Classifications

• • 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
• • 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
  • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
  • A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
• • 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
  • 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
  • A61K33/04—Sulfur, selenium or tellurium; Compounds 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
  • A61K33/30—Zinc; Compounds 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
  • A61P27/02—Ophthalmic agents

Definitions

• the present invention relates to a vitamin 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.
• the present invention relates to an antioxidant , omega-3-fatty acids and lutein supplement composition that decreases visual acuity loss by reducing the risk of developing age-related macular degeneration (AMD). It further relates to an antioxidant, omega-3-fatty acids, chromium and selenium composition. It also relates to an antioxidant , omega-3-fatty acids, chromium, selenium and zinc composition. Moreover, said compositions typically exhibit a favorable role in other chronic pathologies of the eye such as retinitis pigmentosa.
• an antioxidant is selected from vitamin E, vitamin C 1 beta-carotene and lutein and mixtures thereof.
• beta-carotene is omitted from these antioxidants.
• the present invention likewise provides a method of treating / preventing a human or other animal suffering from AMD or being at risk of developing AMD comprising administering an effective amount of any of the compositions disclosed herein.
• the compounds of the invention can be administered by oral, intraperitoneal, intravenous, subcutaneous, transcutaneous or intramuscular routes.
• a preferred route of administration is the oral route.
• the preferred vitamin composition of the present invention is a formulation of essential ingredients preferably in quantities set forth below in Table 1 , to be ingested daily. Table 1
• the preferred daily dosage of the subject composition as specified above may be administered in the form of one or more tablets.
• Most preferably the daily dosage of the subject composition is provided in the form of one tablet taken three times daily, for a total of 3 tablets a day, or in the form of 1 tablets taken twice daily, for a total of 2 tablets a day.
• twice or three times daily dosing in one or more tablets per dose provides improved absorption and better maintenance of blood levels of the essential ingredients.
• Tablets of the preferred formulation of the subject composition may contain larger or smaller quantities of essential ingredients per tablet than the minimum quantities per tablet specified above. Larger quantities of essential ingredients, to compensate for some degradation which may occur over time. Smaller quantities of essential ingredients, for example, to take into account the food intake situation of a patient / animal.
• the listed quantities of ingredients as contained in a composition of the present invention may typically range from 20 % below the indicated quantities of each ingredient up to 20% above the indicated quantities of each ingredient. Therefore, as used herein, an addressed concentration shall encompass +/- 20% by weight of an addressed and listed ingredient.
• 10 mg vitamin E shall for example encompass a range from 8 - 12 mg vitamin E.
• the subject composition By providing larger quantities of essential ingredients in each tablet, one is ensured that even with ingredient degradation, one hundred percent of the ingredient amount specified on the tablet sale label is provided upon oral administration of the tablet through to the specified expiration date of the tablet.
• 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. For example, depending on the source of beta-carotene, a quantity of approximately 5 to 10 percent more beta-carotene may be necessary per tablet to provide the specified amount of beta-carotene per tablet as that listed on the tablet sale label through to the expiration date of the product. 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.
• the product shelf life for nutritional or dietary supplements is approximately two to three years. Tablet formulations may also vary somewhat depending on slight deviations from manufacturing specifications within controlled tolerance ranges as customary within the field of art. Hence, typically a deviation of + / - 20% (smaller / larger) amounts in a preferred composition are still suitable to exhibit a pharmacological efficacy. Variations contemplated in administering the subject composition to humans or other animals include, but are not limited to, providing time-release tablets or tablets manufactured to be administered as a single dose or as other multiple part dosages.
• each tablet of the subject composition preferably contains the following essential ingredients in the quantities specified below including overages to compensate for ingredient degradation.
• formulations of the subject composition are provided below in accordance with a 3- tablet oral daily dosage regime.
• a tablet does also pertain to a capsule, dragee, pellet, suppository and the like. Hence the term tablet pertains in particular to the quantity contained in one respective piece.
• 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 60 mg of vitamin C.
• Ascorbic acid is the preferred source of vitamin C in the subject tablets, although other sources such as for example sodium ascorbate could alternatively be used.
• a pharmaceutical composition of the present invention contains 60 mg vitamin C per tablet.
• a total daily dosage vitamin C is typically present in an amount of from 10 - 150 mg, more preferably from 30 - 100 mg, and in particular from 40 - 80 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 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 10 mg of vitamin E per tablet.
• Dl-alpha tocopheryl acetate is the preferred source of vitamin E in the subject tablets although other sources of vitamin E, such as for example trimethyl 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 dl-alpha tocopheryl acetate.
• 1mg D alpha tocopheryl acetate corresponds to 1.5 IU.
• a total daily dosage vitamin E is typically present in an amount of from 5 - 30 mg, especially from 7 - 20 mg, and in particular from 10 - 15 mg.
• 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.
• RDA for zinc is approximately 10 mg.
• Zinc plays an antioxidant role as a cofactor for enzymes that directly participate in oxidant defense.
• Zinc concentrations in the retina and choroid are among the highest in the body .
• Zinc is also considered to have an interaction with vitamine A in the generation of the visual pigments of the retina.
• the subject composition provides approximately 15 mg zinc per tablet.
• Zinc is preferred in the form of zinc oxide in subject tablets 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 total daily dosage zinc is typically present in an amount of from 5 - 45 mg, more preferably from 10 - 40 mg, and in particular from 25 - 35 mg.
• chromium refers to a Cr 3+ - salt.
• a preferred chromium salt is chromium trichloride hexahydrate, chromium sulfate or chromium oxide, and more preferably chromium trichloride hexahydrate.
• Chromium is in particular important for two reasons : for oxidative balance for insulinemia balance , diabetes is often associated to AMD
• Chromium e.g. in the form of chromium trichloride hexahydrate is preferably used in a composition of the present invention.
• Other chromium salts might be used as well, such as e.g. sulfate, oxide and the like.
• the subject composition provides approximately 25 micrograms of chromium per tablet.
• chromium On a total daily dosage, chromium may typically be present in an amount of from 5 - 75 micrograms, more preferably from 10 - 50 micrograms, and especially from 20 - 40 micrograms.
• Lutein like beta-carotene, 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 carotinoids.
• 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.
• 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 approximately 6 mg of pure lutein per tablet.
• Lutein in the form of pure Flora GIo (supplier Roche) 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.
• an addressed composition contains approximately 1 - 20 mg, more preferably 2 - 17 mg, and even more preferably 3 - 14 mg lutein per day.
• OMEGA-3-FATTY ACIDS Fatty acids from the omega 3 group are mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). These fatty acids modify for example the composition with respect to the membranous permeability. They may also modify the distribution of membranous proteinic receptor.
• EPA eicosapentaenoic acid
• DHA docosahexaenoic acid
• DHA may impart further effects to the retina, namely : direct positive effect on the structure and the maintenance of lipid balance of external photoreceptors segments.
• anti-apoptotic action anti oxidant action increase mitochondrial activity
• omega-3-fatty acids are docohexaenoic acid (DHA) or eicosapentaenoic acid (EPA).
• the maximum dosage recommended for EPA / DHA supplementation is for example 300 mg / kg (Simopoulos et al.Conference report : workshop on the essentiality of and recommended dietary intakes for omega -6- and omega-3-fatty acids. J Am Coll Nutr, 1999;
• the maximum recommended daily dosage of omega-3 fatty acid is
• EPA is the physiologic precursor of DHA .
• the preferred source for omega-3 fatty acid is fish oil.
• the fish oil content 33% DHA / 23%
• the source of the fish oil may have an influence on the content of DHA and EPA.
• the subject composition provides approximately 200 mg of an omega-3-fatty acid per tablet, more preferably 200 mg of fish oil, having 33% DHA / 23% EPA.
• fish oil contains fatty acids esterified by glycerol, and is thus a triglyceride.
• fatty acids are classified in 2 groups, namely saturated fatty acids and non-saturated fatty acids.
• omega-6 fatty acids and the omega-3 fatty acids.
• Sources are :
• Natural fish oil as triglyceride form with approximately 18% EPA and 12% DHA (by weight).
• compositions of the present invention may typically contain :
• a composition may typically contain between 20 and 100 mg (average
• the subject composition provides approximately 10 - 600 mg, more preferably 20 - 500 mg, and even more preferably 30 - 400 mg omega-3 fatty acid per day.
• Beta-carotene a pro-form of vitamin A, is a lipid-soluble orange pigment found in many vegetables. Beta-carotene is converted to vitamin A in the body with an efficiency of approximately 50 percent. The recommended daily dosage of vitamin A is 5,000 IU corresponding to 3 mg. Beta-carotene has one of the highest antioxidant potentials of the antioxidants.
• the rhodopsine visual pigment necessary for scotopic vision, depends on the Vitamine A physiological amount .
• beta carotene as an antioxidant will protect the lutein from oxidation.
• beta-carotene is omitted from the composition of the present invention.
• Such a composition is preferably recommended for smokers.
• the subject composition preferably provides approximately 2 mg beta-carotene (3334 IU) per tablet.
• Each mg beta-carotene corresponds to a potency of 1 ,667 IU vitamin A.
• beta- carotene be present in a composition of the present invention, then it would preferably contain approximately 0.5 - 6 mg, more preferably 1 - 4 mg, and even more preferably 2 - 3 mg beta-carotene per day.
• the DHA supplementation requires supplementation with selenium that plays a protective role on the membranous lipids.
• Selenium exhibits also an anti oxidant role as a cofactor for enzymes (such as glutathione peroxydase) that participate directly in the oxidant defense.
• enzymes such as glutathione peroxydase
• AMD prevention namely thioredoxine reductase and selenoprotein P.
• the thioredoxine reductase would act in cell rapid increase and in the apoptosis defence.
• the selenoprotein P which represents the blood circulate form of selenium, should protect the endothelial cells of the vessels from oxidative components.
• the association vitamine E and selenium is important, because vitamine E is a liposoluble antioxidant, and has a complementary action with respect to the Selenium. Therefore, it must not be omitted as a trace element and is a mandatory ingredient in a composition of the present invention.
• selenium refers to a selenite salt, such as sodium selenite.
• Selenium may also be used in the form of selenomethionine or as sodium selenate, or as a mixture thereof.
• a preferred selenium is sodium selenite.
• the subject composition provides approximately 50 micrograms selenium per tablet.
• selenium is typically present in an amount of about 15 - 150 micrograms, more preferably from 20 - 100 micrograms and in particular from 30 - 70 micrograms.
• the present invention pertains to a composition consisting approximately or exactly of from 10 - 150 mg of vitamin C, of from 5 - 30 mg of vitamin E, of from 1 - 20 mg of lutein, of from 5 - 30 mg zinc, of from 15 - 150 micrograms selenium, of from 5 - 75 micrograms chromium, and of from 10 - 600 mg of an omega-3-fatty acid.
• a precisely defined composition is in particular useful in the manufacture of a medicament to treat and/or prevent, e.g. when given on a daily basis, e.g. in one or in more fractions, e.g.
• the invention also relates to a method of treating and/or preventing age related macular degeneration or any other pathological disorder of the retina in a subject, comprising administering an effective amount of a composition as defined hereinabove.
• compositions 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 and/or may comprise excipients, for example preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, salts for regulating osmotic pressure and/or buffers and are prepared in a manner known per se, for example by means of conventional dissolving and lyophilizing processes.
• the said solutions or suspensions may comprise viscosity-increasing agents, typically sodium carboxymethylcellu- lose, 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.
• 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
• binders such as starches,
• compositions for oral administration also include hard capsules consisting of gelatin, and also soft, 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.

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• 2005
  • 2005-03-16 FR FR0502582A patent/FR2883182B1/fr active Active
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