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• • 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
  • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
  • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
• • 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
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate

Definitions

• the retina has one of the highest concentrations of omega-3 fatty acids in the body.
• the macula is an oval-shaped highly pigmented yellow spot (its Latin definition means spot or stain) roughly in the center of the retina of the human eye. It has a diameter of less than 10 mm and is often histologically defined as having two or more layers of ganglion cells.
• the macula allows us to appreciate details and perform tasks that require central vision like reading.
• Macular degeneration is a medical condition usually of older adults which results in a loss of vision in the center of the visual field (the macula) because of damage to the retina. It occurs in “dry” and "wet” forms. Macular degeneration can make it difficult or impossible to read or recognize faces, although enough peripheral vision remains to allow other activities of daily life.
• AMD age-related macular degeneration
• AMD AMD 90 percent of AMD patients and usually begins with the formation of tiny yellow deposits called drusen in the macula. Drusen usually do not cause serious loss of vision, but can cause distortion of vision. However, sometimes drusen will cause the macula to thin and break down, slowly leading to vision loss.
• the wet form of AMD occurs in about 10 percent of AMD patients. It is caused by the growth of abnormal blood vessels beneath the macula that can leak fluid and blood. The wet form of AMD typically causes significant vision problems in the affected eye and can progress very rapidly, causing permanent central vision loss. The exact cause of AMD is not known, although AMD may be hereditary. Currently, there is no effective therapy that is capable of significantly slowing the degenerative progression of macular degeneration.
• Oxidative processes have been proposed to play at least a contributing role in a steadily growing number of diseases, such as neurodegenerative disorders, cataract, and age-related macular degeneration (AMD).
• ALD age-related macular degeneration
• oxidative stress free radicals
• oxygen which is necessary for life in providing aerobic respiration, may also be toxic.
• the outer retina and, in particular, the outer segments of photoreceptors contain high concentrations of polyunsaturated fatty acids (PUFAs) in the membranes. This region is also exposed to a relatively high oxygen tension which is close to that found in arterial blood.
• PUFAs polyunsaturated fatty acids
• ROP is a disease of the eyes of prematurely born infants in which the retinal blood vessels increase in number and branch excessively, sometimes leading to bleeding or scarring. Infants who progress to a severe form of ROP are in danger of becoming permanently blind.
• diabetic retinopathy a disease in which blood vessels swell and leak fluid or grow abnormally on the surface of the retina
• AMD age-related macular degeneration
• Omega-3 fatty acids create chemical compounds known as bioactive mediators, which protect against the growth of abnormal blood vessels, a condition that characterizes some forms of retinopathy. In part, this occurs because these mediators suppress a type of inflammatory protein called tumor necrosis factor alpha (TNF-alpha). TNF-alpha is found in one type of cell, called microglia, that can be closely associated with retinal blood vessels.
• TNF-alpha tumor necrosis factor alpha
• AREDS Age-Related Eye Disease Study
• DHA docosahexaenoic acid
• AREDS 2 is a multi-center randomized trial designed to assess the effects of oral supplementation of high doses of macular xanthophylls (lutein and zeaxanthin) and/or omega -3 LCPUFAs (DHA and EPA) for the treatment of AMD and cataract.
• macular xanthophylls lutein and zeaxanthin
• omega -3 LCPUFAs DHA and EPA
• beta-carotene may be supplemented to a patient using 110 a commercially available form of beta-carotene, suggesting one such product sold by Hoffman-LaRoche under the trademark "Solatene.”
• Synthetic beta- carotene consists of one molecule called “bans beta carotene.”
• synthetic beta-carotene may cause an increased risk of lung cancer and disease of the blood vessels.
• This invention describes a method to prevent the onset or to slow down the
• DHA is a ligand for the Peroxisome Proliferator Activated Receptor gamma (PPARy), which is expressed in the retinal pigment epithelium (RPE), a pigmented cell layer that nourishes retinal visual cells and is involved in the phagocytosis of the outer segments of
• RPE retinal pigment epithelium
• PPARs Peroxisome Proliferator-activated Receptors
• PPARs are a group of nuclear receptors proteins that work as transcription factors regulating the expression of genes. PPARs are involved, among others, in lipid and glucidic metabolism and 130 accordingly to these functions synthetic agonists (thiazolidinediones and fibrates) have been marketed for years for treatment of type 2 diabetes or hypercholesterolemia.
• PPARs in general are members of a superfamily of ligand-activated transcription factors and as stated above, DHA is one of their naturally occurring ligands, 135 specifically for the subtype PPARy.
• PPARy play an important role in lipid degeneration, in regulation of reactive oxygen species and in the regulation of the chemical signal named "vascular endothelial growth factor” (VEGF). All of these molecules have been referred as related to the pathogenesis of age related macular degeneration.
• VEGF vascular endothelial growth factor
• RPE retinal pigment epithelium
• ROS reactive oxygen species
• PPARy upregulates the expression of antioxidant genes such as glutamate cysteine ligase and heme-oxidase-1.
• those antioxidants work through 165 MAPK kinase patways to curb ROS (S. Qin, A. P. McLaughlin, and G. W. De Vries,
• hypoxia increases the secretion of vascular endothelial growth factor
• VEGF vascular endothelial growth factor
• PPARy has an antagonistic relationship with VEGF, inhibiting therefore the neovascularization typical of the wet form of macular degeneration (T.Murata et al., "Peroxisome 175 proliferator-activated receptor-)/ ligands inhibit choroidal neovascularization,”/ni e5i/ ' gai/Ve Ophthalmology and Visual Science, vol. 41, no. 8, pp. 2309-2317, 2000).
• one aspect of the invention is related to high concentrates of docosahexaenoic acid (DHA) ethyl esters in order to maintain the levels of DHA in 180 the photoreceptor cells and thus improving the retinal pigment, known as rhodopsine, regeneration, preserving the ability of the retina to process images.
• DHA docosahexaenoic acid
• compositions comprising a therapeutically effective amount of zeaxanthine and docosahexaenoic acid (DHA) 185 are disclosed.
• the invention is based, in part, on the synergistic effect between docosahexaenoic acid (DHA) and carotenoids.
• Lutein and zeaxanthin belong to the xanthophyll class of carotenoids, also known as oxycarotenoids, which are natural fat-soluble yellowish pigments.
• Zeaxanthin is derived exclusively from dietary sources, such as dark green leafy vegetables 190 and oranges. Zeaxanthin is believed to rebuild the ocular pigment density of the macula, thereby protecting against radiation damage of the retina, in the same way as protects plants from solar radiation.
• Lutein and zeaxanthin are transported within the blood primarily on the surface of HDL (about 53%), but also on LDL (about 31%) and VLDL (about 16%).
• zeaxanthin and DHA appear to alter the lipoprotein profile, resulting in increase zeaxanthin concentration in the macula.
• supplemental zeaxanthin and DHA can be used to prevent or slow the progression of AMD.
• the composition should contain at least 2mg per dose.
• Table 1 presents the minimum contains in the formulation:
• Vitamin E tocopherols 0,4 mg

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• 2010
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