JP2009515821A - Composition for treating eye diseases - Google Patents

Abstract

  The present invention relates to pharmaceutical compositions containing a mixture of carotenoids and adjuvants that provide synergistic therapeutic potential. The composition of the present invention can be administered orally or topically to the eye to prevent or reduce eye diseases such as age-related macular degeneration (AMD), glaucoma, diabetic retinopathy and cataract. Or useful for treatment.

Description

  The present invention relates to the field of ophthalmology, and in particular to compositions useful for treating age-related macular degeneration (AMD) and other eye diseases. The new formulation contains a mixture of carotenoids and their biologically active adjuvants, providing a synergistic therapeutic potential.

Eye Pathology Eye diseases including age-related macular degeneration (AMD), cataracts, diabetic retinopathy and glaucoma are the leading causes of blindness affecting millions of people worldwide. As global populations age, the number of individuals attacked is expected to increase considerably.

  Macular degeneration, or age-related macular degeneration (AMD), strikes the central part of the retina and is the leading cause of blindness in people over the age of 65 in the United States. AMD attacks 13 million people and causes disabilities to about 1.2 million people. The prevalence of AMD increases with age from 16.8% in 55-64 year old patients to 25.6% in 65-74 year old patients and even 42% in 75 year old and older patients . There are two types of AMD: dry and wet. Dry AMD accounts for about 90% of all patients and is sometimes referred to as atrophic, non-exudative, or drusen macular degeneration. In dry AMD, deposits called drusen accumulate in the retinal pigment epithelium (RPE) tissue below the macula. These deposits are thought to cause progressive degeneration of these cells and interfere with the function of photoreceptors in the macula. Vision loss from dry AMD appears very gradually over the years. Dry AMD often progresses to wet AMD. In wet AMD, abnormal blood vessels grow under the macula. These blood vessels leak blood and secretions into the macula, thereby damaging photoreceptor cells. Wet AMD can progress rapidly and cause severe damage to central vision. If wet AMD is diagnosed early, laser surgery can prevent extensive loss of central vision by destroying leaky blood vessels. Non-surgical treatment is not effective.

  Diabetic retinopathy (DR) is a complication of diabetes caused by changes in retinal blood vessels. Damaged blood vessels in the retina leak blood and grow fragile brush-like tributaries and scar tissue. This blurs or distorts the visual image that the retina sends to the brain. DR is a leading cause of blindness in the United States, and untreated diabetes has a higher risk of blindness than the general population.

  Cataract is the leading cause of blindness in the world and the leading cause of reversible blindness for people over the age of 65. Cataract is a loss of transparency of the ocular lens, causing blurred vision, dazzling, light sensitivity, reduced night vision, halo around light, and color distortion. In the United States, about 4 million people have cataracts and 40,000 people develop cataracts a year. With life expectancy over 76 years of age, the prevalence of cataracts is expected to double in the next 12 years. Cataract surgery is the most common surgical procedure for the elderly.

  Glaucoma is the leading cause of irreversible blindness in the world, the second most common cause of irreversible blindness in the United States, and the most common cause of blindness among blacks. In the United States, it is estimated that 2.5 million people have glaucoma. Worldwide, about 66.8 million people have vision impairments from glaucoma, and 6.7 million suffer from blindness. Glaucoma is not a single disease, but rather a group of disorders that damage the optic nerve. This pattern usually occurs in the presence of high intraocular pressure, but may occur at normal or even less than normal intraocular pressure.

  Dietary nutritional supplements have been shown to be effective in reducing the risk of certain eye diseases and treating the diseases. The Age-Related Eye Disease Study (AREDS), the main clinical trial conducted to evaluate the effects of high oral doses of antioxidants and zinc on the progression of AMD and cataracts ) Revealed that high levels of high oxidizer and zinc intake reduced the risk of developing advanced AMD by about 25%. The composition of AREDS contains vitamin A, vitamin C, vitamin E, and inorganic zinc and copper. Ingestion of this composition has been shown to be associated with side effects including genitourinary problems, anemia, skin yellowing, and increased lung cancer risk in smokers.

  Another study, the Lutein Antioxidant Supplement Trial (LAST), evaluated the effect of lutein administered orally and with antioxidants on atrophic (dry) AMD. Both treatments significantly improved several measures of visual function including glare healing, contrast sensitivity, and visual acuity. The long-term safety of dietary lutein nutritional supplements has not yet been established.

Dietary antioxidants Carotenoids are naturally occurring pigments found in certain plants and algae. For example, tomato red and corn yellow are derived from carotenoids. Mammals are not capable of synthesizing carotenoids in situ and must acquire them through the diet. High dietary intake of carotenoids has been shown to be associated with reduced prevalence of certain types of cancer, cardiovascular disease, and hypertension. The photoprotective effect of the skin is also associated with a high dietary intake of carotenoids.

  Epidemiological studies have shown that dietary antioxidants such as carotenoids delay the progression of eye diseases, including the progression of cataracts and AMD. Carotenoids such as lycopene, the main carotenoid of tomatoes, were the subject of a more thorough investigation. Epidemiological studies have established that low serum concentrations of carotenoids, especially lycopene, are associated with the risk of AMD. Other carotenoids, including lutein and zeaxanthin, have been shown to have a prophylactic role in the progression of cataracts and macular degeneration (Mares-Perlman, 2002).

Lycopene Lycopene is the main carotenoid present in the diet and provides the well known red color of tomato products. Over 80% of the dietary intake of lycopene comes 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 a total natural antioxidant that contains tomato lycopene, tocopherol, β-carotene, phytoene, fetofluene, tomato oil, phospholipids, and other important bioactive phytochemicals naturally present in tomato oleoresin. It is available as a drug formulation under the name Lyc-O-Mato® (LycoRed, Israel).

  Lycopene has been shown to provide eye protection and intrinsic protection of UV-induced skin damage when administered orally. Several studies have shown that cataract suppressive effects of dietary lycopene in animals (Pollack et al.). Lycopene prevents galactose-induced morphological changes in cultured human lens cells, suggesting its use as a cataract suppressant (Mohanty, I. et al.). Without wishing to be bound by theory, lycopene has a protective effect against lutein and zeaxanthin.

Lutein and zeaxanthin Lutein and its stereoisomer, zeaxanthin, belong to the xanthophyl family of carotenoids, are the only two known carotenoids that accumulate specifically from plasma and deposit in the lens and the macula. The macular pigment functions as a filter to protect photosensitive photoreceptor cells that contain lutein and zeaxanthin and are also known to scavenge reactive oxygen species (ROS). Dietary intake of these carotenoids results in increased macular pigment and improves vision in patients with AMD and other eye diseases (reviewed in Alves-Rodrigues and Shao papers).

  Green leafy vegetables are the best dietary source of lutein, and spinach, kale and parsley have high concentrations. Purified crystalline lutein is classified as safe (GRAS) and is generally recognized and can be added to food and beverages. Pure lutein can also be isolated from certain plants. For example, US Pat. No. 5,382,714 describes a method for isolating, purifying, and recrystallizing lutein from saponified marigold oleoresin, and US Pat. No. 5,648,564 describes edible xanthophylls from plants. The method of crystal formation, isolation and purification is described, and lutein is the preferred product.

  Seddon reported the most important direct relationship between carotenoid intake and AMD risk (Seddon et al., 1994). Lutein and zeaxanthin were most strongly associated with reduced AMD risk. Oral administration of 6% wt / wt per day was found to reduce the risk of disease by 57%.

Carnosic acid, phytoene and phytofluene Carnosic acid is an antioxidant extracted from rosemary (Rose marinus sp.) And other herbs, and it has been shown to synergistically inhibit LDL oxidation in combination with lycopene. It was. Phytoene and phytofluene are carotenoids found in tomatoes and can be found in tomato oleoresin.

Phase II enzymes The biochemical mechanisms generally associated with the protective effects of fruits and vegetables, especially tomatoes, are not completely understood. In recent years, evidence has accumulated that the beneficial effects are due, at least in part, to induction of phase II detoxification enzymes (Talalay, 2000). These enzymes detoxify by converting many harmful substances into hydrophilic metabolites that can be easily excreted from the body.

Consistent induction of phase II enzymes such as NAD (P) H: quinone oxidoreductase (NQO1) and γ-glutamylcysteine synthetase (GCS) is known in the promoter or enhancer region known as the antioxidant response element (ARE). Mediated through cis-regulatory DNA sequences located in 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. Main ARE activating transcription factor Nrf2 (nuclear factor E ₂ 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 is bound by the inhibitory protein Keap1. When attacked with an inducer, it is released from Keap1 and translocates to the nucleus. Recently, some inventors of the present invention have found that in transiently transfected cancer cells, lycopene is capable of transactivating expression of a reporter gene fused to an ARE sequence (Ben Dor Et al., 2005). A mixture of two other tomato carotenoids, phytoene and phytofluene, was also effective in activating ARE. By activating this system, tomato carotenoids induce the production of phase II detoxification enzymes.

Carotenoid Formulations Certain formulations containing carotenoids are disclosed in the art. US Pat. Nos. 6,261,598 and 6,509,029 (hereinafter '598 and' 029, respectively) disclose oil-containing dispersions and emulsions or dry powders made therefrom, each containing a mixture of β-carotene, lycopene and lutein. is doing. US Patent Application Publication No. 2003/0031706 discloses carotenoid compositions containing a specific mixture of β-carotene, lycopene and lutein. The '598 and' 029 patents include oral compositions containing Lyc-O-Mato®, particularly gelatin capsules containing high concentrations of carotenoids due to the high phospholipid content and viscosity of oily dispersions The formulations taught and taught from oral compositions contain pure crystalline carotenoids.

  US Pat. No. 6,103,756 teaches an oral composition containing effective amounts of vitamins, minerals, and plant extracts. Essential ingredients include, inter alia, vitamins A, C and E, and bilberry, lutein and lycopene extracts.

  U.S. Pat. No. 6,573,299 teaches a composition for topical application to the outer eyelid containing at least one penetration enhancer and at least one alpha-hydroxy acid. Their composition that penetrates the underlying tissue through the skin improves age-related changes to the eyelids such as wrinkles and dry skin, and disorders associated with aging eyes, including diseases such as cataracts and AMD It is said that.

  U.S. Patent Application Publication No. 2003/0050283 relates to an ophthalmic composition for treating pathological retinal disorders that contains, in addition to cardiolipin, at least one negatively charged phospholipid as an essential element.

  U.S. Pat. No. 6,291,519 provides damage to mammalian eye tissue by applying to the eye a composition containing vitamin A and vitamin E in an amount effective for absorption of UV radiation, ozone destruction, or both. Methods for preventing are taught.

  U.S. Pat. No. 5,527,533 teaches a method for improving the visual acuity of an individual suffering from retinal damage or disease comprising administering a therapeutically effective amount of the carotenoid, astaxanthin found in aqueous animals. Yes. Although parenteral, oral and topical compositions are disclosed, the invention is illustrated only by parenteral and oral compositions.

  US Patent Application Publication No. 2004/0258769 teaches a composition for intraocular injection containing anecoltab acetate acetate associated with a daily dosage regimen for ophthalmic vitamins.

  There remains an unmet need in the art for compositions that are effective in preventing and treating eye diseases such as AMD, cataracts, diabetic retinopathy and glaucoma.

  The present invention relates to compositions effective for treating ocular diseases. The composition comprises a mixture of phytochemicals that produce a synergistic effect in reducing and treating eye diseases including glaucoma, cataracts, diabetic retinopathy (DR) and age-related macular degeneration (AMD) . Specifically, the composition is effective to prevent progression of dry AMD (non-angiogenic) to wet AMD (angiogenic).

  Certain carotenoids and other phytochemicals are known to be effective in reducing certain eye disease risks and can even improve visual function when taken at high concentrations. The compositions of the present invention are considerably superior to known formulations because they contain a mixture of carotenoids and plant-derived adjuvants that act synergistically to give unexpected results at low concentrations of lycopene. Provide the benefits of. Thus, the concentration of lycopene that provides a therapeutic effect is low (eg, 10 times lower) compared to the corresponding formulations that do 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 defined as percent weight (% w / w) per total weight.

  In one 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 embodiments, lutein is prepared synthetically. In other embodiments, lutein is isolated and purified from natural sources.

  The composition of the present invention further contains zeaxanthin, which is a stereoisomer of lutein. In one 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 natural sources.

  In other embodiments, zeaxanthin is included in the lutein fraction. According to these embodiments, the combined concentration of lutein and zeaxanthin ranges from about 0.035% to about 7% w / w, preferably from about 1.5% to about 2.5% w / w, and more. Preferably, the combined amount of lutein and zeaxanthin is about 2% to about 2.2% w / w.

  Lycopene is preferably provided in the composition as a natural compound. In some embodiments, lycopene is provided as an extract, for example, an extract of a tomato oleoresin such as Lyc-O-Mato®. In some embodiments, the lycopene extract further contains phytoene, phytofluene, lutein, and zeaxanthin. According to one exemplary embodiment, lycopene is present in the composition of the present invention 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 1.5% w / w is more preferred.

  Phytoene and phytofluene are provided as adjuvants in the compositions of the present invention. In an exemplary embodiment, phytoene and phytofluene are present at a concentration of about 10% of lycopene. In another exemplary embodiment, each of phytoene and phytofluene is provided at a concentration ranging from 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, with both phytoene and phytofluene 0.15 combined, corresponding to about 10% of the lycopene content. A concentration of% w / is more preferred.

  Carnosic acid or a derivative thereof (eg, carnosol, 6,7-dehydrocarnosic acid or 7-ketocarnosic acid) is also provided as an adjunct in the composition of the present invention. Carnosic acid or a derivative thereof is 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 presently preferred embodiment, the composition further comprises a tomato oleoresin.

According to one embodiment, the composition of the present invention comprises:
About 0.025% w / w to about 5% w / w lutein;
About 0.001% w / w to about 2% w / w zeaxanthin;
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 phytoene;
About 0.0025% w / w to about 1.25% w / w phytofluene,
From about 0.025% w / w to about 2.5% w / w carnosic acid or a 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 lycopene, about 2% w / w combined lutein and zeaxanthin, about 0.15 combined phytoene and phytofluene. % W / w, about 1% w / w carnosic acid or a derivative thereof, and a pharmaceutically acceptable carrier or excipient. In one embodiment, the composition further contains a tomato oleoresin.

  Optionally, additional therapeutic agents including vitamins, minerals, other carotenoids, and micronutrients can be incorporated into the compositions of the present invention.

  In some embodiments, the composition further contains a zinc source, which may be zinc oxide or a zinc salt. Any zinc salt that is compatible with the eye 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 zinc concentration of about 0.25% w / w to about 15% w / w is provided. In a preferred embodiment, a zinc concentration of about 7.5% w / w is provided, preferably in the form of zinc gluconate.

  In certain embodiments, a source of copper is provided in the compositions of the present invention. In some embodiments, cupric oxide is preferred. In some embodiments, the copper is provided at a concentration of about 0.01% w / w to about 5% w / w, preferably 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. Derivatives including the preferred vitamin provitamin are acceptable. In some preferred embodiments, vitamin A is provided as provitamin A, specifically β-carotene. In some embodiments, a combination of the above vitamins is included in the composition. Vitamin E, vitamin C and β-carotene are preferably added. Vitamin E and vitamin C can each be included in the compositions of the present invention at a concentration of about 0.25% w / w to about 25% w / w. A preferred concentration of vitamin E and vitamin C is about 12.5%. β-carotene can be included in the compositions of the present invention at a concentration of about 0.025% to 2.5% w / w. A preferred concentration of β-carotene is about 0.75% w / w.

According to some embodiments, the composition of the 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 (eg β-carotene) Vitamin C, zinc and copper, and a pharmaceutically acceptable carrier or excipient. In a preferred embodiment, the composition comprises
About 0.025% w / w to about 5% w / w lutein;
About 0.001% w / w to about 2% w / w zeaxanthin;
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 phytoene;
About 0.0025% w / w to about 1.25% w / w phytofluene,
About 0.025% w / w to about 2.5% w / w carnosic acid or a derivative thereof;
About 0.25% w / w to about 25% w / w vitamin E;
About 0.25% w / w to about 25% w / w vitamin C;
About 0.025% w / w to about 2.5% w / w of β-carotene,
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 presently preferred embodiment, the composition comprises about 1.5% w / w lycopene, combined about 2% w / w lutein and zeaxanthin, combined about 0.15% w / w phytoene. And phytofluene, about 1% w / w carnosic acid or derivatives thereof, about 12.5% w / w vitamin E, about 12.5% w / w vitamin C, about 0.75% w / w Contains β-carotene, about 7.5% w / w zinc, about 0.25% w / w copper, and a pharmaceutically acceptable carrier or excipient.

  The present invention relates to a pharmaceutical composition for oral use or for topical administration to the eye. In one embodiment, the composition is used for oral use in tablets, caplets, capsules, microcapsules, pellets, pills, powders, syrups, gels, slurries, granules, suspensions, dispersions, emulsions, solutions. , Solutions, dragees, beads, beadlets, and the like. A beadlet is a bead-shaped polysaccharide complex in which droplets containing an active substance are embedded. 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 a beadlet based on alginate, gelatin or other natural or synthetic polymer.

  The present invention also relates to a composition formulated for application to the eye. The composition can be formulated as a solution, cream, paste, ointment, emulsion, including submicron emulsions, gel, thermogel, or suspension.

  The composition can also be formulated as a dry formulation for reconstitution as a solution, dispersion, emulsion or suspension, for example as a powder, granule, microcapsule or capsule.

  In some embodiments, the composition is provided in an aqueous or non-aqueous medium and is preferably sterile (microbe free).

  In another aspect, the invention contains lutein, lycopene, phytoene, phytofluene and carnosic acid, and a pharmaceutically acceptable carrier or excipient in an amount effective to prevent, alleviate or treat eye disease. Provided is a method for the prevention, alleviation or treatment of eye diseases comprising the step of administering an effective amount of the composition. Non-limiting examples of eye diseases include AMD (both wet and dry), glaucoma, diabetic retinopathy and cataract.

  Further embodiments of the present invention and the full scope of applicability will become apparent from the detailed description given hereinafter. However, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description, the detailed description and specific examples illustrate preferred embodiments of the invention. However, it should be understood that it is provided merely as an example.

  The present invention is based on the surprising discovery that compositions containing a mixture of carotenoids and other phytochemicals are effective in treating eye diseases. While not wishing to be bound by any particular theory or mechanism, lycopene and the adjuncts carnosic acid, phytoene and phytofluene appear to act synergistically in the formulations of the present invention. This synergistic effect is still 10 times lower than the amount of lycopene in a lower amount of lycopene, for example, a formulation that does not contain carnosic acid, phytoene and phytofluene, while still achieving a beneficial therapeutic effect Enable. Lycopene in turn 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 a preferred embodiment, lycopene is provided as a natural tomato extract that can be extracted from tomato oleoresin.

In a specific embodiment, the composition of the present invention comprises
About 0.025% w / w to about 5% w / w lutein;
About 0.001% w / w to about 2% w / w zeaxanthin;
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 phytoene;
About 0.0025% w / w to about 1.25% w / w phytofluene,
From about 0.025% w / w to about 2.5% w / w carnosic acid or a 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 lycopene, about 2% w / w combined lutein and zeaxanthin, about 0.15 combined phytoene and phytofluene. % W / w, about 1% w / w carnosic acid or a derivative thereof, and a pharmaceutically acceptable carrier or excipient.

  In another presently preferred embodiment, the composition further comprises a tomato oleoresin. Tomato oleoresin can be obtained from tomato or tomato products by methods well known to those skilled in the art.

  Additional therapeutic agents can be added to the composition. Therapeutic agents include anti-inflammatory drugs, itching prevention, pain relieving drugs, antibiotics, humectants, moisturizers, 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 retinol, retinol esters, retinoic acid, and the like. Vitamin E is understood to include α-tocopherol, and isomers and racemates of α-tocopherol, and derivatives thereof (eg, tocopherol acetate). Vitamin C can be provided by itself or as a derivative of ascorbic acid. For example, ascorbyl palmitate, a fat-soluble ester, is stable and acceptable in the composition of the present invention.

  Vitamin E is present in the composition in a concentration range of about 0.25% w / w to about 25% w / w, preferably about 0.1% w / w to about 15%, more preferably about It can be included at a concentration of 12.5% w / w. While not wishing to be bound by any particular mechanism or theory, vitamin E is believed to increase lycopene stability and cellular uptake.

  Vitamin A or a derivative thereof, such as β-carotene, is present in the composition in a concentration range of about 0.025% w / w to about 2.5% w / w, preferably about 0.75% w / w. Can be included in concentration.

  Vitamin C and its derivatives including ascorbic acid are optionally included in the composition of the present invention. In certain embodiments, vitamin C is in the range of about 0.25% w / w to about 25% w / w, preferably about 0.1% to about 15%, more preferably about 12.5%. Included at a concentration of% w / w.

  Minerals can be added to the formulations of the present invention. Preferred minerals include zinc and copper, preferably added together to reduce the risk of anemia associated with zinc. Zinc in the form of zinc salt or zinc oxide is preferably included in the composition in the range of about 0.25% w / w to about 15% w / w, and about 7.5% w / w zinc Is preferred. Preferred 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 certain embodiments, the composition contains zinc gluconate. The copper source can be included in a concentration range of about 0.01% w / w to about 5% w / w. In a preferred embodiment, cupric oxide is included at a concentration of about 0.25% w / w.

According to some embodiments, the composition of the 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 (eg β-carotene) Vitamin C, zinc and copper, and a pharmaceutically acceptable carrier or excipient. In a preferred embodiment, the composition comprises
About 0.025% w / w to about 5% w / w lutein;
About 0.001% w / w to about 2% w / w zeaxanthin;
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 phytoene;
About 0.0025% w / w to about 1.25% w / w phytofluene,
About 0.025% w / w to about 2.5% w / w carnosic acid or a derivative thereof;
About 0.25% w / w to about 25% w / w vitamin E;
About 0.25% w / w to about 25% w / w vitamin C;
About 0.025% w / w to about 2.5% w / w of β-carotene,
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 presently preferred embodiment, the composition comprises about 1.5% w / w lycopene, combined about 2% w / w lutein and zeaxanthin, combined about 0.15% w / w phytoene. And phytofluene, about 1% w / w carnosic acid or derivatives thereof, about 12.5% w / w vitamin E, about 12.5% w / w vitamin C, about 0.75% w / w Contains β-carotene, about 7.5% w / w zinc, about 0.25% w / w copper, and a pharmaceutically acceptable carrier or excipient.

Mechanism of Action While not wishing to be bound by any particular mechanism and theory, lycopene in turn induces an antioxidant response element (ARE) that induces the expression of phase II detoxification enzymes. It is thought that the therapeutic effect is exhibited. These enzymes detoxify many harmful substances by converting them into hydrophilic metabolites that can be easily excreted from the body. Examples of phase II enzymes are NAD (P) H: quinone oxidoreductase (NQO1) and g-glutamylcysteine synthetase (GCS). The main ARE-activated transcription factor Nrf2 plays a central role in the induction of antioxidants and detoxified genes.

  In one non-limiting embodiment described herein for purposes of illustration and not limitation, lycopene increases the activity of ARE by forming a Keap1 adduct. This in turn can cause dissociation from Nrf2 and activation of the latter. Keap1 is a cysteine-rich cytoplasmic protein that negatively regulates Nrf2 activation. The central domain of Keap1 is the most cysteine-rich domain and is essential for cytoplasmic sequestration and inhibition of Nrf2. The dissociation of Nrf2 from Keap1 represents a regulatory step that allows Nrf2 to translocate to the nucleus and activate transcription of ARE-dependent genes. The dissociation of Nrf2 from Keap1-Nrf2 can be regulated by the redox state of these specific cysteine residues. Adducts of specific aldehydes were observed by LC-MS-MS analysis of purified human Keap1. The formation of these adducts was consistent with Nrf2 stabilization, nuclear Nrf2 translocation and ARE-dependent gene activation.

  As considered herein, lycopene and adjuvants (ie carnosic acid, phytoene and phytofluene) in the formulations of the invention act synergistically to give unexpected results at low concentrations of lycopene . Thus, the concentration of lycopene that provides a therapeutic effect is low (eg, 2-fold, 5-fold, or even 10-fold lower) compared to the corresponding formulations that do not contain these adjuvants. This provides significant advantages over known formulations.

Formulations As disclosed herein, the compositions of the present invention contain lutein, lycopene, zeaxanthin, phytoene, phytofluene and carnosic acid in combination with chemical ingredients such as physiologically suitable carriers and excipients. To do.

  A pharmaceutical composition for use in accordance with the present invention comprises one or more physiologically acceptable carriers containing excipients and auxiliaries that facilitate the processing of the active compound into a pharmaceutically usable formulation. Can be formulated by conventional methods. Carotenoids are formulated as pharmaceutical compositions in various forms, such as liquids, solids, and semi-solids, and are administered to mammalian subjects such as human patients. The pharmaceutical composition can be oral, topical, parenteral, paracranial, transmucosal, transdermal, intramuscular, intravenous, intradermal, subcutaneous, intraperitoneal, intraventricular, intracranial, or intratumoral. Administration to a subject can be by any method known to those skilled in the art.

  For oral administration, the compounds can be formulated by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Compositions include but are not limited to tablets, caplets, capsules, microcapsules, pellets, pills, powders, syrups, gels, slurries, granules, suspensions, dispersions, emulsions, solutions, solutions, dragees, beads and It can be formulated in any solid or liquid dosage form known in the art, including beadlets. Oral compositions can be formulated as immediate release formulations or as controlled or sustained release formulations that allow for prolonged release of the active ingredient (s) over a predetermined period of time.

  Suitable excipients for solid formulations include, but are not limited to, bulking agents such as sugars including lactose, sucrose, mannitol, or sorbitol; starches such as corn starch, wheat starch, rice starch, potato starch Excipients; gelatin; gum tragacanth; excipients based on cellulose such as microcrystalline cellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, methylhydroxypropylcellulose, hydroxypropylcellulose. Polymers such as polyvinylpyrrolidone (PVP) and cross-linked PVP can also be used. In addition, the composition comprises a binder (eg, gum arabic, corn starch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone), a disintegrant (eg, corn starch, potato starch, alginic acid, silicon dioxide, Croscarmellose sodium, crospovidone, guar gum, sodium starch glycolate), surfactant (eg, sodium lauryl sulfate), and lubricant (eg, stearic acid, magnesium stearate, polyethylene glycol, sodium lauryl sulfate) Can be contained.

  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, alcohol / water solutions, emulsions or suspensions, including saline and buffered media. Examples of oils include, but are not limited to, oils of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, olive oil, sunflower oil and fish liver oil.

  Preferred oral pharmaceutical compositions include capsules made from gelatin and soft sealed capsules made from gelatin and a plasticizer such as glycerol or sorbitol. In soft capsules, the active ingredients 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, capsules that exclude ingredients of animal origin are acceptable to vegetarians and vegans.

  Soft gelatin capsules and methods for their preparation are well known in the art. Non-limiting examples can be found in US Pat. 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 further relates to a composition formulated for application to the eye. The composition can be formulated as eye drops, solutions (aqueous and non-aqueous), creams, pastes, ointments, gels, emulsions, suspensions, and the like.

  For ocular administration, the compositions can be readily formulated by combining the active compound with pharmaceutically acceptable carriers well known in the art. Such carriers allow the compounds of the present invention to be formulated as solutions, gels, emulsions, thermogels, slurries, suspensions, etc., for use by the patient in the eye. 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 acceptable excipients and additives well known to those skilled in the art, such as stabilizers, solubilizers, tonicity enhancing agents, buffer substances, preservatives, thickeners, complexing agents, and other excipients Agents, as well as additional therapeutic agents, can be included in the compositions of the present invention.

  The solubilizer may be, for example, tyloxapol, fatty acid glycerol polyethylene glycol ester, fatty acid polyethylene glycol ester, polyethylene glycol, glycerol ester or a mixture of these compounds. Castor oil, for example the commercial product Cremophor® or Cremophor® RH40. Another example of a solubilizer is tyloxapol. The concentration used depends in particular on the concentration of the active ingredient. The amount added is typically sufficient to solubilize the active ingredient. For example, the concentration of the solubilizer is 0.1 to 5000 times the concentration of the active ingredient.

  Examples of buffer substances are acetate, ascorbate, borate, bicarbonate / carbonate, citrate, gluconate, lactate, phosphate, propionate and TRIS (tromethamine) buffer. . The amount of buffer substance added is, for example, that required to ensure and maintain a physiologically acceptable pH range. The pH range is typically in the range of 5-9, preferably 5.2-8.5.

The tonicity enhancing agent is selected from ionic or nonionic agents. For example, the ionic compound, for _{example, CaCl 2, KBr, KCl,} LiCl, NaI, alkali metal halide or alkaline earth metals such as NaBr or NaCl, or boric acid is included. Nonionic tonicity enhancing agents are, for example, urea, glycerol, sorbitol, mannitol, propylene glycol, or dextrose. For example, a sufficient tonicity enhancer is added to impart an osmolality of approximately 50-1000 mOsmol to the ready-to-use ophthalmic formulation.

  Examples of preservatives are quaternary ammonium salts such as benzalkonium chloride, benzoxonium chloride or polymeric quaternary ammonium salts; alkylmercury salts of thiosalicylic acid (eg thiomersal); phenylmercuric nitrate, phenylacetic acid Mercury or phenylmercuric borate; parabens such as methyl paraben or propyl paraben; alcohols such as chlorobutanol, benzyl alcohol or phenylethanol; guanidine derivatives such as chlorohexidine or polyhexamethylene biguanide; or sorbic acid. If appropriate, a sufficient amount of preservative is added to the ophthalmic composition to ensure protection against secondary contamination during use caused by microorganisms.

  The compositions of the present invention can be prepared using, for example, non-toxic excipients such as emulsifiers, wetting agents or fillers such as polyethylene glycol (PEG 200, 300, 400 and 600) or Carbowax® (Carbowax 1000, 1500). 4000, 6000, and 10,000). Other excipients that can be used if desired are listed below, but they do not limit the range of possible excipients in any way. They are complexing agents such as disodium EDTA or EDTA; antioxidants such as ascorbic acid, acetylcysteine, cysteine, sodium bisulfite, butyl-hydroxyanisole, butyl-hydroxytoluene; thiourea, thiosorbitol, dioctyl sulfosuccinate Stabilizers such as sodium or monothioglycerol; or other excipients such as lauric acid sorbitol ester, triethanolamine oleate or palmitic acid ester, for example.

  Optionally, the suspension can also contain suitable stabilizers or agents that increase the solubility of the compound to allow the preparation of concentrated solutions. For example, US Pat. No. 5,576,311, the contents of which are hereby incorporated by reference, includes a stable aqueous suspension of a drug dripped for therapeutic administration to the eye containing a suspension of the cyclodextrin type. Is taught. Other useful formulations include ophthalmic submicron emulsions, such as those disclosed in US Pat. No. 5,496,811, the contents of which are incorporated herein by reference as if fully set forth herein. Non-ophthalmic drug delivery vehicles.

  The amount and type of excipient added is in the range of about 0.0001 to about 90% by weight to suit individual requirements and generally.

  The amount of composition administered will, of course, depend on many factors, including the subject being treated, the severity of the affliction, the manner of administration, and the judgment of the prescribing physician. However, the dosage employed will generally depend on several factors including the age and sex of the patient, the precise disorder being treated, and its severity.

  Preferably, the formulation is in unit dosage form intended for oral administration. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as tablets, capsules, and powders in bottles or ampoules. The unit dosage form can also be a capsule, cachet, or tablet itself, or any suitable number of these in packaged form.

  The dosage regimen of the composition of the invention can be varied depending on the particular application and the efficacy of the active ingredient. Determination of suitable dosages is within the skill of those in the art. Conveniently, administration once a day is preferred. Alternatively, the total daily dose can be divided and administered during the day divided into twice a day, three times a day, etc. Administration twice a week, once a week, twice a month, once a month is also envisaged.

Therapeutic Use In another aspect, the invention comprises administering an effective amount of a composition comprising lutein, lycopene, phytoene, phytofluene and carnosic acid, and a pharmaceutically acceptable carrier or excipient. A method for preventing, reducing or treating an eye disease is provided. Non-limiting examples of eye diseases include AMD (both wet and dry), glaucoma, diabetic retinopathy and cataract.

  Thus, in one embodiment, the present invention comprises lutein, lycopene, phytoene, phytofluene and carnosic acid, and a pharmaceutically acceptable carrier or excipient in an amount effective to prevent, treat or reduce AMD. A method of preventing, reducing or treating AMD, comprising administering an effective amount of the composition. 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 contains lutein, lycopene, phytoene, phytofluene and carnosic acid, and a pharmaceutically acceptable carrier or excipient in an amount effective to prevent, treat or alleviate glaucoma. A method for the prevention, reduction or treatment of glaucoma comprising the step of administering an effective amount of the composition is provided.

  In another embodiment, the present invention provides lutein, lycopene, phytoene, phytofluene and carnosic acid in an amount effective to prevent, treat or alleviate diabetic retinopathy, and a pharmaceutically acceptable carrier or excipient. A method of preventing, reducing or treating diabetic retinopathy comprising the step of administering an effective amount of a composition comprising

  In another embodiment, the present invention contains lutein, lycopene, phytoene, phytofluene and carnosic acid, and a pharmaceutically acceptable carrier or excipient in an amount effective to prevent, treat or alleviate cataract. Provided is a method of preventing, reducing or treating cataract comprising the step of administering an effective amount of the composition.

  As used herein, the term “reduce” means to relieve, relieve or alleviate any symptom of the eye disease. As used herein, the term “treat” includes prophylactic treatment and palliative treatment.

  As used herein, the term “administering” refers to contacting a subject with a formulation of the invention. In one embodiment, the present invention includes administering a formulation of the present invention to a human subject.

  In order to more fully describe some embodiments of the invention, the following examples are provided. However, in no way should those examples be construed as limiting the broad scope of the invention. Those skilled in the art can readily devise many variations and modifications of the principles disclosed herein without departing from the scope of the invention.

Example 1 Oral Composition A formulation was prepared as follows.
Formulation 1:
About 6 mg lycopene (about 1.5% w / w),
About 8 mg lutein and zeaxanthin (about 2% w / w in combination),
About 0.6 mg phytoene and phytofluene (about 0.15% in combination), and about 4 mg carnosic acid (about 1% w / w).
Formulation 2:
Formulation 2 comprises all ingredients of Formulation 1, plus 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),
Contains about 50 mg vitamin E (about 12.5% w / w) and about 50 mg vitamin C (about 12.5% w / w).
Formulation 3:
Formulation 3 contains the following ingredients.

  The composition was mixed with mineral oil and / or vegetable oil and prepared as a soft gelatin capsule containing a total weight of about 400 mg.

  Alternatively, the composition was mixed with fillers and excipients and prepared as a solid oral dosage form containing a total weight of about 400 mg.

Example 2 Ophthalmic Composition Each of the above preparations 1 to 3 was mixed with an ophthalmologically acceptable carrier to prepare an ophthalmic preparation.

  While particular embodiments of the present invention have been illustrated and described, it will be clear that the invention is not limited to the embodiments described herein. Numerous modifications, changes, variations, substitutions and equivalents will be apparent to those skilled in the art without departing from the spirit and scope of the invention as described by the appended claims.

(References)

Claims (34)

  A pharmaceutical composition comprising lutein, zeaxanthin, lycopene, phytoene, phytofluene, carnosic acid, and a pharmaceutically acceptable carrier or excipient.   The composition of claim 1, wherein the lycopene is provided as a natural tomato extract.   The composition of claim 2, wherein the lycopene is extracted from a tomato oleoresin.   The lycopene, phytoene, phytofluene and carnosic acid act synergistically to achieve the therapeutic effect of lycopene at a lower concentration compared to the corresponding formulation without phytoene, phytofluene and carnosic acid. 2. The composition according to 1. About 0.025% w / w to about 5% w / w lutein;
About 0.001% w / w to about 2% w / w zeaxanthin;
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 phytoene;
About 0.0025% w / w to about 1.25% w / w phytofluene,
2. The composition of claim 1, comprising from about 0.025% w / w to about 2.5% w / w carnosic acid or a derivative thereof, and a pharmaceutically acceptable carrier or excipient. In total, about 2% w / w lutein and zeaxanthin,
About 1.5% w / w lycopene,
In total about 0.15% w / w phytoene and phytofluene,
6. The composition of claim 5, comprising about 1% w / w carnosic acid or a derivative thereof, and a pharmaceutically acceptable carrier or excipient.   The composition of claim 1 further comprising at least one mineral.   The composition according to claim 7, wherein the mineral is zinc.   9. The composition of claim 8, wherein the zinc is provided as zinc oxide.   The composition according to claim 7, wherein the mineral is copper.   The composition of claim 10, wherein the copper is provided as cupric oxide.   The composition according to claim 1, further comprising at least one vitamin.   13. The composition of claim 12, wherein the at least one vitamin is selected from the group consisting of vitamin A, vitamin C, vitamin E, derivatives thereof, and combinations thereof.   The composition of claim 1, comprising lutein, zeaxanthin, lycopene, phytoene, phytofluene, carnosic acid, β-carotene, vitamin E, vitamin C, zinc, copper, and a pharmaceutically acceptable carrier or excipient. object. About 0.025% w / w to about 5% w / w lutein;
About 0.001% w / w to about 2% w / w zeaxanthin;
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 phytoene;
About 0.0025% w / w to about 1.25% w / w phytofluene,
About 0.025% w / w to about 2.5% w / w carnosic acid or a derivative thereof;
About 0.25% w / w to about 25% w / w vitamin E;
About 0.25% w / w to about 25% w / w vitamin C;
About 0.025% to about 2.5% w / w of β-carotene,
About 0.25% w / w to about 15% w / w mg zinc;
15. The composition of claim 14, comprising from about 0.01% w / w to about 5% w / w copper and a pharmaceutically acceptable carrier or excipient. In total, about 2% w / w lutein and zeaxanthin,
About 1.5% w / w lycopene,
In total about 0.15% w / w phytoene and phytofluene,
About 1% w / w carnosic acid or a derivative thereof,
About 12.5% w / w vitamin E,
About 12.5% w / w vitamin C,
About 0.75% w / w β-carotene,
About 7.5% w / w zinc,
15. The composition of claim 14, comprising about 0.25% w / w copper and a pharmaceutically acceptable carrier or excipient.   The composition of claim 1, wherein the lycopene induces the production of a phase II enzyme.   The composition according to claim 1, further comprising a tomato oleoresin.   19. A composition according to any one of claims 1 to 18, wherein the composition is formulated for oral administration.   A form selected from the group consisting of tablets, caplets, capsules, microcapsules, pellets, pills, powders, syrups, gels, slurries, granules, suspensions, dispersions, emulsions, solutions, solutions, dragees, beads, beadlets The composition of claim 19.   21. The composition of claim 20, wherein the capsule is selected from soft gelatin capsules and hard gelatin capsules.   19. A composition according to any one of claims 1 to 18, wherein the composition is formulated for topical administration to the eye.   23. The composition of claim 22, in a form selected from the group consisting of solutions, eye drops, solutions, creams, pastes, ointments, emulsions, submicron emulsions, gels, thermogels, semi-solids, solids and suspensions.   An effective amount of a composition comprising an amount of lutein, lycopene, phytoene, phytofluene, zeaxanthin and carnosic acid, and a pharmaceutically acceptable carrier or excipient effective to prevent, reduce or treat eye disease A method for preventing, alleviating or treating an eye disease, comprising administering to a subject in need thereof.   25. The method of claim 24, wherein the formulation is administered orally.   25. The method of claim 24, wherein the formulation is administered topically to the eye.   25. The method of claim 24, wherein the eye disease is selected from the group consisting of glaucoma, cataract, diabetic retinopathy (DR) and age-related macular degeneration (AMD).   28. The method of claim 27, wherein the eye disease is dry AMD.   28. The method of claim 27, wherein the eye disease is wet AMD. About 6 mg lycopene (about 1.5% w / w),
About 8 mg lutein and zeaxanthin (about 2% w / w),
About 0.6 mg phytoene and phytofluene (about 0.15%),
About 4 mg carnosic acid (about 1% w / w),
About 50 mg of vitamin E (about 12.5% w / w),
About 50 mg of vitamin C (about 12.5% w / w),
About 3 mg β-carotene (about 0.75%),
About 30 mg of zinc (about 7.5% w / w),
A pharmaceutical composition comprising about 1 mg of copper (about 0.25% w / w) and a pharmaceutically acceptable carrier or excipient.   The composition according to claim 30, further comprising a tomato oleoresin.   31. A composition according to claim 30, in a form selected from soft gelatin capsules and hard gelatin capsules.   32. The composition of claim 30, wherein the zinc is provided as zinc oxide. 32. The composition of claim 30, wherein the copper is provided as cupric oxide.