EP2124615A1 - Unctuous compositions - Google Patents

Unctuous compositions

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Publication number
EP2124615A1
EP2124615A1 EP08701507A EP08701507A EP2124615A1 EP 2124615 A1 EP2124615 A1 EP 2124615A1 EP 08701507 A EP08701507 A EP 08701507A EP 08701507 A EP08701507 A EP 08701507A EP 2124615 A1 EP2124615 A1 EP 2124615A1
Authority
EP
European Patent Office
Prior art keywords
protective colloid
active ingredient
formulation according
oil
hydrophobic protective
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP08701507A
Other languages
German (de)
French (fr)
Inventor
Jesper Feldthusen Jensen
Ingrid Martin
Christian KÖPSEL
Helmut Auweter
Angelika-Maria Pfeiffer
Erik LÜDDECKE
Dieter Feuerstein
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
BASF SE
Original Assignee
BASF SE
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 BASF SE filed Critical BASF SE
Priority to EP08701507A priority Critical patent/EP2124615A1/en
Publication of EP2124615A1 publication Critical patent/EP2124615A1/en
Withdrawn legal-status Critical Current

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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
    • A23D—EDIBLE OILS OR FATS, e.g. MARGARINES, SHORTENINGS, COOKING OILS
    • A23D9/00—Other edible oils or fats, e.g. shortenings, cooking oils
    • A23D9/007—Other edible oils or fats, e.g. shortenings, cooking oils characterised by ingredients other than fatty acid triglycerides
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/105—Aliphatic or alicyclic compounds
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/142—Amino acids; Derivatives thereof
    • A23K20/147—Polymeric derivatives, e.g. peptides or proteins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/158—Fatty acids; Fats; Products containing oils or fats
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/179—Colouring agents, e.g. pigmenting or dyeing agents
    • 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
    • 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
    • A23L33/115—Fatty acids or derivatives thereof; Fats or oils
    • 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
    • A23L33/15—Vitamins
    • A23L33/155—Vitamins A or D
    • 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
    • A23L5/00—Preparation or treatment of foods or foodstuffs, in general; Food or foodstuffs obtained thereby; Materials therefor
    • A23L5/40—Colouring or decolouring of foods
    • A23L5/42—Addition of dyes or pigments, e.g. in combination with optical brighteners
    • A23L5/43—Addition of dyes or pigments, e.g. in combination with optical brighteners using naturally occurring organic dyes or pigments, their artificial duplicates or their derivatives
    • A23L5/44—Addition of dyes or pigments, e.g. in combination with optical brighteners using naturally occurring organic dyes or pigments, their artificial duplicates or their derivatives using carotenoids or xanthophylls
    • 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
    • A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
    • A61K8/645—Proteins of vegetable origin; Derivatives or degradation products thereof
    • 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
    • A61K8/92—Oils, fats or waxes; Derivatives thereof, e.g. hydrogenation products thereof
    • A61K8/922—Oils, fats or waxes; Derivatives thereof, e.g. hydrogenation products thereof of vegetable origin
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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

Definitions

  • the present invention relates to oily formulations, processes for their preparation and their use as additives to animal feeds and foods.
  • carotenoid primary particles with a particle size in the nanometer range is crucial in order to achieve sufficient bioavailability and color yields.
  • two methods have become known:
  • EP 1 213 013 A describes the preparation of an aqueous carotenoid dispersion in the presence of a hydrocolloid, such as casein or gelatin.
  • the active ingredient is flocculated together with the hydrocolloid by adjusting the pH to the isoelectric point, then the flocculated material is separated and dried. Dispersing the powdered product obtained then gives an oily suspension.
  • An analogous process using water-immiscible solvents is described in EP 937 412 A.
  • WO 03/102116 describes oily solutions of a carotenoid.
  • the preparation of these oily solutions is carried out by dissolving the carotenoids in an organic solvent, such as N-methylpyrrolidone, in the presence of a lipophilic dispersant and removing the solvent.
  • the resulting powder is then concentrated in a low concentration in an oil, e.g. As fish oil, solved.
  • WO 2006/125591 describes the preparation of an oily carotenoid composition.
  • the carotenoid is dispersed in an oil phase, the dispersion is heated for a short time to dissolve the carotenoid, and the resulting solution is cooled by mixing with further oil having a lower temperature than the oil solution.
  • the oily composition contains only a small amount of carotenoid, i. Large quantities of the composition must be used to achieve the desired effect. The method is therefore not economical.
  • WO 96/13178 describes the preparation of stable lycopene concentrates by milling the lycopene in a liquid medium in which the lycopene is substantially insoluble.
  • the liquid medium used is glycerol, propylene glycol or ethanol.
  • an oily formulation containing a solid active ingredient and a hydrophobic protective colloid dispersed or dissolved in an edible oil.
  • the present invention therefore relates to an oily formulation in the form of a dispersion (suspension) comprising at least one active substance, at least one hydrophobic protective colloid and at least one edible oil.
  • Suitable active ingredients are solid active ingredients which are dispersible in the edible oil.
  • the active compounds generally have a particle size in the range from 50 nm to 10 .mu.m, preferably 100 nm to 5 .mu.m, particularly preferably 100 nm to 3 .mu.m, 150 nm to 2 .mu.m and in particular 200 nm to 1 .mu.m.
  • the active ingredients are carotenoids.
  • the known, from natural sources or synthetically accessible representatives can be used. Examples of these are ⁇ -carotene, lycopene, lutein, astaxanthin, astaxanthin derivatives (such as, for example, astaxanthin dimethyl disuccinate or astaxanthin dipalmitate), zeaxanthin, cryptoxanthin, citranaxanthin, canthaxanthin, echinenone, bixin, ⁇ -apo-4-carotenal, ⁇ -apo-8-carotenal, ⁇ -apo-4-carotenoic acid ester, individually or as a mixture.
  • astaxanthin Preference is given to astaxanthin, astaxanthin derivatives (such as, for example, astaxanthin dimethyl disuccinate or astaxanthin dipalmitate), ⁇ -carotene, ⁇ -apo-8-carotenal, ⁇ -apo-8'-carotenoic acid ethyl ester, canthaxanthin, citranaxanthin, echinenone, lutein, Lycopene and zeaxanthin.
  • astaxanthin Astaxanthin derivatives (such as astaxanthin dimethyl disuccinate or astaxanthin dipalmitate), and canthaxanthin, and especially astaxanthin.
  • the formulations according to the invention also contain a hydrophobic protective colloid.
  • a hydrophobic protective colloid is to be understood as meaning a protective colloid which is insoluble in water, not water-dispersible and non-swellable. However, it is soluble in aqueous ethanol or isopropanol containing at least 40% by weight of ethanol or isopropanol.
  • the protective colloid is considered soluble if more than 0.5% by weight of the hydrocolloid dissolves in aqueous ethanol or isopropanol with at least 40% by weight of alcohol.
  • the protective colloids have affinity for phenyl, octyl or butyl-Sepharose.
  • a preferred group of hydrophobic protective colloids are the prolamines. These are proteins that occur in cereal species. Examples of suitable prolamins are zein (from maize), gliadin (from wheat and oats), secalin (from rye), hordein (from barley), orycin (from rice) and kafarin (from millet, sorghum).
  • hydrophobic protective colloids particularly proteins that have been produced and / or modified by fermentation or that have been prepared synthetically.
  • the edible oil may be of synthetic, mineral, vegetable or animal origin. Examples are sesame oil, corn oil, cottonseed oil, soybean oil, peanut oil, esters of medium-chain fatty acids, oleostearin, paraffin oil, glyceryl stearate, isopropyl myristate, diisopropyl adipate, cetylstearyl 2-ethylhexanoate, hydrogenated polyisobutene, caprylic / cabrine triglycerides, palm oil, palm kernel oil, lanolin and PUFAs (polyunsaturated fatty acids such as eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and alpha-linolenic acid.
  • EPA eicosapentaenoic acid
  • DHA docosahexaen
  • edible oils which are liquid at 30 ° C.
  • vegetable oils such as sunflower oil, palm oil, palm kernel oil, sesame oil, maize germ oil, cottonseed oil, soybean oil, peanut oil, esters of medium-chain triglycerides (songeant MCT oils), fish oils, such as mackerel, sprat or salmon oil.
  • fish oils such as mackerel, sprat or salmon oil.
  • fish oils such as mackerel, sprat or salmon oil.
  • fish oils such as mackerel, sprat or salmon oil.
  • the oils mentioned for animal nutrition as well as the esters of medium-chain triglycerides are advantageous.
  • the active ingredients are in the formulations according to the invention generally in an amount in the range of 0.1 to 50 wt .-%, preferably 0.2 to 30 wt .-% and in particular 1, 0 to 15 wt .-%, based on the Total weight of oily formulation, included.
  • the amount of hydrophobic protective colloid is generally in the range of 1 to 75% by weight, preferably 2 to 70% by weight, and more preferably 5 to 65% by weight, based on the total weight of the formulation.
  • the weight ratio of active ingredient to hydrophobic protective colloid is generally in the range of 5: 1 to 1:10, preferably 3: 1 to 1: 5.
  • the amount of edible oil is generally in the range of 20 to 98.9 wt .-%, preferably 30 to 98 wt .-%, particularly preferably 40 to 97 wt .-% and in particular 50 to 95 wt .-%, based on the total weight of the oily formulation.
  • stabilizers such as ⁇ -tocopherol, t-butylhydroxytoluene, t-butylhydroxyanisole, ascorbic acid or ethoxyquin.
  • the formulations according to the invention may also contain auxiliaries, such as thickeners, hard fats, chelating agents, for example alkali metal or alkaline earth metal salts of citric acid, phytic acid or phosphoric acid and / or emulsifiers.
  • auxiliaries such as thickeners, hard fats, chelating agents, for example alkali metal or alkaline earth metal salts of citric acid, phytic acid or phosphoric acid and / or emulsifiers.
  • emulsifiers are Ascorbyl palmitate, polyglycerol fatty acid esters such as polyglycerol-3-polyricinoleate (PGPR 90), sorbitan fatty acid esters such as sorbitan monostearate (span 60), PEG (20) sorbitol monooleate, propylene glycol fatty acid esters or phospholipids such as lecithin.
  • Milling is carried out until an average particle size of the active ingredient crystals and of the hydrophobic protective colloid of ⁇ 5 ⁇ m, preferably ⁇ 1 ⁇ m, is reached.
  • Conventional devices known to the person skilled in the art for example colloid mills, ball mills, such as Dynomill type KDL, etc., can be used as the device for grinding.
  • alkanols are, for example, methanol, ethanol, isopropanol, etc. In general, not more than 10% by weight of water, alkanol or a mixture thereof is added to the mixture to be admixed.
  • the solid active ingredient and the hydrophobic protective colloid are dissolved in a polar solvent.
  • a polar solvent water-miscible, thermally stable, volatile solvents containing only carbon, hydrogen and oxygen, such as alcohols, ethers, esters, ketones and acetals, are used as the polar solvent.
  • solvents that are miscible with water at least 10% is used, have a boiling point below 200 0 C and / or have less than 10 carbon atoms.
  • methanol, ethanol, n-propanol, isopropanol, 1, 2-butanediol 1-methyl ether, 1, 2-propanediol n-propyl ether, tetrahydrofuran or acetone It is also possible to use a mixture of these solvents with water, the amount of solvent being at least 40% by weight. Examples of such mixtures are mixtures of ethanol or isopropanol with water.
  • the dissolution of the active ingredient and the hydrophobic protective colloid in the solvent used is carried out by first adding the two components in the solvent a temperature ranging from room temperature to about the boiling point of the solvent used dispersed. The dispersion is then mixed with further solvent heated to a higher temperature to dissolve the components.
  • the temperature of the further solvent is generally in the range of 150 to 250 0 C, being operated under a pressure which is established at the temperature used.
  • the resulting solution is mixed with water to give a dispersion of the drug particles in the solvent-water mixture.
  • the particle size of the active ingredient particles is generally in the range of 50 nm to 800 nm.
  • the amount of added water is generally one to ten times the amount of the solvent used.
  • the pH of the added water is adjusted to be at least 2 pH units away from the isoelectric point of the protective colloid used. For example, the pH is adjusted to a value of at least 9 and in particular to a value of at least 10 when using zein.
  • the solvent is removed in the usual manner or brings the active ingredient / protective colloid particles to flocculate. This is done by adjusting the pH of the drug dispersion to the isoelectric point of the protective colloid.
  • the flocculated particles which are an active ingredient-hydrophobic protective colloid aggregate, are then recovered in a conventional manner, for example by filtration, centrifuging or spray-drying, and optionally dried.
  • a liquid formulation is obtained by taking up the resulting powdery product in the desired edible oil.
  • the formulations according to the invention can be diluted before use by adding fats or oils to the respective use concentration.
  • the dilution can be carried out, for example, with stirring at elevated temperatures, such as 30 to 80 ° C.
  • the formulations are suitable inter alia as additives to animal feeds and food preparations or compound feeds, as agents for the production of pharmaceutical and cosmetic preparations and for the preparation of dietary supplement preparations in the human and animal sector.
  • the suspensions can be used as feed use in animal nutrition, for example, by mixing in feed pellets in the extrusion or by applying or spraying on feed pellets.
  • the application as a feed additive is effected in particular by direct spraying of the formulations according to the invention, for example as a so-called "post-pelleting application.”
  • the feed pellets are loaded with the formulations under reduced pressure.
  • Typical applications in the food sector include, for example, the vitaminization and coloring of beverages, dairy products such as yoghurt, milk mix drinks or milk ice cream, as well as pudding powders, egg products, baking mixes and confectionery.
  • the oily suspensions can be used, for example, for decorative personal care products, for example in the form of a cream, a lotion, as a lipstick or make-up.
  • the invention furthermore relates to dietary supplements, animal feeds, foods and pharmaceutical and cosmetic preparations which comprise the formulations according to the invention. Preference is given to animal feed, in particular feed pellets, which are loaded with the formulations.
  • dietary supplements as well as pharmaceutical preparations are u.a. Tablets, dragees and preferably hard and soft gelatin capsules to understand which comprise the formulations according to the invention.
  • the preparation was carried out in a device of the type described in EP 065 193.
  • 40 g of crystalline astaxanthin, 60 g of zein, 2 g of ascorbyl palmitate and 4 g of ethoxyquin in 600 g of an isopropanol / water mixture (60:40) were suspended at room temperature in a heated receiver at a temperature of 30 ° C.
  • the active ingredient suspension was then heated to 87.8 0 C and at a flow rate of 2.14 kg / h with further I- sopropanol / water mixture (60:40), which had a temperature of 290 0 C, with a
  • the active substance particles had a particle size of 150 nm in the isopropanol / water mixture at an E 1/1 value of 110.
  • the pH of the dispersion was adjusted to pH 5.1 with 1 M HCl to flocculate the astaxanthin / zein particles.
  • the flocculated particles were dried and dispersed in soybean oil to give a 9.5 wt% dispersion of astaxanthin.
  • the active ingredient content of this dispersion remained unchanged over a period of 6 months.
  • the oily dispersion can be applied directly to animal feed pellets by dilution with oil.
  • This drug solution was immediately followed with an aqueous phase of a solution of 83.5 soy protein and 177 g of lactose in 11,010 g of distilled water in which the pH had been adjusted to pH 9.5 with 1 M NaOH at a flow rate of 32.5 kg / h mixed.
  • the particles of active substance formed in the mixture had a particle size of 107 nm in the isopropanol / water mixture at an E 1/1 value of 124.
  • the dispersion was concentrated to about 23.7% by weight of dry content on a thin-film evaporator and finally spray-dried.
  • the dry powder had an astaxanthin content of 23% by weight.
  • the water-redispersed dry powder had a particle size of 317 nm and had an E 1/1 value of 101.
  • the E 1/1 value is the specific extinction of a 0.5% strength by weight dispersion of a 20% strength by weight dry powder in a 1 cm cuvette at the absorption maximum.
  • the resulting astaxanthin powder could not be homogeneously dispersed in an oil.
  • the powder In order to apply this powder to feed pellets, the powder must first be dissolved in water and then the aqueous solution emulsified into an oil.

Abstract

The present invention relates to unctuous compositions comprising at least one solid active ingredient, at least one hydrophobic protective colloid, and at least one edible oil. The active ingredient is preferably a carotenoid. Preferred protective colloids are prolamines. The inventive compositions are simple to produce, have good bioavailability and dyestuff yield, and are used as an addition to animal feed agents, foods and dietary supplements, and pharmaceutical and cosmetic agents.

Description

Ölige Formulierungen Oily formulations
Die vorliegende Erfindung betrifft ölige Formulierungen, Verfahren zu ihrer Herstellung sowie ihre Verwendung als Zusatz zu Tierfuttermitteln und Lebensmitteln.The present invention relates to oily formulations, processes for their preparation and their use as additives to animal feeds and foods.
Die Formulierung von Carotinoiden stellt aufgrund ihrer Schwerlöslichkeit in Wasser und ihrer chemischen Instabilität eine besondere Herausforderung dar. Es gab daher zahlreiche Versuche, Carotinoidformulierungen bereitzustellen, die einerseits stabil sind und andererseits gute Bioverfügbarkeit aufweisen und bei der Anwendung die gewünschten Farbausbeu- ten liefern. Flüssige Carotinoidformulierungen sind von besonderem Interesse, weil die Gewinnung der Carotinoide in Pulverform und die Zubereitung einer flüssigen Formulierung durch den Anwender entfallen.The formulation of carotenoids presents a particular challenge because of their poor solubility in water and their chemical instability. There have therefore been numerous attempts to provide carotenoid formulations which are both stable and have good bioavailability and provide the desired color efflorescence when applied. Liquid carotenoid formulations are of particular interest because of the elimination of the carotenoids in powder form and the preparation of a liquid formulation by the user.
Die Herstellung von Carotinoid-Primärpartikeln mit einer Teilchengröße im Nanometerbe- reich ist entscheidend, um ausreichende Bioverfügbarkeit und Farbausbeuten zu erzielen. Um derartige Partikel herzustellen, sind vor allem zwei Methoden bekannt geworden:The production of carotenoid primary particles with a particle size in the nanometer range is crucial in order to achieve sufficient bioavailability and color yields. In order to produce such particles, especially two methods have become known:
(1 ) ein Emulgier/Fällungsprozess (Mikronisierung), wie er beispielsweise in der EP 410 236 A beschrieben ist. Gemäß der EP 065 193 A erfolgt die Herstellung von fein verteilten pulver- förmigen Carotinoidpräparaten dadurch, dass man ein Carotinoid in einem flüchtigen, mit(1) an emulsification / precipitation process (micronization), as described for example in EP 410 236 A. According to EP 065 193 A, the preparation of finely divided powdered carotenoid preparations is carried out by reacting a carotenoid in a volatile, with
Wasser mischbaren organischen Lösungsmittel bei erhöhter Temperatur und gegebenenfalls unter erhöhtem Druck löst, das Carotinoid durch Mischen mit einer wässrigen Lösung eines Schutzkolloids ausfällt, aufkonzentriert und anschließend sprühtrocknet. Die EP 1 213 013 A beschreibt die Herstellung einer wässrigen Carotinoiddispersion in Anwesenheit eines Hyd- rokolloids, wie Casein oder Gelatine. Dabei wird der Wirkstoff zusammen mit dem Hydrokol- loid durch Einstellen des pH-Wertes auf den isoelektrischen Punkt ausgeflockt, anschließend wird das ausgeflockte Material abgetrennt und getrocknet. Dispergieren des erhaltenen pul- verförmigen Produktes ergibt dann eine ölige Suspension. Ein analoges Verfahren unter Verwendung von mit Wasser nicht mischbaren Lösungsmitteln ist in der EP 937 412 A be- schrieben.Dissolves water-miscible organic solvent at elevated temperature and optionally under elevated pressure, the carotenoid precipitates by mixing with an aqueous solution of a protective colloid, concentrated and then spray-dried. EP 1 213 013 A describes the preparation of an aqueous carotenoid dispersion in the presence of a hydrocolloid, such as casein or gelatin. The active ingredient is flocculated together with the hydrocolloid by adjusting the pH to the isoelectric point, then the flocculated material is separated and dried. Dispersing the powdered product obtained then gives an oily suspension. An analogous process using water-immiscible solvents is described in EP 937 412 A.
(2) Ein Zerkleinerungsprozess, insbesondere durch Mahlung, wie er beispielsweise in WO 91/06292 und WO 94/1941 1 beschrieben ist. Die Vermahlung der Carotinoide erfolgt mittels einer Kolloidmühle, in wässrigen oder öligen Medien, wobei einer Partikelgröße im Nanome- terbereich erzielt wird. Die WO 96/23429 beschreibt die Herstellung von öligen Astaxanthin-Suspensionen mit Partikelgrößen < 2 μm durch Vermählen von Astaxanthin, wobei während oder nach dem Vermählen ein Öl zugegeben wird. Die Anwendung von Schutzkolloiden oder Emulgatoren ist nicht offenbart. Es wird darauf hingewiesen, dass die Partikel zur Agglomeration neigen. Dementsprechend wird eine weitere Stabilisierung durch Aufbewahren der Suspension unter der Verfestigungstemperatur in Betracht gezogen.(2) A crushing process, in particular by grinding, as described for example in WO 91/06292 and WO 94/1941 1. The grinding of the carotenoids takes place by means of a colloid mill, in aqueous or oily media, whereby a particle size in the nanometer range is achieved. WO 96/23429 describes the preparation of oily astaxanthin suspensions with particle sizes <2 μm by grinding astaxanthin, wherein an oil is added during or after the grinding. The use of protective colloids or emulsifiers is not disclosed. It should be noted that the particles tend to agglomerate. Accordingly, further stabilization by keeping the suspension below the solidification temperature is contemplated.
In der WO 03/102116 sind ölige Lösungen eines Carotinoids beschrieben. Die Herstellung dieser öligen Lösungen erfolgt durch Lösen der Carotinoide in einem organischen Lösungs- mittel, wie N-Methylpyrrolidon, in Anwesenheit eines lipophilen Dispergiermittels und Entfernen des Lösungsmittels. Das erhaltene Pulver wird dann in geringer Konzentration in einem Öl, z. B. Fischöl, gelöst.WO 03/102116 describes oily solutions of a carotenoid. The preparation of these oily solutions is carried out by dissolving the carotenoids in an organic solvent, such as N-methylpyrrolidone, in the presence of a lipophilic dispersant and removing the solvent. The resulting powder is then concentrated in a low concentration in an oil, e.g. As fish oil, solved.
Die WO 2006/125591 beschreibt die Herstellung einer öligen Carotinoid-Zusammensetzung. Dabei wird das Carotinoid in einer Ölphase dispergiert, die Dispersion wird für kurze Zeit erhitzt, um das Carotinoid in Lösung zu bringen, und die erhaltene Lösung wird durch Vermischen mit weiterem Öl, das eine niedrigere Temperatur als die Öllösung aufweist, gekühlt. Die ölige Zusammensetzung enthält eine nur geringe Menge an Carotinoid, d.h. es müssen große Mengen der Zusammensetzung eingesetzt werden, um den gewünschten Effekt zu erzielen. Das Verfahren ist deshalb nicht wirtschaftlich.WO 2006/125591 describes the preparation of an oily carotenoid composition. The carotenoid is dispersed in an oil phase, the dispersion is heated for a short time to dissolve the carotenoid, and the resulting solution is cooled by mixing with further oil having a lower temperature than the oil solution. The oily composition contains only a small amount of carotenoid, i. Large quantities of the composition must be used to achieve the desired effect. The method is therefore not economical.
Die WO 96/13178 beschreibt die Herstellung stabiler Lycopin-Konzentrate durch Vermählen des Lycopins in einem flüssigen Medium, in dem das Lycopin im Wesentlichen unlöslich ist. Als flüssiges Medium werden Glycerin, Propylenglykol oder Ethanol verwendet.WO 96/13178 describes the preparation of stable lycopene concentrates by milling the lycopene in a liquid medium in which the lycopene is substantially insoluble. The liquid medium used is glycerol, propylene glycol or ethanol.
Den Methoden des Standes der Technik ist gemeinsam, dass sie entweder Produkte mit nicht zufriedenstellender Stabilität oder Bioverfügbarkeit ergeben oder dass die Herstellung aufwendig ist.The methods of the prior art have in common that they either give products with unsatisfactory stability or bioavailability or that the production is complicated.
Der vorliegenden Erfindung liegt daher die Aufgabe zugrunde, flüssige Carotinoidformulie- rungen zur Verfügung zu stellen, die einfach herstellbar sind und dennoch Produkte ergeben, deren Stabilität und Bioverfügbarkeit mit den bekannten Produkten vergleichbar sind.It is therefore an object of the present invention to provide liquid carotenoid formulations which are easy to prepare and nevertheless give products whose stability and bioavailability are comparable to the known products.
Überraschenderweise wurde nun gefunden, dass diese Aufgabe durch eine ölige Formulie- rung gelöst wird, die in einem essbaren Öl einen festen Wirkstoff und ein hydrophobes Schutzkolloid dispergiert oder gelöst enthält. Gegenstand der vorliegenden Erfindung ist daher eine ölige Formulierung in Form einer Dispersion (Suspension), umfassend mindestens einen Wirkstoff, mindestens ein hydrophobes Schutzkolloid und mindestens ein essbares Öl.Surprisingly, it has now been found that this object is achieved by an oily formulation containing a solid active ingredient and a hydrophobic protective colloid dispersed or dissolved in an edible oil. The present invention therefore relates to an oily formulation in the form of a dispersion (suspension) comprising at least one active substance, at least one hydrophobic protective colloid and at least one edible oil.
Als Wirkstoff kommen feste Wirkstoffe in Betracht, die in dem essbaren Öl dispergierbar sind. Die Wirkstoffe weisen im Allgemeinen eine Teilchengröße im Bereich von 50 nm bis 10 μm, vorzugsweise 100 nm bis 5 μm, besonders bevorzugt 100 nm bis 3 μm, 150 nm bis 2 μm und insbesondere 200 nm bis 1 μm auf.Suitable active ingredients are solid active ingredients which are dispersible in the edible oil. The active compounds generally have a particle size in the range from 50 nm to 10 .mu.m, preferably 100 nm to 5 .mu.m, particularly preferably 100 nm to 3 .mu.m, 150 nm to 2 .mu.m and in particular 200 nm to 1 .mu.m.
Vorzugsweise handelt es sich bei den Wirkstoffen um Carotinoide. Dabei können die bekannten, aus natürlichen Quellen oder synthetisch zugänglichen Vertreter eingesetzt werden. Beispiele hierfür sind ß-Carotin, Lycopin, Lutein, Astaxanthin, Astaxanthin-Derivate (wie z.B. Astaxanthin-dimethyl-disuccinat oder Astaxanthin-dipalmitat), Zeaxanthin, Cryptoxanthin, Citranaxanthin, Canthaxanthin, Echinenon, Bixin, ß-Apo-4-carotinal, ß-Apo-8-carotinal, ß- Apo-4-carotinsäureester, einzeln oder als Mischung. Bevorzugt sind Astaxanthin, Astaxanthin-Derivate (wie z.B. Astaxanthin-dimethyl-disuccinat oder Astaxanthin-dipalmitat), ß- Carotin, ß-Apo-8-carotinal, ß-Apo-8'-carotinsäureethylester, Canthaxanthin, Citranaxanthin, Echinenon, Lutein, Lycopin und Zeaxanthin. Besonders bevorzugt sind Astaxanthin, Astaxanthin-Derivate (wie z.B. Astaxanthin-dimethyl-disuccinat oder Astaxanthin-dipalmitat), und Canthaxanthin und insbesondere Astaxanthin.Preferably, the active ingredients are carotenoids. The known, from natural sources or synthetically accessible representatives can be used. Examples of these are β-carotene, lycopene, lutein, astaxanthin, astaxanthin derivatives (such as, for example, astaxanthin dimethyl disuccinate or astaxanthin dipalmitate), zeaxanthin, cryptoxanthin, citranaxanthin, canthaxanthin, echinenone, bixin, β-apo-4-carotenal, β-apo-8-carotenal, β-apo-4-carotenoic acid ester, individually or as a mixture. Preference is given to astaxanthin, astaxanthin derivatives (such as, for example, astaxanthin dimethyl disuccinate or astaxanthin dipalmitate), β-carotene, β-apo-8-carotenal, β-apo-8'-carotenoic acid ethyl ester, canthaxanthin, citranaxanthin, echinenone, lutein, Lycopene and zeaxanthin. Particularly preferred are astaxanthin, astaxanthin derivatives (such as astaxanthin dimethyl disuccinate or astaxanthin dipalmitate), and canthaxanthin, and especially astaxanthin.
Die erfindungsgemäßen Formulierungen enthalten außerdem ein hydrophobes Schutzkolloid. Unter einem hydrophoben Schutzkolloid ist ein Schutzkolloid zu verstehen, das in Wasser nicht löslich, nicht wasserdispergierbar und nicht quellbar ist. Es ist jedoch in wässrigem Ethanol oder Isopropanol, das wenigstens 40 Gew.-% Ethanol oder Isopropanol enthält, löslich. Das Schutzkolloid wird als löslich betrachtet, wenn sich mehr als 0,5 Gew.-% des Hyd- rokolloids in wäßrigem Ethanol oder Isopropanol mit mindestens 40 Gew.-% Alkohol lösen. Die Schutzkolloide besitzen Affinität zu Phenyl-, Octyl- oder Butyl-Sepharose.The formulations according to the invention also contain a hydrophobic protective colloid. A hydrophobic protective colloid is to be understood as meaning a protective colloid which is insoluble in water, not water-dispersible and non-swellable. However, it is soluble in aqueous ethanol or isopropanol containing at least 40% by weight of ethanol or isopropanol. The protective colloid is considered soluble if more than 0.5% by weight of the hydrocolloid dissolves in aqueous ethanol or isopropanol with at least 40% by weight of alcohol. The protective colloids have affinity for phenyl, octyl or butyl-Sepharose.
Eine bevorzugte Gruppe hydrophober Schutzkolloide sind die Prolamine. Es handelt sich dabei um Proteine, die in Getreidearten vorkommen. Beispiele geeigneter Prolamine sind Zein (aus Mais), Gliadin (aus Weizen und Hafer), Secalin (aus Roggen), Hordein (aus Gerste), Orycin (aus Reis) und Kafarin (aus Hirse, Sorghum).A preferred group of hydrophobic protective colloids are the prolamines. These are proteins that occur in cereal species. Examples of suitable prolamins are zein (from maize), gliadin (from wheat and oats), secalin (from rye), hordein (from barley), orycin (from rice) and kafarin (from millet, sorghum).
In Betracht kommen außerdem hydrophobe Schutzkolloide, insbesondere Proteine, die durch Fermentation hergestellt und/oder modifiziert worden sind oder die synthetisch hergestellt worden sind. Das essbare Öl kann synthetischer, mineralischer, pflanzlicher oder tierischer Herkunft sein. Beispiele sind Sesamöl, Maiskeimöl, Baumwollsaatöl, Sojabohnenöl, Erdnussöl, Ester mittel- kettiger pflanzlicher Fettsäuren, Oleostearin, Paraffinöl, Glycerylstearat, Isopropylmyristat, Diisopropyladipat, 2-Ethylhexansäurecetylstearylester, hydriertes Polyisobuten, Caprylsäu- re/Cabrinsäure-Triglyceride, Palmöl, Palmkernöl, Lanolin und PUFAs (polyunsaturated fatty acids, wie Eicosapentaensäure (EPA), Docosahexaensäure (DHA) und alpha-Linolensäure.Also contemplated are hydrophobic protective colloids, particularly proteins that have been produced and / or modified by fermentation or that have been prepared synthetically. The edible oil may be of synthetic, mineral, vegetable or animal origin. Examples are sesame oil, corn oil, cottonseed oil, soybean oil, peanut oil, esters of medium-chain fatty acids, oleostearin, paraffin oil, glyceryl stearate, isopropyl myristate, diisopropyl adipate, cetylstearyl 2-ethylhexanoate, hydrogenated polyisobutene, caprylic / cabrine triglycerides, palm oil, palm kernel oil, lanolin and PUFAs (polyunsaturated fatty acids such as eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and alpha-linolenic acid.
Bevorzugt sind essbare, bei 30 0C flüssige Öle, wie Sonnenblumenöl, Palmöl, Palmkernöl, Sesamöl, Maiskeimöl, Baumwollsaatöl, Sojabohnenöl, Erdnussöl, Ester mittelkettiger Triglyceride (songeannte MCT Öle), Fischöle, wie Makrelen-, Sprotten- oder Lachsöl. Für die Tierernährung besonders bevorzugt sind Fischöle, Maiskeimöl, Sonnenblumenöl, Sojaöl und Erdnussöl. Für den Food-/Pharmabereich sind die für die Tierernährung genannten Öle sowie die Ester mittelkettiger Triglyceride von Vorteil.Preference is given to edible oils which are liquid at 30 ° C., such as sunflower oil, palm oil, palm kernel oil, sesame oil, maize germ oil, cottonseed oil, soybean oil, peanut oil, esters of medium-chain triglycerides (songeant MCT oils), fish oils, such as mackerel, sprat or salmon oil. Especially preferred for animal nutrition are fish oils, corn oil, sunflower oil, soybean oil and peanut oil. For the food / pharmaceutical sector, the oils mentioned for animal nutrition as well as the esters of medium-chain triglycerides are advantageous.
Die Wirkstoffe sind in den erfindungsgemäßen Formulierungen im Allgemeinen in einer Menge im Bereich von 0,1 bis 50 Gew.-%, vorzugsweise 0,2 bis 30 Gew.-% und insbesondere 1 ,0 bis 15 Gew.-%, bezogen auf das Gesamtgewicht der öligen Formulierung, enthalten.The active ingredients are in the formulations according to the invention generally in an amount in the range of 0.1 to 50 wt .-%, preferably 0.2 to 30 wt .-% and in particular 1, 0 to 15 wt .-%, based on the Total weight of oily formulation, included.
Die Menge an hydrophobem Schutzkolloid liegt im Allgemeinen im Bereich von 1 bis 75 Gew.-%, vorzugsweise 2 bis 70 Gew.-% und insbesondere 5 bis 65 Gew.-%, bezogen auf das Gesamtgewicht der Formulierung.The amount of hydrophobic protective colloid is generally in the range of 1 to 75% by weight, preferably 2 to 70% by weight, and more preferably 5 to 65% by weight, based on the total weight of the formulation.
Das Gewichtsverhältnis von Wirkstoff zu hydrophobem Schutzkolloid liegt im Allgemeinen im Bereich von 5:1 bis 1 :10, vorzugsweise 3:1 bis 1 :5.The weight ratio of active ingredient to hydrophobic protective colloid is generally in the range of 5: 1 to 1:10, preferably 3: 1 to 1: 5.
Die Menge an essbarem Öl liegt im Allgemeinen im Bereich von 20 bis 98,9 Gew.-%, vorzugsweise 30 bis 98 Gew.-%, besonders bevorzugt 40 bis 97 Gew.-% und insbesondere 50 bis 95 Gew.-%, bezogen auf das Gesamtgewicht der öligen Formulierung.The amount of edible oil is generally in the range of 20 to 98.9 wt .-%, preferably 30 to 98 wt .-%, particularly preferably 40 to 97 wt .-% and in particular 50 to 95 wt .-%, based on the total weight of the oily formulation.
Zur Erhöhung der Stabilität des Wirkstoffes gegen oxidativen Abbau ist es vorteilhaft, Stabilisatoren wie α-Tocopherol, t-Butylhydroxytoluol, t-Butylhydroxyanisol, Ascorbinsäure oder Ethoxyquin zuzusetzen.To increase the stability of the active ingredient against oxidative degradation, it is advantageous to add stabilizers such as α-tocopherol, t-butylhydroxytoluene, t-butylhydroxyanisole, ascorbic acid or ethoxyquin.
Die erfindungsgemäßen Formulierungen können außerdem Hilfsstoffe, wie Verdicker, Hartfette, Chelatbildner, beispielsweise Alkali- oder Erdalkalisalze der Citronensäure, Phythin- säure oder Phosphorsäure und/oder Emulgatoren enthalten. Beispiele für Emulgatoren sind Ascorbylpalmitat, Polyglycerin-Fettsäureester, wie Polyglycerin-3-polyricinoleat (PGPR 90), Sorbitan-Fettsäureester, wie Sorbitanmonostearat (span 60), PEG(20)-Sorbitolmonooleat, Propylenglykol-Fettsäureester oderPhospholipide, wie Lecithin.The formulations according to the invention may also contain auxiliaries, such as thickeners, hard fats, chelating agents, for example alkali metal or alkaline earth metal salts of citric acid, phytic acid or phosphoric acid and / or emulsifiers. Examples of emulsifiers are Ascorbyl palmitate, polyglycerol fatty acid esters such as polyglycerol-3-polyricinoleate (PGPR 90), sorbitan fatty acid esters such as sorbitan monostearate (span 60), PEG (20) sorbitol monooleate, propylene glycol fatty acid esters or phospholipids such as lecithin.
Die Herstellung der erfindungsgemäßen Formulierungen kann nach mehreren Verfahren erfolgen. Gemäß einem ersten Verfahren wird der Wirkstoff in dem verwendeten Öl vermählen. Das hydrophobe Schutzkolloid kann vollständig oder teilweise von Anfang an vorhanden sein oder während des Mahlens zugegeben werden. Es kann in pulverförmiger Form oder als Lösung zugegeben werden. Wenn es als Lösung zugegeben wird, verwendet man als Lösungsmittel zweckmäßigerweise einen Mono- oder Polyalkohol, gegebenenfalls im Gemisch mit Wasser, oder einen Carbonsäureester oder Gemische davon. Beispiele für geeignete Lösungsmittel sind Isopropanol/Wasser (8:2), Propylenglykol, Ethylenglykol, Triethy- lenglykol oder Ethyllactat. Das Mahlen wird so lange durchgeführt, bis eine mittlere Teilchengröße der Wirkstoffkristalle und des hydrophoben Schutzkolloids von < 5 μm, vorzugsweise < 1 μm, erreicht ist. Als Vorrichtung zum Vermählen können übliche, dem Fachmann bekannte Vorrichtungen, beispielsweise Kolloidmühlen, Kugelmühlen, wie Dynomill Typ KDL, etc., eingesetzt werden.The formulations according to the invention can be prepared by a plurality of processes. According to a first method, the active ingredient is ground in the oil used. The hydrophobic protective colloid may be wholly or partially present from the beginning or added during milling. It can be added in powder form or as a solution. If it is added as a solution, the solvent used is conveniently a mono- or polyalcohol, optionally in admixture with water, or a carboxylic acid ester or mixtures thereof. Examples of suitable solvents are isopropanol / water (8: 2), propylene glycol, ethylene glycol, triethylene glycol or ethyl lactate. Milling is carried out until an average particle size of the active ingredient crystals and of the hydrophobic protective colloid of <5 μm, preferably <1 μm, is reached. Conventional devices known to the person skilled in the art, for example colloid mills, ball mills, such as Dynomill type KDL, etc., can be used as the device for grinding.
Es kann zweckmäßig sein, dem zu vermählenden Gemisch eine geringe Menge an Wasser oder Alkanol oder einem Gemisch davon zuzusetzen. Geeignete Alkanole sind beispielsweise Methanol, Ethanol, Isopropanol etc. Im Allgemeinen werden nicht mehr als 10 Gew.-% an Wasser, Alkanol oder einem Gemisch davon dem zu vermählenden Gemisch zugesetzt.It may be appropriate to add to the mixture to be admixed a small amount of water or alkanol or a mixture thereof. Suitable alkanols are, for example, methanol, ethanol, isopropanol, etc. In general, not more than 10% by weight of water, alkanol or a mixture thereof is added to the mixture to be admixed.
Gemäß einem weiteren Verfahren werden der feste Wirkstoff und das hydrophobe Schutz- kolloid in einem polaren Lösungsmittel gelöst. Als polares Lösungsmittel verwendet man insbesondere wassermischbare, thermisch stabile, flüchtige, nur Kohlenstoff, Wasserstoff und Sauerstoff enthaltende Lösungsmittel, wie Alkohole, Ether, Ester, Ketone und Acetale. Zweckmäßig verwendet man solche Lösungsmittel, die mindestens zu 10 % wassermischbar sind, einen Siedepunkt unter 200 0C aufweisen und/oder weniger als 10 Kohlenstoffatome haben. Besonders bevorzugt verwendet man Methanol, Ethanol, n-Propanol, Isopropanol, 1 ,2-Butandiol-1-methylether, 1 ,2-Propandiol-n-propylether, Tetrahydrofuran oder Aceton. Es kann auch ein Gemisch dieser Lösungsmittel mit Wasser zur Anwendung kommen, wobei die Menge an Lösungsmittel mindestens 40 Gew.-% beträgt. Beispiele für derartige Gemische sind Gemische von Ethanol oder Isopropanol mit Wasser.According to another method, the solid active ingredient and the hydrophobic protective colloid are dissolved in a polar solvent. In particular, water-miscible, thermally stable, volatile solvents containing only carbon, hydrogen and oxygen, such as alcohols, ethers, esters, ketones and acetals, are used as the polar solvent. Suitably such solvents that are miscible with water at least 10% is used, have a boiling point below 200 0 C and / or have less than 10 carbon atoms. Particular preference is given to using methanol, ethanol, n-propanol, isopropanol, 1, 2-butanediol 1-methyl ether, 1, 2-propanediol n-propyl ether, tetrahydrofuran or acetone. It is also possible to use a mixture of these solvents with water, the amount of solvent being at least 40% by weight. Examples of such mixtures are mixtures of ethanol or isopropanol with water.
Das Lösen des Wirkstoffes und des hydrophoben Schutzkolloids in dem verwendeten Lösungsmittel erfolgt, indem man die beiden Komponenten zunächst in dem Lösungsmittel bei einer Temperatur im Bereich von Raumtemperatur bis etwa Siedetemperatur des verwendeten Lösungsmittels dispergiert. Die Dispersion wird anschließend mit weiterem Lösungsmittel, das auf eine höhere Temperatur erhitzt ist, vermischt, wobei sich die Komponenten lösen. Die Temperatur des weiteren Lösungsmittels liegt im Allgemeinen im Bereich von 150 bis 250 0C, wobei unter einem Druck gearbeitet wird, der sich bei der zur Anwendung kommenden Temperatur einstellt. Unmittelbar anschließend (innerhalb von 0,1 bis 30 Sekunden) wird die erhaltene Lösung mit Wasser vermischt, wobei eine Dispersion der Wirkstoffteilchen in dem Lösungsmittel-Wasser-Gemisch erhalten wird. Die Teilchengröße der Wirkstoffteilchen liegt im Allgemeinen im Bereich von 50 nm bis 800 nm. Die Menge an zugegebenem Wasser beträgt im Allgemeinen das Ein- bis Zehnfache der Menge des verwendeten Lösungsmittels. Der pH-Wert des zugesetzten Wassers wird so eingestellt, dass er um mindestens 2 pH-Einheiten vom isoelektrischen Punkt des verwendeten Schutzkolloids entfernt ist. Beispielsweise wird der pH-Wert bei Verwendung von Zein auf einen Wert von mindestens 9 und insbesondere auf einen Wert von mindestens 10 eingestellt.The dissolution of the active ingredient and the hydrophobic protective colloid in the solvent used is carried out by first adding the two components in the solvent a temperature ranging from room temperature to about the boiling point of the solvent used dispersed. The dispersion is then mixed with further solvent heated to a higher temperature to dissolve the components. The temperature of the further solvent is generally in the range of 150 to 250 0 C, being operated under a pressure which is established at the temperature used. Immediately thereafter (within 0.1 to 30 seconds), the resulting solution is mixed with water to give a dispersion of the drug particles in the solvent-water mixture. The particle size of the active ingredient particles is generally in the range of 50 nm to 800 nm. The amount of added water is generally one to ten times the amount of the solvent used. The pH of the added water is adjusted to be at least 2 pH units away from the isoelectric point of the protective colloid used. For example, the pH is adjusted to a value of at least 9 and in particular to a value of at least 10 when using zein.
Zur weiteren Aufarbeitung gibt es zwei Alternativen. Aus der erhaltenen Wirkstoffdispersion wird das Lösungsmittel in üblicher Weise entfernt oder man bringt die Wirkstoff/Schutzkolloid-Teilchen zum Ausflocken. Dies erfolgt dadurch, dass man den pH-Wert der Wirkstoffdispersion auf den isoelektrischen Punkt des Schutzkolloids einstellt. Die ausge- flockten Teilchen, die ein Wirkstoff-hydrophobes Schutzkolloid-Aggregat darstellen, werden dann in üblicher weise gewonnen, beispielsweise durch Filtrieren, Zentrifugieren oder Sprühtrocknen, und gegebenenfalls getrocknet. Eine flüssige Formulierung wird durch Aufnehmen des erhaltenen pulverförmigen Produktes in dem gewünschten essbaren Öl erhalten.For further processing, there are two alternatives. From the resulting active ingredient dispersion, the solvent is removed in the usual manner or brings the active ingredient / protective colloid particles to flocculate. This is done by adjusting the pH of the drug dispersion to the isoelectric point of the protective colloid. The flocculated particles, which are an active ingredient-hydrophobic protective colloid aggregate, are then recovered in a conventional manner, for example by filtration, centrifuging or spray-drying, and optionally dried. A liquid formulation is obtained by taking up the resulting powdery product in the desired edible oil.
Einzelheiten des Verfahrens und weitere Verfahrensvarianten sind in der EP 1 213 013 und EP 1 219 292 beschrieben, deren Offenbarungsgehalt in vollem Umfang zum Gegenstand der vorliegenden Erfindung gemacht wird.Details of the process and further process variants are described in EP 1 213 013 and EP 1 219 292, the disclosure content of which is fully incorporated in the subject matter of the present invention.
Die erfindungsgemäßen Formulierungen können vor der Anwendung durch Zusatz von Fetten oder Ölen auf die jeweilige Gebrauchskonzentration verdünnt werden. Die Verdünnung kann beispielsweise unter Rühren bei erhöhten Temperaturen, wie 30 bis 80 0C, erfolgen.The formulations according to the invention can be diluted before use by adding fats or oils to the respective use concentration. The dilution can be carried out, for example, with stirring at elevated temperatures, such as 30 to 80 ° C.
Die Formulierungen eignen sich unter anderem als Zusatzstoff zu Tierfuttermitteln und Le- bensmittelzubereitungen bzw. Mischfutter, als Mittel für die Herstellung pharmazeutischer und kosmetischer Zubereitungen sowie für die Herstellung von Nahrungsergänzungspräpa- raten im Human- und Tierbereich. Bevorzugt lassen sich die Suspensionen als Futtermittel- zusatz in der Tierernährung einsetzen, beispielsweise durch Einmischen in Futtermittel pel- lets bei der Extrusion oder durch Auftragen bzw. Aufsprühen auf Futtermittelpellets. Die Anwendung als Futtermittelzusatz erfolgt insbesondere durch direktes Aufsprühen der erfindungsgemäßen Formulierungen, beispielsweise als sogenannte „post-pelleting application". Vorzugsweise belädt man die Futtermittelpellets mit den Formulierungen unter vermindertem Druck.The formulations are suitable inter alia as additives to animal feeds and food preparations or compound feeds, as agents for the production of pharmaceutical and cosmetic preparations and for the preparation of dietary supplement preparations in the human and animal sector. Preferably, the suspensions can be used as feed use in animal nutrition, for example, by mixing in feed pellets in the extrusion or by applying or spraying on feed pellets. The application as a feed additive is effected in particular by direct spraying of the formulations according to the invention, for example as a so-called "post-pelleting application." Preferably, the feed pellets are loaded with the formulations under reduced pressure.
Typische Einsatzgebiete im Lebensmittelbereich sind beispielsweise die Vitaminierung und Färbung von Getränken, Milchprodukten wie Joghurt, Milchmixgetränken oder Milchspeise- eis sowie von Puddingpulvern, Eiprodukten, Backmischungen und Süßwaren. Im Kosmetikbereich können die öligen Suspensionen beispielsweise für dekorative Körperpflegemittel, beispielsweise in Form einer Creme, einer Lotion, als Lippenstift oder Make-up, verwendet werden.Typical applications in the food sector include, for example, the vitaminization and coloring of beverages, dairy products such as yoghurt, milk mix drinks or milk ice cream, as well as pudding powders, egg products, baking mixes and confectionery. In the cosmetics industry, the oily suspensions can be used, for example, for decorative personal care products, for example in the form of a cream, a lotion, as a lipstick or make-up.
Gegenstand der Erfindung sind ferner Nahrungsergänzungsmittel, Tierfuttermittel, Lebensmittel sowie pharmazeutische und kosmetische Zubereitungen, welche die erfindungsgemäßen Formulierungen umfassen. Bevorzugt sind Tierfuttermittel, insbesondere Futtermittelpellets, die mit den Formulierungen beladen sind.The invention furthermore relates to dietary supplements, animal feeds, foods and pharmaceutical and cosmetic preparations which comprise the formulations according to the invention. Preference is given to animal feed, in particular feed pellets, which are loaded with the formulations.
Unter Nahrungsergänzungspräparaten sowie pharmazeutischen Zubereitungen sind u.a. Tabletten, Dragees sowie bevorzugt Hart- und Weichgelatinekapseln zu verstehen, welche die erfindungsgemäßen Formulierungen umfassen.Among dietary supplements as well as pharmaceutical preparations are u.a. Tablets, dragees and preferably hard and soft gelatin capsules to understand which comprise the formulations according to the invention.
Die nachfolgenden Beispiele erläutern die Erfindung, ohne sie zu begrenzen.The following examples illustrate the invention without limiting it.
Beispiel 1example 1
Herstellung einer öligen Astaxanthin-DispersionPreparation of an oily astaxanthin dispersion
Die Herstellung erfolgte in einer Vorrichtung des in EP 065 193 beschriebenen Typs. In einer beheizbaren Vorlage wurden bei einer Temperatur von 30 0C 40 g kristallines Astaxanthin, 60 g Zein, 2 g Ascorbylpalmitat und 4 g Ethoxyquin in 600 g eines Isopropanol/Wasser- Gemisches (60:40) bei Raumtemperatur suspendiert. Die Wirkstoffsuspension wurde dann auf 87,8 0C erwärmt und mit einer Flussrate von 2,14 kg/h kontinuierlich mit weiterem I- sopropanol/Wasser-Gemisch (60:40), das eine Temperatur von 290 0C hatte, mit einerThe preparation was carried out in a device of the type described in EP 065 193. 40 g of crystalline astaxanthin, 60 g of zein, 2 g of ascorbyl palmitate and 4 g of ethoxyquin in 600 g of an isopropanol / water mixture (60:40) were suspended at room temperature in a heated receiver at a temperature of 30 ° C. The active ingredient suspension was then heated to 87.8 0 C and at a flow rate of 2.14 kg / h with further I- sopropanol / water mixture (60:40), which had a temperature of 290 0 C, with a
Flussrate von 3,0 kg/h vermischt. Es stellte sich eine Mischungstemperatur von 170 0C und ein Druck von 54,8 bar ein. Die erhaltene Lösung wurde unmittelbar anschließend (< 1 sec) mit 16 643 g destilliertem Wasser, dessen pH-Wert mit 1 M NaOH auf pH 11 eingestellt worden war, mit einer Flussrate von 50,5 kg/h vermischt, wobei eine kolloidale Wirkstoffdispersion erhalten wurde.Flow rate of 3.0 kg / h mixed. It turned a mixture temperature of 170 0 C and a pressure of 54.8 bar. The resulting solution was immediately followed (<1 sec) with 16 643 g of distilled water, the pH of which had been adjusted to pH 11 with 1 M NaOH, at a flow rate of 50.5 kg / h, whereby a colloidal drug dispersion was obtained.
Die Wirkstoffteilchen wiesen im Isopropanol/Wasser-Gemisch bei einem E 1/1 -Wert von 1 10 eine Teilchengröße von 150 nm auf.The active substance particles had a particle size of 150 nm in the isopropanol / water mixture at an E 1/1 value of 110.
Anschließend wurde der pH-Wert der Dispersion mit 1 M HCl auf pH 5,1 eingestellt, um die Astaxanthin/Zein-Teilchen auszuflocken. Die ausgeflockten Teilchen wurden getrocknet und so in Sojaöl dispergiert, dass eine 9,5 Gew.-%ige Astaxanthin-Dispersion erhalten wurde. Der Wirkstoffgehalt dieser Dispersion blieb über einen Zeitraum von 6 Monaten unverändert. Die ölige Dispersion kann direkt durch Verdünnen mit Öl auf Futtermittelpellets aufgebracht werden.Subsequently, the pH of the dispersion was adjusted to pH 5.1 with 1 M HCl to flocculate the astaxanthin / zein particles. The flocculated particles were dried and dispersed in soybean oil to give a 9.5 wt% dispersion of astaxanthin. The active ingredient content of this dispersion remained unchanged over a period of 6 months. The oily dispersion can be applied directly to animal feed pellets by dilution with oil.
Beispiel 2 (Vergleich)Example 2 (comparison)
Herstellung einer Astaxanthin-Formulierung unter Verwendung eines hydrophilen SchutzkolloidsPreparation of an astaxanthin formulation using a hydrophilic protective colloid
In einer beheizbaren Vorlage wurden analog dem Beispiel 1 beschriebenen Verfahren bei einer Temperatur von 30 0C 83,5 g kristallines Astaxanthin und 20 g α-Tocopherol in 626 g eines azeotropen Isopropanol/Wasser-Gemisches bei Raumtemperatur suspendiert. Die Wirkstoffsuspension wurde dann auf 90 0C erwärmt und mit einer Flussrate von 2,1 kg/h kontinuierlich mit weiterem Isopropanol/Wasser-Azeotrop, das eine Temperatur von 220 0C hat- te, mit einer Flussrate von 2,6 kg/h vermischt, wobei sich das Astaxanthin bei einer Mischungstemperatur von 165 0C und einem Druck von 55 bar auflöste. Diese Wirkstofflösung wurde unmittelbar anschließend mit einer wässrigen Phase aus einer Lösung von 83,5 Sojaprotein und 177 g Lactose in 11 010 g destilliertem Wasser, in welcher der pH-Wert mit 1 M NaOH auf pH 9,5 eingestellt worden war, mit einer Flussrate von 32,5 kg/h vermischt.83.5 g of crystalline astaxanthin and 20 g of α-tocopherol in 626 g of an azeotropic isopropanol / water mixture were suspended at room temperature in a heated template analogously to Example 1 at a temperature of 30 0 C at room temperature. The active ingredient suspension was then heated to 90 0 C and at a flow rate of 2.1 kg / h with further isopropanol / water azeotrope, the te a temperature of 220 0 C HAT, at a flow rate of 2.6 kg / h mixed, wherein the astaxanthin dissolved at a mixing temperature of 165 0 C and a pressure of 55 bar. This drug solution was immediately followed with an aqueous phase of a solution of 83.5 soy protein and 177 g of lactose in 11,010 g of distilled water in which the pH had been adjusted to pH 9.5 with 1 M NaOH at a flow rate of 32.5 kg / h mixed.
Die bei der Mischung entstandenen Wirkstoffteilchen wiesen im Isopropanol/Wasser- Gemisch bei einem E 1/1 -Wert von 124 eine Teilchengröße von 107 nm auf.The particles of active substance formed in the mixture had a particle size of 107 nm in the isopropanol / water mixture at an E 1/1 value of 124.
Anschließend wurde die Dispersion an einem Dünnfilmverdampfer auf ca. 23,7 Gew.-% Tro- ckengehalt aufkonzentriert und schließlich sprühgetrocknet. Das Trockenpulver wies einen Astaxanthin-Gehalt von 23 Gew.% auf. Das in Wasser redispergierte Trockenpulver hatte eine Teilchengröße von 317 nm und wies einen E 1/1 -Wert von 101 auf. Der E 1/1 -Wert ist die spezifische Extinktion einer 0,5 Gew.-%igen Dispersion eines 20 Gew.-%igen Trockenpulvers in einer 1-cm-Küvette im Absorptionsmaximum.Subsequently, the dispersion was concentrated to about 23.7% by weight of dry content on a thin-film evaporator and finally spray-dried. The dry powder had an astaxanthin content of 23% by weight. The water-redispersed dry powder had a particle size of 317 nm and had an E 1/1 value of 101. The E 1/1 value is the specific extinction of a 0.5% strength by weight dispersion of a 20% strength by weight dry powder in a 1 cm cuvette at the absorption maximum.
Das entstandene Astaxanthinpulver ließ sich nicht homogen in ein Öl dispergieren. Um die- ses Pulver auf Futtermittelpellets aufbringen zu können, muss das Pulver zuerst in Wasser gelöst und anschließend die wässrige Lösung in ein Öl einemulgiert werden.The resulting astaxanthin powder could not be homogeneously dispersed in an oil. In order to apply this powder to feed pellets, the powder must first be dissolved in water and then the aqueous solution emulsified into an oil.
Beispiel 3Example 3
Herstellung einer öligen Astaxanthin-Formulierung durch MahlungPreparation of an oily astaxanthin formulation by grinding
50 g Astaxanthin (5 Gew.-%), 40 g α-Tocopherol (4 Gew.-%) und 5 g Ascorbylpalmitat (0,5 Gew.-%) werden mit 755 g Sonnenblumenöl (75,5 Gew.-%) vermischt. Diese Mischung wurde vermählen und während der ersten 15 Minuten wurden 150 g Zein (15 Gew.-%) langsam zugegeben. Mahldauer: 4 Stunden bei 64 bis 74 0C und einer Durchflussrate von 60 bis 80 g/min (Spezifikationen der Mühle Dynomill: 0,05 mm Reibspalt, 2986 rpm, 470 ml mit ZrO2 stabilisierten Kugeln mit einem Durchmesser von 0,3 mm). Mittels Fraunhoferbeugung wurde eine Partikelgröße des Astaxanthin-Zein-Agglomerats von D 4,3 = 9,5 μm gemessen. Die Astaxanthin-Primärpartikel waren erheblich kleiner, die mittels Transmissionselektronenmik- roskopie bestimmte Größe der Astaxanthin-Kristalle betrug 200 bis 600 nm. 50 g of astaxanthin (5% by weight), 40 g of α-tocopherol (4% by weight) and 5 g of ascorbyl palmitate (0.5% by weight) are mixed with 755 g of sunflower oil (75.5% by weight). mixed. This mixture was ground and 150 g of zein (15% by weight) was added slowly during the first 15 minutes. Grinding time: 4 hours at 64 to 74 0 C and a flow rate of 60 to 80 g / min (specifications of the Dynomill mill: 0.05 mm friction gap, 2986 rpm, 470 ml ZrO 2 stabilized spheres with a diameter of 0.3 mm ). By Fraunhoferbeugung a particle size of the astaxanthin-zein agglomerate of D 4.3 = 9.5 microns was measured. The astaxanthin primary particles were considerably smaller, and the size of the astaxanthin crystals determined by transmission electron microscopy was 200 to 600 nm.

Claims

Patentansprüche claims
1. Ölige Formulierung, umfassend mindestens einen festen Wirkstoff, mindestens ein hydrophobes Schutzkolloid und mindestens ein essbares Öl.An oily formulation comprising at least one solid active ingredient, at least one hydrophobic protective colloid and at least one edible oil.
2. Formulierung nach Anspruch 1 , wobei der Wirkstoff ein Carotinoid ist.A formulation according to claim 1, wherein the active ingredient is a carotenoid.
3. Formulierung nach Anspruch 2, wobei der Wirkstoff Astaxanthin ist.A formulation according to claim 2, wherein the active ingredient is astaxanthin.
4. Formulierung nach einem der vorhergehenden Ansprüche, wobei das hydrophobe Schutzkolloid ein Prolamin ist.A formulation according to any one of the preceding claims wherein the hydrophobic protective colloid is a prolamine.
5. Formulierung nach Anspruch 4, wobei das Prolamin ausgewählt ist unter Zein, GNa- din, Zein, Kafarin, Secalin, Hordein und Orycin.5. A formulation according to claim 4, wherein the prolamine is selected from zein, gamma-dine, zein, kafarin, secalin, hordein and orycin.
6. Formulierung nach einem der vorhergehenden Ansprüche, wobei das Gewichtsverhältnis von Wirkstoff zu hydrophobem Schutzkolloid im Bereich von 5:1 bis 1 :10 liegt.A formulation according to any one of the preceding claims wherein the weight ratio of active agent to hydrophobic protective colloid is in the range of 5: 1 to 1:10.
7. Verfahren zur Herstellung der Formulierung nach einem der Ansprüche 1 bis 6, wobei der feste Wirkstoff in mindesten einem essbaren Öl in Anwesenheit mindestens eines hydrophoben Schutzkolloids vermählen wird.A process for the preparation of the formulation of any one of claims 1 to 6, wherein the solid agent is ground in at least one edible oil in the presence of at least one hydrophobic protective colloid.
8. Verfahren zur Herstellung der Formulierung nach einem der Ansprüche 1 bis 6, wobei man8. A process for the preparation of the formulation according to any one of claims 1 to 6, wherein
a) den festen Wirkstoff und das hydrophobe Schutzkolloid in einem polaren Lösungsmittel dispergiert, b1 ) das Lösungsmittel entfernt oder b2) den Wirkstoff zusammen mit dem hydrophoben Schutzkolloid ausflockt und den ausgeflockten Feststoff gewinnt und c) den gemäß b1 ) oder b2) erhaltenen Feststoff in einem Öl dispergiert.a) dispersing the solid active substance and the hydrophobic protective colloid in a polar solvent, b1) removing the solvent or b2) flocculating the active ingredient together with the hydrophobic protective colloid and recovering the flocculated solid, and c) obtaining the solid obtained according to b1) or b2) in one Oil dispersed.
9. Verfahren nach Anspruch 8, wobei man als Lösungsmittel ein Gemisch aus Wasser und einem mit Wasser mischbaren Alkohol verwendet. 9. The method of claim 8, wherein the solvent used is a mixture of water and a water-miscible alcohol.
10. Verwendung der öligen Formulierung nach einem der Ansprüche 1 bis 6 als10. Use of the oily formulation according to any one of claims 1 to 6 as
Zusatz zu Tierfuttermitteln, Lebensmitteln und Nahrungsergänzungsmitteln sowie pharmazeutischen und kosmetischen Mitteln.Additive to animal feed, food and nutritional supplements and pharmaceutical and cosmetic products.
1 1. Tierfuttermittel, Lebensmittels und Nahrungsergänzungsmittel, umfassend die ölige Formulierung gemäß einem der Ansprüche 1 bis 6. 1 1. Animal feed, food and dietary supplement, comprising the oily formulation according to one of claims 1 to 6.
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