EP3220903A1

EP3220903A1 - Compositions comprising a compound from the family of avermectins and an agonist compound for at least one of the retinoic acid receptors for treating acne

Info

Publication number: EP3220903A1
Application number: EP15798055.8A
Authority: EP
Inventors: Jean-Paul Chappuis; Jean JACOVELLA
Original assignee: Galderma SA
Current assignee: Galderma SA
Priority date: 2014-11-20
Filing date: 2015-11-19
Publication date: 2017-09-27
Also published as: US20180325859A1; US10653659B2; WO2016079262A1

Abstract

The invention relates to one of the compositions comprising a compound of the family of avermectins, preferably ivermectin, and an agonist compound for at least one of the retinoic acid receptors, in particular used in the treatment of acne.

Description

COMPOSITIONS COMPRISING A COMPOUND OF THE AVERMECTIN FAMILY AND AN AGONIST COMPOUND OF AT LEAST ONE OF THE RETINOIC ACID RECEPTORS FOR THE TREATMENT OF ACNE

The present invention relates to compositions especially used in the treatment of acne.

BACKGROUND OF THE INVENTION

Acne is a common and multifaceted skin disorder of hair follicles and sebaceous glands resulting in comedone formation. It affects virtually all adolescents and may also persist in adulthood. Adult women can be particularly affected and experience premenstrual eruptions.

Genetic predisposition, overproduction of sebum (seborrhea), androgens, disorders of follicular keratinisation (comedogenesis) and bacterial colonization accompanied by inflammatory factors are different factors that play a determining role in the formation of acne.

There are several forms of acne and the common factor of all of them being the attack of the pilosebaceous follicles. For example, acne conglobata, keloid acne, drug acne, recurrent miliary acne, necrotic acne, neonatal acne, premenstrual acne, occupational acne, senile acne, solar acne and common acne.

Common acne or acne vulgaris, also called juvenile polymorphic acne, is the most common and includes four stages:

stage 1 corresponds to comedonal acne and is characterized by a large number of open and / or closed comedones and microcysts;

stage 2, or papulopustular acne, is of mild to moderate severity and is characterized by the presence of open and / or closed comedones, microcysts, but also papules and red pustules. It mainly affects the face and leaves some scars;

stage 3, or papulo-comedian acne, is more serious and extends to the back, thorax and shoulders. It is accompanied by a large number of scars; Stage 4, or nodulo-cystic acne, is accompanied by numerous scars. It presents nodules and also purple pustules voluminous and painful.

These different forms of acne are traditionally treated using different active agents. These include for example anti-seborrhea and anti-infective agents such as benzoyl peroxide marketed by Pierre Fabre as the Eclaran ^®. We can also mention retinoids such as tretinoin, marketed by Galderma under the name Retacnyl ^®, or isotretinoin, sold by Roche Laboratories under the name Accutane ^®, for their ability to act on the proliferation and differentiation keratinocytes. Naphthoic acid derivatives, such as adapalene, described in particular in application FR 2 837 101, or derivatives thereof, described in patent EP 0 850 909, are also recognized as active substances for the treatment of acne. However, the use of these assets and, in particular retinoids, cause numerous adverse effects in the patient. In particular, retinoid-based treatments may result in skin dryness, irritation, erythema, peeling and tingling or burning for treated patients. Thus, the use of such treatments also requires the application of multiple moisturizers, humectants and softeners to relieve the patient.

In addition, these various treatments are often associated with an antibiotic treatment such as tetracycline, erythromycin, minocycline and doxycycline to treat acne lesions, but their low lipid solubility requires regular and frequent administration which can cause phenomena. resistance and promote the development of these resistant organisms, as well as problems of intolerance in the patient. Thus, it is clear that there is a need to provide more effective treatments for acne that does not have adverse effects in the patient. In particular, there is currently no treatment that acts on both factors in the formation of acne and the resulting inflammatory reactions.

SUMMARY OF THE INVENTION

It is to Applicant's merit to have discovered that a combination of a compound of the avermectin family, in particular ivermectin, with an agonist compound of at least one of the retinoic acid receptors makes it possible to obtain a more effective treatment of acne with fewer side effects.

In particular, such a combination makes it possible both to act on the inflammatory and non-inflammatory lesions of acne with a synergistic effect. Moreover, the combination of these two active agents makes it possible to obtain a certain advantage in terms of efficacy and tolerance for the patient by, in particular, attenuating the irritant effect caused by the use of the agonist compounds of at least one of the retinoic acid.

The object of the present invention is therefore to provide a composition comprising a compound of the avermectin family and an agonist compound of at least one of the retinoic acid receptors for its use in the treatment of acne.

In a preferred embodiment, the compound of the avermectin family is ivermectin.

In a first particular embodiment, the agonist compound of at least one of the retinoic acid receptors is of formula (I):

(I) in which :

R 1 represents a hydrogen atom, an alkyl group of 1 to 4 carbon atoms or a group -CF ₃ ;

R ₂ represents a hydrogen atom, an alkyl or alkoxy group of 1 to 4 carbon atoms or a chlorine atom;

R ₃ represents a hydrogen atom, an alkyl or alkoxy group of 1 to 10 carbon atoms and preferably 1 to 6 carbon atoms, linear or branched, optionally substituted with a methoxy group, or a linear or branched alkyl group; from 1 to 10 carbon atoms containing an ether function; R ₄ and R ₅ represent a hydrogen atom or an alkyl group of 1 to 3 carbon atoms, or R ₄ and R ₅ may together with the -NC (= Y) - bond form a pyrrolidine pyrrolidone ring; piperidine or piperidone;

Y represents two hydrogen atoms or a heteroatom, preferably oxygen or sulfur;

Ar represents a 1,4-phenyl, 2,5-pyridyl, 5,2-pyridyl or 2,5-thiophenyl ring;

X represents an oxygen atom optionally substituted with an alkyl or alkylamine group of 1 to 4 carbon atoms or a single bond C-C;

A represents a hydroentene atom or the following formula (IA):

in which :

Q represents an oxygen atom or an -NH- bond;

R ₆ represents a hydrogen atom, an alkyl group of 1 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms or a -C (O) CH ₃ or -C (O) CH ₂ CH _{3 group} ;

R ₇ and R ₇ represent, independently of one another, a hydrogen atom or a hydroxyl group, provided that R ₇ and R ₇ are not simultaneously a hydroxyl group; and n = 0, 1, 2, 3, 4 or 5;

and the optical and geometric isomers of said compounds of formula (I) as well as their pharmaceutically acceptable salts. Preferably, the compound of formula (I) is 3 "-tertio-butyl-4 '- (2-hydroxyethoxy) -4''-pyrrolidin-1-yl [1, 1'; 3 ', 1 4-Terphenyl-4-carboxylic acid.

In a second particular embodiment, the agonist compound of at least one of the retinoic acid receptors is of formula (II):

in which :

R 1 "represents a group -CH ₃ , a group -CH ₂ -O-R ₄ ", a group -O-R ₄ ", a group -CO-R 5", R 4 "and R 5" being as defined below,

Ar "represents a group chosen from the following groups of formulas (a) to (f):

R ₆ "and R 7" being as defined below,

> R ₂ "represents the group -OCH ₃ , or - (X) m- (CH ₂ ) nY- (CH ₂ ) p -R ₈ ", the values m, n and p and the groups X, Y and Rs "being as defined below,

R ₃ "represents a hydrogen atom, a halogen atom, an alkyl group of 1 to 6 carbon atoms or a group -O-R ₄ ",

R4 "represents a hydrogen atom, an alkyl group of 1 to 6 carbon atoms or a group -CO-R9",

R5 "represents a hydrogen atom, an alkyl group of 1 to 6 carbon atoms, a group -OR10" or a group

I

R _{1 2} "

in which Ru "and R12", which may be identical or different, represent a hydrogen atom, an alkyl group of 1 to 6 carbon atoms, a mono or polyhydroxyalkyl group, a optionally substituted aryl group or a residue of amino acid or peptide or sugar or taken together, form a heterocycle,

m is an integer equal to 0 or 1,

n is an integer inclusive of between 1 and 6,

p is an integer inclusive of between 1 and 6,

X represents O or S (O) q,

Y represents O, S (O) q or NR ₇ ",

q is an integer inclusive between 0 and 2,

R ₆ "represents a hydrogen atom, a halogen atom, an alkyl group of 1 to 6 carbon atoms or a group -O-R 4",

R ₇ "represents a hydrogen atom, an alkyl group of 1 to 6 carbon atoms or a group -CO-R ₉ ",

R8 "represents a mono or polyhydroxyalkyl group, the hydroxyls of which are optionally protected in the form of methoxy, ethoxy or acetoxy or acetonide, a -CO-R5" group, an optionally substituted aryl or aralkyl group,

R ₉ "represents an alkyl group of 1 to 6 carbon atoms,

Rio "represents a hydrogen atom, an alkyl group, an alkenyl group, a mono or polyhydroxyalkyl group whose hydroxyls are optionally protected in the form of methoxy, ethoxy or acetoxy or acetonide, an optionally substituted aryl or aralkyl group or a sugar residue or an amino acid or peptide residue,

and the optical and geometric isomers of said compounds of formula (II) as well as their pharmaceutically acceptable salts.

Preferably, the compound of formula (II) is adapalene.

In a third particular embodiment, the agonist compound of at least one of the retinoic acid receptors is of formula (III):

in which :

Ri "'represents a hydrogen atom, an alkyl group of 1 to 18 carbon atoms, an alkenyl group of 1 to 18 carbon atoms, an alkynyl group of 1 to 18 carbon atoms, an aryl group, heteroaryl, cycloalkyl group , or heterocycloalkyl.

Preferably, the compound of formula (III) is taarotene.

In a fourth particular embodiment, the agonist compound of at least one of the retinoic acid receptors is of formula (IVA) or (IVB):

(IVB) in which:

Ri "" represents a group -CH ₂ OH, -CHO, or a group CO2R2 "" in which R2 "" represents a hydrogen atom, an alkyl group of 1 to 18 carbon atoms, an alkenyl group of 1 to 18 carbon atoms, an alkynyl group of 1 to 18 carbon atoms, an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group.

Preferably, the compound of formula (IVA) or (IVB) is retinoic acid, retinol, retinal, etretinate or acitretin.

In a fifth particular embodiment, the agonist compound of at least one of the retinoic acid receptors is bexarotene.

In one embodiment, the compound of the avermectin family present in the compositions of the invention represents between 0.001 and 10, preferably between 0.001 and 5%, even more preferably between 0.1 and 2% and even more preferably 1% by weight, relative to the total weight of the composition.

In another embodiment, the agonist compound of at least one of the retinoic acid receptors represents between 0.001 and 10, preferably between 0.001 and 5, even more preferentially between 0.01 and 1, and still more more preferably 0.1 or 0.3% by weight, based on the total weight of the composition.

In a preferred embodiment, the compound of the avermectin family represents 1% by weight and the agonist compound of at least one of the retinoic acid receptors represents between 0.1 and 1, preferentially 0.1 or 0, 3% by weight, relative to the total weight of the composition.

In particular, the compositions used in the invention are intended to be administered topically and are preferably in the form of a gel, a lotion or a cream.

Another subject of the invention relates to a kit comprising (a) a first composition comprising a compound of the avermectin family, preferably ivermectin, and (b) a second composition, distinct from the first, comprising an agonist compound of at least one of the retinoic acid receptors, preferably adapalene.

In a preferred embodiment, the kit is used in the treatment of acne.

A further object of the invention is a composition, preferably in topical form, comprising ivermectin and adapalene in a physiologically acceptable medium.

LEGEND OF FIGURES

FIGS. 1A to 1C: Quantification of the production of inflammatory cytokines IL12p40 (FIG. 1A), TNFα (FIG. 1B), and IFNγ (FIG. 1C) with ivermectin and retinoic acid alone or in combination. Figures 2A and 2B: Quantification of IL12p40 (Figure 2A) and IFNy (Figure 2B) inflammatory cytokine production with ivermectin and adapalene alone or in combination. Figures 3A-3C: Quantification of the production of inflammatory cytokines IL12p40 (Figure 3A), TNFα (Figure 3B), and IFNy (Figure 3C) with ivermectin and trifarotene alone or in combination.

Figures 4A-4C: Quantification of the production of inflammatory cytokines IL12p40 (Figure 4A), TNFα (Figure 4B), and IFNy (Figure 4C) with ivermectin and tazarotene alone or in combination.

DETAILED DESCRIPTION OF THE INVENTION The inventors have identified a new use of a composition in the treatment of acne and have surprisingly discovered that the combination of the two active ingredients, which is a compound of the avermectin family, in particular the ivermectin, and an agonist compound of at least one of the retinoic acid receptors was effective in treating acne. In particular, it has been demonstrated that such a combination is effective in treating the different forms of acne, acting on both inflammatory and non-inflammatory lesions, and improving tolerance for the treated patient, including reducing adverse effects due to the use of retinoic acid receptor agonists known to be particularly irritating.

The invention therefore relates to a composition comprising a compound of the avermectin family and an agonist compound of at least one of the retinoic acid receptors for its use in the treatment of acne. The invention also relates to a combination of a compound of the avermectin family and an agonist compound of at least one of the retinoic acid receptors for use in the treatment of acne.

The invention also relates to methods or methods employing a composition comprising a compound of the avermectin family, preferably ivermectin, and an agonist compound of at least one of the acid receptors retinoic as defined in the present application for its administration in a therapeutically effective amount in a patient suffering from acne.

The invention also relates to a method for treating acne comprising administering a therapeutically effective amount of a compound of the avermectin family, preferentially ivermectin, and an agonist compound of at least one of the receptors. retinoic acid, to a patient with acne. Preferably, the method comprises administering a composition as defined herein comprising the avermectin family compound and the agonist compound of at least one of the retinoic acid receptors in a therapeutically effective amount.

The invention also relates to the use of a composition as defined in the present application comprising a compound of the avermectin family and an agonist compound of at least one of the retinoic acid receptors for the preparation of a medicament to treat acne.

Retinoic Acid Receptor Agonists It is well known that all-trans retinoic acid acts on the differentiation and proliferation of cells by interacting with retinoic acid nuclear receptors (RARs). RAR receptors activate the transcription of specific genes by binding to elements of the DNA sequence, known as RAR response elements (RARE), as heterodimers with retinoid X receptors (RXRs). Three human RAR receptor subtypes have been identified and described: RARa, RARP and RARy. Many chemical compounds are described in the prior art as ligands to retinoic acid receptors and are used in compositions for treating various dermatological disorders. The dissociation constants are determined using standard tests for those skilled in the art. These tests are described in particular in the following references: (1) "Selective Synthetic Ligands for Nuclear Retinoic Acid Receptor Subtypes" in RETINOIDS, Progress in Research and Clinical Applications, Chapter 19 (pp. 261-267), Marcel Dekker Inc, edited by Maria A. Librea and Lester Packer; (2) "Synthetic Retinoids: Receptor Selectivity and Biological Activity" in Pharmacol Skin, Basel, Karger, 1993, Volume. 5, pp 117-127; (3) "Selective Synthetic Ligands for Human Nuclear Retinoic Acid Receptors" in Skin Pharmacology, 1992, Vol. 5, pp 57-65; (4) "Identification of Synthetic Retinoids with Selectivity for Human Nuclear Retinoic Acid Receptors" in Biochemical and Biophysical Research Communications, Vol. 186, No. 2, July 1992, pp. 977-983, and (5) "Selective High Affinity RAR-a Gold RAR-p Retinoic Acid Receptor Ligands" in Mol Pharmacol., Vol 40, pp 556-562. of these tests is incorporated in this application for reference.

The test described in patent FR 2,735,370 makes it possible to identify the agonist compounds of the RXRs receptors. The description of this test is incorporated in this application for reference. This test includes the following steps:

(i) a sufficient amount of a compound which is an active ligand of at least one steroid / thyroid receptor superfamily, other than a specific RXRs receptor ligand and capable of heterodimerization with RXR receptors, is applied topically on part of the skin of a mammal, including the ear of the mammal,

(ii) a molecule capable of exhibiting RXRs receptor agonist activity is administered systemically or topically on the same mammal or part of the mammalian skin before, during or after step (i), and

(iii) the response is evaluated on the part of the skin thus treated of the mammal.

Thus, the response to topical application to a mammalian ear of a compound that is an active ligand of at least one steroid / thyroid receptor superfamily, other than a specific RXRs receptor ligand and may be heterodimerized with RXR receptors which corresponds to an increase in the thickness of this ear may be inhibited by the systemic or topical administration of an RXR agonist molecule. In the context of the present invention, the term "agonist compound of at least one of the retinoic acid receptors" means any compound capable of binding to at least one of the RARs and / or RXRs receptors and whose agonist activity. is identified and evaluated in the tests referenced above and in particular in patent FR 2 735 370.

In a particular embodiment, the agonist compound of at least one of the retinoic acid receptors is of formula (I):

in which :

Y represents two hydrogen atoms or a heteroatom, preferably oxygen or sulfur;

Ar represents a 1,4-phenyl, 2,5-pyridyl, 5,2-pyridyl or 2,5-thiophenyl ring;

A represents a hydrogen atom or the following formula (IA):

in which :

Q represents an oxygen atom or an -NH- bond;

and the optical and geometric isomers of said compounds of formula (I) as well as their pharmaceutically acceptable salts.

Preferably, the agonist compound of at least one of the retinoic acid receptors of formula (I) is a compound described in patent EP 1 831 149, the description of the compounds being incorporated herein by reference. Even more preferentially, the agonist compound of at least one of the retinoic acid receptors of formula (I) is 3 '' -tertiobutyl-4 '- (2-hydroxyethoxy) -4' '-pyrrolidinic acid. 1 -yl- [1,1 ', 3', 1 "] -terphenyl-4-carboxylic acid.

In another particular embodiment, the agonist compound of at least one of the retinoic acid receptors is of formula (II):

in which :

R 1 "represents a group -CH ₃ , a group -CH ₂ -O-R ₄ ", a group -O-R ₄ ", a group -CO-R 5", R ₄ "and R 5" being as defined below. after,

Ar "represents a group chosen from the following groups of formulas (a) to (f):

and R ₇ "being as defined below,

> R ₂ "represents the group -OCH ₃ , or - (X) m- (CH ₂ ) nY- (CH ₂ ) pR ₈ ", the values m, n and p and the groups X, Y and Rs "being such as defined below,

R ₃ "represents a hydrogen atom, a halogen atom, an alkyl group of 1 to 6 carbon atoms or a group -O-R 4",

R ₄ "represents a hydrogen atom, an alkyl group of 1 to 6 carbon atoms or a group -CO-R ₉ ",

in which Ru "and Ri ₂ ", which may be identical or different, represent a hydrogen atom, an alkyl group of 1 to 6 carbon atoms, a mono or polyhydroxyalkyl group, an optionally substituted aryl group or an amino acid or peptide or sugar or taken together, form a heterocycle,

m is an integer equal to 0 or 1,

n is an integer inclusive of between 1 and 6,

p is an integer inclusive of between 1 and 6,

X represents O or S (O) q,

Y represents O, S (O) q or NR ₇ ",

q is an integer inclusive between 0 and 2,

R ₆ "represents a hydrogen atom, a halogen atom, an alkyl group of 1 to 6 carbon atoms or a group -O-R ₄ ",

R ₇ "represents a hydrogen atom, an alkyl group of 1 to 6 carbon atoms or a group -CO-R ₉ ", Rs "represents a mono- or polyhydroxyalkyl group whose hydroxyls are optionally protected in the form of methoxy, ethoxy or acetoxy or acetonide, a -CO-R5" group, an optionally substituted aryl or aralkyl group,

R 9 "represents an alkyl group of 1 to 6 carbon atoms,

Preferably, the compound is of formula (II) in which:

Ri "represents a group -CO-Rs" with R5 "representing a group -OR10", Rio "being a hydrogen atom,

Ar "represents a group of formula (c) with R ₆ " representing a hydrogen atom,

R2 "represents a group -OCH3, and

R3 "represents a hydrogen atom.

Advantageously, the compound of formula (II) is 6- [3- (1-adamantyl) -4-methoxyphenyl] -2-naphthoic acid or adapalene.

An object of the invention is a composition, preferably in topical form, comprising ivermectin and adapalene in a physiologically acceptable medium.

In another particular embodiment, the agonist compound of at least one of the retinoic acid receptors is of formula (III):

in which Ri "'represents a hydrogen atom, an alkyl group of 1 to 18 carbon atoms, an alkenyl group of 1 to 18 carbon atoms, an alkynyl group of 1 to 18 carbon atoms, an aryl group, heteroaryl, cycloalkyl group , or heterocycloalkyl.

In a preferred embodiment, the compound is of formula (III), in which R 1 "represents an alkyl group of 1 to 18 carbon atoms, preferably 1 to 6 carbon atoms, and even more preferably, 2 carbon atoms.

Advantageously, the compound of formula III is ethyl 6- [2- (4,4-dimethylthiochroman-6-yl) ethynyl] nicotinate or tazarotene. In another particular embodiment, the agonist compound of at least one of the retinoic acid receptors is of formula (IVA) or (IVB):

(IVB) in which:

R 1 "" represents a group -CH ₂ OH, -CHO, or a group C0 ₂ R ₂ "" in which R ₂ "" represents a hydrogen atom, an alkyl group of 1 to 18 carbon atoms, an alkenyl group from 1 to 18 carbon atoms, an alkynyl group of 1 to 18 carbon atoms, an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group.

Preferably, Ri "" represents a group -CH ₂ OH, -CHO, or a group C0 ₂ R ₂ "" in which R ₂ "" represents a hydrogen atom, or an alkyl group of 1 to 6 carbon atoms , preferably to two carbon atoms.

Advantageously, the compound of formula (IVA) or (IVB) is retinoic acid, retinol, retinal, etretinate or acitretin.

In another particular embodiment, the agonist compound of at least one of the retinoic acid receptors is bexarotene of formula (V):

In the context of the invention the terms below have the following meanings:

The term "alkyl" represents a saturated, linear or branched aliphatic group, typically of 1 to 18 carbon atoms, of 1 to 10 carbon atoms, preferably of 1 to 6 carbon atoms and even more preferably of 1 to 4 carbon atoms; carbon atoms. Examples of alkyl groups of 1 to 10 carbon atoms are methyl, ethyl, isopropyl, butyl, tert-butyl, hexyl, nonyl and dodecyl. Alkyl groups of 1 to 6 carbon atoms are, for example, methyl, ethyl, isopropyl, butyl, tert-butyl and hexyl.

The term "alkenyl" represents an alkyl group as defined above further comprising one or more double bonds.

The term "alkynyl" represents an alkyl group as defined above further comprising one or more triple bonds.

The term "alkoxy" represents an alkyl group as defined above and linked to the molecule by a -O- (ether) bond. For example, an alkoxy group of 1 to 6 carbon atoms includes methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, tert-butyloxy, pentyloxy and hexyloxy.

The term monohydroxyalkyl represents an alkyl group as defined above substituted by a hydroxyl group. For example, hydroxymethyl, 2-hydroxyethyl, 2 or 3-hydroxypropyl groups may be mentioned.

The term polyhydroxyalkyl represents an alkyl group as defined above substituted by at least two hydroxyl groups. Examples that may be mentioned include 2,3-hydroxypropyl, 2,3,4-trihydroxybutyl and 2,3,4,5-tetrahydroxypentyl groups or the pentaerythritol residue.

The term "halogen" corresponds to a fluorine, chlorine, bromine or iodine atom. The term "Ar" or "aryl" corresponds to a mono- or bi-ring having 6 to 12 carbon atoms of formula C _n H ( _n-2 ). For example, phenyl, biphenyl or naphthyl groups may be mentioned.

The term "heteroaryl" corresponds to an aromatic mono- or polycycle comprising between 5 and 14 atoms with at least one heteroatom such as a nitrogen atom, an oxygen atom or a sulfur atom. Examples of heteroaryl include pyridyl, dihydroypyridyl, thiazolyl, thiophenyl, furanyl, azocinyl, pyranyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, pyrrolinyl and the like. tetrahydroquinolinyl, tetrahydroisoquinolinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H, 6H-1,5,2-dithiazinyl, thianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxanthinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl , indolizinyl, isoindolyl, 3H-indolyl, 1H-indazolyl, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl , phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazoliny el, indolinyl, isoindolinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, benzothienyl, benzothiazolyl, isatinyl, pyrimidinyl, pyrazinyl, s-triazinyl, oxazolyl and thiofuranyl.

The term "cycloalkyl" corresponds to an alkyl group as defined above connected by a bond at its two ends. For example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl may be mentioned as cycloalkyl of 3 to 6 carbon atoms.

The term "heterocycloalkyl" represents a cycloalkyl group as defined above with at least one heteroatom such as a nitrogen atom, an oxygen atom or a sulfur atom.

The term "aralkyl" corresponds to an aryl group bonded to an alkyl group as defined above.

"Sugar residue" means a radical derived from glucose, mannose galactose or glucuronic acid. "Amino acid residue" is understood to mean, in particular, a residue derived from an amino acid such as lysine, glycine or aspartic acid and "peptide residue" more particularly means a residue of dipeptide or tripeptide resulting from the combination of amino acids.

- The link "" found in particular in the formulas (IVA) and (IVB) represents the two types of Z and E isomerism.

The term "pharmaceutically acceptable salt (s)" refers to salts of a compound of interest that possess the desired biological activity. Pharmaceutically acceptable salts include salts of acidic or basic groups present in the specified compounds. The pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, hydrochloride, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate salts. , bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, ptoluenesulfonate and pamoate (i.e., 1,1'-methylene -bis- (2-hydroxy-3-naphthoate)). Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and diethanolamine salts. A list of pharmaceutically acceptable salts is notably published in the review by Berge et al. (J. Pharm Sci 1977, 66 (1), 1-19).

The agonist compounds of the RARs and RXRs receptors as described above make it possible to treat acne, in particular by acting on the non-inflammatory lesions of acne, by their anti-comedogenic properties, and by their effects on differentiation and the proliferation of keratinocytes.

In a particular embodiment, the agonist compound of at least one of the retinoic acid receptors present in the composition represents between 0.001 and 10, preferably between 0.001 and 5, even more preferentially between 0.1 and 1, and still more preferably 0.1 or 0.3% by weight, based on the total weight of the composition. avermectin

The class of avermectins is a group of macrocyclic lactones produced by the bacterium Streptomyces avermitilis (Reynolds JEF (Ed) (1993) Martindale, The Extra Pharmacopoeia, 29th Edition, Pharmaceutical Press, London). Among these macrocyclic lactones belonging to the avermectin class, mention may be made of ivermectin, avermectin, abamectin, doramectin, eprinomectin, selamectin, aversectin B, AB or C, emamectin B1 and their derivatives, or latidectin. According to the invention, the compound of the avermectin family is preferably ivermectin.

Ivermectin is a mixture of 22,23-dihydroavermectin Bi _a and 22,23-dihydroavermectin Bit ,. Ivermectin contains mainly 22,23-dihydroavermectin Bla.

Ivermectin is known in the prior art for its antiparasitic properties, especially against Demodex, and anthelmintics. In the mid-1980s, the molecule was presented as a broad-spectrum pest control drug for veterinary use (CAMPBELL, WC, et al., (1983).) Ivermectin: a patented new antiparasitic agent, Science, 221, 823-828.) . It is effective against most common intestinal worms (except tapeworms), most mites, and some lice. It has a significant affinity for glutamate-dependent chloride channels, in particular those dependent on the neuromediator GABA (gamma-amino-butyric acid), present in the nerve and muscle cells of invertebrates, conferring on it an antiparasitic activity. More particularly, its binding on these channels promotes an increase in membrane permeability to chloride ions resulting in hyperpolarization of the nerve or muscle cell. This results in neuromuscular paralysis that can lead to the death of certain parasites. Ivermectin also interacts with other chlorine channels.

Ivermectin has also been used in the treatment of acne vulgaris. US Pat. No. 6,399,652 describes the use of ivermectin in the treatment of acne in addition to another composition containing another active ingredient which may be peroxide. benzoyl, resorcinol, salicylic acid, opioid, tretinoin, antibiotic or isotretinoin.

The presence of ivermectin in the compositions of the invention advantageously makes it possible, by virtue of its anti-inflammatory properties, to treat the inflammatory lesions of acne and to improve cutaneous tolerance by softening the irritating effect of agonist compounds on the skin receptors. retinoic acid. In addition, ivermectin also reduces and eliminates the parasite Demodex for which an increase in its density has been observed in patients suffering from acne (Zhao et al., J Zhejiang Univ Sci B., 2012, 13 , 192-202).

In a particular embodiment, the compound of the avermectin family present in the composition represents between 0.001 and 10, preferably between 0.001 and 5, still more preferably between 0.1 and 2%, and even more preferably 1. % by weight, relative to the total weight of the composition.

additives

The compositions of the invention may comprise a physiologically acceptable medium, that is to say a medium that is compatible with the skin, the mucous membranes and / or the superficial body growths. The compositions of the invention may also comprise a pharmaceutically or cosmetically acceptable vehicle, that is to say a vehicle adapted for use in contact with human cells, without toxicity, intolerance, irritation, undue allergic response and the like, and proportionate to a reasonable benefit / risk ratio.

The compositions of the invention may furthermore comprise any additive or adjuvant conventionally used in the pharmaceutical, dermatological or cosmetic field, compatible with the compound of the avermectin family and the agonist compound of at least one of the retinoic acid receptors. in the presence. Mention may in particular be made of sequestering agents, chelating agents of antioxidants, sunscreens, preservatives, for example DL-alpha-tocopherol, fillers, electrolytes, humectants, dyes, bases or acids which are usual, mineral or perfumes, essential oils, cosmetic active ingredients, moisturizers, vitamins, essential fatty acids, sphingolipids, self-tanning compounds such as DHA, soothing and protective agents for the skin such as allantoin, propenetrating agents, emulsifiers, gelling agents, thickeners, buffering agents, lipophilic excipients, disintegrating agents, soluble agents, compressing agents or a mixture thereof. Of course, those skilled in the art will take care to choose this or these optional additional compounds, and / or their amount, such that the advantageous properties of the composition according to the invention are not, or not substantially impaired.

As preservatives or anti-bacterial agents, there may be mentioned, for example, quaternary ammoniums such as benzalkonium chloride; phenoxyethanol; benzyl alcohol; benzoyl peroxide, dapsone, clindamycin, salicylic acid, diazolidinyl urea; parabens, such as methylparaben, propylparaben or butylparaben; benzoic acid and its sodium or potassium salts such as sodium benzoate; sorbic acid and its sodium or potassium salts such as potassium sorbate; mercurial derivatives such as phenylmercury salts (acetate, borate or nitrate) or thiomersal; or their mixtures.

As humectants, mention may in particular be made of glycerine and sorbitol. As chelating agents, mention may be made, for example, of ethylenediaminetetraacetic acid (EDTA), as well as its derivatives or its salts, dihydroxyethyl glycine, citric acid, tartaric acid or their mixtures.

As propenetrating agents, mention may in particular be made of propylene glycol, dipropylene glycol, propylene glycol dipelargonate, lauroglycol and ethoxydiglycol.

As fats which may be used in the invention, mention may be made, in a nonlimiting manner, of oils, and in particular mineral oils (liquid petroleum jelly), oils of plant origin (avocado oil, soybean oil), animal oils (lanolin), synthetic oils (perhydrosqualene), silicone oils (cyclomethicone) and fluorinated oils (perfluoropolyethers). It is also possible to use fatty alcohols such as cetyl alcohol, fatty acids, waxes and gums, in particular silicone gums, as fatty substances.

Examples of emulsifiers and coemulsifiers that can be used in the invention include, for example, fatty acid and polyethylene glycol esters, such as PEG-100 stearate, PEG-50 stearate and PEG-40 stearate; fatty acid esters of polyol such as glyceryl stearate, sorbitan tristearate and oxyethylenated sorbitan stearates available under the trade names Tween 20 or Tween 60, for example; and their mixtures.

As gelling agents, by way of non-limiting examples, mention may be made of the family of polyacrylamides, such as the mixture Sodium acryloyldimethyltaurate copolymer / isohexadecane / polysorbate 80 sold under the name Simulgel ™ 600 by the company Seppic ™, the polyacrylamide / isoparaffin mixture C13- 14 / laureth-7 as, for example, that sold under the name of Sepigel 305 ™ by the company Seppic ™, the family of acrylic polymers coupled to hydrophobic chains such as the PEG-150 / decyl / SMDI copolymer sold under the name Aculyn 44 ™ (polycondensate comprising at least one element, a polyethylene glycol containing 150 or 180 moles of ethylene oxide, decyl alcohol and methylene bis (4-cyclohexylisocyanate) (SMDI), at 35% by weight in a mixture of propylene glycol (39%) and water (26)), the family of modified starches such as modified potato starch sold under the name Solanace ™ Structure or mixtures thereof.

The preferred gelling agents are derived from the family of polyacrylamides such as Simulgel 600 ™ or Sepigel 305 ™ or mixtures thereof.

The composition may comprise one or more thickeners, which make it possible to obtain an adequate viscosity, selected from the group consisting of polysaccharides, cellulose derivatives and carboxyvinyl polymers of the type Carbopol. These polymers include, but are not limited to Carbopol 934P, Carbopol 71G ^®, Carbopol ^® 971P and Carbopol ^® 974P.

The composition may comprise one or more thickening agents selected from cellulose derivatives. Cellulose derivatives useful as thickeners include, but are not limited to, methylcellulose, ethylcellulose, ethylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose and hydroxyalkylcelluloses such as hydroxyethylcellulose, hydroxymethylcellulose hydroxypropylcellulose and hydroxypropyl methylcellulose, and a combination thereof.

The composition may comprise one or more thickeners selected from polysaccharides. The polysaccharides which may be used as thickening agents include, but are not limited to, xanthan gum, gum tragacanth, carrageenans such as λ-carrageenan, κ-carrageenan or ι-carrageenan, galactomannans such as carob seeds, guar seed meal or tara seed meal, gellan gum, gum arabic, karaya gum, pectins, starch and its derivatives obtained by esterification or etherification, and tamarind, and a combination of these.

The composition may also comprise, as thickeners, a mixture of one or more cellulose derivatives and one or more polysaccharides.

These additives may be present in the composition in a proportion of 0.0001 to 10% by weight relative to the total weight of the composition. The concentration of these active principles and / or additives in the composition may vary according to the nature of said additives and according to the intended mode of administration.

Application

Administration may be oral, topical, ocular, intraocular, intravenous, parenteral, subcutaneous, epicutaneous, intradermal, transdermal, intramuscular, enteral, rectal, intranasal, sublingual, oral, intra-respiratory or nasal inhalation.

When the administration is carried out topically on the skin, the composition may be described as a dermatological composition. The composition intended to be administered topically is more particularly intended for the treatment of skin and mucous membranes. By topical application is meant the application or spreading of the composition according to the invention to the surface of the skin or mucosa. Among these routes of administration, the topical route is particularly preferred.

It is envisaged for topical application compositions in the form of solutions, lotions, gels, ointments, emulsions of liquid or semi-liquid consistency of the milk type, obtained by dispersion of a fatty phase in a aqueous phase (O / W) or conversely (W / O), or powders, soaked swabs, sprays, suspensions or emulsions of soft, semi-liquid or solid consistency of the cream, ointment or microemulsion type , micro-capsules, microparticles or vesicular dispersions of ionic and / or nonionic type. It may also be in the form of microspheres or nanospheres or lipid or polymeric vesicles or polymeric patches and hydrogels allowing controlled release. These compositions are prepared according to the usual methods.

For topical administration, the composition is advantageously in the form of a gel, a lotion or a cream.

A preferred composition of the invention is a topical composition comprising between 0.001 and 10% by weight of the compound of the avermectin family and between 0.001 and 5% by weight of the agonist compound of at least one of the retinoic acid receptors by relative to the total weight of the composition.

Preferably, the compound of the avermectin family represents between 0.001 and 5, between 0.1 and 2, and even more preferably 1% by weight, relative to the total weight of the composition. Preferably, the agonist compound of the acid receptors retinoic acid represents between 0.001 and 10%, preferably between 0.001 and 5%, even more preferentially between 0.1 and 1%, and even more preferably 0.1 or 0.3% by weight, relative to the total weight. of the composition. According to a preferred embodiment, the composition according to the invention comprises 1% by weight relative to the total weight of the composition of a compound of the avermectin family, preferably ivermectin, and 0.1% or 0.3% by weight relative to the total weight of the composition of an agonist compound of at least one of the retinoic acid receptors, preferably adapalene.

According to another preferred embodiment, the composition according to the invention comprises 1% by weight relative to the total weight of the composition of a compound of the avermectin family, preferably ivermectin, and between 0.001 and 1%, preferably 0.005% by weight relative to the total weight of the composition of an agonist compound of at least one of the retinoic acid receptors, preferably the compound 3 "-tertiobutyl-4 '- ( 2-hydroxyethoxy) -4'-pyrrolidin-1-yl [1,1,3 ', Γ'] -terphenyl-4-carboxylic acid.

The present invention also relates to a kit comprising (a) a first composition comprising a compound of the avermectin family, preferably ivermectin, and (b) a second composition, distinct from the first, comprising an agonist compound of least one of the retinoic acid receptors, preferably adapalene.

In a particular embodiment, the kit as defined above is used in the treatment of acne, preferably concomitantly or separately.

In another particular embodiment, the kit is intended for topical application.

Preferably, the composition (a) of the kit comprises between 0.001 and 10%, preferably between 0.1 and 2%, and even more preferably 1% by weight of ivermectin relative to the total weight of the composition. We can cite for example the formulation marketed by Galderma under the name Soolantra comprising 1% by weight of ivermectin.

Preferably, the composition (b) of the kit comprises between 0.001 and 10, preferably between 0.001% and 5%, more preferably between 0.1 and 1, and even more preferably 0, 1% or 0.3% by weight of adapalene with respect to the total weight of the composition. There may be mentioned for example the formulation range marketed by Galderma under the name Differin ^® including Differin ^® 0.3% and Differin ^® 0, 1% respectively comprising 0.3% and 0.1% by weight of adapalene.

In the context of the invention, the terms "treatment" or "treating" refer to an improvement, prophylaxis, or reversal of a disease or disorder, or at least one symptom that can be discerned from that -this. These terms also encompass an improvement, prophylaxis, or inversion of at least one measurable physical parameter associated with the disease or disorder being treated, which is not necessarily discernible in or by the subject being treated. The terms "treatment" or "treating" also refer to the inhibition or slowing down of the progression of a disease or disorder, physically, for example, the stabilization of a discernible symptom, physiologically, e.g. a physical parameter, or both. These terms further designate the delay of the onset of a disease or disorder.

In some embodiments, compounds of interest are administered as a preventive measure. In the present context, this preventive measure refers to a reduction in the risk of acquiring a specified disease or disorder but also a reduction, inhibition or slowing down of the onset of symptoms related to this disease, which is acne. Typical symptoms of acne are, for example, open and / or closed comedones, papules, pustules, nodules and cysts appearing mainly on the face, neck and thorax. the cutaneous regions with the largest number of sebaceous glands.

In the context of the invention, the term "treatment of acne", the treatment of acne including in its various forms. Acne treatment includes acne conglobata, keloid acne, drug acne, recurrent miliary acne, necrotic acne, neonatal acne, premenstrual acne, professional acne, senile acne, solar acne , acne inversa and common acne. For the purposes of the present invention, the term "patient" means any mammal, and more particularly human beings, men or women, children and adolescents.

The actual amount of the compound of the avermectin family and the agonist compound of at least one of the retinoic acid receptors and optionally other additives to be used according to the invention depends on the desired therapeutic or cosmetic effect. , and can therefore vary to a large extent. Those skilled in the art, in particular the physician can easily, on the basis of his general knowledge determine the appropriate amounts. Thus, and according to a preferred embodiment, the pharmaceutical composition (s) are (are) administered 1 to 2 times / day. Preferably, the treatment may have a duration ranging from 1 week to 6 months, renewable, and preferably from 2 weeks to 4 months.

The courses can be renewed in cycle with or without rest period.

In the context of the invention, the term "effective therapeutic dose" means the therapeutic dose which prevents, eliminates or reduces the deleterious effects of acne treated in the patient. It is understood that the dose administered may be adapted by those skilled in the art depending on the patient, the type of acne, the mode of administration, etc.

The following examples illustrate the invention without limiting its scope.

EXAMPLES

Example 1 Impact on the Expression of Inflammatory Cytokines Material and Method

Overexpression of inflammatory cytokines has been demonstrated in patients with acne. Indeed, the study of the team of Sugisaki et al (J. Dermatol Sci. 2009; 55 (l): 47-52) demonstrated an increase in the expression of interferon gamma, interleukin 12p40 and IL8 by peripheral blood mononuclear cells from patients with acne. Similarly, the team of Kistowska et al, has demonstrated the production of several inflammatory cytokines IL-Ιβ, IL-6, TNFα, and IL-8 by monocytes exposed to the bacterium Propionibacterium acnes whose role in the pathology of acne is recognized (Kistowska et al., J Invest Dermatol., 2014; 134 (3): 677-85). Therefore, the expression of some of these cytokines with ivermectin alone, with the retinoic acid receptor agonist alone and with the combination of ivermectin with a retinoic acid receptor agonist was measured .

Specifically, peripheral blood mononuclear cells were incubated for 24 hours in 96-well plates lined with an anti-CD3 antibody in order to activate them and induce the secretion of inflammatory cytokines, in the presence or absence of the various active agents and the combination to be tested.

After recovery of the supernatants, the production of tumor necrosis factor (TNFα), interleukin 12p40 (IL12p40) and interferon gamma (IFNy) was quantified using an immunoassay. Results

The results are shown in the Figures. These in vitro results show that the production of TNFα, IL12p40 and IFNγ is significantly reduced by the combination of ivermectin and a retinoic acid receptor agonist, in contrast to is observed with ivermectin or retinoic acid receptor agonist alone.

These results therefore make it possible to demonstrate an improved effect of the combination of ivermectin and an agonist with retinoic acid receptors to reduce the production of certain inflammatory cytokines observed in patients suffering from acne. More specifically, these in vitro results have made it possible to demonstrate a synergistic effect of the combination of ivermectin and a RAR receptor agonist compound for the treatment and / or prevention of acne.

Example 2: Comparative clinical study

A comparative study was conducted in patients with acne. The patients initially received a first treatment (Treatment A) with topical or oral retinoids, in combination with other active ingredients commonly used to improve the efficacy or tolerance of retinoids. These same patients then received a second treatment (Treatment B) based on ivermectin and were followed over several months.

The satisfaction score shown in Table 1 below is obtained for each treatment and is determined on a scale of 0 to 5.

Table 1: Satisfaction Score

SCORE MEANING

0 Absolutely not satisfied

1 Lowly satisfied 2 Moderately satisfied

3 Satisfied

4 Very satisfied

5 Extremely satisfied

The active ingredients used and the administration regimen of each treatment (mode of administration and duration of treatment) as well as the patient satisfaction score obtained for each treatment are illustrated in Table 2 below.

Treatment A corresponds in particular to the use of products comprising one or more retinoids currently marketed, sold with or without a prescription and very commonly recommended by dermatologists for the treatment of acne. By way of example, mention may be made of: Differin 0.3% ^® , Epiduo ^® , Metrogel ^® and Epiduo forte ^® marketed by Galderma Laboratories, Accutane ^® by Roche Laboratories and Ziana ^® by MediCis Laboratories.

The retinoids present in these products and used in the patients followed are in particular adapalene, retinol, tazarotene, tretinoin and isotretinoin. The anti-bacterial agents used in combination with these retinoids include benzoyl peroxide, dapsone, clindamycin phosphate and salicylic acid.

Table 2:

Patient Treatment (Ingredients) Administration Rate Score Observations

Application on the whole

A: 0.05% retinol, peroxide

face every day in bed 0 Abandoned benzoyl 10%

during 6 months.

1

B: Ivermectin 1%, Application to all

Maintained in the 0.1% adapalene, peroxide face every day at 5

benzoyl time 0.1% for 2 months.

A: 0.05% retinol, peroxide

Application on the whole

benzoyl 2.5%, acid 0 Not tolerated face every day at bedtime.

salicylic 0.5%

2

B: Ivermectin 1%, Application to all

Maintained in the adapalene 0.1%, peroxide face every day at 4

2.5% benzoyl time for 2 months.

A: Application Phosphate on the whole of

clindamycin 1.2%, face every day at bedtime at very little

3 1

0.025% tretinoin, with the exception of dapsone of effectiveness adapalene 0.1%, peroxide applied throughout 2.5% benzoyl, dapsone face every day in the morning,

5% for 14 months.

B: Ivermectin 1%, Application to all

Maintained in the adapalene 0.3%, peroxide face every day at 4

2.5% benzoyl time for 6 weeks.

Application on the whole

Irritation

A: adapalene 0.3% face every day at the couch 1

significant for 10 months.

Application on the whole

B: Ivermectin 1%, Maintained in the face every day at bedtime 4

adapalene 0.3% time for 2 weeks.

Application on the whole

A: tretinoin 0.05% face every day at bed 0 Abandoned for 6 months.

Application on the whole

B: Ivermectin 1%, Maintained in the face every day at bedtime 5

tretinoin 0.05% time for 1 month.

Application on the whole

A: adapalene 0.3%,

face every day at the bench 0 Abandoned benzoyl peroxide 2.5%

during 6 months.

B: Ivermectin 1%, Application to all

Maintained in the adapalene 0.3%, peroxide face every day at 5

2.5% benzoyl time for 2 months.

Application on the whole

A: tretinoin 0.05% face every day at bed 0 Abandoned for several years.

B: Ivermectin 1%, Application to all

Maintained in the adapalene 0.3%, peroxide face every day at 5

2.5% benzoyl time for a few weeks.

Application on the whole

A: adapalene 0.3%,

face every day at bedtime

0.05% tretinoin, tazarotene

for several years at 1 Abandoned 0.1%, oral isotretinoin 1- except for isotretinoin

200 mg / kg

administered orally.

Application on the whole

B: Ivermectin 1%, Maintained in the face every day at bedtime 5

adapalene 0.3% time for a few weeks

A: adapalene 0.3%, Application on the whole

0 Not tolerated benzoyl peroxide 2.5% face every day at the couch.

B: Ivermectin 1%, Application to all

Maintained in the adapalene 0.3%, peroxide face every day at 5

2.5% benzoyl time for a few weeks.

Application on the whole

A: adapalene 0.3% 0 Not tolerated face every day at bedtime.

Application on the whole

B: Ivermectin 1%, Maintained in the face every day at bedtime 5

adapalene 0.3% time for a few weeks.

Application on the whole

face every day at bedtime

A: 5% dapsone, adapalene for one week, to

0 Not tolerated 0.3%, retinol 0.05% except dapsone which is

applied daily to

morning for a week.

Application on the whole

B: Ivermectin 1%, retinol Maintained in the face every day at bedtime 5

0.05% time for 2 weeks.

A: retinol 0.05%, phosphate Application over all 0 Not tolerated clindamycin 1.2%, face every day at bedtime

0.025% tretinoin,

metronidazole 1%

Application on the whole

B: ivermectin 1%, retinol Maintained in the face every day at bedtime 4

0.05% time

during 3 months.

Application on the whole

A: adapalene 0.1%, face every day at the couch,

benzoyl peroxide 2.5%, with the exception of dapsone which 0 Not tolerated dapsone 5% is applied daily to

13

morning.

B: Ivermectin 1%, Application to all

Maintained in the 0.1% adapalene, peroxide face every day at 5

2.5% benzoyl time for 1 month.

A: retinol 0.05%, adapalene Application across the

0 Not tolerated 0.3% face every day at bedtime.

14 B: Ivermectin 1%, Application throughout

Maintained in the 0.1% adapalene, peroxide face every day at 5

2.5% benzoyl time for 1 month.

A: tretinoin 0.05%, retinol Application throughout

0 Not tolerated 0.05% face every day at bedtime.

15 Application on the whole of

B: Ivermectin 1%, retinol Maintained in the face every day at bedtime 5

0.05% time

during 2 months.

Application on the whole

A: retinol 0.05% face every day at bed 0 Abandoned for several years.

16

B: Ivermectin 1%, Application to all

Maintained in the 0.1% adapalene, peroxide face every day at 5

2.5% benzoyl time for 1 month.

The results above demonstrate the beneficial effects of ivermectin in retinoid-based acne treatments.

These beneficial effects have been observed in the tolerance of retinoids, including a significant decrease in skin irritation that is often associated with the use of retinoids.

These beneficial effects have also been observed in the efficacy of acne treatment with a greater decrease in pimples and redness achieved with retinoid-based treatment including ivermectin compared to retinoid-based therapy. not including ivermectin.

Claims

A composition comprising a compound of the avermectin family and an agonist compound of at least one of the retinoic acid receptors for use in the treatment of acne.

2. Composition for its use according to claim 1, characterized in that the compound of the avermectin family is ivermectin.

3. Composition for use according to claim 1 or 2, characterized in that the agonist compound of at least one of the retinoic acid receptors is of formula (II):

in which :

Ar "represents a group chosen from the following groups of formulas (a) to (f):

R ₆ "and R 7" being as defined below,

R ₃ "represents a hydrogen atom, a halogen atom, an alkyl group of 1 to 6 carbon atoms or a group -O-R ₄ ", R ₄ "represents a hydrogen atom, an alkyl group of 1 to 6 carbon atoms or a group -CO-R ₉ ",

I

R1 2 "

in which Ru "and R12", identical or different, represent a hydrogen atom, an alkyl group of 1 to 6 carbon atoms, a mono or polyhydroxyalkyl group, an optionally substituted aryl group or an amino acid or peptide residue or sugar or taken together form a heterocycle,

m is an integer equal to 0 or 1,

n is an integer inclusive of between 1 and 6,

p is an integer inclusive of between 1 and 6,

X represents O or S (O) q,

Y represents O, S (O) q or NR ₇ ",

q is an integer inclusive between 0 and 2,

R7 "represents a hydrogen atom, an alkyl group of 1 to 6 carbon atoms or a group -CO-R9",

R ₉ "represents an alkyl group of 1 to 6 carbon atoms,

Rio "represents a hydrogen atom, an alkyl group, an alkenyl group, a mono or polyhydroxyalkyl group whose hydroxyls are optionally protected in the form of methoxy, ethoxy or acetoxy or acetonide, an optionally substituted aryl or aralkyl group or a sugar residue or an amino acid or peptide residue, and the optical and geometric isomers of said compounds of formula (II) as well as their pharmaceutically acceptable salts.

4. Composition for its use according to claim 3, characterized in that the agonist compound of at least one of the retinoic acid receptors is adapalene.

5. Composition for use according to claim 1 or 2, characterized in that the agonist compound of at least one of the retinoic acid receptors is of formula (I):

(I)

in which :

Y represents two hydrogen atoms or a heteroatom, preferably oxygen or sulfur;

Ar represents a 1,4-phenyl, 2,5-pyridyl, 5,2-pyridyl or 2,5-thiophenyl ring; X represents an oxygen atom optionally substituted with an alkyl or alkylamine group of 1 to 4 carbon atoms or a single bond CC;

A represents a hydrogen atom or the following formula (IA):

in which :

Q represents an oxygen atom or an -NH- bond;

6. Composition for its use according to Claim 5, characterized in that the agonist compound of at least one of the retinoic acid receptors is 3'-tert-butyl-4 '- (2-hydroxyethoxy) acid. 4 '' -Pyrrolidin-1-yl [1,1 ', 3', 1 "] -terphenyl-4-carboxylic acid.

7. Composition for its use according to claim 1 or 2, characterized in that the agonist compound of at least one of the retinoic acid receptors is of formula (III):

in which : Ri "'represents a hydrogen atom, an alkyl group of 1 to 18 carbon atoms, an alkenyl group of 1 to 18 carbon atoms, an alkynyl group of 1 to 18 carbon atoms, an aryl group, heteroaryl, cycloalkyl group , or heterocycloalkyl.

8. Composition for its use according to claim 7, characterized in that the agonist compound of at least one of the retinoic acid receptors is taarotene.

9. Composition for use according to claim 1 or 2, characterized in that the agonist compound of at least one of the retinoic acid receptors is of formula (IVA) or (IVB):

in which :

R 1 "" represents a group -CH ₂ OH, -CHO, or a group C0 ₂ R ₂ "" in which R ₂ "" represents a hydrogen atom, an alkyl group of 1 to 18 carbon atoms, a group alkenyl of 1 to 18 carbon atoms, an alkynyl group of 1 to 18 carbon atoms, an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group.

10. Composition for use according to claim 9, characterized in that the agonist compound of at least one of the retinoic acid receptors is retinoic acid, retinol, retinal, etretinate or acitretin.

11. Composition for its use according to claim 1 or 2, characterized in that the agonist compound of at least one of the retinoic acid receptors is bexarotene.

12. Composition for its use according to any one of claims 1 to 11, characterized in that the compound of the avermectin family represents between 0.001 and 10, preferably between 0.001 and 5, still more preferably between 0.1 and 2% and even more preferably 1% by weight, relative to the total weight of the composition.

13. Composition for use according to any one of the claims

1 to 12, characterized in that the agonist compound of at least one of the retinoic acid receptors represents between 0.001 and 10, preferably between 0.001 and 5, more preferentially between 0.1 and 1% and even more preferentially 0, 1 or 0.3% by weight, relative to the total weight of the composition.

14. Composition for use according to any one of claims 1 to 13, characterized in that the compound of the avermectin family represents 1% by weight and the agonist compound of at least one of the retinoic acid receptors represents 0.1 or 0.3% by weight, relative to the total weight of the composition.

15. Composition for its use according to any one of claims 1 to 14, characterized in that it is intended for topical administration.

16. Composition for use according to any one of claims 1 to 15, characterized in that it is in the form of a gel, a lotion or a cream.

Kit comprising (a) a first composition comprising a compound of the avermectin family, preferably ivermectin, and (b) a second composition, distinct from the first, comprising an agonist compound of at least one of the retinoic acid, preferably adapalene.

18. Kit according to claim 17 for its use in the treatment of acne.

19. A composition, preferably in topical form, comprising ivermectin and adapalene in a physiologically acceptable medium.