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    • 专利摘要:
    The present invention describes a method for preparing a solid formulation of at least one water soluble, poorly water soluble or water insoluble active compound suitable for the food and animal feed sector or for pharmaceutical and cosmetic uses. The present invention also relates to an oily suspension in which the formulation is present as a dispersed phase and the use of the formulation as an additive in animal feed, food, pharmaceutical and cosmetic preparations.
    公开号:KR20020042467A
    申请号:KR1020010074554
    申请日:2001-11-28
    公开日:2002-06-05
    发明作者:헬무트 오우베터；헤리베르트 본；에릭 뤼데케；빌리 힌츠；프란크 룬제；안젤리카-마리아 파이퍼
    申请人:스타르크, 카르크；바스프 악티엔게젤샤프트；
    IPC主号:
    专利说明:

    Process for the Preparation of Solid Formulations of Water-Soluble, Poorly-Soluble or Water-Insoluble Active Compounds {Production of Solid Preparations of Water-Soluble, Sparingly Water-Soluble or Water-Insoluble Active Compounds}
    [1] The present invention relates to a process for the preparation of a solid formulation of at least one water soluble, poorly water soluble or water insoluble active compound suitable for the food and animal feed sector or for pharmaceutical and cosmetic uses. The present invention also relates to oily suspensions containing these preparations and their use as additives in animal feed, food, pharmaceutical and cosmetic preparations.
    [2] Numerous active compounds suitable for the food and animal feed sector or for pharmaceutical and cosmetic applications, such as fat-soluble vitamins, carotenoids, as well as natural pigments, curcumin and carmine, are in the form of specially stabilized preparations due to their water insolubility and susceptibility to oxidation. Can be used. Among other things, direct use of such crystalline materials for coloring aqueous foods or as active compounds in feed additives or in cosmetic preparations is generally not possible. High requirements regarding bioavailability, colorability, and especially dispersibility in aqueous media as well as lipophilic media can only be met by special formulations.
    [3] When coloring foods directly, satisfactory color results can only be achieved by preparations in which the active compound, for example carotenoids, is present in finely divided form and suitably protected from oxidation by protective colloids. These formulations used in animal feeds increase the bioavailability of the active compounds and thus indirectly improve the coloring effect, for example in egg yolk coloring or fish coloring.
    [4] A large variety of formulation methods are already known in the literature, aimed at reducing the crystal size of the active compounds to a particle size range of less than 10 μm.
    [5] In particular, many of the methods described in Chima 21, 329 (1967), WO 91/06292 and WO 94/19411 use colloid mills to polish carotenoids. To achieve a particle size of 2 to 10 μm.
    [6] There is also a mixed emulsification / spray drying process as described, for example, in German Patent Publication No. 12 11 911 or European Patent Publication No. 0 410 236.
    [7] According to EP 0 065 193, the finely divided powdered carotenoid formulations can be used, for example, to prepare β-carotene in a volatile water miscible organic solvent at a temperature of 50 to 200 ° C., possibly at elevated pressure for a period of less than 10 seconds. It is prepared by dissolving. β-carotene is precipitated into the resulting molecular dispersion by immediate rapid mixing with an aqueous solution of protective colloid at 0-50 ° C. This produces a orange-yellow colloidal dispersible β-carotene hydrosol. This dispersion is subsequently spray dried to form a free flowing dry powder which is dissolved in water to form a clear tangerine dispersion.
    [8] A method analogous to the preparation of finely divided powdered carotenoid formulations is described in European Patent Publication No. 0 937 412 using water immiscible solvents.
    [9] WO 98/26008 relates to the use of mixtures of low molecular weight and high molecular weight protective colloids to prepare redispersible xanthophyll containing dry powders.
    [10] Carotenoids are increasingly used as feed additives in animal nutrition in the form of liquid formulations. This is particularly advantageous in that weighing can be simpler and more accurate. It is also possible in post-pelleting applications not to feed feed pellets with liquid formulations of feed additives until after their preparation. This means that even oxidation- and heat-sensitive additives such as carotenoids can be used without relatively large losses.
    [11] Examples of post-pellet use (PPA) can be found in particular in British Patent Publication No. 2 232 573 and European Patent Publication No. 0 556 883 and the literature cited therein.
    [12] WO 96/23420 describes an oily suspension of crystalline astaxanthin with a particle size of less than 2 μm. Suspensions of this type are prepared in particular by grinding astaxanthin crystals in oil. The publication also includes the use of a suspension for filling the extruded feed after extrusion. However, the stability of such suspensions and the bioavailability of astaxanthin present therein are not always sufficient for many applications.
    [13] Carotenoid emulsions as a special form of liquid formulations often have the disadvantage of being unstable due to physical (occurring phase separation) and chemical (occurring unwanted hydrolysis and / or redox reactions, chemical incompatibility of the individual dissolved components), In addition, the risk of microbial contamination can often occur.
    [14] In another process described in WO 94/19411, crystalline β-carotene is polished, for example in the presence of an aqueous protective colloidal solution, and then heated to a melting point for a short time to convert to amorphous deformation.
    [15] This formulation and the described aqueous carotenoid dispersions and O / W emulsions comprising the active compound in the presence of a stabilizing protective colloid are also incompatible as they are incompatible with the oil.
    [16] European Patent Publication No. 0 845 503 discloses an oil miscible carotenoid with a dual dispersion system wherein particles stabilized with protective colloids of one or more carotenoids are dispersed in oil as dispersion medium in an aqueous dispersion phase with a particle diameter of less than 100 μm. Liquid formulations are described.
    [17] It is an object of the present invention to propose a process for the preparation of solid preparations of water-soluble, poorly water-soluble or water-insoluble active compounds. It is also intended to make formulations with high concentrations of active compounds available.
    [18] It is also an object of the present invention to provide an oil miscible carotenoid liquid formulation suitable for application to feed pellets, especially in the animal nutrition sector.
    [19] The inventors have found that the above object according to the present invention,
    [20] (a) dissolving or dispersing at least one water-soluble, poorly water-soluble or water-insoluble active compound suitable for the food and animal feed sector or for pharmaceutical and cosmetic uses in an aqueous molecular or colloidal dispersion of proteinaceous protective colloid,
    [21] (b) aggregate the proteinaceous protective colloid together with the active compound from the dispersion,
    [22] (c) separating the flocculated solids from water and any solvents used additionally and subsequently converting them to dry powders, thereby at least one water soluble, watery egg suitable for the food and animal feed sector or for pharmaceutical and cosmetic applications. It has been found that this is accomplished by the process of preparing solid preparations of soluble or water insoluble active compounds.
    [23] Suitable active compounds for the purposes of the present invention in the food and animal nutrition sector or for pharmaceutical and cosmetic applications include, for example, the following compounds.
    [24] Fat-soluble vitamins such as K vitamins, vitamin A and derivatives thereof (eg vitamin A acetate, vitamin A propionate or vitamin A palmitate), vitamin D 2 and vitamin D 3 , and also vitamin E and derivatives thereof . Vitamin E in this context is natural or synthetic α-, β-, γ- or δ-tocopherol, preferably natural or synthetic α-tocopherol and also tocotrienols. Vitamin E derivatives are, for example, tocopheryl-C 1 -C 20 -carboxylic acid esters such as tocopheryl acetate or tocopheryl palmitate;
    [25] Water-soluble vitamins such as ascorbic acid and salts thereof (eg sodium ascorbate) and vitamin C derivatives (eg sodium, calcium or magnesium ascorbyl-2-monophosphate, or calcium ascorbyl-2-polyphosphate) ), Calcium pantothenate, panthenol, vitamin B 1 (thiamine) (as hydrochloride, nitrate or pyrophosphate), vitamin B 2 (riboflavin) and its phosphates, vitamin B 6 and its salts, vitamin B 12 , biotin, folic acid and folic acid derivatives (Eg, tetrahydrofolic acid, 5-methyltetrahydrofolic acid, 5-formyltetrahydrofolic acid), nicotinic acid and nicotinamide;
    [26] Polyunsaturated fatty acids, for example linoleic acid, linolenic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid;
    [27] Natural food pigments such as carotenoids, curcumin, carmine or chlorophyll;
    [28] Water-insoluble or poorly water-soluble organic UV filter substances, for example compounds selected from the group consisting of triazines, anilides, benzophenones, triazoles, cinnamids and sulfonated benzimidazoles.
    [29] Active compounds as light screens in cosmetic applications are especially 1,3,5-triazine derivatives of the general formula (1).
    [30]
    [31] Wherein the substituents have the following meanings independently of one another.
    [32] R is hydrogen, halogen, OH, C 1 -C 20 -alkyl, C 1 -C 20 -alkoxy, C 1 -C 20 -alkoxyalkyl, C 1 -C 20 -hydroxyalkoxy, NR 1 R 2 , or A radical of formula 1a;
    [33]
    [34] Wherein R, R 1 and R 2 are hydrogen, C 1 -C 20 - alkyl, one or more C 1 -C 4 - alkyl which may be substituted with C 6 -C 12 - aryl, one or more C 1 -C 4 - alkyl, C 7 -C 10 -aralkyl which may be substituted by, heteroaryl which may be substituted by one or more C 1 -C 4 -alkyl, or C 5 -C 8 -cycloalkyl;
    [35] R 3 to R 5 are hydrogen, OH, NR 9 R 10 , C 1 -C 20 -alkoxy, C 6 -C 12 -aryl which may be substituted by one or more C 1 -C 4 -alkyl, one or more C 1- C 7 -C 10 -aralkyl which may be substituted by C 4 -alkyl, heteroaryl which may be substituted by one or more C 1 -C 4 -alkyl, or C 5 -C 8 -cycloalkyl;
    [36] R 6 to R 8 are hydrogen, C 1 -C 20 -alkoxy, —C (═O) —R 11 , —C (═O) —XR 12 , SO 2 R 13 or CN;
    [37] R 9 to R 11 is hydrogen, C 1 -C 20 - alkyl, one or more C 1 -C 4 - alkyl which may be substituted with C 6 -C 12 - aryl, one or more C 1 -C 4 - alkyl, optionally substituted with C 7 -C 10 -aralkyl which may be substituted, heteroaryl which may be substituted by one or more C 1 -C 4 -alkyl, or C 5 -C 8 -cycloalkyl;
    [38] R 12 is hydrogen, C 1 -C 20 - alkyl, one or more C 1 -C 4 - alkyl which may be substituted with C 6 -C 12 - aryl, one or more C 1 -C 4 - alkyl which may be substituted with C 7 -C 10 -aralkyl, heteroaryl which may be substituted with one or more C 1 -C 4 -alkyl, C 5 -C 8 -cycloalkyl, or a radical of the formula Sp-Sil;
    [39] R 13 is C 1 -C 20 - alkyl, C 5 -C 8 - cycloalkyl, one or more C 1 -C 4 - alkyl which may be substituted with C 6 -C 12 - aryl, one or more C 1 -C 4 - C 7 -C 10 -aralkyl which may be substituted by alkyl, or heteroaryl which may be substituted by one or more C 1 -C 4 -alkyl;
    [40] X is O or NR 14 ;
    [41] R 14 is hydrogen, C 1 -C 20 - alkyl, one or more C 1 -C 4 - alkyl which may be substituted with C 6 -C 12 - aryl, one or more C 1 -C 4 - alkyl which may be substituted with C 7 -C 10 -aralkyl, heteroaryl, which may be substituted with one or more C 1 -C 4 -alkyl, or C 5 -C 8 -cycloalkyl;
    [42] Sp is a spacer;
    [43] Sil is a radical in the group consisting of silanes, oligosiloxanes and polysiloxanes.
    [44] The alkyl radicals for R, R 1 and R 2 , and R 9 to R 14 are branched or unbranched C 1 -C 20 -alkyl chains, preferably methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethyl Propyl, n-hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2 -Dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl , 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, n-heptyl, n-octyl, 2-ethylhexyl, 1,1,3-trimethylhexyl, 1,1,3,3-tetramethylpentyl, n-nonyl, n-decyl, n-undecyl, 1-methylundecyl, n-dodecyl, 1,1,3,3,5,5-hexamethyl Hexyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexa A chamber, n- heptadecyl, n- octadecyl, n- n- nonadecyl or eicosyl.
    [45] Halogen for R is fluorine, bromine, iodine or preferably chlorine.
    [46] Considered alkoxy radicals for R and R 3 to R 8 are straight and branched radicals having 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, particularly preferably 1 to 8 carbon atoms.
    [47] Examples are methoxy, ethoxy, isopropoxy, n-propoxy, 1-methylpropoxy, n-butoxy, n-pentoxy, 2-methylpropoxy, 3-methylbutoxy, 1,1- Dimethylpropoxy, 2,2-dimethylpropoxy, hexoxy, 1-methyl-1-ethylpropoxy, heptoxy, octoxy, 2-ethylhexoxy.
    [48] The hydroxyalkoxy radicals contemplated for R are the aforementioned alkoxy radicals with additional terminal hydroxyl functionalities.
    [49] The cycloalkyl radicals for R 1 to R 5 and R 9 to R 14 are preferably branched or unbranched C 3 -C 10 -cycloalkyl radicals, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , Cycloheptyl, 1-methylcyclopropyl, 1-ethylcyclopropyl, 1-propylcyclopropyl, 1-butylcyclopropyl, 1-pentylcyclopropyl, 1-methyl-1-butylcyclopropyl, 1,2-dimethylcyclo Propyl, 1-methyl-2-ethylcyclopropyl, cyclooctyl, cyclononyl or cyclodecyl. Preference is given to C 5 -C 8 -cycloalkyl, for example cyclopentyl, cycloheptyl, cyclooctyl and especially cyclohexyl.
    [50] The cycloalkyl radical is one or more, for example 1 to 3 halogens (eg fluorine, chlorine or bromine), cyano, nitro, amino, C 1 -C 4 -alkylamino, C 1 -C 4 -dialkyl May be unsubstituted or substituted with radicals or other radicals such as amino, hydroxyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, or in the ring 1 to 3 heteroatoms, for example, It may contain sulfur, nitrogen (its free valences may be saturated with hydrogen or C 1 -C 4 -alkyl) or oxygen.
    [51] Examples of C 6 -C 12 -aryl are especially phenyl, naphthyl and biphenyl.
    [52] Examples of C 7 -C 10 -aralkyl are benzyl, phenylethyl, α-methylphenylethyl and α, α-dimethylbenzyl.
    [53] Heteroaryl radicals are advantageously single or condensed aromatic ring systems having at least one heteroaromatic 3- to 7-membered ring. Heteroatoms that may be present in the ring or ring system are one or more nitrogen, sulfur and / or oxygen atoms.
    [54] Substituents of the aforementioned aryl, aralkyl and heteroaryl radicals contemplated are C 1 -C 4 -alkyl groups such as methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl and 1,1-dimethylethyl.
    [55] The term spacer for Sp in this context means a divalent branched or unbranched C 3 -C 12 -alkylene or C 3 -C 12 -alkenylene chain linking a silane, oligosiloxane or polysiloxane moiety to a triazine radical. do.
    [56] Examples of C 3 -C 12 -alkylene chains are propylene, 2-methylpropylene, butylene, pentylene and hexylene.
    [57] Examples of C 3 -C 12 -alkenylene chains are 2-propen-2-ylene, 2-methyl-3-propenylene, 3-butene-3-ylene and 4-penten-4-ylene.
    [58] Preferred spacers are-(CH 2 ) 3 -,-(CH 2 ) 4 -,-(CH 2 ) 5 -,-[CH (CH 3 )]-(CH 2 )-,-(CH 2 ) 2 -CH = CH-, -C (= CH 2 ) -CH 2- , -C (= CH 2 )-(CH 2 ) 2 -O- (CH 2 ) 4 -and-(CH 2 ) 4 -O- (CH 2 ) 2 .
    [59] The term silane in this context is the radical SiR 15 R 16 R 17 , wherein R 15 , R 16 and R 17 are independently of each other C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy or phenyl.
    [60] Examples include Si (CH 2 -CH 3 ) 3 , Si (CH 2 -CH 2 -CH 3 ) 3 , Si (isopropyl) 3 , Si (tert-butyl) 3 , Si (tert-butyl) ( CH 3 ) 2 , Si (CH 3 ) 2 (hexyl), Si (OCH 3 ) 3 , Si (OEt) 3 and SiPh 3 .
    [61] The term oligosiloxane is of the formula SiR 18 m (OSiR 18 3 ) n {where m = 0, 1 or 2; n = 3, 2 or 1, m + n = 3}, R 18- [Si (R 18 ) 2 -O-] r -Si (R 18 ) 2 -A and R 18- [Si (R 18) ) 2 -O-] r -Si (A) (R 18 ) -O-Si (R 18 ) 3 {where A is a chemical bond or spacer, and R 18 is a C 1 -C 6 -alkyl radical or a phenyl radical R is a value from 1 to 9}.
    [62] The term polysiloxane is for example formula A- [Si (R 19 ) 2 -O] s -Si (R 19 ) 2 -A or (R 19 ) 3 -Si- [O-Si (R 19 ) 2 ]] t- [O-Si (R 19 )-(A)] q -O-Si (R 19 ) 3 {where A is a chemical bond or spacer, and R 19 is a C 1 -C 6 -alkyl radical or a phenyl radical And s and t are values of 4 to 250, and q is a value of 1 to 30.
    [63] Examples of silanyltriazines in which R 12 is a radical of the formula Sp-Sil can be found in EP 0 933 376.
    [64] Most prominent are the triazine compounds of formula 1b.
    [65]
    [66] Wherein R 3 to R 5 are in the ortho position relative to the phenylamino radical of the triazine.
    [67] Preferred for use as light-shielding agents are dry powders comprising at least one 1,3,5-triazine derivative of formula 1b in which the substituents independently of one another have the following meanings:
    [68] R 3 to R 5 are hydrogen or OH;
    [69] R 6 to R 8 are C 1 -C 12 -alkoxy or —C (═O) —XR 12 ;
    [70] X is O or NR 14 ;
    [71] R 12 and R 14 are hydrogen or C 4 -C 8 -alkyl.
    [72] A particularly advantageous UVB filter is 2,4,6-trianilino-p- (carbo-2'-ethylhexyl-1'-oxy) -1,3,5-triazine, which is a trade name Uvinul®. T150, available from BASF Aktiengesellschaft.
    [73]
    [74] Uvinul® T150 is characterized by good UV absorption with an extremely high extinction coefficient of> 1500 at 314 nm.
    [75] In addition, poorly water-soluble or water-insoluble organic UV filter materials in the triazine group include the following compounds described in WO 94/05645 and EP 0 444 323.
    [76]
    [77]
    [78]
    [79]
    [80]
    [81]
    [82]
    [83]
    [84]
    [85] Preferred anilide is a compound of formula (2) wherein W 1 and W 2 are independently of each other C 1 -C 18 -alkyl or C 1 -C 18 -alkoxy.
    [86]
    [87] Particular preference is given to N- (2-ethoxyphenyl) -N '-(2-ethylphenyl) ethanediamide.
    [88] Preferred triazoles are compounds of formula (3) wherein, independently of one another, T 1 is C 1 -C 18 -alkyl or hydrogen and T 2 and T 3 are C 1 -C 18 -alkyl.
    [89]
    [90] A more preferred class of compounds of the water insoluble triazole is a compound of formula 3a, wherein T 4 and T 5 are independently of each other C 1 -C 18 -alkyl.
    [91]
    [92] Also representative of the preferred water-insoluble triazoles are the compounds of formulas 3b and 3c, wherein T 6 and T 7 are independently of each other C 1 -C 18 -alkyl, preferably tert-butyl, —C ( CH 3 ) 2 -CH 2 -C (CH 3 ) 3 or 2-ethylhexyl. For particularly preferred compounds of formula 3a, both radicals T 6 and T 7 are both —C (CH 3 ) 2 —CH 2 —C (CH 3 ) 3 . T 8 in formula 3c is also C 1 -C 18 -alkyl, preferably methyl.
    [93]
    [94]
    [95] Preferred synamides are compounds of the formula (4) wherein, independently of one another, Y 1 and Y 2 are hydrogen or C 1 -C 4 -alkyl, preferably methyl or ethyl, and Y 3 is aryl, preferably phenyl or 4-methoxyphenyl.
    [96]
    [97] Preferred sulfonated benzimidazoles are compounds of the formula (5) wherein M is hydrogen, an alkali metal, preferably sodium, or an alkaline earth metal, for example magnesium, calcium or zinc.
    [98]
    [99] Preferred benzophenones are compounds of formula (6), wherein, independently of one another, M 1 to M 4 are hydrogen or C 1 -C 4 alkyl, M 1 and M 4 are preferably methyl or ethyl and M 2 and M 3 Is preferably hydrogen.
    [100]
    [101] Further water soluble, poorly water soluble or water insoluble active compounds are minerals, amino acids, proteins or enzymes.
    [102] Minerals include, for example, iron sulfate, zinc sulfate, manganese sulfate, copper sulfate, calcium sulfate, sodium sulfate, copper oxide, magnesium oxide, calcium fluoride, potassium chloride, potassium iodide, sodium chloride, calcium iodide, calcium phosphate, magnesium phosphate and potassium phosphate , Sodium phosphate or iron phosphate, cobalt carbonate, sodium selenite or silicic acid and salts thereof. For example, the amount of minerals used in the animal nutrition sector depends on the individual case requirements for the animals to be reared.
    [103] The amino acid may generally be any known physiologically suitable α-amino acid. Preferably, they are alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, hypuric acid, serine and taurine. Lysine, methionine and cysteine are particularly preferred.
    [104] Enzymes in this context are preferably phosphatase, glucanase and suitably esterase or lipase, the latter in encapsulated form.
    [105] Other active compounds may be the following compounds:
    [106] Compounds with vitamin or coenzyme characteristics, for example choline chloride, carnitine, γ-butyrobetaine, lipoic acid, creatine, ubiquinone, S-methylmethionine, S-adenosylmethionine.
    [107] -Feed antibiotics for drug-mixed feed and microorganisms for improving digestion.
    [108] Water-insoluble active compounds in this context are compounds having a water solubility at 20 ° C. of less than 0.05% by weight, preferably less than 0.01% by weight.
    [109] A poorly water-soluble active compound is a compound having a water solubility at 20 ° C. of less than 5% by weight, preferably less than 1% by weight, particularly preferably less than 0.5% by weight, more particularly preferably 0.5 to 0.05% by weight.
    [110] A water soluble active compound in this context is a compound having a water solubility at 20 ° C. of greater than 5 wt%, preferably greater than 10 wt%, particularly preferably greater than 20 wt%, more particularly preferably greater than 60 wt% to be.
    [111] In step (a), the food and animal feed is dispersed by dispersing at least one poorly water-soluble or water-insoluble active compound suitable for the food and animal feed sector or for pharmaceutical and cosmetic uses in an aqueous molecular dispersion or colloidal dispersion of proteinaceous protective colloid. Preference is given to a process for preparing a solid formulation of at least one poorly water soluble or water insoluble active compound suitable for the sector or for pharmaceutical and cosmetic uses.
    [112] The term dispersion is particularly preferably the preparation of aqueous suspensions and aqueous emulsions. More particularly preferably, the dispersing step (a) comprises at least one of the aforementioned aqueous molecular dispersions or colloidal dispersions of proteinaceous protective colloids, wherein the dispersed phase comprises at least one of the aforementioned solid active compounds as nanoparticulates. Preparation of a suspension of one solid active compound.
    [113] Suitable proteinaceous protective colloids according to the invention are water soluble proteins as well as water soluble proteins of animal or plant origin. Preferred protective colloids are casein, caseinate, beef gelatin, pork gelatin or fish gelatin, especially acid- or base-digested gelatin with a bloom number of 0 to 250 (e.g. gelatin A 100, A 200, B 100 and B200), and low molecular weight enzymatically degraded gelatin species with a bloom number of 0 and a molecular weight of 15,000 to 25,000 D (e.g., Collagel A and Gelitasol P (Stoess, Eberbach)). And mixtures of these gelatin types. In some cases, however, milk powder, whole milk or skim milk is suitable as a protective colloid. Representative examples of plant proteins are gluten, zein, soy protein, and pea protein. Particularly preferred protective colloids are casein and caseinate.
    [114] For further details on the aforementioned protective colloids, see R.A. Morton, Fat Soluble Vitamins, Intern. Encyclopedia of Food and Nutrition, Vol. 9, Pergamon Press 1970, pp. 128-131.
    [115] The water solubility or water expandability of the aforementioned polymers depends on the temperature, pH and ionic strength of the solution.
    [116] The term “agglomeration” refers to a process in the colloidal system that causes deposition of flakes in the form of flakes dispersed in the colloidal system, resulting in sol / gel transition. Particles can generally be aggregated by adding a coagulant aid, electrolyte, polyelectrolyte, colloid of opposite charge, or by heating to denature the protein. An advantageous method for flocculating the proteinaceous protective colloid in method step (b) is characterized by setting the pH of the dispersion to a value in the range of isoelectric points of the protein used as the protective colloid. According to the invention the range comprises 1 pH unit, preferably 0.5 pH unit, particularly preferably 0.1 to 0.2 pH unit, above and below the isoelectric point. More particularly preferably, aggregation is initiated by setting the pH of the dispersion to a value corresponding to the isoelectric point of the protein used as protective colloid.
    [117] The agglomerated solid can be separated from water and any additionally used organic solvent in a manner known per se, for example by filtration or centrifugation.
    [118] The material can be converted into a dry powder, possibly also in the presence of a coating material, in particular by spray drying, freeze drying or drying in a fluidized bed. Suitable coating materials are especially corn starch, silicic acid or tricalcium phosphate.
    [119] During lyophilization of the separated solids, an antifreeze material such as trehalose or polyvinylpyrrolidone can be added.
    [120] A preferred embodiment of the abovementioned method is a method of grinding before flocculating the suspension produced in process step (a). In this case, preferably the active compound is suspended in crystalline form prior to the polishing operation.
    [121] Polishing can be carried out in a manner known per se, for example using a ball mill. Depending on the type of mill used, the average particle size D [4.3] of the particles measured by the Fraunhofer diffraction method is 0.1 to 100 μm, preferably 0.2 to 50 μm, particularly preferably 0.5 to 30 μm, More particularly preferably the polishing is continued until it is 0.8 to 20 μm, in particular 1.0 to 10 μm. The term D [4.3] refers to the volume-weighted average diameter (see handbook on the Malvern Mastersizer S, Malvern Instruments Ltd., UK).
    [122] More detailed information on polishing and the equipment used therefor can be found in particular in Ullmann's Encyclopedia of Industrial Chemistry, Sixth Edition, 1999, Electronic Release, Size Reduction, Chapter 3.6 .: Wet Grinding and European Patent Publication No. 0 498 824. You can find it.
    [123] In addition, a preferred variant of the method of the invention is that the dispersion in step (a)
    [124] (a 1 ) dissolving at least one of the aforementioned active compounds in a water miscible organic solvent or a mixture of water and a water miscible organic solvent, or
    [125] (a 2 ) at least one of the aforementioned active compounds is dissolved in a water immiscible organic solvent,
    [126] (a 3 ) mixing the solution obtained in step (a 1 ) or (a 2 ) with an aqueous molecular dispersion or colloidal dispersion of proteinaceous protective colloid, wherein the hydrophobic phase of the active compound is produced as a nanodispersed phase .
    [127] The water miscible solvents used in step (a 1 ) are mainly water miscible thermally stable volatile solvents containing only carbon, hydrogen and oxygen, for example alcohols, ethers, esters, ketones and acetals. For convenience, solvents are used that are at least 10% water miscible, or have a boiling point of less than 200 ° C. and / or have fewer than 10 carbon atoms. Especially preferably, methanol, ethanol, n-propanol, isopropanol, 1,2-butanediol 1-methyl ether, 1,2-propanediol 1-n-propyl ether, tetrahydrofuran or acetone are used.
    [128] For the purposes of the present invention the term "water immiscible organic solvent" is an organic solvent having a water solubility of less than 10% at atmospheric pressure. Possible solvents contemplated herein are in particular halogenated aliphatic hydrocarbons (eg methylene chloride, chloroform and carbon tetrachloride), carboxylic acid esters (eg dimethyl carbonate, diethyl carbonate, propylene carbonate, ethyl formate, Methyl, ethyl or isopropyl acetate) and ethers (eg, methyl tert-butyl ether). Preferred water immiscible organic solvents are compounds selected from the group consisting of dimethyl carbonate, propylene carbonate, ethyl formate, ethyl acetate, isopropyl acetate and methyl tert-butyl ether.
    [129] When using a water immiscible solvent according to process step (a 2 ), the dispersion obtained after process step (a 3 ) is freed from the water immiscible solvent, for example by distillation, before agglomerating the protein in step (b). It may be advantageous to.
    [130] In addition, the method of the present invention is preferably a method for producing a carotenoid-containing dry powder.
    [131] Particularly preferred carotenoid-containing dry powders according to the invention are astaxanthin, β-carotene, β-apo-8'-carotenal, β-apo-8'-carotenic acid ethyl ester, canthaxanthin, citranaxanthin, It includes an active compound selected from the group consisting of echinene, lutein, lycopene and zeaxanthin.
    [132] In a more particularly preferred method of producing the above-mentioned carotenoid-containing dry powder,
    [133] (a) at least one carotenoid is dissolved in a water miscible organic solvent or a mixture of water and a water miscible organic solvent at a temperature of at least 30 ° C.,
    [134] (b) mixing the resulting solution with an aqueous casein solution or an aqueous caseinate solution,
    [135] (c) the casein or caseinate is aggregated from the dispersion together with the carotenoid at the pH of the dispersion within the region of the isoelectric point of the casein or caseinate,
    [136] (d) The aggregated solid is separated from water and a solvent and dried.
    [137] The above-mentioned carotenoid-containing preparations generally contain at least one carotenoid in a water miscible organic solvent at a temperature of 30 ° C. or higher, preferably 50 to 240 ° C., in particular 100 to 200 ° C., particularly preferably 140 to 180 ° C. Properly prepared by dissolving under pressure.
    [138] The action of high temperature under some circumstances can reduce the desired high proportion of all trans isomers, so that the carotenoid (s) are as fast as possible, for example in seconds, for example from 0.1 to 10 seconds, particularly preferably Dissolve within 1 second. For rapid production of molecular dispersions it may be advantageous to use elevated pressures, for example in the range from 20 to 80 bar, preferably from 30 to 60 bar.
    [139] Subsequently, the cooled molecular aqueous or colloidal dispersion of casein or caseinate is added directly to the resulting molecular dispersion in such a way that the temperature of the mixture is set to about 35 to 80 ° C.
    [140] The solvent component is transferred to the aqueous phase and the hydrophobic phase of the carotenoid (s) forms a nanodisperse phase.
    [141] For a more detailed description of the above mentioned method and apparatus for dispersion, reference is made to European Patent No. 0 065 193 at this point.
    [142] The casein or caseinate is agglomerated in method step (c) at a pH of the dispersion, in particular in the range from 4.0 to 5.5, preferably from 4.4 to 5.2, particularly preferably from 4.6 to 5.0, more particularly preferably from 4.7 to 4.9. Most preferably, the casein or caseinate aggregates at pH 4.8.
    [143] Advantageous protective colloids are low and / or high molecular weight casein or caseinate or mixtures thereof. Preferably, Na caseinates having a molecular weight of 10,000 to 100,000, particularly preferably of M0,000 of 20,000 to 60,000, for example, Lacto Bretagne Associes of Lactobacillus Associes having an MW of approximately 38,000. Na, France).
    [144] Details of casein / caseinate used are described in particular in Ullmann's Encyclopedia of Industrial Chemistry, 6th edition, 1998 Electronic Release, Chapter 11.1., Wiley VCH, Weinheim, Germany; And CD Roempp Chemie Lexikon [Roempp's Chemistry Lexicon] Version 1.0, Stuttgart / New York: Georg Thieme Verlag 1995] and references cited therein.
    [145] In some cases it may be convenient to add sugars or sugar alcohols, such as sucrose, glucose, lactose, invert sugar, plasticizers such as sorbitol, mannitol or glycerol to increase the mechanical stability of the final product. .
    [146] In order to increase the stability of the active compounds against oxidative degradation, it is advantageous to add stabilizers such as α-tocopherol, tertiary butylated hydroxytoluene, tertiary butylated hydroxyanisole, ascorbic acid or ethoxyquine. Do. They can be added in the aqueous or solvent phase, but preferably they are dissolved in the solvent phase together with the active compound.
    [147] Under some circumstances physiologically acceptable oils in the solvent phase, such as sesame oil, corn oil, cottonseed oil, soybean oil or peanut oil, and esters of heavy chain plant fatty acids, from 0 to 500% by weight, preferably based on the active compound (s) It may also be advantageous to additionally dissolve at a concentration of preferably 10 to 300% by weight, particularly preferably 20 to 100% by weight, which is then finely mixed with the active compound and the additives when precipitated together with the aqueous phase to precipitate. do.
    [148] The invention also relates to a solid formulation of at least one of the aforementioned water soluble, poorly water soluble or water insoluble active compounds suitable for the food and animal feed sector or for pharmaceutical and cosmetic uses, obtainable by one of the methods mentioned at the outset. It is about.
    [149] Preferred herein are solid formulations comprising at least one poorly water soluble or water insoluble active compound suitable for the food and animal feed sector or for pharmaceutical and cosmetic applications.
    [150] The active compound content in the dry powder of the present invention is in the range from 0.1 to 80% by weight, preferably from 1.0 to 75% by weight, particularly preferably from 5.0 to 70% by weight, more particularly preferably from 20 to 65% by weight.
    [151] Preferred solid preparations in this context are carotenoid-containing dry powders, in particular astaxanthin, β-carotene, β-apo-8'-carotenal, β-apo-8'-carotenic acid ethyl ester, canthaxanthin, citranak It is a dry powder containing a carotenoid selected from the group consisting of xanthine, echinenone, lutein, lycopene and zeaxanthin.
    [152] Outside the pH of the isoelectric point of the proteinaceous protective colloid used in the aqueous system, the solid formulation of the present invention can be redispersed again without any problem.
    [153] The dry powders of the invention are particularly suitable as additives in food and animal feed and as additives in cosmetic and pharmaceutical formulations. Typical applications for carotenoid-containing dry powders in the animal feed sector are, for example, the coloring of fish in aquaculture and the coloring of egg yolk and broiler husks in poultry breeding.
    [154] For the abovementioned uses, dry powders are advantageously used in the form of oily suspensions.
    [155] The present invention therefore also comprises at least one water-soluble, poorly water-soluble or water-insoluble active compound suitable for the food and animal feed sector or for pharmaceutical and cosmetic uses surrounded by one or more protective colloids, provided that the water-soluble high-amines are dispersed. Oily suspension which does not.
    [156] The abovementioned water soluble vitamins are in particular ascorbic acid and salts thereof (e.g. sodium ascorbate) and vitamin C derivatives (e.g. sodium, calcium or magnesium ascorbyl-2-monophosphate, or calcium ascorbyl-2-polyphosphate). , Calcium pantothenate, panthenol, vitamin B 1 (thiamine) (as hydrochloride, nitrate or pyrophosphate), vitamin B 2 (riboflavin) and its phosphates, vitamin B 6 and its salts, vitamin B 12 , biotin, folic acid and folic acid derivatives ( Tetrahydrofolic acid, 5-methyltetrahydrofolic acid, 5-formyltetrahydrofolic acid), nicotinic acid and nicotinamide.
    [157] Preferred embodiments of the oily suspensions of the invention are dispersed phases,
    [158] (a) dissolving or dispersing at least one water-soluble, poorly water-soluble or water-insoluble active compound suitable for the food and animal feed sector or for pharmaceutical and cosmetic uses in an aqueous dispersion or colloidal dispersion of proteinaceous protective colloid,
    [159] (b) aggregate the proteinaceous protective colloid together with the active compound from the dispersion,
    [160] (c) at least one water soluble suitable for the food and animal feed sector or for pharmaceutical and cosmetic applications, obtainable by separating the flocculated solids from water and optionally any solvents used and subsequently converting them to dry powders. And solid preparations of poorly water-soluble or water-insoluble active compounds.
    [161] Preference is also given to oily suspensions comprising at least one carotenoid as active compound.
    [162] Carotenoids that can be used in the context of the present invention are known representatives of this kind of materials which are available from natural sources or synthetically. These are, for example, β-carotene, lycopene, lutein, astaxanthin, zeaxanthin, kryptoxanthin, citranaxanthin, canthaxanthin, echinenone, bixin, β-apo-4-carotenal, β- Apo-8-carotenal, β-apo-8-carotenic acid ethyl ester (individually or as a mixture). Astaxanthin, β-carotene, β-apo-8'-carotenal, β-apo-8'-carotenic acid ethyl ester, canthaxanthin, citranaxanthine, echinenone, lutein, lycopene and zeaxanthin At least one carotenoid from the group consisting of is preferred. Particularly preferred carotenoids are astaxanthin and canthaxanthin, and astaxanthin is more particularly preferred.
    [163] The disperse phase is a protective colloid, in addition to the above-mentioned proteinaceous compounds such as gelatin (e.g. beef gelatin, pork gelatin or fish gelatin), gelatin hydrolysates, casein, caseinates, whey proteins and plant proteins. Starch, dextrin, pectin, gum arabic, modified starch such as Na octenyl succinate starch, high-amylose starch (eg Hylon®, National Starch) (individually or mixtures As). Typical examples of plant proteins are gluten, zein, soy protein, rice protein, potato protein and pea protein. However, polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose and alginate can also be used. Preferred protective colloids are at least one proteinaceous protective colloid, or modified starch, selected from the group consisting of casein, caseinate, soy protein, soy protein hydrolysate, porcine gelatin and fish gelatin.
    [164] More details on the aforementioned protective colloids can be found in R.A. Morton, Fat Soluble Vitamins, Intern. Encyclopedia of Food and Nutrition, Vol. 9, Pergamon Press 1970, pp. 128-131.
    [165] Protective colloids can be mixed with emulsifiers to improve their properties.
    [166] The oily formulations of the invention, in particular the carotenoid containing oily suspensions, are in particular characterized by a moisture content of 0.1 to 6% by weight, preferably 0.2 to 4% by weight, particularly preferably 0.5 to 3% by weight.
    [167] The average particle size D [4.3] of the dispersed phase of the oily suspension ranges from 0.1 to 100 μm, preferably from 0.2 to 50 μm, particularly preferably from 0.5 to 30 μm, more particularly preferably from 0.8 to 20 μm, in particular from 1.0 to 10 μm. Is in. The term D [4.3] refers to the volume-weighted mean diameter in this context (see handbook on the Malvern Mastersizer S, Malvern Instruments Ltd., UK).
    [168] In a preferred carotenoid-containing oily suspension, at least one carotenoid is present in amorphous or partially amorphous form. The proportion of carotenoids present in amorphous form as determined from the x-ray diffraction diagrams ranges from 30 to 100%, preferably from 40 to 99%, particularly preferably from 60 to 98%, more particularly preferably from 70 to 95% Is in.
    [169] Because of the high degree of amorphousness of the active compounds, especially carotenoids, in oily suspensions, these formulations exhibit particularly high bioavailability, with very good color results, for example in coloring egg yolk or fish, eg salmon.
    [170] The content of the active compound in the oily suspension is generally from 0.1 to 50% by weight, preferably from 0.2 to 30% by weight, particularly preferably from 0.5 to 20% by weight, more particularly preferably from 1.0 to 15, based on the total amount of the oily suspension. Weight percent.
    [171] The dispersion medium used may be solid or liquid at 20 ° C. and may be of animal origin as well as synthetic, mineral or plant origin. Representative examples include, in particular, sesame oil, corn oil, cottonseed oil, soybean oil or peanut oil, esters of medium-chain plant fatty acids, edible resins, oleostearin and paraffin oils, glyceryl stearate, isopropyl myristate, diisopropyl adipate , 2-ethylhexanoic acid cetyl stearyl ester, hydrogenated polyisobutene, petrolatum, caprylic / capric triglyceride, microcrystalline wax, lanolin and stearic acid.
    [172] Edible oils in this context liquid at 20 ° C., for example, sunflower oil, palm oil, sesame oil, corn oil, cottonseed oil, soybean oil or peanut oil, esters of medium chain triglycerides, and also fish oils, for example mackerel oil, herring Oil and salmon oil are preferred. Particularly preferred for animal nutrition are fish oil, corn oil, sunflower oil, soybean oil and peanut oil. An additional advantage in the food / pharmaceutical sector is esters of medium chain triglycerides.
    [173] Depending on the dispersion medium (oil or hard fat) used, the suspensions of the present invention may exist in free flowing form as a solid / liquid system, or depending on their viscosity and melting point of the dispersion medium, ie heterogeneous solids / It can exist as a solid system.
    [174] For example, in order to avoid sedimentation of the carotenoid-containing particles in the oily suspension when stored for a relatively long time, in some cases the abovementioned hard fats (eg edible resins or oleostearins) are also preferred as dispersion media.
    [175] The amount of dispersion medium is generally from 20 to 99.9% by weight, preferably from 50 to 99% by weight, particularly preferably from 55 to 97% by weight and more particularly preferably from 60 to 99% by weight, based on the total mass of the oily suspension. .
    [176] In some cases, oily suspensions also contain adjuvants, such as thickening agents, hard fats, chelating agents, for example alkali metal or alkaline earth metal salts of citric acid, phytic acid or phosphoric acid, and / or emulsifiers. May be necessary.
    [177] Emulsifiers or solubilizers that can be used are, for example, ascorbyl palmitate, polyglycerol esters of fatty acids, sorbitan esters of fatty acids, propylene glycol esters or lecithins of fatty acids.
    [178] The present invention also provides
    [179] (a) dissolving or dispersing at least one water-soluble, poorly water-soluble or water-insoluble active compound suitable for the food and animal feed sector or for pharmaceutical and cosmetic uses in an aqueous molecular or colloidal dispersion of proteinaceous protective colloid,
    [180] (b) aggregate the proteinaceous protective colloid together with the active compound from the dispersion,
    [181] (c) at least one water soluble suitable for the food and animal feed sector or for pharmaceutical and cosmetic applications, obtainable by separating the flocculated solids from water and optionally any solvents used and subsequently converting them to dry powders. The present invention relates to an oily suspension containing a solid preparation of a poorly water-soluble or water-insoluble active compound as the dispersed phase.
    [182] In the case of an oily suspension comprising the flocculated solids described above as the dispersed phase, the amount of the dispersion medium is generally 50 to 99.9% by weight, preferably 70 to 99.8% by weight, particularly preferably 80, based on the total mass of the oily suspension. To 99.5% by weight, more particularly preferably 90 to 99% by weight.
    [183] The invention also
    [184] (a) grinding a dry powder comprising at least one carotenoid surrounded by one or more protective colloids in an average particle size of 0.1 to 100 μm in at least one oil, or
    [185] (b) grinding the dry powder comprising at least one carotenoid surrounded by one or more protective colloids to an average particle size of 0.1 to 100 μm without using a continuous phase, and then grinding the ground particles to at least one oil Suspended in, or
    [186] (c) grinding the carotenoid-containing suspension comprising at least one carotenoid surrounded by at least one protective colloid as a solid dispersed phase and water or a mixture of water and a water miscible solvent as a dispersion medium to an average particle size of 0.1 to 100 μm, Then freeing the solid from water or a water / solvent mixture, and suspending the resulting ground particles in at least one oil,
    [187] Carotenoid-containing oily suspensions, preferably astaxanthin, β-carotene, β-apo-8'-carotenal, β-apo-8'-carotenic acid ethyl ester, canthaxanthin, citranaxanthin as active compounds, A method for preparing an oily suspension comprising at least one carotenoid selected from the group consisting of echinenone, lutein, lycopene and zeaxanthin.
    [188] Grinding in all three method variants can be performed in a manner known per se, for example using a ball mill. Depending on the type of mill used, the average particle size D [4.3] of the particles measured by the Fraunhofer diffraction method is 0.1 to 100 μm, preferably 0.2 to 50 μm, particularly preferably 0.5 to 30 μm, more particularly preferred. Preferably polishing is continued until it is between 0.8 and 20 μm, in particular between 1.0 and 10 μm.
    [189] More detailed information on grinding and the equipment used for it can be found in particular in Ullmann's Encyclopedia of Industrial Chemistry, Sixth Edition, 1999, Electronic Release, Size Reduction, Chapter 3.6 .: Wet Grinding.
    [190] The water miscible solvents used in method variant (c) are especially water miscible thermally stable volatile solvents containing only carbon, hydrogen and oxygen, for example alcohols, ethers, esters, ketones and acetals. For convenience, solvents are used that are at least 10% water miscible, or have a boiling point of less than 200 ° C. and / or have fewer than 10 carbon atoms. Particular preference is given to methanol, ethanol, n-propanol, isopropanol, 1,2-butanediol 1-methyl ether, 1,2-propanediol 1-n-propyl ether, tetrahydrofuran or acetone.
    [191] The water or water / solvent mixture can be separated in a manner known per se in the process (c), for example by distillation, suitably under reduced pressure. Distillation is generally carried out after polishing, but can also be carried out during the polishing process.
    [192] In the process of the invention, the oil used as the dispersion medium is an edible oil that is liquid at 20 ° C., or hard fat that is solid at 20 ° C.
    [193] More details on the protective colloids and dispersion media used are given in the description of the oily suspensions already presented at the outset.
    [194] The dry powder used for polishing can be any solid formulation known in the art, in which at least one carotenoid is generally surrounded by a protective colloid.
    [195] European Patent Publication No. 0 065 193, European Patent No. 0 832 569, German Patent Publication No. 199 19 751, International Patent Application Publication No. WO 98/26008, European Patent Publication No. 0 937 412, International Patent Application Publication Preference is given to dry powders prepared as specified in WO 91/062292 and WO 94/19411.
    [196] The dry carotenoid powders described in EP 0 065 193 are readily dissolved in carotenoids in water-miscible organic solvents at elevated temperatures, and rapidly precipitated in the form of colloidal dispersions by quickly mixing the carotenoids from the resulting solution with aqueous solutions of protective colloids. It is obtainable by the method of converting the resulting dispersion into dry powder.
    [197] According to European Patent Publication No. 0 832 569, the dispersion prepared according to European Patent Publication No. 0 065 193 is heated at a temperature of 40 to 90 ° C. followed by spray drying, whereby the active compound particles are represented by x-ray diffraction. When a substantially amorphous dry carotenoid powder is obtained.
    [198] The dry powder described in German Patent Publication No. 199 19 751 comprises at least one xanthophyll selected from the group consisting of astaxanthin, lutein and zeaxanthin embedded in a matrix of casein as a protective colloid.
    [199] The dry powder described in WO 98/26008 comprises at least one xanthophyll embedded in a matrix of a mixture of low and high molecular weight protective colloids.
    [200] European Patent Publication No. 0 937 412 discloses (a) suspending a carotenoid in the presence of an antioxidant and / or oil in a water immiscible solvent; (b) heating the suspension to a temperature in the range of 100 to 250 ° C; (c) the solution obtained according to step (b) is mixed with a protective colloidal aqueous solution at a temperature of 20 to 100 ° C; (d) to a powdered carotenoid formulation obtainable by separating the organic solvent and converting the dispersion into a dry powder.
    [201] Dry powders disclosed in WO 91/062292 are obtainable by grinding the carotenoids in an aqueous protective colloidal solution and subsequently spray drying the polished aqueous carotenoid suspension.
    [202] In WO 94/19411, crystalline carotenoids are ground in the presence of an aqueous solution of protective colloid, converted to amorphous deformation by short heating to melting point and then spray dried.
    [203] For further details on the preparation of these dry powders, see the specifications of the aforementioned publications.
    [204] The dry carotenoid powders used to prepare the oily suspensions of the invention may comprise other auxiliaries, for example plasticizers, emulsifiers and / or stabilizers, in addition to the protective colloid.
    [205] Plasticizers used are sugars or sugar alcohols such as sucrose, glucose, lactose, invert sugar, sorbitol, mannitol or glycerol.
    [206] The ratio of protective colloid and plasticizer to carotenoids is generally 0.5 to 65% by weight of dry powder, preferably 1 to 25% by weight of carotenoids, 10 to 50% by weight, preferably 15 to 35% by weight of protective colloid And 20 to 70% by weight, preferably 30 to 60% by weight of a plasticizer, wherein all the percentages are based on the dry mass of the powder with or without a small amount of stabilizer will be.
    [207] In order to increase the stability of the carotenoids against oxidative degradation, from 0 to 10% by weight, preferably 0.5 to 7.5% by weight, based on the total amount of dry powder, at least one stabilizer, for example α-tocopherol, 3 It may be advantageous to add a tertiary butylated hydroxytoluene, tertiary butylated hydroxyanisole, ascorbic acid or ethoxyquine.
    [208] Emulsifiers are for example, ascorbyl palmitate, polyglycerol esters of fatty acids at concentrations of from 0 to 200% by weight, preferably from 5 to 150% by weight, particularly preferably from 10 to 80% by weight, based on the carotenoids in the dry powder. , Sorbitan esters of fatty acids, propylene glycol esters or lecithins of fatty acids.
    [209] In the case of mixtures of carotenoids, it is also possible to grind all components used in the suspension in the polishing method of the invention as a whole mixture. However, each carotenoid to be polished can also be individually polished to a high concentration in the oils used. The final formulation is then prepared by mixing each individual suspension.
    [210] The oily suspensions of the invention can be diluted to their respective service concentration prior to use by adding fat or oil. These can be diluted, for example, by stirring at elevated temperature, for example, 30 to 80 ° C.
    [211] The abovementioned suspensions are particularly suitable as additives for animal feed and food preparations or mixed feeds, for the preparation of pharmaceutical and cosmetic preparations and for the preparation of food supplement preparations in the human and animal sector.
    [212] Preferably, the suspension can be used as feed additive in animal nutrition, for example, by incorporation into feed pellets during extrusion or by applying or spraying onto feed pellets.
    [213] Use as feed additives is particularly carried out by spraying the suspensions of the invention with or without dilution, for example directly onto animal feed pellets, with or without dilution, which is called application after pelletization.
    [214] A preferred embodiment of the spraying method is to fill the feed pellets with an oily suspension under reduced pressure.
    [215] Examples are found especially in British Patent Publication No. 2 232 573 and European Patent Publication No. 0 556 883.
    [216] Typical applications in the food sector are, for example, the addition and coloring of beverages, dairy products (eg yogurt, flavored milk drinks or dairy ice creams), and pudding powders, egg products, baking mixtures and confections.
    [217] In the cosmetics sector, oily suspensions can be used, for example, in the form of creams, lotions, lipsticks or make-ups in decorative body care products.
    [218] The invention also relates to food supplements, animal feeds, food and pharmaceutical and cosmetic preparations containing an oily suspension as described at the outset.
    [219] The invention preferably relates to animal feed, in particular feed pellets, filled with suspension.
    [220] Food supplement formulations and pharmaceutical formulations comprising the suspensions of the invention are especially tablets, dragees, and preferably hard and soft gelatin capsules.
    [221] Cosmetic preparations which may comprise the suspensions of the invention are for example cosmetic preparations which can be applied externally, especially decorative body care products such as face makeup and lipsticks in the form of creams and lotions.
    [222] In the case of the active compound (shading agent) absorbing UV light described at the outset, the shading agent-containing solid preparation of the present invention and the oily dispersion prepared therefrom can also be applied to human skin or human hair with high UV content of solar radiation or artificial light. It is suitable as a light stable UV filter (alone or in combination with a compound which absorbs the UV range) in cosmetic and pharmaceutical formulations for protection against. The cosmetic and pharmaceutical formulations themselves are clearly stabilized at the same time in order to remain active for as long as possible.
    [223] Accordingly, the present invention also relates to formulations of poorly water-soluble or water-insoluble organic UV filter materials as photo-stable UV filters in cosmetic or pharmaceutically suitable carriers (the formulations being the solid formulations of the invention mentioned above or oil-based suspensions prepared therefrom). ) To protect human skin or human hair from UV light in the range of 280 to 400 nm, comprising an active amount alone or in combination with a compound that absorbs the UVA and UVB ranges known per se for cosmetic and pharmaceutical formulations. A light-shielding agent-containing cosmetic and pharmaceutical formulation.
    [224] The amount of poorly water-soluble or water-insoluble organic UV filter material in the form of a formulation of the present invention for use in cosmetic and pharmaceutical formulations is from 0.05 to 20% by weight, preferably from 0.1 to 10% by weight, particularly preferably based on the total amount of cosmetic and pharmaceutical formulations. Preferably in the range of 1 to 7% by weight.
    [225] Light-shielding agent-containing cosmetic and pharmaceutical formulations are generally based on a carrier comprising at least one oil phase. However, formulations based entirely on aqueous are also possible. Accordingly, the compositions contemplated are oils, oil-in-water and water-in-oil emulsions, creams and pastes, protective lipstick compositions or fat-free gels.
    [226] The emulsions contemplated are in particular O / W macroemulsions, O / W microemulsions or O / W / O emulsions, which also comprise the amino substituted hydroxybenzophenones of the formula (1) in dispersion, which emulsions are described in German Patent Publication No. 197 26. Obtainable by a phase-inversion technique according to 121.
    [227] Conventional cosmetic auxiliaries that can be considered as additives are, for example, co-emulsifiers, fats and waxes, stabilizers, viscous agents, biogenic active compounds, film-forming agents, perfumes, dyes, varnishes Preservatives, pigments, electrolytes (eg magnesium sulfate) and pH adjusting agents. Co-emulsifiers contemplated are preferably known W / O emulsifiers and also O / W emulsifiers, for example polyglycerol esters, sorbitan esters or partially esterified glycerides. Typical examples of fats are glycerides; The wax is in particular beeswax, paraffin wax or microwax (possibly in combination with hydrophilic wax). Stabilizers that can be used are metal salts of fatty acids, for example magnesium stearate, aluminum stearate and / or zinc stearate. Suitable viscosifiers are, for example, crosslinked polyacrylic acids and their derivatives, polysaccharides, in particular xanthan gum, guar gum, agar, alginates and tylos, carboxymethylcellulose and hydroxyethylcellulose, also fatty alcohols, mono Glycerides and fatty acids, polyacrylates, polyvinyl alcohol and polyvinylpyrrolidone. Bioactive compounds are, for example, plant extracts, protein hydrolysates and vitamin complexes. Conventional film formers include, for example, hydrocolloids (eg chitosan, microcrystalline chitosan or quaternized chitosan), polyvinylpyrrolidone, vinylpyrrolidone / vinyl acetate copolymers, acrylic acid based polymers, quaternized cellulose Derivatives and similar compounds. Suitable preservatives are, for example, formaldehyde solutions, p-hydroxybenzoate or sorbic acid. Brighteners contemplated are, for example, glycol distearate esters (eg ethylene glycol distearate), and also fatty acids and fatty acid monoglycol esters. Dyes that can be used are described, for example, in "Kosmetische Faerbemittel (Cosmetic Dye)" of the Farbstoffkommission der Deutschen Forschungsgemeinschaft (Dye Commission of the German Academic Union); It is an approved and suitable material for cosmetic purposes as compiled in Verlag Chemie, Weinheim, 1984]. These dyes are usually used at concentrations of from 0.001 to 0.1% by weight, based on the total mixture.
    [228] Additional content of antioxidants is generally preferred. Thus, any antioxidant suitable or customary for cosmetic and / or dermatological use may be used as the preferred antioxidant.
    [229] Advantageously, antioxidants include amino acids (eg glycine, histidine, tyrosine, tryptophan) and derivatives thereof, imidazoles (eg urocanoic acid) and derivatives thereof, peptides such as D, L-carnosine, D- Carnosine, L-carnosine and its derivatives (e.g. anserine), carotenoids, carotenes (e.g. β-carotene, lycopene) and its derivatives, chlorogenic acid and its derivatives, lipoic acid and its derivatives (e.g. dihydrolipoic acid), oro Thioglucose, propylthiouracil and other thiols (e.g. thiorodoxin, glutathione, cysteine, cystine, cystamine and its glycosyl, N-acetyl, methyl, ethyl, propyl, amyl, butyl and lauryl, palmitoyl, oleic) 1, γ-linoleyl, cholesteryl and glyceryl esters and salts thereof, dilauryl thiodipropionate, distearyl thiodipropionate, thiodipropionic acid and derivatives thereof (esters, ethers, peptides, lipids , Nucleotides, nucleosides and salts) and sulfoximine compounds (e.g. butionine sulfoximine, homocysteine sulfoximine, butionine sulfone, penta-, hexa- and heptathione sulfoximine) (very low acceptable doses (e.g. , pmol to μmol / kg)), and also (metal) chelating agents (e.g. α-hydroxy fatty acids, palmitic acid, phytic acid, lactoferrin), α-hydroxy acids (e.g. citric acid, lactic acid, malic acid), Humic acid, bile acids, bile extracts, bilirubin, biliverdine, EDTA and derivatives thereof, unsaturated fatty acids and derivatives thereof (e.g., γ-linolenic acid, linoleic acid, oleic acid), folic acid and derivatives thereof, ubiquinone and ubiquinol and derivatives thereof, Vitamin C and derivatives thereof (e.g. ascorbyl palmitate, Mg ascorbyl phosphate, ascorbyl acetate), tocopherols and derivatives (e.g. vitamin E acetate, tocotrienols), vitamin A and derivatives (vitamin A palmitate), And Ben Coniferryl benzoate of the joining resin, root acid and its derivatives, α-glycosylurine, ferulic acid, furfurylideneglucitol, carnosine, butylated hydroxytoluene, butylated hydroxyanisole, nordihydrogua Izal resinic acid, nordihydroguaiaretic acid, trihydroxybutyrophenone, uric acid and its derivatives, mannose and its derivatives, zinc and its derivatives (e.g. ZnO, ZnSO 4 ), selenium and its derivatives (e.g. Selenomethionine), stilbenes and derivatives thereof (eg, stilbene oxide, trans-stilbene oxide).
    [230] The amount of the aforementioned antioxidant (at least one compound) in the formulation is preferably from 0.001 to 30% by weight, particularly preferably from 0.05 to 20% by weight, in particular from 1 to 10% by weight, based on the total weight of the preparation.
    [231] When vitamin E and / or its derivatives are antioxidant (s), it is advantageous to select each concentration in the range of 0.001 to 10% by weight, based on the total weight of the formulation.
    [232] If vitamin A and / or its derivatives or carotenoids are antioxidant (s), it is advantageous to select each of them in the range of 0.001 to 10% by weight, based on the total weight of the formulation.
    [233] Typical oil components in cosmetics are, for example, paraffin oil, glyceryl stearate, isopropyl myristate, diisopropyl adipate, 2-ethylhexanoic acid cetyl stearyl ester, hydrogenated polyisobutene, petrolatum, caprylic acid Capric acid triglycerides, microcrystalline waxes, lanolin and stearic acid.
    [234] The total amount of adjuvant and additive may be 1 to 80% by weight, preferably 6 to 40% by weight, based on the medium, and the non-aqueous portion ("active substance") is 20 to 80% by weight, preferably 30 to 70 Weight percent. The medium can be prepared in a manner known per se, ie, by high temperature, low temperature, high temperature-high temperature / low temperature or by PIT emulsification. This is a pure mechanical process, with no chemical reactions.
    [235] Thus, the above shading preparations may be present in liquids, pastes or solids, for example as water-in-oil creams, oil-in-water creams and lotions, aerosol foam creams, gels, oils, fat sticks, powders, sprays or aqueous alcoholic lotions. .
    [236] Finally, other components which absorb the UV range and are known per se can be used together if they are stable within the overall range of the combination of UV filters used according to the invention.
    [237] Most of the light-shielding agents in cosmetic and pharmaceutical formulations that act to protect the human epidermis consist of compounds that absorb UV light in the UVB region, ie in the range from 280 to 320 nm. For example, the content of the UVA absorbent used according to the invention is 10 to 90% by weight, preferably 20 to 50% by weight, based on the total amount of UVB and UVA absorbent material.
    [238] Any UVA and UVB filter material is contemplated as the UV filter material used in combination with the formulations used according to the invention. Examples include the following materials.
    [239] number matter CAS number (= acid) One 4-aminobenzoic acid 150-13-0 2 3- (4'-trimethylammonium) benzylidenebornan-2-one methyl sulfate 52793-97-2 3 3,3,5-trimethylcyclohexyl salicylate (homo salatum) 118-56-9 4 2-hydroxy-4-methoxybenzophenone (oxybenzonium) 131-57-7 5 2-phenylbenzimidazole-5-sulfonic acid and its potassium, sodium and triethanolamine salts 27503-81-7 6 3,3 '-(1,4-phenylenedimethine) bis (7,7-dimethyl-2-oxobicyclo [2.2.1] heptan-1-methanesulfonic acid) and salts thereof 90457-82-2 7 4-bis (polyethoxy) aminobenzoic acid polyethoxyethyl ester 113010-52-9 8 4-dimethylaminobenzoic acid 2-ethylhexyl ester 21245-02-3 9 Salicylic acid 2-ethylhexyl ester 118-60-5 10 4-methoxycinnamic acid 2-isoamyl ester 71617-10-2 11 4-methoxycinnamic acid 2-ethylhexyl ester 5466-77-3 12 2-hydroxy-4-methoxybenzophenone-5-sulfonic acid (sulisobenzonium) and sodium salt 4065-45-6 13 3- (4'-sulfo) benzylidenebornan-2-one and salts 58030-58-6 14 3-benzylidenebornan-2-one 16087-24-8 15 1- (4'-isopropylphenyl) -3-phenylpropane-1,3-dione 63260-25-9 16 4-isopropylbenzyl salicylate 94134-93-7 17 2,4,6-trianilino- (o-carbo-2'-ethyl-1'-hexyloxy) -1,3,5-triazine 88122-99-0 18 3-imidazol-4-ylacrylic acid and ethyl esters thereof 104-98-3 19 2-cyano-3,3-diphenylacrylic acid ethyl ester 5232-99-5 20 2-cyano-3,3-diphenylacrylic acid 2'-ethylhexyl ester 6197-30-4 21 Menthyl o-aminobenzoate or: 5-methyl-2- (1-methylethyl) -2-aminobenzoate 134-09-8 22 Glyceryl p-aminobenzoate or: 4-aminobenzoic acid 1-glyceryl ester 136-44-7 23 2,2'-dihydroxy-4-methoxybenzophenone (dioxybenzone) 131-53-3 24 2-hydroxy-4-methoxy-4-methylbenzophenone (mexonone) 1641-17-4 25 Triethanolamine salicylate 2174-16-5 26 Dimethoxyphenylglyoxalate or: 3,4-dimethoxyphenylglyoxalate sodium 4732-70-1 27 3- (4'-sulfo) benzylidenebornan-2-one and its salts 56039-58-8 28 4-tert-butyl-4'-methoxydibenzoylmethane 70356-09-1 29 2,2 ', 4,4'-tetrahydroxybenzophenone 131-55-5 30 2,2'-methylenebis [6 (2H-benzotriazol-2-yl) -4- (1,1,3,3-tetramethylbutyl) phenol] 103597-45-1 31 2,2 '-(1,4-phenylene) bis-1H-benzimidazole-4,6-disulfonic acid, Na salt 180898-37-7 32 2,4-bis [4- (2-ethylhexyloxy) -2-hydroxy] phenyl-6- (4-methoxyphenyl)-(1,3,5) -triazine 187393-00-6 33 3- (4-methylbenzylidene) campo 36861-47-9 34 4-bis (polyethoxy) paraaminobenzoic acid polyethoxyethyl ester 113010-52-9 35 2,4-dihydroxybenzophenone 131-56-6 36 2,2'-dihydroxy-4,4'-dimethoxybenzophenone-5,5'-disodium sulfonate 3121-60-6
    [240] Polymeric or polymeric bond filter materials may also be used according to the invention.
    [241] The cosmetic and dermatological preparations of the invention advantageously also contain metal oxides and / or other poorly water soluble or water insoluble metal compounds, in particular titanium (TiO 2 ), zinc (ZnO), iron (eg Fe 2 O 3 ), zircon (ZrO 2 ), silicon (SiO 2 ), manganese (eg MnO), aluminum (Al 2 O 3 ), oxides of cerium (eg Ce 2 O 3 ), mixed oxides of the corresponding metals and mixtures of these oxides Based inorganic pigments. Especially preferably, such pigments are based on TiO 2 and ZnO.
    [242] Although not obligatory, it is particularly advantageous in the present invention if the inorganic pigment is present in hydrophobic form, ie surface treated in a water repellent manner. Such surface treatment may be to provide the pigment with a thin hydrophobic coating in a manner known per se as described in German Patent Publication No. 33 14 742.
    [243] In order to protect human hair from UV radiation, the shading formulations of the invention are incorporated in shampoos, lotions, gels, hairsprays, aerosol foam creams or emulsions at a concentration of 0.1 to 10% by weight, preferably 1 to 7% by weight. You can. Each formulation may be used herein, in particular for washing, dyeing or styling hair.
    [244] The formulations used according to the invention are generally characterized by a particularly high absorption capacity in the UVA radiation region with a pronounced band structure. In addition, they are readily soluble in cosmetic oils and can be easily incorporated into cosmetic formulations. Emulsions prepared using such formulations are particularly characterized by their high stability, formulation I itself by its high photostability, and formulations prepared using it are characterized by a satisfactory hand to its skin.
    [245] The UV filter action of the formulations of the invention can also be used to stabilize the active compounds and adjuvants in cosmetic and pharmaceutical formulations.
    [246] The formulations of the present invention are characterized by a particularly high absorption capacity in the UVB radiation range with a pronounced band structure and high shading coefficient.
    [247] In particular, the high shading coefficient of the formulation, measured even at low concentrations of UV-absorbing active compounds, is surprising.
    [248] In the following examples, the procedure of the method of the invention is described in more detail.
    [249] <Example 1>
    [250] Astaxanthin Dry Powder
    [251] 45 g of crystalline astaxanthin was suspended in 375 g of an isopropanol / water azeotrope mixture at room temperature. This active compound suspension was then heated to 96 ° C. and at a flow rate of 2.1 kg / h and continued mixing with additional isopropanol / water azeotrope at a temperature of 227 ° C. and a flow rate of 2.7 kg / h, the astaxanthin Silver was dissolved at a mixture temperature of 169 ° C. and a pressure of 60 bar. The resulting active compound solution was then mixed with an aqueous phase consisting of a solution of 80 g of Na caseinate in 12 liters of distilled water with a pH of 8.0 using 18 ml of 1 M NaOH at a flow rate of 56.1 kg / h.
    [252] The nanoparticulate active compound particles formed during mixing had a particle size of 100 nm in the isopropanol / water mixture. The active compound dispersion was then set to pH 4.8 using 1M HCl to aggregate the active compound / caseinate particles. The aggregated particles were filtered through a filter bag and subsequently lyophilized to give a dry powder having an astaxanthin content of 36% by weight.
    [253] <Example 2>
    [254] Astaxanthin Dry Powder
    [255] 50 g of crystalline astaxanthin and 5.6 g of ethoxyquine were suspended in 416 g of an isopropanol / water azeotrope mixture at room temperature. The active compound suspension was then heated to 97 ° C. and at a flow rate of 2.1 kg / h and continued mixing with additional isopropanol / water azeotrope at a temperature of 216 ° C. and a flow rate of 2.7 kg / h, the astaxanthin It was dissolved at a mixture temperature of 169 ° C. and a pressure of 60 bar. The active compound solution was then mixed with an aqueous phase consisting of a solution of 23.3 g of Na caseinate in 14 liters of distilled water with a pH of 8.3 using 5 ml of 1 M NaOH at a flow rate of 55.6 kg / h.
    [256] The active compound particles formed during mixing had a particle size of 116 nm in the isopropanol / water mixture. This active compound dispersion was then set to pH 4.8 using 1M HCl to aggregate the active compound / caseinate particles. The suspension was then filtered through a filter bag and the filter cake was dried. The resulting solids had an astaxanthin content of 62% by weight.
    [257] <Example 3>
    [258] Lycopene dry powder
    [259] 45 g of crystalline lycopene, 3.6 g of palmitic acid and 6.6 g of tocopherol were suspended in 388 g of an isopropanol / water azeotrope mixture at room temperature. The active compound suspension was then heated to 94 ° C. and at a flow rate of 2.0 kg / h and continued mixing with additional isopropanol / water azeotrope at a temperature of 206 ° C. and a flow rate of 3.3 kg / h, wherein the lycopene was 171 ° C. Was dissolved at a mixture temperature of 63 bar and a pressure of 63 bar. The resulting active compound solution was then mixed with an aqueous phase consisting of a solution of 80 g of Na caseinate in 7 liters of distilled water with a pH of 8.0 using 19 ml of 1 M NaOH at a flow rate of 33.8 kg / h.
    [260] The active compound particles formed during mixing had a particle size of 125 nm in the isopropanol / water mixture. The active compound dispersion was then set to pH 4.8 using 1M HCl to aggregate the active compound / caseinate particles. The suspension was then filtered through a filter bag and lyophilized. The dried filter cake had a lycopene content of 32% by weight.
    [261] <Example 4>
    [262] β-carotene dry powder
    [263] 45 g of β-carotene, 3.6 g of ascorbyl palmitate and 6.6 g of tocopherol were suspended in 388 g of an isopropanol / water azeotrope mixture at room temperature. The active compound suspension was then heated to 96 ° C. and at a flow rate of 2.1 kg / h and continued mixing with additional isopropanol / water azeotrope at a temperature of 210 ° C. and a flow rate of 3.0 kg / h, wherein the β-carotene was It was dissolved at a mixture temperature of 170 ° C. and a pressure of 62 bar. The active compound solution was then mixed with an aqueous phase consisting of a solution of 80 g of Na caseinate in 7 liters of distilled water with a pH of 8.0 using 18 ml of 1 M NaOH at a flow rate of 35.5 kg / h.
    [264] The active compound particles formed during the mixing had a particle size of 138 nm in the isopropanol / water mixture. This active compound dispersion was then set to pH 4.8 using 1M HCl to aggregate the active compound / caseinate particles. The suspension was then filtered through a filter bag. The filter cake was then dried through freeze drying. The dried filter cake had a β-carotene content of 32% by weight.
    [265] Example 5
    [266] Astaxanthin Dry Powder (Acid Procedure)
    [267] 45 g of crystalline astaxanthin and 4.5 g of vanillin were suspended in 375 g of an isopropanol / water azeotrope mixture at room temperature. The active compound suspension was then heated to 98 ° C. and at a flow rate of 2.1 kg / h and continued mixing with additional isopropanol / water azeotrope at a temperature of 230 ° C. and a flow rate of 2.8 kg / h, the astaxanthin Dissolve at a mixture temperature of 171 ° C. and a pressure of 61 bar. The active compound solution was then made up of a solution consisting of a solution of 80 g of Na caseinate (lacto-bretan associated) in 12,000 g of distilled water with 88 g of 1M HCl at a flow rate of 55.2 kg / h at a pH of 2.9 Mixed with the appearance.
    [268] The active compound particles formed during mixing had a particle size of 1.2 μm in an isopropanol / water mixture. The active compound dispersion was then set to pH 4.8 using 1M NaOH to aggregate the active compound / caseinate particles. The suspension was then filtered through a filter bag. The filter cake was then dried through freeze drying. The dried filter cake had an astaxanthin content of 35% by weight.
    [269] <Example 6>
    [270] Polishing of Lycopene with Caseinate
    [271] 3.3 g of crystalline lycopene, 2.5 g of Na caseinate and 0.33 g of ascorbyl palmitate were suspended in 40 g of deionized water at room temperature and the pH of the suspension was made alkaline using 3 g of 1M NaOH. The active compound suspension was then dispersed on a Red Devil mixer in a 100 ml glass flask with about 200 g of zircon oxide ceramic polishing beads of diameter 1 mm. After a polishing time of 3, 6 and 12 hours, samples were taken to characterize the progress of the polishing. At these time points the mean particle size was 651 nm with 67% deviation, 487 nm with 50% deviation and 494 nm with 55% deviation. The pH of the final sample was 7.7 at an E1 / 1 value of 136.
    [272] This active compound dispersion was then set to pH 4.8 using 1M HCl to aggregate the active compound / caseinate particles. After filtration through a filter bag, the filter cake was lyophilized.
    [273] <Example 7>
    [274] Astaxanthin suspension in oil
    [275] To prepare a highly concentrated astaxanthin oily suspension, 20 g of astaxanthin dry powder obtained according to Example 2 were added 1.0 g of ethoxyquine, 1.0 g of preservative (BHT) and emulsifier (Span 65, Sigma). ) Suspended with Ultra Turrax for 5 minutes in 100 g of neutral oil (Delios SK, Gruenau) with 4.0 g. The resulting oil suspension, stable against sedimentation, had an astaxanthin content of 8.5% by weight and a secondary particle size of 34 μm.
    [276] <Example 8>
    [277] Astaxanthin suspension in oil
    [278] 2 kg of a 30% by weight mixture of astaxanthin-containing dry powder (Lucantin® Pink 10% strength, BASF AG) and 70% by weight soybean oil is stirred using a van stirrer until the suspension is homogeneous. It was. The mixture was then transferred to a stirrable reservoir from which the suspension was transferred by peristaltic pump through a continuous ball mill (Dyno Mill KDL Spezial). The polishing vessel of the ball mill was filled with 400 g of glass balls (800-1200 μm in diameter). The finely divided suspension coming out of the mill was collected and measured using a particle control device (Malvern Mastersizer). The polishing operation was repeated until 90% of the suspended particles had a particle size of less than 10 μm [D (0.9) <10 μm]. This corresponds to an average particle size D [4.3] of 5.2 μm.
    [279] After separating the milling body, part of the suspension was diluted with 10 times the amount of oil used and left for 12 hours. All undiluted or diluted suspensions showed no sedimentation over this period.
    [280] According to the present invention there is provided a process for preparing a solid formulation of at least one water soluble, poorly water soluble or water insoluble active compound suitable for the food and animal feed sector or for pharmaceutical and cosmetic uses. Also provided are oily suspensions containing these formulations, and their use as additives in animal feed, food, pharmaceutical and cosmetic formulations.
    权利要求:
    Claims (40)
    [1" claim-type="Currently amended] (a) dissolving or dispersing at least one water-soluble, poorly water-soluble or water-insoluble active compound suitable for the food and animal feed sector or for pharmaceutical and cosmetic uses in an aqueous molecular or colloidal dispersion of proteinaceous protective colloid,
    (b) aggregate the proteinaceous protective colloid together with the active compound from the dispersion,
    (c) separating the flocculated solids from water and any solvents used additionally and subsequently converting them to dry powders, thereby at least one water soluble, watery egg suitable for the food and animal feed sector or for pharmaceutical and cosmetic applications. A process for preparing a solid formulation of a soluble or water insoluble active compound.
    [2" claim-type="Currently amended] The method according to claim 1, wherein at least one poorly water-soluble or water-insoluble active compound suitable for the food and animal feed sector or for pharmaceutical and cosmetic uses in method step (a) is added to an aqueous molecular dispersion or colloidal dispersion of proteinaceous protective colloid. A process for preparing a solid formulation of at least one poorly water soluble or water insoluble active compound suitable for the food and animal feed sector or for pharmaceutical and cosmetic uses.
    [3" claim-type="Currently amended] The method of claim 2, wherein said dispersing step (a) is preparation of an aqueous molecular dispersion of a proteinaceous protective colloid or a suspension of at least one solid active compound in a colloidal dispersion.
    [4" claim-type="Currently amended] 4. A method according to claim 3, wherein the suspension prepared in process step (a) is ground before flocculation.
    [5" claim-type="Currently amended] The method of claim 2 wherein the dispersion in step (a) is
    (a 1 ) dissolving at least one poorly water-soluble or water-insoluble active compound in a water miscible organic solvent or a mixture of water and a water miscible organic solvent, or
    (a 2 ) dissolving at least one poorly water soluble or water insoluble active compound in a water immiscible organic solvent,
    (a 3 ) mixing the solution obtained in step (a 1 ) or (a 2 ) with an aqueous molecular dispersion or a colloidal dispersion of proteinaceous protective colloid, wherein the hydrophobic phase of the active compound is produced as a nanodispersed phase. Way.
    [6" claim-type="Currently amended] The method of claim 5, wherein when performing process step (a 2 ), the water immiscible solvent is distilled off before flocculating the protective colloid.
    [7" claim-type="Currently amended] The method according to any one of claims 1 to 6, wherein in step (b) the aggregation is initiated by setting the pH of the dispersion to a value in the isoelectric point range of the protein used as protective colloid.
    [8" claim-type="Currently amended] The method of claim 1, wherein the protective colloid is casein or caseinate.
    [9" claim-type="Currently amended] The method according to any one of claims 1 to 8, which comprises the preparation of a carotenoid-containing dry powder.
    [10" claim-type="Currently amended] The method according to claim 9, wherein astaxanthin, β-carotene, β-apo-8'-carotenal, β-apo-8'-carotenic acid ethyl ester, canthaxanthin, citranaxanthine, echinenone, lutein, A method of preparing a dry powder comprising a carotenoid selected from the group consisting of lycopene and zeaxanthin.
    [11" claim-type="Currently amended] The method of claim 9,
    a) at least one carotenoid is dissolved in a water miscible organic solvent or a mixture of water and a water miscible organic solvent at a temperature of 30 ° C. or higher,
    (b) mixing the resulting solution with an aqueous casein solution or an aqueous caseinate solution,
    (c) the casein or caseinate is aggregated from the dispersion together with the carotenoid at the pH of the dispersion within the isoelectric point range of the casein or caseinate,
    (d) separating the aggregated solid from water and a solvent and drying.
    [12" claim-type="Currently amended] A solid preparation of at least one water soluble, poorly water soluble or water insoluble active compound, suitable for the food and animal feed sector or for pharmaceutical and cosmetic uses, obtainable by the method according to claim 1.
    [13" claim-type="Currently amended] A solid formulation according to claim 12 comprising at least one poorly water soluble or water insoluble active compound suitable for the food and animal feed sector or for pharmaceutical and cosmetic uses.
    [14" claim-type="Currently amended] The solid preparation according to claim 12 or 13, wherein the active compound content is 0.1 to 80% by weight.
    [15" claim-type="Currently amended] The solid preparation according to claim 13 or 14, which is a carotenoid-containing dry powder.
    [16" claim-type="Currently amended] The method of claim 15, wherein astaxanthin, β-carotene, β-apo-8′-carotenal, β-apo-8′-carotenic acid ethyl ester, canthaxanthin, citranaxanthine, echinenone, lutein, Dry powder comprising a carotenoid selected from the group consisting of lycopene and zeaxanthin.
    [17" claim-type="Currently amended] Use of the solid preparation according to claim 12 as an additive in food, animal feed, pharmaceutical and / or cosmetic preparations.
    [18" claim-type="Currently amended] 18. The use according to claim 17, wherein said solid preparation is used in the form of an oily suspension.
    [19" claim-type="Currently amended] Use for preparing an oily suspension of the solid preparation according to claim 12.
    [20" claim-type="Currently amended] An oily suspension comprising at least one water soluble, poorly water soluble or water insoluble active compound suitable for the food and animal feed sector or for pharmaceutical and cosmetic uses surrounded by one or more protective colloids as a dispersed phase, wherein the oil free suspension does not contain water soluble vitamins.
    [21" claim-type="Currently amended] The method of claim 20,
    (a) dissolving or dispersing at least one water-soluble, poorly water-soluble or water-insoluble active compound suitable for the food and animal feed sector or for pharmaceutical and cosmetic uses in an aqueous molecular or colloidal dispersion of proteinaceous protective colloid,
    (b) aggregate the proteinaceous protective colloid together with the active compound from the dispersion,
    (c) at least one water soluble suitable for the food and animal feed sector or for pharmaceutical and cosmetic applications, obtainable by separating the flocculated solids from water and optionally any solvents used and subsequently converting them to dry powders. Oily suspension comprising a solid formulation of a poorly water-soluble or water-insoluble active compound as the dispersed phase.
    [22" claim-type="Currently amended] 22. The oily suspension according to claim 20 or 21, wherein the active compound content is 0.1 to 50% by weight based on the total amount of the oily suspension.
    [23" claim-type="Currently amended] 23. The method of any one of claims 20 to 22, wherein the active compound is astaxanthin, β-carotene, β-apo-8'-carotenal, β-apo-8'-carotenic acid ethyl ester, canthaxanthin. And an oily suspension comprising at least one carotenoid selected from the group consisting of citranaxanthin, echinenone, lutein, lycopene and zeaxanthin.
    [24" claim-type="Currently amended] The carotenoid-containing oily suspension according to claim 23, wherein the water content is 0.1 to 6% by weight.
    [25" claim-type="Currently amended] 25. The carotenoid containing oily suspension according to claim 23 or 24, wherein the average particle size of the solid phase is in the range of 0.1 to 100 mu m.
    [26" claim-type="Currently amended] 26. The carotenoid-containing oily suspension according to any one of claims 23 to 25, wherein said at least one carotenoid is present in amorphous or partially amorphous form.
    [27" claim-type="Currently amended] 27. The carotenoid-containing oily suspension according to any one of claims 23 to 26 comprising at least one proteinaceous protective colloid or modified starch as protective colloid.
    [28" claim-type="Currently amended] (a) dissolving or dispersing at least one water-soluble, poorly water-soluble or water-insoluble active compound suitable for the food and animal feed sector or for pharmaceutical and cosmetic uses in an aqueous molecular or colloidal dispersion of proteinaceous protective colloid,
    (b) aggregate the proteinaceous protective colloid together with the active compound from the dispersion,
    (c) at least one water soluble suitable for the food and animal feed sector or for pharmaceutical and cosmetic applications, obtainable by separating the flocculated solids from water and optionally any solvents used and subsequently converting them to dry powders. And an oily suspension containing a solid preparation of a poorly water-soluble or water-insoluble active compound as the dispersed phase.
    [29" claim-type="Currently amended] The oily suspension according to claim 28 wherein the active compound content is from 0.1 to 50% by weight, based on the total amount of the oily suspension.
    [30" claim-type="Currently amended] The method according to claim 28 or 29, wherein astaxanthin, β-carotene, β-apo-8′-carotenal, β-apo-8′-carotenic acid ethyl ester, canthaxanthin, citranac as active compounds An oily suspension comprising at least one carotenoid selected from the group consisting of xanthine, echinenone, lutein, lycopene and zeaxanthin.
    [31" claim-type="Currently amended] (a) grinding a dry powder comprising at least one carotenoid surrounded by one or more protective colloids in an average particle size of 0.1 to 100 μm in at least one oil, or
    (b) grinding the dry powder comprising at least one carotenoid surrounded by one or more protective colloids to an average particle size of 0.1 to 100 μm without using a continuous phase, and then grinding the ground particles to at least one oil Suspended in, or
    (c) polishing the carotenoid-containing suspension comprising at least one carotenoid surrounded by at least one protective colloid as a solid phase and water or a mixture of water and a water miscible solvent as a dispersion medium to an average particle size of 0.1 to 100 μm, and then A process for the preparation of a carotenoid-containing oily suspension according to claim 23 which comprises releasing the solid phase from water or a water / solvent mixture and suspending the resulting polished particles in at least one oil.
    [32" claim-type="Currently amended] The method of claim 31, wherein said oil is an edible oil that is liquid at 20 ° C.
    [33" claim-type="Currently amended] 32. The method of claim 31, wherein the oil is a hard fat solid that is solid at 20 ° C.
    [34" claim-type="Currently amended] Use of the oily suspensions according to claims 20 to 30 for the preparation of food supplements and as additives in animal feed, food, pharmaceutical and cosmetic preparations.
    [35" claim-type="Currently amended] 35. The use of claim 34, wherein the oily suspension comprises a carotenoid.
    [36" claim-type="Currently amended] 36. The use of claim 34 or 35 as a feed additive in animal nutrition.
    [37" claim-type="Currently amended] 37. The use of claim 36 for incorporation into feed pellets.
    [38" claim-type="Currently amended] 37. The use of claim 36 for applying to food pellets.
    [39" claim-type="Currently amended] The use according to claim 38, wherein said feed pellets are filled with an oily suspension under reduced pressure.
    [40" claim-type="Currently amended] A food supplement, animal feed, food, or pharmaceutical or cosmetic preparation comprising an oily suspension according to any of claims 20 to 30.
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    同族专利:
    公开号 | 公开日
    KR100760764B1|2007-10-04|
    BR0105753A|2002-07-02|
    AU9514601A|2002-05-30|
    JP2002255931A|2002-09-11|
    US20020110599A1|2002-08-15|
    CA2363823A1|2002-05-29|
    CN1364426A|2002-08-21|
    AU783606B2|2005-11-17|
    US7105176B2|2006-09-12|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    2000-11-29|Priority to DE10059213.9
    2000-11-29|Priority to DE10059213A
    2001-06-22|Priority to DE10129713A
    2001-06-22|Priority to DE10129713.0
    2001-11-28|Application filed by 스타르크, 카르크, 바스프 악티엔게젤샤프트
    2002-06-05|Publication of KR20020042467A
    2007-10-04|Application granted
    2007-10-04|Publication of KR100760764B1
    优先权:
    申请号 | 申请日 | 专利标题
    DE10059213.9|2000-11-29|
    DE10059213A|DE10059213A1|2000-11-29|2000-11-29|Preparing solid composition of poorly soluble compounds, useful e.g. for carotenoid animal feed additives, by flocculating a dispersion with protective colloid|
    DE10129713A|DE10129713A1|2001-06-22|2001-06-22|Preparations based on water-soluble or -insoluble active agents, for use in foods, animal feed, pharmaceuticals or cosmetics, are obtained by flocculation together with protein-containing protective colloids|
    DE10129713.0|2001-06-22|
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