WO2008046521A1 - Preparation for oral administration (ii) - Google Patents
Preparation for oral administration (ii) Download PDFInfo
- Publication number
- WO2008046521A1 WO2008046521A1 PCT/EP2007/008596 EP2007008596W WO2008046521A1 WO 2008046521 A1 WO2008046521 A1 WO 2008046521A1 EP 2007008596 W EP2007008596 W EP 2007008596W WO 2008046521 A1 WO2008046521 A1 WO 2008046521A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- esters
- extracts
- contain
- preparations according
- sterols
- Prior art date
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- 239000003755 preservative agent Substances 0.000 description 1
- 150000003138 primary alcohols Chemical class 0.000 description 1
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- 229920002414 procyanidin Polymers 0.000 description 1
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- OXGUCUVFOIWWQJ-HQBVPOQASA-N quercitrin Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1OC1=C(C=2C=C(O)C(O)=CC=2)OC2=CC(O)=CC(O)=C2C1=O OXGUCUVFOIWWQJ-HQBVPOQASA-N 0.000 description 1
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- 238000011084 recovery Methods 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- IKGXIBQEEMLURG-NVPNHPEKSA-N rutin Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@H](OC=2C(C3=C(O)C=C(O)C=C3OC=2C=2C=C(O)C(O)=CC=2)=O)O1 IKGXIBQEEMLURG-NVPNHPEKSA-N 0.000 description 1
- 235000014438 salad dressings Nutrition 0.000 description 1
- CZDNLUMNELLDDD-JAIJEDJZSA-N salicortin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC=CC=C1COC(=O)[C@@]1(O)C(=O)CCC=C1 CZDNLUMNELLDDD-JAIJEDJZSA-N 0.000 description 1
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- 150000003873 salicylate salts Chemical class 0.000 description 1
- YHBIHSCTXBGAIK-UHFFFAOYSA-N salicyloylsalicylin Natural products OC1C(O)C(O)C(CO)OC1OC1=CC=CC=C1COC(=O)C1=CC=CC=C1O YHBIHSCTXBGAIK-UHFFFAOYSA-N 0.000 description 1
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- 150000007949 saponins Chemical class 0.000 description 1
- 235000017709 saponins Nutrition 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 235000003441 saturated fatty acids Nutrition 0.000 description 1
- 150000004671 saturated fatty acids Chemical class 0.000 description 1
- 235000013580 sausages Nutrition 0.000 description 1
- NIABBGMPPWXWOJ-UHFFFAOYSA-N schaftoside Natural products OC1C(O)C(O)C(CO)OC1OC1=C(O)C(OC2C(C(O)C(O)CO2)O)=C(OC(=CC2=O)C=3C=CC(O)=CC=3)C2=C1O NIABBGMPPWXWOJ-UHFFFAOYSA-N 0.000 description 1
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- 239000011669 selenium Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
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- 229940032094 squalane Drugs 0.000 description 1
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- TUHBEKDERLKLEC-UHFFFAOYSA-N squalene Natural products CC(=CCCC(=CCCC(=CCCC=C(/C)CCC=C(/C)CC=C(C)C)C)C)C TUHBEKDERLKLEC-UHFFFAOYSA-N 0.000 description 1
- 229940094908 stearyl myristate Drugs 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- HCXVJBMSMIARIN-PHZDYDNGSA-N stigmasterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)/C=C/[C@@H](CC)C(C)C)[C@@]1(C)CC2 HCXVJBMSMIARIN-PHZDYDNGSA-N 0.000 description 1
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- BFDNMXAIBMJLBB-UHFFFAOYSA-N stigmasterol Natural products CCC(C=CC(C)C1CCCC2C3CC=C4CC(O)CCC4(C)C3CCC12C)C(C)C BFDNMXAIBMJLBB-UHFFFAOYSA-N 0.000 description 1
- 150000003440 styrenes Chemical class 0.000 description 1
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- 235000013616 tea Nutrition 0.000 description 1
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- TUNFSRHWOTWDNC-UHFFFAOYSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 0.000 description 1
- HBPNTDBLHQHPLH-UHFFFAOYSA-N tetradecyl 16-methylheptadecanoate Chemical compound CCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCCCC(C)C HBPNTDBLHQHPLH-UHFFFAOYSA-N 0.000 description 1
- AVKVDDQTHIQFSC-UHFFFAOYSA-N tetradecyl docosanoate Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCC AVKVDDQTHIQFSC-UHFFFAOYSA-N 0.000 description 1
- DHZWALZKPWZSMA-UHFFFAOYSA-N tetradecyl oleate Natural products CCCCCCCCCCCCCCOC(=O)CCCCCCCC=CCCCCCCCC DHZWALZKPWZSMA-UHFFFAOYSA-N 0.000 description 1
- DZKXJUASMGQEMA-UHFFFAOYSA-N tetradecyl tetradecanoate Chemical compound CCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCC DZKXJUASMGQEMA-UHFFFAOYSA-N 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
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- UIERETOOQGIECD-ONEGZZNKSA-N tiglic acid group Chemical group C(\C(\C)=C\C)(=O)O UIERETOOQGIECD-ONEGZZNKSA-N 0.000 description 1
- 239000011573 trace mineral Substances 0.000 description 1
- 235000013619 trace mineral Nutrition 0.000 description 1
- AQWHMKSIVLSRNY-UHFFFAOYSA-N trans-Octadec-5-ensaeure Natural products CCCCCCCCCCCCC=CCCCC(O)=O AQWHMKSIVLSRNY-UHFFFAOYSA-N 0.000 description 1
- UOGHEBWTVNXYEN-UHFFFAOYSA-N tremulacin Natural products OCC1OC(Oc2ccccc2COC(=O)C3(O)CC(=O)CC=C3)C(OC(=O)c4ccccc4)C(O)C1O UOGHEBWTVNXYEN-UHFFFAOYSA-N 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
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- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
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- CSNXTSWTBUEIJB-UHFFFAOYSA-N vicenin-II Natural products OC1C(O)C(O)C(CO)OC1OC1=C(O)C(OC2C(C(O)C(O)C(CO)O2)O)=C(OC(=CC2=O)C=3C=CC(O)=CC=3)C2=C1O CSNXTSWTBUEIJB-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/27—Asclepiadaceae (Milkweed family), e.g. hoya
-
- 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
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
- A23L33/11—Plant sterols or derivatives thereof, e.g. phytosterols
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
- A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- 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 invention is in the field of nutritional supplements and relates to new preparations for oral intake containing specific sterols or sterol esters together with Hoodia extracts.
- 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.
- Peterson et al. in J. Nutrit. 50, 191 (1953) Phytostenols, so vegetable stenols, and their esters with fatty acids proposed.
- the patents US Pat. No. 3,089,939, US Pat. No. 3,203,862 and German Laid-Open Application DE-OS 2035069 (Procter & Gamble) also point in the same direction.
- 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 to be precipitated by water.
- storage-stable emulsions of styrene esters in sugar or polyglycerol esters are proposed in European Patent Application EP 0289636 A1 (Ashai).
- sitostanol esters for reducing the blood cholesterol content in margarine, butter, mayonnaise, salad dressings and the like is proposed in European Patent EP 0594612 Bl (Raision).
- the object of the present invention has therefore been to provide new preparations for oral intake, which allow to reduce the concentration of undesired cholesterol in the blood faster with equal amounts of active ingredient or to achieve a corresponding effect with a reduced amount of active ingredient.
- the invention relates to preparations for oral administration, containing
- Sterols - sometimes referred to as sterols - are steroids characterized by a single hydroxyl group in the C3 position. Furthermore, sterols, which usually have from 27 to 30 carbon atoms, may also have a double bond, which is preferably in the 5/6 position. The hydrogenation of this double bond - also called hardening - leads to special sterols, which are referred to as conditions.
- the following figure shows the structure of the most prominent member of the group of sterols, cholesterol, which belongs to the group of zoosterols.
- plant sterols Due to their superior physiological properties, plant sterols, the so-called phytosterols such as ergosterol, stigmasterol and especially sitosterol and its hydrogenation product sitostanol are the preferred types of sterols.
- their esters can also be used with saturated and / or unsaturated fatty acids in which the acyl radicals can then have 6 to 22 carbon atoms and 0 or 1 to 6 double bonds.
- Typical examples are the esters of ⁇ -sitosterol or ⁇ -sitostanol with caproic, caprylic, 2-ethylhexanoic, capric, lauric, isotridecanoic, myristic, palmitic, palmitic, stearic, isostearic, oleic, elaidic, petroselic, linoleic, linolenic Arachin acid, gadoleic acid, behenic acid and erucic acid and their technical mixtures, eg occur in the pressure splitting of natural fats and oils, in the reduction of aldehydes from the Roelen oxosynthesis or the dimerization of unsaturated fatty acids.
- CLA conjugated linoleic acid
- Hoodia specifically Hoodia gordonü
- Hoodia gordonü 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:
- the oral preparations may contain as optional component (c) further plant extracts which have advantageous physiological properties.
- these are selected from the group formed by Ginkgo biloba, Camellia sinensis, Oleacea europensis, Glycyrhiza glabra, Vaccinium myrtulus, Trifolium pratense, Litchi sinensis, Vitis vinifera, Brasica oleracea, Punica granatum, Petroselinium crispum, Centella asiatica, Passiflora incarnata, Medicago sativa, Valeriana officinalis, Castanea sativa, Salix alba and Hapagophytum procumbens.
- the active ingredients of the extracts obtained from the leaves of the ginkgo tree are flavonoid glycosides which include (iso) quercitin glycosides, kaempferol, kaempferol-3 rhamnoside, isorhamnetin, luteoline glycosides, siterolactyl glycosides, and especially hexacyclic Terpene lactones, the so-called ginkgolides A, B, C, J, M and bilobalides.
- the leaves of green tea contain a variety of substances, such as e.g. Polysaccharides, volatile oils, vitamins, minerals, purines and in addition to alkaloids, such as caffeine, in particular polyphenols, which are usually catechins and flavonoids and are also referred to as "tea tannins”.
- substances such as e.g. Polysaccharides, volatile oils, vitamins, minerals, purines and in addition to alkaloids, such as caffeine, in particular polyphenols, which are usually catechins and flavonoids and are also referred to as "tea tannins”.
- the main constituent of the leaves of the olive tree ⁇ Oleacea europensis is the antioxidant oleuropein, which is also the main source of hydroxytyrosol.
- the main constituent of the extract of the sweet root Glyzyrrhiza glabra is glycyrrhetinic acid.
- Extracts of the common blueberry ⁇ Vaccinium myrtillus contain a mixture of at least 15 different anthocyanosides, such as the following:
- the extracts contain from 20 to 25% by weight of anthocyanosides, from 5 to 10% by weight of tannins and small amounts of various alkaloids, e.g. Myrtin and epimyrtin,
- Phenolic acids and glycosides of quercitrin, isoquercitrin and hyperoside are listed.
- the main constituents of the extracts of the red clover ⁇ Trifolium pratense are isoflavones, such as e.g. Daidzein, genestein, formononentin and biochanin A, as well as their glucosides, e.g. Ononine or sissostrine:
- Extracts derived from the shells of the Litchi fruit have high levels of flavone derivatives, e.g. 2-phenyl-4H-1-benzopyrans, flavanes, flavan-3-ols (catechins, catechol oligomers), flavan-3,4-diols (leucoanthocyanides), flavones, flavonols and flavonones.
- the main component is made up of condensed tannins, so-called procyanodols (OPC).
- PPC procyanodols
- Procyanidin, proanthocyanin, procyanidols, oligoprocyanidine, leucoanthocyanidin, leucodelphinin, leucocyanine and anthocyanogen preferably proanthocyanidin A2 (OPC A2) behave like vitamin P, especially with regard to the inhibition of matrix metalloproteinases.
- Extracts of leaves, roots and in particular grapevines are polyphenols of the OPC type described above.
- the main constituents of cauliflower extracts are amino acids, in particular methionine and cysteine, and glucosinolates, e.g. Glucoraphaine.
- pomegranate (Punica granatum) are found in addition to sugars and citric acid in particular delphinidin-l, 2-glycosides and their aglycones.
- the main constituent of the parsley fat oil (Petroselinium crispum) is the petroselinic acid.
- the extracts show high levels of apiol (l-allyl-2,5-dimethoxy-3,4- (methylenedioxy) benzene,), as well as apiin, myristicin, pinene and selenium.
- the main constituents of the extracts of Centella asiatica are highly condensed naphthenic acids, especially asiatic acid, madecassic acid and their glycosides.
- Extracts of passion fruit ⁇ Passiflora incarnata) are rich in flavones of the type of apigenin and luteolin and their C-glycosides.
- Extracts of alfalfa are rich in isoflavones, e.g. Daidzein, genestein, formononetin, biochanin A and tricine:
- the main constituents of extracts of Valeriana officinalis are valeric acid, valerianone and borneol esters.
- Horse chestnut extracts (Castanea sativa) contain mainly saponins and escin, which is the mixture of two glycosides whose aglycones are derived from proteoscenin, while the sugars are either glucuronic 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
- beta-escin is an amorphous powder which melts at 225-227 0 C is readily soluble in water
- beta-escin which is also referred to as Flogencyl
- the main constituents of the Salix alba extracts are phenol glycosides and, in particular, salicylates, such as, for example, Salicin, salicortin and tremulacin:
- the main constituents of Devil's Claw Extracts are iridoid glucosides, harpagosides, harpagids and procumbides.
- glycosylated phytosterols e.g., ⁇ -sitosterol
- flavonoids e.g., kaempferol, luteolin
- phenolic acids e.g., phenolic acids
- glycosidic phenylpropanoic acid esters e.g., verbacosides, isoactosides.
- the preparation of the stearic 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, remaering, 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.
- solvents for carrying out the extractions may be organic solvents, water (preferably hot water at a temperature of about 80 ° C and especially of above 95 ° C) or mixtures of organic solvents and water, in particular low molecular weight alcohols with more or less high Water contents, to be used.
- solvents for carrying out the extractions may be organic solvents, water (preferably hot water at a temperature of about 80 ° C and especially of above 95 ° C) or mixtures of organic solvents and water, in particular low molecular weight alcohols with more or less high Water contents, to be used.
- 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 0 C, preferably at 30 to 90 0 C, in particular at 60 to 80 0 C.
- 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 for extractions at temperatures above 40 0 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.
- 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.
- 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.
- 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).
- 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
- the components (a) and (b) are preferably used in a weight ratio of 99: 1 to 80:20, special synergistic effects being observed in the range from 98: 2 to 85:15 and in particular 95: 5 to 90:10.
- the optional plant extracts of component (c) may constitute from 1 to 25, preferably from 5 to 20 and especially from 8 to 12,% by weight.
- the oral preparations are used in encapsulated form-for example in the form of conventional gelatin macrocapsules-but preferably in microencapsulated form.
- a typical gelatin capsule may contain, for daily ingestion, 3 g CLA and 150 mg hoodia extract.
- microcapsule is understood by those skilled spherical aggregates having 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 specifically, it is finely dispersed liquid or solid phases coated with film-forming polymers, in the preparation of which the polymers precipitate on the material to be enveloped after emulsification and coacervation or interfacial polymerization.
- molten waxes are taken up in a matrix ("microsponge") which, as microparticles, can additionally be enveloped by film-forming polymers.
- microscopically small capsules also called nanocapsules, can be dried like powders.
- Alongside mononuclear microcapsules are also multinuclear aggregates Also known as microspheres, which contain two or more cores distributed in the continuous shell material, mononuclear or multinucleated microcapsules may also be enclosed by an additional second, third, etc.
- Shell materials are, for example, gum arabic, agar-agar, agarose, maltodextrins, alginic acid or its salts, for example sodium or calcium alginate, fats and fatty acids, cetyl alcohol, collagen, chitosan, lecithins, gelatin, albumin, shellac, polysaccharides, such as starch or dextran , Polypeptides, protein hy drolysate, sucrose and waxes.
- Semisynthetic shell materials include chemically modified celluloses, especially cellulose esters and ethers, e.g.
- Synthetic envelope materials are, for example, polymers such as polyacrylates, polyamides, polyvinyl alcohol or polyvinylpyrrolidone.
- microcapsules of the prior art are the following commercial products (in each case the shell material is indicated in brackets): Hallcrest microcapsules (gelatine, gum arabic), Coletica thalaspheres (marine collagen), Lipotec millicapsules (alginic acid, agar-agar), induchem Unispheres (Lactose, microcrystalline cellulose, hydroxypropyl methylcellulose); Unicerin C30 (lactose, microcrystalline cellulose, hydroxypropyl methylcellulose), Kobo Glycospheres (modified starch, fatty acid esters, phospholipids), Softspheres (modified agar agar) and Kuhs Probiol Nanospheres (phospholipids) as well as Primaspheres and Primasponges (chitosan, alginates) and Primasys (phospholipids).
- 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
- the active ingredient is alternately coated with layers of differently charged polyelectrolytes (layer-by-layer technology).
- those substances which have the property of forming gels in aqueous solution at temperatures above 40 ° C. are preferably considered as gelling agents.
- Typical examples are heteropolysaccharides and proteins.
- Preferred thermogelling heteropolysaccharides are agaroses which, in the form of the agar agar to be obtained from red algae, may also be present together with up to 30% by weight of non-gel-forming agaropectins.
- the main constituent of the agaroses are linear polysaccharides of D-galactose and 3,6-anhydro-L-galactose, which are linked alternately to ⁇ -1,3- and ⁇ -1,4-glycosidically.
- the heteropolysaccharides preferably have a molecular weight in the range of 110,000 to 160,000 and are both colorless and tasteless.
- Pectins, xanthans (including xanthan gum) as well as their mixtures come into consideration as alternatives. There are also those types are preferred, the aqueous solution still form gels in l-wt .-%, which do not melt below 80 0 C and solidify again above 40 ° C. From the
- thermogeling proteins are exemplified by the different types of gelatin.
- 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:
- chitosans are cationic biopolymers under these conditions.
- the positively charged chitosans can interact with oppositely charged surfaces and are therefore used in cosmetic hair and body care products and pharmaceutical preparations used.
- For the production of chitosans is based on chitin, preferably the shell remains of crustaceans, which are available as cheap raw materials in large quantities available.
- the chitin is thereby used in a process first described by Hackmann et al. has been described, usually initially deproteinized by the addition of bases, demineralized by the addition of mineral acids and finally deacetylated by the addition of strong bases, wherein the molecular weights may be distributed over a broad spectrum.
- the chitosans are generally used in the form of their salts, preferably as glycolates.
- the matrix may optionally be dispersed in an oil phase prior to the formation of the membrane.
- oils for this purpose for example, Guerbet alcohols based on fatty alcohols having 6 to 18, preferably 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 -Co -
- Carboxylic acids with linear C 6 -C 22 -fatty alcohols such as, for example, myristyl myristate, myristyl palmitate, myristyl stearate, myristyl isostearate, myristyl oleate, myristyl behenate, myristyl erucate, cetyl myristate, cetyl palmitate, cetyl stearate, cetyl isostearate, cetyl oleate, cetyl behenate, cetyl erucate, stearyl myristate, stearyl palmitate, stearyl stearate , Stearylisostearat, stearyl oleate, stearyl behenate, Stearylerucat, isostearyl, isostearyl palmitate, Isostearylstearat, I- sostearylisostearat, Isostearyloleat, isostearyl behenate
- C 2 2 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, for example, propylene glycol, dimerdiol or trimer triol) and / or guerbet alcohols, triglycerides based on C 6 -C 10 fatty acids, liquid mono- / di- / triglyceride mixtures 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 2 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 to
- 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 is in the range of 150,000 to 250,000.
- Salts of alginic acid are to be understood as meaning both their complete and their partial neutralization products, in particular the alkali salts and, preferably, the sodium alginate ("algin") and the ammonium and alkaline earth salts, particularly preferred are mixed alginates, such as, for example, sodium / magnesium
- anionic chitosan derivatives such as, for example, carboxylating and, in particular, succinylation products
- poly (meth) acrylates having average molecular weights in the range of 5,000 to 50,000 daltons and the various carboxymethylcelluloses in question.
- anionic polymers it is also possible to use anionic surfactants or low molecular weight inorganic salts, such as, for example, pyrophosphates, for the formation of the enveloping membrane.
- aqueous solution of the gelling agent preferably the agar agar ago and heated them under reflux.
- 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.
- water-insoluble constituents for example inorganic pigments, can also be added at this time to adjust the viscosity, these being added as a rule in the form of aqueous or aqueous / alcoholic dispersions. It may also be useful to emulsify or disperse the active ingredients of the matrix
- the matrix of gelling agent, cation polymer and active ingredients 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 0 C while cooling the oil phase to 10 to 20 0 C.
- the actual encapsulation takes place, ie the formation of the enveloping membrane by contacting the cationic polymer in the matrix with the anionic polymers.
- 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 - To treat polymers and thereby - 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 .-%.
- the solution of the polymers contains other ingredients, such as emulsifiers or preservatives.
- microcapsules After filtration, microcapsules are obtained, which on average have a diameter in the range of preferably about 0.01 to 1 mm. It is advisable to sieve the capsules in order to Ensures uniform size distribution.
- the microcapsules thus obtained may have any shape in the production-related framework, but they are preferably approximately spherical.
- the encapsulation can also be carried out using cationic polymers exclusively, taking advantage of their property of coagulating at pH values above the pKa value.
- an O / W emulsion is initially prepared for producing the microcapsules according to the invention, which contains an effective amount of emulsifier in addition to the oil body, water and the active ingredients.
- this preparation is mixed with vigorous stirring with an appropriate amount of an aqueous anionic polymer solution.
- the membrane formation takes place by adding the chitosan solution.
- the pH is raised to 5 to 6, for example by addition of triethanolamine or another base. This leads to an increase in the viscosity, which can be increased by adding further thickening agents, such as e.g.
- polysaccharides especially xanthan gum, guar guar, agar, alginates and Tyloses, carboxymethyl cellulose and hydroxyethyl cellulose, high molecular weight polyethylene glycol mono- and diesters of fatty acids, polyacrylates, polyacrylamides and the like can still be supported.
- the microcapsules of the aqueous phase for example by decantation, filtration or
- the formation of the microcapsules takes place around a preferably solid, for example, crystalline core, by coating it in layers with oppositely charged polyelectrolytes.
- a preferably solid, for example, crystalline core by coating it in layers with oppositely charged polyelectrolytes.
- compositions according to the invention exhibit an improved excretion of undesired cholesterol from the blood when taken orally.
- a further subject of the invention therefore relates to the use of mixtures containing
- 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 quantities of 0.01 to 10, preferably 0.1 to 5 and in particular 1 to 2 wt .-% may be included.
- 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 glycerol 90 ml water and then with a preparation of 2.5 g sodium alginate in the form of a 10 wt .-% aqueous solution, 1 g ß- Sitosterol, 1 g of dried Hoodia gordonii extract, 0.5 g of Phenonip® and 0.5 g of polysorbate-20 (Tween® 20, ICI) in 64 g of 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.
- agar-agar were dissolved in 200 ml of water in the boiling heat. Subsequently, the mixture was 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 an ester from ⁇ -sitosterol and CLA, 1 g of dried Hoodia gordonii extract, 0.5 g of Ginkgo biloba extract, 0.5 g of Phenonip® and 0.5 g of polysorbate-20 (Tween® 20, ICI) in 64 g of water. The resulting matrix was filtered, warmed to 60 ° C. and placed in a 1 % By weight solution of chitosan glycolate in water. To obtain microcapsules of the same
- 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 glycerol 90 ml water and then with a preparation of 2.5 g sodium alginate in the form of a 10 wt .-% aqueous solution, 1 g ß- Sitosterol palmitate, 1 g dried Hoodia gordonii extract, 0.5 g dried Vitis vinifera extract, 0.5 g Phenonip® and 0.5 g polysorbate-20 (Tween® 20, ICI) in 64 g of 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.
- 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 glycerol 90 ml water and then with a preparation of 2.5 g sodium alginate in the form of a 10 wt .-% aqueous solution, 1 g ß- Sitosterol palmitate, 1 g of dried Hoodia gordonii extract, 0.5 g of dried Camellia sinensis extract, 0.5 g of Phenonip® and 0.5 g of polysorbate-20 (Tween® 20, ICI) in 64 g of water.
- the matrix obtained was filtered, heated to 60 0 C and poured into a 1% by weight solution of chitosan glycolate dropped into water. To obtain microcapsules of the same diameter, the preparations were then sieved.
- Gelatine capsules (weight about 1.5 g) containing ⁇ -sitosterol or ⁇ -sitosterol esters and Hoodia and optionally other plant extracts and 0.5% by weight of radiolabeled cholesterol were prepared.
- 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. Which he- results, which represent 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 Vl to V3 are for comparison.
- This effect is tended to be reversed by replacing up to 20% by weight of the ⁇ oodia portion with other plant extracts, e.g. Gingko or red clover improved.
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Abstract
Preparations for oral administration comprising (a) sterols or sterol esters and (b) hoodia extracts or the steroid glycosides obtainable therefrom, and the use of (a) with (b) for producing foodstuffs and hypocholesteremic medicaments are proposed.
Description
Zubereitungen zur oralen Aufnahme (II) Preparations for oral administration (II)
Gebiet der ErfindungField of the invention
Die Erfindung befindet sich auf dem Gebiet der Nahrungsmittelzusatz- bzw. - ergänzungsstoffe und betrifft neue Zubereitungen zur oralen Aufnahme, enthaltend spezielle Sterole bzw. Sterolester zusammen mit Hoodia-Extrakten.The invention is in the field of nutritional supplements and relates to new preparations for oral intake containing specific sterols or sterol esters together with Hoodia extracts.
Stand der TechnikState of the art
Unter hypochloesterinämischen Wirkstoffen werden Mittel verstanden, die zu einer Verminderung des Cholesteringehaltes im Serum von Warmblütern führen, ohne dass dadurch eine Hemmung oder Verringerung der Bildung von Cholesterin im Blut eintritt. Für diesen Zweck wurden bereits von Peterson et al. in J. Nutrit. 50, 191 (1953) Phytostenole, also pflanzliche Stenole, und deren Ester mit Fettsäuren vorgeschlagen. In die gleiche Richtung weisen auch die Patentschriften US 3,089,939, US 3,203,862 sowie die deutsche Offenlegungsschrift DE- OS 2035069 (Procter & Gamble). Die Wirkstoffe werden üblicherweise Brat- oder Speiseölen zugesetzt und dann über die Nahrung aufgenommen, wobei die Einsatzmengen jedoch in der Regel gering sind und üblicherweise unter 0,5 Gew.-% liegen, um zu verhindern, daß die Speiseöle eintrüben oder die Stenole bei Zusatz von Wasser ausgefallt werden. Für den Einsatz im Nahrungsmittelbereich, in Kosmetika, pharmazeutischen Zubereitungen und im Ag- rarsektor werden in der europäischen Patentanmeldung EP 0289636 Al (Ashai) lagerstabile Emulsionen der Stenolester in Zucker- oder Polyglycerinestern vorgeschlagen. Die Einarbeitung von Sitostanolestern zur Verminderung des Blutcholesteringehaltes in Margarine, Butter, Mayonnaise, Salatsaucen und dergleichen wird in der Europäischen Patentschrift EP 0594612 Bl (Raision) vorgeschlagen. In der Internationalen Patentanmeldung WO 98/23277 Al (Henkel) werden Kombinationen von Phytostenolen und/oder Phytostenolestern mit Potenzie- rungsmitteln zur Herstellung von hypocholesterinämischen Mitteln offenbart. Phytostenolester wie das gamma-Oryzanol und fünf ähnliche Verbindungen vermindern über die Hemmung der Phospholipase A2 - Aktivität die Aufnahme von Cholesterol über den Darm, so beschrieben in der japanischen Offenlegungsschrift JP 07 330611(Yakult Honsha Co. Ltd). Die bekannten
hypocholesterinämischen Mittel auf Basis von Sterolen oder Sterolestern werden zwar bereits in großem Umfang Nahrungsmitteln zugesetzt, es besteht jedoch ein nachhaltiges Interesse, deren Wirksamkeit weiter zu verbessern.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, Peterson et al. in J. Nutrit. 50, 191 (1953) Phytostenols, so vegetable stenols, and their esters with fatty acids proposed. The patents US Pat. No. 3,089,939, US Pat. No. 3,203,862 and German Laid-Open Application DE-OS 2035069 (Procter & Gamble) also point in the same direction. 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 to be precipitated by water. For use in the food industry, in cosmetics, pharmaceutical preparations and in the agricultural sector, storage-stable emulsions of styrene esters in sugar or polyglycerol esters are proposed in European Patent Application EP 0289636 A1 (Ashai). The incorporation of sitostanol esters for reducing the blood cholesterol content in margarine, butter, mayonnaise, salad dressings and the like is proposed in European Patent EP 0594612 Bl (Raision). International Patent Application WO 98/23277 A1 (Henkel) discloses combinations of phytostenols and / or phytostenol esters with potentiating agents for the preparation 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 Japanese Laid-Open Patent Publication JP 07 330611 (Yakult Honsha Co. Ltd.). The well-known Although hypocholesterolemic agents based on sterols or sterol esters are already being widely added to foods, there is a sustained interest in further improving their effectiveness.
Die Aufgabe der vorliegenden Erfindung hat somit darin bestanden, neue Zubereitungen für die orale Aufnahme zur Verfügung zu stellen, die es erlauben, mit gleichen Wirkstoffmengen die Konzentration unerwünschten Cholesterins im Blut rascher zu senken oder einen entsprechenden Effekt mit einer verminderten Wirkstoffmenge zu erzielen.The object of the present invention has therefore been to provide new preparations for oral intake, which allow to reduce the concentration of undesired cholesterol in the blood faster with equal amounts of active ingredient or to achieve a corresponding effect with a reduced amount of active ingredient.
Beschreibung der ErfindungDescription of the invention
Gegenstand der Erfindung sind Zubereitungen zur oralen Aufnahme, enthaltendThe invention relates to preparations for oral administration, containing
(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.(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.
Es wurde gefunden, dass gegenüber dem Stand der Technik die Kombination aus den Sterolen bzw. Sterolestern und den Steroidglycosid-reichen Hoodia-Extrakten bei oraler Verabreichung zu einer rascheren Entfernung des unerwünschten Cholesterins aus dem Serum führt, was besonders überraschend ist, da Hoodia-Extrakte und ihre aktiven Prinzipien für sich genommen keinerlei hypocholesterinämische Aktivität besitzen. Weiterhin wurde beobachtet, dass sich die Cholesterinausscheidung durch Beimischung zusätzlicher Pflanzenextrakte tendenziell weiter verbessern lässt.It has been found that, compared with the prior art, the combination of the sterols or sterol esters and the steroid glycoside-rich Hoodia extracts when administered orally leads to a more rapid removal of the undesired cholesterol from the serum, which is particularly surprising since Hoodia extracts and their active principles in themselves have no hypocholesterolemic activity. Furthermore, it has been observed that the cholesterol excretion tends to be further improved by adding additional plant extracts.
Sterole und SterolesterSterols and sterol esters
Sterole - gelegentlich auch als Sterine bezeichnet - stellen Steroide dar, die durch eine einzel- ne Hydroxylgruppe in C3-Stellung gekennzeichnet sind. Des Weiteren können Sterole, die üblicherweise 27 bis 30 Kohlenstoffatome aufweisen, auch über eine Doppelbindung verfügen, die sich vorzugsweise in der 5/6-Stellung befindet. Die Hydrierung dieser Doppelbindung - auch als Härtung bezeichnet - führt zu speziellen Sterolen, die als Stande bezeichnet werden. Die nachfolgende Abbildung zeigt die Struktur des bekanntesten Vertreters aus der Gruppe der Sterole, des Cholesterols, das zur Gruppe der Zoosterole gehört.
Sterols - sometimes referred to as sterols - are steroids characterized by a single hydroxyl group in the C3 position. Furthermore, sterols, which usually have from 27 to 30 carbon atoms, may also have a double bond, which is preferably in the 5/6 position. The hydrogenation of this double bond - also called hardening - leads to special sterols, which are referred to as conditions. The following figure shows the structure of the most prominent member of the group of sterols, cholesterol, which belongs to the group of zoosterols.
Aufgrund ihrer überlegenen physiologischen Eigenschaften stellen pflanzliche Sterole, die so genannten Phytosterole, wie Ergosterol, Stigmasterol und insbesondere Sitosterol sowie dessen Hydrierungsprodukt Sitostanol die bevorzugten Steroltypen dar. Alternativ können anstelle der Sterole bzw. Stande auch deren Ester mit gesättigten und/oder ungesättigten Fettsäuren eingesetzt werden, wobei die Acylreste dann 6 bis 22 Kohlenstoffatome und 0 bzw. 1 bis 6 Doppelbindungen aufweisen können. Typische Beispiele sind die Ester von ß-Sitosterol oder ß-Sitostanol mit Capronsäure, Caprylsäure, 2-Ethylhexansäure, Caprinsäure, Laurinsäure, Isotridecansäure, Myristinsäure, Palmitinsäure, Palmoleinsäure, Stearinsäure, Isostearinsäure, Ölsäure, Elaidinsäure, Petroselinsäure, Linolsäure, Linolensäure, Elaeostearinsäure, Arachin- säure, Gadoleinsäure, Behensäure und Erucasäure sowie deren technische Mischungen, die z.B. bei der Druckspaltung von natürlichen Fetten und Ölen, bei der Reduktion von Aldehy- den aus der Roelen'schen Oxosynthese oder der Dimerisierung von ungesättigten Fettsäuren anfallen. Ganz besonders bevorzugt sind jedoch die Ester der beiden vorgenannten Sterole mit konjugierter Linolsäure (CLA).Due to their superior physiological properties, plant sterols, the so-called phytosterols such as ergosterol, stigmasterol and especially sitosterol and its hydrogenation product sitostanol are the preferred types of sterols. Alternatively, instead of the sterols or esters, their esters can also be used with saturated and / or unsaturated fatty acids in which the acyl radicals can then have 6 to 22 carbon atoms and 0 or 1 to 6 double bonds. Typical examples are the esters of β-sitosterol or β-sitostanol with caproic, caprylic, 2-ethylhexanoic, capric, lauric, isotridecanoic, myristic, palmitic, palmitic, stearic, isostearic, oleic, elaidic, petroselic, linoleic, linolenic Arachin acid, gadoleic acid, behenic acid and erucic acid and their technical mixtures, eg occur in the pressure splitting of natural fats and oils, in the reduction of aldehydes from the Roelen oxosynthesis or the dimerization of unsaturated fatty acids. However, very particular preference is given to the esters of the two abovementioned conjugated linoleic acid (CLA) sterols.
Hoodia-ExtrakteHoodia extracts
Hoodia, speziell Hoodia gordonü, ist eine Kaktuspflanze, die in Südafrika beheimatet und der einheimischen Bevölkerung seit langem als Mittel zur Bekämpfung des Hungergefühls bekannt ist. Es wird berichtet, dass in früheren Zeiten Buschmänner bei ihren Jagdzügen nur durch das Kauen von Hoodiawurzeln mehrere Wochen praktisch ohne Nahrung auskamen. In den vergangenen Jahren wurde gefunden, dass die erstaunlichen Eigenschaften dieser Pflanze mit ihrem hohen Gehalt an speziellen aktiven Steroidglykosiden zusammenhängen. In 2001/2002 gelang es erstmals, eine dieser Spezies zu isolieren und zu charakterisieren; sie wird in der Literatur seitdem als Substanz P57 bezeichnet:
Hoodia, specifically Hoodia gordonü, 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:
Aus der Patentliteratur ist bislang wenig über Hoodia und Hoodia-Extrakte bekannt. Aus der internationalen Patentanmeldung WO 98/046243 Al (CSIR) sind jedoch pharamzeutische Zubereitungen auf Basis von Extrakten von Pflanzen des Genus Trichocaulon oder Hoodia bekannt, die über eine appetitzügelnde Wirkung verfügen sollen.Little is known about hoodia and hoodia extracts from the patent literature. However, international patent application WO 98/046243 A1 (CSIR) discloses pharamceutical preparations based on extracts of plants of the genus Trichocaulon or Hoodia which are said to have an appetite-suppressing action.
Pflanzenextrakteplant extracts
In einer bevorzugten Ausführungsform der vorliegenden Erfindung können die oralen Zubereitungen als optionale Komponente (c) weitere Pflanzenextrakte enthalten, die über vorteilhafte physiologische Eigenschaften verfügen. Typischerweise sind diese ausgewählt aus der Gruppe, die gebildet wird von Ginkgo biloba, Camellia sinensis, Oleacea europensis, GIy- zyrrhiza glabra, Vaccinium myrtülus, Trifolium pratense, Litchi sinensis, Vitis vinifera, Bras- sica oleracea, Punica granatum, Petroselinium crispum, Centella asiatica, Passiflora incar- nata, Medicago sativa, Valeriana officinalis, Castanea sativa, Salix alba sowie Hapagophy- tum procumbens. Im Folgenden wird kurz auf die Zusammensetzung und die wesentlichen aktiven Wirkstoffe in den Extrakten eingegangen.In a preferred embodiment of the present invention, the oral preparations may contain as optional component (c) further plant extracts which have advantageous physiological properties. Typically, these are selected from the group formed by Ginkgo biloba, Camellia sinensis, Oleacea europensis, Glycyrhiza glabra, Vaccinium myrtulus, Trifolium pratense, Litchi sinensis, Vitis vinifera, Brasica oleracea, Punica granatum, Petroselinium crispum, Centella asiatica, Passiflora incarnata, Medicago sativa, Valeriana officinalis, Castanea sativa, Salix alba and Hapagophytum procumbens. The following briefly describes the composition and the essential active substances in the extracts.
• Ginkgo biloba• Ginkgo biloba
Die aktiven Wirkstoffe der Extrakte, die aus den Blättern des Ginkgobaumes (Ginkgo biloba) gewonnen werden, sind Flavonoidglycosides, welche unter anderem (Iso)Quercitin- glycoside, Kaempferol, Kaempferol-3-rhamnoside, Isorhamnetin, Luteolinglycoside, Si- tosterolglycoside und insbesondere hexacyclische Terpenlactone, die sogenannten Ginkgolide A, B, C, J, M und Bilobalide enthalten.
The active ingredients of the extracts obtained from the leaves of the ginkgo tree (Ginkgo biloba) are flavonoid glycosides which include (iso) quercitin glycosides, kaempferol, kaempferol-3 rhamnoside, isorhamnetin, luteoline glycosides, siterolactyl glycosides, and especially hexacyclic Terpene lactones, the so-called ginkgolides A, B, C, J, M and bilobalides.
Isorhamnetin (R , 11 _ = H), Kaempferol (R 11 _ = OH), Ginkgolid A (R . 1' - = , OMe)Isorhamnetin (R, 1 1 _ = H), kaempferol (R 1 _ 1 = OH), ginkgolide A (R 1 '-. =, OMe)
• Camellia sinensisCamellia sinensis
Die Blätter des Grünen Tees enthalten eine Vielzahl von Stoffen, wie z.B. Polysaccharide, flüchtige Öle, Vitamine, Mineralien, Purine und neben Alkaloiden, wie dem Koffein, insbesondere Polyphenole, bei denen es sich in der Regel um Catechine und Flavonoide handelt und die auch als „Tee-Tannine" bezeichnet werden.The leaves of green tea contain a variety of substances, such as e.g. Polysaccharides, volatile oils, vitamins, minerals, purines and in addition to alkaloids, such as caffeine, in particular polyphenols, which are usually catechins and flavonoids and are also referred to as "tea tannins".
• Oleacea europensis• Oleacea europensis
Der Hauptbestandteil der Blätter des Olivenbaums {Oleacea europensis) ist das Antioxi- dants Oleuropein, das auch die wichtigste Quelle für Hydroxytyrosol darstellt.The main constituent of the leaves of the olive tree {Oleacea europensis) is the antioxidant oleuropein, which is also the main source of hydroxytyrosol.
Oleuropeinoleuropein
• Glyzyrrhiza slabra• Glycyrrhiza slabra
Hauptbestandteil des Extraktes der Süßwurzel Glyzyrrhiza glabra ist die Glyzyrrhetinsäu- re.The main constituent of the extract of the sweet root Glyzyrrhiza glabra is glycyrrhetinic acid.
Glyzzyrhetinsäure
Vaccinium myrtillusGlyzzyrhetinsäure Vaccinium myrtillus
Extrakte der gemeinen Blaubeere {Vaccinium myrtillus) enthalten eine Mischung von wenigstens 15 verschiedenen Anthocyanosides, wie beispielsweise dem folgenden:Extracts of the common blueberry {Vaccinium myrtillus) contain a mixture of at least 15 different anthocyanosides, such as the following:
Üblicherweise, weisen die Extrakte 20 bis 25 Gew.-% Anthocyanoside, 5 bis 10 Gew.-% Tannine sowie geringe Mengen verschiedener Alkaloide, wie z.B. Myrtin und Epimyrtin,Usually, the extracts contain from 20 to 25% by weight of anthocyanosides, from 5 to 10% by weight of tannins and small amounts of various alkaloids, e.g. Myrtin and epimyrtin,
Phenolsäuren sowie Glycoside von Quercitrin, Isoquercitrin und Hyperosid auf.Phenolic acids and glycosides of quercitrin, isoquercitrin and hyperoside.
• Trifolium pratense• Trifolium pratense
Die Hauptbestandteile der Extrakte des Rotklees {Trifolium pratense) sind Isoflavone, wie z.B. Daidzein, Genestein, Formononentin and Biochanin A sowie deren Glucosides wie z.B. Ononin oder Sissostrin:The main constituents of the extracts of the red clover {Trifolium pratense) are isoflavones, such as e.g. Daidzein, genestein, formononentin and biochanin A, as well as their glucosides, e.g. Ononine or sissostrine:
• Litchi sinensis• Litchi sinensis
Extrakte, die aus den Schalen der Litchifrucht {Litchi sinensis) gewonnen werden, weisen hohe Gehalte an Flavonerivaten auf, wie z.B. 2-Phenyl-4H-l-benzopyranen, Flavanen, Flavan-3-olen (Catechinen, Catechinoligomeren), Flavan-3,4-diolen (Leucoanthocyani- den), Flavonen, Flavonolen und Flavononen. Der Hauptbestandteil wird jedoch ausge- macht von kondensierten Tanninen, sogenannten Procyanodolen (OPC). Diese Stoffe enthalten 2 bis 8 Monomere des Catechins oder eines Catechintyps, wie z.B. Procyanidin, Proanthocynidin, Procyanidole, Oligoprocyanidin, Leucoanthocyanidin, Leucodelphinin, Leucocyanin and Anthocyanogen. OPC, vorzugsweise Proanthocyanidin A2 (OPC A2) verhalten sich wie Vitamin P, vor allem mit Hinblick auf die Inhibierung von Matrixme- tallproteinasen.Extracts derived from the shells of the Litchi fruit (Litchi sinensis) have high levels of flavone derivatives, e.g. 2-phenyl-4H-1-benzopyrans, flavanes, flavan-3-ols (catechins, catechol oligomers), flavan-3,4-diols (leucoanthocyanides), flavones, flavonols and flavonones. The main component, however, is made up of condensed tannins, so-called procyanodols (OPC). These substances contain 2 to 8 monomers of catechin or a catechin type, e.g. Procyanidin, proanthocyanin, procyanidols, oligoprocyanidine, leucoanthocyanidin, leucodelphinin, leucocyanine and anthocyanogen. OPC, preferably proanthocyanidin A2 (OPC A2) behave like vitamin P, especially with regard to the inhibition of matrix metalloproteinases.
Oligomeres Proanthocyanidin
• Vitis viniferaOligomeric proanthocyanidin • Vitis vinifera
Die Hauptbestandteile Extrakte aus Blättern, Wurzeln und insbesondere Schalen der Weintraube (Vitis vinifera) sind Polyphenole vom oben beschriebenen OPC-Typ.The main constituents Extracts of leaves, roots and in particular grapevines (Vitis vinifera) are polyphenols of the OPC type described above.
• Brassica oleracea• Brassica oleracea
Die Hauptbestandteile der Extrakte des Blumenkohls (Brassica oleracea) sind Aminosäu- ren, insbesondere Methionin und Cystein sowie die Glucosinolate, wie z.B. Glucorapha- nin.The main constituents of cauliflower extracts (Brassica oleracea) are amino acids, in particular methionine and cysteine, and glucosinolates, e.g. Glucoraphaine.
• Punica granatum• Punica granatum
In den Extrakten des Granatapfels (Punica granatum) finden sich neben Zuckern und Zitronensäure insbesondere Delphinidin-l,2-glykoside sowie deren Aglykone.In the extracts of pomegranate (Punica granatum) are found in addition to sugars and citric acid in particular delphinidin-l, 2-glycosides and their aglycones.
• Petroselinium crispumPetroselinium crispum
Hauptbestandteil des fetten Öls der Petersilie (Petroselinium crispum) ist die Petroselin- säure. Die Extrakte hingegen zeigen hohe Gehalte an Apiol (l-Allyl-2,5-dimethoxy-3,4- (methylendioxy)benzol,), sowie Apiin, Myristicin, Pinen und Selinen.The main constituent of the parsley fat oil (Petroselinium crispum) is the petroselinic acid. The extracts, however, show high levels of apiol (l-allyl-2,5-dimethoxy-3,4- (methylenedioxy) benzene,), as well as apiin, myristicin, pinene and selenium.
Apiol
• Centella asiaticaapiol • Centella asiatica
Hauptbestandteile der Extrakte der Centella asiatica sind hochkondensierte Naphthensäu- ren, speziell Asiaticasäure, Madecassicasäure sowie deren Glycoside.The main constituents of the extracts of Centella asiatica are highly condensed naphthenic acids, especially asiatic acid, madecassic acid and their glycosides.
Asiaticoside Madecassosidβ
Passiflora incarnataAsiaticoside Madecassosidβ Passiflora incarnata
Extrakte der Passionsfrucht {Passiflora incarnata) sind reich an Flavonen vom Typ des Apigenins und Luteolins sowie deren C-Glycoside.Extracts of passion fruit {Passiflora incarnata) are rich in flavones of the type of apigenin and luteolin and their C-glycosides.
Apigenin LuteolinApigenin Luteolin
Des Weiteren enthalten sie 2"-B-D-Glucosides, Schaftoside and Isoschaftoside, Isovite- xin, Isoorientin, Vicenin-2, Incenin-2, Daponanin sowie Spurenelement, nämlich vor allem Kalzium, Phosphor und Eisen.In addition, they contain 2 "-B-D-glucosides, Schaftoside and Isoschaftoside, Isovitexin, Isoorientin, Vicenin-2, Incenin-2, Daponanin and trace elements, namely calcium, phosphorus and iron.
• Medicaso sativa• Medicaso sativa
Extrakte der Alfalfa (Medicago sativa) sind reich an Isoflavonen, wie z.B. Daidzein, Genestein, Formononetin, Biochanin A und Tricin :Extracts of alfalfa (Medicago sativa) are rich in isoflavones, e.g. Daidzein, genestein, formononetin, biochanin A and tricine:
Formononetin Bioachanin AFormononetin Bioachanin A
Tricintricine
• Valeriana officinalis• Valeriana officinalis
Die Hauptbestandteile von Extrakten der Valeriana officinalis sind Valeriansäure, Valeri- anon sowie Borneolester.The main constituents of extracts of Valeriana officinalis are valeric acid, valerianone and borneol esters.
• Castanea sativa• Castanea sativa
Rosskastanienextrakte {Castanea sativa) enthalten hauptsächlich Saponine sowie Escin, welches die Mischung zweier Glycoside darstellt, deren Aglycone sich von Proteoesci- genin ableiten, während es sich bei den Zuckern entweder um Glucoronsäure oder zwei Molekülen D-Glucose handelt. Die beiden Glycoside unterscheiden sich in der Natur der Acylgruppen in der C22-Position.
Horse chestnut extracts (Castanea sativa) contain mainly saponins and escin, which is the mixture of two glycosides whose aglycones are derived from proteoscenin, while the sugars are either glucuronic acid or two molecules of D-glucose. The two glycosides differ in the nature of the acyl groups in the C22 position.
R = Tiglicsäure oder AngelicasäureR = tiglic acid or angelic acid
Während α-Escin ein amorphes Pulver darstellt, welches bei 225 bis 227 0C schmilzt und leicht wasserlöslich ist, liegt ß-Escin (das auch als Flogencyl bezeichnet wird) in Form von Schuppen vor, die praktisch wasserunlöslich, aber leicht löslich in Alkohol sind.While α-escin is an amorphous powder which melts at 225-227 0 C is readily soluble in water, is beta-escin (which is also referred to as Flogencyl) in the form of flakes before, which are practically insoluble in water but readily soluble in alcohol ,
• Salix alba• Salix alba
Hauptbestandteile der Extrakte von Salix alba sind Phenolglykoside und insbesondere Sa- licylate wie z.B. Salicin, Salicortin und Tremulacin:The main constituents of the Salix alba extracts are phenol glycosides and, in particular, salicylates, such as, for example, Salicin, salicortin and tremulacin:
Salicin
• Harpagophytum procumbenssalicin • Harpagophytum procumbens
Die Hauptbestandteile der Extrakte der Teufelskralle {Harpagophytum procumbens) sind Iridoidglucoside, Harpagoside, Harpagide und Procumbide.The main constituents of Devil's Claw Extracts (Harpagophytum procumbens) are iridoid glucosides, harpagosides, harpagids and procumbides.
Iridoidglucosid R = H = Harpagid R = PhCH=CHCO- = HarpagosidIridoid glucoside R = H = harpagide R = PhCH = CHCO = harpagoside
Des Weiteren findet man Stachylose und glycosylierte Phytosterole (z.B. ß-Sitosterol), Flavonoide (z.B. Kaempferol, Luteolin), Phenolsäuren und glycosidische Phenylpropan- säureestern (z.B. Verbacoside, Isoacteoside).Furthermore, one finds stachylosis and glycosylated phytosterols (e.g., β-sitosterol), flavonoids (e.g., kaempferol, luteolin), phenolic acids, and glycosidic phenylpropanoic acid esters (e.g., verbacosides, isoactosides).
Extraktionextraction
Die Herstellung der steoridglycosid-haltigen Hoodia-Extrakte kann in an sich bekannter Wei- se erfolgen, d.h. beispielsweise durch wässrigen, alkoholischen oder wässrig-alkoholischen Auszug der Pflanzen bzw. Pflanzenteile bzw. der Blätter oder Früchte. Geeignet sind alle herkömmlichen Extraktionsverfahren wie z.B. Mazeration, Remazeration, Digestion, Bewegungsmazeration, Wirbelextraktion, Ultraschallextraktion, Gegenstromextraktion, Perkolati- on, Reperkolation, Evakolation (Extraktion unter vermindertem Druck), Diakolation oder Festflüssig-Extraktion unter kontinuierlichem Rückfluss. Für den großtechnischen Einsatz vorteilhaft ist die Perkolationsmethode. Als Ausgangsmaterial können frische Pflanzen oder Pflanzenteile eingesetzt werden, üblicherweise wird jedoch von getrockneten Pflanzen und/oder Pflanzenteilen ausgegangen, die vor der Extraktion mechanisch zerkleinert werden können. Hierbei eignen sich alle dem Fachmann bekannten Zerkleinerungsmethoden, als Bei- spiel sei die Gefriermahlung genannt. Als Lösungsmittel für die Durchführung der Extraktionen können organische Lösungsmittel, Wasser (vorzugsweise heißes Wasser einer Temperatur von über 80 °C und insbesondere von über 95 °C) oder Gemische aus organischen Lösungsmitteln und Wasser, insbesondere niedermolekulare Alkohole mit mehr oder weniger hohen
Wassergehalten, verwendet werden. Besonders bevorzugt ist die Extraktion mit Methanol, Ethanol, Pentan, Hexan, Heptan, Aceton, Propylenglykolen, Polyethylenglykolen sowie E- thylacetat sowie Mischungen hieraus sowie deren wässrige Gemische. Die Extraktion erfolgt in der Regel bei 20 bis 100 0C, bevorzugt bei 30 bis 90 0C, insbesondere bei 60 bis 80 0C. In einer bevorzugten Ausführungsform erfolgt die Extraktion unter Inertgasatmosphäre zur Vermeidung der Oxidation der Wirkstoffe des Extraktes. Dies ist insbesondere bei Extraktionen bei Temperaturen über 40 0C von Bedeutung. Die Extraktionszeiten werden vom Fachmann in Abhängigkeit vom Ausgangsmaterial, dem Extraktionsverfahren, der Extraktionstemperatur, vom Verhältnis Lösungsmittel zu Rohstoff u.a. eingestellt. Nach der Extraktion können die erhaltenen Rohextrakte gegebenenfalls weiteren üblichen Schritten, wie beispielsweise Aufreinigung, Konzentration und/oder Entfärbung unterzogen werden. Falls wünschenswert, können die so hergestellten Extrakte beispielsweise einer selektiven Abtrennung einzelner unerwünschter Inhaltsstoffe, unterzogen werden. Die Extraktion kann bis zu jedem beliebigen Extraktionsgrad erfolgen, wird aber gewöhnlich bis zur Erschöpfung durchgeführt. Typische Ausbeuten (= Trockensubstanzmenge des Extraktes bezogen auf eingesetzte Rohstoffmenge) bei der Extraktion getrockneter Blätter liegen im Bereich von 3 bis 15, insbesondere 6 bis 10 Gew.-%. Die vorliegenden Erfindung umfasst die Erkenntnis, dass die Extraktionsbedingungen sowie die Ausbeuten der Endextrakte vom Fachmann ja nach gewünschtem Einsatzgebiet gewählt werden können. Diese Extrakte, die in der Regel Aktivsubstanzgehalte (= Feststoff- gehalte) im Bereich von 0,5 bis 10 Gew.-% aufweisen, können als solche eingesetzt werden, es ist jedoch ebenfalls möglich, das Lösungsmittel durch Trocknung, insbesondere durch Sprüh- oder Gefriertrocknung vollständig zu entfernen. Die Extrakte können auch als Ausgangsstoffe für die Gewinnung der oben genannten reinen Wirkstoffe dienen, sofern diese nicht auf synthetischem Wege einfacher und kostengünstiger hergestellt werden können. Demzufolge kann der Wirkstoffgehalt in den Extrakten 5 bis 100, vorzugsweise 50 bis 95 Gew.-% betragen. Die Extrakte selbst können als wässrige und/oder in organischen Solventien gelöste Zubereitungen sowie als sprüh- bzw. gefriergetrocknete, wasserfreie Feststoffe vorliegen. Als organische Lösungsmittel kommen in diesem Zusammenhang beispielsweise die aliphatischen Alkohole mit 1 bis 6 Kohlenstoffatomen (z.B. Ethanol), Ketone (z.B. Aceton), Halogenkohlenwasserstoffe (z.B. Chloroform oder Methylenchlorid), niedere Ester oder PoIy- ole (z.B. Glycerin oder Glycole) in Frage. Speziell verwiesen sei auf das Herstellverfahren, welches in der bereits genannten WO 98/046243 Al offenbart und hiermit durch direkte Bezugnahme von der Lehre der vorliegenden Patentanmeldung eingeschlossen wird.The preparation of the stearic 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, remaering, 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 methods of comminution known to those skilled in the art are suitable here, for example freeze-milling. As solvents for carrying out the extractions may be organic solvents, water (preferably hot water at a temperature of about 80 ° C and especially of above 95 ° C) or mixtures of organic solvents and water, in particular low molecular weight alcohols with more or less high Water contents, to be used. 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 0 C, preferably at 30 to 90 0 C, in particular at 60 to 80 0 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 for extractions at temperatures above 40 0 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 as a rule have active substance contents (= solids contents) in the range from 0.5 to 10% by weight, can be used as such, but it is also possible to remove the solvent by drying, in particular by spraying or Completely remove lyophilization. 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 method disclosed in the already mentioned WO 98/046243 Al and hereby incorporated by direct reference to the teaching of the present patent application.
Vorzugsweise werden die Komponenten (a) und (b) im Gewichtsverhältnis 99:1 bis 80:20 eingesetzt, wobei besondere synergistische Effekte im Bereich von 98:2 bis 85:15 und insbesondere 95:5 bis 90:10 zu beobachten sind. Bezogen auf die Hoodia-Extrakte können die optionalen Pflanzenextrakte der Komponente (c) 1 bis 25, vorzugsweise 5 bis 20 und insbesondere 8 bis 12 Gew.-% ausmachen.
VerkapselungThe components (a) and (b) are preferably used in a weight ratio of 99: 1 to 80:20, special synergistic effects being observed in the range from 98: 2 to 85:15 and in particular 95: 5 to 90:10. Based on the Hoodia extracts, the optional plant extracts of component (c) may constitute from 1 to 25, preferably from 5 to 20 and especially from 8 to 12,% by weight. encapsulation
In einer besonderen Ausführungsform der vorliegenden Erfindung werden die oralen Zubereitungen in verkapselter Form - beispielsweise in Gestalt üblicher Gelatinemakrokapseln - vorzugsweise aber in mikroverkapselter Form eingesetzt. Eine typische Gelatinekapsel kann für die tägliche orale Aufnahme beispielsweise 3 g CLA und 150 mg Hoodia-Extrakt enthalten.In a particular embodiment of the present invention, the oral preparations are used in encapsulated form-for example in the form of conventional gelatin macrocapsules-but preferably in microencapsulated form. For example, a typical gelatin capsule may contain, for daily ingestion, 3 g CLA and 150 mg hoodia extract.
Unter dem Begriff "Mikrokapsel" werden vom Fachmann sphärische Aggregate mit einem Durchmesser im Bereich von etwa 0,0001 bis etwa 5 mm verstanden, die mindestens einen festen oder flüssigen Kern enthalten, der von mindestens einer kontinuierlichen Hülle umschlossen ist. Genauer gesagt handelt es sich um mit filmbildenden Polymeren umhüllte feindisperse flüssige oder feste Phasen, bei deren Herstellung sich die Polymere nach Emulgie- rung und Koazervation oder Grenzflächenpolymerisation auf dem einzuhüllenden Material niederschlagen. Nach einem anderen Verfahren werden geschmolzene Wachse in einer Matrix aufgenommen („microsponge"), die als Mikropartikel zusätzlich mit filmbildenden Polymeren umhüllt sein können. Die mikroskopisch kleinen Kapseln, auch Nanokapseln genannt, lassen sich wie Pulver trocknen. Neben einkernigen Mikrokapseln sind auch mehrkernige Aggregate, auch Mikrosphären genannt, bekannt, die zwei oder mehr Kerne im kontinuierlichen Hüllmaterial verteilt enthalten. Ein- oder mehrkernige Mikrokapseln können zudem von einer zusätzlichen zweiten, dritten etc. Hülle umschlossen sein. Die Hülle kann aus natürlichen, halbsynthetischen oder synthetischen Materialien bestehen. Natürlich Hüllmaterialien sind beispielsweise Gummi Arabicum, Agar-Agar, Agarose, Maltodextrine, Alginsäure bzw. ihre Salze, z.B. Natrium- oder Calciumalginat, Fette und Fettsäuren, Cetylalkohol, Collagen, Chitosan, Lecithine, Gelatine, Albumin, Schellack, Polysaccharide, wie Stärke oder Dextran, Polypeptide, Proteinhydrolysate, Sucrose und Wachse. Halbsynthetische Hüllmaterialien sind unter anderem chemisch modifizierte Cellulosen, insbesondere Celluloseester und -ether, z.B. CeI- luloseacetat, Ethylcellulose, Hydroxypropylcellulose, Hydroxypropylmethylcellulose und Carboxymethylcellulose, sowie Stärkederivate, insbesondere Stärkeether und -ester. Synthetische Hüllmaterialien sind beispielsweise Polymere wie Polyacrylate, Polyamide, Polyvinylal- kohol oder Polyvinylpyrrolidon.The term "microcapsule" is understood by those skilled spherical aggregates having 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 specifically, it is finely dispersed liquid or solid phases coated with film-forming polymers, in the preparation of which the polymers precipitate on the material to be enveloped after emulsification and coacervation or interfacial polymerization. According to another method, molten waxes are taken up in a matrix ("microsponge") which, as microparticles, can additionally be enveloped by film-forming polymers.The microscopically small capsules, also called nanocapsules, can be dried like powders.Alongside mononuclear microcapsules are also multinuclear aggregates Also known as microspheres, which contain two or more cores distributed in the continuous shell material, mononuclear or multinucleated microcapsules may also be enclosed by an additional second, third, etc. shell The shell may be made of natural, semisynthetic or synthetic materials Shell materials are, for example, gum arabic, agar-agar, agarose, maltodextrins, alginic acid or its salts, for example sodium or calcium alginate, fats and fatty acids, cetyl alcohol, collagen, chitosan, lecithins, gelatin, albumin, shellac, polysaccharides, such as starch or dextran , Polypeptides, protein hy drolysate, sucrose and waxes. Semisynthetic shell materials include chemically modified celluloses, especially cellulose esters and ethers, e.g. Cellulose acetate, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and carboxymethylcellulose, and also starch derivatives, in particular starch ethers and esters. Synthetic envelope materials are, for example, polymers such as polyacrylates, polyamides, polyvinyl alcohol or polyvinylpyrrolidone.
Beispiele für Mikrokapseln des Stands der Technik sind folgende Handelsprodukte (in Klam- mern angegeben ist jeweils das Hüllmaterial) : Hallcrest Microcapsules (Gelatine, Gummi Arabicum), Coletica Thalaspheres (maritimes Collagen), Lipotec Millicapseln (Alginsäure, Agar-Agar), Induchem Unispheres (Lactose, mikrokristalline Cellulose, Hydroxypropylmethylcellulose); Unicerin C30 (Lactose, mikrokristalline Cellulose, Hydroxypropyl-
methylcellulose), Kobo Glycospheres (modifizierte Stärke, Fettsäureester, Phospholipide), Softspheres (modifiziertes Agar-Agar) und Kuhs Probiol Nanospheres (Phospholipide) sowie Primaspheres und Primasponges (Chitosan, Alginate) und Primasys (Phospholipide).Examples of microcapsules of the prior art are the following commercial products (in each case the shell material is indicated in brackets): Hallcrest microcapsules (gelatine, gum arabic), Coletica thalaspheres (marine collagen), Lipotec millicapsules (alginic acid, agar-agar), induchem Unispheres (Lactose, microcrystalline cellulose, hydroxypropyl methylcellulose); Unicerin C30 (lactose, microcrystalline cellulose, hydroxypropyl methylcellulose), Kobo Glycospheres (modified starch, fatty acid esters, phospholipids), Softspheres (modified agar agar) and Kuhs Probiol Nanospheres (phospholipids) as well as Primaspheres and Primasponges (chitosan, alginates) and Primasys (phospholipids).
Chitosanmikrokapseln und Verfahren zu ihrer Herstellung sind Gegenstand früherer Patenan- meidungen der Patentanmelderin [WO 01/01926, WO 01/01927, WO 01/01928, WO 01/01929]. Mikrokapseln mit mittleren Durchmessern im Bereich von 0,0001 bis 5, vorzugsweise 0,001 bis 0,5 und insbesondere 0,005 bis 0,1 mm, bestehend aus einer Hüllmembran und einer die Wirkstoffe enthaltenden Matrix, können beispielsweise erhalten werden, indem manChitosan 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
(al) aus Gelbildnern, kationischen Polymeren und Wirkstoffen eine Matrix zubereitet,(al) preparing a matrix from gelling agents, cationic polymers and active ingredients,
(a2) gegebenenfalls die Matrix in einer Ölphase dispergiert,(a2) optionally dispersing the matrix in an oil phase,
(a3) die dispergierte Matrix mit wässrigen Lösungen anionischer Polymere behandelt und gegebenenfalls dabei die Ölphase entfernt.(a3) treating the dispersed matrix with aqueous solutions of anionic polymers and optionally removing the oil phase.
oderor
(bl) 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;(bl) preparing a matrix of gelling agents, anionic polymers and active ingredients, (b2) optionally dispersing the matrix in an oily phase, (b3) treating the dispersed matrix with aqueous cationic polymer solutions and optionally removing the oily phase;
oderor
(cl) aus Gelbildnern und Wirkstoffen eine Matrix zubereitet, (c2) die Matrix mit einer Kationpolymerlösung versetzt und(cl) preparing a matrix from gelling agents and active ingredients, (c2) adding a cationic polymer solution to the matrix and
(c3) die Mischung auf einen pH- Wert einstellt der oberhalb des pKs- Wertes des Kationpolymers liegt;(c3) adjusting the mixture to a pH above the pKa of the cationic polymer;
oderor
(dl) wässrige Wirkstoffzubereitungen mit Ölkörpern in Gegenwart von Emulgatoren zu(dl) aqueous active compound preparations with oil bodies in the presence of emulsifiers
O/W-Emulsionen verarbeitet,O / W emulsions processed,
(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;(d2) treating the resulting emulsions 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;
oder
den Wirkstoff abwechselnd mit Schichten aus unterschiedlich geladenen Polyelektrolyten einhüllt (layer-by-layer-Technologie) .or the active ingredient is alternately coated with layers of differently charged polyelectrolytes (layer-by-layer technology).
• Gelbildner• gelling agent
Im Sinne der Erfindung werden als Gelbildner vorzugsweise solche Stoffe in Betracht gezogen, welche die Eigenschaft zeigen in wässriger Lösung bei Temperaturen oberhalb von 40 °C Gele zu bilden. Typische Beispiele hierfür sind Heteropolysaccharide und Proteine. Als thermogelierende Heteropolysaccharide kommen vorzugsweise Agarosen in Frage, welche in Form des aus Rotalgen zu gewinnenden Agar-Agar auch zusammen mit bis zu 30 Gew.-% nicht-gelbildenden Agaropektinen vorliegen können. Hauptbestandteil der Agarosen sind lineare Polysaccharide aus D-Galaktose und 3,6-Anhydro-L-galaktose, die alternierend ß-1,3- und ß-l,4-glykosidisch verknüpft sind. Die Heteropolysaccharide besitzen vorzugsweise ein Molekulargewicht im Bereich von 110.000 bis 160.000 und sind sowohl färb- als auch geschmacklos. Als Alternativen kommen Pektine, Xanthane (auch Xanthan Gum) sowie deren Mischungen in Frage. Es sind weiterhin solche Typen bevorzugt, die noch in l-Gew.-%iger wässriger Lösung Gele bilden, die nicht unterhalb von 80 0C schmelzen und sich bereits oberhalb von 40 °C wieder verfestigen. Aus derFor the purposes of the invention, those substances which have the property of forming gels in aqueous solution at temperatures above 40 ° C. are preferably considered as gelling agents. Typical examples are heteropolysaccharides and proteins. Preferred thermogelling heteropolysaccharides are agaroses which, in the form of the agar agar to be obtained from red algae, may also be present together with up to 30% by weight of non-gel-forming agaropectins. The main constituent of the agaroses are linear polysaccharides of D-galactose and 3,6-anhydro-L-galactose, which are linked alternately to β-1,3- and β-1,4-glycosidically. The heteropolysaccharides preferably have a molecular weight in the range of 110,000 to 160,000 and are both colorless and tasteless. Pectins, xanthans (including xanthan gum) as well as their mixtures come into consideration as alternatives. There are also those types are preferred, the aqueous solution still form gels in l-wt .-%, which do not melt below 80 0 C and solidify again above 40 ° C. From the
Gruppe der thermogelierenden Proteine seien exemplarisch die verschiedenen Gelatine- Typen genannt.Group of thermogeling proteins are exemplified by the different types of gelatin.
• Chitosane• Chitosan
Chitosane stellen Biopolymere dar und werden zur Gruppe der Hydrokolloide gezählt. Chemisch betrachtet handelt es sich um partiell deacetylierte Chitine unterschiedlichen Molekulargewichtes, die den folgenden - idealisierten - Monomerbaustein enthalten: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:
Im Gegensatz zu den meisten Hydrokolloiden, die im Bereich biologischer pH- Werte negativ geladen sind, stellen Chitosane unter diesen Bedingungen kationische Biopolymere dar. Die positiv geladenen Chitosane können mit entgegengesetzt geladenen Oberflächen in Wechselwirkung treten und werden daher in kosmetischen Haar- und Körperpflegemit- teln sowie pharmazeutischen Zubereitungen eingesetzt. Zur Herstellung der Chitosane geht man von Chitin, vorzugsweise den Schalenresten von Krustentieren aus, die als billige Rohstoffe in großen Mengen zur Verfugung stehen. Das Chitin wird dabei in einem Verfahren, das erstmals von Hackmann et al. beschrieben worden ist, üblicherweise zunächst durch Zusatz von Basen deproteiniert, durch Zugabe von Mineralsäuren deminera- lisiert und schließlich durch Zugabe von starken Basen deacetyliert, wobei die Molekulargewichte über ein breites Spektrum verteilt sein können. Vorzugsweise werden solche Typen eingesetzt, wie die ein durchschnittliches Molekulargewicht von 10.000 bis 500.000 bzw. 800.000 bis 1.200.000 Dalton aufweisen und/oder eine Viskosität nach Brookfield (1 Gew.-%ig in Glycolsäure) unterhalb von 5000 mPas, einen Deacetylie- rungsgrad im Bereich von 80 bis 88 % und einem Aschegehalt von weniger als 0,3 Gew.- Unlike most hydrocolloids, which are negatively charged at biological pHs, chitosans are cationic biopolymers under these conditions. The positively charged chitosans can interact with oppositely charged surfaces and are therefore used in cosmetic hair and body care products and pharmaceutical preparations used. For the production of chitosans is based on chitin, preferably the shell remains of crustaceans, which are available as cheap raw materials in large quantities available. The chitin is thereby used in a process first described by Hackmann et al. has been described, usually initially deproteinized by the addition of bases, demineralized by the addition of mineral acids and finally deacetylated by the addition of strong bases, wherein the molecular weights may be distributed over a broad spectrum. Preference is given to using those types which have an average molecular weight of from 10,000 to 500,000 or from 800,000 to 1,200,000 daltons and / or a Brookfield viscosity (1% strength by weight in glycolic acid) below 5,000 mPas, a degree of deacetylation in the range of 80 to 88% and an ash content of less than 0.3 wt.
% besitzen. Aus Gründen der besseren Wasserlöslichkeit werden die Chitosane in der Regel in Form ihrer Salze, vorzugsweise als Glycolate eingesetzt.% own. For reasons of better solubility in water, the chitosans are generally used in the form of their salts, preferably as glycolates.
• Ölphase• oil phase
Die Matrix kann vor der Bildung der Membran optional in einer Ölphase dispergiert werden. Als Öle kommen für diesen Zweck beispielsweise Guerbetalkohole auf Basis von Fettalkoholen mit 6 bis 18, vorzugsweise 8 bis 10 Kohlenstoffatomen, Ester von linearen C6-C22-Fettsäuren mit linearen C6-C22-Fettalkoholen, Ester von verzweigten C6-Co-The matrix may optionally be dispersed in an oil phase prior to the formation of the membrane. As oils for this purpose, for example, Guerbet alcohols based on fatty alcohols having 6 to 18, preferably 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 -Co -
Carbonsäuren mit linearen C6-C22-Fettalkoholen, wie z.B. Myristylmyristat, Myristylpal- mitat, Myristylstearat, Myristylisostearat, Myristyloleat, Myristylbehenat, Myristylerucat, Cetylmyristat, Cetylpalmitat, Cetylstearat, Cetylisostearat, Cetyloleat, Cetylbehenat, Cety- lerucat, Stearylmyristat, Stearylpalmitat, Stearylstearat, Stearylisostearat, Stearyloleat, Stearylbehenat, Stearylerucat, Isostearylmyristat, Isostearylpalmitat, Isostearylstearat, I- sostearylisostearat, Isostearyloleat, Isostearylbehenat, Isostearyloleat, Oleylmyristat, O- leylpalmitat, Oleylstearat, Oleylisostearat, Oleyloleat, Oleylbehenat, Oleylerucat, Behe- nylmyristat, Behenylpalmitat, Behenylstearat, Behenylisostearat, Behenyloleat, Behenyl- behenat, Behenylerucat, Erucylmyristat, Erucylpalmitat, Erucylstearat, Erucylisostearat, Erucyloleat, Erucylbehenat und Erucylerucat. Daneben eignen sich Ester von linearen C6-Carboxylic acids with linear C 6 -C 22 -fatty alcohols, such as, for example, myristyl myristate, myristyl palmitate, myristyl stearate, myristyl isostearate, myristyl oleate, myristyl behenate, myristyl erucate, cetyl myristate, cetyl palmitate, cetyl stearate, cetyl isostearate, cetyl oleate, cetyl behenate, cetyl erucate, stearyl myristate, stearyl palmitate, stearyl stearate , Stearylisostearat, stearyl oleate, stearyl behenate, Stearylerucat, isostearyl, isostearyl palmitate, Isostearylstearat, I- sostearylisostearat, Isostearyloleat, isostearyl behenate, Isostearyloleat isonanonoate, O- leylpalmitat, nylmyristat oleyl stearate, oleyl isostearate, oleyl oleate, Oleylbehenat, oleyl, behenyl, behenyl palmitate, behenyl, Behenylisostearat , Behenyl oleate, behenyl behenate, behenyl erucate, erucyl myristate, erucyl palmitate, erucyl stearate, erucyl isostearate, erucyl oleate, erucyl behenate and erucyl erucate. Also suitable are esters of linear C 6 -
C22-Fettsäuren mit verzweigten Alkoholen, insbesondere 2-Ethylhexanol, Ester von Hy- droxycarbonsäuren mit linearen oder verzweigten C6-C22-Fettalkoholen, insbesondere Dioctyl Malate, Ester von linearen und/oder verzweigten Fettsäuren mit mehrwertigen
Alkoholen (wie z.B. Propylenglycol, Dimerdiol oder Trimertriol) und/oder Guerbetalko- holen, Triglyceride auf Basis C6-C10-Fettsäuren, flüssige Mono-/Di-/Triglycerid- mischungen auf Basis von C6-C18-Fettsäuren, Ester von C6-C22-Fettalkoholen und/oder Guerbetalkoholen mit aromatischen Carbonsäuren, insbesondere Benzoesäure, Ester von C2-Ci2-Dicarbonsäuren mit linearen oder verzweigten Alkoholen mit 1 bis 22 Kohlenstoffatomen oder Polyolen mit 2 bis 10 Kohlenstoffatomen und 2 bis 6 Hydroxylgruppen, pflanzliche Öle, verzweigte primäre Alkohole, substituierte Cyclohexane, lineare und verzweigte C6-C22-Fettalkoholcarbonate, Guerbetcarbonate, Ester der Benzoesäure mit linearen und/oder verzweigten C6-C22-Alkoholen (z.B. Finsolv® TN), lineare oder ver- zweigte, symmetrische oder unsymmetrische Dialkylether mit 6 bis 22 Kohlenstoffatomen pro Alkylgruppe, Ringöffnungsprodukte von epoxidierten Fettsäureestern mit Polyolen, Siliconöle und/oder aliphatische bzw. naphthenische Kohlenwasserstoffe, wie z.B. wie Squalan, Squalen oder Dialkylcyclohexane in Betracht.C 2 2 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, for example, propylene glycol, dimerdiol or trimer triol) and / or guerbet alcohols, triglycerides based on C 6 -C 10 fatty acids, liquid mono- / di- / triglyceride mixtures 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 2 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, Guerbetcarbonate, esters of benzoic acid with linear and / or branched C 6 -C 22 alcohols (eg Finsolv® TN), linear or ver - branched, symmetrical or asymmetrical dialkyl ethers having 6 to 22 carbon atoms per alkyl group, ring-opening products of epoxidized fatty acid esters with polyols, silicone oils and / or aliphatic or na phthenic hydrocarbons such as squalane, squalene or dialkylcyclohexanes.
• Anionpolvmere• anion polvmer
Die anionische Polymere haben die Aufgabe, mit den Chitosanen Membranen zu bilden. Für diesen Zweck eignen sich vorzugsweise Salze der Alginsäure. Bei der Alginsäure handelt es sich um ein Gemisch carboxylgruppenhaltiger Polysaccharide mit folgendem idealisierten Monomerbaustein: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:
Das durchschnittliche Molekulargewicht der Alginsäuren bzw. der Alginate liegt im Bereich von 150.000 bis 250.000. Dabei sind als Salze der Alginsäure sowohl deren vollständige als auch deren partiellen Neutralisationsprodukte zu verstehen, insbesondere die Alkalisalze und hierunter vorzugsweise das Natriumalginat („Algin") sowie die Ammonium- und Erdalkalisalze, besonders bevorzugt sind Mischalginate, wie z.B. Natri- um/Magnesium- oder Natrium/Calciumalginate. In einer alternativen Ausführungsform der Erfindung kommen für diesen Zweck jedoch auch anionische Chitosanderivate, wie z.B. Carboxylierungs- und vor allem Succinylierungsprodukte in Frage. Alternativ kommen auch Poly(meth)acrylate mit durchschnittlichen Molekulargewichten im Bereich von
5.000 bis 50.000 Dalton sowie die verschiedenen Carboxymethylcellulosen in Frage. Anstelle der anionischen Polymeren können für die Ausbildung der Hüllmembran auch anionische Tenside oder niedermolekulare anorganische Salze, wie beispielsweise Py- rophosphate eingesetzt werden.The average molecular weight of the alginic acids or alginates is in the range of 150,000 to 250,000. Salts of alginic acid are to be understood as meaning both their complete and their partial neutralization products, in particular the alkali salts and, preferably, the sodium alginate ("algin") and the ammonium and alkaline earth salts, particularly preferred are mixed alginates, such as, for example, sodium / magnesium However, in an alternative embodiment of the invention, anionic chitosan derivatives, such as, for example, carboxylating and, in particular, succinylation products, are also suitable for this purpose Alternatively, poly (meth) acrylates having average molecular weights in the range of 5,000 to 50,000 daltons and the various carboxymethylcelluloses in question. Instead of the anionic polymers, it is also possible to use anionic surfactants or low molecular weight inorganic salts, such as, for example, pyrophosphates, for the formation of the enveloping membrane.
• Herstellverfahren Mikrokapseln• Production process microcapsules
Zur Herstellung der Mikrokapseln stellt man üblicherweise eine 1 bis 10, vorzugsweise 2 bis 5 Gew.-%ige wässrige Lösung des Gelbildners, vorzugsweise des Agar-Agars her und erhitzt diese unter Rückfluss. In der Siedehitze, vorzugsweise bei 80 bis 100°C, wird eine zweite wässrige Lösung zugegeben, welche das Kationpolymer, vorzugsweise das Chito- san in Mengen von 0,1 bis 2, vorzugsweise 0,25 bis 0,5 Gew.-% und den Wirkstoffen in Mengen von 0,1 bis 25 und insbesondere 0,25 bis 10 Gew.-% enthält; diese Mischung wird als Matrix bezeichnet. Die Beladung der Mikrokapseln mit Wirkstoffen kann daher ebenfalls 0,1 bis 25 Gew.-% bezogen auf das Kapselgewicht betragen. Falls gewünscht, können zu diesem Zeitpunkt zur Viskositätseinstellung auch wasserunlösliche Bestandteile, beispielsweise anorganische Pigmente zugegeben werden, wobei man diese in der Regel in Form von wässrigen oder wässrig/alkoholischen Dispersionen zusetzt. Zur Emul- gierung bzw. Dispergierung der Wirkstoffe kann es ferner von Nutzen sein, der MatrixFor 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. At the boiling point, 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, can also be added at this time to adjust the viscosity, these being added as a rule in the form of aqueous or aqueous / alcoholic dispersions. It may also be useful to emulsify or disperse the active ingredients of the matrix
Emulgatoren und/oder Lösungsvermittler hinzuzugeben. Nach der Herstellung der Matrix aus Gelbildner, Kationpolymer und Wirkstoffen kann die Matrix optional in einer Ölpha- se unter starker Scherung sehr fein dispergiert werden, um bei der nachfolgenden Verkap- selung möglichst kleine Teilchen herzustellen. Dabei hat es sich als besonders vorteilhaft erwiesen, die Matrix auf Temperaturen im Bereich von 40 bis 60 0C zu erwärmen, während man die Ölphase auf 10 bis 20 0C kühlt. Im letzten, nun wieder obligatorischen Schritt erfolgt dann die eigentliche Verkapselung, d.h. die Ausbildung der Hüllmembran durch Inkontaktbringen des Kationpolymers in der Matrix mit den anionischen Polymeren. Hierzu empfiehlt es sich, die gegebenenfalls in der Ölphase dispergierte Matrix bei einer Temperatur im Bereich von 40 bis 100, vorzugsweise 50 bis 60 °C mit einer wässrigen, etwa 1 bis 50 und vorzugsweise 10 bis 15 Gew.-%ige wässrigen Lösung des Anion- polymers zu behandeln und dabei - falls erforderlich - gleichzeitig oder nachträglich die Ölphase zu entfernen. Die dabei resultierenden wässrigen Zubereitungen weisen in der Regel einen Mikrokapselgehalt im Bereich von 1 bis 10 Gew.-% auf. In manchen Fällen kann es dabei von Vorteil sein, wenn die Lösung der Polymeren weitere Inhaltsstoffe, beispielsweise Emulgatoren oder Konservierungsmittel enthält. Nach Filtration werden Mikrokapseln erhalten, welche im Mittel einen Durchmesser im Bereich von vorzugsweise etwa 0,01 bis 1 mm aufweisen. Es empfiehlt sich, die Kapseln zu sieben, um eine mög-
liehst gleichmäßige Größenverteilung sicherzustellen. Die so erhaltenen Mikrokapseln können im herstellungsbedingten Rahmen eine beliebige Form aufweisen, sie sind jedoch bevorzugt näherungsweise kugelförmig. Alternativ kann man die Anionpolymere auch zur Herstellung der Matrix einsetzen und die Verkapselung mit den Kationpolymeren, speziell den Chitosanen durchfuhren.Add emulsifiers and / or solubilizers. After the matrix of gelling agent, cation polymer and active ingredients has been prepared, 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 0 C while cooling the oil phase to 10 to 20 0 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 - To treat polymers and thereby - 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 advisable to sieve the capsules in order to Ensures uniform size distribution. 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 the encapsulation with the cationic polymers, especially the chitosans durchfuhr.
Alternativ kann die Verkapselung auch unter ausschließlicher Verwendung von Kationpolymeren erfolgen, wobei man sich deren Eigenschaft zu Nutze macht, bei pH- Werten oberhalb des pKs- Wertes zu koagulieren.Alternatively, the encapsulation can also be carried out using cationic polymers exclusively, taking advantage of their property of coagulating at pH values above the pKa value.
In einem zweiten alternativen Verfahren wird zur Herstellung der erfindungsgemäßen Mikrokapseln wird zunächst eine O/W-Emulsion zubereitet, welche neben dem Ölkörper, Wasser und den Wirkstoffen eine wirksame Menge Emulgator enthält. Zur Herstellung der Matrix wird diese Zubereitung unter starkem Rühren mit einer entsprechenden Menge einer wässrigen Anionpolymerlösung versetzt. Die Membranbildung erfolgt durch Zugabe der Chitosanlösung. Der gesamte Vorgang findet vorzugsweise im schwach sauren Bereich bei pH = 3 bis 4 statt. Falls erforderlich erfolgt die pH-Einstellung durch Zugabe von Mineralsäure. Nach der Membranbildung wird der pH- Wert auf 5 bis 6 angehoben, beispielsweise durch Zugabe von Triethanolamin oder einer anderen Base. Hierbei kommt es zu einem Anstieg der Viskosität, die durch Zugabe von weiteren Verdickungs- mitteln, wie z.B. Polysacchariden, insbesondere Xanthan-Gum, Guar-Guar, Agar-Agar, Alginaten und Tylosen, Carboxymethylcellulose und Hydroxyethylcellulose, höhermolekularen Polyethylenglycolmono- und -diestern von Fettsäuren, Polyacrylaten, Polyacrylamiden und dergleichen noch unterstützt werden kann. Abschließend werden die Mikrokapseln von der wässrigen Phase beispielsweise durch Dekantieren, Filtrieren oderIn a second alternative method, an O / W emulsion is initially prepared for producing the microcapsules according to the invention, which contains an effective amount of emulsifier in addition to the oil body, water and the active ingredients. To prepare the matrix, this preparation is mixed with vigorous stirring with an appropriate amount of an aqueous anionic polymer solution. The membrane formation takes place by adding the chitosan solution. The entire process preferably takes place in the weakly acidic range at pH = 3 to 4. If necessary, the pH is adjusted by adding mineral acid. After membrane formation, the pH is raised to 5 to 6, for example by addition of triethanolamine or another base. This leads to an increase in the viscosity, which can be increased by adding further thickening agents, such as e.g. Polysaccharides, especially xanthan gum, guar guar, agar, alginates and Tyloses, carboxymethyl cellulose and hydroxyethyl cellulose, high molecular weight polyethylene glycol mono- and diesters of fatty acids, polyacrylates, polyacrylamides and the like can still be supported. Finally, the microcapsules of the aqueous phase, for example by decantation, filtration or
Zentrifugieren abgetrennt.Centrifuged separated.
In einem dritten alternativen Verfahren erfolgt die Bildung der Mikrokapseln um einen vorzugsweise festen, beispielsweise kristallinen Kern, indem dieser schichtweise mit ent- gegengesetzt geladenen Polyelektrolyten eingehüllt wird. In diesem Zusammenhang sei auf das Europäische Patent EP 1064088 Bl (Max-Planck Gesellschaft) verwiesen.
Gewerbliche AnwendbarkeitIn a third alternative method, the formation of the microcapsules takes place around a preferably solid, for example, crystalline core, by coating it in layers with oppositely charged polyelectrolytes. In this connection, reference is made to the European patent EP 1064088 Bl (Max Planck Society). Industrial Applicability
Die erfindungsgemäßen Zubereitungen zeigen bei oraler Aufnahme eine verbesserte Ausscheidung von unerwünschtem Cholesterin aus dem Blut Ein weiterer Gegenstand der Erfin- düng betrifft daher die Verwendung von Mischungen, enthaltendThe preparations according to the invention exhibit an improved excretion of undesired cholesterol from the blood when taken orally. A further subject of the invention therefore relates to the use of mixtures containing
(a) Sterole und Sterolester und(a) sterols and sterol esters and
(b) Hoodia-Extrakte bzw. die daraus erhältlichen Steroidglycoside, insbesondere Substanz P57 sowie die zugehörigen Homologen, Analogen und Isomeren.(b) Hoodia extracts or the steroid glycosides obtainable therefrom, in particular substance P57 and the associated homologues, analogs and isomers.
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 erfϊndungsgemäßen Zubereitungen in Mengen von 0,01 bis 10, vorzugsweise 0,1 bis 5 und insbesondere 1 bis 2 Gew.-% enthalten sein können.
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 quantities of 0.01 to 10, preferably 0.1 to 5 and in particular 1 to 2 wt .-% may be included.
BeispieleExamples
Beispiel 1example 1
In einem 500-ml-Dreihalskolben mit Rührer und Rückflusskühler wurden in der Siedehitze 3 g Agar-Agar in 200 ml Wasser gelöst. Anschließend wurde die Mischung innerhalb von etwa 30 min unter starkem Rühren zunächst mit einer Lösung von 10 g Glycerin 90 ml Wasser und dann mit einer Zubereitung von 2,5 g Natriumalginat in Form einer 10 Gew.-%igen wässrigen Lösung, 1 g ß-Sitosterol, 1 g getrockneter Hoodia gordonii Extrakt, 0,5 g Phenonip® und 0,5 g Polysorbat-20 (Tween® 20, ICI) in 64 g Wasser versetzt. Die erhaltene Matrix wurde filtriert, auf 60 °C erwärmt und in eine 1 Gew.-%ige Lösung von Chitosanglycolat in Wasser getropft. Zum Erhalt von Mikrokapseln gleichen Durchmessers wurden die Zubereitungen anschließend gesiebt.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 glycerol 90 ml water and then with a preparation of 2.5 g sodium alginate in the form of a 10 wt .-% aqueous solution, 1 g ß- Sitosterol, 1 g of dried Hoodia gordonii extract, 0.5 g of Phenonip® and 0.5 g of polysorbate-20 (Tween® 20, ICI) in 64 g of 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.
Beispiel 2Example 2
In einem 500-ml-Dreihalskolben mit Rührer und Rückflusskühler wurden in der Siedehitze 3 g Agar-Agar in 200 ml Wasser gelöst. Anschließend wurde die Mischung innerhalb von etwaIn 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. Subsequently, the mixture was within about
30 min unter starkem Rühren zunächst mit einer Lösung von 10 g Glycerin 90 ml Wasser und dann mit einer Zubereitung von 2,5 g Natriumalginat in Form einer 10 Gew.-%igen wässrigen30 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
Lösung, 1 g ß-Sitosterolstearat, 1 g getrockneter Hoodia gordonii Extrakt, 0,5 g Trifolium pratense Extrakt, 0,5 g Phenonip® und 0,5 g Polysorbat-20 (Tween® 20, ICI) in 64 g Wasser versetzt. Die erhaltene Matrix wurde filtriert, auf 60 0C erwärmt und in eine 1 Gew.-%igeSolution, 1 g of β-sitosterol stearate, 1 g of dried Hoodia gordonii extract, 0.5 g of Trifolium pratense extract, 0.5 g of Phenonip® and 0.5 g of polysorbate-20 (Tween® 20, ICI) in 64 g of water. The resulting matrix was filtered, heated to 60 ° C. and into a 1% by weight
Lösung von Chitosanglycolat in Wasser getropft. Zum Erhalt von Mikrokapseln gleichenSolution of chitosanglycolate dripped in water. To obtain microcapsules same
Durchmessers wurden die Zubereitungen anschließend gesiebt.Diameter, the preparations were then sieved.
Beispiel 3Example 3
In einem 500-ml-Dreihalskolben mit Rührer und Rückflusskühler wurden in der Siedehitze 3 g Agar-Agar in 200 ml Wasser gelöst. Anschließend wurde die Mischung innerhalb von etwa 30 min unter starkem Rühren zunächst mit einer Lösung von 10 g Glycerin 90 ml Wasser und dann mit einer Zubereitung von 2,5 g Natriumalginat in Form einer 10 Gew.-%igen wässrigen Lösung, 1 g eines Esters aus ß-Sitosterol und CLA, 1 g getrockneter Hoodia gordonii Extrakt, 0,5 g Ginkgo biloba Extrakt, 0,5 g Phenonip® und 0,5 g Polysorbat-20 (Tween® 20, ICI) in 64 g Wasser versetzt. Die erhaltene Matrix wurde filtriert, auf 60 0C erwärmt und in eine 1
Gew.-%ige Lösung von Chitosanglycolat in Wasser getropft. Zum Erhalt von Mikrokapseln gleichen Durchmessers wurden die Zubereitungen anschließend gesiebt.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. Subsequently, the mixture was 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 an ester from β-sitosterol and CLA, 1 g of dried Hoodia gordonii extract, 0.5 g of Ginkgo biloba extract, 0.5 g of Phenonip® and 0.5 g of polysorbate-20 (Tween® 20, ICI) in 64 g of water. The resulting matrix was filtered, warmed to 60 ° C. and placed in a 1 % By weight solution of chitosan glycolate in water. To obtain microcapsules of the same diameter, the preparations were then sieved.
Beispiel 4Example 4
In einem 500-ml-Dreihalskolben mit Rührer und Rückflusskühler wurden in der Siedehitze 3 g Agar-Agar in 200 ml Wasser gelöst. Anschließend wurde die Mischung innerhalb von etwa 30 min unter starkem Rühren zunächst mit einer Lösung von 10 g Glycerin 90 ml Wasser und dann mit einer Zubereitung von 2,5 g Natriumalginat in Form einer 10 Gew.-%igen wässrigen Lösung, 1 g ß-Sitosterolpalmitat, 1 g getrockneter Hoodia gordonii Extrakt, 0,5 g getrockneter Vitis vinifera Extrakt, 0,5 g Phenonip® und 0,5 g Polysorbat-20 (Tween® 20, ICI) in 64 g Wasser versetzt. Die erhaltene Matrix wurde filtriert, auf 60 °C erwärmt und in eine 1 Gew.- %ige Lösung von Chitosanglycolat in Wasser getropft. Zum Erhalt von Mikrokapseln glei- chen Durchmessers wurden die Zubereitungen anschließend gesiebt.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 glycerol 90 ml water and then with a preparation of 2.5 g sodium alginate in the form of a 10 wt .-% aqueous solution, 1 g ß- Sitosterol palmitate, 1 g dried Hoodia gordonii extract, 0.5 g dried Vitis vinifera extract, 0.5 g Phenonip® and 0.5 g polysorbate-20 (Tween® 20, ICI) in 64 g of 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.
Beispiel 4Example 4
In einem 500-ml-Dreihalskolben mit Rührer und Rückflusskühler wurden in der Siedehitze 3 g Agar-Agar in 200 ml Wasser gelöst. Anschließend wurde die Mischung innerhalb von etwa 30 min unter starkem Rühren zunächst mit einer Lösung von 10 g Glycerin 90 ml Wasser und dann mit einer Zubereitung von 2,5 g Natriumalginat in Form einer 10 Gew.-%igen wässrigen Lösung, 1 g ß-Sitosterolpalmitat, 1 g getrockneter Hoodia gordonii Extrakt, 0,5 g getrockneter Camellia sinensis Extrakt, 0,5 g Phenonip® und 0,5 g Polysorbat-20 (Tween® 20, ICI) in 64 g Wasser versetzt. Die erhaltene Matrix wurde filtriert, auf 60 0C erwärmt und in eine 1 Gew.- %ige Lösung von Chitosanglycolat in Wasser getropft. Zum Erhalt von Mikrokapseln gleichen Durchmessers wurden die Zubereitungen anschließend gesiebt.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 glycerol 90 ml water and then with a preparation of 2.5 g sodium alginate in the form of a 10 wt .-% aqueous solution, 1 g ß- Sitosterol palmitate, 1 g of dried Hoodia gordonii extract, 0.5 g of dried Camellia sinensis extract, 0.5 g of Phenonip® and 0.5 g of polysorbate-20 (Tween® 20, ICI) in 64 g of water. The matrix obtained was filtered, heated to 60 0 C and poured into a 1% by weight solution of chitosan glycolate dropped into water. To obtain microcapsules of the same diameter, the preparations were then sieved.
Beispiele 5 bis 9, Vergleichsbeispiele Vl bis V3Examples 5 to 9, Comparative Examples VI to V3
Es wurden Gelatinekapseln (Gewicht ca. 1,5 g) mit einem Gehalt an ß-Sitosterol bzw. ß- Sitosterolester sowie Hoodia- und gegebenenfalls weiteren Pflanzenextrakten sowie 0,5 Gew.- % radioaktiv markiertem Cholesterin hergestellt. Zur Untersuchung der hypocholesterinämi- schen Wirkung ließ man männliche Ratten (Einzelgewicht ca. 200 g) über Nacht fasten. Am folgenden Tag wurde den Versuchstieren jeweils eine zerkleinerte Gelatinekapsel mit etwas kochsalzhaltigem Wasser über eine Magensonde eingeführt. Nach 3, 6, 12, 24 und 48 h wurde den Tieren Blut abgenommen und der Gehalt an radioaktivem Cholesterin bestimmt. Die Er-
gebnisse, die den Mittelwert der Messungen von 10 Versuchstieren darstellen, sind in Tabelle 1 zusammengefasst. Die Angaben zur Abnahme der Radioaktivität verstehen sich jeweils in Bezug auf eine Blindgruppe von Versuchstieren, denen lediglich Gelatinekapseln mit einem Gehalt von 20 Gew.-% Vitamin E und einer entsprechenden Menge radioaktiv markiertem Cholesterin verabreicht worden war. Die Mischungen 5 bis 9 sind erfindungsgemäß, die Mischungen Vl bis V3 dienen dem Vergleich.Gelatine capsules (weight about 1.5 g) containing β-sitosterol or β-sitosterol esters and Hoodia and optionally other plant extracts and 0.5% by weight of radiolabeled cholesterol were prepared. 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. Which he- results, which represent 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 Vl to V3 are for comparison.
Tabelle 1 Hypocholesterinämische Wirkung (Mengenangaben als Gew.-% bezogen auf Gelatinekapsel)Table 1 Hypocholesterolemic action (amounts as% by weight based on gelatin capsule)
Diskussion der Ergebnisse:Discussion of the results:
• Ηoodia-Extrakt alleine besitzt keine hypocholesterinämische Wirkung (Beispiel Vl)• Ηoodia extract alone has no hypocholesterolemic effect (Example VI)
• Mischungen aus 90 Gew.-% Sterolen bzw. Sterolestern und 10 Gew.-% Ηoodia-Extrakt zeigen anfangs die gleiche hypocholesterinänmische Leistung wie die reinen Sterole bzw. Sterolester, nach 12 h beschleunigt sich jedoch die Ausscheidung von Cholesterin.• Mixtures of 90 wt .-% sterols or sterol esters and 10 wt .-% Ηoodia extract initially show the same hypocholesterolänmische performance as the pure sterols or sterol esters, but after 12 hours, the excretion of cholesterol accelerates.
• Dieser Effekt wird tendenziell durch Ersatz von bis zu 20 Gew.-% des Ηoodia-Anteils gegen andere Pflanzenextrakte wie z.B. Gingko oder Rotklee verbessert.
This effect is tended to be reversed by replacing up to 20% by weight of the Ηoodia portion with other plant extracts, e.g. Gingko or red clover improved.
Claims
1. Zubereitungen zur oralen Aufnahme, enthaltend1. Preparations for oral administration, containing
(a) Sterole bzw. Sterolester und(a) sterols or sterol esters and
(b) Hoodia-Extrakte bzw. die daraus erhältlichen Steroidglycoside, insbesondere Sub- stanz P57 sowie die zugehörigen Homologen, Analogen und Isomeren.(b) Hoodia extracts or the steroid glycosides obtainable therefrom, in particular substance P57, and the associated homologues, analogs and isomers.
2. Zubereitungen nach Anspruch 1, dadurch gekennzeichnet, dass sie als Komponente (a) Sitosterol oder Sitostanol enthalten.2. Preparations according to claim 1, characterized in that they contain as component (a) sitosterol or sitostanol.
3. Zubereitungen nach Anspruch 2, dadurch gekennzeichnet, dass sie als Komponente (a) Sitosterolester oder Sitostanolester enthalten.3. Preparations according to claim 2, characterized in that they contain as component (a) sitosterol esters or sitostanol esters.
4. Zubereitungen nach mindestens einem der Ansprüche 1 bis 3, dadurch gekennzeichnet, dass sie als Komponente (a) Ester von Sitosterol oder Sitostanol mit konjugierter Linolsäure enthalten.4. Preparations according to at least one of claims 1 to 3, characterized in that they contain as component (a) esters of sitosterol or sitostanol with conjugated linoleic acid.
5. Zubereitungen nach mindestens einem der Ansprüche 1 bis 4, dadurch gekennzeichnet, dass sie als Komponente (b) Substanz P57 sowie die zugehörigen Homologen, Analogen und Isomeren enthalten.5. Preparations according to at least one of claims 1 to 4, characterized in that they contain as component (b) substance P57 and the associated homologues, analogs and isomers.
6. Zubereitungen nach mindestens einem der Ansprüche 1 bis 5, dadurch gekennzeichnet, dass sie als optionale Komponente (c) Extrakte von weiteren Pflanzen enthalten, die ausgewählt sind aus der Gruppe, die gebildet wird von Ginkgo biloba, Camellia si- ntnsis, Oleacea europensis, Glyzyrrhiza glabra, Vaccinium myrtillus, Trifolium praten- se, Litchi sinensis, Vitis vinifera, Brassica oleracea, Punica granatum, Petroselinium crispum, Centella asiatica, Passiflora incarnata, Medicago sativa, Valeriana officinalis, Castanea sativa, Salix alba sowie Hapagophytum procumbens sowie deren Gemischen.6. Preparations according to at least one of claims 1 to 5, characterized in that they contain as optional component (c) extracts of other plants which 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 and Hapagophytum procumbens and their mixtures ,
7. Zubereitungen nach mindestens einem der Ansprüche 1 bis 6, dadurch gekennzeich- net, dass sie die Komponenten (a) und (b) im Gewichtsverhältnis 99:1 bis 80:20 enthalten. 7. Preparations according to at least one of claims 1 to 6, characterized marked, that they contain the components (a) and (b) in a weight ratio of 99: 1 to 80:20.
8. Zubereitungen nach mindestens einem der Ansprüche 1 bis 7, dadurch gekennzeichnet, dass sie in verkapselter Form vorliegen.8. Preparations according to at least one of claims 1 to 7, characterized in that they are present in encapsulated form.
9. Verwendung von Mischungen, enthaltend9. Use of mixtures containing
(a) Sterole bzw. Sterolester und(a) sterols or sterol esters and
(b) Hoodia-Extrakte bzw. die daraus erhältlichen Steroidglycoside(b) Hoodia extracts or the steroid glycosides obtainable therefrom
zur Herstellung von Nahrungsmitteln und Nahrungsmittelzusatzstoffen.for the production of food and food additives.
10. Verwendung von Mischungen, enthaltend10. Use of mixtures containing
(a) Sterole bzw. Sterolester und(a) sterols or sterol esters and
(b) Hoodia-Extrakte bzw. die daraus erhältlichen Steroidglycoside(b) Hoodia extracts or the steroid glycosides obtainable therefrom
zur Herstellung eines hypocholesterinämischen Medikamentes. for the preparation of a hypocholesterolemic drug.
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WO2005099737A1 (en) * | 2004-04-07 | 2005-10-27 | Rutgers, The State University Of New Jersey | Appetite-suppressing compositions and methods |
US20050276869A1 (en) * | 2004-06-14 | 2005-12-15 | Century Systems | Appetite-suppressing, lipase-inhibiting herbal composition |
WO2006051334A1 (en) * | 2004-11-15 | 2006-05-18 | Phyto Research Ltd | Plant cells and uses thereof |
WO2006079056A1 (en) * | 2005-01-20 | 2006-07-27 | Stephen Holt | Herbal compositions containing hoodia |
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WO2005099737A1 (en) * | 2004-04-07 | 2005-10-27 | Rutgers, The State University Of New Jersey | Appetite-suppressing compositions and methods |
US20050276869A1 (en) * | 2004-06-14 | 2005-12-15 | Century Systems | Appetite-suppressing, lipase-inhibiting herbal composition |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009045837A1 (en) * | 2007-09-28 | 2009-04-09 | Zomanex, Llc | Methods and formulations for converting intravenous and injectable drugs into oral dosage forms |
AU2008309010B2 (en) * | 2007-09-28 | 2012-07-19 | Zomanex, Llc | Methods and formulations for converting intravenous and injectable drugs into oral dosage forms |
Also Published As
Publication number | Publication date |
---|---|
DE102006048530A1 (en) | 2008-04-17 |
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