WO2009023411A1

WO2009023411A1 - Compositions and methods for treating or controlling anterior- and posterior-segment ophthalmic diseases

Info

Publication number: WO2009023411A1
Application number: PCT/US2008/070951
Authority: WO
Inventors: Keith Wayne Ward; Srini Venkatesh; Tim Tak Lam; Toan P. Vo
Original assignee: Bausch & Lomb Incorporated
Priority date: 2007-08-09
Filing date: 2008-07-24
Publication date: 2009-02-19

Abstract

A composition for treating or controlling at least one of anterior- and posterior- segment diseases, conditions, or disorders that have an etiology in, or produce, inflammation comprises an osteopontin antagonist. The composition also can include anti-oxidant drugs, other anti-inflammatory agents, anti-angiogenic agents, or combinations thereof. The composition can be formulated for topical application, injection, or implantation. The composition can be administered alone or in combination with another procedure chosen to enhance the outcome of the treatment.

Description

COMPOSITIONS AND METHODS FOR TREATING OR CONTROLLING ANTERIOR- AND POSTERIOR-SEGMENT OPHTHALMIC DISEASES

BACKGROUND OF THE INVENTION

The present invention relates to compositions and methods for treating or controlling anterior- and posterior-segment ophthalmic diseases. In particular, the present invention relates to compositions that comprise an osteopontin antagonist and methods for the treatment or control of anterior- and posterior-segment ophthalmic diseases using such compositions.

Ophthalmic conditions may be classified as anterior-segment diseases, such as corneal edema, anterior uveitis, pterygium, Pinguecula, iritis, keratitis (such as immune stromal or interstitial keratitis), corneal ulcer, corneal opacifications with an exudative or inflammatory component, conjunctivitis, and allergy- and laser-induced exudation; or posterior-segment diseases, such as optic nerve degeneration, exudative macular degeneration, macular edema, diabetic retinopathy, age-related macular degeneration, and retinopathy of prematurity. Many anterior-segment diseases have etiology in inflammation. Others have inflammatory sequelae. Posterior-segment diseases comprise the largest number of causes for vision loss. There has been growing evidence that many posterior-segment diseases also have etiology in inflammation.

Among the posterior-segment diseases, diabetic retinopathy is the leading cause of blindness in adults between the ages of 18 to 72 who suffer from diabetes. In the early stage, the vasculature of the retina is increasingly obstructed by the adhesion of cells involved in immunological response, such as leucocytes, on molecules, such as intercellular adhesion molecule- 1 ("ICAM-I") or vascular cell adhesion molecule- 1 ("VCAM-I"), which are overexpressed on the endothelial layer of inflammed vasculature. The vasculature obstruction results in ischemia and leads to hypoxia condition in the surrounding tissues, especially the retina. In response to such a condition, new blood vessels begin to proliferate uncontrollably. These new blood vessels are typically leaky, resulting in fluid accumulation under the retina and eventually the vision-threatening condition known as macular edema. (See; e.g., A.P. Adamis, British J. Ophthalmol., Vol. 86, 363 (2002); S. Ishida et al., Invest. Ophthalmol. & Vis. ScL, Vol. 44, No. 5, 2155 (2003).) Vascular endothelial growth factor ("VEGF"), a hypoxia-induced pro-inflammatory angiogenic factor, has been found at elevated levels in the diabetic retina during both the nonproliferative and proliferative stage. VEGF also induces the expression of ICAM- 1 and VCAM- 1 on endothelial cells. (I. Kim et al., Biol. Chem., Vol. 276, No. 10, 7614 (2001 ).) In addition, experimental investigations in animals have shown that mRNA expression for the pro-inflammatory cytokines IL- 1 (interleukin-1 ) and TNF-α (tumor necrosis factor-α) is increased in the retina early in the course of diabetes, and moreover, inhibition of TNF-α has demonstrated beneficial effects in the prevention of diabetic retinopathy. (J.F. Navarro and C. Mora, Nephrol. Dial. Transplant, Vol. 20, 2601 (2005).) Thus, experimental evidence strongly suggests a central and causal role of chronic inflammation in the pathogenesis of diabetic retinopathy and macular edema. (A.M. Joussen et al., FASEB J., Vol. 18, 1450 (2004).)

Macular degeneration, another posterior-segment degenerative condition, is the most common cause of central vision loss in those 50 or older, and its prevalence increases with age. Age-related macular degeneration ("AMD") is the more common form of the condition. The other form, which is sometimes called "juvenile macular degeneration" ("JMD") is most commonly caused by an inherited condition. It is estimated that 50 million people worldwide suffer from AMD. It has recently been discovered that mutations in two genes encoding proteins in the so-called complement cascade account for most of the risk of developing AMD. This complex molecular pathway is the body's first line of defense against invading bacteria, but if overactive, the pathway can produce tissue-damaging inflammation, which underlies the vision- destroying changes that particularly strike the macula. Proteins associated with immune system activity have been found in or near drusen in eyes with AMD. Over time, the drusen grow as they accumulate inflammatory proteins and other materials, and the inflammation persists, causing additional damage to the retina and eventual vision loss. (See; e.g., Science, Vol. 31 1 , 1704 (2006).)

Glaucoma is an optic neuropathy with characteristic structural damage to the optic nerve, associated with progressive retinal ganglion cell death, loss of nerve fibers, and visual field loss. On the basis of its etiology, glaucoma has been classified as primary or secondary. Primary glaucoma is an independent syndrome in adults and may be classified as either chronic open-angle or chronic (acute) angle-closure. Primary open-angle glaucoma is the most commonly occurring form of glaucoma, which appears to have no attributable underlying cause. Angle-closure glaucoma usually afflicts those persons having "shallow" angles in the anterior chamber and results from the sides (or angles) of the chamber coming together and blocking aqueous outflow through the trabecular meshwork. Secondary glaucoma, as the name suggests, results from preexisting ocular diseases such as uveitis, intraocular tumor, or enlarged cataract.

An intraocular pressure ("IOP") that is high compared to the population mean is a risk factor for the development of glaucoma. However, many individuals with high IOP do not have glaucomatous loss of vision. Conversely, there are glaucoma patients with normal IOP. Therefore, continued efforts have been devoted to elucidate the pathogenic mechanisms of glaucomatous optic nerve degeneration.

It has been postulated that optic nerve fibers are compressed by high IOP, leading to an effective physiological axotomy and problems with axonal transport. High IOP also results in compression of blood vessels supplying the optic nerve heads ("ONHs"), leading to the progressive death of retinal ganglion cells ("RGCs")- See; e.g., M. Rudzinski and H.U. Saragovi, Curr. Med. Chem. - Central Nervous System Agents, Vol. 5, 43 (2005).

In addition, there is growing evidence that other molecular mechanisms also cause direct damage to RGCs: existence of high levels of neurotoxic substances such as glutamate and nitric oxide and pro-inflammatory processes. Id. At low concentrations, NO plays a beneficial role in neurotransmission and vasodilation, while at higher concentrations, it is implicated in having a role in the pathogenesis of stroke, demyelination, and other neurodegenerative diseases. R.N. Saha and K. Pahan, Antioxidants & Redox Signaling, Vol. 8, No. 5 & 6, 929 (2006). NO has been recognized as a mediator and regulator of inflammatory responses. It possesses cytotoxic properties and is produced by immune cells, including macrophages, with the aim of assisting in the destruction of pathogenic microorganisms, but it can also have damaging effects on host tissues. NO can also react with molecular oxygen and superoxide anion to produce reactive nitrogen species that can modify various cellular functions. R. Korhonen et al., Curr. Drug Target - Inflam. & Allergy, Vol. 4, 471 (2005). Furthermore, oxidative stress, occurring not only in the trabecular meshwork ("TM") but also in retinal cells, appears to be involved in the neuronal cell death affecting the optic nerve in primary open-angle glaucoma ("POAG"). A. Izzotti et al., Mutat. Res., Vol. 612, No. 2, 105 (2006).

In addition, tumor necrosis factor-α ("TNF-α"), a pro-inflammatory cytokine, has recently been identified to be a mediator of RGC death. TNF-α and TNF-α receptor- 1 are up-regulated in experimental rat models of glaucoma. In vitro studies have further identified that TNF-α-mediated RGC death involves the activation of both receptor- mediated caspase cascade and mitochondria-mediated caspase-dependent and caspase- independent components of cell death cascade. G. Tezel and X. Yang, Expt'l Eye Res., Vol. 81, 207 (2005). Moreover, TNF-α and its receptor were found in greater amounts in retina sections of glaucomatous eyes than in control eyes of age-matched normal donors. G. Tezel et al., Invest. Ophthalmol, ά Vis. ScL, Vol. 42, No. 8, 1787 (2001).

Other posterior-segment conditions include "posterior uveitis," which is a term given to a collection of inflammatory conditions associated with the posterior segment of the eye. Posterior uveitis includes, but is not limited to, choroiditis (inflammation of the choroid), retinitis (inflammation of the retina), optic neuritis (inflammation of the optic nerve), and vasculitis (inflammation of the blood vessels at the back of the eye). Ocular complications of posterior uveitis may produce profound and irreversible loss of vision, when unrecognized or treated improperly. The most frequent complications include glaucoma, retinal detachment, neovascularization of the retina or optic nerve, and cystoid macular edema (the most common cause of decreased vision from uveitis).

Thus, it has been established that a great number of serious eye conditions involve inflammation, as either a cause or an effect.

Research conducted during the last two decades has identified osteopontin ("OPN") as among the important mediators of inflammation. OPN is a multifunctional phosphoprotein secreted by many cell types, such as osteoblasts, T- and B-lymphocytes, neutrophils, macrophages, epithelial cells, and vascular smooth muscle cells. M. Kurata et al., Clin. ScL, Vol. 1 1 1, 319 (2006); J. Sodek et al., J. Dent. Res., Vol. 85, No. 5, 404 (2006). OPN acts as an extracellular matrix protein with diverse biological activities mediated by several cell-surface receptors, such as integrin receptors that recognize the RGD sequence. Classical pro-inflammatory cytokines, such as TNF-α, IL- l β, EL-3, IL- 6, IL- 12, GM-CSF (granulocyte-macrophage colony-stimulating factor), and TGF-β, strongly induce the expression of OPN. K. Yumoto et al., PNAS, Vol. 99, No.7, 4556 (2002); A. O'Regan, Cytokine & Growth Factor Rev., Vol. 14, 479 (2003). OPN, in turn, activates macrophages and T-cells via integrin (e.g.; α_vβi, α_vβ₃, and α_vβs) and CD44 receptors to produce more TNF-α and also other immunological cytokines (e.g., IL- 12 and IFN-γ). In addition, OPN act as a chemokine, attracting macrophages and T-cells to, and retaining them at, inflamed sites. OPN also induces human monocytes to express pro-angiogenic chemokines, such as EL-6 and IL-8. D. Leali et al., J. Immunol., Vol. 171, 1085 (2003). Thus, OPN plays an important role during both acute and chronic inflammation, resulting in complications.

Glucocorticoids ("GCs") are among the most potent drugs used for the treatment of inflammatory diseases. GCs exert their anti-inflammatory action by binding to the glucocorticoid receptor and negatively regulate (transrepress) the transcritption and expression of pro-inflammatory cytokines, such as IL- lβ, IL-2, IL-3, IL-6, IL-1 1 , TNF- α, GM-CSF, and chemokines that attract inflammatory cells to the site of inflammation, including IL-8, RANTES, MCP-I (monocyte chemotactic protein- 1), MCP-3, MCP-4, MIP- lα (macrophage-inflammatory protein- lα), and eotaxin. PJ. Barnes, CHn. ScL, Vol., Vol. 94, 557-572 ( 1998). However, long-term treatment with GCs is often associated with numerous adverse side effects, such as diabetes, osteoporosis, hypertension, glaucoma, or cataract. These side effects, like other physiological manifestations, are results of aberrant expression of genes responsible for such diseases, which are positively regulated (transactivated) by GCs.

Therefore, there is a continued need to provide pharmaceutical compounds and compositions to treat or control ophthalmic diseases, conditions, or disorders, which compounds and compositions cause a lower level of at least an adverse side effect than at least a prior- art glucocorticoid used to treat or control the same diseases, condition, or disorders.

SUMMARY OF THE INVENTION

In general, the present invention provides pharmaceutical compounds and compositions for treating or controlling in a subject at least one of anterior- and posterior-segment ophthalmic diseases, conditions, or disorders.

In one aspect, such a disease, condition, or disorder has an etiology in, or produces, inflammation.

In still another aspect, such a disease, condition, or disorder comprises a complication resulting from an inflammatory ocular disease, condition, or disorder.

In yet another aspect, such compounds and compositions of the present invention result in a lower level of at least an adverse side effect than at least a prior-art glucocorticoid used to treat or control the same disease, condition, or disorder.

In still another aspect, said anterior-segment ophthalmic diseases, conditions, or disorders are selected from the group consisting of corneal edema, anterior uveitis, pterygium, Pinguecula, iritis, keratitis (such as immune stromal or interstitial keratitis), corneal ulcer, corneal opacifications with an exudative or inflammatory component, conjunctivitis, allergy- and laser-induced exudation, and combinations thereof.

In yet another aspect, said posterior-segment ophthalmic diseases, conditions, or disorders are selected from the group consisting of neurodegenerative diseases, glaucoma, diabetic retinopathy ("DR"), age-related macular degeneration ("AMD," including dry and wet AMD), juvenile macular degeneration ("JMD"), diabetic macular edema ("DME"), posterior uveitis, choroidal neovascularization ("CNV"), cystoid macular edema ("CME"), and combinations thereof. In a further aspect, the pharmaceutical compounds and compositions comprise at least an inhibitor of an activity of, or an antagonist to, OPN (such an inhibitor or antagonist hereinafter sometimes referred to as "OPN antagonist").

In yet another aspect, a composition for treating or controlling in a subject at least one of anterior- and posterior-segment ophthalmic diseases, conditions, or disorders that have an etiology in, or produce, inflammation comprises: (a) an OPN antagonist; and (b) an anti-inflammatory drug.

In still another aspect, a composition for treating or controlling in a subject at least one of anterior- and posterior-segment ophthalmic diseases, conditions, or disorders that have an etiology in, or produce, inflammation comprises: (a) an OPN antagonist; and (b) an anti-oxidant drug.

In yet another aspect, a pharmaceutical composition of the present invention comprises an ophthalmic topical formulation; injectable formulation; or implantable formulation, system, or device.

In a further aspect, said at least an adverse side effect is demonstrated in vitro or in vivo.

In another aspect, the present invention provides a method for treating or controlling in a subject at least one of anterior- and posterior-segment ophthalmic diseases, conditions, or disorder that have an etiology in, or produce, inflammation. The method comprises administering a composition comprising at least an OPN antagonist into a subject in need of such treatment or control.

In still another aspect, the method further comprises performing an additional procedure in the subject to enhance the treatment or control of the disease, condition, or disorder.

Other features and advantages of the present invention will become apparent from the following detailed description and claims. DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term "control" also includes amelioration, reduction, alleviation, and prevention.

As used herein, the term "OPN antagonist" also includes compounds or materials that inhibit or impede the transcription or expression of osteopontin. The term "OPN antagonist" also includes a prodrug, a pharmaceutically acceptable salt, hydrate, or ester thereof.

In one aspect, such diseases, conditions, or disorders have an etiology in, or produce, inflammation.

In still another aspect, such diseases, conditions, or disorders comprise a complication resulting from an inflammatory ocular disease, condition, or disorder.

In yet another aspect, such compounds and compositions of the present invention result in a lower level of at least an adverse side effect than at least a prior-art glucocorticoid ("GC") used to treat or control the same disease, condition, or disorder.

As mentioned above, GCs have often been used to treat or control inflammation. GCs act to repress the transcription of pro-inflammatory genes (transrepression mechanism), but also to activate some other genes (transactivation mechanism). Activation of some of these other genes results in the upregulation of molecules that can activate undesirable biological pathways. For example, steroid- induced diabetes and glaucoma appear to be produced by the transactivation action of GCs on genes responsible for these diseases. H. Schacke et al., Pharmacol. Ther., Vol. 96, 23-43 (2002). Thus, while the transactivation of certain genes by GCs produces beneficial effects, the transactivation of other genes by the same GCs can produce undesired side effects. Therefore, it is very desirable to provide pharmaceutical compounds and compositions that produce differentiated levels of transactivation and transrepression activity on GC-responsive genes to treat, reduce, or ameliorate diseases conditions, or disorder that have etiology in, or produce, inflammation.

In one aspect, a compound or composition of the present invention causes a lower level of at least an adverse side effect than at least a prior-art glucocorticoid used to treat or control the same disease, condition, or disorder. In one aspect, such a disease, condition, or disorder has an etiology in inflammation or an inflammatory sequela. In another aspect, such a disease, condition, or disorder has an etiology or results in chronic inflammation.

In one aspect, a level of said at least an adverse side effect is determined in vivo or in vitro. For example, a level of said at least an adverse side effect is determined in vitro by performing a cell culture and determining the level of a biomarker associated with said side effect. Such biomarkers can include proteins (e.g., enzymes), lipids, sugars, and derivatives thereof that participate in, or are the products of, the biochemical cascade resulting in the adverse side effect. Representative in vitro testing methods are further disclosed hereinbelow.

In another aspect, said at least an adverse side effect is selected from the group consisting of glaucoma, cataract, hypertension, hyperglycemia, hyperlipidemia (increased levels of triglycerides), and hypercholesterolemia (increased levels of cholesterol). A side effect such as hypertension, hyperglycemia, hyperlipidemia, or hypercholesterolemia can be a systemic side effect. In one embodiment, a level of said at least an adverse side effect is determined at about one day after said compounds or compositions are first administered to, and are present in, said subject. In another embodiment, a level of said at least an adverse side effect is determined about 14 days after said compounds or compositions are first administered to, and are present in, said subject. In still another embodiment, a level of said at least an adverse side effect is determined about 30 days after said compounds or compositions are first administered to, and are present in, said subject. Alternatively, a level of said at least an adverse side effect is determined about 2, 3, 4, 5, or 6 months after said compounds or compositions are first administered to. and are present in, said subject

In another aspect, said at least a prior-art glucocorticoid used to treat, reduce, ameliorate, or alleviate the same condition or disorder is administered to said subject at a dose and a frequency sufficient to produce an equivalent beneficial effect on said condition or disorder as a compound or composition of the present invention after about the same elapsed time

In still another aspect, said at least a prior-art glucocorticoid is selected from the group consisting of 21-acetoxypregnenolone, alclometasone, algestone, amcinomde, beclomethasone, betamethasone, budesomde, chloropredmsone, clobetasol, clobetasone, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desomde, desoximetasone, dexamethasone, diflorasone, diflucortolone, difluprednate, enoxolone, fluazacort, flucloronide, flumethasone, flunisohde, fluocinolone acetonide, fluocinomde, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenohde, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halometasone, halopredone acetate, hydrocortarnate, hydrocortisone, loteprednol etabonate, mazipredone, medrysone, mepredmsone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylamino-acetate, prednisolone sodium phosphate, prednisone, predmval, prednylidene, πmexolone, tixocortol, tπamcinolone, triamcinolone acetonide, tπamcinolone benetomde, triamcinolone hexacetonide, their physiologically acceptable salts, combinations thereof, and mixtures thereof In one embodiment, said at least a prior-art glucocorticoid is selected from the group consisting of dexamethasone, prednisone, prednisolone, methylprednisolone, medrysone, triamcinolone, loteprednol etabonate, physiologically acceptable salts thereof, combinations thereof, and mixtures thereof In another embodiment, said at least a prior-art glucocorticoid is acceptable for ophthalmic uses

In one aspect, a pharmaceutical compound or composition of the present invention compπses an OPN antagonist The term "OPN antagonist" was defined herein earlier In another aspect, a composition of the present invention comprises an OPN antagonist in an amount effective to treat or control in a subject at least one of anteπor- and posterior-segment ophthalmic diseases, conditions, or disorders

In still another aspect, said at least one disease, condition, or disorder has an etiology in inflammation

In still another aspect, said at least one disease, condition, or disorder comprises a complication resulting from an inflammatory ocular disease, condition, or disorder

In still another aspect, a composition of the present invention comprises an antagonist to osteopontin in an amount effective to treat or control in a subject at least one of anteπor- and posterior- segment ophthalmic diseases, conditions, or disorders, wherein said diseases, conditions, or disorders produces an inflammatory sequela

In yet another aspect, such compounds and compositions of the present invention result in a lower level of at least an adverse side effect than at least a prior-art glucocorticoid used to treat or control the same disease, condition, or disorder

In still another aspect, said anterior-segment ophthalmic diseases, conditions, or disorders are selected from the group consisting of corneal edema, anteπor uveitis (such as iritis, iridocyclitis), pterygium, Pinguecula, keratitis (such as immune stromal or interstitial keratitis), corneal ulcer, corneal opacifications with an exudative or inflammatory component, conjunctivitis, allergy- and laser-induced exudation, and combinations thereof

In yet another aspect, said posterior-segment ophthalmic diseases, conditions, or disorders are selected from the group consisting of neurodegenerative diseases, glaucoma, diabetic retinopathy ("DR"), age-related macular degeneration ("AMD," including dry and wet AMD), juvenile macular degeneration ("JMD"), diabetic macular edema ("DME"), posterior uveitis (includes, but is not limited to, choroiditis (inflammation of the choroid), retinitis (inflammation of the retina), chorioretinitis (inflammation of the choroid and retina), uveoretinitis (inflammation of the uveo-retina), optic neuritis (inflammation of the optic nerve), and vasculitis (inflammation of the blood vessels at the back of the eye)), choroidal neovascularization ("CNV"), cystoid macular edema ("CME"), and combinations thereof.

In a further aspect, said posterior-segment ophthalmic diseases, conditions, or disorders are selected from the group consisting of pathological angiogenesis.

OPN AND INFLAMMATORY DISEASES

The healthy ocular microenvironment has the capacity to suppress immune effector responses and inflammation. This capacity, a part of what is known as ocular immune privilege, serves the purpose of limiting the extent to which innate and adaptive immunity can cause intraocular inflammation, and thus, preserving the integrity of the visual axis and thereby preventing blindness. In the normal, healthy eye, potent immune regulatory forces are operative to maintain ocular homeostasis. Ocular inflammation, resulting from the body's inability to control exaggerated immune response, whether expressed within the cornea or within the uveal tract, is a frequent cause of visual impairment.

OPN has been identified as a major effector of inflammation. OPN is upregulated in a variety of cells in response to a broad range of stress-related conditions, such as osteoblasts, ThI- and B-lymphocytes, neutrophils, macrophages, natural killer ("NK") cells, epithelial cells, and vascular smooth muscle cells. The level of OPN in the eyes of an experimental autoimmune uveoretinitis ("EAU") mouse model was found to be 3.7 times that of a normal mouse eye. E.F. Foxman et al., /. Immunol., Vol. 168, 2483 (2002). In addition, injurious stimuli that induce the release of growth factors, such as fibroblast growth factor ("FGF'), which promotes integrin and protease-mediated smooth muscle and endothelial cell migration, also stimulate the expression of OPN. H. Rangaswami et al., Trends in Cell Biol., Vol. 16, No. 2, 79 (2006). OPN is recognized as a key cytokine involved in immune cell recruitment and type-1 (ThI ) cytokine expression at sites of injury. Macrophages are also a primary target of OPN. In turn, recruited T-lymphocytes and activated macrophages further produce OPN. J. Sodek et al., supra. It is also possible that OPN promotes the survival of these immune cells by activating the PI-3-kinase/Akt pathway, further exacerbating the inflammatory condition and increasing tissue destruction. Thus, uncontrolled expression of OPN, initiated by a minor injury or stress, can be amplified and result in chronic inflammation or other complications and damages to otherwise healthy tissues. For example, iridocyclitis (inflammation of the iris and ciliary body) affects both aqueous production and resistance to aqueous outflow, upsetting their balance and leading to elevated intraocular pressure ("IOP"). Increased IOP can eventually lead to optic nerve damage and blindness. However, the prior art does not recognize, disclose, or suggest the use of OPN antagonists to treat or control ocular inflammatory diseases, conditions, or disorders.

Thus, in one aspect, the present invention provides a composition and a method for treating or controlling an ophthalmic condition that has etiology in, or produces, inflammation. The composition comprises an OPN antagonist. The method comprises administering an effective amount of such a composition to a subject in need of treatment or control of an ophthalmic condition that has etiology in, or produces, inflammation.

The inflammation can be an anterior- or posterior-segment inflammation or both. Non-limiting types of such ophthalmic inflammation are disclosed herein above.

OPN AND POSTERIOR-SEGMENT DISEASES

OPN has been shown to promote both the growth and migration of vascular smooth muscle cells. OPN cooperates with vascular endothelial growth factor ("VEGF"), a potent angiogenic protein with a selective mitogenic effect on vascular endothelial cells, in neovascularization in adenocarcinoma. N. Shijubo et al., Am. J. Respir. Crit. Care Med., Vol. 160, 1269 ( 1999). It has been demonstrated that OPN is involved in angiogenesis in several other types of cancer. OPN mRNA increased two folds in ischemia-induced retina, and VEGF-induced tube formation was inhibited by treatment with an anti-OPN antibody. H. Takagi et al., Japan J. Ophthalmol, Vol. 46, 270 (2002). OPN levels were found to increase above the baseline level in the vitreous of patients with diabetic retinopathy. S. Kase et al., Ophthalm. Res., Vol. 39, 143 (2007). Furthermore, OPN was found to be upregulated in vitro in rat aortic vascular smooth muscle cells under high glucose condition. CP. Sodhi et al., Diabetes, Vol. 50, 1482 (2001 ). As mentioned elsewhere herein, OPN is upregulated in inflammatory conditions. However, the prior art does not recognize, disclose, or suggest that OPN may be a direct link between inflammation and diabetic complications; in particular, diabetic neovascularization; or that OPN antagonists be used for treating or controlling such diseases, conditions, or disorders.

Many posterior-segment diseases or conditions have etiology in inflammation, as discussed above. For example, posterior uveitis, including choroiditis, retinitis, optic neuritis, vasculitis, uveoretinitis, and chorioretinitis are posterior-segment inflammatory diseases. Other posterior-segment diseases have a less obvious inflammatory component. For example, macular degeneration has recently been found to have an etiology in an overactive complement cascade. Inflammation also can cause cystoid macular edema. Some of the causes of cystoid macular edema include inflammation due to cataract or other invasive ocular surgery, retinal vein occlusion (which can result from vasculitis, glaucoma, or diabetic complications), posterior uveitis, and pars planitis.

Thus, in one aspect, a composition of the present invention comprising an OPN antagonist is used for the treatment or control of a posterior-segment disease, condition, or disorder that has etiology in inflammation.

In another aspect, a composition of the present invention comprising an OPN antagonist is used for the treatment or control of a disease, condition, or disorder involving aberrant ocular angiogenesis, such as one selected from the group consisting of macular degeneration (e.g., dry or wet AMD), macular edema, choroidal neovascularization, and combinations thereof.

In still another aspect, a composition of the present invention comprising an OPN antagonist is used for the treatment or control of an ocular disease, condition, or disorder that comprises a complication of diabetes mellitus. such as diabetic retinopathy or diabetic macular edema.

OPN AND NEURODEGENERATION

Increasing evidence implicates inflammatory processes in pathology of the nervous system, acting through their effects on cell survival and regeneration. For example, inflammatory processes have a direct negative effect on axon regeneration. Upregulation of OPN has been found in several neurological conditions. For example, OPN has been identified as the most prominent cytokine expressed within multiple sclerosis ("MS") lesions. OPN levels in plasma of active relapsing-remitting ("RR") MS patients were elevated. Furthermore, they were significantly increased one month prior to increase in lesion counts. M.H.J. Vogt et al., /. NeuroimmunoL, Vol. 155, 155 (2004). In view of the infiltration of monocyte-derived macrophages and T lymphocytes in the early stage of development of MS lesions (or plaques), such increased OPN levels are most likely a result of the increased number of these immune cells. Moreover, OPN expression has been reported in reactive astrocytes in brain lesions in MS and a lippolysaccharide-induced neuroinflammation model. OPN also was found to be overproduced by activated microglia and microphages following ischemic injury. J-S. Choi et al., Brain Res., Vol. 1 151, 195 (2007).

OPN-like immunoreactivity was detected in normal rat ganglion cells, but the role of OPN in the pathogenesis of retinal diseases has not been conclusively demonstrated. W-K. Ju et al., Brain Res., Vol. 852, 217 (2000). However, OPN was strongly expressed by macrophages at the crush site of optic nerve, but not sciatic nerve, in a rat model. Furthermore, in vitro data showed that OPN inhibited axon outgrowth of developing neurons. P. Kϋry et al., FASEB J., at www.fasebi.org/cgi/doi/10.1096/fi.04- 1777fje. Thus, recent evidence suggests that upregulation of OPN at the site of injury contributes to the continued worsening of many degenerative conditions of the central nervous system ("CNS") that have etiology in inflammation. However, the prior art does not recognize, disclose, or suggest the use of OPN antagonists to treat or control CNS diseases, conditions, or disorders; in particular, ocular neurodegenerative diseases, conditions, or disorders. Moreover, the prior art does not recognize, disclose, or suggest the use of OPN antagonists for ocular neuroprotection.

In one aspect, the present invention provides a composition for treating or controlling an ophthalmic neurodegenerative disease, condition, or disorder that is recognized to have etiology, or to result, in inflammation. Non-limiting examples of such a disease, condition, or disorder include optic neuritis, ischemic optic neuropathy, glaucoma, and combinations thereof.

In another aspect, the present invention provides a composition for ophthalmic neuroprotection.

In still another aspect, a composition of the present invention provides protection against a risk of neurological damage resulting from glaucoma.

In one embodiment, the composition comprises an OPN antagonist. In another embodiment, the composition comprises an OPN antagonist and an anti-oxidant drug.

In still another aspect, the present invention provides a method for treating or controlling an ophthalmic neurodegenerative disease, condition, or disorder that is recognized to have etiology, or to result, in inflammation; or for protecting a subject against a risk of neurological damage resulting from glaucoma. The method comprises administering into a subject an effective amount of a composition comprising an OPN antagonist. In one embodiment, the composition further comprises an anti-oxidant drug.

OPN ANTAGONISTS

In one aspect, an OPN antagonist included in a composition, and used in a method, of the present invention comprises an anti-OPN antibody. In certain embodiments, such an antibody inhibits the binding of an integrin, which recognizes the RGD sequence, the SVVYGLR sequence (SEQ. NO. 1), the FPTDLPA sequence (SEQ. NO. 2), or a combination thereof, to human OPN or a fragment thereof, as disclosed, for example, in U.S. Patent 7,241 ,873 or U.S. Patent Application Publication 2006/0292648, which are incorporated herein by reference.

In another aspect, such an antibody comprises a humanized antibody. In still another aspect, such a humanized antibody comprises Fv domains of murine anti-OPN monoclonal antibody and Fc domains of a human immunoglobulin molecule. Murine anti-OPN monoclonal antibody may be obtained from IBL, Guna, Japan. In still another aspect, such a humanized antibody comprises CDRs (complementary determining regions) from the heavy- and light-chain variable domains of murine monoclonal anti- OPN antibody grafted into the appropriate framework regions of human variable domains and Fc domains of a human immunoglobulin molecule. Processes for humanization of non-human antibodies are known, such as that disclosed by S.L. Morrison et al., PNAS, Vol. 81, 6851 (1984). In addition, human immunoglobulin transgenic mice provide an alternative technique for generation of monoclonal antibodies that are well tolerated in human. See; e.g., D.M. Fishwild et al., Nat. Biotech., Vol. 14, 845 (1996). Still another method for obtaining humanized murine monoclonal antibodies is disclosed in U.S. Patent 7,087,409; which is incorporated herein by reference.

In still another aspect, an anti-OPN antibody comprises an isolated antibody that binds to a polypeptide having at least 95% amino acid sequence identity to a human OPN or to a polypeptide having at least 95% amino acid sequence identity to a human OPN lacking its associated signal peptide. The amino acid sequence of human OPN is known and is disclosed, for example, in U.S. Patent Application Publication 2007/0041983, which is incorporated herein by reference.

In yet another aspect, an OPN antagonist included in a composition, and used in a method, of the present invention comprises an antisense oligodeoxynucleotide ("ODN") that blocks, prevents, or inhibits the expression of the OPN gene. In one embodiment, such an antisense ODN comprises the nucleotide sequence of 5'- ACC ATGAG ACTGGC AGTG-3' (SEQ. NO. 3), as disclosed in H. Okada et al., Am. J. Physiol. Renal Physiol., Vol. 278, 1 10 (2000). In one embodiment, such an OPN gene is a human OPN gene. In a further aspect, an OPN antagonist included in a composition, and used in a method, of the present invention comprises the soluble extracellular domain of CD44 (sCD44"). A method for producing recombinant sCD44 is disclosed in T. Ahrens et al., Oncogene, Vol. 20, 3399 (2001).

In still another aspect, an OPN antagonist included in a composition, and used in a method, of the present invention comprises an antibody to human CD44, which antibody prevents the binding of soluble OPN to the cell-surface CD44 receptor, and the activation of a CD44-mediated biochemical pathway. Such an antibody may be further humanized by a method disclosed above. Anti-CD44 antibodies may be obtained from BD Sciences, San Jose, California.

In yet another aspect, an OPN antagonist included in a composition, and used in a method, of the present invention comprises an antibody to a human integrin that recognizes the RGD sequence, the SVVYGLR sequence (SEQ. NO. 1), or both, which antibody prevents the binding of soluble OPN to the cell-surface integrin receptor, and the activation of an integrin-mediated biochemical pathway. Such an antibody may be further humanized by a method herein disclosed above. Anti-integrin antibodies may be obtained from BD Sciences, San Jose, California. In one embodiment, such integrin is selected from the group consisting of α_vβi, α_vβ₃, α_vβs, α₄pi, αgβi, and combinations thereof.

In a further aspect, an OPN antagonist included in a composition, and used in a method, of the present invention comprises the soluble extracellular domain of a human integrin that recognizes the RGD sequence, the SVVYGLR sequence (SEQ. NO. 1), or both. Such a soluble extracellular domain of a human integrin binds to soluble OPN and prevents the binding of the latter to a cell-surface integrin. In one embodiment, such integrin is selected from the group consisting of α_vβi, α_vβ₃, α_vβ₅, α₄βi, ctgβi, and combinations thereof.

In a further aspect, an OPN antagonist included in a composition, and used in a method, of the present invention comprises a small-molecule inhibitor of OPN expression. In one embodiment, such an inhibitor of OPN expression comprises a pyridazine derivative represented by Formula I (as disclosed in U.S. Patent Application Publication 2007/0021418, which is incorporated herein by reference), or a salt thereof.

wherein:

R¹ means a phenyl or pyridyl group which may be substituted by 1 to 3 substituents selected from halogen atoms and Ci_-6 alkoxy groups;

R" means a phenyl group which may be substituted at the 4-position thereof with a C i-6 alkoxy group or Ci-6 alkoxythio group and may also be substituted at one or two other positions thereof a like number of substituents selected from halogen atoms, C i_-6 alkoxy groups and C]_-6 alkoxythio groups;

R³ means a hydrogen atom; a Ci-6 alkoxy group; a halogenated C_1-6 alkyl group; a C₃-₆ cycloalkyl group; a phenyl, pyridyl or phenyloxy group which may be substituted by 1 to 3 substituents selected from halogen atoms, C ₁-₆ alkyl groups, C₁^ alkoxy groups, carboxyl groups, C₂-7 alkoxycarbonyl groups, nitro groups, amino groups, Ci-₆ alkylamino groups and Ci_-6 alkylthio groups; a substituted or unsubstituted piperidino, piperidyl, piperazino or morpholino group; a substituted or unsubstituted aminocarbonyl group; a C₂-7 alkylcarbonyl groups; or a substituted or unsubstituted piperazinocarbonyl group;

A means a single bond, a Ci_-6 linear or branched alkylene group, or a C₂-9 linear or branched alkenylene group; and

X means an oxygen atom or a sulfur atom, with a proviso that A is a single bond when R³ is a halogenated Ci_-6 alkyl group. In certain embodiments, the inhibitor of OPN expression is selected from the group consisiting of 5-(4-chlorophenyl)-6-[4-(methylthio)phenyl]-2-(2-pyridylmethyl)- 2H-pyridazine-3-thione, 5-(4-chlorophenyl)-6-[4-(methylthio)phenyl]-2-(3- pyridylmethyl)-2H-pyridazin-3-one, 5,6-bis(4-methoxyphenyl)-2-(4-chlorocinnamyl)- 2H-pyridazin-3-one, 2-benzyl-5-(4-chlorophenyl)-6-[4-(methylthio)phenyl ]-2H- pyridazin-3-one, 2-(4-chlorobenzyl)-6~(4-methoxyphenyl)-5-(4~pyridinyI)-2H-pyridazin- 3-one, 5,6-bis(4-methoxyphenyl)-2-ethyl-2H-pyridazin-3-one, combinations thereof, and salts thereof.

In still another aspect, an OPN antagonist included in a composition, and used in a method, of the present invention comprises a statin (or 3-hydroxy-3- methylglutaryl coenzyme A ("HMG-CoA") reductase inhibitor). In one embodiment, the statin is selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, a combination of ezetimibe and simvastatin (Vytorin^*), and combinations thereof. Pivastatin calcium has been found to inhibit the expression of OPN mRNA in the kidney and aorta of diabetic subjects (see; e.g., U.S. Patent Application Publication 2004/0087597, which is incorporated herein by reference).

OPN AND REACTIVE OXYGEN SPECIES

Although the pro-inflammatory property of OPN has received much attention, OPN has been shown to beneficially suppress the production of reactive nitric oxide by macrophages by inhibiting the induction of the inducible nitric oxide synthase (iNOS) gene (See; e.g., J.A. Scott et al, Am. J. Physiol. Heart Cir. Physiol., Vol. 275, 2258 ( 1998); S-M. Hwang et al., J. Biol. Chem., Vol. 269, No. 1, 71 1 (1994); H. Guo et al., J. Immunol, Vol. 166, 1079 (2001): and P. Y. Wai et al., Surgery, Vol. 140, 132 (2006)). However, the prior art does not recognize, disclose, or suggest that there may be a need to prevent the overexpression of inducible NO when an OPN inhibitor is used in therapy.

In one aspect of the present invention, a composition for treating or controlling in a subject at least one of anterior- and posterior-segment ophthalmic diseases, conditions, or disorders that have an etiology in, or produce, inflammation comprises: (a) an OPN antagonist or a prodrug thereof; and (b) an anti-oxidant drug.

In another aspect of the present invention, said anti-oxidant drug comprises an iNOS inhibitor. In one embodiment, said iNOS inhibitor comprises IS^-nitro-L- arginine methyl ester ("L-NAME"). In another embodiment, said iNOS inhibitor comprises a multiheterocyclic compound disclosed in U.S. Patent Application Publication 2006/01 16515, which is incorporated herein by reference. In another embodiment, said iNOS inhibitor comprises a compound disclosed in U.S. Patent 7,012,098; which is incorporated herein by reference.

In still another aspect, said anti-oxidant drug comprises vitamin C (ascorbic acid), vitamin E, or vitamin E salt (such as α-tocopheryl acetate or α-tocopheryl succinate).

In yet another aspect, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

The concentration of an OPN antagonist in such a pharmaceutical composition can be in the range from about 0.0001 to about 1000 mg/ml (or, alternatively, from about 0.001 to about 500 mg/ml, or from about 0.001 to about 300 mg/ml, or from about 0.001 to about 250 mg/ml, or from about 0.001 to about 100 mg/ml, or from about 0.001 to about 50 mg/ml, or from about 0.01 to about 300 mg/ml, or from about 0.01 to about 250 mg/ml, or from about 0.01 to about 100 mg/ml, or from about 0.1 to about 100 mg/ml, or from about 0.1 to about 50 mg/ml).

In one embodiment, a composition of the present invention is in a form of a suspension or dispersion. In another embodiment, the suspension or dispersion is based on an aqueous solution. For example, a composition of the present invention can comprise sterile saline solution. In still another embodiment, micrometer- or nanometer- sized particles of an OPN antagonist can be coated with a physiologically acceptable surfactant (non-limiting examples are disclosed below), and then the coated particles are dispersed in a liquid medium. The coating can keep the particles in a suspension. In another aspect, a composition of the present invention can further comprise a non-ionic surfactant, such as polysorbates (such as polysorbate 80 (polyoxyethylene sorbitan monooleate), polysorbate 60 (polyoxyethylene sorbitan monostearate), polysorbate 20 (polyoxyethylene sorbitan monolaurate), commonly known by their trade names of Tween® 80, Tween® 60, Tween® 20), poloxamers (synthetic block polymers of ethylene oxide and propylene oxide, such as those commonly known by their trade names of Pluronic®; e.g., Pluronic® F127 or Pluronic® F108) ), or poloxamines (synthetic block polymers of ethylene oxide and propylene oxide attached to ethylene diamine, such as those commonly known by their trade names of Tetronic®; e.g., Tetronic® 1508 or Tetronic® 908, etc., other nonionic surfactants such as Brij®, Myrj®, and long chain fatty alcohols (i.e., oleyl alcohol, stearyl alcohol, myristyl alcohol, docosohexanoyl alcohol, etc.) with carbon chains having about 12 or more carbon atoms (e.g., such as from about 12 to about 24 carbon atoms). Such compounds are delineated in Martindale, 34^th ed., pp 141 1-1416 (Martindale, "The Complete Drug Reference," S. C. Sweetman (Ed.), Pharmaceutical Press, London, 2005) and in Remington, "The Science and Practice of Pharmacy," 21^SI Ed., p. 291 and the contents of chapter 22, Lippincott Williams & Wilkins, New York, 2006); the contents of these sections are incorporated herein by reference. The concentration of a non-ionic surfactant, when present, in a composition of the present invention can be in the range from about 0.001 to about 5 weight percent (or alternatively, from about 0.01 to about 4, or from about 0.01 to about 2, or from about 0.01 to about 1, or from about 0.01 to about 0.5 weight percent).

In addition, a composition of the present invention can include additives such as buffers, diluents, carriers, adjuvants, or other excipients. Any pharmacologically acceptable buffer suitable for application to the eye may be used. Other agents may be employed in the composition for a variety of purposes. For example, buffering agents, preservatives, co-solvents, oils, humectants, emollients, stabilizers, or antioxidants may be employed. Water-soluble preservatives which may be employed include sodium bisulfite, sodium bisulfate, sodium thiosulfate, benzalkonium chloride, chlorobutanol, thimerosal, ethyl alcohol, methylparaben, polyvinyl alcohol, benzyl alcohol, and phenylethyl alcohol. These agents may be present in individual amounts of from about 0.001 to about 5% by weight (preferably, about 0.01% to about 2% by weight). Suitable water-soluble buffering agents that may be employed are sodium carbonate, sodium borate, sodium phosphate, sodium acetate, sodium bicarbonate, etc., as approved by the United States Food and Drug Administration ("US FDA") for the desired route of administration. These agents may be present in amounts sufficient to maintain a pH of the system of between about 2 and about 1 1. As such, the buffering agent may be as much as about 5% on a weight to weight basis of the total composition. Electrolytes such as, but not limited to, sodium chloride and potassium chloride may also be included in the formulation.

In one aspect, the pH of the composition is in the range from about 4 to about 1 1. Alternatively, the pH of the composition is in the range from about 5 to about 9, from about 6 to about 9, or from about 6.5 to about 8. In another aspect, the composition comprises a buffer having a pH in one of said pH ranges.

In another aspect, the composition has a pH of about 7. Alternatively, the composition has a pH in a range from about 7 to about 7.5.

In still another aspect, the composition has a pH of about 7.4.

In yet another aspect, a composition also can comprise a viscosity-modifying compound designed to facilitate the administration of the composition into the subject or to promote the bioavailability in the subject. In still another aspect, the viscosity- modifying compound may be chosen so that the composition is not readily dispersed after being administered into the vistreous. Such compounds may enhance the viscosity of the composition, and include, but are not limited to: monomeric polyols, such as, glycerol, propylene glycol, ethylene glycol; polymeric polyols, such as, polyethylene glycol; various polymers of the cellulose family, such as hydroxypropylmethyl cellulose ("HPMC"), carboxymethyl cellulose ("CMC") sodium, hydroxypropyl cellulose ("HPC"); polysaccharides, such as hyaluronic acid and its salts, chondroitin sulfate and its salts, dextrans, such as, dextran 70; water soluble proteins, such as gelatin; vinyl polymers, such as, polyvinyl alcohol, polyvinylpyrrolidone, povidone; carbomers, such as carbomer 934P, carbomer 941, carbomer 940, or carbomer 974P; and acrylic acid polymers. In general, a desired viscosity can be in the range from about 1 to about 400 centipoise ("cps") (or mPa.s).

In yet another aspect, the composition comprises: (a) at least an OPN antagonist; and (b) a material selected from the group consisting of (i) anti-oxidant drugs; (ii) anti-inflammatory agents other than an OPN antagonist; (iii) anti-angiogenic agents; and (iv) combinations thereof; said OPN antagonist, anti-inflammatory agent, or anti-angiogenic agent being present in amounts effective to treat or control at least one of anterior- and posterior-segment diseases, conditions, or disorders. In one embodiment, such an anti- inflammatory agent is selected from the group consisting of non-steroidal anti-inflammatory drugs ("NSAIDs"), peroxisome proliferator-activated receptor ("PPAR") ligands, combinations thereof, and mixtures thereof.

The concentration of each of anti-oxidant drugs, anti-inflammatory agents other than an OPN antagonist, anti-angiogenic agents, when present in such a pharmaceutical composition, can be in the range from about 0.0001 to about 1000 mg/ml (or, alternatively, from about 0.001 to about 500 mg/ml, or from about 0.001 to about 300 mg/ml, or from about 0.001 to about 250 mg/ml, or from about 0.001 to about 100 mg/ml, or from about 0.001 to about 50 mg/ml, or from about 0.01 to about 300 mg/ml, or from about 0.01 to about 250 mg/ml, or from about 0.01 to about 100 mg/ml, or from about 0.1 to about 100 mg/ml, or from about 0.1 to about 50 mg/ml).

Non-limiting examples of the NSAIDs are: aminoarylcarboxylic acid derivatives (e.g., enfenamic acid, etofenamate, flufenamic acid, isonixin, meclofenamic acid, mefenamic acid, niflumic acid, talniflumate, terofenamate, tolfenamic acid), arylacetic acid derivatives (e.g., aceclofenac, acemetacin, alclofenac, amfenac, amtolmetin guacil, bromfenac, bufexamac, cinmetacin, clopirac, diclofenac sodium, etodolac, felbinac, fenclozic acid, fentiazac, glucametacin, ibufenac, indomethacin, isofezolac, isoxepac, lonazolac, metiazinic acid, mofezolac, oxametacine, pirazolac, proglumetacin, sulindac, tiaramide, tolmetin, tropesin, zomepirac), arylbutyric acid derivatives (e.g., bumadizon, butibufen, fenbufen, xenbucin), arylcarboxylic acids (e.g., clidanac, ketorolac, tinoridine), arylpropionic acid derivatives (e.g., alminoprofen, benoxaprofen, bermoprofen, bucloxic acid, carprofen, fenoprofen, flunoxaprofen, flurbiprofen, ibuprofen, ibuproxam, indoprofen, ketoprofen, loxoprofen, naproxen, oxaprozin, piketoprolen. pirprofen, pranoprofen, protizinic acid, suprofen, tiaprofenic acid, ximoprofen, zaltoprofen), pyrazoles (e.g., difenamizole, epirizole), pyrazolones (e.g., apazone, benzpiperylon, feprazone, mofebutazone, morazone, oxyphenbutazone, phenylbutazone, pipebuzone, propyphenazone, ramifenazone, suxibuzone, thiazolinobutazone), salicylic acid derivatives (e.g., acetaminosalol, aspirin, benorylate, bromosaligenin, calcium acetylsalicylate, diflunisal, etersalate, fendosal, gentisic acid, glycol salicylate, imidazole salicylate, lysine acetylsalicylate, mesalamine, morpholine salicylate, 1 -naphthyl salicylate, olsalazine, parsalmide, phenyl acetylsalicylate, phenyl salicylate, salacetamide, salicylamide o-acetic acid, salicylsulfuric acid, salsalate, sulfasalazine), thiazinecarboxamides (e.g., ampiroxicam, droxicam, isoxicam, lornoxicam, piroxicam, tenoxicam), ε-acetamidocaproic acid, S-(5'-adenosy I)-L- methionine, 3-amino-4-hydroxybutyric acid, amixetrine, bendazac, benzydamine, α- bisabolol, bucolome, difenpiramide, ditazol, emorfazone, fepradinol, guaiazulene, nabumetone, nimesulide, oxaceprol, paranyline, perisoxal, proquazone, superoxide dismutase, tenidap, zileuton, their physiologically acceptable salts, combinations thereof, and mixtures thereof.

In another aspect of the present invention, an anti- inflammatory agent is a PPAR-binding molecule. In one embodiment, such a PPAR-binding molecule is a PPARa-, PPARδ-, or PPARγ-binding molecule. In another embodiment, such a PPAR- binding molecule is a PPARα, PPARδ, or PPARγ agonist. Such a PPAR ligand binds to and activates PPAR to modulate the expression of genes containing the appropriate peroxisome proliferator response element in its promoter region.

PPARγ agonists can inhibit the production of TNF-α and other inflammatory cytokines by human macrophages (C-Y. Jiang et al., Nature, Vol. 391, 82-86 (1998)) and T lymphocytes (A.E. Giorgini et al., Horm. Metab. Res. Vol. 31, 1-4 (1999)). More recently, the natural PPARγ agonist 15-deoxy-Δ-12, 14-prostaglandin J2 (or "15-deoxy- Δ- 12J4-PG J2"), has been shown to inhibit neovascularization and angiogenesis (X. Xin et al., J. Biol Chem. Vol. 274:91 16-9121 ( 1999)) in the rat cornea. Spiegelman et al., in U.S. Patent 6,242, 196, disclose methods for inhibiting proliferation of PPARγ- responsive hyperproliferative cells by using PPARγ agonists; numerous synthetic PPARγ agonists are disclosed by Spiegelman et al., as well as methods for diagnosing PPARγ- responsive hyperproliferative cells. All documents referred to herein are incorporated by reference. PPARs are differentially expressed in diseased versus normal cells. PPARγ is expressed to different degrees in the various tissues of the eye, such as some layers of the retina and the cornea, the choriocapillaris, uveal tract, conjunctival epidermis, and intraocular muscles (see, e.g., U.S. Patent 6,316,465).

In one aspect, a PPARγ agonist used in a composition or a method of the present invention is a thiazolidinedione, a derivative thereof, or an analog thereof. Non- limiting examples of thiazolidinedione-based PPARγ agonists include pioglitazone, troglitazone, ciglitazone, englitazone, rosiglitazone, and chemical derivatives thereof. Other PPARγ agonists include Clofibrate (ethyl 2-(4-chlorophenoxy)-2- methylpropionate), clofibric acid (2-(4-chlorophenoxy)-2-methylpropanoic acid), GW 1929 (N-(2-benzoy lpheny I)-O- { 2-(methy 1-2-pyridiny lamino)ethyl } -L-tyrosine), GW 7647 (2-{ {4-{2-{ {(cyclohexylamino)carbonyl }(4- cyclohexylbutyl)amino}ethyl}phenyl}thio}-2-methylpropanoic acid), and WY 14643 ({ {4-chloro-6-{(2,3-dimethylphenyl)amino}-2-pyrimidinyl}thio}acetic acid). GW 1929, GW 7647, and WY 14643 are commercially available, for example, from Koma Biotechnology, Inc. (Seoul, Korea). In one embodiment, the PPARγ agonist is 15- deoxy-Δ-12, 14-PG J2.

Non-limiting examples of PPAR-α agonists include the fibrates, such as fenofibrate and gemfibrozil. A non-limiting example of PPAR-δ agonist is GW5O1516 (available from Axxora LLC, San Diego, California or EMD Biosciences, Inc., San Diego, California).

In a further aspect, an anti-angiogenic agent included in a pharmaceutical composition of the present invention is selected from the group consisting of: (i) compounds that interact with and inhibit a downstream activity of extracellular VEGF; (ii) compounds that interact with at least a VEGF receptor and render it substantially unavailable for interacting with VEGF; (iii) compounds that reduce a level of expression of VEGF; and (iv) combinations thereof. In one embodiment, compounds that interact with and inhibit a downstream activity of extracellular VEGF comprise a nucleic acid ligand that binds to extracellular VEGF and substantially prevents it from participating in the angiogenic cascade. Non- limiting examples of such a nucleic acid ligand are the VEGF aptamers disclosed in U.S. Patents 6,426,335; 6, 168,778; 6, 147,204; 6,051 ,698; and 6,01 1 ,020; which are incorporated herein by reference in their entirety. In one embodiment, such a nucleic acid ligand comprises the VEGF antagonist aptamer known by its trade name "Macugen®", being marketed by OSI EyeTech Pharmaceuticals (Melleville, New York). In another embodiment, a compound that interacts with and inhibits a downstream activity of extracellular VEGF comprises an anti-VEGF antibody, such as the recombinant monoclonal antibody known as Lucentis^® (ranibizumab, developed by Genentech, South San Francisco, California) or Avastin^® (bevacizumab, also developed by Genentech).

In one aspect of the present invention, compounds that interact with at least a VEGF receptor and render it substantially unavailable for interacting with VEGF comprises VEGF tyrosine kinase inhibitors, which can be a small synthetic molecule or protein or protein fragment that binds to the transmembrane VEGF receptors and neutralizes their activation, such as rendering them incapable of initiating or participating further in the expression of VEGF or other angiogenic factors.

Non-limiting examples of synthetic VEGF tyrosine kinase inhibitors include the compounds disclosed in U.S. Patents 6,958,340; 6,514,971; 6,448,077; and U.S. Patent Application Publications 2005/0233921, 2005/0244475, 2005/0143442, and 2006/0014252; which are incorporated herein by reference in their entirety.

In another aspect, a level of VEGF can be reduced by interfering with the transcription of the VEGF gene by binding a small organic VEGF-gene inhibitor to said gene, such as one of the compounds disclosed in U.S. Patent Application Publication 2003/0282849, which is incorporated herein by reference. Other suitable anti -angiogenic agents that can be used in a composition of the present invention are disclosed in U.S. Patent Application having Serial No. 1 1/733,282, which is incorporated herein by reference.

In still another aspect, a method for preparing a composition of the present invention comprises combining: (i) at least an OPN antagonist; and (ii) a material selected from the group consisting of anti-oxidant drugs, anti-inflammatory agents other than OPN antagonists, anti-angiogenic agents, and combinations thereof; and (iii) a pharmaceutically acceptable carrier. In one embodiment, such a carrier can be a sterile saline solution or a physiologically acceptable buffer. In another embodiment, such a carrier comprises a hydrophobic medium, such as a pharmaceutically acceptable oil. In still another embodiment, such as carrier comprises an emulsion or dispersion of a hydrophobic material and water.

Physiologically acceptable buffers include, but are not limited to, a phosphate buffer or a Tris-HCl buffer (comprising tris(hydroxyrnethyl)aminomethane and HCl). For example, a Tris-HCl buffer having pH of 7.4 comprises 3 g/1 of tris(hydroxymethyl)aminomethane and 0.76 g/1 of HCl. In yet another aspect, the buffer is 1OX phosphate buffer saline ("PBS") or 5X PBS solution.

Other buffers also may be found suitable or desirable in some circumstances, such as buffers based on HEPES (N-{2-hydroxyethyl}peperazine-N'-{2-ethanesulfonic acid}) having pK_a of 7.5 at 25 ⁰C and pH in the range of about 6.8-8.2; BES (N,N-bis{2- hydroxyethyl }2-aminoethanesulfonic acid) having pK_a of 7.1 at 25°C and pH in the range of about 6.4-7.8; MOPS (3-{N-morpholino}propanesulfonic acid) having pK_a of 7.2 at 25°C and pH in the range of about 6.5-7.9; TES (N-tris{hydroxymethyl}-methyl- 2-aminoethanesulfonic acid) having pK_a of 7.4 at 25⁰C and pH in the range of about 6.8- 8.2; MOBS (4-{N-morpholino}butanesulfonic acid) having pK_a of 7.6 at 25⁰C and pH in the range of about 6.9-8.3; DIPSO (3-(N,N-bis{2-hydroxyethyl}amino)-2- hydroxypropane) ) having pK_a of 7.52 at 25°C and pH in the range of about 7-8.2; TAPSO (2-hydroxy-3 { tris(hydroxymethyl)methylamino}- l -propanesulfonic acid) ) having pK_a of 7.61 at 25°C and pH in the range of about 7-8.2; TAPS ({(2-hydroxy-l, l - bis(hydroxymethyl)ethyl)arnino}- l -propanesulfonic acid) ) having pK_a of 8.4 at 25°C and pH in the range of about 7.7-9.1 ; TABS (N-tris(hydroxymethyl)methyl-4- aminobutanesulfonic acid) having pKa of 8.9 at 25⁰C and pH in the range of about 8.2- 9.6; AMPSO (N-( 1 , 1 -dimethyl-2-hydroxyethyl)-3-amino-2-hydroxypropanesulfonic acid) ) having pK_a of 9.0 at 25°C and pH in the range of about 8.3-9.7; CHES (2- cyclohexylamino)ethanesulfonic acid) having pKa of 9.5 at 25°C and pH in the range of about 8.6- 10.0; CAPSO (3-(cyclohexylamino)-2-hydroxy-l -propanesulfonic acid) having pK_a of 9.6 at 25⁰C and pH in the range of about 8.9- 10.3; or CAPS (3- (cyclohexylamino)-l -propane sulfonic acid) having pK_a of 10.4 at 25°C and pH in the range of about 9.7- 1 1.1.

In certain embodiments, a composition of the present invention is formulated in a buffer having a slight acidic pH, such as from about 5.5 to about 6.8. In such embodiments, the buffer capacity of the composition desirably allows the composition to come rapidly to a physiological pH after being administered to into the patient.

EXAMPLE 1

Two mixtures I and II are made separately by mixing the ingredients listed in Table 1. Five parts (by weight) of mixture I are mixed with twenty parts (by weight) of mixture II for 15 minutes or more. The pH of the combined mixture is adjusted to 6.2- 6.4 using 1 N NaOH or 1 N HCl solution to yield a composition of the present invention.

Table 1

EXAMPLE 2:

Two mixtures I and II are made separately by mixing the ingredients listed in Table 2. Five parts (by weight) of mixture I are mixed with twenty parts (by weight) of mixture II for 15 minutes or more. The pH of the combined mixture is adjusted to 6.2- 6.4 using 1 N NaOH or 1 N HCl solution to yield a composition of the present invention.

Table 2

EXAMPLE 3:

Two mixtures I and II are made separately by mixing the ingredients listed in Table 3. Five parts (by weight) of mixture I are mixed with twenty parts (by weight) of mixture II for 15 minutes or more. The pH of the combined mixture is adjusted to 6.2- 6.4 using 1 N NaOH or 1 N HCl solution to yield a composition of the present invention.

Table 3

EXAMPLE 4:

Two mixtures I and II are made separately by mixing the ingredients listed in Table 4. Five parts (by weight) of mixture I are mixed with twenty parts (by weight) of mixture II for 15 minutes or more. The pH of the combined mixture is adjusted to 6.2- 6.4 using 1 N NaOH or 1 N HCl solution to yield a composition of the present invention.

Table 4

Note: "HAP" denotes hydroxyalkyl phosphonates, such as those known under the trade name Dequest®.

EXAMPLE 5:

The ingredients listed in Table 5 are mixed together for at least 15 minutes. The pH of the mixture is adjusted to 6.2-6.4 using 1 N NaOH or 1 N HCl solution to yield a composition of the present invention.

Table 5

Note: "BAK" denotes benzalkonium chloride.

EXAMPLE 6:

The ingredients listed in Table 6 are mixed together for at least 15 minutes. The pH of the mixture is adjusted to 6.2-6.4 using 1 N NaOH or 1 N HCl solution to yield a composition of the present invention.

Table 6

EXAMPLE 7:

The ingredients listed in Table 7 are mixed together for at least 15 minutes. The pH of the mixture is adjusted to 6.2-6.4 using 1 N NaOH or 1 N HCl solution to yield a composition of the present invention.

Table 7

EXAMPLE 8:

The ingredients listed in Table 8 are mixed together for at least 15 minutes. The pH of the mixture is adjusted to 6.2-6.4 using 1 N NaOH or 1 N HCl solution to yield a composition of the present invention.

Table 8

EXAMPLE 9:

The ingredients listed in Table 9 are mixed together for at least 15 minutes. The pH of the mixture is adjusted to 6.2-6.4 using 1 N NaOH or 1 N HCl solution to yield a composition of the present invention.

Table 9

EXAMPLE 10:

The ingredients listed in Table 10 are mixed together for at least 15 minutes. The pH of the mixture is adjusted to 6.2-6.4 using 1 N NaOH or 1 N HCl solution to yield a composition of the present invention.

Table 10

In another aspect, an OPN antagonist and an anti-inflammatory agent are incorporated into a formulation for topical administration, systemic administration, periocular injection, or intravitreal injection. An injectable intravitreal formulation can desirably comprise a carrier that provides a sustained-release of the active ingredients, such as for a period longer than about 1 week (or longer than about 1, 2, 3, 4, 5, or 6 months). In certain embodiments, the sustained-release formulation desirably comprises a carrier that is insoluble or only sparingly soluble in the vitreous. Such a carrier can be an oil-based liquid, emulsion, gel, or semisolid. Non-limiting examples of oil-based liquids include castor oil, peanut oil, olive oil, coconut oil, sesame oil, cottonseed oil, corn oil, sunflower oil, fish-liver oil, arachis oil, and liquid paraffin.

In one embodiment, a compound or composition of the present invention can be injected intravitreally, for example through the pars plana of the ciliary body, to treat or prevent glaucoma or progression thereof or to provide ocular neuroprotection using a fine-gauge needle, such as 25-35 gauge. Typically, an amount from about 25 μl to about 100 μl of a composition comprising an OPN antagonist is administered into a patient. A concentration of such OPN antagonist is selected from the ranges disclosed above.

In another aspect, an OPN antagonist is incorporated into an ophthalmic device that comprises a biodegradable material, and the device is implanted into a subject to provide a long-term (e.g., longer than about 1 week, or longer than about 1, 2, 3, 4, 5, or 6 months) treatment of the chronic ocular inflammatory condition. Such a device may be implanted by a skilled physician in the subject's ocular or periocular tissue.

In still another aspect, a method for treating or controlling at least one of anterior- and posterior-segment diseases, conditions, or disorders, which have an etiology in inflammation, comprises: (a) providing a composition comprising an OPN antagonist; and (b) administering to a subject an amount of the composition at a frequency sufficient to treat, reduce, ameliorate, or alleviate the condition or disorder in the subject.

In one embodiment, the OPN antagonist is selected from among those disclosed above.

In another embodiment, such inflammation is a chronic inflammation.

In still another embodiment, such a disease, condition, or disorder is selected from the group consisting of corneal edema, anterior uveitis (such as iritis, iridocyclitis), pterygium, Pinguecula, keratitis (such as immune stromal or interstitial keratitis), corneal ulcer, corneal opacifications with an exudative or inflammatory component, conjunctivitis, allergy- and laser-induced exudation, and combinations thereof.

In still another embodiment, such a disease, condition, or disorder is selected from the group consisting of neurodegenerative diseases, glaucoma, diabetic retinopathy ("DR"), age-related macular degeneration ("AMD," including dry and wet AMD), juvenile macular degeneration ("JMD"), diabetic macular edema ("DME"), posterior uveitis (includes, but is not limited to, choroiditis (inflammation of the choroid), retinitis (inflammation of the retina), chorioretinitis (inflammation of the choroid and retina), uveoretinitis (inflammation of the uveo-retina), optic neuritis (inflammation of the optic nerve), and vasculitis (inflammation of the blood vessels at the back of the eye)), choroidal neovascularization ("CNV"), cystoid macular edema ("CME"), and combinations thereof.

In another embodiment, the composition further comprises: (i) an antiinflammatory agent other than an OPN antagonist; (ii) an anti-angiogenic agent; or (iii) a combination thereof. Such an anti-inflammatory agent or anti-angiogenic agent is selected from among those disclosed above. The concentration of the OPN antagonist, the anti-inflammatory agent or anti-angiogenic agent is selected from among the ranges disclosed above.

In another aspect, an OPN antagonist, with or without an additional antiinflammatory agent and/or an anti-angiogenic agent, is incorporated into a formulation for topical administration, systemic administration, periocular injection, or intravitreal injection. An injectable intravitreal formulation can desirably comprise a carrier that provides a sustained-release of the active ingredients, such as for a period longer than about 1 week (or longer than about 1, 2, 3, 4, 5, or 6 months).

In still another aspect, an OPN antagonist is incorporated into an ophthalmic device that comprises a biodegradable material, and the device is implanted into a subject to provide a long-term (e.g., longer than about 1 week, or longer than about 1, 2, 3, 4, 5, or 6 months) treatment of a posterior-segment disease. Such a device may be implanted by a skilled physician in the back of the eye of the patient for the sustained release of the active ingredient or ingredients. A typical implant system or device suitable for use in a method of the present invention comprises a biodegradable matrix with the active ingredient or ingredients impregnated or dispersed therein. Non-limiting examples of ophthalmic implant systems or devices for the sustained-release of an active ingredient are disclosed in U.S. Patents 5,378,475; 5,773,019; 5,902,598; 6,001,386; 6,051,576; and 6,726,918; which are incorporated herein by reference. In yet another aspect, a composition of the present invention is administered once a week, once a month, once a year, twice a year, four times a year, or at a suitable frequency that is determined to be appropriate for treating or controlling the disease, condition, or disorder.

In a further aspect, the present invention provides a method for treating or controlling at least one of anterior- and posterior-segment diseases, conditions, or disorders that have an etiology in inflammation (in particular, chronic inflammation). The method comprises: (a) administering an amount of a composition comprising an OPN antagonist to a subject at a first frequency sufficient to treat or control the disease, condition, or disorder in the subject; and (b) performing a procedure selected from the group consisting of protocoagulation, photodynamic therapy, and a combination thereof in the subject at a second frequency sufficient to treat or control the disease, condition, or disorder in the subject. In one embodiment, the composition further comprises an antiinflammatory agent other than an OPN antagonist, an anti-angiogenic agent, or a combination thereof. Non-limiting examples of these materials are disclosed herein above.

In one embodiment, the first frequency and the second frequency are the same. In another embodiment, the first frequency and the second frequency are different. In still another embodiment, said administering and said performing are carried out sequentially. In yet another embodiment, said performing is carried out before said administering. In a further embodiment, said performing is carried out after said administering. The first frequency and the second frequency can be, for example, once a week, once a month, once a year, twice a year, four times a year, or other frequencies, said first frequency and second frequency being chosen as deemed appropriate for the condition and treatment objective by a skilled medical practitioner.

In photocoagulation therapy, high-energy light from a laser is directed to the leaky vasculature to coagulate the fluid in and around the new leaky vessels, relying on the transfer of thermal energy generated by the laser to the pathological tissue. Photocoagulation systems are currently available. In photodynamic therapy ("PDT"), a photosensitizer (light-activated drug) is administered into the patient, typically via the intravenous route followed by application of light of appropriate wavelength directed at the pathological tissue, such as the leaky vasculature. The light sources most commonly used are non-thermal lasers or light- emitting diodes ("LEDs"). After exposure to light at a wavelength absorbed by the photosensitizer, an energy transfer cascade is initiated, culminating in the formation of reactive oxygen, which generates free radicals. These free radicals, in turn, disrupt cellular structures or functions, leading to death of endothelial cells and, thus, prevention of further neovascularization. Non-limiting examples of photosensitizers and methods for PDT include those disclosed in U.S. Patents 7,015,240 and 7,060,695; which are incorporated herein by reference.

COMPARISON OF GLUCOCORTICOIDS AND OPN ANTAGONISTS

One of the most frequent undesirable actions of a glucocorticoid therapy is steroid diabetes. The reason for this undesirable condition is the stimulation of gluconeogenesis in the liver by the induction of the transcription of hepatic enzymes involved in gluconeogenesis and metabolism of free amino acids that are produced from the degradation of proteins (catabolic action of glucocorticoids). A key enzyme of the catabolic metabolism in the liver is the tyrosine aminotransferase ("TAT"). The activity of this enzyme can be determined photometrically from cell cultures of treated rat hepatoma cells. Thus, the gluconeogenesis by a glucocorticoid can be compared to that of an OPN antagonist by measuring the activity of this enzyme. For example, in one procedure, the cells are treated for 24 hours with the test substance (an OPN antagonist or glucocorticoid), and then the TAT activity is measured. The TAT activities for the selected OPN antagonist and glucocorticoid are then compared. Other hepatic enzymes can be used in place of TAT, such as phosphoenolpyruvate carboxykinase, glucose-6- phosphatase, or fructose-2,6-biphosphatase. Alternatively, the levels of blood glucose in an animal model may be measured directly and compared for individual subjects that are treated with a glucocorticoid for a selected condition and those that are treated with an OPN antagonist for the same condition. Another undesirable result of glucocorticoid therapy is GC-induced cataract. The cataractogenic potential of a compound or composition may be determined by quantifying the effect of the compound or composition on the flux of potassium ions through the membrane of lens cells (such as mammalian lens epithelial cells) in vitro. Such an ion flux may be determined by, for example, electrophysiological techniques or ion-flux imaging techniques (such as with the use of fluorescent dyes). An exemplary in- vitro method for determining the cataractogenic potential of a compound or composition is disclosed in U.S. Patent Application Publication 2004/0219512, which is incorporated herein by reference.

Still another undesirable result of glucocorticoid therapy is hypertension. Blood pressure of similarly matched subjects treated with a glucocorticoid or an OPN antagonist for an inflammatory condition may be measured directly and compared.

Yet another undesirable result of glucocorticoid therapy is increased IOP. IOP of similarly matched subjects treated with a glucocorticoid or an OPN antagonist for an inflammatory condition may be measured directly and compared.

SEQUENCE LISTING

<110> Bausch & Lomb incorporated

<120> Compositions and Mthods for Treating or Controlling Anterior- or Posterior-Segment Ophthalmic Diseases

<130> P04313

<160> 3

<170> Patentln version 3.4

<210> 1

<211> 7

<212> PRT

<213> Homo sapiens

<400> 1

Ser VaI val Tyr Gly Leu Arg <210> 2

<211> 7

<212> PRT

<213> Homo sapi ens

<400> 2

Phe Pro Thr Asp Leu Pro Ala 1 5

<210> 3

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Anti sense ODN to OPN DNA

<400> 3 accatgagac tggcagtg 18

While specific embodiments of the present invention have been described in the foregoing, it will be appreciated by those skilled in the art that many equivalents, modifications, substitutions, and variations may be made thereto without departing from the spirit and scope of the invention as defined in the appended claims.

Claims

WHAT IS CLAIMED IS:

1. A composition comprising: (a) an OPN antagonist; and (b) a material selected from the group consisting of: (i) anti-oxidant drugs; (ii) anti-inflammatory agents other than said OPN antagonist; (iii) anti-angiogenic agents; and (iv) combinations thereof.

2. The composition of claim 1, wherein (a) the OPN antagonist; and (b) the antioxidant drugs, the anti-inflammatory agents, or the anti-angiogenic agents are present in the composition in amounts sufficient to be effective for treating or controlling at least one of anterior- and posterior-segment diseases, conditions, or disorders, which have an etiology in, or produce, inflammation.

3. The composition of claim 2, wherein the diseases, conditions, or disorders are selected from the group consisting of corneal edema, anterior uveitis, iritis, iridocyclitis, pterygium, Pinguecula, keratitis immune stromal keratitis, interstitial keratitis, corneal ulcer, corneal opacifications with an exudative or inflammatory component, conjunctivitis, allergy- and laser-induced exudation, and combinations thereof.

4. The composition of claim 2, wherein the diseases, conditions, or disorders are selected from the group consisting of neurodegenerative diseases, glaucoma, diabetic retinopathy ("DR"), dry AMD, wet AMD, juvenile macular degeneration ("JMD"), diabetic macular edema ("DME"), posterior uveitis, choroiditis, retinitis, chorioretinitis, uveoretinitis, optic neuritis, vasculitis, choroidal neovascularization ("CNV"), cystoid macular edema ("CME"), and combinations thereof.

5. The composition of claim 2, wherein the OPN antagonist comprises a material selected from the group consisting of an anti-OPN antibody; an antisense ODN blocking or inhibiting an expression of an OPN gene; sCD44, an anti-CD antibody; a soluble extracellular domain of an integrin receptor that recognizes a sequence selected from the group consisting of an RGD sequence, an SVVYGLR sequence (SEQ. NO. 1), an FPTDLPA sequence (SEQ. NO. 2), and combinations thereof; an anti-integrin antibody; and combinations thereof; wherein said integrin is selected from the group consisting of α_vβi, α_vβ₃, α_vβ₅, α₄β_{l 7} αgβi, and combinations thereof.

6. The composition of claim 5, wherein said anti-OPN antibody is humanized and comprises an amino acid sequence that recognizes a sequence selected from the group consisting of an RGD sequence, an SVVYGLR sequence (SEQ. NO. 1 ), an FPTDLPA sequence (SEQ. NO. 2), and combinations thereof.

7. The composition of claim 2, wherein the OPN antagonist comprises a pyridazine derivative represented by Formula I, or a salt thereof

wherein:

R¹ means a phenyl or pyridyl group which may be substituted by 1 to 3 substituents selected from halogen atoms and Ci -₆ alkoxy groups;

R' means a phenyl group which may be substituted at the 4-position thereof with a C i-6 alkoxy group or Ci -β alkoxy thio group and may also be substituted at one or two other positions thereof a like number of substituents selected from halogen atoms, Ci-6 alkoxy groups and Ci .6 alkoxythio groups;

R³ means a hydrogen atom; a Ci_-6 alkoxy group; a halogenated Ci .₆ alkyl group; a C3-6 cycloalkyl group; a phenyl, pyridyl or phenyloxy group which may be substituted by 1 to 3 substituents selected from halogen atoms, Ci_-6 alkyl groups, Ci-6 alkoxy groups, carboxyl groups, C_2-7 alkoxycarbonyl groups, nitro groups, amino groups, Ci_-6 alkylamino groups and C ₁-₆ alkylthio groups; a substituted or unsubstituted piperidino, piperidyl, piperazino or morpholino group; a substituted or unsubstituted aminocarbonyl group; a C₂-7 alkylcarbonyl groups; or a substituted or unsubstituted piperazinocarbonyl group;

A means a single bond, a Ci-₆ linear or branched alkylene group, or a C₂-9 linear or branched alkenylene group; and

X means an oxygen atom or a sulfur atom, with a proviso that A is a single bond when R³ is a halogenated C₁^ alkyl group.

8. The composition of claim 7, wherein said pyridazine derivative is selected from the group consisiting of 5-(4-chlorophenyl)-6-[4-(methylthio)phenyl]-2-(2- pyridylmethyl)-2H-pyridazine-3-thione, 5-(4-chlorophenyl)-6-[4-(methylthio)phenyl]-2- (3-pyridylmethyl)-2H-pyridazin-3-one, 5,6-bis(4-methoxyphenyl)-2-(4-chlorocinnamyl)- 2H-pyridazin-3-one, 2-benzyl-5-(4-chlorophenyl)-6-[4-(methylthio)phenyl ]-2H- pyridazin-3-one, 2-(4-chlorobenzyl)-6-(4-methoxyphenyl)-5-(4-pyridinyl)-2H-pyridazin- 3-one, 5.6-bis(4-methoxyphenyl)-2-ethyl-2H-pyridazin-3-one, combinations thereof, and salts thereof.

9. The composition of claim 2, wherein the OPN antagonist comprises a statin (3- hydroxy-3-methylglutaryl coenzyme A).

10. The composition of claim 9, wherein the statin is selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, a combination of ezetimibe and simvastatin (Vytorin^®), and combinations thereof.

1 1. The composition of claim 2, wherein the composition causes a lower level of at least an adverse side effect in a subject than at least a glucocorticoid used to treat or control the same disease, condition, or disorder.

12. A composition comprising: (a) an OPN antagonist; and (b) an anti-oxidant drug, wherein said OPN antagonist comprises an anti-human OPN antibody that recognizes a sequence selected from the group consisting of an RGD sequence, an SVVYGLR sequence (SEQ. NO. 1 ), an FPTDLPA sequence (SEQ. NO. 2), and combinations thereof; and said anti-oxidant is selected from the group consisting of iNOS inhibitors, vitamin C, vitamin E, vitamin E salts, and combinations thereof; and wherein each of said OPN antagonist and anti-oxidant drug is present in an amount sufficient to treat or control at least one of anterior- and posterior-segment diseases, conditions, or disorders.

13. A composition comprising: (a) an OPN antagonist; and (b) an anti-oxidant drug, wherein the OPN antagonist comprises a pyridazine derivative represented by Formula I, or a salt thereof

wherein:

R means a phenyl group which may be substituted at the 4-position thereof with a Ci -₆ alkoxy group or Cj_-6 alkoxy thio group and may also be substituted at one or two other positions thereof a like number of substituents selected from halogen atoms, Ci-₆ alkoxy groups and Cj_-6 alkoxythio groups;

R³ means a hydrogen atom; a Ci -β alkoxy group; a halogenated Ci_-6 alkyl group; a C₃-₆ cycloalkyl group; a phenyl, pyridyl or phenyloxy group which may be substituted by 1 to 3 substituents selected from halogen atoms, Cj_₆ alkyl groups, C|-6 alkoxy groups, carboxyl groups, C₂-7 alkoxycarbonyl groups, nitro groups, amino groups, Cue alkylamino groups and Ci_-6 alkylthio groups; a substituted or unsubstituted piperidino, piperidyl, piperazino or morpholino group; a substituted or unsubstituted aminocarbonyl group; a C₂-7 alkylcarbonyl groups; or a substituted or unsubstituted piperazinocarbonyl group;

A means a single bond, a Ci_6 linear or branched alkylene group, or a C₂-9 linear or branched alkenylene group; and

X means an oxygen atom or a sulfur atom, with a proviso that A is a single bond when R³ is a halogenated C ₁-₆ alkyl group; and

said anti-oxidant is selected from the group consisting of iNOS inhibitors, vitamin C, vitamin E, vitamin E salts, and combinations thereof; and

wherein each of said OPN antagonist and anti-oxidant drug is present in an amount sufficient to treat or control at least one of anterior- and posterior- segment diseases, conditions, or disorders.

14. A composition comprising: (a) an OPN antagonist; and (b) an anti-oxidant drug, wherein the OPN antagonist comprises a statin that is selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, a combination of ezetimibe and simvastatin (Vytorin^®), and combinations thereof; said anti-oxidant is selected from the group consisting of iNOS inhibitors, vitamin C, vitamin E, vitamin E salts, and combinations thereof; and wherein each of said OPN antagonist and anti-oxidant drug is present in an amount sufficient to treat or control at least one of anterior- and posterior-segment diseases, conditions, or disorders.

15. A method for treating or controlling at least one of an anterior- and posterior- segment diseases, conditions, or disorders, which have an etiology in, or produce, inflammation, the method comprising: (a) providing a composition comprising an OPN antagonist; and (b) administering to a subject an amount of the composition at a frequency sufficient to treat or control said at least one disease, condition, or disorder in the subject.

16. The method of claim 15, wherein the diseases, conditions, or disorders are selected from the group consisting of corneal edema, anterior uveitis, iritis, iridocyclitis, pterygium, Pinguecula, keratitis immune stromal keratitis, interstitial keratitis, corneal ulcer, corneal opacifications with an exudative or inflammatory component, conjunctivitis, allergy- and laser-induced exudation, and combinations thereof.

17. The method of claim 15, wherein the diseases, conditions, or disorders are selected from the group consisting of neurodegenerative diseases, glaucoma, diabetic retinopathy ("DR"), dry AMD, wet AMD, juvenile macular degeneration ("JMD"), diabetic macular edema ("DME"), posterior uveitis, choroiditis, retinitis, chorioretinitis, uveoretinitis, optic neuritis, vasculitis, choroidal neovascularization ("CNV"), cystoid macular edema ("CME"), and combinations thereof.

18. The method of claim 15, wherein the OPN antagonist comprises a material selected from the group consisting of an anti-OPN antibody; an antisense ODN blocking or inhibiting an expression of an OPN gene; sCD44, an anti-CD antibody; a soluble extracellular domain of an integrin receptor that recognizes a sequence selected from the group consisting of an RGD sequence, an SVVYGLR sequence (SEQ. NO. 1), an FPTDLPA sequence (SEQ. NO. 2), and combinations thereof; an anti-integrin antibody; and combinations thereof; wherein said integrin is selected from the group consisting of α_vβi, α_vβ₃, α_vβ₅,

ctgβi, and combinations thereof.

19. The method of claim 15, wherein the OPN antagonist comprises a pyridazine derivative represented by Formula I, or a salt thereof

wherein: R means a phenyl or pyridyl group which may be substituted by 1 to 3 substituents selected from halogen atoms and Ci ₆ alkoxy groups;

R^" means a phenyl group which may be substituted at the 4-position thereof with a Ci ₆ alkoxy group or Ci (, alkoxythio group and may also be substituted at one or two other positions thereof a like number of substituents selected from halogen atoms, Ci ₆ alkoxy groups and Ci 6 alkoxythio groups;

R³ means a hydrogen atom; a Ci ₆ alkoxy group; a halogenated Ci ₆ alkyl group; a C_{3 6} cycloalkyl group; a phenyl, pyπdyl or phenyloxy group which may be substituted by 1 to 3 substituents selected from halogen atoms, Ci ₆ alkyl groups, Ci 6 alkoxy groups, carboxyl groups, C₂ 7 alkoxycarbonyl groups, nitro groups, amino groups, Ci β aikylamino groups and Cj ₆ alkylthio groups; a substituted or unsubstituted pipeπdino, pipeπdyl, piperazino or morphohno group; a substituted or unsubstituted aminocarbonyl group; a CT ₇ alkylcarbonyl groups; or a substituted or unsubstituted piperazinocarbonyl group,

A means a single bond, a Ci 6 linear or branched alkylene group, or a C_{2 9} linear or branched alkenylene group; and

X means an oxygen atom or a sulfur atom, with a proviso that A is a single bond when R³ is a halogenated Ci β alkyl group.

20. The method of claim 15, wherein the OPN antagonist comprises a statin selected from the group consisting of atorvastatin, ceπvastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, a combination of ezetimibe and simvastatin (Vytoπn^®), and combinations thereof.

21. The method of claim 15, wherein the composition further comprises a material selected from the group consisting of: (1) anti-oxidant drugs; (11) anti-inflammatory agents other than said OPN antagonist, (111) anti-angiogenic agents; and (iv) combinations thereof.

22. The method of claim 15, wherein said composition is administered topically, intravitreally, intraocularly, or systemically in the subject.

23. The method of claim 15, wherein said composition is included in an ocular device, which is implanted in an eye of the subject.

24. The method of claim 22, further comprising performing a procedure on said subject, said procedure being selected from the group consisting of photocoagulation, photodynamic therapy, and a combination thereof.

25. A method for providing ocular neuroprotection to a subject, the method comprising: (a) providing a composition comprising an OPN antagonist; and (b) administering to a subject an amount of the composition at a frequency sufficient to provide ocular neuroprotection in the subject.

26. The method of claim 25, wherein the composition further comprises an antioxidant drug.

27. A method for manufacturing a composition for treating at least one of anterior- and posterior-segment diseases, conditions, or disorders that have an etiology in, or produce, inflammation, the method comprising:

(a) providing an OPN antagonist;

(b) providing a material selected from the group consisting of: (i) antioxidant drugs; (ii) anti-inflammatory agents other than said OPN antagonist; (iii) anti-angiogenic agents; and (iv) combinations thereof; and

(c) combining (i) said OPN antagonist; and (ii) said material with a pharmaceutically acceptable carrier.