DE19634374A1 - Vesicle dispersion preparation - Google Patents

Abstract

Production of a vesicle-dispersion by dispersion of vesicle-forming lipids (L) in an aqueous medium is claimed. (L) comprises a mixture of (A) an alkyl glycoside of formula R1O(G)x (I) and (B) a 12-22C linear fatty alcohol in a weight ratio (A):(B) of 1:(0.1-2). R1 = a glycosidically-bonded 12-22C linear alkyl; (G)x = the residue of a mono- or oligoglycoside with an oligomerisation degree (x); x = 1-2.

Description

The invention relates to a method for producing vesicle dispersions, in which an alkyl glycoside / fatty alcohol mixture is used as the vesicle-forming lipid.

Vesicles are usually spherical lipid vesicles made up of a single or several lipid bilayers are formed and an aqueous phase inside lock in. They can have a diameter of 20 nm to 10 µm. Because theirs Formation was first observed in phospholipids, especially for vesicles based on phospholipids, also known as liposomes.

In the meantime, numerous lipids have been discovered in aqueous media Form double-layer membranes, which can with the help of mechanical energy, for. B. in the form by ultrasound or by the incorporation of co-lipids, curving and becoming vesicles or close liposomes. The stability of such vesicles against others Components of the dispersion is very different and numerous vesicles are formed under the influence of z. B. solvents or surface-active substances destroyed.

Alkyl glycosides are known as vesicle-forming lipids, e.g. B. from Chem. Pharm. Bull. 33 (2), 753-759 (1985) or from Biochem. Biophys. Res. Comm. Vol. 100, No. 3, 1055- 1062 (1981).  

Because of the increasing importance, the vesicle dispersions for inclusion and Transport of active substances through living tissue, e.g. B. through the skin, in medicine and have gained in cosmetics, new vesicle-forming lipids and Processes for the production of vesicle dispersions searched. Such lipids a special meaning, the vesicles with higher stability against disturbing Components and can form against mechanical and thermal stress.

It has now been found that the aforementioned characteristics are particularly high are met if a mixture of an alkyl glycoside is used as the vesicle-forming lipids and a linear fatty alcohol is used.

The invention therefore relates to a method for producing vesicle disperser sions by dispersing vesicle-forming lipids in an aqueous medium, where as vesicle-forming lipid a mixture of an alkyl glycoside (A) of the formula (I)

R¹O (G) _x (1),

in which R¹ is a glycosidically bonded, linear alkyl group with 12-22 carbon atoms and (G) _{x is} the remainder of a mono- or oligoglycoside with a degree of oligomerization x = 1 to 2 and a fatty alcohol (B) with 12-22 carbon atoms in the weight ratio A: B = 1: (0.1-2) is used.

The alkylglycosides (A) of the formula I are known surfactants and are produced on an industrial scale. In the known synthetic processes, they are obtained as a mixture with the fatty alcohols of the formula R ¹ OH used for acetalization and are separated from these alcohols by special separation processes. The alkyl glycosides of the formula I can be derived from aldoses or ketoses with 5 or 6 carbon atoms.

Those derived from glucose are preferred and available on an industrial scale Alkyl glucosides. The technical products are usually Mixtures of mono- and oligoglucosides by the mean oligomerization degrees x are marked. Preferred for the purposes of the invention are Monoglucosides and mixtures with lower oligomers with values of x = 1-2.

The linear fatty alcohols (B) are produced on an industrial scale by hydrogenating Fatty acids or fatty acid methyl esters obtained. Usually also fall here Fatty alcohol mixtures, the chain length distribution of which in the starting fatty acid corresponds. These fatty alcohols can be distilled into the Single alcohols are separated. But are suitable for the method according to the invention also mixtures of alcohols with 12 to 22 carbon atoms or fractions with z. B. 12 to 16 or with 16 to 18 carbon atoms.

Those obtained in the production of alkyl glycosides are particularly preferred Use mixtures of alkylglycosides (A) and fatty alcohols (B) of the formula R¹OH, regarding the mixing ratio of alkyl glycoside (A) and fatty alcohol (B) arbitrarily adjusted by partial separation or by adding fatty alcohol can be.

The vesicle dispersions according to the invention are suitable for the inclusion of Active ingredients and to transport these active ingredients through the skin and therefore adjust valuable carrier system for the application of cosmetic and pharmacological Active substances, in particular they are suitable for the inclusion of water-soluble active substances in the aqueous phase enclosed by the vesicles. The vesicle membrane can also incorporate many lipid-soluble (water-insoluble) active substances into the lipid bilayer.

Another object of the invention is therefore a process for the inclusion of water-soluble or lipid-soluble cosmetic or pharmaceutical active ingredients in vesicles by mixing the vesicle-forming lipids with the lipid-soluble active ingredients and optionally with a water-soluble solvent, dissolving the water-soluble active ingredients in water and the lipid phase in the aqueous Dispersed phase, characterized in that the vesicle-forming lipid is a mixture of an alkylglycoside (A) of the formula (I) R¹O (G) _x , in which R ^{1 is} a glycosidically bound, linear alkyl group having 12 to 22 C atoms and (G ) _{x is} the remainder of a mono- or oligoglycoside with the average degree of oligomerization x = 1 to 2 and uses a linear fatty alcohol (B) with 12 to 22 carbon atoms in the weight ratio A: B = 1: (0.1 - 2).

As water-soluble active ingredients such. B. water-soluble vitamins, e.g. B. salts of Ascorbic acid, amino acids and water-soluble polypeptides, water-soluble dyes, antibacterial substances, anti-inflammatory substances and many others are used. As lipid-soluble substances such. B. oil-soluble vitamins, e.g. B. tocopherols, UV Filter substances or other water-soluble active substances are included.

Active ingredients are those which are soluble in water at 20 ° C at least 1% by weight are clearly dissolved and such substances are understood as oil-soluble, which are at least 1% by weight clearly soluble in paraffin oil at 20 ° C. The aqueous phase can contain the solutes up to the saturation limit. The lipid phase in the consists essentially of the membrane lipids, should not exceed 10% by weight of the Lipid phase, preferably not more than 5% by weight of the lipid phase of oil-soluble Contain active ingredients.

The vesicle dispersions according to the invention are produced according to known methods for liposome dispersions described in the literature. Of particular interest are processes that are not only laboratory-scale, but are also feasible on an industrial scale.

Such methods are e.g. B. the high pressure homogenization and in particular the Solvent injection. Solvent injection is particularly special  Significance for the implementation of the method according to the invention, since the Alkylglycosides and fatty alcohols have a very good solubility in common and physiologically acceptable solvents such as B. ethanol or glycerin. The main phase transition temperature is also suitable for those which are suitable according to the invention Mixtures of alkyl glycoside and fatty alcohol in the temperature range below 100 ° C, which leads to spontaneous formation of vesicles without applying pressure and at temperatures contributes significantly below 100 ° C.

The process according to the invention is therefore particularly preferred if the vesicle-forming lipid mixture of alkyl glycoside (A) and fatty alcohol (B) in one water-soluble solvents, preferably in ethanol, glycerol or mixtures thereof, dissolves and the solution is dispersed in the aqueous phase. The dispersion takes place preferably by passing the solution through a nozzle under pressure into the aqueous phase injected. This creates the necessary shear forces to make the solution particularly fine to disperse.

One can see the breakdown of the organic phase and the formation of vesicles from the promote the resulting lipid bilayers even further if you use the dispersion undergoes an ultrasound treatment.

A preferred embodiment of the present invention is that as vesicle-forming lipids a mixture of an alkyl glycoside (A) of the formula I, a Fatty alcohol (B) with 12 to 22 carbon atoms in the weight ratio A: B = 1: (0.1-2) and another co-lipid (C) from the group of sterols or dicetyl phosphate in Weight ratio A: C = 1: (0.02-0.5) is used.

The co-lipids are in the vesicle-forming lamellar lipid bilayers installed and force this on a curvature, so that the formation of the spherical Vesicle is relieved. Suitable co-lipids for use in the  Processes according to the invention are especially sterols, e.g. B. cholesterol or phytosterols, e.g. B. in the form of technical mixtures as they occur in the refining of soybean oil and are sold under the trademark "Generol".

But also certain charged amphiphilic substances, e.g. B. the dicetyl phosphate (phosphorus acid dihexadecyl ester) are suitable as co-lipids. The charge increases electrostatic repulsion of the double layers, this increases the storage Amounts of aqueous phase favored.

Another object of the invention is a dispersion of spherical vesicles, which include an aqueous phase in which a water-soluble cosmetic or pharmaceutical active ingredient may be dissolved and whose vesicle membrane consists of multilamellar lipid bilayers, in which lipid-soluble active ingredients are optionally embedded, characterized in that as vesicle-forming Lipids a mixture of an alkylglycoside (A) of the formula I R¹O (G) _x , in which R is a glycosidically bonded, linear alkyl group having 12 to 22 C atoms and (G) _x the rest of a mono- or oligoglycoside with the average degree of oligomerization x = 1-2 and contains a linear fatty alcohol (B) with 12 to 22 carbon atoms in the weight ratio A: B = 1: (0.1-2).

The dispersions according to the invention preferably contain as vesicle-forming lipids Mixture of an alkylglycoside (A) of formula I, a linear fatty alcohol (B) with 12 to 22 carbon atoms and a further co-lipid (C) from the group of sterols or Dicetyl phosphate in the weight ratio A: C = 1: (0.02-0.5).

The vesicle dispersions according to the invention contain the aqueous phase in excess. The lipid phase preferably makes up only 0.1-10% by weight of the dispersion. But there are Process become known, such dispersions the water z. B. by gentle To freeze freeze while maintaining almost water-free preparations that be rehydrated when water is added and form vesicle dispersions. Such  Freeze-dried dispersions are also the subject of the invention if the Vesicle membrane as lipids is a mixture of an alkyl glycoside of formula I and contains a fatty alcohol in a weight ratio of 1: (0.1-2).

Examples

Mixtures were used as vesicle-forming lipids

• A) cetostearyl glucoside of the formula R ¹ O (G) _x , in which
  R¹ = cetyl and stearyl groups (50 mol% each)
  G = glucoside residue, x = 1.4
• B) cetostearyl alcohol, a mixture of 50 mol% cetyl alcohol and 50 mol% Stearyl alcohol

in the weight ratio A: B = 1: 1 and 1: 0.11.

I. Preparation of the vesicle dispersion

The lipids were dissolved in ethanol in the stated ratio and the solution (20 ° C) in an aqueous phosphate buffer solution (20 ° C) using an injection syringe introduced with stirring.

II. Checking stability

The stability test specimen was carried out by comparing the mean vesicle diameter 60 minutes after production and after 18 days of stress storage. The Stress storage consisted of storage at 5 ° C (3 days), 40 ° C (3 days), 5 ° C (3 days), 40 ° C (3 days), 5 ° C (3 days), 40 ° C (3 days) and cooling to 20 ° C.

The particle diameter was measured using Fraunhofer diffraction (Sympatec Helos) after a short ultrasound treatment (60 seconds to des integration of vesicle aggregates). The numbers mean:

Average: 50 vol .-% of the particles are smaller than the given average
Limits: 10% by volume of the particles are smaller than the lower limit and
90 vol .-% of the particles are smaller than the upper limit.

Table I

III. Comparative test of surfactant compatibility

There were vesicle dispersions according to the ethanol injection method according to the recipes doors 3 and V2 (comparison).

Table II

A part by weight of dispersions 3 (and V2) was in 4 parts by weight of an aqueous Surfactant solution (12.5 wt .-% Na lauryl ether (2 EO) sulfate, Na salt in water) drips. A dispersion was obtained which contained 10% by weight of surfactant and 0.4% by weight Contained lipids.  

This solution was photometric for transmission of light of 650 nm at 20 ° C tested against water (100%). After 10 days at 40 ° C, this measurement of permeability repeated.

The sharp increase in the permeability of sample V2 is considered a decrease in the vesicle Concentration interpreted. The vesicles of sample 3 have a significantly higher surfactant stability.

Claims (6)

1. A process for the preparation of vesicle dispersions by dispersing vesicle-forming lipids in an aqueous medium, characterized in that a mixture of an alkylglycoside (A) of the formula (I) R¹O (G) _x (I), in as a vesicle-forming lipids R¹ is a glycosidically bonded, linear alkyl group with 12-22 C atoms and (G) _{x is} the remainder of a mono- or oligoglycoside with a degree of oligomerization x = 1 to 2, and a linear fatty alcohol (B) with 12-22 C- Atoms in the weight ratio A: B = 1: (0.1-2). 2. Process for the inclusion of water-soluble or lipid-soluble cosmetic or pharmaceutical active ingredients in vesicles by mixing the vesicle-forming lipids with the lipid-soluble active ingredient and optionally with a water-soluble solvent and dissolving the water-soluble active ingredient in water and dispersing the lipid phase in the aqueous phase, characterized that as a vesicle-forming lipids a mixture of an alkyl glycoside (A) of the formula I R¹O (G) _x (I) in R ^{1 is} a glycosidically bound, linear alkyl group with 12-22 C atoms and (G) _x the rest of a Mono- or oligoglycoside with the average degree of oligomerization x = 1 to 2, and a linear fatty alcohol (B) with 12-22 carbon atoms in the weight ratio A: B = 1: (0.1-2). 3. The method according to any one of claims 1 or 2, characterized in that the vesicle-forming lipids in a water-soluble solvent, preferably in Ethanol, glycerin or mixtures thereof, dissolves and the solution in the aqueous phase dispersed. 4. The method according to any one of claims 1 or 2, characterized in that as vesicle-forming lipids a mixture of an alkyl glycoside (A) of the formula I, a Fatty alcohol (B) with 12-22 carbon atoms in the weight ratio A: B = 1: (0.1-2), and another co-lipid (C) from the group of sterols or dicetyl phosphate in Weight ratio A: C = 1: (0.02-0.5) is used. 5. Aqueous dispersion of spherical vesicles, which include an aqueous phase, in which a water-soluble cosmetic or pharmaceutical active ingredient is optionally dissolved and whose vesicle membrane consists of multilamellar lipid bilayers, in which lipid-soluble active ingredients are optionally embedded, characterized in that a mixture of one as vesicle-forming lipids Alkylglycoside (A) of the formula IR ¹ O (G) _x (I), in which R¹ is a glycosidically bonded, linear alkyl group with 12-22 C atoms and (G) _x the rest of a mono- or oligoglycoside with a medium degree of oligomerization x = 1 to 2 and contains a linear fatty alcohol (B) with 12-22 carbon atoms in the weight ratio A: B = 1: (0.1-2). 6. Aqueous dispersion of spherical vesicles according to claim 5, characterized in that that as the vesicle-forming lipid, a mixture of an alkyl glycoside (A) of the formula I,  a linear fatty alcohol (B) with 12-22 carbon atoms in the weight ratio A: B = 1:   (0,1-2) and another co-lipid (C) from the group of sterols or Dicetyl phosphate in the weight ratio A: C = 1: (0.02-0.5) is included.