BACKGROUND OF THE INVENTION 1'his invention relates generally to methods and compositions for treating and preventing eye diseases such as macular degeneration, diabetic retinopathy, glaucoma, and cataracts. These diseases are the major causes of blindness in the U. S. and Europe. ROBBINS PATHOLOGIC BASIS OF DISEASE 1369 (Cotran et al., eds., 6thed. 1999) (hereinafter "ROBBINS Traditional approaches in treating eye disease include surgical methods, photodynamic methods and drug therapy, as well as attempts to regenerate deteriorating cells.

Newer approaches include nutritional means such as altering a patient's diet or adding nutritional supplements and vitamins. These methods are preventative as well as therapeutic.

Macular degeneration effects a portion of the eye's retina, the macula, that enables fine vision. Otherwise known as age-related macular degeneration (AMD), it is a leading cause of blindness in the U. S. Head, 4 (5) ALTERNATIVE MEDICINE REVIEW 342-59 (1999).

AMD is currently treated using laser surgery. For example, one treatment attempts to eliminate vascular abnormalities (also referred to as neo-vascularization) within the eye by irradiating target ocular tissue with laser light. See U. S. Pat. No. 5,910, 510. Another laser treatment calls for pretreating the AMD patient with fluorescent dyes and tissue-reactive substances encapsulated within heat-sensitive liposomes. The heat sensitive liposomes are subsequently irradiated with a laser at a predetermined anatomical locus within the eye. U. S.

Pat. No. 5,935,942.

Both of these laser approaches are problematic, however, because neither prove effective when macular degeneration reaches later stages. In addition, unlike cataract disease where the diseased lens can be replaced, the diseased macula (part of the retina) cannot be

replaced because the retina is part of the central nervous system. Therefore, preventative measures are extremely important in reducing the incidence and severity of macular degeneration. Head, at342-43..

Current preventative measures include dietary supplementation such as increasing the dietary intake of beta-carotene. See U. S. Pat. No. 5,457,135. Another preventative measure administers a composition with antioxidants such as vitamins C and E ; cofactors for activatingmetallbenzymes,such as copper, selenium, manganese and zinc stearate, and glutathione enhancers such as L-cysteine, pyridoxine, and riboflavin. See Ú. S. Pat.

No. 5, 156,852...'''''..-.

Other such methods administer a composition compnsing lutein, (Seè U. S. Pat. No.

5, 976, 568), or lutein in combination with docosahexaenoic acid (DHA), zeasanthin, vitamin C, an anthocyanoside, such as bilberry extract, and a citrus bioflavonoid, such as lemon. See U. S. Pat. No, 5, 955,102.

A additional dietary approach for treating AMD involves administering. of a glutathione-enhancing agent, such as mercaptopropionylglycine, and at least one antioxidant such as vitamin C, a-tocopherol (vitamin E), ß-carotene, retinol (vitamin A), lutein and zeaxanthin. See U. S. Pat. No. 5,596, 011.

Cataracts are another eye disease that may be treated or prevented by the present invention. Cataracts are opacities in the eye's crystalline lens, caused by metabolic diseases such as diabetes, physical agents. (e. g., ultraviolet light trauma, radiation therapy) and ocular diseases (e. g., uveitis, glaucoma, intraocular tumors, retinitis pigmentosa).. The most common type of cataract, senile cataract, is attributed to the aging process. ROBBINS, at 1367.

Nutritional methods of treating or preventing cataracts include administering a. composition that includes an antioxidant such as a proanthocyanidin oligomer or a salt thereof, where the proanthocyanidin oligomer is extracted from grape seeds, grape peel, and/or pressed grape cake. See U. S. Pat. No. 5,804,597.

Another method is based on the premise that endogenous reduced glutathione (GSH), and other thiol-containing molecules act as free radical scavengers, and that depletion of these molecules in the body is linked to the formation of cataracts. Specifically, the method involves administering sulfhydryl compounds to GSH-depleted cataract-susceptible cells, in order to bolster the reducing capability of these cells. See U. S. Pat. No. 5,688,828.

Glaucoma, another leading cause of blindness in the U. S., is characterized by heightened intraocular pressure and may be treated by the present invention. Normal

intraocular pressure the human eye ranges from 22 to 40 mmHg, as'opposed to glaucoma- diseased eyes, where intraocular pressures of greater than 40 mm Hg are common. MURRAY & PIZZARNO ; EVCYCLOPEDIA NATURAL MEDICINE 485 (2nd ed. 1998)..

Current therapeutic methods for treating glaucoma include administering a non- steroidal glucocorticoid antagonist that binds to endogenous glucocorticoids in the body, consequently preventing glucocorticoids from binding to trabec. ular meshwork cells. U. S.

Pat. No. 6, 051,573.....

Another ocular disease that may be treated by thepresentinventionisdiabetic retinopathy, which develops in 60 percent of diabetics within fifteen to twenty years after the original diagnosis of diabetes. ROBBINS, at 1369. Traditional methods of treating diabetic.. retinopathy include administering, either prophylactically or therapeutically, a form of genistein which inhibits the protein tyrosihe'kinase pathway. See U. S. Pat. No. 5,919,813.

Another treatment approach involves administering, either acetylL-camitine, a derivative thereof, or a pharmacologically acceptable salt thereof. Seé U. S. Pat. No.

5,883,127.- Another method advises administering a compound having both a potent calcium antagonist and potent antioxidant. See U. S. Pat. No. 5,691, 360.

Yet another treatment for diabetic retinopathy attempts to protect the eye by administering a mimetic of super oxide dismutase (SOD) or extracellular SOD comprising a porphyrin moiety. See U. S. Pat. No. 5,994,339..- The. compositions and method-described herein provide a novel approach to maintaining eye health, and treating or preventing eye disease. These compositions may include various antioxidants, vitamins, carotenoids and flavonoids, and are preferably taken orally.

SUMMARY OF THE INVENTION Ari object of the present invention is to provide compositions and related methods useful in protecting the structure and function of an eye. In a preferred embodiment, the composition comprises alpha-lipoic acid in an amount ranging from 10 mg to 80 mg, natural mixed tocopherols in amount ranging from 10 IU to 80 IU, vitamin C in an amount ranging from 30 mg to 240 mg, citrus bioflavonoids in amount ranging from 80 mg to 400 mg, pine bark extract in an amount ranging from 15 mg to 120 mg, lutein is present in an amount

ranging from 30 mg to 240 mg, natural mixed carotenoids an amount ranging from 25 mg to 200 mg, and vitamin A in an amount ranging from 650 IU to 2400 FU.- Another object of the present invention is to provide a composition and. related. method of protecting the structure and function of an eye comprising the step of administering to a subject a composition comprising alpha-lipoic acid, natural mixed . tocopherols, vitamin C, citrus bioflavonoids, pine bark extract, lutein, natural mixed carotenoids, andvitaminA.,.,..

A further object of the present invention is to provide a method of protecting the structure and function of an eye by protecting cells from damaging effects of free radicals. comprising the step of administering to a subject a natural supplement composition comprising alpha-lipoic acid, natural mixed tocopherols, vitamin C, citrus bioflavonoids, pine bark extract, lutein, natural mixed carotenoids, and vitamin A.

The present invention also provides a method of preventing cataracts by protecting cells from damaging effects of free radicals comprising the step of administering to a subject a natural supplement composition comprising alpha-lipoic acid, natural mixed tocopherols, vitamin C, citrus bioflavonoids, pine bark extract, lutein, natural mixed carotenoids, and vitamin At-' An additional object of the present invention is to provide a method of preventing or treating AMD comprising. the step of administering to a subject a natural supplement compositioncomprisingalpha-Iipoic acid, natural mixed tocopherols, vitamin C, citrus bioflavonoids, pine bark extract, lutein, natural mixed carotenoids, and vitamin A.

The present invention is also directed to a method of preventing or treating diabetic retinopathy by protecting cells from damaging effects of free radicals comprising the step of administering to a subject a natural supplement compositiori comprising alpha-lipoic acid, natural mixed tocopherols, vitamin C,, citrus bioflavonoids, pine bark extract, lutein, natural mixed carotenoids, and vitamin A.

Further, the present invention relates to a method of preventing or treating cataracts, age-related macular degeneration, or diabetic retinopathy by protecting cells from damaging effects of free radicals comprising the step of administering to a subject a natural supplement composition comprising alpha-lipoic acid, natural mixed tocopherols, vitamin C, citrus bioflavonoids, pine bark extract, lutein, natural mixed carotenoids, and vitamin A.

In a preferred embodiment, the composition may be administered orally and to a human.

The preparations may be in solid form, for instance, in capsule, powder or granule, or tablet form or in the form of suppositories for rectal administration. Alternatively, the compositions. may be dispersed into. a suitable liquid..

Another embodiment of the invention involves administering the composition of the present invention to a human in one or more tablets or capsules as a material dietary supplement. In yet another embodiment of the invention, the composition is administered to a human as a pharmaceutical composition.

DETAILED DESCRIPTION The novel compositions and related methods of the preferable embodiment comprise a mixture of antioxidant vitamins, carotenoids, and flavonoids useful in the prevention and treatment of eye disease.

Diabetic retinopathy and macular degeneration involve retinal disease. The retina is'a neuronal network that surrounds a large portion of the eye, excluding the lens and iris, and enables. central vision. The retina includes several neuronal layers (termed pars nervosa) including a nerve fiber layer, ganglion cell layer, inner plexiform-layer, inner nuclear layer, outer plexiform layer, outer nuclear layer, as well as photoreceptor cells known as rods and cones, which constitute the retina's outer neuronal layer. DORLAND'S MEDICAL DICTIONARY 1454 (28th ed. W. B. Saunders Co. 1994) (hereinafter"DORLAND'S"). The retinal pigment epithelium lies outside these neuronal layers, protecting the retina's rods and cones, and providing a blood-retinal barrier. The macula is located in the central region of the retina wherevisualperception is most acute, and is made of light sensitive tissue'WEssTÈR's II NEW RIVERSIDE UNIVERSITY DICTIONARY 713 (Riverside Pub. Co. 1988). The macula enables fine, sharp, straight-ahead vision required for e : g., reading and driving. National Eye Institute, <http://www. nei. nih. gov/publications/armd-p. htm> (visited June 2000). The photoreceptor cells of the retina are protected by the sclera which forms the outermost membrane of the eye. The sclera is nourished by the blood vessels of the uvea, which contains the iris, ciliary body, and choroid. Id., at 1453.

The actual process of vision begins with electrical impulses, generated from visible light, impinging on the photosensitive rods and cones, which is subsequently transmitted to the inner nuclear layer of the retina. The primary function of the rods and cones is to convert visible light into a physio-chemical signal, which is transmitted to the nerve fiber layer.

These nerve fibers are directly connected to the ganglion cells which extend from the nerve

fiber layer to the optic nerve, and finally to synapses in specific regions of the brain.

DÒRLAND'S, at 1368 : Although the rods and cones arestructurallyprotectedbecause they lie in the interior region of the eye, they are nevertheless exposed to light whenever the eye is open, given their specific purpose. The exposure of the retina to large amounts of light, as well as high concentrations of elemental oxygen that are naturally prevalent in the-eye, results in the generation of singlet oxygen, and ultimately free radical damage, Fekrat et al., 7 (65) CURRENT OPINION IN OPTHALMOLOGY 65-72 (1996). The human eye also contains higher amounts of polyunsaturated fats compared to other tissues of the body, and-peroxidation of these polyunsaturated fats by hydroxyl radicals (OH-) and superoxide (02') radicals, generated from light and oxygen, can result in the formation'of further eye-damaging free.

'.radicals.M Another route of free radical damage, associated with macular degeneration, results from post-ischemic reflow, which follows ischemic assault (lack of blood flow) often associated with,'e. g., stroke and heart attack. More specifically ; the ischemic assault is followed by reperfusion (the reoxygenation of eye tissues), characterized by unusually high concentrations of oxygen in the retina, eventually causing superoxide free radical damage.

See, e.g., ROBBINS, at 11-12.

Anotherdebilitating eye disease, diabetic retinopathy, is categorized as either background or nonproliferative retinopathy, or proliferativeretinopathy.Background, or non-proliferative retinopathy, is the more common complication, and is characterized by a number of structural capillary alterations. Specifically, these alterations include a thickening of the retina's basement capillaries; degeneration of pericyte cells that provide arterioles with contractile function ; capillary microaneurysms ; capillary obstructions and nonperfusion that lead to hypoxia of retinal tissues; arteriolar hyalnization; and, alteration in retinal vein caliber. Id., at 1369-70.

Proliferative retinopathy relates to neovascularization and fibroplasia, and occurs in response to severe hypoxia and ischemia in retinal tissues. Specifically, neovascularization produces abnormal capillaries that are only partially formed and lack proper support, leading to the proliferation of the capillaries between the retina and vitreous cavity of the eye, and eventually into the vitreous cavity itself. Bleeding results from the movement of these abnormal blood vessels caused by normal vitreous shifting during eye movement.

Neovascularization finally leads to fibrosis, which increases the traction on the retina, often culminating in retina detachment. Id., at 1370.

Diabeticretinopathydevelops, in part, as a consequence of the inappropriately high levels and incorrect forms of glycop'roteins that result from high blood glucose. More specifically, these glycoproteins generate free radicals, resulting in oxidative tissue damage and depletion of glutathione. Furthermore, these glycoproteins bind indiscriminately with lipids, form advanced glycated end products, and deposit in the blood vessels of the retina, thus contributing toneovascularization. Moreover, the decreased red blood cell fluidity and increased blood viscosity (which worsen as retinopathy progresses) contribute to blood vessel blockage and decreased oxygenation, also compounding neovascularization. Antioxidants may slow this process. Head, at 348-49 ; ROBBINS, at 919-20.

Additionally, sorbitol accumulation associated with diabetic hyperglycemia may contribute to diabetic retinopathy. In particular, the accumulation of sorbitol, which is produced by the enzyme aldose reductase,. causes increased cellular osmolarity leading to an influx of water and impaired intracellular ion pumps, damaging eye cells and retinal capillaries. Head, at 348 ; ROBBINS, at 920. These same mechanisms contribute to diabetic cataracts as well. ROBBINS, at 920 ; MURRAY ET AL., HARPER'S BIOCHEMISTRY 228-29.

(25th ed. Appleton & Lange 2000).

Cataracts, are white, opaque blemishes on the normally transparent lens of the eye that occur whentheprotein structure of the lens is damaged. MURRAY & PIzzoRNO, at 319.

Cataracts cause a tremendous financial burden in the U. S. and are the most. common major surgical procedure performed among U. S. medicare recipients. Id. Ås discùssed abovè, cataracts may also follow sorbitol accumulation, a complication resulting from diabetes.

Hence, natural aldose reductase inhibitors including quercetin, hesperidin, and naringin have been recommend for diabetic patients. Head, at 348.

Another eye disease glaucoma, threatens the vision of approximately two million people in the U. S. alone. MURRAY ET AL., at 485. Glaucoma is characterized by increased intraocular pressure. producing tissue damage such as degeneration of retinal ganglion cells and axons. There are two types of glaucoma : "acute" and "chronic". Acute glaucoma symptoms include increased intraocular pressure predominately occurring on one side of the head only, severe throbbing with blurred vision, pupil dilation in one eye, as well as nausea.

If acute glaucoma is not treated within twelve to forty-eight hours of initial symptoms, blindness can result in as little as two to five days. Id. at 488. Chronic glaucoma is

characterized by persistent elevation of pressure within the eye, followed by increased loss of peripheral vision, and ultimately tunnel vision. Id. at 485. Chronic glaucoma usually has'no early symptoms There are several theories concerning the causes of glaucoma. One theory is that abnormalities in the composition of the protein, collagen, which is prevalent in supportive structures of the eye, leads to blockage of the flow of aqueous humour and consequently elevated intraocular pressure. MURRAY ET AL., at 485. Regardless of its cause, the rise in intraocular pressure directly causes degeneration of the retinal ganglion cells and axons. This may occur because the increased pressure contributes directly to axonal necrosis, and/or impairs the vascular supply to the optic nerve, eventually leading to ischemic necrosis of the nerve fibers. ROBBINS, atl375.

AMD is an irreversible blinding disease of the. retina. AMD is categorized into two discrete types : wet AMD and dry AMD. Dry AMD effects 90 percent of those diagnosed with the disease, and involves the atrophy of photosensitive tissues and the retinal pigmented epithelium. Gradual central vision loss begins typically in only one eye. Wet AMD effects the remainder of those diagnosed with AMD, and results from neovascularization of blood vessels located behind the retina, toward the macula. These abnormal blood vessels generate blood and fluid that leak under the macula, displacing it from the back of the eye, resulting in severe loss of central vision in a very short amount of time.

See <http://www. nei. nih : gov/publications/armd-p. htm>.

Factors promoting macular degeneration include heredity ; cigarette smoking, light exposure, light iris pigmentation, chemical. exposure, and cardiovascular disease.

Additionally, free radical damage from light exposure in the form of ultraviolet, visible, or ionizing radiation has been found, in animal tests, to cause lipid peroxidation of photoreceptor membranes, similar to the deterioration of macular cells in humans. Id., Head, at344.

Two approaches in slowing the process of macular degeneration include limiting the amount of exposure to light and supplementing the diet with antioxidants. Indeed, antioxidants such as vitamin C, vitamin E, and carotenoids such as lutein and zeaxanthin are normally found in high proportions in the retina Head, at 343.

The present invention provides compositions including various antioxidants, vitamins, carotenoids and flavonoids, that may be used to maintain eye health as well treat and prevent eye diseases such as those discussed above.

In a preferred embodiment, the compositions of the present invention may comprise mixed tocopherols (e. g., vitamin E complex) in amounts preferably ranging from-between about 10 RJ and 80 IU. Specifically, mixed tocopherols is a mixture which may comprise d- alpha, d-beta, d-gamma, and d-delta tocopherols. Vitamin E, a lipid-phase antioxidant (also called d-alpha tocopherol), is one of two primary antioxidants in the human body. MURRAY ET AL., at 75. Vitamin E is a recognized antioxidant that prevents oxidative damage and protein glycosylation. Ceriello et al., 9 DIABETES MED. 297-99 (1992). Other studies have shown a inverse correlation between the severity of AMD and serum vitamin E levels. Belda et al., 107 (2) MECHANICS AGE LEVEL. 159-64 (1999). Anotherstudyshows an inverse association between the intake of vitamin E and the incidence of large drusen, a symptom of AMD. VandenLangenberg et'al., 148 (2) AM. J. EPIDEMIOL. 204-14 (1998). Further, normal levels of vitamin E in rats have been found to protect photoreceptor membranes from oxidative damage and retard the process of phagocytosis. Robison et al., 18 (7) INVESTIGATIONAL OPTHALMOLOGY VISION SCI. 683-90 (1979). A preferred embodiment of the compositions of the present invention comprises about 20 IU of natural mixed' tocopherols The compositions of the present invention also may preferably comprise vitamin C in amounts ranging from about 30 mg to about 240 mg. Vitamin C, (also called ascorbic acid or ascorbate) is an aqueous-phase antioxidant that, along with vitamin E, is a primary antioxidant in the human body. MURRAY ET AL., at 75. The protective effect of vitamin C on retinal pigment epithelium tissue as well as photoreceptor cells of the eye has been demonstrated and may be linked to vitamin C's capacity to prevent rod outer segment shedding and phagocytosis under intense light. Blanks et al., 33 (10) INVEST. OPHTHALMOL.

Vis. Scr. 2814-21 (1992). In addition, photoreceptors of the eye, which are made of polyunsaturated fatty acids, such as docosahexaenoic acid, are subject to free radical damage.

Studies conclude that vitamin C protects eyes against the damaging effects of the sun if taken prior to exposure to the sun. Organisciak et al., 3 CURRENT EYE RES. 257-67 (1984) ; Organisciak et al., 26 INVEST. OPHTHALMOL. Vis. SCI. 1580-88 (1985). A preferred embodiment of the invention includes about 60 mg of vitamin C.

The compositions of the present invention preferably may comprise vitamin A, in amounts ranging from between about 650 IU and 2400 IU. Vitamin A is a generic term for compounds, derived from animal sources, that exhibit biological activities characteristic of vitamin A. In addition, vitamin A, similar to vitamin E, is a lipid-phase antioxidant. Id., at

642. In the human body, the primary functions of vitamin A are carried out by retinol and its two derivatives retinal and retinoic acid. Id. In vegetables, vitamin A exists as a provitamin. in the form of the yellow pigment p-carotene. Also termed"carotenoids", substances such-as p-carotene have effective antioxidant capabilities even at low oxygen concentrations. The antioxidant activity of vitamin A complements vitamin E, which is more effective as an antioxidant at high oxygen concentrations. Low serum concentrations of vitamin A and vitamin E have been linked to the formation of senile cataracts. MURRAY ET AL. at 645.

Vitamin A levels in rats have a significant influence on the extent of retinal damage induced by vitamin E deficiency. Robison et al., 18 (7) INVEST. OPHTHALMOL. Vis. Sci. 683-90 (1979). In a preferred embodiment, the invention, may also comprise vitamin A preferably in amounts ranging from 650 IU to 2400 IU.' The novel compositions of the present invention may also comprise natural mixed carotenoids, such as lutein and zeaxanthin, preferably in amounts ranging between about 30 mg and 240 mg. Lutein and zeaxanthin are the two major components of macular pigment.

The concentration of lutein and zeaxanthin is strongly influenced by dietary intake of dark green leafy vegetables. Pratt, 70 (1) J. AM. OPTONI. Assoc. 39-47 (1999). Zeaxanthin appears to be preferentially taken up by cones, while lutein has an affinity for rods. Head, at 346. Supplementation with lutein has been shown to increase macular pigment optical density in twenty to forty days after commencing lutein administration. Landrum et al., 65 (1) Exp. EYE RES. 57-62 (1997). Further studies have shown an inverse correlation between high intakes of lutein and the incidence of cataracts. Lyle et al., 149 (9) AM. J. EpiDEMlOL.801-09 (1999). Other sources for the carotenoids lutein and zeaxanthin include egg yolks. The benefit of introducing these carotenoids into the diet through this route is counterbalanced, however, by potential LDL-cholesterol elevation caused by consumption of egg yolks.

Handelman et al., 70 (2) AM. J. CLIN. NUTR. 247-51 (1999). Additional studies conclude that carotenoids such as lutein and zeaxanthin, which are found primarily concentrated in the foveal region of the retina, function in the human retina as antioxidants by inhibiting the -peroxidation of long-chain polyunsaturated fatty acids, lending support for their protective role in AMD. Rapp et al., 41 (5) INVEST. OPHTHALMOL. VIS. SCI. 1200-09 (2000); Snodderly, 62 (Suppl. 6) AM. J. CLIN. NUTR. 1448-61 (1995). A preferred embodiment of the compositions of the present invention preferably comprises about 50 mg of mixed carotenoids.

The novel compositions of the present invention may also preferably comprise, alpha- lipoic acid in an amount ranging from about 10'mg to about 80 mg. Alpha-lipoic acid is a powerful antioxidant that has been shown to increase quantities. of glutathione, ascorbate, and vitamin E in the lens. Treatment with alpha-lipoic acid alsovrestores the activities of glutathione peroxidase, catalase, and ascorbate free radical reductase in the lenses of animals.

Alpha-lipoic acid may take over some of the functions of glutathione, making it a potential therapeutic aid in preventing cataracts. Maitra et al., 18 (4) FREE RADICAL BIOL. MED. 823-29 (1995).-A further study concludes that alpha-lipoic acid prevents diabetes-induced changes in rats such as lens antioxidant status and glucose utilization. Obrosova et al., 41 (12) DIABETOLOGIA may preferably comprise about 20 mg of alpha-lipoic acid.

The novel compositions of the present invention may also comprise citrus bioflavonoids in an amount, preferablyranging from between about 80 mg and about 400 mg.

Citrus bioflavonoids include limonene, naringin and flavone glyscosides, and have been found to have remarkable antioxidant properties. Kroyer, 25 (1) ERNAHRUNGSWlss 63-69 (1986). Additionally, the flavanon glycoside, hesperidin, also possesses anti-inflammatory qualities. Emim et al., 46 (2) J. PHARM. PHARMACOL. 118-22 (1994). Natural sources of citrus bioflavonoids such as naringin are available from such sources as lemons, oranges, and leaves of Agathosma betulina, Barosma betulina, Hyssopus officinalis. In a preferred embodiment, the present composition may comprise about 100 mg of citrus bioflavenoids.'In another preferred embodiment, the citrus bioflavonoids comprise at least 13 percent flavonoids.

The noveLcompositions of the present invention may also comprise pine bark extract, preferably in an amount ranging from between about 15 mg and about 120 mg. Pine bark extract includes proanthocyanidins, which have demonstrated their usefulness in the treatment of venous and capillary disorders, and disorders of the retina such as diabetic retinopathy and macular degeneration. MURRAY ET AL., at 95,'see also U. S. Patent No.

4, 698, 360. Proanthocyanidins, which are also found in red wine and grape seed, are twenty- to fifty-times more potent as antioxidants than either vitamin E or vitamin C. Id.

Additionally, pine bark extract significantly enhances antioxidant defenses,. Rimbach et al., 4 (4) REDOX. REP. 171-77 (1999), and is highly effective in protecting neuronal cells against cytotoxicity, Kobayashi'et al., 32 (2) FREE RAD [CAL RES. 115-24 (2000).

Further, regarding its antioxidant effects, pine bark extract has the ability to regenerate the ascorbyl radical and protect endogenous vitamin E and glutathione from

oxidative stress. Packer et al., 27 (5-6) FREE RADICAL BIOL. MED. 704-24 (1999). Moreover, pine bark extract has demonstrated it's effectiveness as an antioxidant in bovine retinas against lipid peroxidation. Ueda et al., 28 (3) OPHTHALMIC RES. 184-92 (1996). Pine bark extract was found to inhibit free radical oxidative reactions in bovine retinas. Finally, when combined with vitamin E and coenzyme Q (10), pine bark extract synergistically enhanced the antioxidant effects of these compounds Chida et al., 31 (6) OPHTHALMIC RES. 407-15 (1999).

Pine bark extract is obtained from the French maritime pine, Pinus maritina.. It is available commercially as-Pycnogenol. Pycnogenol is a standardized extract containing flavonoids, predominantly procyandins and phenolic acids. Pine bark extract is highly bioavailable and displays greater biologic effects as an extract than do its purified components. Packer et al., 27 (5-6) FREE RADICAL BIOL. MED. 704-24 (1999). In a preferred : embodiment of the present invention the compositions comprise about 30 mg pine bark extract. In another preferred embodiment, the pine bark extract comprises at least 95 percent proanthocyanidins.

Pine bark extract is available commercially around the world, through distributors such as TSN Labs, Inc. (Midvale, UT) and Amira (Alachua, FL). Lutein is also commercially available from Amira and other distributors well known to those of ordinary skill in the art. Alpha-lipoic acid, natural mixed tocopherols, vitamin C, citrus bioflavonoids, natural mixed carotenoids, and vitamin A are available commercially, in bulk and in wholesale, from suppliers well known to those with ordinary skill in the art. Specifically, natural mixed tocopherols may be obtained from Ava Health (Grove City, OH) and Wholesale Vitamins USA, Inc. (Brooklyn, NY)..

According to one embodiment of the invention, the composition is formulated for oral administration. The compositions produced in accordance with this invention may be used in different types of pharmaceutical preparations. The preparations will preferably be intended for internal administration, primarily for oral administration. Dosage forms include tablets, capsules, powders, dispersions, suspensions and solutions. Tablets and capsules represent the most advantageous oral dosage unit form. Any method known to those of ordinary skill in the art may be used to prepare capsules, tablets, or other dosage formulations. Tablets or capsules can be coated by methods well known to those of ordinary skill in the art. In a preferred embodiment of the invention, the composition is in capsule form. Alternatively, the compositions may be dispersed into a suitable liquid.

The pharmaceutical preparations can be formulated by combining, the inventive compositions with the conventional pharmaceutical additives and exipients, normally used in- the desired forms of the preparations, with the aid of known methods. Such additions may, comprise, for example, additional carriers, binders, preservatives, lubricants, glidants, disintegrants, flavorants, dyestuffs and like substances, all of which are well known in the art.

Reference may be made to REMINGTON'S PHARMACEUTICAL SCIENCES 17TH. ED. (1985),. for other additives that would be suitable for combination with the present compositions. As will be appreciated, the pharmaceutical exipients used to prepare compositions in accordance with the present invention will depend on the administrable form to be used.

Another embodiment of the invention involves administering the composition of the present invention to a human in one or more tablets or capsules as a dietary supplement. In yet another embodiment of the invention, the composition is administered to a human as a pharmaceutical composition. The administration of the composition is preferably in accordance with a predetermined regimen, which may be at least once daily and over an extended period of time as a chronic treatment, and could last for one year or more, including the life of the subject, and may be prophylatic in nature. The dosage administered will depend upon administration frequency, the blood level of the components of the composition desired, other concurrent therapeutic treatments, the condition's severity, whether the treatment is for prophylaxis or therapy, the patient's age, the degree of eye disease, and the like.

-The invention will be further illustrated by the following non-limiting examples.

Example 1 A composition of the following formulation was prepared in capsule form by standard methods known to those skilled in the art: Alpha-lipoic acid 20 mg Natural Mixed Tocopherols 20 IU VitaminC60mg Citrus bioflavonoids'100 mg Pine bark extract 30 mg Lutein 60 mg Natural Mixed Carotenoids 50 mg Vitamin A 800 ru

Two to three capsules per day is the recommended dosage.

Example 2 A study is undertaken to evaluate the effectiveness of the composition of the present invention in the treatment of patients diagnosed with macular degeneration. The objective of the study is to determine whether oral intake of the composition results in decreasing or eliminating the progression of the disease.

A double-blind, placebo controlled study is conducted over a twelve-month period. A .... total of sixty subjects (30 men and 30 women) aged 40 to 85 years, suffering from AMD, are chosen for the study. An initial assessment of visual impairment is conducted utilizing methods such as funduscopy which allows close-range ophthalmoscopic observation of the fundus (i. e., base of the eye), Amsler grid, computerized threshold campimetry, and fluorescein analysis, which involves injecting a dye intravenously into a subject to determine' adequacy of circulation in the eye. Factors considered in the initial assessment include number and size of drusen, quantity of exudate associated with drusen, changeability of ocular fundus, degree of deterioration of photopic visual acuity, degree of deterioration of contrast sensitivity, and degree of deterioration of central vision field.

The sixty subjects are separated into two separate groups of fifteen men and fifteen women. In the first group, each subject is administered 2 to 3 capsules, daily, of the composition as described in example 1. In the second group (control) each subject is administered 2 to 3 placebo capsules, daily.

An assessment of visual impairment for each subject is measured at one-month intervals for a twelve month period as described above and the data is evaluated using multiple linear regression analysis and a standard students t-test. In each analysis the baseline value of the outcome variable is included in the model as a covariant. Treatment by covariant interaction effects is tested by the method outlined by Weigel & Narvaez, 12 CONTROLLED CLtN [CAL TRIALS 378-94 (1991). If there are no significant interaction effects, the interaction terms are removed from the model. The regression model assumptions of . normality and homogeneity. of variance of residuals are evaluated by inspection of the plots of residuals versus predicted values. Detection of the temporal onset of effects is done sequentially by testing for the presence of significant treatment effects at, 18, 12, and 6 weeks, proceeding to the earlier time in sequence only when significant effects have been identified at each later time period. Changes from the baseline within each group are evaluated using

paired t-tests. In addition, analysis of variance is performed on all baseline measurements and measurable subject characteristics to assess homogeneity between groups. All statistical procedures are conducted using the Statistical Analysis System (SAS. Institute Inc, Cary, NC). An alpha level of 0.05 is used in all statistical tests.

A statistically significant improvement in the progression of macular density decrease is observed in the treated subjects upon completion of the study but not the controls. The differences between the macular density in the treated subjects and controls are statistically significant. Therefore, the study confirms that oral administration of the composition of the present invention is effective in the treatment of patients diagnosed with AMD.

Example 3 A study is undertaken to evaluate the effectiveness of the composition of the present invention in the treatment of patients diagnosed with cataracts. The objective of the study is to determine whether the oral intake of the composition results in decreasing or eliminating the progression of the disease.

A. double-blind, placebo controlled study is conducted over a twelve-month period. A total of sixty subjects (30 men and 30 women) aged 40 to 85 years, suffering from cataracts, are chosen for the study. An initial assessment of visual impairment is conducted utilizing instrumentation which determines the level of lens opacity in each subject's eyes.

The sixty subjects are separated into two separate groups of fifteen men and fifteen women. In the first group, each subject is administered 2 to 3 capsules, daily, of the composition, as described in example 1. In the second group (control) each subject is administered 2 to 3 placebo capsules, daily.

An assessment of visual impairment for each subject based upon lens opacity is measured at one-month intervals for a twelve month period as described above and the data is evaluated using multiple linear regression analysis and a standard students t-test. In each analysis the baseline value of the outcome variable is included in the model as a covariant.

Treatment by covariant interaction effects is tested by the method outlined by Weigel & Narvaez, 12 CONTROLLEDCLINICALTRIALS 378-94 (1991). If there are no significant interaction effects, the interaction terms are removed from the model. The regression model assumptions of normality and homogeneity of variance of residuals are evaluated by inspection of the plots of residuals versus predicted values. Detection of the temporal onset of effects is done sequentially by testing for the presence of significant treatment effects at

18, 12, and 6 weeks, proceeding to the earlier time in sequence only when significant effects have been identified. at each later time period. Changes from the baseline within each group are evaluated usingpairedt-tests.Inaddition, analysis of variance is performed on all baseline measurements and measurable subject characteristics to assess homogeneity between groups. All statistical procedures are conducted using the Statistical Analysis System (SAS Institute Inc., Cary, NC). An alpha level of 0.05 is. used in all statistical tests.

A statistically. significant decrease in the progression of lens opacity is observed in the treated subjects upon completion of the study but not the controls. The differences between lens opacity in the treated subjects and controls are statistically significant. Therefore, this study confirms that oral administration of the composition of the present invention is. effective in the treatment of patients diagnosed with cataracts.

Example 4 A study is undertaken to evaluate the effectiveness of the composition of the present invention in the treatment of patients diagnosed with diabetic retinopathy. The objective of the study is to determine whether the oral intake of the composition results in decreasing or eliminating the progression of the disease.

A double-blind, placebo controlled study is conducted over a twelve-month period. A total of sixty subjects (30 men and 30 women) aged 40 to 85 years, suffering from diabetic retinopathy, are chosen for the study. An initial assessment of visual impairment is conducted utilizing instrumentation which determines the level of retinal neovascularization within each subject's eyes.

The sixty subjects are separated into two separate groups of fifteen men and fifteen women. In the first group, each subject is administered 2 to 3 capsules, daily, of the composition, as described in example 1. In the second group (control) each subject is administered 2 to 3 placebo capsules, daily.

An for each subject is measured at one-month intervals for a twelve month period as described above in order to assess the progression of retinal neovascularization and the data is evaluated using multiple linear regression analysis and a standard students t-test. In each analysis the baseline value of the outcome variable is included in the model as a covariant.

Treatment by covariant interaction effects is tested by the method outlined by Weigel & Narvaez, 12 CONTROLLED CLINICAL TRIALS 378-94 (1991). If there are no significant

interaction effects, the interaction terms are. removed from the model. The regression model assumptions of normality and homogeneity of variance of residuals are evaluated by' inspection of the plotsofresidualsversus'predictedvalues.-Detection of the temporal onset of effects is done sequentially by testing for thepresence of significant treatment effects at 18, 12, and 6 weeks, proceeding to the earlier time in sequence only when significant effects have been identified at each later time period. Changes from the baseline within each group are evaluated using paired t-tests. In addition, analysis of variance is performed on all baseline measurements and measurable subject characteristics to assess homogeneity between groups. All statistical procedures are conducted using the Statistical. Analysis System (SAS Institute Inc.,, Cary, NC). An alpha level of 0. 05 is used in all statistical tests.

A statistically significant decrease in the progression of neovascularization caused by diabetic retinopathy is observed in the treated subjects upon completion of the study but not the controls.. The differences between retinal neovascularization in the treated subjects and. controls are statistically significant. Therefore, this study confirms that oral administration of the composition of the present invention is effective in the treatment of patients diagnosed with diabetic retinopathy. diabetic retinopathy.

Example 5 A study is undertaken to evaluate the effectiveness of the composition of the present invention in the treatment of patients diagnosed with glaucoma. The objective of the study is to determine whether the oral intake of the composition results in decreasing or eliminating the progression of the disease.

A double-blind,placebocontrolled study is conducted over a twelve-month period. A total of sixty subjects (30 men and 30 women) aged 40 to 85 years, suffering from glaucoma, are chosen for the study. An initial assessment of visual impairment is conducted utilizing instrumentation which determines the level of intraocular pressure in each subject's eyes.

The sixty subjects are separated into two separate groups of fifteen men and fifteen women. In the first group, each subject is administered 2 to 3 capsules, daily, of the composition, as described in example 1. In the second group (control) each subject is administered 2 to 3 placebo capsules, daily.

An assessment of intraocular pressure for each subject is measured at one-month intervals for a twelve month period as described above and the data is evaluated using

multiple linear regression analysis and a standard students t-test. In each analysis the baseline value of the outcome variable is included in the model as a covariant. Treatment by covariant interaction effects is tested by the method outlined by Weigel & Narvaez, 12 CONTROLLED CLINICAL TRIALS 378-94 (1991). If there are no significant interaction effects, the interaction terms are removed from the model. The regression model assumptions of normality and homogeneity of variance of residuals are evaluated by inspection of the plots of residuals versus predicted values. Detection of the temporal onset of effects is done sequentially by testing-for the presence of significant treatment effects at 18,12, and 6-weeks, proceeding to the earlier time in sequence only when significant effects have been identified at each later time period. Changes from the baseline within each group are evaluated using paired t-tests. In addition, analysis of variance is performed on all baseline measurements and measurable subject characteristics to assess homogeneity between groups. All statistical procedures are conducted using the Statistical Analysis System (SAS Institute Inc., Cary ;, NC). An alpha level of 0.05 is used in all statistical tests, A statistically significant decrease. in the amount of intraocular pressure is observed in the treated subjects upon completion of the study but not the controls. The differences between the intraocular pressure in the treated subjects and controls are statistically significant. Therefore, this study confirms that oral administration of the composition of the present invention is effective in the treatment of patients diagnosed with'glaucoma.

Those skilled in the art will : find it apparent that various modifications and variations can be made to the formulations of this invention. Thus, the present invention is intended to cover such modifications and variations, provided that they come. within the scope of the appended claims and their equivalents.

The disclosures of all publications cited above are expressly incorporated by reference in their entireties to the same extent as if each were incorporated by reference individually.