Title:  Stable multiple X/O/Y-emulsion

United States Patent:  6,171,600

Assignee:  IFAC GmbH (Velbert, DE)

Filed:  May 23, 1997

PCT NO:  PCT/EP94/03955

102(e) Date:  May 23, 1997

PCT PUB. Date:  June 8, 1995

Foreign Application Priority Data:  Dec 02, 1993[DE] (43 41 113)

The stable multiple emulsion of the X/O/Y type contains at least one X/O phase in which X is an oil-immiscible component and O an oil phase. The X/O phase can contains an active substance, possibly in solid form, for example for medical, cosmetic or technical applications. The Y phase can be an aqueous phase, an aqueous liquid, preferably liquid-crystalline, gel or a W/O/W emulsion and serves as carrier for the at least one X/O phase. The X/O phase is produced using an emulsifier that has an HLB value equal to or less than 6 and/or is a W/O emulsifier. The preparation of the X/O phase itself and its diffusion in the Y phase are done with standard stirring tools. The drops of the X/O phase have long-term stability and, even when greatly diluted, do not interact with the Y phase or the drops or other X/O phases dispersed therein.

Description of the Invention

This application is a 371 of PCT/EP94/03955 filed Nov. 29, 1994.

The present invention relates to a stable multiple emulsion of the X/O/Y type.

Stable multiple emulsions of the W/O/W type are known, for example, from German Published Patent Application No. 4,131,678 and are described in a number of literature publications such as "Multiple Emulsions" by M. Frenkel et al. in J. Colloid Interface Sci., Vol. 94, pp. 174 to 178, 1982; "The Formulation and Stability of Multiple Emulsions" by A. T. Florence et al. in Int. J. of Pharmaceutics, Vol. 11, pp. 277 to 308, 1982; "Correlation between Nature of Emulsifier and Multiple Emulsion Stability" by S. Magdassi et al. in Drug Development and Industrial Pharmacy, Vol. 11, pp. 791 to 798, 1985.

Accordingly a multiple emulsion generally consists of a W/O phase, i.e. a water-in-oil phase comprising drops of a hydrophilic liquid which are dispersed in a hydrophobic liquid, and an aqueous phase in which these drops are dispersed. The internal component of the W/O phase may be constituted by, for example, an aqueous solution. The hydrophobic external component usually is selected from silicone oil, paraffin oil, triglyceride, fatty alcohol, ester oil or the like as well as mixtures thereof.

Such multiple emulsion can only be produced with the aid of emulsifiers. According to a generally acknowledged selection system, cf. Encyclopedia of Emulsion Technology, Ed. P. Becker, Marcel Dekker, New York, 1988, the emulsifiers are differentiated in accordance with an HLB value in correspondence with the ratio of their hydrophilic and hydrophobic portions; the HLB value is the hydrophilic portion percentage, divided by 5, of the emulsifier total molecular weight. Emulsifiers for forming W/O emulsions and having HLB values in the range of 3 to 6 are distinguished from emulsifiers forming wetting agents and having HLB values in the range of 7 to 9 and from emulsifiers for forming O/W emulsions and having HLB values in the range of 8 to 18.

In W/O/W emulsions of the initially mentioned type the aqueous phase is intended to serve as carrier for transporting the drops of the W/O phase to their place of action in a manner such that the compound present in the drops can not mix with or come into contact with the water. Important criteria therefore are the following:

1. Stability of the W/O phase against effects of temperature;

2. Stability of the W/O phase against coalescence;

3. Insensitivity to shearing forces occurring during preparation of the emulsion; and

4. Independence of the stability on the volume ratio of the W/O phase and the aqueous phase.

Hitherto known multiple emulsions satisfy these requirements only imperfectly; up to now, improvements could only be achieved by requiring passage through relatively complicated method steps when preparing the emulsion in order to be able to meet the desired stability requirements. Alternatively, specifically selected and composed emulsifiers had to be employed in order to realize the desired stability. According to the initially mentioned German Published Patent Application No. 4,131,678 a mixture of emulsifiers is required, one of which is a W/O emulsifier having an HLB value in the range of far below 3 to close to 5 and an other one of which has an HLB value in the range of 10 and far above.

Exclusively aqueous phases and oil phases were used in hitherto known W/O/W emulsions. The use of non-aqueous phases therein has never been considered.

In correspondence therewith it is the object of the invention to provide a simply composed multiple emulsion which can be produced in simple manner and which is significantly improved over known emulsions of the W/O/W type in terms of the afore noted stability criteria and its utility.

In particular, the inventive stable multiple emulsion should permit the inclusion of solids.

In order to achieve these objects, the invention provides a stable multiple emulsion of the X/O/Y type wherein X is a component immiscible with oil, O is an oil phase and Y is an aqueous phase, and which contains an emulsifier selected from the group of emulsifiers having an HLB value of .gtoreq.6 and/or constituting a W/O emulsifier.

Advantageously, the emulsifier is selected from the group consisting of glycerol esters, sorbitan esters, sorbitol esters, polyglycerol esters, fatty alcohols, propylene glycol esters, alkyl glucoside esters, carbohydrate esters, lecithin, silicone copolymers, their mixtures or derivatives.

The emulsions prepared with the aid of one of such emulsifiers are obtained by means of a simple mixing operation with stirring whereby the stability of such multiple emulsions is affected neither by the inputted stirrer energy nor by the type of stirrer. In fact, any commercially available stirrer may be utilized for producing the inventive multiple emulsion.

The thus prepared multiple emulsions according to the invention possess long-time stability and meet the usual stability requirements in the temperature range of -5^oC. to +45^oC. The multiple emulsions according to the invention are stable in a highly water-diluted condition (1:100): Coalescence does not occur even after aggregation and creaming because the creamed material can be completely redispersed simply by shaking and the thus restored emulsion again is just as stable as the originally prepared emulsion.

The inventive stable multiple emulsions are particularly distinguished by the fact that the drops contained therein have a size distribution between 1 .mu.m and 10 .mu.m and thus have a relatively small, in fact, smaller drop size than the known multiple emulsions which is of considerable advantage for many applications.

In particular, however, according to the invention, it is possible dispersing a number of X/O phases separately from each other in the aqueous phase and therein long-time stability is given in the sense as noted hereinbefore. The drops of the different X/O phases will remain completely separated from each other and there does not occur any intermixing, exchange or the like with the external aqueous phase. This is of specific significance in all cases in which the X/O phases contain different active ingredients which are intended to be administered separately but in a common carrier in, for instance, medical or cosmetic applications.

For this purpose, the Y phase or aqueous phase preferably constitutes an aqueous liquid, an aqueous gel or a multiple W/O/W emulsion. In the latter case there is thus achieved the advantage that the W/O/W emulsion can be mixed with one or more X/O emulsions in almost any desired volume ratio without loss in stability which can not be achieved or only to a limited extent when using pure water.

Claim 1 of 31 Claims

What is claimed is:

1. Stable multiple emulsion of the X/O/Y type in which X constitutes a component immiscible with oil and O is an oil phase and Y an aqueous phase and which contains at least one emulsifier selected from the group consisting of emulsifiers having an HLB value.ltoreq.6 and/or a W/O emulsifier with the proviso that no water-soluble emulsifier is present in the aqueous phase when a W/O emulsion is dispersed therein.

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