PHARMACEUTICAL COMPOSITION FOR TOPICAL USE COMPRISING AT LEAST ONE AZOLATED LOCAL ANTIFUNGAL SUBSTANCE

Abstract

Disclosed is a pharmaceutical composition for topical. use in the form of a water-in-oil emulsion including, for 100% of the weight thereof: from 0.3% to 5% by weight of at least one azolated local antifungal substance;—from 60% to 90% by weight of a gelled aqueous phase (A1);—from 9.7% to 35% by weight of a fatty phase (A2) including at least one oil and an emulsifying system including a combination of at least one emulsifying surfactant (S1) selected from the elements of the group consisting of alkylpolyglycoside compositions and alkylpolyglycoside and fatty alcohol compositions, and of at least one emulsifying surfactant (S2) selected from the elements of the group consisting of polyglycerol esters, alkoxylated polyglycerol esters, polyglycol polyhydroxystearates, polyglycerol polyhydroxystearates and alkoxylated polyglycerol polyhydroxystearates.

Claims

1. A pharmaceutical composition (El) suitable for topical use which is in the form of a water-in-oil emulsion comprising, for 100% of the weight thereof: from 0.3% to 5% by weight of at least one local azole antifungal substance; from 60% to 90% by weight of a gelled aqueous phase (A1); from 9.7% to 35% by weight of a fatty phase (A2) comprising at least one oil and an emulsifying system comprising a combination of at least one emulsifying surfactant (S1) chosen from the elements of the group consisting of compositions of alkyl polyglycosides, and compositions of alkyl polyglycosides and of fatty alcohols, and of at least one emulsifying surfactant (S2) chosen from the elements of the group consisting of polyglycerol esters, alkoxylated polyglycerol esters, polyglycol polyhydroxystearates, polyglycerol polyhydroxystearates, and alkoxylated polyglycerol polyhydroxystearates.

2. The pharmaceutical composition of claim 1, wherein the gelled aqueous phase comprises, for 100% of the weight thereof: from 0.5% to 10% by weight of a crosslinked anionic polyelectrolyte (AP), from 90% to 99.5% by weight of water.

3. The pharmaceutical composition of claim 2, wherein the crosslinked anionic polyelectrolyte (AP) comprises a proportion of greater than or equal to 25 mol % of monomer units derived from 2-methyl-2-[(1-oxo-2-propenyl)amino]-1-propanesulfonic acid in free acid or partially or totally salified form.

4. The pharmaceutical composition of claim 1, wherein the local azole antifungal substance is chosen from the elements, which are in neutral form or in the form of salts, of the group consisting of (RS)-1-[phenyl(4-phenylphenyl)methyl]-1H-imidazole or bifonazole, in the form of the R enantiomer of formula (Ia.sub.1) (CAS number=91487-85-3) or of the S enantiomer of formula (Ia.sub.2) (CAS number=91487-86-4): ##STR00018## (R,S)-1-{2-[(4-chlorophenyl)methoxy]-2-(2,4-dichlorophenyl)ethyl}-1H-imidazole (CAS number=27220-47-9) or econazole, in the form of the R enantiomer of formula (Ib.sub.1) or of the S enantiomer of formula (Ib2): ##STR00019## (R,S)-1-[2-(2,4-dichlorophenyl)-2-{[4-(phenylsulfanyl)phenyl]methoxy}ethyl]-1H-imidazole or fenticonazole (CAS number=72479-26-6) of formula (Ic): ##STR00020## (R,S)-1-{2-[(2,6-dichlorobenzyl)oxy]-2-(2,4-dichlorophenyl)ethyl}-1H-imidazole or isoconazole (CAS number=27523-40-6) in the form of the R enantiomer of formula (Id.sub.1) or in the form of the S enantiomer of formula (Id2): ##STR00021## 1-[4-(4-{[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy}phenyl)piperazin-1-yl]ethan-1-one or ketoconazole (CAS number=65277-42-1) in the form of the R enantiomer of formula (Ie.sub.1) or in the form of the S enantiomer of formula (Ie.sub.2): ##STR00022## (R,S)-1-{2-[(2,4-dichlorobenzyl)oxy]-2-(2,4-dichlorophenyl)ethyl}-1H-imidazole or miconazole (CAS number=22916-47-8) in the form of the R enantiomer of formula (If.sub.1) or in the form of the S enantiomer of formula (If.sub.2): ##STR00023## 1-[(Z)-2-[2-(4-chlorophenoxy)ethoxy]-2-(2,4-dichlorophenyl)-1-methylvinyl]-1H-imidazole (CAS number=74512-12-2) or omoconazole of formula (Ig): ##STR00024## (1Z)-N-[(2,4-dichlorobenzyl)oxy]-1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanimine or oxiconazole (CAS number=64211-45-6) of formula (Ih): ##STR00025## (R,S)-1-{2-[(7-chloro-1-benzothiophen-3-yl)methoxy]-2-(2,4-dichlorophenyl)ethyl}-1H-imidazole or sertaconazole (CAS number=99592-32-2) of formula (Ii): ##STR00026## (R,S)-1-{2-[(2-chlorothiophen-3-yl)methoxy]-2-(2,4-dichlorophenyl)ethyl}-1H-imidazole or tioconazole (CAS number=65899-73-2) in the form of the R enantiomer of formula (Ij.sub.1) or in the form of the S enantiomer of formula (Ij.sub.2): ##STR00027## 1-[(2-chlorophenyl)(diphenyl)methyl]-1H-imidazole or clotrimazole (CAS number=23593-75-1) of formula (Ik). ##STR00028##

5. The pharmaceutical composition of claim 1, wherein the local azole antifungal substance is chosen from the elements of the group consisting of the hydrochloride, phosphate, nitrate, propionate and citrate salts of the compounds of formulae (Ia.sub.1), (Ia.sub.2), (Ib.sub.1), (Ib.sub.2), (Ic), (Id.sub.1), (Id.sub.2), (Ie.sub.1), (Ie.sub.2), (If.sub.1), (If.sub.2), (Ig), (Ih), (Ii), (Ij.sub.1), (Ij.sub.2) and (Ik).

6. The pharmaceutical composition of claim 1, wherein the emulsifying surfactant (S.sub.1) consists of at least one alkyl polyglycoside composition (C.sub.1) represented by formula (VIII):
R.sub.1-O-(G)x-H (VIII) wherein x represents a decimal number between 1.05 and 2.5, G represents the glucosyl or α,β-D-glucopyranosyl radical, obtained from the removal of the hemiacetal hydroxyl group from α,β-D-glucopyranose, and R.sub.1 represents a radical chosen from the elements of the group consisting of the radicals n-dodecyl, n-tetradecyl, n-hexadecyl, n-octadecyl, n-eicosyl and n-behenyl, said composition (C.sub.1) consisting of a mixture of compounds represented by formulae (VIII.sub.1), (VIII.sub.2), (VIII.sub.3), (VIII.sub.4) and (VIII.sub.5):
R.sub.1-O-(G).sub.1-H   (VIII.sub.1)
R.sub.1-O-(G).sub.2-H   (VIII.sub.2)
R.sub.1-O-(G).sub.3-H   (VIII.sub.3)
R.sub.1-O-(G).sub.4-H   (VIII.sub.4)
R.sub.1-O-(G).sub.5-H   (VIII.sub.5), in the respective molar proportions a.sub.1, a.sub.2, a.sub.3, a.sub.4 and a.sub.5, such that: the sum a.sub.1+a.sub.2+a.sub.3+a.sub.4+a.sub.5 as is equal to 1, and that the sum a.sub.1+2a.sub.2+3a.sub.3+4a.sub.4+5a.sub.5 is equal to x.

7. The pharmaceutical composition of claim 1, wherein the emulsifying surfactant (S.sub.1) consists of at least one composition (C.sub.2) comprising, for 100% of the weight thereof: from 10% to 50% by weight of at least one alkylpolyglycoside composition (C.sub.1) represented by formula (VIII):
R.sub.1-O-(G)x-H   (VIII), wherein x represents a decimal number between 1.05 and 2.5, G represents the glucosyl or α,β-D-glucopyranosyl radical, obtained from the removal of the hemiacetal hydroxyl group from α,β-D-glucopyranose, and R.sub.1 represents a radical chosen from the elements of the group consisting of the radicals n-dodecyl, n-tetradecyl, n-hexadecyl, n-octadecyl, n-eicosyl and n-behenyl, said composition consisting of a mixture of compounds represented by formulae (VIII.sub.1), (VIII.sub.2), (VIII.sub.3), (VIII.sub.4) and (VIII.sub.5):
R1-O-(G)1-H   (VIII1)
R1-O-(G)2-H   (VIII2)
R1-O-(G)3-H   (VIII3)
R1-O-(G)4-H   (VIII4)
R1-O-(G)5-H   (VIII5) in the respective molar proportions a.sub.1, a.sub.2, a.sub.3, a.sub.4 and a.sub.5, such that: the sum a.sub.1+a.sub.2+a.sub.3+a.sub.4+a.sub.5 as is equal to 1, and that the sum a.sub.1+2a.sub.2+3a.sub.3+4a.sub.4+5a.sub.5 is equal to x; and from 90% to 50% by weight of at least one fatty alcohol of formula (IX):
R″.sub.1—OH   (IX), wherein R″.sub.1 represents a radical chosen from the elements of the group consisting of the radicals n-dodecyl, n-tetradecyl, n-hexadecyl, n-octadecyl, n-eicosyl and n-behenyl, where R′.sub.1 may be identical to or different from R.sub.1.

8. The pharmaceutical composition of claim 1, wherein the emulsifying surfactant (S.sub.2) consists of at least one polyglycol polyhydroxystearate represented by the formula (XII): ##STR00029## wherein y2 represents an integer greater than or equal to 2 and less than or equal to 50, R.sub.4 represents a hydrogen atom, a methyl radical or an ethyl radical, and Z.sub.2 represents a radical of formula (XIII): ##STR00030## wherein y′.sub.2 represents an integer greater than or equal to 0 and less than or equal to 10, more particularly greater than or equal to 1 and less than or equal to 10, and Z′.sub.2 represents a radical of formula (XIII) as defined above, where Z′.sub.2 may be identical to or different from Z.sub.2, or a hydrogen atom.

9. The pharmaceutical composition of claim 1, wherein the weight ratio between the emulsifying surfactant (S.sub.1) and the emulsifying surfactant (S.sub.2) is greater than or equal to ¼ and less than or equal to 1.

10. The pharmaceutical composition of claim 1, wherein said composition is intended to be used for therapy in a human or animal mammal.

11. A method for treating mycoses of the skin, the scalp, the mouth and/or the gynecological system in human or animal mammals, comprising administering a therapeutically effective dose of the composition of claim 1 to a human or animal mammal in need thereof.

12. The pharmaceutical composition of claim 1, further comprising at least one or more auxiliary compounds chosen from foaming and/or detergent surfactants, thickening and/or gelling surfactants, thickening and/or gelling agents, stabilizers, film-forming compounds, solvents and cosolvents, hydrotropic agents, plasticizing agents, opacifying agents, pearlescent agents, superfatting agents, sequestering agents, chelating agents, antioxidants, fragrances, essential oils, preservatives, conditioning agents, deodorants, and mineral fillers or pigments.

13. The pharmaceutical composition of claim 8, wherein y′.sub.2 represents an integer greater than or equal to 1 and less than or equal to 10.

14. The pharmaceutical composition of claim 2, wherein the local azole antifungal substance is chosen from the elements, which are in neutral form or in the form of salts, of the group consisting of (RS)-1-[phenyl(4-phenylphenyl)methyl]-1H-imidazole or bifonazole, in the form of the R enantiomer of formula (Ia.sub.1) (CAS number=91487-85-3) or of the S enantiomer of formula (Ia.sub.2) (CAS number=91487-86-4): ##STR00031## (R,S)-1-{2-[(4-chlorophenyl)methoxy]-2-(2,4-dichlorophenyl)ethyl}-1H-imidazole (CAS number=27220-47-9) or econazole, in the form of the R enantiomer of formula (Ib.sub.1) or of the S enantiomer of formula (Ib.sub.2): ##STR00032## (R,S)-1-[2-(2,4-dichlorophenyl)-2-{[4-(phenylsulfanyl)phenyl]methoxy}ethyl]-1H-imidazole or fenticonazole (CAS number=72479-26-6) of formula (Ic): ##STR00033## (R,S)-1-{2-[(2,6-dichlorobenzyl)oxy]-2-(2,4-dichlorophenyl)ethyl}-1H-imidazole or isoconazole (CAS number=27523-40-6) in the form of the R enantiomer of formula (Id.sub.1) or in the form of the S enantiomer of formula (Id.sub.2): ##STR00034## 1-[4-(4-{[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3 -dioxolan-4-yl]methoxy}phenyl)piperazin-1-yl]ethan-1- one or ketoconazole (CAS number=65277-42-1) in the form of the R enantiomer of formula (Ie.sub.1) or in the form of the S enantiomer of formula (Ie.sub.2): ##STR00035## (R,S)-1-{2-[(2,4-dichlorobenzyl)oxy]-2-(2,4-dichlorophenyl)ethyl}-1H-imidazole or miconazole (CAS number=22916-47-8) in the form of the R enantiomer of formula WO or in the form of the S enantiomer of formula (If.sub.2): ##STR00036## 1-[(Z)-2-[2-(4-chlorophenoxy)ethoxy]-2-(2,4-dichlorophenyl)-1-methylvinyl]-1H-imidazole (CAS number=74512-12-2) or omoconazole of formula (Ig): ##STR00037## (1Z)-N-[(2,4-dichlorobenzyl)oxy]-1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanimine or oxiconazole (CAS number=64211-45-6) of formula (Ih): ##STR00038## (R,S)-1-{2-[(7-chloro-1-benzothiophen-3-yl)methoxy]-2-(2,4-dichlorophenyl)ethyl}-1H-imidazole or sertaconazole (CAS number=99592-32-2) of formula (Ii): ##STR00039## (R,S)-1-{2-[(2-chlorothiophen-3-yl)methoxy]-2-(2,4-dichlorophenyl)ethyl}-1H-imidazole or tioconazole (CAS number=65899-73-2) in the form of the R enantiomer of formula (Ij.sub.1) or in the form of the S enantiomer of formula (Ij.sub.2): ##STR00040## 1-[(2-chlorophenyl)(diphenyl)methyl]-1H-imidazole or clotrimazole (CAS number=23593-75-1) of formula (Ik). ##STR00041##

15. The pharmaceutical composition of claim 3, wherein the local azole antifungal substance is chosen from the elements, which are in neutral form or in the form of salts, of the group consisting of (RS)-1-[phenyl(4-phenylphenyl)methyl]-1H-imidazole or bifonazole, in the form of the R enantiomer of formula (Ia.sub.1) (CAS number=91487-85-3) or of the S enantiomer of formula (Ia.sub.2) (CAS numbe=91487-86-4): ##STR00042## (R,S)-1-{2-[(4-chlorophenyl)methoxy]-2-(2,4-dichlorophenyl)ethy}-1H-imidazole (CAS number=27220-47-9) or econazole, in the form of the R enantiomer of formula (Ib.sub.1) or of the S enantiomer of formula (Ib.sub.2): ##STR00043## (R,S)-1-[2-(2,4-dichlorophenyl)-2-{[4-(phenylsulfanyl)phenyl]methoxy}ethyl]-1H-imidazole or fenticonazole (CAS number=72479-26-6) of formula (Ic): ##STR00044## (R,S)-1-{2-[(2,6-dichlorobenzyl)oxy]-2-(2,4-dichlorophenyl)ethyl}-1H-imidazole or isoconazole (CAS number=27523-40-6) in the form of the R enantiomer of formula (Id.sub.1) or in the form of the S enantiomer of formula (Id.sub.2): ##STR00045## 1-[4-(4-{[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy}phenyl)piperazin-1-yl]ethan-1-one or ketoconazole (CAS number=65277-42-1) in the form of the R enantiomer of formula (Iei) or in the form of the S enantiomer of formula (Ie2): ##STR00046## (R,S)-1-{2-[(2,4-dichlorobenzyl)oxy]-2-(2,4-dichlorophenyl)ethyl}-1H-imidazole or miconazole (CAS number=22916-47-8) in the form of the R enantiomer of formula (If.sub.1) or in the form of the S enantiomer of formula (If.sub.2): ##STR00047## 1-[(Z)-2-[2-(4-chlorophenoxy)ethoxy]-2-(2,4-dichlorophenyl)-1-methylvinyl]-1H-imidazole (CAS number=74512-12-2) or omoconazole of formula (Ig): ##STR00048## (1Z)-N-[(2,4-dichlorobenzyl)oxy]-1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanimine or oxiconazole (CAS number=64211-45-6) of formula (Ih): ##STR00049## (R,S)-1-{2-[(7-chloro-1-benzothiophen-3-yl)methoxy]-2-(2,4-dichlorophenyl)ethyl}-1H-imidazole or sertaconazole (CAS number=99592-32-2) of formula (Ii): ##STR00050## (R,S)-1-{2-[(2-chlorothiophen-3-yl)methoxy]-2-(2,4-dichlorophenyl)ethyl}-1H-imidazole or tioconazole (CAS number=65899-73-2) in the form of the R enantiomer of formula (Ij.sub.1) or in the form of the S enantiomer of formula (Ij.sub.2): ##STR00051## 1-[(2-chlorophenyl)(diphenyl)methyl]-1H-imidazole or clotrimazole (CAS number=23593-75-1) of formula (Ik). ##STR00052##

16. The pharmaceutical composition of claim 2, wherein the local azole antifungal substance is chosen from the elements of the group consisting of the hydrochloride, phosphate, nitrate, propionate and citrate salts of the compounds of formulae (Ia.sub.1), (Ia.sub.2), (Ib.sub.1), (Ib.sub.2), (Ic), (Id.sub.1), (Id.sub.2), (Ie.sub.1), (Ie.sub.2), (If.sub.1), (If.sub.2), (Ig), (Ih), (Ii), (Ij.sub.1), (Ij.sub.2) and (Ik).

17. The pharmaceutical composition of claim 3, wherein the local azole antifungal substance is chosen from the elements of the group consisting of the hydrochloride, phosphate, nitrate, propionate and citrate salts of the compounds of formulae (Ia.sub.1), (Ia.sub.2), (Ib.sub.1), (Ib.sub.2), (Ic), (Id.sub.1), (Id.sub.2), (Ie.sub.1), (Ie.sub.2), (If.sub.1), (If.sub.2), (Ig), (Ih), (Ii), (Ij.sub.1), (Ij.sub.2) and (Ik).

18. The pharmaceutical composition of claim 4, wherein the local azole antifungal substance is chosen from the elements of the group consisting of the hydrochloride, phosphate, nitrate, propionate and citrate salts of the compounds of formulae (Ia.sub.1), (Ia.sub.2), (Ib.sub.1), (Ib.sub.2), (Ic), (Id.sub.1), (Id.sub.2), (Ie.sub.1), (Ie.sub.2), (If.sub.1), (If.sub.2), (Ig), (Ih), (Ii), (Ij.sub.1), (Ij.sub.2) and (Ik).

19. The pharmaceutical composition of claim 2, wherein the emulsifying surfactant (S.sub.1) consists of at least one alkyl polyglycoside composition (C.sub.1) represented by formula (VIII):
R.sub.1-O-(G)x-H   (VIII) wherein x represents a decimal number between 1.05 and 2.5, G represents the glucosyl or α,β-D-glucopyranosyl radical, obtained from the removal of the hemiacetal hydroxyl group from α,β-D-glucopyranose, and R.sub.1 represents a radical chosen from the elements of the group consisting of the radicals n-dodecyl, n-tetradecyl, n-hexadecyl, n-octadecyl, n-eicosyl and n-behenyl, said composition (C.sub.1) consisting of a mixture of compounds represented by formulae (VIII.sub.1), (VIII.sub.2), (VIII.sub.3), (VIII.sub.4) and (VIII.sub.5):
R.sub.1-O-(G).sub.1-H   (VIII.sub.1)
R.sub.1-O-(G).sub.2-H   (VIII.sub.2)
R.sub.1-O-(G).sub.3-H   (VIII.sub.3)
R.sub.1-O-(G).sub.4-H   (VIII.sub.4)
R.sub.1-O-(G).sub.5-H   (VIII.sub.5), in the respective molar proportions a.sub.1, a.sub.2, a.sub.3, a.sub.4 and a.sub.5, such that: the sum a.sub.1+a.sub.2+a.sub.3+a.sub.4+a.sub.5 as is equal to 1, and that the sum a.sub.1+2a.sub.2+3a.sub.3+4a.sub.4+5a.sub.5 is equal to x.

20. The pharmaceutical composition of claim 3, wherein the emulsifying surfactant (S.sub.1) consists of at least one alkyl polyglycoside composition (C.sub.1) represented by formula (VIII):
R.sub.1-O-(G)x-H   (VIII) wherein x represents a decimal number between 1.05 and 2.5, G represents the glucosyl or α,β-D-glucopyranosyl radical, obtained from the removal of the hemiacetal hydroxyl group from α,β-D-glucopyranose, and R.sub.1 represents a radical chosen from the elements of the group consisting of the radicals n-dodecyl, n-tetradecyl, n-hexadecyl, n-octadecyl, n-eicosyl and n-behenyl, said composition (C.sub.1) consisting of a mixture of compounds represented by formulae (VIII.sub.1), (VIII.sub.2), (VIII.sub.3), (VIII.sub.4) and (VIII.sub.5):
R.sub.1-O-(G).sub.1-H   (VIII.sub.1)
R.sub.1-O-(G).sub.2-H   (VIII.sub.2)
R.sub.1-O-(G).sub.3-H   (VIII.sub.3)
R.sub.1-O-(G).sub.4-H   (VIII.sub.4)
R.sub.1-O-(G).sub.5-H   (VIII.sub.5), in the respective molar proportions a.sub.1, a.sub.2, a.sub.3, a.sub.4 and a.sub.5, such that: the sum a.sub.1+a.sub.2+a.sub.3+a.sub.4+a.sub.5 is equal to 1, and that the sum a.sub.1+2a.sub.2+3a.sub.3+4a.sub.4+5a.sub.5 is equal to x.

Description

DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0112] Preparation and evaluation of water-in-oil emulsions according to the invention and of comparative water-in-oil emulsions.

1) Preparation of the Water-In-Oil Emulsions

[0113] Three water-in-oil emulsions according to the invention, denoted (F.sub.1) to (F.sub.5), and three water-in-oil emulsions according to the prior art, denoted (F′.sub.1) to (F.sub.4), the proportions by weight of the constituents of which are recorded in table 1 below, the contents by weight of the polyelectrolytes being indicated as a percentage of polymeric solids, are prepared by performing the following process.

The constituents of the fatty phase are introduced successively into a beaker, mixed and brought to a temperature of 20° C. after an 80° C. heating step; the mixing is performed using a mechanical stirrer equipped with a propeller-type stirring spindle at a speed of 100 rpm. The glycerol and water are mixed at ambient temperature in a beaker using a mechanical stirrer at a speed of 2000 rpm and the thickener is then added gradually. The stirring is maintained for a duration which makes it possible to obtain an aqueous phase which is in the form of a homogeneous gel. The fatty phase is added in one go to the aqueous gel at ambient temperature and at a moderate stirring speed (75 to 300 rpm) using a stirrer equipped with an anchor-type spindle. This stirring is then maintained for 10 minutes and no cooling step is necessary.

TABLE-US-00001 TABLE 1 (F.sub.1) (F.sub.2) (F.sub.3) (F′.sub.1) (F′.sub.2) (F′.sub.3) (F.sub.4) (F.sub.5) (F′.sub.4) Fatty phase Econazole 1% 0% 0% 0% 1% 1% 1% 1% 1% nitrate Clotrimazole 0% 1% 1% 0% 0% 0% 0% 0% 0% Lanol ™ 15%  15%  8% 15%  8% 15%  15%  15%  15%  2681.sup.(1) Sepineo ™ SE 1% 3% 3% 1% 1% 0% 0% 0% 0% 68.sup.(2) Montanov ™ 0% 0% 0% 0% 0% 0% 1% 0% 0% L.sup.(8) Montanov ™ 0% 0% 0% 0% 0% 0% 0% 1% 0% 202.sup.(9) Sepicide ™ 1% 1% 1% 1% 1% 1% 1% 1% 1% HB.sup.(3) Simaline ™ 3% 3% 3% 3% 3% 3% 3% 3% 3% WO.sup.(4) Montane ™ 0% 0% 0% 0% 0% 1.2%.sup.  0% 0% 0% 80.sup.(6) Aqueous phase Sepineo ™ 3% 3% 3% 3% 3% 0% 3% 3% P600.sup.(5) PEG-400.sup.(7) 25%  15%  15%  25%  25%  25%  25%  25%  3% Ethanol 8% 8% 8% 8% 8% 8% 8% 8% 25%  Water q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. 8% 100% 100% 100% 100% 100% 100% 100% 100% .sup.(1)Land ™ 2681, or Coco-Caprylate/Caprate. .sup.(2)Sepineo ™ SE 68 is a mixture comprising, for 100% of the weight thereof, from 78% to 85% by weight of a mixture of n-hexadecanol and n-octadecanol, and from 15% to 22% by weight of a mixture of n-hexadecyl glucoside with a mean degree of polymerization of 1.20 and n-octadecyl glucoside with a mean degree of polymerization of 1.20, used as emulsifying agent. .sup.(3)Sepicide ™ HB is a mixture of phenoxyethanol, methylparaben, ethylparaben, butylparaben and n-propylparaben, used as a preservative. .sup.(4)Simaline ™ WO, or PEG 30 Dipolyhydroxystearate, is an emulsifying surfactant. .sup.(5)Sepineo ™ P600 is a self-invertible inverse latex comprising, for 100% of the weight thereof, between 30% and 40% by weight of a crosslinked copolymer of acrylamide and of sodium acryloyldimethyltaurate, used as a thickening agent. .sup.(6)Montane ™ 80 is a composition comprising sorbitan monooleate, used as water-in-oil type emulsifying agent. .sup.(7)PEG-400 is a polyethylene glycol with a molecular weight of approximately 400 g .Math. mol.sup.−1.
2 Demonstration of the properties of the water-in-oil emulsions (F.sub.1) to (F.sub.3) according to the invention and of the water-in-oil emulsions (F′.sub.1) to (F′.sub.3) according to the prior art. 2.1 Characterization of the appearance and the viscosity of the water-in-oil emulsions (F.sub.1) to (F.sub.3) according to the invention and of the water-in-oil emulsions (F′.sub.1) to (F′.sub.3) according to the prior art.

[0114] The emulsions (F.sub.1) to (F.sub.3) and (F′.sub.1) to (F′.sub.3) obtained according to the process described above are then stored in an insulated climatic chamber regulated at a temperature of 25° C. for 3 months. After the conclusion of this period of three months, the appearance (APP) of each emulsion prepared is observed and the dynamic viscosity (μ) of each emulsion is measured (in mPas) by means of a viscometer at 25° C. (Brookfield LVT, speed 6).

An aliquot of these same emulsions (F.sub.1) to (F.sub.3) and (F′.sub.1) to (F′.sub.3) obtained according to the process described above are also stored in an insulated climatic chamber regulated at a temperature of 45° C. for three months. After the conclusion of this period of three months, the appearance (APP) of each emulsion prepared is observed and the dynamic viscosity (μ) of each emulsion is measured (in mPas) by means of a viscometer at 25° C. (Brookfield LVT, speed 6).

[0115] 2.2 Characterization of the direction of the emulsions (F.sub.1) to (F.sub.3) according to the invention and of the emulsions (F′.sub.1) to (F′.sub.3) according to the prior art.

[0116] The conductivity (σ) of the emulsions (F.sub.1) to (F.sub.3) according to the invention and of the emulsions (F′.sub.1) to (F′.sub.3) is measured at 25° C., after a period of storage of said emulsions of one day in an insulated climatic chamber regulated at a temperature of 25° C., by means of an LF 196™ brand conductivity meter from the company WTW equipped with a TetraCon™ 96 electrode. If, for a given emulsion, (σ)≤0.5 μS.Math.cm.sup.−1, the emulsion is considered to be non-conductive and consequently the external phase is considered not to be the aqueous phase but the oily phase.

[0117] If, for a given emulsion, (σ)>0.5 μS.Math.cm.sup.−1, the emulsion is considered to be conductive and consequently the external phase is considered not to be the oily phase but the aqueous phase.

[0118] This same measurement of the conductivity of the emulsions (F.sub.1) to (F.sub.3) according to the invention and of the emulsions (F′.sub.1) to (F′.sub.3) is measured at 25° C. after three months at 25° C., and after three months at 45° C.

2.3 Results obtained for the water-in-oil emulsions (F.sub.1) to (F.sub.3) according to the invention and for the water-in-oil emulsions (F′.sub.1) to (F′.sub.3) according to the prior art.

[0119] The evaluation methods described in paragraphs 2.1 and 2.2 were applied to the water-in-oil emulsions (F.sub.1) to (F.sub.3) according to the invention and to the water-in-oil emulsions (F′.sub.1) to (F′.sub.3) according to the prior art. The results obtained are recorded in table 2 below.

TABLE-US-00002 TABLE 2 (F.sub.1) (F.sub.2) (F3) (F′.sub.1) (F′.sub.2) (APP) at 1 Homogeneous Homogeneous Homogeneous Homogeneous Homogeneous day liquid liquid liquid liquid liquid (visual) O/W (σ) at 1 ≤0.5 μS .Math. cm.sup.−1 ≤0.5 μS .Math. cm.sup.−1 ≤0.5 μS .Math. cm.sup.−1 ≤0.5 μS .Math. cm.sup.−1 >0.5 μS .Math. cm day at 25° C. (APP) at 7 Homogeneous Homogeneous Homogeneous Homogeneous Homogeneous days at liquid liquid liquid liquid liquid 25° C. O/W (σ) at 3 ≤0.5 μS .Math. cm.sup.−1 ≤0.5 μS .Math. cm.sup.−1 ≤0.5 μS .Math. cm.sup.−1 ≤0.5 μS .Math. cm.sup.−1 >0.5 μS .Math. cm months at 25° C. (F′.sub.3) (F4) (F5) (F′.sub.4) (APP) at 1 Homogeneous Homogeneous Homogeneous Homogeneous day liquid liquid liquid liquid (visual) O/W (σ) at 1 >0.5 μS .Math. cm.sup.  ≤0.5 μS .Math. cm.sup.−1 ≤0.5 μS .Math. cm.sup.−1 ≤0.5 μS .Math. cm.sup.−1 day at 25° C. (APP) at 7 Homogeneous Homogeneous Homogeneous Liquid with days at liquid liquid liquid slight 25° C. O/W exudation (σ) at 3 >0.5 μS .Math. cm.sup.−1 >0.5 μS .Math. cm.sup.−1 >0.5 μS .Math. cm.sup.−1 Not measured months at 25° C.
2.4 Analysis of the results

[0120] The water-in-oil emulsions (F.sub.1) to (F.sub.3) according to the invention are therefore characterized by: [0121] a stability of their water-in-oil form after 3 months of storage at a temperature of 25° C.; the observed appearance after this period of storage is still homogeneous; [0122] a stability of their water-in-oil form after 3 months of storage at a temperature of 45° C.; the observed appearance after this period of storage is still homogeneous; [0123] dynamic viscosity values measured after 3 months of storage at 25° C. by means of a Brookfield LV viscometer at 25° C. and at a speed of 6 rpm of between 27 000 mPa.Math.s (for (F.sub.2)) and 65 000 mPa.Math.s (for (F.sub.1)).

[0124] The formulation (F.sub.1) differs from (F.sub.2) by the absence of econazole nitrate within it; (F.sub.1) is in the form of a water-in-oil emulsion while the formulation of (F.sub.2) does not make it possible to obtain a water-in-oil emulsion but rather a water-in-oil emulsion.

[0125] When the weight content of oil (Lanol™ 2681) in the formulation is increased to 15% in the formulation (F.sub.1), the emulsion obtained is of the water-in-oil type whereas the emulsion obtained is of the oil-in-water type for the formulation (F2) containing 8% of Lanol™ 2681.

The formulation (F.sub.3), differs from the formulation (F.sub.1) only in the nature of the surfactant, that is to say sorbitan oleate (Montane™ 80) for the formulation (F.sub.3) instead of cetearyl polyglucoside/cetearyl alcohol for the formulation (F.sub.3), does not make it possible to obtain a water-in-oil emulsion after storage at 25° C. and at 45° C. for three months.
The formulation (F4) contains only one water-in-oil surfactant, PEG 30 dipolyhydroxystearate (sold under the trade name SimalineTM WO) which is a water-in-oil surfactant, and does not make it possible to obtain a water-in-oil emulsion which is stable after storage at 45° C. for three months because a phase separation and a heterogeneous appearance are observed from the end of the first month of storage.