DE19634373A1 - 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 an alkyl glycoside fatty acid ester of formula R1O(G)x(COR2)y (I). R1 = a glycosidically-bonded 8-18C alkyl; R2CO = a 12-18C linear acyl; (G)x = the residue of a mono- or oligoglycoside with an average oligomerisation degree (x); x = 1-2; y = the average degree of acylation and is 1-2. Also claimed are (i) a process for the coacervation of water- or lipid-soluble cosmetic or pharmaceutical ingredients in vesicles where (L) is mixed with the oil-soluble active ingredient and optionally with a water-soluble solvent, and the water-soluble active ingredient is dissolved in water and the lipid phase is dispersed in the aqueous phase (N.B. R1 is now stated to have 6-18C); and (ii) aqueous dispersions of spherical vesicles formed using (L) and optionally a co-lipid (II) which enclose an aqueous phase optionally containing a dissolved active ingredient an d the vesicle membrane comprises a multilaminar lipid double layer which optionally holds a fat-soluble active ingredient (N.B. R1 is now stated to have 6-16C).

Description

The invention relates to a method for producing vesicle dispersions, in which an alkyl glycoside fatty acid ester 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 compared to usual form disruptive components or against mechanical or thermal stress can.

It has now been found that the aforementioned properties are particularly high can be met if the vesicle-forming lipids are alkyl glycoside fatty acid esters 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 at least one alkylglycoside fatty acid ester of the formula (1)

R¹O (G) _x (COR²) _y (I),

in which R¹ is a glycosidically bonded alkyl group with 8-18 C atoms, R²CO is a linear acyl group with 12-18 C atoms and (G) _{x is} the remainder of a mono- or oligoglycoside with the average degree of oligomerization x = 1 to 2 and y the average degree of acylation is 1 to 2.

The alkyl glycoside fatty acid esters are known compounds and their manufacturers treatment can be carried out according to methods known from the literature. So z. B. in EP 334 498 A1 Manufacturing process described in which an alkyl glucoside in the presence of a lipolytic enzyme is esterified with a fatty acid to form 6-acyl-1-alkylglucoside. Out EP-A 144 894 is the preparation of 6-acyl-1-alkylglucosides by other processes described.  

Direct esterification processes for the production of alkyl glucoside fatty acid esters are described in JAOCS 36, (1959), p. 553 for methyl glucoside; they can also be opened analogously use other alkyl glucosides. Another method of making Alkylglycoside fatty acid esters by transesterification of fatty acid methyl esters Sample part described.

The alkyl glycosides of the formula R 10 (G) _{x which are} suitable from starting compounds for the preparation of the esters of the formula 1 can be derived from aldoses or ketoses having 5 or 6 carbon atoms. The alkyl glucosides derived from glucose are preferred and available on an industrial scale. The technical products are usually mixtures of mono- and oligoglucosides, which are characterized by the average degree of oligomerization x. For the purposes of the invention, preference is given to the monoglucosides and mixtures with lower oligomers with values of x = 1-2.

In the esterification of the alkyl glycosides, especially by the catalytic process the direct esterification with fatty acids or fatty acid chlorides or during the transesterification with fatty acid methyl esters, in addition to the formation of monoesters Esterification of further hydroxyl groups of the alkyl glycoside. Although the monoesters for industrial mixtures are also preferred for the purposes of the present invention with proportions of up to 60 mol% of diesters and higher esters and up to 30 % By weight of unesterified alkyl glycoside is suitable if the average degree of acetylation y im Range from 1 to 2. The average degree of acetylation y is calculated from the molar proportions of monoester (M), diester (D) and triester (T)

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 ingredients. In particular, they are suitable for the inclusion of water-soluble active ingredients 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 method for inclusion water-soluble or lipid-soluble cosmetic or pharmaceutical active ingredients in Vesicles by combining the vesicle-forming lipids with the lipid-soluble active ingredients and optionally mixed with a water-soluble solvent, the water-soluble Active ingredients dissolved in water and the lipid phase dispersed in the aqueous phase, thereby characterized in that the vesicle-forming lipid is at least one alkyl glycoside Fatty acid esters of the formula I are used.

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-insoluble 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 inventive method, since the Alkylglycoside fatty acid esters of formula I have a very good solubility in common and physiologically acceptable and water-soluble solvents such as. B. ethanol or Have glycerin. The main phase transition temperatures are also Alkylglycoside fatty acid esters in the temperature range below 100 ° C, which leads to spontaneous Formation of vesicles without applying pressure and at temperatures below 100 ° C contributes significantly.

The process according to the invention, in which the vesicle-forming lipid of formula 1 in a water-soluble solvent, preferably in Bthanol, glycerin or mixtures thereof, dissolves and the solution in the aqueous phase dispersed. The dispersion is preferably carried out by passing the solution through a Injected nozzle under pressure into the aqueous phase. This creates the necessary Shear forces to disperse the solution particularly finely.

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 fatty acid ester of the formula I. (A) and a co-lipid (B).  

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. A preferred vesicle-forming lipid is Mixture of an alkylglycoside fatty acid ester of the formula I (A) and a co-lipid (B) from the group of sterols, dicetyl phosphate or mixtures thereof in Weight ratio A: B = 1: (0.02-0.5) used.

Another object of the invention is a dispersion of spherical vesicles, the include aqueous phase in which optionally a water-soluble cosmetic or Active pharmaceutical ingredient is dissolved and their vesicle membrane from multilamellar There are lipid bilayers in which lipid-soluble active ingredients are embedded are characterized in that the vesicle-forming lipids are alkyl glycoside Contain fatty acid esters of the general formula I (A) and optionally co-lipids (B) are.

A sterol or dicetyl phosphate or a mixture thereof is preferred as the co-lipid (B) Suitable substances in the weight ratio A: B = 1: (0.02-0.5). The invention Vesicle dispersions contain the aqueous phase in excess. The lipid phase does preferably only 0.1-10% by weight of the dispersion. However, methods are known become such dispersions the water z. B. by gentle freeze drying withdraw and thereby get almost water-free preparations when adding water  are rehydrated again and form vesicle dispersions. Such freeze-dried Dispersions are also the subject of the invention if the vesicle membrane is used as Contains lipids alkylglycoside fatty acid esters of the general formula I.  

Examples 1. Preparation of alkyl glucoside fatty acid esters (AGFE)

The following alkyl glucoside fatty acid esters were made by transesterification of fatty acid methyl esters with an alkyl glucoside as alcohol component. It was the degree of esterification is controlled by the amount of methanol released. Excess fatty acid methyl ester was removed from the transesterification by distillation mixture separated. Excess alkyl glucoside remained in the product.

In the following table are the alkyl glucoside fatty acid esters according to formula I by their Structural features and their composition characterized. The share of un esterified alkyl glucoside (in% by weight rest APG) in the total product is also in the Table listed.

Table I

2. Preparation of vesicle dispersions

There have been vesicle dispersions using the alkyl glucoside fatty acid esters manufactured using the following processes:

1. Ultrasonic method (examples 1 and 8)

The lipid was in the aqueous phosphate buffer, which was at a temperature above that Phase transition temperature of the lipid (about 10 ° C above) was heated, mechanically dispersed and then finely dispersed in an ultrasonic bath for 15 minutes. One formed milky dispersion.

11. Solvent injection procedure (Example 2-7)

The lipid was dissolved in a water-soluble solvent (Examples 2 to 7: ethanol, Examples 9 to 11: glycerol) and by means of a syringe to a temperature above the phase transition temperature (10 ° C above) heated aqueous phosphate buffer injected. A fine, milky dispersion spontaneously formed.

The composition of the vesicle dispersions is listed in Tables II and III.  

Table II

Table III

3. Comparative test of surfactant compatibility

There were vesicle dispersions according to the ethanol injection method according to the recipes doors 12 and 13V (comparison).

Table IV

A part by weight of the dispersions 12 (and 13V) 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 permeability of sample 13V is thought to be a decrease in vesicle Concentration indicated by solubilization in the surfactant micelles. The vesicles of the Sample 12 has 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 at least one alkylglycoside fatty acid ester of the formula (I) is used as the vesicle-forming lipid, R¹O (G) _x (COR²) _y (I ) in which R¹ is a glycosidically bonded alkyl group with 8-18 C atoms, R² CO is a linear acyl group with 12-18 C atoms and (G) x is the remainder of a mono- or oligoglycoside with the average degree of oligomerization x = 1 to 2 and y is the average degree of acylation 1 to 2. 2. 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 oil-soluble active ingredient and optionally with a water-soluble solvent, dissolving the water-soluble active ingredients in water and dispersing the lipid phase in the aqueous phase, characterized that an alkylglycoside fatty acid ester of the formula I is used as the vesicle-forming lipid, R¹O (G) _x (COR²) _y (I) in which R¹ is a glycosidically bonded alkyl group with 6-18 C atoms, R²CO is an acyl group with 12-18 C -Atoms and (G) x is the residue of a mono- or oligoglycoside with the average degree of oligomerization x = 1 to 2 and y is the average degree of acylation 1 to 2. 3. The method according to any one of claims 1 or 2, characterized in that one vesicle-forming lipid of formula I in a water-soluble solvent, preferred in ethanol, glycerin or mixtures thereof, 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 lipid a mixture of an alkyl glycoside fatty acid ester Formula I (A) and a co-lipid (B) from the group of sterols, dicetyl phosphate or mixtures thereof in the weight ratio A: B = 1: (0.02-0.5). 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 incorporated, characterized in that alkyl glycoside fatty acid esters are used as vesicle-forming lipids of the general formula I R¹O (G) _x (COR²) _y (I), in which R¹ is a glycosidically bonded alkyl group with 6-16 C atoms, R²CO is an acyl group with 12-18 C atoms and (G) x the rest of one Mono- or oligoglycosides with an average degree of oligomerization x = 1 to 2 and y the average degree of acylation is 1 to 2 and optionally contain co-lipids. 6. Aqueous dispersion of spherical vesicles according to claim 5, characterized in that that as a vesicle-forming lipid, a mixture of an alkyl glycoside fatty acid ester of the formula I (A) and a co-lipid (B), preferably a sterol or dicetyl phosphate, in a weight ratio of 1: (0.02-0.5) is contained.