WO1987006128A1 - Acide ascorbique revetu de catechine, et procede d'obtention - Google Patents

Acide ascorbique revetu de catechine, et procede d'obtention Download PDF

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Publication number
WO1987006128A1
WO1987006128A1 PCT/US1987/000403 US8700403W WO8706128A1 WO 1987006128 A1 WO1987006128 A1 WO 1987006128A1 US 8700403 W US8700403 W US 8700403W WO 8706128 A1 WO8706128 A1 WO 8706128A1
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WIPO (PCT)
Prior art keywords
ascorbic acid
layer
catechin
dosage structure
plant polyphenol
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PCT/US1987/000403
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English (en)
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Charles A. B. Clemetson
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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
    • A61K31/365—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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings

Definitions

  • This invention relates to the coating of pharmaceuticals with a heavy-metal-chelating substance to prevent, or at least minimize the development of mutagenic activity in the body due to "free-radical” formation resulting from oxidation of the pharmaceuticals after ingestion. More particularly, the invention relates to the coating of ascorbic acid (Vitamin C) with d-catechin to produce a layered dosage structure which protects the Vitamin C from cupric ions and other heavy metal ions which act as oxidation catalysts, by binding and inactivating the heavy metal catalysts before they can react with the vitamin.
  • ascorbic acid Vitamin C
  • this copper is present in the water as cupric ions.
  • ascorbic acid is normally a safe and valuable substance for human consumption, since ascorbic acid oxidation is virtually arrested by the acid in the stomach during digestion. Furthermore', the heavy metals present in- drinking water are usually chelated by food proteins and amino-acids before reaching the alkaline medium of the jejumum. However, about 10% of the population has no hydrochloric acid in the stomach, a condition known as achlorhydria, and these people are most likely to be adversely affected by ascorbic acid when taken with copper- containing tap water on an empty stomach. Indeed, there is a strong association between achlorhydria and cancer of the stomach.
  • Carcinogens are Mutagens: A Simple Test System Combining Liver Homogenates for Activation and Bacteria for Detection. Pro ⁇ . Natl. Acad. Sci. U.S.A. 70 No. 8. 2281-2283.
  • Fecalase a model for activation of dietary glycosides to mutagens by intestinal flora. Pro ⁇ . Natl. Acad. S ⁇ i. U.S.A. 77. No. 8. pp. 4961-4965.
  • bioflavonoids Cg-C 3 -C 6
  • bioflavonoids Cg-C 3 -C 6
  • suspensions of several bioflavonoids were found to be more effective as antioxidants for ascorbic acid, than were the small amounts of the bioflavonoids that would dissolve in aqueous media.
  • traces of heavy metal catalysts in the salts from which phosphate buffers had been prepared were being attached to the surface of the chelating bioflavonoid particles.
  • bioflavonoid-metal complex could be filtered off and the filtrates still showed the same antioxidant effect as though the bioflavonoid were still present.
  • the 5 choice of bioflavonoids for use in the invention has been found to be somewhat limited, since research by Brown, Dietrich and Brown (1977) , Brown & Dietrich (1979) and Brown (1980) has shown that bioflavonoid compounds having the 3- hydroxyl, 4-carbonyl couplet in the gamma pyrone ring, such
  • the bioflavonoids of plants are desirable materials.
  • a relatively insoluble, non-toxic, non- mutagenic heavy-metal chelating agent such as d-catechin (+ catechin) and other catechins, tannins and fibers which will chelate and inactivate or precipitate copper or other heavy metal catalysts present in drinking water, before the water can gain access to the vitamin or other medicament core.
  • Another object of this invention is to use the bioflavonoids of plants as natural, nontoxic constituents of vegetable foods, to coat ascorbic acid tablets and other vitamins and medicaments in layered dosage structures in order to chelate heavy metals and prevent the heavy-metals from gaining access to and catalyzing oxidation of the vitamins or other medicaments.
  • Yet another object of the invention is to provide a sugar coated, d-catechin encapsulated ascorbic acid tablet, vitamin or medicament with an inner layer of gelatin located between the d-catechin outer layer and the inner ascorbic acid core in dosage structures containing the medicament.
  • a still further object of this invention is to provide dosage structures which are characterized by catechin-coated vitamins, pills, tablets, granules, capsules and other non- toxic, non-mutagenic, bioflavonoid, tannin and catechin- coated formulations, medications and/or medicaments and dosage structures, in order to protect the oxidation- vulnerable vitamin, mediation or medicament core from oxidation which is catalyzed by heavy metal ions to form mutagenic compounds.
  • Another object of the invention is to provide a method of protecting ascorbic acid from contact with heavy metal ions which includes coating the ascorbic acid with at least one layer of a non-toxic, non-mutagenic bioflavonoid, catechin, tannin or other chelating fiber such as d- catechin.
  • the invention also includes a method of protecting ascorbic acid medicaments from heavy metal catalyzed oxidation, which method includes coating the ascorbic acid with d-catechin.
  • FIGURE 1 is a plan view, partially in section, of a dosage structure containing an ascorbic acid core and a d- catechin coating;
  • FIGURE 2 is a plan view, partially in section, of a o dosage structure containing an ascorbic acid core, a gelatin layer and a d-catechin coating;
  • FIGURE 3 is a sectional view of a dosage structure containing an ascorbic acid core, an inner- layer of gelatin, a first layer of d-catechin, an intermediate layer of 5 gelatin, a second layer of d-catechin and a sugar coating;
  • FIGURE 4 is a plan view, partially in section, of a dosage structure containing an ascorbic acid core, a layer of d-catechin and a sugar coating;
  • FIGURE 5 is a plan view, partially in section, of a dosage structure containing an ascorbic acid core, a layer of gelatin, a layer of d-catechin and a sugar coating;
  • FIGURE 6 is a representation of the chemical formula for d-catechin
  • FIGURE 7 is a generic formula for a family of flavones, flavanones, flavonols, flavanonols and flavanes, wherein the respective "R" and number combinations represent certain elements or compounds attached to the basic ring structure and delineated, along with d-catechin, in the Table below to define the respective members of the family;
  • FIGURE 8 consists of four graphs, A-D, of the concentrations of ascorbic acid and djhydroascorbic acid plotted versus the time of heavy metal-catalyzed oxidation and hydrolysis, respectively, of these compounds.
  • FIGURE 9 is a representation of the chemical changes that occur when ascorbic acid comes in contact with copper in the presence of oxygen.
  • FIGURE 10 is a representation of the chelation or binding and inactivation of copper by d-catechin, which is used to coat ascorbic acid in this invention. Description of the Preferred Embodiments
  • a first dosage structure is illustrated by reference numeral 1.
  • the first dosage structure 1 is characterized by an ascorbic acid core 2 of selected dosage with a catechin coating 3 encapsulating the ascorbic acid core 2, as illustrated.
  • FIGURE 2 illustrates a second dosage structure 4 which is likewise provided with an ascorbic acid core 2 of selected dosage and further including a gelatin core layer 5 of desired thickness which contains the ascorbic acid core 2 and an outer catechin coating 3 of selected thickness.
  • FIGURE 3 illustrates a third dosage structure 6 which includes an ascorbic acid core 2 of selected dosage; a gelatin core layer 5 encapsulating the ascorbic acid core 2; a catechin inner layer 7 of selected thickness covering the gelatin core layer 5; a gelatin outer layer 8 coating the catechin inner layer 7; a catechin outer layer 9 encapsulating the gelatin outer layer 8 and a sugar coating 10, provided as an outer covering for the third dosage structure 6.
  • FIGURE 4 illustrates a fourth dosage structure 11 which is characterized by an ascorbic acid core 2 of selected dosage, a catechin outer layer 9 of selected thickness and a sugar coating 10 which encapsulates both the catechin outer layer 9 and the ascorbic acid core 2.
  • FIGURE 5 represents a fifth dosage structure 12 having an ascorbic acid core 2 of selected dosage, a gelatin core layer 5 covering the ascorbic core 2, a catechin outer layer 9 of selected thickness encapsulating the gelatin core layer 5 and an outer sugar coating 10 which covers the catechin outer layer 9.
  • first dosage structure 1, second dosage structure 4, third dosage structure 6, fourth dosage structure 11 and fifth dosage structure 12 are illustrated in spherical configuration, dosage structures having alternative shapes and selected sizes are also applicable in the invention.
  • the catechin coated dosage structures illustrated in FIGURES 1-5 are not all inclusive of the possible combinations for dosage structures utilizing catechin coated ascorbic acid, but are illustrative only, and it is understood that other combinations and alternative pharmaceutical cores may also be utilized in combination with d-catechin according to the teaching of this invention, in order to minimize undesirable catalyzing of the pharmaceutical core by heavy metal ions.
  • the d- ⁇ atechin coating 3 and the ascorbic acid core 2 contain about 200 mg each of d-catechin and ascorbic acid.
  • a suitable dosage in the range of from about 50 to about 500 mg of d-catechin coating 3 may be used to coat each ascorbic core 2, which may also contain 50 to 500 mg of ascorbic acid, in each of the first dosage structure 1, second dosage structure 4, fourth dosage structure 11 and fifth dosage structure 12.
  • both the catechin inner layer 7 and the catechin outer layer 9 most preferably contain about 100 mg of d-catechin, while the ascorbic acid core 2 contains about 200 mg of ascorbic acid.
  • a thicker coating or coatings of d- catechin can be used under circumstances where heavy metal ions are known to be present in drinking water or other ingested material in above average concentrations.
  • the ascorbic acid core 2 can be characterized as a pill, tablet, granule, capsule or other ascorbic acid structure, rather than a spherical core of ascorbic acid as illustrated in the drawing, the drawing representation being illustrative of the dosage structure.
  • the first dosage structure 1, second dosage structure 4, third dosage structure 6, fourth dosage structure 11 and the fifth dosage structure 12 are not all inclusive of the possible combinations for dosage structures utilizing catechin-coated ascorbic acid according to the teaching of this invention.
  • the use of the gelatin core layer 5 in the second dosage structure 4 and fifth dosage structure 12 and the gelatin core layer 5 and outer layer 8 in the third dosage structure 6 serves to prolong dissolving of the respective dosage structures to facilitate better interaction between the catechin in the dosage structures and any heavy metal ions which may be located in drinking water or in the stomach of the person ingesting the dosage structures.
  • the provision of a sugar coating 10 in the third dosage structure 6, fourth dosage structure 11 and the fifth dosage structure 12 serves to act as a container for the catechin, to prevent crumbling of the dosage structure prior to consumption and to make the dosage structure more palatable.
  • FIGURE 6 of the drawing a representation of the formula of d-catechin is illustrated, using conventional nomenclature.
  • d-catechin as well as isomers of d-catechin and tannins which are catechin polymers, as well as alternative forms of non-toxic and non-mutagenic chelating fibers and other chelating antioxidant coatings can be used according to the teaching of this invention to chelate heavy metal ions and reduce the oxidation of ascorbic acid in dosage structures which are designed according to the teaching of this invention.
  • a one-tenth molar phosphate buffer of pH 7.4 was prepared from reagent grade Na 2 HP0 4 and NaH 2 P0 4 , using glass distilled water. One hundred ml of this buffer was warmed to 37°C in a water bath and 2 ml of a fresh solution of ascorbic acid (1 mg/ml) at about 5°C was added to give an initial ascorbic acid concentration of 19.6 mcg/ml. Samples (4 ml each) were removed and added to cold 3 percent HP0 3 (6 ml) at five-minute intervals for 30 minutes to arrest oxidation.
  • the pH 7.4 phosphate buff r selected for subsequent experiments was found, on emission spectroscopy of its component salts, to contain iron, tin, magnesium and traces of copper; its total heavy metal content as Pb from the listed analysis of the lots of monobasic and dibasic sodium phosphate was approximately 13 mcg/100 ml; it gave a time (t) of 20 minutes.
  • test substance such as 1, 3, 10, 30, 100, 300 and 1000 mg
  • flasks were placed in flasks and made up to 100 ml with the same buffer.
  • These suspensions of flavonoids, catechins, or related substances were allowed to stand for one hour; their pH was checked and re-adjusted -feo 7.4 (7.38-7.42) when necessary. They were then warmed to 37°C before adding ascorbic acid for comparative experiments. Two controls of ascorbic acid in buffer alone were used with each set of tests.
  • Test blanks consisting of test substance in phosphate buffer without ascorbic acid were run for the higher concentrations of each test substance; when these differed appreciably from the results obtained for a plain buffer 5 blank, it was necessary to run test blanks for lower concentrations and to discard the results obtained with higher concentrations which interfered with the method. Some interference by color was observed with cyanidin chloride, and interference by reduction of indophenol was
  • EXAMPLE II A procedure similar to that set forth in Example I was followed in another study of the oxidation of L-ascorbic acid in 0.10 molar sodium phosphate buffer containing traces of heavy metal impurities at a pH of 7.4 at a lower temperature of (23°C) ; the Hughes (1956) homocysteine method was used so as to analyze both for the reduced form of ascorbic acid (AA) and for the oxidized form- dehydro- ascorbic acid (DHA) . The results of this study are shown in the time and concentration graphs A-D in FIGURE 8.
  • graphs A and B illustrates the loss of AA by heavy metal catalyzed oxidation to DHA, wherein the "ascorbic-free- radical" intermediate is formed, and also spontaneous hydrolysis of DHA, wherein vitamin C (AA & DHA) is lost.
  • Graph A illustrates a study of ascorbic acid in phosphate buffer alone and graph B shows a study conducted using the same buffer after treatment with d-catechin; the catechin was added to the phosphate bu fer to form a suspension, which was shaken well for one minute; all of the undissolved catechin was then removed by filtration (along with the ⁇ helated heavy metals) before addition of ascorbic acid.
  • the difference in the rate of oxidation of ascorbic acid as a result of catechin treatment is clearly shown by contrasting graphs A and B. Similar results are obtained when d-catechin is not removed by filtration before adding the ascorbic acid.
  • cupric ions catalyze the conversion of ascorbic acid 15 to dehydroascorbic acid 17 by a two-stage oxidation.
  • a highly reactive, short-lived compound, monodehydroascorbic acid or "ascorbate-free- radical" 16 is released; it is the release of this intermediate "ascorbate-free-radical” 16 which causes the ascorbic acid 15 to become mutagenic in the presence of copper.
  • Dehydroascorbic acid 17 is an unstable compound, with a short half-life, and undergoes spontaneous hydrolysis, as illustrated to form diketogulonic acid 18, with loss of vitamin C activity, as illustrated. Referring to FIGURE 10, binding of copper by d-catechin molecule is illustrated.

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  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

Le revêtement ou enrobage de certains produits pharmaceutiques tels que l'acide ascorbique avec une substance de chélation de métaux lourds, telle que la catéchine, dans le but d'empêcher le développement de mutagènes comme le ''radical libre ascorbate'' dans le corps dû à l'action d'ions cupriques sur l'acide ascorbique est décrit. Dans un mode préférentiel de réalisation, des tablettes ou noyaux particulaires d'acide ascorbique sont enrobés avec d-catéchine dans le but de produire des structures de dosage qui protègent l'acide ascorbique contre l'oxydation catalysée par des ions de métaux lourds. Au fur et à mesure que l'enrobage de catéchine est libéré dans l'estomac, il lie les ions de métaux lourds par chélation et empêche ou réduit au minimum l'interaction du cuivre et de l'acide ascorbique.
PCT/US1987/000403 1986-04-07 1987-02-24 Acide ascorbique revetu de catechine, et procede d'obtention Ceased WO1987006128A1 (fr)

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US84910486A 1986-04-07 1986-04-07
US849,104 1986-04-07

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996013179A3 (fr) * 1994-11-01 1996-06-27 Procter & Gamble Compositions de complements alimentaires a effet physiologique
DE19807774A1 (de) * 1998-02-24 1999-08-26 Beiersdorf Ag Verwendung von Flavonen bzw. Flavanonen bzw. Flavonoiden zum Schutze von Ascorbinsäure und/oder Ascorbylverbindungen gegen Oxidation
KR20010079021A (ko) * 2001-06-05 2001-08-22 강성종 산화억제제의 안정제와 안정제를 첨가한 제품.

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US207013A (en) * 1878-08-13 Improvement in coated compressed medicaments
US462990A (en) * 1891-11-10 William oppenheimek
US2348503A (en) * 1941-08-23 1944-05-09 Atlantic Coast Fisheries Co Vitamin preparation and method of making same
US2410110A (en) * 1943-01-14 1946-10-29 Brewer & Company Inc Method of making tablets
US2811483A (en) * 1954-12-09 1957-10-29 Pfizer & Co C Pharmaceutical composition and process for preparing the same
US2853421A (en) * 1956-10-04 1958-09-23 Merck & Co Inc Gelatin pan coating
US3125491A (en) * 1962-04-06 1964-03-17 Chew able hematinic vitamin tablet
US3247064A (en) * 1962-03-30 1966-04-19 Shionogi & Co Multivitamin tablet stabilized with porous silica
US3275519A (en) * 1965-10-01 1966-09-27 Jacob A Glassman Peroral pellet and the method of making same
US3887705A (en) * 1972-05-17 1975-06-03 Fabre Sa Pierre Medicaments intended for the prevention and treatment of capillary-venous deficiencies
US3888990A (en) * 1970-03-13 1975-06-10 Zyma Sa Medicaments containing epicatechin-2-sulfonic acids and salts thereof
US4166861A (en) * 1976-03-23 1979-09-04 Inverni Della Beffa S.P.A. Pharmacologically active polyphenolic substances
US4203997A (en) * 1977-02-17 1980-05-20 Merck Patent Gesellschaft Mit Beschrankter Haftung Directly-pressable ascorbic acid-containing granulates
US4268517A (en) * 1979-08-30 1981-05-19 Continental Pharma Pharmaceutical composition and therapeutical method for treating degenerative affections of the articular cartilage
US4285964A (en) * 1979-08-30 1981-08-25 Continental Pharma Salts of (+)-catechine, their preparation and use, and compositions containing these salts
US4495177A (en) * 1983-01-17 1985-01-22 Shaklee Corporation Gel tableting agent
US4507314A (en) * 1983-07-20 1985-03-26 Midit, Societe Fiduciaire Drug for treating affections provoked by a too high histamine level, of the gastroduodenal mucosa and allergic affections
US4515804A (en) * 1982-02-24 1985-05-07 Zyma Sa Crystal modifications of (+)-catechin and pharmaceutical preparations containing them

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CH408284A (de) * 1958-06-26 1966-02-28 Philips Nv Verfahren zum Stabilisieren kristallinischer Verbindungen gegen Oxydation
FR2073251A1 (en) * 1969-12-03 1971-10-01 Therapeuti Bureau Et Flavanol polyacid complexes - useful for stabilizing and purifying flavanol monomers for antiscorbutic use

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US2348503A (en) * 1941-08-23 1944-05-09 Atlantic Coast Fisheries Co Vitamin preparation and method of making same
US2410110A (en) * 1943-01-14 1946-10-29 Brewer & Company Inc Method of making tablets
US2811483A (en) * 1954-12-09 1957-10-29 Pfizer & Co C Pharmaceutical composition and process for preparing the same
US2853421A (en) * 1956-10-04 1958-09-23 Merck & Co Inc Gelatin pan coating
US3247064A (en) * 1962-03-30 1966-04-19 Shionogi & Co Multivitamin tablet stabilized with porous silica
US3125491A (en) * 1962-04-06 1964-03-17 Chew able hematinic vitamin tablet
US3275519A (en) * 1965-10-01 1966-09-27 Jacob A Glassman Peroral pellet and the method of making same
US3888990A (en) * 1970-03-13 1975-06-10 Zyma Sa Medicaments containing epicatechin-2-sulfonic acids and salts thereof
US3887705A (en) * 1972-05-17 1975-06-03 Fabre Sa Pierre Medicaments intended for the prevention and treatment of capillary-venous deficiencies
US4166861A (en) * 1976-03-23 1979-09-04 Inverni Della Beffa S.P.A. Pharmacologically active polyphenolic substances
US4203997A (en) * 1977-02-17 1980-05-20 Merck Patent Gesellschaft Mit Beschrankter Haftung Directly-pressable ascorbic acid-containing granulates
US4268517A (en) * 1979-08-30 1981-05-19 Continental Pharma Pharmaceutical composition and therapeutical method for treating degenerative affections of the articular cartilage
US4285964A (en) * 1979-08-30 1981-08-25 Continental Pharma Salts of (+)-catechine, their preparation and use, and compositions containing these salts
US4515804A (en) * 1982-02-24 1985-05-07 Zyma Sa Crystal modifications of (+)-catechin and pharmaceutical preparations containing them
US4495177A (en) * 1983-01-17 1985-01-22 Shaklee Corporation Gel tableting agent
US4507314A (en) * 1983-07-20 1985-03-26 Midit, Societe Fiduciaire Drug for treating affections provoked by a too high histamine level, of the gastroduodenal mucosa and allergic affections

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996013179A3 (fr) * 1994-11-01 1996-06-27 Procter & Gamble Compositions de complements alimentaires a effet physiologique
DE19807774A1 (de) * 1998-02-24 1999-08-26 Beiersdorf Ag Verwendung von Flavonen bzw. Flavanonen bzw. Flavonoiden zum Schutze von Ascorbinsäure und/oder Ascorbylverbindungen gegen Oxidation
KR20010079021A (ko) * 2001-06-05 2001-08-22 강성종 산화억제제의 안정제와 안정제를 첨가한 제품.
WO2002098411A1 (fr) * 2001-06-05 2002-12-12 Sung-Zong Kang Stabilisateurs d'antioxydants, formulations et produits d'antioxydants additionnes de stabilisateurs

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JPH01500113A (ja) 1989-01-19
EP0263132A1 (fr) 1988-04-13

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