WO1997021097A1 - Use of polymeric materials for simulating skin, particularly in a diffusion cell - Google Patents

Abstract

The use of a polymeric material consisting of a cross-linked acrylic or methacrylic polymer produced by polymerising a monofunctional acrylic or methacrylic monomer having a molecular weight of 50-900 and a polyfunctional acrylic or methacrylic monomer having at least two polymerisable double bonds, as an agent for simulating a skin or mucosal barrier to determine the behaviour of topical pharmaceuticals or cosmetics, is disclosed. In particular, the use of said polymers for studying the diffusion of a cosmetic or dermatological product, and measuring the sun protection coefficient or occlusive properties thereof, as well as the use of said polymers as a carrier for topical cosmetic or pharmaceutical and particularly dermatological compositions, are disclosed. Cells for measuring the penetration and/or diffusion of the products to be tested, wherein the above-mentioned polymers are used as the receiving portion, are also disclosed.

Description

Use of polymeric materials for mimicking the skin, in particular in a diffusion cell

The present invention relates to new polymeric agents intended to mimic the skin barrier or the mucosal barrier to evaluate the behavior of cosmetic or pharmaceutical products for topical use.

The new polymeric agents developed in the context of the present invention find their application in particular for carrying out the following operations: 1) Predictive measurement of the penetration of pharmacologically active molecules or molecules capable of presenting toxicity at the cutaneous level.

2) Study of the penetration of a product as a function of the hydration rate of the polymer network, which makes it possible to mimic the diffusion of molecules as a function of the degree of skin hydration with the existence of a water gradient as in the skin.

3) Study of variations in hydration of the polymer network after application of a product, that is to say measurement of the occlusive or emollient power of skin formulations.

4) Measurement of the effectiveness of UV filtering products and in particular cosmetic products containing sunscreens or filters.

5) Evaluation of the disposition of solid particles on the surface of the skin, in particular in the case of make-up).

6) Study of the spreading of cosmetic or dermatological products on the skin surface, using polymeric materials having surface properties close to those of the skin.

Currently, the main penetration measurements, through the skin of cosmetic or pharmaceutical products for topical use, are carried out on human or animal skin in vivo or ex vivo with generally radiolabelled molecules, in combination with strippings and / or skin sections (JC Jamoullc, Ann. Dermatol. Venerol 1988, 115, 627-640 and RC Scott et al., J. Invest. Dermatol. 1991, 96, 921-925 and D.Friend J. Controlled Release 1992, 18 , 235-248).

In vitro methods mainly use synthetic polymeric materials. These materials can be microporous and associated with lipid mixtures (D. Kittayanomd et al, J. Soc. Chem., 1992, 43, 237-249; W. Abraham et al., J. Invest. Dcrmat. 1989, 93, 809-813). These in vitro experiments are often done with the help of diffusion cells whose uses and geometries are very variable (BW Cleary in Skin Permeation Fundamentals and Application p. 211, Edited by JL Zatz, Allured Publishing Corp., Wheaton, Il USA, 1993). However, the results obtained by these in vitro methods are in fact somewhat inconsistent with reality (JE Rivière in Skin Permeation Fundamentals and Application p.113, Edited by JL Zatz, Allured Publishing Corp., Wheaton, Il USA, 1993) because l use of these diffusion cells requires the presence of a receiving liquid in which the material or materials are impregnated or even saturated. Thus, the material or materials used, with conventional diffusion cells, are in a state of hydration which is not controllable and often not very comparable to the conditions of the skin in vivo (17 to 40% of water in the stratum corneum and 70% in the dermis). Consequently, the current diffusion cells do not make it possible to obtain controlled hydration conditions which are comparable to those of the skin and they do not allow the joint use of means of detection in situ during the diffusion of products.

The main methods of in vitro measurement of sun protection factors (designated herein by the acronym SPF corresponding to the corresponding English name "Sun Protection Factor") are based on animal skin ex vivo or according to the method of Diffey and Robson on a polymeric substrate (Transpore from 3M Santé, Malakoff, France), as exposed by RM Sayre, Cosmetics "fe toiletries, 1993,108,111-114. The comparison between these main methods (AD Pearse, C. Edwards, International Journal of cosmetic Science 1993, 15, 234-244) shows that the 3M Transpore substrate overestimates the SPF values for sun products whose SPF is greater than 20 .

The classification of cosmetic or dermatological compositions and, if appropriate, incorporated excipients according to their capacity to maintain and improve the hydration of the skin is of great interest for pharmacology and cosmetology. Most of the methods used to determine the loss of transepidermal water, also known as TEWL according to English terminology, are in vivo methods (BM Morrison, J. Soc. Cosmet. Chem., 1992, 43, 161-167). There are also in vitro methods for determining occlusive power (A. Strufimann et al, International Journal of cosmetic Science 1993, 15,

227-233) whose particularity is to determine the permeability to water in the gaseous state through a matrix of polytetrafluoroethylene impregnated with an emollient.

The Applicants have now discovered that a new family of polymers, all consisting of crosslinked acrylic or methacrylic polymers, could be used as agents intended to mimic the effect of the skin barrier or of the barrier constituted by a mucosa to evaluate the behavior of the products or compositions for cosmetic or pharmaceutical use, in particular dermatological use, for topical use.

The use of products of this family makes it possible to solve most of the problems posed by the usual techniques for evaluating cosmetic or dermatological products by presenting the following advantages: The present invention makes it possible to dispense with the use of human skin or animal, which allows, among other things, the use of radiolabelled molecules.

The present invention makes it easy to prepare a polymeric material with controlled hydration rate. The control of the hydration of the polymeric material makes it possible in particular to prepare a model of the different parts of the skin (stratum corneum, epidemic, dermis) with their own hydration rates or even a model of the whole of the skin, in imposing a water content gradient comparable to that of the skin or a mucous membrane.

This model will be particularly useful for studying different properties of substances applied to the skin, in particular the penetration properties of this substance through the different layers of the skin.

The present invention also makes it possible to prepare, at low cost, the desired quantity of synthetic polymeric material with the desired geometry and, by preparation in a spectrophotometer tank, to detect in situ the diffusion of the molecule as a function of time and / or of depth by a method as simple as UV or visible absorption, or even fluorescence.

It is also possible to use this synthetic polymeric material by modifying it on the surface by applying sebum or a mixture of the main constituents thereof. The polymeric material can also be used as a support for a natural or artificial skin sample, thus constituting a new cell intended to study the diffusion of cosmetic and / or pharmaceutical compositions, in particular dermatological compositions for topical use. Such a cell will prove to be particularly useful in the case of compositions of hydrophobic nature for which the cells currently existing are ill-suited since they function with an aqueous receptor liquid such as an aqueous albumin solution.

Such cells are commonly known as Franz cells. As a device incorporating a cell of this type, mention may be made of the LG-1083 system from the company LGA, Berkeley, California, USA.

The present invention also makes it possible, on the one hand, to determine the SPF factors by a spectrophotometric method and, on the other hand, to adjust the spreading properties of the sun products by reproducing the skin relief and by modifying the physico-chemical properties. of surface of substrates. In addition, the present invention makes it possible to take into account the penetration factor of solar products in a realistic manner, which is not the case with currently existing in vitro models.

These various improvements allow a better definition of the material to be used for SPF determinations.

The present invention makes it possible to determine in vitro the properties of an excipient, in particular its occlusive properties or to determine its role in the penetration of the compositions.

The invention also provides a particularly advantageous means for determining the capacity of a cosmetic or dermatological formulation to retain water in the liquid state in the material which is the subject of the invention. The invention makes it possible to reproduce practically the actual process of evaporation of the water present in the liquid state in the skin through the composition applied to it, unlike the techniques used hitherto consisting of observing the passage water in the form of a gas through a material soaked in an occlusive agent.

In addition, the ability of the material to retain water itself can be modulated by adding hydrophobic and / or hydrophilic molecules and / or lipids or other surfactants. Therefore, all skin categories (oily, dry and intermediate) can be imitated. In particular, it is possible to imitate the lipid functions of the skin by incorporating a greater or lesser quantity of lipids or sebum in the polymeric material so as to study the functionality of the lipids of the stratum corneum according to the water absorption process described by SE Friberg et al, International Journal of Cosmetic Science 1990, 12.5-12.

The present invention also makes it possible, by adding solid particles, to mimic the geometry (plane or spherical) and the hydrophilic and / or hydrophobic characters of internal constitutive structures of the skin such as comeocytes and keratinocytes. The description and the examples which follow illustrate more specifically particular applications of the useful materials described according to the invention. This description is made in particular with reference to the illustrative figures 1 to 11 which represent respectively:

FIG. 1: a cell which is particularly useful for the study of diffusion phenomena using the polymers of the invention,

- Figure 2: an example of a diffusion curve representing the absorbance as a function of time.

- Figure 3: an example of a curve representing the derivative of absorbance as a function of time, - Figure 4: curves showing the effect of the width of the slot of the diffusion cell on the curve representing the absorbance as a function of time,

FIG. 5: the penetration profiles of tretinoin in different excipients using the material of Example 1, FIG. 6: the SPF calibration curve produced with a 3M Transpore commercial membrane,

- Figure 7: the calibration curve produced under the same conditions as that of Figure 6 with a membrane made of the material of Example 19, - Figure 8: the weight loss curves of different materials according to the invention corresponding to their water holding power.

- Figure 9 and 10: the occlusive power curves of two materials of the invention in the presence of different excipients. - Figure 11: a new cell for the diffusion study in which the material of the invention serves as a support for an epidermis sample.

More precisely according to one of its essential characteristics, the invention relates to the use of the polymeric material consisting of a crosslinked acrylic or methacrylic polymer resulting from the polymerization of a monofunctional acrylic or methacrylic monomer of molecular weight between 50 and 900 and of a polyfunctional acrylic or methacrylic monomer having at least two polymέrisable double bonds, as an agent intended to mimic the skin barrier or the barrier constituting a mucosa for evaluating the behavior of cosmetic or pharmaceutical products or compositions for topical use.

The crosslinking rate of the polymers used by the volume R occupied by an elementary mesh is characterized in the present invention. This volume R will advantageously be between 3 and 100 nm ³ , preferably between 8 and 16 nm ³ .

According to another variant of the invention, the polymeric materials used advantageously have a surface tension of between 20.10 ^-3 N / m and 50.10 ^"3 N / m, preferably between 25.10 ^{" 3} N / m and 40.10 ^"3 N / m .

Such values are particularly interesting since they correspond to those obtained in the case of human skin.

In particular, the authors N. DENIAU et al. quote in their article

"Immobilization of particulate Systems on the skin by the mean of emulsions",

Drug Development & Industrial Pharmacy, 19 (13) 1521-1540 (1993), on page

1529, for human skin values of surface tensions between 26.8 mN / m and 37 mN / m.

This surface tension can be obtained directly during the preparation of the polymer. It can also be obtained by coating a layer of sebum or an amphiphilic liquid on the surface of said material.

The thickness of this layer will be thin enough to correspond to a maximum additional mass of 2 mg / cm ² .

According to another advantageous variant, the monofunctional monomer consists of a polymerizable function and of a group consisting of n hydrophobic units and / or p hydrophilic units, n and p being integers the sum of which is between 1 and 15. The developed formulas of different hydrophobic and hydrophilic groups are abundantly described in the literature (J. Pore, Emulsions, micro-emulsions, multiple emulsions, Technical editions of the industries of

Corps Gras, 1992, p.45; Galenica 5 Dispersed systems, I Surface active agents and emulsions Ed Technique et documentation Lavoisier, 1983, p.159).

These lists of hydrophilic and hydrophobic groups are incorporated in the present document with reference.

More specifically, the monomers are part of the family of acrylic and methacrylic monomers. The monofunctional monomers are advantageously chosen from monomers comprising a polymerizable function comprising a double bond and a group consisting of n hydrophobic units and / or p hydrophilic units, n and p being integers the sum of which is between 1 and 15, preferably between 10 and 15, advantageously equal to 14 and of molecular weight varying from 50 to 900.

The n / p ratio advantageously varies from 0 to 10 (it is obvious that in this case p is never equal to zero).

The hydrophobic groups are preferably:

- methyl groups -CH3 - hydrocarbon chains - (CH2) _X with 1 ≤ x ≤ 30

- propylene oxide groups - (CH ₂ -CH ₂ -CH ₂ -O) _x with 1 ≤ x ≤ 30

- isopropylene oxide groups

30 - butylene oxide groups

- (CH ₂ _CH2-CH ₂ -CH2-O) _x - with 1 ≤ x ≤ 30

- isopropylacrylamide groups

O

II

- C-NH

1

CH

/ \ CH ₃ CH ₃ Hydrophilic groups are preferably

- ethylene oxide groups (CH ₂ -CH ₂ -O) _x with 1 ≤ x ≤ 30

- dihydroxypropyl groups

OL -CH- Œ,

I OH OH

- hydroxyl groups -OH

- amide groups

O

II -C -NH—

- quaternary ammonium groups

- ammonium chlorides

CH ^ + CH ₂ -

CR /, ^ CH ^

- dihydroxyethyl groups

-CH— THAT ^ OH OH

- amines - NH ₂ .

The multifunctional monomers have between 2 to 6 double bonds, preferably 2.

These multifunctional monomers also include advantageously hydrophobic units advantageously in the form of saturated carbon chains, and / or p hydrophilic units advantageously in the form of a chain of ethoxy groups, n 'and p' being two. integers between 0 and 30, preferably between 1 and 10 and at least one of which is different from 0.

When n 'or p' is greater than 5, we can speak of macro-monomers. These monomers can consist of a single hydrophilic group, for example, (-NH-CH2-NH-).

In a particularly preferred manner, the multifunctional monomer comprises a chain of hydrophilic groups, in particular a chain of ethoxy groups.

An example of a particularly preferred polymeric material according to the invention consists of polymers obtained by polymerization of a methacrylate having a chain consisting of a succession of n hydrophobic groups consisting of isopropylene oxide, of p hydrophilic groups consisting of oxide ethylene and an alkyl chain comprising x carbon atoms in the presence of a crosslinking agent consisting of a polyethylene glycol dimethacrylate containing in its chain p 'ethylene oxide groups, n and p being integers whose sum is equal to 14, x being between 1 and 10, preferably equal to 8, p 'being an integer between 2 and 30, preferably equal to 9. The mono- and multifunctional monomers described above are commercially available, by example at Nippon Oils and Fats, Tokyo, Japan; Rohm Gmbh, Darmstadt, Germany; Cray Valley, Exton, PA USA; Ciba Geigy Rueil Malmaison France; EASTMAN KODAK Company Rochester, New York USA; Biorad, Ivry sur Seine, France; UCB Chemicals, Drogenbos, Belgium. By way of example of monofunctional monomers, mention will be made, classifying them according to their supplier:

- Rohm: methacrylate of 2 ethylhexyl ester of methacrylic acid C17.4 diethylene glycol methacrylate 2-hydroxyethylacrylate

- Cray Valley: isobornylacrylate (SR506) tetrahydrofurfurylacrylate (SR285)

2 (1 ethoxy ethoxy) ethylacrylate (SR256) isodecyl acrylate (SR395)

2 phenoxyethylacrylate (SR339) - Nippon Oils and Fats:

. polypropylene ethylene oxide monomethacrylate sold under the name

"50 POEP 800 B Blcmmer"

. polyethylene oxide tetrahydrofuran monomethacrylate marketed under the name "70 PEP 350 B Blemmer"

. polypropylene glycol monomethacrylate marketed under the name "PP 500

Blemmer "

. polyethylene glycol monomethacrylate marketed under the name "PE200

Blemmer ". Polyethylene glycol monomethacrylate marketed under the name" PE350

Blemmer "

. polyethylene tetrahydrofuran monomethacrylate marketed under the name "55

PEP 800 Blemmer "

. glycerol monomethacrylate marketed under the name "GLM Blemmer" 2-hydroxy ammonium chloride 3-methacryl oxypropyltrimethyl ammonium chloride marketed under the name "QA Blemmer".

- Kodak:

N - isopropylacrylamide

- Sigma: acrylamide

- Staff: didodecyldimethylammonium acrylate

By way of example of multifunctional monomers, mention will be made of:

- Rohm:

1.12 dodecanediol dimethacrylate trimethylolpropane triacrylate

Polyethylene glycol 400 dimethacrylate Ethylene glycol dimethacrylate Diethylene glycol dimethacrylate Triethylene glycol dimethacrylate Tetraethylene glycol dimethacrylate

- Cray Valley:

1.6 hexane dioldiacrylate (SR238)

- Biorad:

N, N'-methylene bis acrylamide

- UCB: oligomeric polyesteracrylate (Ebccryl450) Oligomeric polyesteracrylate (EbecrylδO)

The crosslinked acrylic or methacrylic polymers used according to the invention consist of a succession of elementary meshes of which each node is linked to a first hydrophobic segment obtained during the polymerization of the polymerizable functions of the monofunctional monomer and carrying at least one pendant group consisting of 'at least one hydrophilic unit and / or at least one hydrophobic unit and with a second segment comprising the non-polymerizable functions of the polyfunctional monomer. Due to the hydrophilic and / or hydrophobic nature of the monofunctional and multifunctional monomers, the assembly of polymeric meshes composed of 4 hydrophilic and / or hydrophobic segments is possible. The set of meshes constitutes the mimetic polymeric material.

In the present specification, all the specific polymers thus defined will be designated by polymers, polymer networks, polymer materials or, more simply, materials.

A polymeric mesh is the repetitive unit between two multifunctional monomers of the material. Between these multifunctional monomers there are monofunctional monomers having pendant groups consisting of hydrophilic and / or hydrophobic units.

A motif consists of several hydrophilic or hydrophobic groups.

A segment consists of patterns between 2 nodes. A node is formed by the polymerizable function of a multifunctional monomer. A polymerizable function is, in the context of the invention, a chemical double bond carrying, where appropriate, a methyl group.

A mesh is thus made of 2 types of segments: a segment formed by a multifunctional monomer and a segment formed by the polymerizable functions of the monofunctional monomers. The segments are hydrophilic and / or hydrophobic depending on the groups and the hydrophilic or hydrophobic units. For the present invention, the polymeric mesh is preferably made of two hydrophobic segments of the polymerizable function of the monofunctional monomers and of two hydrophilic segments of the multifunctional monomers.

This hydrophilic and hydrophobic nature of the materials makes it possible to better mimic this same character existing in the surface layers of the skin over a depth of 300 microns.

As is apparent from the description which follows, and in particular when the polymeric materials are used for in situ diffusion and the determination of SPF by spectrophotomerism, the. choice and association of the monomers will be done so as to preferably obtain an optically transparent system between 300 and 800 nm and allowing spectrometric measurements in UV, in particular between 320 and 400 nm. Transparency must be stable over a period of at least one month.

In the composition of materials, the ratio of monofunctional to multifunctional monomers is variable in all proportions. However, the preferential weight ratio is between 1 and 10.

Among these optically acceptable materials, a distinction is made: - those which have an essentially hydrophilic character due to the predominant presence of hydrophilic groups and for which the addition of deionized water before polymerization does not disturb the optical qualities described above,

- those which are essentially hydrophobic in character due to the predominant presence of hydrophobic groups and whose optical qualities are reduced by the addition of water before polymerization.

It is important to note that all of these two groups do not exclude the possibility of adding water after polymerization.

For certain materials of the first group, their capacity to integrate water before polymerization is very variable and their optical transparency is decreased above a certain amount of water. In this case, mention may be made of materials composed of monofunctional and / or multifunctional monomers such that a double bond is associated with a unit consisting of n hydrophobic groups and a unit consisting of p hydrophilic groups knowing that n + p is between 2 and 15. Examples 9 and 10 illustrate the proportions of the monomers and their compositions in different solutions.

It is also possible within the framework of the invention to include in the materials which are the subject of the invention lipids, in particular phospholipids, or surfactants. The inclusion of such constituents in the materials is advantageously carried out in proportions such that it does not too much affect the optical transparency, which means that the transmission of light through this material is greater than 80%.

These composite products constitute new products in themselves, regardless of their use. When the polymeric materials are used for the determination of the occlusive power, they need not be optically transparent. Thus the inclusion of solid particles intended to mimic the geometry of the corneocytes, such as for example mica or the solid particles resulting from the condensation of L-lysine and of lauric acid, in particular marketed under the name of amihope by AJINOMOTO, Tokyo, Japan, is possible.

Hydrophobic particles will preferably be chosen, the surface of which is modified by adsorption of amphiphilic lipids such as phospholipids, in particular lecithins.

Such polymers including these solids also constitute patentable products in themselves, independently of their use.

The polymers constituting the polymeric materials useful according to the invention can be easily obtained from the two types of monomers concerned by radical polymerization using oxidoreductive systems or gamma or UV radiation, in the presence or not of a photoinitiator as conventionally described in Polymer Chemistry, PC Hiemenz, Marcel Dekker Ed, 1984. However, to preserve the optical quality of the materials, hydrogen peroxide and UVA and UVB radiation will preferably be used as free radical initiators. The useful materials according to the invention can be in various forms depending on the desired application. Thus the materials may be in the form of thin layers of the order of a few microns to a few millimeters, cubic or even cylindrical. These materials may, as appears from the description and examples which follow, according to their hydration rate and according to the intended application, be used either alone to directly mimic the barrier effect of the stratum corneum, of the epidermis or the dermis, either as a support for a fragment of stratum corneum or of natural or reconstituted epidermis so as to constitute a composite material which can be used as a cell for studying the diffusion of cosmetic or dermatological compositions or products.

Examples of reconstructed epidermis include those described in the following publications:

- Vivien HW Mak et al, The journal of Investigativc Dermatology, vol. 96, no ^. 3, 1991; p. 323-327

- Nicole Basset-Séguin, Diff erentiation (1990), 44, p. 232-238. According to another of its essential characteristics, the invention relates to a method for studying the diffusion of a cosmetic or pharmaceutical product for topical use through the skin or a mucosa, characterized in that it consists in determining the penetration profile and of diffusion through a sample of a polymer as defined above, as a function of the distance from the surface of said sample and / or of time, by a spectrophotometric or spectroscopic method using in particular infrared, X-rays, the fluorescence or radiometric or by a chromatographic analysis method.

The measurements of penetration and diffusion profiles as a function of time will advantageously be carried out in spectrophotometric cuvettes, insofar as the molecules which diffuse are detectable by UV-VISIBLE spectrophotometry methods. This spectrophotometric method is in no way limiting for the present invention. We can also use all forms of IR, Microwave, X, fluorescence, radiometry, electronics and / or all chromatographic analyzes. To determine the penetration profiles, a polymeric material contained in a quartz cell is advantageously used, for example a cell from Hellma France.

As illustrated in FIG. 1, for the measurement as a function of time or diffusion, a cover is advantageously applied to the two opposite faces of the quartz tank so as to leave a slot (1), for example 1 mm wide and 1 cm long, this slit being for example 0.5 mm below the tangent to the meniscus (2) formed after polymerization of the material (3), the slit is thus positioned in the center of the beam of the spectrophotometer and the measurement penetration of an active ingredient is therefore carried out at constant distance from the meniscus situated on the surface of the material. The alignment of the slot on the tank is done using an optical aligner preferably provided with a micrometric screw allowing alignment with an accuracy of 10 microns.

More precisely, the diffusion curves are established by representing the absorbance (Abs) as a function of time.

From the diffusion curves, it is possible to obtain with precision the slope S ^ s of the inflection point "of the diffusion curve corresponding to a stationary diffusion regime.

Thus, the plotting of the diffusion curve, an example of which is given in FIG. 2 which represents the absorption (Abs) as a function of time, makes it possible in particular to determine, for a given concentration c, the value Abs∞ of the plateau of the absorbance and that Sabs of the point of inflection of the curve, as well as the value Tlib of the time of release of the product.

Furthermore, FIG. 3 represents the derivative of the absorbance as a function of time. This derivative allows to obtain with precision the Sabs slope of the inflection point of the diffusion curve.

As we have seen above, according to a particularly advantageous variant, the invention relates to a method for studying the diffusion of a cosmetic or pharmaceutical product for topical use through the skin or a mucous membrane according to which the diffusion is determined according to of time by spectrophotometry, the sample of polymeric material being introduced into the cell of the spectrophotometer, said cell being provided with a slot making it possible to perform the spectrophotometric measurement at constant distance from the surface of said sample. A spectrophotometric cell in which the polymerization is advantageously carried out directly in situ and which is provided with a slot situated at constant distance from the meniscus surface of the polymerized product contained in said polymer is thus advantageously used for the study of the diffusion of the active principles. cell.

This slot has the effect of considerably reducing the acquisition time for small quantities of detectable product. This type of diffusion cell in itself constitutes an invention in its own right for the study of diffusion phenomena in situ, and this, regardless of the nature of the material through which the diffusion is studied.

Using Fick's laws, it is very easy to establish the equations necessary for determining the diffusion coefficient D, the permeability Kp and the partition coefficient K of the active principle (s):

Thus: S _aDS * Δx ²

D =

K • Abs ₀ where

. D is the diffusion coefficient expressed in ern ^ / s. S _a 5 _s is the inflection point of the curve expressed in absorbance / second. Δx is the width of the slit expressed in cm

with:

AbsQ = εCQ I

or

. AbsQ designates absorbance

. ε denotes the extinction coefficient for a concentration of the active principle expressed as a percentage by weight relative to the total weight of the composition and at a given wavelength

. Q) is the concentration of the active ingredient expressed as a percentage by weight relative to the total composition.

. I: width of the tank expressed in "cm Abs∞ K =

AbsQ

D ^» K

Kp = -

Δx

It is noted by referring to the formula of the diffusion coefficient above, that Sabs is inversely proportional to the square of the width of the slit Δx.

Furthermore, the tests carried out have made it possible to clearly establish that the slit makes it possible to arrive more quickly at the value Abs∞, which is the value of the absorbance corresponding to the level of the diffusion curve.

Thus, FIG. 4, on which the curves denoted 1, 2 and 3 of absorbance as a function of time have been represented, obtained using slots of respective widths 1 mm (curve 1), 2 mm (curve 2) and 8 mm (curve 3), clearly highlights the fact that one can considerably modify the time at the end of which the value Abs∞ is reached by playing on the width of the slit.

The mimetic power vis-à-vis the skin of the polymeric materials described above, with regard to the diffusion of cosmetic and / or dermatological products, has been clearly established and is very clearly apparent from the examples in the appendix, and this as well for products with a particularly hydrophobic character such as for example tretinoin with a particularly hydrophilic character such as for example esculin.

However, and this in particular in the case of hydrophobic products, the inventors have discovered that the polymeric products described above could be advantageously used to support a sample of natural or artificial epidermis, and thus form a real cell making it possible to mimic the diffusion of cosmetic or dermatological products or compositions for topical use through the skin. It is possible, thanks to the present invention, to study the diffusion of all kinds of products, in particular hydrophobic. For this type of application, it is advantageous to use polymeric materials having a hydration rate of between 0 and 40% by weight, advantageously of the order of 20%.

In this particular case, the use of a slit cell as described above will prove to be particularly advantageous.

FIG. 11 shows such a diffusion cell comparable to that of FIG. 1 but in which the surface 2 of the polymer is covered with a fragment 4 of epidermis ex vivo or reconstituted.

For the study of the diffusion of cosmetic or pharmaceutical products for topical use through the skin or a mucous membrane, use will be made, in a particularly advantageous manner, of a polymer resulting from the polymerization of a methacrylate having a chain consisting of a succession of n groups. hydrophobes consisting of isopropylene oxide, p hydrophilic groups consisting of ethylene oxide and an alkyl chain comprising x carbon atoms in the presence of a crosslinking agent consisting of a polyethylene glycol dimethacrylate containing in its chain p 'groups of ethylene oxide, n and p being integers the sum of which is equal to 14, x being between 1 and 10, preferably equal to 8, p' being an integer between 2 and 30, preferably equal to 9. When the absorption and diffusion determination technique uses a spectrophotometric method, a polymer will of course be used according to the inv ention transparent between 300 and 800 nanometers and having an acceptable transparency in the UV characterized by a transmittance greater than 80%, allowing spectrophotometric measurements in the UV, in particular between 320 and 400 nanometers.

It is easy to understand that in the cells described above, the walls, in quartz for example, simply serve as a support for the material which they contain and which therefore constitutes, for its part, the essential element of said complete cell intended to measure the penetration or the distribution of a composition or a product for cosmetic or dermatological use.

Thus, the invention relates, according to another aspect, to a cell intended to measure the penetration and / or diffusion of cosmetic products, the receiving part of which consists of a polymer as defined above. The advantage of such a cell is considerable since it allows, by playing on the hydration rate of the polymer to dispense with the use of a receiving liquid for the implementation of cells of the prior art .

In these cells, the polymer can also, as previously expressed, be coated on the surface with a sample of natural or artificial epidermis.

According to another of its aspects, the invention relates to a method for measuring the sun protection coefficient (SPF) of a cosmetic or pharmaceutical product for dermatological use, characterized in that it consists in spreading said product on the surface of a sample of a polymer as defined above, and to compare the transmission of radiation through said sample with that through the same sample before spreading the product.

Generally, in in vitro SPF studies, there are two distinct parts to consider. On the one hand, the support on which the solar product is spread and, on the other hand the calculation method for determining the SPF. The calculation method selected for this study was adopted in 1989 by the "International Commission on Illumination" (B.L. Diffey et al, J. Soc. Cosmet. Chem, 1989, 40, 127-133).

As is conventional in the techniques for determining SPF in vitro, the polymer samples of the invention are advantageously used on the surface of which an imprint reproducing the relief of the skin is deposited beforehand.

The method of preparation of these imprinted polymers is described in the examples in the appendix as well as the technique used for spreading solar products on the surface of the materials.

The details of the radiation transmission measurements used through the sample are also given in the examples.

Among the various polymers described above, advantageously used, in the case of the measurement of the sun protection coefficient of a cosmetic or pharmaceutical product for dermatological use, the polymer obtained by polymerization of 2-hydroxyethylacrylate in the presence of a crosslinking agent consisting of N, N'-methylene-bis-acrylamide.

According to another of these aspects, the invention also relates to a method for measuring the occlusive or emollient power of a product for use cosmetic or dermatological, characterized in that it consists in studying the variations in hydration of a sample of a polymer described above after application of said product to the surface of said polymer.

Among the various polymers described above, advantageously used, in the case of occlusive power, polymers obtained by polymerization of acrylamide or dioctadecyl dimethyl ammonium acrylate, with a crosslinking agent consisting of N, N'-methylene -bis- acrylamide.

It is advantageous to incorporate into the polymeric materials chosen for this application solid particles intended to mimic the geometry of the corneocytes, in particular mica particles or solid particles resulting from the condensation of L-lysine and lauric acid, such as products marketed under the name of amihope by AJINOMOTO, Tokyo, Japan, the surface of which is preferably modified by adsorption of amphiphilic liquids such as phospholiquids, in particular lecithins.

We can also choose for this application to include in the polymeric material a lamellar phase by introducing a nonionic surfactant, for example BRIJ30® during the polymerization step.

The advantage of the polymers according to the invention is that they make it possible to classify the excipients according to their capacity to prevent dehydration of the skin.

As emerges from the description of the materials described above and from the examples of synthesis given in the remainder of this document, the invention provides a means of preparing crosslinked acrylic or methacrylic polymers, the hydrophilicity and hydrophobicity of which are varied as desired. , in particular by a judicious choice of the nature of the monomers used and their respective proportions.

Among these crosslinked acrylic or methacrylic polymers, a certain number are new in themselves. These are, in particular, polymers obtained by polymerization of a methacrylate having a chain consisting of a succession of n hydrophobic groups consisting of isopropylene oxide, p hydrophilic groups consisting of ethylene oxide and d 'an alkyl chain comprising x carbon atoms in the presence of a crosslinking agent consisting of a polyethylene glycol dimethacrylate containing in its chain p' ethylene oxide groups, n and p being integers whose sum is equal to 14, x being between 1 and 10, preferably equal to 8, p 'being an integer between 2 and 30, preferably equal to 9.

These new products, because it is possible to vary their hydrophilic and hydrophobic character at will, will find interesting applications in the cosmetic or pharmaceutical industry, in particular dermatology, in particular as a carrier for medicinal or cosmetic active substances for a topical administration.

Thus, these polymers can be easily used to prepare pastilles, commonly designated by the English term "patch", in which one can incoφor a cosmetic or pharmaceutical active principle, in particular dermatological. The basic monomers constituting the polymeric material used for the preparation of such a support will be chosen as a function of the nature of the active principle, in particular as a function of its solubility and of the desired diffusion conditions for the product. Thus, patches with anti-wrinkle activity can be easily prepared by incoφoration in a tablet of a polymer of the invention of an effective amount of at least one cosmetic agent active for this purpose.

By way of example, mention may be made of a patch prepared by incoφoration in one of the polymers of the invention of vitamin A palmitate in proportions of 0.2% by weight relative to the weight of the polymer.

EXAMPLES

The following examples are given purely by way of illustration of the invention.

They show in a particularly clear manner the ease with which the polymers of the invention can be produced.

They also illustrate the advantage of these polymers as agents intended to mimic the skin barrier or the barrier constituted by a mucosa in order to evaluate the behavior of cosmetic or pharmaceutical products for topical use.

The examples are classified as follows: I - Examples of preparation of useful polymeric materials according to the invention,

II - Characterization of the surface properties of the polymeric materials of the invention, III- Demonstration of the application of the materials described above for the study of the diffusion of cosmetic and / or pharmaceutical products, IV- Demonstration of the utility of the polymers of the invention for measuring the sun protection coefficients, V - Determination of the occlusive power.

I - EXAMPLES OF PREPARATION OF POLYMERIC MATERIALS USEFUL ACCORDING TO

THE INVENTION

Example 1 fMBOl / 93 ^:

4 g of 50 POEP 800 B Blemmer, sold by Nippon Oils and Fats, are mixed at room temperature with 0.5 g of polyethylene glycol 400 dimethacrylate in a glass flask with slow stirring.

The polymerization is carried out as follows: 100 microliters of H ₂ O ₂ at 30% by volume are added. The solution is degassed by adapting the outlet of the flask to a vacuum pump and keeping the flask in an ultrasonic tank for 30 minutes.

The contents of the flask are then poured between two glass plates or into a sprectrophotometer tank depending on the application envisaged. Then the polymerization is carried out under a UV lamp, with an energy greater than 40 m W / cm ² , placed at a distance of 5 cm from the material to be polymerized, this for at least 5 minutes in melting ice.

Example 2 TML 01/93 ^: 5 g of 2-hydroxyethylacrylate are mixed with 0.5 g of polyethylene glycol 400 dimethacrylate. Then the polymerization is carried out as in Example 1. Example 3 (ML 02/931:

5 g of GLM Blemmer, sold by Nippon Oils and Fats, are mixed with 0.5 g of polyethylene glycol 400 dimethacrylate. Then the polymerization is carried out as in Example 1.

Example 4 (ML 03/931:

4 g of OA Blemmer, sold by Nippon Oils and Fats, are mixed with 0.5 g of polyethylene glycol 400 dimethacrylate. Then the polymerization is carried out as in Example 1.

Example 5 (ML 04/931:

2 g of acrylamide are mixed with 0.5 g N, N 'methylene bis acrylamide in 7.5 g of deionized water. Then the polymerization is carried out as in Example 1.

Example 6 (ML04 Ethyl / 931:

2 g of acrylamide are mixed with 0.5 g of polyethylene glycol 400 dimethacrylate in 7.5 g of deionized water. Then the polymerization is then carried out as in Example 1.

Example 7 (ML 05/931:

5 g of 70 PEP-350 B Blemmer, sold by Nippon Oils and Fats, are mixed with 0.5 g of polyethylene glycol 400 dimethacrylate. Then the polymerization is carried out as in Example 1.

Example 8 (ML 06V.

2 g of isopropylacrylamide are mixed with 0.5 g N, N 'methylene bis acrylamide in 7.5 g of deionized water. Then the polymerization is carried out as in Example 1.

Example 9:

This example presents another mode of preparation of polymeric material according to the invention in which the preparation is carried out in several stages: a) Example 9a (MM14 / 931:

A solution 1 is prepared by mixing 21 g of acrylamide with 0.482 g of N, N 'methylene-bis-acrylamide, making up to 100 g with water, the whole is brought to 60 ° C. for 15 minutes. 100 microliters of H ₂ O ₂ at 30% by volume are then added.

It is degassed under vacuum and in the presence of ultrasound as in Example 1, then it is brought to 60 ° C. for 5 minutes.

A solution 2 is prepared by mixing 0.15 g of dimethyldidodecylammonium bromide in 10 g of solution 1. It is subjected to ultrasound for 3 minutes at 50 Watts with an ultrasonic probe of 1 cm in diameter in melting ice until to obtain a bluish color of the final solution.

Then the polymerization is carried out as in Example 1.

b) Example 9b (MM01 / 93): The procedure is as in Example 9a.

Solution 1:

2 g of 50 POEM 800 B Blemmer, sold by Nippon Oils and Fats, are mixed with 0.25 g of polyethylene glycol 400 dimethacrylate, 0.5 g of sodium dodecyl sulfate (SDS). Stir with heating at 60 ° C for 10 minutes and add 50 microlifres of H ₂ O ₂ at 30% by volume.

Solution 2:

3 g of 70 POEM 350 B Blemmer, sold by Nippon Oils and Fats, and 0.1 g of N, N 'methylene bis acrylamide are mixed. It is adjusted to 4 g with deionized water and 100 microliters of H ₂ O ₂ at 30% by volume are added.

Then mixed x grams of solution 1 with y grams of solution 2. It is thus possible to vary the solution 2 / solution 1 ratio (y / x = R), R being less than 1.

The mixture is subjected to ultrasound on contact with melting ice for 3 minutes with an ultrasonic probe at 50W until a bluish transparency is obtained. It is then degassed under vacuum in an ultrasonic tank for 15 minutes.

The polymerization is carried out under the same conditions as Example 1 for 12 minutes. Example 10 (MM16 / 931:

The procedure is as in Example 9b, but solution 1 does not contain SDS and solution 2 is only deionized water.

Example 11 (MB 041:

4 g of 50 POEP 800 B Blemmer, sold by Nippon Oils and Fats, are mixed with 0.5 g of 1.12 dodecanediol dimethacrylate. Then the polymerization is carried out as in Example 1.

Example 12 (MB1:

4 g of 2 Ethylhexyl methacrylate are mixed with 0.5 g of 1.12 dodecanediol dimethacrylate.

Then the polymerization is carried out as in Example 1.

Example 13 (MB 031:

4 g of methacrylic acid C 17 ester are mixed with 0.5 g of 1.12 dodecanediol dimethacrylate.

Then the polymerization is carried out as in Example 1.

Example 14 (MM 01/941:

2 g of acrylamide are mixed with 0.5 g of N, N 'methylene-bis-acrylamide in 7.5 g of deionized water. Then mixing with a surfactant sold under the name Brij 30, by ICI Surfactant, Clamart, France, in the proportions 70 // 30 in% by weight. Then the polymerization is carried out as in Example 1 but at room temperature. The result is an opalescent material composed of an internal lamellar phase.

Example 15: A polymeric material is produced according to Example 1 and then a material is poured over it according to Example 14. A material having two stages is thus produced. Then the polymerization is carried out as in Example 1. Example 16 (MC 04/931: Two solutions marked 1 and 2 are prepared: Solution 1:

2 g of acrylamide are mixed with 0.5 g N, N 'methylene bis acrylamide in 7.5 g of deionized water. Solution 2:

0.5 g of N-Lauroyl-L-lysine, sold under the name Amiope LL by AJINOMOTO, Tokyo, Japan, and 0.1 g of lecithin are mixed in 10 ml of ethanol. Stirred for 1 hour and the product passes to a rotary evaporator at 35 ^° C until the alcohol has evaporated and then placed in an oven at 33 ^° C. for 2 days.

Solution 1 is then mixed with solution 2 in the desired proportions. Depending on the desired application, the amihope can be ordered or organized into strips by simple shearing. The polymerization is carried out according to Example 1.

Example 17 - Preparation of the acry te of dioctadecyldimethylammonium: A peristaltic pump with a flow rate of 2 ml / min is used. An ion exchange column containing Amberlyst IRA 400 Resin, 5 ml (7 meq) is prepared. Then pass through the column successively: 100 ml MeOH, 1.26 g of acrylic acid diluted in 100 ml MeOH (17 mmol), 1.27 g of dioctadecyldimethylammonium bromide. Dilute in 100 ml of MeOH (2 mmol) and elute with 100 ml MeOH.

The alcohol is evaporated from the final eluent on a rotary evaporator at 50 ° C. until a film is obtained on the flask. It is recrystallized from acetone in ice and filtered under suction. rinses with acetone at 0 * C.

Example 18 (MM 14/931:

0.5 g of dioctadecyldimethylammonium acrylate, prepared according to Example 17, is mixed with 0.5 g N, N 'methylene bis acrylamide and 1.5 g of acrylamide in 7.5 g of deionized water

Then the polymerization is carried out as in Example 1. Example 19 (ML 01/941:

7.85 g of 2-hydroxyethylacrylatc are mixed with 0.16 g of N, N 'methylene bis acrylamide in 2 g of deionized water.

Then the polymerization is carried out as in Example 1.

Example 20 (ML 03/941:

7.85 g of hydroxypropylacrylate are mixed with 0.16 g of N, N 'methylene bis acrylamide in 2 g of deionized water.

Then the polymerization is carried out as in Example 1.

Example 21 (MM03 / 931:

7.85 g of 50 POEP 800 B Blemmer, sold by Nippon Oils and Fats, are mixed with 0.02 g N, N 'methylene bis acrylamide in 2 g of deionized water. Then the polymerization is carried out as in Example 1.

II - CHARACTERISAΗON OF THE SURFACE PROPERTIES OF POLYMERIC MATERIALS

The materials which are the subject of the invention have a critical surface tension which is variable as desired and which can be close to that of the skin, which is generally between approximately 25 mN / m to approximately 40 mN / m.

A contact angle goniometer (Rame-hart, model 100-00) and a series of liquids of known surface tension (YC KO, J. of Colloïd and Interface. Science, 1981, 82,25-37) were used to critical surface tension measurements. The results are as follows:

Materials according to:

- example 1: 32 mN / m

- example 2: 41 mN / m

- Example 3: 30 mN / m

III - STUDY OF THE DIFFUSION

In order to demonstrate the mimetic power of the skin of these materials, molecules of cosmetic and / or dermatological interest were tested. These molecules have also been selected for their very different hydrophilic or hydrophobic characteristics.

Thus tretinoin or retinoic acid is a hydrophobic molecule used in the treatment of acne. Esculin is a hydrophilic molecule used in the treatment of visceral hemorrhages, it is also used as a preventive of solar burns as an absorbent of ultraviolet light.

Another example of a hydrophilic molecule tested is fluorescein.

The selected products have been tested in various excipients which are specified below:

III.1 - Excipients used

11 Excipients for tretinoin:

A gel, a cream, liposomes and gelled liposomes were prepared in order to determine the influence of the excipient on the release and diffusion of tretinoin. Different concentrations of tretinoin were prepared for each excipient of 0.005; 0.01 and 0.02% by weight.

a) Freezing:

The gel studied corresponds to the composition given in Table 1 below:

Table 1

b) Cream:

The cream studied in this example is obtained by mixing an aqueous phase whose composition is given in table 2 below and a fatty phase whose composition in% by weight is given in table 3 below:

Table 2

c) Liposomes:

A composition containing liposomes is prepared from the raw materials indicated in Table 4 below, with their percentage by weight: Table 4

Then all of this preparation is diluted to 50% in deionized water.

The size of the liposomes was measured using an Autosizer 2C from

Malvem. The average diameter of the liposomes is 244.8 ± 1.2 nm.

d) gelled liposomes:

The liposomes obtained, below are put in a Carbopol gel

940.

The final proportions in deionized water are as follows: liposome preparation: 50% carbopol 940: 0.6%

21 Excipients for esculin: The excipients used for esculin are commercially available: Hydrocérine®, Solucire® and Lanacire®, available from the company RoC, SA, Colombes, France.

The concentration of esculin is 4%. Preparation for all of the excipients Esculin, in aqueous solution or in powder form, is incorporated into the excipient according to the procedure described for each of them by their supplier.

To obtain an excipient / esculin formulation at 4% in water, 2 g of esculin are dissolved in 5 ml of water; a 40% solution in esculin is thus obtained; then take lg of this esculin solution which is added to 9g of excipient. 31 Excipients for fluorescein:

The diffusion of fluorescein is studied in an aqueous solution at pH 10.

III.2 - Experimental parameters:

Detection and measurement are carried out using a Cary I, UV-Visible spectrophotometer from Varian.

The polymers used are in each case polymerized directly in the spectrophotometer cell and the cell can be equipped, as shown in FIG. 1, with a cover so as to produce a slit of 1 cm in length and 1 mm in height, located 0.5 mm below the tangent to the meniscus formed on the surface of the material after polymerization. This cache is used for diffusion measurements as a function of time.

III.3 - Determination of penetration profiles

For the measurement as a function of the thickness (penetration profiles), the sample holder of the spectrophotometer is modified in order to orient the cell horizontally (peφendicular to the beam slit).

The spectrophotometer is equipped with a stepping motor connected to the CARY 1 control computer. This motor is adjusted for a measurement interval of 0.1 mm, the average acquisition of each point is 1.2 second. The cell moves at a speed of 5 mm / min and the bandwidth of the beam known as SBW (Standard Band Width) is 1 nm. The spectrophotometer is in double beam use, that is to say with a reference beam.

When the polymers are used as a support for a natural or reconstituted epidermis, a sample of such an epidermis cut to the dimensions of this surface is deposited, as shown in FIG. 11, simply on the free surface of the polymeric material, avoiding the formation of air bubbles at the interface of the two materials. III.4 - Determination of diffusion

Six scattering cells are placed in a 6 + 6 sample holder, with six other identical scattering cells for the reference beam. At the start of each diffusion study, it is necessary to balance the intensity of the beams transmitted between the diffusion cell and its reference.

The parameters of the spectrophotometer are as follows: SBW: 2.00 nm; the average acquisition of each point is at least: 2 seconds, the acquisition time varies depending on the case as well as the length or wavelengths of observation. This wavelength is:

For tretinoin: 350 nm For esculin: 350 nm For fluorcscein: 488 nm

III.5 - Results obtained

11 Diffusion of tretinoin:

FIG. 5 represents different penetration profiles (curves 1 to 5) at

160 hours or at 190 hours of the tretinoin contained in the various excipients described above in III.1 through the polymeric material prepared according to Example 1 for a spectrometric measurement carried out at 351 nm. The curves noted 1 to 5 in FIG. 5 represent respectively:

- curve 1: the penetration profile at 160 hours of the gel at 0.01% by weight of tretinoin, - curve 2: the penetration profile at 160 hours of gelled liposomes containing 0.01% by weight of tretinoin,

- curve 3: the penetration profile at 160 hours of liposomes containing 0.01% by weight of tretinoin,

- curve 4: the penetration profile at 190 hours of the 0.2% by weight tretinoin gel,

- curve 5: the 190-hour penetration profile of the cream containing 0.2% by weight of tretinoin.

In the range of concentrations used, the diffusion of tretinoin is very little different from one concentration to another. Table 5 below below gives an average value for six experiments carried out at three concentrations: 0.005, 0.01 and 0.02%, with the excipients described above.

Table 5

Table 6 below gives the values of the diffusion coefficients of the excipients, that is to say without tretinoin.

Table 6

The results obtained relate to the release times of the tretinoin for a concentration of 0.01% in tretinoin in the excipients described above, namely the following:

Gel: 250 minutes Cream: 300 minutes

Liposomes: 750 minutes

Gelified liposomes: 750 minutes We note several points of similarity between this in vitro experiment and in vivo experiments (V. MASINI et al., Journal of Pharmaceutical Sciences, 1993, vol. 82 (n ^* l) p. 17): lipids diffuse faster than tretinoin, release of tretinoin is delayed by liposomes and tretinoin gel penetrates faster than liposomes. We can also speak of co-penetration between excipients and tretinoin within the material.

21 Diffusion of esculin

The material used is that of Example 1 observation wavelength: 350 nm

The results obtained are recorded in Table 7 below:

Table 7

The release times of the esculin contained at 4% by weight in different excipients are as follows depending on the excipient:

Lanacire® and water 6%: 207 minutes Hydrocérine® and water 6%: 517 minutes Solucire® and water 6%: 724 minutes 31 Diffusion of fluorescein The results obtained for the diffusion of fluorescein in aqueous solution at pH 10, through a material obtained by polymerization of a mixture of the monomers used according to example 1 (MB01 / 93) and according to example 5 (ML04 / 93), are recorded in table 8 below. The ratio R is the mass ratio of the monomers used (ML04 / 93)

R =

(MB01 / 93)

Table 8

41 Study of the Diffusion of a Commercial Cosmetic Product The polymer of Example 1 is used, the polymerization of which is carried out, as before, directly in the tank of the spectrophotometer provided with a slot of 1 mm. A cell is thus produced in accordance with that shown in FIG. 11. A sample of stratum comeum (horny layer of the epidermis) of the same surface is placed on the free surface of the polymer to study the diffusion of a commercial cream intended for the hand protection.

The results obtained, as part of a statistical study on 2 different manufacturing batches at 2 different hydration rates of 0 and 20% respectively, are collated in Table 9 below:

Table 9

in which :

- Tep + 500 represents the diffusion time in minutes of the substance through the thickness of the epidermis and 500 μm of polymeric material.

- D'M represents the coefficient of diffusion of the substance through the polymeric material in the presence of the epidermis.

It should be remembered that the stratum comeum itself has a hydration rate of approximately 20% initially; it is nevertheless subjected to great dehydration since the temperature of the UV spectrophotometer is 33 ° C.

From this study, it emerges that: - the age of the donor has no direct influence on the dissemination measures,

- the hydration rate of the material has no clear influence in these diffusions contrary to what has been observed in the case of a polymeric material alone, - the partition coefficient is similar to that of the case of a polymeric material alone while the permeability is much lower (by a coefficient 3),

- finally, the diffusion speeds are also reduced by a coefficient 3 on average and the release times are 2 to 3 times higher. Thus, the presence of stratum comeum necessarily slows diffusion since the active ingredients are forced to cross it before reaching the matrix.

Calculations of the length of the diffusion path in the epidermis (L *) which is the length of the path actually traveled by a diffusing molecule between the coméocytes through the stratum comeum, gave the results recorded in table 10 below. :

Table 10

(1) As an example, the value of L * given in the article by Renate LIECKFELDT in J. Pharm. Pharmacol. 1995, 47, 26-29 is 883 μm. The average values of stratum comeum thickness range between 20 and 30 μm; it is estimated that, in vivo, the length of the "tortuous path" L * is 30 to 40 times greater than the thickness (between 800 μm and 1000 μm).

The calculation method used leads to slightly higher values. However, it should be noted that for a rate of hydration of the matrix of 20%, the value of L * obtained is closer to those calculated in vivo.

Thus, for diffusions in the presence of natural or artificial epidermis, it is preferable to use materials having a hydration rate as close as possible to that of the stiatum comeum, that is to say 20%. This indeed makes it possible to ensure a better mimicry of the stratum comeum within the matrix and to obtain better results of calculation of L *.

IV - MEASUREMENT OF SUN PROTECTION COEFFICIENTS

IV.l - Preparation of the skin relief:

An imprint of about 12 cm ^ of the forearm of a volunteer is made with an insulating silicone film.

The proportions of insulator and activator are 2 g and 4 drops respectively. The exposure time on the forearm is approximately 10 minutes.

IV.2 - Preparation of counterprints:

The silicone imprint is maintained at the bottom of a 55 mm inside diameter beaker, imprint up.

The pre-matrix consisting of the basic constituents of the materials of the invention before polymerization is poured into the beaker and then exposed to UV for 2.5 to 6 minutes depending on the material to be produced and 10 cm from the Blue Light 2000 UV lamp. 800 W.

The material thus polymerized is then peeled off from the silicone imprint and cut to size 12 x 35 mm.

IV .3 - Spreading of solar products.

The procedure followed is that of the FDA, i.e. 2 ml / cm ^ The dimensions of the surface of the polymerized material (or of the 3M Transpore membrane studied for comparison) being 12x35 mm, 8.4 mg of sunscreen should be applied.

However, when spreading the sunscreen on the material, there is approximately 2 mg of sunscreen on the "gloved finger".

We therefore make the correction and apply with the gloved finger, in small touches using a spatula, 10.4 mg of sunscreen on the entire surface of the material.

The solar product is spread out, making small rotary movements, for 10 seconds, so as to obtain a homogeneous spreading. It is noted that the pressure during spreading is light so as not to crush the relief carried by the material.

IV.4 - Measurement of the transmission: The materials are placed on Quartz plates of dimensions

12 x 45 mm, and are kept vertical thanks to a sample holder to make UV-Visible absorption in a thin layer.

The spectral bandwidth is fixed at 1.5 nm, the running speed at 300 nm / min, the average signal integration at 0.2 s, the Visible-UV lamp change is carried out at 400 nm.

The incident ray has a height of 8 mm and a width of the order of a tenth of a mm.

Transmission is first taken for support without solar product and then for support with solar product from 290 to 400 nm every 5 nm. The spectrum establishment time is less than 5 min.

IV.5 - CALCULATION OF THE SPF:

The sun protection factor (SPF) as defined by DIFFEY BL, ROBSON J., J. Soc. Cosmet. Chem. 1989, vol. 40, p. 127-133, is expressed by the relation: 400

Σ E (λ) ε (λ)

290

SPF = 400

∑ E (λ) ε (λ)

290 ^PF ^ in which:

E (λ) denotes the global irradiance at 40 * North latitude at noon ε (λ) represents the action spectrum of erythema. The term "erythema action spectrum" means ε (λ), the intensity of the reaction ε (redness in particular) of the skin undergoing a monochromatic light irradiation as a function of the wavelength λ of this irradiation

PF (λ) = T1 T2 where Tl and T2 respectively represent the light transmission without and with the solar product

PF values are calculated by the ratio of transmissions between 290 and

400 nm every 5 nm.

IV.6 - Results and calibration of synthetic supports

The calibration curves established on the one hand with 3M Transpore supports and on the other hand with the ML 01/94 material (obtained according to example 19) were calculated from SPF measurements of commercial products (see list below). -after) and on 3 to 4 series of two measures (i.e. 6 to 8 different measures in total).

These calibration curves are represented respectively by FIGS. 6 and 7 which give respectively for the Transpore 3M membrane and for the material obtained according to example 19 the values of SPF in vitro as a function of SPF in vivo.

A series of two measurements is made at two different places on the same support. This is in perfect agreement with the random aspect of the spreading. Indeed, we have the choice to make two measurements either to make two weighings and therefore two spreads, or to make the measurement at two different places on the support. These two criteria give the same results with respect to the mean and standard deviation calculations. List of products used commercially available

SPF moisturizing sunscreen: 2-3 SPF water-resistant filtering sunscreen SPF: 4-6 SPF water-resistant filtering sunscreen: 7-9 SPF filtering sun milk: 2-3 SPF filtering sun milk: 4-6 SPF filtering sun milk: 7-9 SPF filtering sun milk: 10-15

The SPF values indicated for each of the above products are the values mentioned by the manufacturer.

We note that for small values of SPF, the curve is linear while for large values of SPF, this linearity is not preserved: the curve is exponential.

This change in the curve is due to a phenomenon of surface tension as well as to a concentration effect of the filter. The solar filter will spread all the better on the support (that is to say in the form of layers) that it will have a great affinity with it. This affinity results in the concept of surface and interfacial tension and is seen on the curve by an exponential growth of the SPF.

From the comparative examination of FIGS. 6 and 7, it appears that the material BG

ML 01/94 provides better linearity than the Transpore membrane

3M. Indeed its exponential curve "merges" with its linear straight line for SPF varying from 0 to 10 approximately while for the Transpore 3M, the supeφosition of the two curves takes place for SPF varying from 0 to 7.5 only.

V - DETERMINATION OF OCCLUSIVE POWER

The objective of this study is to highlight the possibilities of using the materials of the invention to allow the classification of excipients according to their capacity to prevent dehydration of the skin.

Firstly, among the materials of the invention, a choice is established according to their ability to retain water within them. These experiences are called water loss on the blanks because the materials are not covered with occlusive products.

In a second step, known excipients of occlusive power are spread over the surface of the materials.

1) Spreading of the formulation:

The formulations tested are solucire®, hydrocerine® and lanacire®.

For each series, the same experiment, called "blank", is carried out in parallel on the material without formulation.

The various excipients are applied at the rate of 2 mg of excipient per cm "of material surface.

The excipient is spread out by making small rotary movements, for 10 seconds so as to obtain a homogeneous spreading of the formulation.

21 Measurement of water loss:

The materials and excipients thus prepared are then placed in a climatic chamber where the temperature is 33 ° C., external temperature of the skin and the humidity rate of 50%, relative ambient rate, this in order to place the materials in conditions very close to reality.

Each cap is weighed every 30 minutes to determine the water loss, this for an average of 6 hours.

The climatic chamber used is the Humidity Cabinet LHU 212 from Espec. This device allows you to set the temperature and humidity in the enclosure in a certain area.

The humidity rate (RH%) at temperature T ^* C is equal to:

air pressure prevailing in the enclosure RH% = pressure of the saturated water vapor at T "C

The device gives the humidity level by measuring the difference between the temperature of the air prevailing in the enclosure and the temperature of the water contained in a tank in the enclosure according to a temperature-RH conversion table. % (Handbook of chemistry and physics, CRC). The water loss Δwater of the material is expressed by the relation

Δ

Δeau = x 100 Skin

in which :

Δ = P _t0 - P _t

or

P _to represents the weight of the membrane just after application,

P _t , the weight of the membrane at t min after application of the formulation

and

^p water = ^p to ^{x% water}

where% water represents the percentage of water by weight initially contained in the material.

The higher the water loss (that is to say the greater the water Δ), the lower the occlusive power of the formulation.

3) Preparation of materials for the study of occlusive power:

The materials used in this part are those described in part I of the examples. However, the prepared mixture, also called "pre¬ material", is subjected to the procedure described below. Each of the different pre-materials is placed under vacuum for 20 minutes then poured into a 32 mm diameter stopper up to a height of approximately 15 mm. These plugs are then placed in ice, under the Blue Light 2000 UV 800 W lamp of the solar simulator for the polymerization, this for a time specific to each material, given in table 11 below: Table 11

It is observed that just after the polymerization, the materials have a milky white appearance in the center while the outline is clear. This milky white appearance disappears by returning to room temperature and becomes clear again.

This reflects the presence of a water gradient in the material by analogy with the hydration gradient present in the skin. Indeed, the material is rich in water on the contour like the dermis which contains 70% water and is poor in water in the center as the skin is on the surface or in the subcutaneous tissues which contain only 17 to 41 % water.

41 Results obtained: a) Water retention power of the material alone The curves representing, as a function of time, the weight loss of different materials given in FIG. 8 correspond to the water retention power of each of the following materials: curve 1 : ML04 / 93 (example 5) curve 2: ML04 Ethyl / 93 (example 6) curve 3: MC04 / 93 (example 16) curve 4: MM14 / 93 (example 18) curve 5: MM01 / 94 (example 14) curve 6: ML03 / 93 (example 4) curve 7: MM01 / 93 (example 9b) curve 8: MM16 / 93 (example 10) curve 9: ML05 / 93 (example 7)

The greater the weight loss of water, the lower the occlusive power of the material itself.

It appears that the materials' ability to lose water can be linked to their structure.

The internal structural aspect of the network is, in fact, decisive. In fact, the more dense and complex the structure, the more the material retains the water within it. The structural influence is all the more marked since for the same "lipid" network and the same hydrophilic network, a vesicular structure retains water molecules (liquid) much less than a lamellar structure. In fact, the liquid water molecules travel a path within the material towards the surface where evaporation occurs:

This difference in retention is therefore explained by a difference in the length of the path to travel to reach the surface.

The influence of other types of hydrophilic network is manifested by the capacity of the material to form hydrogen bonds or to "complex" the molecules of liquid water. The formation of bonds between the monomers of the hydrophilic network and the molecules of water explains this phenomenon of retention of water which cannot migrate towards the surface.

b) Occlusive power of different excipients The following three commercial excipients have been selected for this study:

- Solucire®

- Hydrocerine®

- Lanacire® known for their very different hydrophobic or hydrophilic characteristics, the first being very hydrophilic, the second very hydrophobic.

The curves given in FIGS. 9 and 10 respectively illustrate the occlusive powers of these excipients on the materials ML02 / 93 and ML04 / 93. These curves represent for each material the percentages of weight loss as a function of time for each of the following excipients:

- Solucire®: curve 1 - Hydrocérine®: curve 2

- Lanacire®: curve 3, as well as in the absence of excipient: curve 4.

It is observed, from FIG. 9, that on the MLO2 material, the occlusive powers of the different excipients are of the same order. On the other hand, it appears in FIG. 10, that on the ML04 material, the most occlusive excipient is hydrocerine®, followed by lanacire® and by solucire®.

Claims

1. Use of a polymeric material consisting of a crosslinked acrylic or methacrylic polymer resulting from the polymerization of a monofunctional acrylic or methacrylic monomer of molecular weight between 50 and 900 and of a polyfunctional acrylic or methacrylic monomer having at least two polymerizable double bonds, as an agent intended to mimic the skin barrier or the barrier constituting a mucosa for evaluating the behavior of cosmetic or pharmaceutical products for topical use.

2. Use according to claim l, characterized in that the crosslinking rate of said acrylic or methacrylic polymers, represented by the volume R occupied by an elementary mesh, is such that R is between 3 and 100 nm ³ , advantageously between 8 and 16 nm ³ -

3. Use according to one of claims 1 or 2, characterized in that said polymeric materials have a surface tension between 20 and 50 ¹⁰ - ³ N / m, preferably between 25 and 40 ^{10 "3} N / m.

4 Use according to one of claims 1 to 3, characterized in that the polyfunctional monomer comprises 2 to 6 polymerizable double bonds, preferably 2.

5. Use according to one of claims 1 or 4, characterized in that the monofunctional monomer consists of a polymerizable function and of a group consisting of n hydrophobic units and / or p hydrophilic units, n and p being integers the sum of which is between 1 and 15.

6. Use according to claim 5, characterized in that the sum (n + p) is between 10 and 15, preferably equal to 14.

7. Use according to one of claims 1 to 6, characterized in that the polyfunctional unit consists of two double bonds associated with n ¹ hydrophobic units and p 'hydrophilic units, n' and p 'being two integers between 0 and 30 and at least one of which is different from 0.

8. Use according to one of claims 1 to 7, characterized in that said polymeric material results from the polymerization of a methacrylate having a chain consisting of a succession of n hydrophobic groups consisting of isopropylene oxide, p hydrophilic groups consisting of ethylene oxide and an alkyl chain comprising x carbon atoms in the presence of a crosslinking agent consisting of a polyethylene glycol dimethacrylate containing in its chain p 'ethylene oxide groups, n and p being integers the sum of which is equal to 14, x being between 1 and 10, preferably equal to 8, p' being an integer between 2 and 30, preferably equal to 9.

9. Use according to one of claims 1 to 8, characterized in that the polyfunctional monomer comprises a succession of units of hydrophilic nature, preferably ethoxy groups.

10. Use according to one of claims 1 to 9, characterized in that said crosslinked acrylic or methacrylic polymer consists of a succession of elementary meshes each node of which is linked to a first hydrophobic segment obtained during the polymerization of the polymerizable functions of the monofunctional monomer and carrying at least one pendant group consisting of at least one hydrophilic unit and / or of at least one hydrophobic unit and with a second segment comprising the non-polymerizable functions of the polyfunctional monomer.

11. Use according to claim 10, characterized in that said second segment containing the non-polymerizable functions of the functional monomer consists of a chain of 1 to 20 hydrophilic units.

12. Use according to one of claims 1 to 11, characterized in that said crosslinked acrylic or methacrylic polymers are transparent polymers between 300 and 800 nm and allowing spcctrometric measurements in UV, in particular between 320 and 400 nm.

13. Use according to one of claims 1 to 12, characterized in that the weight ratio between monofunctional monomers and polyfunctional monomers is between 1 and 10.

14. Use according to one of claims 1 to 13, characterized in that said polymeric materials also contain lipids, in particular phospholipids, or surfactants.

15. Use according to one of claims 1 to 14 characterized in that said materials also contain solid particles intended to mimic the geometry of the comeocytes.

16. Use according to claim 15, characterized in that said particles are hydrophobic particles whose surface is modified by adsoφtion of amphiphilic lipids.

17. Use according to one of claims 1 to 16, characterized in that said polymeric material is covered on the surface with a sample of epidermis, stratum comeum or reconstituted epidermis.

18. Method for studying the diffusion of a cosmetic or pharmaceutical product for topical use through the skin or a mucous membrane, characterized in that it consists in determining the penetration and diffusion profile through a sample of a polymer such as defined in one of claims 1 to 17, as a function of the distance from the surface of said sample and / or of time, by a spectrophotometric or spectroscopic method using in particular infrared, microwave, X-rays, the fluorescence or radiometry or by a chromatographic analysis method.

19. The method of claim 18, characterized in that the diffusion is determined as a function of time by spectrophotometry, the polymer sample being introduced into the tank of the spectrophotometer.

20. The method of claim 19, characterized in that said tank is provided with a slot for performing the spectrophotometric measurement at constant distance from the surface of said sample.

21. Method according to one of claims 18 to 20, characterized in that the polymer used results from the polymerization of a methacrylate having a chain consisting of a succession of n hydrophobic groups consisting of isopropylene oxide, p hydrophilic groups consisting of ethylene oxide and an alkyl chain comprising x carbon atoms in the presence of a crosslinking agent consisting of a polyethylene glycol dimethacrylate containing in its chain p 'ethylene oxide groups, n and p being integers the sum of which is equal to 14, x being between 1 and 10, preferably equal to 8, p 'being an integer between 2 and 30, preferably equal to 9.

22. Cell intended to measure the penetration and / or diffusion of cosmetic and / or pharmaceutical products, in particular dermatological products, for topical use, characterized in that its receiving part of said products consists of a material as described in one of claims 1 to 17.

23. Method for measuring the sun protection coefficient of a cosmetic or pharmaceutical product for dermatological use, characterized in that it consists in spreading said product on the surface of a sample of a polymer as defined in one of claims 1 to 17 and to compare the transmission of a radiation through said sample with that through the same sample before spreading the product.

24. The method of claim 23, characterized in that a polymer sample is used on the surface of which an imprint reproducing the relief of the skin has been previously deposited.

25. Method according to one of claims 23 or 24, characterized in that said polymer is constituted by polymerization of 2-hydroxyethylacrylate in the presence of a crosslinking agent consisting of N, N'-methylene-bis-acrylamide.

26. A method for measuring the occlusive power of a product for cosmetic or dermatological use, characterized in that it consists in studying the variations in the hydration of a sample of a polymer according to one of claims 1 to 17 after applying said product to the surface of said polymer.

27. Crosslinked acrylic polymers capable of being obtained by polymerization of a methacrylate having a chain consisting of a succession of n hydrophobic groups consisting of isopropylene oxide, of p hydrophilic groups consisting of ethylene oxide and an alkyl chain comprising x carbon atoms in the presence of a crosslinking agent consisting of a polyethylene glycol dimethacrylate containing in its chain p 'ethylene oxide groups, n and p being integers whose sum is equal to 14, x being between 1 and 10, preferably equal to 8, p 'being an integer between 2 and 30, preferably equal to 9.

28. Use of a polymer according to claim 27 as a carrier for active medicinal or cosmetic substances for topical administration of said substances.