Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2000-03-15
2002-12-10
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S464000, C424S457000, C424S458000, C424S484000
Reexamination Certificate
active
06491948
ABSTRACT:
The present invention relates to novel compositions comprising ascorbic acid in a sustained release form and isoquercetin both with an increased bioavailability. These compositions are useful as food supplements possessing preventive properties against damage to human brain tissue due to oxidative stress. Specifically, these damages lead to memory loss, decline of cognitive abilities, premature aging.
BACKGROUND OF THE INVENTION
Study of biochemical events accompanying memory formation and memory regulation led us to an invention based on the novel concept of preventing an oxidative destabilization of DNAs, RNAs and proteins involved in neuronal memory processes [See Cohen, N. J., Eichenbaum, H. B. (1993) Memory, amnesia and the hippocampal system, Cambridge, Mass.: MIT Press; Olton, D. S. (1983) Memory functions and the hippocampus, in Seifert, W. (ed.) Neurobiology of the hippocampus, New York: Academic Press].
In vivo ascorbic acid (vitamin C) exists in three forms:
a) as an ascorbate in form of an ascorbate monoanion,
b) as a free radical, called semidehydroascorbic acid which could be reversibly oxidized to dehydroascorbic acid or reversibly reduced to ascorbate monoanion, and
c) as dehydroascorbic acid (oxidized form of semidehydroascorbic acid).
Only ascorbate possesses specific vitamin C activity as a cofactor for enzymes. Observed physiological activities of semidehydroascorbic acid and dehydroascorbic acid formed in vivo from ascorbate are considered to be based on their reversible reductions to ascorbates. See Buettner, G. R. (1993). The pecking order of free radicals and antioxidants: lipid peroxidation, alpha-tocopherol, and ascorbate, Arch. Biochem. Biophys. 300, 535-543; Dharival, K. R. et al. (1991), Semihydroascorbic acid as an intermediate in norepinephrine biosynthesis in chromaffin granules, J. Biol. Chem. 266, 12908-12914; and Welch, R. W. et al. (1995), Accumulation of vitamin C (ascorbate) and its oxidized metabolite dehydroascorbic acid occurs by separate mechanisms, J. Biol. Chem. 270, 12584-12592.
The second form of ascorbic acid, semidehydroascorbic acid (ascorbate free radical) participates in univalent redox systems that is in the antioxidant defense activity. See Bors, W. et al. (1995), Interaction of Flavonoids with Ascorbate and Determination of their Univalent Redox Potentials: a Pulse Radiolysis Study, Free Radical Biology and Medicine, vol. 19, No. 1, 45-52. This means semidehydroascorbic acid participates most likely in free radical scavenging activities. According to the article Gordon, M. H. (1996), Dietary Antioxidants in Disease Prevention, Natural Product Reports, pp. 265-273, “ascorbate appears to be the most important non-protein antioxidant in plasma” p. 270. Ascorbic acid is not able to cross blood-brain barrier. In contrast, dehydroascorbic acid readily enters the brain. See Agus, D. B. et al. (1997), Vitamin C crosses the blood-brain barrier in the oxidized form through the glucose transporters, J. Clin. Invest., 100 (11) 2842-2848. After entering the brain dehydroascorbic acid is reduced and retained as ascorbic acid.
Structures of body tissues are susceptible to damages caused by the oxidative stress, e.g. by the accumulation of reactive oxygen species during aging, chronic environmental stress, inflammations or general metabolic dysfunctions. The role of free radicals and reactive oxygen species in aetiology of a variety of human diseases including brain dysfunctions is well established. See: Gordon, (1996) supra. Uncontrolled generation of free radicals, especially chronic exposure to reactive oxygen species leads to chronic intracellular damage, to oxidative stress and premature aging. Oxidative stress and the decreased ability of the body to maintain the regulation of intermediary redox systems play a crucial role in age-related brain function decline, memory loss, and a number of neurodegenerative disorders. The formation and accumulation of free radicals lead to excessive lipid peroxidation, amyloid deposition, degeneration of brain and peripheral neurons, and cell death. See Floyd, R. A., Carney, J. M. (1996), Free radical damage to protein and DNA: mechanisms involved and relevant observations on brain underoing oxidative stress, Ann. Neurol., 32, 522-527.
Cells of the human body including brain cells possess metabolic antioxidant defenses which are supported by dietary antioxidants. The early observations of the antioxidant defense metabolic processes involved vitamin C and flavonoids. See Bezssonoff, N. (1926), L'effet antiscorbutique est-il du a deux substances differentes?, C.r. Acad. Sci., Paris 183, 1309-1310; Bull. Soc. Chim. Biol. (1927) 9, 568-579; Bentsath, A., Szent-Gyorgyi, A. et al. (1936), Vitamin natur of flavones, Nature (London) 138, 798; Bentsath, A., Szent-Gyorgyi, A. et al. (1937), Vitamin P, Nature (London) 139, 326-327; and Blanc, B. and Von der Muehl, M. (1967), Interaction d'une flavonoide et vitamine C; son influence sur le poids du cobaye et le contenu en vitamine C de ses organs, Int. Z. VitaminForsch., 37,156-169.
Oxidation of the ascorbate in the human body by xenobiotics often leads to the accumulation of semidehydroascorbic acid or dehydroascorbic acid in organs where these forms interfere with the regular metabolism. Vitamin C is believed to play a critical role in the central nervous system. See Englard, S. and Seifter, S. (1986). The biochemical functions of ascorbic acid, Ann. Rev. Nutr. 6, 365-406; Padh, H. (1990), Cellular function of ascorbic acid, Biochem. Cell. Biol., 68, 1166-1173. It is involved in catecholamine biosysnthesis (as a cofactor of dopamine-beta-hydroxylase). It also acts as free radical scavenger inhibiting the peroxidation of membrane phospholipids. The decrease of the concentration of ascorbate in brain tissue may lead to serious metabolic dysfunctions.
The concentration of vitamin C in brain is higher than in other organs. See Kaufman, S. (1966), Coenzymes and hydroxylases: ascorbate and dopamine-beta-hydroxylase: tetrahydropteridines and phenylalanine and tyrosine hydroxylases, Pharmacol. Rev., 18, 61-69. Particularly, it is 10 times higher than in blood serum. See Honig, D. (1975), Distribution of ascorbic acid, metabolites and analogues in man and animals, Ann. N.Y. Aca. Sci., 258, 103-118. An active transport mechanism exists for carrying ascorbic acid from blood to brain. It has been found that dehydroascorbic acid is transported through facilitative glucose transporters. See Vera, J. C. et al. (1993), Mammalian facilitative hexose transporters mediate the transport of dehydroascorbic acid, Nature, 364, 79-82. The concentration of vitamin C in brain may be increased by increasing the blood concentration of dehydroascorbic acid.
The possibilities to protect ascorbic acid in vivo were based on very early observations of Szent-Gyorgyi group mentioned above that the ascorbic acid activity in humans and guinea pigs is intensified by the great group of “vegetable dyes, the flavons or flavonols”. It has been known that flavonoids are contributing to the maintenance of the concentration of the administered ascorbate in adrenals, kidneys, spleen, and the liver of the organisms investigated and improve the antiscorbutic effect of the dosages of ascorbate used. See Cotereau, H. et al. (1948), Influence of vitamin P (C2) Upon the amount of ascorbic acid in the organs of the guinea pig, Nature, 161, 557-558; Crampton, E. W. et al. (1950), A qualitative estimation of the effect of rutin on the biological potency of vitamin C, J. Nutr., 41, 487-498; Blanc, B. and Von der Muehl, M., supra; and Zloch, Z. (1973), Einfluss von Bioflavonoiden auf den Vitamin C-Wert kristallliner Deydroascorbinsaure, Int. J. Vit. Nutr. Res. 43, 378-386.
The mechanism of this effect, called “the vitamin C-economizing function” of some flavonoids (“facteur d'economie de L'acide ascorbique” of Bezssonoff, 1926 and 1927, supra) has been recognized in many laboratories. For example, it was found that, among flavonoids tested, flavonols have the strongest ability to
Buchholz Herwig A.
Meduski Jerzy D.
Bennett Rachel M.
Merck Patent GmbH
Millen White Zelano & Branigan P.C.
Page Thurman K.
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