Title:  Method for releasing an active principle contained a multiple emulsion

United States Patent:  6,627,603

Issued:  September 30, 2003

Inventors:  Bibette; Jerome (Bordeaux, FR); Ficheux; Marie-Fran.cedilla.oise (Gradignan, FR); Leal Calderon; Fernando (La Brede, FR); Bonnakdar; Lida (Talence, FR)

Assignee:  Centre National de la Recherche Scientifiquue (C.N.R.S.) (Paris, FR)

Appl. No.:  284062

Filed:  August 10, 1999

PCT Filed:  August 5, 1998

PCT NO:  PCT/FR98/01748

PCT PUB.NO.:  WO99/07463

PCT PUB. Date:  February 18, 1999

Abstract

A method for the controlled release of an active principle contained in a multiple water-in-oil-in-water emulsion characterized in that the multiple emulsion comprises an invert emulsion Ei with an aqueous phase A1 containing at least a hydrophilic active principle. The emulsion Ei is dispersed in the form of direct emulsion droplets Ed, in a continuous aqueous phase A2, with the two emulsions Ed and Ei stabilized by at least a surfactant, present in their respective continuous phases. The multiple emulsion is brought in the presence of an effective amount of an agent for transforming it into a direct emulsion and induce the release of the active principle, contained in the aqueous phase A1 of emulsion Ei, in the aqueous phase A2.

SUMMARY OF THE INVENTION

Consequently, the present invention provides a process for releasing, in a controlled way, an active principle present in a multiple emulsion of water-in-oil-in-water type, characterized in that

the said emulsion comprises an inverse emulsion Ei with an aqueous phase A1 in which is incorporated at least one hydrophilic active principle, the said emulsion Ei being dispersed in the form of droplets of direct emulsion Ed in an aqueous phase A2 with the emulsions Ei and Ed stabilized by at least one surfactant present in their respective continuous phases, and in that

the said multiple emulsion is brought into the presence of a sufficient amount of an agent to convert it into a direct emulsion, so as to induce the release of the active principle present in the aqueous phase A1 of the emulsion Ei into the aqueous phase A2.

According to a favoured embodiment of the invention, the surfactant involved in the aqueous phase A2 of the emulsion Ed is present at a concentration below its critical concentration threshold.

Within the meaning of the invention, a critical concentration threshold is understood to define the value of surfactant concentration beyond which destabilization of the multiple emulsion is induced with the effect of releasing the active principle.

If the concentration of hydrophilic surface-active agent present in the aqueous phase A2 is below this concentration threshold, then no coalescence is observed for a period of the order of several months.

Conversely, if the concentration of hydrophilic surface-active agent present in the aqueous phase A2 is greater than or equal to this concentration threshold, then coalescence and therefore release take place over a time scale varying from a few days to a few minutes. The higher this concentration, the shorter the release time.

The release of the active principle will be regarded as complete when virtually all the droplets of the aqueous phase A1 have been released into the external aqueous phase A2. The release of the active principle will therefore be assessed as fast or slow according to the time taken to carry out the release of the droplets.

Advantageously, it thus proves to be possible to control the release of the active principle over a longer or shorter period of time by adjusting the difference in concentration between the critical concentration threshold and the final concentration obtained by addition of surfactant.

In fact, it has been observed that this concentration threshold could be expressed with respect to the critical micelle concentration, CMC, of the surfactant under consideration.

The critical micelle concentration is defined as the concentration beyond which the surface-active molecules combine together to form spherical clusters known as micelles (see, for example, "Galenica 5, agents de surfaces et emulsions" ["Surfactants and emulsions"], vol. 5.1, page 101, editor: Techniques et Documentation [Techniques and Documentation] (Lavoisier)).

However, the value of this concentration threshold, expressed with respect to the CMC, also varies according to the HLB value of the surfactant.

Thus, for a certain range of HLB values, the corresponding surfactants should be present in the aqueous phase A2 at a concentration below their critical micelle concentrations, if it is desired to avoid release of the active principle.

On the other hand, for another range of HLB values, the corresponding surfactants may be present up to a concentration far greater than their CMC, without this release of the active principle being observed.

As a general rule, for surfactants having an HLB of the order of 40, that is to say very hydrophilic, the concentration threshold is between 1 and 20 CMC.

In the case of surfactants having an HLB of between approximately 12 and 20, this concentration threshold is greater than 100 CMC.

Likewise, the diameter of the internal water droplets A1, the diameter of the droplets of emulsion Ed, the chemical nature of the active principle present in the aqueous phase A1 and the amount and type of surface-active agent present in the oily phase of the emulsion Ei affect the value of this critical concentration threshold.

All these parameters are therefore to be taken into consideration in assessing the critical concentration threshold for a specific surfactant present in the continuous aqueous phase A2 of the emulsion Ed.

This critical concentration threshold can be easily assessed, for a surfactant of given HLB, from preliminary tests according to the procedure described in Example 1 below.

This assessment can, for example, be carried out according to the procedure which consists in:

preparing a multiple emulsion which incorporates the active principle in its internal aqueous phase and which comprises a surfactant in the external aqueous phase A2 in an amount sufficient to stabilize the said emulsion,

adding, to the aqueous phase A2 of the said emulsion, increasing amounts of the said surfactant,

quantitatively determining, on conclusion of each addition of the said surfactant, the concentration of active principle which has or has not been released into the external aqueous phase, and

recording the concentration of surfactant beyond which a significant acceleration in the release kinetics is observed.

Generally, the concentration of surfactant is recorded beyond which 90% of the active principle initially present within the internal phase is found in the external aqueous phase in a time period of approximately 10 hours.

As regards the technique of quantitative determination used to estimate the concentration of the released active principle, it varies, of course, as a function of the nature of this active principle. It can be a conductimetric or potentiometric measurement, when the active principle is an ionic species, or alternatively a fluorescence spectroscopy technique, if the active principle is fluorescent.

Of course, a person skilled in the art is in a position to select the appropriate quantitative determination technique.

Advantageously, it therefore proves to be possible to induce the release of the active principle present in the claimed emulsion by bringing the direct emulsion Ed into contact with an agent, such that it causes, because of its presence and optionally its concentration, a transfer of the internal water droplets A1 to the aqueous phase A2, thus converting the multiple emulsion into a simple direct emulsion with release of the active principle into the external environment.

DETAILED DESCRIPTION OF THE INVENTION

According to a favoured embodiment of the invention, this agent is preferably a surfactant which is identical to the surfactant which is present in the aqueous phase A2 of the emulsion Ed and which is as defined below. Because of its presence, it shifts the initial concentration of this surfactant beyond its critical concentration threshold and thus triggers the coalescence phenomenon favourable to the release of the active principle.

However, it is also possible to envisage this release being induced by an agent with a nature different from that of the surfactant employed in the aqueous phase A2. It can thus be another surfactant or alternatively a compound already present in the external environment into which the release of the active principle is envisaged.

This agent can in particular be a polymer of polyvinylpyrrolidone or polyethylene glycol type or alternatively a hydrocolloid, such as xanthan gum, guar or carrageenan, and their derivatives.

The surfactant present in the aqueous phase A2 is preferably a water-soluble surfactant having an HLB of greater than 14.

Mention may in particular be made, as illustrations of water-soluble agents of this type, of lecithins which are soluble in water, sucrose esters, fatty acid esters (including the "Tweens"), polyoxyethylenated alkylamides, triglyceride sulphates, alkyl sulphates (including sodium dodecyl sulphate, SDS), alkyl ether sulphates, alkyl sulphonates, alkylamine salts (including Tetradecyl Trimethylammonium Bromide, TTAB), fatty amines, lipoamino acids (including bovine or human serum albumin, beta-lactoglobulin or casein), alkyl betaines, alkyl polyglycol ethers, alkylene oxide copolymers, modified polyesters and polymeric silicone surface-active agents.

As regards the surfactant present in the continuous oily phase of the emulsion Ei, it is preferably a fat-soluble surfactant with an HLB of less than 7.

The fat-soluble surfactants which can be employed in the emulsion according to the invention can be selected from lecithins which are soluble in fat, esters of sorbitan and fatty acids (including the "Span" esters), polyalkylene dipolyhydroxystearates, fatty acids, monoglycerides, polyglycerol esters, polyglycerol polyricinoleate and esters of lactic and tartaric acid.

The continuous phase of the emulsion Ei is an oily phase preferably composed of at least one oil selected from vegetable, animal or mineral oils.

The inverse emulsion Ei preferably comprises approximately 50% to 99% by volume of this continuous phase per 1% to 50% of aqueous phase A1.

As for the direct emulsion Ed, it preferably comprises from 50% to 99% by volume of aqueous phase A2 per 1% to 50% of this inverse emulsion Ei.

As regards the hydrophilic active principle present in the claimed emulsion, it can be a compound which is active in one of the following fields, namely pharmaceutical, cosmetic, plant-protection or foodstuff fields, and/or surfacings of paint or road type, for example.

It can thus be selected from vitamins (E, C), enzymes, insulin, analgesics, antimitotics, anti-inflammatories or antiglaucomas, vaccines, anti-cancer agents, narcotic antagonists, detoxification agents (salicylates, barbiturates), depilatory agents, agents for correcting or masking taste, water-soluble salts, breaking agents (bitumen emulsions), acids, bases, vinegar, glucose, colorants, preservatives or their mixtures.

Of course, the concentration of this active principle in the aqueous phase A1 is to be defined in each specific case by a person skilled in the art according to the expected effectiveness.

The invention is of particular use in accelerating the breaking of bitumen emulsions when they are spread over carriageways. In this specific application, a breaking agent, generally a salt or solution at basic pH, is incorporated in a multiple emulsion and its release is brought about by bringing the said emulsion into contact with the bitumen emulsion. In this specific case, it is the presence of the surfactant present in the bitumen emulsion which initiates the release of this breaking agent. This therefore results in an acceleration in the breaking of the bitumen, induced specifically by this breaking agent.

The present invention is targeted in particular at the application of the claimed process in the release of a breaking agent in the field of road surfacing and more particularly in the context of the application of a bitumen-based surfacing.

In another field of activity, such as that of pharmaceuticals, the invention also makes possible the release time of the active principle.

This is advantageous in two respects; it results in better assimilation of the active principle by the treated organism and an optimisation in the effectiveness of the active principle.

Claim 1 of 9 Claims

What is claimed is:

1. A process for releasing an active principle comprising a multiple emulsion wherein the multiple emulsion comprises a water-in-oil-in water emulsion comprising an inverse emulsion Ei with an aqueous phase A1, in dispersion in the form of droplets of direct emulsion Ed, in a continuous aqueous phase A2, wherein the emulsion Ed is stabilized by a surfactant having an HLB of greater than 14 present in its continuous phase; the emulsion Ei is stabilized by a surfactant having an HLB of less than 7 present in its continuous phase; and the amount of the surfactant present in the aqueous phase A2 of the emulsion Ed is adjusted to an amount greater than the critical concentration threshold of this surfactant, for converting said multiple emulsion into a direct-emulsion, with a concentration threshold being between 7 and 20 CMC (Critical Micelle Concentration) for a surfactant having an HLB of the order of 40 and greater than 100 CMC for a surfactant having an HLB between 14 and 20 CMC; wherein the active principle is in solution in the aqueous phase A1 and said active principle is released into the aqueous phase A2 by adjusting the concentration of the surfactant present in said aqueous phase A2 with the release time being shorter at concentrations equal to or greater than this surfactant's critical concentration threshold.

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