EP1937240A2 - Compositions pour le traitement de maladies oculaires - Google Patents

Compositions pour le traitement de maladies oculaires

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Publication number
EP1937240A2
EP1937240A2 EP06796159A EP06796159A EP1937240A2 EP 1937240 A2 EP1937240 A2 EP 1937240A2 EP 06796159 A EP06796159 A EP 06796159A EP 06796159 A EP06796159 A EP 06796159A EP 1937240 A2 EP1937240 A2 EP 1937240A2
Authority
EP
European Patent Office
Prior art keywords
composition according
lycopene
vitamin
lutein
phytoene
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP06796159A
Other languages
German (de)
English (en)
Inventor
Yoav Sharoni
Joseph Levy
Yoram Sela
Zohar Nir
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Lycored Ltd
Original Assignee
Lycored Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Lycored Ltd filed Critical Lycored Ltd
Publication of EP1937240A2 publication Critical patent/EP1937240A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/01—Hydrocarbons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/07—Retinol compounds, e.g. vitamin A
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/34—Copper; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/12—Ophthalmic agents for cataracts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to the field of ophthalmology, in particular to compositions useful in treating 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.
  • AMD age-related macular degeneration
  • AMD cataracts, diabetic retinopathy and glaucoma
  • Dry AMD accounts for about 90 percent of all cases and is sometimes referred to as atrophic, nonexudative, or drusenoid macular degeneration.
  • deposits called drusen accumulate in the retinal pigment epithelium (RPE) tissue beneath the macula. These deposits are thought to interfere with the function of photoreceptors in the macula, causing progressive degeneration of these cells.
  • Vision loss from dry AMD occurs very gradually over the course of many years. Dry AMD often progresses into wet AMD.
  • wet AMD abnormal blood vessels grow beneath the macula. These vessels leak blood and fluid into the macula, thereby damaging photoreceptor cells.
  • Wet AMD progresses rapidly and can cause severe damage to central vision. If wet AMD is diagnosed early, laser surgery can prevent extensive central vision loss by destroying the leaky blood vessels. No nonsurgical treatments are available.
  • Diabetic Retinopathy is a complication of diabetes that is caused by changes in the blood vessels of the retina. Damaged blood vessels in the retina may leak blood and grow fragile, brush-like branches and scar tissue. This can blur or distort the vision images that the retina sends to the brain. DR is a leading cause of blindness in the United States and untreated diabetics are more at risk for 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 age 65. Cataracts are a loss of the transparency of the lens of the eye causing blurred vision, glare, sensitivity to light, poor night vision, halos around lights and color distortion. About 4 million people have cataracts in the United States, and 40,000 develop cataracts each year. With the life expectancy over 76 years, the incidence 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.
  • 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 can also occur with normal or even below-normal eye pressure.
  • AREDS Age-Related Eye Disease Study
  • Dietary supplements have been shown to be effective in reducing the risk of and in treating certain eye diseases.
  • the Age-Related Eye Disease Study (AREDS) a major clinical trial performed to evaluate the effect of high oral doses of antioxidants and zinc on the progression of AMD and cataract, showed that the consumption of high levels of antioxidants and zinc reduce the risk of developing advanced AMD by about 25 percent.
  • the AREDS composition comprises vitamin A, vitamin C, vitamin E and the minerals zinc and copper. Intake of this composition was shown to be associated with side effects, including genitourinary problems, anemia, skin yellowing and an increased risk of lung cancer in smokers.
  • Lutein Antioxidant Supplement Trial (LAST) 5 evaluated the effects of orally administered lutein and lutein combined with antioxidants on atrophic (dry) AMD. Both treatments significantly improved some measures of visual function, including glare recovery, contrast sensitivity, and visual acuity. The long-term safety of dietary lutein supplementation has not yet been determined.
  • Carotenoids are naturally occurring pigments found in certain plants and algae. For example, the red color of tomatoes and yellow color of corn derive from carotenoids. Mammals are incapable of synthesizing carotenoids in situ and must obtain them through their diet. 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 anti-oxidants such as carotenoids delay the progression of eye disease, including the progression of cataracts and AMD. Carotenoids such as lycopene, the main tomato carotenoid, became the subject of more intensive investigation.
  • Lycopene is the major carotenoid present in the diet and provides the familiar red color of tomato products. More than 80% of 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 obtainable under the name Lyc-O-Mato® (LycoRed, Israel) as an all-natural antioxidant formula containing tomato lycopene, tocopherols, beta- carotene, phytoene, phytofluene, tomato oil, phospholipids, and other important bioactive phytochemicals naturally occurring in tomato oleoresin.
  • Lycopene has been shown to provide eye protection and endogenous protection of UV induced skin damage when administered orally.
  • Several studies have shown an anti- cataract effect of dietary lycopene in animals (Pollack, et al.). Lycopene prevents galactose- induced morphological changes in cultured human lens cells, suggesting its use as an anti- cataract agent (Mohanty, L, et al). Without wishing to be bound to theory, it is believed that lycopene has a protective effect on lutein and zeaxanthin.
  • Lutein and Zeaxanthin Lutein and its stereoisomer zeaxanthin belong to the xanthophyll family of carotenoids and are the only two known carotenoid specifically accumulated from plasma and deposited in the lens and macula lutea.
  • the macular pigment comprises lutein and zeaxanthin, and functions as a filter to protect the light-sensitive photoreceptor cells that are also known to scavenge reactive oxygen species (ROS). Dietary intake of these carotenoids results in 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, kale and parsley providing high levels.
  • Purified crystalline lutein has been classified generally recognized as safe (GRAS) and can be added to food and beverages. Pure lutein may also be isolated from certain plants.
  • GRAS generally recognized as safe
  • US Patent No. 5,382,714 describes a process for isolation, purification, and recrystallization of lutein from saponified marigold oleoresin
  • US Patent No. 5,648,564 teaches a process for the formation, isolation and purification of comestible xanthophyll crystals from plants, with lutein a preferred product.
  • Seddon (Seddon et al, 1994) reported the first direct relationship between carotenoid intake and AMD risk. Lutein and zeaxanthin were most strongly associated with a decreased AMD risk. An oral dose of 6% wt/wt per day was shown to translate into a 57% lower risk of disease. Carnosic Acid. Phytoene and Phytofluene
  • Carnosic acid is an antioxidant extracted from rosemary (Rosemarinus spp) and other herbs, which has been shown to inhibit LDL oxidation in a synergistic manner with lycopene.
  • Phytoene and phytofluene are carotenoids found in tomatoes, and may be found in tomato oleoresin.
  • phase II detoxification enzymes detoxify many harmful substances by converting them to hydrophilic metabolites that can be excreted readily from the body.
  • phase II enzymes such as NAD(P)H: quinone oxidoreductase (NQOl) and ⁇ -glutamylcysteine synthetase (GCS) is mediated through cis- regulatory DNA sequences located in the promoter or enhancer region, which are known as antioxidant responsive elements (ARE). 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 major ARE activating transcription factor Nrf2 (nuclear factor E 2 - related factor 2) plays a central role in the induction of antioxidant and detoxifying genes.
  • Nrf2 is located in the cytoplasm and is bound to an inhibitory protein, Keapl. Upon challenge with inducing agents, it is released from Keapl and translocates 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 capable of transactivating the expression of reporter genes fused with ARE sequences (Ben Dor et al, 2005). A mixture of two other tomato carotenoids, phytoene and phytofluene, was also effective in activation of ARE. By activating this system, tomato carotenoids induce the production of phase II detoxification enzymes. Carotenoid Formulations
  • Patent Nos. 6,261,598 and 6,509,029 disclose oil containing dispersion and an emulsion or dry powder produced therefrom, respectively, comprising a mixture of ⁇ -carotene, lycopene and lutein.
  • No. 2003/0031706 discloses carotenoid formulations comprising specific mixtures of ⁇ - carotene, lycopene and lutein.
  • the '598 and '029 patents teach away from an oral composition comprising Lyc-O-Mato ® , in particular a high concentration carotenoid- containing gelatin capsule due to the high phospholipid content and viscosity of the oily dispersion and the exemplified formulations comprise pure crystalline carotenoids.
  • US Patent 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 bilberry, lutein and lycopene extracts.
  • compositions for topical application to the outer eyelid comprising at least one permeation enhancer and at least one alpha hydroxy acid.
  • compositions which penetrate the skin and permeate the underlying tissues, are said to improve disorders associated with the aging eye including age-related changes to the eyelids such as wrinkles and dry skin and diseases such as cataracts and AMD.
  • US Patent Application Publication No. 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. That composition may further comprise at least one carotenoid.
  • US Patent 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-irradiation, destroy ozone, or both.
  • US Patent No. 5,527,533 teaches a method of improving the vision of an individual suffering from retinal damage or disease, comprising administering a therapeutically effective amount of astaxanthin, a carotenoid found in aquatic animals.
  • Parenteral, oral and topical compositions are disclosed, however the invention is exemplified only by parenteral and oral compositions.
  • compositions for intraocular injection comprising anecortave acetate in conjunction with a daily regimen of ocular vitamins.
  • compositions that are effective in preventing and treating eye diseases such as AMD, cataract, diabetic retinopathy and glaucoma.
  • the present invention relates to compositions effective in treating eye diseases.
  • the compositions comprise a mixture of phytochemicals, which produce a synergistic effect in attenuating and treating eye diseases including glaucoma, cataracts, diabetic retinopathy (DR) and age-related macular degeneration (AMD).
  • DR diabetic retinopathy
  • AMD age-related macular degeneration
  • the compositions are effective in preventing the progression of dry AMD (non-neovascular) to wet AMD (neo vascular).
  • compositions of the present invention offer a significant advantage over known formulations, as they include a mixture of carotenoids and plant derived adjuvants that act synergistically and afford unexpected results at low concentrations of lycopene. As such, the concentration of lycopene which provides a therapeutic effect is lower (e.g., 10- fold lower) as compared with a corresponding formulation not containing these adjuvants.
  • the present invention provides a composition comprising lutein, zeaxanthin, lycopene, phytoene, phytofluene and carnosic acid, and a pharmaceutically acceptable carrier or excipient.
  • 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.
  • lutein is synthetically prepared. In other embodiments lutein is isolated and purified from a natural source.
  • the present composition further comprises zeaxanthin, a stereoisomer of lutein.
  • 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.
  • zeaxanthin is synthetically prepared. In other embodiments zeaxanthin is isolated and purified from a natural source.
  • zeaxanthin is contained in the lutein fraction.
  • the total concentration of lutein and zeaxanthin is about 0.035% to about 7% w/w, preferably in the range of about 1.5% to about 2.5% w/w, more preferably about 2% to about 2.2% w/w total lutein and zeaxanthin.
  • Lycopene is preferably provided in the composition as a natural compound.
  • lycopene is provided as an extract, example, as an extract of tomato oleoresin, such as Lyc-O-Mato®.
  • the lycopene extract further comprises phytoene, phytofluene, lutein and zeaxanthin.
  • lycopene is provided in the present 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 1.5% w/w is more preferred.
  • phytoene and phytofluene are provided as adjuvants in the present compositions.
  • phytoene and phytofluene are present at about 10% of the concentration of lycopene.
  • 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, corresponding to about 10% of the lycopene content, is more preferred.
  • Carnosic acid or derivatives thereof (e.g., carnosol, 6,7-dehydrocarnosic acid or 7- ketocarnosic acid) is also provided as an adjuvant in the present compositions.
  • Carnosic acid or its derivatives 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
  • the composition further comprises tomato oleoresin.
  • 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/wmg phytoene; from about 0.0025% w/w to about 1.25% w/wphytofluene; from about 0.025% w/w to about 2.5% w/w carnosic acid or derivative thereof; and a pharmaceutically acceptable carrier or excipient.
  • the composition of the present invention comprises; about 1.5% w/w lycopene; about 2% w/w total of lutein and zeaxanthin, about
  • composition further comprises tomato oleoresin.
  • compositions of the present invention can optionally be incorporated in the compositions of the present invention.
  • the composition further comprises a source of zinc, which can be zinc oxide or a zinc salt.
  • a source of zinc which can be zinc oxide or a zinc salt.
  • Any zinc salt that is compatible with the eye is acceptable.
  • 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.
  • a concentration of about 0.25% to about 15% w/w zinc is provided.
  • a concentration of about 7.5% w/w zinc is provided; preferably in the form of zinc gluconate.
  • a source of copper is provided in the present composition.
  • cupric oxide is preferred.
  • a 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.
  • the vitamins can be provided as natural or synthetically produced compounds. Derivatives, including provitamins of the preferred vitamins are acceptable.
  • vitamin A is provided as provitamin A, specifically ⁇ -carotene.
  • combinations of the above vitamins are included in the composition.
  • the addition of vitamin E, vitamin C and ⁇ -carotene is preferred.
  • Vitamin E and vitamin C can each be included in the present composition at a concentration of about 0.25% to about 25% w/w. Preferable concentrations of vitamin E and vitamin C are about 12.5%.
  • ⁇ -carotene can be included in the present composition at a concentration of about 0.025% to 2.5% w/w. Preferable concentrations of ⁇ -carotene are about 0.75% w/w.
  • 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.
  • 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/wmg phytoene; from 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 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 ⁇ -carotene; from about 0.25% w/w to about 15% w/w mg zinc; from about 0.01% w/wto about 5% w/w copper; and a pharmaceutically acceptable
  • the composition comprises: about 1.5% w/w lycopene; about 2% w/w total of lutein and zeaxanthin, about 0.15% w/w total of phytoene and phytofluene; about 1% w/wcarnosic acid or a derivative thereof; about 12.5% w/w vitamin E; about 12.5% w/w vitamin C; about 0.75% w/w ⁇ -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 pharmaceutical compositions for oral use or for topical administration to the eye.
  • the composition is formulated for oral use in a form selected from a tablet, caplet, capsule, microcapsule, pellet, pill, powder, syrup, gel, slurry, granule, suspension, dispersion, emulsion, liquid, solution, dragee, bead and beadlet and the like.
  • a beadlet is a polysaccharide complex, in the shape of a bead, in which small droplets containing the active material are embedded.
  • the composition is formulated as a soft gelatin capsule or as a hard gelatin capsule.
  • the composition is formulated as a beadlet based on alginates, gelatin or other natural or synthetic polymers.
  • the present invention also relates to a composition formulated for application to the eye.
  • the composition can be formulated as a liquid, cream, paste, ointment, emulsion including submicron emulsion, gel, thermogel, or suspension.
  • composition can also be dispensed as dry formulation, for example as powder, granules, microcapsules or capsules, for reconstitution as a liquid, dispersion, emulsion or suspension.
  • the composition is provided in an aqueous or non-aqueous medium, and is preferably sterile (microbe-free).
  • the present invention provides a method of preventing, attenuating 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 attenuate or treat the eye disease.
  • eye diseases include AMD (both wet and dry), glaucoma, diabetic retinopathy and cataract.
  • the present invention is based on the surprising discovery that a composition comprising a mixture of carotenoids and other phytochemicals is effective in treating eye diseases.
  • lycopene and the adjuvants carnosic acid, phytoene and phytofluene work synergistically in the formulations of the invention.
  • This synergistic effect allows for the inclusion of lower amounts of lycopene e.g., 10 times lower than the amount of lycopene in known formulations, i.e., formulations which do not contain carnosic acid, phytoene and phytofluene, while still achieving a beneficial therapeutic effect.
  • Lycopene in turn, has a protective effect on lutein and zeaxanthin.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising lutein, zeaxanthin, lycopene, phytoene, phytofluene, carnosic acid; and a pharmaceutically acceptable carrier or excipient.
  • lycopene is provided as a natural tomato extract, which can be extracted from tomato oleoresin.
  • 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/wmg phytoene; from 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 derivative thereof; and a pharmaceutically acceptable carrier or excipient.
  • the composition of the present invention comprises; about 1.5% w/w lycopene; about 2% w/w total of lutein and zeaxanthin, about 0.15% w/w total of phytoene and phytofluene; about 1% w/w carnosic acid or a derivative thereof; and a pharmaceutically acceptable carrier or excipient.
  • the composition further comprises tomato oleoresin.
  • the tomato oleoresin can be obtained from tomato or tomato products in accordance with methods well known to a person of skill in the art.
  • Therapeutic agents include anti-inflammatory, antipruritic, pain relievers, antibiotics, wetting agents, moisturizing agents, vitamins, minerals, micronutrients and other phytochemicals, including carotenoids.
  • vitamins include vitamin A, vitamin C and vitamin E, and derivatives thereof.
  • the vitamins may be provided as natural or synthetically produced compounds.
  • vitamin A is provided as provitamin A, specifically as ⁇ -carotene.
  • Other acceptable forms of vitamin A include retinal, esters of retinol, retinoic acid, and the like.
  • Vitamin E is meant to include ⁇ -tocopherol and isomers and racemates of ⁇ -tocopherol and derivatives thereof (e.g., 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 the present compositions.
  • Vitamin E can be included in the composition at a concentration range of about
  • vitamin E increases the stability and cellular uptake of lycopene.
  • Vitamin A or derivatives thereof, for example ⁇ -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.
  • 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 about 12.5% w/w.
  • 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 a 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 zinc.
  • 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.
  • the composition comprises zinc gluconate.
  • a source of copper can be included at a concentration range of about 0.01% w/w to about 5% w/w.
  • cupric oxide is included at a concentration of about 0.25% w/w.
  • 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.
  • 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/wmg phytoene; from 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 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 ⁇ -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
  • the composition comprises: about 1.5% w/w lycopene; about 2% w/w total of lutein and zeaxanthin, about 0.15% w/w total of phytoene and phytofluene; about 1% w/wcarnosic acid or a derivative thereof; about 12.5% w/w vitamin E; about 12.5% w/w vitamin C; about 0.75% w/w ⁇ -carotene; about 7.5% w/w zinc; about 0.25% w/w copper; and a pharmaceutically acceptable carrier or excipient.
  • ARE antioxidant response element
  • phase II detoxification enzymes detoxify many harmful substances by converting them into hydrophilic metabolites that can be excreted readily from the body.
  • phase II enzymes are NAD(P)H:quinone oxidoreductase (NQOl) and g glutamylcysteine synthetase (GCS).
  • NAD(P)H quinone oxidoreductase
  • GCS glutamylcysteine synthetase
  • Nrf2 The major ARE-activating transcription factor Nrf2 plays a central role in the induction of antioxidant and detoxifying genes.
  • lycopene increases the activity of ARE by forming Keapl adducts. This may cause in turn its dissociation from Nrf2 and the activation of the latter.
  • Keapl is cysteine- rich cytoplasmic protein that negatively regulates the activation of Nrf2.
  • the central domain of Keapl is the most cysteine-rich domain and is required for cytoplasmic sequestration and inhibition of Nrf2.
  • Dissociation of Nrf2 from Keapl represents a regulatory step that allows Nrf2 to translocate to the nucleus and activate transcription of ARE-dependent genes.
  • Nrf2 The dissociation of Nrf2 from Keapl -Nrf2 may be regulated by the redox status of these specific cysteine residues.
  • Adducts of specific aldehydes were observed in LC-MS-MS analyses of purified human Keapl. The formation of these adducts was coincident with. Nrf2 stabilization, nuclear Nrf2 translocation and ARE dependent gene activation.
  • the lycopene and the adjuvants i.e., carnosic acid, phytoene and phytofluene
  • concentration of lycopene which provides a therapeutic effect is lower (e.g., 2 fold, 5 fold or even 10-fold lower) as compared with a corresponding formulation not containing these adjuvants. This provides a significant advantage over known formulations.
  • compositions of the present invention comprise lutein, lycopene, zeaxanthin phytoene, phytofluene and carnosic acid, in combination with chemical components such as physiologically suitable carriers and excipients.
  • Pharmaceutical compositions for use in accordance with the present invention can be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
  • the carotenoids are formulated as pharmaceutical compositions and administered to a mammalian subject, such as a human patient in a variety of forms such as liquid, solid, and semisolid.
  • compositions can be administered to a subject by any method known to a person skilled in the art, such as orally, topically, parenterally, paracancerally, transmucosally, transdermally, intramuscularly, intravenously, intradermally, subcutaneously, intraperitonealy, intraventricularly, intracranially or intratumorally.
  • the compounds can be formulated by combining the active compounds with pharmaceutically acceptable carriers known in the art.
  • compositions can be formulated in any solid or liquid dosage form known in the art, including but not limited to, tablet, caplet , capsule, microcapsule, pellet, pill, powder, syrup, gel, slurry, granule, suspension, dispersion, emulsion, liquid, solution, dragee, bead and beadlet.
  • the oral compositions can be formulated as immediate release formulations, or as controlled or sustained release formulations allowing for extended release of the active ingredient(s) over a predetermined time period.
  • 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 maize starch, wheat starch, rice starch, potato starch and the like, gelatin, gum tragacanth, cellulose based excipients as microcrystalline cellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, methylhydroxypropylcellulose, hydroxypropylcellulose and the like. Polymers such as polyvinylpyrrolidone (PVP) and cross-lined PVP can also be used.
  • the compositions may further comprise binders (e.g.
  • disintegrating agents e.g. cornstarch, potato starch, alginic acid, silicon dioxide, croscarmelose sodium, crospovidone, guar gum, sodium starch glycolate
  • surfactants e.g. sodium lauryl sulfate
  • lubricants e.g. stearic acid, magnesium stearate, polyethylene glycol, sodium
  • pharmaceutically acceptable carriers may be aqueous or non-aqueous solutions, suspensions, emulsions or oils.
  • 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 buffered media.
  • oils include but are not limited to petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, mineral oil, olive oil, sunflower oil, and fish-liver oil.
  • Preferred oral pharmaceutical compositions include capsules made of gelatin as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added.
  • the capsules exclude components of animal origin and are acceptable for vegetarians and vegans.
  • Soft gelatin capsules and methods of preparing them are known in the art. Non- limiting examples can be found in US Patent Nos. 6,217,902; 6,258,380; 5,916,591, and 4,891,229, all of which are incorporated herein by reference.
  • the present invention further relates to a composition formulated for application to the eye.
  • the composition can be formulated as drops, solution (aqueous and non-aqueous), cream, paste, ointment, gel, emulsions, suspension, and the like
  • the composition can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the compounds of the invention to be formulated as liquids, gels, emulsions, thermogels, slurries, suspensions, and the like, for ophthalmic use by a patient.
  • the composition can be formulated as a solid, for resuspension.
  • pharmaceutical compositions for ophthalmic administration include aqueous solutions of the active ingredients in water-soluble form.
  • compositions of the present invention may be included in the compositions of the present invention, for example stabilizers, solubilizers, tonicity enhancing agents, buffer substances, preservatives, thickeners, complexing agents and other excipients, as well as additional therapeutic agents.
  • a solubilizer can be for example, tyloxapol, fatty acid glycerol polyethylene glycol esters, fatty acid polyethylene glycol esters, polyethylene glycols, glycerol ethers or mixtures of those compounds.
  • a specific example of a solubilizer well tolerated by the eye 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 amount added is typically sufficient to solubilize the active ingredient.
  • the concentration of the solubilizer is from 0.1 to 5000 times the concentration of the active ingredient.
  • buffer substances are acetate, ascorbate, borate, hydrogen carbonate/carbonate, citrate, gluconate, lactate, phosphate, propionate and TRIS (tromethamine) buffers.
  • the amount of buffer substance added is, for example, that necessary to ensure and maintain a physiologically tolerable pH range.
  • the pH range is typically in the range of from 5 to 9, preferably from 5.2 to 8.5.
  • Tonicity enhancing agents are selected from ionic and non-ionic agents.
  • iom ' c compounds include alkali metal or alkaline earth metal halides, such as, for example, CaCl 2 KBr, KCl, LiCl, NaI, NaBr or NaCl 5 or boric acid.
  • Non-ionic tonicity enhancing agents are, for example, urea, glycerol, sorbitol, mannitol, propylene glycol, or dextrose.
  • sufficient tonicity enhancing agent is added to impart to the ready- for-use ophthalmic composition an osmolality of approximately from 50 to 1000 mOsmol.
  • preservatives examples include quaternary ammonium salts such as benzalkonium chloride, benzoxonium chloride or polymeric quaternary ammonium salts, alkyl-mercury salts of thiosalicylic acid, such as, for example, thiomersal, phenylniercuric 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, chlorohexidine or polyhexamethylene biguanide, or sorbic acid. Where appropriate, a sufficient amount of preservative is added to the ophthalmic composition to ensure protection against secondary contaminations during use caused by microbes.
  • a sufficient amount of preservative is added to the ophthalmic composition to ensure protection
  • compositions of the present invention may comprise further non-toxic excipients, such as, for example, emulsifiers, wetting agents or fillers, such as, for example, the polyethylene glycols (PEG200, 300, 400 and 600) or Carbowax ® (CarbowaxlOOO,
  • excipients that may be used if desired are listed below but they are not intended to limit in any way the scope of the possible excipients. They can be complexing agents, such as disodium-EDTA or EDTA, antioxidants, such as ascorbic acid, acetylcysteine, cysteine, sodium hydrogen sulfite, butyl-hydroxyanisole, butyl- hydroxytoluene; stabilizers, such thiourea, thiosorbitol, sodium dioctyl sulfosuccinate or monothioglycerol; or other excipients, such as, for example, lauric acid sorbitol ester,
  • Methanol amine oleate or palmitic acid ester Methanol amine oleate or palmitic acid ester.
  • the suspension may also contain suitable stabilizers or agents, which increase the solubility of the compounds, to allow for the preparation of concentrated solutions.
  • suitable stabilizers or agents which increase the solubility of the compounds, to allow for the preparation of concentrated solutions.
  • US Patent No. 5,576,311 the contents of which are incorporated by reference herein, teaches stable aqueous suspension of drugs suitable for therapeutic administration to the eye comprising cyclodextrin type-suspending agents.
  • Other useful formulations include submicron ocular emulsions, for example an ocular drug delivery vehicle as disclosed in US Patent No. 5,496,811, the contents of which are incorporated by reference as if fully set forth herein.
  • the amount and type of excipient added is in accordance with the particular requirements and is generally in the range of from approximately 0.0001 to approximately 90% by weight.
  • the amount of a composition to be 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 dose employed will generally depend on a number of factors, including the age and sex of the patient, the precise disorder being treated, and its severity.
  • the preparations are in unit dosage form, intended for oral administration.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active components.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, for example, tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can also be a capsule, cachet, or tablet itself or it can be the appropriate number of any of these in packaged form.
  • the dosing schedule of the compositions of the present invention can vary according to the particular application and the potency of the active ingredients. Determination of the proper dosage is within the skill of the art. For convenience, a single daily dose is preferred. Alternatively, the total daily dosage may be divided and administered in portions during the day such as twice daily, thrice daily and the like. Biweekly, weekly, bimonthly and monthly administration are also contemplated.
  • the present invention provides a method of preventing, attenuating 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.
  • eye diseases include AMD (both wet and dry), glaucoma, diabetic retinopathy and cataract.
  • the present invention provides a method of preventing, attenuating 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 attenuate AMD.
  • AMD includes both dry and wet AMD, as well as the transition from dry AMD to wet AMD.
  • the present invention provides a method of preventing, attenuating 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 attenuate glaucoma.
  • the present invention provides a method of preventing, attenuating 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 attenuate diabetic retinopathy.
  • the present invention provides a method of preventing, attenuating or treating cataract, 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 attenuate cataract.
  • the term “attenuating” means to soothe, calm or ease the symptoms of any of the aforementioned eye diseases.
  • the term “treating” includes preventative as well as disorder remittive treatment.
  • the term “administering” refers to bringing a subject in contact with the formulation of the present invention.
  • the present invention encompasses administering the formulations of the present invention to a human subject.
  • Example 1 Oral Compositions
  • Preparation 1 about 6 mg lycopene (about 1.5% w/w); about 8 mg lutein and zeaxanthin (combined - about 2% w/w); about 0.6 mg of phytoene and phytofluene (combined - about 0.15%); and about 4 mg carnosic acid (about 1% w/w).
  • Preparation 2 contains all of the ingredients of preparation 1 and in addition: about 3 mg ⁇ -carotene (about 0.75%); about 30 mg zinc (about 7.5% w/w); about 1 mg copper (about 0.25% w/w); about 50mg vitamin E (about 12.5% w/w); and about 50 mg vitamin C (about 12.5% w/w).
  • Preparation 3 comprises the following ingredients
  • compositions are mixed with mineral oil and or vegetable oil and are prepared as soft gelatin capsules containing about 400 mg total weight.
  • compositions are admixed with fillers and excipients and are prepared as solid oral dosage forms containing about 400 mg total weight.

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Abstract

L'invention concerne des compositions pharmaceutiques qui comprennent un mélange de caroténoïdes et d'adjuvants offrant un potentiel synergique thérapeutique. Les compositions de l'invention, qui peuvent être administrées par voie orale ou topique dans l'oeil, permettent de prévenir, d'atténuer ou de traiter des maladies oculaires de type dégénérescence maculaire liée à l'âge (DMLA), glaucome, rétinopathie diabétique et cataractes.
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UA103340C2 (ru) * 2008-11-03 2013-10-10 ДЖУЛИАНИ С.п.А. Терапевтическое, диетологическое или косметическое применение соединений со специфическим антиапоптозным дейсвием на каспазу-3 и композиция, которая содержит эти соединения
CN102355894B (zh) * 2009-01-19 2016-06-15 利科雷德有限公司 类胡萝卜素和多酚的协同组合
WO2011076869A1 (fr) * 2009-12-22 2011-06-30 Aakerlund Hans-Erik Matériau isolé de plante verte
JP2011256118A (ja) * 2010-06-07 2011-12-22 Kao Corp Ｉｌ−８及びｇｍ−ｃｓｆ発現抑制剤
US20140065196A1 (en) * 2010-10-04 2014-03-06 Cupron, Inc. Cosmetic skin care compositions
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CN103798808A (zh) * 2012-11-15 2014-05-21 中国科学院大连化学物理研究所 一种营养素配方及在缓解视疲劳的食品或药物中的应用
CA2992879C (fr) 2014-08-11 2022-10-25 Board Of Supervisors Of Louisiana State University And Agriculatural And Mechanical College Administration d'antioxydants bioactifs nano-encapsules
AU2015351930B2 (en) * 2014-11-25 2021-08-12 Lycored Ltd. Biologically-active tomato composition having reduced amount of lycopene
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