CYCLODEXTRIN FORMULATIONS

1. CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 62/698,714, filed July 16, 2018, the contents of all of which are incorporated herein by reference thereto.

2. BACKGROUND

[0002] Inflammatory diseases or disorders of the eye encompass a broad spectrum of diseases and disorders with differing etiology. Diseases and disorders of the eye characterized by an inflammatory component include, among others, allergic conjunctivitis, scleritis, blepharitis, keratitis, retinitis, choroiditis, dry -eye syndrome (keratoconjunctivitis sicca), cyclitis, iridocyclitis, iritis, meibomian gland dysfunction, sarcoidosis, and uveitis. Inflammation of the eye can also occur in reaction to injury or trauma, such as inflammation associated with eye surgery, e.g., cataract surgery, laser surgery, keratotomy, keratoplasty, corneal surgery, and vitrectomy. Infections of the eye, including fungal infections (e.g., keratomycosis, fungal keratitis, etc.), bacterial infections, protozoal, and viral infections, can lead to conjunctivitis, keratitis, and blepharitis that can have inflammation as one of its complications.

[0003] Standard treatments for eye diseases and disorders having an inflammatory response include, among others, corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDS), anti-histamines (e.g., for inflammation associated with eye allergies), and cyclosporine (e.g., for dry -eye). These therapeutic agents act on specific biological targets related to the inflammatory response. However, the inflammatory reaction is multifaceted, involving multiple cell types (e.g., T-cells,

macrophages/monocytes, and neutrophils) and different biochemical mediators (e.g., pro- inflammatory cytokines, chemokines, fibrogenic growth factors, and prostaglandins). Desirable are formulations that target different aspects of the inflammatory response for treating eye disorders characterized by an associated inflammatory reaction.

3. SUMMARY

[0004] The present disclosure relates to a composition of cyclodextrin and a therapeutic agent for treating inflammatory diseases or disorders of the eye. In one aspect, the composition for treating eye inflammation comprises a cyclodextrin and a therapeutic agent selected from an anti-histamine, alpha- adrenergic agonist, non-steroidal anti-inflammatory drug (NSAID), mast cell inhibitor or stabilizer, corticosteroid, adhesion molecule inhibitor, T-cell activation inhibitor and combinations thereof.

[0005] In some embodiments, the composition comprises a cyclodextrin and an anti-histamine. In some embodiments, the anti-histamine is selected from the group consisting of ketotifen, phenylephrine, tetrahydrozaline, pheniramine, alcaftadine, azelastine, emedastine, epinastine, and bepotastine.

[0006] In some embodiments, the composition comprises a cyclodextrin and an alpha-adrenergic agonist. In some embodiments, the alpha-adrenergic agonist is selected from the group consisting of oxymetazoline, brimonidine, cirazoline, apraclonidine hydrochloride, and naphazoline.

[0007] In some embodiments, the composition comprises a cyclodextrin and a non-steroidal antiinflammatory drug. In some embodiments, the non-steroidal anti-inflammatory drug is selected from the group consisting of diclofenac, flurbiprofen, ketorolac, bromfenac, indomethacin and nepafenac.

[0008] In some embodiments, the composition comprises a cyclodextrin and a mast cell inhibitor or stabilizer. In some embodiments, the mast cell inhibitor or stabilizer is selected from the group consisting of cromolyn, nedocromil, pemirolast, nedocromil sodium, tranilast, lodoxamide (e.g., lodoxamide tromethane), and lodoxamine (e.g., lodoxamine ethyl).

[0009] In some embodiments, the composition comprises a cyclodextrin and an anti-inflammatory steroid. In some embodiments, the anti-inflammatory steroid is a corticosteroid. In some embodiments, the steroid is selected from the group consisting of lotoprednol, rimexolone, difluprednate, fluorometholone, prednisone and prednisolone.

[0010] In some embodiments, the composition comprises a cyclodextrin and an adhesion molecule inhibitor, in particular an integrin antagonist. In some embodiments, the integrin agonist is lifitegrast (lymphocyte function-associated antigen 1 - LFA-1 antagonist).

[0011] In some embodiments, the composition comprises a cyclodextrin and a T-cell activation inhibitor. In some embodiments, the T-cell activation inhibitor is selected from the group consisting of cyclosporine, tacrolimus, pimecrolimus, and rapamycin.

[0012] In some embodiments, the composition comprises a cyclodextrin and two or more of therapeutic agents selected from anti-histamine, alpha-adrenergic agonist, non-steroidal antiinflammatory drug ( S AID), mast cell inhibitor or stabilizer, corticosteroid, adhesion molecule inhibitor, and T-cell activation inhibitor.

[0013] In some embodiments, the cyclodextrin in the compositions is selected from a-cyclodextrin, b-cyclodextrin, g-cyclodextrin, derivatives thereof, and combinations thereof. In some embodiments, the cyclodextrin or derivative thereof is selected from carboxy alkyl cyclodextrin, hydroxyalkyl cyclodextrin, sulfoalkylether cyclodextrin, alkyl cyclodextrin, and combinations thereof. In some embodiments, the cyclodextrin or derivatives thereof is sulfoalkylether^-cyclodextrin or hydroxy alky I-b-cyclodc.x trim particularly sulfobutylether^-cyclodextrin or hydroxypropyl-b- cyclodextrin. In some embodiments, the cyclodextrin is present in excess of the therapeutic agent. [0014] In some embodiments, the composition further comprises one or more ophthalmic pharmaceutically acceptable additive or excipient. In some embodiments, the one or more pharmaceutically acceptable additive or excipient is selected from a tonicity agent, solubilizing agent, stabilizing agent, preservative, buffering agent, wetting agent, viscosity enhancing agent, lubricating agent, chelating agent, and antioxidant.

[0015] In another aspect, the composition comprising a cyclodextrin and a therapeutic agent is used for treating an eye disease or disorder having an inflammatory response, or in some embodiments, for treating an inflammatory eye disease or disorder. In some embodiments, the compositions herein are used for treating allergic conjunctivitis, scleritis, blepharitis, keratitis, retinitis, cyclitis, iridocyclitis choroiditis, dry -eye syndrome (keratoconjunctivitis sicca), iritis, meibomian gland dysfunction, sarcoidosis, or uveitis.

[0016] In some embodiments, the compositions are used in treating inflammation of the eye associated with injury or trauma to the eye. In some embodiments, the compositions are used for treating inflammation associated with cataract surgery, laser surgery, keratotomy, keratoplasty, corneal surgery, accidental (non-iatrogrenic) trauma or vitrectomy.

[0017] In some embodiments, the compositions herein are used for treating ocular inflammation associated with eye infections. In some embodiments, the compositions are used for treating inflammation associated with fungal (e.g., keratomycosis, fungal keratitis, etc.), bacterial, protozoal or viral infections, including conjunctivitis, keratitis, cyclitis, iridocyclitis and blepharitis associated with eye infections.

[0018] In some embodiments, the compositions herein are used for treating irritation or inflammation associated with exposure of the eye to chemical irritants. These include irritants such as smoke, volatile organic compounds, cosmetics), dust, and use of computer monitors.

[0019] In a further aspect, the present disclosure provides a kit comprising the composition described herein for use in the methods. In some embodiments, the composition in the kit can comprise a composition of the present disclosure formulated as an ophthalmic solution, where the solution is provided in a single use vial, such as a disposable plastic squeeze vial, particularly a vial with a non- resealable snap-off or tear-off cap. In some embodiments, one or more of the single use vials are provided in the kit.

4. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] FIG. 1 depicts effect of vehicle containing cyclodextrin (¨) and vehicle without cyclodextrin (D) on ocular itch score in a conjunctival allergen provocation test (CAPT). 5. DETAILED DESCRIPTION

[0021] The present disclosure relates to active agents formulated with cyclodextrin for treating inflammatory disorders or conditions of the eye. In addition to enhancing delivery of active agents to the eye, the cyclodextrins can also have pharmacological activity, for example by acting to sequester mediators and biological effectors (e.g., prostaglandins, aldehydes, etc.) of the inflammatory response in the eye. Cyclodextrins also can reduce amyloid b present in the eye of aging eye mice and sequester lipofuscin arising from errant retinaldehyde metabolism and reduce its accumulation in the retinal pigment epithelium (RPE). Further evidence supporting the pharmacologic activity of cyclodextrin include results from clinical studies showing that vehicle containing cyclodextrin provide relief from seasonal allergic conjunctivitis. Accordingly, the present disclosure provides compositions of therapeutic agents used to treat inflammatory disorders or conditions of the eye formulated with cyclodextrin, where the concentration of cyclodextrin is at levels sufficient to provide pharmacological effects in addition to the therapeutic agent.

[0022] Cyclodextrins are compounds composed of sugar molecules bound together in a ring (i.e., cyclic oligosaccharides). In some embodiments, the sugar molecules of the cyclodextrin are composed of a-D-glucopyranosyl units connected via oc(l,4) linkages. The number of sugar units can range from 5 to 32 or more. Naturally occurring cyclodextrins include, among others, oc-cyclodextrin (6 glucopyranosyl units), b-cyclodextrin (7 glucopyranosyl units) and g-cyclodextrin (8 glucopyranosyl units). Cyclodextrins are in the form of a toroid or cone shaped structure in which the interior is generally more hydrophobic than the hydrophilic exterior. Because of this unique structure, cyclodextrins can form inclusion complexes with other hydrophobic compounds that fit in the interior cavity of the cyclodextrin while remaining water soluble due to the hydrophilic exterior.

[0023] The size of the internal cavity of a cyclodextrin is determined, in part, by the number of sugar molecules, e.g., glucopyranose units. For example, the number of glucopyranose units in the cyclodextrin can vary, for example from 6 to 12 or higher. Structural studies of such cyclodextrins indicate that the secondary hydroxyl groups (e.g., C2 and C3) of the glucopyranose units are located on the wider edge of the toroidal structure, while the primary hydroxyl groups (e.g., Ce) are on the other edge. The apolar C3 and C5 hydrogens and also the ether like oxygen atoms face the inside of the torus structure. The spatial distribution of the polar and apolar groups result in a molecule having a relatively hydrophilic exterior, which allows the cyclodextrin to be soluble in water, and an internal hydrophobic matrix, which can accommodate and form inclusion complexes with various hydrophobic guest molecules. The number of guest molecules accommodated within the internal hydrophobic cavity can vary, for example, from 1 to 3 guest molecules. In some instances, multiple number of cyclodextrins can combine to form inclusion complexes with a single guest molecule. [0024] Classes of cyclodextrins include oc-cyclodextrin, b-cyclodextrin, and g- cyclodextrin a-, b-, and g-cyclodextrin have 6, 7 and 8 a-(l,4) linked glycosyl units, respectively. The a-, b-, and g- cyclodextrins are naturally occurring cyclodextrins. Useful cyclodextrins for the compositions herein include, among others, maltosyl, glucosyl, and maltotriosyl derivatives of b- and g-cyclodextrins (see, e.g., U.S. Patent No. 4,668,626; U.S. Patent No. 5,024,998; incorporated herein by reference in their entirety). Other useful cyclodextrin derivatives have been synthesized by modification of the hydroxyl groups on the glycosyl units, for example by amination, esterification or etherification. These modifications to the cyclodextrin can result in changes to the cavity volume, solubility, and differential reactivity with guest molecules. In some embodiments, the cyclodextrin is

6 ^A ,6 ^B ,6 ^c ,6 ^D ,6 ^E ,6 ^F ,6 ^G ,6 ^H -Octakis-S-(2-carboxyethyl)-6 ^A ,6 ^B ,6 ^c ,6 ^D ,6 ^E ,6 ^F ,6 ^G ,6 ^H -octathio-y-cyclodextrin (i.e., S-2-carboxyethyl-octathio-Y-cyclodextrin, also referred to as sugammadex) and/or

6 ^A ,6 ^B ,6 ^C ,6 ^D ,6 ^E ,6 ^F ,6 ^G -Heptakis-S-(2-carboxyethyl)-6 ^A ,6 ^B ,6 ^c ,6 ^D ,6 ^F ,6 ^F ,6 ^G -heptathio-Y-cyclodextrin (i.e., S-2-carboxyethyl-heptathio-Y-cyclodextrin).

[0025] Cyclodextrins have been used in various ophthalmic formulations, particularly to enhance the solubility of poorly water soluble ophthalmic drugs and to enhance their bioavailability. Exemplary formulations employing cyclodextrins for ophthalmic applications have been described for, among others, anti-glaucoma agent arylsulfonylureido benzenesulfonamide (Bragagni et al., 2015, Bioorg Med Chem. 23(18):6223-7), cyclosporine (Johannsdottir et al., 2015, Inti J Pharm. 493(l-2):86-95), corticosteroids (e.g., Loftsson et al., 2002, Acta Ophthalmol Scand. 80: 144-150), dexamethasone (e.g., Loftsson et al., 2007, J Pharm Pharmacol 59: 629-635), ciprofloxacin (Bozkir et al., 2012, Acta Pol Pharm. 69(4):719-24), and olopatadine (U.S. Patent No. 8,791, 154; Torkildson et al., 2015, Clin Ophthamol. 9: 1703-1723).

[0026] In the present disclosure, the composition for treating eye inflammation comprises a cyclodextrin and a therapeutic agent selected from an anti-histamine, alpha-adrenergic agonist, nonsteroidal anti-inflammatory drug (NSAID), mast cell inhibitor or stabilizer, corticosteroid, adhesion molecule inhibitor, and T-cell activation inhibitor.

[0027] In some embodiments, the therapeutic agent is an anti-histamine. In some embodiments, the anti-histamine is selected from the group consisting of ketotifen, phenylephrine, tetrahydrozaline, pheniramine, alcaftadine, azelastine, emedastine, epinastine, cetirizine, and bepotastine.

[0028] In some embodiments, the therapeutic agent is an alpha-adrenergic agonist. In some embodiments, the alpha-adrenergic agonist is selected from the group consisting of oxymetazoline, tetrahydrozoline, xylometazoline, brimonidine, cirazoline, apraclonidine hydrochloride, and naphazoline. [0029] In some embodiments, the therapeutic agent is a non-steroidal anti-inflammatory drug. In some embodiments, the non-steroidal anti-inflammatory drug is selected from the group consisting of diclofenac, flurbiprofen, ketorolac, bromfenac, indomethacin and nepafenac.

[0030] In some embodiments, the therapeutic agent is a mast cell inhibitor or stabilizer. In some embodiments, the mast cell inhibitor or stabilizer is selected from the group consisting of cromolyn sodium, nedocromil, pemirolast, nedocromil sodium, tranilast, lodoxamide (e.g., lodoxamide tromethane), and lodoxamine (e.g., lodoxamine ethyl).

[0031] In some embodiments, the therapeutic agent is an anti-inflammatory steroid. In some embodiments, the anti-inflammatory steroid is a corticosteroid. In some embodiments, the steroid is selected from the group consisting of lotoprednol, rimexolone, difluprednate, fluorometholone, prednisone and prednisolone.

[0032] In some embodiments, the therapeutic agent is an adhesion molecule inhibitor, in particular an integrin antagonist. In some embodiments, the integrin agonist is lifitegrast (lymphocyte function- associated antigen 1 - LFA-1 antagonist).

[0033] In some embodiments, the therapeutic agent is a T-cell activation inhibitor. In some embodiments, the T-cell activation inhibitor is selected from the group consisting of cyclosporine, tacrolimus, pimecrolimus, and rapamycin. In some embodiments, the therapeutic agent does not include cyclosporine. That is, in some embodiments, cyclosporine is specifically excluded from the scope of therapeutic agents used for formulation with cyclodextrin and use in treating ophthalmic inflammatory diseases or disorders.

[0034] In some embodiments, the cyclodextrin in the compositions is selected from oc-cyclodextrin, b-cyclodextrin, g-cyclodextrin, derivatives thereof, and combinations thereof. In some embodiments, the cyclodextrin is selected from b-cyclodextrin, g-cyclodextrin, derivatives thereof, and combinations thereof.

[0035] In some embodiments, the cyclodextrin or derivative thereof is selected from carboxy alkyl cyclodextrin, hydroxyalkyl cyclodextrin, sulfoalkylether cyclodextrin, and alkyl cyclodextrin. In various embodiments, the alkyl group in the cyclodextrin is methyl, ethyl, propyl, butyl, pentyl, or hexyl.

[0036] In some embodiments, the cyclodextrin is oc-cyclodextrin or a derivative thereof. In some embodiments, the a-cyclodextrin or a derivative thereof is selected from carboxy alkyl-oc-cyclodextrin, hydroxyalkyl-oc-cyclodextrin, sulfoalkylether-oc-cyclodextrin, alkyl-oc-cyclodextrin, and combinations thereof. In some embodiments, the alkyl group in the oc-cyclodextrin derivative is methyl, ethyl, propyl, butyl, pentyl or hexyl.

[0037] In some embodiments, the cyclodextrin is b-cyclodextrin or a derivative thereof. In some embodiments, the b-cyclodextrin or derivative thereof is selected from carboxyalkyl^-cyclodextrin, hydroxyalkyl^-cyclodextrin, sulfoalkylether^-cyclodextrin, alkyl^-cyclodextrin, and combinations thereof. In some embodiments, the alkyl group in the b-cyclodextrin derivative is methyl, ethyl, propyl, butyl, pentyl or hexyl.

[0038] In some embodiments, the b-cyclodextrin or a derivative thereof is hydroxyalkyl-b- cyclodextrin or sulfoalkylether^-cyclodextrin. In some embodiments, the hydroxyalkyl-b- cyclodextrin is hydroxypropyl^-cyclodextrin. In some embodiments, the hydroxypropyl-b- cyclodextrin is 2-hydroxypropyl^-cyclodextrin. In some embodiments, the sulfoalkylether-b- cyclodextrin is sulfobutylether^-cyclodextrin. In some embodiments, b-cyclodextrin or a derivative thereof is alkyl^-cyclodextrin, in particular methyl^-cyclodextrin. In some embodiments using methyl^-cyclodextrin, the b-cyclodextrin is randomly methylated b-cyclodextrin.

[0039] In some embodiments, the cyclodextrin is g-cyclodextrin or a derivative thereof. In some embodiments, the g-cyclodextrin or derivative thereof is selected from carboxyalkyl-y-cyclodextrin, hydroxy alky I-g-cyclodc.xtrin. sulfoalkylether-Y-cyclodextrin, and alkyl-y-cyclodextrin. In some embodiments, the alkyl group in the g-cyclodextrin derivative is methyl, ethyl, propyl, butyl, pentyl, or hexyl. In some embodiments, the g-cyclodextrin or derivative thereof is hydroxy alky 1-g- cyclodextrin or sulfoalkylether-Y-cyclodextrin. In some embodiments, the hydroxyalkyl-g- cyclodextrin is hydroxypropyl-Y-cyclodextrin, such as 2-hydroxypropyl-Y-cyclodextrin. In some embodiments, the g-cyclodextrin or derivative thereof is S-2-carboxyalkyl-thio-Y-cyclodextrin, such as S-2-carboxyethyl-thio-Y-cyclodextrin.

[0040] In some embodiments, the g-cyclodextrin is sugammadex, also known in the art as Brdion®.

[0041] In some embodiments, the cyclodextrin is a mixture of cyclodextrins. Such mixtures can be a combination of: oc-cyclodextrin and b-cyclodextrin, including combinations of oc-cyclodextrin and b- cyclodextrin derivatives; oc-cyclodextrin and g-cyclodextrin, including combinations of oc-cyclodextrin and g-cyclodextrin derivatives; b-cyclodextrin and g-cyclodextrin, including combinations of b- cyclodextrin and g-cyclodextrin derivatives; or oc-cyclodextrin, b-cyclodextrin, and g-cyclodextrin, including combinations of oc-cyclodextrin, b-cyclodextrin, and g-cyclodextrin derivatives.

[0042] In some embodiments, various salts of the cyclodextrin or salts of the cyclodextrin derivative can be used in the compositions herein. In some embodiments, the salts are pharmaceutically acceptable salt(s), which refers to those salts of compounds, i.e., cyclodextrin, that are safe and effective for use in mammals and that possess the desired biological activity. Pharmaceutically acceptable salts include salts of acidic or basic groups present in the cyclodextrins. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzensulfonate, and p-toluenesulfonate salts. Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and diethanolamine salts. In some embodiments, the cyclodextrin is in the form of a sodium or potassium salt. Guidance on suitable pharmaceutically acceptable salts and their application to drug formulations can be found in various references, such as Remington's Pharmaceutical Sciences, 17th Ed., Mack Publishing Company, Easton, PA., 1985, and Berge, et al., 1977,“Pharmaceutical Salts,” J Pharm Sci. 66: 1-19, both of which are incorporated herein by reference.

[0043] In some embodiments, the cyclodextrin (e.g., a-, b-, or g-cyclodextrin), such as in a composition, in particular an ophthalmic solution, is present at about 0.1% to about 50% w/v, about 0.1% to about 45% w/v, about 0.1% to about 40% w/v, about 0.1% to about 35% w/v, about 0.1% to about 30% w/v, about 0.1% to about 25% w/v, about 0.1% to about 20% w/v, about 0.2% to about 15% w/v, about 0.5% to about 10% w/v, about 0.5% to about 7.5% w/v, or about 1% to about 5% w/v. In some embodiments, the cyclodextrin (e.g., a-, b-, or g-cyclodextrin), such as in a composition, in particular an ophthalmic solution, is present at about 1% to about 50% w/v, about 2% to about 50% w/v, about 5% to about 50% w/v, about 10% to about 50% w/v, about 15% to about 50% w/v, about 20% to about 50% w/v, about 25% to about 50% w/v, about 30% to about 50% w/v, about 1% to about 45% w/v, about 2% to about 45% w/v, about 5% to about 45% w/v, about 10% to about 45% w/v, about 15% to about 45% w/v, about 20% to about 45% w/v, about 25% to about 45% w/v, about 30% to about 45% w/v, about 1% to about 40% w/v, about 2% to about 40% w/v, about 5% to about 40% w/v, about 10% to about 40% w/v, about 15% to about 40% w/v, about 20% to about 40% w/v, about 25% to about 40% w/v, about 30% to about 40% w/v, about 1% to about 35% w/v, about 2% to about 35% w/v, about 5% to about 35% w/v, about 10% to about 35% w/v, about 15% to about 35% w/v, about 20% to about 35% w/v, about 25% to about 35% w/v, about 1% to about 30% w/v, about 2% to about 30% w/v, about 5% to about 30% w/v, about 10% to about 30% w/v, about 15% to about 30% w/v, about 20% to about 30% w/v, about 1% to about 25% w/v, about 2% to about 25% w/v, about 5% to about 25% w/v, about 10% to about 25% w/v, about 15% to about 25% w/v, about 1% to about 20% w/v, about 2% to about 20% w/v, about 5% to about 20% w/v, about 10% to about 20% w/v, or about 15% to about 25% w/v. [0044] In some embodiments, the cyclodextrin (e.g., a-, b-, or g-cyclodextrin), such as in a composition, in particular an ophthalmic solution, is present at about 10% w/v or greater, about 15% w/v or greater, about 20% w/v or greater, about 25% w/v or greater, about 30% w/v or greater, about 35% w/v or greater, or about 40% w/v or greater, up to 50% w/v. In some embodiments, the cyclodextrin is present at about 10% to about 50% w/v, about 12% to about 50% w/v, about 14% to about 50% w/v, about 16% to about 50% w/v, about 18% to about 50% w/v, about 20% to about 50% w/v, about 22% to about 50% w/v, about 24% to about 50% w/v, about 26% to about 50% w/v, about 28% to about 50% w/v, about 30% to about 50% w/v, about 32% to about 50% w/v, about 34% to about 50% w/v, about 36% to about 50% w/v, about 38% to about 50% w/v, about 40% to about 50% w/v, about 42% to about 50% w/v, or about 44% to about 50% w/v.

[0045] In some embodiments, an exemplary cyclodextrin is sulfobutylether-P-cyclodextrin, which can be present at about 0.1% to about 50% w/v, about 0.1% to about 45% w/v, about 0.1% to about 40% w/v, about 0.1% to about 35% w/v, about 0.1% to about 30% w/v, about 0.1% to about 25% w/v, about 0.1% to about 20% w/v, about 0.2% to about 15% w/v, about 0.5% to about 10% w/v, about 0.5% to about 7.5% w/v, or about 1% to about 5% w/v. In some embodiments, the sulfobutylether-b- cyclodextrin can be present at about 1% to about 50% w/v, about 2% to about 50% w/v, about 5% to about 50% w/v, about 10% to about 50% w/v, about 15% to about 50% w/v, about 20% to about 50% w/v, about 25% to about 50% w/v, about 30% to about 50% w/v, about 1% to about 45% w/v, about 2% to about 45% w/v, about 5% to about 45% w/v, about 10% to about 45% w/v, about 15% to about 45% w/v, about 20% to about 45% w/v, about 25% to about 45% w/v, about 30% to about 45% w/v, about 1% to about 40% w/v, about 2% to about 40% w/v, about 5% to about 40% w/v, about 10% to about 40% w/v, about 15% to about 40% w/v, about 20% to about 40% w/v, about 25% to about 40% w/v, about 30% to about 40% w/v, about 1% to about 35% w/v, about 2% to about 35% w/v, about 5% to about 35% w/v, about 10% to about 35% w/v, about 15% to about 35% w/v, about 20% to about 35% w/v, about 25% to about 35% w/v, about 1% to about 30% w/v, about 2% to about 30% w/v, about 5% to about 30% w/v, about 10% to about 30% w/v, about 15% to about 30% w/v, about 20% to about 30% w/v, about 1% to about 25% w/v, about 2% to about 25% w/v, about 5% to about 25% w/v, about 10% to about 25% w/v, about 15% to about 25% w/v, about 1% to about 20% w/v, about 2% to about 20% w/v, about 5% to about 20% w/v, about 10% to about 20% w/v, or about 15% to about 25% w/v.

[0046] In some embodiments, the sullbbutylether^-cyclodextrin, such as in a composition, in particular an ophthalmic solution, is present at about 10% w/v or greater, about 15% w/v or greater, about 20% w/v or greater, about 25% w/v or greater, about 30% w/v or greater, about 35% w/v or greater, or about 40% w/v or greater, up to 50% w/v. In some embodiments, the sulfobutylether-b- cyclodextrin is present at about 10% to about 50% w/v, about 12% to about 50% w/v, about 14% to about 50% w/v, about 16% to about 50% w/v, about 18% to about 50% w/v, about 20% to about 50% w/v, about 22% to about 50% w/v, about 24% to about 50% w/v, about 26% to about 50% w/v, about 28% to about 50% w/v, about 30% to about 50% w/v, about 32% to about 50% w/v, about 34% to about 50% w/v, about 36% to about 50% w/v, about 38% to about 50% w/v, about 40% to about 50% w/v, about 42% to about 50% w/v, or about 44% to about 50% w/v.

[0047] In some embodiments, an exemplary cyclodextrin is hydroxypropyl-ft-cyclodcxtrin. which can be present at about 0.1% to about 50% w/v, about 0.1% to about 45% w/v, about 0.1% to about 40% w/v, about 0.1% to about 35% w/v, about 0.1% to about 30% w/v, about 0.1% to about 25% w/v, about 0.1% to about 20% w/v, about 0.2% to about 15% w/v, about 0.5% to about 10% w/v, about 0.5% to about 7.5% w/v, or about 1% to about 5% w/v. In some embodiments, the hydroxypropyl-b- cyclodextrin can be present at about 1% to about 50% w/v, about 2% to about 50% w/v, about 5% to about 50% w/v, about 10% to about 50% w/v, about 15% to about 50% w/v, about 20% to about 50% w/v, about 25% to about 50% w/v, about 30% to about 50% w/v, about 1% to about 45% w/v, about 2% to about 45% w/v, about 5% to about 45% w/v, about 10% to about 45% w/v, about 15% to about 45% w/v, about 20% to about 45% w/v, about 25% to about 45% w/v, about 30% to about 45% w/v, about 1% to about 40% w/v, about 2% to about 40% w/v, about 5% to about 40% w/v, about 10% to about 40% w/v, about 15% to about 40% w/v, about 20% to about 40% w/v, about 25% to about 40% w/v, about 30% to about 40% w/v, about 1% to about 35% w/v, about 2% to about 35% w/v, about 5% to about 35% w/v, about 10% to about 35% w/v, about 15% to about 35% w/v, about 20% to about 35% w/v, about 25% to about 35% w/v, about 1% to about 30% w/v, about 2% to about 30% w/v, about 5% to about 30% w/v, about 10% to about 30% w/v, about 15% to about 30% w/v, about 20% to about 30% w/v, about 1% to about 25% w/v, about 2% to about 25% w/v, about 5% to about 25% w/v, about 10% to about 25% w/v, about 15% to about 25% w/v, about 1% to about 20% w/v, about 2% to about 20% w/v, about 5% to about 20% w/v, about 10% to about 20% w/v, or about 15% to about 25% w/v.

[0048] In some embodiments, the hydroxypropyl-p-cyclodcxLrin. such as in a composition, in particular an ophthalmic solution, is present at about 10% w/v or greater, about 15% w/v or greater, about 20% w/v or greater, about 25% w/v or greater, about 30% w/v or greater, about 35% w/v or greater, or about 40% w/v or greater, up to 50% w/v. In some embodiments, the hydroxypropyl-b- cyclodextrin is present at about 10% to about 50% w/v, about 12% to about 50% w/v, about 14% to about 50% w/v, about 16% to about 50% w/v, about 18% to about 50% w/v, about 20% to about 50% w/v, about 22% to about 50% w/v, about 24% to about 50% w/v, about 26% to about 50% w/v, about 28% to about 50% w/v, about 30% to about 50% w/v, about 32% to about 50% w/v, about 34% to about 50% w/v, about 36% to about 50% w/v, about 38% to about 50% w/v, about 40% to about 50% w/v, about 42% to about 50% w/v, or about 44% to about 50% w/v.

[0049] In some embodiments, an exemplary cyclodextrin is hydroxypropyl-Y-cyclodextrin, which can be present at about 0.1% to about 50% w/v, about 0.1% to about 45% w/v, about 0.1% to about 40% w/v, about 0.1% to about 35% w/v, about 0.1% to about 30% w/v, about 0.1% to about 25% w/v, about 0.1% to about 20% w/v, about 0.2% to about 15% w/v, about 0.5% to about 10% w/v, about 0.5% to about 7.5% w/v, or about 1% to about 5% w/v. In some embodiments, the hydroxypropyl-Y- cyclodextrin can be present at about 1% to about 50% w/v, about 2% to about 50% w/v, about 5% to about 50% w/v, about 10% to about 50% w/v, about 15% to about 50% w/v, about 20% to about 50% w/v, about 25% to about 50% w/v, about 30% to about 50% w/v, about 1% to about 45% w/v, about 2% to about 45% w/v, about 5% to about 45% w/v, about 10% to about 45% w/v, about 15% to about 45% w/v, about 20% to about 45% w/v, about 25% to about 45% w/v, about 30% to about 45% w/v, about 1% to about 40% w/v, about 2% to about 40% w/v, about 5% to about 40% w/v, about 10% to about 40% w/v, about 15% to about 40% w/v, about 20% to about 40% w/v, about 25% to about 40% w/v, about 30% to about 40% w/v, about 1% to about 35% w/v, about 2% to about 35% w/v, about 5% to about 35% w/v, about 10% to about 35% w/v, about 15% to about 35% w/v, about 20% to about 35% w/v, about 25% to about 35% w/v, about 1% to about 30% w/v, about 2% to about 30% w/v, about 5% to about 30% w/v, about 10% to about 30% w/v, about 15% to about 30% w/v, about 20% to about 30% w/v, about 1% to about 25% w/v, about 2% to about 25% w/v, about 5% to about 25% w/v, about 10% to about 25% w/v, about 15% to about 25% w/v, about 1% to about 20% w/v, about 2% to about 20% w/v, about 5% to about 20% w/v, about 10% to about 20% w/v, or about 15% to about 25% w/v.

[0050] In some embodiments, the hydroxypropyl-Y-cyclodextrin, such as in a composition, in particular an ophthalmic solution, is present at about 10% w/v or greater, about 15% w/v or greater, about 20% w/v or greater, about 25% w/v or greater, about 30% w/v or greater, about 35% w/v or greater, or about 40% w/v or greater, up to 50% w/v. In some embodiments, the hydroxypropyl-Y- cyclodextrin is present at about 10% to about 50% w/v, about 12% to about 50% w/v, about 14% to about 50% w/v, about 16% to about 50% w/v, about 18% to about 50% w/v, about 20% to about 50% w/v, about 22% to about 50% w/v, about 24% to about 50% w/v, about 26% to about 50% w/v, about 28% to about 50% w/v, about 30% to about 50% w/v, about 32% to about 50% w/v, about 34% to about 50% w/v, about 36% to about 50% w/v, about 38% to about 50% w/v, about 40% to about 50% w/v, about 42% to about 50% w/v, or about 44% to about 50% w/v.

[0051] In embodiments where mixtures of cyclodextrins are used, including any of the mixtures described above, for example mixtures of sulfobutylether-P-cyclodextrin and hydroxypropyl-b- cyclodextrin or hydroxypropyl-y-cyclodextrin and hydroxy propyl-p-cyclodc\Lrin. the total amount of cyclodextrin can be at about 0.1% to about 50% w/v, about 0.1% to about 45% w/v, about 0.1% to about 40% w/v, about 0.1% to about 35% w/v, about 0.1% to about 30% w/v, about 0.1% to about 25% w/v, about 0.1% to about 20% w/v, about 0.2% to about 15% w/v, about 0.5% to about 10% w/v, about 0.5% to about 7.5% w/v, or about 1% to about 5% w/v. In some embodiments, the total amount of cyclodextrin can be present at about 1% to about 50% w/v, about 2% to about 50% w/v, about 5% to about 50% w/v, about 10% to about 50% w/v, about 15% to about 50% w/v, about 20% to about 50% w/v, about 25% to about 50% w/v, about 30% to about 50% w/v, about 1% to about 45% w/v, about 2% to about 45% w/v, about 5% to about 45% w/v, about 10% to about 45% w/v, about 15% to about 45% w/v, about 20% to about 45% w/v, about 25% to about 45% w/v, about 30% to about 45% w/v, about 1% to about 40% w/v, about 2% to about 40% w/v, about 5% to about 40% w/v, about 10% to about 40% w/v, about 15% to about 40% w/v, about 20% to about 40% w/v, about 25% to about 40% w/v, about 30% to about 40% w/v, about 1% to about 35% w/v, about 2% to about 35% w/v, about 5% to about 35% w/v, about 10% to about 35% w/v, about 15% to about 35% w/v, about 20% to about 35% w/v, about 25% to about 35% w/v, about 1% to about 30% w/v, about 2% to about 30% w/v, about 5% to about 30% w/v, about 10% to about 30% w/v, about 15% to about 30% w/v, about 20% to about 30% w/v, about 1% to about 25% w/v, about 2% to about 25% w/v, about 5% to about 25% w/v, about 10% to about 25% w/v, about 15% to about 25% w/v, about 1% to about 20% w/v, about 2% to about 20% w/v, about 5% to about 20% w/v, about 10% to about 20% w/v, or about 15% to about 25% w/v.

[0052] In some embodiments of the mixtures of cyclodextrins, the total amount of cyclodextrin is at about 10% w/v or greater, about 15% w/v or greater, about 20% w/v or greater, about 25% w/v or greater, about 30% w/v or greater, about 35% w/v or greater, or about 40% w/v or greater, up to 50% w/v. In some embodiments, the total amount of cyclodextrin is at about 10% to about 50% w/v, about 12% to about 50% w/v, about 14% to about 50% w/v, about 16% to about 50% w/v, about 18% to about 50% w/v, about 20% to about 50% w/v, about 22% to about 50% w/v, about 24% to about 50% w/v, about 26% to about 50% w/v, about 28% to about 50% w/v, about 30% to about 50% w/v, about 32% to about 50% w/v, about 34% to about 50% w/v, about 36% to about 50% w/v, about 38% to about 50% w/v, about 40% to about 50% w/v, about 42% to about 50% w/v, or about 44% to about 50% w/v.

[0053] In some embodiments of cyclodextrin mixtures, the amount of b-cyclodextrin or derivative thereof (e.g., sulfobutylether-P-cyclodextrin or hydroxy propyl-p-cyclodcxtrin) when present is greater than 20% w/v. In some embodiments, the amount of b-cyclodextrin or derivative thereof in the mixture is at about 25% w/v or greater, at about 30% w/v or greater, at about 35% w/v or greater, at about 40% or greater, or at least 40% w/v up to 45% w/v. In some embodiments, depending on the total amount of cyclodextrin in the formulation, the amount of b-cyclodextrin or derivative thereof in the mixture is at about 22% to about 45% w/v, about 24% to about 45% w/v, about 26% to about 45% w/v, about 28% to about 45% w/v, about 30% to about 45% w/v, about 32% to about 45% w/v, about 34% to about 45% w/v, about 36% to about 45% w/v, about 38% to about 45% w/v, or about 40% to about 45% w/v.

[0054] In some embodiments, the cyclodextrin, such as in a composition thereof, in particular an ophthalmic solution, is present at about 0.1% w/v, about 0.2% w/v, about 0.5% w/v, about 1% w/v, about 2% w/v, about 3% w/v, about 4% w/v, about 5% w/v, about 6% w/v, about 7% w/v, about 8% w/v, about 9% w/v, about 10% w/v, about 12% w/v, about 14% w/v, about 16% w/v, about 18% w/v, about 20% w/v, about 25% w/v, about 30% w/v, about 35% w/v, about 40% w/v, about 45% w/v, or about 50% w/v.

[0055] In some embodiments, a b-cyclodextrin, e.g., sulfobutylether^-cyclodextrin, can be present at about 0.1% w/v, about 0.2% w/v, about 0.5% w/v, about 1% w/v, about 2% w/v, about 3% w/v, about 4% w/v, about 5% w/v, about 6% w/v, about 7% w/v, about 8% w/v, about 9% w/v, about 10% w/v, about 12% w/v, about 14% w/v, about 16% w/v, about 18% w/v, about 20% w/v, about 25% w/v, about 30% w/v, about 35% w/v, about 40% w/v, about 45% w/v, or about 50% w/v. In some embodiments, a b-cyclodextrin, e.g., hydroxypropyl^-cyclodextrin, can be present at about 0.1% w/v, about 0.2% w/v, about 0.5% w/v, about 1% w/v, about 2% w/v, about 3% w/v, about 4% w/v, about 5% w/v, about 6% w/v, about 7% w/v, about 8% w/v, about 9% w/v, about 10% w/v, about 12% w/v, about 14% w/v, about 16% w/v, about 18% w/v, about 20% w/v, about 25% w/v, about 30% w/v, about 35% w/v, about 40% w/v, about 45% w/v, or about 50% w/v.

[0056] In some embodiments, a g-cyclodextrin, e.g., hydroxypropyl-Y-cyclodextrin, can be present at about 0.1% w/v, about 0.2% w/v, about 0.5% w/v, about 1% w/v, about 2% w/v, about 3% w/v, about 4% w/v, about 5% w/v, about 6% w/v, about 7% w/v, about 8% w/v, about 9% w/v, about 10% w/v, about 12% w/v, about 14% w/v, about 16% w/v, about 18% w/v, about 20% w/v, about 25% w/v, about 30% w/v, about 35% w/v, about 40% w/v, about 45% w/v, or about 50% w/v.

[0057] In some embodiments where mixtures of cyclodextrins are used, including any of the mixtures described above, for example mixtures of sulfobutylether^-cyclodextrin and

hydroxypropyl^-cyclodextrin, the total amount of cyclodextrin can be present at about 0.1% w/v, about 0.2% w/v, about 0.5% w/v, about 1% w/v, about 2% w/v, about 3% w/v, about 4% w/v, about 5% w/v, about 6% w/v, about 7% w/v, about 8% w/v, about 9% w/v, about 10% w/v, about 12% w/v, about 14% w/v, about 16% w/v, about 18% w/v, about 20% w/v, about 25% w/v, about 30% w/v, about 35% w/v, about 40% w/v, about 45% w/v, or about 50% w/v.

[0058] It is to be understood that while the cyclodextrin amounts (e.g., concentration) for administration are given for exemplary cyclodextrins sulfobutylether-P-cyclodextrin, hydroxypropyl- b-cyclodextrin, and hydroxypropyl-Y-cyclodextrin, equivalent concentrations of the other specific cyclodextrins can be readily determined by the person of skill in the art.

[0059] In some embodiments, as discussed above, the concentration of cyclodextrin or a derivative thereof is sufficient to provide a pharmacological effect in addition to the therapeutic agent formulated with the cyclodextrin. In some embodiments, the cyclodextrin or derivative thereof is present in an amount sufficient to provide an effective amount (e.g., concentration) of free, uncomplexed cyclodextrin to provide a therapeutic benefit, in addition to the therapeutic benefit provided by the therapeutically active agent. For example, the cyclodextrin or derivative thereof is present in an amount (e.g., concentration) sufficient to provide an effective amount (or concentration) of free, uncomplexed cyclodextrin to sequester or bind an inflammatory mediator or an initiator of inflammation (e.g., prostaglandin), toxic aldehydes (e.g., malondialdehyde, 4 hydroxynonenal, etc.), and/or other compounds involved in an ophthalmic inflammatory disorder, such as lipofuscin and b- amyloid, in addition to the amount or concentration needed to enhance solubility and/or

bioavailability of the therapeutic agent. In some embodiments, the cyclodextrin or derivative thereof is present at least in 1 mole (molar) excess of the amount of the pharmaceutically activity agent which forms inclusion complexes with the cyclodextrin. In some embodiments, the cyclodextrin or derivative thereof relative to the amount of the pharmaceutically activity agent is present at least about 1 mole (molar) excess to about 500 mole (molar) excess, about 1.5 mole (molar) excess to about 100 mole (molar) excess; about 2 mole (molar) excess to about 75 mole (molar) excess; about 5 mole (molar) excess to about 50 mole (molar) excess; about 8 mole (molar) excess to about 40 mole (molar) excess; or about 10 mole (molar) excess to about 30 mole (molar) excess.

[0060] In some embodiments, the cyclodextrin or derivative thereof relative to the amount of the therapeutic agent which forms inclusion complexes with cyclodextrin is present at least in about 1.5 mole (molar) excess, 2 mole (molar) excess, 3 mole (molar) excess, 4 mole (molar) excess, 5 mole (molar) excess, 6 mole (molar) excess, 7 mole (molar) excess, 8 mole (molar) excess, 9 mole (molar) excess, 10 mole (molar) excess, 15 mole (molar) excess, 20 mole (molar) excess, 30 mole (molar) excess, 40 mole (molar) excess, 50 mole (molar) excess, 75 mole (molar) excess, 100 mole (molar) excess, 200 mole (molar) excess, 300 mole (molar) excess, 400 mole (molar) excess, or 500 mole (molar) excess. [0061] In some embodiments, the mole (or molar) ratio of the amount of cyclodextrin or derivative thereof to the amount of the pharmaceutically active agent which forms inclusion complexes with the cyclodextrin is at least about 2: 1 to about 500: 1; about 2: 1 to about 400: 1 ; about 2: 1 to about 300: 1; about 2: 1 to about 200: 1; about 5: 1 to about 150: 1; about 10: 1 to about 100: 1; about 15: 1 to about 50: 1; or about 20: 1 to about 40: 1.

[0062] In some embodiments, the mole (or molar) ratio of the amount of cyclodextrin or derivative thereof to the amount of the therapeutic agent is present in a ratio of at least about 2: 1, about 3: 1, about 4: 1, about 5: 1, about 6: 1, about 7: 1, about 8: 1, about 9: 1, about 10: 1, about 15: 1, about 20: 1, about 30: 1, about 40: 1, about 50: 1, about 100: 1, about 150: 1, about 200: 1, about 300: 1, about 400: 1, or about 500: 1.

[0063] In some embodiments, therapeutic agent is present at a therapeutically effective dose in the formulation. In some embodiments, therapeutic agent is present at least about 0.05% w/v, 0.1% w/v, about 0.2% w/v, about 0.3% w/v, about 0.4% w/v, about 0.5% w/v, about 0.6% w/v, about 0.7% w/v, about 0.8% w/v, about 0.9% w/v, about 1% w/v, about 1.5% w/v, about 2% w/v, about 3% w/v, about 4% w/v, or about 5% w/v. In some embodiments, a therapeutic agent is present at about 0.05% w/v to about 5% w/v, about 0.1% w/v to about 5% w/v, about 0.2% w/v to about 4% w/v, about 0.3% to about 3% w/v, about 0.4% w/v to about 2% w/v, or about 0.5% w/v to about 1.5% w/v. The concentration of the therapeutic agent in the composition can be determined for each therapeutic agent, taking into consideration the eye disorder or condition being treated and the efficacy of the therapeutic agents in the compositions.

[0064] In some embodiments, a first cyclodextrin can be used to enhance the solubility of the pharmaceutically active agent, and a second cyclodextrin different from the first cyclodextrin can be used to effect an additional therapeutic effect, for example by binding or sequestering an

inflammatory mediator or an initiator of inflammation. Mixtures of cyclodextrin have been described in the present disclosure. In various embodiments, the compositions can be prepared as solutions, suspensions, ointments, gels and other dosage forms for administration, particularly for topical administration. For ophthalmic topical administration, the dosage form includes solutions, ointments, gels (e.g., viscous or semi-viscous), emulsions, suspensions and solid eye drops and the like. In particular, aqueous solutions are generally preferred, based on ease of formulation and administration by a patient or medical professional. In some embodiment, the compositions are lyophilized formulations, which can be reconstituted with an ophthalmically acceptable solvent for

administration.

[0065] In some embodiments, the composition of cyclodextrin and therapeutic agent for use in the methods is formulated with one or more ophthalmic pharmaceutically acceptable additive or excipient. “Pharmaceutically acceptable” as used herein refers to materials or substances that are generally not toxic or injurious to a subject. Accordingly, in some embodiments, an ophthalmic composition comprising a cyclodextrin or derivative thereof, and a therapeutic agent as described herein, further comprises one or more of an ophthalmic pharmaceutically acceptable additive or excipient. “Additive” in the context of a pharmaceutical composition is intended to include any pharmaceutically acceptable carrier, diluent or excipient, particularly a carrier, diluent, or excipient suitable for ophthalmic use.“Excipient” refers to an ingredient or component that provides one or more of bulk, imparts satisfactory processing characteristics, helps control the dissolution rate or otherwise gives additional desirable characteristics to the compositions. Included within this term, inter alia, are compounds available to those of ordinary skill in the art, as described, for example, in the Handbook of Pharmaceutical Excipients, 4th Ed., American Pharmaceutical Association, Washington, D.C. and Pharmaceutical Press, London, England, 2003), incorporated herein by reference in its entirety. In particular, the excipients are selected such that the composition, particularly an ophthalmic composition, does not trigger pain and/or a secretion of tears.

[0066] In some embodiments, the one or more ophthalmic pharmaceutically acceptable additive or excipient is selected from a tonicity agent, solubilizing agent, stabilizing agent, preservative, buffering agent, wetting agent, viscosity enhancing agent, lubricating agent, chelating agent, and antioxidant.

[0067] In some embodiments, the cyclodextrin compositions can have one or more tonicity agents, which can be used to adjust the tonicity of the composition, for example, to the tonicity of natural tears. Suitable tonicity agents include, by way of example and not limitation, dextrans (e.g., dextran 40 or 70), dextrose, mannitol, glycerin, potassium chloride, propylene glycol, and sodium chloride. Equivalent amounts of one or more salts made up of cations, for example, such as potassium, ammonium and anions such as chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, bisulfate, the salts sodium bisulfate and ammonium sulfate, can also be used. The amount of tonicity agent will vary, depending on the particular agent to be added. In general, however, the compositions can have a tonicity agent in an amount sufficient to cause the final composition to have an ophthalmically acceptable osmolarity. In some embodiments, the cyclodextrin compositions have an osmolarity of about 200 to about 1000 mOsm/L or about 200 to about 500 mOsm/L, or any specific value within said ranges (e.g., 200 mOsm/L, 210 mOsm/L, 220 mOsm/L, 230 mOsm/L, 240 mOsm/L, 250 mOsm/L, 260 mOsm/L, 270 mOsm/L, 280 mOsm/L, 290 mOsm/L, 300 mOsm/L, 310 mOsm/L, 320 mOsm/L, 330 mOsm/L, 340 mOsm/L, 350 mOsm/L, 360 mOsm/L, 370 mOsm/L, 380 mOsm/L, 390 mOsm/L or 400 mOsm/L). In a particular embodiment, the ophthalmic formulations are adjusted with a tonicity agent to an osmolarity of ranging from about 250 to about 450 mOsm/L, or about 250 to about 350 mOsm/L. [0068] In some embodiments, the composition can have one or more preservatives, for example, to extend shelf life and/or limit bacterial growth in the solutions during storage as well as when administered therapeutically onto the eye. In some embodiments, the preservative is, among others, benzalkonium chloride, benzethonium chloride, benzododecinium bromide, cetylpyridinium chloride, chlorobutanol, ethylenediamine tetracetic acid (EDTA), thimerosol, phenylmercuric nitrate, phenylmercuric acetate, methyl/propylparabens, phenylethyl alcohol, sodium benzoate, sodium propionate, sorbic acid, boric acid, or sodium perborate. The amount of preservative in the solution can be a level that enhances the shelf life, limits bacterial growth, or otherwise preserves the ocular composition, e.g., ophthalmic solution, with minimal toxicity to the eye tissues (see, e.g., The United States Pharmacopeia, 22nd rev., and The National Formulary, 17th Ed. Rockville, MD). Amounts of preservative suitable for use in the ocular formulations can be determined by the person skilled in the art. In some embodiments, the preservatives can be used at an amount of from about 0.001% to about 1.0% w/v. For example, the preservative is present from about 0.005% to about 0.05% w/v, 0.005% to about 0.04% w/v, 0.01% to about 0.03% w/v, 0.01% to about 0.02% w/v, or from about 0.01% to about 0.015% w/v. In some embodiments, the amount of preservative can be about 0.005% w/v, about 0.01% w/v, about 0.012% w/v, about 0.014% w/v, about 0.016% w/v, about 0.018% w/v, about 0.02% w/v, about 0.03% w/v, about 0.04% w/v, or about 0.05% w/v. In some embodiments, no preservatives are used in the compositions.

[0069] In some embodiments, the composition can have one or more buffering agents for adjusting and/or maintaining the pH of the ocular solution at a specified pH range. Generally, buffer capacity should be large enough to maintain the product pH for a reasonably long shelf-life but also low enough to allow rapid readjustment of the product to physiologic pH upon administration. Generally, buffer capacities of from about 0.01 to 0.1 can be used for ophthalmic solutions, particularly at concentrations that provide sufficient buffering capacity and minimizes adverse effects, e.g., irritation, to the eye. Exemplary buffering agents include, by way of example and not limitation, various salts (e.g., sodium, potassium, etc.), acids or bases, where appropriate, of the following agents, including, among others, acetate, borate, phosphate, bicarbonate, carbonate, citrate, tetraborate, biphosphate, tromethamine, hydroxyethyl morpholine, and THAM (trishy droxymethylamino-methane). In some embodiments, the buffering agent can be present from about 0.01 mM to about 100 mM, about 0.05 mM to about 100 mM, about 0.5 mM to about 100 mM, from about 1 mM to about 50 mM, from about 1 mM to about 40 mM, from about 1 mM to about 30 mM, from about 1 mM to about 20 mM, or from about 1 mM to about 10 mM. In some embodiments, the buffering agent can be present at about 0.01 mM, about 0.05 mM, about 0.1 mM, about 0.2 mM, about 0.5 mM, about 1 mM, about 5 mM, about 10 mM, about 20 mM, about 30 mM, about 40 mM, about 50 mM, or about 100 mM. [0070] In some embodiments, an exemplary buffering agent is phosphate, particularly sodium phosphate, which can be prepared by standard procedures, for example by mixing appropriate amounts of one or more monobasic phosphates, dibasic phosphates, and the like. In particular, useful phosphate buffers are prepared from phosphate salts of alkali and/or alkaline earth metals, such as sodium or potassium phosphate, including sodium monobasic phosphate, sodium dibasic phosphate, potassium monobasic phosphate, and potassium dibasic phosphate. In some embodiments, the phosphate buffer can be present from about 0.5 mM to about 100 mM, from about 1 mM to about 50 mM, from about 1 mM to about 40 mM, from about 1 mM to about 30 mM, from about 1 mM to about 20 mM, or from about 1 mM to about 10 mM. In some embodiments, the phosphate buffer can be present at about 0.5 mM, about 1 mM, about 5 mM, about 10 mM, about 20 mM, about 30 mM, about 40 mM, about 50 mM, or about 100 mM.

[0071] In some embodiments, the compositions can have one or more wetting agents. Generally, wetting agents can hydrate and limit drying of the eye. Wetting agents generally are hydrophilic polymers, including, by way of example and not limitation, polysorbate 20 and 80, poloxamer 282, and tyloxapol. In some embodiments, wetting agents also include, among others, cellulose based polymers, such as hydroxypropylmethylcellulose (HPMC) and carboxymethylcellulose (CMC); polyvinylpyrrolidone; and polyvinyl alcohol. In some embodiments, the concentration of wetting agent ranges from about 0.1% to about 2% w/v, about 0.5% to about 1% w/v, or any specific value within the ranges. In some embodiments, the concentration of wetting agent ranges from about 0.1% to about 1.0% w/v, or any specific value within said range (e.g., 0.1-0.2%, 0.2-0.3%, 0.3-0.4%, 0.4- 0.5%, 0.5-0.6%, 0.6-0.7%, 0.7-0.8%, 0.8-0.9%, 0.9-1.0%; about 0.2%, about 0.21%, about 0.22%, about 0.23%, about 0.24%, about 0.25%, about 0.26%, about 0.27%, about 0.28%, about 0.29%, about 0.30%, about 0.70%, about 0.71%, about 0.72%, about 0.73%, about 0.74%, about 0.75%, about 0.76%, about 0.77%, about 0.78%, about 0.79%, about 0.80%, about 0.81%, about 0.82%, about 0.83%, about 0.84%, about 0.85%, about 0.86%, about 0.87%, about 0.88%, about 0.89%, or about 0.90%).

[0072] In some embodiments, the compositions can have one or more viscosity enhancing agents. The viscosity enhancing agent typically enhances the viscosity of the ocular solution to increase retention time of the solution on the eye, and in some instances, to provide a protective layer on the eye surface. Viscosity enhancing agents include, among others, carbopol gels, dextran 40 (molecular weight of 40,000 Daltons), dextran 70 (molecular weight of 70,000 Daltons), gelatin, glycerin, CMC, hydroxy ethyl cellulose, HPMC, methylcellulose, ethylcellulose, polyethylene glycol, poloxamer 407, polysorbate 80, propylene glycol, polyvinyl alcohol, and polyvinylpyrrolidone (povidone), in various molecular weights and in various compatible combinations. In some embodiments, the ophthalmic compositions containing the cyclodextrin has a viscosity that ranges from about 10 to about 150 centipoise (cpi), about 15 to about 120 cpi, about 20 to about 90 cpi (or any specific value within said ranges). In some embodiments, the ophthalmic compositions containing the cyclodextrin has a viscosity that ranges from about 15 cpi to about 30 cpi, or any specific value within the range (i.e., about 15 cpi, about 16 cpi, about 17 cpi, about 18 cpi, about 19 cpi, about 20 cpi, about 20 cpi, about 22 cpi, about 23 cpi, about 24 cpi, about 25 cpi, about 26 cpi, about 27 cpi, about 28 cpi, about 29 cpi, about 30 cpi). In some embodiments, the ophthalmic compositions containing the cyclodextrin has a viscosity that ranges from about 70 cpi to about 90 cpi, or any specific value within said range (i.e., about 70 cpi, about 71 cpi, about 72 cpi, about 73 cpi, about 74 cpi, about 75 cpi, about 76 cpi, about 77 cpi, about 78 cpi, about 79 cpi, about 80 cpi, about 81 cpi, about 82 cpi, about 83 cpi, about 84 cpi, about 85 cpi, about 86 cpi, about 87 cpi, about 88 cpi, about 89 cpi or about 90 cpi). In particular, a viscosity of from about 25 to about 50 cps are suitable for ophthalmic solutions.

[0073] In some embodiments, the compositions can have one or more lubricating agents. Ocular lubricants can approximate the consistency of endogenous tears and aid in natural tear build-up. Lubricating agents can include non-phospholipid and phospholipid-based agents. Ocular lubricants that are non-phospholipid based include, but are not limited to, propylene glycol; ethylene glycol; polyethylene glycol; hydroxypropylmethylcellulose; carboxymethylcellulose;

hydroxypropylcellulose; dextrans, such as, dextran 70; water soluble proteins, such as gelatin; vinyl polymers, such as polyvinyl alcohol, polyvinylpyrrolidone, povidone; petrolatum; mineral oil; and carbomers, such as, carbomer 934P, carbomer 941, carbomer 940, and carbomer 974P. Non phospholipid lubricants can also include compatible mixtures of any of the foregoing agents.

[0074] In some embodiments, the compositions can include one or more antioxidants. Suitable antioxidants, include, by way of example and not limitation, EDTA (e.g., disodium EDTA), sodium bisulphite, sodium metabisulphite, sodium thiosulfate, thiourea, and alpha-tocopherol.

[0075] In some embodiments, the compositions can include one or more chelating agents, such as, among others, monomeric poly acids such as EDTA, cyclohexanediamine tetraacetic acid (CDTA), hydroxy ethylethylenediamine triacetic acid (HEDTA), diethylenetriamine pentaacetic acid (DTP A), dimercaptopropane sulfonic acid (DMPS), dimercaptosuccmic acid (DMSA), aminotrimethylene phosphonic acid (ATP A), citric acid, ophthalmologically acceptable salts thereof, and combinations of any of the foregoing. In some embodiments, the biocompatible chelating agent can be present at about 0.1 wt. % to 10 wt %, 0.6 wt.% to 10 wt.%, about 1.0 wt.% to 5.0 wt.% of the formulation.

[0076] In various embodiments, the pH of the composition can be within 1.0 to 1.5 pH units from physiological pH, particularly the physiological pH in the external environment of the eye. The pH of human tears is approximately pH 7.4. Hence, the pH of the ophthalmic solution can be about 1.0 to 1.5 pH units above or below pH 7.4. In some embodiments, the pH of the ophthalmic solution is from about pH 6.0 to about pH 8.5. In some embodiments, the pH of the ophthalmic solution is from about pH 6.0 to about pH 8.0. In some embodiments, the pH of the ophthalmic solution is from about 6.5 to about 8.0. In some embodiments, the pH of the ophthalmic solution is from about 7.0 to about 8.0. In some embodiments, the pH of the ophthalmic solution is from about 7.0 to about 7.5. In some embodiments, the pH of the ophthalmic solution is about 6.5, about 7, about 7.5, about 8, or about 8.5. A person of skill in the art can select a pH that balances the stability of the composition and the tolerability of the eye to differences in pH from the natural condition. As is well known in the art, the pH of the solution can be adjusted by use of appropriate buffering agents and/or with an appropriate base (e.g., sodium hydroxide) or acid (e.g., hydrochloric acid).

[0077] In some embodiments, the excipients or carriers include a wetting agent and/or a viscosity enhancing agent (e.g., polyvinyl alcohol), antioxidant (e.g., EDTA), buffer, and optionally a preservative (e.g., benzalkonium chloride).

[0078] In some embodiments, the excipients comprise a viscosity enhancing agent (e.g., polyethylene glycol 400), wetting/lubricating agent (e.g., hydroxypropyl methylcellulose), buffer, and optionally a preservative (e.g., benzalkonium chloride and/or boric acid).

[0079] In some embodiments, the excipients include a viscosity enhancing agent (e.g.,

hydroxypropyl methylcellulose), wetting/lubricating agent (e.g., polysorbate 80), preservative (e.g., benzalkonium chloride, boric acid and/or EDTA), buffer (e.g., sodium citrate), and tonicity agent (e.g., sodium chloride).

Methods of Use

[0080] In another aspect, the compositions of a cyclodextrin and a therapeutic agent as described herein are used for treating inflammatory disorders or conditions of the eye. In some embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of a composition comprising a cyclodextrin and a therapeutic agent effective to treat an eye disease or disorder having or accompanied by an inflammatory reaction, for example, an inflammatory disease or disorder of the eye. As used herein, the terms“treating” or“treatment” of a disease, disorder, or syndrome, includes (i) preventing the disease, disorder, or syndrome from occurring in a subject, i.e., causing the clinical symptoms of the disease, disorder, or syndrome not to develop in an animal that may be exposed to or predisposed to the disease, disorder, or syndrome but does not yet experience or display symptoms of the disease, disorder, or syndrome; (ii) inhibiting the disease, disorder, or syndrome, i.e., arresting its development; and (iii) relieving the disease, disorder, or syndrome, i.e., causing regression of the disease, disorder, or syndrome. As is known in the art, adjustments for systemic versus localized delivery, age, body weight, general health, sex, diet, time of administration, drug interaction and the severity of the condition may be necessary, and is ascertainable by one of ordinary skill in the art.

[0081] As used herein, the term“prophylactic treatment” refers to treatment of a subject who does not display signs or symptoms of a disease, pathology, or medical disorder, or displays only early signs or symptoms of a disease, pathology, or disorder, for the purpose of diminishing, preventing, or decreasing the risk of developing the disease, pathology, or medical disorder. A prophylactic treatment functions as a preventative treatment against a disease or disorder.

[0082] In various embodiments, the composition is administered in a therapeutically effective amount. As used herein, the term“therapeutically effective amount” refers to any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease or disorder, or a decrease in the rate of advancement of a disease or disorder, and also includes amounts effective to enhance normal physiological function. In some embodiments, the compositions are administered in an effective amount. As used herein, the term“effective amount” refers to that amount of a drug or

pharmaceutical agent that will result in the desired biological or medical response that is being sought of a tissue, system, animal or human.

[0083] In some embodiments, a method of beating an ocular inflammatory condition comprises administering a therapeutically effective amount of a composition comprising cyclodexbin and a therapeutic agent selected from an anti-histamine, alpha-adrenergic agonist, non-steroidal antiinflammatory drug ( S AID), mast cell inhibitor or stabilizer, corticosteroid, adhesion molecule inhibitor, and T-cell activation inhibitor.

[0084] In some embodiments of the method, the composition administered comprises cyclodexbin and an anti-histamine. In some embodiments, the anti-histamine is selected from the group consisting of ketotifen, phenylephrine, tebahydrozaline, pheniramine, alcaftadine, azelastine, emedastine, epinastine, cetirizine, and bepotastine.

[0085] In some embodiments of the method, the composition administered comprises a cyclodexbin and an alpha-adrenergic agonist. In some embodiments, the alpha-adrenergic agonist is selected from the group consisting of oxymetazoline, tebahydrozoline, xylometazoline, brimonidine, cirazoline, apraclonidine hydrochloride, and naphazoline.

[0086] In some embodiments of the method, the composition administered comprises a cyclodexbin and an NSAID. In some embodiments, the NSAID is selected from the group consisting of diclofenac, flurbiprofen, ketorolac, bromfenac, indomethacin, and nepafenac. [0087] In some embodiments of the method, the composition administered comprises a cyclodextrin and a mast cell inhibitor or stabilizer. In some embodiments, the mast cell inhibitor or stabilizer is selected from cromolyn sodium, nedocromil, pemirolast, nedocromil sodium, tranilast, lodoxamide (e.g., lodoxamide tromethane), and lodoxamine (e.g., lodoxamine ethyl).

[0088] In some embodiments of the method, the composition administered comprises a cyclodextrin and a corticosteroid. In some embodiments, the corticosteroid is selected from the group consisting of lotoprednol, rimexolone, difluprednate, fluorometholone, prednisone and prednisolone.

[0089] In some embodiments of the method, the composition administered comprises a cyclodextrin and an adhesion molecule inhibitor. In some embodiments, the adhesion molecule inhibitor is an integrin antagonist. In some embodiments, the integrin antagonist is lifitegrast (lymphocyte function- associated antigen 1 - LFA-1 antagonist).

[0090] In some embodiments of the method, the composition administered comprises a cyclodextrin and a T-cell activation inhibitor. In some embodiments, the T-cell activation inhibitor is selected from the group consisting of cyclosporine, tacrolimus, pimecrolimus, and rapamycin.

[0091] In the embodiments herein, each any everyone one of the compositions of cyclodextrin and therapeutic agents described herein can be applied to the methods herein. These include compositions comprising different forms of cyclodextrins and at the various cyclodextrin concentrations, and compositions of cyclodextrin and therapeutic agents formulated with one or more ophthalmic pharmaceutically acceptable additive or excipient. In some embodiments, the composition of cyclodextrin and therapeutic agent comprises an additive or excipient selected from a tonicity agent, preservative, buffering agent, wetting agent, viscosity enhancing agent, lubricating agent, chelating agent, and antioxidant, as specified above.

[0092] In some embodiments, the compositions herein are used for treating eye diseases or disorders having an inflammatory reaction, or for treating an inflammatory disease or disorder of the eye. In some embodiments, the compositions herein are used for treating allergic conjunctivitis, scleritis, blepharitis, keratitis, retinitis, choroiditis, dry-eye syndrome (keratoconjunctivitis sicca), iritis, meibomian gland dysfunction, sarcoidosis, and uveitis. In some embodiments, a method for treating an inflammatory disorder of the eye comprises administering a subject in need thereof a

therapeutically effective amount of a composition described herein, wherein the inflammatory disorder of the eye is allergic conjunctivitis, scleritis, cyclitis, iridocyclitis, blepharitis, keratitis, retinitis, choroiditis, dry -eye syndrome (keratoconjunctivitis sicca), iritis, meibomian gland dysfunction, sarcoidosis, or uveitis. [0093] In some embodiments, treatment of allergic conjunctivitis includes treatment of specific forms of allergic conjunctivitis, including, treatment of allergic conjunctivitis, perennial allergic conjunctivitis, vernal keratoconjunctivitis, and atopic keratoconjunctivitis.

[0094] In some embodiments, the compositions herein are used in treating inflammation of the eye associated with injury or trauma to the eye. In some embodiments, the compositions are used for treating inflammation associated with eye surgery, e.g., cataract surgery, laser surgery, keratotomy, keratoplasty, corneal surgery, accidental (non-iatrogenic) trauma and vitrectomy. In some embodiments, a method for treating an inflammation associated with the eye injury or trauma comprises administering a subject in need thereof a therapeutically effective amount of a composition described herein, wherein the inflammation is associated with eye surgery, for example, cataract surgery, laser surgery, keratotomy, keratoplasty, corneal surgery, accidental (non-iatrogenic) trauma or vitrectomy.

[0095] In some embodiments, the compositions herein are used in treating inflammation of the eye associated with eye infections. In some embodiments, the compositions are used for treating inflammation associated with infections of the eye, such as fungal infections (e.g., keratomycosis, fungal keratitis, etc.), bacterial infections, protozoal infections (lead to keratitis) and viral infections, including conjunctivitis, keratitis, and blepharitis. In some embodiments, a method for treating an inflammation associated with an eye infection comprises administering a subject in need thereof a therapeutically effective amount of a composition described herein. In some embodiments, the inflammatory disorder or condition associated with an eye infection is conjunctivitis, keratitis, cyclitis, iridocyclitis or blepharitis.

[0096] In some embodiments, the compositions herein are used in treating irritation or inflammation associated with exposure of the eye to chemical irritants (e.g., smoke, volatile organic compounds, cosmetics), dust, computer monitor use, sunlight (e.g., photokeratitis), UV light, and desiccation. In some embodiments, a method for treating irritation or inflammation associated with exposure of the eye to chemical irritants (e.g., smoke, volatile organic compounds, cosmetics, etc.), dust, computer monitor use, sunlight (e.g., photokeratitis), UV light, and desiccation comprises administering a subject in need thereof a therapeutically effective amount of a composition described herein.

[0097] In the various embodiments of the methods, the subject to be treated is a mammal, for example a dog, a cat, a horse, or a rabbit. In some embodiments, the subject is a non-human primate, for example a monkey, chimpanzee, or gorilla. In some embodiments, the subject is a human, sometimes referred to herein as a patient.

[0098] In various embodiments, the cyclodextrin compositions are administered in an amount which is effective for the intended use. The particular dosages are also selected based on a number of factors including the age, sex, species, condition of the subject, and the specified disease or disorder.

Effective amounts can also be extrapolated from dose-response curves derived from in vitro test systems or from animal models, or clinical trials. Particular dosages may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens can be adjusted over time according to the subject’s need and in some embodiments the professional judgment of a person administering or supervising the administration of the cyclodextrin compositions. Generally, a dosing regimen is determined using techniques known to one skilled in the art.

[0099] In some embodiments, the composition is administered as needed, for example based on guidance from a medical professional skilled in the art and/or as assessed by the patient. In some embodiments, the composition is administered at least once per week. In some embodiments, the composition is administered at least once every two days. In some embodiments, the composition is administered at least once per day. In some embodiments, the composition is administered at least twice per day, at least three times per day, at least four times per day, at least five times per day, at least six times per day, or at least 8 times a day.

[0100] In some embodiments, for topical ophthalmic administration, each administration comprises one or more aliquots of the composition (e.g., ophthalmic solution). Each aliquot can be a defined volume, for example about 10 pL to about 100 pL about 20 pL to about 80 pL, or about 30 pL to about 60 pL. In some embodiments, each aliquot is about 10 pL, about 20 pL, about 30 pL, about 40 pL, about 50 pL, about 60 pL, about 70 pL, about 80 pL, about 90 pL, or about 100 pL. In some embodiments, the aliquot administered is an estimated volume, for example an applied drop using a dropper or a squeeze vial. In some embodiments, one or more drops, at least two drops, at least three drops, at least 4 drops, at least 5 drops, or at least 6 drops are topically applied to an eye or to each of both eyes at each administration. In some embodiments, each administration comprises sequential administration, for example, a first administration of one or more aliquots (e.g., one or more drops), a first time period for allowing absorption of the composition, followed by a second administration of one or more aliquots (e.g., one or more drops).

[0101] Generally, for topical administration the composition is allowed to remain in contact with the eye for a therapeutically effective time period. In some embodiments, the composition is allowed to remain in contact with the eye for at least about 0.1 min, 0.2 min 0.25 min, 0.3 min, 0.5 min, 1 min,

1.5 min, 2 min or longer, 5 min or longer, 10 min or longer for example, as determined by the medical professional skilled in the art.

[0102] In some embodiments, the treatment duration is for a time resulting in reducing, ameliorating, or mitigating one or more symptoms of the inflammatory disorder or condition of the eye being treated. In some embodiments, the duration of treatment is at least 2 days, at least 3 days, at least 5 days, at least 7 days (i.e., one week), at least 10 days, at least 14 days (i.e., two weeks), at least 17 days, at least 21 days (i.e., three weeks), or at least 28 days (i.e., four weeks) or more. In some embodiments, the treatment duration is one month or more, two months or more, three months or more, or four months or more.

[0103] In some embodiments, the duration of treatment is about 2 days to about 4 months, about 7 days (i.e., one week) to about 3 months, about 14 days (i.e., two weeks) to about 2 months, or about 21 days (i.e., three weeks) to about 6 weeks (i.e., 1.5 months).

[0104] In some embodiments, the treatment includes an initiation phase followed by a maintenance phase. In some embodiments, the patient is administered the composition at least four times per day, at least five times per day, at least six times per day, or at least 8 times a day during the initiation phase, followed by administration one times per day, two times per day, three time per day up to four times a day, or administered as needed. In some embodiments, the initiation phase can be up to one week, two weeks, three week or up to four weeks.

[0105] In some embodiments, as discussed above, the compositions can be administered

prophylactically to a subject previously diagnosed but showing no symptoms of the eye disorder or condition. The prophylactic treatment can follow the dosages and administration schedules discussed above.

5.1. Kits

[0106] In another aspect, any of the composition described herein, particularly an ophthalmic solution, can be provided in a kit, for example packaged as either a single dose product, such as a single use vial, or a multi-dose product, such as a multi-use vial. In some embodiments, the single dose product is sterile and all of the composition in the package is intended to be consumed in a single application to one or both eyes of a patient.

[0107] In some embodiments, the composition is a multi-dose product, which is also sterile when packaged. For the multi-dose product, the composition can contain a preservative and/or antimicrobial agent to ensure that the composition will not become contaminated from repeated opening and handling of the container. The standards for the level of antimicrobial activity is specified in reference publications, such as the United States Pharmacopoeia (“USP”) and corresponding publications in other countries.

[0108] In some embodiments, any of the compositions described herein can be used as a contact lens storage solution. In some embodiments, the compositions are used for patients wearing a contact lens. In some embodiments, the kit can comprise a contact lens stored in any of the compositions described herein, and an ophthalmic solution comprising any of the compositions herein for use by the patient wearing the contact lens. In some embodiments, the composition used as the contact lens storage solution has the same active ingredient and the ophthalmic solution in the kit.

[0109] Packaging of the compositions as single dose product can reduce or eliminate the need for an antimicrobial preservative in the composition, which preservative may cause ocular irritation, particularly in patients suffering from pre-existing ocular irritation. The single dose products can be provided as small volume plastic vials, particularly disposable single use plastic squeeze vials, where the single use vials have a non-resealable snap cap or tear-off cap.

[0110] While the compositions are preferably formulated as ready to use aqueous solutions, i.e., solution which does not require any dilution or preparation before use, alternative formulations are can be used. For example, the compositions, optionally prepared with one or more of an ophthalmic pharmaceutically acceptable additives and/or excipients, can be lyophilized or otherwise provided as a dried powder or solid form ready for reconstitution with a solvent, such as sterile water (e.g., deionized or distilled). In some embodiments, the compositions are pyrogen and/or endotoxin free, as required for marketing approval by the appropriate governmental agency. In various embodiments, the sterile compositions can be prepared by appropriate sterilization procedures known in the art. In some embodiments, the composition is produced under sterile conditions, and the mixing and packaging is conducted under sterile conditions. In some embodiments, the compositions may be filter sterilized and fdled in vials, including unit dose vials providing sterile unit dose formulations.

In some embodiments, the composition and/or agents of the compositions is sterilized by steam, g- radiation, or by appropriate chemical sterilization procedures.

[0111] The present disclosure further provides a pharmaceutical pack or kit comprising one or more containers filled with a liquid or lyophilized composition of the present disclosure. In some embodiments, the composition is an aqueous formulation of the compositions described herein. In some embodiments, the composition is in a lyophilized form.

[0112] In some embodiments, the kit further comprises instructions for use in the treatment of any of the indications described herein, as well as side effects and dosage information for one or more routes of administration, in particular as required by an appropriate government agency. While the instructional materials typically comprise written or printed materials, any medium capable of storing such instructions and communicating them to an end user is contemplated. Such media include but are not limited to electronic storage media (e.g., magnetic discs, tapes, cartridges, chips), optical media (e.g., CD ROM), and the like. Such media may include addresses to internet sites that provide such instructional materials. [0113] The following examples are provided to further illustrate the methods of the present disclosure, and the compounds and compositions for use in the methods. The examples described are illustrative only and are not intended to limit the scope of the invention in any way.

6. EXAMPLES

Example 1 : Comparison of Ophthalmic Solution Containing Cyclodextrin to

Vehicle Containing No Cyclodextrin in Allergic Conjunctivitis

[0114] FIG. 1 compares the effect of a cyclodextrin containing vehicle vs. a non-cyclodextrin vehicle on ocular itching in a conjunctival allergen provocation test (CAPT) model. CAPT is an accepted clinical trials model used for evaluating the activity of ophthalmic anti-allergy medications (see, e.g., Abelson et al., 1998, Am J Ophthalmol. 125(6):797-804; incorporated herein by reference).

[0115] The data in FIG. 1 are drawn from two independent allergic conjunctivitis clinical trials utilizing CAPT with subjects exposed to seasonal allergens. The non-cyclodextrin vehicle data is from an allergic conjunctivitis study of Goldstein et al., 2015, Eye & Contact Lens, 41(3): 145-155, while the cyclodextrin-containing vehicle data is from a clinical trials study evaluating aldehyde trapping compound ADX-102 (aka, NS2) for treatment of allergic conjunctivitis. While these allergic conjunctivitis clinical trials were rim independently, each study was a randomized, double-masked and vehicle-controlled study conducted in the CAPT model, and the subjects were challenged with seasonal allergens which included ragweed, grass, trees and perennials, thereby allowing for a comparison of the results from the separate studies.

[0116] In CAPT subjects treated with ophthalmic solution containing sulfobutylcthcr-p-cyclodcxtrin (SBE-p-CD). 9.5%w/v (¨), a marked reduction in ocular itching from the baseline was observed. The observed reduction of approximately 0.5 point for ocular itch in the first 15 minutes was sustained over 60 minutes post allergen challenge.

[0117] In CAPT subjects treated with an aqueous non-cyclodextrin vehicle (D), minimal reduction in ocular itching from the baseline was observed. The small reduction of ocular itch observed occurred during the first 15 minutes of exposure. However, ocular itching was observed to increase during the remainder of the 60 minutes exposure period.

[0118] The reduction in ocular itching observed in the comparison of the two data sets supports the view that a composition of cyclodextrin formulation provides therapeutic benefit over an aqueous vehicle containing no cyclodextrin. [0119] All publications, patents, patent applications and other documents cited in this application are hereby incorporated by reference in their entireties for all purposes to the same extent as if each individual publication, patent, patent application or other document were individually indicated to be incorporated by reference for all purposes.