WO2009098186A1 - Organic compounds - Google Patents

Organic compounds Download PDF

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Publication number
WO2009098186A1
WO2009098186A1 PCT/EP2009/051163 EP2009051163W WO2009098186A1 WO 2009098186 A1 WO2009098186 A1 WO 2009098186A1 EP 2009051163 W EP2009051163 W EP 2009051163W WO 2009098186 A1 WO2009098186 A1 WO 2009098186A1
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Prior art keywords
copper
omega
composition
vitamin
composition according
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PCT/EP2009/051163
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French (fr)
Inventor
Georg Ludwig Kis
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Novartis Ag
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Publication of WO2009098186A1 publication Critical patent/WO2009098186A1/en

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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
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/115—Fatty acids or derivatives thereof; Fats or oils
    • A23L33/12—Fatty acids or derivatives thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/15—Vitamins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/16—Inorganic salts, minerals or trace elements
    • 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
    • A61K31/28—Compounds containing heavy metals
    • A61K31/30—Copper compounds
    • 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
    • A61K31/28—Compounds containing heavy metals
    • A61K31/315—Zinc compounds
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the present invention relates to a nutritional or dietary supplement composition that strengthens and promotes retinal health through the prevention, stabilization, reversal and/or treatment of visual acuity loss in people with certain ocular diseases. More specifically, the present invention relates to an antioxidant and lutein supplement composition that decreases visual acuity loss by reducing the risk of developing late stage or advanced age- related macular degeneration in people with early age-related macular degeneration.
  • Another object of the present invention is to provide a safe nutritional or dietary supplement composition for the prevention, stabilization, reversal and/or treatment of macular degeneration and/or visual acuity loss, in particular in accordance to all specified examples and claims of the present disclosure.
  • Another object of the present invention is to provide an effective and safe method of preventing, stabilizing, reversing and/or treating macular degeneration and/or visual acuity loss.
  • Another object of the present invention is to provide a method of manufacturing a safe nutritional or dietary supplement composition for the prevention, stabilization, reversal and/or treatment of macular degeneration and/or visual acuity loss.
  • the preferred nutritional or dietary supplement composition of the present invention is a formulation of essential ingredients preferably in quantities set forth below, e.g. in Table 1 and/or , to be ingested daily.
  • Table 1 The preferred nutritional or dietary supplement composition of the present invention is a formulation of essential ingredients preferably in quantities set forth below, e.g. in Table 1 and/or , to be ingested daily.
  • composition e.g. in the form of a capsule or capsules (up to 4 capsules a day), contains in a preferred embodiment the following ingredients:
  • Ingredients Amount 500 mg Calcium ascorbate dihydrate, USP Vitamin E 400 IU Alpha tocopheryl acetate, USP Zinc 35 mg Zinc oxide Copper 1.2 mg Copper oxide, Copper sulfate, Copper gluconate or Copper carbonate (Copper being present in the shell and/or in the fill)
  • DHA Docosahexaeonic acid
  • EPA Eicosapentaenoic acid
  • the copper salt e.g. Copper sulfate, Copper gluconate or Copper carbonate
  • the shell of a capsule which contains the below ingredients.
  • the excipients for making such shell are for example:
  • the preferred daily dosage of the subject composition as specified above may be administered in the form of one or more dosage units, e.g. capsules, dragees, or the like, preferably capsules. Most preferably the daily dosage of the subject composition is provided in the form of one dosage unit taken four times daily, for a total of 4 dosage units a day, or in the form of one dosage unit taken three times daily, for a total of 3 dosage units a day, or in the form of one dosage unit taken twice daily, for a total of 2 dosage units a day. Compared to taking the total daily dose once a day, twice, three or four times daily dosing in one or more dosage units per dose provides improved absorption and better maintenance of blood levels of the essential ingredients.
  • compositions e.g. capsules of the preferred formulation of the subject composition may contain larger or smaller quantities of essential ingredients per capsule than the minimum quantities per capsule specified above.
  • essential ingredients Larger quantities of essential ingredients, to compensate for some degradation which may occur over time. This aspect is common if the essential ingredient is an antioxidant, e.g. vitamin C, E, or lutein. Smaller quantities of essential ingredients, for example, to take into account the food intake situation of a patient / animal.
  • an antioxidant e.g. vitamin C, E, or lutein.
  • metal salts e.g. zinc, copper salts
  • the metal salts are typically not subject to degradation, therefore typically no larger quantities than those listed are present.
  • the listed quantities of ingredients as contained in a composition of the present invention may typically range from 5 % below the indicated quantities of each ingredient up to 5% above the indicated quantities of each ingredient. Therefore, an addressed concentration may encompass +/- 5% by weight of an addressed and listed ingredient, unless designated differently.
  • 400 IU vitamin E may for example encompass a range from 380 to 420 mg vitamin E.
  • the full amount of the ingredient amount specified on the capsule sale label is provided upon oral administration of the capsule through to the specified expiration date of the capsule.
  • Another consideration in formulating the subject composition is that depending on the source and/or manufacturing process of the individual ingredients, individual ingredient degradation rates may vary. Accordingly, the specific formulation of the subject composition will vary depending on the sources of the individual ingredients and the specified length of product shelf life before expiration. Typically, the product shelf life for nutritional or dietary supplements is approximately two to three years. Capsule formulations may also vary somewhat depending on slight deviations from - A -
  • Variations contemplated in administering the subject composition to humans or animals include, but are not limited to, providing time-release capsules or capsules manufactured to be administered as a single dose or as other multiple part dosages. Additionally, alternative avenues of administration besides oral administration are contemplated herein such as for example, but not limited to, intraperitoneal, intravenous, subcutaneous, sublingual, transcutaneous, intramuscular or like forms of administration.
  • the preferred route of administration is the oral route.
  • tablet, capsule, dragee, pellet, suppository, formulation are interchangeably used unless specified differently.
  • tablet, capsule, dragee, pellet, suppository, formulation pertains especially to all the components contained in one respective dosage unit or galenic unit or piece, which are comprised in a composition of the present invention.
  • ingredients comprised in a composition of the present invention are now described with their contemplated function. Moreover the quantitative amount and the quality required is described, in particular if deemed important.
  • Vitamin C is a well known water-soluble antioxidant. Humans depend on external sources of vitamin C to meet their vitamin C requirements. Vitamin C in the form of ascorbate is found in the aqueous humor of human eyes.
  • Vitamin C typically protects the retina against the side effects of light.
  • the subject composition provides a daily dose of preferably 500 mg of vitamin C or ascorbic acid.
  • vitamin C is equal to ascorbic acid and vice versa.
  • Calcium ascorbate is the preferred source of vitamin C in a capsule, although other sources such as for example free ascorbic acid or sodium ascorbate could alternatively be used.
  • a pharmaceutical composition of the present invention contains 500 mg calcium ascorbate. Typically, about 30% overages are included in a composition of the present invention to compensate for degradation.
  • composition of the present invention contains 605.2 mg calcium ascorbate dihydrate
  • a total daily dosage vitamin C is typically present in an amount of from 400 to 600 mg, more preferably from 450 to 550 mg, also preferably from 470 to 530 mg, and even more preferably from 480 to 520 mg.
  • Vitamin E is also a well-known antioxidant. Vitamin E can work synergistically with vitamin C in protecting vital cell function from normal oxidants.
  • the DHA (docosahexanoic acid) supplementation of the present invention requires supplementation in Vitamin E that plays a protective role on the membranous lipids.
  • Vitamin E is a relatively non-toxic fat-soluble vitamin. Vitamin E is readily oxidized thereby significantly reducing its activity during periods of storage prior to ingestion. Once ingested, vitamin E is stored within the body and can contribute to the total body pool of vitamin E for up to one year.
  • the subject composition provides approximately 400 IU of vitamin E per capsule.
  • d,l-alpha tocopheryl acetate stands for vitamin E and is the preferred source of vitamin E in the subject capsules although other sources of vitamin E, such as for example d,l-alpha tocopheryl acetate and/or vitamin E succinate, may be used in the alternative.
  • 1.0 mg of vitamin E is equal to 1 IU of d,l-alpha tocopheryl acetate.
  • 1 mg d- alpha tocopheryl acetate corresponds to 1.5 IU d,l-alpha tocopheryl acetate.
  • a pharmaceutical composition of the present invention contains approximately 439 mg d,l-alpha tocopheryl acetate, which amount typically includes 10% overages for degradation.
  • a total daily dosage vitamin E is typically present in an amount of from 350 to 450 IU, especially from 380 to 420 IU, and in particular from 390 to 410 IU.
  • Zinc is important in maintaining the health of an eye's retina and is an essential part of more than 100 enzymes involved in digestion, metabolism, reproduction and wound healing.
  • the RDA for zinc is approximately 40 mg.
  • Zinc plays a role as a cofactor for enzymes that directly participates in oxidant defense.
  • Zinc concentrations in the retina and choroid are among the highest in the body.
  • the subject composition provides approximately 35 mg zinc per capsule.
  • Zinc is preferred in the form of zinc oxide in subject capsules due to the fact zinc oxide provides the most concentrated form for elemental zinc and is well tolerated in the digestive system.
  • other forms of zinc such as for example zinc gluconate, zinc citrate, zinc acetate, zinc chloride, zinc lactate, or zinc sulfate may alternatively be used or be used in combination with zinc oxide in the subject composition.
  • zinc refers to a zinc salt, and more preferably to zinc oxide, zinc chloride or zinc gluconate, most preferably to zinc gluconate.
  • a pharmaceutical composition of the present invention contains 43.6 mg zinc gluconate.
  • a total daily dosage zinc is typically present in an amount of from 20 to 42 mg, more preferably from 30 to 41 mg, especially preferred from 34 to 41 mg and in particular from 37 to 40 mg.
  • Copper like zinc, is another important cofactor for metalloenzymes, and is a second necessary cofactor for superoxide bismuthase.
  • the total daily dosage of copper is typically approximately 1.2 mg.
  • the daily dosage composition according to the invention comprises Copper.
  • Copper or a copper salt are used interchangeably and pertain preferably Cu 2+ but may also include Cu + .
  • a copper salt comprises preferably a pharmaceutically acceptable anion such as chloride, oxide, hydroxide, gluconate, carbonate, sulfate or the like.
  • copper is typically present in an amount of from 0.4 to 1.6 mg, more preferably from 0.6 to 1.4 mg, and in particular from 0.8 to 1.35 mg, particularly preferred 1.2 mg.
  • copper typically no overages are required, since copper is not subject to degradation.
  • Omega-3-fatty acids and a number of vitamins and other pharmaceutically effective compounds or compositions can be susceptible to decomposition when in contact with copper salts.
  • This decomposition is primarily a problem during storage of such compounds and / or compositions and in particular when water is present. Said presence of water applies also to minute amounts of water, such as humidity per se, traces of water in one of the components of a composition and/or of a compound, or from environmental humidity.
  • the copper salt is provided with a proper masking or coating.
  • This masking or coating typically suppresses an interaction with said copper sensitive compound and/or composition.
  • the copper salt is for example masked or coated with - or embedded in - gelatin or liposomes and/or both such as for example a coated copper salt is embedded in gelatin.
  • There are other ways of protecting copper salts e.g. by encapsulating it with mono- and di-glycerides, as for example known from the product Descote® which is commercially available.
  • Copper salts can form a stable complex with an appropriate cyclodextrin compound, which would typically release its free copper salt at a later stage, e.g. when deemed required e.g. upon enzymatic resolution of the complex in the gut.
  • Copper salts might be coated with a zwitterionic phospholipid including but not limited to phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, spingomyelin and other ceramides, as well as various other zwitterionic phospholipids.
  • a zwitterionic phospholipid including but not limited to phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, spingomyelin and other ceramides, as well as various other zwitterionic phospholipids.
  • the term masked, coated or embedded copper or copper salt pertains to a copper salt and a masking, coating or embedding agent, which effectively prevents a direct interaction of said copper salt with said copper sensitive compound and/or composition.
  • a digestible capsule material is for example the shell material described in the above Table 2, but is in general any capsule or capsule shell or shell material being used in the state-of-the-art for pharmaceutical / dietary / nutraceutical capsules, typically being organic polymeric compositions and typically being pharmaceutically compatible (non-toxic, bio-degradable, digestible in the gut or stomach as deemed suitable).
  • a digestible capsule material in particular a gastrointestinal tract digestible capsule material, containing a masked and/or coated copper salt represent said masking and/or coating material for said copper salt.
  • Another preferred embodiment is to a digestible capsule material as defined in the previous paragraph, wherein said copper salt is already coated with a coating, and said coating might be the same or another masking material than said capsule material;
  • copper in the form of cupric oxide is preferred in the present compositions, although other forms of copper such as for example copper carbonate, copper gluconate or copper sulfate may alternatively be used or used in combination with copper oxide in the subject composition.
  • copper in the form of copper sulfate, copper gluconate and/or copper carbonate is preferred in the present compositions, although other forms of copper such as copper oxide may alternatively be used or used in combination with copper sulfate, copper gluconate and/or copper carbonate in the subject composition.
  • a pharmaceutical composition of the present invention contains 4.7 mg Copper sulfate (in the shell) 8.58 mg Copper gluconate (in the shell), 2.14 mg Copper carbonate (in the shell) or 1.5 mg copper oxide (in the fill).
  • Lutein is a carotenoid. Lutein is also an antioxidant found in the retina of healthy eyes.
  • Lutein and zeaxanthine are xanthophylls , belonging to the group of carotenoids.
  • Lutein and zeaxanthine are pigments found in retina; mostly in the macula area , where they play a filter role from blue light and probably an anti oxidant role. These pigments are not synthesized in vivo , thus an external (food) supplementation is required for the macular pigment composition.
  • Lutein is the precursor of zeaxanthin. Epidemiologic studies suggests that lutein consumption might be inversely related to eye diseases such as AMD . Studies in human show that lutein supplementation results in increased macular pigment.
  • the subject composition preferably provides preferably 10 mg of pure lutein per capsule.
  • Lutein in the form of pure Flora GIo (supplier DSM or Kemin) is preferably used.
  • This source provides crystalline lutein and zeaxanthin, from marigold oleoresins extracted from marigold flowers (tagetes).
  • Lutein, zeaxanthin and other caroteno ⁇ ds represent, according to their label, 80 % of the weight of the raw material called "FloraGLO crystalline Lutein". This is taken into account when provided in a composition of the present invention.
  • a pharmaceutical composition of the present invention contains 55 mg lutein (20% in safflower oil), which amount includes 10% overages for degradation.
  • an addressed composition contains approximately from 1 to 20 mg, more preferably from 3 to 17 mg, and even more preferably from 7 to 14 mg lutein per day.
  • Zeaxanthin like lutein is a carotenoid. Zeaxanthin is also an antioxidant found in the retina of healthy eyes. Preferably a total daily dosage may range from approximately from 100 to
  • a total daily dosage range from approximately from 1.7 to 2.3 mg.
  • a pharmaceutical composition of the present invention contains 2000 microgram zeaxanthin.
  • Fatty acids from the omega 3 group are mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).
  • Other omega 3 fatty acid are alpha-linolenic acid (ALA), stearidonic acid (SA), eicosatetraenoic acid (ETA) and docosapentaenoic acid (DPA)
  • ALA alpha-linolenic acid
  • SA stearidonic acid
  • ETA eicosatetraenoic acid
  • DPA docosapentaenoic acid
  • the protective role of DHA towards AMD may emerge from different mechanisms such as improving the rhodopsine (retinal pigment) regeneration at the pair pigmentary epithelium - photoreceptor level and/or may play a role in the setting up of a lipid background that would improve the rhodopsine activity.
  • omega 3 fatty acids are docohexaenoic acid and eicosapentaenoic acid.
  • the daily dosage of omega-3 fatty acids is approximately 1200 mg/day.
  • DHA DHA
  • EPA EPA is described as the physiologic precursor of DHA.
  • the preferred source for omega-3 fatty acids is fish oil.
  • the source of the fish oil may have an influence on the content of DHA and EPA.
  • the DHA : EPA ratio can range from 1 : 4; 1 :
  • the subject composition provides approximately from 1000 to 1800 mg, more preferably from 1050 to 1350 mg, more especially preferably 1100 to 1300 mg, and in particular from 1150 to 1250 omega-3 fatty acids per day.
  • Omega 3 fatty acids according to the present invention can be in the form of triglycerides, in the form or ethyl esters or in the form of methyl esters (supplier EPAX,
  • Preferred omega-3 fatty acids are in the form of triglycerides, e.g. commercialized by EPAX under the names EPAX 6000 TG or EPAX 1050 TG.
  • Free radicals initiate local molecular instability leading to cellular damage. Formation of free radicals is caused by metabolism, sunlight (blue-light spectrum), other free radicals, lack of antioxidants, and other factors. This process may lead to deteriorating vision due to age- related macular degeneration (AMD) and/or diabetic retinopathy (DR). Antioxidant supplementation with certain nutrients may counteract the chain reaction of free radical damage by neutralizing the electron imbalance. Replenishing the antioxidant potential of the retina may effectively decrease oxidant stress and slow or decrease retinal deterioration. There is a strong scientific evidence that the ingredients of the present invention provide help to patients with AMD, i.e. reduced risk of developing advanced AMD and reduced risk of vision loss.
  • AMD age-related macular degeneration
  • DR diabetic retinopathy
  • the formulation of the present invention may not only treat but also prevent retinal degeneration.
  • Another advantage of this invention is the use of a combination of omega 3 fatty acids with specific, more stable vitamin molecules and also specific, more stable zinc and copper containing molecules.
  • antioxidant vitamins Vit. C and E
  • minerals Zn and/or Cu
  • Lutein and/or Zeaxanthin are believed to rebuild the ocular pigment density of the macula, thereby providing protection against radiation damage of the retina.
  • Omega 3 fatty acids containing high amounts of docosahexaeonic acid (DHA) and eicosapentaeonic acid (EPA) are contemplated of triggering / maintaining the levels of DHA in the photoreceptor cells protecting the ability of the eye to translate light impulses into nervous inputs for the brain (retina's ability to process images). They might also protect the photoreceptor cells from cell death.
  • EPA is contemplated of inhibiting COX1 and COX2 activity which may control / reduce inflammatory events in the eye.
  • compositions of the present invention typically exhibit highly improved stability, which improved stability ensures an better treatment procedure since stable formulations provide reproducible treatments.
  • the compounds containing metal ions are typically selected such that they are not water soluble, since water soluble metal compounds are typically responsible for the decomposition of the other active ingredients, especially the vitamins.
  • compositions, capsules, formulations or capsules of the present invention are prepared in a manner known per se, for example by means of conventional mixing, granulating, coating, dissolving or lyophilizing processes.
  • compositions may be sterilized, e.g. batch-wise, ingredients-wise as deemed appropriate and/or may comprise excipients, for example stabilizers, coloring agents, firming agents, wetting agents and/or emulsifiers, solubilizers, salts for regulating osmotic pressure ' and/or buffers and are prepared in a manner known perse, for example by means of conventional dissolving and lyophilizing processes.
  • excipients for example stabilizers, coloring agents, firming agents, wetting agents and/or emulsifiers, solubilizers, salts for regulating osmotic pressure ' and/or buffers and are prepared in a manner known perse, for example by means of conventional dissolving and lyophilizing processes.
  • the said solutions or suspensions may comprise viscosity-increasing agents, typically sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone, or gelatins, or also solubilizers, for example Tween 80 [polyoxyethylene(20)sorbitan mono-oleate; trademark of ICI Americas, Inc, USA].
  • viscosity-increasing agents typically sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone, or gelatins, or also solubilizers, for example Tween 80 [polyoxyethylene(20)sorbitan mono-oleate; trademark of ICI Americas, Inc, USA].
  • Suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations, and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and also binders, such as starches, for example corn, wheat, rice or potato starch, methylcellulose, hydroxypropyl methyl- cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone, and/or, if desired, disintegrators, such as the above-mentioned starches, also carboxymethyl starch, cross- linked polyvinylpyrrolidone, alginic acid or a salt thereof, such as sodium alginate.
  • Additional excipients are especially flow conditioners and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol, or derivatives thereof.
  • Compositions for oral administration also include hard or soft capsules consisting of gelatin, sealed capsules consisting of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the hard capsules may contain the active ingredient in the form of granules, for example in admixture with fillers, such as corn starch, binders, and/or glidants, such as talc or magnesium stearate, and optionally stabilizers.
  • the active ingredient is preferably dissolved or suspended in suitable liquid excipients, such as fatty oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of ethylene or propylene glycol, to which stabilizers and detergents, for example of the polyoxyethylene sorbitan fatty acid ester type, may also be added.
  • suitable liquid excipients such as fatty oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of ethylene or propylene glycol, to which stabilizers and detergents, for example of the polyoxyethylene sorbitan fatty acid ester type, may also be added.
  • the assays to measure the percentage in weight of EPA and DHA after storage are carried out by gas chromatography by the standard method described in the European Pharmacopoeia 5.4.
  • Omega 3 fatty acids denote the sum of alpha-linolenic acid (ALA), stearidonic acid (SA), eicosatetraenoic acid (ETA) and docosapentaenoic acid (DPA).
  • ALA alpha-linolenic acid
  • SA stearidonic acid
  • ETA eicosatetraenoic acid
  • DPA docosapentaenoic acid
  • This comparative stability test demonstrates that the omega 3 fatty acids in the form of triglycerides form are significantly more stable than omega 3 fatty acids in the form of ethyl esters.

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Abstract

The present invention relates to a nutritional or dietary supplement composition that strengthens and promotes retinal health.

Description

Organic Compounds
The present invention relates to a nutritional or dietary supplement composition that strengthens and promotes retinal health through the prevention, stabilization, reversal and/or treatment of visual acuity loss in people with certain ocular diseases. More specifically, the present invention relates to an antioxidant and lutein supplement composition that decreases visual acuity loss by reducing the risk of developing late stage or advanced age- related macular degeneration in people with early age-related macular degeneration.
Accordingly, it is an object of the present invention to provide a nutritional or dietary supplement composition effective in the prevention, stabilization, reversal and/or treatment of macular degeneration and/or visual acuity loss.
Another object of the present invention is to provide a safe nutritional or dietary supplement composition for the prevention, stabilization, reversal and/or treatment of macular degeneration and/or visual acuity loss, in particular in accordance to all specified examples and claims of the present disclosure.
Another object of the present invention is to provide an effective and safe method of preventing, stabilizing, reversing and/or treating macular degeneration and/or visual acuity loss.
Another object of the present invention is to provide a method of manufacturing a safe nutritional or dietary supplement composition for the prevention, stabilization, reversal and/or treatment of macular degeneration and/or visual acuity loss.
The following detailed description is provided to enable any person skilled in the art to which the present invention pertains to make and use the same, and sets forth the best mode contemplated by the inventors of carrying out the subject invention.
The preferred nutritional or dietary supplement composition of the present invention is a formulation of essential ingredients preferably in quantities set forth below, e.g. in Table 1 and/or , to be ingested daily. Table 1
Each composition, e.g. in the form of a capsule or capsules (up to 4 capsules a day), contains in a preferred embodiment the following ingredients:
Ingredients Amount Source Vitamin C 500 mg Calcium ascorbate dihydrate, USP Vitamin E 400 IU Alpha tocopheryl acetate, USP Zinc 35 mg Zinc oxide Copper 1.2 mg Copper oxide, Copper sulfate, Copper gluconate or Copper carbonate (Copper being present in the shell and/or in the fill)
Lutein 10 mg FloraGlo 20% natural source or pure
Zeaxanthin 2 mg From lutein and/or added in pure form
DHA 400 mg
EPA 600 mg
Total Omega 3 fatty acids 1200 mg Omega-3 acid triglycerides Ph. Eur.
DHA = Docosahexaeonic acid EPA = Eicosapentaenoic acid
Table2
In a preferred embodiment, the copper salt (e.g. Copper sulfate, Copper gluconate or Copper carbonate) is incorporated in the shell of a capsule which contains the below ingredients. Specifically, the excipients for making such shell are for example:
Gelatin 175 bloom bovine
- Glycerine 99%, USP
- Soybean oil flakes (hydrogenated), NF
- Soybean oil USP
Colorants (if required), organic and/inorganic e.g. Titanium dioxide USP
The preferred daily dosage of the subject composition as specified above may be administered in the form of one or more dosage units, e.g. capsules, dragees, or the like, preferably capsules. Most preferably the daily dosage of the subject composition is provided in the form of one dosage unit taken four times daily, for a total of 4 dosage units a day, or in the form of one dosage unit taken three times daily, for a total of 3 dosage units a day, or in the form of one dosage unit taken twice daily, for a total of 2 dosage units a day. Compared to taking the total daily dose once a day, twice, three or four times daily dosing in one or more dosage units per dose provides improved absorption and better maintenance of blood levels of the essential ingredients.
Compositions, e.g. capsules of the preferred formulation of the subject composition may contain larger or smaller quantities of essential ingredients per capsule than the minimum quantities per capsule specified above.
Larger quantities of essential ingredients, to compensate for some degradation which may occur over time. This aspect is common if the essential ingredient is an antioxidant, e.g. vitamin C, E, or lutein. Smaller quantities of essential ingredients, for example, to take into account the food intake situation of a patient / animal.
The metal salts, e.g. zinc, copper salts, are typically not subject to degradation, therefore typically no larger quantities than those listed are present.
Typically, the listed quantities of ingredients as contained in a composition of the present invention may typically range from 5 % below the indicated quantities of each ingredient up to 5% above the indicated quantities of each ingredient. Therefore, an addressed concentration may encompass +/- 5% by weight of an addressed and listed ingredient, unless designated differently. For illustration purposes, 400 IU vitamin E may for example encompass a range from 380 to 420 mg vitamin E.
By providing larger quantities of essential ingredients in each capsule, one is ensured that even with ingredient degradation, the full amount of the ingredient amount specified on the capsule sale label is provided upon oral administration of the capsule through to the specified expiration date of the capsule. Another consideration in formulating the subject composition is that depending on the source and/or manufacturing process of the individual ingredients, individual ingredient degradation rates may vary. Accordingly, the specific formulation of the subject composition will vary depending on the sources of the individual ingredients and the specified length of product shelf life before expiration. Typically, the product shelf life for nutritional or dietary supplements is approximately two to three years. Capsule formulations may also vary somewhat depending on slight deviations from - A -
manufacturing specifications within controlled tolerance ranges as customary within the field of art.
Variations contemplated in administering the subject composition to humans or animals include, but are not limited to, providing time-release capsules or capsules manufactured to be administered as a single dose or as other multiple part dosages. Additionally, alternative avenues of administration besides oral administration are contemplated herein such as for example, but not limited to, intraperitoneal, intravenous, subcutaneous, sublingual, transcutaneous, intramuscular or like forms of administration.
The preferred route of administration is the oral route.
As used herein the terms tablet, capsule, dragee, pellet, suppository, formulation are interchangeably used unless specified differently. Hence the term tablet, capsule, dragee, pellet, suppository, formulation pertains especially to all the components contained in one respective dosage unit or galenic unit or piece, which are comprised in a composition of the present invention.
The ingredients comprised in a composition of the present invention are now described with their contemplated function. Moreover the quantitative amount and the quality required is described, in particular if deemed important.
VITAMIN C
Vitamin C is a well known water-soluble antioxidant. Humans depend on external sources of vitamin C to meet their vitamin C requirements. Vitamin C in the form of ascorbate is found in the aqueous humor of human eyes.
Vitamin C typically protects the retina against the side effects of light.
The U.S. recommended dietary allowance (RDA) for vitamin C in the form of ascorbic acid is
90 mg.
The subject composition provides a daily dose of preferably 500 mg of vitamin C or ascorbic acid. As used herein, vitamin C is equal to ascorbic acid and vice versa.
Calcium ascorbate, especially calcium ascorbate dihydrate, is the preferred source of vitamin C in a capsule, although other sources such as for example free ascorbic acid or sodium ascorbate could alternatively be used. In a preferred aspect a pharmaceutical composition of the present invention contains 500 mg calcium ascorbate. Typically, about 30% overages are included in a composition of the present invention to compensate for degradation.
In a preferred aspect a pharmaceutical composition of the present invention contains 605.2 mg calcium ascorbate dihydrate
On a total daily dosage vitamin C is typically present in an amount of from 400 to 600 mg, more preferably from 450 to 550 mg, also preferably from 470 to 530 mg, and even more preferably from 480 to 520 mg.
VITAMIN E
Vitamin E is also a well-known antioxidant. Vitamin E can work synergistically with vitamin C in protecting vital cell function from normal oxidants. The DHA (docosahexanoic acid) supplementation of the present invention requires supplementation in Vitamin E that plays a protective role on the membranous lipids. Vitamin E is a relatively non-toxic fat-soluble vitamin. Vitamin E is readily oxidized thereby significantly reducing its activity during periods of storage prior to ingestion. Once ingested, vitamin E is stored within the body and can contribute to the total body pool of vitamin E for up to one year.
Preferably the subject composition provides approximately 400 IU of vitamin E per capsule.
As used herein, d,l-alpha tocopheryl acetate stands for vitamin E and is the preferred source of vitamin E in the subject capsules although other sources of vitamin E, such as for example d,l-alpha tocopheryl acetate and/or vitamin E succinate, may be used in the alternative.
1.0 mg of vitamin E is equal to 1 IU of d,l-alpha tocopheryl acetate. Alternatively, 1 mg d- alpha tocopheryl acetate corresponds to 1.5 IU d,l-alpha tocopheryl acetate.
In a preferred aspect a pharmaceutical composition of the present invention contains approximately 439 mg d,l-alpha tocopheryl acetate, which amount typically includes 10% overages for degradation.
On a total daily dosage vitamin E is typically present in an amount of from 350 to 450 IU, especially from 380 to 420 IU, and in particular from 390 to 410 IU.
ZINC
Zinc is important in maintaining the health of an eye's retina and is an essential part of more than 100 enzymes involved in digestion, metabolism, reproduction and wound healing. The RDA for zinc is approximately 40 mg. Zinc plays a role as a cofactor for enzymes that directly participates in oxidant defense. Zinc concentrations in the retina and choroid are among the highest in the body.
Studies have shown that Zinc slows visual field loss in AMD patients.
Preferably, the subject composition provides approximately 35 mg zinc per capsule.
Zinc is preferred in the form of zinc oxide in subject capsules due to the fact zinc oxide provides the most concentrated form for elemental zinc and is well tolerated in the digestive system. However, other forms of zinc such as for example zinc gluconate, zinc citrate, zinc acetate, zinc chloride, zinc lactate, or zinc sulfate may alternatively be used or be used in combination with zinc oxide in the subject composition. As used herein, zinc refers to a zinc salt, and more preferably to zinc oxide, zinc chloride or zinc gluconate, most preferably to zinc gluconate.
In a preferred aspect a pharmaceutical composition of the present invention contains 43.6 mg zinc gluconate.
For zinc, typically no overages are required, since zinc is not subject to degradation.
On a total daily dosage zinc is typically present in an amount of from 20 to 42 mg, more preferably from 30 to 41 mg, especially preferred from 34 to 41 mg and in particular from 37 to 40 mg.
COPPER
Copper, like zinc, is another important cofactor for metalloenzymes, and is a second necessary cofactor for superoxide bismuthase. The total daily dosage of copper is typically approximately 1.2 mg.
Copper deficiency leading to anemia (lack of oxygen flowing in the blood) has been reported when high levels of zinc are taken. For this reason, the daily dosage composition according to the invention comprises Copper.
Copper or a copper salt are used interchangeably and pertain preferably Cu2+ but may also include Cu+ . A copper salt comprises preferably a pharmaceutically acceptable anion such as chloride, oxide, hydroxide, gluconate, carbonate, sulfate or the like.
On a total daily dosage copper is typically present in an amount of from 0.4 to 1.6 mg, more preferably from 0.6 to 1.4 mg, and in particular from 0.8 to 1.35 mg, particularly preferred 1.2 mg. For copper, typically no overages are required, since copper is not subject to degradation.
Omega-3-fatty acids and a number of vitamins and other pharmaceutically effective compounds or compositions can be susceptible to decomposition when in contact with copper salts. This decomposition is primarily a problem during storage of such compounds and / or compositions and in particular when water is present. Said presence of water applies also to minute amounts of water, such as humidity per se, traces of water in one of the components of a composition and/or of a compound, or from environmental humidity.
According to a preferred embodiment of the composition of the invention the copper salt is provided with a proper masking or coating. This masking or coating typically suppresses an interaction with said copper sensitive compound and/or composition. The copper salt is for example masked or coated with - or embedded in - gelatin or liposomes and/or both such as for example a coated copper salt is embedded in gelatin. There are other ways of protecting copper salts, e.g. by encapsulating it with mono- and di-glycerides, as for example known from the product Descote® which is commercially available.
Copper salts can form a stable complex with an appropriate cyclodextrin compound, which would typically release its free copper salt at a later stage, e.g. when deemed required e.g. upon enzymatic resolution of the complex in the gut.
Copper salts might be coated with a zwitterionic phospholipid including but not limited to phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, spingomyelin and other ceramides, as well as various other zwitterionic phospholipids.
As used herein, the term masked, coated or embedded copper or copper salt pertains to a copper salt and a masking, coating or embedding agent, which effectively prevents a direct interaction of said copper salt with said copper sensitive compound and/or composition.
As used herein, a digestible capsule material is for example the shell material described in the above Table 2, but is in general any capsule or capsule shell or shell material being used in the state-of-the-art for pharmaceutical / dietary / nutraceutical capsules, typically being organic polymeric compositions and typically being pharmaceutically compatible (non-toxic, bio-degradable, digestible in the gut or stomach as deemed suitable). In a preferred embodiment, a digestible capsule material, in particular a gastrointestinal tract digestible capsule material, containing a masked and/or coated copper salt represent said masking and/or coating material for said copper salt.
Another preferred embodiment is to a digestible capsule material as defined in the previous paragraph, wherein said copper salt is already coated with a coating, and said coating might be the same or another masking material than said capsule material;
When the copper is present in the fill (i.e. un-masked, un-coated or un-embedded copper), copper in the form of cupric oxide is preferred in the present compositions, although other forms of copper such as for example copper carbonate, copper gluconate or copper sulfate may alternatively be used or used in combination with copper oxide in the subject composition.
When the copper is present in the shell (i.e. masked, coated or embedded copper), copper in the form of copper sulfate, copper gluconate and/or copper carbonate is preferred in the present compositions, although other forms of copper such as copper oxide may alternatively be used or used in combination with copper sulfate, copper gluconate and/or copper carbonate in the subject composition.
In a preferred aspect a pharmaceutical composition of the present invention contains 4.7 mg Copper sulfate (in the shell) 8.58 mg Copper gluconate (in the shell), 2.14 mg Copper carbonate (in the shell) or 1.5 mg copper oxide (in the fill).
LUTEIN
Lutein, is a carotenoid. Lutein is also an antioxidant found in the retina of healthy eyes.
Lutein and zeaxanthine are xanthophylls , belonging to the group of carotenoids.
Lutein and zeaxanthine are pigments found in retina; mostly in the macula area , where they play a filter role from blue light and probably an anti oxidant role. These pigments are not synthesized in vivo , thus an external (food) supplementation is required for the macular pigment composition.
Lutein is the precursor of zeaxanthin. Epidemiologic studies suggests that lutein consumption might be inversely related to eye diseases such as AMD . Studies in human show that lutein supplementation results in increased macular pigment.
It appears from our studies that the supplementation of 10 mg / day decreases the AMD incidence. Therefore, the subject composition preferably provides preferably 10 mg of pure lutein per capsule.
Lutein in the form of pure Flora GIo (supplier DSM or Kemin) is preferably used. This source provides crystalline lutein and zeaxanthin, from marigold oleoresins extracted from marigold flowers (tagetes). Lutein, zeaxanthin and other carotenoϊds represent, according to their label, 80 % of the weight of the raw material called "FloraGLO crystalline Lutein". This is taken into account when provided in a composition of the present invention.
In a preferred aspect a pharmaceutical composition of the present invention contains 55 mg lutein (20% in safflower oil), which amount includes 10% overages for degradation.
Also preferably, an addressed composition contains approximately from 1 to 20 mg, more preferably from 3 to 17 mg, and even more preferably from 7 to 14 mg lutein per day.
ZEAXANTHIN:
Zeaxanthin, like lutein is a carotenoid. Zeaxanthin is also an antioxidant found in the retina of healthy eyes. Preferably a total daily dosage may range from approximately from 100 to
3000 microgram (from 0.1 to 3 mg) depending upon whether zeaxanthin is used to supplement or substitute and/or lutein.
More preferably a total daily dosage range from approximately from 1.7 to 2.3 mg.
In a preferred aspect a pharmaceutical composition of the present invention contains 2000 microgram zeaxanthin.
OMEGA-3-FATTY ACIDS
Fatty acids from the omega 3 group are mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Other omega 3 fatty acid are alpha-linolenic acid (ALA), stearidonic acid (SA), eicosatetraenoic acid (ETA) and docosapentaenoic acid (DPA) These fatty acids modify for example the composition with respect to the membranous permeability. They may also modify the distribution of membranous proteinic receptor. Thus the protective role of DHA towards AMD may emerge from different mechanisms such as improving the rhodopsine (retinal pigment) regeneration at the pair pigmentary epithelium - photoreceptor level and/or may play a role in the setting up of a lipid background that would improve the rhodopsine activity.
Preferred examples of omega 3 fatty acids are docohexaenoic acid and eicosapentaenoic acid.
/
In a preferred aspect the daily dosage of omega-3 fatty acids is approximately 1200 mg/day.
The supplementation in both EPA /DHA might be beneficial because the retina contains
DHA, and EPA is described as the physiologic precursor of DHA.
The preferred source for omega-3 fatty acids is fish oil. The source of the fish oil may have an influence on the content of DHA and EPA. The DHA : EPA ratio can range from 1 : 4; 1 :
3; 1 : 2; 1 : 1; 2 : 1; 3 : 1 to 4 : 1 (including 1 : 1.43)
Preferably the subject composition provides approximately from 1000 to 1800 mg, more preferably from 1050 to 1350 mg, more especially preferably 1100 to 1300 mg, and in particular from 1150 to 1250 omega-3 fatty acids per day.
The Omega 3 fatty acids according to the present invention can be in the form of triglycerides, in the form or ethyl esters or in the form of methyl esters (supplier EPAX,
Ocean Nutrition, Polaris, DSM)
Preferred omega-3 fatty acids are in the form of triglycerides, e.g. commercialized by EPAX under the names EPAX 6000 TG or EPAX 1050 TG.
Advantages of the present invention:
Free radicals initiate local molecular instability leading to cellular damage. Formation of free radicals is caused by metabolism, sunlight (blue-light spectrum), other free radicals, lack of antioxidants, and other factors. This process may lead to deteriorating vision due to age- related macular degeneration (AMD) and/or diabetic retinopathy (DR). Antioxidant supplementation with certain nutrients may counteract the chain reaction of free radical damage by neutralizing the electron imbalance. Replenishing the antioxidant potential of the retina may effectively decrease oxidant stress and slow or decrease retinal deterioration. There is a strong scientific evidence that the ingredients of the present invention provide help to patients with AMD, i.e. reduced risk of developing advanced AMD and reduced risk of vision loss.
In addition, the formulation of the present invention may not only treat but also prevent retinal degeneration.
Another advantage of this invention is the use of a combination of omega 3 fatty acids with specific, more stable vitamin molecules and also specific, more stable zinc and copper containing molecules.
Specifically, antioxidant vitamins (Vit. C and E) and minerals (Zn and/or Cu) may block the damage of the eye by free radicals. Additionally Lutein and/or Zeaxanthin are believed to rebuild the ocular pigment density of the macula, thereby providing protection against radiation damage of the retina. Omega 3 fatty acids containing high amounts of docosahexaeonic acid (DHA) and eicosapentaeonic acid (EPA) are contemplated of triggering / maintaining the levels of DHA in the photoreceptor cells protecting the ability of the eye to translate light impulses into nervous inputs for the brain (retina's ability to process images). They might also protect the photoreceptor cells from cell death. EPA is contemplated of inhibiting COX1 and COX2 activity which may control / reduce inflammatory events in the eye.
The compositions of the present invention typically exhibit highly improved stability, which improved stability ensures an better treatment procedure since stable formulations provide reproducible treatments.
This above stability is improved by the following measures:
The compounds containing metal ions are typically selected such that they are not water soluble, since water soluble metal compounds are typically responsible for the decomposition of the other active ingredients, especially the vitamins.
In case of the vitamins also the more stable compounds, i.e. alpha-tocopheryl acetate instead of alpha-tocopherol and calcium asorbate instead of ascorbic acid are used for the preparation of the compositions. This unique combination produced a synergistic stability improvement of the compositions in accordance of the present invention.
Manufacturing / Preparation The compositions, capsules, formulations or capsules of the present invention are prepared in a manner known per se, for example by means of conventional mixing, granulating, coating, dissolving or lyophilizing processes.
The compositions may be sterilized, e.g. batch-wise, ingredients-wise as deemed appropriate and/or may comprise excipients, for example stabilizers, coloring agents, firming agents, wetting agents and/or emulsifiers, solubilizers, salts for regulating osmotic pressure ' and/or buffers and are prepared in a manner known perse, for example by means of conventional dissolving and lyophilizing processes. The said solutions or suspensions may comprise viscosity-increasing agents, typically sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone, or gelatins, or also solubilizers, for example Tween 80 [polyoxyethylene(20)sorbitan mono-oleate; trademark of ICI Americas, Inc, USA].
Suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations, and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and also binders, such as starches, for example corn, wheat, rice or potato starch, methylcellulose, hydroxypropyl methyl- cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone, and/or, if desired, disintegrators, such as the above-mentioned starches, also carboxymethyl starch, cross- linked polyvinylpyrrolidone, alginic acid or a salt thereof, such as sodium alginate. Additional excipients are especially flow conditioners and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol, or derivatives thereof.
Compositions for oral administration also include hard or soft capsules consisting of gelatin, sealed capsules consisting of gelatin and a plasticizer, such as glycerol or sorbitol. The hard capsules may contain the active ingredient in the form of granules, for example in admixture with fillers, such as corn starch, binders, and/or glidants, such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquid excipients, such as fatty oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of ethylene or propylene glycol, to which stabilizers and detergents, for example of the polyoxyethylene sorbitan fatty acid ester type, may also be added. Exemple 1
Stability of Omega 3 fatty acids after 30 days' storage at 40°C (ambient humidity, i.e. 50-
70% relative humidity)
(Change in the content of the Omega 3 fatty acids' components)
The assays to measure the percentage in weight of EPA and DHA after storage are carried out by gas chromatography by the standard method described in the European Pharmacopoeia 5.4.
Figure imgf000014_0001
** Other Omega 3 fatty acids denote the sum of alpha-linolenic acid (ALA), stearidonic acid (SA), eicosatetraenoic acid (ETA) and docosapentaenoic acid (DPA).
This comparative stability test demonstrates that the omega 3 fatty acids in the form of triglycerides form are significantly more stable than omega 3 fatty acids in the form of ethyl esters.

Claims

Claims
1. A composition comprising on a daily dosage basis: approximately from 400 to 600 mg of vitamin C, approximately from 350 to 450 IU of vitamin E, approximately from 1 to 20 mg lutein; approximately of 20 to 42 mg zinc; approximately 1000 to 1800 mg omega 3 fatty acids, and approximately from 0.8 to 1.35 mg copper.
2. Composition according to claim 1, comprising zeaxanthin, preferably in an amount of approximately from 1.7 to 2.3 mg.
3. Composition according to claim 1, wherein said omega 3 fatty acids comprise docosahexaeonic acid and eicosapentaenoic acid.
4. Composition according to claim 1 , wherein said omega 3 fatty acids comprise approximately from 300 to 450 mg of docosahexaeonic acid (DHA).
5. Composition according to claim 1 , wherein said omega 3 fatty acids comprise approximately from 540 to 660 mg of eicosapentaenoic acid (EPA).
6. Composition according to claim 1 , wherein said omega 3 fatty acids is in the form of triglycerides.
7. Composition according to claim 1 , wherein said copper is a copper salt selected from the group consisting of copper chloride, copper oxide, copper hydroxide, copper gluconate, copper carbonate and copper sulfate.
8. Composition according to claim 1 , wherein said copper is a masked or coated copper.
9. Composition according to claim 8, wherein said coating is a zwitterionic phospholipid including but not limited to phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, spingomyelin and other ceramides, as well as various other zwitterionic phospholipids.
10. Composition according to claim 8, wherein said copper is a copper cyclodextrin complex.
11. Composition according to claim 1 wherein said vitamin C comprises or substantially consists of calcium ascorbate, said vitamin E comprises or substantially consists of d,l alpha tocopheryl acetate, said zinc comprises or substantially consists of zinc oxide, and said copper is selected from the group consisting of copper chloride, copper oxide, copper hydroxide, copper gluconate, copper carbonate and copper sulfate.
12. A composition according to claim 1 , which is a tablet, capsule or pellet, and comprises:
500 mg of Vitamin C (Calcium ascorbate dihydrate, USP)
- 400 IU Vitamin E (Alpha tocopheryl acetate, USP),
- 40 mg Zinc gluconate,
- 4.7 mg Copper sulfate or 1.5 mg Copper oxide, 2.14 mg Copper carbonate, 8.58 mg Copper gluconate,
- 400 mg DHA,
- 600 mg EPA,
- 1200 mg of Total Omega 3 fatty acids (Omega-3 fatty acids triglycerides Ph.Eur), 10 mg Lutein (FloraGlo 20% natural source (comprising some zeaxanthin) or pure)
- 2mg Zeaxanthin (synthetic origin), optionally comprising the following excipients for making a shell:
- Gelatin 175 bloom bovine,
- Glycerine USP 99%,
- Soybean oil flakes (hydrogenated) NF, Soybean oil USP, and
- Titanium dioxide USP.
13. composition according to claim 12, wherein Copper sulfate, Copper carbonate or Copper gluconate is masked or coated in the shell.
14. Use of a composition in accordance to any of the preceding claims in the preparation of a medicament for the treatment and/or prevention of age related macular degeneration (AMD) and/or diabetic retinophathy (DR).
15. Use according to claim 14, wherein said treatment and/or prevention is reducing the risk of developing advanced AMD and reducing the risk of vision loss
16. Method of treating and/or preventing AMD and/or DR in a subject being in need thereof, comprising administering an effective amount of a composition in accordance to any of the preceding claims.
17. Method of manufacturing a stable composition of claim 1 , which method comprises admixing in a conventional manner vitamin C which comprises or substantially consists of calcium ascorbate, vitamin E which comprises or substantially consists of d,l alpha tocopheryl acetate, zinc which comprises or substantially consists of zinc oxide or zinc gluconate, copper which comprises or substantially consists of Copper oxide, Copper sulfate, Copper carbonate or Copper gluconate, and an omega 3 fatty acid which comprises or substantially consists of Omega-3 fatty acid in the form of triglycerides.
18. A composition comprising in total the amounts indicated and being presented in one, two, three, four or more dosage units of said total amount (in weight % of the total):
500 mg Calcium ascorbate dihydrate, USP
- 400 mg Alpha tocopheryl acetate, USP
- 40 mg Zinc gluconate
- 4.7 mg Copper sulfate or 1.5 mg Copper oxide, 2.14 mg Copper carbonate, 8.58 mg Copper gluconate,
- 400 mg DHA
- 600 mg EPA
1200 mg of Total Omega 3 fatty acids (Omega-3 fatty acid triglycerides Ph. Eur) 10 mg Lutein (FloraGlo 20% natural source (comprising some Zeaxanthin) 2 mg Zeaxanthin (synthetic origin), optionally comprising excipients for making a shell, i.e. Gelatin 175 bloom bovine
- Glycerine USP 99%, Soybean oil flakes (hydrogenated) NF Soybean oil USP, and - Titanium dioxide USP.
19. Composition according to claim 18, wherein Copper sulfate, Copper carbonate or Copper gluconate is masked or coated in the shell.
20. A composition, a method or a use in accordance to any of the preceding claims, wherein the composition is in the form of a tablet, capsule, dragee, pellet, or suppository.
21. Composition, method of manufacture, method of improving the stability, method of treatment or use substantially as hereinbefore defined and/or described.
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