EP2506726A1

EP2506726A1 - Composition acting as an emulsifier for water-soluble solubilisates of hydrophobic compounds

Info

Publication number: EP2506726A1
Application number: EP10785350A
Authority: EP
Inventors: Dariush Behnam
Original assignee: Aquanova AG
Current assignee: Aquanova AG
Priority date: 2009-12-01
Filing date: 2010-11-30
Publication date: 2012-10-10
Also published as: WO2011066937A1; DE202009016292U1

Abstract

The invention relates to a composition having an HLB value greater than 10, which acts as an emulsifier for a solubilisate of at least one raw material and/or active substance which is insoluble or only soluble with difficulty in water, and one or more sucrose esters of an edible fatty acid (E473) in combination with at least one constituent which is a carrier of at least one OH group, in particular water and/or ethanol and/or glycerol.

Description

Emulsifying composition for water-soluble solubilisates of hydrophobic compounds

DESCRIPTION:

1.) Fat absorption In contrast to the naturally water-soluble compounds, e.g. Ascorbic acid and B vitamins, the human organism to take lipophilic micronutrients, it must be converted in two steps in a water-soluble packaging.

In Figure 1, the absorption of fat-soluble compounds such as vitamins A, D, E and K (12) after oral intake (1) via the gastrointestinal tract (2), mucosa cell (3), Lympfweg (4) and blood (5) in a

Body cell (6) shown schematically.

Step 1 (1): Formation and reception of

physiological and / or product micelles (9)

Lipophilic micronutrients, such as vitamins A, D, E and K, but also carotenoids, omega-3 fatty acids, alpha-lipoic acid and coenzyme Q10, etc., can be produced almost exclusively with the help of bile salts, bile acids and the enzymes of the pancreas, which are indispensable for the formation of the so-called physiological micelle in the small intestine. Only in this way, or by such packaging, hydrophobic compounds, such as fat-soluble vitamins, various barriers of the intestinal mucosa can be overcome and absorbed. Through the process of micelle formation, the fat-soluble compounds, such as vitamins A, D, E and K, omega-3 fatty acid, alpha-lipoic acid, coenzyme Q10, etc. are brought into a water-soluble packaging form and can only in the thin water film of the cell membranes The mucosal cells (3) of the small intestine penetrate and be absorbed.

This 1st step; that is the icellierung of the lipophilic substances, is regarded as indispensable condition for the fat absorption and likewise as

Prerequisite for the following 2nd step.

Step 2 (8): Free, fat-soluble micronutrients (10) are made water-soluble by means of lipoprotein chylomircones and are thus removed from the lymphatic system (4).

recorded

After the absorption of the fat-soluble micronutrients in the cells of the small intestine they are there free and not in micellar bound form. Here, the fat-soluble micronutrients to be delivered into the blood (5) through which in the Intestinal cells formed transporter "Lypoproteine- Chylomikronen" again made water soluble.

Conclusion :

Like the compounds that are naturally present in water-soluble form, such as vitamin C and B vitamins, the fat-soluble ones can also be used

Micronutrients first through a water-soluble

Packaging like the micelle are absorbed.

FIG. 2 schematically shows on the left a conventional fine emulsion in aqueous solution and in the middle a micellar solution. The conventional fine emulsion in aqueous solution is cloudy and unstable, the

Absorption takes place only with the help of physiological

Micelle formation. The micellar solution is clear and stable, the absorption occurs without the physiological micelle formation. An assessment of the role of the micelle as a natural principle and, in comparison, the role of the applicant

Produtmicelle (10) of renowned scientists was presented together with the application for the file. 2.1 Conventional emulsion in aqueous solution

FIG. 3 shows photographic images of conventional emulsions in aqueous solution. 2.2 Micellar formulation in aqueous solution

FIG. 4 shows photographic images of micellar formulations in aqueous solution. 2.3 Carrier systems for fat-soluble substances:

FIG. 5 shows a comparison of AQUANOVA solubilisates with liposomes and conventional emulsions as a function of the particle size. Aquanova solubilisates (20) are acid stable, no phase separation. Nano / fine emulsions, ^v emulsions, liposomes (30) are acid unstable,

Phase separation in an acidic environment.

AQUANOVA solubilisates Conventional with emulsions,

Micellencharakteristik micro and

nanoemulsions

Optics Completely and water-insoluble irreversible (turbid to water-soluble, opalescent in completely transparent aqueous in aqueous solution media)

Stability Thermal, Mechanical Thermal,

and gastric acid stable mechanically unhod and microbiologically gastric acid less susceptible to instability and microbiologically susceptible

Characteristic for higher and faster low and oral application slow intestinal absorption

(Food) (without involvement of absorption (with

Bile acids) help the

Bile acids)

Characteristic for higher and faster low and dermal application penetration slow (Skin Care) Penetration

Incorporation into optimal and direct laborious and end products training in partial

End products, problematic regardless of the incorporation into the nature of the end product end product and without

matrix design

Loading capacity of micelles: 9200 nm ³ Liposomes: 5600 for outer diameter ³

diameter = 30

nm

Previously known micellar formulations as

Carrier systems:

Not least by various patent applications of the company AQUANOVA is known that with the aid of e.g. Polysorbates product micelles can be prepared in the context of this application. But it is also known that the polysorbates cause a significant sensory problem in the products in question (food,

Dietary supplements) and are also only partially approved.

It was also possible with the help of lecithin or

Phospholipids pseudo-micellar structures too

create, however, neither the necessary pH or

have thermal or mechanical stability. These are only included in aqueous solution

Room temperature and in the middle pH range relative clear. The described instability of this type of pseudomicella, which is destroyed in the gastrointestinal tract, no benefits and no optimization of fat absorption can be expected.

4.) Object of the invention:

The invention is due to the mentioned in the above-mentioned position 3 serious disadvantages of polysorbate or lecithin-containing micelle formers, the object of proposing a natural analogous carrier system "product micelle", which at least partially the replacement of polysorbates and / or phospholipids allows the creation of product micelles and, when used, leads to solubilisates which are found in foods or

Nutritional supplements have the required thermal, pH and mechanical stability and whose product micelles so intact after oral ingestion reaches the mucosa cells of the small intestine, thus absorbing the trapped in the micelle

Micronutrients, especially those of the fat-soluble

Vitamins such as vitamins A, D, E and K, carotenoids, omega-3 fatty acids, alpha-lipoic acid and coenzyme Q10, to optimize.

For this purpose, sugar esters of fatty acids (E 473) and auxiliaries are used. These form according to the invention, an emulator system by either individual sugar esters of fatty acids (E 473) or mixtures of at least two sugar esters of fatty acids, each in a

A composition combined with at least one further constituent, which carrier is at least one OH group, such as water and / or ethanol and / or Glycerol, are used as an emulsifier and are used in combination with polysorbates or in their place. Suitable sugar esters of fatty acids are, in particular, sucrose mono-laurate, sucrose-di-laurate,

Sucrose-mono-palmitate, sucrose-di-palmitate, sucrose-mono-

Stearate and sucrose-di-stearate. The effective as an emulsifier combination of at least one sugar ester

Fatty acids and a carrier of at least one OH group may further comprise at least one medium chain

Triglyceride (medium chain triglyceride, MCT).

The invention provides a composition having an HLB value greater than 10, which acts as an emulsifier for a solubilizate of at least one raw and / or active substance which is not or only sparingly soluble in water, and one or more sugar esters of a fatty acid (E 473) in combination with at least one constituent which is a carrier of at least one OH group, in particular water and / or ethanol and / or glycerol.

In particular, the composition may consist of one or more sugar esters of a fatty acid fatty acid (E 473) and at least one constituent which is a carrier of at least one OH group, in particular water and / or ethanol and / or glycerol.

The invention further provides a solubilizate which contains at least one raw and / or active substance which is insoluble or sparingly soluble in water, the raw and / or active substance being selected in particular from the coarse containing the vitamins A, D, E and K,

Carotenoids, flavonoids, omega-3 fatty acids, enzymes, coenzymes, dyes, plant extracts, 237

8th

Secondary plant substances (isoflavones), polyphenols,

essential oils and antioxidants such as alpha-lipoic acid and / or carnosic acid and quercetin, and wherein the solubilizate contains at least one emulsifier-acting composition described above. The solubilizate can in particular from the at least one raw and / or

Active substance which is insoluble or sparingly soluble in water, the raw and / or active substance being selected in particular from the coarse containing vitamins A, D, E and K, carotenoids, flavonoids, omega-3 fatty acids, enzymes, Coenzymes, dyes, plant extracts,

Secondary plant materials (isoflavones), polyphenols, essential oils and antioxidants such as alpha-lipoic acid and / or carnosic acid and quercetin, and at least one, as described above acting as an emulsifier composition.

Suitable compositions which act as emulsifier are, for example, the following, wherein in percent (%) the respective weight fraction is indicated:

Emulsifier Composition A

Emulsifier Composition B

Quantity in g

660 sugar esters of fatty acids (E473), thereof

41% sucrose mono-laurate

32% sucrose-mono-palmitate

9.0% sucrose-di-laurate

8.5% sucrose di palmitate

7.0% sucrose mono-sterate

2.5% sucrose di-stearate

340% ethanol 96%

Emulsifier composition C

To prepare the emulsifier compositions, all components are mixed together at room temperature, stirred well and thereby homogenized. For support, a slight warming to, for example, about 48 ° C to 52 ° C can be performed.

4.) Exemplary embodiments of solubilizates of various raw materials and active ingredients using emulsifier A and / or B and / or C.

In the formulations, an AGT material no. specified. This is a test number that assigns the applicant for each substance used and on the basis of which the identity of the ingredient used in each case for the solubilizate can be traced. For these solubilisates were partially the

Particle size distributions measured and the turbidity determined. 4.1 A

4.2 A

4.3 A

4.4 A

4.5A

4.6A

4.7A

4.8A

4.9A

Haze is here at about 8 FNU

4.9 B

AQUANOVA recipe

Default BM: 14.08.2009

Date of creation: 17.08.2009

Replaces recipe from:

rebuilding

AGT No .: 5020-05H

Designation: NovaSOL ^® E

Water and fat soluble 20% Vitamin E-Actetate Solubilisate (with Emulsifier B)

Ingredients:

215.2 g vitamin E acetate _ DL-a-tocopherol acetate; BASF

(AGT Material No.: 10721/005)

6.4 g of DL-α-tocopherol, BASF

(AGT Material No .: 10711/005)

778.4 g emulsifier B

Execution :

- Heat the emulsifier to 65 - 70 ° C

- Incorporate both vitamin E components with stirring and homogenize well (78 - 80 ° C)

- - Cool down (less than or equal to 60 ° C) and fill

Look: Yellow, transparent, viscous 4.10 B

AQUANOVA recipe

EW-No. : EW0127 / 2 / H

Name: Water and fat soluble solubilisate for vitamins A, D, E and K (in combination) (according to DGE recommendations) Ingredients:

784.44g emulsifier B

197 g vitamin E acetate = DL-ot-tocopherol acetate; BASF

(AGT Material No.: 10721/005), corresponds to 132.5 g of tocopherol equivalents (TE = active vitamin E)

=> through 8 = 16.5 g TE

16.2 g of retinol palmitate, 1.7 million I.U./g, oily; BASF,

(AGT No.: 10700/005) (= 8.85 g of retinol or

Retinol equivalent (RE), => by 8 = 1.1 g = 3.67 million I.U.)

0.6 g of vitamin KI (synonyms: 2-methyl-1,4-naphthoquinone or phylloquinone) (AGT Material No.: 10760/070) => 0.6 g by 8 = 0.075 g

1.76 g vitamin D3; Colecalciferol, oily; 1 million I.E./g .;

Brenntag / DSM (AGT No.: 10750/037) (= 44 mg of vitamin

D3 => by 8 = 5.5 mg vitamin D3 = 220000IE)

Execution :

- Heat emulsifier B to 68 - 72 ° C

- In separate jar, heat vitamin E acetate to 50 -

60 ° C

- Add the individual vitamins A, D and K to the vitamin E acetate, stir well with stirring and do everything very well homogenize - care must be taken that no residues stick to the edge of the vessel (50 - 60 ° C) - incorporate this vitamin mixture in the preheated emulsifier B and homogenize everything very well (70 - 80 ° C). If necessary, a small portion of the

Separate emulsifier and thus swing out the vessel with the vitamin mixture after emptying to ensure a transfer of the complete vitamin mixture

- Cool down and fill at less than or equal to 60 ° C

4.11 (with polysorbate)

AQUA OVA recipe

Default BM: 24.01.2006

Date of creation: 04.02.20096

Replaces recipe from:

02.11.2006

EW-No. : EW0114 / 1

Name: NovaSOL ^® D Water and fat soluble vitamin D3 solubilisate

Ingredients:

110 g of vitamin D3; oily - cholecalciferol,; 1 million

I.E./g .; Brenntag / DSM (AGT No .: 10750/037)

890 g polysorbate 80; Crillet 4, CRODA or Lamesorb SMO 20; Cognis (AGT Material No.: 10530/111 or / 016) Execution :

- Preheat polysorbate 80 and vitamin D3 a little bit (approx.

70 ° C) for better flowability

- Add vitamin D to the polysorbate with constant stirring, heat well (85 - 90 ° C) and homogenize

- Allow to cool and fill at <60 ° C

Appearance: pale yellow, viscous

4.1 C

4.2C

4.3 C

4.4 C

4.5 C

4.6 C

All solubilisates (samples) mentioned in point 4.), after heating to about 60 ° C and adding to room temperature water, even at multiple

Daily dosage of the raw materials or active substances contained therein, a crystal-clear and thermally, mechanically and pH-stable

Solution.

5.) Turbidity measurements:

Even with a multiple daily dosage of micronutrients involved z. B. in one liter of beverage is the turbidity of the solution, on a scale between 0.0 to 2000, below 100 FNU or in some cases even below 5 FNU and thus with the clarity of a pure drinking or

Mineral water comparable.

Turbidity-rich according to ISO 7027 / EN 27027

Measuring scale: 0.00 to 2000.00 FNU

No. Example / sample dilution in result FNU

1000g drink

5.1 A 5% Vitamin A 500 mg 22.0

5.2 A 5% Vitamin D3 1 mg 0.2

5.3 A 5% Vitamin E acetate 5 g 54.0

5.4 A 5% lipoic acid 8 g 76.0

5.5 A 5% Ubiquinone (Q10) See item 5.6 See item 5.6

1 9 17.5

5.6 A 4.2% ubiquinone (Q10) 6 g 18.6

4.2% vitamin E acetate

5.7 A 5% Omega-3 - 5 g 65.0

fatty acids

5.8 A 3% Lutein 1 g 78.0

5.9 A 1% Apocarotenal 0.5 g 8.0

5.9 B 20% Vitamin A-1, 25 g 0.6

acetate

5.10 B Vitamin combination g <0.1

from A, D, E and K (s.

recipe)

5.1 1 10% Vitamin D3 0.5 mg <0.1

5.1 C 5% Vitamin A 500 mg 9.5

5.2 C 5% Vitamin D3 1 mg <0, 1

5.3 C 5% Vitamin E acetate 5 g <0, 1

5.4 C 5% α-lipoic acid 8 g 17.1

5.5 C 5% ubiquinone (Q10) i g 47.0

5.6 C 3% lutein 1 g 36 6.) Stability:

On the one hand to show the stability of the micelle and on the other hand the uniform micelle structure in size (nm), a solubilizate with a complex combination of 4 fat-soluble vitamins (A, D, E + K) was deliberately investigated from the many embodiments of the solubilisate. In order to demonstrate stability, in the solution containing said vitamin micelles, the pH of 1.1 (gastric acid) and a temperature of 37 ° C (body temperature) were chosen. The mean diameter of the micelle (apart from analytically determined measurement tolerances) is 11 nm.

Particle size measurements were made with the ParticleMetrix NANOTRAC Backscatter Particle Analyzer. The measuring principle is based on dynamic light scattering (DLS) in a 180 ° heterodyne backscatter arrangement. With this geometry, the scattered light becomes part of the

Laser beam mixed. This has the same positive effect in terms of signal-to-noise ratio as the superposition of all wavelengths of light in a Fourier spectrometer. In Figure 6, the measuring principle is graphically illustrated in a schematic representation.

The laser light of a wavelength of 780 nm is coupled on one side of a light fiber fork:

Inhaled light (41). Back comes in the same fiber, the proportion of the glass wall of the measuring container

reflected laser light, irradiated together and reflected light (42) and the backscattered light (43) from the sample. Both split evenly on the two light guide branches. In the detector (60) of the second branch of the optical fiber fork, the mixed light, the scattered and reflected light (44) is registered. The

Fluctuation of the signal resulting from the Brown's motion in the scattered light and thus in the overall signal is converted into a particle size distribution via the Stokes-Einstein relationship and a fast Fourier analysis. The color of the sample does not affect the quality of the sample

Measurement. The detectable particle size range extends from 0.8 nm to 6500 nm. The measurements were carried out in 1000 times the aqueous dilution. The

Solubilisate was dissolved with stirring in water. It is completely soluble in water. This solution is stable, transparent.

The turbidity of a sample is due to the fact that incident light is scattered on the suspended particles of undissolved, finely divided substances. If a straight light beam strikes these particles (50), the light is scattered in all directions. For turbidity measurement, a scattered light measurement was carried out with infrared light. At low turbidity levels, a small number of undissolved ingredients can be assumed.

An analysis report of the ParticleMetrix GmbH on the measurements according to the principle "Nanotrac" was together with the

Registration filed.

It will be apparent to those skilled in the art that the invention is not limited to the embodiments described above, but rather in many ways can be varied. In particular, the features of the individual embodiments can also be combined or replaced with each other.

Claims

A composition having an HLB value of greater than 10, which acts as an emulsifier for a solubilizate of at least one crude and / or active substance which is sparingly or sparingly soluble in water, and one or more sugar esters of a fatty acid (E 473) in combination with at least one

Component which carrier is at least one OH group, in particular water and / or ethanol and / or glycerol contains.

A composition according to claim 1, wherein the at least one sugar ester of fatty acids is selected from the group consisting of sucrose mono-laurate, sucrose-di-laurate, sucrose-mono-palmitate, sucrose-di-palmitate, sucrose-mono-stearate and

Sucrose-di-stearate.

A composition according to claim 1 or 2, wherein the combination of effective emulsifier

at least one sugar ester of fatty acids and a carrier of at least one OH group of further at least one medium-chain triglyceride (medium chain triglycerides, MCT) is added.

Micelle-forming, in particular polysorbate- and lecitin-free, emulsifier composition,

in particular according to one of claims 1 to 3, for the solubilization of hydrophobic raw and / or

Active ingredients for homogeneous and stable

Enrichment of food, in particular of clear drinks and / or liquid

Dietary supplements, with hydrophobic

Micronutrients containing a combination of sugar esters of fatty acids (E 473) with an HLB value greater than 10 such as

a) sucrose mono-palmitate C28 H52 O12 b) sucrose mono-stearate C4 H82 O13 c) sucrose mono-laurate C ₂ H44 O 12

d) sucrose -di-laurate c ₃₆ HG6 O13 and adjuvants: e) glycerol

f) ethanol

g) water and

h) Medium Chain Triglycerides (MCT)

Active ingredients for homogeneous and stable

Enrichment of foods, especially clear drinks and / or liquid

Dietary supplements, with hydrophobic

Micronutrients containing a combination of sugar esters of fatty acids (E 473) with an HLB value of greater than 10 such as a) sucrose mono-laurate C ₂ H 44 0 12

b) sucrose-mono-palmitate C28 H52 0l2 c) sucrose -di-laurate c ₃₆ Ηβ6 o ₁₃ d) sucrose -di-palmitate C4 Ηδ2 O13 e) sucrose mono-stearate C ₃₀ H ₅₆ Oi ₂ f) sucrose di-stearate Cs H ₉₀ O _i3 and adjuvant: g) ethanol

Active ingredients for homogeneous and stable

Enrichment of foods, especially clear drinks and / or liquid

Dietary supplements, with hydrophobic

C) Combination of A) and B)

Solubilisat, which contains at least one raw and / or active substance which is not or only slightly soluble in water,

wherein the raw and / or active ingredient

is selected in particular from the coarse containing vitamins A, D, E and K, carotenoids, flavonoids, omega-3 fatty acids, enzymes, coenzymes, dyes, plant extracts,

Secondary plant substances (isoflavones),

Including polyphenols, essential oils and antioxidants such as alpha-lipoic acid and / or carnosic acid and quercetin, and wherein the solubilizate contains at least one composition acting as an emulsifier according to any one of the preceding claims.

A water-soluble solubilizate according to claim 7 and according to the working examples 4.1 A to 4.9 B and 4.10 B and 4.1 C to 4.6 C with a concentration of the raw materials and active substances contained therein of up to 20% and containing micelle-forming emulsifier composition according to the preceding claims.

Soluble water solubilisate of micronutrients according to the preceding claims and according to the embodiments 4.1 A to 4.9 B and 4.10 B and 4.1 C to 4.6 C, containing micelle-forming emulsifier according to any one of the preceding claims.

Water-soluble solubilisate according to one of the preceding claims containing fat-soluble or hydrophobic raw materials and active ingredients of the groups

^■ Vitamins (fat-soluble): A, D, E and K

^■ carotenoids: beta carotene, curcumin, lutein

■ flavonoids: quercetin,

rutin

^■ enzymes / co-enzymes (fat-soluble): Q10

^■ Dyes (hydrophobic): apocarotenal, paprika extract ^■ Plant extracts:

Rosemary extract, grape seed extract

^■ Polyphenols: Resveratrol

^■ Essential oils: orange oil,

Citral

^■ Antioxidants:

mixed tocopherols

^■ Omega-3 fatty acids

Liquid food and nutritional supplement containing micelle-forming

Emulsifier composition and water-soluble

Solubilisates according to claims 1 to 4.

Liquid product according to one of the preceding claims, characterized in that the hydrophobic raw materials and active substances contained therein are present in uniform micellar structures and therefore have optimum thermal, mechanical and pH stability as well as transparency.

Water-soluble solubilisate according to one of the preceding claims with a concentration of the raw materials and active substances contained therein between 0.5 and 25 wt .-%.

14. Water-soluble solubilisates according to one of

previous claims for use in the field of food,

Nutritional supplements, cosmetics,

Care products and pharmaceuticals.