Pharmaceutical Compositions of Mycophenolic Acid and / or Betamethasone for the Treatment of Eye Diseases - Patent application

Abstract

Pharmaceutical compositions and methods for treating eye diseases in a subject are provided. [Solution] A pharmaceutical composition and method for treating an eye disease in a subject comprising betamethasone or a pharma- ceutical acceptable salt thereof in a concentration of 0.01% w / w to 0.08% w / w, mycophenolic acid or a pharma- ceutical acceptable salt thereof in a concentration of 0.05% w / w to 0.30% w / w, or both betamethasone and mycophenolic acid or their salts.

Description

[Technical field]

[0001] This application claims priority to U.S. Provisional Patent Application No. 17 / 582,627, filed January 24, 2022, U.S. Provisional Patent Application No. 63 / 317,770, filed March 8, 2022, U.S. Provisional Patent Application No. 63 / 402,704, filed August 31, 2022, and U.S. Provisional Patent Application No. 63 / 415,419, filed October 12, 2022.

[0002] The present invention relates to pharmaceutical compositions for the treatment of ocular diseases, and more particularly to compositions comprising mycophenolic acid or a pharma- ceutical acceptable salt thereof (e.g., mycophenolate sodium) and / or betamethasone or a pharma- ceutical acceptable salt thereof (e.g., betamethasone sodium phosphate) for the treatment of ocular diseases such as, but not limited to, dry eye disease, blepharitis, meibomian gland disease (MGD), hyperemia, uveitis, and for use as a post-operative treatment for the eye. [Background technology]

[0003] Ophthalmic diseases are conditions that affect the health of the eye. Some of the more common eye diseases are surface diseases, which refer to damage to the surface layers of the eye, i.e., the cornea and conjunctiva. Some of the more common ocular surface diseases include dry eye disease, blepharitis, and meibomian gland disease (MGD), which may be precursors to blepharitis and / or dry eye disease and acute and chronic ocular allergies. Many patients are diagnosed with more than one of these.

[0004] The American Academy of Ophthalmology (AAO) defines dry eye syndrome / dry eye disease (DED) in a Preferred Practice Pattern report as a group of disorders of the tear film due to reduced tear production or tear film instability, accompanied by ocular discomfort and / or visual symptoms, and ocular surface inflammatory disorders. AA0 (2018). Ocular surface discomfort is often described as dryness, burning, itching, or a gritty / gritty sensation. Baudouin (2014). Some patients with DED have primary Sjögren's syndrome, an autoimmune disease that primarily affects the exocrine glands and causes Sjögren's syndrome (dryness of the exocrine glands, especially the eyes and mouth). The prevalence of clinically diagnosed dry eye is 0.4% to 0.5% in all ages, and is highest in women and older adults (over 65 years). AAO (2018).

[0005] The ocular surface and lacrimal glands function as an integrated unit. Any change in the composition or volume of the tear film can lead to instability of the tear film, which can result in ocular irritation and symptoms, and damage the ocular surface epithelium. Stern (2014), Baudouin (2014), Hyon (2014). Dysfunction of this integrated unit can result from aging, a decrease in supportive factors (such as androgen hormones), systemic inflammatory diseases (such as Sjögren's syndrome or rheumatoid arthritis), ocular surface diseases (such as herpes simplex virus (HSV) keratitis), or surgery (e.g., LASIK) that disrupts trigeminal afferent sensory nerves and systemic diseases or medications that disrupt the efferent cholinergic nerves that stimulate tear secretion. AAO (2018).

[0006] One of the core mechanisms of DED is evaporation-induced tear hyperosmolality, which is the hallmark of the disease. It damages the ocular surface both directly and by causing inflammation. Craig (2017). A wide range of forms of DED are recognized: aqueous dry eye (ADDE) and evaporative dry eye (EDE). Baltatzis (2003).

[0007] In ADDE, reduced tear secretion, under conditions of normal ocular evaporation, results in tear hyperosmolarity. In the Western world, the most common cause of ADDE is inflammatory infiltration of the lacrimal gland, most severely associated with autoimmune diseases such as Sjögren's syndrome and, to a lesser extent, non-Sjögren's syndrome.

[0008] In EDE, tear hyperosmolarity is caused by excessive evaporation from the exposed tear film in the presence of normally functioning lacrimal glands. Because tear osmolarity is a function of tear evaporation in either ADDE or EDE, tear hyperosmolarity is generated by evaporation from the ocular surface, and in that sense, all forms of DED are evaporative. In other words, EDE is more accurately considered to be a hyperevaporative state.

[0009] Current treatments for DED include the use of artificial tears (topical lubricant preparations), topical corticosteroids, punctal plugs, ocular immunomodulators, lymphocyte function-associated antigen 1 (LFA-1) antagonists, and devices or medications that stimulate tearing.

[0010] Artificial tears are the most common treatment strategy for patients with DED of all severity. Jones (2017). Most clinical trials involving topical lubricant formulations have documented some improvement (but not resolution) of subjective symptoms and improvement in some objective parameters. However, the improvements noted are not necessarily superior to those seen with vehicle or other nonpreservative artificial lubricants. The elimination of preservatives and the development of newer, less toxic preservatives have improved the tolerability of ocular lubricants by dry eye patients.

[0011] Although considered effective, topical corticosteroid anti-inflammatory products (e.g., prednisolone acetate 1.0% ophthalmic suspension (OMNIPRED), difluprednate 0.05% ophthalmic emulsion (DUREZOL), and prednisolone acetate 1.0% ophthalmic suspension (PREDFORTE) are not approved for the treatment of DED. This class of medications is generally not recommended for long-term use due to the associated risk of side effects such as glaucoma, cataracts, infection, and delayed wound healing, but is sometimes used off-label short-term (pulse) for the treatment of DED (Omnipred PI (2006), PredForte PI (2018)). An exception is loteprednol etabonate 0.25% (EYSUVIS), which was approved by the Food and Drug Administration (FDA) in 2020 for the short-term treatment of signs and symptoms of dry eye syndrome (DES).

[0012] Punctal occlusion is a non-pharmacological intervention for dry eye when artificial tears and other treatments do not effectively improve symptoms. Evidence from a systematic review of punctal plug trials suggests that improvement in symptoms and commonly tested indications of dry eye is inconclusive. Ervin (2018).

[0013] RESTASIS cyclosporine ophthalmic emulsion 0.05% is a calcineurin inhibitor immunosuppressant that has been shown to increase tear production in patients presumed to have suppressed tear production due to ocular inflammation associated with sicca conjunctivitis (KCS). RESTASIS PI (2017). The most common side effect noted in clinical trials following use of RESTASIS was ocular burning (17%). Lifitegrast ophthalmic solution 5% (XIIDRA) is a lymphocyte function-associated antigen-1 (LFA-1) antagonist indicated for the treatment of signs and symptoms of DED. XIIDRA PI (2016). The exact mechanism of action of lifitegrast in DED is unknown. The most common side effects reported in 5% to 25% of clinical trial patients were instillation site irritation, loss of taste, and decreased vision.

[0014] Mechanical trigeminal nerve stimulation is another approach that has been used in the past to increase tear production, including the use of microelectrical pulses. This is the approach pursued in the TRUE TEAR device, which was approved by the FDA to achieve that goal, but has since been discontinued. The parasympathetic nervous system (PNS) controls tear film homeostasis by innervating the tear functional units (LFUs), including the cornea, conjunctiva, lacrimal gland, meibomian gland, and goblet cells, via the trigeminoparasympathetic pathway. In addition, there are other (multiple) pharmacological agents, such as Varenicline Solution Nasal Spray 0.03 mg (TYRVAYA), approved to stimulate tear production through similar pathways. However, side effects seen with the use of TYRVAYA include sneezing, coughing, throat irritation, and nasal irritation. Summary of the Invention [Problem to be solved by the invention]

[0015] Therefore, there is a need for new therapies for the treatment of DED and other ocular disorders that do not suffer from the problems mentioned above. [Means for solving the problem]

[0016] Summary of the Invention The present invention is directed to therapeutic compositions and their use for the treatment and prevention of ocular diseases. Improvements herein include improved alleviation of signs and symptoms of ocular diseases when mycophenolic acid, betamethasone, or both mycophenolic acid and betamethasone are administered. Moreover, the above is achieved in different embodiments using one or more of the following: surprisingly low doses of mycophenolic acid, surprisingly low doses of betamethasone, surprisingly short pulse treatment periods, and synergistic therapeutic effects that occur when a combination of betamethasone and mycophenolic acid is administered. Clinical trials have confirmed that each of these treatments is not only effective in treating signs and symptoms of ocular surface diseases, but also without the side effects associated with traditional steroid-based treatments. Diseases that can be treated include ocular surface diseases such as dry eye disease, blepharitis, and meibomian gland disease. Other diseases that can be treated include ocular hyperemia and uveitis. The compositions can also be used for connective epithelial healing and after a subject has undergone ocular surgery.

[0017] In accordance with the above, a pharmaceutical composition for topical administration to the eye of a subject is disclosed, the composition comprising or consisting essentially of a main active ingredient selected from the group consisting of betamethasone or a pharma- ceutically acceptable salt thereof (e.g., betamethasone sodium phosphate), mycophenolic acid or a pharma- ceutically acceptable salt thereof (e.g., mycophenolate sodium), or a combination of betamethasone and mycophenolic acid or a pharma- ceutically acceptable salt(s) thereof, in a pharma- ceutically acceptable carrier. In some embodiments, the betamethasone or salt is provided at a concentration of 0.01% w / w to 0.08% w / w. In other embodiments, the betamethasone or salt is provided at a concentration of 0.08% w / w to 0.1% w / w or 0.1% w / w to 0.2% w / w. In some embodiments, the mycophenolic acid or salt is provided at a concentration of 0.01% to 0.30% w / w, and in further embodiments, the mycophenolic acid or salt is provided at a concentration of 0.05% to 0.30% w / w. In some embodiments, the betamethasone or salt is provided at a concentration of 0.01% to 0.08% w / w, and the mycophenolic acid or salt is provided at a concentration of 0.05% to 0.30% w / w.

[0018] Thus, in some embodiments, betamethasone or a salt, mycophenolic acid or a salt, or a combination of betamethasone and mycophenolic acid or salt(s) is the only active ingredient in the composition. However, in other embodiments, the composition contains one or more additional active ingredients. In particular, glycosaminoglycans such as chondroitin sulfate also add beneficial effects. Thus, in some embodiments, the pharmaceutical composition comprises or consists essentially of a glycosaminoglycan, such as chondroitin sulfate; betamethasone or a pharma- ceutically acceptable salt thereof, mycophenolic acid or a pharma- ceutically acceptable salt thereof, or betamethasone and mycophenolic acid or a pharma- ceutically acceptable salt thereof; and a pharma- ceutically acceptable carrier. Preferably, the glycosaminoglycan is chondroitin sulfate at a concentration of 0.1% w / w to 5.0% w / w.

[0019] In embodiments with or without glycosaminoglycans, any one or more of the pharmaceutical compositions may also include a detergent agent and optionally other ingredients or excipients. A preferred detergent agent is dextran or dextran-70. Preferably, dextran is provided at a concentration of 0.1% w / w to 5.0% w / w.

[0020] Thus, the use of betamethasone or a pharma- ceutically acceptable salt thereof, mycophenolic acid or a pharma- ceutically acceptable salt thereof, or a combination of both betamethasone and mycophenolic acid or a pharma- ceutically acceptable salt thereof in the preparation of a pharmaceutical composition, e.g., a medicament, for the treatment of an ocular disease is also disclosed. Examples of ocular diseases include dry eye disease, blepharitis, meibomian gland disease, conjunctival hyperemia, uveitis, and ocular allergy. In some embodiments, the pharmaceutical composition or medicament is for use after ocular surgery. Exemplary amounts of betamethasone or salt include 0.01% w / w to 0.08% w / w, 0.08% w / w to 0.1% w / w, or 0.1% w / w to 0.2% w / w. Exemplary amounts of mycophenolic acid or salt include 0.05% w / w to 0.30% w / w. In some embodiments, betamethasone or a salt, mycophenolic acid or a salt, or both betamethasone and mycophenolic acid or their salt(s) are the only active ingredient(s), while in other embodiments, a glycosaminoglycan such as chondroitin sulfate is also provided. A detergent agent may also be provided.

[0021] Accordingly, there is also provided a method for treating an eye disease in a subject, comprising administering to a subject suffering from an eye disease a therapeutically effective amount of a pharmaceutical composition, the pharmaceutical composition comprising or consisting essentially of a main active ingredient selected from the group consisting of betamethasone or a pharma- ceutically acceptable salt thereof (e.g., betamethasone sodium phosphate), mycophenolic acid or a pharma- ceutically acceptable salt thereof (e.g., mycophenolate sodium), and a combination of both betamethasone and mycophenolic acid or their pharma- ceutically acceptable salt(s). Ocular surface diseases that can be treated with the pharmaceutical composition include dry eye disease, blepharitis, meibomian gland disease, conjunctival hyperemia, uveitis, and ocular allergy. The eye of a subject after undergoing ophthalmic surgery can also be treated with one or more pharmaceutical compositions. In a preferred embodiment, the pharmaceutical composition is administered topically as an eye drop, optionally for weeks or months.

[0022] When the pharmaceutical composition comprises betamethasone or a betamethasone salt (e.g., betamethasone sodium phosphate), it can be provided at a first preferred concentration of 0.01% w / w to 0.08% w / w. Such an embodiment can be administered for only 1, 2, 3 or 4 weeks as a pulse approach. In an exemplary embodiment, the treatment is for an eye disease exhibiting conjunctival hyperemia. In such a case, when the main active ingredient is betamethasone sodium phosphate and it is administered for 1, 2, 3 or 4 weeks, it can reduce conjunctival hyperemia for an extended period of time, such as an additional 30, 60 or more days after administration. Alternatively, betamethasone or its salt can be administered at 0.01% w / w to 0.08% w / w for many months without significant adverse events.

[0023] In other embodiments, betamethasone or a betamethasone salt (e.g., betamethasone sodium phosphate) is provided at a concentration of 0.1%, 0.2% or about 0.2%. This embodiment is preferably administered one to several times per day for up to 14 days or two weeks.

[0024] In embodiments with a main active ingredient comprising or consisting essentially of mycophenolic acid or a pharma- ceutically acceptable salt thereof, it is preferably provided in a concentration of 0.05% w / w to 0.30% w / w. Such an embodiment can be administered for only 1, 2, 3 or 4 weeks as a pulse approach. In an exemplary embodiment, the treatment is for an ocular disease exhibiting conjunctival hyperemia. In such a case, if the main active ingredient is mycophenolic acid and it is administered for 1, 2, 3 or 4 weeks, it can reduce conjunctival hyperemia for an extended period of time, such as an additional 30, 60 or more days after administration. Alternatively, mycophenolic acid or a salt thereof can be administered at 0.05% w / w to 0.30% w / w for many months without significant adverse events.

[0025] In a related embodiment, a method of post-operative eye treatment is also provided, the method comprising topically administering to the eye of a subject who has undergone eye surgery a therapeutically effective amount of a pharmaceutical composition comprising, or consisting essentially of, a principal active ingredient selected from the group consisting of betamethasone or a pharma- ceutical acceptable salt thereof (e.g., betamethasone sodium phosphate), mycophenolic acid or a pharma- ceutical acceptable salt thereof (e.g., mycophenolate sodium), or a combination of both betamethasone and mycophenolic acid or a pharma- ceutical acceptable salt thereof. Preferred compositions comprise 0.01% w / w to 0.08% w / w of betamethasone sodium phosphate, 0.05% w / w to 0.30% w / w of mycophenolic acid, or both 0.01% w / w to 0.08% w / w of betamethasone sodium phosphate and 0.05% w / w to 0.30% w / w of mycophenolic acid. Such treatments can be administered periodically (e.g., once to three times daily) for periods ranging from one week to many months, e.g., one, two, three, four weeks or one, two, three, or more months, without the adverse effects associated with high concentration steroid-based treatment approaches. In cases where severe inflammation occurs, an additional pharmaceutical composition containing 0.2% w / w betamethasone sodium phosphate may be preferred for short-term treatment (e.g., only up to one to two weeks with minimal daily dosage).

[0026] In yet another related embodiment, a method for treating ocular redness is provided, comprising administering to the eye of a subject suffering from redness a therapeutically effective amount of a pharmaceutical composition comprising or consisting essentially of a main active ingredient selected from the group consisting of mycophenolic acid or a pharma- ceutically acceptable salt thereof (e.g., mycophenolate sodium), betamethasone or a pharma- ceutically acceptable salt thereof (e.g., betamethasone sodium phosphate), or a combination of both mycophenolic acid and betamethasone or a pharma- ceutically acceptable salt(s) thereof. In some embodiments, the pharmaceutical composition comprises or consists essentially of mycophenolic acid or salt at a concentration of 0.05% to 0.30% w / w, or betamethasone sodium phosphate at a concentration of 0.01% to 0.08% w / w. In some embodiments, the composition comprises or consists essentially of mycophenolic acid at a concentration of 0.05% to 0.30% w / w and betamethasone sodium phosphate at a concentration of 0.01% to 0.08% w / w. Treatment can be administered periodically (e.g., 1 to 3 times daily) for a period ranging from one week to many months (1, 2, 3, 4 weeks, or 1, 2, 3, or more months).

[0027] In another related embodiment, a method of treating uveitis is provided, comprising administering to an eye of a subject suffering from uveitis a therapeutically effective amount of a pharmaceutical composition comprising or consisting essentially of a main active ingredient selected from the group consisting of mycophenolic acid or a pharma- ceutically acceptable salt thereof (e.g., mycophenolate sodium), betamethasone or a pharma- ceutically acceptable salt thereof (e.g., betamethasone sodium phosphate), or both mycophenolic acid and betamethasone or a pharma- ceutically acceptable salt thereof. In some embodiments, the composition comprises or consists essentially of mycophenolic acid or salt at a concentration of 0.05% to 0.30% w / w, or betamethasone or salt at a concentration of 0.01% to 0.08% w / w. In some embodiments, the composition comprises or consists essentially of mycophenolic acid or salt at a concentration of 0.05% to 0.30% w / w and betamethasone or salt at a concentration of 0.01% to 0.08% w / w. In some embodiments, the composition also includes a glycosaminoglycan, such as chondroitin sulfate. Treatment can be administered periodically (e.g., 1 to 3 times daily) for a period ranging from one week to many months (1, 2, 3, 4 weeks, or 1, 2, 3, or more months).

[0028] In another related embodiment, a method for healing conjunctival epithelial cells is provided, comprising administering to an eye of a subject suffering from conjunctival epithelial cell damage a therapeutically effective amount of a pharmaceutical composition comprising or consisting essentially of a main component selected from the group consisting of mycophenolic acid or a pharma- ceutically acceptable salt thereof (e.g., mycophenolate sodium), betamethasone or a pharma- ceutically acceptable salt thereof (e.g., betamethasone sodium phosphate), or both mycophenolic acid and betamethasone or a pharma- ceutically acceptable salt thereof. In some embodiments, the composition comprises or consists essentially of mycophenolic acid or salt at a concentration of 0.05% to 0.30% w / w, or betamethasone or salt at a concentration of 0.01% to 0.08% w / w. In some embodiments, the composition comprises or consists essentially of mycophenolic acid or salt at a concentration of 0.01% to 0.5% w / w / w and betamethasone or salt at a concentration of 0.01% to 0.08% w / w. In some embodiments, the composition also includes a glycosaminoglycan, such as chondroitin sulfate. In some embodiments, the epithelial cells in need of healing are damaged by ocular surgery. The treatment can be administered periodically (e.g., 1-3 times daily) for a period ranging from one week to many months (1 week, 2 weeks, 3 weeks, 4 weeks, or 1 month, 2 months, 3 months, or more). [Brief description of the drawings]

[0029] [Figure 1] FIG. 1 is a graph summarizing the results of a study evaluating the reduction in conjunctival hyperemia in subjects over time after treatment with mycophenolic acid (MPA) administered in the form of mycophenolate sodium, betamethasone sodium phosphate (BSP), or a combination of MPA and BSP.

[0030] [Diagram 2] Figure 2 is a graph summarizing the results of a study evaluating the reduction over time in University of North Carolina Dry Eye Management Scale (UNC DEMS) scores between treatments with mycophenolate sodium (MPA), betamethasone sodium phosphate (BSP), and a combination of MPA and BSP.

[0031] [Diagram 3] FIG. 3 is a graph summarizing the results of a study evaluating the reduction in hyperemia in subjects over time following treatment with 0.3% MPA / 0.1% BSP (SURF-100); 5% lifitegrast (XIIDRA); 0.05% cyclosporine (RESTASIS); 0.1% MPA; 0.3% MPA; and vehicle controls for the SURF-100 and MPA solutions.

[0032] [Figure 4] FIG. 4 is a graph comparing UNC DEMS values ​​over approximately 70 consecutive days in subjects treated with 0.02% BSP or 0.04% BSP over a two week pulse dosing period.

[0033] [Diagram 5] FIG. 5 is a graph comparing the absolute change from baseline in conjunctival hyperemia over approximately 70 consecutive days in subjects treated with 0.02% BSP or 0.04% BSP over a two week pulse dosing period.

[0034] [Figure 6] FIG. 6 is a graph comparing the absolute change from baseline in the anesthetic Schirmer test over approximately 70 consecutive days for subjects treated with 0.02% BSP or 0.04% BSP over a two-week pulse dosing period.

[0035] [Figure 7] FIG. 7 is a graph comparing the absolute change from baseline in tear film breakup time (TBUT) analysis over approximately 70 consecutive days in subjects treated with 0.02% BSP or 0.04% BSP over a two-week pulse dosing period. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0036] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The subject matter described herein may be embodied in different forms and should not be construed as being limited to the following exemplary embodiments. Indeed, many modifications and other embodiments of the subject matter disclosed herein will come to mind to one of ordinary skill in the art to which the presently disclosed subject matter pertains having the benefit of the teachings presented in the description contained herein. Thus, it is to be understood that the presently disclosed subject matter is not to be limited to the particular embodiments disclosed, and that modifications and other embodiments are intended to be included within the scope of the disclosed subject matter.

[0037] A. Terms and Definitions Unless a specific definition is provided, the nomenclature used in connection with analytical chemistry, organic synthesis, and inorganic chemistry, and the laboratory procedures and techniques described herein are those known in the art. Standard chemical symbols are used interchangeably with the full names represented by such symbols. Thus, for example, the terms "hydrogen" and "H" are understood to have the same meaning. Standard techniques may be used for chemical synthesis, chemical analysis, formulation of compositions, and testing thereof. The aforementioned techniques and procedures may generally be performed according to conventional methods well known in the art.

[0038] The term "about" as used herein means that the number referred to includes 1-10% of the stated number plus or minus the stated number. For example, a component that constitutes "about" 90% of a solution may be 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, depending on the amount of the remaining components. A pH of "about" 7.3 may be 7.1, 7.2, 7.3, 7.4, or 7.5. Whenever it appears in this specification, a numerical range such as "1 to 20" refers to each integer within the range. That is, it means that each numerical value up to 20 is included, such as 1 only, 2 only, 3 only, etc.

[0039] The term "active ingredient" refers to an ingredient that provides pharmacological activity or a direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or affects the structure or any function of the mammalian, i.e., human, body. In contrast, inactive ingredients are usually considered excipients. As used herein, "principal active ingredient" refers to the first active ingredient when multiple active ingredients may be present in the composition.

[0040] The term "administration of a pharmaceutical composition" or "administering a pharmaceutical composition" is defined to include the act of providing a compound or pharmaceutical composition of the present invention to a subject in need of treatment. A "pulse" administration approach refers to a shortened period of time, such as administration for 1 week, 2 weeks, 3 weeks, or 4 weeks. "Administration for up to 4 weeks" means administration for a period of up to 4 weeks, such as 1 week, 2 weeks, 3 weeks, 4 weeks, etc. Unless otherwise specified, the preferred route of administration is topical application to the subject's eye. When provided as an eye drop, "administration of a pharmaceutical composition" is preferably one drop per eye, but can be two or three drops per eye. The term "subject" refers to a mammal, preferably a human.

[0041] The term "albumin" refers to any nonglycosylated protein found in plasma.

[0042] The term "betamethasone or a pharma- ceutically acceptable salt thereof at a concentration of 0.01% w / w to 0.08% w / w" means that when betamethasone is provided in the form of betamethasone sodium phosphate, the concentration of betamethasone sodium phosphate will be 0.01% w / w to 0.08% w / w. Because betamethasone has a molecular weight that is approximately 25% lower than betamethasone sodium phosphate (betamethasone has a molecular weight of 392, whereas betamethasone sodium phosphate has a molecular weight of 516), these ranges can differ by up to or about 25% when using betamethasone alone to achieve the same concentration of betamethasone.

[0043] The terms "consisting essentially of" and "consisting essentially of" refer to the inclusion of the specified material or ingredient without the inclusion of additional ingredients or components that substantially alter the therapeutic effect. The term "consisting essentially of" is not intended to exclude excipients such as pharmaceutical carriers, lubricants, stabilizers, flavorings, detergents, etc., unless expressly stated. The terms "consisting essentially of" and "consist essentially of" can be substituted with "containing as the only active ingredient(s)" or "the only ingredient that affects the underlying disease or condition."

[0044] The term "consecutive" refers to a series of events that follows one after the other without interruption. A "70 consecutive day period" refers to a period that spans 1,680 hours (70 days x 24 hours). Relief of symptoms for a "70 consecutive day period" means relief of symptoms on the first day and after 70 days. It is desirable, but not required, that symptoms be relieved on each successive day.

[0045] The term "corticosteroid" refers to any steroid hormone, both synthetic and derived from the adrenal cortex of vertebrates (including both glucocorticoids and mineralocorticoids), and belonging to the subgenus of steroids that are derivatives of corticosterone.

[0046] The term "day" refers to a 24-hour period.

[0047] The term "detargescent agent" refers to a compound capable of maintaining the corneal stroma of the eye in a relatively dehydrated state to the degree necessary to ensure corneal transparency. A "detargescent agent" can affect the detargescence of the cornea.

[0048] The term "glycosaminoglycan" refers to any unbranched polysaccharide having a disaccharide repeating unit. A preferred glycosaminoglycan for use in the methods and compositions described throughout this disclosure is chondroitin sulfate. Other glycosaminoglycans include dermatan sulfate, dermatin sulfate, heparan sulfate, keratin sulfate, keratan sulfate, and hyaluronic acid.

[0049] The term "minimum daily dose" preferably refers to a dose per eye per day, but may be 2 or 3 drops. One skilled in the art will appreciate that the amount of eye drops may vary depending on the formulation, but is generally about 40 μL to 50 μL.

[0050] The term "mycophenolic acid" or "MPA" refers to the compound having the IUPAC name 6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1H-2-benzofuran-5-yl)-4-methylhex-4-enoic acid and the following chemical structure: [ka] or a pharma- ceutically acceptable salt of mycophenolic acid, including, but not limited to, mycophenolate or sodium mycophenolate.

[0051] The term "mycophenolic acid or a pharma- ceutically acceptable salt thereof in a concentration of 0.05% w / w to 0.30% w / w" means that the concentration of mycophenolic acid in the composition is 0.05% w / w to 0.30% w / w. Thus, if mycophenolic acid is provided in the form of mycophenolate or mycophenolate sodium, the amount of mycophenolate or mycophenolate sodium may be increased to achieve 0.05% w / w to 0.30% w / w of mycophenolic acid due to its higher molecular weight. The molecular weight of mycophenolate or mycophenolate sodium is about 7% higher than mycophenolic acid, and therefore it is provided in an amount about 7% higher to achieve the same amount of mycophenolic acid.

[0052] The term "ocular disease" refers to a medical condition related to the eye, and includes "ocular surface disease" (including "dry eye", "dry eye syndrome" and "dry eye disease"), which is defined as one or more conditions associated with or caused by reduced or insufficient tear production, or increased or excessive tear film evaporation, or both, and characterized by redness, itching, and / or burning of the eye. Ocular surface disease is further defined to include keratoconjunctivitis, temporary dry eye disease, chronic dry eye disease, refractory dry eye disease, age-related dry eye, neurotrophic ocular surface disease, meibomian gland disease (MGD), and blepharitis. Ocular surface diseases, such as at least some of the above, also commonly occur after ocular surgery. Ocular diseases also include ocular allergies.

[0053] As used herein, "or" means "and / or" unless otherwise stated. Furthermore, use of the term "including" and other forms such as "includes" and "includes" is not limiting.

[0054] The term "pharmaceutical composition" is defined as a chemical or biological compound or substance, or a mixture or combination of two or more such compounds or substances, intended for use in the medical diagnosis, cure, treatment or prevention of a disease or pathology. A "pharmaceutical composition" comprises an active ingredient provided in a pharma- ceutical acceptable carrier.

[0055] The term "pharmaceutically acceptable" when used in reference to a carrier, whether a diluent or excipient, is defined as a carrier that is compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0056] The term "salt" refers to an ionic compound that is the product of the neutralization reaction of an acid and a base. When used in medicine, the term "salt" refers to a pharmaceutically acceptable salt. For example, mycophenolate sodium is a pharmaceutically acceptable salt of mycophenolic acid, and betamethasone sodium phosphate is a pharmaceutically acceptable salt of betamethasone.

[0057] The terms "solvate" and "hydrate" are used herein to indicate that a compound or substance is physically or chemically combined with a solvent for the "solvate," such as water (for a "hydrate").

[0058] The term "therapeutically effective amount" is defined as that amount of a compound or pharmaceutical composition that elicits the biological or medical response in a tissue, system, animal or human that is sought by a researcher, physician or other clinician.

[0059] The terms "treat," "treating," and "treatment" refer to the reduction or amelioration of one or more signs or symptoms of an ocular disease or disorder. In medical terms, the term "symptom" refers to a feeling or sensation that a subject may have, and the term "sign" refers to an observable characteristic. When "symptom" or "sign" is disclosed herein, it is intended that either or both are encompassed. Examples of signs and symptoms vary depending on the particular ocular disease or disorder being treated, but may include redness or redness, itchiness, burning eye, eye discomfort, and eyelid discomfort.

[0060] B. Pharmaceutical Compositions The present disclosure describes pharmaceutical compositions comprising mycophenolic acid or a pharma- ceutically acceptable salt thereof (e.g., mycophenolate sodium) and / or betamethasone or a pharma- ceutically acceptable salt thereof (e.g., betamethasone sodium phosphate) having improved efficacy for the treatment of ocular diseases.

[0061] Among the improvements disclosed herein are the surprisingly discovered synergistic effects in the treatment of ocular diseases when mycophenolic acid and betamethasone or their pharma- ceutically acceptable salts are combined. An example of these synergistic effects can be seen, for example, in Figure 1, where a significant reduction in ocular hyperemia is consistently observed in subjects suffering from ocular surface diseases when a combination of 0.3% mycophenolic acid (MPA) and 0.01% betamethasone sodium phosphate (BSP) is applied topically, compared to when 0.3% MPA and 0.01% BPA are administered without the other. As further confirmation of these synergistic effects, Figure 2 shows a significant reduction in scores using the University of North Carolina Dry Eye Management Scale (UNC-DEMS) in subjects suffering from ocular surface diseases when a combination of 0.3% mycophenolic acid (MPA) and 0.01% betamethasone sodium phosphate (BSP) is applied topically, compared to when 0.3% MPA and 0.01% BPA are administered without the other. As shown in Figure 2, the subjects were rated as improved by their treatment with 0.3% MPA or 0.01% BPA individually, but to roughly the same extent as each other. However, there was a significant improvement in scores with the combined treatment. This is more surprising when looking at the results in Figure 3, where 0.1% MPA works much better than 0.3% MPA, indicating that lower doses of MPA are more effective than higher doses. Furthermore, the synergistic combination of MPA and BSP was compared to the traditional treatments of XIIDRA and RESTASIS. Figure 3 shows that when subjects with ocular surface disease were topically applied with a combination of 0.3% MPA and 0.01% BSP (SURF-100), the subjects' congestion was significantly reduced compared to XIIDRA and RESTASIS. Also shown in Figure 3 is the reduction in congestion when 0.3% MPA was topically applied, and the unexpectedly high reduction in congestion when 0.1% MPA was topically applied. Additionally, subjects studied reported no adverse events associated with XIIDRA and RESTASIS when the MPA, BSP, or MPA / BSP formulations were used.

[0062] Other studies have also investigated possible extended benefits after short-term and low-dose administration of betamethasone sodium phosphate (BSP) alone. The details of the study are described in more detail in Example 8, but subjects suffering from eye disease with symptoms and signs such as redness of the eye, eye discomfort, and poor tear film quality were administered 0.02% BSP or 0.04% BSP twice daily for 2 weeks only. In summary, Figure 4 shows that eye discomfort was significantly reduced in both groups over the entire study period (70 days). Figure 5 shows that redness was significantly reduced in both groups over the entire study period. Figures 6 and 7 confirm that the tear film was improved over the entire treatment period. Furthermore, no adverse effects were reported with the administration of corticosteroids.

[0063] Thus, the pharmaceutical compositions described herein are effective at very low concentrations, e.g., 0.01% w / w betamethasone sodium phosphate and 0.05% w / w mycophenolic acid. Among significant improvements over the prior art, the significantly reduced concentration of steroid compounds compared to currently prescribed steroid-based formulations eliminates or at least significantly reduces adverse effects such as elevated intraocular pressure, which is a risk factor for glaucoma, cataracts, infection, and delayed wound healing. To this end, the disclosed compositions are suitable for long-term administration and significantly reduce redness, itching, and inflammation in subjects suffering from ocular diseases that exhibit these signs and symptoms, such as, but not limited to, dry eye disease, blepharitis, meibomian gland disease, and ocular allergies.

[0064] The disclosed pharmaceutical compositions are useful for treating, preventing, and / or alleviating the signs and symptoms of ocular diseases, such as ocular surface diseases (e.g., dry eye disease, blepharitis, meibomian gland disease, ocular allergies). In various embodiments, the compositions comprise 0.01% w / w to 0.08% w / w of betamethasone or a pharma- ceutically acceptable salt thereof; and / or 0.05% to 0.30% w / w of mycophenolic acid or a pharma- ceutically acceptable salt thereof. In some embodiments, these are the only active ingredients, while in other embodiments, one or more additional ingredients are provided.

[0065] Betamethasone and betamethasone pharma- ceutically acceptable salts, such as betamethasone sodium phosphate, belong to a class of medicines called corticosteroids. Corticosteroids are a type of anti-inflammatory drug. They generally relieve inflamed areas of the body. They reduce swelling, redness, itching, and allergic reactions. Corticosteroids are prescribed for several different treatments. EYEBET, which is not currently available in the United States, is a 0.1% solution of betamethasone sodium phosphate for the short-term treatment of inflammation. Possible side effects of EYEBET include eye irritation, burning, stinging, and itching. Vision may also become blurred or cloudy. Additionally, long-term use of 0.1% betamethasone sodium phosphate may lead to the formation of posterior subcapsular cataracts. Within the present invention, betamethasone and its pharma- ceutically acceptable salts, when used topically in the treatment of ocular diseases such as dry eye disease or after undergoing ocular surgery, may be used at significantly lower concentrations than previously suggested, such as 0.01% to 0.08% w / w (e.g., 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08% w / w or amounts therebetween). These concentration guidelines are based on the amount of betamethasone sodium phosphate. Those skilled in the art to which the present invention pertains will appreciate that the concentration of the betamethasone compound may differ by as much as about 25% in the formulation, since betamethasone has a molecular weight that is about 25% less than betamethasone sodium phosphate (betamethasone sodium phosphate has a molecular weight of 516 compared to betamethasone's molecular weight of 392). Thus, betamethasone is added in an amount that is about 25% less than betamethasone sodium phosphate. This low concentration, whether betamethasone sodium phosphate or betamethasone, significantly reduces the adverse effects of steroids commonly seen at higher doses. This was confirmed when testing the effect of low doses of betamethasone administered over an extended period of time. Notably, betamethasone sodium phosphate was administered at low doses without subjects reporting adverse events (Example 7; Figures 1-2).Subsequent trials have also shown that lower doses of pulsed betamethasone sodium phosphate (e.g., for 2 weeks) can provide relief of signs and symptoms of eye disease for several months thereafter without adverse events (Example 8; Figures 4-7). Although these low doses of betamethasone worked surprisingly well, higher doses such as 0.09% to 0.1% can also be used, and doses of 0.1% to 0.2% can also be used sparingly, such as for no more than 2 weeks.

[0066] Mycophenolic acid is an immunosuppressant, and therefore reduces the activity of the immune system. In particular, it prevents the proliferation of T cells, lymphocytes, and the formation of antibodies from B cells. It is most widely known for its use in organ transplantation, such as after kidney, heart, and liver transplants. It is also used to treat autoimmune diseases such as Crohn's disease and systemic lupus erythematosus. Mycophenolic acid has also been proposed for use in inflammatory eye diseases; however, these studies relied on oral treatment rather than topical application to the eye. For example, Willeke (2017) conducted a study in 11 subjects with primary Sjögren's syndrome and found that orally administered mycophenolate sodium (MPS) resulted in subjective improvement of ocular dryness on a visual analogue scale in subjects and reduced the demand for artificial tear supplementation.

[0067] Surprisingly, it has been found that administration of very low concentrations of mycophenolic acid can significantly reduce certain signs and symptoms associated with ocular surface disease. Surprisingly, FIG. 3 shows that 0.1% w / w of mycophenolic acid was more effective than 0.3% w / w. Thus, in some embodiments, a composition is provided that comprises or consists essentially of mycophenolic acid or a pharma- ceutically acceptable salt thereof, and optionally a glycosaminoglycan. Exemplary amounts of mycophenolic acid are 0.01% w / w to 0.5% w / w. In some embodiments, the dosage of mycophenolic acid or a pharma- ceutical acceptable salt thereof is 0.01% w / w, 0.02% w / w, 0.03% w / w, 0.4% w / w, 0.05% w / w, 0.06% w / w, 0.07% w / w, 0.8% w / w, 0.9% w / w, 0.10% w / w, 0.11% w / w, 0.12% w / w, 0.13% w / w, 0.14% w / w, 0.15% w / w, 0.16% w / w, 0.17% w / w, 0.18% w / w, 0.19% w / w, 0.20% w / w, 0.21% w / w, 0.22% w / w, 0.23% w / w, 0.24% w / w, 0.25% w / w, 0.26% w / w, 0.27% w / w, 0.28% w / w, 0.29% w / w, 0.30% w / w, 0.31% w / w, 0.32% w / w, 0.33% w / w, 0.34% w / w, 0.35% w / w, 0.36% w / w, 0.37% w / w, 0.38% w / w, 0.39% w / w, 0.40% w / w, 0.41% w / w, 0.42% w / w, 0.43% w / w, 0.44% w / w, 0.45% w / w, 0.46% w / w, 0.47% w / w, 0.48% w / w, 0.49% w / .22%w / w, 0.23%w / w, 0.24%w / w, 0.25%w / w, 0.26%w / w, 0.27%w / w, 0.28%w / w, 0.2 9%w / w, 0.30%w / w, 0.31%w / w, 0.32%w / w, 0.33%w / w, 0.34%w / w, 0.35%w / w, 0.36% The concentration guidelines are based on the amount of mycophenolic acid. When salts such as mycophenolate or mycophenolate sodium are used, the amount can be adjusted so that the mycophenolic acid is in the range described.

[0068] As shown in Figures 1-3, mycophenolic acid, when combined with a significantly reduced dosage of betamethasone sodium phosphate, when applied topically to a subject's eye, provides an effective and synergistic treatment for ocular surface diseases, such as dry eye disease. In particular, a pharmaceutical composition formulated as an eye drop for topical use, comprising betamethasone sodium phosphate at a concentration of 0.01% to 0.08% w / w (e.g., 0.01% w / w, 0.02% w / w, 0.03% w / w, 0.04% w / w, 0.05% w / w, 0.06%, 0.07%, 0.08% or any amount therebetween) and mycophenolic acid at a concentration of 0.01% to 0.50% w / w (e.g., 0.01% w / w, 0.02% w / w, 0.03% w / w, 0.04% w / w, 0.05% w / w, 0.06%, 0.07%, 0.08% or any amount therebetween). / w, 0.4%w / w, 0.05%w / w, 0.06%w / w, 0.07%w / w, 0.8%w / w, 0.9%w / w, 0.10%w / w, 0.11%w / w, 0.12%w / w, 0.13%w / w, 0.14%w / w, 0.15%w / w, 0.16%w / w, 0.17%w / w, 0.18%w / w, 0.19%w / w, 0.20%w / w, 0.21%w / w, 0.22%w / w, 0.23%w / w, 0.24%w / w, 0.25% w / w, 0.26%w / w, 0.27%w / w, 0.28%w / w, 0.29%w / w, 0.30%w / w, 0.31%w / w, 0.32%w / w, 0.33 %w / w, 0.34%w / w, 0.35%w / w, 0.36%w / w, 0.37%w / w, 0.38%w / w, 0.39%w / w, 0.40%w / w, 0.4 Combining 0.1% betamethasone sodium phosphate with 0.1% betamethasone sodium phosphate (0.1%, 0.42%, 0.43%, 0.44%, 0.45%, 0.46%, 0.47%, 0.48%, 0.49%, 0.50%, or amounts therebetween) provides effective treatment of signs and symptoms of ocular surface disease, and dry eye disease, etc. Thus, the combination is also useful for treating blepharitis, meibomian gland disease, conjunctival congestion, uveitis, ocular allergies, and after undergoing ocular surgery when subjects are at risk of developing such conditions. In addition to its beneficial effects, the combination eliminates or at least greatly reduces undesirable therapeutic effects seen with off-label use (e.g., multiple days to multiple weeks) of higher concentrations of compounds such as 0.1% betamethasone sodium phosphate.

[0069] In some embodiments, one or more of the pharmaceutical compositions of betamethasone and / or mycophenolic acid or their pharma- ceutically acceptable salts contain at least one glycosaminoglycan. Without being bound to a particular or specific mechanism, it is theorized that glycosaminoglycans may help protect endothelial and epithelial cells susceptible to trauma and / or promote the proliferation of such cells. Non-limiting examples of glycosaminoglycan(s) that can be used include chondroitin, chondroitin sulfate, dermatan sulfate, dermatin sulfate, heparin sulfate, heparan sulfate, keratin sulfate, keratan sulfate, or hyaluronic acid. A preferred glycosaminoglycan is chondroitin sulfate. The total content of glycosaminoglycans in the composition, expressed as mass concentration, is from 0.1% w / w to 5.0% w / w, such as from 0.2% w / w to 4.0% w / w, such as 0.1% w / w, 0.15% w / w, 0.2% w / w, 0.25% w / w, 0.3% w / w, 0.35% w / w, 0.4% w / w, or any amount therebetween.

[0070] The pharmaceutical composition with or without glycosaminoglycan may include at least one detergent. The preferred detergent is dextran, i.e., dextran-70. However, non-limiting examples of other acceptable detergent(s) that can be used in addition to or instead of dextran include any of dextran sulfate, NaCl, dextrose, and sucrose. Such detergents are typically used to provide dehydration to the corneal stroma of the eye as described above, but unexpectedly, the detergents used in the compositions disclosed herein are also beneficial in improving the course of treatment of various superficial ocular diseases, such as dry eye disease, and after ocular surgery. The total content of detergent(s) in the composition, expressed as a mass concentration, may be 0.1% w / w to 5.0% w / w, for example 0.2% w / w to 4.0% w / w, for example 0.25% w / w.

[0071] In some embodiments, any one or more of the compositions may also include one or more antioxidants, such as ascorbic acid or ascorbic acid derivatives, erythorbic acid, and sodium ascorbate; thiol derivatives, such as thioglycerol, cysteine, acetylcysteine, cystine, dithioerythreitol, dithiothreitol, glutathione; tocopherol; butylated hydroxyanisole (BHA); butylated hydroxytoluene (BHT); sulfites, such as sodium sulfate, sodium bisulfite, sodium hydrogen sulfite, sodium acetone bisulfite, sodium metabisulfite, sodium sulfite, sodium formaldehyde sulfoxylate, and sodium thiosulfate; and nordihydroguaiaretic acid.

[0072] In related embodiments of the present invention, pharmaceutical compositions are provided for the treatment, prevention, and / or alleviation of ocular surface diseases, with fewer components than those listed above. In various embodiments, the compositions may comprise or consist of 0.01% to 0.08% w / w of betamethasone or a pharma- ceutically acceptable salt thereof, or 0.05% w / w to 0.30% w / w of mycophenolic acid or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier suitable for topical administration to the eye. In some embodiments, betamethasone or a salt thereof, and / or mycophenolic acid or a salt thereof are provided as the only active ingredient, while in other embodiments, the compositions may comprise one or more of tacrolimus, cyclosporine, albumin, plasma, platelet-rich plasma, serum, and their pharma- ceutically acceptable salts, hydrates, solvates, esters, or derivatives or analogs thereof.

[0073] In embodiments where the composition comprises, consists of, or consists essentially of betamethasone and / or mycophenolic acid or their pharma- ceutically acceptable salt(s), the formulation can be in solution as part of a polycarbophil-based formulation or as part of a non-polycarbophil-based formulation. In various embodiments, the total content of mycophenolic acid in the composition expressed as mass concentration is between 0.01% w / w and 0.5% w / w, e.g., 0.01% w / w, 0.02% w / w, 0.03% w / w, 0.4% w / w, 0.05% w / w, 0.06% w / w, 0.07% w / w, 0.8% w / w, 0.9% w / w, 0.10% w / w, 0.1 ... / w, 0.12%w / w, 0.13%w / w, 0.14%w / w, 0.15%w / w, 0.16%w / w, 0.17%w / w, 0.18%w / w, 0.19%w / w, 0.20%w / w, 0.21%w / w, 0.22%w / w, 0.23%w / w, 0.24%w / w, 0.25%w / w, 0.26%w / w, 0.27%w / w, 0.28%w / w, 0.29%w / w, 0.30%w / w, 0.31%w / w, 0.32%w / w, 0.33%w / w, 0.34%w / w, 0.35%w / w, 0.36%w / w, 0.37%w / w, 0.38 %w / w, 0.39%w / w, 0.40%w / w, 0.41%w / w, 0.42%w / w, 0.43%w / w, 0.44%w / w, 0.45%w / w, 0.46%w / w, 0.47%w / w, 0.48% w / w, 0.49% w / w, 0.50% w / w, while the total content of betamethasone or a salt (e.g. betamethasone sodium phosphate) in the composition expressed as mass concentration may be from 0.01% w / w to 0.08% w / w, for example 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, and 0.08% w / w.

[0074] In some embodiments, any one or more of the compositions may also include one or more antioxidants selected from the group consisting of ascorbic acid or ascorbic acid derivatives, erythorbic acid, and sodium ascorbate; thiol derivatives, such as thioglycerol, cysteine, acetylcysteine, cystine, dithioerythreitol, dithiothreitol, glutathione; tocopherol; butylated hydroxyanisole (BHA); butylated hydroxytoluene (BHT); sulfites such as sodium sulfate, sodium bisulfite, sodium acetone bisulfite, sodium metabisulfite, sodium sulfite, sodium formaldehyde sulfoxylate, and sodium thiosulfate; and nordihydroguaiaretic acid.

[0075] The pharmaceutical compositions disclosed herein are preferably formulated for use as eye drops for topical administration to the eye, and therefore contain a pharma- ceutically acceptable carrier that is acceptable for administration to the eye.In such an embodiment, the carrier comprises pure deionized water or balanced salt solution.In some embodiments, the pharmaceutical composition is formulated as a gel or ointment for topical application to the eye, which will tend to be absorbed by the eye more slowly.In still other embodiments, the carrier may further comprise, in addition to water and / or balanced salt solution, additional products, such as, but not limited to, those described below, as an option.

[0076] In some embodiments, the carrier comprises one or more lubricants, such as glycerol, glycerin, or glycerine. Alternatively, if desired, another compound may be used as a lubricant in addition to or instead of glycerol, glycerin, or glycerine. Non-limiting examples of acceptable lubricant(s) that may be used include any of polyvinylpyrrolidone, sorbitol, polyethylene glycol, hydroxypropylmethylcellulose, carboxypropylmethylcellulose, and polyvinyl acetate. As a general guidance, the lubricant is provided at 0.1% w / w to 5.0% w / w, such as between 0.1% w / w to 1.0% w / w, such as 0.2% w / w.

[0077] Other products that can be used in the carrier include any excipient suitable for use in eye drop formulations. For example, the excipient can be a non-ionic polyoxyethylene-polyoxypropylene block copolymer having the following general structure: [ka] In the above formula, x is an integer of 8 or more, and y is an integer of 38 or more.

[0078] If a non-ionic polyoxyethylene-polyoxypropylene block copolymer is used as an excipient, its content in the total composition may be from 0.01% w / w to 1.0% w / w, for example from 0.1% w / w to 1.0% w / w, for example 0.2% w / w.

[0079] One non-limiting example of a specific non-ionic polyoxyethylene-polyoxypropylene block copolymer that can be used as a solubilizing and stabilizing agent in the pharmaceutical compositions of the present invention is the product known under the trade name POLOXAMER 407 (poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol)), having a polyoxypropylene portion with a molecular weight of about 4,000 daltons, a polyoxyethylene content of about 70%, and a total molecular weight between about 9,840 daltons and about 14,600 daltons.

[0080] Another type of product that can be used in the excipient portion of the pharmaceutical formulation can be water-soluble methylcellulose and hydroxypropyl methylcellulose polymers, such as the METHOCEL family of products, e.g., the hydroxypropyl methylcellulose product METHOCEL E4M. The composition can also include an amount of preservative(s), such as benzalkonium chloride, if desired.

[0081] Yet another type of product that can be used in the excipient portion of the pharmaceutical formulation is a polycarbophil polymer product (i.e., a polymer product based on polyacrylic acid crosslinked with divinyl glycol), which is available under various trade names such as FIBERCON, EQUALACTIN, KONSYL FIVER, etc. When a polycarbophil product such as Noveon AA-1 is used, it may be present as part of the mycophenolic acid solution, as previously discussed.

[0082] Additionally, surfactants and / or antifoaming agents may be incorporated into the carrier. As a non-limiting example, the carrier may include PLURONIC F-127.

[0083] In yet another embodiment, the carrier comprises: sodium thiosulfate, sodium chondroitin sulfate, dextran-70, disodium edetate, poloxamer 407, glycerin, hypromellose, potassium chloride, sodium phosphate dibasic anhydrous, sodium phosphate monobasic anhydrous, sodium hydroxide, hydrochloric acid, and sterile water.

[0084] Pharmaceutical compositions will typically have an osmolality of from 100 to 500 milliosmoles per liter (mOsm / L), e.g., from 150 mOsm / L to 450 mOsm / L, e.g., from 200 mOsm / L to 400 mOsm / L. Tonicity adjusters, such as sodium chloride, may also be used in the composition.

[0085] The pharmaceutical composition can be formulated using a one-batch method, in which the components of the pharmaceutical formulation are combined in a single container; however, the components can be added to the container simultaneously or sequentially. Alternatively, if desired, a two-batch or multi-batch method can be used, in which each component of the pharmaceutical formulation is combined in a separate container, and the contents of each container are subsequently combined. The resulting product can then be transferred to a single-dose vial by sterile filtration, sealed, cooled, and sealed (pouched). Finally, the product can be subjected to complete sterility and endotoxin analysis according to commonly used methods known to those of ordinary skill in the art.

[0086] B. Uses of the Pharmaceutical Compositions Each of the above pharmaceutical compositions can be used to treat, prevent, and / or alleviate ocular diseases or their signs and symptoms, such as ocular surface diseases including, but not limited to, keratoconjunctivitis sicca, temporary dry eye disease, chronic dry eye disease, refractory dry eye disease, age-related dry eye, neurotrophic ocular surface disease, blepharitis, meibomian gland disease, ocular hyperemia, ocular allergies, and the like. The pharmaceutical compositions are also particularly useful for administration following ophthalmic surgery, where such diseases or conditions are more likely to occur. The compositions provide great relief to patients with such ailments. Among other benefits, the unpleasant "stinging" or "burning" sensation in the eye that is routinely experienced with preparations containing steroids is eliminated or at least significantly reduced after the compositions are administered. Furthermore, the compositions significantly reduce or eliminate the adverse effects commonly associated with long-term, high-dose use of steroids, such as elevated intraocular pressure, cataracts, infection, and delayed wound healing, which are risk factors for glaucoma. As such, unlike conventional steroid formulations, the compositions can be administered on a regular basis (e.g., daily or twice daily) for extended periods of time, such as for one (1) week, two (2) weeks, three (3) weeks, four (4) weeks, or one (1) month, two (2) months, three (3) months, or more.

[0087] To this end, there is provided a method of treating an ocular disorder, such as an ocular disease, such as dry eye disease, comprising administering to a subject suffering from the ocular disease a therapeutically effective amount of a pharmaceutical composition comprising or consisting essentially of a principal active ingredient(s) selected from the group consisting of: betamethasone or a pharma- ceutical acceptable salt thereof (e.g., betamethasone sodium phosphate), preferably at 0.01% w / w or more; and / or mycophenolic acid or a pharma- ceutical acceptable salt thereof (e.g., mycophenolate sodium) at a concentration of from 0.01% w / w to 0.50% w / w (e.g., 0.01% w / w, 0.02% w / w, 0.03% w / w, 0.4% w / w, 0.05% w / w, 0.06% w / w, 0.07% w / w, 0.08% w / w or any amount therebetween). w / w, 0.7%w / w, 0.8%w / w, 0.9%w / w, 0.10%w / w, 0.11% w / w, 0.12%w / w, 0.13%w / w, 0.14%w / w, 0.15%w / w, 0.16%w / w, 0.17%w / w, 0.18%w / w, 0.19%w / w, 0.20%w / w, 0.21%w / w, 0.22%w / w, 0.23%w / w, 0.24%w / w, 0.25%w / w, 0.26%w / w, 0.27%w / w, 0.28%w / w, 0.29%w / w, 0.30 %w / w, 0.31%w / w, 0.32%w / w, 0.33%w / w, 0.34%w / w, 0.35%w / w, 0.36%w / w, 0.37%w / w, 0.38%w / w, 0.39%w / w, 0.40% w / w, 0.41% w / w, 0.42% w / w, 0.43% w / w, 0.44% w / w, 0.45% w / w, 0.46% w / w, 0.47% w / w, 0.48% w / w, 0.49% w / w, 0.50% w / w, and amounts therebetween; and a pharma- ceutically acceptable carrier for topical administration to the eye. These concentration guidelines are based on the amount of betamethasone sodium phosphate. One skilled in the art to which this invention pertains will appreciate that the concentration of betamethasone may vary by as much as about 25% in the formulation.Because betamethasone has a molecular weight that is about 25% less than betamethasone sodium phosphate (betamethasone sodium phosphate has a molecular weight of 516 compared to betamethasone's molecular weight of 392). In some embodiments, mycophenolic acid or a pharma- ceutically acceptable salt is at a concentration of 0.05% w / w to 0.30% w / w. These concentration guidelines are based on the amount of mycophenolic acid. When using salts such as mycophenolate or mycophenolate sodium, the amount can be adjusted so that mycophenolic acid is in the ranges described. In some embodiments, the pharmaceutical composition consists essentially of betamethasone or a salt, and / or mycophenolic acid or a salt, and a pharma- ceutically acceptable carrier for topical administration to the eye, preferably including a lubricant. In other embodiments, the pharmaceutical composition comprises one or more of a glycosaminoglycan (e.g., 0.1% to 5.0% w / w chondroitin sulfate); a detergence agent (e.g., 0.1% to 5.0% w / w dextran); and other compounds substantially as described above or below or as known in the art to which the invention pertains. Preferably, the pharmaceutical composition is administered by drops (e.g., 1 to 2 drops per eye, twice daily) for one week or more, e.g., one week, two weeks, three weeks, four weeks, or one month, two months, three months, or more than three months.

[0088] In addition to the above, the following pharmaceutical compositions were tested against 0.05% cyclosporine ophthalmic emulsion (RESTASIS) and 5% lifitegrast ophthalmic solution (XIIDRA) as treatment for dry eye disease: a composition containing 0.01% betamethasone sodium phosphate and 0.3% mycophenolic acid (SURF-100), a composition containing 0.1% or 0.3% mycophenolic acid, and a composition containing 0.01% betamethasone sodium phosphate. Subjects were administered twice daily (BID) for 84 days (12 weeks). This study is presented in more detail in Example 7, and exemplary results showing the first 30 days of treatment are provided in Figures 1-3. In summary, the mycophenolic acid and / or betamethasone sodium phosphate formulations were highly effective in reducing the signs and symptoms of dry eye, and subjects reported no adverse events associated with administration of high doses of steroids.

[0089] If the subject is suffering from severe inflammation, betamethasone sodium phosphate can be temporarily increased, for example to 0.2% w / w or about 0.2% w / w, with or without 0.01% w / w to 0.5% w / w mycophenolic acid, for a short period of time (e.g., a few days to up to 2 weeks, at a minimal dose per day).

[0090] In related embodiments, methods of treating the eye after surgery are also provided, which comprise topically administering to the eye of a subject who has undergone ophthalmic surgery, within 14 consecutive days, a pharmaceutical composition comprising or consisting essentially of betamethasone or a pharma- ceutically acceptable salt thereof at a concentration of 0.2% w / w; and, optionally, a glycosaminoglycan. In some embodiments, the method comprises administering, within 14 days thereafter, a second pharmaceutical composition comprising mycophenolic acid or a pharma- ceutically acceptable salt thereof at a concentration of 0.05% w / w to 0.30% w / w; optionally, betamethasone or a pharma- ceutically acceptable salt thereof at a concentration of 0.01% w / w to 0.08% w / w; and, optionally, the same or a different glycosaminoglycan. The second treatment can be administered periodically (e.g., once to three times a day) for a period of one week to many months, for example, one week, two weeks, three weeks, four weeks, or one month, two months, three months, or more. These concentration guidelines are based on the amount of betamethasone sodium phosphate. One skilled in the art to which this invention pertains will appreciate that the concentration of betamethasone can vary by as much as about 25% in a formulation because betamethasone has a molecular weight that is about 25% lower than betamethasone sodium phosphate (betamethasone sodium phosphate has a molecular weight of 516 compared to betamethasone's molecular weight of 392).

[0091] In yet another related embodiment, a method for treating ocular redness is provided, comprising administering to the eye of a subject suffering from redness a therapeutically effective amount of a composition comprising or consisting essentially of mycophenolic acid or a pharma- ceutically acceptable salt thereof (e.g., mycophenolate sodium), betamethasone or a pharma- ceutically acceptable salt thereof (e.g., betamethasone sodium phosphate), or a combination of mycophenolic acid and betamethasone or a pharma- ceutically acceptable salt thereof. Conjunctival redness is a common clinical ophthalmic finding and may be a sign of various ocular diseases, such as conjunctivitis, uveitis, dry eye, allergies, elevated intraocular pressure due to glaucoma, and ophthalmic side effects. Thus, treating conjunctival redness may simultaneously treat an underlying disease selected from conjunctivitis, uveitis, dry eye, allergies, elevated intraocular pressure due to glaucoma, and the like. As demonstrated in Figure 1, administration of 0.3% mycophenolic acid (MPA) and 0.01% betamethasone sodium phosphate (BSP) alone was effective in treating subjects suffering from ocular redness; however, during the first week, BSP worked better than MPA. However, during the study, it surprisingly became apparent that the combination of 0.3% MPA and 0.01% BSP was significantly more effective than MPA alone and BSP alone. It was also surprising that the combination treatment showed significant improvement almost immediately and maintained this significant improvement for at least the first month.

[0092] When compared against XIIDRA and RESTASIS, reduction of conjunctival hyperemia was more effective in subjects treated with MPA and BSP individually, and when treated with the MPA / BSP combination. 0.3% MPA and 0.01% BSP, both alone and in combination (SURF-100), performed better than XIIDRA and RESTASIS. However, surprisingly, 0.1% MPA was also found to be the most effective. This was surprising, as it is a significantly lower dose than previously tested. This suggests that combining 0.01% to 0.30% MPA (e.g., 0.05 to 0.30%) with BSP, e.g., 0.01% to 0.08%, may provide an even better treatment for hyperemia.

[0093] It was also found that conjunctival hyperemia could be significantly reduced over a long period of time after receiving low-dose pulsed administration of betamethasone sodium phosphate. Figure 5 shows that betamethasone sodium phosphate 0.02% w / w or 0.04% w / w administered twice daily for just 2 weeks significantly reduced conjunctival hyperemia for at least 70 days.

[0094] These concentration guidelines are based on the amount of betamethasone sodium phosphate. One skilled in the art to which this invention pertains will appreciate that the concentration of betamethasone can vary by as much as about 25% in a formulation, since betamethasone has a molecular weight that is about 25% lower than betamethasone sodium phosphate (betamethasone sodium phosphate has a molecular weight of 516 compared to betamethasone's molecular weight of 392).

[0095] In yet another related embodiment, a method for treating uveitis is provided, comprising administering to the eye of a subject suffering from uveitis a therapeutically effective amount of a pharmaceutical composition comprising a main active ingredient comprising or consisting essentially of mycophenolic acid or its pharma- ceutical acceptable salt (e.g., mycophenolate sodium), betamethasone or its pharma-ceutical acceptable salt, or a combination of mycophenolic acid and betamethasone, or their salts. Uveitis is inflammation in the eye. The uvea is the middle layer of the eye between the sclera (the white part of the eye) and the retina (the light-sensitive layer at the back of the eye). Uveitis can occur when the body is fighting an infection in the eye, but can also occur when the immune system attacks healthy tissues in the eye. Uveitis can cause pain, redness, and vision loss.

[0096] In some embodiments, the treatment of uveitis can be by administering a pharmaceutical composition of 0.05% to 0.30% w / w mycophenolic acid or salt and / or 0.01 to 0.08% betamethasone or salt. Administration can be topical or by injection. Administration can be regular (e.g., 1 to 3 times daily) for a period of one week to many months (e.g., 1, 2, 3, 4 weeks, or 1, 2, 3, or more months). In some embodiments, treatment is regular until signs and / or symptoms subside. In cases of extreme discomfort, administration can be discontinued with a temporary use of 0.2% w / w betamethasone sodium phosphate solution. These concentration guidelines are based on the amount of betamethasone sodium phosphate. Those skilled in the art to which this invention pertains will appreciate that the concentration of betamethasone can vary by as much as about 25% in formulations. Because betamethasone has a molecular weight that is approximately 25% less than betamethasone sodium phosphate (betamethasone sodium phosphate has a molecular weight of 516 compared to betamethasone's molecular weight of 392). Furthermore, these concentration guidelines are based on the amount of mycophenolic acid. If salts such as mycophenolate or mycophenolate sodium are used, the amount can be adjusted so that mycophenolic acid is present in the stated range.

[0097] In yet another related embodiment, a method of conjunctival epithelial cell healing is provided, the method comprising administering to an eye of a subject suffering from damaged or diseased conjunctival epithelium a therapeutically effective amount of a pharmaceutical composition, the pharmaceutical composition comprising or consisting essentially of a principal active ingredient(s), selected from the group consisting of mycophenolic acid or a pharma- ceutically acceptable salt thereof (e.g., mycophenolate sodium), betamethasone or a pharma- ceutically acceptable salt thereof (e.g., betamethasone sodium phosphate), or a combination of mycophenolic acid and betamethasone or a pharma- ceutically acceptable salt thereof. The conjunctiva is a translucent membrane that covers the sclera along the inner surface of the eyelid. It is covered by two layers of stratified, non-keratinized conjunctival epithelial cells. These cells are covered by a mucin-rich glycocalyx, which promotes adhesion of tears, prevents invasion of pathogens, and provides lubrication. Poor production or maintenance of glycocalyx can lead to ocular surface disease and dry eye. Without being bound by theory, it is believed that administration of the pharmaceutical composition improves tear adhesion and improves lubrication by at least partially acting on the conjunctival epithelium.

[0098] In some embodiments, the treatment of the conjunctival epithelium comprises administering a pharmaceutical composition of 0.05% to 0.30% / w / w of mycophenolic acid or salt (e.g., mycophenolate sodium) and / or 0.01% to 0.08% of betamethasone or salt (e.g., betamethasone sodium phosphate). Administration can be topical or by injection. Administration can be performed periodically (e.g., daily, twice daily) for one or more weeks, e.g., 1 week, 2 weeks, 3 weeks, 4 weeks, or 1 month, 2 months, 3 months or more. In some embodiments, treatment is performed periodically until the signs and / or symptoms subside. These concentration guidelines are based on the amount of betamethasone sodium phosphate. Those skilled in the art to which the present invention pertains will understand that the concentration of betamethasone can vary by as much as about 25% in the formulation. Because betamethasone has a molecular weight that is approximately 25% less than betamethasone sodium phosphate (betamethasone sodium phosphate has a molecular weight of 516 compared to betamethasone's molecular weight of 392). Furthermore, these concentration guidelines are based on the amount of mycophenolic acid. If salts such as mycophenolate or mycophenolate sodium are used, the amount can be adjusted so that mycophenolic acid is present in the stated range.

[0099] In yet another embodiment, the pharmaceutical composition is used in a corneal transplant procedure. Corneal transplant is a surgery in which all or part of a damaged cornea is removed and replaced with healthy donor tissue. Corneal transplant can improve vision and relieve pain. After receiving a corneal transplant, patients are usually given eye drops to help the eye heal and prevent the body from rejecting the donor tissue. The pharmaceutical composition described herein has been shown to reduce conjunctival hyperemia and would have therapeutic utility in subjects receiving corneal transplants. As shown in Figures 1, 3, and 5, the pharmaceutical composition reduces hyperemia in patients suffering from eye conditions, and as shown in Figures 2 and 4, the pain and discomfort of subjects suffering from eye conditions is significantly reduced when mycophenolic acid, betamethasone sodium phosphate, or mycophenolic acid and betamethasone sodium phosphate are administered. Thus, there is provided a use of a pharmaceutical composition in a corneal transplant procedure, the method comprising administering a therapeutically effective amount of the pharmaceutical composition before, during and / or after the corneal transplant procedure, the composition comprising or consisting essentially of a main active ingredient(s) selected from the group consisting of mycophenolic acid or a pharma- ceutical acceptable salt thereof (e.g., mycophenolate sodium), betamethasone or a pharma- ceutical acceptable salt thereof (e.g., betamethasone sodium phosphate), or a combination of both mycophenolic acid and betamethasone or a pharma- ceutical acceptable salt thereof (e.g., betamethasone sodium phosphate).

[0100] When used in corneal transplant procedures, in some embodiments, the pharmaceutical composition comprises or consists essentially of 0.05%-0.30% w / w / w of mycophenolic acid or a salt (e.g., mycophenolate sodium) and / or 0.01%-0.08% of betamethasone or a salt (e.g., betamethasone sodium phosphate). Administration can be topical in the form of eye drops or gel before or after the procedure, in a rinse step during the procedure, or by injection before or during the procedure. In some embodiments, the pharmaceutical composition is provided as a therapeutic rinse during the procedure, followed by eye drops as a post-operative treatment. Depending on the administration stage, it can be performed once or periodically (e.g., 1 to 3 times a day) for a period of one week to many months (1 week, 2 weeks, 3 weeks, 4 weeks, or 1 month, 2 months, 3 months, or more). In some embodiments, treatment is performed periodically after the procedure until the signs and / or symptoms subside. These concentration guidelines are based on the amount of betamethasone sodium phosphate. Those skilled in the art to which this invention pertains will appreciate that the concentration of betamethasone may vary by as much as about 25% in the formulations, since betamethasone has a molecular weight that is about 25% less than betamethasone sodium phosphate (betamethasone sodium phosphate has a molecular weight of 516 compared to betamethasone's molecular weight of 392). Additionally, these concentration guidelines are based on the amount of mycophenolic acid. When mycophenolic acid or a salt such as mycophenolate sodium is used, the amount can be adjusted so that mycophenolic acid is in the ranges described.

[0101] Furthermore, the pharmaceutical compositions described herein are expected to provide a number of medical benefits, such as lubrication of the ocular surface (e.g., cornea and conjunctiva), corneal detourescence, stabilization of cell membranes, and the like, and thus may be useful in the prevention and treatment of other ophthalmic conditions and diseases. The pharmaceutical compositions described herein may further be useful for protecting the ocular surface, corneal epithelial cells, corneal endothelial cells, and / or other ocular tissues during ophthalmic surgery. In addition, the ophthalmic compositions may be useful in wound healing after various injuries to the eye, to reduce corneal edema (e.g., during and after corneal transplant surgery), and to rehabilitate the ocular surface before or after contact lens wear.

[0102] The pharmaceutical formulations described herein are preferably delivered locally, for example via eye drops, although the ordinarily skilled physician can prescribe delivery by any other acceptable method, for example by ophthalmic gel or ointment, if desired and indicated.

[0103] In each of the described uses, the pharmaceutical compositions described herein may be administered as a single dose, in periodic applications, or continuously or substantially continuously maintained on the ocular tissue, as appropriate for the particular use. For example, they may be administered as a single drop, twice a day (BID), once a day, or once every minute for 5 to 10 minutes, or more frequently or less frequently. Clinical trials of pharmaceutical compositions suggest that twice a day (BID) may be preferred; however, it is contemplated that the pharmaceutical compositions may be applied 1 to 16 times a day (e.g., 1 to 8 times a day, 1 to 6 times a day, 1 to 4 times a day, or 1 to 2 times a day), or more frequently or less frequently as needed. At least due in part to the low concentration of the steroid component, the treatment period may be extended to multiple weeks or months without the risks associated with conventional therapies (such as glaucoma, cataracts, infections, delayed wound healing, etc.).

[0104] Although twice daily administration of betamethasone sodium phosphate and mycophenolic acid at the low concentrations described above offers advantages over conventional treatments, one of skill in the art will appreciate that the specific dose level and frequency of administration for a particular patient may vary depending upon a variety of factors including the activity of the particular compound used, the metabolic stability and length of action of that compound, age, body weight, general health, sex, diet, and the severity of the particular disease or condition being treated.

[0105] C. Working Example The following examples are provided to further illustrate the advantages and features of the present invention, but are not intended to limit the scope of the invention. These examples are for illustrative purposes only. USP pharmaceutical grade products were used in preparing the formulations described below. EXAMPLES

[0106] Example 1. Preparation of Pharmaceutical Compositions 1 and 2 Pharmaceutical compositions were prepared as described below. The following products were used in the amounts specified: (a) 0.107 (composition 1) or 0.321 (composition 2) of sodium mycophenolate powder. (b) 0.25 g chondroitin sulfate (bovine); (c) 0.25 g powdered dextran-70; (d) 0.1 g of edetate disodium powder; (e) 0.30 g powdered sodium thiosulfate pentahydrate; (f) 0.03 g potassium chloride; (g) 0.20 g of PLURONIC® F-127; (h) 0.2 g glycerol; (i) 0.9 g of sodium phosphate dibasic anhydrous; (j) 0.18 g of sodium phosphate monobasic anhydrous; (k) 100 mL of sterile water for injection.

[0107] Chondroitin sulfate, dextran, sodium thiosulfate, potassium phosphate, dibasic and monobasic sodium phosphate, potassium chloride, EDTA, and PLURONIC® F-127 were mixed with approximately 90% water and stirred until completely dissolved, after which glycerol was added with continued stirring. The pH of the solution was then adjusted to approximately 7.0 using sodium hydroxide solution before sodium mycophenolate was introduced.

[0108] With continued stirring, the sodium mycophenolate was slowly added to adjust the pH to approximately 7.0-7.4, and the remaining water was added. Additionally, sodium hydroxide may be added after the sodium mycophenolate to obtain the final pH, if necessary. The solution was then filtered through a 0.2 micron filter and placed into a sterile eye drop bottle (Droptainer). EXAMPLES

[0109] Example 2. Preparation of Pharmaceutical Compositions 3 and 4 Pharmaceutical compositions were prepared as described below. The following products were used in the amounts specified: (a) 0.02 (Composition 3) or 0.04 g (Composition 4) of betamethasone sodium phosphate. (b) 0.25 g chondroitin sulfate (bovine); (c) 0.25 powdered dextran-70; (d) 0.1 g of edetate disodium powder; (e) 0.30 g powdered sodium thiosulfate pentahydrate; (f) 0.03 g potassium chloride; (g) 0.20 g of PLURONIC® F-127; (h) 0.2 g glycerol; (i) 0.9 g of sodium phosphate dibasic anhydrous; (j) 0.18 g of sodium phosphate monobasic anhydrous; (k) 100 mL of sterile water for injection.

[0110] Chondroitin sulfate, dextran, sodium thiosulfate, phosphate buffer, potassium chloride, EDTA, and PLURONIC® F-127 were mixed with approximately 90% water and stirred until completely dissolved, after which glycerol was added with continued stirring. The pH of the solution was then adjusted to approximately 7.0 using sodium hydroxide solution before introducing sodium mycophenolate. A 1% betamethasone sodium phosphate stock solution was prepared by dissolving 1 g of betamethasone sodium phosphate powder in 100 mL of water, and the stock solution concentration was confirmed by HPLC. 1 ml of the 1% betamethasone sodium phosphate stock solution was then added to the mixture with continued stirring.

[0111] The pH was adjusted to approximately 7.3-7.4 with sodium hydroxide while stirring, and the remaining water was added. The solution was then filtered through a 0.2 micron filter into sterile dropper bottles or unit dose vials. EXAMPLES

[0112] Example 3. Preparation of Pharmaceutical Compositions 5 and 6 Pharmaceutical compositions were prepared as described below. The following products were used in the amounts specified: (a) 0.01 g of betamethasone sodium phosphate; (b) 0.107 g (composition 5) or 0.321 g (composition 6) of sodium mycophenolate; (c) chondroitin sulfate (bovine), 0.25 g; (d) 0.25 g powdered dextran-70; (e) 0.1 g of edetate disodium powder; (f) 0.30 g powdered sodium thiosulfate pentahydrate; (g) 0.03 g potassium chloride; (h) 0.20 g of PLURONIC® F-127; (i) 0.2 g glycerol; (j) 0.9 g sodium phosphate dibasic anhydrous; (k) 0.18 g of sodium phosphate monobasic anhydrous; (l) 100 mL of sterile water for injection.

[0113] Chondroitin sulfate, dextran, sodium thiosulfate, potassium chloride, EDTA, phosphate buffer and PLURONIC® F-127 were mixed with approximately 90% water and stirred until completely dissolved, after which glycerol was added with continued stirring. The pH of the solution was then adjusted to approximately 7.0 using sodium hydroxide solution before introducing sodium mycophenolate. A 1% betamethasone sodium phosphate stock solution was prepared by dissolving 1 g of betamethasone sodium phosphate powder in 100 mL of water, and the stock solution concentration was confirmed by HPLC. 1 ml of the 1% betamethasone sodium phosphate stock solution was then added to the mixture with continued stirring.

[0114] The mycophenolate sodium was added slowly with continued stirring, the pH was adjusted to about 7.3-7.4 with sodium hydroxide, and the remaining water was added The solution was then filtered through a 0.2 micron filter into sterile dropper bottles or unit dose vials. EXAMPLES

[0115] Example 4. Preparation of Pharmaceutical Composition 7 Pharmaceutical compositions were prepared as described below. The following products were used in the amounts specified: (a) 0.0107 g of sodium mycophenolate; (b) 0.25 g chondroitin sulfate (bovine); (c) 0.25 g powdered dextran-70; (d) 0.1 g of edetate disodium dihydrate; (e) 0.2 g of PLURONIC® F-127; (f) 0.2 g glycerin; (g) 0.30 g powdered sodium thiosulfate pentahydrate; (h) 0.03 g potassium chloride; (i) 0.9 g of sodium phosphate dibasic anhydrous; (j) 0.18 g of sodium phosphate monobasic anhydrous; (k) 100 mL of sterile water for injection.

[0116] Chondroitin sulfate, dextran, EDTA, sodium thiosulfate, glycerol, potassium chloride, potassium phosphate, dibasic and monobasic sodium phosphate, and PLURONIC® F-127 were mixed with approximately 90% water and stirred until completely dissolved, after which the glycerol was added with continued stirring. The pH of the solution was then adjusted to approximately 7.0 using sodium hydroxide solution before sodium mycophenolate was introduced.

[0117] With continued stirring, the sodium mycophenolate was slowly added to adjust the pH to about 7.0-7.4, and the remaining water was added. Additionally, sodium hydroxide may be added after the sodium mycophenolate to obtain the final pH, if necessary. The solution was then filtered through a 0.2 micron filter into a sterile droptainer. EXAMPLES

[0118] Example 5. Preparation of Pharmaceutical Composition 8 Pharmaceutical compositions were prepared as described below. The following products were used in the amounts specified: (a) 0.0214 g of sodium mycophenolate; (b) 0.25 g chondroitin sulfate (bovine); (c) 0.25 g powdered dextran-70; (d) 0.1 g of edetate disodium dihydrate; (e) 0.2 g of PLURONIC® F-127; (f) 0.2 g glycerin; (g) 0.30 g powdered sodium thiosulfate pentahydrate; (h) 0.03 g potassium chloride; (i) 0.9 g of sodium phosphate dibasic anhydrous; (j) 0.18 g of sodium phosphate monobasic anhydrous; (k) 100 mL of sterile water for injection.

[0119] Chondroitin sulfate, dextran, EDTA, sodium thiosulfate, glycerol, potassium chloride, potassium phosphate, dibasic and monobasic sodium phosphate, and PLURONIC® F-127 were mixed with approximately 90% water and stirred until completely dissolved, after which the glycerol was added with continued stirring. The pH of the solution was then adjusted to approximately 7.0 using sodium hydroxide solution before sodium mycophenolate was introduced.

[0120] With continued stirring, the sodium mycophenolate was slowly added to adjust the pH to about 7.0-7.4, and the remaining water was added. Additionally, sodium hydroxide may be added after the sodium mycophenolate to obtain the final pH, if necessary. The solution was then filtered through a 0.2 micron filter into a sterile droptainer. EXAMPLES

[0121] Example 6. Preparation of Pharmaceutical Composition 9 Pharmaceutical compositions were prepared as described below. The following products were used in the amounts specified: (a) 0.0537 g of sodium mycophenolate; (b) 0.25 g chondroitin sulfate (bovine); (c) 0.25 g powdered dextran-70; (d) 0.1 g of edetate disodium dihydrate; (e) 0.2 g of PLURONIC® F-127; (f) 0.2 g glycerin; (g) 0.30 g powdered sodium thiosulfate pentahydrate; (h) 0.03 g potassium chloride; (i) 0.9 g of sodium phosphate dibasic anhydrous; (j) 0.18 g of sodium phosphate monobasic anhydrous; (k) 100 mL of sterile water for injection.

[0122] Chondroitin sulfate, dextran, EDTA, sodium thiosulfate, glycerol, potassium chloride, potassium phosphate, dibasic and monobasic sodium phosphate, and PLURONIC® F-127 were mixed with approximately 90% water and stirred until completely dissolved, after which the glycerol was added with continued stirring. The pH of the solution was then adjusted to approximately 7.0 using sodium hydroxide solution before sodium mycophenolate was introduced.

[0123] With continued stirring, the sodium mycophenolate was slowly added to adjust the pH to about 7.0-7.4, and the remaining water was added. Additionally, sodium hydroxide may be added after the sodium mycophenolate to obtain the final pH, if necessary. The solution was then filtered through a 0.2 micron filter into a sterile droptainer. EXAMPLES

[0124] Example 7. Use of mycophenolic acid and betamethasone sodium phosphate for the treatment of eye diseases A combination of mycophenolic acid (MPA) and betamethasone sodium phosphate (BSP) was evaluated for ocular safety, tolerability, and efficacy. Of these, a combination of 0.3% MPA and 0.01% BSP (also called SURF-100) was compared with 0.1% MPA; 0.3% MPA; 0.01% BSP; vehicle control; 0.05% cyclosporine ophthalmic emulsion (RESTASIS); and 5% liphytograst ophthalmic solution (XIIDRA). The vehicle control contained the following: sodium thiosulfate, sodium chondroitin sulfate, dextran-70, disodium edetate, poloxamer 407, glycerin, potassium chloride, sodium phosphate dibasic anhydrous, sodium phosphate monobasic anhydrous, sodium hydroxide, hydrochloric acid, and sterile water. The subjects were adult subjects with dry eye disease, the composition was administered twice daily (once in the morning and once in the evening) for up to 12 weeks, and the subjects were followed approximately every two weeks after administration.

[0125] At baseline, during the treatment period, and at follow-up visits, the following were assessed: best corrected visual acuity (BCVA), intraocular pressure (IOP), slit-lamp biomicroscopy, ophthalmoscopy, fluorescein corneal staining, conjunctival staining, conjunctival injection, UNC DEMS interview, tear break-up time (TBUT), and Schirmer tear test score. Adverse events were also assessed at each visit.

[0126] Figure 1 shows the results of the conjunctival hyperemia test. In the graph, legend symbols are used only to distinguish treatment timelines from one another. Conjunctival hyperemia is caused by a pathological vasodilatory response of the microvasculature in response to inflammation due to a myriad of infectious and non-infectious etiologies. Although the underlying etiology of ocular surface disease can be difficult to identify on a case-by-case basis, the ocular hyperemia manifested by the condition is consistent and therefore provides an effective measurement for evaluating possible treatments. As shown in Figure 1, the combination of 0.3% MPA and 0.01% BSP significantly reduced conjunctival hyperemia compared to 0.3% MPA or 0.01% BSP alone. Notably, the combination treatment surprisingly reduced conjunctival hyperemia over the first 30 days, showing significant improvement immediately after treatment. In contrast, the reduction in hyperemia was the same or nearly the same over the first 1 to 3 weeks of treatment with MPA or BSP alone, and over the long term, each showed nearly the same efficacy.

[0127] UNC-DEMS is another commonly accepted approach to assess dry eye status and treatment efficacy. In UNC-DEMS, subjects are asked to rate the symptoms and impact they encounter in their daily lives from 1 to 10. As shown in Figure 2, the results are consistent with those depicted in Figure 1. In the graph, legend symbols are used only to distinguish treatment timelines from each other. Again, the combination of 0.3% MPA and 0.01% BSP provided significantly greater relief compared to 0.3% MPA alone and 0.01% BSP alone. Notably, the combination treatment provided a surprising reduction in patients' relief in the first two and a half months, with significant improvements seen immediately after treatment. 0.3% MPA and 0.01% BSP were nearly equally effective as each other and substantially less effective than the combination treatment.

[0128] Figure 3 shows the results of the conjunctival hyperemia test, comparing the combination of 0.3% MPA and 0.01% BSP (also called SURF-100) with 0.1% MPA; 0.3% MPA; 0.01% BSP; vehicle control; 0.05% cyclosporine ophthalmic emulsion (RESTASIS); and 5% liphytograst eye drop (XIIDRA). In the graph, legend symbols are used only to distinguish treatment timelines from each other. Here, over the first month of treatment, SURF-100 was much better than 0.3% MPA; 0.01% BSP; vehicle; RESTASIS; and XIIDRA. Surprisingly, however, 0.1% MPA provided even significantly better conjunctival hyperemia scores, suggesting the use of at least lower doses of 0.1% or 0.05% MPA. EXAMPLES

[0129] Example 8. Efficacy of a short-dose regimen of betamethasone sodium phosphate in the treatment of eye diseases To evaluate the effect of short-term administration of betamethasone sodium phosphate (BSP) in the treatment of ocular disease, subjects with dry eye disease were administered 0.02% BSP or 0.04% BSP twice daily (once in the morning and once in the evening) for 2 weeks and followed up for an additional 2 months.

[0130] At baseline, during the 2-week treatment period, and at follow-up, the following assessments were performed: best corrected visual acuity (BCVA), intraocular pressure (IOP), slit-lamp biomicroscopy, ophthalmoscopy, fluorescein corneal staining, conjunctival staining, conjunctival hyperemia, UNC DEMS interview, tear break-up time (TBUT), and Schirmer tear test score. In addition, adverse events were assessed.

[0131] Figure 4 shows the results of the UNC DEMS symptom questionnaire over 70 days, where subjects were asked to rate the symptoms and effects they encountered on a scale of 1 to 10. In the graph, the legend symbols are used only to distinguish the treatment timelines from each other. Significant improvements were reported in both treatment groups. Interestingly, subjects treated with the higher dose reported greater improvements initially, but subjects treated with the lower dose showed slightly better improvements over the longer term than those treated with the higher dose. Both maintained significant improvements in UNC DEMS scoring throughout the entire follow-up period.

[0132] Figure 5 shows the results of the conjunctival hyperemia test. In the graph, legend symbols are used only to distinguish treatment timelines from each other. Figure 5 shows a significant improvement in conjunctival hyperemia in both the 0.02% BSP and 0.04% BSP treatment groups over the 70 day study period, initially indicating that the higher concentrations were more effective.

[0133] FIG. 6 shows the results of the anesthesia Scharmer test, which is used to quantify tear production for dry eye disease. In the graph, the legend symbols are used only to distinguish the treatment timelines from each other. In general, the test is performed by placing a filter paper on the lower eyelid of the eye. After 5 minutes, the paper is removed and subjected to a test for moisture content. This change in tear production was tracked over time. Over the entire test period, both groups of subjects tested showed improved tear production. Subjects treated with 0.04% BSP showed a greater improvement in tear production initially compared to subjects treated with 0.02% BSP, but subjects treated with the lower dose showed a greater improvement in tear production over time.

[0134] Figure 7 shows the results of the tear breakup time (TBUT) analysis. In the graph, the legend symbols are used only to distinguish the treatment timelines from each other. TBUT is a clinical test to monitor the evaporation of the tear film. To measure TBUT, fluorescein (a fluorescent compound) is placed in the subject's tear film and the subject is asked not to blink while the tear film is observed under a wide beam of cobalt blue illumination. TBUT is recorded as the number of seconds between the last blink and the appearance of the first dry spot in the tear film. A TBUT of less than 10 seconds is considered abnormal. Here, TBUT was measured and compared to the initial time to evaluate any changes. Both 0.02% and 0.04% BSP were successful in reducing evaporation and improving the quality of the tear film, but better results were obtained when using a higher dose of BSP.

[0135] Although the invention has been described with reference to the above examples, it will be understood that modifications and variations are encompassed within the spirit and scope of the invention. Accordingly, the invention is limited only by the following claims.

[0136] References cited AAO (2018). Dry Eye Syndrome, Recommended Practice Patterns, American Academy of Ophthalmology (AAO). Baltatzis S1, Tufail F, Yu EN, Vredeveld CM, Foster CS, Mycophenolate mofetil as an immunomodulatory agent in the treatment of chronic ocular inflammatory diseases. Ophthalmology, 2003;110(5):1061-5. Baudouin C, Aragona P, Van Setten G, et al., Diagnosis of dry eye severity: a clear and practical algorithm, Br J Ophthalmol, 2014;98(9):1168-1176. DOI:10.1136 / bjophthalmol-2013-304619. Craig JP, Nelson JD, Azar DT, et al. TFOS DEWS II Report Executive Summary. Ocular Surface, 2017a;15:802-812. Ervin A, Law A, et al., Punctal occlusion in dry eye syndrome. Cochrane Database Syst Rev., 2018;6;CD006775. doi:10.1002 / 14651858.CD006775.pub3. Hyon JY, Kim HM, Lee Dr et al., Korean guidelines for the diagnosis and management of dry eye: development and validation of clinical effectiveness, Korean J Ophthalmol, 2014;28(3):197-206. Omnipred PI (2006), Prednisolone acetate ophthalmic suspension prescribing information, NDA 17-469 / S-040. PredForte PI (2018). Prednisolone acetate ophthalmic suspension, USP 1% prescribing information. Allergan. RESTASIS PI (2017). Highlights of Prescribing Information (PI) for RESTASIS™ (cyclosporine ophthalmic emulsion) 0.05% topical ophthalmic use. First U.S. approval: 1983. Allergan, Irvine CA. Stern ME, Gao J, Siemasko KF, Beuerman RW, Pflugfelder SC. Role of the lacrimal functional unit in the pathophysiology of dry eye. Exp Eye Res. 2004;78:409-416. Willeke P, Schluter B, Becker H, Schotte H, Domschke W, Gaubitz M. Mycophenolate sodium treatment in patients with primary Sjögren's syndrome: a pilot study. Arthritis Research & Therapy, 2007;9:R115. DOI:10.1186 / ar2322. XIIDRA PI(2016). Topical ophthalmic XIIDRA (lifitegrast eye drop) 5%. First approval in the US: 2016.

Claims

1. 1. A method for treating an eye disease in a subject, the method comprising administering to a subject suffering from an eye disease a therapeutically effective amount of a pharmaceutical composition comprising a principal active ingredient(s) selected from the group consisting of betamethasone or a pharma- ceutical acceptable salt thereof in a concentration of 0.01% w / w to 0.08% w / w, mycophenolic acid or a pharma- ceutical acceptable salt thereof in a concentration of 0.05% w / w to 0.30% w / w, and a combination of betamethasone and mycophenolic acid or a pharma- ceutical acceptable salt thereof.

2. 2. The method of claim 1, wherein said ocular disease is selected from the group consisting of dry eye disease, blepharitis, meibomian gland disease, conjunctival congestion, uveitis, and ocular allergy.

3. 2. The method of claim 1, wherein said pharmaceutical composition consists essentially of said principal active ingredient in a pharma- ceutically acceptable carrier.

4. 2. The method of claim 1, wherein said active ingredient is administered for up to four weeks.

5. 5. The method of claim 4, wherein said administration is carried out for up to two weeks.

6. 2. The method of claim 1, wherein said main active ingredients are a combination of betamethasone sodium phosphate in a concentration of 0.01% w / w to 0.08% w / w and mycophenolic acid or a salt in a concentration of 0.05% w / w to 0.30% w / w.

7. The method of claim 1, wherein said pharmaceutical composition further comprises a glycosaminoglycan, optionally chondroitin sulfate.

8. 8. The method of claim 7, wherein said pharmaceutical composition consists essentially of said principal active ingredient and chondroitin sulfate in said pharma- ceutically acceptable carrier.

9. The method of claim 1, wherein said pharmaceutical composition further comprises a detergent agent.

10. A method for treating an eye after surgery, comprising topically administering to the eye of a subject who has undergone ophthalmic surgery a therapeutically effective amount of a pharmaceutical composition comprising principal active ingredient(s) selected from the group consisting of betamethasone or a pharma- ceutical acceptable salt thereof in a concentration of 0.01% w / w to 0.08% w / w, and mycophenolic acid or a pharma- ceutical acceptable salt thereof in a concentration of 0.05% w / w to 0.30% w / w, and combinations of betamethasone and mycophenolic acid or a pharma- ceutical acceptable salt thereof.

11. 11. The method of claim 10, wherein said active ingredient is administered for up to four weeks.

12. 12. The method of claim 11, wherein said administration is carried out for up to two weeks.

13. 11. The method of claim 10, further comprising administering to said subject betamethasone or a pharma- ceutically acceptable salt thereof at a concentration of 0.2% w / w for no more than 14 consecutive days.

14. A method for treating the eye after surgery, comprising topically administering to the eye of a subject who has undergone ophthalmic surgery a pharmaceutical composition comprising betamethasone or a pharma- ceutical acceptable salt thereof at a concentration of 0.2% w / w; and optionally a glycosaminoglycan, for no more than 14 consecutive days.

15. 15. The method of claim 14, wherein said pharmaceutical composition comprises mycophenolic acid or a pharma- ceutically acceptable salt thereof in a concentration of from 0.05% w / w to 0.30% w / w.

16. 16. The method of claim 15, further comprising administering a second pharmaceutical composition comprising mycophenolic acid or a pharma- ceutically acceptable salt thereof in a concentration of 0.05% w / w to 0.30% w / w after administration of betamethasone or a pharma- ceutically acceptable salt thereof; and optionally the same or a different glycosaminoglycan.

17. 17. The method of claim 16, wherein said second pharmaceutical composition comprises betamethasone sodium phosphate in a concentration of 0.01% w / w to 0.08% w / w.

18. A pharmaceutical composition consisting essentially of betamethasone or a pharma- ceutically acceptable salt thereof in a concentration of 0.01% w / w to 0.08% w / w; a glycosaminoglycan; a pharma- ceutically acceptable carrier; and optionally a detergent agent.

19. 19. The pharmaceutical composition of claim 18, wherein the glycosaminoglycan is chondroitin sulfate.

20. A pharmaceutical composition consisting essentially of mycophenolic acid or a pharma- ceutically acceptable salt thereof in a concentration of 0.05% w / w to 0.30% w / w; a glycosaminoglycan; a pharma- ceutically acceptable carrier; and optionally a detergent agent.

21. 21. The pharmaceutical composition of claim 20, wherein the glycosaminoglycan is chondroitin sulfate.

22. A pharmaceutical composition comprising betamethasone or a pharma- ceutically acceptable salt thereof in a concentration of 0.01% w / w to 0.08% w / w; mycophenolic acid or a pharma- ceutically acceptable salt thereof in a concentration of 0.05% w / w to 0.30% w / w; and a pharma- ceutically acceptable carrier.

23. 23. The pharmaceutical composition of claim 22, further comprising a glycosaminoglycan.

24. 24. The pharmaceutical composition of claim 23, wherein the glycosaminoglycan is chondroitin sulfate.

25. 23. The pharmaceutical composition of claim 22, consisting essentially of betamethasone sodium phosphate in a concentration of 0.01% w / w to 0.08% w / w; mycophenolic acid or a pharma- ceutically acceptable salt thereof in a concentration of 0.05% w / w to 0.30% w / w; a pharma- ceutically acceptable carrier; and optionally a glycosaminoglycan.

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