Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/365—Lactones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
  • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
  • A61K31/716—Glucans
  • A61K31/721—Dextrans
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
  • A61K31/737—Sulfated polysaccharides, e.g. chondroitin sulfate, dermatan sulfate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0048—Eye, e.g. artificial tears
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin

Definitions

• Ocular disorders are those that affect the health of the eye.
• Some of the more common ocular disorders include ocular surface disease, which indicates damage to the surface layers of the eye, namely, the cornea and conjunctiva.
• ocular surface diseases are dry eye disease, blepharitis, and meibomian gland disease (MGD), which can be a precursor to blepharitis and/or dry eye disease and acute and perennial ocular allergy.
• MMD meibomian gland disease
• AAO dry eye syndrome / dry eye disease
• DED dry eye disease
• the ocular surface discomfort is often described as a feeling of dryness, burning, itchiness, or a sandy/gritty sensation. Baudouin (2014).
• a subset of patients with DED have primary Sjogren syndrome, an autoimmune disease mainly affecting the exocrine glands causing a sicca syndrome (dryness of the exocrine glands, particularly the eyes and mouth).
• the prevalence of clinically diagnosed dry eye is 0.4% to 0.5% over all ages and is highest among women and the elderly (65 years and older).
• the ocular surface and tear-secreting glands function as an integrated unit. Any alteration in tear film composition or volume leads to tear film instability, which results in ocular irritation and symptoms and possible damage to the ocular surface epithelium. Stern (2014), Baudouin (2014), Hyon (2014).
• Dysfunction of this integrated unit may develop from aging, a decrease in supportive factors (such as androgen hormones), systemic inflammatory diseases (such as Sjogren syndrome or rheumatoid arthritis), ocular surface diseases (such as herpes simplex virus (HSV) keratitis) or surgeries that disrupt the trigeminal afferent sensory nerves (e.g., LASIK), and systemic diseases or medications that disrupt the efferent cholinergic nerves that stimulate tear secretion.
• supportive factors such as androgen hormones
• systemic inflammatory diseases such as Sjogren syndrome or rheumatoid arthritis
• ocular surface diseases such as herpes simplex virus (HSV) keratitis
• surgeries that disrupt the trigeminal afferent sensory nerves e.g., LASIK
• systemic diseases or medications that disrupt the efferent cholinergic nerves that stimulate tear secretion.
• DED evaporation-induced tear hyperosmolarity
• ADDE tear hyperosmolarity results when lacrimal secretion is reduced, in conditions of normal evaporation from the eye.
• the most common cause of ADDE is inflammatory infiltration of the lacrimal gland, encountered most severely in the DED associated with autoimmune disorders such as Sjogren syndrome and, with lesser severity, in non-Sjbgren syndrome.
• tear hyperosmolarity is caused by excessive evaporation from the exposed tear film in the presence of a normally functioning lacrimal gland. Since tear osmolarity is a function of tear evaporation in either ADDE or EDE, tear hyperosmolarity arises due to evaporation from the ocular surface and, in that sense, all forms of DED are evaporative. In other words, EDE is more accurately considered a hyper-evaporative state.
• topical corticosteroid anti-inflammatory products such as prednisolone acetate 1.0% ophthalmic suspension (OMNIPRED), difluprednate 0.05% ophthalmic emulsion (DUREZOL), prednisolone acetate 1.0% ophthalmic suspension (PREDFORTE) are not approved for the treatment of DED.
• This class of medicines is generally not recommended for long-term use due to the substantial associated risk of side effects such as glaucoma, cataract, infection, and woundhealing delay, but is sometimes used off-label short term (in pulses) for treatment of DED.
• An exception is loteprednol etabonate 0.25% (EYSUVIS), which was approved in 2020 by the Food and Drug Administration (FDA) for short-term treatment of the signs and symptoms of dry eye syndrome (DES).
• FDA Food and Drug Administration
• Punctal occlusion is a non-pharmacological intervention for dry eye when artificial tears or other remedies do not effectively ameliorate symptoms.
• the evidence in the systematic review for punctal plug trials suggests that improvements in symptoms and commonly tested dry eye signs are inconclusive. Ervin (2018).
• the RESTASIS cyclosporine ophthalmic emulsion 0.05% is a calcineurin inhibitor immunosuppressant indicated to increase tear production in patients whose tear production is presumed to be suppressed due to ocular inflammation associated with keratoconjunctivitis sicca (KCS).
• RESTASIS PI (2017). The most common adverse reaction noted in clinical trials following the 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 the signs and symptoms of DED. XIIDRA PI (2016). The exact mechanism of action of lifitegrast in DED is not known.
• the most common adverse reactions reported in 5% to 25% of clinical trial patients were instillation site irritation, dysgeusia and reduced visual acuity.
• the invention is directed to therapeutic compositions and their use for the treatment and prevention of ocular disorders.
• improvements herein include the improved relief of ocular disease signs and symptoms in instances where mycophenolic acid, betamethasone, or both mycophenolic acid and betamethasone are administered.
• the above is accomplished in different embodiments using one or more of: a surprisingly low dosage of mycophenolic acid, a surprisingly low dosage of betamethasone, a surprising short, pulsed treatment period, and a synergistic therapeutic effect that occurs when administering a combination of betamethasone and mycophenolic acid.
• ocular surface diseases such as dry eye disease, blepharitis and meibomian gland disease.
• Other disorders that can be treated include hyperemia of the eye and uveitis.
• the compositions can also be used for conjunctive epithelial healing and after a subject undergoes ocular surgery.
• a pharmaceutical composition for topical administration to the eye of a subject which includes or consists essentially of in a pharmaceutically acceptable carrier, a primary active ingredient selected from the group consisting of betamethasone or a pharmaceutically acceptable salt thereof (e.g. betamethasone sodium phosphate), mycophenolic acid or a pharmaceutically acceptable salt thereof (e.g. mycophenolate sodium), or a combination of betamethasone and mycophenolic acid or pharmaceutically acceptable salt(s) thereof.
• betamethasone or salt is provided at a concentration of 0.01% w/w to 0.08% w/w.
• 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.
• the mycophenolic acid or salt is provided at a concentration of 0.01% w/w to 0.30% w/w and in further embodiments the mycophenolic acid or salt is provided at 0.05% w/w to 0.30% w/w.
• the betamethasone or salt is provided at a concentration of 0.01% w/w to 0.08% w/w and the mycophenolic acid or salt is provided at a concentration of 0.05% w/w to 0.30% w/w.
• the betamethasone or salt, mycophenolic acid or salt, or combination of betamethasone and mycophenolic acid or salt(s) are the sole active ingredients in the composition.
• the composition includes one or more additional active ingredients.
• a glycosaminoglycan such as chondroitin sulfate, also has added beneficial effects.
• the pharmaceutical composition includes or consists essentially of a glycosaminoglycan, such as chondroitin sulfate; betamethasone or a pharmaceutically acceptable salt thereof, mycophenolic acid or a pharmaceutically acceptable salt thereof, or betamethasone and mycophenolic acid or their pharmaceutically acceptable salts thereof; and a pharmaceutically acceptable carrier.
• a glycosaminoglycan such as chondroitin sulfate; betamethasone or a pharmaceutically acceptable salt thereof, mycophenolic acid or a pharmaceutically acceptable salt thereof, or betamethasone and mycophenolic acid or their pharmaceutically acceptable salts thereof; and a pharmaceutically acceptable carrier.
• the glycosaminoglycan is chondroitin sulfate at a concentration of 0.1% w/w to 5.0% w/w.
• any one or more of the pharmaceutical compositions can also include a deturgescent agent and optionally other ingredients or excipients.
• a preferred deturgescent agent is a dextran or Dextran-70.
• the dextran is provided at a concentration of 0.1% w/w to 5.0% w/w.
• a pharmaceutical composition such as a medicament
• ocular disorders include dry eye disease, blepharitis, meibomian gland disease, conjunctival hyperemia, uveitis, and an ocular allergy.
• the pharmaceutical composition or medicament is for use after an 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.
• the betamethasone or salt, mycophenolic acid or salt, or both betamethasone and mycophenolic acid or salt(s) is the only active ingredient(s) but in other embodiments, a glycosaminoglycan such as chondroitin sulfate is also provided.
• a deturgescent agent could also be provided.
• a method of treating an ocular disorder includes administering to a subject suffering from an ocular disorder, a therapeutically effective amount of a pharmaceutical composition, wherein the pharmaceutical composition includes or consists essentially of a primary active ingredient selected from the group consisting of betamethasone or a pharmaceutically acceptable salt thereof (e.g. betamethasone sodium phosphate), mycophenolic acid or a pharmaceutically acceptable salt there (e.g. mycophenolate sodium), and a combination of betamethasone and mycophenolic acid or a pharmaceutically acceptable salt(s) thereof in a pharmaceutically acceptable carrier.
• betamethasone or a pharmaceutically acceptable salt thereof e.g. betamethasone sodium phosphate
• mycophenolic acid or a pharmaceutically acceptable salt there e.g. mycophenolate sodium
• ocular surface disorders that can be treated with the pharmaceutical compositions include dry eye disease, blepharitis, meibomian gland disease, conjunctival hyperemia, uveitis, and an ocular allergy.
• a subject's eye after receiving an ocular surgery can also be treated using one or more of the pharmaceutical compositions.
• the pharmaceutical composition is topically administered as eye drops, optionally over weeks or months.
• the pharmaceutical composition includes betamethasone or the betamethasone salt (e.g. betamethasone sodium phosphate), it can be provided in a first preferred concentration of 0.01% w/w to 0.08% w/w.
• betamethasone salt e.g. betamethasone sodium phosphate
• the treatment is for an ocular disorder displaying conjunctival hyperemia.
• conjunctival hyperemia can be reduced over extended periods such as over an additional 30, 60 or more than 60 days post administration when the primary active ingredient is betamethasone sodium phosphate administered for one, two, three or four weeks.
• betamethasone or its salt can be administered at 0.01% w/w/ to 0.08% w/w over many months without significant adverse events.
• the betamethasone or the 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 only administered one to a few times per day for up to 14 days or two weeks.
• a primary ingredient including or consistent essentially of mycophenolic acid or a pharmaceutically acceptable salt thereof preferably it is provided at a concentration of 0.05% w/w to 0.30% w/w.
• Such embodiments can be administered for only one, two, three or four weeks as a pulse approach.
• the treatment is for an ocular disorder displaying conjunctival hyperemia.
• conjunctival hyperemia can be reduced over extended periods such as over an additional 30, 60 or more than 60 days post administration when the primary active ingredient is mycophenolic acid administered for one, two, three or four weeks.
• mycophenolic acid or its salt can be administered at 0.05% w/w/ to 0.30% w/w over many months without significant adverse events.
• a post-surgical ocular treatment method which includes topically administering to an eye of a subject that has undergone ocular surgery, a therapeutically effective amount of a pharmaceutical composition including or consisting essentially of a primary active ingredient selected from the group consisting of betamethasone or a pharmaceutically acceptable salt thereof (e.g. betamethasone sodium phosphate), mycophenolic acid or a pharmaceutically acceptable salt thereof (e.g. mycophenolate sodium), or a combination of both betamethasone and mycophenolic acid or pharmaceutically acceptable salts thereof.
• betamethasone or a pharmaceutically acceptable salt thereof e.g. betamethasone sodium phosphate
• mycophenolic acid or a pharmaceutically acceptable salt thereof e.g. mycophenolate sodium
• compositions include 0.01% w/w to 0.08% w/w betamethasone sodium phosphate, 0.05 % w/w to 0.30% w/w mycophenolic acid or both 0.01% w/w to 0.08% w/w betamethasone sodium phosphate and 0.05% w/w to 0.30% w/w mycophenolic acid.
• Such treatments can be administered regularly (e.g. one to three times daily) over periods of between one week and many months, such as one week, two weeks, three weeks, four weeks or one month, two months, three months, or more, without adverse effects associate with higher concentration steroid-based therapeutic approaches.
• an additional pharmaceutical composition containing 0.2% w/w betamethasone sodium phosphate may be preferred for short term treatment (eg. only 1 to 2 weeks maximum with minimal dosing per day).
• a method of treating hyperemia of the eye includes administering to the eye of a subject suffering from hyperemia, a therapeutically effective amount of a pharmaceutical composition including or consisting essentially of a primary active ingredient selected from the group consisting of mycophenolic acid or a pharmaceutically acceptable salt thereof (e.g. mycophenolate sodium), betamethasone or a pharmaceutically acceptable salt thereof (e.g. betamethasone sodium phosphate), or a combination of both mycophenolic acid and betamethasone or pharmaceutically acceptable salt(s) thereof.
• a pharmaceutical composition including or consisting essentially of a primary active ingredient selected from the group consisting of mycophenolic acid or a pharmaceutically acceptable salt thereof (e.g. mycophenolate sodium), betamethasone or a pharmaceutically acceptable salt thereof (e.g. betamethasone sodium phosphate), or a combination of both mycophenolic acid and betamethasone or pharmaceutically acceptable salt(s) thereof.
• the pharmaceutical composition includes or consists essentially of mycophenolic acid or salt at a concentration from 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 includes or consists essentially of 0.05% to 0.30% w/w mycophenolic acid and 0.01% to 0.08% betamethasone sodium phosphate.
• the treatment can be administered regularly (e.g. one to three times daily) over periods of between one week and many months, such as one week, two weeks, three weeks, four weeks or one month, two months, three months, or more.
• a method of treating uveitis includes administering to an eye of a subject suffering from uveitis, a therapeutically effective amount of a pharmaceutical composition including or consisting essentially of a primary active ingredient selected from the group consisting of mycophenolic acid or a pharmaceutically acceptable salt thereof (e.g. mycophenolate sodium), betamethasone or a pharmaceutically acceptable salt thereof (e.g. betamethasone sodium phosphate), or mycophenolic acid and betamethasone or pharmaceutically acceptable salts thereof.
• mycophenolic acid or a pharmaceutically acceptable salt thereof e.g. mycophenolate sodium
• betamethasone or a pharmaceutically acceptable salt thereof e.g. betamethasone sodium phosphate
• the composition includes or consists essentially of mycophenolic acid or salt at a concentration from 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 includes or consists essentially of 0.05% to 0.30% w/w mycophenolic acid or salt and 0.01% to 0.08% betamethasone or salt. In some embodiments, the composition also includes a glycosaminoglycan, such as chondroitin sulfate.
• the treatment can be administered regularly (e.g. one to three times daily) over periods of between one week and many months, such as one week, two weeks, three weeks, four weeks or one month, two months, three months, or more.
• a method of conjunctive epithelial cell healing includes administering to an eye of a subject suffering from damage to conjunctive epithelial cells, a therapeutically effective amount of a pharmaceutical composition including or consisting essentially of a primary ingredient selected from the group consisting of mycophenolic acid or a pharmaceutically acceptable salt thereof (e.g. mycophenolate sodium), betamethasone or a pharmaceutically acceptable salt thereof (e.g. betamethasone sodium phosphate), or both mycophenolic acid and betamethasone or their pharmaceutically acceptable salts.
• mycophenolic acid or a pharmaceutically acceptable salt thereof e.g. mycophenolate sodium
• betamethasone or a pharmaceutically acceptable salt thereof e.g. betamethasone sodium phosphate
• the composition includes or consists essentially of mycophenolic acid or salt at a concentration from 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 includes or consists essentially of 0.01% to 0.5% w/w mycophenolic acid or salt and 0.01% to 0.08% betamethasone or salt. 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 from an ocular surgery. The treatment can be administered regularly (e.g. one to three times daily) over periods of between one week and many months, such as one week, two weeks, three weeks, four weeks or one month, two months, three months, or more.
• the treatment can be administered regularly (e.g. one to three times daily) over periods of between one week and many months, such as one week, two weeks, three weeks, four weeks or one
• FIG. 1 is graph summarizing results from a study assessing the decrease in conjunctive hyperemia in subjects over time after treatment with a mycophenolic acid (MPA) administered in the form of mycophenolate sodium, betamethasone sodium phosphate (BSP), or a combination of MPA and
• MPA mycophenolic acid
• BSP betamethasone sodium phosphate
• FIG. 2 is graph summarizing results from a study assessing the decrease of University of North Carolina Dry Eye Management Scale (UNC DEMS) value over time between treatment with (MPA) administered in the form of mycophenolate sodium, betamethasone sodium phosphate (BSP), and a combination of MPA and BSP.
• MPA University of North Carolina Dry Eye Management Scale
• BSP betamethasone sodium phosphate
• FIG. 3 is graph summarizing results from a study assessing the decrease in hyperemia in subjects over time after 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 control for SURF-100 and MPA solutions.
• SURF-100 0.3% MPA/0.1% BSP
• XIIDRA 5% lifitegrast
• RESTASIS 0.05% cyclosporine
• FIG. 4 is graph comparing UNC DEMS values over approximately 70 contiguous days from subjects treated with 0.02% BSP or 0.04% BSP over a two-week pulsed dosing period.
• FIG. 5 is a graph comparing the absolute change from baseline in conjunctival hyperemia over approximately 70 contiguous days from subjects treated with 0.02% BSP or 0.04% BSP over a two-week pulsed dosing period.
• FIG. 6 is a graph comparing the absolute change from baseline in anesthetized Schirmer testing over approximately 70 contiguous days from subjects treated with 0.02% BSP or 0.04% BSP over a two-week pulsed dosing period.
• FIG. 7 is a graph comparing the absolute change from baseline in tear break-up time (TBUT) analysis over approximately 70 contiguous days from subjects treated with 0.02% BSP or 0.04% BSP over a two-week pulsed dosing period.
• betamethasone or a pharmaceutically acceptable salt thereof at a concentration of 0.01% w/w to 0.08% w/w means that when the betamethasone is provided in the form of betamethasone sodium phosphate, the concentration of betamethasone sodium phosphate would be from 0.01% w/w to 0.08% w/w. Since betamethasone has an approximately 25% lower molecular weight than betamethasone sodium phosphate (the molecular weight of betamethasone is 392 compared to 516 for betamethasone sodium phosphate), these ranges can differ up to 25% or about 25% when using betamethasone alone to achieve a same concentration of betamethasone.
• the terms “consisting essentially of” and “consists essentially of” refer to inclusion of the recited ingredients or components without additional components or ingredients that would materially alter the therapeutic effect.
• the term “consisting essentially of” is not intended to exclude excipients, such as pharmaceutical carriers, lubricants, stabilizers, flavorings, deturgescent agents and the like unless expressly mentioned.
• the term “consisting essentially of” and “consists essentially of” may be replaced with "containing as the only active ingredient(s)” or "the only ingredients effecting the underlying disease or condition.”
• minimal dosing per day refers to administration of preferably one drop per eye per day but may be two or three drops.
• volume of an eye drop may vary depending on the formulation but is generally about 40 pL - 50 pL.
• mycophenolic acid refers to the compound having the IUPAC name 6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-lH-2-benzofuran-5-yl)-4-methylhex-4-enoic acid and the following chemical structure: or a pharmaceutically acceptable salt of mycophenolic acid, including but not limited to mycophenolate or mycophenolate sodium.
• mycophenolic acid or a pharmaceutically acceptable salt thereof at a concentration of 0.05% w/w to 0.30% w/w means that the concentration of mycophenolic acid in the composition is from 0.05% w/w to 0.30% w/w. Therefore, when mycophenolic acid is provided in the form of mycophenolate or mycophenolate sodium, the amount of mycophenolate or mycophenolate sodium may be higher due to the higher molecular weight to achieve mycophenolic acid at 0.05% w/w to 0.30% w/w. The molecular weight of mycophenolate or mycophenolate sodium is about 7% higher than mycophenolic acid and would therefore be provided in amount that is about 7% higher to achieve an equal amount of mycophenolic acid.
• ocular disorder 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 several conditions associated with, or caused by, either decreased or insufficient tear production or increased or excessive tear film evaporation, or both, and characterized by redness, itching, and/or burning of the eye.
• An ocular surface disease is further defined as being inclusive of keratoconjunctivitis sicca, episodic dry eye disease, chronic dry eye disease, recalcitrant 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 those listed above also commonly occur following ocular surgery procedures.
• Ocular disorders also include ocular allergy.
• composition is defined as a chemical or a 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 disease or pathology.
• a “pharmaceutical composition” includes an active ingredient provided in a pharmaceutically acceptable carrier.
• pharmaceutically acceptable when used in the context of a carrier, is defined as a carrier, whether diluent or excipient, that is compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
• salt refers to an ionic compound which is a product of the neutralization reaction of an acid and a base.
• salt when used in a pharmaceutical is a pharmaceutically acceptable salt.
• mycophenolate sodium is a pharmaceutically acceptable salt of mycophenolic acid
• betamethasone sodium phosphate is a pharmaceutically acceptable salt of betamethasone.
• solvate and "hydrate” are used herein to indicate that a compound or a substance is physically or chemically associated with a solvent for “solvates” such as water (for “hydrates”).
• terapéuticaally effective amount is defined as the amount of the compound or pharmaceutical composition that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, medical doctor or other clinician.
• the terms “treat”, “treating”, and “treatment” refer to the reduction or amelioration of one or more signs or symptoms of an ocular disorder or disease.
• the term “symptom” refers to feelings or sensations that a subject may have, and the term “sign” refers to observable characteristics. Where “symptom” or “sign” is disclosed herein, one or both is intended to be encompassed. Examples of signs and symptoms can vary depending on the particular ocular disorder or disease being treated but may include hyperemia or redness, itching, burning of the eye, eye discomfort and eyelid discomfort.
• compositions having improved efficacy for the treatment of ocular disorders which contain mycophenolic acid or a pharmaceutically acceptable salt thereof (e.g. mycophenolate sodium) and/or betamethasone or a pharmaceutically acceptable salt thereof (e.g. betamethasone sodium phosphate).
• mycophenolic acid or a pharmaceutically acceptable salt thereof e.g. mycophenolate sodium
• betamethasone or a pharmaceutically acceptable salt thereof e.g. betamethasone sodium phosphate
• FIG. 1 shows a significant reduction in hyperemia of the eye was regularly observed in subjects suffering from an ocular surface disease when a combination of 0.3% mycophenolic acid (MPA) and 0.01% betamethasone sodium phosphate (BSP) was topically applied compared to 0.3% MPA and 0.01% BPA administered without the other.
• MPA mycophenolic acid
• BSP betamethasone sodium phosphate
• FIG. 3 demonstrates a significant reduction in hyperemia in subjects suffering from an ocular surface disease when a combination of 0.3% MPA, 0.01% BSP (SURF-100) was topically applied compared to XIIDRA and RESTASIS. Also shown in FIG. 3 is the reduction in hyperemia when topically administering 0.3% MPA and the unexpectedly high reduction in hyperemia when topically administering 0.1% MPA. Moreover, the subjects tested did not report adverse events associated with XIIDRA and RESTASIS when using the MPA, BSP or MPA/BSP formulations.
• BSP betamethasone sodium phosphate
• the pharmaceutical compositions described herein are effective even at very low concentrations, such as betamethasone sodium phosphate at 0.01% w/w and mycophenolic acid at 0.05% w/w.
• very low concentrations such as betamethasone sodium phosphate at 0.01% w/w and mycophenolic acid at 0.05% w/w.
• adverse effects such as increased intraocular pressure, which is a glaucoma risk factor, cataract, infection, and wound-healing delay are eliminated or at least significantly reduced.
• compositions are suitable for administration for extended periods of time to significantly relieve redness, itching, and burning of the eyes in subjects suffering from ocular disorders presenting such signs and symptoms, such as but not limited to dry eye disease, blepharitis, meibomian gland disease, ocular allergy.
• compositions are useful for treating, preventing, and/or alleviating signs and symptoms of ocular disorders, such as ocular surface disease (e.g. dry eye disease, blepharitis, meibomian gland disease, ocular allergy).
• ocular surface disease e.g. dry eye disease, blepharitis, meibomian gland disease, ocular allergy.
• the compositions include 0.01% w/w to 0.08% w/w/w betamethasone or a pharmaceutically acceptable salt thereof; and/or 0.05% to 0.30% w/w mycophenolic acid or a pharmaceutically acceptable salt thereof.
• these are the sole active ingredients but in other embodiments, one or more additional ingredient is provided.
• Betamethasone and pharmaceutical acceptable salts of betamethasone, such as betamethasone sodium phosphate, are in a class of medications called corticosteroids.
• Corticosteroids are a type of anti-inflammatory drug. They are generally known to provide relief for inflamed areas of the body. They lessen swelling, redness, itching and allergic reaction. Corticosteroids are prescribed as a treatment for several different diseases. EYEBET, which is not currently available in the US, provides a 0.1% solution of betamethasone sodium phosphate for the short-term treatment of inflammation. Among the potential side effects of EYEBET include irritation, burning, stinging, and itching of the eyes. Blurred or clouded vision may also occur.
• betamethasone and its pharmaceutically acceptable salts can be used at a significantly lower concentration than previously suggested, such as from 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) when used topically in the treatment of ocular disorders, such as dry eye disease, or after undergoing ocular surgery.
• concentration guidelines are based on amounts of betamethasone sodium phosphate.
• betamethasone could differ 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 a molecular weight of 392 for betamethasone).
• betamethasone would be added in an amount that is about 25% less compared to betamethasone sodium phosphate.
• this lower concentration significantly reduces the adverse effects of steroids commonly found at higher dosages. This was confirmed when testing the effect of administration of low doses of betamethasone over longer periods of time.
• betamethasone sodium phosphate was administered at low doses without subjects reporting adverse events (see Example 7; FIGS. 1-2). Subsequent testing also showed that pulsed administration of even low doses of betamethasone sodium phosphate (e.g. two weeks) can result in relief of signs and symptoms of ocular disorders for months afterwards without adverse events (see Example 8; FIGS. 4-7). Though these low doses of betamethasone worked surprisingly well, higher doses such as 0.09% to 0.1% may also be used, and dosages of 0.1% to 0.2% can also be used sparingly such as over two weeks or fewer.
• Mycophenolic acid is an immunosuppressant, and thus lowers 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 commonly known for its use in organ transplantation, such as after kidney, heart and liver transplantation. It is also used to treat autoimmune conditions such as Crohn's disease and lupus. Mycophenolic acid has also been proposed for use with inflammatory eye diseases; however, these studies relied on oral treatment rather than topical applications to the eye.
• a composition which includes or consists essentially of mycophenolic acid or its pharmaceutically acceptable salt and optionally a glycosaminoglycan.
• Exemplary amounts of mycophenolic acid are from 0.01% w/w to 0.5% w/w.
• the dosage of mycophenolic acid or its pharmaceutically acceptable salt is selected from the group consisting of 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, 0.3
• combining mycophenolic acid together with the substantially decreased dosage of betamethasone sodium phosphate provides an effective and synergistic treatment for ocular surface disease, such as dry eye disease, when applied topically to the eye of subjects.
• betamethasone sodium phosphate at a concentration from 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 amounts therebetween) and mycophenolic acid at a concentration from 0.01% to 0.50% w/w (e.g.
• this combination is also useful as a treatment for blepharitis, meibomian gland disease, conjunctival hyperemia, uveitis, ocular allergy and as a treatment after undergoing ocular surgery, where the subject is at risk of developing such conditions.
• this combination eliminates or at least significantly reduces unwanted treatment effects found with off label use (e.g. over days to weeks) of higher concentrations of compounds like 0.1% betamethasone sodium phosphate.
• one or more of the pharmaceutical compositions of betamethasone and/or mycophenolic acid or their pharmaceutically acceptable salts include at least one glycosaminoglycan. It can be theorized, without firm commitment to any particular or specific mechanism, that glycosaminoglycans may be useful in protecting endothelial and epithelial cells which are subject to exposure to trauma, and/or to promote the growth of such cells.
• 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; Tocopherols; butylated hydroxyanisol (BHA); butylated hydroxytoluene (BHT); sulfurous acid salts such as sodium sulfate, sodium bisulfite, acetone sodium bisulfite, sodium metabisulfite, sodium sulfite, sodium formaldehyde sulfoxylate, and sodium thiosulfate; and nordihydroguaiaretic acid.
• antioxidants such as ascorbic acid or ascorbic acid derivatives, erythorbic acid, and sodium ascorbate
• Thiol derivatives such as thio
• the betamethasone or salt, and/or mycophenolic acid or salts is provided as a sole active ingredient
• the composition may include one or more of: tacrolimus, cyclosporine, albumin, plasma, platelet-rich plasma, serum, and pharmaceutically acceptable salts, hydrates, solvates, esters thereof or derivatives or analogs thereof.
• the total content of the mycophenolic acid in the composition expressed as the mass concentration may be from 0.01 % w/w to 0.5 % w/w, such as 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/w,
• betamethasone sodium phosphate) in the composition expressed as the mass concentration may be from 0.01 % w/w to 0.08% w/w, such as 0.01%, 0.02%, 0.03%, 0.04% , 0.05%, 0.06%, 0.07%, and 0.08% w/w.
• 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; Tocopherols; butylated hydroxyanisol (BHA); butylated hydroxytoluene (BHT); sulfurous acid salts such as sodium sulfate, sodium bisulfite, acetone sodium bisulfite, sodium metabisulfite, sodium sulfite, sodium formaldehyde sulfoxylate, and sodium thiosulfate; and nordihydroguaiaretic acid.
• antioxidants selected from the group consisting of ascorbic acid or ascorbic acid derivatives, erythorbic acid, and sodium ascorbate; Thi
• the carrier includes one or more lubricating agents, such as glycerol, glycerin, or glycerine.
• lubricating agents such as glycerol, glycerin, or glycerine.
• another compound may be used as a lubricating agent in addition to, or instead of, glycerol, glycerin, or glycerine, if desired.
• acceptable lubricating agent(s) include any of: polyvinyl pyrrolidone, sorbitol, polyethylene glycol, hydroxypropylmethyl cellulose, carboxy propylmethyl cellulose, and polyvinyl acetate.
• lubricants can be provided at 0.1 % w/w to 5.0 % w/w, such as between 0.1% w/w and 1.0 % VJ/VJ, for example 0.2 % VJ/VJ.
• a non-ionic polyoxyethlene-polyoxypropylene block copolymer is used as an excipient, its contents in the overall composition may be from 0.01 % VJ/VJ and 1.0 % VJ/VJ, such as from 0.1 % VJ/VJ to 1.0 % VJ/VJ, for example, 0.2% VJ/VJ.
• One non-limiting example of a specific non-ionic polyoxyethlene-polyoxypropylene block copolymer that can be used as a solubilizing and stabilizing agent in the pharmaceutical compositions of the instant invention is the product known under the trade name POLOXAMER 407 (poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol)), with the molecular weight of the polyoxypropylene portion of about 4,000 Daltons, about a 70% polyoxyethylene content, the overall molecular weight of between about 9,840 Daltons and about 14,600 Daltons.
• POLOXAMER 407 poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol)
• Another type of product that can be used in the excipient portion of the pharmaceutical formulation may be water-soluble methylcellulose and hydroxypropyl methylcellulose polymers, such as METHOCEL family of products, for example, a hydroxypropyl methylcellulose product METHOCEL E4M.
• the compositions may also contain a quantity of preservative(s) such as benzalkonium chloride, if desired.
• Yet another type of product that can be used in the excipient portion of the pharmaceutical formulation may be a polycarbophil polymer product (/.e., a polymeric product based on polyacrylic acid cross-linked with divinyl glycol) which is available under a variety of trade names such as FIBERCON, EQUALACTIN, KONSYL FIVER, etc. If a polycarbophil product such as Noveon AA-1 is used, it may also be present as a part of mycophenolic acid solution, as mentioned above.
• surfactants and/or anti-foaming agents may be provided within the carrier.
• the carrier can include PLURONIC F-127
• the carrier includes the following: sodium thiosulfate, sodium chondroitin sulfate, Dextran-70, edetate disodium, poloxamer 407, glycerin, Hypromellose, potassium chloride, sodium phosphate dibasic anhydrous, sodium phosphate monobasic anhydrous, sodium hydroxide, hydrochloric acid, and sterile water.
• the pharmaceutical compositions can be formulated using a one-batch method, where the components of the pharmaceutical formulation are combined in single container; though the components may be added to the container simultaneously or consecutively.
• a two- or multiple-batch method(s) may be used if desired, where each component of the pharmaceutical formulation is combined in a separate container followed by combining the contents of each container.
• the resulting product may then be transferred by sterile filtration into single dose vials, sealed, cooled, and pouched .
• a complete sterility and endotoxin analysis may be performed on the product according to commonly used methods known to those having ordinary skill in the art.
• Each of the above-described pharmaceutical compositions can be used for treating, preventing, and/or alleviating ocular disorders or signs and symptoms thereof, such as ocular surface disease, e.g., including, without limitation, keratoconjunctivitis sicca, episodic dry eye disease, chronic dry eye disease, recalcitrant dry eye disease, age-related dry eye, neurotrophic ocular surface disease, blepharitis, meibomian gland disease, ocular hyperemia, ocular allergy, and others.
• the pharmaceutical compositions are also particularly useful for administration after ocular surgery, when such disorders or conditions are likely to occur. The compositions bring about a significant relief to the sufferers of such diseases.
• the uncomfortable "stinging” or “burning” feeling in the eye that is routinely experienced in formulations including steroids is eliminated or at least significantly decreased after the composition has been administered.
• the compositions significantly reduce or eliminate the adverse effects commonly associated with long term, higher dosage use of steroids, such as increased intraocular pressure, which is a glaucoma risk factor, cataract, infection, and wound-healing delay.
• the compositions can be administered regularly (e.g. daily or twice daily) for extended periods of time, such as one (1) week, two (2) weeks, three (3) weeks, four (4) weeks or one (1) month, two (2) months, three (3) months, or more.
• a pharmaceutical composition including or consisting essentially of a primary active ingredient(s) selected from the group consisting of betamethasone or a pharmaceutically acceptable salt thereof (e.g. betamethasone sodium phosphate) preferably at a concentration of 0.01% w/w to 0.08% w/w (e.g. 0.01%, 0.02%, 0.03%, 0.04% , 0.05%.
• mycophenolic acid or a pharmaceutically acceptable salt thereof e.g. mycophenolate sodium
• mycophenolate sodium preferably at a concentration of 0.01% w/w to 0.50% w/w
• betamethasone sodium phosphate concentration guidelines are based on amounts of betamethasone sodium phosphate.
• concentration of betamethasone could differ 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 a molecular weight of 392 for betamethasone).
• the mycophenolic acid or pharmaceutically acceptable salt is at a concentration of 0.05% w/w to 0.30% w/w. These concentration guidelines are based on amounts of mycophenolic acid.
• the pharmaceutical composition consists essentially of the betamethasone or salt, and/or the mycophenolic acid or salt and the pharmaceutically acceptable carrier, preferably including a lubricant, for topical administration to the eye.
• the pharmaceutical composition includes one or more of a glycosaminoglycan (e.g. chondroitin sulfate from 0.1% to 5.0% w/w); a deturgescent agent (e.g. dextran from 0.1% to 5.0% w/w); and other compounds substantially as described above or below or as known in the art to which the invention belongs.
• the pharmaceutical composition is administered dropwise (e.g. one to two drops per eye, twice daily) over one or more weeks, such as one week, two weeks, three weeks, four weeks or one month, two months, three months or more.
• compositions were tested against 0.05% cyclosporine ophthalmic emulsion (RESTASIS) and 5% lifitegrast ophthalmic solution (XIIDRA) as a treatment for dry eye disease: a composition containing 0.01% betamethasone sodium phosphate and 0.3% mycophenolic acid (SURF-100), compositions containing either 0.1% or 0.3% mycophenolic acid, and 0.01% betamethasone sodium phosphate. Subjects were dosed twice daily (BID) for 84 days (12 weeks). The study is provided in more detail in Example 7 and exemplary results showing the first 30 days of treatment are provided in FIGS. 1-3. In summary, the mycophenolic acid and/or betamethasone sodium phosphate formulations were highly effective at reducing dry eye signs and symptoms and subjects did not report adverse events associated with administration of higher doses of steroids.
• RESTASIS cyclosporine ophthalmic emulsion
• XIIDRA 5% lifitegrast ophthalmic
• the betamethasone sodium phosphate can be temporarily increased, such as to 0.2% w/w or about 0.2% w/w with or without the mycophenolic acid at 0.01% w/w to 0.5% w/w, for administration over short time frames (e.g. several days to 2 weeks maximum with minimal dosing per day).
• a post-surgical ocular treatment method which includes topically administering to an eye of a subject that has undergone ocular surgery, a pharmaceutical composition including or consisting essentially of betamethasone or a pharmaceutically acceptable salt thereof at a concentration of 0.2% w/w for no more than 14 consecutive days; and optionally a glycosaminoglycan.
• the pharmaceutical composition also includes mycophenolic acid or a pharmaceutically acceptable salt thereof at a concentration of 0.05% w/w/ to 0.30 % w/w.
• the method includes administering a second pharmaceutical composition including mycophenolic acid or a pharmaceutically acceptable salt thereof at a concentration of 0.05% w/w to 0.30% w/w after the no more than 14 days; optionally betamethasone or a pharmaceutically acceptable salt thereof at 0.01% w/w to 0.08% w/w; and optionally a same or different glycosaminoglycan.
• the second treatment can be administered regularly (e.g. one to three times daily) over periods of between one week and many months, such as one week, two weeks, three weeks, four weeks or one month, two months, three months, or more. These concentration guidelines are based on amounts of betamethasone sodium phosphate.
• betamethasone could differ 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 a molecular weight of 392 for betamethasone).
• a method of treating hyperemia of the eye includes administering to an eye of a subject suffering from hyperemia, a therapeutically effective amount of a composition including or consisting essentially of mycophenolic acid or pharmaceutically acceptable salt thereof (e.g. mycophenolate sodium), betamethasone or a pharmaceutically acceptable salt thereof (e.g. betamethasone sodium phosphate), or a combination of mycophenolic acid and betamethasone or their pharmaceutically acceptable salts.
• mycophenolic acid or pharmaceutically acceptable salt thereof e.g. mycophenolate sodium
• betamethasone or a pharmaceutically acceptable salt thereof e.g. betamethasone sodium phosphate
• Conjunctive hyperemia is a common clinical ophthalmological finding and can be a sign of various ocular disorders, such as conjunctivitis, uveitis, dry eye, allergies, elevated intraocular pressure due to glaucoma, and ophthalmic side effects.
• treating conjunctival hyperemia can simultaneously treat an underlying disorder selected from conjunctivitis, uveitis, dry eye, allergies, elevated intraocular pressure due to glaucoma, and others.
• MPA mycophenolic acid
• BSP betamethasone sodium phosphate
• FIG. 5 shows that administering betamethasone sodium phosphate at 0.02% w/w or 0.04% w/w twice daily for only two weeks can significantly reduce conjunctival hyperemia over a period of at least 70 days.
• concentration guidelines are based on amounts of betamethasone sodium phosphate.
• betamethasone could differ 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 a molecular weight of 392 for betamethasone).
• a method of treating uveitis includes administering to an eye of a subject suffering from uveitis, a therapeutically effective amount of a pharmaceutical composition including or consisting essentially of a primary active ingredient including mycophenolic acid or a pharmaceutically acceptable salt thereof (e.g. mycophenolate sodium), betamethasone or a pharmaceutically acceptable salt thereof (e.g. betamethasone sodium phosphate), or a combination of mycophenolic acid and betamethasone or their salts.
• Uveitis is an inflammation inside the eye.
• the uvea is the middle layer of the eye between the sclera (white part of the eyes) and the retina (light-sensitive layer at the back of the eye).
• Uveitis can occur when the body is fighting an infection of the eye, although it can also happen with the immune system attacks healthy tissue in the eyes. Uveitis can cause pain, redness, and vision loss.
• a pharmaceutical composition was prepared as described below. The following products were used in the amounts specified:
• a pharmaceutical composition was prepared as described below. The following products were used in the amounts specified:
• a pharmaceutical composition was prepared as described below. The following products were used in the amounts specified:
• MPA mycophenolic acid
• BSP betamethasone sodium phosphate
• the vehicle control includes the following: sodium thiosulfate, sodium chondroitin sulfate, Dextran-70, edetate disodium, 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 compositions are dosed twice daily (once in the morning and once in the evening) for up to 12 weeks, and the subjects followed up with about every 2 weeks post-dosing.
• FIG. 1 depicts results from the conjunctival hyperemia testing.
• the legend symbols are used solely to distinguish the 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 infection and non-infectious etiologies. While the underlying etiology of ocular surface diseases can be difficult to determine on a case-by-case basis, the ocular hyperemia appearing due to the condition is consistent and therefore provides an effective measurement to assess potential treatments. As shown in FIG.
• the combination of 0.3% MPA and 0.01% BSP provided significantly reduced conjunctival hyperemia compared to 0.3% MPA or 0.01% BSP alone.
• the combined treatment resulted in a surprising decrease in conjunctival hyperemia over the first 30days and showed significant improvement immediately after treatment.
• the decrease in hyperemia was the same or about the same and thus each showed approximately the same efficacy over longer periods of time. .
• UNC-DEMS is another commonly accepted approach to assess dry eye status and treatment effectiveness. Under UNC-DEMS, subjects are asked to rate symptoms and effects encountered on daily life from 1 to 10. As shown in FIG. 2, the results coincide with the results depicted in FIG. 1. In the graph, the legend symbols are used solely to distinguish the treatment timelines from one another.
• the combination of 0.3% MPA and 0.01% BSP provided significantly more relief compared to 0.3% MPA and 0.01% BSP alone.
• the combined treatment resulted in a surprising decrease in patient relief over the first two and half months and showed significant improvement immediately after treatment. Both 0.3% MPA and 0.01% BSP individually were about equally as effective to one another and substantially less effective than the combined treatment.
• FIG. 3 depicts results from conjunctival hyperemia testing comparing 0.3% MPA and 0.01% BSP (SURF-100) to 0.1% MPA; 0.3% MPA; 0.01% BSP; vehicle control; 0.05% cyclosporine ophthalmic emulsion (RESTASIS); and 5% lifitegrast ophthalmic solution (XIIDRA).
• SURF- 100 was far superior to 0.3% MPA; 0.01% BSP; Vehicle; RESTASIS; and XIIDRA over the first month of treatment.
• 0.1% MPA provided even significantly better conjunctival hyperemia scores, which suggests its use at dosages at least as low as 0.1% or 0.05% MPA.
• Example 8 Effect of a Shortened Dosage Regimen of Betamethasone Sodium Phosphate in the Treatment of Ocular Disorders
• BSP betamethasone sodium phosphate
• FIG. 4 depicts results from UNC-DEMS questionnaire regarding symptoms over the 70 day period, where subjects were asked to rate symptoms and effects encountered on daily life from 1 to 10.
• the legend symbols are used solely to distinguish the treatment timelines from one another. Significant improvement was reported in both treatment groups. Interestingly, subjects treated with the higher dose reported greater improvement initially, but subjects treated with the lower dose seemed to show slightly better improvement compared to those treated with the higher dose over the longer term. Both maintained significant improvement in UNC-DEMS scoring over the entirety of the follow-up period.
• FIG. 5 depicts results from conjunctival hyperemia testing.
• the legend symbols are used solely to distinguish the treatment timelines from one another.
• FIG. 5 shows that both 0.02% BSP and 0.04% BSP treatment groups showed significant improvement in conjunctival hyperemia over the entire 70-day test period with the higher concentration being more effective initially.
• FIG. 6 depicts results from Anesthetized Shirmer Testing, which is used to quantify tear production for dry eye disease.
• the legend symbols are used solely to distinguish the treatment timelines from one another. Broadly, the test is performed by placing filter paper inside the lower lid of the eye. After 5 minutes, the paper is removed and tested for moisture content. This change in tear production was tracked over time. Improvement in tear production was found in both groups of tested subjects over the entire testing period. Subjects treated with 0.04% BSP showed greater improvement in tear production initially compared to subjects treated with 0.02% BSP, but subjects treated with the lower dose showed greater improvement in tear production over the longer term.
• FIG. 7 depicts results from tear break-up time (TBUT) analysis.
• TBUT is a clinical test used to monitor tear film evaporation.
• fluorescein a fluorescent compound
• the TBUT is recorded as the number of seconds that elapse between the last blink and the appearance of the first dry spot in the tear film.
• a TBUT under 10 seconds is considered abnormal.
• TBUT was measured and compared to the initial time to assess any change. Both 0.02% and 0.04% BSP were successful at reducing evaporation and thus improving the quality of the tear film, although better results were achieved when using the higher dose of BSP.
• AAO (19. Dry eye syndrome. Preferred Practice Pattern. American Academy of Ophthalmology (AAO).
• RESTASIS PI (2017). RESTASIS® (cyclosporine ophthalmic emulsion) 0.05% for topical ophthalmic use highlights of prescribing information (PI).
• PI prescribing information

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