EP1545488A1

EP1545488A1 - Choline ascorbate formulations

Info

Publication number: EP1545488A1
Application number: EP03769301A
Authority: EP
Inventors: Andreas Habich; Morten M. Hansen; Carsten L. Hansen; Brigitte Yde; Alfred Oftring; Michael SCHÖNHERR; Felicitas Guth; Oliver Hasselwander
Original assignee: BASF SE
Current assignee: BASF SE
Priority date: 2002-09-24
Filing date: 2003-09-22
Publication date: 2005-06-29
Also published as: AU2003277884A1; US20060153912A1; WO2004028525A1; JP2006503842A; CN1700912A; DE10244397A1

Abstract

The invention relates to novel formulations comprising choline ascorbate, methods for production and use thereof in foodstuffs or fodder, or as adjuncts for foodstuffs or fodder or pharmaceuticals.

Description

Choline-Formulierunqen

The invention relates to novel formulations containing choline ascorbate; Process for their production and their use in food or feed or food or feed supplements or pharmaceuticals.

Choline {[(H ₃ C) ₃ N ⁺ -CH ₂ -CH ₂ -OH] OH ^~ } is the basic component of the phospholipids of the phosphoglyceride type and is widespread in the plant and animal kingdom. Choline acts as an important factor in biochemical processes such as methylation. Its deficiency leads to the formation of fatty liver in animals.

Choline is mainly used in the form of choline chloride or choline bitartrate in medicinal products against arterial calcification and liver parenchyma damage. Choline chloride is an important feed additive in animal nutrition.

Choline salts of organic acids, e.g. the above-mentioned choline bitartrate, or choline salicylate, choline hydrogen citrate and choline ascorbate are among others. described in EP-A-0 812 821.

Low-odor choline chloride, bitartrate and dihydrogen citrate with a trimethylamine content of less than 0.2 ppb are described in WO-A-00748986.

Solid choline chloride formulations are known from WO-A-91/15198, in which solid choline chloride is provided with a wax coating. In particular, the β-polymorphic form of glyceryl tristearate is proposed as the covering material.

Choline ascorbate (CAS) is characterized by the fact that it combines two active ingredients that are important for human and animal nutrition - choline and L-ascorbic acid (vitamin C) - in one molecule.

The synthesis of choline ascorbate is described in US-A-2, 823, 166, CH 490322 and FR 1, 242,805. The synthesis of a particularly pure, crystalline choline ascorbate is described in DE-A-101 090 73.

A particular problem with choline ascorbate is its limited thermal and oxidative stability, which changes in particular after a certain time, among other things due to occurrence of discoloration. Solid choline ascorbate, for example, shows a brownish color on the surface after only a few days at 40 ° C and the presence of air humidity. Similar undesirable discolorations are observed in choline ascorbate solutions after some time.

In contrast, other choline salts, e.g. the choline bitartrate, but also L-ascorbic acid and other salts, e.g. Sodium ascorbate, much more stable in color.

Little is known about these decomposition reactions of choline ascorbate. It can be assumed that the presence of the quaternary ammonium (choline) counterion accelerates subsequent oxidative reactions in the ascorbic acid part of the molecule or that amine components released by thermal elimination also cause intensely colored secondary products of ascorbic acid.

This color instability of choline ascorbate is, for example, prohibitive for its use in vitamin formulations.

Choline ascorbate, in particular its crystalline form, is not only sensitive to light and air but also very hygroscopic. In addition, solid, crystalline choline ascorbate has poor flow properties, so that classification is very complex.

Brief description of the invention:

It was therefore an object of the present invention to provide choline ascorbate formulations which at least in part no longer have the disadvantages of the prior art described above.

Surprisingly, it has been possible according to the invention to provide solid choline ascorbate formulations which, in comparison to crude, non-formulated choline ascorbate, have a lower sensitivity of the choline ascorbate to one or more of the external stress factors air, light, moisture, temperature, pH, metal , especially heavy metals, etc.

A “choline ascorbate formulation” in the sense of the present invention includes all formulations which contain choline ascorbate and / or an ascorbate-containing choline salt mixture from a choline salt other than choline ascorbate with ascorbic acid and / or a salt of Contain ascorbic acid. These ascorbate-containing choline salt mixtures can in principle contain choline salt and ascorbic acid or ascorbic acid salt in any molar ratio, such as 1: 3 to 3: 1 or 1: 2 to 2: 1; however, essentially equimolar mixing ratios are preferred.

In a first preferred embodiment, the invention relates to a solid, for example particulate, choline ascorbate-containing formulation comprising choline ascorbate and at least one formulation aid, which is characterized in that it has such a color stability that a solution of this formulation under standard conditions (ie a solution of this formulation in water-methanol (1: 1) in a proportion of about 10% by weight, based on the total weight of the solution; prepared by stirring the formulation in the solvent for 15 minutes at room temperature and, if appropriate, removing undissolved constituents of the formulation) i) a Gardner color number (determined according to DIN ISO 4630 or ASTM D 1544-80) of <4.5, preferably <4, in particular 0.05 to 3 or 0.1 to 2, and / or ii) a color number according to Hazen (determined according to DIN-ISO 6271 or ASTM D 1045-68,

ASTM D 263-49 or ASTM D 1209-69) of <800, preferably <700, in particular 10 to 400 or 20 to 350 or 25 to 300.

A further embodiment of the invention relates to a solid, for example particulate, choline ascorbate-containing formulation comprising choline ascorbate and at least one formulation aid, which is characterized in that it does not melt when stored under standard conditions in moist ambient air. In particular, no dissolving or complete dissolving of the formulation is visually recognizable. No filterable (separable) liquid phase can be observed after storage. Standard storage conditions mean storage of the formulation over a period of 72 hours at room temperature (20-25 ° C) in a humid gas atmosphere, e.g. Air, with a relative gas humidity φ of about 76%, which is established over a saturated aqueous saline solution.

The invention relates in particular to solid formulations which are characterized in that a) choline ascorbate is surface-coated with an inert coating agent; b) choline ascorbate is embedded in an inert matrix; or c) a porous support is loaded with choline ascorbate, and the loaded support is optionally surface-coated with an inert coating agent. In this context, “inert” means in particular that there are essentially no interactions which impair the choline ascorbate stability against discoloration or decomposition.

According to a preferred embodiment of the invention, the formulation additionally comprises an effective amount of at least one additive which further reduces the tendency to discolour choline ascorbate. This additive which reduces the tendency to discolour choline ascorbate can e.g. be present in the mixture or as a mixed crystal with the choline ascorbate and / or in the surface coating, in the inert matrix or in the porous carrier. The stabilizer is preferably present in a proportion of about 0.05 to 30 mol%, based on the molar content of choline ascorbate.

Suitable stabilizers are preferably selected from sulfur-containing, phosphorus-containing or boron-containing compounds; Carboxylic acids and carboxylic acid derivatives; Vitamins and vitamin precursors and derivatives; Natural mixtures; hydroxy or alkoxy aromatic compounds; reductones; or mixtures thereof.

The sulfur-containing stabilizer is selected in particular from cysteine, cystine, N-acetylcysteine, thioglycolate, glutathione, dihydroliponic acid, lipoic acid, sodium dithionite, methionine and thiourea; and optionally salts of these compounds.

The phosphorus-containing stabilizer is selected in particular from phosphorous and hypophosphorous acid, as well as salts thereof. The boron-containing stabilizer is in particular phenylboronic acid and its salts. The stabilizing carboxylic acid or its derivative is selected in particular from uric, lactic, apple, citric and excess ascorbic acid, and ascorbyl palmitate; Examples of suitable derivatives of carboxylic acids are salts or esters, such as, for example, CC ^ alkyl or alkenyl esters. The stabilizing vitamins, vitamin precursors and derivatives are preferably selected from alpha, beta and gamma tocopherol, tocotrienol and water-soluble vitamin E derivatives, such as vitamin E succinate or phosphate; carotenoids; isoflavones; Flavonoids and other naturally occurring polyphenols, such as quercetin, epigallocatechin, gallates, ellagic acid and ferulic acid. A suitable stabilizing mixture of natural substances is, for example, a rosemary extract or green tea extract, as described, for example, in Martinez-Tome, M. et al., J. Food Prot. 2001, 64 (9): 1412-9. Stabilizing hydroxy- or alkoxy-aromatic compounds are selected from 6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline (ethoxyquin), t-butyl hydroxytoluene and t-butylhydroxyanisole. Hydroxyacetone can be mentioned as an example of a suitable reductone.

The stabilizer can also be a functional, stabilizing derivative of one of the above compounds.

Combinations of two or more of the stabilizing additives mentioned above can also be used according to the invention.

Furthermore, according to the invention, in the case of possible optical isomerism, all stereoisomeric forms, e.g. the L or the D isomer, but also stereoisomer mixtures, such as racemic mixtures, can be used.

Salts can be mentioned as examples of suitable functional derivatives of the above compounds. Salts of the above stabilizers are in particular alkali and alkaline earth metal salts, such as e.g. Sodium and potassium salts.

Preferred additives from the list above are S-containing species, such as in particular cysteine, N-acetylcysteine, dihydroliponic acid, glutathione or thioglycolate; and P-containing species such as hypophosphorous or phosphorous acid; and also carboxylic acids, such as ascorbic acid or its salts or esters.

Formulations according to the invention are preferably also characterized in that their choline ascorbate content is in a range from about 5 to 95% by weight, based on the total weight of the formulation.

According to a further preferred embodiment, coated formulations according to the invention are provided with a coating agent which comprises at least one compound selected from:

a) polyalkylene glycols, in particular polyethylene glycols, for example with a number average molecular weight of about 400 to 15,000, such as 400 to 10,000; b) polyalkylene oxide polymers or copolymers, for example with a number average molecular weight of about 4,000 to 20,000, in particular block copolymers of polyoxyethylene and polyoxypropylene; c) substituted polystyrenes, maleic acid derivatives and styrene-maleic acid copolymers; d) vinyl polymers, in particular polyvinylpyrrolidones, for example with a number average molecular weight of about 7,000 to 1,000,000; either alone or in combination with other compounds such as cellulose ethers or starches; e) vinylpyrrolidone / vinyl acetate copolymers, for example with a number average molecular weight of about 30,000 to 100,000; f) polyvinyl alcohols, for example with a number average molecular weight of about 10,000 to 200,000, and polyphthalic acid vinyl esters; g) hydroxypropylmethyl celluloses, for example with a number average molecular weight of about 6000 to 80,000; h) alkyl (meth) acrylate polymers and copolymers, for example with a number average molecular weight of about 100,000 to 1,000,000, in particular ethyl acrylate / methyl methacrylate copolymers and methacrylate / ethyl acrylate copolymers; i) polyvinyl acetate, for example with a number average molecular weight of about 250,000 to 700,000, optionally stabilized with polyvinylpyrrolidone; j) polyalkylenes, in particular polyethylenes; k) aromatic polymers, for example lignins; I) polyacrylic acids; m) polyacrylamides; n) polycyanoacrylates; o) phenoxyacetic acid-formaldehyde resins; p) cellulose derivatives, such as ethyl cellulose, ethyl methyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, cellulose tritphthalate; q) animal, vegetable or synthetic fats and modified fats, such as, for example, polyglycols, fatty alcohols, ethoxylated fatty alcohols, higher fatty acids;

Mono-, di- and triglycerides of higher fatty acids, for example glycerol monostearate, alkylaryl ethoxylates and coconut monoethanolamides; r) animal and vegetable waxes or chemically modified animal and vegetable waxes, such as beeswax, candelilla wax, carnauba wax, montan ester wax and rice germ oil wax, walnut, lanolin, jojoba wax, sasol wax; s) animal and vegetable proteins, such as gelatin, gelatin derivatives, gelatin substitutes, casein, whey, keratin, soy protein; Zein and wheat protein; t) mono- and disaccharides, oligosaccharides, polysaccharides, such as hyaluronic acid, pullulan, elsinan, starches, modified starches, and pectins, alginates, chitosan, carrageenan; u) vegetable oils, such as sunflower, thistle, cottonseed, soybean, corn germ, olive, rapeseed, linseed, olive tree, coconut, palm oil; synthetic or semi-synthetic oils, such as medium-chain triglycerides or mineral oils; animal oils such as herring, sardine and whale oil; v) hardened (hydrogenated or partially hydrogenated) oils / fats, such as, for example, of the abovementioned, in particular hydrogenated palm oil, hydrogenated cottonseed oil, hydrogenated soybean oil; w) lacquer coatings, such as terpenes, in particular shellac, tolu balsam, Peru balsam, sandarak, and silicone resins; x) fatty acids, both saturated and mono- and polyunsaturated C ₆ to C ₂₄ carboxylic acids; y) silicas;

and mixtures thereof.

Adding plasticizers or emulsifiers to fats or waxes before coating may be advantageous to improve the flexibility of the film.

According to a further preferred embodiment, formulations are provided in which the choline ascorbate is embedded in a matrix which comprises at least one compound according to the general definition above, which is used to form a, for example in the range from about 20 to 100 ° C. or 30 to 100 ° C solid matrix is suitable.

A further preferred embodiment relates to formulations containing choline ascorbate, the choline ascorbate being carried by a preferably porous carrier.

Further preferred embodiments relate to solid choline ascorbate formulations which comprise combinations of the features described above. For example, formulations based on porous carriers or formulations which comprise choline ascorbate embedded in a matrix can additionally be provided with a coating agent to treat choline ascorbate e.g. to further stabilize or to give the product modified processing properties.

The solid choline ascorbate formulations according to the invention can be prepared in a variety of ways. Non-limiting examples of suitable manufacturing methods include:

a method of coating solid choline ascorbate particles by coating them a) sprayed with a melt, a solution or a dispersion of a coating agent as defined above in a fluidized bed or performing a powder coating with the coating agent in a fluidized bed; or b) coated in a mixer with a melt, a solution or a dispersion of the coating agent or performing a powder coating with the coating agent, and the coated material obtained in each case is optionally dried, cooled, tempered and / or freed from coarse fractions;

a process in which solid choline ascorbate particles are suspended in a melt comprising a (meltable) coating agent as defined above, the suspension thus obtained is divided and then solidified;

a process in which solid choline ascorbate particles are dispersed in a lipophilic environment, the solid / oil droplets thus obtained are emulsified in an aqueous phase and the emulsion is spray-formulated;

a method in which choline ascorbate particles are coated by coacervation;

a process in which an aqueous protective colloid solution is prepared, choline ascorbate is dissolved or dispersed therein and the mixture obtained is then spray-dried;

a process in which an aqueous, aqueous-organic or organic solution containing choline ascorbate is spray-dried in a fluidized bed and optionally granulated or agglomerated by adding suitable additives;

a process in which a solution, emulsion or suspension comprising choline ascorbate is mixed with a porous carrier and optionally dried; or applying a melt comprising choline ascorbate to the porous support;

a method wherein wet granules comprising a solution containing choline ascorbate or a melt containing choline ascorbate and a carrier; or a moist granulate comprising crystalline choline ascorbate is produced, the wet granulate is extruded, optionally aftertreated, dried and then optionally coated; a process in which an aqueous solution of choline ascorbate is prepared, this is emulsified in a hydrophobic melt and the emulsion solidifies; such as

a process in which a melt comprising choline ascorbate, optionally dispersed in a coating agent and / or optionally in the presence of a powdering agent, is atomized in a cold gas stream.

a process in which an aqueous, aqueous-organic or organic solution of choline ascorbate is evaporated in vacuo, if appropriate in the presence of a carrier and / or of additives, to give a solid. The solid can then, optionally with the addition of a binder, be agglomerated, granulated, compacted and, if necessary, comminuted again, classified and optionally coated with a protective layer.

The above production processes can in particular also be used to produce formulations which contain at least one of the stabilizers mentioned above.

For example, a stabilized formulation containing choline ascorbate can be prepared by i) solid choline ascorbate or a mixture of a solid choline salt with solid ascorbic acid and / or solid ascorbic acid salt with an effective amount of a stabilizing additive as defined above in solid or liquid form mixed; and optionally drying the mixture; or ii) dissolves or disperses an effective amount of a stabilizing additive as defined above in an aqueous, aqueous-alcoholic or alcoholic solution of choline ascorbate or a mixture of a choline salt with ascorbic acid and / or a salt thereof; and the solution or dispersion is optionally concentrated to dryness (preferably to an amorphous solid) or the stabilized formulation crystallizes out of the solution; or iii) a melt or supercooled melt of choline ascorbate or of a mixture of a choline salt with ascorbic acid and / or an ascorbic acid salt is mixed with an effective amount of at least one stabilizing additive as defined above and the mixture is optionally solidified.

These stabilized solids can then be processed using one of the methods described above. The invention also relates to food or feed which, in addition to conventional food or feed constituents, contains a formulation containing choline ascorbate as defined above in a proportion of about 0.001 to 50% by weight, such as. B. 0.5 to 40 wt .-% or 1 to 20 wt .-%, contain. Foodstuffs according to the invention in particular also include baby food.

Another object of the invention relates to food or feed supplements which, in addition to conventional food or feed supplement ingredients, contain a formulation containing choline ascorbate as defined above in a proportion of about 0.01 to 99.9% by weight, such as. B. 0.5 to 80 wt .-% or 5 to 50 wt .-%, contain.

Another object of the invention relates to drugs in solid, liquid or pasty form, which in an pharmaceutically acceptable carrier an effective amount, such as. 0.1 to 99.9% by weight, e.g. B. 1 to 80 wt .-% or 5 to 60 wt .-%, contain a choline ascorbate-containing formulation as defined above.

Finally, the use of a formulation containing choline ascorbate according to the above definition for the production of food and feed as well as food and feed supplements or pharmaceuticals is a further subject of the invention.

Detailed description of the invention

A) Choline ascorbate

In the processes according to the invention, choline ascorbate is used in solid, dissolved or molten form. Solid choline ascorbate can be amorphous or crystalline. A preferred crystalline choline ascorbate is described for example in the older DE-A-101 090 73.

The crystals described therein show the most intense line in the 2 Röntgen X-ray

Powder diffractogram in the range between 3.40 and 4.70 Ä a line at d = 3.80 Ä. The crystalline choline ascorbate also has an intensity ratio of the diffraction lines at d = 3.80 Å and d = 4.55 Å of at least 0.5, preferably at least 0.6, particularly preferably at least 0.7 and at d = 3.80 A. and d = 4.67 A of at least 0.4, preferably at least 0.5, particularly preferably of at least 0.6. In addition to the diffraction lines at d = 3.80, 4.55 and 4.67 A, the crystals have further lines at d = 3.46, 3.78, 6.91, 8.49 and 10.29 Ä.

The choline ascorbate crystals have a purity of> 98%, preferably> 99%, particularly preferably> 99.5%.

This crystalline choline ascorbate is prepared by reacting ascorbic acid with trimethylamine and ethylene oxide, the reaction in the temperature range from - 20 ° C to 80 ° C, preferably -10 ° C to 40 ° C, particularly preferably in the temperature range from 0 ° C to 30 ° C is carried out.

The process is further characterized in that the reaction is carried out in water, in a water-miscible organic solvent or in a mixture of water and a water-miscible organic solvent. The water content in the solvent can be between 0 and 50% by weight, preferably between 0 and 10% by weight.

Suitable water-miscible solvents are, above all, water-miscible, thermally stable, volatile solvents containing only carbon, hydrogen and oxygen, such as alcohols, ethers, esters, ketones and acetals. Solvents which are at least 10% water-miscible, have a boiling point below 200 ° C. and / or have less than 10 carbons are preferably used. Methanol, ethanol, n-propanol, isopropanol, 1, 2-butadiol-1-methyl ether, 1, 2-propanediol-1-n-propyl ether, tetrahydrofuran or acetone are particularly preferably used. Methanol and ethanol are particularly preferred.

The molar ratio of the reactants trimethylamine: ascorbic acid: ethylene oxide is in the range from 0.9-1, 1: 0.9-1, 1: 0.9-2.0, preferably in the range from 1: 1: 1, 2, particularly preferably in the range of 1: 1: 1.05.

The choline ascorbate is preferably crystallized in one of the abovementioned solvents used for the reaction.

It is also possible to first trimethylamine and ethylene oxide in a water-miscible organic solvent or in a mixture of water and a water-miscible organic solvent at temperatures in the range from -20 ° C. to 80 ° C. preferably -10 ° C to 40 ° C, particularly preferably in the temperature range from 0 ° C to 30 ° C and then convert this solution into choline ascorbate by adding a stoichiometric amount of ascorbic acid and then crystallize it out.

As a further possible production variant, choline chloride with sodium ascorbate in water, in a water-miscible organic solvent or in a mixture of water and a water-miscible organic solvent at temperatures in the range from -20 ° C. to 80 ° C., preferably -10 Convert ° C to 40 ° C, particularly preferably in the temperature range from 0 ° C to 30 ° C to crystalline choline ascorbate. The sodium chloride formed in this way is e.g. filtered off.

As already stated above, the invention also extends to the use of mixtures of choline salts (different from choline ascorbate) with ascorbic acid and / or ascorbic acid salts. Examples of choline salts which are suitable according to the invention include: choline chloride, choline bitartrate, tricholine citrate, bis-choline tartrate, bis-choline hydrogen phosphate, choline hydrogen phosphate, bis-choline hydrogen citrate, choline dihydrogen citrate, choline gluconate, choline salicylinate, choline tinoloxinate, choline tinolinoxymate, choline cellulose chlorate.

Examples of suitable ascorbic acid salts are alkali and alkaline earth metal salts, such as sodium ascorbate.

B) Stabilizing additives

The suitability of a compound as a choline ascorbate stabilizing, i.e. the tendency to discolouration of choline ascorbate, additive in formulations according to the invention can be determined in a simple manner by testing a choline ascorbate solution under standardized conditions in the presence of the additive for its tendency to discolour.

The addition preferably comprises at least one stabilizer which causes a 50% by weight aqueous methanolic solution of choline ascorbate or an ascorbate-containing choline salt mixture as defined above in the presence of a certain amount of the stabilizer, such as 1% by weight, based on the total weight of the solution under standard conditions (heating to a temperature of 65 ° C over a period of 7 hours) iii) a color number according to Gardner (determined according to DIN ISO 4630 or ASTM D 1544-80) of <6.3, preferably <5, in particular 0.05 to 3 or 0.1 to 2 and / or iv) a color number according to Hazen (determined according to DIN-ISO 6271 or ASTM D 1045-68, ASTM D 263-49 or ASTM D 1209-69) of <1000, preferably <980, in particular 10 to 400 or 20 to 350 or 25 to 300.

According to a further preferred embodiment, the addition comprises at least one stabilizer which causes a 10% by weight aqueous-methanolic (preferably 1: 1 v / v) solution of choline ascorbate or a mixture of at least one choline salt different from choline ascorbate with ascorbic acid and / or an ascorbic acid salt in the presence of a certain amount of the stabilizer, such as. B. 1 wt .-%, based on the total weight of the solution, under standard conditions (heating to a temperature of 65 ° C, over a period of 7 hours).

i) a Gardner color number (determined according to DIN-ISO 4630 or ASTM D 1544-

80) of <2.0, preferably <1, 5, in particular 0.05 to 1, 5 or 0.1 to 1, 0 and / or ii) a Hazen color number (determined in accordance with DIN-ISO 6271 or ASTM D 1045-68, ASTM D 263-49 or ASTM D 1209-69) of <300, preferably <250, in particular 10 to 50 or 20 to 100 or 25 to 50.

According to the invention, stabilizers are also suitable which have a more negative redox potential than ascorbic acid.

Stabilizers which can be used according to the invention are in the formulations in a proportion of about 0.05 to 30 mol%, preferably about 0.1 to 15 mol% or 0.5 to 10 mol%, in each case based on the molar content of choline ascorbate, or on a different choline salt (when using an ascorbate-containing choline salt mixture).

C) Coating materials

Examples of suitable polyalkylene glycols a) include: polypropylene glycols and in particular polyethylene glycols of different molecular weights, such as, for. B. PEG 4000 or PEG 6000, available from BASF AG under the trade names Lutrol E 4000 and Lutrol E 6000. Examples of the above polymers b) are: polyethylene oxides and polypropylene oxides, ethylene oxide / propylene oxide mixed polymers and block copolymers, composed of polyethylene oxide and polypropylene oxide blocks, such as, for. B. Polymers available from BASF AG under the trade names Lutrol F68 and Lutrol F127.

Of the polymers a) and b) can preferably highly concentrated solutions of up to about 50 wt .-%, such as. B. about 30 to 50 wt .-%, based on the total weight of the solution, can be used advantageously.

Examples of the above polymers d) are: polyvinylpyrrolidones, such as those sold by BASF AG under the trade names Kollidon or Luviskol. Of these polymers, highly concentrated solutions with a solids content of about 30 to 40% by weight, based on the total weight of the solution, can advantageously be used.

An example of the abovementioned polymers e) is a vinylpyrrolidone / vinyl acetate copolymer which is sold by BASF AG under the trade name Kollidon VA64 or Kollicoat SR. Highly concentrated solutions of about 30 to 40% by weight, based on the total weight of the solution, of these copolymers can be used particularly advantageously.

Examples of the above polymers f) are: Products such as those sold by Hoechst under the trade name Mowiol. Of these polymers, solutions with a solids content in the range from about 8 to 20% by weight can advantageously be used.

Examples of suitable polymers g) are: hydroxypropylmethyl celluloses, such as z. B. are sold by Shin Etsu under the trade name Pharmacoat.

Examples of the above-mentioned polymers h) are: alkyl (meth) acrylate polymers and copolymers whose alkyl group has 1 to 4 carbon atoms. Specific examples of suitable copolymers are: ethyl acrylate / methyl methacrylate copolymers, which are marketed, for example, by BASF AG under the trade name Kollicoat EMM 30D or under the trade name Eudragit NE 30 D by Röhm; as well as methacrylate / ethyl acrylate copolymers, such as those from BASF AG under the trade name Kollicoat MAE 30DP or under the trade name Eudragit 30/55 are sold by Röhm. Such copolymers can be processed, for example, as 10 to 40% by weight dispersions according to the invention.

Examples of the above polymers i) are: polyvinyl acetate dispersions which are stabilized with polyvinylpyrrolidone and are marketed, for example, by BASF AG under the trade name Kollicoat SR 30D (solids content of the dispersion about 20 to 30% by weight).

Examples of suitable cellulose derivatives p) include, in particular, cellulose ethers, such as methyl and ethyl cellulose, hydroxypropyl and hydroxypropyl methyl cellulose

(HPMC), e.g. the commercial products of the Methocel, Bebecel and Pharmacoat series; but also microcrystalline cellulose (MCC), e.g. Avicel PH101 or PH 102.

Examples of suitable saccharides t) are alginates, carrageenan, starch and starch derivatives, such as e.g. Esterification products of starch; Gums such as acacia, xanthan and guar gums, as well as gums from Ceratonia siliqua (locust bean gum), hyaluronic acid, pullulan, el-sinan.

Examples of suitable waxes r) include animal waxes such as lanolin, beeswax and walrus; vegetable waxes such as candelilla wax, carnauba wax and rice germ oil wax; and chemically modified waxes such as jojoba wax, sasol wax and montan ester wax.

Examples of suitable oils u) are vegetable oils, such as sunflower, thistle, cottonseed, soybean, corn germ, olive, rapeseed, linseed, olive tree, coconut, oil palm and oil palm oil; animal oils such as Herring, sardine and whale oil; and hydrogenated products derived therefrom; as well as semi-synthetic oils such as medium chain triglycerides and mineral oils. Examples of suitable commercial products are Coatex 01 and 21, Akofine R and Akocote RT

Finished coating compositions, such as e.g. Sepifilm LP consisting of HPMC (70-90%), MCC (8-12%), stearic acid (5-15%) and titanium dioxide (10-20%); or Luster Clear LC 104, consisting of MCC, carrageenan, lactose, soybean lecithin and propylene glycol alginate.

Protective colloids are an independent group of suitable materials. Synthetic and biological polymers are suitable for this purpose. Examples of synthetic po- polymers are neutral polymers such as Kollidon, Luviskol, Lutrol and Mowiol, anionic polymers such as Kollicoat, Eudragit L and polyaspartic acid, and cationic polymers such as terpolymer and Eudragit E. Suitable proteinaceous biopolymers are gelatin, casein and whey, soybean protein and wheat protein ; Suitable polysaccharides are anionic compounds such as gum arabic, HPMC, pectins, alginates, modified starch and shellac; and cationic polysaccharides such as chitosan.

Further suitable coating agents and methods for coating can be found in R. Voigt, Textbook of Pharmaceutical Technology, 1975, Verlag Chemie, in particular chapters 9.4, 9.5, 9.6 and 10.2.

D) carrier

The formulations according to the invention can also contain carriers. For this, e.g. Usual inert carriers can be used. An "inert" carrier must not show any negative interactions with the components used in the formulation according to the invention and must be suitable for use as an auxiliary in the respective uses, e.g. in food, food supplements, animal feed, feed additives, pharmaceutical and cosmetic preparations.

Examples of suitable carrier materials are: low molecular weight inorganic or organic compounds and high molecular weight organic compounds of natural or synthetic origin.

Examples of suitable low molecular weight inorganic carriers are salts such as sodium chloride, calcium carbonate, sodium sulfate and magnesium sulfate or kieselguhr or silicas such as silicon dioxide or silica gels or silica derivatives, such as e.g. Silicates.

Examples of suitable organic carriers are, in particular, sugars, such as, for. B. glucose, fructose, sucrose, dextrins, starch products, especially corn starch and cellulose preparations. Examples of other organic carriers are: corn spindle flour, ground rice husks, semolina bran or cereal flour, such as. B. wheat, rye, barley and oatmeal or bran or mixtures thereof. Further suitable porous carriers are known, for example, from US Pat. No. 6,251,478, as are methods for loading such carriers. Reference is hereby made to the disclosure of this document. The carrier material can be present in the formulation according to the invention on a dry basis in a proportion of about 5 to 95% by weight, preferably about 10 to 85% by weight.

The particle size of the carrier can range, for example, from about 30 to 2500 μm, e.g. 50 to 2000 microns.

Adsorbates according to the invention are preferably based on silica carriers.

E) Other additives

In addition to the components described above, such as choline ascorbate, carrier, stabilizer and coating agent, the formulations according to the invention can contain further additives. Examples include preservatives, antibiotics, antimicrobial additives, antioxidants, chelating agents, physiologically acceptable salts, flavors, colorings and the like. Nutritionally relevant additives can also be present, such as vitamins (for example vitamins A, B _{1 F} B ₂ , B _β , Bι ₂ , C, D ₃ , and / or E, K ₃ , folic acid, nicotinic acid, pantothenic acid) ; Taurine, carboxylic acids and their salts, such as, for example, tricarboxylic acids, such as citrate, isocitrate, trans / cis aconitate, and / or homocitrate, enzymes, carotenoids, minerals, such as, for example, P, Ca, Mg and / or Fe and trace elements, such as Se, Cr, Zn, Mn, proteins, carbohydrates, fats, amino acids. Pyruvic acid, L-carnitine, lipoic acid, coenzyme Q10, aminocarboxylic acids such as, for example, creatine, orotic acid, myoinositol, flavonoids, betaine, p-aminobenzoic acid can also be present.

In addition, "active ingredients" can be included which support the use of the formulation according to the invention in pharmaceutical preparations or whose effect is used to treat diseases, in particular the treatment of cancer, diabetes, AIDS, allergies and cardiovascular diseases.

The above additives, including carrier, coating agent and stabilizer, are also referred to as formulation auxiliaries in the context of the invention.

F) Formulation routes

The choline ascorbate formulations according to the invention are based on solid, ie crystalline or amorphous choline ascorbate, liquid choline ascorbate forms such as solutions gene, dispersions, suspensions or emulsions, or based on choline ascorbate melts. Choline ascorbate does not have to be in pure form for this, but can be used in a mixture with other substances which can be used according to the invention, such as stabilizers or processing aids. For the sake of simplicity, the following sections only refer to choline ascorbate, which should not be interpreted restrictively.

Various formulation paths are now described in more detail. Deviations from this are of course conceivable and can easily be carried out by a person skilled in the art on the basis of the present invention. He can also use extensive specialist literature, e.g. Mollet, formulation technology, publisher Wiley-VCH, Weinheim or Heinze, manual of agglomeration technology, publisher Wiley-VCH, Weinheim; or Hager's Handbuch der Pharmaceuticalen Praxis, Springer-Verlag, Heidelberg.

Unless otherwise stated, the formulation processes described below are not only applicable to choline ascorbate in pure form but also to mixtures of choline ascorbate with other active substances and / or to additives which e.g. to stabilize the formulation, to regulate the bioavailability, or to change its color, to name just a few examples.

1. Encapsulation based on choline ascorbate crystals

1.1 Presentation of the crystals in a fluidized bed or a mixer with simultaneous / subsequent coating of the crystals

Encapsulations can be carried out in mixers or fluidized beds, among other things.

i) Description of mixer:

Mixers which operate batchwise or continuously are preferably used for this purpose. The active ingredient (ie choline ascorbate) is optionally presented together with additives, such as carrier material. Plowshares, shovels, snails or the like ensure a more or less intensive product mixing. Classic examples are ploughshare mixers, cone screw mixers or similar devices. Very flat, box-shaped or trough-shaped designs with one or more screws can also be used. Other designs are high-speed mixers, such as the Turbolizer ® Mixer / Coater from Hosokawa Micron BN. as well as all types of drum coaters. Alternatively, the product can be mixed by moving the entire container. Examples include tumble mixers, drum mixers or the like. Another option is to use pneumatic mixers (see Ullmann's Encyclopedia of Industrial Chemistry, Sixth Edition, Mixing of Solids).

The application of coatings or coatings (in the broadest sense of coating, polymers, waxes, oils, fats, fatty acids etc.) serves to protect the active ingredient, as well as to delay or accelerate the release of the active ingredient, to strengthen the mechanism of action or to achieve additive effects , In individual cases, it is necessary to add powdering agents, such as talc, silicates or the like, when applying the coatings or immediately afterwards, in order to avoid sticking.

The coating material is metered / added, optionally together with additives, as a rule via devices for dropping or spraying. Examples of this are lances, shower heads, single-substance or multi-substance nozzles, in rare cases rotating drip or atomizing devices. In the simplest case, addition is also possible locally as a concentrated jet. Alternatively, the coating material can first be placed in the mixer in order to then add the active ingredient. Another possibility is the addition of initially solid coating material, which melts as a result of the wall heating or due to mechanical energy input and coats the active ingredient.

The coating or coating materials are added at overpressure, normal pressure or under vacuum against atmosphere, preferably at normal pressure and vacuum.

In individual cases, it is advantageous to preheat or cool the active ingredient and / or casing material (change in viscosity, change in wetting properties, influence on the solidification properties) and supply or withdraw heat via the container wall and / or the mixing tools. In some cases it is necessary to remove water or solvent vapor.

To improve the coating properties, it may be advantageous to evacuate the mixer and, if necessary, to cover it with protective gas, such as nitrogen or noble gas. Depending on the carrier material, this must be repeated several times. Active ingredients and envelopes are preferably added at different locations in the mixer.

ii) Description of fluidized bed:

The production can be carried out discontinuously or continuously in fluidized beds. The particles are moved by the fluidizing gas, which can be hot or cooled as required. The fluidizing gas is e.g. Air or inert gas (usually nitrogen but also other conventional inert gases) are suitable. In individual cases, it makes sense to add or remove heat via the container wall and via heat exchanger surfaces immersed in the fluidized bed. Suitable fluidized beds and the necessary peripherals are known from the prior art.

Installations that support a defined product movement often have a favorable effect. Examples of this are rotating displacement bodies or so-called sausage tubes and the like.

The batchwise or continuous metering and, if appropriate, the preheating of the active ingredients and additives can be carried out using the devices described above, which are known to the person skilled in the art.

In individual cases, coated active ingredients can advantageously be produced in a combination of mixer and fluidized bed. The reasons for such a combination are also state of the art and known to the person skilled in the art.

For example, a raw granulate containing choline ascorbate crystals and conventionally produced can be placed in a fluidized bed. This is swirled and coated by spraying on an aqueous or non-aqueous, preferably aqueous, solution or dispersion of an organic polymer. For this purpose, preferably a highly concentrated, still sprayable liquid, such as. B. a 10 to 50 wt .-% aqueous or non-aqueous solution or dispersion of at least one polymer which is selected from polymers de groups a) to f), i) and j) described above.

According to another preferred process variant, a 10 to 40% by weight, preferably about 20 to 35% by weight, sprayable aqueous is used for coating or non-aqueous solution or dispersion of at least one polymer which is selected from polymers of groups g) and h) described above.

In general, aqueous solutions or aqueous dispersions will be preferred for the following reasons: No special measures are necessary to work up or recover the solvents; no special explosion protection measures are required; some coating materials are preferably offered as aqueous solutions or dispersions.

In special cases, however, the use of a non-aqueous solution or dispersion can also be advantageous. The coating material dissolves very well or an advantageously large proportion of the coating material can be dispersed. In this way, a spray liquid with a higher solids content can be sprayed, which leads to shorter process times. The lower enthalpy of evaporation of the non-aqueous solvent also leads to shorter process times.

It is particularly preferred to apply coating materials which are physiologically compatible and contain no water or solvents and thus e.g. can be applied as a melt. Examples of these are the above-mentioned fats, waxes, fatty acids, etc., which of course can contain additives, if necessary. Particularly suitable additives are surface-active substances, such as emulsifiers, which have a favorable effect on the spreading properties of the coating material on the choline ascorbate. Combinations of coating materials which can be sprayed on together or in succession are known to the person skilled in the art. The same applies to influencing the coating quality by changing the process parameters, such as spray pressure, concentration or viscosity of the liquid, spray duration, intermediate spray pauses for solidification or tempering processes.

Dispersions which can be used according to the invention are obtained by dispersing the above polymers in an aqueous or non-aqueous, preferably aqueous, liquid phase, optionally with the use of a conventional dispersing aid, or by providing the above-mentioned waxes or fats as a melt. The spraying of a polymer solution, melt or dispersion is preferably carried out in such a way that the choline ascorbate in solid form (crystals, amorphous solid, optionally in a mixture with auxiliaries or carriers, preferably as raw granules) is placed in a fluidized bed apparatus and, while heating, the Sprayed on the sprayed product. The energy is supplied in the fluidized bed apparatus by contact with heated drying gas, often air. A forward The solution or dispersion can then be useful if it sprays sprayed material with a higher dry matter content or if a reduction in viscosity can be achieved. If organic liquid phases are used, solvent recovery is advisable. The product temperature during the coating can range from about 35 to 50 ° C. In the fluidized bed apparatus, the coating can in principle be carried out using the bottom spray process (nozzle sits in the inflow floor and sprays upwards), the top spray process (coating is sprayed into the fluidized bed from above) or from the side.

According to a second preferred embodiment of the process for fluidized bed coating according to the invention, the raw product is placed in a fluidized bed and powder-coated. The powder coating is preferably carried out with a powder of a solid polymer selected from hydroxypropylmethyl celluloses (HPMC) with a number average molecular weight of about 6,000 to 80,000; mixed with a plasticizer. All other coating materials, which can be in powder form and cannot be applied either as a melt or as a highly concentrated solution (e.g. the case with HPMC, hydroxypropylmethyl cellulose), are also suitable for powder coating.

The powder coating is preferably carried out in such a way that the coating material is metered continuously into the raw product presented in the fluidized bed. The fine particles of the coating material (particle size in the range of about 10 to 100 μm) lie on the relatively rough surface of the raw granulate. The coating material particles are glued to one another by spraying in a plasticizer solution. Examples of suitable plasticizers are polyethylene glycol solutions, triethyl citrate, sorbitol solutions, paraffin oil and the like. To remove the solvent, the coating is carried out with gentle heating. The product temperature can be less than about 60 ° C, such as. B. at about 40 to 50 ° C.

In principle, the powder coating can also be carried out in a mixer. In this case, the powder mixture is metered in and the plasticizer is also injected with a nozzle. Drying takes place by supplying energy via the wall of the mixer and, if necessary, via the stirring tools. Here too, as with coating and drying in a fluidized bed, low product temperatures must be observed. According to a third preferred embodiment of the method according to the invention, the raw product placed in a fluidized bed or mixer is coated by means of a melt. The melt preferably comprises at least one polymer which is selected from

- Polyalkylene glycols, especially polyethylene glycols, with a number average molecular weight of about 1,000 to 15,000, such as. B. about 1,000 to 10,000; and polyalkylene oxide polymers or copolymers, with a number average molecular weight of about 4,000 to 20,000, in particular block copolymers of polyoxyethylene and polyoxypropylene.

The melt coating in a fluidized bed is preferably carried out in such a way that the raw product to be coated is placed in the fluidized bed apparatus. The coating material is melted in an external reservoir and pumped to the spray nozzle, for example, via a heatable line. Heating the nozzle gas is advisable. Spray rate and inlet temperature of the melt must be set so that the coating material still runs well on the surface of the granulate and covers it evenly. It is possible to preheat the granules before spraying the melts. In principle, the melt coating can also be carried out using the bottom spray process or the top spray process. The melt coating in a mixer can be carried out in two different ways. Either the raw product to be coated is placed in a suitable mixer and a melt of the coating material is sprayed into the mixer. Another possibility is to mix the coating material in solid form with the product. By supplying energy via the container wall or the mixing tools, the coating material is melted and thus coats the raw product. Depending on your needs, some release agent can be added from time to time. Suitable release agents are, for example, silica, talc, stearates and tricalcium phosphate.

The polymer solution, dispersion or melt used for coating may optionally contain further additives, such as. B. microcrystalline cellulose, talc and kaolin can be added.

The proportion by weight of the coating to the total weight of the coated product is in the range from about 1 to 85% by weight, preferably 3 to 50% by weight or 5 to 40% by weight, based on the total weight of the finished product. The residual moisture content of the polymer coated product is primarily determined by the hygroscopicity of the polymer material. In general, the residual moisture content is in the range of about 1 to 10 wt .-%, such as. B. 1 to 5 wt .-%, based on the total weight of the coated product.

1.2 Suspending the choline ascorbate crystals in melts with subsequent atomization / division and solidification of the melts

Another alternative is to suspend the choline ascorbate crystals (produced by crystallization, precipitation, drying at normal pressure or in vacuo) or amorphous choline ascorbate in melts from fats, oils, waxes, lipids, lipid-like and lipid-soluble substances with a melting point that is smaller than the melting point of choline ascorbate. These suspensions are then atomized in a cold gas stream - with and without the use of powdering agents - so that coated choline ascorbate powder is formed.

The melts are preferably produced in a first step before the choline ascorbate crystals are added and suspended. The suspension can be carried out batchwise in the stirred tank or continuously, e.g. in suitable pumps, or, in the case of sufficiently high turbulence, simply in injectors and pipes. The use of static mixers is less preferred, but not excluded. The measures for any necessary protective heating of the required system parts - including the lines and atomizing elements - are known to the person skilled in the art.

Air and nitrogen are preferred as the cooling gas. The gas flow can take place in cocurrent, countercurrent or crossflow. The process can be carried out in classic spray towers, prilling towers or other containers. Fluidized beds with and without hold-up (template material) are also suitable. The process can be operated batchwise or continuously. The separation of the solid is e.g. possible in cyclones or filters. Alternatively, the solid matter can be collected with and without after-cooling in fluidized beds or mixers.

Suitable atomizing elements are nozzles (single and dual-substance nozzles or special designs) as well as atomizing wheels or atomizing disks or atomizing baskets - or special designs thereof.

Another alternative is the division and solidification of these hydrophobic melts in liquids, preferably in liquids in which choline ascorbate and the shell material are poorly soluble. Examples of such liquids are, for example, liquid nitrogen, ethanol, isopropanol, butanol, acetone and dichloromethane. Classic solid-liquid separation with subsequent drying then leads to the desired dry powder.

1.3 Disperse the crystals in a lipophilic environment and emulsify these crystal oil droplets in an aqueous protective colloid / sugar phase followed by a spray formulation

Very fine-grained choline ascorbate (produced by precipitation, crystallization, spray drying or grinding) is produced with and without the addition of emulsifiers / stabilizers in a lipophilic environment (such as melting from fats, oils, waxes, lipids, lipid-like and lipid-soluble substances with a melting point that is lower as the melting point of choline ascorbate - hereinafter referred to as oil) initially dispersed. In a further process step, these oil droplets containing the crystalline solid are emulsified in an aqueous protective colloid / sugar phase and then spray-formulated.

With regard to the production and composition of the protective colloid / sugar mixture and the implementation of the spray formulation, the following section 2.2. directed.

1.4 Encapsulation by coacervation

The encapsulation of suspended choline ascorbate particles is accomplished using the coacervation method. This process is carried out using a dispersion liquid containing the coating material in dissolved or colloidal form and choline ascorbate solid particles. Encapsulation of the choline ascorbate particles is induced by reducing the solubility of the coating material. The technique of coacervation is described, for example, in Voigt, Textbook of Pharmaceutical Technology, Verlag Chemie, Chapter 2.4, to which reference is hereby expressly made.

2. Encapsulation, starting from an aqueous solution

2.1 Spray formulation of a protective colloid / sugar / choline ascorbate / water mixture which may contain additives (such as antioxidants, salts)

The process is carried out in accordance with EP-A-0 074 050 or DE-A-101 58 046.0 from BASF AG, to which express reference is hereby made. The production of spray-formulated products takes place in that in a first step an aqueous solution of a protective colloid, preferably gelatin and / or gelatin derivatives and / or gelatin substitutes, such as pectins and gum arabic, with the addition of one or more substances from the group of mono-, di - Or polysaccharides, if necessary also with the addition of corn starch. By adding choline ascorbate, e.g. as a crystalline solid (which will then completely or partially dissolve) or as an aqueous solution, and optionally other additives, such as hydrophilic or hydrophobic stabilizers or antioxidants, a dispersion is then formed with stirring, the aqueous solution of the Colloids represent the homogeneous phase of the dispersion. This dispersion is then spray formulated.

As spray aids such. B. a hydrophobic silica, corn starch or metal salts of higher fatty acids. It is also conceivable to use modified corn starch, talc, hydrophilic silica, tri-calcium phosphate and calcium silicates or

Mixtures of two or more of these substances. Mixtures of the fatty acids and silicas mentioned can also be used for the process. Calcium or magnesium stearate, for example, are suitable as metal salts of the higher fatty acids having 16 to 18 carbon atoms.

Animal proteins such as gelatin, for example from 50 to 250 bloom, or casein are preferred as colloids. The amount of colloid used is generally 5 to 50% by weight, based on the end product, with water contents of the dispersion of 30 to 70% by weight. Alternatively, other protective colloids (selected from the examples listed above) can be used.

The spraying aid can be introduced in an amount of 0.01 to 0.25 times the amount by weight, based on the dispersion, above the fluidized bed with uniform distribution into the spraying space. The spray aids are introduced directly into the spray zone. The layer of the spraying aid which is produced during the spraying stabilizes the particles to such an extent that the particles do not converge when they are touched in the non-solidified state. This makes it possible to carry out direct drying on a subsequent fluid bed dryer. The design of the atomizing unit has no decisive influence on the product. For example, devices such as those described in EP-A-0 074 050 can be used here.

In a process variant, the spray-formulated products can be prepared by spraying the dispersion in a spray tower with the use of a spraying aid and collecting the sprayed particles in a fluidized bed. A hydrophobic silica or the metal salt of a higher fatty acid, e.g. with 16 to 18 carbon atoms or mixtures with hydrophobic silica, in 0.02 to 0.15 times the amount by weight, based on the dispersion (and in the absence of substantial amounts of other conventional spray aids such as starch powder) above the fluidized bed with uniform distribution in the Spray room, and at temperatures at which the possibly gelling colloid of the sprayed particles does not solidify. The particles loaded with the spray aid, the colloid mass of which is essentially not gelled, are collected in a fluidized bed and the particles are dried in a fluidized bed in a manner known per se.

The design of the atomizing unit has no decisive influence on the product. For example, nozzles or rapidly rotating atomizing disks can be used. The temperature of the dispersion to be atomized is also not a critical variable. It is usually 30 to 90 ° C, which gives viscosities of 50 to 1200 mPas for the colloids mentioned. It is crucial that at the time of spraying the particles come into contact with the hydrophobic spraying aid, which is introduced directly into the spraying zone in finely divided form.

The great advantage of the process is that the temperature in the spray room no longer has to be so low that the active ingredient dispersion gels, or that it is no longer necessary to remove so much water from large amounts of auxiliary powder that the droplets solidify. The process enables, for example, spraying at temperatures of 25 to 30 ° C of active ingredient dispersions that no longer solidify even at refrigerator temperatures (+4 ° C). The quantities of spray aid required for this are only 0.02 to 0.15 times the dispersion.

In a further process variant, the spray-formulated product can be produced by spray cooling. In this case, a dispersion containing a protective colloid is preferably produced by means of an atomizing nozzle or an atomizing wheel with a temperature ture, which is above the gel point of the emulsion, for example 30 ° C to 90 ° C and at a viscosity of preferably between 50 and 600 mPas, sprayed in a spray chamber in which the temperature is between 0 ° C and 40 ° C, whereby you get microcapsules.

A spraying aid, e.g. Corn starch or modified corn starch, optionally in a mixture with other spray aids, can be blown into the spray chamber in order to prevent agglomeration of the gelatinized microcapsules and adherence to the chamber walls. The spray aid is preferably added in an amount of 5 to 50%, based on the weight of the end product.

The microcapsules can then be transferred to a fluidized bed, in which they can be dried to a residual water content of between 0 and 10% (preferably between 2 and 5%) if necessary and in which excess spray aid is separated off. The temperature of the drying air is preferably between approximately 0 ° C. and approximately 100 ° C.

A particularly preferred variant is the spray formulation of a highly concentrated solution of choline ascorbate according to the method described above. For this purpose, a solution of choline ascorbate containing 40 to 99% by weight of choline ascorbate in solvent, such as e.g. Water, preferably 60 to 99% by weight, particularly preferably 80 to 95% by weight of choline ascorbate in water. By adjusting the solution temperature, the viscosities suitable for atomization can be achieved. For example, an aqueous solution with a solids content of 95% by weight and a viscosity of less than 1000 mPas can be obtained at temperatures of 60 ° C. If necessary, stabilizing additives are added to this solution. The solution thus obtained can now be spray-formulated using a single-component nozzle at elevated pressure (e.g. between 3 and 300 bar) with the simultaneous use of powdering agents such as hydrophobic silica (e.g. Sipernat D17 from Degussa) or modified corn starch. The particles thus obtained are collected and e.g. dried in the fluidized beds described above or in vacuum equipment and, if necessary, subsequently with a protective layer, such as described above, coated.

It is also conceivable that, based on R.A. Morten: Fat-Soluable Vitamins, Permonon Press, 1970, pages 131 to 145 produces dispersions / emulsions of solid choline ascorbate and then, as described, produces powders according to the invention from them.

2.2 Production of a spray granulate or agglomerate with subsequent coating In this process, an aqueous choline ascorbate solution is added to a fluidized bed and this is converted into a powdery solid. The fluidized bed can again be operated batchwise or continuously. The aqueous choline ascorbate solution is preferably sprayed onto a template in the fluidized bed. The template can be represented by choline ascorbate itself or by a carrier material. It is also possible to start up without a template. The solution can be sprayed again in top spray or bottom spray mode. Atomizing elements inserted laterally in the container wall are also possible. It may be advantageous to adjust the distance between the atomizing elements and the fluidized solid according to the properties of the solid (eg tendency to granulate). Atomizing nozzles are preferably used as atomizing elements (pressure nozzles, such as single-substance nozzles, two-substance nozzles or special designs). The process can be operated with and without dust recirculation.

The person skilled in the art is able to favorably influence the properties of the solids by setting the process parameters and by choosing the right additives. So it is e.g. possible to produce compact granules with high particle and bulk density as well as agglomerates with excellent instant and / or tableting properties.

The desired particle size of the end product can be set within wide limits. The average particle size can be between 20 μm and 5000 μm. It is preferably between 50 μm and 2000 μm and particularly preferably between 150 μm and 600 μm.

If the desired average particle size is, for example, approximately 400 μm, it may be advantageous to start with an average particle size of the original material of approximately 30 to 50 μm. B. by an upstream grinding of coarse choline ascorbate or inert carrier material or z. B. by spray drying in the same or in another suitable apparatus. Under certain circumstances, the original material is also obtained as a cleaning material from filters or cyclones or other solid matter separators or can be bought in in a suitable particle size, which arises from other processes.

The use of special template material can be omitted in continuous processes but also in discontinuous processes if the parameters are selected appropriately.

By spraying the aqueous choline ascorbate solution or by spraying binding liquid alone, it is now possible to produce the desired agglomerates or granules. It is of course possible to coat the solid powder produced with a protective layer in the same or in a different apparatus.

A particularly interesting variant consists in the addition of additives to the aqueous choline ascorbate solution, which on the one hand favorably influence the crystal structure (crystalline or amorphous) and the undesirable tendency of the choline ascorbate to discolor.

Additives to influence the crystal structure (size and / or shape) are known. These are multiply charged ions, organic molecules or surfactants. A distinction is made between so-called tailor-made and multi-functional additives. Tailored additives are very similar to the building blocks of the crystal. They are adsorbed on the growth areas, slow down the growth there and thus enlarge this area. Auxiliary ingredients of up to 10% are required to completely inhibit growth. Multifunctional additives are used more often than custom-made ones, especially for inorganic crystals. Mostly polyphosphonates or polycarboxylates, e.g. Polyacrylates. These polyelectrolytes wet the growth areas and block growth there. Amounts in the ppm range are often sufficient.

In principle, partial or complete replacement of water with organic solvents is also possible.

It is also conceivable the method described in other apparatus, such as. B. mixers to perform.

In a further variant, the above-mentioned protective colloids, sugars, emulsifiers, stabilizers, etc. can be added to the solution prior to the injection or can be supplied separately by an alternative atomizing device.

2.3 Formulation of a choline ascorbate solution with a carrier

Another variant is the addition of the choline ascorbate solution to a carrier. Porous support materials are preferably used. The mixers and fluidized beds described above under point 1.1 are suitable as devices for producing these formulations. Inert materials are usually used as carriers. An "inert" carrier must not show any negative interactions with the components used in the formulation according to the invention and must be harmless for use as an adjuvant in the respective uses, for example in foods, food supplements, animal feed, feed additives, pharmaceutical and cosmetic preparations.

Examples of suitable carrier materials are: low molecular weight inorganic or organic compounds and high molecular weight organic compounds of natural or synthetic origin. Examples of suitable low molecular weight inorganic carriers are salts such as sodium chloride, calcium carbonate, sodium sulfate and magnesium sulfate or kieselguhr or silicas such as silicon dioxide or silica gels or silica derivatives, such as e.g. Silicates.

Examples of suitable organic carriers are, in particular, sugars, such as, for. B. glucose, fructose, sucrose, dextrins, starch products, especially corn starch and cellulose preparations. Examples of other organic carriers are: corn spindle flour, ground rice husks, semolina bran or cereal flour, such as. B. wheat, rye, barley and oatmeal or bran or mixtures thereof.

Examples of preferred porous supports are silicas, e.g. the Sipernat products from Degussa or the Tixosil products from Rhodia, Lyon.

The carrier material can be present in the formulation according to the invention, based on the dry basis, in a proportion of approximately 10 to 85% by weight, preferably approximately 20 to 85% by weight.

2.4 Production of granules or extrudates

For this purpose, for example from a choline ascorbate solution, carriers (such as corn starch or microcrystalline cellulose) and binding substances (such as HPMC, HPC or HMC), a wet granulate is first produced in a mixer. In a further process step, these moist granules are then shaped in an extruder (meat grinder, basket extruder, twin-screw extruder, etc.), optionally aftertreated (compacting, rounding, etc.), dried (for example again in a fluidized bed or a contact dryer) and if necessary coated again. Suitable devices are, for example, those of the NICA-System ® series from Aeromatic-Fielder. The production of granules can also be achieved by introducing carriers and optionally additives in a mixer and, after adding solid choline ascorbate and binder (preferably binding liquid - in the simplest case water), producing compact granules.

The mixer is preferably a paddle mixer or ploughshare mixer. The liquid components are added (dropped or sprayed on) so that a pasty, sticky phase is formed. The paste-like phase is broken up by suitable selection of the speed of the mixing tools and / or high-speed knives and compact granules are formed. Very large chunks are cut up using mixing tools and knives. On the other hand, fine powders are agglomerated.

The mode of operation is discontinuous or continuous. It is often necessary to add or remove heat using a heating jacket. The decisive step is the combination of binding fluid, mechanical energy input through mixing tools and knives and determination of the required granulation time

A coating can be applied downstream in the mixer at a lower speed of the mixing tools and stationary knives or in a downstream mixer of similar design.

The shaping can also be done by pressing the pasty, sticky phase through the die of an extruder. The process is characterized by the fact that extrudates are formed, which are dried if necessary and then coated.

2.5 Emulsifying a choline ascorbate solution in wax with subsequent shaping

Analogous to point 1.2, but starting from the aqueous, aqueous-organic or organic choline ascorbate solution, in a first step, with and without the addition of auxiliaries (emulsifiers, stabilizers), an emulsion of the choline ascorbate in melts from fats, oils, waxes, lipids , lipid-like and lipid-soluble substances. The subsequent shaping takes place again in a cold gas flow according to point 1.2.

3. Encapsulations based on a melt 3.1 Production of a choline ascorbate / wax / fat dispersion with subsequent atomization / division and solidification

An anhydrous melt of choline ascorbate is added with the addition of auxiliaries e.g. dispersed in melts from fats, oils, waxes, lipids, lipid-like and lipid-soluble substances with a melting point that is greater or less than the melting point of choline ascorbate. These dispersions are then atomized in a cold gas stream - with and without the use of powdering agents - so that coated choline ascorbate powder is formed. With regard to the further procedure, reference can be made to the explanations under point 1.2.

3.2. Production of choline ascorbate solids in a vacuum apparatus and optionally subsequent granulation / agglomeration / compacting and optionally with subsequent coating.

In this process, an aqueous solution of choline ascorbate or a solution of choline ascorbate in aqueous organic or organic solvents is evaporated to a solid in a vacuum apparatus, if appropriate using carriers and additives. The solid can be agglomerated, granulated, compacted and, if necessary, comminuted, classified and, if necessary, coated with a protective layer in the same apparatus or in another apparatus, optionally with the addition of binders.

Suitable apparatuses are, for example, classic vacuum dryers, as are known to the person skilled in the art. The choline ascorbate can be presented as a solution or else as a solid. The wall temperature is preferably not above the melting temperature of the choline ascorbate, since decomposition must be expected at higher temperatures. The process is preferably carried out in a pressure range between normal pressure and technically possible negative pressure, particularly preferably at a pressure between 0 and 500 mbar, absolute. A preferred variant is the use of inert gas, such as nitrogen, as stripping gas in order to minimize oxygen and water vapor partial pressure in the vacuum apparatus. If necessary, the desired particle size is set in the vacuum apparatus by adding binding liquid or it is compacted, agglomerated or granulated in downstream apparatus and, if necessary, the resulting particles are coated. 3.3 Spraying and solidifying a melt in the presence of a powdering agent that is incorporated and, if necessary, takes on the function of a coating

A melt of choline ascorbate is atomized, if necessary with the addition of additives, in a cold gas stream - with and without the use of powdering agents, so that coated choline ascorbate powder is formed. The powdering agents (cf. above information) are suitable to prevent only surface solidified drops from flowing together as necessary. SiO ₂ may be mentioned here as an example of a suitable powdering agent.

3.4 Dripping / spraying a melt onto a porous support

Analogous to point 2.3, but with the difference that a choline ascorbate melt is used instead of a solution, emulsion or suspension, choline ascorbate is added to a, preferably porous, carrier and processed further.

3.5 Production of granules / extrudates

Analogous to the procedure according to point 2.4, but using a choline ascorbate melt, corresponding granules / extrudates are produced.

G) Applications of choline ascorbate formulations according to the invention

Choline ascorbate formulations according to the invention, like conventional choline preparations, are used as an additive in food and feed or as an additive in food and feed supplements, such as e.g. Multivitamins. For this purpose, the formulation stabilized according to the invention can be incorporated in the desired amount and in a manner known per se into conventional food and feed or food and feed supplements.

In addition, the choline ascorbate formulations according to the invention are suitable for the production of medicaments, such as in particular preparations for the treatment and / or prevention of cirrhosis or other liver diseases. Potential areas of application include: improving cognitive functions; Treatment and / or prevention of various forms of dementia or Alzheimer's disease; so- like other neurodegenerative diseases; and lowering plasma homocysteine levels and the associated prevention of cardiovascular diseases.

Dietary supplements can also be used for the purpose according to the invention.

The pharmaceutical compositions according to the invention for the treatment of an individual, preferably a mammal, in particular a human, useful or domestic animal, can be produced in a manner known per se. Thus, the stabilized choline ascorbate is usually administered in the form of pharmaceutical compositions which contain a pharmaceutically acceptable excipient with at least one choline ascorbate according to the invention.

Formulation and optionally include other active ingredients. These compositions can be administered, for example, by the oral, rectal, transdermal, sublingual, buccal, subcutaneous, intravenous, intramuscular or intranasal routes.

Examples of suitable pharmaceutical formulations are solid pharmaceutical forms, such as powders, powders, granules, tablets, troches, sachets, cachets, dragees, film-coated tablets, capsules such as hard and soft gelatin capsules, suppositories or vaginal pharmaceutical forms, semi-solid pharmaceutical forms such as ointments, creams, hydrogels, pastes or plasters, and liquid pharmaceutical forms, such as solutions, emulsions, in particular oil-in-water emulsions, suspensions, for example lotions, injection and infusion preparations, eye and ear drops. Implanted delivery devices can also be used for the administration of formulations according to the invention. Liposomes, microspheres or polymer matrices can also be used.

In the preparation of the compositions, choline ascorbate formulations according to the invention are usually mixed or diluted with an excipient. Excipients can be solid, semi-solid or liquid materials that serve as vehicles, carriers or media for the active ingredient.

Suitable excipients include, for example, lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia, calcium phosphate, alginates, tragacanth, gelatin, highly disperse silicon dioxide, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone and its derivatives, cellulose and its derivatives, water, alcohol-water -Mixtures, syrups and methyl cellulose. Furthermore, the formulations can be pharmaceutically acceptable carriers or customary auxiliaries, such as lubricants, for example talc, magnesium stearate, oils of vegetable origin and mineral oil; Wetting agents; emulsifying and suspending agents; preservatives such as methyl and propyl hydroxybenzoates; antioxidants; Antiirritatives; chelating agents; coating aids; Emulsion stabilizers film formers; gelling agents; Odor masking agents; masking flavors; resins; Hydrocolloids; Solvents; Solubilizing agents; Neutralizing agents; permeation; pigments; quaternary ammonium compounds; Refatting and overfatting agents; Ointment, cream or oil base materials; Silicone derivatives; spreading aids; stabilizers; Sterilanzien; Fundamentals of the suppository; Tablet excipients such as binders, fillers, lubricants, disintegrants or coatings; Propellant; Desiccant; Opacifiers; Flow regulators, thickeners; waxes; plasticizers; Include white oils. A relevant design is based on professional knowledge, such as in Fiedler, HP, Lexicon of auxiliary substances for pharmacy, cosmetics and related areas, 4th edition, Aulendorf: ECV-Editio-Cantor-Verlag, 1996, or Hager's Handbuch der Pharmaceuticals Praxis , Springer Verlag, Heidelberg is shown. The excipients can be used individually or in a mixture.

The present invention will now be explained in more detail with reference to the following exemplary embodiments.

General Information:

Unless otherwise stated, the following experiments use choline ascorbate (CAS) with a melting point of 120 to 130 ° C.

The choline ascorbate crystals used in the formulation examples were obtained by cooling crystallization from methanolic solution with subsequent solid / liquid separation and drying.

The CAS solution used in the examples was in each case an aqueous solution. The composition of the solution was usually 40% water and 60% choline ascorbate. The solution was prepared from the above-mentioned choline ascorbate crystals by adding water. If necessary, additives were added to the solution to avoid the tendency to discoloration.

If a CAS melt was assumed in the examples, the above-mentioned choline ascorbate crystals were optionally heated in a mixture with a stabilizer as defined above and heated to above their melting point. Example 1:

Determination of the stability of choline compounds in solution

Solid choline ascorbate is first prepared in a manner known per se according to DE-A-101 090 73. 0.2 mol of trimethylamine in methanol (25% by weight) was admixed with 0.2 mol of ascorbic acid while cooling to 0 ° C. 0.2 mol of ethylene oxide was gassed into this mixture in such a way that the reaction temperature did not exceed 0-5 ° C. After the end of the reaction, the reactor was flushed with nitrogen and further stirred at a temperature between 0 and 5 ° C. The choline ascorbate formed crystallized out of the reaction mixture, was filtered off, washed with methanol and recrystallized again in methanol for further purification. Colorless crystals were obtained in a yield of 80% with a melting point between 123.5 ° and 124.4 ° C. The crystals were characterized as choline ascorbate (anhydrous) by means of elemental analysis, ¹³ C-NMR spectroscopy and single crystal structure analysis.

A 50% solution (in water / methanol 1: 1) of this choline ascorbate (melting point 123-124 ° C) is stirred for several hours at reflux (65 ° C) in an air atmosphere. At the start of the test and after various reaction times, the degree of discoloration is determined using the Gardner color number (DIN-ISO 4630) or Hazen color (DIN-ISO 6271).

Analogously, 50% aqueous methanolic solutions of L (+) - ascorbic acid, sodium ascorbate, and choline bitartrate are examined. The results are summarized in Table 1 below.

Table 1

The test results illustrate the surprisingly high instability of unstabilized choline ascorbate compared to other choline compounds or ascorbic acid, the instability of which was already known.

Example 2:

Preparation of a stabilized choline ascorbate solution

A 50% solution (in water / methanol 1: 1) of choline ascorbate (melting point 123 - 124 ° C), prepared as in Example 1, is without or with a weight percent of various stabilizing additives for several hours at reflux (65 ° C) stirred in an air atmosphere. The stabilizing effect of the respective additive is observed by determining the color number, as described in Example 1.

In addition to additive and reaction time, the following table 2 lists the Gardner and Hazen color numbers as a function of time as evidence of the stabilizing effect of the respective additive.

Table 2

The data in Table 2 above confirm the completely surprising finding according to the invention that despite its extremely strong tendency to discolour, choline ascorbate can be stabilized in an advantageous manner by adding small amounts of suitable stabilizers.

Example 3:

Preparation of a solid stabilized choline ascorbate

Choline ascorbate is transferred to an aqueous solution, a stabilizer according to the invention is added and the mixture is concentrated (vacuum, T = 70-80 ° C.). After cooling, the stabilized product crystallizes out.

Example 4 Preparation of a choline ascorbate formulation by fluid bed coating with a fat

The product to be coated was a supercooled melt of choline ascorbate and cysteine or a crystal mixture thereof, each containing 98% by weight of CAS and 2% by weight of cysteine (with an average particle size of approx. 300 μm). A fat with a melting point of 60 to 64 ° C. (Rucawar FH from Aarhus Olie, Denmark) was used as the coating material.

A laboratory fluidized bed from Niro-Aeromatic, type MP-1, was available for carrying out the experiment. A plastic cone with an inflow floor diameter of 110 mm and a perforated floor with 8% free area were used as the receptacle.

The choline ascorbate (500 g) placed in the fluidized bed was heated to 40 ° C. product temperature while being vortexed with an air volume of 30 m ³ / h. The fat (125 g) was melted in a beaker in an oil bath at 80 ° C and sprayed onto the choline ascorbate at 2 bar spray pressure with heated spray gas from 85 - 90 ° C by vacuum suction via a heated line in a top spray process with a 1.2 mm two-component nozzle , During the spraying process, the air volume was increased to 100 m ³ / h to ensure thorough mixing and an even coating layer. The spray duration was 5 minutes, the product temperature being 40 to 43 ° C and the supply air temperature being approximately 40-50 ° C. Example 5:

Formulation example - multivitamin tablet

A multivitamin tablet of the following composition:

ß-Ca rotin 5 mg

Vitamin E 10 mg

Vitamin C 60 mg

Vitamin D 1, 2 mcg

Thiamine 1.4 mg

Riboflavin 1.6 mg

Pyridoxine HCI 2.2 mg

Vitamin Bι ₂ 1 mcg

Niacin 18 mg

Pantothenic acid 6 mg

Folic acid 200 mcg

Biotin 150 mcg stabilized choline ascorbate 150 mg (prepared according to Example 4) magnesium 100 mg

Zinc 15 mg

Manganese 2.5 mg

Selenium 62 mcg

is prepared in a manner known per se using customary formulation auxiliaries known to the person skilled in the art.

Example 6:

Formulation example - B group vitamin tablet

A vitamin tablet of the following composition:

Vitamin C 500 mg

Thiamine 100 mg Riboflavin 100 mg Vitamin B ₆ 100 mg

Vitamin Bι ₂ 500 mcg

Niacin 100 mg

Pantothenic acid 100 mg

Folic acid 400 mcg

Biotin 50 mcg stabilized choline ascorbate 500 mg (prepared according to Example 4) is prepared in a manner known per se using customary formulation auxiliaries known to the person skilled in the art.

Examples 7a and 7b: Coating choline ascorbate in the fluidized bed

Equipment and procedure as in Example 4. The temperatures and spraying times were adjusted. 400 g of choline ascorbate-containing solid were placed in the cone.

Examples 8a and 8b:

Coating choline ascorbate in a stirring flask a) The product to be coated was again choline ascorbate according to Example 4. 50 g of the solid were placed in a four-necked reaction flask and heated to 60 ° C. in an oil bath with stirring.

Beef tallow with a melting point of 56 - 60 ° C (Edenor NHTI-G from Henkel / Cognis) was used as the coating material. The beef tallow was melted in a beaker at a temperature of 80 ° C. 12.5 g of the Edenor NHTI-G melt was dropped onto the stirred choline ascorbate using a pipette in the four-necked flask. The stirring speed was 250-300 rpm. After adding the melt, the choline ascorbate coated with the beef tallow was cooled with stirring and the melt solidified. Choline ascorbate particles with about 20% coating were obtained.

b) The experiment was repeated with the addition of 33.5 g of the Edenor NHTI-G melt to 50 g of choline ascorbate under comparable conditions. Choline ascorbate particles with about 40% coating were obtained.

Examples 9a to 9c

Coating choline ascorbate in a stirring flask

Equipment and procedure as in Example 8. The temperatures were adjusted to the melting points. Place 50 g of choline ascorbate according to Example 4 in a four-necked reaction flask.

Examples 10a and 10b:

Spray granulation of aqueous choline ascorbate solution in the fluidized bed

a) A laboratory fluidized bed from Niro-Aeromatic, type MP-1, was available for carrying out the experiment. A plastic cone with an inflow floor diameter of 110 mm and a perforated floor with 8% free area were used as the receptacle.

300 g of choline ascorbate (cf. Example 4) were filled into the cone of the fluidized bed as the starting material. 300 g of the same solid was dissolved in 129 g of drinking water.

The choline ascorbate (300 g) placed in the fluidized bed was heated to 47 ° C. product temperature with an air flow of 30-40 m ³ / h. The product temperature was measured in the fluidized bed. The aqueous choline ascorbate solution was sprayed at 1.5 bar spray pressure using a two-component nozzle (nozzle diameter 1.2 mm) by means of vacuum suction using the top spray method. The spraying time was approx. 35 min, the product temperature between 45 and 47 ° C and the supply air temperature approx. 58 - 66 ° C. A product discharge of 568 g of a fine white product was obtained. The loss on drying of the product was approx. 0.6%.

b) The above experiment was repeated without the presence of choline ascorbate in the fluidized bed. For this purpose, 500 g of choline ascorbate (see Example 4) were dissolved in 250 g of drinking water. With almost unchanged operating conditions, it was possible to test within approx. 160 min. to produce approx. 450 g of a white, granulated product. The loss on drying of the product was approx. 0.5%. Thin, loose deposits remained on the wall and filter in the system.

Since the spray granulation in the fluidized bed could be carried out without a template, proof is also provided that classic spray drying is possible under similar conditions.

Examples 11a and 11b:

Spray granulation of aqueous choline ascorbate solution in the fluidized bed with the addition of additives Equipment and procedure as in Example 10: Starting without a template.

Example 12:

Spray formulation of aqueous choline ascorbate solution in the fluidized bed

170 g of drinking water were placed in a beaker and 280 g of the choline ascorbate crystals (see Example 4) were slowly added and dissolved with stirring. An aqueous solution with a solids content of 62% was formed. This solution was sprayed at a temperature of 60 ° C. and a spray pressure of 4 bar with a single-component nozzle in a laboratory spray tower. During the spraying, hydrophobic silica (Sipernat D 17®, Degussa) was blown into the spray zone. A moist powder was obtained, which was then predried in a laboratory chute and dried to completion using a rotary evaporator at a water bath temperature of 50 ° C. and a pressure of 40 mbar within 5 h.

Example 13:

Preparation of a dissolved choline ascorbate formulation for color number determination

A solid CAS formulation is homogenized in a mortar and stirred in a solvent mixture of equal parts of water and methanol for 15 minutes at room temperature. The weight of the formulated product is chosen so that the resulting solution contains about 10% by weight of CAS. Any undissolved constituents are separated off. The Gardner and / or Hazen color number values are immediately determined from the resulting solution.

Example 14: Stabilization of choline ascobate or choline salt / ascorbic acid mixtures with additives

In the following investigations, the stabilizing effect on choline ascorbate and various choline salt / ascorbic acid mixtures was investigated. The test results are summarized in Table 3. The tests were carried out under the following conditions: 10% solutions in water / methanol (1: 1) - 7 h at 65 ° C.

Table 3

As can be seen from the color number values, the stabilizer not only makes choline ascorbate but also mixtures of other choline salts with ascorbic acid significantly more stable in color. Example 15

Determination of the stability to a solid choline ascorbate formulation

humidity

A few grams of a solid choline ascorbate formulated according to the invention are placed in a glass bowl so that the bottom of the bowl is evenly covered with the powdery solid. A desiccator is provided, the atmosphere of which is defined by a saturated aqueous saline solution located in the bottom of the desiccator. The gas atmosphere in the desiccator has a relative gas humidity of approx. 76%. The bowl of choline ascorbate is placed in the desiccator for 3 days and stored at room temperature.

After 3 days, the bowl with choline ascorbate is removed from the desiccator and assessed. Unformulated choline ascorbate is wholly or partly in the form of a liquid. Choline ascorbate formulated according to the invention is also present as a powdery solid after 3 days. A partial or complete flow or loosening of the formulation is not observed. However, the solid may have taken up water during storage and may have restricted flow properties. With filtration (with or without applying a water jet vacuum) via a filter chute, e.g. D2 (40-100 μm), no liquid phase can be separated from formulations according to the invention after standardized storage.

Claims

claims

1. Solid choline ascorbate formulation with reduced sensitivity to external stress factors.

2. Formulation according to claim 1, characterized in that a solution of this formulation under standard conditions i) a Gardner color number (determined according to DIN ISO 4630 or ASTM D 1544-80) of <4.5, and / or ii) one Hazen color number (determined according to DIN-ISO 6271 or ASTM D

1045-68, ASTM D 263-49 or ASTM D 1209-69) of <800.

3. Formulation according to claim 1 or 2, characterized in that it does not melt when stored under standard conditions in moist ambient air.

4. Formulation according to one of claims 1 to 3, characterized in that a) choline ascorbate is surface-coated with an inert coating agent; b) choline ascorbate is embedded in an inert matrix; or c) a porous support is loaded with choline ascorbate, and the loaded support is optionally surface-coated with an inert coating agent.

5. Formulation according to one of the preceding claims, characterized in that it additionally contains an effective amount of at least one additive which further reduces the tendency to discolour choline ascorbate.

6. Formulation according to Claim 5, characterized in that the additive which further reduces the tendency to discolour choline ascorbate is present in a mixture with the choline ascorbate and / or is contained in the surface coating, in the inert matrix or in the porous carrier.

7. Formulation according to claim 5 or 6, characterized in that the stabilizer in a proportion of about 0.05 to 30 mol%, based on the molar content of

Choline ascorbate is included.

8. Formulation according to one of claims 5 to 7, characterized in that the stabilizer is selected from sulfur-containing, phosphorus-containing or boron-containing compounds; Carboxylic acids and carboxylic acid derivatives; Vitamins and vitamin precursors and derivatives; Natural mixtures; hydroxy or alkoxy aromatic

Links; Reductones or mixtures thereof.

9. Formulation according to claim 8, characterized in that a) the sulfur-containing stabilizer is selected from cysteine, cystine, N-acetylcysteine, thioglycolate, glutathione, dihydroliponic acid, lipoic acid,

Sodium dithionite, methionine and thiourea; b) the phosphorus-containing stabilizer is selected from phosphorous and hypophosphorous acid; c) the boron-containing stabilizer is phenylboronic acid; d) the carboxylic acids and carboxylic acid derivatives are selected from urine,

Lactic, malic, citric and excess ascorbic acid; as well as ascorbyl palmitate; e) the vitamins, vitamin precursors and derivatives are selected from alpha, beta and gamma tocopherol, tocotrienol and more water-soluble vitamin E derivatives; carotenoids; isoflavones; Flavonoids and other naturally occurring polyphenols; f) the natural product mixture is a rosemary extract; g) the reductone is hydroxyacetone; and h) the hydroxy- or alkoxy-aromatic compounds are selected from 6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline (ethoxyquin), t-butylhydroxytoluene and t-butylhydroxyanisole; or the stabilizer is a functional, stabilizing derivative of one of the above compounds.

10. Formulation according to one of the preceding claims, characterized in that the choline ascorbate content is in a range from about 5 to 95% by weight, based on the total weight of the formulation.

11. Formulation according to one of the preceding claims, characterized in that it contains a coating composition comprising at least one compound selected from: a) polyalkylene glycols; b) polyalkylene oxide polymers or copolymers; c) substituted polystyrenes, maleic acid derivatives and styrene-maleic acid copolymers; d) vinyl polymers either alone or in combination with others

Compounds such as cellulose ethers or starches; e) vinyl pyrrolidone / vinyl acetate copolymers; f) polyvinyl alcohols and polyphthalic acid vinyl esters; g) hydroxypropylmethyl celluloses; h) alkyl (meth) acrylate polymers and copolymers; i) polyvinyl acetates, optionally stabilized with polyvinyl pyrrolidone; j) polyalkylenes; k) aromatic polymers;

I) polyacrylic acids; m) polyacrylamides; n) polycyanoacrylates; o) phenoxyacetic acid-formaldehyde resins; p) cellulose derivatives; q) animal, vegetable or synthetic fats and modified fats; r) animal and vegetable waxes or chemically modified animal and vegetable waxes; s) animal and vegetable proteins; t) mono- and disaccharides, oligosaccharides, polysaccharides; u) vegetable oils, synthetic or semi-synthetic oils and animal oils; v) hardened (hydrogenated or partially hydrogenated) oils / fats; w) paint coatings; x) fatty acids; y) silicas;

or mixtures thereof is coated.

12. Formulation according to one of claims 1 to 10, characterized in that

^' The choline ascorbate is embedded in a matrix which comprises at least one compound as defined in claim 11, which is used to form one at a

Temperature in the range of about 20 to 100 ° C solid matrix is suitable.

13. Formulation according to one of claims 1 to 10, characterized in that it comprises a porous carrier selected from silicates.

14. A process for the preparation of a formulation containing choline ascorbate according to one of the preceding claims, characterized in that solid choline ascorbate particles are coated by a) in a fluidized bed with a melt, a solution or a dispersion of a coating composition as defined in claim 11 sprayed or in a fluidized bed with a powder coating

Performs coating agent; or b) coated in a mixer with a melt, a solution or a dispersion of the coating composition or carrying out a powder coating with the coating composition; or c) mixed with fat and the fat by mechanical energy input and / or

Heating melts while mixing continues; and if necessary, the coated material obtained in each case is dried, cooled and / or freed from coarse fractions.

15. A process for the preparation of a formulation containing choline ascorbate according to one of claims 1 to 10, characterized in that solid choline ascorbate particles are suspended in a melt comprising a (meltable) coating agent as defined in claim 11, the suspension thus obtained is broken up and then froze.

16. A process for the preparation of a formulation containing choline ascorbate according to one of claims 1 to 10, characterized in that solid choline ascorbate particles are dispersed in a lipophilic environment, the solid / oil droplets thus obtained are emulsified in an aqueous phase and the emulsion is spray-formulated.

17. A process for producing a formulation containing choline ascorbate according to one of claims 1 to 10, characterized in that choline ascorbate particles are coated by coacervation.

18. A method for producing a formulation containing choline ascorbate according to any one of claims 1 to 10, characterized in that an aqueous protective colloid solution is prepared, choline ascorbate is dissolved or dispersed therein and the mixture obtained is then spray-formulated or spray-dried and then optionally coated.

19. A process for the preparation of a formulation containing choline ascorbate according to one of claims 1 to 10, characterized in that an aqueous solution containing choline ascorbate is spray-dried in a fluidized bed and granulated or agglomerated by adding suitable additives.

20. A process for the preparation of a formulation containing choline ascorbate according to one of claims 1 to 10, characterized in that a solution, emulsion or suspension comprising choline ascorbate is mixed with a porous carrier and optionally dried; or a choline ascorbate

Applies melt to the porous carrier.

21. A process for the preparation of a formulation containing choline ascorbate according to any one of claims 1 to 10, characterized in that wet granules comprising a solution or dispersion containing choline ascorbate or a melt containing choline ascorbate and a carrier, or containing solid, crystalline or amorphous, choline ascorbate , produces, extrudes the wet granules, optionally aftertreated, dries and then optionally coated.

22. A process for the preparation of a formulation containing choline ascorbate according to one of claims 1 to 10, characterized in that an aqueous solution of choline ascorbate is prepared, this is emulsified in a hydrophobic melt and the emulsion is solidified.

23. A process for the preparation of a formulation containing choline ascorbate according to one of claims 1 to 10, characterized in that a melt comprising choline ascorbate is atomized in a cold gas stream, optionally in the presence of a powdering agent.

24. Food or feed, characterized in that it contains, in addition to conventional food or feed components, a formulation containing choline ascorbate as defined in one of claims 1 to 13 in a proportion of about 0.001 to 50% by weight.

25. Food or feed supplement, characterized in that it contains, in addition to conventional food or feed supplement components, a formulation containing choline ascorbate as defined in one of claims 1 to 13 in a proportion of approximately 0.01 to 99.9% by weight ,

26. Medicament in solid, liquid or pasty form, characterized in that it contains an effective amount of a formulation containing choline ascorbate according to one of claims 1 to 13 in a pharmaceutically acceptable carrier.

27. Use of a formulation containing choline ascorbate according to one of claims 1 to 13 for the production of food and feed as well as food and feed supplements or medicaments.