DE102006048530A1 - Preparations for oral administration (II) - Google Patents

Abstract

Suggested preparations for oral intake containing (a) sterols or sterol esters and (b) Hoodia extracts or the steroid glycosides obtainable therefrom.

Description

Field of the invention

The Invention is in the field of food additive or supplements and relates to new preparations for oral administration containing special sterols or sterol esters together with Hoodia extracts.

State of the art

Hypocholesterolemic agents are understood to mean agents which lead to a reduction of the cholesterol content in the serum of warm-blooded animals, without this resulting in an inhibition or reduction of the formation of cholesterol in the blood. For this purpose were already from Peterson et al. in J. Nutrit. 50, 191 (1953) Phytostenols, ie vegetable stenols, and their esters with fatty acids suggested. The patents also point in the same direction US 3,089,939 . US 3,203,862 as well as the German disclosure DE-OS 2035069 (Procter & Gamble). The active ingredients are usually added to cooking or edible oils and then absorbed through the diet, but the amounts used are usually low and usually below 0.5 wt .-%, to prevent the edible oils cloud or stenols when added be precipitated from water. For use in the food sector, in cosmetics, pharmaceutical preparations and in the agricultural sector are in the European patent application EP 0289636 A1 (Ashai) storage stable emulsions of Stenolester in sugar or polyglycerol esters proposed. The incorporation of sitostanol esters to reduce the blood cholesterol content in margarine, butter, mayonnaise, salad dressings and the like is described in the European Patent EP 0594612 B1 (Raision) proposed. In the International Patent Application WO 98/23277 A1 (Henkel) discloses combinations of phytostenols and / or phytostenol esters with potentiating agents for the production of hypocholesterolemic agents. Phytostenol esters such as the gamma-oryzanol and five similar compounds reduce the uptake of cholesterol via the intestine via the inhibition of phospholipase A ₂ activity, as described in the Japanese published patent application JP 07 330611 (Yakult Honsha Co. Ltd.). Although the known hypocholesterolemic agents based on sterols or sterol esters are already being added to foods on a large scale, there is a sustained interest in further improving their effectiveness.

The Object of the present invention has thus been new Preparations for the oral intake available to make, which allow with equal amounts of active compound concentration undesirable To lower cholesterol in the blood faster or to have a corresponding one To achieve effect with a reduced amount of active ingredient.

Description of the invention

• (a) Sterole bzw. deren Ester mit C₆-C₂₂ Fettsäuren und
• (b) Hoodia-Extrakte bzw. die daraus erhältlichen Steroidglycoside, insbesondere Substanz P57 sowie die zugehörigen Homologen, Analogen und Isomeren.

The invention relates to preparations for oral administration, containing

• (a) sterols or their esters with C ₆ -C ₂₂ fatty acids and
• (b) Hoodia extracts or the steroid glycosides obtainable therefrom, in particular substance P57 and the associated homologues, analogs and isomers.

It was found that opposite the prior art, the combination of the sterols or sterol esters and the steroid glycoside-rich Hoodia extracts when administered orally to a faster removal of the unwanted cholesterol from the Serum leads, which is particularly surprising is because Hoodia extracts and their active principles taken for themselves no hypocholesterolemic activity have. Furthermore, it was observed that the cholesterol excretion by adding additional plant extracts tends to improve further.

Sterols and sterol esters

Sterols - occasionally also called sterols - make Steroids represented by a single hydroxyl group in C3 position Marked are. Furthermore, sterols, which are commonly Have 27 to 30 carbon atoms, even via a double bond, which is preferably in the 5/6 position. The hydrogenation this double bond - too as a cure designates - leads to special Sterols called stanols. The following illustration shows the structure of the best known representative from the group of Sterols, the cholesterol that belongs to the group of zoosterols.

by virtue of their superior physiological properties represent plant sterols that are so called phytosterols, such as ergosterol, stigmasterol and in particular Sitosterol and its hydrogenation product sitostanol the preferred Sterol types. Alternatively, can instead of the sterols or stanols also their esters with saturated and / or unsaturated fatty acids can be used, wherein the acyl radicals then 6 to 22 carbon atoms and 0 or 1 to 6 double bonds may have. Typical examples are the esters of β-sitosterol or β-sitostanol with caproic acid, caprylic, 2-ethylhexanoic acid, Capric acid, Lauric acid, isotridecanoic, myristic, palmitic acid, palmitoleic, stearic acid, Isostearic acid, oleic acid, elaidic acid, petroselinic acid, linoleic acid, linolenic acid, elaeostearic acid, arachidic acid, gadoleic acid, behenic acid and erucic and their technical mixtures, e.g. in the pressure split of natural fats and oils, in the reduction of aldehydes from Roelen's oxosynthesis or the dimerization of unsaturated fatty acids attack. However, the esters of the two are very particularly preferred the aforementioned sterols with conjugated linoleic acid (CLA).

Hoodia extracts

Hoodia, specifically Hoodia gordonii, is a cactus plant native to South Africa that has long been known to the indigenous people as a means to combat hunger. It is reported that in earlier times Bushmen on their hunting expeditions were practically out of food for several weeks only by chewing Hoodia roots. In recent years it has been found that the amazing properties of this plant are related to its high content of specific active steroid glycosides. In 2001/2002, it was possible for the first time to isolate and characterize one of these species; it has since been referred to in the literature as substance P57:

Little is known about hoodia and hoodia extracts from the patent literature. From the international patent application WO 98/046243 A1 (CSIR), however, pharamzeutische preparations based on extracts of plants of the genus Trichocaulon or Hoodia are known to have an appetite-suppressing effect.

plant extracts

In a preferred embodiment of the present invention the oral preparations as optional component (c) further plant extracts contain that over have advantageous physiological properties. Typically these are selected from the group formed by Ginkgo biloba, Camellia sinensis, Oleacea europensis, Glycyrrhiza glabra, Vaccinium myrtillus, Trifolium Pratense, Litchi sinensis, Vitis vinifera, Brassica oleracea, Punica granatum, Petroselinium crispum, Centella asiatica, Passiflora incarnata, Medicago sativa, Valeriana officinalis, Castanea sativa, Salix alba as well as Hapagophytum procumbens. The following is a brief summary of the composition and the essential active ingredients in the extracts.

• ginkgo biloba

Isorhamnetin (R¹ = H), Kaempferol (R¹ = OH), Ginkgolid A (R¹ = OMe)The active ingredients of the extracts obtained from the leaves of the Ginkgo tree (Ginkgo biloba) are flavonoid glycosides which include (iso) querciting glycosides, kaempferol, kaempferol-3 rhamnoside, isorhamnetin, luteoline glycosides, sitosterol glycosides, and especially hexacyclic terpene lactones, the so-called Ginkgolide A, B, C, J, M and bilobalides included.

Isorhamnetin (R ¹ = H), Kaempferol (R ¹ = OH), Ginkgolide A (R ¹ = OMe)

• Camellia sinensis

Komponenten R1 R2 R3 R4 (–)-Epicatechin H H (–) Epigallocatechin H OH (–) Epicatechin gallate Galloyl H (–) Epigallocatechin gallate Galloyl OH Theflavin H H Theaflavin monogallate A Galloyl H Theaflavin monogallat B H Galloyl Theaflavin digallate Galloyl Galloyl The leaves of green tea contain a variety of substances, such as polysaccharides, volatile oils, vitamins, minerals, purines and in addition to alkaloids, such as caffeine, especially polyphenols, which are usually catechins and flavonoids and also as "Tee-Tatnnine".

components R1 R2 R3 R4 (-) - epicatechin H H (-) epigallocatechin H OH (-) Epicatechin gallate galloyl H (-) Epigallocatechin gallate galloyl OH Theflavin H H Theaflavin monogallate A galloyl H Theaflavin monogallate B H galloyl Theaflavin digallate galloyl galloyl

• Oleacea Europensis

Of the Main component of the leaves of the olive tree (Oleacea europensis) is the antioxidant oleuropein, that is also the main source for Represents hydroxytyrosol.

Oleuropein

oleuropein

• Glycyrrhiza glabra

Main component the extract of the sweet root Glycyrrhiza glabra is glycyrrhetic acid.

Glyzzyrhetinsäure

Glyzzyrhetinsäure

• Vaccinium myrtillus

Extracts of the common blueberry (Vaccinium myrtillus) contain a mixture of at least 15 different anthocyanosides, such as the following:

Usually, the extracts have 20 to 25 wt .-% anthocyanosides, 5 to 10 wt .-% Tannins and small amounts of various alkaloids, e.g. myrtin and epimyrtin, phenolic acids and glycosides of quercitrin, isoquercitrin and hyperoside.

• Trifolium pratense

Isoflavonglucoside R₁ R₂ R₃ R₄ Daizidin H H Glucose H Genistin H H Glucose OH Ononin H CH₃ Glucose H Sissostrin H CH₃ Glucose OH The main constituents of the extracts of red clover (Trifolium pratense) are isoflavones, such as daidzein, genestein, formononentin and biochanin A and their glucosides such as ononine or sissostrin:

isoflavone R ₁ R ₂ R ₃ R ₄ Daizidin H H glucose H genistin H H glucose OH ononin H CH ₃ glucose H Sissostrin H CH ₃ glucose OH

• Litchi sinensis

extracts, those extracted from the shells of Litchi fruit (Litchi sinensis) have high levels of flavone derivatives, e.g. 2-phenyl-4H-1-benzopyrans, Flavans, flavan-3-ols (catechins, catechol oligomers), flavan-3,4-diols (Leucoanthocyanides), flavones, flavonols and flavonones. The main ingredient is, however, made up of condensed tannins, so-called procyanodolen (OPC). These substances contain 2 to 8 monomers of catechin or a catechin type, e.g. Procyanidin, proanthocyanin, procyanidols, Oligoprocyanidine, leucoanthocyanidin, leucodelphinin, leucocyanine and anthocyanins. OPC, preferably proanthocyanidin A2 (OPC A2) behave like vitamin P, especially with regard to inhibition of matrix metalloproteinases.

Oligomeres Proanthocyanidin

Oligomeric proanthocyanidin

• Vitis vinifera

The Main Ingredients Extracts from leaves, roots and in particular Cups of grape (Vitis vinifera) are polyphenols from above described OPC type.

• Brassica oleracea

The Main constituents of cauliflower extracts (Brassica oleracea) are amino acids, in particular methionine and cysteine and the glucosinolates, such as e.g. Glucoraphanin.

• Punica granatum

In The extracts of pomegranate (Punica granatum) are found next to Sugars and citric acid in particular Delphinidin-1,2-glycosides and their aglycones.

• Petroselinium crispum

Main component of the fat oil Parsley (Petroselinium crispum) is the petroselinic acid. The Extracts, however, show high levels of Apiol (1-allyl-2,5-dimethoxy-3,4- (methylenedioxy) benzene,), as well as Apiin, Myristicin, Pinen and Selinen.

Apiol

apiol

• Centella asiatica

Main components The extracts of Centella asiatica are highly condensed naphthenic acids, especially asiatic acid, madecassic acid and their glycosides.

• Passiflora incarnata

extracts Passion fruit (Passiflora incarnata) are rich in flavones of the type of apigenin and luteolin and their C-glycosides.

Of Furthermore, they contain 2 '' - B-D-glucosides, Schaftoside and Isoschaftoside, Isovitexin, Isoorientin, Vicenin-2, Incenin-2, daponanine and trace element, namely calcium, phosphorus and iron.

• Medicago sativa

Extracts of alfalfa (Medicago sativa) are rich in isoflavones, such as daidzein, genestein, formononetin, biochanin A and tricine:

• Valeriana officinalis

The Main constituents of extracts of Valeriana officinalis are valeric acid, valerianone as well as boron-ester.

• Castanea sativa

R = Tiglicsäure oder AngelicasäureHorse chestnut extracts (Castanea sativa) contain mainly saponins and escin, which is the mixture of two glycosides whose aglycones are derived from proteoescenin, while the sugars are either gluconic acid or two molecules of D-glucose. The two glycosides differ in the nature of the acyl groups in the C22 position.

R = tiglic acid or angelic acid

During α-Escin a represents amorphous powder, which melts at 225 to 227 ° C. and slightly water-soluble is β-Escin (also called florfenecyl) in the form of dandruff, practically insoluble in water, but slightly soluble are in alcohol.

• Salix alba

Main components The extracts of Salix alba are phenolic glycosides and in particular Salicylates, e.g. Salicin, salicortin and tremulacin:

Salicin

salicin

• Harpagophytum procumbens

The Main components of Extract of Devil's Claw (Harpagophytum procumbens) are iridoid glucosides, harpagosides, harpagids and procumbides.

Of Further, one finds stachylose and glycosylated phytosterols (e.g., β-sitosterol), Flavonoids (e.g., kaempferol, luteolin), phenolic acids, and glycosidic phenylpropanoic acid esters (e.g., verbacosides, isoactosides).

extraction

The preparation of the stehorid glycoside-containing Hoodia extracts can be carried out in a manner known per se, ie for example by aqueous, alcoholic or aqueous-alcoholic extraction of the plants or plant parts or of the leaves or fruits. Suitable are all conventional extraction methods such as maceration, remaereration, digestion, agitation, vortex extraction, ultrasound extraction, countercurrent extraction, percolation, repercolation, evacuation (extraction under reduced pressure), diaclation or solid-liquid extraction under continuous reflux. For the industrial use advantageous is the percolation method. As a starting material, fresh plants or plant parts can be used, but usually is based on dried plants and / or plant parts, which can be mechanically comminuted prior to extraction. All the comminution methods known to those skilled in the art are suitable here, for example freeze-milling. As solvents for carrying out the extractions, it is possible to use organic solvents, water (preferably hot water at a temperature of above 80 ° C. and in particular above 95 ° C.) or mixtures of organic solvents and water, in particular low molecular weight alcohols with more or less high water contents become. Particularly preferred is the extraction with methanol, ethanol, pentane, hexane, heptane, acetone, propylene glycols, polyethylene glycols and ethyl acetate and mixtures thereof and their aqueous mixtures. The extraction is generally carried out at 20 to 100 ° C, preferably at 30 to 90 ° C, in particular at 60 to 80 ° C. In a preferred embodiment, the extraction is carried out under an inert gas atmosphere to avoid the oxidation of the active ingredients of the extract. This is particularly important in extractions at temperatures above 40 ° C is important. The extraction times are set by the skilled person depending on the starting material, the extraction method, the extraction temperature, the ratio of solvent to raw material and others. After extraction, the resulting crude extracts may optionally be subjected to further conventional steps such as purification, concentration and / or decolorization. If desired, the extracts so prepared may be subjected to, for example, selective separation of individual undesired ingredients. The extraction can be done to any degree of extraction, but is usually done to exhaustion. Typical yields (= dry matter amount of the extract based on the amount of raw material used) in the extraction of dried leaves are in the range from 3 to 15, in particular 6 to 10 wt .-%. The present invention encompasses the finding that the extraction conditions and the yields of the final extracts can be selected by the person skilled in the art according to the desired field of use. These extracts, which generally have active substance contents (= solids contents) in the range of 0.5 to 10 wt .-%, can be used as such, but it is also possible, the solvent completely by drying, in particular by spray or freeze drying to remove. The extracts can also serve as starting materials for the recovery of the above-mentioned pure active ingredients, as long as they can not be synthesized more easily and inexpensively. Accordingly, the active ingredient content in the extracts may be 5 to 100, preferably 50 to 95 wt .-%. The extracts themselves may be present as aqueous and / or dissolved in organic solvents preparations and as spray- or freeze-dried, anhydrous solids. Suitable organic solvents in this context include, for example, the aliphatic alcohols having 1 to 6 carbon atoms (eg ethanol), ketones (eg acetone), halogenated hydrocarbons (eg chloroform or methylene chloride), lower esters or polyols (eg glycerol or glycols). Specifically, reference is made to the manufacturing process, which in the already mentioned WO 98/046243 A1 and hereby by direct reference to the teaching of the present Pa tentanmeldung is included.

Preferably the components (a) and (b) are in the weight ratio 99: 1 used up to 80:20, with special synergistic effects in the Range from 98: 2 to 85:15 and especially 95: 5 to 90:10 are. With regard to Hoodia extracts, the optional plant extracts Component (c) 1 to 25, preferably 5 to 20 and in particular 8 to 12 wt .-% make up.

encapsulation

In a particular embodiment In the present invention, the oral preparations are encapsulated in Shape - for example in the form of usual Gelatin macrocapsules - preferably but used in microencapsulated form. A typical gelatin capsule can for the daily oral intake, for example, 3 g CLA and 150 mg hoodia extract contain.

Under The term "microcapsule" will be understood by those skilled in the art spherical Aggregates with a diameter in the range of about 0.0001 to about 5 mm, containing at least one solid or liquid core, which is enclosed by at least one continuous shell. More accurate said to be coated with film-forming polymers finely dispersed liquid or solid phases in which the polymers are produced Emulsification and coacervation or interfacial polymerization on the wrapping material knock down. By another method are melted Waxes taken in a matrix ("microsponge"), called microparticles additionally wrapped with film-forming polymers could be. The microscopic capsules, also called nanocapsules to dry like powder. In addition to mononuclear microcapsules are also polynuclear aggregates, also called microspheres known, the two or more cores distributed in the continuous shell material. Mononuclear or polynuclear microcapsules can also from an additional second, third, etc. sheath be enclosed. The case can be made of natural, semisynthetic or synthetic materials. Of course, shell materials For example, gum arabic, agar-agar, agarose, maltodextrins, alginic acid or their salts, e.g. Sodium or calcium alginate, fats and fatty acids, cetyl alcohol, Collagen, chitosan, lecithin, gelatin, albumin, shellac, polysaccharides, like strength or dextran, polypeptides, protein hydrolysates, sucrose and waxes. Semisynthetic shell materials include chemically modified celluloses, in particular Cellulose esters and ethers, e.g. Cellulose acetate, ethylcellulose, Hydroxypropylcellulose, hydroxypropylmethylcellulose and carboxymethylcellulose, and starch derivatives, especially starch ethers and -ester. Synthetic wrapping materials are, for example, polymers such as polyacrylates, polyamides, polyvinyl alcohol or polyvinylpyrrolidone.

Examples for microcapsules of the prior art are the following commercial products (in parenthesis the shell material is indicated in each case): Hallcrest Microcapsules (gelatin, gum arabic), Coletica thalaspheres (marine collagen), Lipotec Millicapseln (alginic acid, agar-agar), Induchem Unispheres (lactose, microcrystalline cellulose, hydroxypropylmethylcellulose); Unicerin C30 (lactose, microcrystalline cellulose, hydroxypropyl methylcellulose), Kobo Glycospheres (modified starch, fatty acid esters, phospholipids), softspheres (modified agar-agar) and cow's probiol nanospheres (phospholipids) Primaspheres and Primasponges (chitosan, alginates) and Primasys (Phospholipids).

• (a1) aus Gelbildnern, kationischen Polymeren und Wirkstoffen eine Matrix zubereitet,
• (a2) gegebenenfalls die Matrix in einer Ölphase dispergiert,
• (a3) die dispergierte Matrix mit wässrigen Lösungen anionischer Polymere behandelt und gegebenenfalls dabei die Ölphase entfernt.

oder

• (b1) aus Gelbildnern, anionischen Polymeren und Wirkstoffen eine Matrix zubereitet,
• (b2) gegebenenfalls die Matrix in einer Ölphase dispergiert,
• (b3) die dispergierte Matrix mit wässrigen Kationpolymerlösungen behandelt und gegebenenfalls dabei die Ölphase entfernt;

oder

• (c1) aus Gelbildnern und Wirkstoffen eine Matrix zubereitet,
• (c2) die Matrix mit einer Kationpolymerlösung versetzt und
• (c3) die Mischung auf einen pH-Wert einstellt der oberhalb des pK_S-Wertes des Kationpolymers liegt;

oder

• (d1) wässrige Wirkstoffzubereitungen mit Ölkörpern in Gegenwart von Emulgatoren zu O/W-Emulsionen verarbeitet,
• (d2) die so erhaltenen Emulsionen mit wässrigen Lösungen anionischer Polymere behandelt,
• (d3) die so erhaltene Matrix mit wässrigen Kationpolymerlösungen in Kontakt bringt und
• (d4) die so erhaltenen Verkapselungsprodukte von der wässrigen Phase abtrennt;

oder
den Wirkstoff abwechselnd mit Schichten aus unterschiedlich geladenen Polyelektrolyten einhüllt (layer-by-layer-Technologie).Chitosan microcapsules and processes for their preparation are the subject of prior patent applications by the Applicant [ WO 01/01926 . WO 01/01927 . WO 01/01928 . WO 01/01929 ]. Microcapsules with average diameters in the range of 0.0001 to 5, preferably 0.001 to 0.5 and in particular 0.005 to 0.1 mm, consisting of an enveloping membrane and a matrix containing the active ingredients can be obtained, for example, by

• (a1) preparing a matrix from gelling agents, cationic polymers and active substances,
• (a2) optionally dispersing the matrix in an oil phase,
• (a3) treating the dispersed matrix with aqueous solutions of anionic polymers and optionally removing the oil phase.

or

• (b1) preparing a matrix from gelling agents, anionic polymers and active substances,
• (b2) optionally dispersing the matrix in an oil phase,
• (b3) treating the dispersed matrix with aqueous cationic polymer solutions, optionally removing the oil phase;

or

• (c1) preparing a matrix from gelling agents and active substances,
• (c2) adding a cationic polymer solution to the matrix and
• (c3) the mixture to a pH adjusts the -value is the cationic polymer above the pK _S;

or

• (d1) processed aqueous preparations of active substances with oil bodies in the presence of emulsifiers to O / W emulsions,
• (d2) treating the emulsions thus obtained with aqueous solutions of anionic polymers,
• (d3) contacting the resulting matrix with aqueous cationic polymer solutions, and
• (d4) separating the resulting encapsulated products from the aqueous phase;

or
the active ingredient is alternately coated with layers of differently charged polyelectrolytes (layer-by-layer technology).

• gelling agent

in the According to the invention, the gelling agents are preferably those substances taking into account the characteristic in aqueous solution at temperatures above 40 ° C To form gels. Typical examples are heteropolysaccharides and proteins. As thermogelling heteropolysaccharides are preferably Agaroses in the form of the red algae to be won Agar-agar also together with up to 30 wt .-% non-gel-forming Agaropectins may be present. The main constituent of the agaroses are linear polysaccharides from D-galactose and 3,6-anhydro-L-galactose which are alternately linked β-1,3- and β-1,4-glycosidic. The heteropolysaccharides preferably have a molecular weight in the range of 110,000 to 160,000 and are both color and tasteless. Alternatives include pectins, xanthans (also xanthan Gum) and their mixtures in question. There are still such types preferred, which form gels in 1 wt .-% aqueous solution, not below 80 ° C melt and re-solidify above 40 ° C. From the Group of thermogeling proteins are exemplified by the various Called gelatin types.

• Chitosan

Chitosans are biopolymers and are counted among the group of hydrocolloids. Chemically, they are partially deacetylated chitins of different molecular weight containing the following - idealized - monomer unit:

in the Contrary to most hydrocolloids, which are biological pH values are negatively charged, put chitosans under these conditions cationic biopolymers. The positively charged chitosans can with oppositely charged surfaces interact and are therefore used in cosmetic hair and personal care products and pharmaceutical preparations used. For the production of Chitosans one goes from Chitin, preferably the shell remnants of Crustaceans made out as cheap raw materials in large quantities to disposal stand. The chitin is thereby in a procedure, the first of Hackmann et al. has been described, usually first by Addition of bases deproteinated, demineralized by the addition of mineral acids and finally deacetylated by addition of strong bases, the molecular weights over a broad spectrum can be distributed. Preferably, such types are used as the average Molecular weight of 10,000 to 500,000 or 800,000 to 1,200,000 Dalton and / or have a Brookfield viscosity (1 wt .-% strength in glycolic acid) below 5000 mPas, a degree of deacetylation in the range of Have 80 to 88% and an ash content of less than 0.3 wt .-%. Because of better water solubility The chitosans are usually in the form of their salts, preferably used as glycolates.

• oil phase

The matrix may optionally be dispersed in an oil phase prior to the formation of the membrane. As oils come for this purpose, for example, Guerbet alcohols based on fatty alcohols with 6 to 18, preferably Example, 8 to 10 carbon atoms, esters of linear C ₆ -C ₂₂ fatty acids with linear C ₆ -C ₂₂ fatty alcohols, esters of branched C ₆ -C ₁₃ carboxylic acids with linear C ₆ -C ₂₂ fatty alcohols, such as myristyl myristate, myristyl palmitate, myristyl stearate, Myristylisostearat, myristyl, Myristylbehenat, Myristylerucat, cetyl myristate, cetyl palmitate, cetyl stearate, Cetylisostearat, cetyl oleate, cetyl behenate, Cetylerucat, Stearylmyristat, stearyl palmitate, stearyl stearate, Stearylisostearat, stearyl oleate, stearyl behenate, Stearylerucat, isostearyl, isostearyl palmitate, Isostearylstearat, isostearyl isostearate, Isostearyloleat, isostearyl behenate, Isostearyloleat, oleyl, oleyl palmitate, oleyl stearate, oleyl isostearate, oleate, Oleylbehenat, oleyl, behenyl myristate, behenyl, behenyl, Behenylisostearat, behenyl oleate, behenyl, erucyl, erucyl, erucyl, erucyl, erucyl, erucyl, and erucyl erucate. Also suitable are esters of linear C ₆ -C ₂₂ fatty acids with branched alcohols, in particular 2-ethylhexanol, esters of hydroxycarboxylic acids with linear or branched C ₆ -C ₂₂ fatty alcohols, in particular dioctyl malates, esters of linear and / or branched fatty acids with polyhydric alcohols (such as propylene glycol, dimerdiol or trimer triol) and / or Guerbet alcohols, triglycerides based on C ₆ -C ₁₀ fatty acids, liquid mono- / di- / Triglyceridmisungen based on C ₆ -C ₁₈ fatty acids, esters of C ₆ -C ₂₂ fatty alcohols and / or Guerbet alcohols with aromatic carboxylic acids, in particular benzoic acid, esters of C ₂ -C ₁₂ dicarboxylic acids with linear or branched alcohols having 1 to 22 carbon atoms or polyols having 2 to 10 carbon atoms and 2 to 6 hydroxyl groups, vegetable Oils, branched primary alcohols, substituted cyclohexanes, linear and branched C ₆ -C ₂₂ fatty alcohol carbonates, guerbet carbonates, esters of benzoic acid with li -linear and / or branched C ₆ -C ₂₂ alcohols (such as Finsolv ^® TN), linear or branched, symmetrical or asymmetrical dialkyl ethers having 6 to 22 carbon atoms per alkyl group, ring opening products of epoxidized Fettsäureestern with polyols, silicone oils and / or aliphatic or naphthenic Hydrocarbons such as squalane, squalene or dialkylcyclohexanes into consideration.

• anionic polymers

The anionic polymers have the task of forming membranes with the chitosans. Salts of alginic acid are preferably suitable for this purpose. Alginic acid is a mixture of carboxyl-containing polysaccharides with the following idealized monomer unit:

The average molecular weight of the alginic acids or alginates in the range of 150,000 to 250,000. Both are salts of alginic acid their complete as well as their partial neutralization products, in particular the alkali metal salts and below this preferably the sodium alginate ("Algin") and the ammonium and alkaline earth salts. particularly preferred are mixed alginates, such as e.g. Sodium / magnesium or sodium / calcium alginates. In an alternative embodiment the invention come for However, anionic chitosan derivatives, e.g. carboxylation and especially succinylation products in question. Alternatively come also poly (meth) acrylates with average molecular weights in the range of 5,000 to 50,000 daltons as well as the various carboxymethylcelluloses in question. Instead of anionic polymers can be used for the formation of the envelope membrane also anionic surfactants or low molecular weight inorganic salts, such as pyrophosphates are used.

• manufacturing process microcapsules

For the preparation of the microcapsules is usually prepared from 1 to 10, preferably 2 to 5 wt .-% aqueous solution of the gelling agent, preferably the agar agar ago and heated them under reflux. In the boiling heat, preferably at 80 to 100 ° C, a second aqueous solution is added, which contains the cationic polymer, preferably the chitosan in amounts of 0.1 to 2, preferably 0.25 to 0.5 wt .-% and the active ingredients in amounts of 0.1 to 25 and in particular 0.25 to 10 wt .-%; this mixture is called a matrix. The loading of the microcapsules with active ingredients can therefore also amount to 0.1 to 25% by weight, based on the capsule weight. If desired, water-insoluble constituents, for example inorganic pigments, may also be added at this point in time to adjust the viscosity , which is usually added in the form of aqueous or aqueous / alcoholic dispersions. To emulsify or disperse the active ingredients, it may also be useful to add emulsifiers and / or solubilizers to the matrix. After the preparation of the matrix of gelling agent, cationic polymer and active ingredients, the matrix can optionally be very finely dispersed in an oil phase under high shear in order to produce the smallest possible particles in the subsequent encapsulation. It has proved to be particularly advantageous to heat the matrix to temperatures in the range of 40 to 60 ° C, while the oil phase is cooled to 10 to 20 ° C. In the last, now again obligatory step, the actual encapsulation takes place, ie the formation of the enveloping membrane by contacting the cationic polymer in the matrix with the anionic polymers. For this purpose, it is recommended that the optionally dispersed in the oil phase matrix at a temperature in the range of 40 to 100, preferably 50 to 60 ° C with an aqueous, about 1 to 50 and preferably 10 to 15 wt .-% aqueous solution of the anion polymer to treat and, if necessary, at the same time or subsequently to remove the oil phase. The resulting aqueous preparations generally have a microcapsule content in the range of 1 to 10 wt .-%. In some cases, it may be advantageous if the solution of the polymers contains other ingredients, such as emulsifiers or preservatives. After filtration, microcapsules are obtained, which on average have a diameter in the range of preferably about 0.01 to 1 mm. It is recommended to sift the capsules to ensure the most even size distribution possible. The microcapsules thus obtained may have any shape in the production-related framework, but they are preferably approximately spherical. Alternatively, one can also use the anionic polymers for the preparation of the matrix and perform the encapsulation with the cationic polymers, especially the chitosans.

alternative The encapsulation can also be done using only cationic polymers taking advantage of their property, at pH values to coagulate above the pKs value.

In A second alternative method will be used to prepare the microcapsules of the invention first an O / W emulsion is prepared, which in addition to the oil body, water and the active ingredients contains an effective amount of emulsifier. For the preparation of the matrix This preparation is mixed with vigorous stirring with a suitable Amount of an aqueous anionic polymer added. The membrane formation takes place by adding the chitosan solution. Of the entire process preferably takes place in the weakly acidic range at pH = 3 to 4 instead. If necessary, the pH is adjusted by Addition of mineral acid. After membrane formation, the pH is raised to 5 to 6, for example, by adding triethanolamine or another Base. This leads to an increase in the viscosity, the Addition of further thickening agents, e.g. polysaccharides especially xanthan gum, guar guar, agar, alginates and tyloses, Carboxymethylcellulose and hydroxyethylcellulose, higher molecular weight Polyethylene glycol mono- and diesters of fatty acids, polyacrylates, polyacrylamides and the like still supported can be. Finally For example, the microcapsules of the aqueous phase separated by decantation, filtration or centrifugation.

In a third alternative method, the formation of the microcapsules is carried out around a preferably solid, for example, crystalline core by coating it in layers with oppositely charged polyelectrolytes. In this connection, see the European patent EP 1064088 B1 (Max Planck Society).

Industrial Applicability

• (a) Sterole und Sterolester und
• (b) Hoodia-Extrakte bzw. die daraus erhältlichen Steroidglycoside, insbesondere Substanz P57 sowie die zugehörigen Homologen, Analogen und Isomeren.

zur Herstellung von Nahrungsmitteln und Nahrungsmittelzusatzstoffen, speziell zur Herstellung von hypocholesterinämischen Medikamenten. Typische Beispiele für geeignete Nahrungsmitteln sind Butter, Margarine, Speiseöle, Bratöle und Bratfette, Brotaufstriche, Wurst, Käse, Mayonnaise, Joghurt, Pudding, Milch und Milchgetränke, aber auch Backwaren, Kekse und Keksriegel sowie Süßigkeiten, in denen die erfindungsgemäßen Zubereitungen in Mengen von 0,01 bis 10, vorzugsweise 0,1 bis 5 und insbesondere 1 bis 2 Gew.-% enthalten sein können.The preparations according to the invention exhibit, on ingestion, an improved excretion of undesired cholesterol from the blood. A further subject of the invention therefore relates to the use of mixtures containing

• (a) sterols and sterol esters and
• (b) Hoodia extracts or the steroid glycosides obtainable therefrom, in particular substance P57 and the associated homologues, analogs and isomers.

for the manufacture of food and food additives, especially for the production of hypocholesterolemic drugs. Typical examples of suitable foods are butter, margarine, edible oils, frying oils and frying fats, spreads, sausage, cheese, mayonnaise, yoghurt, pudding, milk and milk drinks, but also baked goods, biscuits and biscuit bars, and sweets in which the inventive preparations in amounts of 0.01 to 10, preferably 0.1 to 5 and in particular 1 to 2 wt .-% may be included.

Examples

example 1

In a 500 ml three-necked flask with stirrer and reflux condenser, 3 g of agar-agar were dissolved in 200 ml of water in the boiling heat. The mixture was then stirred for about 30 minutes with vigorous stirring, first with a solution of 10 g of glycerol, 90 ml of water and then with a preparation of 2.5 g of sodium alginate in the form of a 10% strength by weight aqueous solution, 1 g of β- sitosterol, 1 g of dried Hoodia gordonii extract, 0.5 g of Phenonip ^® and 0.5 g of polysorbate-20 (Tween ^® 20, ICI) was added in 64 g water. The resulting matrix was filtered, heated to 60 ° C and added dropwise to a 1% by weight solution of chitosan glycolate in water. To obtain microcapsules of the same diameter, the preparations were then sieved.

Example 2

In a 500 ml three-necked flask with stirrer and reflux condenser, 3 g of agar-agar were dissolved in 200 ml of water in the boiling heat. The mixture was then stirred for about 30 minutes with vigorous stirring, first with a solution of 10 g of glycerol, 90 ml of water and then with a preparation of 2.5 g of sodium alginate in the form of a 10% strength by weight aqueous solution, 1 g of β- Sitosterolstearat, 1 g of dried Hoodia gordonii extract, Trifolium pratense extract 0.5 g, 0.5 g of Phenonip ^® and 0.5 g of polysorbate-20 (Tween ^® 20, ICI) was added in 64 g water. The resulting matrix was filtered, heated to 60 ° C and added dropwise to a 1% by weight solution of chitosan glycolate in water. To obtain microcapsules of the same diameter, the preparations were then sieved.

Example 3

In a 500 ml three-necked flask with stirrer and reflux condenser, 3 g of agar-agar were dissolved in 200 ml of water in the boiling heat. The mixture was then added over about 30 minutes with vigorous stirring, first with a solution of 10 g of glycerol 90 ml of water and then with a preparation of 2.5 g of sodium alginate in the form of a 10 wt .-% aqueous solution, 1 g of an ester of β-sitosterol and CLA, 1 g of dried Hoodia gordonii extract, 0.5 g Ginkgo biloba extract, 0.5 g of Phenonip ^® and 0.5 g of polysorbate-20 (Tween ^® 20, ICI) was added in 64 g water. The resulting matrix was filtered, heated to 60 ° C and added dropwise to a 1% by weight solution of chitosan glycolate in water. To obtain microcapsules of the same diameter, the preparations were then sieved.

Example 4

In a 500 ml three-necked flask with stirrer and reflux condenser, 3 g of agar-agar were dissolved in 200 ml of water in the boiling heat. The mixture was then stirred for about 30 minutes with vigorous stirring, first with a solution of 10 g of glycerol, 90 ml of water and then with a preparation of 2.5 g of sodium alginate in the form of a 10% strength by weight aqueous solution, 1 g of β- Sitosterolpalmitat, 1 g of dried Hoodia gordonii extract, 0.5 g of dried extract of Vitis vinifera, 0.5 g of Phenonip ^® and 0.5 g of polysorbate-20 (Tween ^® 20, ICI) was added in 64 g water. The resulting matrix was filtered, heated to 60 ° C and added dropwise to a 1% by weight solution of chitosan glycolate in water. To obtain microcapsules of the same diameter, the preparations were then sieved.

Example 4

In a 500 ml three-necked flask with stirrer and reflux condenser, 3 g of agar-agar were dissolved in 200 ml of water in the boiling heat. The mixture was then stirred for about 30 minutes with vigorous stirring, first with a solution of 10 g of glycerol, 90 ml of water and then with a preparation of 2.5 g of sodium alginate in the form of a 10% strength by weight aqueous solution, 1 g of β- Sitosterolpalmitat, 1 g of dried Hoodia gordonii extract, 0.5 g of dried extract of Camellia sinensis, 0.5 g of Phenonip ^® and 0.5 g of polysorbate-20 (Tween ^® 20, ICI) was added in 64 g water. The resulting matrix was filtered, heated to 60 ° C and added dropwise to a 1% by weight solution of chitosan glycolate in water. To obtain microcapsules of the same diameter, the preparations were then sieved.

Examples 5 to 9, Comparative Examples V1 to V3

There were gelatin capsules (weight about 1.5 g) containing β-sitosterol or β-sitosterol esters and Hoodia and optionally further plant extracts and 0.5 wt .-% radioactively labeled cholesterol. To examine the hypocholesterolemic effect, male rats (individual weight about 200 g) were fasted overnight. The following day, the test animals were each introduced a crushed gelatin capsule with a little saline water via a nasogastric tube. After 3, 6, 12, 24 and 48 h, the animals were bled and the content of radioactive cholesterol was determined. The results representing the mean of the measurements of 10 experimental animals are summarized in Table 1. The data on the decrease in radioactivity are in each case with reference to a dummy group of experimental animals to which only gelatin capsules containing 20% by weight of vitamin E and a corresponding amount of radioactively labeled cholesterol had been administered. The mixtures 5 to 9 are according to the invention, the mixtures V1 to V3 are for comparison. Table 1 Hypocholesterolemic action (amounts as% by weight based on gelatin capsule) Composition / effectiveness V1 V2 V3 5 6 7 8th 9 β-sitosterol 10 0 0 9 8th 0 0 0 β-Sitosterolpalmitat 0 10 0 0 0 9 9 9 Hoodia extract 0 0 10 1 1 1 0.8 0.8 Gingko biloba extract 0 0 0 0 1 0 0.2 0 Trifolium pratense extract 0 0 0 0 0 0 0 0.2 Radioactivity [% -rel] - after 3 hours 97 91 100 97 97 91 91 92 - after 6 h 89 79 100 86 86 77 77 76 - after 12 h 81 67 100 78 76 61 59 60 - after 24 h 56 40 100 51 48 36 34 32 - after 48 h 34 21 100 28 25 18 16 16

Discussion of the results:

• • Hoodia Extract alone has no hypocholesterolemic effect (Example V1)
• • mixtures from 90% by weight of sterols or sterol esters and 10% by weight of Hoodia extract initially show the same hypocholesterolemic performance as the pure Sterols or sterol esters, however, accelerates after 12 h Excretion of cholesterol.
• • This one Effect tends to be replaced by up to 20% by weight of the hoodia content against other plant extracts, e.g. Gingko or red clover improved.

Claims (10)

Preparations for oral administration, containing (A) Sterols or sterol esters and (b) Hoodia extracts or the resulting available Steroid glycosides, in particular substance P57 and the associated homologs, Analogs and isomers. Preparations according to Claim 1, characterized that they contain as component (a) sitosterol or sitostanol. Preparations according to Claim 2, characterized that they as component (a) sitosterol esters or sitostanol esters contain. Preparations according to at least one of claims 1 to 3, characterized in that as component (a) esters of Sitosterol or sitostanol with conjugated linoleic acid. Preparations according to at least one of claims 1 to 4, characterized in that it as component (b) substance P57 and the associated Contain homologues, analogs and isomers. Preparations according to at least one of claims 1 to 5, characterized in that as an optional component (c) Containing extracts of other plants that are selected from the group formed by Ginkgo biloba, Camellia sinensis, Oleacea europensis, Glycyrrhiza glabra, Vaccinium myrtillus, Trifolium Pratense, Litchi sinensis, Vitis vinifera, Brassica oleracea, Punica granatum, Petroselinium crispum, Centella asiatica, Passiflora incarnata, Medicago sativa, Valeriana officinalis, Castanea sativa, Salix alba as well Hapagophytum procumbens and their mixtures. Preparations according to at least one of claims 1 to 6, characterized in that it comprises the components (a) and (b) in weight ratio 99: 1 to 80:20 included. Preparations according to at least one of claims 1 to 7, characterized in that they are present in encapsulated form. Use of mixtures containing (a) Sterols or sterol esters and (b) Hoodia Extracts or the products available therefrom Steroidglycoside for the production of food and food additives. Use of mixtures containing (a) Sterols or sterol esters and (b) Hoodia Extracts or the products available therefrom Steroidglycoside for the production of a hypocholesterolemic Drug.