sequential administration comprises administering a first compound, either the glucocorticoid receptor agonist or IOP lowering agent, to a patient in need thereof, then administering the second remaining compound, where each administration is separated by a predetermined interval of time. In embodiments, the interval of time may range from seconds to minutes to hours to days. In embodiments, each of the glucocorticoid receptor agonist and the IOP lowering agent are administered to the eye(s) of a patient in need thereof.

[0208] The order of administering the glucocorticoid receptor agonist and the IOP lowering agent may be determined based on the specific properties of the compounds, the condition being treated, and individual patient factors. The time interval between administrations can be optimized to enhance therapeutic efficacy or minimize potential drug interactions.

[0209] In embodiments, a method of treatment of the present disclosure comprises administering an ophthalmic pharmaceutical composition of the present disclosure to a subject at a therapeutically effective dose for ameliorating, treating, or otherwise correcting an ocular condition. The exact dosage required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease, the particular administered composition, its mode of administration, its mode of activity, and the like. It will be understood, however, that the total daily usage of the compositions may be decided by the attending ophthalmic physician within the scope of sound medical judgment. The specific pharmaceutically effective, dose level for any particular patient will depend upon a variety of factors including the severity of the ocular condition, the specific composition employed, the age, body weight, general health, sex, and diet of the patient, the time of administration, route of administration, the duration of the treatment, and like factors well known in the ophthalmic arts.Atty. Docket No.: PLXB-001 / 03WO

[0210] One of ordinary skill in the art will recognize methods for assessing the therapeutic efficacy of the provided compositions and methods. For example, one having familiarity with the art will understand how to evaluate retinal health and disorders thereof. The retina is a light¬ sensitive layer of tissue in the inner eye of humans, most other vertebrates, and some invertebrates, The retina converts visual input into electrical signals that are transmitted to the brain. Retinal edema is the accumulation of fluid within the layers of the retina as a nonspecific response to a breakdown in the normal blood-retinal barriers in patients with diabetes mellitus, retinal venous occlusion, uveitis, and following intraocular surgery.

[0211] The macula is the central part of the retina. Macular edema, namely edema of the macula, is the most clinically significant retinal edema. Macular edema also occurs in some cases of traction between the vitreous and the retina, in some cases of retinitis pigmentosa, and often found in cases of choroidal neovascularization (also known as ‘wet” macular degeneration). The ultimate result of macular edema is reduced visual acuity,

[0212] Measuring how well a patient can see, or the sharpness of their vision, can be used to assess therapeutic efficacy. Visual acuity measurements can be conducted using standard eye charts, such as Snellen charts for distance vision and Jaeger charts for near vision, or equivalent standardized visual acuity testing methods known in the art. The specific distance for testing may vary based on the chart used and testing environment, typically ranging from 10 to 20 feet for distance vision, and 14 to 16 inches for near vision. Patients are instructed to read the smallest line or text they can discern. Results are initially recorded in the format native to the chart used (e.g., fractions for Snellen, notations for Jaeger). To standardize results across different testing methods, all measurements are converted to decimal notation using appropriate conversion charts or methods recognized in the field of ophthalmology. One of skill in the art will understand a degree of flexibility is involved in selecting the particular testing equipment and related methods, while maintaining consistency in result reporting, enabling accurate comparisons of visual acuity data. In embodiments, visual acuity is measured through Best Corrected Visual Acuity (BCVA),

[0213] Therapeutic efficacy of compositions and methods of the present disclosure can be evaluated with optical coherence tomography (OCT). OCT is a non-contact and non-invasive imaging technique that produces a high resolution cross-sectional retinal image showing the thickened edematous retinal layers in fine detail. OCT can be performed using commercially available OCT systems designed for ophthalmic imaging. The procedure involves positioning the patient appropriately and acquiring high-resolution cross-sectional images of the retina, particularly focusing on the macular region. Multiple scans, e.g., encompassing a 6x6 mm areaAtty. Docket No.: PLXB-001 / 03WOcentered on the fovea, are obtained to ensure comprehensive imaging of the area of interest. Hie OCT images are then analyzed to identify and assess the various retinal layers, measure retinal thickness, and detect the presence of intraretinal fluid or other abnormalities associated with macular edema.

[0214] Quantitative analysis can be performed using the OCT device's software to generate retinal thickness maps and compare measurements to normative data. This non-invasive imaging technique provides detailed visualization of retinal structures, allowing for assessment of edema severity, treatment efficacy, and disease progression. The specific parameters and protocols may be adjusted based on the particular OCT system used and the clinical requirements, as would be understood by one skilled in the art.

[0215] In embodiments, assessments of therapeutic efficacy are determined relative to a patient’s baseline measurement before treatment. In embodiments, assessments of therapeutic efficacy are determined relative to placebo, e.g., saline solution. In embodiments, assessments of therapeutic efficacy are determined relative to administration of a glucocorticoid receptor agonist alone or a IOP lowering agent alone.

[0216] In embodiments, assessments of therapeutic efficacy comprise determining reductions in eye pressure (IOP). In embodiments, compositions and methods of the present disclosure reduces a patient’s IOP by about 0.5 mmHg to about 50 mmHg, about 1.0 mmHg to about 45 mmHg, about 0.8 mmHg to about 38 mmHg, about 1.2 mmHg to about 41 mmHg, about 2 mmHg to about 30 mmHg, about 4 mmHg to about 45 mmHg, about 6 mmHg to about 36 mmHg, about 8 mmHg to about 44 mmHg, about 10 mmHg to about 37 mmHg, about 12 mmHg to about 43 mmHg, and about 14 mmHg to about 39 mmHg. In embodiments, compositions and methods of the present disclosure reduce a patient’s IOP by about 2 mm Hg, about 3 mm Hg, about 4 mm Hg, about 5 mm Hg, about 6 mm Hg, about 7 mm Hg, about 8 mm Hg, about 9 mm Hg, about 10 mm Hg, about 11 mm Hg, about 12 mm Hg, about 13 mm Hg, about 14 mm Hg, about 15 mm Hg, about 16 mm Hg, about 17 mm Hg, about 18 mm Hg, about 19 mm Hg, about 20 mm Hg, about 21 mm Hg, about 22 mm Hg, about 23 mm Hg, about 24 mm Hg, about 25 mm Hg, about 26 mm Hg, about 27 mm Hg, about 28 mm Hg, about 29 mm Hg, or about 30 mm Hg, including all ranges and subranges therebetween.

[0217] As was unexpectedly observed by Applicant, in embodiments, assessments of therapeutic efficacy comprise determining reductions in the number or frequency of injection treatments. In some cases, the need for injection treatments can be obviated altogether by employing the compositions and methods of the disclosure. Injection treatments include but are not limited to intravitreal anti-VEGF injections and intravitreal steroid injections. InAtty. Docket No.: PLXB-001 / 03WOembodiments, the frequency of injections is reduced by 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%. The reduction in frequency of injections can be determined in comparison to a control patient who is not administered the compositions or methods of the present disclosure. Frequency can be evaluated on the order of months, e.g., about 1 month, about 3 months, about 6 months, about 9 months, or about 12 months, or years, e.g., about 1 year, about 2 years, or about 5 years.

[0218] In embodiments, the time period between injections is increased. In embodiments, the time period between injections is increased by at least about 2 months, at least about 4 months, at least about 6 months, at least about 8 months, at least about 10 months, at least about 12 months, at least about 14 months, at least about 16 months, at least about 18 months, at least about 20 months, at least about 22 months, at least about 24 months, at least about 26 months, at least about 28 months, at least about 30 months, at least about 32 months, at least about 34 months, or at least about 36 months. The increased time period can be determined in comparison to a control patient who is not administered the compositions or methods of the present disclosure.

[0219] In embodiments, the total number of injections a patient receives is reduced by about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, or about 90%, including all ranges and subranges therebetween. In embodiments, compositions and methods of the present disclosure remove the need for additional injections. The reduction in total number of injections can be determined in comparison to a control patient who is not administered the compositions or methods of the present disclosure.

[0220] In embodiments, the method of treatment as otherwise described herein is sufficient to achieve at least one clinical endpoint. In embodiments, titration of the dose as otherwise described herein is performed until at least one clinical endpoint is reached. In embodiments, the at least one clinical endpoint includes reduced leakage as measured by fluorescein angiogram, improved perfusion as measured by fluorescein angiogram, improved perfusion as measured by OCT angiography, improved vision, improved visual acuity, subjective improved vision, improved reading speed, improved visual field testing, improved microperimetry testing, improved contrast sensitivity, improved electroretinogram (ERG) testing, resolution of hemorrhages (intraretinal and dot blot hemorrhages), and / or reduction in microaneurysms as measured by direct fundus evaluation, fundoscopy, fundus imaging, or fluorescein angiography.Atty. Docket No.: PLXB-001 / 03WO

[0221] In embodiments, the method of treating as otherwise described herein results in an improvement in visual acuity, such as that measured through Best Corrected Visual Acuity. In embodiments, the patients have a mean loss in visual acuity of no more than about 20 letters, no more than about 15 letters, no more than about 10 letters, no more than about 5 letters, or no more than zero lost letters. In embodiments, at least 70%, or at least 80%, or at least 90% of patients maintain less than about 10, less than about 15 letters, or less than about 20 letters visual acuity loss. In embodiments, the patients have a mean increase in visual acuity of at least about 5 letters, or at least about 7 letters, or at least about 10 letters, or at least about 12 letters, or at least about 15 letters, or at least about 20 letters. In embodiments, at least 70%, at least 80%, or at least about 90% of patien ts gain at least about 5 letters, at least about 10 le tters, or at least about 15 letters, or at least about 20 letters. In embodiments, the visual acuity results are determined after about 5 weeks, about 12 weeks, about 24 weeks, about 26 weeks, about 2 weeks, or about 2 years.

[0222] In embodiments, the method of treating as otherwise described herein results in an improvement as measured by OCT, such as a decrease in average or peak retinal thickness, a decrease in retinal volume, or a decrease in retinal edema. In embodiments, retinal dimensions are measured by OCT.

[0223] In embodiments, administration provides a decrease in retinal thickness and fluid volume (e.g., the central subfield thickness [CSTj of the macula) in the range of about 10% to about 50%. In embodiments, the decrease in retinal thickness is with regard to the peak thickness, or the average thickness, such as the average thickness according to OCT. In embodiments, OCT is performed on a 6 mm x 6 mm square centered on the macula. In embodiments, administration provides a decrease in retinal thickness in the range of about 20 pm to about 200 pm, or about 50 pm to about 150 pm. In embodiments, the administration provides a retinal thickness of no more than 325 pm.

[0224] In embodiments, administration provides a decrease in retinal volume in the range of about 10% to about 50%. In embodiments, administration provides a decrease in retinal volume in the range about 0.5 to about 3 mm3. In embodiments, the retinal volume is measured by OCT.

[0225] In embodiments, the method of treating comprises administration of a glucocorticoid receptor agonist and a IOP lowering agent to a patient with diabetic retinopathy, wherein the administration provides a decrease in microaneury sms, a decrease in hemorrhage, a decrease in retinal ischemia, a decrease in poor perfusion of the retina, and / or an increase in retinal perfusion. In embodiments, the patient has non-proliferative diabetic retinopathy.Atty. Docket No.: PLXB-001 / 03WO

[0226] In embodiments, the method of treating comprising administration of a glucocorticoid receptor agonist and a IOP lowering agent to a patient with proliferative diabetic retinopathy (PDR), wherein the administration provides a decrease in blood leakage, and / or a decrease in PDR-induced retinal angiogenesis. In embodiments, administration provides a decrease in VEGF expression in the retina.

[0227] In embodiments, the method of treating comprising administration of a glucocorticoid receptor agonist and a IOP lowering agent to a patient with macular edema, wherein the administration provides a decrease in retinal thickness and / or retinal volume.

[0228] In embodiments, the method of treating as otherwise described herein comprises administration of a glucocorticoid receptor agonist and a IOP lowering agent to a patient with diabetic retinopathy, wherein the administration results in an improvement, maintenance, or avoided or lessened worsening in the patient’s Diabetic Retinopathy Severity Score (DRSS). In embodiments, the DRSS score improves by at least one step, or at least two steps. In embodiments, the improvement or maintenance of the DRSS score is relative to the patient’s baseline prior to treatment, in embodiments, the patient avoids a worsening of the DRSS score of at least two steps, or more than two steps. In embodiments, administration is provided to a plurality of patients, wherein at least about 30%, or at least about 40%, or at least about 50% of the patients experience at least a two step improvement in DRSS score. In embodiments, the change in DRSS score is evaluated after 6 months, or one year, or two years. In embodiments, the patient avoids appearance or worsening of diabetic macular edema or neovascularization.Atty. Docket No.: PLXB-001 / 03WOEXAMPLES

[0229] The following examples are given for the purpose of illustrating various embodiments of the present disclosure and are not meant to limit the present disclosure in any fashion. Changes therein and other uses which are encompassed within the spirit of the disclosure, as defined by the scope of the claims, will be recognized by those skilled in the art.Example 1: Coadministration of a Glucocorticoid Receptor Agonist and an IOP Lowering Agent Treats Macular Edema Following Retinal Vein Occlusion (MEfRVO)

[0230] In clinical practice, topical coadministration of a glucocorticoid receptor agonist and an IOP lowering agent effectively treated patients suffering from macular edema following retinal vein occlusion (MEfRVO) with surprising efficacy. As another unexpected benefit, the coadministration regimen obviated the need for ocular injections in most patients treated with the combination.

[0231] MEfRVO is a serious eye condition that can quickly progress or lead to loss of vision. Eye injections play a crucial role in treating MEfRVO. Injections must be performed m-office by retina specialists, and a patient may require ongoing injections for one to two years, depending on their condition.

[0232] 39 MEfRVO patients were treated with a combination of a corticosteroid and a carbonic anhydrase inhibitor. The corticosteroid was selected from difluprednate, clobetasol, and clobetasol propionate, and the carbonic anhydrase inhibitor was chosen from dorzolamide and brinzolamide.

[0233] Treatment Regimen: Patients were treated with the combination of a corticosteroid and a carbonic anhydrase inhibitor simultaneously as -well as sequentially. Patient adherence to the regimen was improved when simultaneous dosing was performed. A single dose or a single administration was equivalent to one drop of each drug. Dosing frequency varied from once a day to up to 6 times a day. For patients carrying out sequential dosing, difluprednate three times a day combined with brinzolamide four times a day provided the most significant therapeutic improvements with the lowest side effect profile, particularly with regards to adverse intraocular pressure increase.

[0234] Importantly, it was observed that therapeutic efficacy was highly dependent on coadministration of both drugs. When either drug was not used or inadvertently discontinued, clinical improvement halted, or clinical worsening was observed.Atty. Docket No.: PLXB-001 / 03WO

[0235] FIG. 1 shows retinal scans of patients treated with the exemplary combination of a corticosteroid and a carbonic anhydrase inhibitor. The images show retinal structure prior to and following the coadministration regimen in patients with active and inactive retinal edema.

[0236] Active Retinal Edema: Prior to treatment, 22 of tire 39 patients had active retinal edema. 10 patients were previously untreated, and 12 patients had recurring retinal edema. Following implementation of the described therapeutic regimen, edema was controlled without further need for injections in 50% of treated patients (n=l 1). Additionally, the vision of some patients improved by 3 lines or more, as assessed by visual acuity testing.

[0237] Active retinal edema refers to an ongoing accumulation of fluid in the retina, particularly in the macula, causing swelling and thickening of the retinal tissue. Various underlying conditions can contribute to active retinal edema, including diabetic retinopathy, age-related macular degeneration (AMD), retinal vein occlusion, uveitis, and post-surgical inflammation.

[0238] Inactive Retinal Edema: At tire beginning of treatment, 17 of the 39 patients had inacti ve retinal edema. Following implementation of the described therapeutic regimen, 59% of patients were vision stable and required no additional injections at an average follow-up period of 9-months.

[0239] Even when inactive, retinal edema requires continued observation to detect any recurrence or reactivation. Inactive retinal edema refers to a state where fluid accumulation in the retina has resolved or stabilized, but alterations in retinal architecture may remain, e.g., persistent cystic spaces w ithout active fluid, thickening of retinal layers, and disruption of the retinal pigment epithelium. OCT can be used to evaluate progression in retinal thickness or fluid accumulation over time.

[0240] As shown in FIG. 1, the pathologic cystic spaces of fluid collection resolved after treatment. In cases where pathologic subretinal fluid was noted, the fluid resolved after treatment. Pathologic retinal hemorrhages that w7ere noted in the en-face OCT images also resolved after treatment. Normal fovea! contour and photoreceptor orientation were also restored after treatment.

[0241] Together the results indicate that tire combination of corticosteroid and a carbonic anhydrase inhibitor effectively treat patients experiencing retinal pain, inflammation, and edema, such as in the context of MEfRVO. Removing the need for further injections was an additional and unexpected advantage provided by the therapeutic methods.Atty. Docket No.: PLXB-001 / 03WOExample 2: Methods of Manufacturing Nanoemulsions of a Corticosteroid and a Carbonic Anhydrase Inhibitor

[0242] Corticosteroids pose unique challenges when formulating for ophthalmic applications, including low solubility in aqueous environments, lire following examples illustrate exemplary processes for preparing an ophthalmic pharmaceutical composition of the disclosure.

[0243] Exemplary Process 1 - Ultrasonication: The corticosteroid ingredient and phase excipients were weighed into appropriate containers to prepare stock solutions. An organic solvent was weighed into a sealable vial for dissolution of a solubility-enhancing agent, such as an amphiphilic block copolymer. The amphiphilic block copolymer was dissolved into the organic solvent. Once dissolved, the corticosteroid was added, and the combination was mixed until frilly dissolved, optionally with the aid of heat. The corticosteroid solution was added to water and was homogenized to form a primary’ emulsion. The primary emulsion was placed in an ultrasonic bath with parameters set for cavitation to form a nanoemulsion. Additional sonication may be necessary if the target particle size distribution is not achieved. The nanoemulsion was heated to remove organic solvent.

[0244] The carbonic acid inhibitor was weighed with phase excipients into appropriate containers for stock solution. A solvent solution was prepared, with the pH adjusted to 7.4 + / -0.2, The carbonic acid inhibitor was added to the solvent solution and mixed until fulty dissolved. The corticosteroid nanoemulsion and solution containing the carbonic acid inhibitor were combined. Excipients are added, and the final pH adjusted to 7.4 + / - 0.2. The final weight ratio of corticosteroid to carbonic acid inhibitor was 1:20. The resulting nanosuspension was filtered with a 0.22um PES filter. Tire collected filtrate was filled into dropper bottles,

[0245] Exemplary Process 2 - Dialysis: Tire corticosteroid ingredient and phase excipients were weighed into appropriate containers to prepare stock solutions. An organic solvent was weighed into a sealable vial for dissolution of a solubility-enhancing agent, such as an amphiphilic block copolymer. The amphiphilic block copolymer was dissolved into the organic solvent. Once dissolved, the corticosteroid was added, and the combination was mixed until fully dissolved, optionally with the aid of heat. The corticosteroid solution was added to w ater and is homogenized to form a primary’ emulsion. The emulsion w7as poured into a dialysis container and washed several times to remove organic solvent.

[0246] The carbonic acid inhibitor was weighed with phase excipients into appropriate containers for stock solution. A solvent solution was prepared, with the pH adjusted to 7.4 + / - 0.2. The carbonic acid inhibitor w?as added to the solvent solution and mixed until fullyAtty. Docket No.: PLXB-001 / 03WOdissolved. The corticosteroid nanoemulsion and solution containing the carbonic acid inhibitor were combined. The corticosteroid nanoemulsion and solution containing the carbonic acid inhibitor were combined. Excipients are added, and the final pH is adjusted to 7.40.2. The final weight ratio of corticosteroid to carbonic acid inhibitor is 1:20. The resulting nanosuspension was filtered with a 0.22um PES filter. Tire collected filtrate was filled into dropper bottles.

[0247] Exemplary Process 3 - Type Illb / Type 4 Emulsion: The corticosteroid ingredient and phase excipients were weighed into appropriate containers to prepare stock solutions. An organic solvent was weighed into a sealable vial for dissolution of a solubility-enhancing agent, such as an amphiphilic block copolymer. The amphiphilic block copolymer was dissolved into the organic solvent. Once dissolved, the corticosteroid was added, and the combination was mixed until fully dissolved, optionally with the aid of heat. The corticosteroid solution was added to water and was homogenized to form a primary emulsion. The primary emulsion was placed in an ultrasonic bath with parameters set for cavitation to form a nanoemulsion. Additional sonication was necessary if the target particle size distribution was not achieved. The nanoemulsion was poured into a dialysis container and washed several times to remove organic solvent.

[0248] lire carbonic acid inhibitor was weighed with phase excipients into appropriate containers for stock solution. A solvent solution was prepared, with the pH adjusted to 7,4 + / -0.2. Tlie carbonic acid inhibitor was added to the solvent solution and mixed until fully- dissolved. The corticosteroid nanoemulsion and solution comprising the carbonic acid inhibitor were combined, such as in a mixture. Tire corticosteroid nanoemulsion and solution comprising the carbonic acid inhibitor were combined, such as in a mixture. Excipients were added, and the final pH is adjusted to 7.4 +!- 0.2. Tire final weight ratio of corticosteroid to carbonic acid inhibitor was 1:20. The resulting nanosuspension was filtered with a 0.22um PES filter. The collected filtrate was filled into dropper bottles.

[0249] Exemplary Process 4 - Nanosuspension:1. Vehicle Preparation:1.1 Milling Vehicle Stock (VI) Preparation:

[0250] In a 200 mL glass beaker, 4.0 g polysorbate 80 and 0.5 g oleic acid was weighed and WFI was added to Q. S. to 100.0 g. Probe of the high shear homogenizer was submerged into the beaker. The liquid was processed at 3000 rpm for 5 minutes to obtain a translucent solution and homogenizer stopped.Atty. Docket No.: PLXB-001 / 03WO1.20.1% (w / w) Carbopol 974P Solution (1’2) Preparation:

[0251] 100 mg Carbopol 974P was weighed into a 200-mL glass container with a stir bar. 95 g WFI was added into the beaker. The container was put on a stir plate, capped, and mixed overnight to obtain a clear solution, lire Carbopol 974P solution was neutralized with IN NaOH to pH above 6.0 (about 500 pL NaOH solution to be added). Q. S, the solution with WFI to 100.0 g. Solution was vortexed to mix well and final pH checked.1.310 ) (w / w) PEG8000 Solution (V3) Preparation:

[0252] 5.0 g PEG8000 was weighed into a 100 mL glass container with a stir bar. Q. S. with WFI to 0.0 g. The container was capped, the container was put on a stir plate, and mixed overnight to obtain a clear solution.1.415 ) (w / w) Mannitol Solution (V4) Preparation:

[0253] 7.5 g Mannitol was weighed into a 100 mL glass container with a stir bar. Q. S. with WFI to 50,0 g. The container was capped, the container was put on a stir plate, and mixed overnight to obtain a clear solution.2. Milling Process:2.1 Brinzolamide nanosuspension preparation (Ml, 100 mg / g):2.1.1 In 2-mL milling tubes, 100 mg Brinzolamide was weigh and transferred, along with 500 mg Milling Vehicle Stock (VI), and 400 mg WFI into the tube, r 1.3 g Zirconium beads was weighed and transferred into the tube. Vortexed for 30 seconds to mix well.2.1.2 Wet milling: The tube was placed into a DeltaVita-1 Wet Grinding mill and milled at 1000 rpm for 75 min. The particle size was checked using Dynamic Light Scattering Zeta-sizer. In times the size was above 300 nm, further milling at 1000 rpm for another 20 minutes was performed and size checked. Once tire particle size was below 300 nm, the sample was collected from tire tube using a pipette.2.2 Difluprednate nanosuspension preparation (M2, 50 mg / g):2.2.1 In 2-mL milling tubes, 50 mg Brinzolamide, 125 mg Milling Vehicle Stock (VI), and 825 mg WFI was weighed and transferred into the tube, along with. 1.3 g Zirconium beads. The tube was vortexed well for 30 seconds to mix well.2.2.2 Wet milling: Tire tube was placed into a DeltaVita-1 Wet Grinding mill and milled at 1000 rpm for 45 min. The particle size was checked using DynamicAtty. Docket No.: PLXB-001 / 03WOLight Scatering Zeta-sizer. In times the size was above 300 nm, further milling at 1000 rpm for another 20 minutes was performed and size checked. Once the particle size was below 300 nm, the sample was collected from the tube using a pipette.3. Final Dilution:

[0254] The stock suspensions was diluted with different solutions to get the final drug product based on the concentration below. The final product was filled into vials with stopper and seal and the product vial stored at 2-8 C before further allocation.

[0255] Exemplary Process 5: Lipid Nanoparticles

[0256] Lipid Phase Preparation:• Desired amounts of brinzolamide, difluprednate, cholesterol, oleic acid, and egglecithin E80 were weighed into a 100-mL round bottom flask.• 30 mL DCM / Acetone (1:1 ratio by volume) co-solvent were added to the flask. Ihe flask was swirled by hand to obtain a clear solution.« Ihe solvent mixture was removed using a rotary evaporator with a water bath at 50 °C.Ihe rotary speed was set at 100 rpm. The solvent can be removed in about 5-10 minutes, and once all the solvent is visually removed, was dried for another 30 minutes.• Ihe evaporation was stopped and the flask left in a vacuum oven overnight under vacuum at ambient temperature.

[0257] Aqueous Phase Preparation:• 10 mM citrate buffer preparation: to prepare 1.0 L citrate buffer, 2.57g sodium citrate dihydrate and 242.1 mg citric acid anhydrous were weighed into a I-L volumetric flask, and -800 mL WFI was added to dissolve the solid and Q. S. to IL. The pH was checked (target pH 6.1-6.3).• Desired amount of polysorbate 80 and Hydroxypropyl-beta cyclodextrin HPB was weighed into a separate glass container, add desired amount of citrate buffer into tire container. Bath sonication at ambient temperature was applied for 10-15 minutes to obtain a clear solution.

[0258] Lipid Hydration:• Ihe aqueous phase was transferred into the round bottom flask containing dry lipids.Bath sonication was applied at ambient temperature for about 30 minutes to obtain homogeneous liquid.Atty. Docket No.: PLXB-001 / 03WO

[0259] Size Reduction by Microfluidization:• Hie pressure of Microfluidizer LV-1 was set to 10,000 PSI.• Hie product was processed for 2 passes by LV-1.• Hie formulation was collected and the in-process particle size checked by Malvern Zeta-Sizer.Example 3: Topical Ophthalmic Compositions Containing a Corticosteroid and an 1OP Lowering Agent

[0260] Composition A - Difluprednate and Brinzolamide: An exemplary composition for ophthalmic administration containing was prepared with the following components.Ingredient Amount (% wt / vol)difluprednate 0.04brinzolamide 1.0benzalkonium chloride 0.006polyethoxylated castor oil 2.0polyvinyl alcohol 0.2water q.s. to 100

[0261] Composition B - Difluprednate and Dorzolamide: An exemplary' composition for ophthalmic administration containing was prepared with the following components.Ingredient Amount (% wt / vol)difluprednate 0.05dorzolamide 2.0benzalkonium chloride 0.006boric acid 2.0polyethoxylated castor oil 2.0polysorbate 80 2.0polyvinyl alcohol 0.2EDTA disodium 0.15sodium hydroxide q.s. to pH 5.2-5.8water q.s. to 100

[0262] Composition C - Difluprednate and Brinzolamide Trimethyl Lock (TML) Prodrug: An exemplar}' composition was prepared in accordance with the reprecipitation method described by ikuta, Y., et al. “Creation of Nano Eye-Drops and Effective Drug Delivery to the Interior of the Eye,” Set. Rep. 2017, 7, 44229. Hie composition penetrates the cornea and sclera due to the hydrophobic quality of the nanoparticles.Atty. Docket No.: PLXB-001 / 03WOIngredient Amount (% wt / vol)difluprednate 0.05brinzolamide (nanoparticles) 1.0benzalkonium chloride 0.006boric acid 2.0polyethoxylated castor oil 2.0polysorbate 80 2.0polyvinyl alcohol 0.2EDTA disodium 0.15sodium hydroxide q.s. to pH 5, 2-5, 8water q.s. to 100

[0263] Composition D - Difluprednate and brinzolamide contained in 2-hydroxypropyl- P-cyclodextrin: An exemplary' composition for ophthalmic administration was prepared with the following components.Ingredient Amount (% wt / vol)difluprednate 0.05brinzolamide in 2 -hydroxypropyl - 1.0P-cyclodextrinbenzalkonium chloride 0.006boric acid 2.0polyethoxylated castor oil 2.0polysorbate 80 2.0polyvinyl alcohol 0.2EDTA disodium 0.15sodium hydroxide q.s. to pH 5.2-5.8water q.s. to 100

[0264] Composition E - Difluprednate and brinzolamide: An exemplary composition for ophthalmic administration was prepared with the following components.Ingredient Amount (% wt / vol)difluprednate 0.01-0.2%brinzolamide or dorzolamide 0.01-2.0%benzalkonium chloride 0.004-0.008%polyethoxylated castor oil 1.5 -6.0%N -lauroyl sarcosine 0.03-0.06%edetate disodium 0.001-0.05%polyvinyl alcohol 0.1 -5.0%sodium hydroxide q.s. to pH 5.2-5.8water q.s. to 100

[0265] Composition F - Difluprednate and brinzolamide: An exemplary composition for ophthalmic administration was prepared with the following components.Atty. Docket No.: PLXB-001 / 03WOIngredient Amount (% wt / vol)difluprednate 0.02-0.04%brinzolamide or dorzolamide 0.5-1.5%quaternary ammonium compound 0.0002-0.08%polyethoxylated castor oil 1.5-6.0%polyvinyl alcohol or a derivative 0.1-5.0%thereofsodium hydroxide q.s. to pH 5.2.-5.8water q.s. to 100

[0266] Composition G - Difluprednate and brinzolamide: An exemplary composition for ophthalmic administration was prepared with the following components, forming a nanoemulsion:Ingredient Amount (% wt / wt)difluprednate 0.05%brinzolamide 1.0%Castor oil 5.0%Transcutol P [diethylene glycol 4.8%monoethyl ether]Sodium Citrate Dihydrate 1.1%Citric acid anhydrous 0.01%Kolliphor EL 21.0%Poloxamer 407 1.1%Titriplex III 0.01%[ethylenedinitrilotetraacetic aciddisodium salt dihydrate]Carbopol 97 IP NF Polymer 0.21%water q.s. to 100

[0267] Composition H - Difluprednate and brinzolamide: An exemplary composition for ophthalmic administration was prepared with the following components, forming nanoliposomes:Ingredient Amount (% wt / wt)difluprednate 0.05%brinzolamide 1.0%Phosphatidylcholine (PC) 4.1%Cholesterol 1.24%Super Refined Olive-LQ-(MH) 8.26%(2 -hydroxypropyl)- P-cy clodextrin 0.4%Sodium Citrate Dihydrate 0.4%Citric acid anhydrous 0.015%Sodium Chloride 0.23%Ethyl Alcohol (200 Proof) 0.033%Poloxamer 407 1.01%Atty. Docket No.: PLXB-001 / 03WOSodium Deoxycholate 0.10%Titriplex III 0.01%[ethylenedinitrilotetraacetic aciddisodium salt dihydrate]Carbopol 971 P NF Polymer 0.20%water q.s. to 100

[0268] Composition I - Difluprednate and brinzolamide: An exemplary' composition for ophthalmic administration was prepared with the following components, forming a nanosuspensionIngredient Amount (mg / mL)difluprednate 10 mg / mLbrinzolamide 0.5 mg / mLPolysorbate 80 2 mg / mLOleic Acid 0,25 mg / mLCarbopol 97 IP NF Polymer 0.5 mg / mLPEG 8000 10 mg / mLMannitol 30 mg / mLw'ater q.s. to 100

[0269] Composition J - Difluprednate and brinzolamide: An exemplary composition for ophthalmic administration was prepared with the following components, forming a nanosuspensionIngredient Amount (mg / mL)difluprednate 10 mg / mLbrinzolamide 0,4 mg / mLPolysorbate 80 2 mg / mLOleic Acid 0.25 mg / mLCarbopol 974P NF Polymer 1.6 mg / mLPEG 8000 10 mg / mLMannitol 43 mg / mLwater q.s. to 100

[0270] Composition K - Difluprednate and brinzolamide: An exemplary7composition for ophthalmic administration was prepared wi th the following componen ts, forming nanoparticles Ingredient Amount (mg / mL)difluprednate 10 mg / mLbrinzolamide 0.5 mg / mLPolysorbate 80 20 mg / mLOleic Acid 10 mg / mLCholesterol 5 mg / mLEgg Lecithin E80 25 mg / mL(2-hydroxypropyl)~P-cyclodextrin 450 mg / mLAtty. Docket No.: PLXB-001 / 03WO10 mM citrate bufferExample 4: Formulation Stability

[0271] Composition I of Example 3 was stored for two weeks at 5 °C, with no observed changes to physiochemical stability. In contrast, several alternative formulations (not recited in Example 3) resulted in cloudy appearance, phase separation, increases in viscosity, or precipitation after storage.Example 5: Pharmacokinetics

[0272] Tire rabbit is an appropriate species of choice for the assessment and evaluation of ophthalmic products because rabbits are easy to handle and are a clinically predictable animal model for the evaluation of ocular kinetics. It has been reported that pharmacokinetic parameters such as volume of distribution and clearance differ moderately between rabbit and human. Hence, rabbit to human translation is reliable in ocular pharmacokinetic studies. Also, the relative size of the rabbit eye makes it an appropriate animal model to evaluate ocular endpoints used in preclinical pharmacology and pharmacokinetic studies of new chemical entities and different test article formulations

[0273] Hie study was organized as follows:Cone. (mg / mL), Dose per EyeGroup Test Article Brin + Di flu, (pg), Brin + Di Frequency respectively flu, respectivelyBrinzolamide (1%) + 10.0 + 350 +1 Brinzolamide (QID) Difluprednate (0.05%) 0.5 17.5 Difluprednate (TID), OU PB-01 beta #1 (Brinzolamideand Difluprednate 10.9 + 380 +2 BID, OU Ophthalmic 0.5 16.5Nanosuspension)PB-01 beta #2 (Brinzolamideand Difluprednate 10.1 + 354 +3 BID, OU Ophthalmic Lipid 0.5 18.0Nanoparticles)PB-01 beta #3 (10mg / mLBrinzolamide, 0.5mg / mL 10.0 + 350 +4 BID, OU Difluprednate 0.5 17.5Nanoliposomes)PB-01 beta #4 (10mg / mLBrinzolamide, 0.5mg / mL 10.0 + 350 +5 BID, OU Difluprednate 0.5 17.5Nanoemulsion)

[0274] Pharmacokinetic analyses were performed using non-compartmental methods with sparse sampling in Phoenix WinNonlin (version 8.5, 2.4) from the composite concentrationAtty. Docket No.: PLXB-001 / 03WOversus time data generated for plasma and tissue samples. Tire pharmacokinetic analyses, conducted by Part 58 Consulting LLC, are presented in Appendix V. The reported PK parameters Tmax, Cmax, Cmax / Dose, Tiast, AUCiast, AUCiast / Dose, T1 / 2 are defined below:

[0275] Cmax: The maximum observed concentration

[0276] TmaX; Tire time at which the maximum concentration (Cmax) is observed.

[0277] Cmax (ng / g) / Dose: The dose-normalized Cmax, calculated by dividing the Cmax by the dose in mg per eye. For plasma, the dose is doubled to account for administration to both eyes.

[0278] Ti st: The time at which the last quantifiable concentration of the drug is observed.

[0279] AUCiast: The area under the concentration-time curve from time zero to the last measurable concentration (Tiast).

[0280] T1 / 2: Hie time required for the concentration of a drug to decrease by half during the elimination phase.

[0281] AUCiast / Dose: Tire dose-normalized AUCiast, calculated by dividing the AUCiast by the dose in mg per eye. For plasma, the dose is doubled to account for administration to both eyes.

[0282] Plasma, aqueous humor, cornea, bulbar conjunctiva, palpebral conjunctiva, and retina concentrations of 21 -desacetyl difluprednate and brinzolamide were determined utilizing an LC-MS / MS method developed by PharmOptima. Loteprednol etabonate was used as the internal standard.

[0283] Table 1, Composite PK Parameters of 21 -Desacetyl Difluprednate Following Topical Administration to Rabbits in PlasmaPlasma Group 1 Group 2 Group 3 Group 4 Group 5 Tmax (hours) 0.5 0.5 1.0 1.0 0.5 Cmax (ng / mL) 0.636 0.719 0.634 0.575 0.358 Cmax (Std. Error) 0.210 0.302 0.076 0.108 NA ti / 2 (hours)* 1.46 1.87 2.10 5.24 NA AUCo-iast (ng*h / mL) 1.57 1.29 1.64 3.09 0.090 AUCo-iast (Std. Error) 0.23 0.31 0.17 0.26 NAAUCo-inf (ng*h / mL) 1.86 1.66 2.36 4.82 NA

[0284] Table 2. Composite PK Parameters of 21 -Desacetyl Difluprednate Following Topical Administration to Rabbits in Aqueous HumorAqueous Humor Group 1 Group 2 Group 3 Group 4 Group 5 Tmax (hours) 0.5 0.5 0.5 0.5 1.0 Cmax (ng / mL) 73.5 46.0 43.7 40.5 20.6 Cmax (Std. Error) 8.5 5.9 4.5 4.7 2.2 ti / 2 (hours)* NR 1.00 1.01 0.85 1.54AUCo iast (ng*h / mL) 169 99.6 85.6 97.5 53.4Atty. Docket No.: PLXB-001 / 03WOAUCo-iast (Std. Error) 16 9.3 4.6 6.9 4.2AUCo-int (ng*h / mL) NR 100 86.0 97.7 55.1

[0285] Table 3. Composite PK Parameters of 21 -Desacetyl Difluprednate Following Topical Administration to Rabbits in CorneaCornea Group 1 Group 2 Group 3 Group 4 Group 5 Tmax (hours) 1.0 0.5 0.5 0.5 0.5 Cmax (ng / mL) 202 140 320 227 195 Cmax (Std. Error) 68 47 203 144 81 ti / 2 (hours)* NR 2.44 2.61 2.89 2.58 AUCo-iast (ng*h / mL) 716 361 503 295 645 AUCo-iast (Std. Error) 155 73 130 79 131AUCo-mf (ng*h / mL) NR 400 557 329 735

[0286] Table 4. Composite PK Parameters of 21 -Desacetyl Difluprednate Following Topical Administration to Rabbits in Bulbar ConjunctivaBulbar Conjunctiva Group 1 Group 2 Group 3 Group 4 Group 5 Tmax (hours) 0.5 0.5 0.5 0.5 0.5 Cmax (ng / mL) 372 187 310 257 365 Cmax (Std. Error) 157 44 141 52 52 ti / 2 (hours)* NR 1.92 17.3 3.97 6.97 AUCo-iast (ng*h / mL) 806 507 819 497 1280 AUCo-iast (Std. Error) 184 109 167 122 181AUCo-int (ng*h / mL) NR 542 2680 641 2460

[0287] Table 5, Composite PK Parameters of 21 -Desacetyl Difluprednate Following Topical Administration to Rabbits in Palpebral ConjunctivaPalpebral Conjunctiva Group 1 Group 2 Group 3 Group 4 Group 5 Tmax (hours) 0.5 0.5 0.5 0.5 0.5 Cmax (ng / mL) 510 488 423 396 931 Cmax (Std. Error) 183 21 59 77 85 ti / 2 (hours)* 5.98 3.39 6.9 NR NR AUCo-iast (ng*h / mL) 720 1040 1360 864 2670 AUCo-iast (Std. Error) 114 160 160 149 310AUCo-int (ng*h / mL) 1090 1320 2450 NR NR

[0288] Table 6. Composite PK Parameters of 21 -Desacetyl Difluprednate Following Topical Administration to Rabbits in RetinaRetina Group 1 Group 2 Group 3 Group 4 Group 5 Tmax (hours) 1.0 1.0 0.5 1.0 1.0Cmax (ng / mL) 7.97 7.84 4.47 7.38 5.83Atty. Docket No.: PLXB-001 / 03WOCmax (Std. Error) 1.00 1.54 0.98 0.98 0.79 ti / 2 (hours)* NR 3.07 2.06 2.60 3.75 AUCo-iast (ng*h / mL) 30.7 27.1 10.9 27.4 22.2 AUCo-iast (Std. Error) 3.6 3.6 2.0 4.3 3.1AUCo-int (ng*h / mL) NR 33.9 14.9 31.6 30.4

[0289] 'fable 7. Composite PK Parameters of Brinzolamide Following Topical Administration to Rabbits in PlasmaPlasma Group 1 Group 2 Group 3 Group 4 Group 5 Tmax (hours) 1.0 1.0 1.0 1.0 1.0 Cmax (ng / mL) 23.0 25.2 18.9 8.56 13.8 Cmax (Std. Error) 3.2 1.8 5.9 0.53 2.9 ti / 2 (hours)* 5.63 4.12 5.04 5.36 4.68 AUCoiast (ng*h / mL) 107 121 82.6 50.9 71.9 AUCo-iast (Std. Error) 11 16 13.8 13.3 10.5AUCo-inf (ng*h / mL) 176 167 127 79.7 105

[0290] Table 8. Composite PK Parameters of Brinzolamide Following Topical Administration to Rabbits in Aqueous HumorAqueous Humor Group 1 Group 2 Group 3 Group 4 Group 5 Tmax (hours) 0.5 1.0 1.0 1.0 1.0 Cmax (ng / mL) 1090 203 129 43.6 96.3 Cma>: (Std. Error) 240 46 23 4.9 6.6 ti / 2 (hours)* NR 4.46 2.62 5.71 5.81 AUCo-iast (ng*h / mL) 4500 1020 479 254 594 AUCo-iast (Std. Error) 620 113 44.5 33.0 86.0AUCo-rf (ng*h / mL) NR 1456 555 410 954

[0291] Table 9. Composite PK Parameters of Brinzolamide Following Topical Administration to Rabbits in CorneaCornea Group 1 Group 2 Group 3 Group 4 Group 5 Tmax (hours) 0.5 1.0 0.5 0.5 0.5 Cmax (ng / mL) 11800 3710 2370 905 3110 Cmax (Std. Error) 600 450 500 77.0 370.0 tizz (hours)* 7.56 3.33 2.92 4.31 4.67 AUCo-iast (ng*h / mL) 41500 15600 7080 3860 12500 AUCo-iast (Std. Error) 2700 1200 410 450 1300AUCoint (ng*h / mL) 82700 19700 8350 5310 19100

[0292] Table 10. Composite PK Parameters of Brinzolamide Following Topical Administration to Rabbits in Bulbar ConjunctivaBulbar Conjunctiva Group 1 Group 2 Group 3 Group 4 Group 5Atty. Docket No.: PLXB-001 / 03WOTmax (hours) 0.5 1.0 0.5 0.5 0.5 Cmax (ng / mL) 13800 2400 3270 1190 6550 Cmax (Std. Error) 3400 280 1270 170.0 460 tv? (hours)* 5.30 4.55 NR 3.77 NR AUCoiast (ng*h / mL) 33200 10500 12600 4330 22700 AUCo-iast (Std. Error) 3000 1700 2100 800 3000AUCo-mt (ng*h / mL) 46100 15800 NR 5650 NR

[0293] Table 11. Composite PK Parameters of Brinzolamide Following Topical Administration to Rabbits in Palpebral ConjunctivaPalpebral Conjunctiva Group 1 Group 2 Group 3 Group 4 Group 5 Tmax (hours) 0.5 0.5 0.5 0.5 0.5 Cmax (ng / mL) 12700 3230 2610 1440 7210 Cmax (Std. Error) 5200 380 570 470.0 790 tic (hours)* 7.15 NR 10.6 4.99 NR AUCo-iast (ng*h / mL) 34900 13500 14700 4870 33300 AUCo-iast (Std. Error) 3500 2500 2400 580 4500 AUCo-int (ng*h / mL) 62400 NR 36800 7560 NR

[0294] Table 12. Composite PK Parameters of Brinzolamide Following Apical Administration to Rabbits in RetinaRetina Group 1 Group 2 Group 3 Group 4 Group 5 Tmax (hours) 4.0 0.5 4.0 8.0 0.5 Cmax (ng / mL) 8920 3670 2910 1650 3150 Cmax (Std. Error) 650 310 130 40.0 290 tic (hours)* NR NR NR NR NR AUCo-iast (ng*h / mL) 58600 25300 21900 11900 22200 AUCo-iast (Std. Error) 2900 1500 1300 400 900AUCo-int (ng*h / mL) NR NR NR NR NR

[0295] The pharmacokinetics by tissue are displayed in Figures 2-13.

[0296] The pharmacokinetic data can also be arranged by Group:

[0297] Table 13Difluprednate PlasmaPharmacokinetics Group 1 Group 2 Group 3 Group 4 Group 5Tmax (hours) 0.5 0.5 1.0 1.0 0.5Cmax (ng / mL) 0.636 0.719 0.634 0.575 0.358Cmax (Std. Error) 0.210 0.302 0.076 0.108 NAti / 2 (hours)* 1.46 1.87 2.10 5.24 NAAUCo-iast (ng’h / mL) 1.57 1.29 1.64 3.09 0.090AUCo-iast (Std. Error) 0.23 0.31 0.17 0.26 NAAUCo-int (ng*h / mL) 1.86 1.66 2.36 4.82 NAAtty. Docket No.: PLXB-001 / 03WO*t1 / 2 calculated using the 1, 4, and 8 hour timepointsNR: not reported when R2<0.7NA: not applicable

[0298] Table 14Difluprednate AqueousHumor Pharmacokinetics Group 1 Group 2 Group 3 Group 4 Group 5 (hours) 0.5 0.5 0.5 0.5 1.0 (ng / mL) 73.5 46.0 43.7 40.5 20.6 (Std. Error) 8.5 5.9 4.5 4.7 2.2 ti / 2 (hours)’ NR 1.00 1.01 0.85 1.54 (ng*h / mL) 169 99.6 85.6 97.5 53.4 (Std. Error) 16 9.3 4.6 6.9 4.2AUCc-inf NR 100 86.0 97.7 55.1 *t1 / 2 calculated using the 1, 4, and 8 hour timepointsNR: not reported when R2<0.7

[0299] Table 15Difluprednate CorneaPharmacokinetics Group 1 Group 2 Group 3 Group 4 Group 5 (hours) 1.0 0.5 0.5 0.5 0.5 (ng / mL) 202 140 320 227 195 (Std. Error) 68 47 203 144 81 (hours)’ NR 2.44 2.61 2.89 2.58 (ng’h / mL) 716 361 503 295 645 (Std. Error) 155 73 130 79 131(ng’h / mL) NR 400 557 329 735 *t1 / 2 calculated using the 1, 4, and 8 hour timepointsNR: not reported when R2<0.7

[0300] Table 16Difluprednate BulbarConjunctiva Group 1 Group 2 Group 3 Group 4 Group 5 Pharmacokinetics(hours) 0.5 0.5 0.5 0.5 0.5 (ng / mL) 372 187 310 257 365 (Std. Error) 157 44 141 52 52 (hours)* NR 1.92 17.3 3.97 6.97 (ng’h / mL) 806 507 819 497 1280 (Std. Error) 184 109 167 122 181(ng’h / mL) NR 542 2680 641 2460 *t1 / 2 calculated using the 1, 4, and 8 hour timepointsNR: not reported when R2<0.7Atty. Docket No.: PLXB-001 / 03WO

[0301] Table 17Difluprednate PalpebralConjunctiva Group 1 Group 2 Group 3 Group 4 Group 5 Pharmacokinetics(hours) 0.5 0.5 0.5 0.5 0.5 (ng / mL) 510 488 423 396 931 (Std. Error) 183 21 59 77 85 tv? (hours)* 5.98 3.39 6.9 NR NR720 1040 1360 864 2670 (Std. Error) 114 160 160 149 310AUCo-inf (ng*h / mL) 1090 1320 2450 NR NR*t1 / 2 calculated using the 1, 4, and 8 hour timepointsNR: not reported when R2<0.7

[0302] Table 18Difluprednate RetinaPharmacokinetics Group 1 Group 2 Group 3 Group 4 Group 5 (hours) 1.0 1.0 0.5 1.0 1.0 (ng / mL) 7.97 7.84 4.47 7.38 5.83 (Std. Error) 1.00 1.54 0.98 0.98 0.79 tie (hours)* NR 3.07 2.06 2.60 3.75 (ng*h / mL) 30.7 27.1 10.9 27.4 22.2 (Std. Error) 3.6 3.6 2.0 4.3 3.1NR 33.9 14.9 31.6 30.4 *t1 / 2 calculated using the 1,, and 8 hour timepointsNR: not reported when R2<0.7

[0303] Table 19Group 1 Difluprednate Aqueous Bulbar Palpebral Pharmacokinetics Plasma Humor Cornea Conjunctiva Conjunctiva Retina(hours) 0.5 0.5 1.0 0.5 0.5 1.0 (ng / mL) 0.636 73.5 202 372 510 7.97 (Std. Error) 0.210 8.5 68 157 183 1.00 tie (hours)* 1.46 NR NR NR 5.98 NR (ng*h / mL) 1.57 169 716 806 720 30.7 (Std. Error) 0.23 16 155 184 114 3.6(ng*h / mL) 1.86 NR NR NR 1090 NR *t1 / 2 calculated using the 1, 4, and 8 hour timepointsNR: not reported when R2<0.7Atty. Docket No.: PLXB-001 / 03WO

[0304] Table 20Group 2 Difluprednate Aqueous Bulbar Palpebral Pharmacokinetics Plasma Humor Cornea Conjunctiva Conjunctiva Retina (hours) 0.5 0.5 0.5 0.5 0.5 1.0 (ng / mL) 0.719 46.0 140 187 488 7.84 (Std. Error) 0.302 5.9 47 44 21 1.54 (hours)* 1.87 1.00 2.44 1.92 3.39 3.07 (ng*h / mL) 1.29 99.6 361 507 1040 27.1 (Std. Error) 0.31 9.3 73 109 160 3.6(ng*h / ml_) 1.66 100 400 542 1320 33.9 *t1 / 2 calculated using the 1, 4, and 8 hour timepointsNR: not reported when R2<0.7

[0305] Table 21Group 3 Difluprednate Aqueous Bulbar Palpebral Pharmacokinetics Plasma Humor Cornea Conjunctiva Conjunctiva Retina (hours) 1.0 0.5 0.5 0.5 0.5 0.5 (ng / mL) 0.634 43.7 320 310 423 4.47 (Std. Error) 0.076 4.5 203 141 59 0.98 tie (hours)* 2.10 1.01 2.61 17.3 6.9 2.06 (ng*h / mL) 1.64 85.6 503 819 1360 10.9 (Std. Error) 0.17 4.6 130 167 160 2.0AUCo-inf (ng*h / mL) 2.36 86.0 557 2680 2450 14.9 *t1 / 2 calculated using the 1,, and 8 hour timepointsNR: not reported when R2<0.7

[0306] Table 22Group 4 Difluprednate Aqueous Bulbar Palpebral Pharmacokinetics Plasma Humor Cornea Conjunctiva Conjunctiva Retina (hours) 1.0 0.5 0.5 0.5 0.5 1.0 (ng / mL) 0.575 40.5 227 257 396 7.38 Cmax (Std. Error) 0.108 4.7 144 52 77 0.98 tt / 2 (hours)* 5.24 0.85 2.89 3.97 NR 2.60 (ng*h / mL) 3.09 97.5 295 497 864 27.4 (Std. Error) 0.26 6.9 79 122 149 4.3(ng’h / mL) 4.82 97.7 329 641 NR 31.6 *t1 / 2 calculated using the 1,, and 8 hour timepointsNR: not reported when R2<0.7

[0307] Table 23Group 5 Difluprednate Aqueous Bulbar Palpebral Pharmacokinetics Plasma Humor Cornea Conjunctiva Conjunctiva RetinaAtty. Docket No.: PLXB-001 / 03WOTmax (hours) 0.5 1.0 0.5 0.5 0.5 1.0 Cmax (ng / mL) 0.358 20.6 195 365 931 5.83 Cmax (Std. Error) NA 2.2 81 52 85 0.79 t ie (hours)* NA 1.54 2.58 6.97 NR 3.75 AUCo-iast (ng*h / mL) 0.090 53.4 645 1280 2670 22.2 AUCo-iast (Std. Error) NA 4.2 131 181 310 3.1AUCo-inr (ng*h / ml_) NA 55.1 735 2460 NR 30.4 *t112 calculated using the 1, 4, and 8 hour timepointsNR: not reported when R2<0.7NA: not applicable

[0308] The pharmacokinetic data arranged by Group are displayed in Figures 14-23.Example 6: Method of Administering an Exemplary Composition to a Patient in Need Thereof and Therapeutic Outcomes

[0309] An exemplary' composition of the present disclosure is prescribed to a patient diagnosed with an ocular condition that involves any of ocular pain or inflammation, blood- retinal barrier dysfunction, vascular abnormalities, fluid accumulation, retinal tissue damage, and impaired fluid homeostasis. For example, the patient may be diagnosed with macular edema, MEfRVO, diabetic retinopathy, and macular degeneration, retinal vein occlusion. The condition may be diagnosed in connection with a post-operative complication.

[0310] The patient topically self-adm misters the composition to the eye(s) in a multi -dose per day regimen. Measurements of treatment efficacy are assessed at various time points, e.g., 2 weeks, 1 month, 3 months, and 6 months, after initiating treatment to evaluate both short-term and long-term responses to therapy.

[0311] Markers of therapeutic efficacy are available to one of skill in tire art, including improvements in visual acuity, delayed progression of retinopathy, changes in central macular thickness (CMT) and central subfield thickness, reduced blood vessel leakage, and decreased or resolved fluid accumulation. Such markers can be evaluated, detected, and observed by any of a variety of methods, including optical coherence tomography (OCT), visual acuity testing, fundus photography, fluorescein angiography, slit-lamp biomicroscopy, and combinations thereof.Example 7: Treatment of Diabetic Retinopathy

[0312] A composition comprising brinzolamide and a composition comprising difluprednate were administered to patients suffering from non-proliferative diabetic retinopathy. Fluorescein angiograms and optical retinal imaging revealed improvement in the number of microaneurysms, hemorrhages, and perfusion. Results are shown in Figs. 24-28.Atty. Docket No.: PLXB-001 / 03WO

[0313] A composition composing brinzolamide and a composition comprising difluprednate were administered to patients suffering from proliferative diabetic retinopathy. Fluorescein angiograms and optical retinal imaging revealed improvement in neovascularization and fluid leakage. Results are shown in Figs. 29-34. Improvement in a patient with proliferative diabetic retinopathy and also diabetic macular edema is demonstrated by optical coherence tomography in Fig. 35.

[0314] Surprisingly, TID dosing with difluprednate was found to result in improved vision and reduced edema compared to patients dosed with diflnprednate QID. Further, difluprednate patients dosed TID mostly avoided clinically significant elevations in intraocular pressure (< 6%), while patients dosed QID experienced intraocular pressure at a higher rate (21%). This result aligns with a surprising result from the pharmacokinetic data, where rabbits dosed BID with a fixed-dose nanosuspension comprising brinzolamide and difluprednate displayed a 1 % higher tissue concentration of diflnprednate compared to those dosed TID.Example 8: Treatment of Central Serous Retinopathy

[0315] A composition comprising brinzolamide and a composition comprising difluprednate were administered to a patient suffering from central serous retinopathy. Optical coherence tomography revealed improvement in retinal edema, reflected in Fig. 36.Example 9: Treatment of diabetic macular edema

[0316] A composition comprising brinzolamide and a composition comprising difluprednate were administered to a patient suffering from epire final membrane and diabetic macular edema. Optical coherence tomography revealed improvement disease progression, reflected in Fig. 37.

[0317] A composition comprising brinzolamide and a composition comprising difluprednate were administered to a patient suffering from cystoid macular edema and diabetic macular edema. Optical coherence tomography revealed improvement in retinal edema, reflected in Fig. 38A and B.IN CORPORATION BY REFERENCE

[0318] All references, articles, publications, patents, patent publications, and patent applications cited herein are incorporated by reference in their entireties for all purposes. However, mention of any reference, article, publication, patent, patent publication, and patent application cited herein is not, and should not be taken as, an acknowledgment or any form of suggestion that they constitute valid prior art or form part of the common general knowledge in any country in the world.Atty. Docket No.: PLXB-001 / 03WO

[0319] NUMBERED EMBODIMENTS OF THE DISCLOSURE

[0320] Notwithstanding the appended claims, the disclosure sets forth the following numbered embodiments:1. A topical ophthalmic composition, comprising:a therapeutically effective amount of a corticosteroid anda therapeutically effective amount of an intraocular-pressure lowering agent.2. The topical composition of embodiment 1, wherein the composition comprises a nanoemulsion.3. The topical composition of embodiment 1, wherein the ophthalmic administration of the composition to a patient in need thereof provides a synergistic reduction in ocular tissue pH, intraocular pressure, retinal edema or ocular inflammation compared to the separate administration of the active agents.4. The topical composition of any one of embodiments 1-3, wherein the ophthalmic administration of the composition to the patient in need thereof provides about 30 ng / mL to about 150 ng / mL of the corticosteroid and about 50 ng / mL to about 80 ng / mL of the intraocular-pressure lowering agent in the patient’s aqueous humor and / or retina.5. The topical composition of any one of embodiments 1-4, wherein the ophthalmic administration of the composition to a patient in need thereof provides about 30 ng / mL to about 90 ng / mL of the corticosteroid and about 60 ng / mL to about 80 ng / mL of the intraocular-pressure lowering agent in the patient’s vitreous humor and / or retina.6. Tire topical composition of any one of embodiments 1-5, wherein the once, twice or three times daily ophthalmic administration of the composition to a patient in need thereof provides a reduction in the patient’s IOP of about 2 mmHg to about 30 mmHg.7. The topical composition of any one of embodiments 1-6, wherein the once, twice or three times daily ophthalmic administration of the composition to a patient in need thereofAtty. Docket No.: PLXB-001 / 03WOprovides about a 15% to about 90% reduction in the frequency that the patient requires intravitreal injection of therapeutic agents compared to prior to the administration.8. The topical composition of any one of embodiments 1-7, wherein the viscosity of composition is about 2 cps to about 5 cps.9. The topical composition of any one of embodiments 2-8, wherein the particle size of the emulsion is about 90 nm to about 130 nm.10. The topical ophthalmic composition of any one of embodiments 1-9, wherein the corticosteroid comprises difluprednate, clobetasol, clobetasol propionate, or a mixture thereof.11. The topical ophthalmic composition of any one of embodiments 1-10, wherein the composition comprises about 0.01 wt% to 0.20 wt% of difluprednate.12. The topical ophthalmic composition of any one of embodiments 1-10, wherein the intraocular-pressure lowering agent is dorzolamide, brinzolamide or a combination thereof.13. Tlie topical ophthalmic composition of any one of embodiments 1-12, wherein the composition comprises about 0.01 wt% to about 2.0 wt% of the intraocular-pressure lowering agent.14. The topical ophthalmic composition of any one of embodiment 1-13, wherein the composition comprises about 0.05 wt% of difluprednate and about 1 wt% of brinzolamide.15. Tire topical ophthalmic composition of any one of embodiment 1-14, wherein the composition further comprises one or more of 0.001 wt% to 0.005 wt% of edetate disodium, 0.004 wt% to 0.008 wt% of benzalkonium chloride and a surfactant.16. The topical ophthalmic composition of any one of embodiment 1-14, wherein the composition comprises about 0.02% to 0.04% wt / vol of difluprednate, about 0.5%- 1.5% wt / vol of brinzolamide or dorzolamide, about 0.0002%-0.08% wt / vol of a quaternary’Atty. Docket No.: PLXB-001 / 03WOammonium compound, about 1.5%-6% wt / vol of polyethoxylated castor oil and about 0.1%-5% of polyvinyl alcohol or a derivative thereof in water,17. The topical ophthalmic composition of any one of embodiment 1-17, wherein the composition further comprises a Apisolex™ Polymer.18. A method of treating or preventing one or more of ocular pain, retinal inflammation and retinal edema in a patient in need thereof, the method comprising topically administering the composition of any one of embodiments 1-17 to the patient.19. The method of embodiment 18, wherein the composition is administered once per day.20. The method of embodiment 18, wherein the composition is administered twice per day,21. The method of embodiment 18, wherein the composition is administered three times per day.22. Tlie method of embodiment 18, wherein the composition is administered four times per day.23. The method of any one of embodiments 18-22, wherein the administration provides about 30 ng / mL to about 150 ng / mL of the corticosteroid and about 50 to about 80 ng / ml of the intraocular-pressure lowering agent in the patient’s aqueous humor and / or retina.24. Tire method of any one of embodiments 18-23, wherein the administration provides about 30 ng / mL to about 90 ng / mL of the corticosteroid and about 60 ng / mL to about 80 ng / mL intraocular-pressure lowering agent in the patient’s vitreous humor and / or retina.25. The method of any one of embodiments 18-24, wherein the administration provides a reduction in the patient’s TOP of about 2 mm Hg to about 30 mm Hg.Atty. Docket No.: PLXB-001 / 03WO26. The method of any one of embodiments 18-25, wherein the administration provides a reduction of about 15% to about 90% in the frequency that the patient requires intravitreal injection of therapeutic agents compared to prior to the administration.26.1 Tire method of any one of embodiments 18-26, wherein the patient has retinal edema, retinal neovascularization, choroidal neovascularization, central retinal vein occlusion, branch retinal vein occlusion, myopic choroidal neovascularization, cystoid macular edema, radiation retinopathy, or neovascular glaucoma retinopathy of prematurity.26.2 The method of any one of embodiments 18-26.1, wherein the patient has post¬ operative ocular pain and / or post-operative ocular inflammation.26.3 Tlie method of any one of embodiments 18-26.2, wherein the patient has macular edema following retinal vein occlusion (MEfRVO), central serous retinopathy, uveitis, diabetic retinopathy, diabetic macular edema, or macular degeneration,27. A method of acidifying ocular tissues with a carbonic anhydrase inhibitor in order to improve steroid receptor activation and steroid binding to improve duration and efficacy of a steroid when given in combination with the carbonic anhydrase inhibitor, the method comprising administering a therapeutically effective amount of a composition of any one of embodiments 1-17.

Claims

Atty. Docket No.: PLXB-001 / 03WOCLAIMSWe claim:

1. A topical ophthalmic composition, comprising:a therapeutically effective amount of a corticosteroid anda therapeutically effective amount of a carbonic anhydrase inhibitor, wherein: the corticosteroid comprises difluprednate, and the carbonic anhydrase inhibitor comprises dorzolamide or brinzolamide.

2. Tlie topical composition of claim 1, wherein the composition comprises a nanoemulsion or a nanosuspension.

3. The topical composition of claim 1, wherein the ophthalmic administration of the composition to a patient in need thereof provides a synergistic reduction in ocular tissue pH, intraocular pressure, retinal edema or ocular inflammation compared to the separate administration of the active agents.

4. The topical composition of any one of claims 1-3, wherein the ophthalmic administration of the composition to the patient in need thereof provides about 30 ng / mL to about 150 ng / mL of the corticosteroid and about 50 ng / mL to about 80 ng / mL of the carbonic anhydrase inhibitor in the patient’s aqueous humor and / or retina.

5. Tire topical composition of any one of claims 1-4, wherein the ophthalmic administration of the composition to a patient in need thereof provides about 30 ng / mL to about 90 ng / mL of the corticosteroid and about 60 ng / mL to about 80 ng / mL of the carbonic anhydrase inhibitor in the patient’s vitreous humor and / or retina.

6. The topical composition of any one of claims 1-5, wherein the once, twice, three, or four times daily ophthalmic administration of the composition to a patient in need thereof provides a reduction in the patient’s intraocular pressure (TOP) of about 2 mmHg to about 30 mmHg.Atty. Docket No.: PLXB-001 / 03WO7. The topical composition of any one of claims 1-6, wherein the once, twice, three, or four times daily ophthalmic administration of the composition to a patient in need thereof provides about a 15% to about 90% reduction in the frequency that the patient requires intravitreal injection of therapeutic agents compared to prior to the administration.

8. The topical composition of any one of claims 1-7, wherein the viscosity of composition is about 2 cps to about 5 cps.

9. The topical composition of any one of claims 2-8, wherein the particle size of the nanoemulsion or nanosuspension is about 90 nm to about 130 nm.

10. The topical ophthalmic composition of any one of claims 1-9, wherein the composition comprises about 0.01 wt% to 0.20 wt% of difluprednate.

11. The topical ophthalmic composition of any one of claims 1-10, wherein the composition comprises about 0.01 wt% to about 2.0 wt% of the carbonic anhydrase inhibitor.

12. Tire topical ophthalmic composition of any one of claim 1-11, wherein the composition comprises about 0.05 wt% of difluprednate and about 1 wt% of brinzolamide.

13. The topical ophthalmic composition of any one of claim 1-12, wherein the composition further comprises one or more of 0.001 wt% to 0.005 wt% of edetate disodium, 0.004 wt% to 0.008 wt% of benzalkonium chloride and a surfactant.

14. Tire topical ophthalmic composition of any one of claim 1-12, wherein the composition comprises about 0.02% to 0.04% wt / vol of difluprednate, about 0.5%-1.5% wt / vol of brinzolamide or dorzolamide, about 0.0002%-0.08% wt / vol of a quaternary ammonium compound, about 1.5%-6% wt / vol of polyethoxylated castor oil and about 0.1%- 5% of polyvinyl alcohol or a derivative thereof in water.

15. The topical ophthalmic composition of any one of claim 1-13, wherein the composition further comprises a Apisolex™ Polymer.Atty. Docket No.: PLXB-001 / 03WO16. A method of treating or preventing one or more of ocular pain, retinal inflammation, retinal hemorrhage, and retinal edema in a patient in need thereof, the method comprising topically administering the composition of any one of claims 1 -15 to the patient.

17. The method of claim 16, wherein the composition is administered once per day.

18. The method of claim 16, wherein the composition is administered twice per day.

19. The method of claim 16, wherein the composition is administered three times per day.

20. Tlie method of claim 16, wherein the composition is administered four times per day.

21. The method of claim 16, wherein the composition is administered at a first dosing frequency for an induction period, and then administered at a second dosing frequency for a subsequent maintenance period.

22. The method of claim 21, wherein the induction period is from about 3 months to about 12 months.

23. The method of claim 21 or claim 22, wherein the first dosing frequency is twice per day, and the second dosing frequency is once per day, or every other day.

24. The method of any one of claims 16-23, wherein the administration provides about 30 ng / mL to about 150 ng / mL of the corticosteroid and about 50 to about 80 ng / ml of the carbonic anhydrase inhibitor in the patient's aqueous humor and / or retina.

25. The method of any one of claims 16-24, wherein the administration provides about 30 ng / mL to about 90 ng / mL of the corticosteroid and about 60 ng / mL to about 80 ng / mL carbonic anhydrase inhibitor in the patient’s vitreous humor and / or retina.

26. Tire method of any one of claims 16-25, wherein the administration provides a reduction in the patient’s IOP of about 2 mm Hg to about 30 mm Hg.Atty. Docket No.: PLXB-001 / 03WO27. The method of any one of claims 16-26, wherein the administration provides a reduction of about 15% to about 90% in the frequency that the patient requires intravitreal injection of corticosteroid compared to prior to the administration.

28. The method of any one of claims 16-27, wherein the patient has ocular pain, ocular inflammation, post-operative ocular pain, post-operative ocular inflammation, macular edema, macular edema following retinal vein occlusion (MEfRVO), diabetic retinopathy, diabetic macular edema, macular degeneration, retinal edema, retinal neovascularization, non-choroidal neovascularization, central retinal vein occlusion, branch retinal vein occlusion, myopic choroidal neovascularization, cystoid macular edema, uveitis, radiation retinopathy, neovascular glaucoma retinopathy of prematurity, retinal hemorrhage, preretinal hemorrhage, vitreous hemorrhage, and excess subretinal fluid.

29. The method of any one of claims 16-27, wherein the patient has macular edema following retinal vein occlusion (MEfRVO), central serous retinopathy, uveitis, diabetic retinopathy, diabetic macular edema, or macular degeneration.

30. A method of acidifying ocular tissues with a carbonic anhydrase inhibitor in order to improve steroid receptor activation and steroid binding to improve duration and efficacy of a steroid when given in combination with the carbonic anhydrase inhibitor, the method comprising administering a therapeutically effective amount of a composition of any one of claims 1-15.

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