WO2012088044A2

WO2012088044A2 - Compositions and methods for improving ocular surface health, corneal clarity, optical function and maintaining visual acuity

Info

Publication number: WO2012088044A2
Application number: PCT/US2011/066036
Authority: WO
Inventors: James Mcmillan
Original assignee: James Mcmillan
Priority date: 2010-12-20
Filing date: 2011-12-20
Publication date: 2012-06-28
Also published as: WO2012088044A3

Abstract

In one aspect, the invention provides an ophthalmic composition comprising active Vitamin D and at least one topical steroid in a formulation suitable for topical administration to the eye. In some embodiments, the composition comprises an amount of active Vitamin D and at least one topical steroid in an amount effective to provide at least one of: relief of symptoms of dry eyes and ocular surface disease, reduction in ocular vascular injection (redness), enhancement of corneal clarity, structural integrity and/or refractive ability, and/or inhibition of steroid-induced rise in intraocular pressure when administered topically to the eye. In some embodiments, the composition comprises calcitriol and difluprednate.

Description

COMPOSITIONS AND METHODS FOR IMPROVING OCULAR SURFACE HEALTH, CORNEAL CLARITY, OPTICAL FUNCTION AND MAINTAINING

VISUAL ACUITY CROSS-REFERENCES TO RELATED APPLICATIONS

This application claims the benefit of Application No. 61/425,082, filed December 20, 2010, and Application No. 61/478,028, filed April 21, 2011, the disclosures of which are incorporated herein by reference in their entirety. BACKGROUND

Keratitis, ulceration and dystrophies are forms of corneal disease, in many cases caused or exacerbated by dysfunction of the tear layer or other forms of ocular surface disease. In corneal disease patients, cell hyperplasia, migration, and pathophysiological changes may occur at the disease site, and these processes and the metabolites of such cells may adversely affect corneal transparency and refraction. Inflamed keratocytes have been noted to produce excessive metabolites. Apart from inflammation, there are also corneal diseases in which collagenase and isomeric proteins are seen as metabolites of the corneal epithelial cells and activated keratocytes. Keratoconus is a degenerative disorder of the eye in which structural changes within the cornea cause it to thin and take on a more conical shape than its normal gradual, aspheric curve. Keratoconus can cause substantial distortion of vision, blurring, multiple images, glare, and sensitivity to light, itching, and poor night vision. Its findings and symptoms may be linked wih and/or exacerbated by coexistent dry eyes.

The National Eye Institute defines "dry eye" as "a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface. It is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface." Keratoconjunctivitis sicca is the formal name long associated with the condition. It may be caused by reduced lacrimation, increased evaporative tear loss, or a combination of the two, leading to damage to the cornea and conjunctiva. Keratoconjunctival dryness is contributed to by environmental factors, including exposure to low humidity, decreased blink rate while watching a computer or television screen, windy conditions, airborne chemicals or particulate matter, as well as sources of visible and invisible radiation, particularly ultraviolet light. Keratoconjunctival dryness is particularly made manifest via injury to and eventual shedding or loss of corneal epithelial cells and conjunctival goblet and epithelial cells. Tears are either insufficient in volume for the cornea and conjunctiva, or else an abnormal decrease in one of the three major tearfilm layers (mucin, aqueous, oil) occurs, accompanied, and perpetuated by, inflammation of the cornea and/or conjunctiva. Conventional treatments for keratoconjunctival dryness include artificial tears, lacrimal drainage plugs, hot packs for the eyelid oil glands, pharmaceuticals such as topical cyclosporine, and anti-evaporative ointments and goggles.

Accordingly, a need exists for compositions and methods for treating corneal diseases and conditions and for enhancing corneal clarity, structural integrity and/or refractive ability, and for maintaining visual acuity and avoidance of refractive errors during growth and developmental periods.

SUMMARY

This summary is provided to introduce a selection of concepts in a simplified form that are further described below in the Detailed Description. This summary is not intended to identify key features of the claimed subject matter, nor is it intended to be used as an aid in determining the scope of the claimed subject matter.

In accordance with the foregoing, in one aspect, the invention provides an ophthalmic composition comprising active Vitamin D and at least one topical steroid in a formulation suitable for topical administration to the eye. In some embodiments, the composition comprises an amount of active Vitamin D and at least one topical steroid in an amount effective to enhance at least one of corneal clarity, structural integrity and/or refractive ability, when administered topically to the eye. In some embodiments, the composition comprises calcitriol and difluprednate.

In another aspect, the invention provides a method of improving corneal clarity, structural integrity, ocular surface health and/or refractive ability in an eye(s) of a subject comprising: (a) administering Vitamin D to the subject, and (b) administering at least one topical steroid to the eye(s) of a subject at least once a day for a time period sufficient to improve at least one of corneal clarity, structural integrity, ocular surface health, and/or refractive ability in the eye. In some embodiments, the vitamin D is administered to the subject systemically in an amount sufficient to achieve a serum 25(OH)D3 level of at least 30 ng/cc. In some embodiments, the vitamin D is administered topically to the subject's eye(s). In some embodiments, the method comprises administering an ophthalmic composition comprising a combination of active Vitamin D and at least one topical steroid to the subject's eye(s).

In another aspect, the invention provides a method for reducing intra-ocular pressure in a subject being treated with a topical steroid, comprising administering to the subject an amount of Vitamin D sufficient to reduce the intra-ocular pressure.

In another aspect, the invention provides a method for reducing intra-ocular pressure in a subject suffering from glaucoma, comprising administering to the subject an amount of Vitamin D sufficient to reduce the intra-ocular pressure.

In another aspect, the invention provides a method for modulating the developmental refractive qualities of the eyes of a subject, thereby limiting or preventing at least one of the following: development of myopia, regular and/or irregular astigmatism and/or aberrations of focus during the subject body's growth and developmental periods, comprising administering Vitamin D to the subject in an amount sufficient to achieve a serum 25(OH)D3 level of at least 30 ng/c for a time period of at least one month or longer during a growth and development period (i.e., the first three decades of life, inclusive of adolescence) of the subject.

DETAILED DESCRIPTION

Unless specifically defined herein, all terms used herein have the same meaning as they would to one skilled in the art of the present invention.

In one aspect, the present invention provides ophthalmic compositions comprising active Vitamin D and at least one topical steroid in a formulation suitable for topical administration to the eye. The ophthalmic compositions may be used for the treatment of corneal diseases and conditions, such as, for example, Keratoconus, Keratoconjunctival dryness, and other diseases and conditions described herein.

In accordance with the foregoing, the present inventor has surprisingly discovered that the combination of activated Vitamin D (e.g., calcitriol) and at least one topical steroid, such as a corticosteroid, provides a therapeutic synergy, yielding a rapid beneficial impact on corneal structural and optical qualities. In particular, the inventor has discovered that the combination of activated Vitamin D/calcitriol and a corticosteroid yields the following observable and easily documentable effects, not previously described: (1) rapid improvement in corneal clarity/transparency; (2) rapid improvement in regularity of astigmatism, with potential for improved optical function and/or correction, with or without assistive lenses; and (3) rapid improvement of the signs and/or symptoms of ocular surface disease, including reduction of inflammatory activity and improvement of symptoms associated with dysfunction of the tear/lubrication system. Furthermore, the present inventor has discovered and documented a significant reduction in intra-ocular pressures in subjects being treated with Vitamin D forms, potentially providing protection against the disease glaucoma, for which elevation of intra-ocular pressure is the major risk factor, and providing the potential to counteract the known adverse risk of intra-ocular pressure rises in patients undergoing treatment with topical cortecosteroids.

The ophthalmic compositions of the invention comprise active Vitamin D and at least one topical steroid in a formulation suitable for topical administration to the eye. Cholecalciferol, known as Vitamin D3, is a hormone. In the natural state, it is produced from cholesterol in the skin, under the influence of ultraviolet light. There are no natural food sources of Vitamin D3 sufficient to meet our bodies' needs. The biochemical pathways in mammals involving compounds/metabolites collectively referred to as "Vitamin D," and its forms and derivatives have been implicated in a multitude of anatomic and physiologic processes. It has been determined that a deficiency in stored Vitamin D3 contributes to a number of ocular conditions, as well as metabolic and immune system-related conditions which affect the eyes.

The Vitamin D for use in the ophthalmic composition may be either natural or artificially synthesized compositions or their analogs. Active Vitamin D is formed by hydroxylation of the CI position of the A-ring of the sterol nucleus, side-chain C25, or both CI and C25 include calcitriol (la,25-dihydroxy vitamin D), la,24-dihydroxy vitamin D, alphacalcidol (la-monohydroxyvitamin D), calcifediol (25-monohydroxyvitamin D), la,24,25-trihydroxy vitamin D, l ,25-dihydroxyvitamin D, oxacalcitriol, calcipotriol and KH1060.

The best recognized end product and most physiologically active metabolite of these pathways is considered to be calcitriol. Calcitriol, also called la,25-dihydroxy cholecalciferol or la,25-dihydroxyvitamin D₃, is the hormonally active form of Vitamin D with three hydroxyl groups (abbreviated l,25-(OH)2D3 or simply l,25(OH)2D). It has been shown to modulate the level of calcium (Ca²⁺) in the blood by increasing the uptake of calcium from the gut into the blood, decreasing the transfer of calcium from blood to the urine by the kidney, and increasing the release of calcium into the blood from bone. It has also been shown to impact more than 300 other biochemical pathways in the body in multiple organ systems and involving most body tissues.

Analogs of the Vitamin D form cholecalciferol (D3) include cholecalciferol sulfate, while artificially synthesized active Vitamin D analogs include alphacalcidol (la-monohydroxy vitamin D), 22-oxacalcitriol (OCT), calcipotriol (MC903), KH1060, and dihydrotachysterol.

The viscosity and amphipathic nature of tear components effect the behavior of the natural tear and preparations designed to interact with the natural tear. Accordingly, in some embodiments, the Vitamin D and corticosteroid containing ophthalmic solution of the invention is mixed in a solution, suspension or emulsion formulated to be compatible with the tearfilm components and ocular surface. Such embodiments may comprise one or more of polysorbate, polyvinyl alcohol, hydroxypropylmethylcellulose, hyaluronate, chondroitin sulfate, oils, and fatty acid emulsions to form a topical delivery preparation, either as a drop or ointment, so that the Vitamin D form and topical steroid will remain on the surface of the eye sufficiently and encourage absorption. This enables the ophthalmic composition to be highly effective in preventing and treating eye surface and corneal disease. The concentration of Vitamin D in the ophthalmic composition of this invention, since it is intended for topical administration, may be about 100 micrograms/ml or less, or at least about 0.001 micrograms/ml. The volume of one eye drop is normally about 20-40 microliters. In some embodiments, the ophthalmic composition comprises an active Vitamin D, such as calcitriol, at a concentration of from about 0.001 μg/ml to about 100 μg/ml, such as from about 0.01 μg/ml to about 50 μg/ml, such as from about 0.1 μg/ml to about 10 μg/ml, such as from about 1 μg/ml to about 75 μg/ml, such as from about 25 μg/ml to about 50 μg/ml. In one embodiment, the active Vitamin D is administered in an amount ranging from 0.1 to 10 μg/dose/day for local administration.

The ophthalmic composition of the invention further comprises at least one topical steroid. In some embodiments, the topical steroid is a Cortisol derivative. In some embodiments, the topical steroid is a glucocorticoid, selected from the group consisting of difluprednate, prednisolone, dexamethasone, fluocinolone, fluorometholone, loteprednol, medrysone, rimexolone, triamcinolone, cortisone, hydrocortisone, or any others in this class of compounds. In some embodiments, the ophthalmic composition comprises difluprednate (6a,9-difluoroprednisolone 17-butyrate 21-acetate) (CAS number 23674-86-4) which is an antiinflammatory steroid which is known to show superior antiinflammatory action by percutaneous administration (U.S. Patent Nos. 3,780, 177 and 3,784,692). In addition, difluprednate is reported to show superior antiinflammatory action and antiallergic action by percutaneous administration and subcutaneous administration (Pharmacometrics 29(3):343-353 (1985); Pharmacometrics 29(3):355-362 (1985)), as well as antiinflammatory action when topically administered to an eye, as described in U.S. Patent No. 6,1 14,319, incorporated herein by reference.

In some embodiments, the ophthalmic compositions comprises a topical steroid, such as difluprednate, in a concentration of about 0.005-0.5%, such as from about 0.01 to 0.1%.

In one embodiment, the ophthalmic composition comprises a combination of calcitriol and difluprednate. In one embodiment, the ophthalmic composition is provided in a unit dose form for local administration to the eye, the unit dose comprising calcitriol at an amount from 0.1 to 10 μg/dose/day and difluprednate at a concentration of from 0.01 to 0.2%.

In some embodiments, the ophthalmic composition further comprises an ophthalmically acceptable carrier. In some embodiments, the ophthalmic composition is in the form of a solution, such as an eye drop. The active Vitamin D is water-soluble and is easily added to common water-based drop formulations, including those used to suspend steroid formulations designed for ophthalmic use. In another embodiment, the Vitamin D in the ophthalmic composition of this invention can be attached to or encapsulated in an ophthalmological drug delivery system. Such systems include liposomes, microspheres, protein gels, collagen, or therapeutic soft contact lenses.

In some embodiments, the ophthalmic composition comprising active Vitamin D and at least one topical steroid (e.g., difluprednate) further comprises oil, water, and an emulsifier. Any oil may be used in the composition of the invention, as long as it is applicable to the eye, and has low or no toxicity to the eye. Preferably, an oil containing a fatty acid ester of glycerol, such as castor oil, peanut oil, cotton seed oil, soybean oil, olive oil, medium chain fatty acid triglycerides, and the like is used. More preferably, castor oil, medium chain fatty acid triglycerides and the like, in which difluprednate is highly soluble, can be used in the composition. In some embodiments of the present invention, a surfactant, such as a nonionic surfactant having surface activating capability and the like, may be included as an emulsifier. Examples of appropriate nonionic surfactants include polyoxyethylene hydrogenated castor oils and polyoxyethylenesorbitan fatty acid esters, preferably polyoxyethylenesorbitan monooleates, polyoxyethylenesorbitan monolaurates, polyoxyethylenesorbitan monopalmitates, polyoxyethylenesorbitan monostearates, and the like.

The composition of the present invention may contain a water soluble polymer for enhanced stabilization of emulsion. Examples of the water soluble polymer include povidone (polyvinylpyrrolidone), polyvinyl alcohol, hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose and salt thereof, and the like.

The composition of the present invention may contain a buffer. Examples of suitable buffers include acetates such as sodium acetate and the like, phosphates such as sodium dihydrogenphosphate, disodium hydrogenphosphate, potassium dihydrogenphosphate, dipotassium hydrogenphosphate and the like, ε-aminocaproic acid, amino acid salts such as sodium glutamate and the like, boric acid and salt thereof, citric acid and salt thereof, and the like.

The composition of the present invention may contain a preservative. Examples of the preservative include quaternary ammonium salts such as benzalkonium chloride, benzethonium chloride, and the like; cationic compounds such as chlorhexidine gluconate, and the like; p-hydroxybenzoates such as methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, and the like; alcohol compounds such as chlorobutanol, benzyl alcohol, and the like; sodium dehydroacetate; thimerosal; sorbic acid; and the like.

The composition of the present invention may contain an isotonizing agent.

Examples of the isotonizing agent include sodium chloride, glycerol, glucose, mannitol, sorbitol and the like.

The composition of the present invention may also contain various additives, such as a stabilizer, an antioxidant, a chelating agent, a pH adjusting agent, a thickener, and the like. Examples of the antioxidant include ascorbic acid and salt thereof, tocopherol, sodium thiosulfate, sodium hydrogensulfite, pyruvic acid and salt thereof, and the like. The chelating agent is exemplified by sodium edetate, citric acid and salt thereof, and the like. Examples of the pH adjusting agent include hydrochloric acid, phosphoric acid, acetic acid, sulfuric acid, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogencarbonate, aqueous ammonia, and the like.

The composition of the present invention can be provided as an aqueous preparation of oil-in-water type (O/W type) emulsion, microemulsion, and the like.

The composition of the present invention preferably has a pH of 3-8. More preferably the pH is 4-7, at which difluprednate is more stabilized.

In some embodiments, the composition of the present invention is prepared by emulsifying oil, in which difluprednate has been dissolved, and water, using an emulsifier according to a known method. For example, an emulsifier and the above-mentioned additive, as necessary, are added to water, its pH is adjusted to 3-8 with a pH adjusting agent, and oil, in which difluprednate has been dissolved, is added to give an emulsion. For uniform emulsification, a known means, such as a homomixer, homogenizer, microfluidizer, high pressure homogenizer, and the like may be used.

The ophthalmic composition of the invention may be used for topical administration to the eye for the treatment of an ocular disease or condition, including primary and/or adjunctive treatment of anterior segment ocular disease states, postoperative management and enhancement of visual function even in the normal, asymptomatic circumstance, as further described herein.

In another aspect, the invention provides a method of manufacturing an ophthalmic composition comprising active Vitamin D and at least one topical steroid. The methods according to this aspect of the invention comprise combining active Vitamin D and at least one topical steroid in an ophthalmic physiological buffer solution to form an ophthalmic composition. In some embodiments, the method further comprises the addition of at least one solvent medium such as ethanol, ether, or a surfactant such as lecithin or polysorbate. Since Vitamin D is fat-soluble, the ophthalmic composition may contain Vitamin D dissolved in a plant oil such as sesame oil or fat.

In another aspect, the invention provides methods of improving corneal clarity, structural integrity, ocular surface health, and/or refractive ability in an eye(s) of a subject comprising administering at least one topical steroid to the eye(s) of a subject, wherein the subject has a verified serum 25(OH)D3 level of at least 30 ng/cc, such as at least 40 ng/cc, such as at least 50 ng/cc. In some embodiments, the topical steroid administered to the eye is a Cortisol derivative. In some embodiments, the topical steroid is a glucocorticoid, selected from the group consisting of difluprednate, prednisolone, dexamethasone, fluocinolone, fluorometholone, loteprednol, medrysone, rimexolone, triamcinolone, cortisone, and hydrocortisone.

In another aspect, the invention provides a method of improving corneal clarity, structural integrity, ocular surface health, and/or refractive ability in an eye of a subject comprising (a) administering Vitamin D to the subject, and (b) administering at least one topical steroid to the eye of a subject at least once a day for a time period sufficient to improve at least one of corneal clarity, structural integrity, ocular surface health, and/or refractive ability in the eye.

In some embodiments, step (a) comprises systemically administering Vitamin D to the subject (i.e., orally or by injection) in an amount sufficient to achieve a stored level of Vitamin D, also referred to as the "serum 25(OH)D3" measured in nanograms per milliliter (ng/cc) of at least 30 ng/cc in the subject. Such a serum level can typically be obtained by administering 2000-6000 IU per day of Vitamin D3, such as about 5000 IU/day, until the serum level reaches a target level of between 30 and 70 ng/cc, such as at least 40 ng/cc, such as at least 50 ng/cc, or such as at least 60 ng/cc. Once the target level is reached, 2000 to 6000 IU per day is administered long-term. In cases of a severe deficiency, 50,000 IU Vitamin D3 is administered once per week for six weeks, with 4,000 IU per day administered the other six days of each of those weeks.

In some embodiments, step (a) comprises topical administration of an ophthalmic compisition comprising Vitamin D to a subject's eye(s). In some embodiments, the ophthalmic composition comprises active Vitamin D and a topical corticosteroid. In some embodiments, the ophthalmic composition comprises calcitriol and difluprednate.

As used herein, "a subject" includes all mammals, including without limitation humans, non-human primates, dogs, cats, horses, sheep, goats, cows, rabbits, pigs, and rodents. In a preferred embodiment, the compositions are formulated for use in humans.

While the dose of the ophthalmic composition varies depending on the type of ocular disease or condition, symptoms, age, and body weight of the patient, and the like, when it is administered to an adult, for example, the dose is preferably one or two drops per instillation in one eye according to the state of the disease or condition, as an eye drop containing a topical steroid, such as difluprednate, in a concentration of about 0.005-0.5%, and active Vitamin D, such as calcitriol, in a concentration of about 0.001 μg/ml to about 100 μg/ml, wherein the dose frequency is one to four times a day. The compositions of the present invention may be administered on a periodic basis at intervals determined to maintain a desired level of therapeutic effect.

As described in Examples 1-5, and 8 the inventor has unexpectedly discovered that the combination of activated Vitamin D/calcitriol and corticosteroids yields the following: (1) rapid improvement in corneal clarity/transparency; (2) rapid improvement in regularity of astigmatism, with potential for improved optical function and/or correction (i.e., a beneficial modification of refractive power), with or without assistive lenses; and (3) rapid improvement of the signs and/or symptoms of ocular surface disease, including reduction of inflammatory activity, improvement of symptoms associated with dysfunction of the tear/lubrication system and improvement of structural deviations in the human cornea. Concurrently, as described in Example 6, the inventor has observed a decrease in intra-ocular pressure during treatment with forms of Vitamin D, which further imply the potential for primary and/or adjunctive use of Vitamin D for control of intra-ocular pressure elevation, including that invoked by topical steroid use.

In one embodiment, the opthalmic composition is administered to a subject with structural deviation of the cornea, such as Keratoconus, for a time period sufficient to ameliorate at least one symptom associated with the structural deviation. Keratoconus is a degenerative disorder of the eye in which structural changes within the cornea cause it to thin and change to a more conical shape than its normal gradual curve. Keratoconus can cause substantial distortion of vision, such as blurring, with multiple images, glare, and sensitivity to light, itching, and poor night vision all often reported by the patient. It is typically diagnosed in the patient's adolescent years and attains its most severe state in the twenties and thirties, though it is characterized by ongoing degeneration at a variable rate throughout life. The classic symptom of keratoconus is the perception of multiple 'ghost' images, known as monocular polyopia. This effect is most clearly seen with a high contrast field, such as a point of light on a dark background. Instead of seeing just one point, a person with keratoconus sees many images of the point, spread out in a chaotic pattern. This pattern does not typically change from day to day, but over time it often takes on new forms. Patients also commonly notice glare/streaking and/or flaring distortion around light sources. If afflicting both eyes, the deterioration in vision can affect the patient's ability to drive a car or read normal print. Initial treatment focuses on control of visual symptoms using asitgmatic eyeglasses, though the degree of astigmatism tends to eventually render them incapable of comfortable/tolerable wear. Rigid contact lenses, and to a lesser extent (to date), soft contact lenses are also utilized, and can, up to a point, relieve symptoms and provide useful vision. Further progression of the disease may require surgery including intrastromal corneal ring segments, corneal collagen cross- linking, or corneal transplantation. The methods of administering the ophthalmic solution of the present invention, as described herein, can be used to enhance or replace the above- described conventional treatments for Keratoconus.

In another aspect, the invention provides a method for reducing intra-ocular pressure in a subject being treated with a topical steroid, comprising administering to the subject an amount of Vitamin D sufficient to reduce the intra-ocular pressure. As shown in Example 6, the inventor has unexpectedly discovered that administration of Vitamin D significantly reduces intra-ocular pressure in subjects undergoing treatment for glaucoma with topical corticosteroids. In some embodiments, the Vitamin D is administered systemically to the subject (i.e., orally or by injection) in an amount sufficient to achieve a stored level of Vitamin D, also referred to as the "serum 25(OH)D3" measured in nanograms per milliliter (ng/cc) of at least 30 ng/cc in the subject. Such a serum level can typically be obtained by administering 2000-10,000 IU per day of Vitamin D3, such as about 5000 to 6000 IU/day until the serum level reaches a target level of between 30 and 70 ng/cc, such as at least 40 ng/cc, such as at least 50 ng/cc, or such as at least 60 ng/cc. In some embodiments, the Vitamin D is administered topically to the eye(s) of the subject, as described herein. In some embodiments, an ophthalmic composition comprising a combination of an active Vitamin D and a topical corticosteroid is administered to the subject in order to protect against potential adverse effects of the topical corticosteroid, which, in isolation, can increase intra-ocular pressure or counteract the beneficial effect of medications used to treat glaucoma and/or high intra-ocular pressure (e.g., Alphagan, Xalatan, Travatan, and/or Trimoptic).

In another aspect, the invention provides a method for modulating the developmental refractive qualities of the eyes of a subject, thereby limiting or preventing at least one of the following: development of myopia, regular and/or irregular astigmatism and/or aberrations of focus during the subject body's growth and developmental periods, comprising administering Vitamin D to the subject in an amount sufficient to modulate the developmental refractive qualities of the eyes of the subject. In some embodiments, the Vitamin D is administered systemically in an amount sufficient to achieve a serum 25(OH)D3 level of at least 30 ng/c for a time period of at least one month or longer during the growth and development period (i.e., the first three decades of life, inclusive of the adolescence period) of the subject. In some embodiments, an active form of Vitamin D (or a form of Vitamin D intended to become activated) is topically administered to the eye(s) of the subject in an amount sufficient to modulate the developmental refractive qualities of the eye(s) of the subject for a time period of at least one month or longer during the growth and development period (i.e., the first three decades of life, inclusive of the adolescence period) of the subject. The ophthalmic compositions comprising active Vitamin D described herein may be used in accordance with this aspect of the invention. In some embodiments, the active form of Vitamin D is calcitriol. In some embodiments, the calcitriol is administered in an ophthalmic composition at a concentration of from 0.001 μg/ml to 100 μg/ml.

In accordance with this aspect of the invention, the Vitamin D may be administered to the subject systemically (i.e., orally or by injection) in an amount sufficient to achieve a stored level of Vitamin D, also referred to as the "serum 25(OH)D3" measured in nanograms per ml (ng/cc) of at least 30ng/cc in the subject. Such a serum level can typically be obtained by administering 2000-6000 IU per day of Vitamin D3, such as about 5000 IU/day until the serum level reaches a target level of between 30 and 70 ng/cc, such as at least 40 ng/cc, such as at least 50 ng/cc, or such as at least 60 ng/cc. Once the target level is reached, 2000 to 6000 IU per day is administered long-term. In accordance with this aspect of the invention, the Vitamin D is administered in an amount sufficient to achieve a serum 25(OH)D3 level of at least 30 ng/c for a time period of at least one month or longer during the growth and development period (i.e., the first three decades of life, inclusive of the period of adolescence) of the subject.

In some embodiments, the method comprises administering the Vitamin D

(systemically or topically) during the period of adolescence in a subject. For example, in a human subject, the period of adolescence of the subject is typically from the age of about 8 years old to about 18 years old, accordingly, the method encompasses administration of the Vitamin D to a human subject within this age span (such as, for example, a 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 year old). In some embodiments, the method comprises daily administration of at least 2000 IU to a human subject in the age range of from 8 to 15 in order to maintain the serum 25(OH)D3 level of at least 30 ng/c for a period of at least one month or longer during the growth and development period of the subject. In some embodiments, the Vitamin D is administered in the form of a children's multivitamin oral tablet or capsule wherein at least 2000 IU of Vitamin D is included in the tablet or capsule.

The following examples merely illustrate the best mode now contemplated for practicing the invention, but should not be construed to limit the invention. All literature citations herein are expressly incorporated herein by reference.

Example 1

This Example describes the discovery of previously unsuspected structural deviations in the human cornea, even in asymptomatic individuals, with the Oculus Pentacam, an opthalmic imaging device.

Methods:

An ophthalmic imaging device, the Oculus Pentacam, reveals unsuspected evidence of structural deviations in the human cornea to be a common occurrence, even in asymptomatic individuals. The Oculus Pentacam allows for real time capture of 25,000 true elevation points in 2 seconds with generation of cross-sectional and 3D high resolution images, allowing for precise calculation and comparison of multiple optical and structural qualities of the cornea. Structural deviations in the cornea are most pronounced in subjects having symptoms of ocular surface disease, and are most dramatic in cases classified as keratoconus. The structural deviations observed with the Oculus Pentacam include irregular/asymmetric distortion and various forms of opacity/localized haze/nebula of the corneal stroma.

Evidence is growing that a substantial percentage of the world's population is chronically, significantly deficient in the necessary forms of Vitamin D, ultimately due to inadequate exposure to, or interaction with, natural sunlight, the ultraviolet B component of sunlight being necessary to drive endogenous production of the active form of Vitamin D. The resulting deficiency in Vitamin D has been linked to various diseases, often involving structural and inflammatory elements. Inflammatory processes have been demonstrated and/or implicated in a variety of opthalmic disease states, and the dependence of ocular function on precise maintenance of elements of ocular structure (curvature, clarity/translucence, uniformity, symmetery, etc.) suggests particular vulnerability to primary and secondary effects of deficiency of Vitamin D forms. The inventor has observed subtle "disc" of central, stromal opacification linkable to chronic Vitamin D3 deficiency. This correlates with complaints of "veils" and glare in older patients with a history of prior cataract surgery and no other recognized pathology.

The inventor has also observed focal or multifocal, usually inferior, zones of irregular astigmatism, usually "steep" or "tear drop" in shape, suggesting decentration of apical lens power following the mechanics of an arch. Extremes are consistent with keratoconus diagnosis, but milder findings appear to be universally associated with dry eye complaints and examination findings, which negatively impact manifest refraction accuracy and stability. Subtle, peri-central changes of this nature have been a consistent finding in developing myopia and may have very significant mechanistic implications. Variations in anterior and posterior corneal surface elevation and thickness were found to coincide with visible and latent pathology (e.g., scars, regions of external compression or exposure/evaporative tear loss, etc). Inferior focal thinning and anterior surface depression was observed in dry eye disease. Evidence of surface compression was observed with chronic lid margin disease.

As described in the following Examples, the structural deviations in the cornea can be demonstrated to improve to some extent with oral Vitamin D supplementation, and to some extent with application of corticosteroids, however, a more rapid and substantially greater beneficial effect (i.e., synergistic) in terms of extent of resolution/optimization was unexpectedly observed after treatment with a combination of calcitriol and corticosteroid. The most beneficial effect was observed after treatment of the surface of the eye with a topical solution comprising calcitriol and the corticosteriod difluprednate.

Example 2

Preparation of a topical opthalmic composition comprising calcitriol and the corticosteroid difluprednate.

Methods:

Difluprednate is a corticosteroid, a derivative of prednisolone obtained by fluorination at the 6- and 9-positions, followed by esterification of the 17 and 21- hydroxyl groups with butyric acid and acetic acid, respectively. Durezol™ (difluprednate ophthalmic emulsion) 0.05% is a sterile, topical anti-infammatory corticosteroid for ophthalmic use. The chemical name is 6a,9-difuoro-l 1 β, 17,21 -trihydroxypregna- 1,4- diene-3,20-dione 21-acetate 17-butyrate (CAS number 23674-86-4). 0.4 niL of calcitriol injection, 1 mcg/ml in sterile, buffered water (American Regent formulation) was mixed with 0.4 ml of difluprednate ophthalmic (Durezol™, Alcon Laboratories) to yield a combined solution with calcitriol concentration of 0.5 mcg/ml suitable for ophthalmic topical administration by pH and chemical composition. The topical opthalmic solution was maintained in a sterile environment protected from air and light exposure.

Example 3

This Example describes the treatment of a human subject with a topical opthalmic solution containing calcitriol and the corticosteroid difluprednate, prepared as described in Example 2.

Methods:

Prior to treatment, the subject had undergone two years of oral Vitamin D3 supplementation and had a documented serum calcidiol (also called 25(OH)D3, or 25-hydroxyvitamin D3) level in the optimal range (blood serum level of at least 50 ng/cc), yet nonetheless showed relative corneal distortion with infero-nasal displacement, relative to the axis of vision, of maximal corneal power and minimum thickness. There was also a distinct central nebula/hazy region of the corneal stroma observable via the Oculus Pentacam. This "inferior steepening" and development of overtly visible corneal haze, in a more pronounced form, are characteristic of the disease entity keratoconus. These findings were documented to be stable over the two months prior to the first installation of the topical opthalmic solution of the invention. The fellow eye (i.e., left eye) of the same individual possessed features mirroring the right eye.

Over the course of three weeks, the topical opthalmic solution, prepared as described in Example 2, was applied as one drop, two times per day, to the right eye of the adult volunteer subject. As a control, the left eye of the same subject was given one drop, two times per day of the standard difluprednate ophthalmic composition (Durezol™, Alcon, Inc.).

Results:

After three weeks, the right eye, receiving the topical opthalmic solution comprising the combination of calcitriol and difluprednate, showed significant reduction in stromal haze and "inferior steepening," gain in central corneal thickness, and a substantial drop in refractive astigmatism. In contrast, the fellow left control eye showed no beneficial change in shape or astigmatism, rather inferior steepening actually increased slightly, though it did show a modest improvement in thickness.

TABLE 1 : Corneal Clarity (as % reflectance)

TABLE 2: Corneal Indices (8 mm zone)

ISV= "Index of Surface Variance": Deviation of individual corneal radii from the mean value. ISV is elevated in cases of astigmatism, scarred cornea, keratoconus, etc. A decrease in this value indicates a beneficial effect of treatment to correct/resolve defects.

IVA= "Index of vertical asymmetry": Indication of the degree of asymmetry with respect to the horizontal meridian, elevated in oblique astigmatism, keratoconus and corneal ectasia.

KI= Keratoconus Index: Elevated index is associated with distortions, including keratoconus.

IHD= Index of height decentration: Calculated from Fourier analysis of height values, gives the degree of decentration in the vertical direction. Sensitive for detecting distortion, especially keratoconus.

Conclusion:

The topical opthalmic solution of the present invention thus evoked a significant improvement in corneal clarity, refractive status and structural integrity in the treated eye in just three weeks, despite pre-existing therapy with oral Vitamin D3. It is possible that the pre-existing therapy with oral Vitamin D3 may have played a role in the observed improvement in thickness of the control eye when treated with topical steroid alone due to the presence of systemic calcitriol in the ocular tissues via natural distribution. The ISV data shows a greater beneficial effect after combination treatment, some effect in steroid only. The IVA data shows about an equally beneficial effect with either the combination or steriod only. The KI data shows a significant beneficial effect with the combination treatment, no effect with steroid only.

These results demonstrate that the topical administration of an opthalmic composition comprising a combination of activated Vitamin D/calcitriol and corticosteroids yields rapid improvement in reducing stromal haze and "inferior steepening," gain in central corneal thickness, and a substantial drop in refractive astigmatism. These results show a significantly greater effect when the compounds are administered in combination as compared to the effect observed with either compound alone, even with prolonged application. Example 4

Methods:

A 38 year old man presented with a complaint of chronic "red eyes." He was otherwise asymptomatic. Corneal findings by Oculus Pentacam confirmed typical inferior-shifted astigmatism and faint apical haze/nebulae of both corneas. Previously, one week of topical prednisolone acetate 1.0% yielded an approximate 50% reduction in conjunctival injection/"redness", which, once off therapy, rapidly returned over the following week. One month of topical cyclosporine 0.05% (Restasis™, Allergan, Inc.) had no impact on his condition of chronic red eyes.

The subject's serum level of 25(OH)D3 was tested and found to be significantly low, and was optimized, but this treatment alone had no impact on his condition of chronic red eyes.

After optimizing the 25(OH)D3 serum level, topical corticosteriod (prednisolone acetate 1%) was then reintroduced. Less than 12 hours later, all injection/"redness" had resolved. The topical corticosteriod was tapered off over one week and there has been no recurrence of symptoms over the ensuing year.

Conclusion:

Although the delivery of active Vitamin D3 was not achieved topically in this instance, this Example demonstrates the synergistic nature of interaction between administration of Vitamin D3 and a topical administration of a coricosteroid to the affected eye.

Example 5

This Example describes the treatment of a representeative human subject diagnosed with Keratoconus with a topical corticosteroid and oral D3.

Methods:

The present inventor has observed multiple cases of Oculus Pentacam- documented improvement in symptoms of dry eye and ocular surface disease, as well as enhancement of corneal clarity, symmetry, and regularity of astigmatism in more than fifty subjects in the setting of optimized Vitamin D3/cholecalciferol intake followed by administration of a topical corticosteroid. The duration of steroid treatment was typically less than one month with stability and/or ongoing improvement in corneal behavior persisting after treatment with the steroid. Typically, treatment with a corticosteroid involves an initial higher dose, followed by a reduced dosage over time, referred to as a "tapered" dosage, in order to prevent a rebound reaction in the body.

Representative data compiled from 30 selected cases is as follows.

Relief of symptoms (irritation, redness, foreign body sensation, dryness: partial: 8; complete: 22.

Reduction in Index of Vertical asymmetry (IV A), a surface parameter related to corneal distortion linked to inadequate stromal hydration: mean: 28%, range: 14%-36%.

The representative patient shown in Table 3 was treated with a topical steroid twice per day for two weeks, followed by once per day for two weeks.

Results:

Table 3 below provides the results of a sample patient with diagnosed ketratoconus, which is a representative sample of the 30 cases tested to date.

TABLE 3 : Corneal Indices 8mm zone , Sam le atient with Dia nosed Keratoconus

ISV= "Index of Surface Variance": Deviation of individual corneal radii from the mean value. ISV is elevated in cases of astigmatism, scarred cornea, keratoconus, etc. A decrease in this value indicates a beneficial effect of treatment to correct/resolve defects. IVA= "Index of vertical asymmetry": Indication of the degree of asymmetry with respect to the horizontal meridian, elevated in dry eye stromal dehydration, oblique astigmatism, keratoconus and corneal ectasia.

TKC= Likelihood of Keratoconus: *= Normal; KC 1-2 = mild Keratoconus; KC 2-3 = Moderate Keratoconus (Pentacam analysis determined from balance of indices).

The results in Table 3 show meaningful reduction in keratoconus indicating indices over a 5 week period of treatment with oral D3 and a topical corticosteroid.

Example 6

This Examples demonstrates that administration of Vitamin D significantly reduces intra-ocular pressure in subjects undergoing medical treatment for glaucoma.

Rationale: Glaucoma is a disease of nerve loss which results from prolonged high pressure in the eyes, in a similar fashion to the way a stroke may follow upon long-term high blood pressure. Therefore, medications used to treat eye pressure are designed to prevent glaucoma, and/or to stabilize the condition and prevent further injury in subjects who are already diagnosed with glaucoma. Steroids have the problem of relatively commonly (about 1 in 30 people) causing a rise in intra-ocular pressure as an adverse effect, and in some instances the use of steroids will lead to damage in the nerves (steroid-induced glaucoma). Therefore, in one embodiment, the use of systemic Vitamin D or the topical administration to the eye(s) of an ophthalmic solution containing Vitamin D in a subject suffering from Glaucoma is useful to reduce the intra-ocular pressure in the subject. In another embodiment, the use of systemic Vitamin D or the topical administration to the eye(s) of an opthalmic solution containing Vitamin D is administered to a subject undergoing treatment with an opthalmic solution containing a topical steroid, in order to offset the intra-ocular pressure rise, and thereby prevent the onset of steroid-induced glaucoma.

Methods:

Three adult patient volunteers were taking anti-glaucoma medications and were treated with D3 as shown in TABLES 4-6. Each patient was taking one or more oral anti-glaucoma medications to control intra-ocular pressure as shown in TABLES 4-6. Patient #1 had undergone D3 supplementation (6000 IU/day) for a period of about 4 months prior to the measurment on 12/11/2008 (beginning D3 supplementation after the measurement on 8/11/2008).

Patient #2 had undergone D3 supplementation (10,000 IU/day) for a period of about 3 weeks prior to the measurement on 2/3/2009 (beginning D3 supplementation after the measurement on 1/13/2009).

Patient #3 had undergone D3 supplementation (6000 IU/day) for a period of about 4 months prior to the measurement on 2/18/2010 (beginning D3 supplementation after the measurement on 10/21/2009).

The intra-ocular pressure of the right and left eyes of each patient were measured by Goldman aplanation tonometry before and during administration of D3.

Results:

TABLE 4: Patient #1 Intra-ocular ressure versus D3 intake

"ABLE 5: Patient #2 Intra-ocular pressure versus D3 intake

Date Glaucoma IOP Right IOP Left D3 Number of

Treatment Eye Eye supplement medications taken to

(mmHg) (mmHg) (IU/day)

control intraocular pressure

10/16/2007 Daily Travatan 21 22 0 2

plus Timoptic

XE 0.5%

2/5/2008 Daily Travatan 19 20 0 2

plus Timoptic

XE 0.5%

5/20/2008 Daily Travatan 16 14 0 2

plus Timoptic

XE 0.5%

8/18/2008* Daily Travatan 13 13 0 2

plus Timoptic

XE 0.5%

1/13/2009 Daily Travatan 22 28 0 2

plus Timoptic

XE 0.5%

2/3/2009 Daily Travatan 13 15 10,000 2

plus Timoptic

XE 0.5%

4/29/2009 Travatan 13 13 8,000 1

7/28/2009 Travatan 13 14 8,000 1

10/22/2009 Travatan 15 14 6,000 1

1/12/2010 Travatan 21 22 6,000 1 2/9/2010 Travatan 16 23 8,000 1

5/3/2010 Travatan 14 19 8,000 1

9/2/2010 Travatan 12 14 8,000 1

indicates peak sun exposure (August)

As shown in Table 5, the intra-ocular pressure of Patient #2 was the lowest on 4/29/2009, despite a reduction in the number of medications taken by the subject to control the intra-ocular pressure. As further shown in Table 5, on 1/12/2010, the intra-ocular pressure rose after a reduction in the dosage of D3 administered. On 5/3/2010, the intra-ocular pressure dropped down again after the dosage of D3 was increased.

TABLE 6: Patient #3 Intra-ocular ressure versus D3 intake

As shown in Table 6, the lowest intra-ocular pressure measurement was on 2/18/2010, which correlated with the first supplementation of D3, despite a reduction in the number of medications taken by the subject to control the intra-ocular pressure.

As shown above in Tables 4-6, the inventor has discovered that administration of Vitamin D significantly reduces intra-ocular pressure in subjects undergoing medical treatment for glaucoma (e.g., Alphagan, Xalatan, Travatan, Trimoptic). It is known that elevation in intra-ocular pressure is a major risk factor for glaucoma patients undergoing treatment with topical steroids. These results demonstrate administration of Vitamin D to subjects undergoing treatment for glaucoma significantly reduces intra-ocular pressure and thus appears to provide a synergistic protective effect against corticosteroid-induced intra-ocular pressure rise.

Example 7

This Example describes the treatment of two children (a 13 year old girl and a 10 year old boy) with oral Vitamin D, resulting in reduction in focal, peri-axial astigmatic irregularity and steepening in both eyes of each subject.

Methods:

A 13 -year-old girl had baseline developmental myopia, with manifest refraction, right eye, of -0.50 - 0.25 x 90 and left eye of -0.25 - 0.25 x 59. Over the ensuring two years, serial Pentacam findings demonstrated bilateral development of focal, peri-axial corneal steepening and gradual rise to right eye manifest refraction, at age 15, of -1.50 - 0.25 x 93 and left of -1.00 - 0.25 x 50. Oral vitamin D3 intake of 2000 IU/day was started. Seventeen months later, at age 17, despite passage through the period of peak growth, the manifest refraction of the right eye declined slightly to -1.50 sphere and the left demonstrated minimal change, at -1.25 sphere. Pentacam imaging revealed reduction in the focal, peri-axial astigmatic irregularity and steepening in both eyes.

A 10 year old boy had baseline developmental myopia, with manifest refraction, right eye, of -0.50 - 0.25 x 88 and left eye of -0.50 - 0.25 x 177. Over the ensuring two years, serial Pentacam findings demonstrated bilateral development of focal, peri-axial corneal steepening and gradual rise in myopia to right eye manifest refraction of -1.25 - 0.25 x 85 and left of -1.25 sphere. Oral vitamin D3 intake of 2000 IU/day was started. Seven months later, at age 13, despite entering the peak growth period, the manifest refraction of the right eye declined slightly to -1.25 - 0.25 x 85 and the left remained stable at -1.25 sphere. Both eyes demonstrated reduction in focal, peri-axial astigmatic irregularity and steepening.

The results in this Example demonstrates that administration of Vitamin D to an adolescent subject in an amount sufficient to achieve a serum 25(OH)D3 level of at least 30 ng/cc (i.e. 2000 IU/day) for a time period of at least 6 months, is effective to modulate the developmental refractive qualities of the eyes of the adolescent subject, thereby limiting or preventing at least one of the following: development of myopia, regular and/or irregular astigmatism and/or aberrations of focus during the subject body's growth and developmental periods. These results are consistent with the results obtained in Examples 1-6 where an enhancement or improvement in corneal clarity, structural integrity, and/or refractive ability would be expected to have a beneficial impact on the development of optimal vision and avoidance of refractive errors during the bodies growth and developmental periods because feedback mechanisms are believed to exist, governing such development and have been demonstrated to be responsive to the quality of image focus available to the neural retina.

Example 8

Additional Representative Case Studies.

Case Study #1 : Subject with Dry Eyes and Irregular Astigmatism treated with topical steroid and Calcitriol.

Subject: A 61 year old executive unable to be refracted to full 20/20 vision in either eye, with a history of ocular irritation, mixed regular and irregular astigmatism and intermittent mild elevation of intraocular pressure in both eyes (to R24, L22 mmHg at highest). Oral vitamin D3 was consistent for over three months at 3000 IU/day. Most recent intraocular pressures were R14 and LI 4 mmHg. Uncorrected visual acuity was R 20/60 and L 20/80.

Treatment: 0.4 meg Calcitriol injection formulation was combined with 0.4 mL of difluprednate to produce a 0.8 cc mixture, and then applied as one drop two times per day to the left eye for a total of four weeks. As a control, difluprednate alone was applied to the right eye, same schedule.

Results: Following the treatment, the eyes were asymptomatic and the uncorrected visual acuity had improved to R 20/40 and L 20/60. The prescription of the left eye decreased by 0.25 diopter; the right was unchanged. 20/20 acuity was achieved for both eyes. Intraocular pressures were R 18 and L14 mmHg, suggesting a possible mild steroid response in the right eye (difluprenate) and no steroid response in the left eye (Calcitriol- difluprednate combination). There was greater reduction in corneal irregularity and the Zernlike Aberration index in the left eye (Calcitriol-difluprednate) than the right eye (difluprednate).

Case Study #2: Subject with Dry Eyes and Irregular Astigmatism treated with topical Calcitriol and Steroid

Subject: A 60 year old registered nurse, unable to be refracted to a full 20/20 vision in either eye, with a history of intermittent redness and irritation, mixed regular and irregular astigmatism. Oral vitamin D3 was consistent for over three months at 3000 IU/day. The most recent intraocular pressures were R 15 and LI 5 mmHg. Uncorrected visual acuity was R 20/70 and L 20/25. The left eye had recently undergone repair for a retinal detachment and then subsequently required cataract surgery. Subjectively, the left eye vision was still not perceived to be uniformly clear and she complained of ongoing glare.

Treatment: 0.4 meg Calcitriol injection formulation was combined with 0.4 mL difluprednate to produce a 0.8 cc mixture, and then applied as one drop two times per day to the left eye for a total of four weeks. As a control, difluprednate alone was applied to the right eye, same schedule.

Results: Following the treatment, the eyes were comfortable. The refractive astigmatism decreased by 0.25 diopter in both eyes and 20/20 acuity was achieved for both. Intraocular pressures were R16 and L14 mmHg. Though the change was of very low magnitude for either eye, the relative change was notable: rise in the right (difluprednate alone) and decrease in the left (Calcitriol-difluprednate combination). There was greater reduction in corneal irregularity in the left eye (Calcitriol- difluprednate) than in the right (difluprednate).

Case Study #3 : Subject with Keratoconus treated with topical steroid and oral vitamin D3

Subject: A 32 year old programmer with the complaint that he "used to have good vision." He experienced an approximately four year history of rapid decline in subjective vision, R>L eye. The Pentacam findings were consistent with Keratoconus diagnosis, with the right eye graded "KC 2-3" and the left eye "KC 1-2."

The initial refraction: R -1.50-1.75 x 22 (giving 20/50 with difficulty).

L piano - 1.50 x 122 (giving 20/20 with difficulty).

Treatment: given oral vitamin D3 5000 IU/day, and two, two week long courses of topical prednisolone drops.

Results: Subjective vision was much improved and the subject returned to driving and watching TV without eyeglass correction.

Refraction after treatment:

R +1.25-2.75 x 55 (giving 20/20)

L -0.50-0.75 x 1 18 (giving 20/15)

Central corneal thickness improved by more than 14 microns on the right eye and by 24 microns on the left eye, with the left eye keratoconus grade reduced to "none."

Case Study #4: Subject with Post-LASIK and Dry Eyes - synergy of treatment with Vitamin D3 and topical steroid

Subject: A 39 year old software engineer, 10 years after LASIK surgery for > 10 diopters myopia, complains of poor vision with and without glasses. Acuity uncorrected: R 20/50 (-2); L 20/40 (-2).

Prescription:

R - 3.00 - 2.25 x 10 (giving 20/25 (-2)

L piano - 1.50 x 75 (giving 20/25 (+/-)

Treatment: oral vitamin D3 at 5000 IU/day and three courses of difluprednate twice per day for one week, then once per day for one week.

Results: Subject said vision was much better, acuity uncorrected: R 20/25 (-2); L 20/30 (+/-).

Prescription:

R +0.25 - 1.75 x 120 (giving 20/25 (+/-)

L +0.50 - 1.50 x 95 (giving 20/25 (+/-)

Case Study #5: Subject with Dry Eyes - synergy of treatment with Vitamin D3 and topical steroid

Subject: 51 year old engineer presented for third opinion for astigmatism, dry eyes, no toleration for contact lenses. Had been treated with antibiotic drops, prednisolone acetate (1%), oral tetracycline, but no treatments had helped.

Initial prescription: R -4.00 - 1.00 x 168 (giving 20/20 (-1))

L -4.25 - 1.00 x 10 (giving 20/20 (-2))'

Treatment: Oral vitamin D3 at 5000 IU/day for 8 weeks and one course of difluprednate, twice per day for one week, then once per day for one week.

Results: The subject is wearing contact lenses again with good comfort, subjective vision is excellent with both glasses and contacts.

Prescription after treatment:

R -3.75 - 0.75 x 168 (giving 20/20 (+))

L -3.75 - 0.50 x 172 (giving 20/20 (+))

While illustrative embodiments have been illustrated and described, it will be appreciated that various changes can be made therein without departing from the spirit and scope of the invention.

Claims

CLAIMS The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. An ophthalmic composition comprising active Vitamin D and at least one topical steroid in a formulation suitable for topical administration to the eye.

2. The composition of Claim 1, wherein the composition comprises an amount of active Vitamin D and at least one topical steroid in an amount effective to enhance at least one of corneal clarity, structural integrity and/or refractive ability, when administered topically to the eye.

3. The composition of Claim 1, wherein the topical steroid is a Cortisol derivative.

4. The composition of Claim 1, wherein the topical steroid is a corticosteroid.

5. The composition of Claim 4, wherein the corticosteroid is selected from the group consisting of difluprednate, prednisolone, dexamethasone, fluocinolone, fluorometholone, loteprednol, medrysone, rimexolone, triamcinolone, cortisone and hydrocortisone

6. The composition of Claim 4, wherein the corticosteroid is difluprednate.

7. The composition of Claim 1, wherein the active Vitamin D is calcitriol.

8. The composition of Claim 6, wherein the difluprednate is present at a concentration of from 0.005 to 0.5%.

9. The composition of Claim 7, wherein the calcitriol is present at a concentration of from 0.001 μg/ml to 100 μg/ml.

10. A method of improving at least one of corneal clarity, structural integrity, ocular surface health and/or refractive ability in an eye of a subject comprising; administering at least one topical steroid to the eye of a subject, wherein the subject has a verified serum 25(OH)D3 level of at least 30 ng/cc.

1 1. A method of improving at least one of corneal clarity, structural integrity, ocular surface health and/or refractive ability in an eye of a subject comprising:

(a) administering Vitamin D to the subject, and

(b) administering at least one topical steroid to the eye of a subject for at least once a day for a time period sufficient to improve at least one of corneal clarity, structural integrity, ocular surface health and/or refractive ability in the eye.

12. The method of Claim 11, wherein step (a) comprises systemic administration of Vitamin D sufficient to result in a serum 25(OH)D3 level of at least 30 ng/cc in the subject.

13. The method of Claim 11, wherein step (a) comprises topical administration of calcitriol to the eye.

14. The method of Claim 11, wherein the at least one topical steroid comprises a Cortisol derivative.

15. The method of Claim 14, wherein the topical steroid is difluprednate.

16. The method of Claim 13, wherein a composition comprising at least one topical steroid and calcitriol is administered topically to the eye.

17. The method of Claim 13, wherein the calcitriol is administered at least once a day for a period of from at least 1 week to at least 3 weeks.

18. The method of Claim 16, wherein the composition comprises calcitriol at a concentration of from 0.001 μg/ml to 100 μg/ml.

19. The method of Claim 16, wherein the composition comprises a Cortisol derivative at a concentration of from 0.005 to 0.5%.

20. The method of Claim 16, wherein the composition is administered to the subject at least once a day for a period of from at least 1 week to at least 3 weeks.

21. A method for reducing intra-ocular pressure in a subject being treated with a topical steroid, comprising administering to the subject an amount of Vitamin D sufficient to reduce the intra-ocular pressure.

22. The method of Claim 21, wherein the subject is suffering from glaucoma.

23. The method of Claim 21, wherein the Vitamin D is administered systemically.

24. The method of Claim 23, wherein the Vitamin D is administered in an amount sufficient to raise the subjects serum level of Vitamin D to a level of at least 30 ng/cc.

25. The method of Claim 21, wherein the Vitamin D is administered topically to the eye(s) of the subject.

26. The method of Claim 21 or 22, wherein the subject is treated with a composition comprising a combination of at least one topical steroid and Vitamin D.

27. A method for reducing intra-ocular pressure in a subject suffering from glaucoma, comprising administering to the subject an amount of Vitamin D sufficient to reduce the intra-ocular pressure.

28. The method of Claim 27, wherein the Vitamin D is administered systemically in an amount sufficient to raise the subjects serum level of Vitamin D to a level of at least 30 ng/cc.

29. The method of Claim 27, wherein the Vitamin D is administered topically to the eye(s) of the subject.

30. The method of Claim 29, wherein the topical administration of Vitamin D comprises administering calcitriol at a concentration of from 0.001 μg/ml to 100 μg/ml.

31. A method for modulating the developmental refractive qualities of the eye(s) of a subject, thereby limiting or preventing at least one of the following: development of myopia, regular and/or irregular astigmatism and/or aberrations of focus during the subject body's growth and developmental periods, comprising administering Vitamin D to the subject in an amount sufficient to modulate the developmental refractive qualities of the eye(s) of the subject for a time period of at least one month or longer during a growth and development period during the first three decades of the life of the subject.

32. The method of Claim 31, wherein the Vitamin D is administered systemically to achieve a serum 25(OH)D3 level of at least 30 ng/c for the time period of at least one month or longer during the growth and developmental period of the subject.

33. The method of Claim 31, wherein the Vitamin D is in an active form or in a form intended to become activated, and is administered topically to one or both eyes of the subject for the time period of at least one month or longer during the growth and developmental period of the subject.

34. The method of Claim 31, wherein the subject is a human subject of an age in the range of 8 years old to 18 years old.

35. The method of Claim 33, wherein the active form of Vitamin D is calcitriol.

36. The method of Claim 35, wherein the calcitriol is administered in an ophthalmic composition at a concentration of from 0.001 μg/ml to 100 μg/ml.