MX2008004981A - Compositions for treatment of eye diseases. - Google Patents

Abstract

The present invention relates to pharmaceutical compositions comprising a mixture of carotenoids and adjuvants, which provides synergistic therapeutic potential. The compositions of the present invention, which can be administered orally or topically to the eye, are useful in preventing, attenuating or treating eye diseases such as age-related macular degeneration (AMD), glaucoma, diabetic retinopathy and cataracts.

Description

COMPOSITIONS FOR THE TREATMENT OF EYE DISEASES FIELD OF THE INVENTION The present invention relates to the field of ophthalmology, in particular to compositions useful in the treatment of age-related macular degeneration (AMD) and other eye diseases. The novel formulations comprise a mixture of carotenoids and their biologically active adjuvants, and provide synergistic therapeutic potential.

BACKGROUND OF THE INVENTION Pathologies of the Eyes Eye diseases, including age-related macular degeneration, cataracts, diabetic retinopathy and glaucoma, are the leading cause of blindness affecting millions of people worldwide. As the global population ages, the number of affected individuals is expected to increase substantially. Macular degeneration, or age-related macular degeneration (AMD), affects the central part of the retina and is the leading cause of blindness in people over 65 years of age in the United States of America. AMD affects 13 million people and causes dysfunction in around 1.2 million. The prevalence of AMD increases with age from 16.8% in patients from 55-64 to 25.6% in patients of 65-74 and up to 42% in patients above 75. There are two types of AMD: dry and wet. Dry AMD accounts for about 90 percent of all cases and is sometimes referred to as atrophic, non-exudative, or drusenoid macular degeneration. In dry AMD, deposits called drusen accumulate in the retinal pigment epithelial tissue (RPE) below the macula. These deposits are thought to interfere with the function of photoreceptors in the macula, which causes progressive degeneration of these cells. The loss of vision from dry AMD occurs very gradually over the course of many years. Dry AMD frequently progresses in wet AMD. In wet AMD, abnormal blood vessels grow behind the macula. These vessels leak blood and fluid into the macula, thereby damaging the photoreceptor cells. Wet AMD progresses rapidly and can cause severe damage to the central vision. If wet AMD is diagnosed early, laser surgery can prevent the loss of extensive central vision by destroying cracked blood vessels. Non-surgical treatments are available. Diabetic retinopathy (DR) is a complication of diabetes that is caused by changes in the blood vessels of the retina. Damaged blood vessels in the retina can leak blood and grow into branched, brittle, branched and scar tissue types. This can tarnish or distort the vision images that the retina sends to the brain. DR is the leading cause of blindness in the United States of America and diabetics without treatment are more at risk of blindness than the general population. Cataracts are the leading cause of blindness in the world, and the leading cause of reversible visual loss for people over 65 years of age. Cataracts are a loss of the transparency of the lenses of the eye which causes blurred vision, dazzling, sensitivity to light, poor night vision, lights around the aurora and color distortion. About 4 million people have cataracts in the United States of America, and 40,000 develop cataracts each year. With the life expectancy above 76 years, the incidence of cataracts is expected to double in the following 12 years. Cataract surgery is the most common surgical procedure for advanced age. Glaucoma is the leading cause of irreversible blindness in the world, the second most common cause of irreversible blindness in the United States of America, and the most common cause of blindness among black people. An estimated 2.5 million people in the US have glaucoma. To level Worldwide, it is estimated that around 66.8 million people have visual impairment of glaucoma, with 6.7 million suffering from blindness. Glaucoma is not a simple disease, but on the contrary it is a group of disorders that damage the optic nerve. This pattern usually occurs in the presence of high intraocular pressure, but it can also occur with normal or even below normal eye pressure.

Dietary supplements have been shown to be effective in reducing the risk of and in the treatment of certain eye diseases. The Age-Related Eye Disease Study (AREDS), a major clinical trial conducted to evaluate the effect of high oral doses of antioxidants and zinc on the progress of AMD and cataracts, shows that the consumption of High antioxidants and zinc reduces the risk of developing advanced AMD by about 25 percent. The composition of AREDS comprises vitamin A, vitamin C, vitamin E and the minerals zinc and copper. The intake of this composition was shown to be associated with side effects, including genitourinary problems, anemia, yellowing of the skin and an increased risk of lung cancer in smokers. Another study, the Lutein Antioxidant Complement Assay (LAST), evaluates the effects of orally administering lutein and lutein combined with antioxidants in AMD atrophic (dry). Both treatments significantly improve some measures of visual function, including dazzle recovery, contrast sensitivity, and visual acuity. The long-term safety of the dietary lutein supplement has not been determined yet.

Antioxidants in Diet Carotenoids are pigments that occur naturally in certain plants and algae. For example, the red color of tomatoes and the yellow color of corn are derived from carotenoids. Mammals are unable to synthesize carotenoids in situ and must obtain them through their diet. The high dietary intake of carotenoids has been shown to be associated with reduced incidence of certain types of cancers, cardiovascular disease, and hypertension; a dermal photoprotective effect is also associated with a high dietary intake of carotenoids. Epidemiological studies have shown that dietary antioxidants such as carotenoids slow the progress of eye diseases, including the progress of cataracts and AMD. Carotenoids such as lycopene, the main carotenoid in tomatoes, have become the most intensive research subject. Epidemiological studies have established that a low serum concentration of Carotenoids, especially lycopene, is associated with AMD risk. Other carotenoids, including lutein and zeaxanthin, have been shown to have a protective role in the development of cataracts and macular degeneration (Mares-Perlman, 2002).

Lycopene Lycopene is the main carotenoid present in the diet and which provides the familiar red color of tomato products. More than 80% of the dietary intake of lycopene is derived from tomato sources, such as ketchup, tomato juice, spaghetti sauce, tomato soup and pizza sauce. Lycopene can be prepared synthetically or can be obtained as a natural tomato extract. For example, lycopene is obtained under the name Lyc-O-Mato® (LycoRed, Israel) as an all-natural antioxidant formula containing tomato lycopene, tocopherols, beta-carotene, phytoeneum, phyto-flune, tomato oil, phospholipids, and other important bioactive phytochemicals that occur naturally in tomato oleoresin. Lycopene has been shown to provide eye protection and endogenous UV protection that induces damage to the skin when administered orally. Several studies have shown an anti-cataract effect of dietary lycopene in animals (Pollack, et al.). Lycopene prevents the morphological changes induced by galactose in lens cells cultured human, suggesting its use as an anti-cataract agent (Mohanty I., et al). Without wishing to be bound by theory, lycopene is considered to have a protective effect on lutein and zeaxanthin.

Lutein and Zeaxanthin Lutein and its stereoisomer zeaxanthin belong to the xanthofyl family of carotenoids and are the only two known carotenoids that accumulate specifically from plasma and are deposited in lenses and the macular luteum. The macular pigment comprises lutein and zeaxanthin, and functions as a filter to protect light-sensitive photoreceptor cells that are also known to purify reactive oxygen species (ROS). The dietary intake of these carotenoids results in an increased macular pigment and improved vision in patients with AMD and other ocular diseases (reviewed in Alves-Rodrigues and Shao). Green leafy vegetables are the best dietary source of lutein, with spinach, cabbage and parsley providing high levels. Purified crystalline lutein has been classified as generally recognized as safe (GRAS) and can be added to foods and beverages. Pure lutein can also be isolated from certain plants. For example, Patent E.U.A. Do not. 5,382,714 discloses a process for isolating, purifying, and recrystallizing lutein from saponified marigold oleoresin, and Patent E.U.A. No. 5,648,564 teaches a process for the formation, isolation and purification of edible xanthophyll crystals of plants, with lutein a preferred product. Seddon (Seddon et al, 1994) reports the first direct relationship between carotenoid intake and risk of AMD. Lutein and zeaxanthin are associated more strongly with a reduced risk of AMD. An oral dose of 6% w / w per day showed that it translates into a 57% lower risk of the disease.

Carnosic Acid, Phytoene, and Fitofluene Carnosic acid is an antioxidant extracted from rosemary (Rosemarinus species) and other herbs, which have been shown to inhibit oxidation in a synergistic manner with lycopene. Phytoene and phytofluene are carotenoids found in tomatoes, and can be found in tomato oleoresin.

Phase II Enzymes The biomechanical mechanisms involved in the protective effects of fruits and vegetables in general and tomatoes in particular are not fully understood. In recent years, Evidence has accumulated indicating that the beneficial action is due, at least in part, to the induction of Phase II detoxification enzymes (Talalay, 2000). These enzymes detoxify many harmful substances by converting them to hydrophilic metabolites that can be quickly excreted from the body. Coordinated induction of phase II enzymes, such as NAD (P) H: quinone oxidoreductase (NQO1) and β-glutamylcysteine synthetase (GCS) is mediated through cis regulatory DNA sequences located in the promoter or augmentation region, which are known as antioxidant response elements (ARE). The stimulation of the ARE transcription system is an established mechanism for the mobilization of the body's defense system against carcinogens and other harmful compounds. The transcription factor that activates the main ARE Nrf2 (nuclear factor E2- related factor 2) plays a central role in the induction of antioxidant and detoxifying genes. Under basal conditions, Nrf2 is located in the cytoplasm and binds to an inhibitory protein, Keapl. During stimulation with induction agents, it is released from Keapl and transublic to the nucleus. . It has recently been shown by some of the applicants of the present invention that in transiently transfected cancer cells, lycopene is able to transactivate the expression of reporter genes merged with ARE sequences (Ben Dor et al, 2005). A mixture of two other carotenoids of tomato, phytoene and phyto-fluene was also effective in the activation of ARE. By activating this system, tomato carotenoids induce the production of phase II detoxification enzymes.

Carotenoid Formulations Certain formulations comprising carotenoids have been described in the art. The Patents E.U.A. Nos. 6,261,598 and 6,509,029 (hereinafter '598 and? 029, respectively) describe oil-containing dispersion and an emulsion or dry powder produced therefrom, respectively, comprising a mixture of β-carotene, lycopene and lutein. The Patent Application Publication E.U.A. No. 2003/0031706 discloses carotenoid formulations comprising specific mixtures of β-carotene, lycopene and lutein. The '598 and? 029 patents teach about an oral composition comprising Lyc-O-Mato®, in particular a gelatin capsule containing carotenoid in high concentration due to the high content of phospholipid and the viscosity of the oily dispersion and the Exemplified formulations comprise pure crystalline carotenoids. The Patent E.U.A. No. 6,103,756 teaches oral compositions comprising effective amounts of vitamins, minerals, and plant extracts. The essential ingredients include, inter alia, vitamins A, C and E, and extracts of cranberry, lutein and lycopene. The Patent E.U.A. No. 6,573,299 teaches compositions for topical application to the outer eyelid comprising at least one permeation enhancer and at least one alpha hydroxy acid.

Those compositions, which penetrate the skin and permeate the fundamental tissues, are said to improve disorders associated with eye aging including age-related changes to the eyelids such as wrinkles and dry skin and diseases such as cataracts and AMD. The Patent Application Publication E.U.A. Do not. 2003/0050283 relates to an ophthalmic composition for the treatment of pathological retinal disorders comprising as an essential element at least one negatively charged phospholipid, other than cardiolipin. Such a composition may further comprise at least one carotenoid.

The Patent E.U.A. No. 6,291,519 teaches a method for preventing damage to mammalian eye tissues by applying to the eye a composition comprising an amount of vitamin A and an amount of vitamin E effective to absorb UV radiation, destructive ozone, or both. The Patent E.U.A. No. 5,527,533 teaches a method for improving the vision of an individual suffering from damage or retinal disease, which comprises administering an amount Therapeutically effective of astaxanthin, a carotenoid found in aquatic animals. Parenteral, oral and topical compositions are described, however, it is exemplified only by oral and parenteral compositions. The patent application E.U.A. No. 2004/0258769 teaches compositions for intraocular injection comprising anecortavo acetate in conjunction with a daily regimen of ocular vitamins. There remains a need not covered in the art for compositions that are effective in preventing and treating diseases of the eyes such as AMD, cataracts, retinopathy and glaucoma.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to effective compositions for treating diseases in the eyes. The compositions comprise a mixture of phytochemicals, which produce a synergistic effect in the alleviation and treatment of diseases of the eyes including glaucoma, cataracts, diabetic retinopathy (DR) and age-related macular degeneration (AMD). Specifically, the compositions are effective in preventing the progress of dry AMD (non-neovascular) to wet AMD (neovascular). Certain carotenoids and other phytochemicals are known to be effective in reducing the risk of certain diseases of the eyes and can even improve visual function when ingested in high concentrations. The compositions of the present invention offer a significant advantage over known formulations in that they include a mixture of carotenoids and plant-derived adjuvants that act synergistically and provide unexpected results at low concentrations of lycopene. As such, the concentration of lycopene that provides a therapeutic effect is lower (for example 10 times lower) compared to a corresponding formulation does not contain these adjuvants. In one aspect, the present invention provides a composition comprising lutein, zeaxanthin, lycopene, phytoene, phytofluene and carnosic acid, and a pharmaceutically acceptable carrier or excipient. The components of the composition are given as weight percent by total weight (% w / w). In an exemplary embodiment, lutein is present in the composition in a concentration range of about 0.025% w / w to about 5% w / w. A range of about 0.25% w / w to about 2.5% w / w is preferred, and a concentration of about 2% w / w is more preferred. In some modalities, lutein is prepared synthetically. In other modalities, lutein is isolated and purified from a natural source.

The present composition further comprises zeaxanthin, a stereoisomer of lutein. In an exemplary embodiment, zeaxanthin is present in the composition in a concentration range of about 0.001% w / w to about 2% w / w. A range of about 0.025% w / w to about 1% w / w is preferred, and a concentration of about 0.5% w / w is more preferred. In some embodiments, zeaxanthin is prepared synthetically. In other embodiments, zeaxanthin is isolated and purified from a natural source. In other embodiments, zeaxanthin is contained in the lutein fraction. According to these embodiments, the total lutein and zeaxanthin concentration is about 0.035% up to about 7% w / w, preferably in the range of about 1.5% up to about 2.5% w / w, more preferably around 2% up to about 2.2% total p / p of lutein and zeaxanthin. Lycopene is preferably provided in the composition as a natural compound. In some embodiments, lycopene is provided as an extract, for example, as an extract of tomato oleoresin, such as Lyc-O-ato®. In some embodiments, the lycopene extract also comprises phytoene, phytofluene, lutein and zeaxanthin. According to an exemplary embodiment, lycopene is provided in the current composition in a concentration range of about 0.025% w / w to about 5% p / p. A range of about 0.25% w / w to about 2.5% w / w is preferred, and a concentration of about 1.5% w / w is more preferred. Phytoene and phytofluene are provided as adjuvants in the present compositions. In an exemplary embodiment, phytoene and phytofluene occur at about 10% of the lycopene concentration. In another exemplary embodiment, each of phytoene and phytofluene are provided in a concentration range of about 0.0025% w / w to about 1.25% w / w. A range of about 0.025% w / w to about 0.25% w / w of each phytochemical is preferred, and a concentration of 0.15% w / w total of both phytoene and phytofluene, which corresponds to about 10% of the content of lycopene, is more preferred. Carnosic acid or derivatives thereof (eg, carnosol, 6,7-dehydrocarnosic acid or 7-ketocarnosic acid) is also provided as an adjuvant in current compositions. The carnosic acid or its derivatives are preferably provided in a concentration range of about 0.025% w / w to about 2.5% w / w. A range of about 0.25% w / w to about 2% w / w is preferred, and a concentration of 1% w / w is more preferred. In another currently preferred embodiment, the composition further comprises tomato oleoresin.

According to one embodiment, the composition of the present invention comprises from about 0.025% w / w to about 5% w / w lutein; from about 0.001% w / w to about 2% w / w zeaxanthin; from about 0.025% w / w to about 5% w / w mg lycopene; from about 0.0025% w / w to about 1.25% w / w mg of phytoene; from about 0.0025% w / w to about 1.25% w / w of phytofluene; from about 0.025% w / w to about 2.5% w / w of carnosic acid or derivative thereof; and a pharmaceutically acceptable carrier or excipient.

In a presently preferred embodiment, the composition of the present invention comprises; about 1.5% w / w of lycopene; about 2% total p / p of lutein and zeaxanthin, about 0.15% p / p total phytoene and phyto-flux; about 1% w / w of carnosic acid or a derivative thereof; and a pharmaceutically acceptable carrier or excipient. In one embodiment, the composition further comprises tomato oleoresin. Additional therapeutic agents, including vitamins, minerals, other carotenoids, and micronutrients they may optionally be incorporated into the compositions of the present invention. In some embodiments the composition further comprises a source of zinc, which can be zinc oxide or a zinc salt. Any zinc salt that is compatible with the eyes is acceptable. Examples of zinc salts include but are not limited to zinc chloride, zinc acetate, zinc gluconate, zinc carbonate, zinc sulfate, zinc borate, zinc nitrate and zinc silicate. In some embodiments a concentration of about 0.25% up to about 15% w / w zinc is provided. In preferred embodiments a concentration of about 7.5% w / w zinc is provided; preferably in the form of zinc gluconate. In certain embodiments a copper source is provided in the current composition. In some embodiments, cupric oxide is preferred. In some embodiments copper is provided at a concentration of about 0.01% to about 5% w / w; preferably at a concentration of about 0.25% w / w. Certain preferred vitamins include vitamin A, vitamin C and vitamin E. Vitamins can be provided as natural or synthetically produced compounds. The derivatives, including provitamins of the preferred vitamins are acceptable. In some preferred modalities Vitamin A is provided as provitamin A, specifically β-carotene. In some embodiments, combinations of the above vitamins are included in the composition. The addition of vitamin E, vitamin C and β-carotene is preferred. Vitamin E and vitamin C can each be included in the current composition at a concentration of about 0.25% up to about 25% w / w. The preferable concentrations of vitamin E and vitamin C are around 12.5%. The ß-carotene can be included in the current composition at a concentration of about 0.025% up to 2.5% w / w. The preferable concentrations of β-carotene are about 0.75% w / w. According to some embodiments, the composition of the present invention comprises lutein, zeaxanthin, lycopene, phytoene, phytofluene, carnosic acid or a derivative thereof, vitamin E or a derivative thereof, vitamin A or a derivative thereof (e.g. -carotene), vitamin C, zinc and copper; and a pharmaceutically acceptable carrier or excipient. In a preferred embodiment, the composition comprises: from about 0.025% w / w to about 5% w / w lutein; from about 0.001% w / w to about 2% w / w zeaxanthin; from about 0.025% w / w to about 5% w / w mg lycopene; from about 0.0025% w / w to about 1.25% w / w mg of phytoene; from about 0.0025% w / w to about 1.25% w / w of phytofluene; from about 0.025% w / w to about 2.5% w / w of carnosic acid or derivative thereof; from about 0.25% w / w to about 25% w / w vitamin E; from about 0.25% w / w to about 25% w / w vitamin C; from about 0.025% to about 2.5% w / w of ß-carotene; from about 0.25% w / w to about 15% w / w mg zinc; from about 0.01% w / w to about 5% w / w copper; and a pharmaceutically acceptable carrier or excipient. In another currently preferred embodiment, the composition comprises: about 1.5% w / w lycopene; about 2% total p / p of lutein and zeaxanthin, about 0.15% p / p total phytoene and phyto-flux; about 1% w / w of carnosic acid or a derivative thereof; around 12.5% w / w of vitamin E; around 12.5% w / w of vitamin C; about 0.75% w / w of β-carotene; about 7.5% w / w zinc; around 0.25% w / w copper; and a pharmaceutically acceptable carrier or excipient. The present invention relates to pharmaceutical compositions for oral use or for topical administration to the eyes. In one embodiment the composition is formulated for oral use in a selected form of a tablet, oblong tablet, capsule, microcapsule, pelletizer, pill, powder, syrup, gel, thickened mixture, granule, suspension, dispersion, emulsion, liquid, solution, dragee, pearl and pearl oblong and the like. An oblong pearl is a complex of polysaccharide, in the form of a pearl, in which small drops containing the active material are enclosed. In certain preferred embodiments the composition is formulated as a soft gelatin capsule or as a hard gelatin capsule. In other embodiments, the composition is formulated as oblong pearls based on alginates, gelatin or other natural or synthetic polymers. The present invention also relates to a composition formulated for application to the eyes. The composition can be formulated as a liquid, cream, paste, ointment, emulsion including submicron emulsion, gel, thermal gel, or suspension. The composition can also be dispensed as a dry formulation, for example as powder, granules, microcapsules or capsules, for reconstitution as a liquid, dispersion, emulsion or suspension. In some embodiments the composition is provided in an aqueous or non-aqueous medium, and is preferably sterile (microbe-free). In another aspect, the present invention provides a method for preventing, alleviating or treating an eye disease comprising the step of administering an effective amount of a composition comprising lutein, lycopene, phytoene, phytofluene and carnosic acid.; and a pharmaceutically acceptable carrier or excipient, in an amount effective to prevent alleviating or treating eye disease. Non-limiting examples of eye diseases include AMD (both wet and dry), glaucoma, diabetic retinopathy and cataracts. Additional modalities and the full scope of the applicability of the present invention will be apparent from the detailed description given hereafter. However, it will be understood that the detailed description and specific examples, while indicating the preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will be apparent to those skilled in the art. in art from this detailed description.

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the surprising discovery that a composition comprising a mixture of carotenoids and other phytochemicals is effective in treating diseases of the eyes. Without wishing to adhere to any particular theory or mechanism, it is considered that lycopene and the adjuvants carnosic acid, phytoene and phytofluene work synergistically in the formulations of the invention. This synergistic effect allows the inclusion of minor amounts of lycopene for example, 10 times less than the amount of lycopene in known formulations, that is, formulations that do not contain carnosic acid, phytoene and phytofluene, while still maintaining a beneficial therapeutic effect. Lycopene, again, has a protective effect on lutein and zeaxanthin. Accordingly, the present invention provides a pharmaceutical composition comprising lutein, zeaxanthin, lycopene, phytoene, phytofluene, carnosic acid; and a pharmaceutically acceptable carrier or excipient. In preferred embodiments, lycopene is provided as a natural tomato extract, which can be extracted from tomato oleoresin. In specific embodiments, the composition of the present invention comprises from about 0.025% w / w to about 5% w / w lutein; from about 0.001% w / w to about 2% w / w zeaxanthin; from about 0.025% w / w to about 5% w / w mg lycopene; from about 0.0025% w / w to about 1.25% w / w mg of phytoene; from about 0.0025% w / w to about 1.25% w / w of phytofluene; from about 0.025% w / w to about 2.5% w / w of carnosic acid or derivative thereof; and a pharmaceutically acceptable carrier or excipient. In a presently preferred embodiment, the composition of the present invention comprises; about 1.5% w / w of lycopene; about 2% total p / p of lutein and zeaxanthin, about 0.15% p / p total phytoene and phyto-flux; about 1% w / w of carnosic acid or a derivative thereof; and a pharmaceutically acceptable carrier or excipient. In another currently preferred embodiment, the composition further comprises tomato oleoresin. The tomato oleoresin can be obtained from tomato or tomato products according to methods well known to the person skilled in the art.

Additional therapeutic agents can be added to the composition. Therapeutic agents include antiinflammatories, antipruritics, pain relievers, antibiotics, wetting agents, moisture promoting agents, vitamins, minerals, micronutrients and other phytochemicals, including carotenoids. Certain preferred vitamins include vitamin A, vitamin C and vitamin E, and derivatives thereof. Vitamins can be provided as natural or synthetically produced compounds. In some preferred embodiments vitamin A is provided as provitamin A, specifically as β-carotene. Other acceptable forms of vitamin A include retinal, retinol esters, retinoic acid, and the like. Vitamin E is a means to include -tocopherol and isomers and racemates of -tocopherol and derivatives thereof (for example, tocopherol acetate). Vitamin C can be provided per se or as a derivative of ascorbic acid. For example, ascorbic palmitate, a fat-soluble ester, is stable and acceptable in current compositions. Vitamin E can be included in the composition at a concentration range of about 0.25% w / w to about 25% w / w, preferably at a concentration range of about 0.1% to about 15%, more preferably at a concentration of around 12.5% p / p. Without wishing to be bound by any particular mechanism or theory, it is considered that vitamin E increases the stability and cellular absorption of lycopene. Vitamin A or derivatives thereof, for example β-carotene, can be included in the composition at a concentration range of about 0.025% w / w to about 2.5% w / w; preferably at a concentration of about 0.75% w / w. Vitamin C and derivatives thereof, including ascorbic acid, are optionally included in the composition of the present invention. In certain embodiments, vitamin C is included in a range of about 0.25% w / w to about 25% w / w, preferably at a concentration range of about 0.1% to about 15%, more preferably at a concentration of around 12.5%p / p- Minerals can also be added to the formulations of the present invention. Preferred minerals include zinc and copper, which are preferably added together to reduce the risk of zinc-related anemia. Zinc, in the form of a zinc salt or zinc oxide, is preferably included in the composition at a range of about 0.25% w / w to about 15% w / w, preferably about 7.5% w / w. p of zinc. Preferred zinc salts include but are not limit zinc chloride, zinc acetate, zinc gluconate, zinc carbonate, zinc sulfate, zinc borate, zinc nitrate and zinc silicate. In specific embodiments, the composition comprises zinc gluconate. A copper source can be included in a concentration range of about 0.01% w / w to about 5% w / w. In preferred embodiments, cupric oxide is included at a concentration of about 0.25% w / w. According to some embodiments, the composition of the present invention comprises lutein, zeaxanthin, lycopene, phytoene, phytofluene, carnosic acid or a derivative thereof, vitamin E or a derivative thereof, vitamin A or a derivative thereof ( for example ß-carotene), vitamin C, zinc and copper; and a pharmaceutically acceptable carrier or excipient. In a preferred embodiment, the composition comprises: from about 0.025% w / w to about 5% w / w lutein; from about 0.001% w / w to about 2% w / w zeaxanthin; from about 0.025% w / w to about 5% w / w mg lycopene; from about 0.0025% w / w to about 1.25% w / w mg of phytoene; from about 0.0025% w / w to about 1.25% w / w of phytofluene; from about 0.025% w / w to about 2.5% w / w of carnosic acid or derivative thereof; from about 0.25% w / w to about 25% w / w vitamin E; from about 0.25% w / w to about 25% w / w vitamin C; from about 0.025% to about 2.5% w / w of ß-carotene; from about 0.25% w / w to about 15% w / w mg zinc; from about 0.01% w / w to about 5% w / w copper; and a pharmaceutically acceptable carrier or excipient. In another currently preferred embodiment, the composition comprises: about 1.5% w / w lycopene; about 2% total p / p of lutein and zeaxanthin, about 0.15% p / p total phytoene and phyto-flux; about 1% w / w of carnosic acid or a derivative thereof; around 12.5% w / w of vitamin E; around 12.5% w / w of vitamin C; about 0.75% w / w of β-carotene; about 7.5% w / w zinc; around 0.25% w / w copper; and a pharmaceutically acceptable carrier or excipient.

Mechanism of Action Without wanting to be linked by any particular mechanism and theory, it is considered that lycopene can exert its therapeutic effects by inducing the antioxidant response element (ARE), which again induces the expression of phase II detoxification enzymes. These enzymes detoxify many harmful substances by converting them into hydrophilic metabolites that can be quickly excreted from the body. Examples of phase II enzymes are NAD (P) H: quinone oxidoreductase (NQO1) and glutamylcysteine synthetase (GCS). The Nrf2 transcription factor activated by the main ARE plays a central role in the induction of antioxidant and detoxifying genes. In a non-limiting embodiment described herein for purposes of illustration and not limitation, lycopene increases ARE activity by forming Keapl adducts. This can cause its dissociation of Nrf2 again and the activation of the latter. Keapl is a cytoplasmic protein rich in cysteine that negatively regulates the activation of Nrf2. The central domain of Keapl is the domain that is richest in cysteine and is required for cytoplasmic sequestration and Nrf2 inhibition. The dissociation of Nrf2 from Keapl represents a regulatory step that allows Nrf2 to be transubed to the nucleus and the activated transcription of genes dependent on ARE. The dissociation of Nrf2 from Keapl-Nrf2 can be regulated by the redox state of these specific cysteine residues. The adducts of the specific aldehydes were observed in the LC-MS-MS analyzes of the purified human Keapl. The transformation of these adducts coincided with the stabilization of Nrf2, translocation of nuclear Nrf2 and activation of genes dependent on ARE. As contemplated herein, lycopene and adjuvants (ie, carnosic acid, phytoene and phytofluene) in the formulations of the present invention act synergistically and provide unexpected results at low concentrations of lycopene. As such, the concentration of lycopene that provides a therapeutic effect is lower (eg, 2 times, 5 times or even 10 times lower) compared to a corresponding formulation that does not contain these adjuvants. This provides an important advantage over known formulations.

Formulations As described herein, the compositions of the present invention comprise lutein, lycopene, zeaxanthin phytoene, phytofluene and carnosic acid, in combination with chemical components such as physiologically appropriate carriers and excipients.

Pharmaceutical compositions for use in accordance with the present invention can be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compounds into preparations that can be used pharmaceutically. The carotenoids are formulated as pharmaceutical compositions and are administered to the mammalian subject, such as a human patient in a variety of forms such as liquid, solid and semisolid. The pharmaceutical compositions can be administered to a subject by any of the methods known to a person skilled in the art, such as orally, topically, parenterally, paracancerally, transmucosally, transdermally, intramuscularly, intravenously, intradermally, subcutaneously, intraperitonally, intraventricularly, intracranially or intratumorally For oral administration, the compounds can be formulated by combining the active compounds with pharmaceutically acceptable carriers known in the art. The compositions can be formulated in any solid or liquid dosage form known in the art, including but not limited to, tablet, caplet, capsule, microcapsule, pelletizer, pill, powder, syrup, gel, thickened mixture, granule, suspension, dispersion. , emulsion, liquid, solution, dragee, pearl and pearl oblong. The oral compositions may be formulated as immediate release formulations, or as controlled or sustained release formulations that allow for extended release of the active ingredients for a predetermined period of time. Suitable excipients for solid formulations include but are not limited to fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; starch-based excipients such as corn starch, wheat starch, rice starch, potato starch and the like, gelatin, tragacanth gum, cellulose-based excipients such as microcrystalline cellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, methylhydroxypropylcellulose, hydroxypropylcellulose and the like. Polymers such as polyvinylpyrrolidone (PVP) and cross-linked PVP can also be used. In addition, the compositions may further comprise binders (e.g., acacia, corn starch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone), disintegrating agents (e.g., corn starch, potato, alginic acid, silicon dioxide, croscarmellose sodium, crospovidone, guar gum, sodium starch glycolate), surfactants (for example sodium lauryl sulfate), and lubricants (for example, stearic acid, magnesium stearate, polyethylene glycol, sodium lauryl sulfate). For liquid formulations, pharmaceutically acceptable carriers can be aqueous or non-aqueous solutions, suspensions, emulsions or oils. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, and injectable organic esters. Aqueous carriers include water, alcoholic / aqueous solutions, emulsions or suspensions, including saline and buffer medium. Examples of oils include, but are not limited to, petroleum, animal, plant, or synthetic origin, for example, peanut oil, soybean oil, mineral oil, olive oil, sunflower oil, and liver oil. of fish. Preferred oral pharmaceutical compositions include capsules made of gelatin as well as sealed, soft capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. In soft capsules, the active compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers can be added. In certain preferred embodiments the capsules exclude components of animal origin and are acceptable for vegetarians and strict vegetarians.

Soft gelatin capsules and methods for preparing them are known in the art. Non-limiting examples can be found in US Patents. Nos. 6,217,902; 6,258,380; 5,916,591, and 4,891,229, all of which are incorporated herein by reference. In another embodiment, the present invention also relates to a composition formulated for application to the eyes. The composition can be formulated as drops, solution (aqueous and non-aqueous), cream, paste, ointment, gel, emulsions, suspension, and the like. For ophthalmic administration, the composition can be rapidly formulated by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers allow the compounds of the invention to be formulated as. liquids, gels, emulsions, thermal gels, syrups, suspensions, and the like, for ophthalmic use by a patient. Alternatively the composition can be formulated as a solid, for resuspension. In other embodiments, pharmaceutical compositions for ophthalmic administration include aqueous solutions of the active ingredients in water soluble form. Other excipients and acceptable additives known to the person skilled in the art may be included in the compositions of the present invention, for example stabilizers, solubilizers, agents that increase the tonicity, buffer substances, preservatives, thickeners, complexing agents and other excipients, as well as additional therapeutic agents. A solubilizer can be, for example, tyloxapol, polyethylene glycol glycerol fatty acid esters, polyethylene glycol fatty acid esters, polyethylene glycols, glycerol ethers or mixtures of those compounds. A specific example of a well-tolerated solubilizer by the eyes is a polyoxyethylated castor oil for example, the commercial products Cremophor® or Cremophor® RH40. Another example of a solubilizer is tyloxapol. The concentration used depends especially on the concentration of the active ingredient. The added amount is typically sufficient to solubilize the active ingredient. For example, the concentration of the solubilizer is from 0.1 to 5000 times the concentration of the active ingredient. Examples of buffer substances are buffer solutions of acetate, ascorbate, borate, hydrogen carbonate / carbonate, citrate, gluconate, lactate, phosphate, propionate and TRIS (tromethamine). The amount of added buffer is, for example, that necessary to ensure and maintain a physiologically tolerable pH range. The pH range is typically in the range from 5 to 9, preferably from 5.2 to 8.5.

The agents that increase the tonicity are selected from ionic and non-ionic agents. For example, ionic compounds include alkali metal or alkaline earth metal halides, such as, for example, CaCl 2 KBr, KCl, LiCl, Nal, NaBr, or NaCl, or boric acid. Non-ionic tonicity enhancing agents are, for example, urea, glycerol, sorbitol, mannitol, propylene glycol, or dextrose. For example, sufficient tonicity enhancing agent is added to impart an osmolarity of approximately 50 to 1000 mOsmol to the ophthalmic composition ready for use. Examples of preservatives are quaternary ammonium salts such as benzalkonium chloride, benzoxonium chloride or polymeric quaternary ammonium salts, alkaline mercury salts of thiosalicylic acid, such as, for example, thiomersal, phenylmercuric nitrate, phenylmercuric acetate or phenylmercuric borate, parabens, such as, for example, methylparaben or propylparaben, alcohols, such as, for example, chlorobutanol, benzyl alcohol or phenyl ethanol, guanidine derivatives, such as, for example, chlorhexidine or polyhexamethylene biguanide, or sorbic acid. Where appropriate, a sufficient amount of preservative is added to the ophthalmic composition to ensure protection against secondary contamination during use, caused by microbes.

The compositions of the present invention may comprise additional non-toxic excipients, such as, for example, emulsifiers, wetting agents or fillers, such as, for example, polyethylene glycols (PEG200, 300, 400 and 600) or Carbowax® (Carbo axlOOO). , 1500, 4000, 6000 and 10000). Other excipients that may be used if desired are listed below but are not intended to limit the scope of the possible excipients in any way. These may be complexing agents, such as disodium EDTA or EDTA, antioxidants, such as ascorbic acid, acetylcysteine, cysteine, sodium acid sulfite, butyl-hydroxyanisole, butyl-hydroxytoluene; stabilizers, such as thiourea, thiosorbitol, sodium dioctyl sulfosuccinate or monothioglycerol; or other excipients, such as, for example, sorbitol ester of lauric acid, triethanolamine oleate or palmitic acid ester. Optionally, the suspension may also contain stabilizers or appropriate agents, which increase the solubility of the compounds, to allow the preparation of concentrated solutions. For example, Patent E.U.A. No. 5, 576, 311, the contents of which are incorporated herein by reference, teaches a stable aqueous suspension of drugs suitable for therapeutic administration to the eye comprising cyclodextrin-type suspension agents. Other useful formulations include emulsions submicron eyepieces, for example an ocular drug delivery vehicle as described in Patent E.Ü.A. No. 5,496,811, the contents of which are incorporated for reference as fully set forth herein. The amount and type of excipient added is in accordance with the particular requirements and is generally in the range from about 0.0001 to about 90% by weight. The amount of a composition to be administered, of course, will depend on many factors including the subject to be treated, the severity of the affliction, the manner of administration, and the judgment of the prescribing physician. However, the dose used generally depends on a number of factors, including the age and sex of the patient, the precise disorder to be treated, and its severity. Preferably, the preparations are in unit dosage form, intended for oral administration. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active components. The unit dose form can be a packaged preparation, the package contains discrete quantities of the preparation, for example, tablets, capsules, and powders in vials or ampoules. The unit dosage form can also be a capsule, wafer, or tablet by itself or it can be the appropriate number of any of these in packaged form. The dosage program of the compositions of the present invention may vary according to the particular application and potency of the active ingredients. The determination of the appropriate dose is within the skill of the art. For convenience, a simple daily dose is preferred. Alternatively, the total daily dose can be divided and administered in portions during the day such as twice a day, three times a day and the like. The administration is also contemplated twice a week, weekly, twice a month and monthly.

Therapeutic Use In another aspect, the present invention provides a method for preventing, alleviating or treating an eye disease comprising the step of administering an effective amount of a composition comprising lutein, lycopene, phytoene, phytofluene and carnosic acid; and a pharmaceutically acceptable carrier or excipient. Non-limiting examples of eye diseases include AMD (both wet and dry), glaucoma, diabetic retinopathy and cataracts. Thus, in one embodiment, the present invention provides a method for preventing, alleviating or treating AMD. comprising the step of administering an effective amount of a composition comprising lutein, lycopene, phytoene, phytofluene and carnosic acid; and a pharmaceutically acceptable carrier or excipient, in an amount effective to prevent, treat or alleviate AMD. As used herein, the term "AMD" includes both dry and wet AMD, as well as the transition from dry AMD to wet AMD. In another embodiment, the present invention provides a method for preventing, alleviating or treating glaucoma comprising the step of administering an effective amount of a composition comprising lutein, lycopene, phytoene, phytofluene and carnosic acid; and a pharmaceutically acceptable carrier or excipient, in an amount effective to prevent, treat or alleviate glaucoma. In another embodiment, the present invention provides a method for preventing, alleviating or treating diabetic retinopathy comprising the step of administering an effective amount of a composition comprising lutein, lycopene, phytoene, phytofluene and carnosic acid; and a pharmaceutically acceptable carrier or excipient, in an amount effective to prevent, treat or alleviate diabetic retinopathy. In another embodiment, the present invention provides a method for preventing, alleviating or treating cataracts, comprising the step of administering an effective amount of a composition comprising lutein, lycopene, phytoene, phytofluene and carnosic acid; and a pharmaceutically acceptable carrier or excipient, in an amount effective to prevent, treat or alleviate cataracts. As used herein, the term "relieve" means to soften, soothe or reduce the symptoms of any of the aforementioned eye diseases. As used herein, the term "treating" includes a preventive treatment as well as mitigating the disorder. As used herein, the term "administer" refers to contacting a subject with the formulation of the present invention. In one embodiment, the present invention encompasses administering the formulations of the present invention to a human subject. The following examples are presented in order to more fully illustrate some embodiments of the invention. However, this should not be constructed, as limiting the broad scope of the invention. One of skill in the art can quickly discern many variations and modifications of the principles described herein without departing from the scope of the invention.

EXAMPLES Example 1: Oral Compositions The preparations were prepared as follows: Preparation 1: about 6 mg of lycopene (about 1.5% w / w); about 8 mg of lutein and zeaxanthin (combined -about 2% w / w); about 0.6 mg of phytoene and phytofluene (combined -about 0.15%); and about 4 mg of carnosic acid (about 1% P / P) · Preparation 2: Preparation 2 contains all the ingredients of preparation 1 and in addition: about 3 mg of β-carotene (about 0.75%); about 30 mg of zinc (about 7.5% w / w); about 1 mg of copper (about 0.25% w / w); around 50mg of vitamin E (about 12.5% p / p) and around 50 mg of vitamin C (around 12.5% w / w).

Preparation 3: Preparation 3 comprises the following ingredient Ingredient mg (%) L 1 Lut ß-car LR2 ZnO CuO Acetate Acid 6% G 20% G 30G 40% ascorbic Tocopherol 1 Lycopene 6 100 (1.5) 2 Lutein / zea 8 (2) 40 3 ß-carotene 3 10 (0.75) 4 4 (1) 10 carnosic acid 5 Phy + Phf 0.6 100 (0.15) 6 Vitamin E 50 50 (12.5) 7 Vitamin C 50 50 (12.5) 8 Zinc 30 37.5 (7.5) 9 Copper 1 1.25 (0.25) Total (mg) 152.6 298.75 Lyc-O-Mato® 2 Carnosic acid The above compositions are mixed with mineral oil or vegetable oil and prepared as soft gelatine capsules containing about 400 mg by total weight.

Alternatively, the above compositions are mixed with fillers and excipients and are prepared as solid oral dosage forms containing about 40 mg total weight.

Example 2 - Ophthalmic Compositions Each of preparations 1 to 3 above was mixed with an ophthalmically acceptable carrier and formulated in ophthalmic formulations. Although certain embodiments of the invention have been illustrated and described, it is clear that the invention is not limited to the embodiments described herein. Numerous modifications, changes, variations, substitutions and equivalents are apparent to those in the art without departing from the spirit and scope of the present invention as described by the claims, which follow.

REFERENCES Alves-Rodrigues, A. and Shao, A. "The science behind luteine." Toxicology Letters, 150: 57-83, 2004. Ben-Dor A, Steiner M, Gheber L, Danilenko M, Dubi N, Linnewiel K, Zick A, Sharoni Y, and Levy J. Carotenoids activate the antioxidant response element transcription system. Mol. Cancer Therp 4 (1): 177-186. 2005 ares-Perlman JA, Millen AE, Ficek TL, Hankinson SE. "The body of evidence to support a protective role for luteine and zeaxanthin in delaying chronic disease." J Nutr. 2002 Mar; 132 (3): 518S-524S. Mohanty, I, Joshi, S, Trivedi, D, Srivastava, S., and Gupta, S.K. "Lycopene prevents sugar-induced morphological changes and modulates antioxidant statues of human lens epithelium." British J Nutrition, 88: 347-354, 2002. Pollack A, Madar Z, Eisner Z, Nyska A, and Oren, P. Inhibitory effect of lycopene on cataract development in galactosamic rats. Metab Pediatr Syst Ophthalmol. 1996-1997; 19-20: 31-6. Seddon JM, Ajani UA, Sperduto RD, Hiller R, Blair N, Burton TC, Farber MD, Gragoudas ES, Haller J, Miller DT, et al. Dietary carotenoids, vitamins A, C, and E, and advanced age-related macular degeneration. Eye Disease Case-Control Study Group. JAMA 272 (18): 1413-20, 1994 Talalay P. Chemoprotection against cancer by induction ase 2 enzymes. Biofactors; 12: 5-11. 2000

Claims (34)

1. CLAIMS 1. A pharmaceutical composition characterized in that it comprises: lutein, zeaxanthin, lycopene, phytoene, phytofluene, carnosic acid; and a pharmaceutically acceptable carrier or excipient. 2. The composition in accordance with the claim 1, characterized in that lycopene is provided as a natural tomato extract. 3. The composition in accordance with the claim 2, characterized in that lycopene is extracted from tomato oleoresin. 4. The composition according to claim 1, characterized in that lycopene, phytoene, phytofluene and carnosic acid act synergistically to achieve the therapeutic effect of lycopene at a lower concentration compared to the corresponding formulation that does not contain phytoene, phyto-fluene and carnosic acid . 5. The composition according to claim 1, characterized in that it comprises from about 0.025% w / w to about 5% w / w lutein; from about 0.001% w / w to about 2% w / w zeaxanthin; from about 0.025% w / w to about 5% w / w mg lycopene; from about 0.0025% w / w to about 1.25% w / w mg of phytoene; from about 0.0025% w / w to about 1.25% w / w of phytofluene; from about 0.025% w / w to about 2.5% w / w of carnosic acid or derivative thereof; and a pharmaceutically acceptable carrier or excipient. 6. The composition according to claim 5, characterized in that it comprises: about 2% w / w total of lutein and zeaxanthin; about 1.5% w / w of lycopene; about 0.15% p / p total phytoene and phyto-flux; about 1% w / w of carnosic acid or a derivative thereof; and a pharmaceutically acceptable carrier or excipient. 7. The composition according to claim 1, characterized in that it also comprises at least one mineral. 8. The composition according to claim 7, characterized in that the mineral is zinc. 9. The composition according to claim 8, characterized in that the zinc is provided as zinc oxide. 10. The composition according to claim 7, characterized in that the mineral is copper. 11. The composition according to claim 10, characterized in that the copper is provided as cupric oxide. 12. The composition according to claim 1, characterized in that it also comprises at least one vitamin. The composition according to claim 12, characterized in that at least one vitamin is selected from the group consisting of vitamin A, vitamin C, vitamin E, derivatives thereof and combinations thereof. The composition according to claim 1, characterized in that it comprises lutein, zeaxanthin, lycopene, phytoene, phytofluene, carnosic acid, β-carotene, vitamin E, vitamin C, zinc, copper, and a pharmaceutically acceptable carrier or excipient. 15. The composition according to claim 14, characterized in that it comprises: from about 0.025% w / w to about 5% w / w lutein; from about 0.001% w / w to about 2% w / w zeaxanthin; from about 0.025% w / w to about 5% w / w mg lycopene; from about 0.0025% w / w to about 1.25% w / w mg of phytoene; from about 0.0025% w / w to about 1.25% w / w of phytofluene; from about 0.025% w / w to about 2.5% w / w of carnosic acid or derivative thereof; from about 0.25% w / w to about 25% w / w vitamin E; from about 0.25% w / w to about 25% w / w vitamin C; from about 0.025% to about 2.5% w / w of ß-carotene; from about 0.25% w / w to about 15% w / w mg zinc; from about 0.01% w / w to about 5% w / w copper; and a pharmaceutically acceptable carrier or excipient. 16. The composition according to claim 14, characterized in that it comprises about 2% w / w total of lutein and zeaxanthin; about 1.5% w / w of lycopene; about 0.15% p / p total phytoene and phyto-flux; about 1% w / w of carnosic acid or a derivative thereof; around 12.5% w / w of vitamin E; around 12.5% w / w of vitamin C; about 0.75% w / w of β-carotene; about 7.5% w / w zinc; around 0.25% w / w copper; and a pharmaceutically acceptable carrier or excipient. 17. The composition according to claim 1, characterized in that the lycopene induces the production of phase II enzymes. 18. The composition according to claim 1, characterized in that it also comprises tomato oleoresin. 19. The composition according to any of claims 1-18, characterized in that the composition is formulated for oral administration. The composition according to claim 19, characterized in that it is in a form selected from the group consisting of a tablet, oblong tablet, capsule, microcapsule, pelletizer, pill, powder, syrup, gel, thick mixture, granule, suspension, dispersion, emulsion, liquid, solution, dragee, pearl and pearl oblong. 21. The composition according to claim 20, characterized in that the capsule is selected from a soft gelatin capsule and a hard gelatin capsule. 22. The composition according to any of claims 1-18, characterized in that the composition is formulated for topical administration to the eyes. 23. The composition according to claim 22, characterized in that it is in a form selected from the group consisting of a solution, eye drops, liquid, cream, paste, ointment, emulsion, submicron emulsion, gel, thermal gel, semi-solid , solid and suspension. 24. A method for preventing, alleviating or treating an eye disease, characterized in that it comprises administering to a subject in need thereof an effective amount of a composition comprising lutein, lycopene, phytoene, phyto-fluene zeaxanthin and carnosic acid; and a pharmaceutically acceptable carrier or excipient, in an amount effective to prevent, alleviate or treat eye disease. 25. The method according to claim 24, characterized in that the formulation is administered orally. 26. The method according to claim 24, characterized in that the formulation is administered topically to the eyes. 27. The method according to claim 24, characterized in that the eye disease is selected from the group consisting of glaucoma, cataracts, diabetic retinopathy (DR) and age-related macular degeneration (AMD). 28. The method according to claim 27, characterized in that the eye disease is dry AMD. 29. The method according to claim 27, characterized in that the eye disease is wet AMD. 30. A pharmaceutical composition, characterized in that it comprises: about 6 mg of lycopene (about 1.5% w / w); about 8 mg of lutein and zeaxanthin (about 2% w / w); about 0.6 mg of phytoene and phytofluene (around 0.15%); about 4 mg of carnosic acid (about 1% w / w); around 50mg of vitamin E (around 12.5% w / w); around 50mg of vitamin C (around 12.5% w / w) around 3 mg of ß-carotene (around 0.75%); about 30 mg of zinc (about 7.5% w / w); about 1 mg of copper (about 0.25% w / w); Y and a pharmaceutically acceptable carrier or excipient. 31. The composition according to claim 30, characterized in that it also comprises tomato oleoresin. 32. The composition in accordance with the claim 30, characterized in that it is in a selected form of a soft gelatin capsule and a hard gelatin capsule. 33. The composition according to claim 30, characterized in that the zinc is provided as zinc oxide. 34. The composition according to claim 30, characterized in that the copper is provided as cupric oxide.