FI115527B - Use of plant sterol derivatives and products containing them - Google Patents

Description

115527

USE OF PLANTISTEROL DERIVATIVES AND PRODUCTS THEREOF

Background of the Invention

The invention relates to sterols, and in particular to hydrophilic derivatives of plant sterols. The invention relates to the use of these plant sterol derivatives and to compositions of substances containing them.

Plant sterols and some sterol derivatives have many interesting properties and uses, especially in medicine. These compounds have been found to have therapeutic effects e.g. fat 10 metabolism, heart, kidney and prostate function, inflammation and certain cancers. Of particular interest is the use of plant sterols to lower blood cholesterol levels. For example, the cholesterol-lowering effect of β-sitosterol has been known since the 1950s. The effect is based on the fact that β-sitosterol blocks the absorption of cholesterol in the marsh. For this reason, β-sitosterol has been used for decades as a blood cholesterol lowering drug and a natural product. In addition to β-sitosterol, β-sitostanol has been found to have similar and even more favorable properties. However, the major problem with the use of these compounds, and plant sterols in general, is their low solubility in oils and fats and the complete impurity of Liu-20 in water.

Thanks to the hydroxyl group contained in the sterols, the sterols can form esters with e.g. fatty acids, carboxylic acids, carboxylic acid anhydrides or carboxylic acid chlorides. By making such ester derivatives, an attempt has been made to modify the oil, fat and water solubility of the sterols.

*>. Solubility in oils / fats has been improved by transesterification of plant sterols with fatty acids. For example, WO 92/19640 I (Raision Margarine Oy) describes a cholesterol lowering agent containing a fatty acid ester of β-sitostanol or a mixture of such fatty acid esters.

The β-sitostanol fatty acid ester used in the composition is prepared by a transesterification reaction using, for example, starting material. rapeseed oil methyl ester and sitostanol. However, in this way, the water solubility of the plant sterols is not improved.

EP 0 007 474 B1 (Roecar Holdings) seeks to improve the water solubility of sterols 35 by forming di- and trihemesters of sterol glycosides, e.g. di- and trisuccinates, and salts thereof. These sterol-2 115527 derivatives are prepared by the reaction of sterol glycoside with carboxylic anhydride. The compounds are reported to be therapeutically active e.g. anti-inflammatory drugs and anti-cancer medicines. However, these compounds have the disadvantage that they are not stable in aqueous solutions and, furthermore, due to the method of their preparation, the compounds are not always completely non-toxic.

Brief Description of the Invention

It is therefore an object of the invention to find novel compositions containing plant-sterol derivatives of non-toxic and naturally occurring compounds which are hydrophilic and thus more soluble in polar solutions such as alcoholic solutions and in particular aqueous solutions. The invention also relates to a new use of plant sterol derivatives. The objects of the invention are achieved by use and by a product characterized by what is stated in the independent claims. Preferred embodiments of the invention are claimed in the dependent claims.

The hydrophilicity and water solubility of the plant sterols have been improved by esterifying a plant sterol such as β-sitosterol with a fruit acid, e.g. citric acid, to give a hydrophilic plant sterol and a fruit acid ester. The products thus obtained are non-toxic and consist of herbal compounds already present in many foods, making them very suitable for medicinal and food use. The term '' hydrophilicity 'refers to the ability of a compound used in the present invention to form hydrogen bonds with the surrounding solution and thus the tendency of the compound to dissolve better than one OH-containing sterol molecule.

: / *. DETAILED DESCRIPTION OF THE INVENTION: Y; The invention relates to the use of a sterol derivative as an additive in material compositions selected from cosmetic products and polymers and wherein the sterol derivative is an ester of plant sterol and fruit acid.

Plant sterols in the context of the present invention refer to plant sterols (including their saturated forms, stanols) that can be isolated from plants. These also include steroid precursors synthetically produced sterols of the plant sterols type. In the sterols of the invention, the OH group of the sterol is preferably in the 3-position of the steroid backbone, more preferably in the β-position. The numbering of the steroid backbone is shown below: ς Γη 131 16

CD

jl 14 1 15 P ίΐο 8j

A B

k 10

Plant sterols include, for example, all wood sterols. Such wood-based sterols are typically found, for example, in the neutral fraction of pulp cooking, and include, e.g., β-sitosterol and campesterol, and their saturated forms, β-sitostanol and campestanol, and stigmasterol. The structures of these wood-based ste-15 roles are shown below: /, HO j

: H

'' Β-Sitostanol * t <v ·: ^ rn *

; HO

': 20. β-Sitosterol 4 115527 HO!

B

Campestanol 10 15

HO

Campesterol 20 ^ iffi '25

HO

Other suitable plant sterols include, for example, ergosterol, desmosterol, sargasterol, brassicasterol and fucosterol, and saturated forms thereof. The structure of these compounds is shown below: I 35 5 115527 5

HO

Ergosterol ίο

HO

15

Desmosterol / 20

HO

25

Sargasterol * ho 35 ', Fukosterol 6 115527 5

HO

Brassicasterol 10 Especially preferably, the plant sterol is β-sitosterol, stigmasterol or β-sitostanol.

Fruit acids in the context of the present invention refer to organic carboxylic acids which can be isolated from fruits and the like. These also include the corresponding fruit acids which can be synthetically or biochemically produced, in particular enzymatically. The fruit acids used according to the invention are typically hydroxycarboxylic acids. Particularly preferred are α-hydroxycarboxylic acids (containing a hydroxyl group on the adjacent carbon atom of the carboxyl group). The hydroxycarboxylic acids and α-hydroxycarboxylic acids used in the invention are typically saturated aliphatic carboxylic acids, preferably lower aliphatic carboxylic acids. The term "lower" as used herein refers to carboxylic acids containing up to 10 carbon atoms, most preferably up to 6 carbon atoms. The acids are thus preferably C 2 -C 10 -; carboxylic acids, particularly preferably C2-C6 carboxylic acids. Acids Butter; The salts may be mono-, di-, or tricarboxylic acids, preferably tricarboxylic acids, and may contain more than one hydroxyl group. Typical α-hydroxycarboxylic acids used in accordance with the invention are citric acid; po, malic acid, tartaric acid, lactic acid and glycolic acid.

Where the fruit acid moiety of a compound contains more than 30 single carboxylic acid groups (di- and tricarboxylic acids) formed. the remaining free carboxylic acid group or free carboxylic acid groups of the sterol ester may be in the form of an ester, a free acid or a salt. The ester is then 1 'y' preferably an alkyl ester, preferably a lower alkyl ester (C 1 -C 4 alkyl ester) such as methyl, ethyl or propyl ester (iso- or n-propyl). The salt 35 is preferably an alkali metal or alkaline earth metal salt, particularly preferably a potassium or 'sodium salt.

; ; f I I

7, 115527

The plant sterol fruit acid esters for use according to the invention can be prepared by esterifying the plant sterol and the fruit acid by an exchange esterification reaction.

In the transesterification reaction, the starting sterol is transesterified with an ester of a fatty acid, the latter typically being an alkyl ester, preferably a lower alkyl ester (C 1 -C 10 alkyl ester) such as methyl, ethyl or propyl ester. The propyl ester may be an n-propyl ester or an isopropyl ester.

The following is an example of the transesterification of β-sitostanol 10 with trimethyl citrate to give the monoester of β-sitostanol and trimethyl citrate as the final product:

B

/ - °

. , -O

The exchange esterification is typically carried out at a temperature of 50-230 ° C, preferably 120-180 ° C. The reaction is typically carried out under reduced pressure, preferably 1 to 900 mbar, using an inert protective gas such as nitrogen. The reaction can also be carried out either under vacuum alone or in a protective gas.

The exchange esterification is carried out in the presence of a catalyst which is preferably an alkali metal alkoxide, i.e. a compound of an alkali metal and an alcohol, in particular potassium methoxide, potassium ethoxide, potassium n-propoxide, potassium i-propoxide, potassium i-butoxide, potassium n-butoxide, potassium butoxide, sodium methoxide, sodium ethoxide, sodium n-propoxide, sodium i-propoxide, sodium n-butoxide or sodium t-butoxide. The catalyst is typically used in an amount of 0.05 to 5.0% by weight based on the total amount of starting materials.

The fatty acid used as the second starting material for the transesterification is preferably in the form of an alkyl ester, preferably a lower alkyl ester (C1-C10 alkyl ester). Alkyl esters of fatty acids are commercially available but can also be prepared by known esterification methods by esterifying the fatty acid with, for example, methanol, ethanol or propanol-15a (n- or i-propanol) to afford the methyl, ethyl and propyl esters of the fatty acid, respectively.

The boiling points of alkyl esters of fruit acids are generally above 200 ° C. Therefore, temperatures over 200 ° C can be used for transesterification. The compounds of the invention may also be prepared at temperatures below 100 ° C. However, the preferred temperature used for the transesterification is 120-180 ° C.

The exchange esterification reaction liberates alcohol, which removal of the reaction mixture improves the yield. Therefore, the reaction is typically carried out in a vacuum under reduced pressure in an inert gas. It is also possible to remove the resulting al - 1: 1 alcohol from the reaction mixture with only under-25 pressure or with a hateful shielding gas. Nitrogen is preferably used as the shielding gas and the pressure may be from 1 to 900 mbar.

»·

The exchange esterification may be carried out in the absence or in the solvent.

• · · • ·

Suitable solvents include inert solvents such as hexane, cyclohexane and toluene. Preferably, the compounds are prepared in the absence of a solvent in the form of a sterile reaction or a fatty acid ester acting as a sterol solvent.

The exchange esterification may be carried out in a batch or continuous reactor. The reaction is preferably carried out in a stirred reactor.

The compounds to be used according to the invention can be prepared by a 35-exchange esterification reaction under mild reaction conditions in a harmless and non-toxic *. or non-toxic chemicals. Unexpectedly, fruit acids such as sit-11 115527 tartaric acid were found to remain stable under the reaction conditions used.

When the fatty acid used as the starting material is in the form of an alkyl ester, the esterification of the sterol and the fatty acid, where the free carboxylic acid groups of the 5 fatty acids (in the case of di- and tricarboxylic acids) are the alkyl ester. Such an alkyl ester form is soluble as such in the esters and in the fatty acid oils. The alkyl ester form is thus suitable as such for use in products containing esters of fruit acids and oils of fruit acid.

The solubility of the aforementioned alkyl ester in the form of an alkyl ester in the form of a fatty acid mono-ester can be further improved by saponification of the alkyl ester groups of the compound to the alkali metal salt form. The saponification may be carried out in a solvent containing a base such as sodium hydroxide or potassium hydroxide. Suitable solvents include alcohols and hydrocarbon solvents. Suitable alcohols include ethanol, propanols and butanols, and suitable hydrocarbon solvents e.g. hexane, cyclohexane and toluene. The compound in alkaline salt form has particularly good solubility in aqueous solutions and other polar solutions.

The salt groups of the sterol and the monoester of the fatty acid in the alkaline salt form can be further converted to the free acids. This is done by hydrolysis of hap-20, where a homogeneous acid (e.g. mineral acid or hydrochloric acid) or a heterogeneous acid (e.g. ion exchange resin such as a strong cation exchange resin) can be used.

The compounds for use in the invention may also be prepared by direct esterification of the fruit acids with sterols. The direct esterification may be carried out in a pure reaction or in a solvent. The catalyst can be either: \! a homogeneous acid catalyst (such as mineral acid or p-toluenesulfonic acid) or a heterogeneous acid catalyst (such as sulfonated polystyrene-divinylbenzene).

The compounds for use in the invention may also be prepared by esterifying sterols with more reactive acid chlorides than carboxylic acids. or by acylation reactions between the acid anhydrides and the sterols themselves.

t

The invention also relates to cosmetic products and polymers which contain esters of plant sterols and fruit acids or mixtures thereof. The products may additionally contain one or more fatty acids and / or their alkyl esters, preferably lower alkyl esters.

10 115527

Cosmetics can be, for example, makeup, skin grease and lotions.

Polymers are typically biodegradable polymers in which sterol derivatives act as biodegradation enhancers.

The following examples illustrate the preparation of compounds for use in accordance with the invention.

Example 1

An ester of citric acid and wood-derived plant sterol (a mixture of visterol ester 10) was prepared by a transesterification reaction as follows:

The reactor was charged with 50.1 g plant stanol mixture (containing 91.9 wt% β-sitostanol and 5.7 wt% campestanol, manufactured by UPM-Kymmene Corporation, Lappeenranta) and 450.2 g citric acid triethyl ester or triethyl citrate (commercial grade, purity> 98 wt%). The reactor was purged with nitrogen and heated.

15 Stirring was started and the stirring speed was adjusted to 350 rpm. A slight vacuum of 800 mbar was aspirated into the reactor, after which the temperature was raised to 150 ° C. The reaction mixture was heated for 45 min before the catalyst was added. Sodium ethoxide (0.102 g) was added as a catalyst. After addition of the catalyst, the reaction was continued for 6.5 hours. The catalyst was decomposed by adding water to the reaction mixture and the unreacted plant stanol was extracted with hexane. A product was obtained containing the desired reaction product and triethyl citrate. The reaction product was an ester of β-sitostanol and triethyl citrate, where one of the acid groups of citric acid forms an ester with β-sitosterol and the other two are in the form of the ethyl ester. The reaction product also contained small amounts of the corresponding campestanol barrier.

A mixture of the reaction product and triethyl citrate was saponified in ethanol: * ·, · KOH. The saponified mixture was very soluble in aqueous solutions.

The unsaponifiable end product was analyzed by mass spectrometry using direct ionization. Analytical results showed that the product consists of a compound having a mass number of 644-648. This is equivalent to β-βΐ ^^ ηοΙΐη / β ^ ΚοβίβΓοΙΐη. . and triethyl citrate monoester (two free carboxyl groups of citric acid in ethyl form). The product also contained small amounts of the corresponding camphor ester.

The hydrophilicity and water solubility of the product thus obtained were greatly improved.

• * · 11 115527

Example 2

An ester of citric acid and wood-derived plant sterol (mixture of plant sterol esters) was prepared by a transesterification reaction as follows:

Trimethyl citrate used as the second reaction component was prepared from 5 citric acid and methanol at 40 ° C using Amberlyst 15 cation exchange resin (Rohm & Haas, USA) as catalyst. The reaction time was 24 h after which the catalyst and methanol were removed from the reaction mixture.

For transesterification, 41 g of plant sterol mixture (containing 36 wt% β-sitostanol, 52 wt% β-sitosterol, 7 wt% campestol-10, plus small amounts of campestanol and stigmasterol) were charged to the reactor by UPM-Kymmene Corporation, Lappeenranta) and 23 g of trimethyl citrate prepared above. The reaction was carried out in nitrogen gas at 160 ° C. The reaction time was 8 h and the stirring speed was 500 rpm. 0.2 g of sodium ethoxide was used as the catalyst. The final product was analyzed by mass spectrometry using direct ionization, whereby a molecular peak of 616-620 was found in the mass spectrum, corresponding to the ester of β-sitosterol and trimethyl citrate, with one of the citric acid groups forming an ester with β-sitosterol. The product also contained the corresponding β-sitostanol ester as well as small amounts of the corresponding campesterol, campestano-20 l and stigmasterol esters.

The product of this example also had improved hydrophilicity and water solubility.

Similarly, the maleic, tartaric, lactic and Glycolic acid esters of sterols of wood-derived sterols can also be prepared by a transesterification reaction. Citric acid esters of ergosterol, desmosterol, sargasterol, brassicasterol and fucosterol can also be prepared in the same way, esters of tartaric, tartaric, lactic and glycolic acids.

30

It will be obvious to a person skilled in the art that as technology advances, the basic idea of the invention can be implemented in many different ways. The invention and its embodiments are thus not limited to the examples described above, but may vary within the scope of the claims.

* * *

Claims (11)

1. Use of a sterol derivative as an additive in chemical compositions selected from cosmetic products and polymers, characterized in that the sterol derivative is an ester of a plant sterol and a fruit acid. Use according to claim 1, characterized in that the plant sterol is a sterol, whose OH group is in the 3-position of the steroid body, preferably in the / position. Use according to claim 1 or 2, characterized in that the plant sterol is a tree-based sterol. Use according to any one of claims 1-3, characterized in that the plant sterol is β-sitosterol, β-sitostanol, campesterol, campestanol or stigmasterol. Use according to claim 4, characterized in that the plant sterol is β-sitosterol or γ-sitostanol. Use according to any of the preceding claims, characterized in that the fruit acid is a hydroxycarboxylic acid. Use according to claim 6, characterized in that the fructic acid is σ-hydroxycarboxylic acid. Use according to claim 7, characterized in that the a-hydroxycarboxylic acid is citric acid, malic acid, tartaric acid, lactic acid or glycolic acid. Use according to claim 8, characterized in that the α-: hydroxycarboxylic acid is citric acid. 10. Cosmetic product, characterized in that it contains «1 ·: a sterol derivative as defined in any one of claims 1 to 9, or a mixture. of it. 11. Polymer, characterized in that it contains a sterol / 1 derivative as defined in any one of claims 1 to 9, or a mixture thereof. »» T * · »I» »• t I t M • I •» 1 t »» »