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WO2001013901A2 - Systeme d'administration pharmaceutique de vitamine c et vitamine e et utilisation d'une combinaison de ces vitamines permettant de prevenir ou de traiter des conditions provoquant un stress oxydatif - Google Patents

Systeme d'administration pharmaceutique de vitamine c et vitamine e et utilisation d'une combinaison de ces vitamines permettant de prevenir ou de traiter des conditions provoquant un stress oxydatif Download PDF

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Publication number
WO2001013901A2
WO2001013901A2 PCT/DK2000/000459 DK0000459W WO0113901A2 WO 2001013901 A2 WO2001013901 A2 WO 2001013901A2 DK 0000459 W DK0000459 W DK 0000459W WO 0113901 A2 WO0113901 A2 WO 0113901A2
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Prior art keywords
vitamin
μmol
litre
delivery system
tocopherol
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WO2001013901A3 (fr
Inventor
Bent HØJGAARD
Henrik Enghusen Poulsen
Jukka Salonen
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Ferrosan ApS
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Ferrosan ApS
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Priority to JP2001518039A priority Critical patent/JP2003507419A/ja
Priority to PL00356667A priority patent/PL356667A1/xx
Priority to AU65589/00A priority patent/AU6558900A/en
Priority to NZ517833A priority patent/NZ517833A/en
Priority to EP00952964A priority patent/EP1210079A2/fr
Publication of WO2001013901A2 publication Critical patent/WO2001013901A2/fr
Publication of WO2001013901A3 publication Critical patent/WO2001013901A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/12—Ophthalmic agents for cataracts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • This invention relates to a pharmaceutical delivery system for obtaining a controlled ratio of antioxidants. It further relates to a principle of antioxidant levels in blood plasma.
  • the present invention proposes a pharmaceutical delivery system for oral delivery of the antioxidants vitamin C and vitamin E to obtain high concentrations thereof and a controlled ratio between the vitamins in blood plasma in humans and animals.
  • ROS reactive oxygen species
  • ROS can occur as part of many cellular processes including mitochondrial respiration, immune cell responses, cell injury, heat, radiation of many origins, from metabolism of drugs and other chemicals. ROS are thought to be involved in almost all disease processes and the ageing process. For example, modification can occur to lipids in the LDL (light density lipoprotein) particle in the blood (3). This modification leads to increased formation of fatty streaks in the arterial wall and subsequent formation of arterisclerotic plaques (3b, 4) which can compromise blood supply to organs, causing manifest disease, e.g. coronary heart attack.
  • LDL light density lipoprotein
  • antioxidants include enzymes, substances produced in the body and substances that are only found in food. Examples of the latter are antioxidant vitamins (E, C, A) and similar substances (flavonoids, lycopene, beta-carotene). The substances have different properties, some being water-soluble others being fat-soluble (2).
  • LDL particle low density lipoproteins
  • APO-B100 protein moiety APO-B100
  • Macrophages can transform into foam cells when large amounts of LDL are taken up. The foam cells deposit in the arterial wall and contribute to the development of artheriosclerotic plaques (4).
  • Water-soluble antioxidants are taken up quickly, but are also eliminated quickly from the body by urinary excretion (6). Fat-soluble antioxidants are taken up more slowly and eliminated slowly from the body (7). This means that the concentration ratio of e.g. a water-soluble and a fat-soluble antioxidant vitamin will vary after intake.
  • Vitamin E is the most important antioxidant in the LDL particle.
  • Vitamin C ascorbic acid (AA)
  • Vitamin C can prevent this process by interacting with the tocopheryl radical. This results in reduction of the tocopheryl radical to tocopherol and the formation of oxidised vitamin C, dehydro-ascorbic acid, DHAA (10).
  • DHAA is taken up by the liver and reduced to vitamin C (11).
  • US 5897879 discloses a sustained-release pharmaceutical delivery system for the administration of an antioxidant drug to a patient in need of such drug, wherein the said delivery system comprises the said drug in combination with a matrix, the said matrix comprising a polymer selected from the group consisting of a polymer which does not interact with the said drug and a mixture of such polymers, and the said polymeric matrix is present in amounts from about 20% (w/w) to about 80% (w/w).
  • the drug can inter alia be vitamin E, vitamin C or a combination thereof. In the case of combination both drug components have a sustained-release form, and they are released together. This known system does not give effective high, constant concentrations of vitamin C and E.
  • WO 97/00672 discloses an effervescent composition
  • an effervescent composition comprising at least one active ingredient selected from the group consisting of a nutritional supplement, a dietary supplement and combinations thereof in amounts sufficient to provide a dosage form of the said active ingredient as few as once in a 24-hour period, the said active ingredients being both a free form component and a microencapsulated component which has sustained-release properties, and an effective amount of an effervescent agent.
  • the active agent is selected from the group consisting of carnitine, calcium, magnesium, ascorbic acid, vitamin E and combinations thereof.
  • the active agents are micro-encapsulated together.
  • This known composition provides immediate and sustained release of both vitamin C and vitamin E.
  • the vitamins are released together from the same delivery principle(s), and they do not provide a high, constant vitamin concentration, in the preferred ratio in the blood plasma.
  • EP 176772 discloses a process for increasing the delayed-release activity of vitamin C and vitamin E by incorporating both vitamins in a neutral oil and encapsulating the oil. Both vitamins are present in the same delivery principal.
  • EP 0820703 discloses compositions for nutritional integration comprising hydrosoluble vitamins and liposoluble vitamins, characterised in that the hydrosoluble vitamins have a prolonged-release formulation and the liposoluble vitamins have a rapid-release formulation.
  • the present invention solves the problem of providing high concentrations of vitamin C and E in the preferred ratio by using a pharmaceutical delivery system for oral delivery of vitamin C and vitamin E to obtain high concentrations thereof in a controlled ratio in blood plasma in humans or animals by a delivery system with slow release of vitamin C and plain release of vitamin E.
  • the present invention seeks to provide a method of providing oxidation resistance without the use of selenium or ⁇ -carotene by providing high concentrations of vitamin C and E at a controlled ratio in blood plasma.
  • the present invention relates to a pharmaceutical delivery system for oral delivery of the antioxidants vitamin C and vitamin E to obtain high concentrations thereof and a controlled ratio between vitamin C and vitamin E in blood plasma in humans or animals, characterised in that it has a slow release formulation of vitamin C and a plain release formulation of vitamin E.
  • the invention relates to a method of treating or preventing oxidative stress disorders and associate diseases comprising the administration to an individual a combination of vitamin C and vitamin E in sufficient amounts so as to raise, within 8 weeks of the first administration, the concentration of said vitamins in blood plasma sufficiently and to a ratio of from 1 :1 to 3:1 , preferably 2.2:1.
  • the invention further relates to a method of treating or preventing oxidative stress disorders and associate diseases comprising the daily administration to an individual at least one dosage unit comprising a combination of vitamin C and vitamin E in sufficient amounts so as to raise the concentration of said vitamins in blood plasma sufficiently and to a controlled ratio wherein said vitamin C is formulated in a slow- release preparation and vitamin E is formulated in plain-release formulation.
  • the invention relates to the use of a combination of vitamin C and vitamin E for the preparation of a drug or drug system for treating or preventing atherosclerosis or other diseases or conditions responsive to antioxidants, wherein said vitamins are incorporated in the patients blood plasma in high concentrations and in a controlled ratio characterised in that the drug or drug system has a slow release of vitamin C and a normal release of vitamin E.
  • vitamin E ⁇ -tocopheryl acetate
  • the preferred delivery system comprising a slow release of vitamin C and plain release of vitamin E provides a high, constant concentration of the vitamins in the blood of a human in need of the vitamins. Furthermore, it was found that said delivery system provided vitamins C and E in a ratio and at plasma concentrations surprisingly effective for oxidative resistance.
  • a formulation is disclosed wherein a vitamin E matrix is plainly released, and vitamin C is slowly released thus providing the desired and optimum plasma vitamin C and E concentrations over time.
  • vitamin E in the formulation of the present invention given in a conventional tablet was found to be well absorbed. Vitamin E is therefore to be administered in a form for plain release such as a conventional tablet, which disintegrates within 30 minutes, making vitamin E accessible for absorption.
  • vitamin E and vitamin C are considered two of the most important dietary antioxidants. Vitamin E may also have other anti-atherogenic properties. When vitamin E works as an antioxidant it is oxidised to harmful ⁇ -tocopheroxyl radical, which needs to get reduced back to ⁇ -tocopherol. Vitamin C can regenerate ⁇ - tocopheroxyl radical to ⁇ -tocopherol.
  • slow release formulation is intended to mean a formulation whereby the tablets thereof are coated or uncoated containing excipients or prepared by special procedures which, separately or together, are designed to modify the rate or the place at which the active ingredient is released, as is defined by the US Pharmacopoeia for modified-release tablets.
  • the term used herein is intended to mean a formulation within the threshold of dissolution in vitro as defined by Test A described herein.
  • the term "plain release formulation” is intended to mean a formulation whereby the tablets thereof are designed to release at least 90% of vitamin E within 30 minutes in vitro under conditions of Test B. According to the US Pharmacopoeia, tablets without modified release are to disintegrate within 60 minutes. For nutritional supplements, according to the US Pharmacopoeia, tablets without modified release, should release at least 75% of the index ingredient within 60 minutes.
  • vitamin C is intended to mean ascorbic acid equivalents such as salts of the ascorbate such as sodium ascorbate, calcium ascorbate and ascorbyl palmitate.
  • vitamin E is intended to mean ⁇ -tocopherol equivalents and may be, for example, any natural or synthetic vitamin E chosen from the group comprising d- ⁇ - tocopheryl acetate, d- ⁇ -tocopheryl acid succinate, d- ⁇ -tocopherol, d- ⁇ -tocopherol, d- ⁇ -tocopherol, d- ⁇ -tocopherol, d- ⁇ -tocotrienol, d- ⁇ -tocotrienol, d- ⁇ -tocotrienol, d- ⁇ - tocotrienol, dl- ⁇ -tocopherol, dl- ⁇ -tocopheryl acetate, dl- ⁇ -tocopheryl calcium succinate, dl- ⁇ -tocopheryl nicotinate, dl- ⁇ -tocopheryl linoleate/oleate and all other possible stereo isomeric forms of the above compounds.
  • the present invention seeks to provide a method of providing oxidation resistance without the use of and ⁇ -carotene or selenium by providing high concentrations of vitamin C and E at a controlled ratio in blood plasma.
  • the present invention solves the problem of providing high concentrations of vitamin C and E in the preferred ratio by using a pharmaceutical delivery system for oral delivery of vitamin C and vitamin E in order to obtain high concentrations thereof in a controlled ratio in blood plasma in humans or animals by a delivery system with slow release of vitamin C and plain release of vitamin E.
  • the present invention is based on the notion that a certain ratio between vitamin C (ascorbic acid) and vitamin E ( ⁇ -tocopherol) is necessary for optimum protection of LDL particles.
  • the system of the invention provides a ratio of concentrations between vitamin C and vitamin E in the blood plasma from 1 :5 to 5:1 , preferably from 1 :1 to 3:1.
  • the amount of vitamin C is preferably higher than that of vitamin E.
  • the most preferred ratio is 2.2:1.
  • This ratio as measured in the blood plasma 8 weeks from the onset of a regimen comprising the at least once daily oral administration of the delivery system, is achieved no more than 8 weeks from the onset of said regimen, such as no more than 7, 6, 5, or 4 weeks.
  • the present inventors have found a steady state is achieved in the blood plasma of vitamins C and E in the desired ratio, by means of measurements taken anytime after 8 weeks. Once the ratios achieved, the ratio is maintained for at least as long as the regimen is followed. Measurements taken 3 years from the onset of a regimen showed similar ratios as measurements taken 8 weeks from the onset of the regimen.
  • the concentration of vitamin E in human blood plasma should be raised to at least 20 ⁇ mol/litre, preferably at least 30 ⁇ mol/litre, such as at least 40 or 50 ⁇ mol/litre, preferably at least 55 ⁇ mol/litre, and the concentration of vitamin C to at least 40 ⁇ mol/litre preferably at least 60 ⁇ mol/litre, such as at least 70, 80 , 90 ⁇ mol/litre, preferably at least 100 ⁇ mol/litre.
  • concentrations preferred for each of the vitamins concomitantly present in the blood plasma are 180 ⁇ mol/litre vitamin C and 81.8 ⁇ mol/litre vitamin E; 160 ⁇ mol/litre vitamin C and 72.7 ⁇ mol/litre vitamin E; 140 ⁇ mol/litre vitamin C and 66.6 ⁇ mol/litre vitamin E; 120 ⁇ mol/litre vitamin C and 54.5 ⁇ mol/litre vitamin E; 100 ⁇ mol/litre vitamin C and 45.5 ⁇ mol/litre vitamin E; 80 ⁇ mol/litre vitamin C and 36.4 ⁇ mol/litre vitamin E; 70 ⁇ mol/litre vitamin C and 31.8 ⁇ mol/litre vitamin E; 60 ⁇ mol/litre vitamin C and 27.3 ⁇ mol/litre vitamin E; 50 ⁇ mol/litre vitamin C and 22.7 ⁇ mol/litre vitamin E.
  • the relative concentrations of vitamins C and E concomitantly present in the blood plasma are from about 102 to about 142 ⁇ mol/litre and from about 46 to about 65 ⁇ mol/litre, respectively, such as 112 ⁇ mol/litre of vitamin C and 51 ⁇ mol/litre of vitamin E, 122 ⁇ mol/litre of vitamin C and 55.5 ⁇ mol/litre of vitamin E, 132 ⁇ mol/litre of vitamin C and 60 ⁇ mol/litre of vitamin E, or 142 ⁇ mol/litre of vitamin C and 65 ⁇ mol/litre of vitamin E, especially preferred concentrations of the vitamins in human blood plasma are 132 ⁇ mol/litre of vitamin C and 60 ⁇ mol/litre of vitamin E.
  • concentrations as measured in the blood plasma 8 weeks from the onset of a regimen comprising the at least once daily oral administration of the delivery system, are achieved no more than 8 weeks from the onset of said regimen, such as no more than 7, 6, 5, or 4 weeks.
  • the present inventors have found a steady state is obtained in the blood plasma of the concentrations of vitamins C and E by means of measurements taken anytime after 8 weeks. Once the concentrations achieved, they are maintained for at least as long as the regimen is followed. Measurements taken 3 years from the onset of a regimen showed the same concentrations as measurements taken 8 weeks from the onset of the regimen.
  • ratios or concentrations may be achieved by administration of a daily dose of at least 1 dosage unit.
  • the amount of each of the vitamins in each of the dosage units will quite obviously vary.
  • at most 8 dosage units are administered for each daily dose, such as at most 4 dosage units, at most 3 dosage units, at most 2 dosage units, at most 1 dosage unit.
  • 1 or 2 dosage units are administered to achieve the daily dose, most preferably 2 dosage units.
  • the daily dose of each of the vitamins corresponds to 60 mg - 2 g of vitamin C and 10 mg - 800 mg of vitamin E.
  • the daily dose of vitamin C is a dose corresponding to 100 mg - 1.5 g of ascorbic acid, such as 200 mg - 1 g, most preferably corresponding to 250 mg -750 mg of ascorbic acid, preferably 300 mg - 600 mg, particularly corresponding to 500 mg of ascorbic acid.
  • the daily dose of vitamin E is a dose corresponding to 50 mg - 500 mg of ⁇ -tocopherol, such as 100 mg - 250 mg, most preferably corresponding to 150 mg -200 mg of ⁇ - tocopherol, preferably 175 mg -190 mg, particularly corresponding to 180-185 mg of of ⁇ -tocopherol, such as 180, 181 , 182, 183, 184 or185 mg, preferably 182 mg.
  • each dosage unit comprises i) at most 1 g of vitamin C, such as at most 500 mg such as at most 400 mg, 300 mg, preferably 250 mg of vitamin C and ii) at most 400 mg of vitamin E, such as at most 300 mg, 200 mg or 150 mg, preferably about 100 mg, such as 90 mg, 91 mg, 92, 93, 94, 95, 96, 97, 98, 99, or 100 mg of vitamin E.
  • the delivery system comprises a daily dose corresponding to 500 mg of vitamin C in a slow release formulation and 182 mg of vitamin E in a plain release formulation.
  • the delivery system comprises a dosage unit formulation administered twice daily comprising 250 mg of vitamin C in a slow release formulation and 91 mg of vitamin E in a plain release formulation.
  • the delivery system may comprise of dosage units with non-identical amounts of the vitamins such that a dosage unit comprises substantially all of the daily dose of vitamin C and only a fraction of the vitamin E daily dose and one or more dosage units to be administered during the day comprise the remaining fractions of the daily dose of vitamin E and is/are substantially devoid of vitamin C.
  • the delivery system may comprise of dosage units with non-identical amounts of the vitamins such that a dosage unit comprises substantially all of the daily dose of vitamin E and only a fraction of the vitamin C daily dose and one or more dosage units to be administered during the day comprise the remaining fractions of the daily dose of vitamin C and is/are substantially devoid of vitamin E.
  • the ratios or concentrations of vitamin C and vitamin E can be achieved by a number of types of dosage units such as tablets.
  • the delivery system may comprise of dosage units formulated for oral administration such as a hard or chewable tablet, capsule, granulates or powders so long as the system is characterised by slow release of vitamin C and plain release of vitamin E. Powders or granulates for example, may be powdered or granulated blends of the a formulation of vitamin C and a formulation of vitamin E in one sachet or in separate sachets. Similarly, capsules may comprise each of the two formulations.
  • a further object of the present invention is to provide a delivery system to obtain a controlled increase in blood plasma levels of both vitamin C and E, as measured after 8 weeks.
  • Levels of the vitamins preferably increase from 50 to 100% for vitamin E, such as from 60 to 80%, preferably from 70 to 80%, and from 30 to 80% for vitamin C, such as from 40 to 70%, preferably from 40 to 65%.
  • the high concentrations of vitamin C and E as measured after 3 years of administration of the system according to the present invention, were such that to equate to an increase of about 71% to 76% in blood plasma vitamin E and an increase of about 46% to 60% of vitamin C (see Table 4). It is understood that these increases of plasma levels are the result of the delivery system according to the present invention without the assistance of supplementation of ⁇ -carotene or selenium either of which can on their own contribute to high levels of at least vitamin E.
  • the system can be a pharmaceutical delivery system comprising a tablet comprising two or more different delivery principles, wherein (A) one delivery principle comprises (i) vitamin C (ii) a pharmaceutically acceptable excipient for controlling the slow release of vitamin C, (iii) other pharmaceutically acceptable excipients (B), another delivery principle comprises (i) vitamin E (ii) pharmaceutically acceptable excipients.
  • the system is a the tablet comprising two layers whereby vitamin C is in one layer and vitamin E is in the other layer.
  • the delivery system of the invention can be any system providing a high concentration of vitamin C and vitamin E at the same time in the blood.
  • the system can of course be any known delivery system providing slow release of vitamin C and plain release of vitamin E.
  • the formulation of vitamin C in the delivery system according to the present invention preferably is such that less than 40% of vitamin C is dissolved after 1 hour under the conditions of Test A, from 50 to 80% of vitamin C is dissolved after 3 hours under the conditions of Test A, and more than 90% of vitamin C is dissolved after 7 hours under the conditions of Test A.
  • Sustained release formulations are known to give lower peak values than other administration forms, but keep the desired plasma level for a longer time (17). With repeated dosages of the sustained release formulation, a much more constant plasma level may be obtained compared to conventional tablets. Sustained release formulation can be achieved by different techniques, such as matrix tablets, erosion tablets, lattice tablets, or by coating of the tablet or the active ingredient.
  • Sustained release formulations for oral use may be constructed to release vitamin C by controlling the dissolution of vitamin C, its diffusion or both. Dissolution or diffusion controlled release may be achieved by appropriate coating of a tablet capsule, pellet or granulate formulation of vitamin C.
  • the matrix principle which is a preferred embodiment of the tablet formulation for vitamin C, is achieved by mixing the active ingredient with hydrocolloid macromolecular excipients in large amounts, typically more than 25%. When ingested, the tablet forms a highly viscous gelatinous mass at the surface maintaining the shape of the tablet. The active component is slowly released from the surface of the gelatinous mass, at a rate which is controlled by its diffusion through the gel-barrier.
  • the following macromolecular excipients can be used for creating this gel: methylcellulose, hydroxypropyl methylcellose, carboxymethyl starch or other modified cellulosic substances, hydrophilic gums such as pectinates or alginates.
  • Erosion tablets differ from the matrix tablet in that the excipients used are lipids, which will not dissolve or gel in the stomach, but slowly be eroded, thus releasing the active ingredient.
  • the following lipids are frequently used for this purpose: stearic acid, glycerol monostearate, stearyl alcohol, cetyl alcohol, and hydrogenated fats.
  • Lattice tablets differ from the former types in that the excipient chosen is insoluble in the stomach. The tablet will therefore not disintegrate, and the active ingredient is released by diffusion, leaving the lattice unchanged.
  • excipients for lattice tablets polyvinyl acetate, polyvinyl chloride or polyethylene may be used.
  • the sustained release effect can also be achieved either by coating the tablet or by coating the active particles or pellets made herefrom (micro- encapsulation).
  • the coating must be made of an insoluble polymer, whereby the active ingredient must traverse by diffusion.
  • polymers for film coating ethyl cellulose, polymethacrylates or lipids may be used.
  • a sustained release coating may be selected from coatings comprising cellulose derivatives such as hydroxypropyl methylcellulose, methylcellulose, methylhydroxycellulose, methylhydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethylcellulose, cellulose acetate, cellulose propionate, cellulose butyrate, cellulose valerate, cellulose acetate proprionate and cellulose acetate butyrate; acrylate polymers such as acrylic resins, polymethylacrylate, methylmethacrylate, 2-hydroxymethacrylate, polyethylene glycol methacrylate, methacrylate hydrogels; vinyl polymers such as polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidine, polyvinyl pyrrolidone, polyvinyl formal, polyvinyl butyryl, vinyl chloride-vinyl acetate coplymer, vinyl chloride- propylene-vinyl acetate copolymer; silicon polymers such as ladder polymer of sesquiphenyl siloxane and
  • the coating may be admixed with various excipients such as plasticizers and anti- adhesives such as colloidal silicum dioxide, flavouring agents, lubricating agents and pigments in a manner known to the person skilled in the art.
  • excipients such as plasticizers and anti- adhesives such as colloidal silicum dioxide, flavouring agents, lubricating agents and pigments in a manner known to the person skilled in the art.
  • Tablet strengthening agents such as silica, may also be added to the formulation as may binding agents, inert fillers, flavouring agents or lubricating agents.
  • vitamin C is formulated for sustained release by a matrix principle in at least one layer of a tablet whereas vitamin E is released plainly or immediately from a non-identical layer of the tablet.
  • a tablet may comprise of at least two non-identical layers wherein vitamin C is comprised within at least one layer and vitamin E is comprised within at least one non-identical layer.
  • a vitamin E layer may enrobe or surround substantially the entire vitamin C layer.
  • the formulation is of a tablet in the matrix technique with hydroxypropyl methylcellulose as the gel forming excipient.
  • Figure 2 shows the release pattern measured on different batches. The graph of Figure 2 demonstrates that vitamin C is released over 7 hours, and that the production process is reproducible in relation to release of vitamin C.
  • Vitamin C may be selected from ascorbic acid itself or a derivative or a salt thereof, such as sodium ascorbate, calcium ascorbate or ascorbyl palmitate.
  • the delivery system according to the present invention is characterised in part by a slow release formulation of Vitamin C.
  • the delivery system comprises a bi-layer tablet formulated with vitamin C and vitamin E.
  • the vitamin E layer is preferably formulated as a conventional tablet meeting the normal requirements for disintegration.
  • the formulation comprises ascorbic acid and d- ⁇ - tocopheryl acetate as sources for the active components.
  • the delivery system according to the present invention is characterised in part by a plain release of vitamin E.
  • the formulation of vitamin E is such that the tablet or moiety of the tablet comprising vitamin E, releases vitamin E in vitro within 30 minutes by at least 90% under conditions of Test B, preferably within 15 minutes.
  • Figure 3 depicts the degree of dissolution of a preferred embodiment of the present invention wherein the percentage of release of vitamin E as a function of time is depicted and compared to a formulation with sustained release of vitamin E.
  • the preferred in vitro release profile in order to provide the appropriate ratio of vitamins C and E with the appropriate concentration in blood plasma is such that less than 40% of vitamin C is dissolved within 1 h and at least 90% of vitamin E is dissolved within 30 minutes.
  • Table 3 shows the release profile of products currently on the market. Even those products which comprise additional antioxidants do not have the preferred release profile to achieve the desired result.
  • Figure 3 demonstrates the release profile for vitamin E of a preferred embodiment of the invention Furthermore, it compares the profile of a product which had a similar release profile for vitamin C with the preferred profile according to Table 3 The graph clearly demonstrates that despite the similarity after 60 minutes, the profile is markedly different and does not reach the preferred release of at least 90% after at most 30 minutes, such of at least 90% after at most 15 minutes for vitamin E
  • a delivery system according to the present invention and the resultant blood plasma concentration and ratios of vitamin C and E performed well during in vivo studies
  • the system according to the present invention was found to be beneficial for prevention/treatment of oxidative stress related indications
  • the present inventors conducted experiments which have as at least one objective the study of the effect of reasonable supplemented doses of vitamin E and vitamin C and their combination on the progression of common carotid atherosclerosis in middle-aged high-risk men and women in three years As men and cigarette smokers are at enhanced oxidative stress and lipid peroxidation (18, 23), a greater atherosclerotic progression retarding effect was hypothesised a priori in men and in smokers than in women and in non-smokers Because of the synergism between vitamin E and vitamin C in the human body, the greatest protective effect was hypothesised by the combined supplementation
  • an object of the invention is the use of a combination of vitamin C and vitamin E for the preparation of a drug, drug system or delivery system for treating or preventing oxidative stress related indications wherein said vitamins are incorporated in the patients blood plasma in high concentrations and in a controlled ratio, characterised in that the drug has a slow release of vitamin C and a normal release of vitamin E
  • a further object to of the invention is the use of a delivery system as described herein for the prevention/treatment of oxidative stress related indications such as atherosclerosis or other diseases or conditions responsive to antioxidants
  • An object of the invention is thus the use of a combination of vitamin C and vitamin E for the preparation of a delivery system for the treatment or prevention of atherosclerosis, cancer, type I and type II diabetes and diabetic nephropathy, for skin repair and scar tissue formation, for the protection or treatment against central nervous system disorders and degeneration and neural degeneration in general such as for example in Alzheimer's Disease, for anti-inflammatory effects, for improvements in fertility / fecundity, for protection against the effects of the sun, for the treatment or prevention of cataracts, for anticoagulation, or as an antidote for nitrate-tolerance.
  • the system according to the present invention may alternatively be used for patients having vitamin C and/or E deficiency, but especially for preventing or treating conditions or diseases involving oxidative stress, such as arteriosclerosis, cancer, cataract, diabetes I and II, and ageing. Many human studies have been performed in these areas regarding the role of vitamins E or C in these conditions relating to oxidative stress from endogenous or exogenous sources.
  • a further object of the invention is to provide a method of treating or preventing oxidative stress disorders and associate diseases comprising the administration to an individual a combination of vitamin C and vitamin E in sufficient amounts so as to raise, within 8 weeks of the first administration, the concentration of said vitamins in blood plasma sufficiently and to a ratio of from 1 :1 to 3:1 , preferably 2.2:1.
  • the invention provides method of treating or preventing oxidative stress disorders and associate diseases comprising the daily administration to an individual at least one dosage unit comprising a combination of vitamin C and vitamin E in sufficient amounts so as to raise the concentration of said vitamins in blood plasma sufficiently and to a controlled ratio wherein said vitamin C is formulated in a slow-release preparation and vitamin E is formulated in plain-release formulation.
  • the blood plasma concentrations are raised sufficiently or to the preferred ratio at most 8 weeks from the first administration, such as at most 7 weeks of the first administration, such at most 6 weeks, preferably at most 5 weeks, most preferably at most 4 weeks.
  • the blood plasma concentration of vitamin E is at least 20 ⁇ mol/litre, preferably at least 30 ⁇ mol/litre, such as at least 40 or at least 50 ⁇ mol/litre, most preferably at least 55 ⁇ mol/litre and the concentration of vitamin C is raised to at least 40 ⁇ mol/litre, preferably at lease 60 ⁇ mol/litre, such as at least 70, 80 , 90 ⁇ mol/litre, most preferably at least 100 ⁇ mol/litre.
  • the concentrations of vitamins C and E concomitantly present in the blood plasma are from 102 to about 142 ⁇ mol/litre and from about 46 to about 65 ⁇ mol/litre, respectively, such as 112 ⁇ mol/litre of vitamin C and 51 ⁇ mol/litre of vitamin E, 122 ⁇ mol/litre of vitamin C and 55.5 ⁇ mol/litre of vitamin E, 132 ⁇ mol/litre of vitamin C and 60 ⁇ mol/litre of vitamin E, or 142 ⁇ mol/litre of vitamin C and 65 ⁇ mol/litre of vitamin E, especially preferred concentrations of the vitamins in human blood plasma are 132 ⁇ mol/litre of vitamin C and 60 ⁇ mol/litre of vitamin E.
  • the administration is of an at least once daily dose of dosage units comprising slow release formulation vitamin C and plain release vitamin E, preferably at most 8 dosage units, such as at most 6 dosage units, such as at most 5 dosage units, such as 4, 3, 2, or 1 , preferably 2 or 1 , most preferably 2 dosage units.
  • the method of the invention preferably comprises dosage units wherein the slow release formulation releases less than 40% of vitamin C after 1 hour under the conditions of Test A, from 50 to 80% of vitamin C is released after 3 hours under the conditions of Test A, and more than 90% of vitamin C is dissolved after 7 hours under the conditions of Test A and the plain release formulation releases at least 90% of vitamin E is dissolved in less than 30 minutes under the conditions of Test B, such as in less than 15 minutes.
  • the method of the invention preferably comprises the daily dose of vitamin E corresponding to 50 mg - 500 mg of ⁇ -tocopherol, such as 100 mg - 250 mg, most preferably to 150 mg -200 mg of ⁇ -tocopherol, preferably 175 mg -190 mg, particularly corresponding to 180-185 mg of ⁇ -tocopherol, most preferably 182 mg.
  • the method of the invention preferably comprises the daily dose of vitamin C corresponding to 100 mg - 1.5 g of ascorbic acid, such as 200 mg - 1 g, most preferably corresponding to 250 mg -750 mg of ascorbic acid, preferably 300 mg - 600 mg, particularly corresponding to 500 mg of ascorbic acid.
  • each dosage unit preferably comprises i) from approximately 200 to 300 mg of vitamin C, such as 200, 225, 250, 275, or 300 mg, preferably 250 mg of vitamin C and n) approximately 80 to 120 mg of vitamin E, such as from 80 to 100 mg preferably about 90 mg, such as 91 mg, 92, 93, 94, 95, 96, 97, 98, 99 mg of vitamin E, preferably 91 mg
  • Figure 1 summarises the plasma vitamin E measurement in the MASIstudy (13) at baseline and after two months supplementation This figure shows the results of plasma vitamin E concentrations before and after 8 weeks supplementation with 7 different treatments
  • PL depicts placebo
  • VitE depicts a tablet with 91 mg vitamin E in normal release formulation
  • E+C depicts a dosage unit with 250 mg vitamin C in a slow release formulation plus 91 mg vitamin E in a slow release formulation
  • Cplain is a plain formulation of vitC
  • Cslow is a formulation of slow release vitC
  • Q 10 o ⁇ l is Coenzyme Q 10 formulated in oil
  • Q ⁇ 0 gr is Coenzyme Q 10 in granulate formulation
  • Cplain Cslow
  • Q10oil and Q10gr are all formulations not containing vitamin E and can be regarded as non placebo controls
  • a tablet according to the invention was prepared as follows:
  • Active ingredients Vitamin E 91 mg
  • Vitamin E as 102 kg D- ⁇ -tocopherol acetate concentrate (powder form) was mixed with Silica, Colloidal Anhydrous (5-15 kg) and microcrystalline cellulose (50-100 kg). Magnesium stearate (approx. 1kg) was added and mixed again.
  • Vitamin C as 135 kg Ascorbic Acid 97% was mixed with hydroxypropyl methylcellulose K100 M (50-100 kg). Magnesium stearate (approx. 1/4 - 1 _ kg) was added and mixed again.
  • Bi-layered tablets with the Vitamin E mix as one layer and the Vitamin C mix as the second layer were compressed at 12 mm tooling.
  • Figure 2 shows the release pattern for Vitamin C measured on different batches and Figure 3 the release pattern for Vitamin E measured on one batch.
  • Test A conforms with the European Pharmacopeia regulation 711 Dissolution to determine the dissolution for a tablet or capsule.
  • Apparatus 2 of the regulation was employed with the following specifications: Rotation speed 50 rpm Medium 1000 mL of 0.1 N hydrochloric acid
  • Test B comprised of the use of an apparatus wherein a glass flask on a heated (37°C) water bath containing 15 mL of water. At the prescribed timepoints, the dissolution media was transferred to a clean flask. The first flask with the rest of the tablet was washed with 25 mL ethanol (99%). The ethanol was decanted to the second flask containing the dissolution media. Vitamin E was assayed by gas chromatographic procedures known to the person skilled in the art. The test was run in duplicate.
  • the combined formulation gave a 72 - 89 percent increase in plasma vitamin E and a 60- 72 percent increase in plasma vitamin C in plasma (morning values).
  • the mean plasma ⁇ -tocopherol concentration increased in the placebo group from 31.0 to 33.2 ⁇ mol/L (by 7.2%), in the vitamin E group from 31.7 to 60.1 ⁇ mol/L (by 89.2%), in the vitamin C group from 32.3 to 33.9 mol/L (by 5.1 %) and in the group randomised to both vitamins from 32.1 to 55.2 ⁇ mol /L (by 71.9%).
  • the respective changes of plasma total ascorbate concentration were -5.0, 3.8, 71.5 and 59.9%.
  • the progression rate of the thickness of the arteria intima was reduced from 0.020 mm/yr on placebo to 0.011 mm/yr after the combined formulation p ⁇ 0.05. This corresponds to almost halving the progression of the process that can later manifest itself as arteriosclerosis.
  • the thickness of the carotid intima was measured with ultrasound, this measurement has shown to be predictive of coronary heart disease and may be predictive of other artehosclerotic manifestations as well.
  • Vitamin E and vitamin C are considered two of the most important dietary antioxidants (21 , 23, 33-35). Vitamin E may also have other antiatherogenic properties (36). When vitamin E works as an antioxidant it is oxidised to harmful ⁇ - tocopheroxyl radical, which needs to get reduced back to ⁇ -tocopherol. Vitamin C can regenerate ⁇ -tocopheroxyl radical to ⁇ -tocopherol (32). Theoretically, supplementing high-risk individuals with high doses of vitamin E alone could even promote rather than reduce lipid peroxidation (38). Also, in our prospective population study, vitamin C deficiency was associated with increased risk of coronary events (39). For these reasons we designed a randomised clinical trial in which both vitamin E and vitamin C were supplemented in a factorial design.
  • the respective means in women were 0.016, 0.015, 0.017 and 0.016 mm/year.
  • the ASAP study was designed to test the main study hypothesis that the supplementation of 45-69 -year old smoking and non-smoking men and postmenopausal women with either 200 mg of d- ⁇ -tocopheryl acetate or 500 mg of vitamin C daily or both will retard the progression of common carotid atherosclerosis, the elevation of blood pressure and the progression of cataracts. This report concerns the effect on atherosclerosis.
  • ASAP is a clinical placebo- controlled double-masked 2x2 factorial trial. All subjects had hypercholesterolemia, defined as serum cholesterol of 3 5.0 mmol/L at screening.
  • Subjects were not entered into the trial if they had: premenopause or regular oral estrogen substitution therapy in women, regular intake of antioxidants, acetosalicylic acid or any other drug with antioxidative properties, severe obesity (BMI > 32 kg/m 2 ), type 1 diabetes, cataracts extracted bilaterally making opacity assessment impossible, uncontrolled hypertension (sitting diastolic BP >105 mmHg), any condition limiting mobility, making study visits impossible, severe disease shortening life expectancy, or other disease or condition worsening the adherence to the measurements or treatment.
  • the study consisted of 8-week dietary counseling and placebo lead-in phase and a 3-year double-masked phase, for which the subjects were randomly allocated to either (i) 100 mg of d- ⁇ -tocopheryl acetate twice daily (272 IU of vitamin E a day), ii) 250 mg slow-release ascorbic acid twice daily, (iii) both d- ⁇ -tocopheryl acetate and ascorbic acid in a single tablet, or (iv) placebo only. After the double-blind 3-year period, the study is continuing for another three years as an open study. The doses were chosen on the basis of pilot and kinetic studies (13, 15).
  • the subjects were randomised separately in four strata of approximately equal size: (1) smoking ( 3 5 cigarettes/day) men, (2) nonsmoking men, (3) smoking postmenopausal women, and (4) nonsmoking postmenopausal women. All subjects gave a written informed consent. The subjects came to baseline visits and were randomised. Following-up visits were 6, 12, 18, 24, 30 and 36 months later. Supplements were given, returned tablets were counted and ultrasonographic assessment of common carotid artery (CCA) intima- media thickness (IMT) was carried out at all these seven visits.
  • CCA common carotid artery
  • IMT intima- media thickness
  • Ultrasound image analysis Computer analysis of ultrasound images to measure IMT was performed with a reading station equipped with Data Translation DT 2861 video frame grabber interfaced to a Panasonic AG 7355 VCR. The Prosound software, utilising automated boundary detection, was used. IMT was determined as the average difference at on the average 100 points between intima/lumen and media/adventitia interface (42).
  • Measurement Variability Three technicians scanned 10 subjects twice at a weeks' interval in 1995. The videotapes from all scannings were read by one observer. The repeat correlations for the mean CCA-IMT were 0.988, 0.995 and 0.998 and pairwise inter-observer correlations 0.975, 0.983 and 0.995.
  • Atherosclerotic progression was defined a priori as the linear regression slope of the mean common carotid IMT over six or seven points of follow-up time (0, 6, 12, 18, 24, 30 and 36 months). For 34 subjects, one follow-up was missing. First, the mean CCA-IMT from the right and the left side was averaged, and then the slope was computed across time-specific means.
  • Ascorbic acid was stabilised in heparin plasma with metaphosphoric acid immediately after plasma separation, and frozen at -80°C. Combined ascorbic acid and dehydroascorbic acid were determined with an HPLC method (39). Heparin plasma for ⁇ -tocopherol was extracted with ethanol and hexane and measured by a reversed phase HPLC method (15). Cholesterol and triglycerides were determined with enzymatic colorimetric methods (30). Serum LDL cholesterol was measured based on precipitation using polyvinyl sulfate and HDL cholesterol after precipitation with magnesium chloride (30).
  • Plasma fibrinogen concentration was determined with a clotting method (30), plasma homocysteine with an HPLC method (44), and serum ferritin by an immunoradiometric assay (Bio Rad, Quantimune, Hercules, CA). Dietary intake of foods and nutrients was assessed at baseline by 4-day instructed food recording. Physical activity was assessed by 12-month checked questionaire (43). Blood pressure was measured manually in sitting position after a rest of 10 minutes, three measurements at 3 minutes' intervals.
  • the distributions of the main baseline characteristics of male and female study participants are shown in Table 6.
  • the smoking men had lower serum total, LDL and HDL cholesterol, plasma total ascorbate, ⁇ -tocopherol and b-carotene concentrations and greater both baseline mean IMT and increase of the mean IMT in three years (not shown) than the other groups.
  • Both smoking men and smoking women had lower dietary vitamin C intake and higher dietary saturated fat intake and plasma fibrinogen than the non-smokers.
  • the respective means in women were 0.016, 0.015, 0.017 and 0.016 mm/year (not significant).
  • Table 7 The mean adjusted 3-year change* of the mean carotid artery intima-media thickness in participants who received vitamin E and C supplements in a multivariate general linear model.
  • Covariates in the model for both men and women are serum cholesterol and ferritin concentrations, and three indicator variables for baseline examination months.
  • KAPS Kuopio Atherosclerosis Prevention Study

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Abstract

L'invention concerne un système d'administration pharmaceutique qui comprend une préparation de vitamine C (acide ascorbique) à diffusion lente et une préparation à diffusion simple de vitamine E (tocophérol) qui s'est révélé efficace pour augmenter et stabiliser les concentrations de ces vitamines dans le plasma sanguin à un taux d'environ 2.2:1. La concentration permanente et le taux de ces antioxydants s'avèrent importants dans la prévention et le traitement du stress oxydatif lié aux troubles tels que l'artériosclérose, le diabète et les troubles dégénérescents neuronaux comme la maladie d'Alzheimer.
PCT/DK2000/000459 1999-08-20 2000-08-18 Systeme d'administration pharmaceutique de vitamine c et vitamine e et utilisation d'une combinaison de ces vitamines permettant de prevenir ou de traiter des conditions provoquant un stress oxydatif Ceased WO2001013901A2 (fr)

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JP2001518039A JP2003507419A (ja) 1999-08-20 2000-08-18 ビタミンｃとビタミンｅの医薬デリバリーシステムと酸化ストレスを含む症状の予防または治療へのビタミンｃとビタミンｅの組合せ使用
PL00356667A PL356667A1 (en) 1999-08-20 2000-08-18 A pharmaceutical delivery system for vitamin c and vitamin e and use of a combination of vitamin c and e for preventing or treating conditions involving oxidative stress
AU65589/00A AU6558900A (en) 1999-08-20 2000-08-18 A pharmaceutical delivery system for vitamin c and vitamin and use of a combination of vitamin C and E for preventing or treating conditions involving oxidative stress
NZ517833A NZ517833A (en) 1999-08-20 2000-08-18 Oral delivery of antioxidants vitamin C and vitamin E combinations in slow- and plain-release formulations for treating oxidative stress
EP00952964A EP1210079A2 (fr) 1999-08-20 2000-08-18 Systeme d'administration pharmaceutique de vitamine c et vitamine e et utilisation d'une combinaison de ces vitamines permettant de prevenir ou de traiter des conditions provoquant un stress oxydatif

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000078296A3 (fr) * 1999-06-17 2002-05-30 Basf Ag Tococotrienol et/ou derives de tocotrienol pour le traitement therapeutique ou prophylactique de troubles provoques par le glutamate et/ou le calcium
WO2005023239A1 (fr) * 2003-09-05 2005-03-17 Matthias Rath Composition pharmaceutique, comprenant notamment de la vitamine c, du magnesium et de l'extrait de the vert, destinee a retarder des maladies cardiovasculaires
JP2006515872A (ja) * 2003-01-17 2006-06-08 バイタル ヘルス サイエンシズ プロプライアタリー リミティド 抗増殖性質を有する化合物
EP1496893A4 (fr) * 2002-03-28 2007-03-28 Oxis Int Inc Methodes de neuroprotection, compositions et methodes de criblage associees
US10071030B2 (en) 2010-02-05 2018-09-11 Phosphagenics Limited Carrier comprising non-neutralised tocopheryl phosphate
US10188670B2 (en) 2011-03-15 2019-01-29 Phosphagenics Limited Composition
US10973761B2 (en) 2015-12-09 2021-04-13 Phosphagenics Limited Pharmaceutical formulation
US11753435B2 (en) 2016-12-21 2023-09-12 Avecho Biotechnology Limited Process

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CA2611831C (fr) 2005-06-17 2014-09-16 Vital Health Sciences Pty Ltd. Charge comprenant un ou plusieurs derives de di- et/ou monophosphate d'agent de transfert d'electrons ou des complexes de ceux-ci
EP2552486B1 (fr) 2010-03-30 2020-08-12 Phosphagenics Limited Timbre transdermique
EP4215200A4 (fr) * 2020-09-17 2024-10-09 Resonac Corporation Activateur d'autophagie

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US4122157A (en) * 1977-03-04 1978-10-24 Richardson-Merrell Inc. Nitrofurantoin sustained release tablet
US4369172A (en) * 1981-12-18 1983-01-18 Forest Laboratories Inc. Prolonged release therapeutic compositions based on hydroxypropylmethylcellulose
DE3569080D1 (en) * 1984-08-30 1989-05-03 Rodisma Pharma Prod Gmbh Process for sustaining the release of vitamins c and e
RU2063750C1 (ru) * 1993-07-21 1996-07-20 Сергеев Александр Васильевич Состав, обладающий адаптогенным действием
JPH07227256A (ja) * 1993-12-24 1995-08-29 Takeda Chem Ind Ltd 経口液剤
IL109539A0 (en) * 1994-05-03 1994-08-26 Yissum Res Dev Co Substained-release pharmaceutical system for the delivery of antioxidants
US5560928A (en) * 1995-06-23 1996-10-01 Defelice; Stephen L. Nutritional and/or dietary composition and method of using the same
US5773031A (en) * 1996-02-27 1998-06-30 L. Perrigo Company Acetaminophen sustained-release formulation
IT1283478B1 (it) * 1996-07-22 1998-04-21 Roberto Valducci Composizioni per integrazione nutrizionale comprendenti vitamine idrosolubili a rilascio prolungato
FR2772615B1 (fr) * 1997-12-23 2002-06-14 Lipha Comprime multicouche pour la liberation instantanee puis prolongee de substances actives

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000078296A3 (fr) * 1999-06-17 2002-05-30 Basf Ag Tococotrienol et/ou derives de tocotrienol pour le traitement therapeutique ou prophylactique de troubles provoques par le glutamate et/ou le calcium
EP1496893A4 (fr) * 2002-03-28 2007-03-28 Oxis Int Inc Methodes de neuroprotection, compositions et methodes de criblage associees
JP2006515872A (ja) * 2003-01-17 2006-06-08 バイタル ヘルス サイエンシズ プロプライアタリー リミティド 抗増殖性質を有する化合物
EP1589964A4 (fr) * 2003-01-17 2007-11-21 Vital Health Sciences Pty Ltd Composes possedant des proprietes antiproliferatives
WO2005023239A1 (fr) * 2003-09-05 2005-03-17 Matthias Rath Composition pharmaceutique, comprenant notamment de la vitamine c, du magnesium et de l'extrait de the vert, destinee a retarder des maladies cardiovasculaires
JP2008509877A (ja) * 2003-09-05 2008-04-03 ラート・マティアス 通常、ビタミンｃ、マグネシウム、緑茶抽出物を含む心血管系疾患を抑制するための医薬調合物
US10071030B2 (en) 2010-02-05 2018-09-11 Phosphagenics Limited Carrier comprising non-neutralised tocopheryl phosphate
US10188670B2 (en) 2011-03-15 2019-01-29 Phosphagenics Limited Composition
US10973761B2 (en) 2015-12-09 2021-04-13 Phosphagenics Limited Pharmaceutical formulation
US11753435B2 (en) 2016-12-21 2023-09-12 Avecho Biotechnology Limited Process

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