EP4274549A1

EP4274549A1 - Pharmaceutical composition comprising, as thickening agent, a composition having polar media thickening properties

Info

Publication number: EP4274549A1
Application number: EP21844310.9A
Authority: EP
Inventors: Miruna BODOC; Stéphane MONTEILLET
Original assignee: Societe dExploitation de Produits pour les Industries Chimiques SEPPIC SA
Current assignee: Societe dExploitation de Produits pour les Industries Chimiques SEPPIC SA
Priority date: 2021-01-07
Filing date: 2021-12-22
Publication date: 2023-11-15
Also published as: WO2022148660A1; FR3118578B1; FR3118578A1; CN116601208A; US20240091150A1

Abstract

Pharmaceutical composition (F) comprising at least one active pharmaceutical principle and, as thickening agent, a composition (C_A) in the form of a self-reversible water-in-oil-type emulsion comprising, for 100% of its mass, a mass content of greater than or equal to 20% of a polymer (P) consisting of monomer units derived from glutamic acid (GA), partially or totally salified, and units derived from at least one cross-linking agent (AR) bearing at least two glycidyl functions.

Description

Pharmaceutical composition comprising as thickening agent a composition which exhibits thickening properties of polar media

The present invention relates to a pharmaceutical composition (F) comprising at least one pharmaceutical active ingredient and, as thickening agent, a composition (C A ) in the form of a self-inverting water-in-oil type emulsion and the process for the preparation of such a composition.
Polymers are widely used today in pharmaceutical formulations for topical use and represent the second family of products most used in this type of complex formulations. The pharmaceutical compositions contain polar phases such as, for example, phases consisting of water, and in most cases require the use of rheology modifying agents, such as, for example, polymers to increase the viscosity of these polar phases, as well as to impart a well-defined rheological behavior.
Among the rheology-modifying polymers of the polar phases, we can cite natural polymers, such as for example polysaccharides based on oses or polysaccharides based on derivatives of oses or else synthetic polymers, polyelectrolyte type, anionic or cationic, amphiphilic, linear or branched, reticulated or non-reticulated. Predominantly present on the market for ingredients intended for pharmaceutical formulations for topical use, synthetic polymers have the property of being deployed, in the polar phase, under the effect of electrostatic repulsions due to the presence of charges (negative and/or positive ) on the polymer backbone, linear or branched, non-crosslinked or crosslinked. These rheology modifiers bring both an increase in the viscosity of the polar phase, as well as a certain consistency and/or a stabilizing effect to the pharmaceutical formulation for topical use.
In order to meet the needs of formulators, various recent scientific works have reported the development of new, innovative and varied polymeric systems. Thus, polymers used in pharmacology can play a functional role as film-forming agents, rheology modifiers, agents allowing the stabilization of fatty phases in oil-in-water emulsions and water-in-oil stabilization of particles.
The rheology modifying polymers of polar phases, more particularly of aqueous phases, are mainly polyelectrolytes, result from the radical polymerization of (meth)acrylic type monomers, that is to say acrylic acid, methacrylic acid , esters derived from acrylic acid or methacrylic acid, or alternatively acrylamide or methacrylamide derivatives.
Developing new biobased and biodegradable rheology modifiers, as efficient as the synthetic polymers currently used, still constitutes a major challenge and a challenge for suppliers of pharmaceutical ingredients. Indeed, until now the solutions mainly used to thicken polar phases involve ingredients from raw materials of petrochemical origin and in particular acrylic acid and its derivatives, methacrylic acid and its derivatives .
Given the growing concern of consumers for economy and sustainable development, the substitution of raw materials of petrochemical origin by raw materials of renewable origin to prepare polymers is a priority research area.
To date, it is described in the literature the use of various natural polymers or coming from renewable raw materials, whose monomeric units come from the family of sugars (glucose, arabinose, xylose, galactose, mannose, ribose, glucuronic acid , etc…) or from the family of amino acids (glutamic acid, aspartic acid, lysine, etc…). These polymers are mostly linear or branched depending on the plant from which they come or according to their manufacturing process.
As an example of a polymer of natural origin, mention may be made of polyglutamic acid (PGA), which is today the subject of numerous research works. It is a predominantly linear polymer and consists of monomeric glutamic acid (GA) units. Glutamic acid is an amino acid characterized by an amine function in position and by two carboxylic acid functions (or carboxylates depending on the pH) in the α and γ positions (cf chemical formula n°1).
Chemical structure of glutamic acid (GA)
One of the ways to increase the branching of a synthetic, natural or of natural origin polymer consists in carrying out crosslinking reactions. The cross-linking of polymer chains aims to connect several polymer chains to each other which, when added to a polar phase, and more particularly to water, appear as a three-dimensional network insoluble in water. water, but swellable with water and then leading to the production of an aqueous gel.
The preparation of cross-linked polymers can be carried out:

In one step by reacting the monomers and the crosslinking agent during the polymerization reaction, or
In at least two steps, the first of which consists in preparing the polymer, and the second consists in reacting the polymer with a crosslinking agent to obtain a crosslinked polymer.

There are different crosslinking reactions of gamma-polyglutamic acid (PGA), which makes it possible to obtain polymers of natural origin with improved thickening properties in polar media, and in particular aqueous ones. Among the crosslinking agents known to be used in the polyglutamic acid (PGA) crosslinking reaction, the polyepoxide derivatives are the most α described because they make it possible to implement crosslinking processes under environmentally friendly conditions ( moderate temperature, reaction in aqueous media, and in the absence of harmful solvents).
However, the implementation of these processes requires diluting the (PGA) to high levels, which leads to the production of a composition in the form of an aqueous gel comprising, for 100% of its mass, a mass content less than or equal to 10% of a polymer (P) and difficult to implement by formulators.
From there, a problem which arises is to provide an easy-to-use pharmaceutical composition, comprising polymers of natural origin, and whose raw materials are renewable and which have thickening properties of polar media and more particularly of aqueous media.
A solution of the present invention is a pharmaceutical composition (F) comprising at least one pharmaceutical active ingredient and, as thickening agent, a composition (C A ) in the form of a self-inverting water-in-oil type emulsion comprising for 100% of its mass a mass content greater than or equal to 20% of a polymer (P) consisting of monomeric units derived from glutamic acid (GA), partially or totally salified, and in units derived from at least a crosslinking agent (RA) bearing at least two glycidyl functions.
By "emulsion of the water-in-oil type" is meant within the meaning of the present invention a heterogeneous mixture of two immiscible liquids, one being dispersed in the form of small droplets in the other, said mixture being thermodynamically unstable and stabilized by the presence of a surfactant system comprising at least one emulsifying surfactant.
By "emulsion of the water-in-oil self-inverting type" is meant, within the meaning of the present invention, an emulsion of the water-in-oil type as defined above, in which the emulsifying surfactants present confer on the emulsion a hydrophilic-lipophilic balance (HLB) such that once said emulsion has been added to a polar phase, such as for example water, the direction of the emulsion will change to pass from the water-in-oil form to the oil- in water, then making it possible to bring the polymer (P) into contact with the polar phase to be thickened.
In the polymer (P) present in the composition (C A ) which is the subject of the present invention, the monomeric units derived from glutamic acid (GA), partially or totally salified, are linked together:
either in such a way that the amine function of a monomeric unit of glutamic acid (GA) is covalently linked with the carboxylic function located in the alpha α position of a second monomeric unit of glutamic acid (GA); the resulting polymer is then called “α-polyglutamic acid” or PAGA (cf. chemical formula n°2) partially or totally salified,
Chemical structure of α-polyglutamic acid or PAGA.

either in such a way that the amine function of a monomeric unit of glutamic acid (GA) is covalently linked to the carboxylic function of the side chain located in the gamma (γ) position of a second monomeric unit of glutamic acid (GA); the resulting polymer is then called “γ-polyglutamic acid” or PGGA (cf chemical formula n°3) partially or totally salified.

Chemical structure of ϒ-polyglutamic acid or PGGA.
In general, the PGA can be prepared chemically according to peptide synthesis methods known to those skilled in the art, in particular passing through stages of selective protection(s), activation, coupling and deprotection(s). The coupling generally consists of a nucleophilic attack of the amine function of a monomeric glutamic acid unit on an activated carboxylic acid function of another monomeric glutamic acid unit.
PGGA can also be obtained by processes comprising at least one microbial fermentation step involving the use of at least one bacterial strain.
Within the meaning of the present invention, in the polymer (P) as defined previously, the term “salified” indicates that the “pendant” carboxylic acid function present on each monomeric unit of glutamic acid (GA) of the polymer (in the gamma position in the case of PAGA or alpha in the case of PGGA) is in an anionic or carboxylate form. The counter-ion of this carboxylate function is a cation derived, for example, from salts of alkali metals such as sodium, potassium or from salts of nitrogenous bases such as amines, lysine or monoethanolamine (HO-CH2-CH2 -NH2).
By “crosslinking agent (RA)”, is meant, within the meaning of the present invention, a chemical molecule whose structure makes it possible to bond covalently to at least two polymer chains.
By “crosslinking agent (RA) carrying at least two glycidyl functions”, is meant within the meaning of the present invention a crosslinking agent (RA) as defined above whose molecular structure comprises at least two glycidyl units or functions of formula ( I'):
(I'),
The cross-linking of the polymer chains of the polymer (P) takes place according to a reaction between the terminal free amine function (-NH2) and/or one or more "pendent" or terminal carboxylic or carboxylate functions (-COOH or -COO - ) present in the structure of said polymer (P), and at least one epoxy group present in the structure of the crosslinking agent (AR) bearing at least two glycidyl functions.
The crosslinking agent (RA) may be chosen from the members of the group consisting of:

Ethylene Glycol Di Glycidyl ether of formula (I)

(I)

the compound of formula (II)

(II)
With R representing the hydrogen atom or the radical [ ], and n which represents an integer greater than or equal to one and less than or equal to 10;
When R represents the hydrogen atom and n is equal to 1, the compound of formula (II) is more particularly the compound of formula (IIa) or Glycérol Diglycidyl ether
When R represents the [ ] and n is equal to 1, the compound of formula (II) is more particularly the compound of formula (IIb) or Glycerol Triglycidyl ether
When R represents the hydrogen atom and n is equal to 2, the compound of formula (II) is more particularly the compound of formula (IIc) or DiGlycérol Di Glycidyl ether
When R represents the [ ] and n is equal to 2, the compound of formula (II) is more particularly the compound of formula (IId) or Di Glycerol Tetra Glycidyl ether

The 1,3 propanediol DiGlycidyl ether of formula (III)

The 1,2 propanediol DiGlycidyl ether of formula (IV)

The 1,4 butanediol Di Glycidyl ether of formula (V)

1,2 butanediol Di Glycidyl ether of formula (VI)

The 1,3 butanediol Di Glycidyl ether of formula (VII)

The 1,6 hexanediol DI Glycidyl ether of formula (VIII)

The compound of formula (IX)

With R1 representing the hydrogen atom or the [ ];
When R1 represents the hydrogen atom, the compound of formula (IX) is more particularly the compound of formula (IXa) or trimethylol ethane DiGlycidyl ether
When R1 represents the [ ], the compound of formula (IX) is more particularly the compound of formula (IXb) or trimethylol ethane TriGlycidyl ether

The compound of formula (X)

with R1 representing the hydrogen atom or the glycidyl radical [ ];
When R1 represents the hydrogen atom, the compound of formula (X) is more particularly the compound of formula (Xa) or trimethylol propane DiGlycidyl ether
When R1 represents the glycidyl radical [ ], the compound of formula (X) is more particularly the compound of formula (Xb) or trimethylol propane TriGlycidyl ether

The compound of formula (XI)

with R1 and R2, independent, which represent the hydrogen atom or the glycidyl radical [ ]
When R1 and R2 each represent the hydrogen atom, the compound of formula (XI) is more particularly the compound of formula (XIa) or Pentaerythritol Di Glycidyl ether
When R1 represents the hydrogen atom and R2 represents the glycidyl radical [ , the compound of formula (XI) is more particularly the compound of formula (XIb) or Pentaerythritol Tri Glycidyl ether
When R1 and R2 each represent the glycidyl radical [ ], the compound of formula (XI) is more particularly the compound of formula (XIc) or Pentaerythritol Tetra Glycidyl ether

The compound of formula (XII)

with m representing an integer greater than or equal to 2

The compound of formula (XIII)

With R3 representing the hydrogen atom or the [ ], and x, y, z, o, p and q, independent of each other, represent an integer greater than or equal to 2 and less than or equal to 10.
Depending on the case, the pharmaceutical composition may have one or more of the following characteristics:

in the composition (C A ), the mass content of the polymer (P) is greater than or equal to 20% and less than or equal to 60%;
in composition (C A ), the polymer (P) is gamma-polyglutamic acid in acid form, or partially or totally salified.
in the composition (C A ), the polymer (P), for 100% molar of monomeric units derived from glutamic acid (GA), partially or totally salified, the crosslinking agent (RA) represents 0.5% at 20% molar;
the composition (C A ) has a viscosity of between 100 mPa.s and 10,000 mPa.s (measured with a Brookfield brand viscometer, RVT type, speed 5 revolutions/minute);
composition (CA) further comprises a monomeric unit derived from the compound of formula (X'):

With R4 representing a linear or branched, saturated or unsaturated, functionalized or unfunctionalized hydrocarbon radical and comprising from 6 to 22 carbon atoms.
According to a particular aspect, R4 representing a hydrocarbon radical chosen from the elements of the group consisting of the radical heptyl, octyl, nonyl, decyl, undecyl, undecenyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, hydroxyoctadecyl, oleyl, linoleyl, linolenyl, eicosyl and dodecosyl.
According to another particular aspect, in said polymer (P), for 100% of the mass of monomeric units derived from glutamic acid (GA), partially or totally salified, the monomeric units derived from the compound of formula (X′) represent from 1% to 50% by weight.

the pharmaceutical composition (F) comprises between 0.1% and 10% by weight of said composition (C A );
the pharmaceutical active principle is chosen from antibacterial agents, antimicrobial agents, antiparasitic agents, antihelminthic agents, anticoccidial agents, anti-cryptosporidian agents, anti-protozoal agents, antimycotic agents, non-steroidal anti-inflammatory agents , antiallergic and immunomodulating agents, analgesic agents, antihistamine agents, local anesthetic agents, antisecticidal agents, antiseptic agents, antifungal agents.

For exemple :

said pharmaceutical composition (F) will comprise as pharmaceutical active ingredient a non-steroidal anti-inflammatory and said pharmaceutical composition (F) will be intended to reduce and/or eliminate local pain, post-traumatic inflammation of joints, muscles, tendons or ligaments, localized forms of soft tissue rheumatism, localized forms of degenerative rheumatism, actinic keratosis caused by overexposure to sunlight, acute migraine, pain associated with bone metastases, fever due to malignant lymphogranulomatosis (Hodgkin's lymphoma), E. multi-drug resistant coli, Shy-Drager syndrome and diabetes mellitus.
said pharmaceutical composition (F) will comprise as active pharmaceutical ingredient a local anesthetic and said pharmaceutical composition (F) will be intended for use in treating pain, pruritus and/or anorectal disorders in humans or animals.
said pharmaceutical composition (F) will comprise an antifungal as pharmaceutical active ingredient and said pharmaceutical composition (F) will be intended for use in treating mycoses of the skin, scalp, mouth and/or gynecological apparatus in human or animal mammal.

The present invention also relates to a process for the preparation of a pharmaceutical composition (F) according to the invention, comprising:
- a step A) for preparing the composition (C A ) comprising the following sub-steps:

preparation of an aqueous solution comprising polyglutamic acid (PGA), partially or totally salified, with said aqueous solution comprising for 100% of its mass between 5% and 70% by mass of partially or totally salified PGA and a crosslinking agent (RA ) comprising at least two glycidyl functions,
adjusting the pH of the aqueous solution obtained in step a) to a pH between 3 and 11;
preparation of an organic phase containing at least one volatile oil, at least one other non-volatile oil (H) and at least one emulsifying surfactant of the water-in-oil type (S 1 );
pre-emulsification by adding, with stirring, the organic phase obtained in step c) to the aqueous solution obtained in step b);
emulsification of the pre-emulsion obtained in step d) by homogenization with stirring;
distillation of the water and volatile oil contained in the emulsion obtained in step e);
addition of at least one emulsifying surfactant of the oil-in-water type (S 2 ) so as to obtain the composition (C A ).

- A step B) of mixing at least one composition (C A ) prepared during step A) with at least one pharmaceutical active principle and at least one pharmaceutically acceptable medium, such as for example water.
Depending on the case, the method according to the invention may have one or more of the characteristics below:

in step a) the polyglutamic acid (PGA) is gamma-polyglutamic acid (PGGA);
in step a) all of the monomeric units constituting gamma-polyglutamic acid (PGGA) are derived from sodium glutamate, potassium glutamate, ammonium glutamate, calcium glutamate, magnesium glutamate or of a mixture of these forms;
in step a) the crosslinking agent (RA) is present in mass proportions of between 0.5% and 10% by mass relative to the mass of polyglutamic acid (PGA);
the crosslinking agent (RA) is chosen from the members of the group consisting of the compounds of formula (I), (II), (IIa), (IIb), (IIc), (III), (IV), (V ), (VI), (VII), (VIII), (IX), (IXa), (IXb), (X), (Xa), (Xb), (XI), (XIa), (XIb), (Xc), (XII), (XIII);
in step c) the at least water-in-oil type emulsifier (S 1 ) is chosen from the elements of the group consisting of sorbitan esters, polyglycerol esters, alkoxylated polyglycerol esters, polyhydroxystearates polyglycols, polyglycerol polyhydroxystearates, alkoxylated polyglycerol polyhydroxystearates;
in step c) the organic solution comprises for 100% of its own mass between 10% and 30% by mass of at least one emulsifying agent of the water-in-oil type (S 1 ), preferably between 15% and 20 % mass;
in step c) the water-in-oil type emulsifier (S 1 ) is a polyglycerol polyhydroxystearate;
in step g) the at least oil-in-water type emulsifying surfactant (S 2 ) is chosen from the elements of the group consisting of a polyethoxylated fatty alcohol, a polyethoxylated hexitan ester, an alkylpolyglycoside, a composition of alkylpolyglycoside and fatty alcohols, a polyglycerol ester, a composition of polyglycerol ester and polyglycerol;
in step d) is carried out so that the mass ratio between the aqueous solution and the organic phase is between 90/10 and 10/90, preferably between 20/80 and 40/60;
in step a), the aqueous solution further comprises at least one compound of formula (X'):

With R4 representing a linear or branched, saturated or unsaturated, functionalized or unfunctionalized hydrocarbon radical and comprising from 6 to 22 carbon atoms.
According to a particular aspect, R4 represents a hydrocarbon radical chosen from the elements of the group consisting of the radical heptyl, octyl, nonyl, decyl, undecyl, undecenyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, hydroxyoctadecyl, oleyl, linoleyl, linolenyl, eicosyl and dodecosyl.
According to another particular aspect, the content of compound of formula (X′) in the polar solution is comprised, for 100% by mass of said aqueous solution, between 0.05% and 35% by mass, it being understood that the sum of the proportions by mass of the polymer (P), of the crosslinking agent (AR), of the water and of the compound of formula (X′) is equal to 100%.

in step e) the homogenization is carried out under mechanical shearing agitation.
in step f) the distillation is carried out under vacuum and hot. This has the effect of cross-linking the polyglutamic acid and concentrating the emulsion;
in steps c) and f) the volatile oil is a light isoparaffin comprising from 8 to 11 carbon atoms. This isoparaffin may be chosen from those sold under the names ISOPAR TM G, ISOPAR TM L or ISOPAR TM H or ISOPAR TM J.

The choice of a concentrated inverse emulsion process makes it possible to solubilize the starting poly-gamma glutamic acid (PGGA), its possible co-constituents, as well as the crosslinking agent(s) in the aqueous phase of the emulsion. The realization of the emulsion makes it possible to create droplets isolated from each other making possible the crosslinking of the PGA without caking of the reaction medium due to the increase in viscosity of the aqueous phase during the crosslinking step. The concentration step by distillation of a light fatty phase leads to obtaining a product in liquid form with an active ingredient content of more than 20%.
According to one particular aspect, in the composition (CA) which is the subject of the present invention, the mass content of the polymer (P) is greater than or equal to 20% and less than or equal to 60%; and more particularly greater than or equal to 20% and less than or equal to 40%.
PGGA can exist in different conformational forms in solution in water. These depend on the inter and intra molecular hydrogen bonds and therefore on the pH, the polymer concentration, the ionic strength of the solution, as well as the temperature. The chains of the PGGA can thus adopt a helix shape , of β-sheet aggregates or else be in a disordered and random state.
According to a particular aspect, in the composition (CA) which is the subject of the present invention, the polymer (P) is in helical conformation when it is present in a solution at a mass content of less than or equal to 0.1% and of which said solution shows a pH value less than or equal to 7.
According to a particular aspect, in the composition (CA) which is the subject of the present invention, the polymer (P) is in sheet conformation when it is present in a solution at a mass content of less than or equal to 0.1% and of which said solution shows a pH value above 7.
According to a particular aspect of the composition (CA) which is the subject of the present invention, in the polymer (P), for 100% molar of monomeric units derived from glutamic acid (GA), partially or totally salified, the crosslinking agent (AR) represents from 1% to 20% molar, and even more particularly from 1% to 18% molar.
According to another particular aspect, the composition (C A ) has a viscosity of between 1,000 mPa.s and 10,000 mPa.s (measured with a Brookfield brand viscometer, RVT type, speed 5 rpm), more particularly between 1000 mPa.s and 5000 mPa.s.
According to another particular aspect, the crosslinking agent (RA) is ethylene glycol diglycidyl ether of formula (I).
According to another particular aspect, in step a) of the process which is the subject of the present invention, the partially or totally salified polyglutamic acid (PGA) is in the form of a potassium, sodium or ammonium salt, and more particularly in the form of a sodium salt.
According to another particular aspect, in step a) of the process which is the subject of the present invention, the aqueous solution comprises, for 100% of its mass, between 5% and 60% by mass, more particularly between 10% and 50% by mass, of partially or totally salified polyglutamic acid (PGA).
According to another particular aspect, in step a) of the process which is the subject of the present invention, the crosslinking agent (RA) is chosen from at least one of the members of the group consisting of the compounds of formulas (I), (II) , (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII) and (XIII) as previously defined.
According to another aspect, in step c) of the process which is the subject of the present invention, the term "volatile oil" denotes a fatty substance which is liquid at a temperature of 25° C. at atmospheric pressure, and whose flash point is between 40 °C and 100°C.
According to a more particular aspect, by "volatile oil" is meant within the meaning of the present invention an element of the group consisting of branched alkanes, comprising from seven to forty carbon atoms, such as isododecane, isopentadecane, isohexadecane , isoheptadecane, isooctadecane, isononadecane or isoeicosane), or mixtures of some of them such as those mentioned below and identified by their INCI name: C7-8 isoparaffin, C8-9 isoparaffin, C9-11 isoparaffin, C9-12 isoparaffin, C9-13 isoparaffin, C9-14 isoparaffin, C9-16 isoparaffin, C10-11 isoparaffin, C10-12 isoparaffin, C10-13 isoparaffin, C11-12 isoparaffin, C11-13 isoparaffin, C11-14 isoparaffin.
According to an even more particular aspect, by "volatile oil" is meant within the meaning of the present invention at least one element of the group consisting of isododecane, isohexadecane, C7-8 isoparaffin, C8-9 isoparaffin, C9 -11 isoparaffin, C11-13 isoparaffin, C11-14 isoparaffin.
According to another even more particular aspect of the present invention, the volatile oil is chosen from an element of the group consisting of C8-9 isoparaffin, C9-11 isoparaffin, C11-13 isoparaffin, C11-14 isoparaffin.
According to another even more particular aspect of the present invention, the “volatile oil” is chosen from an element of the group consisting of the isoparaffins marketed under the brand names ISOPARTM G, ISOPARTM L or ISOPARTM H or ISOPARTM J.
According to another aspect, in step c) of the process which is the subject of the present invention, the term “oil (H)” denotes a liquid fatty substance at a temperature of 25° C. at atmospheric pressure, in particular:

Linear alkanes comprising eleven to nineteen carbon atoms;
Branched alkanes, comprising from eleven to forty carbon atoms, such as isododecane, isopentadecane, isohexadecane, isoheptadecane, isooctadecane, isononadecane or isoeicosane), or mixtures of certain of between them such as those cited below and identified by their INCI name: C12-14 isoparaffin, C12-20 isoparaffin, C13-14 isoparaffin, C13-16 isoparaffin.
Cyclo-alkanes optionally substituted by one or more linear or branched alkyl radicals,
White mineral oils, such as those marketed under the following names:

Marcol™52, Marcol™82, Drakeol™6VR, Eolane™130, Eolane™150, Hemisqualane (or 2,6,10-trimethyl-dodecane; CAS number: 3891-98-3), squalane (or 2 ,6,10,15,19,23-hexamethyltetracosane), hydrogenated polyisobutene or hydrogenated polydecene;

Mixtures of alkanes comprising from 15 to 19 carbon atoms, said alkanes being linear alkanes, branched alkanes and cyclo-alkanes, and more particularly the mixture (M1) which comprises for 100% of its mass:

a mass proportion of branched alkanes greater than or equal to 90% and less than or equal to 100%
a mass proportion of linear alkanes greater than or equal to 0% and less than or equal to 9%
a mass proportion of cycloalkanes greater than or equal to 0% and less than or equal to 1%, and

more particularly said mixture (M1) is characterized in that it comprises for 100% of its mass:

a mass proportion greater than or equal to 95% of branched alkanes, linear alkanes and cycloalkanes and less than or equal to 100% containing 15 to 19 carbon atoms, and
a mass proportion greater than or equal to 0% and less than or equal to 5% of branched alkanes, linear alkanes and cycloalkanes containing less than 14 carbon atoms, and linear alkanes and cycloalkanes containing more than 20 carbon.

By "linear alkanes" present in the mixture (M1) as defined above, and comprising from 15 to 19 carbon atoms, is meant more particularly within the meaning of the present invention the elements chosen from the group consisting of n- pentadecane, n-hexadecane, n-heptadecane, n-octadecane and n-nonadecane.
By "branched alkanes" present in the mixture (M1) as defined above, and comprising from 15 to 19 carbon atoms, is meant more particularly within the meaning of the present invention the elements chosen from the group consisting of the iso -pentadecane, iso-hexadecane, iso-heptadecane, iso-octadecane and iso-nonadecane.
The mixture (M1) is more particularly the mixture marketed under the brand name Emogreen™ L15 or else the mixture marketed under the brand name Emogreen™ L19.

The fatty alcohol ethers of formula (XIV):

Z1-O-Z2 (XIV),
in which Z1 and Z2, which are identical or different, represent a linear or branched alkyl radical comprising from five to eighteen carbon atoms, for example dioctyl ether, didecyl ether, didodecyl ether, dodecyl octyl ether, dihexadecyl ether, (1,3 -dimethyl butyl) tetradecyl ether, (1,3-dimethyl butyl) hexadecyl ether, bis(1,3-dimethyl butyl) ether or dihexyl ether.

Mono-esters of fatty acids and alcohols of formula (XV):

R'1-(C=O)-O-R'2 (XV),
in which R'1-(C=O) represents an acyl radical, saturated or unsaturated, linear or branched, containing from eight to twenty-four carbon atoms, and R'2 represents, independently of R'1, a hydrocarbon chain saturated or unsaturated, linear or branched containing from one to twenty-four carbon atoms, for example methyl laurate, ethyl laurate, propyl laurate, isopropyl laurate, butyl laurate, 2-butyl laurate, laurate hexyl, methyl cocoate, ethyl cocoate, propyl cocoate, isopropyl cocoate, butyl cocoate, 2-butyl cocoate, hexyl cocoate, methyl myristate, ethyl myristate, propyl myristate , isopropyl myristate, butyl myristate, 2-butyl myristate, hexyl myristate, octyl myristate, methyl palmitate, ethyl palmitate, propyl palmitate, palmitate d isopropyl, butyl palmitate, 2-butyl palmitate, hexyl palmitate, octyl palmitate, m ethyl, ethyl oleate, propyl oleate, isopropyl oleate, butyl oleate, 2-butyl oleate, hexyl oleate, octyl oleate, methyl stearate, ethyl stearate, propyl stearate, isopropyl stearate, butyl stearate, 2-butyl stearate, hexyl stearate, octyl stearate, isostearate of methyl, ethyl isostearate, propyl isostearate, isopropyl isostearate, butyl isostearate, 2-butyl isostearate, hexyl isostearate, isostearyl isostearate;

Die-esters of fatty acids and glycerol of formulas (XVI) and (XVII):

R’3-(C=O)-O-CH2-CH(OH)-CH2-O-(C=O)-R’4 (XVI)
R’5-(C=O)-O-CH2-CH[O-(C=O)-R’6]-CH2-OH (XVII),
in which R'3-(C=O) and R'4-(C=O), R'5-(C=O), R'6-(C=O), identical or different, represent an acyl group , saturated or unsaturated, linear or branched, containing from eight to twenty-four carbon atoms.

Tri-esters of fatty acids and glycerol of formula (XVIII):

R’7-(C=O)-O-CH2-CH[O-(C=O)-R’’8]-CH2-O-(C=O)-R’’9 (XVIII),
in which R'7-(C=O), R'8-(C=O) and R'9-(C=O), which are identical or different, represent an acyl group, saturated or unsaturated, linear or branched, comprising eight to twenty-four carbon atoms.
According to another particular aspect of the present invention, said oil (H) is chosen from:

Undecane, tridecane, isododecane or isohexadecane,
Mixtures of alkanes and isoalkanes and cycloalkanes such as the mixture (M1) as defined previously and the mixtures marketed under the names Emogreen™L15, Emogreen™L19, Emosmart™L15, Emosmart™L19, Emosmart™V21, Isopar ™M;

- White mineral oils marketed under the names Marcol™52, Marcol™82,
Drakeol™6VR, Eolane™130 or Eolane™150;
- Hemisqualane, squalane, hydrogenated polyisobutene or hydrogenated polydecene;
- Dioctyl ether or didecyl ether;
- Isopropyl myristate, hexyl palmitate, octyl palmitate, isostearyl isostearate, octanoyl/decanoyl triglyceride, hexadecanoyl/octadecanoyl triglyceride, triglycerides from rapeseed oil, sunflower oil, linseed oil or palm oil.
According to another aspect, in step c) of the process that is the subject of the present invention, the term "emulsifying surfactant of the water-in-oil type (S1)" denotes an emulsifying surfactant having an HLB value ("Hydrophile Lipophile Balance ” or hydrophilic-lipophilic balance) sufficiently low to induce the formation of a water-in-oil type emulsion, namely an emulsion in which the aqueous phase will be dispersed and stabilized in the oily organic phase.
As emulsifying surfactant of the water-in-oil type, mention may be made, for example, of the esters of anhydro hexitol and of aliphatic, linear or branched, saturated or unsaturated carboxylic acids, comprising from 12 to 22 carbon atoms optionally substituted with one or several hydroxyl groups, and more particularly the esters of anhydro hexitol chosen from anhydro-sorbitols and anhydro-mannitols and of aliphatic, linear or branched, saturated or unsaturated carboxylic acids, containing from 12 to 22 carbon atoms optionally substituted with one or more hydroxyl groups.
In step c) of the process that is the subject of the present invention, the emulsifying system (S1) of the water-in-oil type is more particularly chosen from the elements of the group consisting of
sorbitan laurate, for example that marketed under the name Montane™20,
sorbitan palmitate, for example that marketed under the name Montane™40,
sorbitan stearate, for example that marketed under the name Montane™60,
sorbitan oleate, for example that marketed under the name Montane™80,
sorbitan sesquioleate, for example that marketed under the name Montane™83,
sorbitan trioleate, for example that marketed under the name Montane™85,
sorbitan isolataurate,
sorbitan isostearate, for example that marketed under the name Montane™70,
mannitan laurate, mannitan oleate, or a mixture of these esters; polyesters with a molecular weight of between 1000 and 3000 g/mol and resulting from the condensation between a poly(isobutenyl) succinic acid or its anhydride, such as HYPERMER™ 2296, or the mixture marketed under the brand name SIMALINE™IE 501 a.
As emulsifying surfactant of water-in-oil type (S1), mention may be made, for example, of polyglycerol esters, a compound of formula (XIX):
(XX)
in which Z represents an acyl radical of formula R2-C(=O)-, in which R2 represents an aliphatic hydrocarbon radical, saturated or unsaturated, linear or branched, containing from 11 to 35 carbon atoms and more particularly a radical chosen from the dodecanoyl, tetradecanoyl, hexadecanoyl, octadecanoyl, eicosanoyl, docosanoyl, oleyl, linoleyl, linolenoyl or isostearyl radicals, Z' represents the acyl radical of formula R2-C(=O)- as defined above, with Z' identical or different from Z, or the hydrogen atom, and y represents an integer greater than or equal to 2 and less than or equal to 20.
According to a more particular aspect, the compound of formula (XIX) is chosen from the elements of the group consisting of decaglycerol oleate, decaglycerol isostearate, decaglycerol monolaurate, decaglycerol mono-linoleate, mono-myristate of decaglycerol.
As emulsifying surfactant of water-in-oil type (S1), mention may be made, for example, of alkoxylated polyglycerol esters, a compound of formula (XX):
(XX),
in which Z1 represents an acyl radical of formula R'2-C(=O)-, in which R'2 represents an aliphatic hydrocarbon radical, saturated or unsaturated, linear or branched, containing from 11 to 35 carbon atoms, and more particularly a radical chosen from the dodecanoyl, tetradecanoyl, hexadecanoyl, octadecanoyl, eicosanoyl, docosanoyl, oleyl, linoleyl, linolenoyl or isostearyl radicals, Z1' represents the acyl radical of formula R'2-C(=O)- as defined above above, with Z1' identical to or different from Z1, or the hydrogen atom, R3 represents the hydrogen atom, the methyl radical, or the ethyl radical, y1 represents an integer greater than or equal to 2 and less or equal to 20, v1, v2, v3, identical or different, represent an integer greater than or equal to 0 and less than or equal to 50, and the sum [(y1. v1) + (y1. v2) + v3)] is an integer greater than or equal to 1 and less than or equal to 50.
As emulsifying surfactant of the water-in-oil type (S1), mention may be made, for example, of the polyglycol polyhydroxystearates of formula (XXI):
(XXI),
formula (XXI) in which y2 represents an integer greater than or equal to 2 and less than or equal to 50, Z4 represents the hydrogen atom, the methyl radical, or the ethyl radical, Z3 represents a radical of formula (XXII) :
(XXII),
formula (XXII) in which y'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'3 represents a radical of formula (XXII) as defined above, with Z3' identical to or different from Z3, or the hydrogen atom.
As an example of an emulsifying surfactant of the water-in-oil type of formula (XXI) which can be used to prepare the emulsifying system (S1), there is PEG-30 dipolyhydroxystearate marketed under the name SIMALINE™ WO, or else the mixtures comprising PEG-30 dipolyhydroxystearate and sold under the names SIMALINE™IE 201 A and SIMALINE™IE 201 B, or else the mixture comprising Trimethylolpropane-30 tripolyhydroxystearate sold under the name SIMALINE™IE 301 B.
As emulsifying surfactant of the water-in-oil type (S1), mention may be made, for example, of the polyglycerol polyhydroxystearates, represented by the formula (XXIII):
(XXIII),
in which Z3 represents a radical of formula (XXIII) as defined above, Z'3 represents a radical of formula (XXII) as defined above, with Z3' identical to or different from Z3, or the atom d hydrogen, y3 represents an integer greater than or equal to 2 and less than or equal to 20.
As emulsifying surfactant of the water-in-oil type (S1), mention may be made, for example, of alkoxylated polyglycerol polyhydroxystearates, a compound represented by the formula (XXIV):
(XXIV),
in which Z4 represents a radical of formula (XXII) as defined above, Z'4 represents a radical of formula (XXII) as defined above, with Z4' identical to or different from Z4, or the atom d 'hydrogen, y4 represents an integer greater than or equal to 2 and less than or equal to 20, v'1, v'2, v'3, identical or different, represent an integer greater than or equal to 0 and less than or equal to 50, and the sum [(y4. v'1) + (y4. v'2) + v'3)] is an integer greater than or equal to 1 and less than or equal to 50.
According to another aspect, in step g) of the process which is the subject of the present invention, the term “emulsifying surfactant of the oil-in-water type (S2)” denotes an emulsifying surfactant having a sufficiently high HLB value to induce the formation of an emulsion of the oil-in-water type, namely an emulsion in which the oily organic phase will be dispersed and stabilized in the aqueous phase.
According to another aspect, in step g) of the process which is the subject of the present invention, as surfactant of the oil-in-water type (S2), mention may be made of the “polyethoxylated fatty alcohols” designated by the compounds of formula (XXV):
R''-O-(CH2-CH2-O) n' -OH (XXV),
with R'' representing a linear or branched, saturated or unsaturated hydrocarbon radical, which may bear hydroxyl groups, and comprising from six to twenty-two carbon atoms, and with n' representing an integer greater than or equal to four and less than or equal to one hundred.
According to a more particular aspect, in formula (XXV), R'' represents a linear or branched hydrocarbon radical, saturated and containing from ten to twenty-two carbon atoms.
According to an even more particular aspect, the compound of formula (XXV) is a linear decyl alcohol ethoxylated with six moles of ethylene oxide, a linear decyl alcohol ethoxylated with eight moles of ethylene oxide, a linear lauryl alcohol ethoxylated with six moles of ethylene oxide, linear lauryl alcohol ethoxylated with seven moles of ethylene oxide, linear lauryl alcohol ethoxylated with eight moles of ethylene oxide, linear tridecyl alcohol ethoxylated with six moles of ethylene oxide, a linear tridecyl alcohol ethoxylated with eight moles of ethylene oxide, a linear tridecyl alcohol ethoxylated with nine moles of ethylene oxide.
According to another aspect, in step g) of the process which is the subject of the present invention, as surfactant of oil-in-water type (S2), mention may be made of polyethoxylated hexitan esters, and particularly polyethoxylated sorbitan esters, whose chain aliphatic hydrocarbon contains from 12 to 22 carbon atoms and whose number of ethylene oxide units is between 5 and 40, for example ethoxylated sorbitan oleate with 20 moles of ethylene oxide marketed under the name commercial Montanox™80, or sorbitan laurate ethoxylated with 20 moles of ethylene oxide marketed under the trade name Montanox™20.
According to another aspect, in step g) of the process which is the subject of the present invention, as surfactant of the oil-in-water type (S2), mention may be made of the compositions of alkyl polyglycosides (C1) represented by the formula (XXVI):
R’’1-O-(G)x-H (XXVI)
in which x, or average degree of polymerization, represents a decimal number between 1.05 and 5, G represents the residue of a reducing sugar, and R''1 represents an aliphatic hydrocarbon radical, saturated or unsaturated, linear or branched , optionally substituted with one or more hydroxyl groups, containing from 12 to 36 carbon atoms, the said composition (C1) consisting of a mixture of compounds represented by the formulas (XXVI1), (XXVI2), (XXVI3), (XXVI4) and (XXVI5):
R’’1-O-(G)1-H (XXVI1)
R’’1-O-(G)2-H (XXVI2)
R’’1-O-(G)3-H (XXVI3)
R’’1-O-(G)4-H (XXVI4)
R’’1-O-(G)5-H (XXVI5)
in the respective molar proportions a1, a2, a3, a4 and a5, such that:
- The sum a1+ a2 + a3 + a4 + a5 is equal to 1 and that
- The sum a1 + 2a2 + 3a3 + 4a4 + 5a5 is equal to x.
By aliphatic hydrocarbon radical, saturated or unsaturated, linear or branched, containing from 12 to 36 carbon atoms, optionally substituted with one or more hydroxyl groups, is meant for the radical R''1 in the formula (XXVI) as defined above above more particularly the n-dodecyl radical, the n-tetradecyl radical, the n-hexadecyl radical, the n-octadecyl radical, the n-eicosyl radical, the n-docosyl radical, the 12-hydroxy octadecyl radical.
By reducing sugar, in the definition of formula (XXVI) as defined above, is meant the saccharide derivatives which do not have in their structures a glycoside bond established between an anomeric carbon and the oxygen of an acetal group such as that they are defined in the reference work: “Biochemistry”, Daniel Voet/Judith G. Voet, p. 250, John Wyley & Sons, 1990. The oligomeric structure (G)x can occur in all forms of isomerism, whether optical isomerism, geometric isomerism or position isomerism; it can also represent a mixture of isomers.
In formula (XXVI) as defined above, the R1-O- group is linked to G via the anomeric carbon of the saccharide residue, so as to form an acetal function.
According to a particular aspect in the definition of formula (XXVI) as defined above, G represents the residue of a reducing sugar chosen from glucose, dextrose, sucrose, fructose, idose, gulose, galactose, maltose, isomaltose, maltotriose, lactose, cellobiose, mannose, ribose, xylose, arabinose, lyxose, allose, altrose, dextran or tallose; and more particularly G represents the residue of a reducing sugar chosen from the residues of glucose, xylose and arabinose.
According to an even more particular aspect, in the definition of formula (XXVI) x, or average degree of polymerization, represents a decimal number greater than or equal to 1.05 and less than or equal to 2.5, more particularly greater than or equal to 1.05 and less than or equal to 2.0, and even more particularly greater than or equal to 1.25 and less than or equal to 2.0.
According to another aspect, in step g) of the process which is the subject of the present invention, as surfactant of the oil-in-water type (S2), mention may be made of the compositions (C2) comprising for 100% of their mass:

From 10% to 50% by mass, more particularly from 15% to 40% by mass, and even more particularly from 20% to 30% by mass, of at least one composition (C1) represented by formula (XXVI) as defined previously ,
From 90% to 50% by mass, more particularly from 85% to 60% by mass, and even more particularly from 80% to 70% by mass, of at least one fatty alcohol of formula (XXVII):

R'''1-OH (XXVII),

in which R'''1, identical to or different from R''1, represents an aliphatic hydrocarbon radical, saturated or unsaturated, linear or branched, optionally substituted with one or more hydroxyl groups, containing from 12 to 36 carbon atoms, and preferably 12 to 22 carbon atoms.

As emulsifying surfactant of the oil-in-water type (S2), mention may be made, for example, of the polyglycerol esters of formula (XXVIII):
R12-(C=O)-[O-CH2-CH(OH)-CH2]p12-OH (XXVIII),
formula (XVIII) in which p12 represents an integer greater than or equal to one and less than or equal to fifteen; and in which the group R1-(C=O)- represents a saturated or unsaturated, linear or branched, aliphatic radical comprising from six to twenty-two carbon atoms.
As emulsifying surfactant of the oil-in-water type (S2), mention may be made, for example, of the compositions (C13) comprising for 100% of their masses:

From 10% by mass to 60% by mass of at least one compound of formula (XXIX):

HO-[CH2-CH(OH)-CH2-O] n12-H (XXIX)
formula (I) in which n12 represents an integer greater than or equal to one and less than or equal to fifteen; and

From 40% by mass to 90% by mass of at least one compound of formula (XXVIII) as defined above.

Finally, a subject of the present invention is also the use of said composition (C A ) as defined above, as a thickening and/or emulsifying and/or stabilizing agent for an aqueous liquid pharmaceutical composition for topical use.
According to a particular aspect, said use consists in thickening polar phases such as for example aqueous, alcoholic or aqueous-alcoholic phases or polar phases comprising polyols such as glycerol.
According to another particular aspect, said use consists in stabilizing an emulsion of the oil-in-water type, or of the water-in-oil type, by conferring a homogeneous appearance on said emulsion during storage under different conditions, and more particularly at 25 °C for a period at least equal to one month, and more particularly at 4°C for a period at least equal to one month, and more particularly at 45°C for a period at least equal to one month.
According to another particular aspect, said use consists in stabilizing solid particles in pharmaceutical compositions (F) for topical use.
These solid particles to be suspended can take on different geometries, regular or irregular, and take the form of beads, balls, rods, flakes, lamellae or polyhedrons. These solid particles are characterized by an average apparent diameter of between one micrometer and five millimeters, more particularly between ten micrometers and one millimeter.
Among the solid particles which can be suspended and stabilized by the polymer (P) as defined above in pharmaceutical compositions for topical use, there are micas, iron oxide, titanium oxide, zinc oxide, aluminum oxide, talc, silica, kaolin, clays, boron nitride, calcium carbonate, magnesium carbonate, magnesium hydrogen carbonate, inorganic color pigments, polyamides such as nylon-6, polyethylenes, polypropylenes, polystyrenes, polyesters, acrylic or methacrylic polymers such as polymethylmethacrylates, polytetrafluoroethylene, crystalline or microcrystalline waxes, porous spheres, selenium sulphide, zinc pyrithione , starches, alginates, plant fibers, Loofah particles, sponge particles.
Said pharmaceutical composition (F) for topical use, object of the present invention, is in particular in the form of an aqueous solution, an emulsion or a microemulsion with a continuous aqueous phase, an emulsion or a microemulsion oily continuous phase, an aqueous gel, a foam, or in the form of an aerosol. It can be applied directly to the surface of the skin or via any type of support intended to be brought into contact with the surface of the skin (paper, wipe, textile).
In general, said pharmaceutical composition for topical use (F) which is the subject of the present invention, further comprises at least one or more auxiliary compounds chosen from fatty phases, foaming and/or detergent surfactants, thickening and/or gelling surfactants , thickening and/or gelling agents, stabilizing agents, film-forming compounds, solvents and co-solvents, hydrotropic agents, plasticizers, opacifying agents, pearlescent agents, superfatting agents, sequestrants, chelating agents , antioxidants, fragrances, essential oils, preservatives, conditioning agents, deodorants.
In general, the pharmaceutical for topical use (F) according to the invention may comprise excipients and/or active principles usually used in the field of formulations for topical use, in particular pharmaceutical or dermopharmaceutical.
As regards the auxiliary compounds, among the foaming and/or detergent anionic surfactants which can be combined with the pharmaceutical composition (F) for topical use according to the invention, mention may be made of alkali metal salts, alkaline metal salts, salts, ammonium salts, amine salts, salts of amino alcohols of alkyl ether sulphates, alkyl sulphates, alkylamidoether sulphates, alkylarylpolyether sulphates, monoglyceride sulphates, alpha-olefin sulphonates, paraffin sulfonates, alkyl phosphates, alkyl ether phosphates, alkyl sulfonates, alkylamide sulfonates, alkylaryl sulfonates, alkyl carboxylates, alkyl sulfosuccinates, alkyl ether sulfosuccinates, alkylamide sulfosuccinates, alkyl sulfo-acetates, alkyl sarcosinates, acylisethionates, N-acyl taurates, acyl lactylates, N-acyl derivatives of amino acids, N-acyl derivatives of peptides, N-acyl derivatives of proteins , fatty acids .
Among the foaming and/or detergent amphoteric surfactants optionally present in the pharmaceutical composition (F) for topical use according to the invention, mention may be made of alkylbetaines, alkylamidobetaines, sultaines, alkylamidoalkylsulfobetaines, imidazoline derivatives, phosphobetaines, amphopolyacetates and amphopropionates.
Among the foaming and/or detergent cationic surfactants optionally present in the pharmaceutical composition (F) for topical use according to the invention, mention may be made in particular of quaternary ammonium derivatives.
Among the nonionic foaming and/or detergent surfactants optionally present in the composition (F) for topical use according to the invention, mention may be made more particularly of the alkylpolyglycosides comprising an aliphatic radical, linear or branched, saturated or unsaturated, and comprising 8 to 12 carbon atoms; castor oil derivatives, polysorbates, coconut amides, N-alkylamines.
Examples of thickening and/or gelling surfactants optionally present in the pharmaceutical composition (F) for topical use according to the invention include:

fatty esters of optionally alkoxylated alkylpolyglycosides, and more particularly ethoxylated methylpolyglucoside esters such as PEG 120 methyl glucose trioleate and PEG 120 methyl glucose dioleate marketed respectively under the names GLUCAMATE™ LT and GLUMATE™ DOE120;
alkoxylated fatty esters such as PEG 150 pentaerythrytyl tetrastearate sold under the name CROTHIX™ DS53, PEG 55 propylene glycol oleate sold under the name ANTIL™ 141;
polyalkylene glycol carbamates with fatty chains such as PPG 14 laureth isophoryl dicarbamate sold under the name ELFACOS™ T211, PPG 14 palmeth 60 hexyl dicarbamate sold under the name ELFACOS™ GT2125 .

As examples of emulsifying surfactants optionally present in the pharmaceutical composition (F) for topical use according to the invention, mention may be made of nonionic surfactants, anionic surfactants, cationic surfactants.
As examples of emulsifying nonionic surfactants optionally present in the pharmaceutical composition (F) for topical use according to the invention, ethoxylated castor oil and ethoxylated hydrogenated castor oil, for example the product marketed under the name SIMULSOL™ 989 ; compositions comprising glycerol stearate and poly(ethoxylated) stearic acid with between 5 moles and 150 moles of ethylene oxide, for example the composition comprising stearic acid (ethoxylated) with 135 moles of ethylene and glycerol stearate marketed under the name SIMULSOL™ 165; ethoxylated sorbitan esters, for example the products marketed under the name MONTANOX™; ethoxylated mannitan esters; sucrose esters; methylglucoside esters.
As examples of emulsifying anionic surfactants optionally present in the pharmaceutical composition (F) for topical use according to the invention, mention may be made of decyl phosphate, cetyl phosphate marketed under the name AMPHISOL™, glyceryl stearate citrate; cetearyl sulfate; the composition arachidyl/behenyl phosphates and arachidyl/behenyl alcohols marketed under the name SENSANOV™WR; soaps, for example sodium stearate or triethanolammonium stearate, N-acylated derivatives of salified amino acids such as, for example, stearoyl glutamate.
As examples of emulsifying cationic surfactants optionally present in the pharmaceutical composition (F) for topical use according to the invention, mention may be made of amine oxides, quaternium-82, cetyl trimethyl ammonium chloride, hexadecyl trimethyl ammonium bromide, cetyl pyridinium chloride, benzalkonium chloride, benzethonium chloride, and the surfactants described in document WO96/00719 and mainly those whose fatty chain comprises at least 16 carbon atoms.
As examples of opacifying and/or pearlescent agents optionally present in the pharmaceutical composition (F) for topical use according to the invention, mention may be made of sodium palmitate, sodium stearate, sodium hydroxystearate, magnesium palmitate , magnesium stearate, magnesium hydroxystearate, ethylene glycol monostearate, ethylene glycol distearate, polyethylene glycol monostearate, polyethylene glycol distearate, fatty alcohols containing 12 to 22 carbon atoms.
As examples of texture agents optionally present in the pharmaceutical composition (F) for topical use according to the invention, mention may be made of N-acylated derivatives of amino acids, for example lauroyl lysine marketed under the name AMINOHOPE™LL , octenyl starch succinate marketed under the name DRYFLO™, myristyl polyglucoside marketed under the name MONTANOV 14, cellulose fibers, cotton fibers, chitosan fibers, talc, sericite, mica.
As examples of solvents and co-solvents optionally present in the pharmaceutical composition (F) for topical use according to the invention, mention may be made of water, organic solvents, for example glycerol, diglycerol, glycerol oligomers, ethylene glycol, propylene glycol, butylene glycol, hexylene glycol, diethylene glycol, xylitol, erythritol, sorbitol, water-soluble alcohols such as ethanol, isopropanol or butanol, mixtures of water and said organic solvents, propylene carbonate, ethyl acetate, benzyl alcohol, dimethyl sulfoxide (DMSO).
As examples of agents for improving skin penetration optionally present in the pharmaceutical composition (F) for topical use according to the invention, mention may be made of glycol ethers such as, for example, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether , ethylene glycol monopropyl ether, ethylene glycol monoisopropyl ether, ethylene glycol monobutyl ether, ethylene glycol monophenyl ether, ethylene glycol monobenzyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether and diethylene glycol mono-n-butyl ether, diethylene glycol monoethyl ether (or Transcutol-P), fatty acids such as oleic acid, fatty acid glycerol esters such as for example glycerol behenate, glycerol palmitostearate, behenoyl macroglycerides, polyoxyethylene-2-stearyl ether, polyoxyethylene-2-oleyl ethers, terpenes such as D-Limonene, essential oils such as essential oil eucalyptus.
As examples of thickening and/or gelling agents optionally present in the pharmaceutical composition (F) for topical use according to the invention, mention may be made of polysaccharides consisting solely of oses, such as glucans or glucose homopolymers, glucomannoglucans, xyloglycans, the galactomannans whose degree of substitution (DS) of the D-galactose units on the main chain of D-mannose is between 0 and 1, and more particularly between 1 and 0.25, such as the galactomannans originating from the gum cassia (DS = 1/5), locust bean gum (DS = 1/4), tara gum (DS = 1/3), guar gum (DS = 1/2), fenugreek gum (DS = 1).
As examples of thickening and/or gelling agents optionally present in the pharmaceutical composition (F) for topical use according to the invention, mention may be made of polysaccharides consisting of derivatives of oses, such as sulphated galactans and more particularly carrageenans and l agar, uronans and more particularly algins, alginates and pectins, heteropolymers of oses and uronic acids and more particularly xanthan gum, gellan gum, gum arabic and karaya gum exudates, glucosaminoglycans.
As examples of thickening and/or gelling agents optionally present in the pharmaceutical composition (F) for topical use according to the invention, mention may be made of cellulose, cellulose derivatives such as methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, silicates, starch, hydrophilic derivatives of starch, polyurethanes.
As examples of stabilizing agents optionally present in the pharmaceutical composition (F) for topical use according to the invention, mention may be made of microcrystalline waxes, and more particularly ozokerite, mineral salts such as sodium chloride or magnesium.
As examples of thermal or mineral waters which can be combined with the pharmaceutical composition (F) for topical use according to the invention, mention may be made of thermal or mineral waters having a mineralization of at least 300 mg/l, in in particular water from Avene, water from Vittel, water from the Vichy basin, water from Uriage, water from Roche Posay, water from La Bourboule, water from Enghien- les-bains, water from Saint-Gervais-les-bains, water from Néris-les-bains, water from Allevard-les-bains, water from Digne, water from Maizieres, water from Neyrac-les-bains, water from Lons le Saunier, water from Rochefort, water from Saint Christau, water from Fumades and water from Tercis-les-bains.
As examples of active agents which can be combined with the pharmaceutical composition (F) for topical use according to the invention, mention can be made of substances or compositions which provide a beneficial effect to the human or animal subject.
These active agents can be, for example, antibodies, analgesics, anti-inflammatories, cytokines, cytotoxins, growth factors, hormones, lipids, oligonucleotides, polymers, polysaccharides, polypeptides, inhibitors of protease, vitamins, insect repellents, antibiotics, anti-inflammatory agents.
Examples of analgesic and anti-inflammatory agents that can be combined with the pharmaceutical composition (F) for topical use according to the invention include acetaminophen, aspirin, salicylic acid, methyl salicylate , choline salicylate, glycol salicylate, 1-menthol, camphor, mefenamic acid, fluphenamic acid, indomethacin, protizidic acid, fentiazac, tolmetin, tiaprofenic acid, phenylbutazone, oxyphenbutazone, clofezone, pentazocine, mepirizole, hydrocortisone, cortisone, dexamethasone, fluocinolone, triamcinolone, medrysone, prednisolone, flurandrenolide, prednisone, halcinonide, methylprednisolone, fludrocortisone , corticosterone, paramethasone, betamethasone.
As examples of non-steroidal anti-inflammatory agents (or NSAIDs) which can be combined with the pharmaceutical composition (F) for topical use according to the invention, mention may more particularly be made of arylacetic (or arylalkanoic) derivatives and 2-arylpropionics (or profenes), and even more particularly diclofenac, tiaprofenic acid, alminoprofen, etodolac, flurbiprofen, ibuprofen, ketoprofen, naproxen.
As examples of antiseptic agents which can be combined with the pharmaceutical composition (F) for topical use according to the invention, mention may be made of cetrimide, povidone-iodine, chlorhexidine, iodine, benzalkonium chloride, benzoic acid, nitrofurazone, benzoyl peroxide, hydrogen peroxide, hexachlorophene, phenol, resorcinol and cetylpyridinium chloride.
As examples of antisectide agents which can be combined with the pharmaceutical composition (F) for topical use according to the invention, mention may be made of trichlorfone, triflumerone, fenthion, bendiocarb, cyromazine, dislubenzurone, dicyclanil , fluazurone, amitraz, deltamethrin, cypermethrin, chlorfenbinphose, flumethrin, ivermectin, abermectin, avermectin, doramectin, moxidectin, zeti-cypermethrin, diazinone, spinosad, imidacloprid, nitenpyran, pyriproxysene, sipronil, cythioate, lufenurone, selamectin, milbemycin oxime, chlorpyrifose, coumaphose, propetamphose, alpha-cypermethrin, highciscypermethrin, ivermectin, diflubenzurone, cyclodiene, carbamate and benzoyl urea.
As examples of antimicrobial agents which can be combined with the pharmaceutical composition (F) for topical use according to the invention, mention may be made of sulfonamides, aminoglycosides such as, for example, neomycin, tobramycin, gentamycin, amikacin, kanamycin, spectinomycin, paromomycin, netilmicin, polypeptides, cephalosporins, oxazolidinones such as for example ciprofloxacin, levofloxacin, ofloxacin.
As examples of active agents which can be combined with the pharmaceutical composition (F) for topical use according to the invention, mention may be made of vitamin E, Coenzyme Q10, L-carnitine, choline, folic acid , magnesium and its salts, caprylic acid, linoleic acid, lauric acid, taurine, vitamin C, vitamin A, vitamins of group B.

EXAMPLES

The following examples illustrate the invention without however limiting it.
Example 1: Preparation of a concentrated water-in-oil emulsion according to the invention, composed of C15-19 alkanes as fatty phase and of sodium PGGA crosslinked with 1,4-butanediol diglycidyl ether in aqueous phase (pH= 5.5 to 6.0)
The synthesis process comprises the following steps:

Step a): Preparation of a sodium PGGA gel:
110 grams of demineralized water are placed under mechanical stirring provided by a Rayneri TM brand stirrer equipped with a deflocculating-type rotor.
30 grams of sodium PGGA marketed under the brand name “cosmetic grade PolyGammaGlutamate” by the company LUBON are slowly added to the vortex.
Step b): Adjustment of the pH of the reaction medium between 5.5 and 6 at a temperature of 20°C using a 5M HCl solution.
Step c): Addition of 0.45 grams of 1,4-Butanediol diglycidyl ether (sold under the name ERISYS TM GE 21 by the company EMERALD) to the aqueous phase prepared in step b)
Step d): Preparation of the organic phase in a 100 gram beaker:
Weigh 5 grams of sorbitan oleate (marketed under the name MONTANE™80 VG by the company SEPPIC)
Weigh 5 grams of Polyglyceryl-2 Dipolyhydroxystearate (marketed as Dehymuls TM PGPH by BASF)
Weigh 20 grams of C15-19 Alkane (marketed under the name EMOGREEN™ L19 by the company SEPPIC)
Weigh 30 grams of C11-12 Isoparaffin (marketed as ISOPAR H by ExxonMobil Chemical Company)

Homogenize the organic phase by mixing using a magnetic stirrer and a magnetic bar.

Step e): Pre-emulsification: Addition of the organic phase prepared in step d) to the aqueous phase prepared in step c) with mechanical stirring provided by a RayneriTM brand stirrer fitted with a deflocculating-type rotor.
Step f): Shearing emulsification provided by a rotor-stator type system by the Silverson TM L4RT brand mixer for 2 minutes at a speed of 7500 revolutions/min.
Step g): Distillation under vacuum in a reactor under partial vacuum of light oil and water.
Stage h): Addition of an oil-in-water type surfactant to the concentrated emulsion obtained in stage h): weighing of 8 grams of concentrated emulsion and addition of 2 grams of Polyglyceryl-6 laurate.
Stirring the mixture and obtaining a composition (E1)

Example 2: Preparation of a concentrated water-in-oil emulsion according to the invention, composed of ethyl hexyl palmitate as fatty phase and PGGA of sodium, cross-linked with 1,4-butanediol diglycidyl ether in aqueous phase (pH = 5.5 to 6.0)
The synthesis process comprises the following steps:

Step a): Preparation of a sodium PGGA gel:
120 grams of demineralised water are placed in a beaker with stirring provided by a Rayneri™ brand mechanical stirrer fitted with a deflocculator-type mobile device.
20 grams of sodium PGGA, marketed under the brand name “Cosmetic Grade PolyGammaGlutamate”. by the company LUBON, are added slowly in the vortex.
Step b): Addition of 0.50 grams of 1,4-Butanediol diglycidyl ether (sold under the name ERISYS TM GE 21 by the company EMERALD) to the aqueous phase prepared in step a)
Step c): Preparation of the organic phase in a 100 gram beaker:
Weigh 5 grams of sorbitan oleate (marketed under the name MONTANE™80 VG by the company SEPPIC)
Weigh 5 grams of Polyglyceryl-2 Dipolyhydroxystearate (marketed as Dehymuls™ PGPH by BASF)
Weigh 20 grams of ethyl hexyl palmitate (marketed under the name DUB PO by the company stéarinerie dubois)
Weigh 30 grams of C11-12 Isoparaffin (marketed as ISOPAR H by ExxonMobil Chemical Company)

Homogenize the organic phase by mixing using a magnetic stirrer and a bar magnet.n

Step d): Pre-emulsification: Addition of the organic phase prepared in step c) to the aqueous phase prepared in step b) with mechanical stirring provided by a Rayneri™ brand stirrer equipped with a deflocculating-type rotor.
Stage e): Shearing emulsification with a device of the Silverson™ L4RT brand rotor-stator type for 2 minutes at a speed of 7500 revolutions/min.
Stage f): Distillation under vacuum, in a reactor placed under partial vacuum, of light oil and water.
Step g): Addition of surfactant of the oil-in-water type to the concentrated emulsion obtained in step f): weighing of 8 grams of concentrated emulsion obtained in step f) and addition of 2 grams of Polygyceryl- 6 winner.

The mixture is homogenized at room temperature with mechanical stirring at moderate speed to obtain composition (E2).
Example 3: Preparation of a concentrated water-in-oil emulsion according to the invention, composed of a mixture of ethyl hexyl palmitate/alkanes C15-19 as fatty phase and of PGGA of sodium, cross-linked with 1,4-butanediol diglycidyl ether in aqueous phase (pH = 5.5 to 6.0)
The synthesis process comprises the following steps:

Step a): Preparation of a sodium PGGA gel:
100 grams of demineralised water are placed in a beaker with stirring provided by a Rayneri ™ brand mechanical stirrer equipped with a deflocculating-type rotor.
30 grams of PGGA, marketed under the brand name “Cosmetic Grade Sodium PolyGamma Glutamate” by the company LUBON are slowly added to the vortex.
Step b): Adjustment of the pH of the reaction medium between 5.5 and 6 at a temperature of 20°C using a 5M HCl solution.
Step c): Addition of 0.75 grams of 1,4-Butanediol diglycidyl ether (sold under the name ERISYS TM GE 21 by the company EMERALD) to the aqueous phase prepared in step b)
Step d): Preparation of the organic phase in a 100 gram beaker:
Weigh 5 grams of sorbitan oleate (marketed under the name MONTANE™80 VG by the company SEPPIC)
Weigh 5 grams of Polyglyceryl-2 Dipolyhydroxystearate (marketed as Dehymuls™ PGPH by BASF)
Weigh 10 grams of ethyl hexyl palmitate (marketed under the name DUB PO by the company stéarinerie dubois)
Weigh 10 grams C15-19 Alkane (marketed under the name EMOGREEN™ L19 by the company SEPPIC)
Weigh 30 grams of C11-12 Isoparaffin (sold as ISOPAR™ H by ExxonMobil Chemical)

The mixture obtained is stirred using a magnetic stirrer and a magnetic bar.

Step e): Pre-emulsification: Addition of the organic phase prepared in step d) to the aqueous phase prepared in step c) with mechanical stirring using a Rayneri™ brand stirrer equipped with a deflocculating type.
Stage f): Emulsification by shearing agitation with a device of the rotor-stator type with a Silverson™ L4RT brand agitator for 2 minutes at 7500 rpm.
Step g): Distillation under vacuum in a reactor under partial vacuum of light oil and water.
Stage h): Addition of an oil-in-water type surfactant to the concentrated emulsion obtained in stage g): weighing of 8 grams of concentrated emulsion obtained in stage g) and of 2 grams of polyglyceryl -6 laureate.

The mixture is homogenized at room temperature with mechanical stirring at moderate speed to obtain the composition (E 3 ).
Example 4: Preparation of a concentrated water-in-oil emulsion according to the invention, composed of ethyl hexyl palmitate as the fatty phase and of sodium PGGA crosslinked with 1,4-butanediol diglycidyl ether in the organic phase (pH=5 .5 to 6.0) (cross-linking in fatty phase)
The synthesis process comprises the following steps:

Step a): Preparation of a sodium PGGA gel):
120 grams of demineralized water are placed in a beaker under mechanical stirring using a Rayneri ™ brand stirrer equipped with a deflocculator type mobile.
20 grams of PGGA marketed under the brand name “Cosmetic Grade Sodium PolyGamma Glutamate” by the company LUBON are slowly added to the vortex.
Stage b): Adjustment of the pH of the reaction medium between 5.5 and 6 at a temperature of 20°C using a 4M NaOH solution.
Step c): Preparation of the organic phase in a 100 gram beaker:
Weigh 5 grams of sorbitan oleate (marketed under the name MONTANE™80 VG by the company SEPPIC)
Weigh 5 grams of Polyglyceryl-2 Dipolyhydroxystearate (marketed under the name Dehymuls™ PGPH by the company BASF)
Weigh 20 grams of ethyl hexyl palmitate (marketed under the name DUB PO by the company stéarinerie dubois)
Weigh 30 grams of C11-12 Isoparaffin (marketed as ISOPAR H by ExxonMobil Chemical Company)
Weigh 0.50 grams of 1,4-Butanediol diglycidyl ether (marketed under the name ERISYS GE 21 by the company EMERALD)

Stir the mixture of ingredients previously weighed under magnetic stirring using a magnetic bar.

Step d): Pre-emulsification: Addition of the organic phase prepared in step c) to the aqueous phase prepared in step b) with mechanical stirring using a Rayneri™ brand mechanical stirrer fitted with a mobile of the deflocculating type.
Step e): Shearing emulsification with a stirrer fitted with a Silverson™ L4RT rotor-stator system for 2 min at a speed of 7500 rpm
Step f): Vacuum distillation in a partial vacuum reactor of light oil and water.
Stage g): Addition of oil-in-water surfactant to the concentrated emulsion obtained in stage f): weighing of 8 grams of concentrated emulsion and 2 grams of Polyglyceryl-6 laurate, which are added to the mixture obtained at step f). .

The mixture is homogenized at room temperature with mechanical stirring at moderate speed to obtain composition (E4).
Example 5: Preparation of a concentrated water-in-oil emulsion according to the invention, composed of ethyl hexyl palmitate as fatty phase and PGGA of Na crosslinked with 1,4-butanediol diglycidyl ether in aqueous phase (pH=4 )
The synthesis process comprises the following steps:

Step a): Preparation of a sodium PGGA gel:
120 grams of demineralised water are placed in a beaker under mechanical stirring using a Rayneri™ brand stirrer equipped with a deflocculator-type rotor.
20 grams of PGGA marketed under the brand name “Cosmetic Grade Sodium PolyGamma Glutamate” by the company LUBON are slowly added to the vortex.
Stage b): Adjustment of the pH of the reaction medium to 4 at a temperature of 20° C. using a 5M HCl solution.
Step c): Addition of 0.50 grams of 1,4-Butanediol diglycidyl ether (sold under the name ERISYS TM GE 21 by the company EMERALD) to the aqueous phase prepared in step b)
Step d): Preparation of the organic phase in a 100 gram beaker:
Weigh 5 grams of sorbitan oleate (marketed under the name MONTANE™80 VG by the company SEPPIC)
Weigh out 5 grams of Polyglyceryl-2 Dipolyhydroxystearate (marketed as Dehymuls PGPH by the company BASF)
Weigh 20 grams of ethyl hexyl palmitate (marketed under the name DUB PO by the company stéarinerie dubois)
Weigh 30 grams of C11-12 Isoparaffin (marketed as ISOPAR H by ExxonMobil Chemical Company)

Add each of the ingredients to the beaker and stir the mixture with a mechanical stirrer fitted with a magnetic bar.

Stage e): Pre-emulsification: Addition of the organic phase prepared in stage d) to the aqueous phase prepared in stage c) under mechanical stirring with the RayneriTM brand stirrer fitted with a deflocculating-type rotor.
Stage f): Shearing emulsification with Silverson TM L4RT, for 2 minutes at a speed of 7500 revolutions/min.
Step g): Distillation under vacuum in a reactor under partial vacuum of light oil and water.
Stage h): Addition of water-in-oil surfactant in the concentrated emulsion obtained in stage g): weighing of 8 grams of concentrated emulsion obtained in stage eg) and addition of 2 grams of Polyglyceryl-6 laureate.

The mixture is homogenized at room temperature with mechanical stirring at moderate speed to obtain the composition (E5).
Example 6: Preparation of a concentrated water-in-oil emulsion according to the invention, composed of ethyl hexyl palmitate as fatty phase and of sodium PGGA cross-linked with 1,4-butanediol diglycidyl ether in aqueous phase (pH=10)
The synthesis process comprises the following steps:

Step a): Preparation of a sodium PGGA gel:
120 grams of demineralized water are placed under mechanical stirring using a Rayerai t brand stirrer equipped with a deflocculating-type rotor.
20 grams of PGGA marketed under the brand name “Cosmetic Grade Sodium PolyGamma Glutamate” by the company LUBON are slowly added to the vortex.
Stage b): Adjustment of the pH of the reaction medium to 10 at a temperature of 20° C. using a 4M NaOH solution.
Step c): Addition of 0.50 grams of 1,4-Butanediol diglycidyl ether (sold under the name ERISYS TM GE 21 by the company EMERALD) to the aqueous phase prepared in step b)
Step d): Preparation of the organic phase in a 100 gram beaker:
Weigh 5 grams of sorbitan oleate (marketed under the name MONTANE™80 VG by the company SEPPIC)
Weigh 5 grams of Polyglyceryl-2 Dipolyhydroxystearate (marketed as Dehymuls TM PGPH by BASF)
Weigh 20 grams of ethyl hexyl palmitate (marketed under the name DUB PO by the company stéarinerie dubois)
Weigh 30 grams of C11-12 Isoparaffin (marketed as ISOPAR H by ExxonMobil Chemical Company)

Mix the different ingredients and stir the mixture using a magnetic stirrer fitted with a magnetic bar.

Stage e): Pre-emulsification: Addition of the organic phase prepared in stage d) to the aqueous phase prepared in stage c) under mechanical stirring with a Rayneri™ brand stirrer fitted with a deflocculating-type rotor.
Step f): Shearing emulsification with a Silverson™ L4RT brand stirrer for 2 minutes at a speed of 7500 revolutions/min.
Stage g): Distillation under vacuum (either with a rotavapor + flask, or in a vacuum reactor) of light oil and water.
Stage h): Addition of oil-in-water surfactant to the concentrated emulsion obtained in stage g): weighing of 8 grams of concentrated emulsion obtained in stage g) and of 2 grams of Ppolyglyceryl-6 laurate.

The mixture is homogenized at room temperature with mechanical stirring at moderate speed to obtain the composition (E6).
Example 7: Preparation of a concentrated water-in-oil emulsion according to the invention, composed of ethyl hexyl palmitate as fatty phase and sodium PGGA cross-linked with 1,4-butanediol diglycidyl ether and lipophilized with C12-14 glycidyl ether in phase aqueous (pH =?)
The synthesis process comprises the following steps:

Step a): Preparation of a sodium PGGA gel:
120 grams of demineralized water are placed in a beaker under mechanical stirring with a Rayneri TM brand stirrer fitted with a deflocculating-type rotor.
20 grams of PGGA marketed under the brand name “Cosmetic Grade Sodium PolyGamma Glutamate” by the company LUBON are slowly added to the vortex.
Stage b): Adjustment of the pH of the reaction medium between 5.5 and 6 at a temperature of 20°C using a 4M NaOH solution.
Step c) Addition of 0.5 grams of 1,4-Butanediol diglycidyl ether (sold under the name ERISYS™ GE 21 by the company EMERALD) to the aqueous phase prepared in step b)
Step d): Addition of 2.0 grams of C12-C14 glycidyl ether (sold under the name ERISYS™ GE 08 from EMERALD) to the aqueous phase prepared in step c)
Step e): Preparation of the organic phase in a 100 gram beaker:
Weigh 5 grams of sorbitan oleate (marketed under the name MONTANE™80 VG by the company SEPPIC)
Weigh 5 grams of Polyglyceryl-2 Dipolyhydroxystearate (marketed as Dehymuls™ PGPH by BASF)
Weigh 20 grams of ethyl hexyl palmitate (marketed under the name DUB PO by the company stéarinerie dubois)
Weigh 30 grams of C11-12 Isoparaffin (sold as ISOPAR™ H by ExxonMobil Chemical)

Stir the mixture of ingredients with a magnetic stirrer equipped with a magnetic bar.

Step f): Pre-emulsification: Addition of the organic phase prepared in step e) to the aqueous phase prepared in step d) under mechanical stirring with a Rayneri™ brand stirrer equipped with a deflocculating-type rotor.
Step g): Shearing emulsification with a Silverson™ L4RT brand stirrer for 2 minutes at a speed of 7500 revolutions/min.
Step h): Vacuum distillation in a reactor under partial vacuum of light oil and water.
Stage i): Addition of oil-in-water surfactants to the concentrated emulsion obtained in stage g): weighing of 8 grams of concentrated emulsion obtained in stage h) and of 2 grams of Polyglyceryl-6 laurate.

The mixture is homogenized at room temperature with mechanical stirring at moderate speed to obtain the composition (E7).
Example 8: Preparation of a concentrated water-in-oil emulsion according to the invention, composed of ethyl hexyl palmitate as fatty phase and sodium PGGA crosslinked with trimethylol ethane triglycidyl ether in aqueous phase (pH = 6.0)
The synthesis process comprises the following steps:

Step a): Preparation of a sodium PGGA gel:
120 grams of demineralized water are placed under mechanical stirring with a Rayneri TM brand stirrer fitted with a deflocculating-type rotor.
20 grams of PGGA marketed under the brand name “Cosmetic Grade Sodium PolyGamma Glutamate” by the company LUBON are slowly added to the vortex.
Stage b): Adjustment of the pH of the reaction medium between 5.5 and 6.0 at a temperature of 20°C using a 4M NaOH solution.
Step c): Addition of 0.5 grams of Trimethylol ethane triglycidyl ether (sold under the name ERISYS TM GE 31 by the company EMERALD) to the aqueous phase prepared in step b)
Step d): Preparation of the organic phase in a 100 gram beaker:
Weigh 5 grams of sorbitan oleate (marketed under the name MONTANE™80 VG by the company SEPPIC)
Weigh 5 grams of Polyglyceryl-2 Dipolyhydroxystearate (marketed as Dehymuls™ PGPH by BASF)
Weigh 20 grams of ethyl hexyl palmitate (marketed under the name DUB PO by the company stéarinerie dubois)
Weigh 30 grams of C11-12 Isoparaffin (sold as ISOPAR™ H by ExxonMobil Chemical)

Stir the mixture of all the ingredients with a magnetic stirrer equipped with a magnetic bar.

Stage e): Pre-emulsification: Addition of the organic phase prepared in stage d) to the aqueous phase prepared in stage c) under mechanical stirring with a Rayneri™ brand stirrer fitted with a deflocculating-type rotor.
Step f): Shearing emulsification with a Silverson™ L4RT brand stirrer for 2 minutes at a speed of 7500 revolutions/min.
Step g): Vacuum distillation in a partial vacuum reactor of light oil and water.
Stage h): Addition of oil-in-water surfactants to the concentrated emulsion obtained in stage g): weighing of 8 grams of concentrated emulsion obtained in stage f) and of 2 grams of Polyglyceryl-6 laurate.

The mixture is homogenized at room temperature with mechanical stirring at moderate speed to obtain the composition (E8).
Example 9: Preparation of a crosslinked PGA(Na) concentrated inverse latex according to the invention in octyl palmitate
The synthesis process comprises the following steps:

Step a): Production of a sodium PGGA gel with a Rayneri TM brand mechanical stirrer equipped with a deflocculator type mobile:
110 grams of demineralised water are placed under stirring in a beaker and stirred with a Rayneri™ brand mechanical stirrer equipped with a deflocculator-type rotor.
30 grams of PGGA marketed under the brand name “cosmetic grade sodium PolyGamma Glutamate” by the company LUBON are slowly added to the vortex.
Stage b): Adjustment of the pH of the reaction medium to 5.5 - 6 at a temperature of 20°C using a 5M HCl solution.
Step c): Addition of 0.72 grams of 1,4-Butanediol diglycidyl ether (sold under the name ERISYS TM GE 21 by the company EMERALD) to the aqueous phase prepared in step b)
Step d): Preparation of the organic phase in a 100 gram beaker:
Weigh 5 grams of sorbitan isostearate (marketed under the name MONTANE™70 by the company SEPPIC)
Weigh 3 grams of a mixture made up of tall-oil diethanolamide marketed under the brand name SIMALINE™ IE 200 by the company SEPPIC.
Weigh 2 grams of a polymeric surfactant marketed under the brand name Hypermer™ 6212 by the company Croda
Weigh 50 grams of C11-12 Isoparaffin (sold under the name ISOPAR™ H by ExxonMobil Chemical)

Stir the mixture of all the ingredients using a magnetic stirrer fitted with a magnetic bar.

Step e): Pre-emulsification: Addition of the organic phase prepared in step d) to the aqueous phase prepared in step c) with mechanical stirring using a Rayneri™ brand stirrer equipped with a deflocculating-type rotor.
Step f): Shearing emulsification with a Silverson™ L4RT brand mechanical stirrer for 2 minutes at a speed of 7500 revolutions/min.
Step g): Vacuum distillation in a partial vacuum reactor of light oil and water.
Stage h): Addition of oil-in-water surfactant to the concentrated emulsion obtained in stage g): weighing of 8 grams of concentrated emulsion and 1 gram of polysorbate 80 (marketed under the name MONTANOX™ 80 by the SEPPIC company.

The mixture is homogenized at room temperature with mechanical stirring at moderate speed to obtain composition (E9).
Example 10: Preparation of a concentrated water-in-oil emulsion according to the invention, composed of ethyl hexyl palmitate as fatty phase and PGGA of cross-linked sodium by ethylene glycol diglycidyl ether (EGDGE) in aqueous phase (pH = 6.0)
The synthesis process comprises the following steps:

Step a): Preparation of a sodium PGGA gel:
130 grams of demineralized water are placed under mechanical stirring with a Rayneri brand stirrer equipped with a deflocculator-type rotor.
10 grams of PGGA marketed under the brand name “Cosmetic Grade Sodium PolyGamma Glutamate” by the company LUBON are slowly added to the vortex.
Step b): Adjustment of the pH of the reaction medium between 5.5 and 6 at a temperature of 20°C using a 4M NaOH solution.
Step c) Addition of 0.25 grams of Ethylene glycol diglycidyl ether (sold under the name ERISYS™ EGDGE by the company EMERALD) to the aqueous phase prepared in step b)
Step d): Preparation of the organic phase in a 100 gram beaker:
Weigh 5 grams of sorbitan oleate (marketed under the name MONTANE™80 VG by the company SEPPIC)
Weigh 5 grams of Polyglyceryl-2 Dipolyhydroxystearate (marketed as Dehymul™s PGPH by the company BASF)
Weigh 20 grams of ethyl hexyl palmitate (marketed under the name DUB PO by the company stéarinerie dubois)
Weigh 30 grams of C11-12 Isoparaffin (sold as ISOPAR™ H by ExxonMobil Chemical)

Stir the mixture made up of all the ingredients weighed above with a magnetic stirrer fitted with a magnetic bar.

Stage e): Pre-emulsification: Addition of the organic phase prepared in stage d) to the aqueous phase prepared in stage c) under mechanical stirring with a Rayneri™ brand stirrer fitted with a deflocculating-type rotor.
Step f): Shearing emulsification with a Silverson™ L4RT brand stirrer for 2 minutes at a speed of 7500 revolutions/min.
Step g): Distillation under vacuum in a reactor under partial vacuum of light oil and water.
Stage h): Addition of oil-in-water surfactants to the concentrated emulsion obtained in stage f): weighing of 8 grams of concentrated emulsion obtained in stage g) and of 2 grams of Polyglyceryl-6 laurate.

The mixture is homogenized at room temperature with mechanical stirring at moderate speed to obtain the composition (E10).
Example 11: Preparation of a concentrated water-in-oil emulsion according to the invention, composed of ethyl hexyl palmitate as the fatty phase and of sodium PGGA cross-linked with 1,4-butanediol diglycidyl ether in the aqueous phase (pH= 6.0)
The synthesis process comprises the following steps:

Step a): Preparation of a sodium PGGA gel:
100 grams of demineralized water are placed under mechanical agitation by a Rayneri™ brand agitator equipped with a deflocculator-type rotor.
40 grams of PGGA marketed under the brand name “cosmetic grade sodium PolyGamma Glutamate” by the company LUBON are slowly added to the vortex.
Step b): Adjustment of the pH of the reaction medium between 5.5 and 6 at a temperature of 20°C using a 4M NaOH solution.
Step c) Addition of 0.80 grams of 1,4-Butanediol diglycidyl ether (sold under the name ERISYS™ GE 21 by the company EMERALD) to the aqueous phase prepared in step b)
Step d): Preparation of the organic phase in a 100 gram beaker:
Weigh 5 grams of sorbitan oleate (marketed under the name MONTANE™80 VG by the company SEPPIC)
Weigh 5 grams of Polyglyceryl-2 Dipolyhydroxystearate (marketed as Dehymuls™ PGPH by BASF)
Weigh 20 grams of ethyl hexyl palmitate (marketed under the name DUB PO by the company stéarinerie dubois)
Weigh 30 grams of C11-12 Isoparaffin (sold as ISOPAR™ H by ExxonMobil Chemical)

Stir the mixture made up of all the weighed constituents with a magnetic stirrer equipped with a magnetic bar.

Step e): Pre-emulsification: Addition of the organic phase prepared in step d) to the aqueous phase prepared in step c) under mechanical stirring with a Rayneri brand stirrer equipped with a deflocculating-type rotor.
Step f): Shearing emulsification with a Silverson L4RT brand stirrer for 2 minutes at a speed of 7500 revolutions/min.
Step g): Distillation under vacuum in a reactor under partial vacuum of light oil and water.
Stage h): Addition of oil-in-water surfactants to the concentrated emulsion obtained in stage g): weighing of 8 grams of concentrated emulsion obtained in stage g) and of 2 grams of Polyglyceryl-6 laurate. Hustle

The mixture is homogenized at room temperature with mechanical stirring at moderate speed to obtain composition (E11).
Evaluation of the compositions (E1) to (E11) according to the invention. The evaluation of the compositions (E1) to (E11) according to the invention is carried out as described below:

Weigh 192 grams of water in a 400 ml tall beaker
Add under mechanical stirring, with a Rayneri brand stirrer equipped with a deflocculating-type mobile, 8 grams of compositions (E1) to (E11)
Leave to stir until a homogeneous gel is obtained.
Measure the dynamic viscosity of homogeneous gels using a Brookfield RVT brand viscometer, at a speed of 5 revolutions/min, choosing the appropriate spindle.
Add 0.1% by mass of sodium chloride to the gel previously made, and stir with a Rayneri brand mechanical stirrer fitted with a deflocculator-type rotor.
Then measure the dynamic viscosity of such a new gel using a Brookfield RVT brand viscometer at a speed of 5 revolutions/min by choosing the appropriate spindle.

The results are recorded in Table 1 below.

CompositionComposition	Viscosité gel 4% massique de composition Brookfield^TM RVT Vitesse 5 Mobile (x) Gel viscosity 4% by weight of composition Brookfield ^TM RVT Speed 5 Mobile (x)	Viscosité gel 4% massique de composition + 0,1% massique NaCl Brookfield^TM RVT Vitesse 5 Mobile (x)Gel viscosity 4% by weight of composition + 0.1% by weight NaCl Brookfield ^TM RVT Speed 5 Mobile (x)	Equivalent % massique en matière active polymériqueEquivalent % by mass of polymeric active ingredient	Viscosité gel obtenus à l’étape a) du procédé de préparation Brookfield^TM RVT Vitesse 5 Mobile (x)Gel viscosity obtained in step a) of the preparation process Brookfield ^TM RVT Speed 5 Mobile (x)
Essai Témoin “PGGA de sodium de grade cosmétique” commercialisé par la société LUBONControl Test “Cosmetic grade sodium PGGA” marketed by the company LUBON	gel 2% = 176 mPa.s (Mobile 2)frost 2% = 176 mPa.s (Mobile 2)	gel 2% + 0.1% NaCl = 128 mPa.s (Mobile 2)gel 2% + 0.1% NaCl = 128 mPa.s (Mobile 2)	2%2%	gel 2% = 128 mPa.s (Mobile 2)frost 2% = 128 mPa.s (Mobile 2)
Composition(E₁) Composition(E ₁ )	76 200 mPa.s (Mobile 6)76,200 mPa.s (Mobile 6)	73 000 mPa.s (Mobile 6)73,000 mPa.s (Mobile 6)	2%2%	18 120 mPa.s (Mobile 3)18,120 mPa.s (Mobile 3)
Composition(E₂) Composition(E ₂ )	124200 mPa.s (Mobile 6)124200 mPa.s (Mobile 6)	89400 mPa.s (Mobile 6)89400 mPa.s (Mobile 6)	1,6%1.6%	5 040 mPa.s (Mobile 3)5040 mPa.s (Mobile 3)
Composition(E₃) Composition(E ₃ )	91600 mPa.s (Mobile 6)91600 mPa.s (Mobile 6)	816 mPa.s (Mobile 3)816 mPa.s (Mobile 3)	2%2%	18120 mPa.s (Mobile 3)18120 mPa.s (Mobile 3)
Composition(E₄) Composition(E ₄ )	117200 mPa.s (Mobile 6)117200 mPa.s (Mobile 6)	58600 mPa.s (Mobile 6)58600 mPa.s (Mobile 6)	1,6%1.6%	5040 mPa.s (Mobile 3)5040 mPa.s (Mobile 3)
Composition(E₅) Composition(E ₅ )	9820 mPa.s (Mobile 3)9820 mPa.s (Mobile 3)	8860 mPa.s (Mobile 6)8860 mPa.s (Mobile 6)	1,6%1.6%	5040 mPa.s (Mobile 3)5040 mPa.s (Mobile 3)
Composition(E₆)Composition(E ₆ )	131800 mPa.s (Mobile 6)131800 mPa.s (Mobile 6)	102800 mPa.s (Mobile 6)102800 mPa.s (Mobile 6)	1,6%1.6%	5040 mPa.s (Mobile 3)5040 mPa.s (Mobile 3)
Composition(E₇)Composition(E ₇ )	167600 mPa.s (Mobile 6)167600 mPa.s (Mobile 6)	118400 mPa.s (Mobile 6)118400 mPa.s (Mobile 6)	1,6%1.6%	5040 mPa.s (Mobile 3)5040 mPa.s (Mobile 3)
Composition(E₈)Composition(E ₈ )	9540 mPa.s (Mobile 3)9540 mPa.s (Mobile 3)	8860 mPa.s (Mobile 3)8860 mPa.s (Mobile 3)	1,6%1.6%	5040 mPa.s (Mobile 3)5040 mPa.s (Mobile 3)
Composition(E₉)Composition(E ₉ )	91800 mPa.s (Mobile 6)91800 mPa.s (Mobile 6)	34600 mPa.s (Mobile 6)34600 mPa.s (Mobile 6)	1,33%1.33%	18120 mPa.s (Mobile 3)18120 mPa.s (Mobile 3)
Composition(E₁₀)Composition(E ₁₀ )	78000 mPa.s (Mobile 6)78000 mPa.s (Mobile 6)	600 mPa.s (Mobile 2)600 mPa.s (Mobile 2)	1%1%	900 mPa.s (Mobile 3)900 mPa.s (Mobile 3)
Composition(E₁₁)Composition(E ₁₁ )	74800 mPa.s (Mobile 6)74800 mPa.s (Mobile 6)	48400 mPa.s (Mobile 6)48400 mPa.s (Mobile 6)	2,28%2.28%	50000 mPa.s (Mobile 6)50000 mPa.s (Mobile 6)

dynamic viscosities of aqueous gels obtained with compositions (E 1 ) to (E 11 )
* viscosity values of gels at pH 6
The compositions (E1) to (E11) according to the invention make it possible to obtain thickened aqueous gels compared to the aqueous gel obtained from a non-crosslinked sodium gamma-polyglutamate (“control test”).
Thus, at a polymeric mass percentage equal to 2%, the aqueous gels obtained with the compositions (E1) and (E3) respectively show a viscosity of 76,000 mPa.s and 91,600 mPa.s, whereas the aqueous gel obtained with the Non-crosslinked sodium gamma-polyglutamate (“control test”) is characterized by a viscosity of 176 mPa.s.
Similarly, at a polymer mass percentage of less than 2%, the aqueous gels obtained with the compositions (E2), (E4), (E8), (E9) and (E10) respectively show a viscosity of 124,000 mPa.s, 117 200 mPa.s, 9,540 mPa.s, 91,800 mPa.s and 78,000 mPa.s, whereas the aqueous gel obtained with 2% by weight non-crosslinked sodium gamma-polyglutamate (“control test”) is characterized by a viscosity of 176 mPa.s.

Claims

Pharmaceutical composition (F) comprising at least one pharmaceutical active ingredient and, as thickening agent, a composition (C A ) in the form of a self-inverting water-in-oil type emulsion comprising, for 100% of its mass, a mass greater than or equal to 20% of a polymer (P) consisting of monomeric units derived from glutamic acid (GA), partially or totally salified, and in units derived from at least one crosslinking agent (RA) carrying least two glycidyl functions.
Pharmaceutical composition (F) according to Claim 1, characterized in that in the composition (C A ) the mass content of the polymer (P) is greater than or equal to 20% and less than or equal to 60%.
Pharmaceutical composition (F) according to one of Claims 1 or 2, characterized in that in the composition (C A ), the crosslinking agent (AR) is chosen from the members of the group consisting of:

Ethylene Glycol Di Glycidyl Ether of Formula (I)

the compound of formula (II)

With R representing the hydrogen atom or the radical [ ], and n which represents an integer greater than or equal to one and less than or equal to 10;

The 1,3 propanediol DiGlycidyl ether of formula (III)

The 1,2 propanediol DiGlycidyl ether of formula (IV)

The 1,4 butanediol Di Glycidyl ether of formula (V)

- 1,2 butanediol Di Glycidyl ether of formula (VI)

The 1,3 butanediol Di Glycidyl ether of formula (VII)

The 1,6 hexanediol DI Glycidyl ether of formula (VIII)

The compound of formula (IX)

With R1 representing the hydrogen atom or the radical [ ];
When R1 represents the hydrogen atom, the compound of formula (IX) is more particularly the compound of formula (IXa) or trimethylol ethane DiGlycidyl ether

When R1 represents the [ ], the compound of formula (IX) is more particularly the compound of formula (IXb) or trimethylol ethane TriGlycidyl ether

The compound of formula (X)

with R1 representing the hydrogen atom or the glycidyl radical [ ];
When R1 represents the hydrogen atom, the compound of formula (X) is more particularly the compound of formula (Xa) or trimethylol propane DiGlycidyl ether

When R1 represents the glycidyl radical [ ], the compound of formula (X) is more particularly the compound of formula (Xb) or trimethylol propane TriGlycidyl ether

The compound of formula (XI)

with R1 and R2, independent, which represent the hydrogen atom or the glycidyl radical [ ]
When R1 and R2 each represent the hydrogen atom, the compound of formula (XI) is more particularly the compound of formula (XIa) or Pentaerythritol Di Glycidyl ether

When R1 represents the hydrogen atom and R2 represents the glycidyl radical [ ], the compound of formula (XI) is more particularly the compound of formula (XIb) or Pentaerythritol Tri Glycidyl ether

When R1 and R2 each represent the glycidyl radical [ , the compound of formula (XI) is more particularly the compound of formula (XIc) or Pentaerythritol Tetra Glycidyl ether

The compound of formula (XII)

with m representing an integer greater than or equal to 2

The compound of formula (XIII)

With R3 representing the hydrogen atom or the [ ], and x, y, z, o, p and q, independent of each other, represent an integer greater than or equal to 2 and less than or equal to 10.
Pharmaceutical composition (F) according to one of Claims 1 to 3, characterized in that in the composition (C A ) the polymer (P) is gamma-polyglutamic acid (PGGA) in acid form, or partially or totally salified .
Pharmaceutical composition (F) according to one of Claims 1 to 4, characterized in that in the composition (C A ) the polymer (P), for 100% molar of monomeric units derived from glutamic acid (GA), partially or totally salified, the crosslinking agent (RA) represents from 0.5% to 20% molar.
Pharmaceutical composition (F) according to one of Claims 1 to 5, characterized in that the composition (C A ) has a viscosity of between 100 mPa.s and 10,000 mPa.s.
Composition (CA) according to any one of Claims 1 to 6, characterized in that it also comprises a monomeric unit derived from the compound of formula (X'):

With R4 representing a linear or branched, saturated or unsaturated, functionalized or unfunctionalized hydrocarbon radical and comprising from 6 to 22 carbon atoms.
Pharmaceutical composition (F) according to one of Claims 1 to 7, characterized in that it comprises between 0.1% and 10% by weight of the said composition (C A ).
Pharmaceutical composition (F) according to one of Claims 1 to 8, characterized in that the pharmaceutical active principle is chosen from antibacterial agents, antimicrobial agents, antiparasitic agents, antihelminthic agents, anticoccidial agents, anti- cryptosporidians, anti-protozoal agents, antimycotic agents, nonsteroidal anti-inflammatory agents, antiallergic and immunomodulating agents, analgesic agents, antihistamine agents, local anesthetic agents, antisecticidal agents, antiseptic agents, antifungal agents .
Process for the preparation of a pharmaceutical composition (F) as defined in one of Claims 1 to 9, comprising:
- a step A) for preparing the composition (C A ) comprising the following sub-steps:

preparation of an aqueous solution comprising polyglutamic acid (PGA), partially or totally salified, with said aqueous solution comprising for 100% of its mass between 5 and 70% by mass of partially or totally salified PGA and a crosslinking agent (RA) comprising at least two glycidyl functions,

adjustment of the pH of the aqueous solution obtained in step a) to a pH of between 3 and 11;

preparation of an organic phase containing at least one volatile oil, at least one other non-volatile oil (H) and at least one emulsifying surfactant of the water-in-oil type (S 1 );

pre-emulsification by adding, with stirring, the organic phase obtained in stage c) to the aqueous solution obtained in stage b);

emulsification of the pre-emulsion obtained in step d) by homogenization with stirring;

distillation of the water and of the volatile oil contained in the emulsion obtained in step e);

addition of at least one emulsifying surfactant of the oil-in-water type (S 2 ) so as to obtain the composition (C A ).

- A step B) of mixing at least one composition (C A ) prepared during step A) with at least one pharmaceutical active principle and at least one pharmaceutically acceptable medium.
Process according to claim 10, characterized in that in step a) the polyglutamic acid (PGA) is gamma-polyglutamic acid (PGGA)
Process according to Claim 11, characterized in that in step a) all of the monomeric units constituting the gamma-polyglutamic acid (PGGA) are derived from sodium glutamate, potassium glutamate, ammonium glutamate, calcium glutamate, magnesium glutamate or a mixture of these forms.
Process according to one of Claims 10 to 12, characterized in that in step a) the crosslinking agent (RA) is present in mass proportions of between 0.5% and 10% by mass relative to the mass polyglutamic acid (PGA).
Process according to Claim 13, characterized in that the crosslinking agent (RA) is chosen from the members of the group consisting of the compounds of formula (I), (II), (IIa), (IIb), (IIc), (III), (IV), (V), (VI), (VII), (VIII), (IX), (IXa), (IXb), (X), (Xa), (Xb), (XI ), (XIa), (XIb), (XIc), (XII), (XIII)
Process according to one of Claims 10 to 14, characterized in that in step c) the at least water-in-oil type emulsifying agent (S 1 ) is chosen from the elements of the group consisting of esters sorbitan, polyglycerol esters, alkoxylated polyglycerol esters, polyglycol polyhydroxystearates, polyglycerol polyhydroxystearates, alkoxylated polyglycerol polyhydroxystearates.
Process according to one of Claims 10 to 15, characterized in that in step c) the organic solution comprises, for 100% of its own mass, between 10 and 30% by mass of at least one emulsifying agent of the water- in-oil (S 1 ), preferably between 15 and 20% by mass.
Process according to one of Claims 10 to 16, characterized in that in stage c) the emulsifying agent of the water-in-oil type (S 1 ) is a polyglycerol polyhydroxystearate.
Process according to one of Claims 10 to 17, characterized in that in step g) the at least emulsifying surfactant of the oil-in-water type (S 2 ) is chosen from the elements of the group consisting of a polyethoxylated fatty alcohol, a polyethoxylated hexitan ester, an alkylpolyglycoside, a composition of alkylpolyglycoside and fatty alcohols, a polyglycerol ester, a composition of polyglycerol and polyglycerol ester.
Use of the said composition (C A ) as defined in one of Claims 1 to 9, as a thickening and/or emulsifying and/or stabilizing agent for an aqueous liquid pharmaceutical composition for topical use.