WO2007009997A1 - Composition containing micronutrients with improved anti-oxidant activity and the use thereof. - Google Patents

Composition containing micronutrients with improved anti-oxidant activity and the use thereof. Download PDF

Info

Publication number
WO2007009997A1
WO2007009997A1 PCT/EP2006/064385 EP2006064385W WO2007009997A1 WO 2007009997 A1 WO2007009997 A1 WO 2007009997A1 EP 2006064385 W EP2006064385 W EP 2006064385W WO 2007009997 A1 WO2007009997 A1 WO 2007009997A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition according
minutes
carrier
grinding
compositions
Prior art date
Application number
PCT/EP2006/064385
Other languages
French (fr)
Inventor
Paolo Corvi Mora
Tiziana Canal
Federica Ruzzier
Fulvio Fortuna
Original Assignee
Actimex S.R.L.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Actimex S.R.L. filed Critical Actimex S.R.L.
Priority to US11/996,063 priority Critical patent/US20080219963A1/en
Priority to AU2006271635A priority patent/AU2006271635A1/en
Priority to CA002615745A priority patent/CA2615745A1/en
Priority to EP06792518A priority patent/EP1906927A1/en
Priority to JP2008521962A priority patent/JP2009543756A/en
Publication of WO2007009997A1 publication Critical patent/WO2007009997A1/en

Links

Classifications

    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23P—SHAPING OR WORKING OF FOODSTUFFS, NOT FULLY COVERED BY A SINGLE OTHER SUBCLASS
    • A23P10/00—Shaping or working of foodstuffs characterised by the products
    • A23P10/40—Shaping or working of foodstuffs characterised by the products free-flowing powder or instant powder, i.e. powder which is reconstituted rapidly when liquid is added
    • A23P10/47—Shaping or working of foodstuffs characterised by the products free-flowing powder or instant powder, i.e. powder which is reconstituted rapidly when liquid is added using additives, e.g. emulsifiers, wetting agents or dust-binding agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/46—Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/31—Hydrocarbons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/34—Alcohols
    • A61K8/347—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/35—Ketones, e.g. benzophenone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/35—Ketones, e.g. benzophenone
    • A61K8/355—Quinones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
    • A61K8/498—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom having 6-membered rings or their condensed derivatives, e.g. coumarin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4986—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with sulfur as the only hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/73—Polysaccharides
    • A61K8/738—Cyclodextrins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
    • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
    • A61K8/9783—Angiosperms [Magnoliophyta]
    • A61K8/9789—Magnoliopsida [dicotyledons]
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • 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
    • A61P17/18—Antioxidants, e.g. antiradicals
    • 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
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/52—Stabilizers
    • A61K2800/522—Antioxidants; Radical scavengers

Definitions

  • the invention relates to at least ternary compositions that can be obtained through a dry co- grinding process, comprising at least one micronutrient substance particularly with antioxidant activity as active substance, a carrier and at least one co-grinding substance, to a process for the preparation and the pharmaceutical or parapharmaceutical use thereof in the cosmetic and dietary-nutritional fields.
  • antioxidant compounds Due to their protective biological properties against cellular oxidative stress, for some time now, antioxidant compounds have been believed to be of applicational interest in a number of disorders, for clearly therapeutic purposes, or under paraphysiological conditions, for essentially preventive purposes. Indeed, their applications may be manifold and thus find great use in the pharmaceutical and parapharmaceutical fields, particularly in the cosmetics and dietary -nutritional sectors.
  • ubidecarenone is a particularly interesting compound due to its biological activities, and for this reason, it has often been used therapeutically in numerous speciality medications with cardiotonic activities.
  • ubidecarenone is a compound that is very difficult to handle, having a waxy consistency and poor solubility and dispersability.
  • it is characterised by being low-melting, with a melting point of between 45 and 48°C.
  • ubidecarenone In relation to solubility, ubidecarenone is not particularly soluble in water or in aqueous environments ( «0.1 mg/ml), while it is poorly soluble in dioxan, ether and methylene chloride. Furthermore, it has very high affinity for plastics.
  • compositions in fine powder form essentially consisting of active substances that are poorly soluble in aqueous or organic environments this applicant developed a dry co-grinding process in which an active substance is included in a hydrophilic or hydrophobic carrier, depending on the physico- chemical characteristics of the active substance in question, in the presence of an auxiliary co- grinding substance, which allows a significant reduction in co-grinding times, and under milder grinding operational conditions, with undoubted advantages for active substance stability.
  • compositions in fine powder form that are easily dispersible in aqueous environments, and possibly soluble in the same, the applicant has surprisingly found that the compositions obtained showed a significant increase in antioxidant power considering equal active substance content in solution.
  • compositions in fine powder form, with good processability obtainable by means of a dry co-grinding process of an at least ternary composition comprising an active principle, a carrier and at least one auxiliary co- grinding substance, characterised in that said active principle comprises at least one micronutrient substance with antioxidant activity and is present in an amount such that the weight ratio active principle/carrier is less than 1, and said co-grinding process is carried out for less than 90 minutes, whereby the antioxidant activity of said composition is greater than the antioxidant activity of a solution containing the same amount of active substance alone under the same conditions.
  • said carrier is present in an amount not less than 50% w/w of the total of said at least ternary mixture.
  • said enhancement of the antioxidant activity is achieved when the at least ternary composition undergoes a co-grinding process not exceeding 60 minutes.
  • Further objects of the invention include the process for the preparation thereof and the pharmaceutical or parapharmaceutical use thereof in the cosmetic and dietary-nutritional fields.
  • Figure 1 High pressure liquid chromatography (HPLC) of example 6 (lipoic acid/polyvinylpyrrolidone/glycine 1/8.5/0.5) subjected to mechanico-chemical activation for 15 min, and example C (lipoic acid/polyvinylpyrrolidone/glycine 1/8.5/0.5) subjected to mechanico-chemical activation for 90 minutes;
  • HPLC high pressure liquid chromatography
  • Figure 2 antioxidant activity of the composition of example 4 (ubidecarenone/ ⁇ - cyclodextrin/glycine 1/8/1) subjected to mechanico-chemical activation for 15 min;
  • Figure 3 antioxidant activity of the composition of example 8 (resveratrol/ ⁇ - cyclodextrin/glycine 1.5/7/1.5) subjected to mechanico-chemical activation for 60 minutes, and example D (resveratrol/ ⁇ -cyclodextrin/glycine 1.5/7/1.5) subjected to mechanico- chemical activation for 120 minutes.
  • Essential for the scope of reducing the co-grinding time and improving the solubility/dispersibility of the active ingredients included in the ternary compositions, is the presence of an auxiliary co-grinding substance selected from the group consisting of aminoacids, malic acid, fumaric acid, ascorbic acid, citric acid, , polyalcohols, ethylene diamine tetra acetate, surfactants, lecithins, phospholipids and derivatives thereof, while the hydrophilic carrier may be selected from the group consisting of dextrins and derivatives thereof (including cyclic derivatives), dextrans, linear and cross-linked polyvinylpyrrolidones and derivatives thereof, cellulose and derivatives thereof, mannoglucurans, chitosans, galactomannans and sodium starch glycolate, and the hydrophobic carrier may be selected from the group consisting of ethylcellulose, polyacrylates and derivatives, polymethacrylates and derivatives, polystyrene and derivatives
  • auxiliary co-grinding substances were essential, as appears evident from comparison of the ternary compositions with the corresponding binary compositions.
  • active substance/carrier/auxiliary co-grinding substance weight ratios of i) active substance/carrier of between 1:0.1 and 1:100 and preferably between 1:0.5 and 1:50; ii) active substance : auxiliary co-grinding substance of between 1:0.1 and 1:20 and preferably between 1:0.2 and
  • the co-grinding time was comprised between 0.25 and 24 hours.
  • the process that brings about the result above is characterised by a particular ratio between the active principle and the carrier. More precisely, the active principle or substance is present in a w/w ratio with the carrier of less than 1, preferably less than 0.8, more preferably less than 0.5.
  • the carrier is preferably present in a weight percentage of at least 50% on the amount of the at least ternary composition.
  • the carrier is present in a w/w percentage of at least
  • An enhancement of the antioxidant activity can be obtained when the at least ternary mixture is subjected, through a co-grinding process, to mechanico-chemical activation for a period of time of less than 90 minutes, preferably not greater than 60 minutes.
  • the enhancement of the antioxidant activity of said composition is measured by comparison with the antioxidant activity of the same quantity of active substance alone under the same conditions (in solution).
  • the dry co-grinding process may be performed using known means, such as ball mills, blade mills, vibrational mills, centrifugal mills and planetary mills.
  • the preferred active substances or principles generally belong to the class of micronutrients with antioxidant or anti-free radical activity, and may include, but are not limited to ubidecarenone, lipoic acid, lycopene, resveratrol, green tea extracts, astaxantin, pycnogenol, genistein, tocopherols and tocotrienols, retinol, carotenoids, ascorbic acid, glutathione, sulphurated aminoacids and derivatives thereof, flavonoids and mixtures and derivatives thereof, polyphenols and mixtures and derivatives thereof.
  • hydro- or amphiphilic carriers and particularly carriers selected from the group consisting of dextrins and derivatives thereof (also cyclic), dextrans, linear, branched and cross-linked polyvinylpyrrolidones, cellulose and derivatives thereof, mannoglycosans, chitosans, alginates and derivatives thereof, galactomannans and sodium starch glycolate, as inclusion carriers, while the auxiliary co-grinding substances are selected from the group consisting of aminoacids, weak acids (for example malic acid, fumaric acid, ascorbic acid, citric acid), polyalcohols, ethylene diamine tetra-acetic acid and the salts thereof, surfactants, lecithins, phospholipids and derivatives thereof, and preferably from the group consisting of glycine, lysine, serine and disodium ethylene diamine tetra-acetate.
  • auxiliary co-grinding substances are selected from the group consisting of aminoacids, weak acids
  • auxiliary co-grinding substance For the purposes of improving the processability of the ternary mixture consisting of active substance : carrier : auxiliary co-grinding substance, additional (one or more) auxiliary co- grinding substances may be used with various properties and capable of improving, for example, the technological (free flowability, residual humidity) or organoleptic characteristics, such as for example glycyrrhizinate, sorbitol, silicas, chelating agents, aminoacids, sweeteners, inorganic oxides.
  • organoleptic characteristics such as for example glycyrrhizinate, sorbitol, silicas, chelating agents, aminoacids, sweeteners, inorganic oxides.
  • Example 1 Some examples of preparations, on both the laboratory and pilot plant scales, of compositions according to the invention, are described below by way of non-limiting illustration of the present invention.
  • Example 1 Some examples of preparations, on both the laboratory and pilot plant scales, of compositions according to the invention, are described below by way of non-limiting illustration of the present invention.
  • the product in the form of a fine powder, was sieved at 710 ⁇ m.
  • a ubidecarenone/copovidone/glycine ternary composite material was obtained with a weight percentage ratio of 20/75/5.
  • the product in the form of a fine powder, was unloaded and sieved at 355 ⁇ m.
  • a lipoic acid/linear PVP/arginine ternary composite material with a weight ratio of 1/8.5/0.5 was obtained with a lipoic acid content of 10%.
  • resveratrol 22.5 g of beta cyclodextrin 1.5 g of glycine and 1.5g of ammonium glycyrrhizinate were mixed for 10 minutes in a rotating body mixer, then loaded into the jar of a planetary mill and subjected to mechanico-chemical activation for 30 minutes at a speed of 200 rpm. Upon completion of the process, the product, in the form of a fine powder was unloaded and sieved at 355 ⁇ m.
  • a resveratrol/beta-cyclodextrin/gly cine/ammonium glycyrrhizinate quaternary composite material with a weight ratio of 1.5/7.5//0.5/0.5 was obtained with a resveratrol content of 15%.
  • resveratrol, 21.Og of beta-cyclodextrin and 4.5 g of glycine were mixed for 10 minutes in a rotating body mixer, then loaded into the jar of a planetary mill and subjected to mechanico-chemical activation for 60 minutes at a speed of 200 rpm. Upon completion of the process, the product, in the form of a fine powder was unloaded and sieved at 355 ⁇ m.
  • a green tea d.e./ ⁇ - cyclodextrin/serine/ammonium glycyrrhizate quaternary composite material with a weight ratio of 4/5/0.5/0.5 was obtained with a green tea d.e. content of 40%.
  • Quaternary compositions of astaxantin/povidone/ascorbic acid/Zn gluconate 2.5/5.5/1.5/0.5 7.5 g of astaxantin, 16.55 g of povidone, 4.5 g of ascorbic acid, 1.5 g of zinc gluconate were mixed for 10 minutes in a rotating body mixer; the mixture was then loaded into the jar of a planetary mill and subjected to mechanico-chemical activation for 35 minutes at a speed of
  • pycnogenol 7.5 g of pycnogenol, 19.5 g of ⁇ -cyclodextrin and 3 g of glycine were mixed for 10 minutes in a rotating body mixer; the mixture was then loaded into the jar of a planetary mill and subjected to mechanico-chemical activation for 45 minutes at a speed of 150 rpm. Upon completion of the process, the product, in the form of a fine powder, was unloaded and sieved at 355 ⁇ m. A pycnogenol/ ⁇ -cyclodextrin/glycine ternary composite material with a weight ratio of 2.5/6.5/1 was obtained with a pycnogenol content of 25%.
  • a ubidecarenone/copovidone/glycine ternary composite material in a w/w ratio of 3/6/1 was obtained with a ubidecarenone content of 30%.
  • Example C 1 kg of a 20/75/5 w/w ratio mixture of ubidecarenone (200 g), copovidone (750 g) and glycine (50 g), obtained using a rotating body mixer, were loaded into the chamber of a high energy vibrational mill and subjected to mechanico-chemical activation for 120 minutes. Upon completion of the process, a soft unprocessable material was obtained.
  • Example C 1 kg of a 20/75/5 w/w ratio mixture of ubidecarenone (200 g), copovidone (750 g) and glycine (50 g), obtained using a rotating body mixer, were loaded into the chamber of a high energy vibrational mill and subjected to mechanico-chemical activation for 120 minutes. Upon completion of the process, a soft unprocessable material was obtained.
  • Example C 1 kg of a 20/75/5 w/w ratio mixture of ubidecarenone (200 g), copovidone (750 g) and glycine (50 g),
  • Example E 4.5 g of resveratrol, 21 g of ⁇ -cyclodextrin and 4.5 g of glycine were mixed for 10 minutes in a rotating body mixer, then loaded into the jar of a planetary mill and subjected to mechanico- chemical activation for 120 minutes. Upon completion of the process, a sticky unprocessable material was obtained, Example E
  • Quaternary compositions of green tea dry extract/ ⁇ -cvclodextrin/serine/ammonium glvcyrrhizate 4.5/4.5/0.5/0.5
  • antioxidant activity has also been evaluated by means of spectrofluormetric measurements in comparison to solutions of equal concentration of the active substance contained therein.
  • DSC Differential scanning calorimetry
  • DSC is a technique which allows evaluation of the crystallinity of powders based on determination of the heat exchanges occurring in the same during melting subsequent to progressive heating.
  • Antioxidant activity was measured using the ORAC (Oxygen Radical Absorbance Capacity) test. Said test has been developed by Cao et al. in 1993 (Oxygen-radical absorbance capacity assay for antioxidants. Free Rad. Biol. Med. 1993;14: 303-11).
  • the test was based on measuring the inhibition induced by an antioxidant on the loss of activity of a fluorescent indicator, in the presence of oxidants.
  • Antioxidant activity was assessed by spectrofluorometric assay, measuring the decay of the fluorescence of the indicator over time (from 0 to 360 minutes). A measuring the fluorescence of the sodium fluorescein indicator was performed using a spectrofluorimeter at a wavelength of 515 nm.
  • Antioxidant activity is expressed as the antioxidant power in relation to Trolox® at the same concentration of the samples.
  • fig. 1 shows comparative chromatograms of example 6 and example C, while figures 3 and 4 show the antioxidant activities of examples 4 and 8, respectively.
  • Analysis of the results obtained shows that the advantageous effect of strengthening of the antioxidant activities of the at least ternary compositions forming the subject of the invention, obtained by means of a co-grinding process, is dependant on the active substance/carrier ratios and on mechanico-chemical activation, which must be less than 90 minutes. Furthermore, it may be observed that said effect is independent of increasing solubility. Furthermore, it may be observed that the addition of the auxiliary co-grinding substance does not have any significant contribution towards said effect.
  • compositions of the invention may be used to prepare products with more favourable active substance quantity/effect ratios. Indeed, the possibility of limiting the quantity of antioxidant with equal antioxidant effect may have a favourable impact on any potential tolerability/toxicity effects.
  • compositions forming the subject of the present invention may be prepared in powder form, or in mixtures with pharmaceutically, parapharmaceutically, or dietary-nutritional acceptable excipients and diluents. They may additionally be used in various forms, such as for example capsules, tablets, pastes, gels, solutions or suspensions, sprays with pharmaceutically, parapharmaceutically, and dietary-nutritional acceptable excipients and diluents and adapted for such other forms.
  • compositions of the invention may be formulated with cosmetically acceptable excipients or diluents in the form of lotions, creams, ointments, pastes, gels, patches, mousse, foams, sticks and sprays and other topical forms known for such use.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Birds (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Polymers & Plastics (AREA)
  • Mycology (AREA)
  • Emergency Medicine (AREA)
  • Food Science & Technology (AREA)
  • Botany (AREA)
  • Nutrition Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Dermatology (AREA)
  • Organic Chemistry (AREA)
  • Biotechnology (AREA)
  • Biochemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Microbiology (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Toxicology (AREA)
  • Obesity (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Cosmetics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Coloring Foods And Improving Nutritive Qualities (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Plant Substances (AREA)

Abstract

Compositions in fine powder form that can be obtained by means of a dry co-grinding process of an at least ternary mixture consisting of an active substance, a carrier and at least one auxiliary co-grinding substance, wherein the active substance is constituted by one or more micronutrient substances with particular antioxidant activity. Such compositions have shown a significant increase in active substance antioxidant power in comparison to solutions of equal active substance content. Said effect is particularly useful for uses for active substances included in antioxidant compositions in the pharmaceutical, cosmetic and dietary-nutritional fields.

Description

COMPOSITION CONTAINING MICRONUTRIENTS WITH IMPROVED ANTIOXIDANT ACTIVITY AND THE USE THEREOF
DESCRIPTION TECHNICAL FIELD
The invention relates to at least ternary compositions that can be obtained through a dry co- grinding process, comprising at least one micronutrient substance particularly with antioxidant activity as active substance, a carrier and at least one co-grinding substance, to a process for the preparation and the pharmaceutical or parapharmaceutical use thereof in the cosmetic and dietary-nutritional fields. BACKGROUND ART
Due to their protective biological properties against cellular oxidative stress, for some time now, antioxidant compounds have been believed to be of applicational interest in a number of disorders, for clearly therapeutic purposes, or under paraphysiological conditions, for essentially preventive purposes. Indeed, their applications may be manifold and thus find great use in the pharmaceutical and parapharmaceutical fields, particularly in the cosmetics and dietary -nutritional sectors.
However, many of such compounds are difficult to handle during the industrial preparation processes of compositions suitable for the desired pharmaceutical or parapharmaceutical purposes, since, for example, they are frequently, poorly soluble in both aqueous and organic solvent environments, or possess other unfavourable physico-chemical characteristics. Besides the above-mentioned drawbacks, and particularly in relation to those pertaining to solubility, from the technological viewpoint, it is essential to also bear in mind that frequently said compounds may not be subjected to overly drastic processes, in order to avoid their degradation due to oxidation phenomena, which would make them practically unusable for the desired purposes.
The formulation related technological difficulties associated with antioxidants are exemplified by the flavonoids, vitamins, mineral salts, polyphenols, lipoic acid, sulphurated aminoacids, EDTA, glutathiones, carotenoids, melatonin, or even a compound such as ubidecarenone. For example, ubidecarenone is a particularly interesting compound due to its biological activities, and for this reason, it has often been used therapeutically in numerous speciality medications with cardiotonic activities. However, it is also known from the pharmaceutical viewpoint, that it is a compound that is very difficult to handle, having a waxy consistency and poor solubility and dispersability. Furthermore, it is characterised by being low-melting, with a melting point of between 45 and 48°C. In relation to solubility, ubidecarenone is not particularly soluble in water or in aqueous environments («0.1 mg/ml), while it is poorly soluble in dioxan, ether and methylene chloride. Furthermore, it has very high affinity for plastics.
In order to resolve the problems generally associated with preparing compositions in fine powder form essentially consisting of active substances that are poorly soluble in aqueous or organic environments, this applicant developed a dry co-grinding process in which an active substance is included in a hydrophilic or hydrophobic carrier, depending on the physico- chemical characteristics of the active substance in question, in the presence of an auxiliary co- grinding substance, which allows a significant reduction in co-grinding times, and under milder grinding operational conditions, with undoubted advantages for active substance stability. This process, described in patent application WO03/097012, allows the attainment of active substance/carrier/auxiliary co-grinding substance ternary compositions, the solubility and dissolution characteristics of which are significantly improved with respect to the corresponding active substance/carrier binary compositions. SUMMARY
By applying the above described processes to antioxidants in order to obtain compositions in fine powder form that are easily dispersible in aqueous environments, and possibly soluble in the same, the applicant has surprisingly found that the compositions obtained showed a significant increase in antioxidant power considering equal active substance content in solution.
It is therefore an object of the present invention to provide compositions in fine powder form, with good processability, obtainable by means of a dry co-grinding process of an at least ternary composition comprising an active principle, a carrier and at least one auxiliary co- grinding substance, characterised in that said active principle comprises at least one micronutrient substance with antioxidant activity and is present in an amount such that the weight ratio active principle/carrier is less than 1, and said co-grinding process is carried out for less than 90 minutes, whereby the antioxidant activity of said composition is greater than the antioxidant activity of a solution containing the same amount of active substance alone under the same conditions.
According to a preferred aspect of the invention, said carrier is present in an amount not less than 50% w/w of the total of said at least ternary mixture.
According to another preferred aspect of the invention, said enhancement of the antioxidant activity is achieved when the at least ternary composition undergoes a co-grinding process not exceeding 60 minutes. Further objects of the invention include the process for the preparation thereof and the pharmaceutical or parapharmaceutical use thereof in the cosmetic and dietary-nutritional fields.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1: High pressure liquid chromatography (HPLC) of example 6 (lipoic acid/polyvinylpyrrolidone/glycine 1/8.5/0.5) subjected to mechanico-chemical activation for 15 min, and example C (lipoic acid/polyvinylpyrrolidone/glycine 1/8.5/0.5) subjected to mechanico-chemical activation for 90 minutes;
Figure 2: antioxidant activity of the composition of example 4 (ubidecarenone/γ - cyclodextrin/glycine 1/8/1) subjected to mechanico-chemical activation for 15 min; Figure 3: antioxidant activity of the composition of example 8 (resveratrol/β - cyclodextrin/glycine 1.5/7/1.5) subjected to mechanico-chemical activation for 60 minutes, and example D (resveratrol/β-cyclodextrin/glycine 1.5/7/1.5) subjected to mechanico- chemical activation for 120 minutes. DETAILED DESCRIPTION OF THE INVENTION
The objects and advantages of the present invention will be better understood over the course of the following detailed description.
The previously cited patent application WO03/097012 describes a dry co-grinding process wherein an active substance is included in a hydrophilic or hydrophobic carrier, depending on the physico-chemical characteristics of the active substance in question, in the presence of an auxiliary co-grinding substance allowing a significant reduction in co-grinding times. Said process meets the aim of overcoming the technological-pharmaceutical difficulties associated with substances or active principles that are difficult to handle due to their poor solubility and/or stability. Using said process, it is possible to obtain active substance/hydrophilic or hydrophobic carrier/auxiliary co-grinding substance ternary compositions, the solubility and dissolution characteristics of which are significantly improved with respect to the corresponding active substance/carrier binary compositions. Essential for the scope of reducing the co-grinding time and improving the solubility/dispersibility of the active ingredients included in the ternary compositions, is the presence of an auxiliary co-grinding substance selected from the group consisting of aminoacids, malic acid, fumaric acid, ascorbic acid, citric acid, , polyalcohols, ethylene diamine tetra acetate, surfactants, lecithins, phospholipids and derivatives thereof, while the hydrophilic carrier may be selected from the group consisting of dextrins and derivatives thereof (including cyclic derivatives), dextrans, linear and cross-linked polyvinylpyrrolidones and derivatives thereof, cellulose and derivatives thereof, mannoglucurans, chitosans, galactomannans and sodium starch glycolate, and the hydrophobic carrier may be selected from the group consisting of ethylcellulose, polyacrylates and derivatives, polymethacrylates and derivatives, polystyrene and derivatives, sylica. For the purposes pursuant to WO03/097012 the auxiliary co-grinding substances were essential, as appears evident from comparison of the ternary compositions with the corresponding binary compositions. For the ternary composition co-grinding process, active substance/carrier/auxiliary co-grinding substance weight ratios of i) active substance/carrier of between 1:0.1 and 1:100 and preferably between 1:0.5 and 1:50; ii) active substance : auxiliary co-grinding substance of between 1:0.1 and 1:20 and preferably between 1:0.2 and
1:10 are envisaged. The co-grinding time was comprised between 0.25 and 24 hours.
It has now been found that by subjecting an at least ternary mixture containing antioxidants to mechanico-chemical activation through a co-grinding process, an unexpected enhancement of the antioxidant activity at relatively short grinding times is achieved, besides an improvement in solubility or dispersibility in aqueous environment. Furthermore, surprisingly, such enhancement of the antioxidant activity is not always linked to a greater solubility of the compositions.
The process that brings about the result above is characterised by a particular ratio between the active principle and the carrier. More precisely, the active principle or substance is present in a w/w ratio with the carrier of less than 1, preferably less than 0.8, more preferably less than 0.5.
The carrier is preferably present in a weight percentage of at least 50% on the amount of the at least ternary composition. Preferably the carrier is present in a w/w percentage of at least
60% on the amount of the at least ternary composition.
An enhancement of the antioxidant activity can be obtained when the at least ternary mixture is subjected, through a co-grinding process, to mechanico-chemical activation for a period of time of less than 90 minutes, preferably not greater than 60 minutes. The enhancement of the antioxidant activity of said composition is measured by comparison with the antioxidant activity of the same quantity of active substance alone under the same conditions (in solution).
The dry co-grinding process may be performed using known means, such as ball mills, blade mills, vibrational mills, centrifugal mills and planetary mills.
With the term "dry" it is meant in the present description a process in which no solvents whatsoever are employed and the resulting at least ternary composition has less than 10 % by weight of a liquid, preferably less than 5 %, more preferably less than 3%. The preferred active substances or principles generally belong to the class of micronutrients with antioxidant or anti-free radical activity, and may include, but are not limited to ubidecarenone, lipoic acid, lycopene, resveratrol, green tea extracts, astaxantin, pycnogenol, genistein, tocopherols and tocotrienols, retinol, carotenoids, ascorbic acid, glutathione, sulphurated aminoacids and derivatives thereof, flavonoids and mixtures and derivatives thereof, polyphenols and mixtures and derivatives thereof.
For the purposes of the present invention, with the antioxidants, it is preferable to use hydro- or amphiphilic carriers, and particularly carriers selected from the group consisting of dextrins and derivatives thereof (also cyclic), dextrans, linear, branched and cross-linked polyvinylpyrrolidones, cellulose and derivatives thereof, mannoglycosans, chitosans, alginates and derivatives thereof, galactomannans and sodium starch glycolate, as inclusion carriers, while the auxiliary co-grinding substances are selected from the group consisting of aminoacids, weak acids (for example malic acid, fumaric acid, ascorbic acid, citric acid), polyalcohols, ethylene diamine tetra-acetic acid and the salts thereof, surfactants, lecithins, phospholipids and derivatives thereof, and preferably from the group consisting of glycine, lysine, serine and disodium ethylene diamine tetra-acetate.
For the purposes of improving the processability of the ternary mixture consisting of active substance : carrier : auxiliary co-grinding substance, additional (one or more) auxiliary co- grinding substances may be used with various properties and capable of improving, for example, the technological (free flowability, residual humidity) or organoleptic characteristics, such as for example glycyrrhizinate, sorbitol, silicas, chelating agents, aminoacids, sweeteners, inorganic oxides.
Some examples of preparations, on both the laboratory and pilot plant scales, of compositions according to the invention, are described below by way of non-limiting illustration of the present invention. Example 1
Ternary compositions of ubidecarenone/copovidone/glvcine 1/8/1
30 g of a 1/8/1 w/w ratio mixture of ubidecarenone (3 g), copovidone (24 g) and glycine (3 g), obtained using a rotating body mixer, were loaded into the jar of a planetary mill and subjected to mechanico-chemical activation for 15 minutes at a speed of 200 rpm. Upon completion of the process, the product, in the form of a fine powder, was unloaded and sieved at 355 μm. A ubidecarenone/copovidone/glycine ternary composite material in a w/w ratio of 1/8/1 was obtained, with a ubidecarenone content of 10%. Example 2
Ternary compositions of ubidecarenone/β-cyclodextrin/glvcine 1/8/1
1 kg of 1/8/1 w/w ratio mixture of ubidecarenone (100 g), copovidone (800 g) and glycine
(100 g), obtained using a rotating body mixture, was loaded into the chamber of a high energy vibrational mill and subjected to mechanico-chemical activation for 15 minutes. Upon completion of the process, the product, in the form of a fine powder, was unloaded and sieved at 710 μm. A ubidecarenone/copovidone/glycine ternary composite material in a w/w ratio of
1/8/1 was obtained, with a ubidecarenone content of 10%.
Example 3
Ternary compositions of ubidecarenone/copovidone/glycine 20/75/5
1 kg of a 20/75/5 w/w ratio mixture of ubidecarenone (200 g), copovidone (750 g) and glycine (50 g), obtained by using a rotating body mixer, was loaded into the chamber of a high energy vibrational mill and subjected to mechanico-chemical activation for 30 minutes.
Upon completion of the process, the product, in the form of a fine powder, was sieved at 710 μm. A ubidecarenone/copovidone/glycine ternary composite material was obtained with a weight percentage ratio of 20/75/5.
Example 4
Ternary compositions of ubidecarenone/γ-cyclodextrin/glvcine 1/8/1
3 g of ubidecarenone, 24 g of γ-cyclodextrin and 3.0 g of glycine were mixed for 10 minutes in a rotating body mixer; the mixture was then loaded into the jar of a planetary mill and subjected to mechanico-chemical activation for 15 minutes at a speed of 200 rpm. Upon completion of the process, the product, in the form of a fine powder, was unloaded and sieved at 355 μm. A ubidecarenone/γ-cyclodextrin/glycine ternary composite material in a w/w ratio of 1/8/1 was obtained with a ubidecarenone content of 10%.
Example 5
Ternary compositions of lipoic acid/linear polyvinylpyrrolidone/glycine 1/8/1
3 g of lipoic acid, 24 g of linear polyvinylpyrrolidone and 3 g of glycine were mixed for 10 minutes in a rotating body mixer; the mixture was then loaded into the jar of a planetary mill and subjected to mechanico-chemical activation for 15 minutes at a speed of 150 rpm. Upon completion of the process, the product, in the form of a fine powder, was unloaded and sieved at 355μm. A lipoic acid/linear PVP/glycine ternary composite material with a weight ratio of
1/8/1 was obtained with a lipoic acid content of 10%.
Example 6
Ternary compositions of lipoic acid/linear polyvinylpyrrolidone/arginine 1/8.5/0.5 3 g of lipoic acid, 25.5g of linear polyvinylpyrrolidone and 1.5 g of arginine were mixed for
10 minutes in a rotating body mixer; the mixture was then loaded into the jar of a planetary mill and subjected to mechanico-chemical activation for 15 minutes at a speed of 150 rpm.
Upon completion of the process, the product, in the form of a fine powder, was unloaded and sieved at 355 μm. A lipoic acid/linear PVP/arginine ternary composite material with a weight ratio of 1/8.5/0.5 was obtained with a lipoic acid content of 10%.
Example 7
Quaternary compositions of resveratrol/β-cvclodextrin/glvcine/ammonium glycyrrhizate
1.5/7.5/0.5/0.5
4.5 g of resveratrol, 22.5 g of beta cyclodextrin 1.5 g of glycine and 1.5g of ammonium glycyrrhizinate were mixed for 10 minutes in a rotating body mixer, then loaded into the jar of a planetary mill and subjected to mechanico-chemical activation for 30 minutes at a speed of 200 rpm. Upon completion of the process, the product, in the form of a fine powder was unloaded and sieved at 355 μm. A resveratrol/beta-cyclodextrin/gly cine/ammonium glycyrrhizinate quaternary composite material with a weight ratio of 1.5/7.5//0.5/0.5 was obtained with a resveratrol content of 15%.
Example 8
Ternary compositions of resveratrol/β-cyclodextrin/glvcine 1.5/7/1.5
4.5 g of resveratrol, 21.Og of beta-cyclodextrin and 4.5 g of glycine were mixed for 10 minutes in a rotating body mixer, then loaded into the jar of a planetary mill and subjected to mechanico-chemical activation for 60 minutes at a speed of 200 rpm. Upon completion of the process, the product, in the form of a fine powder was unloaded and sieved at 355μm. A resveratrol/beta-cyclodextrin/glycine ternary composite material with a weight ratio of
1.5/7/1.5 was obtained with a resveratrol content of 15%.
Example 9
Ternary compositions of lipoic acid/β-cyclodextrin/arginine 2/7/1
6 g of lipoic acid, 21 g of β-cyclodextrin and 3 g of arginine were mixed for 10 minutes in a rotating body mixer; the mixture was then loaded into the jar of a planetary mill and subjected to mechanico-chemical activation for 30 minutes at a speed of 120 rpm. Upon completion of the process, the product, in the form of a fine powder, was unloaded and sieved at 355μm. A lipoic acid/ β-cyclodextrin/arginine ternary composite material with a weight ratio of 2/7/1 was obtained with a lipoic acid content of 20%.
Example 10
Ternary compositions of green tea dry extract/β-cyclodextrin/glycine 3.5/5.5/1.0 10.5 g of green tea d.e., 16.5 g of β-cyclodextrin and 3 g of glycine were mixed for 10 minutes in a rotating body mixer; the mixture was then loaded into the jar of a planetary mill and subjected to mechanico-chemical activation for 60 minutes at a speed of 150 rpm. Upon completion of the process, the product, in the form of a fine powder, was unloaded and sieved at 355 μm. A green tea d.e./β-cyclodextrin/glycine ternary composite material with a weight ratio of 3.5/5.5/1.0 was obtained with a green tea d.e. content of 35%.
Example 11
Ternary compositions of green tea dry extract/povidone/serine 3.0/6.0/1.0
9 g of green tea d.e., 18 g of povidone and 3 g of serine were mixed for 10 minutes in a rotating body mixer; the mixture was then loaded into the jar of a planetary mill and subjected to mechanico-chemical activation for 30 minutes at a speed of 200 rpm. Upon completion of the process, the product, in the form of a fine powder, was unloaded and sieved at 355μm. A green tea d.e./povidone/serine ternary composite material with a weight ratio of 3/6/1 was obtained with a green tea d.e. content of 30%.
Example 12
Quaternary compositions of green tea dry extract/β-cvclodextrin/serine/ammonium glvcyrrhizate 4/5/0.5/0.5
12 g of green tea d.e., 15 g of β -cyclodextrin, 1.5 g of serine, 1.5 g of ammonium glycyrrhizate were mixed for 10 minutes in a rotating body mixer; the mixture was then loaded into the jar of a planetary mill and subjected to mechanico-chemical activation for 15 minutes at a speed of 250 rpm. Upon completion of the process, the product, in the form of a fine powder, was unloaded and sieved at 355μm. A green tea d.e./β- cyclodextrin/serine/ammonium glycyrrhizate quaternary composite material with a weight ratio of 4/5/0.5/0.5 was obtained with a green tea d.e. content of 40%.
Example 13
Ternary compositions of astaxantin/β-cyclodextrin/glycine 1.5/8/0.5
4.5 g of astaxantin, 24 g of β-cyclodextrin and 1.5 g of glycine were mixed for 10 minutes in a rotating body mixer; the mixture was then loaded into the jar of a planetary mill and subjected to mechanico-chemical activation for 75 minutes at a speed of 120 rpm. Upon completion of the process, the product, in the form of a fine powder, was unloaded and sieved at 355 μm. A astaxantin/β-cyclodextrin/glycine ternary composite material with a weight ratio of 1.5/8/0.5 was obtained with an astaxantin content of 15%.
Example 14
Quaternary compositions of astaxantin/povidone/ascorbic acid/Zn gluconate 2.5/5.5/1.5/0.5 7.5 g of astaxantin, 16.55 g of povidone, 4.5 g of ascorbic acid, 1.5 g of zinc gluconate were mixed for 10 minutes in a rotating body mixer; the mixture was then loaded into the jar of a planetary mill and subjected to mechanico-chemical activation for 35 minutes at a speed of
200 rpm. Upon completion of the process, the product, in the form of a fine powder, was unloaded and sieved at 355μm. A astaxantin/povidone/ascorcic acid/Zn gluconate quaternary composite material with a weight ratio of 2.5/5.5/1.5/0.5 was obtained with an astaxantin content of 25%.
Example 15
Ternary compositions of pycnogenol/β-cyclodextrin/glycine 2.5/6.5/1
7.5 g of pycnogenol, 19.5 g of β-cyclodextrin and 3 g of glycine were mixed for 10 minutes in a rotating body mixer; the mixture was then loaded into the jar of a planetary mill and subjected to mechanico-chemical activation for 45 minutes at a speed of 150 rpm. Upon completion of the process, the product, in the form of a fine powder, was unloaded and sieved at 355μm. A pycnogenol/β-cyclodextrin/glycine ternary composite material with a weight ratio of 2.5/6.5/1 was obtained with a pycnogenol content of 25%.
Example 16
Quaternary compositions of lycopene/chitosan/ammonium glycyrrhizate/glycine 2/6/1.5/0.5
6 g of lycopene, 18 g of chitosan, 4.5 g of ammonium glycyrrhizate and 1.5 g of glycine were mixed for 10 minutes in a rotating body mixer; the mixture was then loaded into the jar of a planetary mill and subjected to mechanico-chemical activation for 25 minutes at a speed of
200 rpm. Upon completion of the process, the product, in the form of a fine powder, was unloaded and sieved at 355μm. A lycopene/chitosan/ammonium glycyrrhizate/glycine quaternary composite material with a weight ratio of 2/6/1.5/0.5 was obtained with a lycopene content of 20%.
Example 17
Quaternary compositions of genistein/β-cvclodextrin/N-acetylcistein/EDTA 1/7.5/1/0.5
3 g of genistein, 22.5 g of β-cyclodextrin, 3 g of N-acetylcistein and 1.5 g of EDTA were mixed for 10 minutes in a rotating body mixer; the mixture was then loaded into the jar of a planetary mill and subjected to mechanico-chemical activation for 30 minutes at a speed of
200 rpm. Upon completion of the process, the product, in the form of a fine powder, was unloaded and sieved at 355 μm. A genistein/β-cyclodextrin/N-acetylcistein/EDTA quaternary composite material with a weight ratio of 1/7.5/1/0.5 was obtained with a genistein content of
10%. Example 18
Ternary compositions of genistein/β-cyclodextrin/methionine 2/7/1
6 g of genistein, 21 g of β-cyclodextrin, 3 g of methionine were mixed for 10 minutes in a rotating body mixer; the mixture was then loaded into the jar of a planetary mill and subjected to mechanico-chemical activation for 30 minutes at a speed of 200 rpm. Upon completion of the process, the product, in the form of a fine powder, was unloaded and sieved at 355 μm. A genistein/β-cyclodextrin/methionine ternary composite material with a weight ratio of 2/7/1 was obtained with a genistein content of 20%.
Example 19
Ternary compositions of genistein/β-cyclodextrin/ascorbic acid 2/7/1
6 g of genistein, 21 g of β-cyclodextrin, 3 g of ascorbic acid were mixed for 10 minutes in a rotating body mixer; the mixture was then loaded into the jar of a planetary mill and subjected to mechanico-chemical activation for 45 minutes at a speed of 120 rpm. Upon completion of the process, the product, in the form of a fine powder, was unloaded and sieved at 355 μm. A genistein/β-cyclodextrin/ascorbic acid ternary composite material with a weight ratio of 2/7/1 was obtained with a genistein content of 20%.
Example 20
Ternary compositions of genistein/β-cyclodextrin/ascorbic acid 1/4/5
3 g of genistein, 12 g of β-cyclodextrin, 15 g of ascorbic acid were mixed for 10 minutes in a rotating body mixer; the mixture was then loaded into the jar of a planetary mill and subjected to mechanico-chemical activation for 45 minutes at a speed of 120 rpm. Upon completion of the process, the product, in the form of a fine powder, was unloaded and sieved at 355 μm. A genistein/β-cyclodextrin/ascorbic acid ternary composite material with a weight ratio of 1/4/5 was obtained with a genistein content of 10%.
Example 21
Ternary compositions of genistein/β-cyclodextrin/N-acetyl methionine 1/4/5
3 g of genistein, 12 g of β-cyclodextrin, 15 g of N-acetyl methionine were mixed for 10 minutes in a rotating body mixer; the mixture was then loaded into the jar of a planetary mill and subjected to mechanico-chemical activation for 75 minutes at a speed of 120 rpm. Upon completion of the process, the product, in the form of a fine powder, was unloaded and sieved at 355μm. A genistein/β-cyclodextrin/N-acetyl methionine ternary composite material with a weight ratio of 1/4/5 was obtained with a genistein content of 10%.
Example 22
Ternary compositions of genistein/β-cyclodextrin/glutamic acid 1/5/4 3 g of genistein, 15 g of β-cyclodextrin, 12 g of glutamic acid were mixed for 10 minutes in a rotating body mixer; the mixture was then loaded into the jar of a planetary mill and subjected to mechanico-chemical activation for 60 minutes at a speed of 150 rpm. Upon completion of the process, the product, in the form of a fine powder, was unloaded and sieved at 355 μm. A genistein/β-cyclodextrin/glutamic acid ternary composite material with a weight ratio of 1/5/4 was obtained with a genistein content of 10%.
Example 23
Ternary compositions of ubidecarenone/copovidone/glycine 3/6/1
1 kg of a 3/6/1 w/w ratio mixture of ubidecarenone (300 g), copovidone (600 g) and glycine
(100 g), obtained using a rotating body mixer, were loaded into a high-energy vibrational mill and subjected to mechanico-chemical activation for 25 minutes. Upon completion of the process, the product, in the form of a fine powder, was unloaded and sieved at 710 μm. A ubidecarenone/copovidone/glycine ternary composite material in a w/w ratio of 3/6/1 was obtained with a ubidecarenone content of 30%.
Example 24
Ternary compositions of ubidecarenone/copovidone/glvcine 25/65/10
1 kg of a 25/65/10 w/w ratio mixture of ubidecarenone (250 g), copovidone (650 g) and glycine (100 g), obtained using a rotating body mixer, was loaded into a high-energy vibrational mill and subjected to mechanico-chemical activation for 25 minutes. Upon completion of the process, the product, in the form of a fine powder, was unloaded and sieved at 710 μm. A ubidecarenone/copovidone/glycine ternary composite material in a w/w ratio of
25/65/10 was obtained with a ubidecarenone content of 25%.
Comparative examples
Example A
Ternary compositions of ubidecarenone/copovidone/glycine 1/8/1
30 g of a 1/8/1 w/w ratio mixture of ubidecarenone (3 g), copovidone (24 g) and glycine (3 g), obtained using a rotating body mixer, were loaded into the jar of a planetary mill and subjected to mechanico-chemical activation for 90 minutes at a speed of 200 rpm. Upon completion of the process, a soft unprocessable material was obtained.
Example B
Ternary compositions of ubidecarenone/copovidone/glycine 2/7.5/0.5
1 kg of a 20/75/5 w/w ratio mixture of ubidecarenone (200 g), copovidone (750 g) and glycine (50 g), obtained using a rotating body mixer, were loaded into the chamber of a high energy vibrational mill and subjected to mechanico-chemical activation for 120 minutes. Upon completion of the process, a soft unprocessable material was obtained. Example C
Ternary compositions of lipoic acid/linear PVP/arginine 1/8.5/0.5
3 g of lipoic acid, 25.5 g of linear polyvinylpyrrolidone and 1.5 g of glycine were mixed for 10 minutes in a rotating body mixer, then loaded into the jar of a planetary mill and subjected to mechanico-chemical activation for 90 minutes at a speed of 150 rpm. Upon completion of the process, a soft unprocessable material is obtained. Example D
Ternary compositions ofresveratrol/β-cyclodextrin/glycine 1.5/7/1.5
4.5 g of resveratrol, 21 g of β-cyclodextrin and 4.5 g of glycine were mixed for 10 minutes in a rotating body mixer, then loaded into the jar of a planetary mill and subjected to mechanico- chemical activation for 120 minutes. Upon completion of the process, a sticky unprocessable material was obtained, Example E
Ternary compositions of green tea dry extract/povidone/serine 3.0/6.0/1.0 9 g of green tea d.e., 18 g of povidone and 3 g of serine were mixed for 10 minutes in a rotating body mixer; the mixture was then loaded into the jar of a planetary mill and subjected to mechanico-chemical activation for 120 minutes. Upon completion of the process, a crusty and not easily processable material was obtained. Example F
Quaternary compositions of green tea dry extract/β-cvclodextrin/serine/ammonium glvcyrrhizate 4.5/4.5/0.5/0.5
13.5 g of green tea d.e., 13.5 g of β-cyclodextrin, 1.5 g of serine, 1.5 g of ammonium glycyrrhizate were mixed for 10 minutes in a rotating body mixer; the mixture was then loaded into the jar of a planetary mill and subjected to mechanico-chemical activation for 120 minutes. Upon completion of the process, a product in the form of a powder with poor morphology was unloaded. A green tea d.e./β-cyclodextrin/serine/ammonium glycyrrhizate quaternary composite material with a weight ratio of 4.5/4.5/0.5/0.5 was obtained with a green tea d.e. content of 45%. Example G
Ternary compositions of astaxantin/β-cyclodextrin/glycine 5.5/4.0/0.5
16.5 g of astaxantin, 12 g of β-cyclodextrin and 1.5 g of glycine were mixed for 10 minutes in a rotating body mixer; the mixture was then loaded into the jar of a planetary mill and subjected to mechanico-chemical activation for 120 minutes. Upon completion of the process, a crust-like product was obtained.
Example H
Ternary compositions of pycnogenol/β-cvclodextrin/glycine 6.5/2.5/1
19.5 g of pycnogenol, 7.5 g of β-cyclodextrin and 3 g of glycine were mixed for 10 minutes in a rotating body mixer; the mixture was then loaded into the jar of a planetary mill and subjected to mechanico-chemical activation for 45 minutes. Upon completion of the process, a crusty product was unloaded. A pycnogenol/β-cyclodextrin/glycine ternary composite material with a weight ratio of 6.5/2.5/1 is obtained with a pycnogenol content of 65%.
Example I
Quaternary compositions of lycopene/chitosan/ammonium glycyrrhizate/glycine 2/6/1.5/0.5
6 g of lycopene, 18 g of chitosan, 4.5 g of ammonium glycyrrhizate and 1.5 g of glycine were mixed for 10 minutes in a rotating body mixer; the mixture was then loaded into the jar of a planetary mill and subjected to mechanico-chemical activation for 120 minutes. Upon completion of the process, a crust-like product was obtained.
Example L
Ternary compositions of genistein/β-cyclodextrin/methionine 2/7/1
6 g of genistein, 21 g of β-cyclodextrin, 3 g of methionine were mixed for 10 minutes in a rotating body mixer; the mixture was then loaded into the jar of a planetary mill and subjected to mechanico-chemical activation for 120 minutes. Upon completion of the process, a sticky unworkable material was obtained.
Example M
Ternary compositions of genistein/β-cyclodextrin/ascorbic acid 5/4/1
15 g of genistein, 12 g of β-cyclodextrin, 3 g of ascorbic acid were mixed for 10 minutes in a rotating body mixer; the mixture was then loaded into the jar of a planetary mill and subjected to mechanico-chemical activation for 45 minutes. Upon completion of the process, the product, in the form of a fine powder, was unloaded and sieved at 355μm. A genistein/β- cyclodextrin/ascorbic acid ternary composite material with a weight ratio of 5/4/1 was obtained with a genistein content of 50%.
Characterisation of the compositions
The compositions, prepared according to the above-described examples, have been characterised in relation to their residual crystallinity and solubility in buffered water at pH=7, in comparison to the active substance contained therein. In addition, the antioxidant activity has also been evaluated by means of spectrofluormetric measurements in comparison to solutions of equal concentration of the active substance contained therein.
A. Solubility
An excess of powder is added to buffered water at pH=7 until a precipitate is obtained. The maximum quantity of active substance present in solution is verified after 24 hours (equilibrium) by means of a suitable analytical method (for example UV spectrophotometry, HPLC).
B. Differential scanning calorimetry (DSC)
DSC is a technique which allows evaluation of the crystallinity of powders based on determination of the heat exchanges occurring in the same during melting subsequent to progressive heating.
C. Antioxidant activity
Antioxidant activity was measured using the ORAC (Oxygen Radical Absorbance Capacity) test. Said test has been developed by Cao et al. in 1993 (Oxygen-radical absorbance capacity assay for antioxidants. Free Rad. Biol. Med. 1993;14: 303-11).
The test was based on measuring the inhibition induced by an antioxidant on the loss of activity of a fluorescent indicator, in the presence of oxidants.
In practice, given a fluorescent indicator (fluorescein) which loses its fluorescence due to the action of an oxidising agent (AAPH), antioxidant activity was evaluated in terms of maintenance of the fluorescence of the indicator over time, due to the ability of the antioxidant to counteract the action of the oxidising agent.
Antioxidant activity was assessed by spectrofluorometric assay, measuring the decay of the fluorescence of the indicator over time (from 0 to 360 minutes). A measuring the fluorescence of the sodium fluorescein indicator was performed using a spectrofluorimeter at a wavelength of 515 nm.
Antioxidant activity is expressed as the antioxidant power in relation to Trolox® at the same concentration of the samples.
The characterisation results are reported in the following Tables 1-8. TABLE 1 - UBIDECARENONE
Figure imgf000016_0001
TABLE 2 - LIPOIC ACID
Figure imgf000016_0002
TABLE 3 - RESVERATROL
Figure imgf000016_0003
TABLE 4 - GREEN TEA (DRY EXTRACT)
Figure imgf000016_0004
TABLE 5 - ASTAXANTIN
Figure imgf000017_0001
TABLE 6 - PYCNOGENOL
Figure imgf000017_0002
TABLE 7 - LYCOPENE
Figure imgf000017_0003
TABLE 8 - GENISTEIN
Figure imgf000017_0004
By way of example, fig. 1 shows comparative chromatograms of example 6 and example C, while figures 3 and 4 show the antioxidant activities of examples 4 and 8, respectively. Analysis of the results obtained shows that the advantageous effect of strengthening of the antioxidant activities of the at least ternary compositions forming the subject of the invention, obtained by means of a co-grinding process, is dependant on the active substance/carrier ratios and on mechanico-chemical activation, which must be less than 90 minutes. Furthermore, it may be observed that said effect is independent of increasing solubility. Furthermore, it may be observed that the addition of the auxiliary co-grinding substance does not have any significant contribution towards said effect.
This indicates that the co-grinding processing parameters, i.e. the defined carrier/active substance w/w ratios and the mechanico-chemical activation times, are the essential conditions for determining the formation of compositions having the characteristics of "multi- composites" which can be exploited due to their increased antioxidant activities in both the pharmaceutical field, for prevention and/or prophylactic therapeutic purposes, and in the parapharmaceutical cosmetic and dietary-nutrition fields. Indeed, the compositions of the invention may be used to prepare products with more favourable active substance quantity/effect ratios. Indeed, the possibility of limiting the quantity of antioxidant with equal antioxidant effect may have a favourable impact on any potential tolerability/toxicity effects. The at least ternary compositions, obtained according to the present invention, in powder form, may thus be made and formulated into products suitable for use for preventive or curative ends as drugs or as dietary supplements or as cosmetics. For such uses, the compositions forming the subject of the present invention may be prepared in powder form, or in mixtures with pharmaceutically, parapharmaceutically, or dietary-nutritional acceptable excipients and diluents. They may additionally be used in various forms, such as for example capsules, tablets, pastes, gels, solutions or suspensions, sprays with pharmaceutically, parapharmaceutically, and dietary-nutritional acceptable excipients and diluents and adapted for such other forms. Furthermore, for parapharmaceutical and cosmetic uses, the compositions of the invention may be formulated with cosmetically acceptable excipients or diluents in the form of lotions, creams, ointments, pastes, gels, patches, mousse, foams, sticks and sprays and other topical forms known for such use.

Claims

1. Composition compositions in powder form, with good processability, obtainable by means of a dry co-grinding process of an at least ternary composition comprising an active principle, a carrier and at least one auxiliary co-grinding substance, characterised in that said active principle comprises at least one micronutrient with antioxidant activity and the weight ratio active principle/carrier is less than 1, and said co-grinding process is carried out for less than 90 minutes, whereby the antioxidant activity of said composition is greater than the antioxidant activity of a solution containing the same amount of active substance alone under the same conditions.
2. Composition according to claim 1, characterised in that said carrier is present in an amount not less than 50% w/w of the total of said at least ternary mixture.
3. Composition according to claim 1, characterised in that said co-grinding process is carried out for a time equal to or less than 60 minutes.
4. Composition according to claim 1 wherein said micronutrient with antioxidant activity is selected from the group consisting of ubidecarenone, lipoic acid, lycopene, resveratrol, green tea extracts, astaxantin, pycnogenol, genistein, tocopherols, tocotrienols, retinol, carotenoids, rhodiola, ascorbic acid, glutathiones, sulphurated aminoacids or derivatives thereof, flavonoids or mixtures or derivatives thereof, polyphenols or mixtures or derivatives thereof.
5. Composition according to claim 1 wherein said carrier is a hydrophilic or amphiphilic carrier selected from the group consisting of linear or cyclic dextrins or derivatives thereof, dextrans, linear, branched or cross-linked polyvinylpyrrolidones, cellulose or derivatives thereof, mannoglycosans, chitosans, alginates or derivatives thereof, galactomannans or sodium starch glycolate.
6. Composition according to claim 1 wherein said co-grinding substance is selected from the group consisting of aminoacids, weak acids, polyalcohols, ethylene diamine tetra acetic acid or salts thereof, surfactants, lecithins, phospholipids or derivatives thereof.
7. Composition according to claim 6 wherein the co-grinding substance is selected from the group consisting of glycine, lysine, serine, arginine, methionine, ascorbic acid, glutamic acid and disodium ethylene diamine tetra acetate.
8. Composition according to claim 1 wherein said active principle is present in a w/w ratio with the carrier of less than 0.9.
9. Composition according to claim 8, wherein said active principle is present in a w/w ratio with the carrier of less than 0.5.
10. Composition according to claim 2 wherein said carrier content is comprised between more than 50 up to 99.8 % by weight on the amount of the ternary composition.
11. Composition according to claim 1 obtained by a dry co-grinding process in a time comprised between 1 and less than 90 minutes.
12. Composition according to claim 1 wherein one or more other auxiliary co-grinding substances are added to the mixture comprising the active substance, the carrier and at least one auxiliary co-grinding substance.
13. Composition according to claim 12 wherein said other co-grinding substances are selected from the group consisting of ammonium glycyrrhizinate, sorbitol, silicas, chelating agents, aminoacids, sweeteners and inorganic oxides.
14. Use of a composition according to any of claims 1 to 13 for the preparation of a medicament in pharmaceutical forms adapted to administration for therapeutic purposes.
15. Use of a composition according to any of the claims 1 to 13 for the preparation of a cosmetic in parapharmaceutical forms that are adapted to dermocosmetic purposes.
16. Use of a composition according to any of the claims 1 to 13 for the preparation of a dietary-nutritional product in parapharmaceutical forms that are adapted to dietary supplementation purposes.
17. Dry co-grinding process for obtaining compositions in the form of fine powders according to any of the claims 1 to 13.
PCT/EP2006/064385 2005-07-19 2006-07-18 Composition containing micronutrients with improved anti-oxidant activity and the use thereof. WO2007009997A1 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
US11/996,063 US20080219963A1 (en) 2005-07-19 2006-07-18 Composition Containing Micronutrients With Improved Anti-Oxidant Activity And The Use Thereof
AU2006271635A AU2006271635A1 (en) 2005-07-19 2006-07-18 Composition containing micronutrients with improved anti-oxidant activity and the use thereof.
CA002615745A CA2615745A1 (en) 2005-07-19 2006-07-18 Composition containing micronutrients with improved anti-oxidant activity and the use thereof
EP06792518A EP1906927A1 (en) 2005-07-19 2006-07-18 Composition containing micronutrients with improved anti-oxidant activity and the use thereof.
JP2008521962A JP2009543756A (en) 2005-07-19 2006-07-18 Composition containing micronutrients with improved antioxidant activity and use thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT000224A ITPD20050224A1 (en) 2005-07-19 2005-07-19 COMPOSITIONS CONTAINING MICRONUTRIENTS IN PARTICULAR ANTIOXIDANT ACTIVITY AND THEIR USE
ITPD2005A000224 2005-07-19

Publications (1)

Publication Number Publication Date
WO2007009997A1 true WO2007009997A1 (en) 2007-01-25

Family

ID=37075748

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2006/064385 WO2007009997A1 (en) 2005-07-19 2006-07-18 Composition containing micronutrients with improved anti-oxidant activity and the use thereof.

Country Status (7)

Country Link
US (1) US20080219963A1 (en)
EP (1) EP1906927A1 (en)
JP (1) JP2009543756A (en)
AU (1) AU2006271635A1 (en)
CA (1) CA2615745A1 (en)
IT (1) ITPD20050224A1 (en)
WO (1) WO2007009997A1 (en)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010100197A1 (en) * 2009-03-03 2010-09-10 Agetis Supplements Resveratrol compositions for use as dietary supplements
JP2010536798A (en) * 2007-08-17 2010-12-02 テバ ファーマシューティカル インダストリーズ リミティド Method and composition for controlling bioavailability of poorly soluble drugs
JP2011500737A (en) * 2007-10-29 2011-01-06 ディーエスエム アイピー アセッツ ビー．ブイ． Composition containing resveratrol and pectin
WO2010089104A3 (en) * 2009-02-04 2011-01-06 Dsm Ip Assets B.V. Resveratrol compositions
ITUD20110196A1 (en) * 2011-12-02 2013-06-03 Asoltech S R L COMPOSITION BASED ON UBIDECARENONE
US9968567B2 (en) 2014-11-14 2018-05-15 Asoltech S.R.L. Composition based on COQ10
JP2020054396A (en) * 2015-07-01 2020-04-09 株式会社東洋新薬 Composition for protection of retina
EA035667B1 (en) * 2017-07-05 2020-07-23 Фримлайн Прайвет Лимитед Pharmaceutical composition for neuropathic pain
EA035709B1 (en) * 2017-09-05 2020-07-29 Фримлайн Прайвет Лимитед Pharmaceutical composition for improving or preventing progression of chronic kidney disease

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2544663B1 (en) 2010-03-12 2018-01-03 Berg LLC Intravenous formulations of coenzyme q10 (coq10) and methods of use thereof
MY183615A (en) 2011-06-17 2021-03-03 Berg Llc Inhalable pharmaceutical compositions
CN104198619B (en) * 2014-09-23 2016-01-13 华润三九（郴州）制药有限公司 A kind of quality determining method of P-Cymene
JP6211558B2 (en) * 2015-05-14 2017-10-11 株式会社東洋新薬 Beauty composition
US10285963B2 (en) * 2015-06-08 2019-05-14 Horacio Astudillo de la Vega Combination of metabolic bio-energetic and nutra-epigentic regulators, nutraceutical compounds in conventional and nanotechnologies combination to revert and prevent the chronic damage accelerated cellular senescence produced by diabetes and other degenerative chronic complex diseases
EP3609474A4 (en) * 2017-04-13 2021-01-27 Pharmako Biotechnologies PTY Limited Cold-water-dispersible chemical delivery system
JP7098198B2 (en) * 2019-10-08 2022-07-11 株式会社東洋新薬 Cosmetology composition
CN114225049B (en) * 2022-01-24 2024-01-16 宁夏医科大学 Resveratrol-amino acid-cyclodextrin or cyclodextrin derivative ternary clathrate, composition, preparation method and application
CN114767640A (en) * 2022-05-24 2022-07-22 长治医学院 Resveratrol oral sustained-release microsphere, preparation method thereof and resveratrol pharmaceutical preparation

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000037109A2 (en) * 1998-12-18 2000-06-29 Euphar Group S.R.L. Clathrates of dehydroepiandrosterone and corresponding pharmaceutical compositions
EP1174109A2 (en) * 2000-07-21 2002-01-23 Beiersdorf Aktiengesellschaft Combinations of active substances respectively adducts from cyclodextrins and at least a quinone and/or at least a hydroquinone and use of such combinations of active substances in cosmetic preparations
WO2003097012A1 (en) * 2002-05-20 2003-11-27 Actimex S.R.L. Co-grinding process for the preparation of a ternary composition
WO2004050063A1 (en) * 2002-12-02 2004-06-17 Actimex S.R.L. Quaternary compounds comprising propolis as the active substance

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07291854A (en) * 1994-04-26 1995-11-07 Tanabe Seiyaku Co Ltd Medicinal preparation improved in solubility
JP3435664B2 (en) * 1999-12-08 2003-08-11 ヤンセンファーマ株式会社 Oral fast disintegrating tablet and method for producing the same
JP2004099442A (en) * 2002-09-04 2004-04-02 Nisshin Pharma Inc Pharmaceutical preparation containing sparingly soluble drug and method for producing the same

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000037109A2 (en) * 1998-12-18 2000-06-29 Euphar Group S.R.L. Clathrates of dehydroepiandrosterone and corresponding pharmaceutical compositions
EP1174109A2 (en) * 2000-07-21 2002-01-23 Beiersdorf Aktiengesellschaft Combinations of active substances respectively adducts from cyclodextrins and at least a quinone and/or at least a hydroquinone and use of such combinations of active substances in cosmetic preparations
WO2003097012A1 (en) * 2002-05-20 2003-11-27 Actimex S.R.L. Co-grinding process for the preparation of a ternary composition
WO2004050063A1 (en) * 2002-12-02 2004-06-17 Actimex S.R.L. Quaternary compounds comprising propolis as the active substance

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010536798A (en) * 2007-08-17 2010-12-02 テバ ファーマシューティカル インダストリーズ リミティド Method and composition for controlling bioavailability of poorly soluble drugs
JP2011500737A (en) * 2007-10-29 2011-01-06 ディーエスエム アイピー アセッツ ビー．ブイ． Composition containing resveratrol and pectin
US8927046B2 (en) 2009-02-04 2015-01-06 Dsm Ip Assets B.V. Resveratrol compositions
WO2010089104A3 (en) * 2009-02-04 2011-01-06 Dsm Ip Assets B.V. Resveratrol compositions
CN102307568A (en) * 2009-02-04 2012-01-04 帝斯曼知识产权资产管理有限公司 Resvertrol compositions
JP2012516834A (en) * 2009-02-04 2012-07-26 ディーエスエム アイピー アセッツ ビー．ブイ． Resveratrol composition
WO2010100197A1 (en) * 2009-03-03 2010-09-10 Agetis Supplements Resveratrol compositions for use as dietary supplements
ITUD20110196A1 (en) * 2011-12-02 2013-06-03 Asoltech S R L COMPOSITION BASED ON UBIDECARENONE
WO2013080028A1 (en) * 2011-12-02 2013-06-06 Asoltech Srl Composition based on ubidecarenone
US9675564B2 (en) 2011-12-02 2017-06-13 Asoltech S.R.L. Composition based on ubidecarenone
US9968567B2 (en) 2014-11-14 2018-05-15 Asoltech S.R.L. Composition based on COQ10
JP2020054396A (en) * 2015-07-01 2020-04-09 株式会社東洋新薬 Composition for protection of retina
EA035667B1 (en) * 2017-07-05 2020-07-23 Фримлайн Прайвет Лимитед Pharmaceutical composition for neuropathic pain
EA035709B1 (en) * 2017-09-05 2020-07-29 Фримлайн Прайвет Лимитед Pharmaceutical composition for improving or preventing progression of chronic kidney disease

Also Published As

Publication number Publication date
AU2006271635A1 (en) 2007-01-25
ITPD20050224A1 (en) 2007-01-20
JP2009543756A (en) 2009-12-10
CA2615745A1 (en) 2007-01-25
US20080219963A1 (en) 2008-09-11
EP1906927A1 (en) 2008-04-09

Similar Documents

Publication Publication Date Title
US20080219963A1 (en) Composition Containing Micronutrients With Improved Anti-Oxidant Activity And The Use Thereof
US20090035440A1 (en) Compositions comprising polyphenol
US7964223B2 (en) Berry preparations and extracts
NO326762B1 (en) Polyphenol fractions of tea, their use, and formulations containing such
Wang et al. Partition and stability of folic acid and caffeic acid in hollow zein particles coated with chitosan
CA2920601C (en) Agent for promoting in vivo absorption of hydroxytyrosol and derivatives thereof and use of same
JP2001520181A (en) Compositions based on plant extracts
JP7236995B2 (en) Compositions containing phenolic compounds with synergistic antioxidant effects
US8367126B2 (en) Berry preparations and extracts
JP2010168318A (en) Polyphenols preparation excellent in preservation stability
KR20150125662A (en) Bioactive compositions from theacea plants and use thereof in beverages, functional foods, nutriceuticals, supplements and the like
Jurca et al. A new natural antioxidant supplement-design and development
US7763282B2 (en) Quaternary compounds comprising propolis as the active substance
EP1618800A1 (en) Active compositions comprising lycopene, cytidin and fatty acids
US11547720B2 (en) Ayurvedic encapsulated gold nanoparticles, fabrication methods and cancer therapeutic methods
EP4241779A1 (en) Aronia extracts and uses thereof
CA2558975A1 (en) Water-soluble bound matter of proanthocyanidin and composition containing the same
Li et al. Development, physical–chemical characterization, and molecular docking simulations of ursolic acid–sodium alginate complexes
FR2773811A1 (en) Stabilization of polyphenols for preventing their oxidation and/or polymerization
Varshosaz et al. Solid Dispersion of Hesperetin Co-crystals Synergistically Attenuates Hepatic Toxicity of Carbon Tetrachloride Oxidative Stress in Rats
US11129789B2 (en) Stabilized cosmetic compositions
JP2006240991A (en) Antioxidant using extract of green algae belonging to the genus monostroma as active ingredient
KR20200094475A (en) Stabilizing method of Myristica fragrans extract and cosmetic composition containing the stabilized Myristica fragrans extract

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 11996063

Country of ref document: US

Ref document number: 2615745

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 2008521962

Country of ref document: JP

Ref document number: 2006271635

Country of ref document: AU

NENP Non-entry into the national phase

Ref country code: DE

WWW Wipo information: withdrawn in national office

Ref document number: DE

WWE Wipo information: entry into national phase

Ref document number: 565405

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: 2006792518

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2006271635

Country of ref document: AU

Date of ref document: 20060718

Kind code of ref document: A

WWP Wipo information: published in national office

Ref document number: 2006271635

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 827/CHENP/2008

Country of ref document: IN

WWP Wipo information: published in national office

Ref document number: 2006792518

Country of ref document: EP