Field of the Invention

The present invention relates to an aqueous formulation of silymarin, to a process for its preparation and to the use of said formulation for the prevention and/or the treatment of liver damage.

Technological background

Silymarin is the standardized extract of the fruit of the milk thistle plant (Silybum marianum) and it contains substantially three flavonoids of the flavonol subclass: silybin, which is predominant, the silydianin and the silychristin.

Silymarin is known to have hepatoprotecting and depurating properties and it is used as adjuvant in the treatment of the liver damage (Malandrino et al. Drugs Future 1990; 15:226-227, Parris Kidd et al. Alternative Medicine Review Vol. 10 (3) 2005, 193-203).

Silymarin is sparingly water-soluble and has a poor bioavailability. The aqueous dispersions of silymarin tend to form aggregates particularly under heating conditions. This problem becomes particularly relevant during the pasteurization process of beverages containing silymarin when the aqueous dispersion is subjected to temperatures of about 80°C.

Description of the invention

It has now been found that the aqueous formulations of silymarin, containing hydrophilic surfactants having middle to high HLB (Hydrophilic Lipophilic Balance) and polyols, do not form aggregates when they are subjected to heating.

An object of the present invention is an aqueous formulation of silymarin containing:

a) a surfactant or a mixture of surfactants having a value of HLB higher than 8, and

b) a polyol or a mixture of polyols.

Preferably the surfactant or the mixture of surfactants has a value of HLB higher than 12.

The surfactants are preferably selected from the group consisting of glycerol esters of fatty acids, sorbitan esters, polysorbates, sucrose esters, lecithins or mixtures thereof.

Glycerol esters of fatty acids are preferably decaglycerol esters of a fatty acid, particularly preferred is decaglycerol monooleate.

Sorbitan esters may be for example sorbitan monolaurates.

Sucrose esters are sucrose esters of a fatty acid, preferred is sucrose monopalmitate.

Polysorbates are preferably polyoxyethylene (20) sorbitan esters of a fatty acid. Particularly preferred is polyoxyethylene (20) sorbitan monostearates.

Preferred lecithins are soybean lecithin or a lysolecithin, in particular defatted lysolecithin.

Preferred polyols utilizable in the formulation of the invention are propylene glycol, glycerol, butanediol, pentanediol, hexanediol and a sugar alcohol or a mixture thereof.

Particularly preferred is glycerol.

The aqueous formulation of the invention may optionally contain ethanol.

The concentration of silymarin in the formulations of the invention is preferably from 0.01 to 10% by weight.

The surfactant or the mixture of surfactants is preferably present in a concentration from 0.01 to 40% by weight.

The polyol or the mixture of polyols is preferably present in a concentration from 1 to 99% by weight.

When present ethanol has a concentration from 0.2 to 20% by weight. A preferred aqueous formulation according the invention contains:

i) silymarin 0.01-10% by weight

ii) soy bean lecithin 0.01-10% by weight

iii) ethanol 0.2-20% by weight

iv) glycerol 1-99% by weight

v) decaglycerol monooleateO.02-40% by weight

vi) water 0-98% by weight

The aqueous formulations according to the invention are prepared according to a process comprising the steps:

a) dissolving silymarin in a polyol or a polyol mixture and optionally ethanol;

b) dissolving soy bean lecithin and the hydrophilic surfactant in a mixture of water and the residual polyol;

c) dissolving the silymarin solution obtained in step a) in the emulsifier solution obtained in step b);

d) dissolving the resulting solution in water;

e) pasteurizing the obtained aqueous solution.

The invention is further illustrated by the following examples:

Example 1

Aqueous formulation containing:

Silymarin ET 5.0% by weight

Glycerol 45.0% by weight

Decaglycerol monooleate 25.0% by weight

Ethanol (99.5 vol%) 10.0% by weight

Soy bean lecithin 5.0% by weight

Water 10.0% by weight

pH 3.0

Process:

Silymarin was dissolved in a mixture ethanol/glycerol at 60°C to obtain the "silymarin solution". The surfactants, decaglycerol monooleate and the soy bean lecithin were dissolved in a mixture of water and the residual glycerol at 80°C to obtain the "emulsifier solution".

The "silymarin solution" was dissolved in the "emulsifier solution" at a temperature under 50°C.

The obtained composition was dispersed in water with the formation of an emulsion wherein the micelles have a mean diameter of 100-200 nm. The aqueous emulsion was pasteurized at 80°C for 30 minutes. No change was observed in the appearance and in the mean diameter of the micelles.

Example 2 (Comparative example)

Aqueous solutions of glycerol (45% by weight), ethanol (10% by weight), decaglycerol monooleate (10% by weight) and soy bean lecithin (5% by weight) were prepared. Silymarin (5% by weight) was dispersed in each of the above solutions. The obtained dispersions of silymarin were heated in order to detect the formation of aggregates. Solution Appearance change

Glycerol aggregation at 40°C

Ethanol aggregation at 40°C

Decaglycerol monooleate aggregation at 40°C

Soy bean lecithin slight aggregation a 80°C

Example 3

Aqueous formulation containing:

Silymarin 5% by weight

Ethanol 10% by weight

Glycerol 45% by weight

Decaglycerol monooleate 30% by weight

Water 10% by weight

The aqueous solution was obtained by the process described in Exampl

Example 4

Aqueous formulation containing:

Silymarin 5% by weight

Ethanol 10% by weight

Glycerol 45% by weight

Defatted lysolecithin 30% by weight

Water 10% by weight

The aqueous solution was obtained by the process described in Exampl Example 5

Aqueous formulation containing:

Silymarin 5% by weight

Glycerol 55% by weight

Defatted lysolecithin 30% by weight

Water 10% by weight

The aqueous solution was obtained by the process described below.

Glycerol and defatted lecithin were mixed and heated. Silymarin was added to the mixture and dissolved by heating. Water was added to obtain the aqueous solution.

The obtained composition was dispersed in water with the formation of an emulsion wherein the micelles have a mean diameter of 100-200 nm. The aqueous emulsion was pasteurized at 80°C for 30 minutes. No change was observed in the appearance and in the mean diameter of the micelles.

Example 6

Aqueous formulation containing:

Silymarin 5% by weight

Ethanol 2% by weight

Glycerol 53% by weight

Defatted lysolecithin 30% by weight

Water 10% by weight

The aqueous solution was obtained by the process described in Example

1.