JP2012184258A - Composition containing at least one derivative of naphthoic acid and at least one polyurethane polymer type compound or derivative thereof, preparation method, and use of the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To promote the local penetration of an insoluble compound dispersed or suspended in a pharmaceutical composition such as a derivative of naphthoic acid.SOLUTION: This is a stable composition lower in irritant property than conventional art, which contains the at least one dispersed derivative of naphthoic acid and the polyurethane polymer type compound or its derivative. It is the composition that can promote the local penetration of the activator in dispersed form.

Description

  The present invention relates to a composition for topical application, in particular for the treatment of acne, a method for the preparation of such a composition and its use as a cosmetic or pharmaceutical product.

Acne is a common multi-element lesion that attacks skin rich in sebaceous glands (face, shoulders, arms). The most common form of skin disease. The following five lesion elements play a critical role in acne formation:
1． Genetic predisposition;
2． Excessive production of sebum (seborrhea);
3． Androgen;
Four. Follicular keratosis (comedogenesis);
Five. Bacterial colonization and inflammatory factors.

  There are several forms of acne, an element common to all is the attack of the pilosebaceous vesicles. In particular, congenital acne, nape keloid acne, medication-related acne, recurrent military acne, necrotic acne, newborn Can include acne, premenstrual acne, occupational acne, rosacea, senile acne, solar acne and simple acne .

Simple acne, also known as polymorphic juvenile acne, is the most common. This acne involves the following four steps, but not all steps are required:
-Step 1 corresponds to a large number of open and / or closed comedones and comedone acne characterized by microcysts;
-Step 2, ie papulopustular acne, shows mild to moderate severity. This acne is characterized by open and / or closed comedones, small cysts, and red papules and pimples. This acne mainly affects the face and leaves some wounds;
-Step 3, ie papulocomedonic acne, is more severe and spreads to the back, chest and shoulders. This acne is accompanied by many wounds;
-Step 4, ie nodulocystic acne, involves many wounds. This acne exhibits a large amount of crimson pimples with small aneurysms and pain.

The various forms of acne described above are activators such as anti-seborrheic and anti-infectives such as benzoyl peroxide (particularly the product Eclaran® marketed by Pierre Fabre), tretinoin Treatment with retinoids such as (especially the product Retacnyl® sold by Garderma) or isotretinoin (product Roaccutane® sold by Laboratoires Roche), or naphthoic acid derivatives Can do. In particular, naphthoic acid, such as 6- [3- (1-adamantyl) -4-methoxyphenyl] -2-naphthoic acid (product Differine® sold by Galderma), commonly known as adapalene Derivatives are widely disclosed and recognized as active agents that have similar effects as tretinoin for the treatment of acne. Adapalene also has the utility of producing few side effects such as inflammatory phenomena, skin dryness or hypersensitivity compared to the other activators described above, which is an indication of product selection. .
Needless to say, compositions have been developed to increase the local penetration of certain activators by including polyurethane polymer type compounds or derivatives thereof in the composition (EP 0 299 758). Specification). The product Avita (R) sold by Bertek Pharmaceuticals Inc. is one example. This product was dissolved in a cream or gel type composition comprising a polyurethane polymer (type 2 polyol prepolymer sold by Bertek Pharmaceuticals) to limit desquamation, irritation and skin dryness, Contains 0.025% by weight of tretinoin relative to the total weight of the composition.
US 2002/01555180 discloses a composition comprising an extract of Saw Palmetto Berries (SPBE) as an activator, in which adapalene is active The agent SPBE has been used as an agent to improve penetration into vesicles and sebaceous glands.

EP 0 299 758 US Patent Application Publication No. US2002 / 01555180

  Applicants have surprisingly found that polyurethane polymers that are known to increase the local penetration of only certain dissolved activators (activators that are free of crystals when viewed under a microscope). Have also demonstrated that local penetration of insoluble compounds dispersed or suspended in pharmaceutical compositions, particularly insoluble compounds such as naphthoic acid derivatives, can also be enhanced.

  However, in the prior art, it has not been suggested that the anti-stimulant effect of polyurethane polymers can be obtained using dispersed and insoluble forms of the activator.

  In view of the foregoing, the problem that the present invention proposes to solve is stable and less irritating than the prior art comprising at least one naphthoic acid derivative in a dispersed form and a polyurethane polymer type compound or derivative thereof. And a method for preparing such a composition, which should promote local penetration of the dispersed form of the activator.

  Therefore, a first aspect of the present invention comprises at least one naphthoic acid derivative and at least one polyurethane polymer type compound or derivative thereof in a physiologically acceptable medium, wherein the naphthoic acid derivative comprises the composition A composition for topical application, in a dispersed form in the product, which does not contain any extract of soap palm berry.

  According to the present invention, the term “dispersed activator” means an activator in the form of solid particles suspended in a vehicle. Such particles are especially larger than 10 μm.

  A second aspect of the invention is a step of mixing a physiologically acceptable vehicle comprising at least one naphthoic acid derivative with at least one polyurethane polymer type compound or derivative thereof, wherein the naphthoic acid derivative is A method for preparing a composition for topical application comprising the step of being in a dispersed form in the composition.

Finally, a third aspect of the present invention is a method for treating and / or preventing skin diseases associated with keratosis related to cell differentiation and proliferation, particularly for acne acne, simple acne, Procomedonic acne, cystic acne, polymorphic acne, acne rosacea, congenital acne, senile acne, secondary acne such as solar radiation acne, medication related acne Use of said composition for the preparation of a pharmaceutical composition for the treatment of acne or occupational acne.
Good chemical properties when the composition comprises at least one naphthoic acid derivative (in dispersed form in the composition) and at least one polyurethane polymer type compound or derivative thereof in a physiologically acceptable medium. Shows stability, high anti-acne effectiveness and good tolerance.

The invention will be more clearly understood by reading the following non-limiting description, which is described with reference to the accompanying drawings (see below).
-Figures 1 to 4 show the inflammatory effect of reference gel containing 0.1% adapalene on BALB / c mouse ear skin after repeated topical application over 6 days, with polyurethane polymer at various concentrations Figure 3 shows the results of a test intended to compare the inflammatory effect of three 0.1% adapalene formulations in gel form with the inflammatory effect of placebo.
-Figures 5 to 8 are reference gels containing 0.1% adapalene, and various concentrations on the dorsal skin of RHINO FVB / N RJ-hrrh mice (Rhino) after repeated topical application over 18 days 2 shows the results of a test intended to evaluate the comedone activity of two 0.1% adapalene formulations in gel form with a polyurethane polymer and placebo.

Figure 1 shows the average thickness kinetics of mouse ears from day 2 to day 19 for the following various test samples: • Acetone (curve (1A)) • Placebo reference gel (curve ( 1B)) • Placebo of Example 2 (1% PP-2) (curve (1C)) • Placebo of Example 3 (3% PP-2) (curve (1D)) • Placebo of Example 4 (10% PP-2) (curve (1E)) Figure 2 shows the average thickness kinetics of mouse ears from day 2 to day 19 for the following various test samples: Acetone (curve (2A)) Acetone + 0.1% adapalene (Curve (2B)) ・ Placebo reference gel (Curve (2C)) ・ Reference gel containing 0.1% adapalene (Curve (2D)) ・ Placebo of Example 2 (1% PP-2) (Curve (2E)) -Example 2 (1% PP-2) (curve (2F)) Figure 3 shows the average thickness kinetics of mouse ears from day 2 to day 19 for the following various test samples: • Acetone (curve (3A)) • Acetone + 0.1% adapalene (Curve (3B)) ・ Placebo reference gel (Curve (3C)) ・ Reference gel containing 0.1% adapalene (Curve (3D)) ・ Placebo of Example 3 (3% PP-2) (Curve (3E)) -Example 3 (3% PP-2) (curve (3F)) Figure 4 shows the average thickness kinetics of mouse ears from day 2 to day 19 for the following various test samples: • Acetone (curve (4A)) • Acetone + 0.1% adapalene (Curve (4B)) ・ Placebo reference gel (Curve (4C)) ・ Reference gel containing 0.1% adapalene (Curve (4D)) ・ Placebo of Example 4 (10% PP-2) (Curve (4E)) -Example 4 (10% PP-2) (curve (4F)) FIG. 5 shows the results of the area under the curve for acceptance evaluation from day 1 to day 19 for the following various test samples: Acetone (control vehicle) (curve (5A)) 0.1% adapalene (3% PP-2) formulation of Example 3 (control vehicle) (curve (5B))-acetone + 0.01% (m / m) 2- (5,5,8,8-tetra Methyl-5,6,7,8-tetrahydronaphthalen-2-yl) benzo [b] thiophene-6-carboxylic acid (positive control) (curve (5C)), acetone + 0.1% (m / m) adapalene ( Curve (5D)) Reference gel containing 0.1% adapalene (Curve (5E)) Formulation of Example 2 (1% PP-2) (Curve (5F)) Formulation of Example 3 (3% PP-2) (curve (5G)) FIG. 6 shows the results of the area under the curve (AUC) of transepidermal water loss (TWL) after 18 days of topical treatment for the following various test samples: Acetone (control vehicle) (curve (6A ))-Formulation of 3% PP-2 of Example 3 without 0.1% adapalene (control vehicle) (curve (6B))-Acetone + 0.01% (m / m) 2- (5, 5,8,8-Tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) benzo [b] thiophene-6-carboxylic acid (positive control) (curve (6C)), acetone + 0.1% (m / m) adapalene (curve (6D)) • Reference gel containing 0.1% adapalene (curve (6E)) • Formulation of Example 2 (1% PP-2) (curve (6F)) • Examples Formulation 3 (3% PP-2) (Curve (6G)) Figure 7 shows the results of measuring the thickness of the epidermis after 18 days of topical treatment for the following various test samples: • Acetone (control vehicle) (curve (7A)) • 0.1% adapalene included (3% PP-2) formulation of Example 3 (control vehicle) (curve (7B)) acetone + 0.01% (m / m) 2- (5,5,8,8-tetramethyl- 5,6,7,8-Tetrahydronaphthalen-2-yl) benzo [b] thiophene-6-carboxylic acid (positive control) (curve (7C)), acetone + 0.1% (m / m) adapalene (curve ( 7D)) • Reference gel with 0.1% adapalene (curve (7E)) • Formulation of Example 2 (1% PP-2) (Curve (7F)) • Formulation of Example 3 (3% PP- 2) (Curve (7G)) FIG. 8 shows the results of counting the number of comedones per centimeter (cm) of the back of Rhino mice after 18 days of topical treatment for the following various test samples: Acetone (control vehicle) ( Curve (8A)) Formulation of 3% PP-2 of Example 3 without 0.1% adapalene (control vehicle) (Curve (8B)) Acetone + 0.01% (m / m) 2 (5,5,8,8-Tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) benzo [b] thiophene-6-carboxylic acid (positive control) (curve (8C)) acetone +0 .1% (m / m) adapalene (curve (8D)) Reference gel containing 0.1% adapalene (curve (8E)) Formulation of Example 2 (1% PP-2) (curve (8F)) -Formulation of Example 3 (3% PP-2) (curve (8G))

  The composition according to the invention comprises at least one naphthoic acid derivative and at least one polyurethane polymer type compound or derivative thereof.

  Naphthoic acid is a compound of the following formula:

  The term “naphthoic acid derivative” means a compound of the following formula (I):

Wherein R is a hydrogen atom, a hydroxyl group, a branched or unbranched alkyl group containing 1 to 4 carbon atoms, an alkoxy group containing 1 to 10 carbon atoms, or a saturated or unsaturated group. Represents an alicyclic group)

  The term “straight or branched alkyl group containing 1 to 4 carbon atoms” preferably means methyl, ethyl, propyl and butyl groups.

  The term “alkoxy group containing 1 to 10 carbon atoms” preferably means a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a hexyloxy group and a decyloxy group.

  The term “alicyclic group” preferably means a monocyclic or polycyclic group such as a 1-methyl-cyclohexyl group or a 1-adamantyl group.

  Naphthoic acid derivatives that can be included in the composition according to the invention include 6- [3- (1-adamantyl) -4-methoxyphenyl] -2-naphthoic acid (adapalene), 6- [3- (1-adamantyl)- 4-hydroxyphenyl] -2-naphthoic acid, 6- [3- (1-adamantyl) -4-decyloxyphenyl] -2-naphthoic acid, and 6- [3- (1-adamantyl) -4-hexyloxy Phenyl] -2-naphthoic acid is advantageously selected.

  The naphthoic acid derivatives described above are generally in a form dispersed in the composition according to the present invention. Therefore, the insoluble naphthoic acid derivative is uniformly dispersed in the composition according to the invention.

  In the composition according to the present invention, the naphthoic acid derivative has a composition of not more than 10% by weight, preferably between 0.001% and 10% by weight, based on the total weight of the composition. Preferentially between 0.01 wt% and 5 wt%, more preferentially 0.05 wt% to 2 wt%, most preferentially 0.1 wt% to 0.3 wt%, relative to the total weight of the object Used at concentrations between. Throughout this specification, unless specified otherwise, when a range of concentrations is given, the upper and lower limits of the range are included.

  Advantageously, the naphthoic acid derivative used in the composition according to the invention is adapalene. The concentration of adapalene used in the composition according to the invention is between 0.01% and 0.5%, preferentially 0.03%, more preferentially between 0.1% and 0.3%, in particular 0.1% and 0.3%.

  Preferably, the naphthoic acid derivative is the only activator present in the composition according to the invention. Preferentially, adapalene is the only activator of the composition.

  The composition according to the invention also comprises a polyurethane polymer type compound or a derivative thereof. The term “polyurethane polymer” means a polyalkylene glycol disclosed in EP 0 299 758 and sold by Bertek Pharmaceuticals Inc. The polyurethane polymers according to the invention have the characteristic property of imparting advantageous properties for cosmetic and pharmaceutical applications. Specifically, polyurethane polymers, due to their high molecular weight, significantly affect drug deposition on and within the skin. Furthermore, the polyurethane polymer preferentially remains in the upper layer of the skin.

  As polyurethane polymers that can be included in the composition according to the invention, mention may be made of polyurethane polymers of the general formula:

(Where
R is CH ₃ or H;
n is an integer selected such that the polyurethane polymer has a molecular weight of at least 1000; n is advantageously between 5 and 55;
m is a number between 1 and 6)

  Non-limiting examples of polyurethane polymers that can be included in the composition according to the invention include polyol prepolymer-2 (PP-2) and polyol prepolymer-14 (PP-14) (poly [oxy (methyl-1,2 -Ethanediyl)], α-hydro-ω-hydroxy-, referred to as a polymer with 1,1′-methylenebis [4-isocyanatocyclohexane]), and polyol prepolymer-15 (poly (oxy-1, 2-ethanediyl), α-hydro-ω-hydroxy-, referred to as a polymer with 1,1′-methylenebis [4-isocyanatocyclohexane]) may be mentioned alone or as a mixture. These three polymers are sold by Bertek Pharmaceuticals, with m ranging from 1 to 4, n = 12 for PP-2, n = 51 for PP-14 and n for PP-15, respectively. This corresponds to the above general formula where = 8.

  Polyol prepolymer-2 (PP-2) is advantageously selected as the polyurethane polymer that can be included in the composition according to the invention.

  In the composition according to the invention, the polyurethane polymer type compound or derivative thereof is not more than 20% by weight, preferably between 0.5% and 20% by weight, more preferentially relative to the total weight of the composition. 1% to 10% by weight, in particular at a concentration of 1%, 3%, 7% or 10% by weight, preferentially at a concentration of 7% or less. Such low concentrations of polyurethane polymer can reduce toxicity and reduce the general irritation of the composition according to the invention.

  The presence of the polyurethane polymer in the composition according to the invention deposited in the stratum corneum allows the formation of a reservoir in the upper layer of the skin. This reservoir allows the naphthoic acid derivative to be released gradually into deeper layers of the epidermis. In addition, it has surprisingly been found that the polyurethane polymer comprised in the composition according to the invention has anti-inflammatory and moisturizing properties which are particularly useful in the case of adapalene formulations. This is advantageous because naphthoic acid derivatives are irritating and have a dehydrating effect on the skin. Therefore, in order to be able to increase the dosage, it is useful to reduce the induced irritation.

  The composition of the present invention can be used in any pharmaceutical form normally used for topical application, especially in aqueous, water-alcohol or oil dispersions, lotion type dispersions, aqueous, anhydrous or fat-soluble gels, aqueous phases. (O / W) or vice versa (W / O) liquid or semi-liquid emulsion type emulsions obtained by dispersing the fatty phase, or soft, semi-liquid or solid consistency Cream, cream-gel or pomade type suspensions or emulsions, or alternatively, microemulsions, microcapsules, microparticles or ionic and / or non-ionic types of vesicular dispersions It can be in the form.

  Preferably, the composition according to the invention is in the form of a lotion, cream-gel, gel or cream.

  The person skilled in the art will carefully select the excipients constituting the composition according to the invention, as a function of the desired formulation form and to note the advantageous properties of the composition according to the invention.

The composition according to the invention may also comprise in particular one or more of the following components:
a) one or more gelling or suspending agents,
b) one or more chelating agents,
c) one or more wetting agents,
d) one or more preservatives.

  Non-limiting examples of gelling or suspending agents that may be included in the composition according to the invention include carbomers sold under the generic name Carbopol®, the name Ultrez 10® by BF Goodrich, or “Electrolyte-non-sensitive” carbomers sold by Carbopol ETD®, polysaccharides (non-limiting examples include xanthan gum, guar gum, chitosan such as Keltrol T® sold by Kelco) , Its derivatives such as cellulose and hydroxyethylcellulose, in particular the product sold under the name Natrosol HHX 250® by the company Aqualon), and acrylamide and acrylamino-2-methyl as a 40% dispersion in isohexadecane Copolymer with sodium propane sulfate and polysorbate 80 sold under the name Simulgel 600® by SEPPIC It can gel.

  Preferred gelling agents that may be mentioned are the carbomers sold especially under the names Carbopol 974P NF and Carbopol 980 NF.

  Non-limiting examples of chelating agents that may be mentioned include ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), ethylenediaminebis (O-hydroxyphenylacetic acid) (EDBHA), hydroxy-2-ethylenediaminetriacetic acid (HEDTA), ethylenediaminebis (O-hydroxy-p-methylphenyl) acetic acid (EDBHMA) and ethylenediaminebis (5-carboxy-2-hydroxyphenyl) acetic acid (EDBCHA).

  A preferred chelating agent that may be mentioned is ethylenediaminetriacetic acid (EDTA), which is sold in particular under the name Titriples III®.

  Propylene glycol, dipropylene glycol, propylene glycol dipelargonate, lauroglycol and ethoxydiglycol, alone or in mixture, as a wetting agent that has the role of reducing surface tension and allowing more liquid to spread As such, it is used preferentially without being limited to the above-mentioned compounds.

  A preferred wetting agent that may be mentioned is propylene glycol.

  Non-limiting examples that may be mentioned as preservatives are benzoic acid and its derivatives with benzyl alcohol, benzalkonium chloride, sodium benzoate, bronopol, chlorhexidine, chlorocresol and its derivatives, alone or as a mixture Contains parabens such as alcohol, pentyl alcohol, phenoxyethanol, sodium sorbate, diazolidinyl urea, propylparaben or methylparaben.

  Preferred preservatives that may be mentioned include parabens and phenoxyethanol or benzalkonium chloride, alone or as a mixture.

  The composition according to the invention may comprise one or more emulsifiers.

  Surfactant emulsifiers are amphoteric compounds that contain a hydrophobic part that has an affinity for oil and a hydrophilic part that has an affinity for water, thereby creating a two-phase linkage. Ionic or nonionic emulsifiers thus stabilize the oil / water emulsion by adsorbing at the interface and forming a layered liquid crystal layer.

  The emulsifying power of a nonionic surfactant is closely related to the polarity of the molecule. This polarity is defined by HLB (hydrophilic / lipophilic balance).

  A high HLB means that the hydrophilic part is dominant, conversely, a low HLB means that the lipophilic part is dominant. For example, an HLB value greater than 10 corresponds to a hydrophilic surfactant.

  Surfactants can be classified according to their structure under the generic name “ionic” (anionic, cationic or amphoteric) or “nonionic”. Nonionic surfactants are surfactants that do not dissociate into ions in water and are therefore insensitive to changes in pH.

  Nonionic surfactants are particularly suitable for preparing the oil-in-water emulsions that are the subject of the present invention. Therefore, the emulsion system that the emulsion of the present invention comprises comprises at least one nonionic surfactant having a predominantly hydrophilic portion, ie having a high HLB value greater than about 10.

  Examples of nonionic surfactants with high HLB values that can be mentioned are POE (20) sorbitan monooleate sold under the name “Tween 80” (HLB = 15); the name “Tween 60” (HLOB = 14.9) POE (20) sorbitan monostearate and other sorbitan esters; POE (21) stearyl ether (HLB = 15.5) or Cognis sold under the name “Eumulgin B2” (HLB = 15.5) Fatty alcohol ethers such as ceteares 20; polyoxyethylene-polyoxypropylene block copolymers such as Synperonic PE / L44.

  Preferably, the high HLB nonionic surfactant has an HLB between 10 and 18.

  Examples of low HLB (lipophilic) nonionic surfactants that can be mentioned are sorbitan esters such as sorbitan monostearate (sold by Unichema under the name Span 60), glyceryl monostearate (Cognis Cutina GMS), including glycerol esters (sold by Cognis under the name Cutina GMSVPH), Spezion C18 pharma, olipal isostearic (gatefosse) and low HLB sucrose esters such as sucrose distearate .

  Preferably, the low HLB nonionic surfactant has an HLB of less than 10.

  Nonionic surfactants can be used alone or as a mixture of two or more in order to form the emulsion system that the emulsion of the present invention comprises.

  Preferably, one or more high HLB nonionic surfactant / low HLB nonionic surfactant pairs can be used as an emulsifying system: in particular, at least one non-HLB having an HLB greater than about 10 A nonionic emulsification system comprising an ionic surfactant and at least one nonionic surfactant having an HLB of less than about 10 can be provided.

  The ratio of each of the two surfactants that form the pair is usually determined by calculating the required HLB of the fatty phase used.

  Preferred emulsifiers that may be mentioned are Tween 80, glyceryl stearate & PEG-100 stearate sold under the name Arlacel 165FL® by Uniqema; PEG6 stearate and PEG32 stearate sold under the name Tefose 1500 by Gattefosse. Glucate SS (methyl glucose sesquistearate) and Glucamate SSE 20 (PEG 20 methyl glucose sesquistearate) sold by Amerchol, sold by Uniqema under the name Brij721® Includes lipophilic emulsifiers such as polyoxyethylene (21) stearyl ether, Eumulgin B2PH, and acrylate / C10-30 alkyl acrylate crosspolymer sold under the name Pemulen TR1 by Noveon.

  The composition according to the invention can also comprise a fatty phase. This fatty phase may comprise, for example, vegetable oils, inorganic oils, animal oils, synthetic oils or silicone oils, and mixtures thereof.

  Examples of inorganic oils that may be mentioned include liquid paraffins of various viscosities such as Primol 352®, Marcol 82® and Marcol 152® sold by Esso.

  Vegetable oils that may be mentioned include sweet almond oil, palm oil, soybean oil, sesame oil and sunflower oil.

  Animal oils that may be mentioned include lanolin, squalene, fish oil, and mink oil with squalene as a derivative sold by the company Laserson under the name Cosbiol®.

  Synthetic oils that may be mentioned are cetearyl isononanoate (for example the product sold under the name Cetiol SN® by Cognis France), diisopropyl adipate (for example the name Ceraphyl 230® by ISF) Products), isopropyl palmitate (eg, the name Crodamol IPP® by Croda), isopropyl adipate (eg the product sold under the name Crodamol DA by Croda), caprylic / capric triglycerides (eg by Huls / Lambert Riviere Including esters such as Miglyol 812 (R) sold.

  Silicone oils that may be mentioned are dimethicone, for example the product sold under the name Dow Corning 200 Fluid®, cyclomethicone, such as the product sold under the name Dow Corning 244 Fluid® by Dow Corning or Includes products sold under the name Mirasil CM5 (registered trademark) by SACI-CFPA.

  Solid fatty substances such as natural or synthetic waxes can also be used. In this case, the skilled person will adjust the heating temperature of the preparation depending on the presence or absence of these solids.

  For the composition according to the invention, liquid paraffin, more specifically Marcol 152® and Miglyol 812® are preferred.

  The composition of the present invention can also contain any additive commonly used in cosmetics or pharmaceuticals, such as surfactants, neutralizers, sunscreens, antioxidants, fillers, electrolytes, dyes, general inorganics. Acids or organic acids or bases, perfumes, essential oils, cosmetic activators, moisturizers, vitamins, sphingolipids, self-tanning compounds such as DHA, skin protectants such as sedatives and allantoin, and pro-penetrating agents, or mixtures thereof Can be included. In particular, the composition according to the invention does not contain any of the following activators: glycolic acid, salicylic acid, retinol, tretinoin, retinaldehyde, azelaic acid and tazarotene. It goes without saying that the person skilled in the art carefully measures this or any of these additional compounds, and / or amounts thereof, so as not to adversely affect or substantially affect the advantageous properties of the composition according to the invention. Will choose.

  These additives may be included in the composition in a proportion of 0.001% to 20% by weight relative to the total weight of the composition.

In one particular embodiment of the invention, the composition is in the form of an oil-in-water (O / W) emulsion lotion, cream or cream-gel type, comprising:
-0.1% to 0.3% naphthoic acid derivatives;
-1% to 10% of one or more polyurethane polymers or derivatives;
-0.1% to 3% gelling or suspending agent;
-0.01% to 1.5% chelating agent;
-0.1% to 10% wetting agent;
-0.1% to 20% emollient;
-0.1% to 30% fat phase;
-0.01% to 3% preservatives;
-0 to 10% emulsifier.

In one particular embodiment of the invention, the composition is in the form of a gel and comprises:
-0.1% to 0.3% naphthoic acid derivatives;
-1% to 10% of one or more polyurethane polymers or derivatives;
-0.1% to 3% gelling agent;
-0.01% to 1.5% chelating agent;
-0.1% to 10% wetting agent;
-0.01% to 3% preservatives.

In another particular embodiment of the invention, the composition is in the form of a lotion and comprises in water:
-0.1% to 0.3% naphthoic acid derivatives;
3% of one or more polyurethane polymers or derivatives, preferentially type 2 polyol prepolymers;
-0.2% gelling or suspending agent;
-0.1% chelating agent;
-2% to 6%, preferentially 4% wetting agent;
-0.1% to 20% emollient;
-7% fat phase;
-1% to 1.5% preservatives;
-4% to 6% emulsifier.

  The subject of the present invention is also the aforementioned composition as a medicament.

  The subject of the present invention is also a method for preparing said composition. The method comprises the step of mixing a physiologically acceptable vehicle comprising at least one naphthoic acid derivative with at least one polyurethane polymer type compound or derivative thereof, wherein the naphthoic acid derivative is contained in the composition. It is distributed.

  Other possible excipients and additives may be introduced depending on the chemical properties of the compound and the formulation form selected.

  The preparation of the composition according to the invention is carried out in 2 or 4 steps depending on the selected formulation form, and the additional 2 steps are carried out only for the preparation of emulsion type forms such as creams, lotions or cream-gels.

  The introduction of the polyol prepolymer into one or the other process depends on the lipophilic or hydrophilic properties of the polyol prepolymer. Therefore, a PP-2 type polyol prepolymer of lipophilic character is introduced into the fat phase of the emulsion after the neutralization step for the gel. A PP-15 type polyol prepolymer that is hydrophilic is introduced into the active aqueous phase after dispersion of the gelling agent.

The preparation of the composition according to the invention is therefore carried out according to the following steps:
a) In order to obtain an active aqueous phase, the naphthoic acid derivative, in water, with at least one wetting agent, at least one chelating agent, at least one gelling agent and optionally a hydrophilic emulsifier and emollient, Mix until the naphthoic acid derivative is completely dispersed;
b) In some cases, to obtain a fatty phase, at least lipophilic emulsifiers, oils and / or solid fatty substances are mixed with preservatives to produce an emulsion;
c) In some cases, in order to obtain an emulsion, the fatty phase obtained in b) is introduced into the active aqueous phase obtained in a);
d) If necessary, in order to obtain the desired pH, the gelling agent neutralizer is introduced into the emulsion obtained in c) or the aqueous phase obtained in a) and the remaining amount of water is added A polyurethane polymer type compound or derivative thereof, depending on its lipophilic or hydrophilic properties, into the active aqueous phase obtained in a) or the fatty phase obtained in b) or during d) To introduce.

More specifically, the method for preparing the composition according to the invention comprises the following steps:
(Step a: Preparation of active aqueous phase)
When preparing purified water, active ingredients (adapalene), oil-in-water emulsions, in some cases hydrophilic emulsifiers (eg Arlacel 165FL or Tween 80), emollients (eg glycerol or propylene glycol), wetting agents (eg Synperonic PE / L62) Or Synperonic PE / L44), a chelating agent (eg EDTA), a gelling agent (eg Carbopol, Pemulen TR1, Xantural, Methocel or Simulgel 600) with stirring using a deflocculator Introduces into a beaker that acts as a reservoir for the product. The mixture is stirred without heating until fully dispersed. If the mixture is homogeneous, the aqueous phase is brought to 60 ° C. on a water bath and a preservative (eg methyl paraben) is introduced.
(Step b (optional): Preparation of fat phase)
Lipophilic emulsifier (eg Glucate SS, Glucamate SSE 20 or Brij 721, Tefose 1500, Eumulgin B2 PH), oily compounds (eg isostearic olepal, Cetiol SN, Crodamol DA, Speziol C18, Miglyol 812 or Cosbiol) and preservatives (eg phenoxyethanol) And propylparaben) are introduced into a further beaker with stirring using a deflocculator. The mixture is brought to 60 ° C. on a water bath and, after homogenization, volatile silicone is introduced into the composition, if present.
(Step c (optional): emulsification)
In order to carry out the emulsification, the fatty phase is gently introduced into the aqueous phase at a temperature of 60 ° C. with stirring using a deflocculator. Heating is maintained for 5 minutes, after which the hot plate is removed and the product is allowed to cool gently. Stirring is adjusted according to viscosity.
Steps b and c are optional and are performed only for the preparation of emulsion type forms such as creams, lotions or cream-gels.
(Process d: Neutralization)
Gelling agent neutralizer (eg, triethanolamine or 10% sodium hydroxide solution) is introduced, if necessary, at 40 ° C. to a pH of 5.5 ± 0.5. Thereafter, the product has a thicker consistency. At the end of production, the pH is checked again. If it is within the standard range, add a sufficient amount of water. To ensure a good dispersion of the adapalene active ingredient, the product is finally homogenized (microscopic observation reveals a uniform dispersion without agglomeration) and then the product is packaged To do.

  The polyurethane polymer type compound is preferably used during step a) (for gel or emulsion formulations containing hydrophilic polymers) or during step b) (for emulsion formulations containing lipophilic polymers) or step d. ) (For gel formulations containing lipophilic polymers), polyol prepolymers introduced depending on the lipophilic or hydrophilic properties.

  The invention also relates to the use of said novel compounds in cosmetics and dermatology.

  In particular, the present invention relates to skin diseases associated with keratosis related to cell differentiation and proliferation, in particular simple acne, acne vulgaris, papulopustular acne, paprocomedonic acne, cystic locus Acne, congenital acne, nape keloid, recurrent acne, necrotic acne, neonatal acne, occupational acne, rosacea, geriatric acne, solar acne and medication It relates to the use of said composition for the manufacture of a pharmaceutical composition for treating and / or preventing related acne.

  More particularly, the present invention relates to the use of said composition for the manufacture of a pharmaceutical composition for preventing or treating simple acne.

  The composition according to the invention is preferentially administered locally.

  In addition, the present invention also provides greasy skin or hair for the treatment of acne-prone skin, in the protection against harmful aspects of sunlight or in the treatment of physiologically greasy skin. It relates to the cosmetic use of the composition according to the invention for dealing with the appearance or for preventing and / or dealing with light-induced or aging-related aging.

  The invention will now be illustrated by the following examples.

Example 1: Production of a gel-type formulation comprising adapalene and a polyurethane polymer
Manufacturing is carried out in four steps:
[Step 1: Preparation of aqueous phase]
Place purified water, EDTA and methylparaben in a beaker. Then, in order to raise a solution to 80 degreeC +/- 5 degreeC, a beaker is left still on a water bath (or on a hotplate), and a paraben is dissolved. The beaker is then agitated with a Rayneri blender equipped with a deflocculating paddle until the whole is dispersed. Carbopol 980 NF is then added as a shower and stirred until the mixture is completely dispersed.
[Step 2: Preparation of active phase]
Place propylene glycol and Synperonic PE / L62 in a further beaker. Thereafter, adapalene is introduced and the beaker is stirred using an Ultra-Turrax blender (paddle: 540 rpm; turbo mixer: 20500 rpm). When adapalene is completely dispersed (microscopic observation reveals a uniform dispersion with no agglomeration), this phase is then added to the remaining formulation.
[Step 3: Neutralization]
A sufficient amount of 10% aqueous sodium hydroxide (m / m) is added to the formulation to bring the formulation to pH 5.5 ± 0.5.
[Process 4]
A polyurethane polymer (polyol prepolymer-2) is introduced.

  The mixture is brought to the required volume with a sufficient amount of water.

Example 2: Gel-type formulation containing 0.1% adapalene and polyol prepolymer-2
The formulation is prepared according to the method described in Example 1.

Example 3: Gel-type formulation containing 0.1% adapalene and polyol prepolymer-2
The formulation is prepared according to the method described in Example 1.

Example 4: Gel-type formulation containing 0.1% adapalene and polyol prepolymer-2
The formulation is prepared according to the method described in Example 1.

Example 5: Chemical stability of the formulation of Example 2

  The chemical stability of the gel formulation described in Example 2 is measured by HPLC at room temperature (RT) for 6 months. This result indicates that the composition is chemically stable at room temperature for 6 months.

Example 6: Chemical stability of the formulation of Example 3

  The chemical stability of the gel formulation described in Example 3 is measured by HPLC at room temperature (RT) for 6 months. This result indicates that the composition is chemically stable at room temperature, for 6 months, and at a constant pH.

  Furthermore, the pH of the composition is measured and shows good stability.

Example 7 General Method for Producing Cream-Gel, Cream or Lotion Type Oil-in-Water Emulsion Formulations According to the Invention
The manufacturing method is carried out in the following four steps:
[Step 1: Preparation of active aqueous phase]
Purified water, active ingredient (adapalene), hydrophilic emulsifiers such as Arlacel 165FL and Tween 80, emollients such as glycerol and propylene glycol, wetting agents such as Synperonic PE / L44, chelating agents such as EDTA, and Carbopol, Pemulen TR1, A gelling agent such as Xantural, Methocel or Simulgel 600 is introduced into a beaker that acts as a reservoir for the final product while stirring using a deflocculator. The mixture is stirred without heating until fully dispersed. If the mixture is homogeneous, the aqueous phase is brought to 60 ° C. on a water bath and methyl paraben is introduced.
[Step 2: Preparation of fat phase]
Glucate SS / Glucamate SSE 20 or lipophilic emulsifiers such as Brij 721, Tefose 1500, Eumulgin B2 PH, oil compounds such as isostearic olepal, Cetiol SN, Crodamol DA, Speziol C18, Miglyol 812 or Cosbiol, and phenoxyethanol and propylparaben The preservative is introduced into a further beaker while stirring using a deflocculator. The mixture is brought to 60 ° C. on a water bath and, after homogenization, volatile silicone is introduced into the composition, if present.
[Step 3: Introduction of polyol prepolymer]
When the polyol prepolymer is polyol prepolymer-2, which is lipophilic, it is weighed and then introduced into the fatty phase. On the other hand, when the polyol prepolymer-15 is hydrophilic, it is introduced into the aqueous phase after the gelling agent is dispersed.
[Step 4: Emulsification]
In order to carry out the emulsification, the fatty phase is gently introduced into the aqueous phase at a temperature of 60 ° C. with stirring using a deflocculator.
Heating is maintained for 5 minutes, after which the hot plate is removed and the product is allowed to cool gently.
Stirring is adjusted according to viscosity. At 40 ° C., a gelling agent neutralizer (eg, triethanolamine or 10% sodium hydroxide solution) is introduced, if necessary, to pH 5.5 ± 0.5. Thereafter, the product has a thicker consistency. At the end of production, the pH is checked again. If it is within the standard range, add a sufficient amount of water. To ensure a good dispersion of the active naadapalene component, the product is finally homogenized (microscopic observation reveals a uniform dispersion without agglomeration) and then packaging the product To do.

Example 8: Cream type formulation containing 0.1% adapalene and polyol prepolymer-2
The formulation is prepared according to the method described in Example 7.

Example 9: Cream-type formulation containing 0.1% adapalene and polyol prepolymer-2
The formulation is prepared according to the method described in Example 7.

Example 10: Cream type formulation containing 0.1% adapalene and polyol prepolymer-15
The formulation is prepared according to the method described in Example 7.

Example 11: Cream-type formulation containing 0.1% adapalene and polyol prepolymer-15
The formulation is prepared according to the method described in Example 7.

Example 12: Lotion type formulation containing 0.1% adapalene and polyol prepolymer-2
The formulation is prepared according to the method described in Example 7.

Example 13: Lotion-type formulation containing 0.1% adapalene and polyol prepolymer-2
The formulation is prepared according to the method described in Example 7.

Example 14: Lotion type formulation containing 0.1% adapalene and polyol prepolymer-2
The formulation is prepared according to the method described in Example 7.

Example 15 Lotion-type formulation containing 0.1% adapalene and polyol prepolymer-2
The formulation is prepared according to the method described in Example 7.

Example 16 Lotion-type formulation containing 0.1% adapalene and polyol prepolymer-2
The formulation is prepared according to the method described in Example 7.

Example 17: Lotion-type formulation containing 0.1% adapalene and polyol prepolymer-2
The formulation is prepared according to the method described in Example 7.

Example 18 Lotion-type formulation containing 0.3% adapalene and polyol prepolymer-2
The formulation is prepared according to the method described in Example 7.

Example 19: Cream type formulation containing 0.3% adapalene and polyol prepolymer-2
The formulation is prepared according to the method described in Example 7.

Example 20: Cream-gel type formulation with 0.3% adapalene and polyol prepolymer-2
The formulation is prepared according to the method described in Example 7.

Example 21: Cream-gel type formulation containing 0.3% adapalene and polyol prepolymer-2
The formulation is prepared according to the method described in Example 7.

Example 22: Lotion type formulation containing 0.1% adapalene and 3% PP-2
The formulation is prepared according to the method described in Example 7.

Example 23: Lotion-type formulation containing 0.3% adapalene and 3% PP-2
The formulation is prepared according to the method described in Example 7.

  Specifications at zero time:

  The physical and chemical stability of this composition was measured. The results are shown below.

  Therefore, the composition is physically and chemically stable.

Example 24: Cream-gel type formulation containing 0.3% adapalene and 3% PP-2
The formulation is prepared according to the method described in Example 7.

  Specifications at zero time:

  The physical and chemical stability of this composition was measured. The results are shown below.

  Therefore, the composition is physically and chemically stable.

Example 25: Lotion type formulation containing 0.3% adapalene and 3% PP-2
The formulation is prepared according to the method described in Example 7.

  Specifications at zero time:

  The physical and chemical stability of this composition was measured. The results are shown below.

  Therefore, the composition is physically and chemically stable.

Example 26: Cream-gel type formulation containing 0.3% adapalene and 3% PP-2
The formulation is prepared according to the method described in Example 7.

  Specifications at zero time:

  The physical and chemical stability of this composition was measured. The results are shown below.

  Therefore, the composition is physically and chemically stable.

Example 27: Lotion type formulation containing 0.3% adapalene and 3% PP-2
The formulation is prepared according to the method described in Example 7.

  Specifications at zero time:

  The physical and chemical stability of this composition was measured. The results are shown below.

  Therefore, the composition is physically and chemically stable.

Example 28: In vitro release-penetration test
This test consists of adapalene (formulation of Example 2) formulated at 0.1% (m / m) in a gel containing 1% PP-2, 0.1% (m / m) in a gel containing 3% PP-2. It is intended to compare in vitro release-penetration of adapalene in the reference gel containing adapalene (formulation of Example 3) formulated with) and a reference gel containing 0.1% adapalene.

The adsorption test was carried out using excised human skin, increased in a stationary state for 16 hours. Three samples of skin obtained from a woman (68 years old) were used. 10 mg of each formulation (10 μg adapalene) was applied to a 1 cm ² area of skin. The adapalene concentration in the liquid fraction collected after the time and the adapalene concentration remaining in the skin at the end of the test were evaluated using HPLC with fluorescence detection (based on valid method. Quantification limit: 1 ng.mL ^-1 ).

  The experimental results are shown in the following table.

  These results indicate that adapalene is mainly distributed in the epidermis (including the stratum corneum) and, to a lesser extent, in the dermis, regardless of the formulation tested. The epidermis / dermis ratio of the formulations of Examples 2 and 3 is significantly higher than the epidermis / dermis ratio of the reference gel containing 0.1% adapalene. These results indicate that the presence of PP-2 in the formulations of the present invention significantly alters the distribution of adapalene in the skin, mainly by retaining adapalene in the stratum corneum and the upper layers of the epidermis. Suggests. This example therefore demonstrates the “reservoir effect” of the formulation according to the invention.

(Example 29: Tolerability test in BALB / c mice)
This study demonstrates the stimulating effect of a reference gel containing 0.1% adapalene, the stimulating effect of three 0.1% adapalene formulations in gel form containing polyurethane polymer at various concentrations, and the stimulating effect of placebo. It is intended to be compared on the ear skin of BALB / c mice after repeated topical application over 6 days.

Daily topical application (20 μl) of test sample is performed once daily per day for 6 days on the inner surface of the ears of BALB / c mice (approximately 8 weeks old female mice) divided into 10 groups . Test samples are shown below:
Group 1: Acetone (control vehicle)
Group 2: Placebo reference gel (control vehicle)
Group 3: Placebo formulation of Example 2 (1% PP-2) (without 0.1% adapalene) (control vehicle)
Group 4: (3% PP-2) placebo formulation of Example 3 (without 0.1% adapalene) (control vehicle)
Group 5: Example 4 (10% PP-2) placebo formulation (without 0.1% adapalene) (control vehicle)
Group 6: Reference gel with 0.1% adapalene Group 7: Example 2 formulation (1% PP-2)
Group 8: Formulation of Example 3 (3% PP-2)
Group 9: Example 4 placebo formulation (10% PP-2)
Group 10: Acetone + 0.1% (m / m) adapalene

  Assessment is performed by measuring ear thickness by Oditest technique and by clinical observation of animals from day 2 to day 19.

  The results are shown in the following table and FIGS.

FIG. 1 shows the average thickness kinetics of mouse ears from day 2 to day 19 for the following various test samples:
・ Acetone (curve (1A))
・ Placebo reference gel (curve (1B))
-Placebo of Example 2 (1% PP-2) (curve (1C))
-Placebo of Example 3 (3% PP-2) (curve (1D))
-Placebo of Example 4 (10% PP-2) (curve (1E))

  These placebo kinetics show that the various placebo preparations used are not irritating and act like acetone.

FIG. 2 shows the average thickness kinetics of mouse ears from day 2 to day 19 for the following various test samples:
・ Acetone (curve (2A))
・ Acetone + 0.1% adapalene (curve (2B))
・ Placebo reference gel (curve (2C))
・ Reference gel containing 0.1% adapalene (curve (2D))
-Placebo of Example 2 (1% PP-2) (curve (2E))
-Example 2 (1% PP-2) (curve (2F))

  These kinetics show that a reference gel containing 0.1% adapalene is irritating from day 6 with a 31% increase in area under the curve relative to placebo (placebo reference gel). Similarly, the acetone + 0.1% adapalene sample is also irritating, showing a 30% increase in the area under the curve for placebo (acetone). Surprisingly, the formulation of Example 2 (1% PP-2) was only half as irritating as the reference gel with 0.1% adapalene, and the placebo (1% PP- The area under the curve for 2)) only increases by 15%.

FIG. 3 shows the average thickness kinetics of mouse ears from day 2 to day 19 for the following various test samples:
・ Acetone (curve (3A))
・ Acetone + 0.1% adapalene (curve (3B))
・ Placebo reference gel (curve (3C))
・ Reference gel containing 0.1% adapalene (curve (3D))
-Placebo of Example 3 (3% PP-2) (curve (3E))
-Example 3 (3% PP-2) (curve (3F))

  Surprisingly, these kinetics also show that the formulation of Example 3 has a weaker irritancy than a reference gel containing 0.1% adapalene. The formulation of Example 3 also increases the area under the curve only 19% relative to the placebo (placebo of Example 2 (3% PP-2)).

FIG. 4 shows the average thickness kinetics of mouse ears from day 2 to day 19 for the following various test samples:
・ Acetone (curve (4A))
・ Acetone + 0.1% adapalene (curve (4B))
・ Placebo reference gel (curve (4C))
・ Reference gel containing 0.1% adapalene (curve (4D))
-Placebo of Example 4 (10% PP-2) (curve (4E))
-Example 4 (10% PP-2) (curve (4F))

  These kinetics show that the formulation of Example 4 is less irritating than the reference gel containing 0.1% adapalene. The formulation of Example 3 (3% PP-2) similarly increases the area under the curve by 22% relative to the placebo (placebo of Example 4 (3% PP-2)).

  A comparison of the kinetics of the various formulations described in Examples 2 to 4 shows that these three formulations have very similar kinetics. It is impossible to distinguish them. Surprisingly, all three of these formulations have less irritation than the reference gel with 0.1% adapalene and 0.1% (m / m) adapalene in acetone.

The test results show the following after repeated topical application of 20 μl of the test sample to the ears of BALB / c mice at D1 to D6.
-The placebos used in the study (“Placebo Reference Gel”, “Example 2 Placebo”, “Example 3 Placebo” and “Example 4 Placebo”, respectively) are non-irritating and overlap completely. Show kinetics that can be;
-The formulations of Examples 2, 3 and 4 used in the test result in an increase in ear thickness of 15%, 19% and 22% for each placebo, respectively. These are all less irritating than the “reference gel with 0.1% adapalene” and are difficult to distinguish from each other.

  This example demonstrates that the formulation according to the invention shows better in vivo tolerance than "reference gel with 0.1% adapalene".

  The following table compares various formulations containing 0.1% adapalene with an untreated placebo and demonstrates the effect of the polyurethane polymer on acceptability.

  Therefore, regardless of the content of polyurethane polymer: 1%, 3% or 10%, the formulation has 2 times better tolerance than without the polyurethane polymer.

(Example 30: Test of comedolytic activity on Rhino mice)
This study shows the comedone activity of a reference gel containing 0.1% adapalene, the comedone action of two 0.1% adapalene formulations in gel form containing polyurethane polymers at various concentrations, and the placebo comedone action. After repeated topical application over 18 days, it is intended to compare on the skin of the back of RHINO FVB / N RJ-hr ^rh mice (Rhino).

Daily topical application of test samples (50 μl) is performed once a day for 18 days on the skin of the back of Rhino mice (approximately 7 weeks old mice) divided into 7 groups. Test samples are shown below:
Group 1: Acetone (control vehicle)
Group 2: (3% PP-2) placebo formulation of Example 3 (without 0.1% adapalene) (control vehicle)
Group 3: Acetone + 0.01% (m / m) 2- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) benzo [b] thiophene-6- Carboxylic acid (positive control)
Group 4: Acetone + 0.1% (m / m) adapalene Group 5: Reference gel containing 0.1% adapalene Group 6: Formulation of Example 2 (1% PP-2)
Group 7: Formulation of Example 3 (3% PP-2)

  Tolerability assessments are performed three times a week for 19 days by clinical observation of the back epidermis using the following observation parameters: edema, erythema and scales.

  Coming activity is measured by measuring transepidermal water loss (TWL) at D4, D11 and D19, by measuring epidermis thickness, by counting the number of comedones / cm, and D1, D4, Assess by measuring the body weight of the animals at D11 and D19.

FIG. 5 shows the results of the area under the curve for acceptance assessment from day 1 to day 19 for the following various test samples:
・ Acetone (control vehicle) (curve (5A))
Formulation (control vehicle) of Example 3 (3% PP-2) without 0.1% adapalene (curve (5B))
Acetone + 0.01% (m / m) 2- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) benzo [b] thiophene-6-carboxylic acid (Positive control) (Curve (5C))
Acetone + 0.1% (m / m) adapalene (curve (5D))
・ Reference gel containing 0.1% adapalene (curve (5E))
-Formulation of Example 2 (1% PP-2) (curve (5F))
-Formulation of Example 3 (3% PP-2) (curve (5G))

  The results of this test show that the formulations of Examples 2 and 3 have weaker irritation than the reference gel containing 0.1% adapalene. These formulations of Example 2 (1% PP-2) and Example 3 (3% PP-2) reduce the area under the curve by 45% and 22% for the reference gel containing 0.1% adapalene, respectively. .

FIG. 6 shows the transepidermal water loss (TWL) area under the curve (AUC) results after 18 days of topical treatment for the following various test samples:
Acetone (control vehicle) (curve (6A))
Formulation (control vehicle) of Example 3 (3% PP-2) without 0.1% adapalene (curve (6B))
Acetone + 0.01% (m / m) 2- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) benzo [b] thiophene-6-carboxylic acid (Positive control) (Curve (6C))
Acetone + 0.1% (m / m) adapalene (curve (6D))
・ Reference gel containing 0.1% adapalene (curve (6E))
-Formulation of Example 2 (1% PP-2) (curve (6F))
-Formulation of Example 3 (3% PP-2) (curve (6G))

  TWL quantifies skin barrier dysfunction by measuring the water vapor gradient established in a 10 mm thick layer on the surface of the skin.

  The results of this test show that the formulations of Examples 2 and 3 increase TWL by 129% and 118%, respectively. These values are acetone + 0.01% (m / m) 2- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) benzo [b] thiophene- Reference gel containing much less than TWL increase observed for 6-carboxylic acid formulation (332%) and acetone + 0.1% (m / m) adapalene formulation (299%) and containing 0.1% adapalene Less than the increase in TWL observed for (152%). Therefore, FIG. 6 shows that the formulations of the present invention provide better protection of the skin barrier than the reference gel containing 0.1% adapalene.

FIG. 7 shows the measurement of epidermal thickness after 18 days of topical treatment for the following various test samples:
Acetone (control vehicle) (curve (7A))
Formulation (control vehicle) of Example 3 (3% PP-2) without 0.1% adapalene (curve (7B))
Acetone + 0.01% (m / m) 2- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) benzo [b] thiophene-6-carboxylic acid (Positive control) (Curve (7C))
Acetone + 0.1% (m / m) adapalene (curve (7D))
・ Reference gel containing 0.1% adapalene (curve (7E))
-Formulation of Example 2 (1% PP-2) (curve (7F))
-Formulation of Example 3 (3% PP-2) (curve (7G))

  The results of this test show that an equivalent increase in epidermal thickness is observed for all formulations containing adapalene.

FIG. 8 shows the results of counting the number of comedones per centimeter (cm) of the back of Rhino mice after 18 days of topical treatment for the following various test samples:
・ Acetone (control vehicle) (curve (8A))
Formulation (control vehicle) of Example 3 (3% PP-2) without 0.1% adapalene (curve (8B))
Acetone + 0.01% (m / m) 2- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) benzo [b] thiophene-6-carboxylic acid (Positive control) (Curve (8C))
Acetone + 0.1% (m / m) adapalene (curve (8D))
・ Reference gel containing 0.1% adapalene (curve (8E))
-Formulation of Example 2 (1% PP-2) (curve (8F))
-Formulation of Example 3 (3% PP-2) (curve (8G))

  The results of this study showed that skin treated with placebo (a 3% PP-2 formulation of Example 3 without acetone or 0.1% adapalene) had a similarly high number of 58-60. Indicates that the surface area per centimeter. On the other hand, skin treated with the formulation containing the active ingredient adapalene (acetone + 0.1% (m / m) adapalene, reference gel containing 0.1% adapalene, formulation of Examples 2 and 3) A similar low number of comedones per centimeter. From FIG. 8, it is clear that the formulation according to the invention has comedone activity comparable to a reference gel containing 0.1% adapalene.

  The following table shows the change in body weight of the seven groups of mice used in the study from day 1 to day 19:

  The results of this study represent that the animals do not show any weight loss after 18 days of topical treatment. Furthermore, the above table shows that there are no significant differences between animals treated with controls and animals treated with various adapalene formulations.

  This example and the above test show that the formulations according to the invention have better comedone activity than a reference gel with 0.1% adapalene, whereas a better in vivo than a reference gel with 0.1% adapalene. Demonstrate that it is acceptable.

Example 31: In vitro release-penetration test
This test consists of adapalene (formulation of Example 23) formulated at 0.3% (m / m) in a lotion containing 3% PP-2, 0.3% (m / m) in a lotion containing 3% PP-2. Is intended to compare the release-penetration of adapalene in a reference gel containing 0.1% adapalene in vitro into the skin without occlusion.

The adsorption test was carried out using excised human skin, increased in a stationary state for 16 hours. Three samples of skin obtained from a woman (68 years old) were used. 30 mg of each formulation (30 μg adapalene) was applied to a 1 cm ² area of skin. The adapalene concentration in the liquid fraction collected after the time and the adapalene concentration remaining in the skin at the end of the test were evaluated using HPLC with fluorescence detection (based on valid method. Quantification limit: 1 ng.mL ^-1 ).

  The experimental results are shown in the following table:

  These results indicate that adapalene is mainly distributed in the stratum corneum in the inventive formulations tested. These results suggest that the presence of PP-2 in the formulation according to the invention does not prevent the penetration of the active ingredient.

Claims (1)

  A composition comprising, in a physiologically acceptable medium, at least one naphthoic acid derivative and at least one polyurethane polymer type compound or derivative thereof, wherein the naphthoic acid derivative is in dispersed form in the composition. A composition that does not contain an extract of Saw Palmetto Belize.