WO1997011688A1

WO1997011688A1 - Use of a vinyl acetate/n-vinyl-2-pyrrolidone copolymer in a transdermal matrix system

Info

Publication number: WO1997011688A1
Application number: PCT/FR1996/001495
Authority: WO
Inventors: Chantal Bon-Lapillonne; Daniel Dhuique-Mayer; Marie-Christine Math
Original assignee: Laboratoires D'hygiene Et De Dietetique
Priority date: 1995-09-27
Filing date: 1996-09-25
Publication date: 1997-04-03
Also published as: FR2739030A1; AU7135096A; FR2739030B1

Abstract

The use of a vinyl acetate/N-vinyl-2-pyrrolidone copolymer (VA - VP), which is effective to reduce skin irritation, in a transdermal matrix system comprising a carrier and an adhesive matrix for the percutaneous delivery of one or more active principles, is disclosed.

Description

USE OF A VINYL ACETATE COPOLYMER AND

OF N-VINYL-2-PYRROLLDONE IN A SYSTEM

TRANSDERMAL MATRIX

Field of the invention

The present invention relates to the use of a copolymer of vinyl acetate and of N-vinyl-2-pyrrolidone (VA / VP) in a transdermal matrix system, said copolymer intervening here as a suppressing or reducing agent. substantially skin irritation. Prior art

The administration of physiologically active agents percutaneously using transdermal systems of the so-called "matrix" type has experienced considerable growth in recent years. Thus, such systems containing nitroglycerin, nicotine and estradiol have been recently marketed.

These systems are generally formed of a support and an adhesive matrix, in which the active principle is dissolved or dispersed, and which is composed of an adhesive base, associated with liquid compounds which act as solubilizers, plasticizers or promoters of skin absorption of the active ingredient.

These systems allow a diffusion rate and a prolonged release of the active principle adapted to the therapeutic doses to be administered as well as good adhesion to the skin during the treatment. But still too often, during frequent or prolonged use of these devices, skin tolerance problems appear. These phenomena, depending on the patient, result in reddening of the skin, tingling or itching, eruptions of pimples, or in some cases even lesions of the skin tissues such as edemas, erythema or scaling phenomena, in particular during removal. of the device. All this often leads the patient to temporarily stop or stop his treatment.

The causes of these irritation phenomena are generally of 3 types: a) mechanical effects such as for example an excessive adhesion which "pulls" on the cutaneous tissue, b) manifestations resulting from the occlusion effect caused by the matrix transdermal device which leads to a maceration phenomenon, and c) the action of a compound or a mixture of compounds on the skin tissue which may translate by a modification of the successive layers of the stratwn corneum for example by denaturing the lipid structure of the skin or by an increase in skin permeability which leads to their accumulation in the skin tissues and can cause various reactions on cell metabolism; this action or reaction of a compound often depends on the chemical structure of the compound used, on its concentration, on its penetration power and especially on the way it is applied to the skin and associated with other constituents.

In the case of matrix systems, these causes can come into play and the phenomena of skin irritation are often the result of these various causes.

To solve this problem, it is possible to increase the permeability of the devices, to decrease the surface of contact with the skin, to remove the irritant agent if it is known or to decrease its concentration, to inactivate its action by reformulating or reducing the cutaneous passage. These various solutions have thus been proposed in the following documents.

(a) JP-A-54-70340 and JP-A-61-210026 propose to modify the permeability of the support to water vapor. However, the occlusiveness of the support often conditions the obtaining of a flow of acceptable active ingredient to obtain the desired therapeutic dose and therefore the permeability margin over which variations can be made to modify the skin irritation which is often too low. .

(b) JP-A-06 256183 proposes the use of a polyoxyalkylene glycol in a formulation based on poly (styrene-isoprene-styrene) copolymer and

DE-A-4230588 proposes the addition of dexpanthenol in the case of a matrix based on a copolymer of ethylene and vinyl acetate.

But in these cases, the addition of these compounds often has a negative influence on the cohesion of the matrix and can cause a creep of the adhesive mass and therefore a detachment of the transdermal system. They can also reduce the adhesive nature of the polymers used. In this case, effectively, the irritation due to a mechanical effect linked to excessive adhesion to the skin is eliminated, but the flow, adhesion and cohesion parameters of the system must again be readjusted. This can then lead to the creation of a new irritation phenomenon by the addition of a new compound or by modification of the proportions in the formulations. (c) EP-A-0446636 proposes the creation of specific copolymers which make it possible to resolve several of the constraints already mentioned. But according to the active principles and the compounds used in the formulation, this solution implies, in order to have an optimal product, to synthesize, for each active principle or class of active principles used or even each targeted formulation, a particular and complex copolymer which, from a point from an industrial point of view turns out to be unprofitable.

(d) US-4855294 recommends the use of glycerin to reduce the irritant action of certain promoters of skin permeation. However, depending on its percentage, the way it is used or according to the compounds with which it is associated in the matrix, the promoter can be irritant or non-irritant. In addition, skin irritation can be caused by other causes or other products within the matrix than the promoters. It is also known that EP-A-0 409 383, WO-A-93/10201,

EP-A-0 054 279, GB-A-2 115 431 and the summary Derwent (DATABASE WPI, week 8451, No. 84-315114) relating to publication JP-A-59 196 817 describe or suggest topical compositions which can contain a VA / VP copolymer and an active ingredient. In particular WO-A-93/10201 evokes the phenomena of irritation of the skin by plasticizers (see page 8 line 36) and the pH (see page 10 line 46). However, these documents as a whole do not describe or suggest the suppression or the substantial reduction of skin irritation by the non-crosslinked VA / VP copolymer according to the invention.

In fact, all of these previously known solutions go against one or more of the characteristics that a matrix transdermal system must have. In conclusion, a compromise between good skin tolerance and the characteristics required of a transdermal system is in fact difficult to obtain. OBJECT OF THE INVENTION It would therefore be desirable to have a new technical solution which is simple and usable for numerous formulations making it possible to obtain matrix systems for percutaneous administration of active principles which cause zero or slight skin irritation, all maintaining their qualities of maneuverability, reliability and therapeutic effectiveness. Subject of the invention

The above-mentioned aim is obtained by the addition in the formulation of the matrix of the transdermal system of a readily available compound which makes it possible to effectively reduce these phenomena of skin irritation, namely a copolymer of vinyl acetate and of N- vinyl-2-pyrrolidone (VA / VP).

According to the present invention, the use of a copolymer of vinyl acetate and of N-vinyl-2-pyrrolidone (VA / VP) is recommended, according to which said VA / VP copolymer is incorporated in the composition of the matrix. a matrix transdermal system for percutaneous administration of one or more active ingredients, for substantially reducing skin irritation, said matrix system being formed of a support and a matrix.

More specifically, the use of a copolymer of vinyl acetate and N-vinyl-2-pyrrolidone (VA / VP) is recommended here, said use being characterized in that said VA / VP copolymer is incorporated into the composition of a matrix of a matrix transdermal system for percutaneous administration of one or more active ingredients, to substantially reduce skin irritation, said matrix which is associated with a support comprising, in addition to said copolymer VA / VP: (a) one or more active ingredients, (b) an adhesive base, and

(c) at least one liquid compound chosen from promoters of skin absorption, plasticizers and solubilizers of the active principle (s). Preferably, 1 to 12 parts by weight of VA / VP copolymer will be used in the composition of the matrix per 100 parts by weight of said matrix. Detailed description of the invention

By VA / VP copolymer is meant here a non-crosslinked copolymer having a vinyl acetate content of between 30 and 70% by weight relative to the total weight of said copolymer.

According to the invention, the vinyl acetate content in the VA / VP copolymer, which is preferred, is between 35 and 45% by weight relative to the total weight of said copolymer, and better said content will advantageously be between 37 and 41% by weight relative to the total weight of said copolymer. According to the invention, the VA / VP copolymer substantially reduces skin irritation in the sense that it suppresses or reduces it to an acceptable level. The VA / VP copolymer, which is well known for its use as a film-forming agent in aerosols, is therefore readily available on the market. of the VA / VP film-forming copolymers are for example sold (i) under the name PVP / VA by the company GAF CORPORATION in the form of powder for the "PVP / VA-S" series or solutions in ethanol or isopro¬ panol respectively for the "PVP / VA-E" and "PVP / VA-I" series and (ii) under the name KOLLIDON® VA by BASF.

Preferred according to the invention among these in particular the copolymer

Uncrosslinked VA / VP marketed under the name PVP / VA-S-630 which contains 40% by weight of vinyl acetate, on the one hand, and the uncrosslinked VA / VP copolymer marketed under the name KOLLIDON® VA 64 which contains 37.7% by weight of vinyl acetate, on the other hand.

By adhesive base is meant here a polymer or a mixture of polymers generally used by a person skilled in the art in the field of adhesives, such as natural gums, polyisoprenes, polyisobutylenes, in particular the products marketed under the name OPPANOL® by the company BASF, triblock copolymers of the poly (styrene-isoprene-styrene) type, in particular the SIS products marketed under the name VECTOR® by the company EXXON CHEMICAL or KRATON® D by the company SHELL, triblock copolymers of the poly type (styrene -ethylene-butylene-styrene), including

® ment the products marketed under the name KRATON G by the company SHELL, triblock copolymers of the ρoly type (styrene-butadiene-styrene), copolymers of ethylene and vinyl acetate (EVA) such as for example

® products marketed under the name LEVAPREN by the company

BAYER, acrylic copolymers such as for example the products marketed by the company NATIONAL STARCH CHEMICAL B.V under the name DUROTAK or GELVA or those marketed by the company ROHM PHARMA under the name EUDRAGIT and silicone type adhesives such as for example polyorganosiloxanes.

If necessary, various additives can be added to the polymers forming the adhesive base, such as for example an agent conferring adhesion, such as a tackifying resin chosen from the resins generally used in the field of adhesives by those skilled in the art, in particular modified polyterpene or terpene resins, hydrogenated rosin resins, polymerized rosin resins, rosin ester resins, liquid polybutene resin etc. or an antioxidant agent commonly used by those skilled in the art such as for example the products sold by the company CIBA-GEIGY under the name IRGANOX ®.

According to the invention, it is recommended that the content of copolymer

VA / VP in the matrix is lower than that of the adhesive base. In particular, use will be made of a weight ratio (VA / VP copolymer) / (adhesive base) of between 1/105 to 12/55, where said adhesive base is advantageously constituted by the mixture of the adhesive polymer material.

(in particular EVA or SIS) and of the agent conferring adhesion (i.e. the tackifying resin). The term active ingredient is understood to mean here any compound or mixture of compounds which can be used transdermally for the purpose of therapeutic treatment.

Thus, as active principles which can be used, there may be mentioned, for example, antiarrhythmics such as propanolol and timolol, antihypertensive agents such as clonidine, captopril and prazosin, coronary vasodilators such as nifedipine, verapamil, isosorbide dinitrate and nitroglycerin, cerebral vasodilators such as nicardipine, cardiotonics, diuretics such as methylclothiazide and spironolactone, bronchodilators such as salbutamol, antiallergics, antihistamines, antipsychotics such as clocapramine, antidepressants, hypnotic agents such as triamines antiepileptics, antiparkinsonians, antiemetics, antidiabetics, anesthetic agents such as lidocaine, anti-inflammatory agents such as ibuprofen, ketoprofen, naproxen, diclofenac, indomethacin and piroxicam, analgesics such as fentanyl, codeine and morphine, the adrenocortic hormones ales such as hydrocortisone, dexamethasone, prednisolone, androgens such as testosterone, estrogens and progestins such as estradiol, estriol, progesterone, norethisterone acetate, disinfectants such as chlorhexidine , antibiotics such as erythromycin, vitamins, anti-tumor agents such as 5-fluorouracil and vinblastine, beta-blockers, nicotine, anticoagulants, antifungals, antimicrobials, antitussives, dermatological agents, immunosuppressants, anticholinergics and antispasmodics such as oxybutynin, agents for treating an enlarged begnin of the prostate such as finasteride, etc.

All these compounds can be present in the form of physiologically acceptable salts such as, for example, sulphate, hydrochloride, lactate, citrate, fumarate, maleate, or in the form of metal salts such as sodium, potassium, calcium salts, etc. By liquid compound chosen from solubilizers, plasticizers and skin absorption promoters is meant here the products generally used by those skilled in the art in matrix systems for their plasticizing, solubilizing properties or their capacity to increase the permeation of the skin barrier. These products can exhibit several of these properties at the same time.

More specifically, by promoter of skin permeation is meant here any compound or mixture of compounds known to those skilled in the art which causes an increase in the flow of active principle through the skin. Examples of promoters of skin permeation that may be mentioned are ethanol, sulfoxides such as dimethyl sulfoxide, acetamide derivatives such as dimethylacetamide, N-alkyl-2-pyrrolidone derivatives and N-alkyl-2-pyrrolidone derivatives- 5 -carboxylate in which the alkyl group contains 1 to 15 carbon atoms such as for example N-octyl- and N-dodecyl-2-pyrrolidone, dodecylazacycloheptan-2-one, alkyl ethers of polyoxyethylene in which the alkyl group comprises 1 to 20 carbon atoms, the N-hydroxyalkylamides of fatty acid obtained from C ₆ -C ₂₀ fatty acids and N- hydroxyalkylamines in particular monoethanolamine, saturated or unsaturated C6-C ₂ o fatty acids such as lauric and oleic, capric, stearic acids, fatty acid and glycol esters such as ethylene glycol monolaurate or propylene glycol mono- or dilaurate, etc.

Examples of plasticizers that may be mentioned are phthalic acid esters such as diethyl phthalate, peglicol 5-oleate, diethyl sebacate, saturated or unsaturated C ₆ -C ₂₀ fatty acid esters such as palmitate diisopropyl, isopropyl myristate, octyl palmitate, C ₆ -C ₂₀ fatty acid esters and glycerol, liquid surfactants and emoliants such as isostearyl isostearate, polyethylene glycol glycerylcocoate, esters or ethers of fatty acids and polyhydric alcohol, aliphatic alcohols higher in C _t2 -C ₂₀ saturated or not such as n-dodecanol, 2-octyl-1-dodecanol or oleic alcohol and oils such castor oil or sesame oil.

Examples of solubilizers that may be mentioned include polyhydric alcohols such as propylene glycol, polyethylene glycol, crotamiton. 2-pyrrolidone derivatives mentioned above, alcohols and fatty acids, etc.

Preferably according to the invention, use is made of a matrix which consists, for 100 parts by total weight, of a mixture of (α) 1 to 12 parts by weight of VA / VP copolymer having a vinyl acetate content of between 35 and 45% by weight relative to the total weight of said copolymer, (β) 20 to 40 parts by weight of poly triblock copolymer (styrene-isoprene-styrene),

(γ) 35 to 65 parts by weight of tackifying resin,

(δ) 2 to 10 parts by weight of N-alkyl-2-pyrrolidone where the alkyl group contains from 8 to 12 carbon atoms, the preferred N-alkyl-2-pyrrolidone being N-octyl-2-pyrrolidone, ( ε) 5 to 20 parts by weight of pegicol 5-oleate, and (ζ) 0, 1 to 5 parts by weight of 17β-estradiol.

The support receiving the matrix may be any support generally used in occlusive or non-occlusive transdermal systems, of appropriate thickness and impermeable to the constituents of the matrix. Preferably, for example, a support in the form of a film of polyethylene, polypropylene, polyester, a complex (or composite) consisting of polyethylene and of a copolymer of vinyl acetate and ethylene, or also foams.

In practice, the surface of the matrix which is not linked to the support may be covered with a peelable protective layer or film before using the device. Said device can itself be packaged in a waterproof protection such as, for example, polyethylene-aluminum complexes.

The use of a copolymer of vinyl acetate and of N-vinyl-2-pyrrolidone in a matrix system to reduce the phenomena of skin irritation has numerous advantages which will now be explained. Initially it is a simple method and usable for many formulations as shown in the examples below. In fact, whether the matrix contains an EVA copolymer or a SIS triblock copolymer, the same result is found. It is the same with the liquid compounds used which are varied. This means in particular that if one obtains a device with good cohesive, adhesive properties and suitable fluxes, it is possible, by adding only the VA / VP copolymer, to obtain a non-irritating product without having to start all over again. formulations. However, when we know the complexity to obtain an optimal formulation on all these levels, in particular in the case of the administration of several active principles, any solution which makes it possible to increase the field and the choice of the possibilities at the level of the formulation is undoubtedly considerable progress. It is thus possible to keep a compound or a mixture of compounds in the matrix or to increase the concentration without any problem of irritation.

Likewise, thanks to the combination of the two monomers (ie vinyl acetate and N-vinyl-2-pyrrolidone), the VA / VP copolymer has excellent compatibility capacities with the copolymers and tackifying resins used in the adhesive bases as well than with the plasticizers and solubilizers used in the matrix which are generally derivatives of fatty substances. Its incorporation, especially at concentrations of 1 to 12% by weight relative to the total weight of the matrix, does not present any problem. In addition, said copolymer is known for its use in adhesive masses to increase adhesion and its power to dissolve certain active principles such as hormones, which makes its use often beneficial for optimizing the properties of the formulation. It is moreover surprising that a product which promotes adhesion and therefore contact with the skin also has the capacity to reduce skin irritation.

Finally, a final non-negligible aspect is the fact that the use by the patient of a more pleasant product leads to better compliance with the prescribed dosage and therefore to greater chances of success of the treatment.

The process for preparing the transdermal matrix device according to the invention comprises the steps consisting in:

(1 °) mix the VA / VP copolymer, its solvent and the ingredients (a) and (c) and stir the resulting mixture, at an appropriate temperature (in particular 45-

85 ° C) for 10 to 60 minutes,

(2 °) incorporate component (b), the adhesive base, with stirring at an appropriate temperature (in particular 45-85 ° C), until the substances of the resulting mixture are completely dissolved,

(3 ^e ) depositing the mixture thus obtained on a support (in particular a temporary support) at room temperature, and (4 °) heating the coating, which has thus been produced, in order to evaporate the solvent, to a temperature greater than or equal to 45 ° C for at least 15 minutes, then, (5 °) if necessary, transfer the matrix of said coating to a final support. Other advantages and characteristics of the invention will be better understood on reading the description which follows of examples of embodiment and comparative tests. Of course, all of these elements are in no way limiting, but given by way of illustration.

For convenience, the following abbreviations have been used in the following: Es: 17β-estradiol

NETA: norethisterone acetate

SIS: triblock poly (styrene-isoprene-styrene) copolymer

EVA: copolymer of ethylene and vinyl acetate.

VA / VP: copolymer of vinyl acetate and N-vinyl-2-pyrrolidone. Example 1

2 g of PVP / VA-S-630 (copolymer of vinyl acetate and N-vinyl-2-pyrrolidone containing 40% by weight of acetate) are incorporated into fractions of 250 ml containing 10 g of ethanol. of vinyl, sold by the company GAF CORPORATION) and the mixture is stirred until said copolymer is completely dissolved. Then introduced 0.83 g of Es (17β-estradiol), 1.6 g of NETA (norethisterone acetate), 4 g of SURFADONE® LP 300 (N-dodecyl-2-pyrrolidone, sold by the company GAF CORPORATION) , 6 g of MOD (2-octyldodecyl myristate, sold by the company GATTEFOSSE), 4 g of crotamiton [(N-ethyl-N (2-methylphenyl) -2-butenamide, product sold by the company BOEHRINGER INGELHEIM)] and 54 g of ethyl acetate.

The mixture obtained is stirred while heating to a temperature comprised

(S) between 65 and 75 ° C. Then, 21.6 g of LEVAPREN 500 HV (EVA copolymer containing 50% by weight of vinyl acetate, sold by the company Bayer) are introduced in fractions and the mixture is stirred obtained, always by heating between 65 and 75 ° C, for about 50 minutes, until complete dissolution of the EVA copolymer. The dry extract is readjusted to 50% by weight and the mixture obtained is allowed to degas. The latter is coated so as to form a deposit of (100 110) g / m ^′ on a temporary support made of silicone polyester. The coated product thus obtained is heated to 70 ° C for at least 15 minutes in order to evaporate the solvents. The matrix thus obtained is then transferred to a final polyester support.

We cut to the desired size and package the products thus cut in heat-sealable bags. Example 2

The procedure is identical to Example 1, but using 0.62 g of

Es, 1.2 g of NETA, 3 g of SURFADONE® LP300, 3 g of MOD (2-octyldodecyl myristate, sold by the company GATTEFOSSE), 3 g of crotamiton, 0.9 g of PVP / VA-S- 630, 10 g of ethanol, 40.5 g of ethyl acetate and 18.3 g of LEVAPREN® 600 HV (EVA copolymer containing 60% by weight of vinyl acetate, sold by the company BAYER). Example 3

0.25 g of Es, 1 g of NETA, 3 g of PVP / VA S-630, 0.1 g of IRGANOX® 565 (antioxidant sold by the company CIBA-GEIGY) are successively introduced into a 250 ml beaker. ), 2 g of SURFADONE® LP 100 (N-octyl-2-pyrrolidone, sold by the company GAF CORPORATION),

5 g of crotamiton and 30 g of ethyl acetate. This mixture is stirred while heating to

® 50 ° C for about 15 minutes. 20 g of ECR 385 (tackifying resin sold by the company EXXON CHEMICAL) and 18.65 g of VECTOR 4411 D (SIS copolymer sold by the company EXXON CHEMICAL) are then incorporated and the whole is stirred at 50 ° C. until complete dissolution of the compounds.

The mixture obtained is coated on a temporary film of silicone polyester at the rate of (100 ± 10) g / m ² , at room temperature (15-25 ° C). The coating thus produced is heated at 50 ° C for at least 30 minutes in order to evaporate the solvent. The matrix thus obtained is then transferred to a final polyester support. Shapes are then cut to the desired dimensions which are packaged in heat-sealable bags. Example 4

The procedure is analogous to Example 3, but in this case the crotamiton is replaced by diethyl phthalate. Therefore, 1 g of NETA, 0.25 g of Es, 3 g of PVP / VA S-630, 0.1 g of IRGANOX® 565, 2 g of SURFADONE® LP 100, 5 g of diethyl phthalate are used. , 30 g of ethyl acetate, 20 g of ECR® 385 and 18.65 g of VECTOR® 4411 D. Example 5

The procedure is analogous to Example 3 starting from 0.75 g of Es, 1 g of KOLLIDON® VA 64 (VA / VP copolymer containing 37.7% by weight of vinyl acetate relative to the total weight of said copolymer, and marketed by the company BASF), 2 g of SURFADONE® LP 100, 5.5 g of pegicol 5-oleate and 30 g of ethyl acetate, stirring at 50 ° C for about 15 minutes, then incorporation of 25, 25 g ECR®385 and 15.5 g VECTOR® 4211 D. Comparative example 1 (CP1)

0.62 g of Es are successively incorporated into a 250 ml beaker.

1.2 g of NETA, 3 g of SURFADONE® LP 300, 4.5 g of M.O.D, 4.5 g of crotamiton and 40.5 g of ethyl acetate.

The mixture obtained is heated with stirring between 65 and 75 ° C. We introduce

® then, in fractions, 16.2 g of LEVAPREN 500 HV and the mixture is still stirred while still heating for approximately 50 minutes until the EVA is completely dissolved. The dry extract is readjusted to 50% and the mixture obtained is allowed to degas.

The latter is coated so as to form a deposit of (100 ± 10) g / m ² on a temporary support made of silicone polyester. The coated product is dried at 70 ° C for about 15 minutes to evaporate the solvent. The matrix thus obtained is transferred to a final polyester support. We cut to the desired size and package the products thus cut in heat-sealable bags. Comparative example 2 (CP2)

The procedure is identical to example CP1, but 0.83 g of Es, 1.6 g of NETA, 4 g of SURFADONE® LP 300, 4 g of MOD, 8 g of crotamiton, 54 g of are used here. ethyl acetate and 21.6 g of LEVAPREN® 600 HV. Comparative example 3 (CP3)

0.25 g of Es, 1 g of NETA, 0.1 g of IRGANOX® 565, 2 g of SURFADONE® LP 100, 7.5 g of crotamiton and 30 g of are successively introduced into a 250 ml beaker. ethyl acetate. This mixture is stirred with heating at 50 ° C for about 15 minutes. 19 g of ECR® 385 are then incorporated (adhesive hydrocarbon resin sold by the company EXXON CHEMICAL) and

20.15 g of VECTOR® 4411 D and the whole is stirred at 50 ° C until complete dissolution of the compounds. The mixture obtained is coated on a temporary film of silicone polyester at the rate of (100 ± 10) g / m ² at room temperature (15-25 ° C).

The coating thus produced is heated at 50 ° C for at least 30 minutes in order to evaporate the solvent. The matrix thus obtained is then transferred to a final polyester support. Shapes are then cut to the desired dimensions which are packaged in heat-sealable bags. Comparative example 4 (CP4)

In this case, the procedure is analogous to example CP3, but the crotamiton is replaced by diethyl phthalate. 0.25 g of

Es, 1 g of NETA, 0, 1 g of IRGANOX® 565, 2 g of SURFADONE® LP 100, 7.5 g of diethyl phthalate, 30 g of ethyl acetate, 19 g of ECR® 385 and 20.15 g of VECTOR® 4411 D. Tests

From the devices described in the examples provided above, measurements of primary skin irritation (CPI) were carried out according to the protocol described below.

The measurement of skin irritation phenomena caused by a transdermal system is evaluated by carrying out primary skin irritation tests in rabbits.

These tests are carried out according to the following references and standards: Testing biomaterials in rabbits for primary skin irritation Standard F 719-81; 1993

American Society for Testing and Material - Annual Book of ASTM Standard Philadelphia USA 1993 pages 185-186; and ISO 10993-10 (Draft 08/1993)

Biological Evaluation of Medical Devices Test for Irritation and Sensitization.

The albino rabbit test is generally the method used and requested by many legislations.

The principle of the test and its implementation are as follows: for each formulation, a batch of 6 albino rabbits is used. A few hours before applying the product, the backs and sides of the rabbits are clipped in order to free up eight test areas. Before the test, the skin of 4 of the 8 prepared sites is abraded to create an area of bare skin. Abrasion is done in such a way as to attack the epidermis without reaching the dermis and excluding any bleeding. Each 2.54 cm ^" transdermal system is placed on an intact area and an abraded area. On each rabbit a control (gauze) is also placed on an intact area and an abraded area.

The sites are immediately covered with a gauze pad and the whole is covered with a sheet of polyethylene.

The animal's trunk is well wrapped with an adhesive tape

("URGO CREPE" of 6 cm manufactured by the company URGO, 21300 CHENOVE, France). Patches are left in contact with the skin for 24 hours. After an additional 24 hours, the dressings are removed and the systems to be tested are removed.

The reactions are observed 1 hour, 24 hours and 48 hours after removing the systems to be tested, they are coded for erythema and edema according to the following numerical scale:

Erythematous (and escarriform) lesions: no erythema 0 very slight erythema (barely perceptible) 1 well-defined erythema (pale pink) 2 moderate to severe erythema (well-defined red area) 3 severe erythema (purple red) with or without bedsores 4

Edematous lesions: no edema 0 very slight edema (barely visible) 1 slight edema (edges of the area well defined by swelling) 2 moderate edema (thickness about 1 mm) 3 severe edema (swelling greater than 1 mm and s' extending outside the area of application) 4 The index of individual primary skin irritation (IIP) of a substance for each animal is the total of the evaluations for erythema and edema on intact and abraded skin, three reading times 1, 24 and 48 hours after removing the dressing, divided by the number of sites read (6).

The average index of primary skin irritation (CPI) is equal to the sum of the IIP for each substance for all the animals tested, sum divided by the number of animals tested (6).

From the average skin irritation index, the results are qualified according to the following scale: if CPI <0.4: negligible irritation if 0.5 <CPI ≤ 1, 9: mild irritation if 2 ≤ CPI <4.9 : moderate irritation if 5 <CPI <8: severe irritation

All the results obtained are collated in Table I below. Analysis of this table shows that, in all cases, the addition of a small amount of 3 to 6% of VA / VP copolymer in the formulation makes it possible to significantly reduce 1TPC. We go through the examples comparatives CP1 to CP4 of an IPC greater than 2 to an IPC of the order of 1 for the matrix devices of Examples 1 to 4 according to the invention containing the VA / VP copolymer.

In addition, this result is found with adhesive matrices of different formulations since in Examples 1 and 2 the adhesive base forming the matrix is an ÊVA copolymer and in Examples 3 and 4 a triblock SIS copolymer.

Likewise, whatever the combination of the compounds (such as N-alkyl-2-pyrrolidone derivatives, crotamiton, diethyl phthalate or 2-octyldodecyl myristate) used in combination with SIS or EVA, always a decrease in the CPI. These compounds, which are known to have an action on the skin layer, may or may not cause skin irritation depending on their concentration or association. According to the examples of the invention, the addition of the VA / VP copolymer substantially decreases or eliminates this phenomenon if the presence of one or more of these compounds is the cause or one of the causes of the irritation.

Finally, it is surprising that the VA / VP copolymer, which is known to increase the adhesive power of the adhesive bases and which therefore reinforces the contact of the matrix systems on the skin, leads to lowering the CPI. It is in fact known to those skilled in the art that the stronger the skin contact, the higher the risk of skin irritation by mechanical effect.

All this clearly demonstrates the advantage of using, in the matrix formulation of a transdermal device, a VA / VP copolymer which makes it possible to obtain, by virtue of its ability to reduce the CPI, products which are better accepted by the patient and to extend the range of formulations available to make such systems.

TABLE I Assessment of the primary skin irritation index

Claims

1. Use of a copolymer of vinyl acetate and of N-vinyl-2-pyrrolidone (VA / VP), said use being characterized in that said copolymer VA / VP is incorporated in the composition of a matrix of a matrix transdermal system for percutaneous administration of one or more active ingredients, for substantially reducing skin irritation, said matrix which is associated with a support comprising, in addition to said VA / VP copolymer:

(a) one or more active ingredients,

(b) an adhesive base, and

(c) at least one liquid compound chosen from promoters of skin absorption, plasticizers and solubilizers of the active principle (s).

2. Use of a VA / VP copolymer according to claim 1, characterized in that the matrix comprises in its composition from 1 to 12 parts by weight of said copolymer per 100 parts by weight of said matrix.

3. Use of a VA / VP copolymer according to any one of claims 1 and 2, characterized in that said VA / VP copolymer has a vinyl acetate content of between 30 to 70%, preferably between 35 and 45% and better between 37 and 41% by weight relative to the total weight of said copolymer.

4. Use of a VA / VP copolymer according to claim 1, characterized in that the adhesive base of the matrix is a copolymer of ethylene and vinyl acetate.

5. Use of a VA / VP copolymer according to claim 1, characterized in that the adhesive base of the matrix is formed from a poly (styrene-isoprene-styrene) triblock polymer combined with a tackifying resin and an antioxidant .

6. Use of a VA / VP copolymer according to claim 1, characterized in that the liquid compound or compounds of the matrix are chosen from diethyl phthalate, pegicol 5-oleate, N-alkyl-2-pyrrolidones in which the alkyl group is C ₁ -C ₁₅ , crotamiton, mono- or diesters of lauric acid and propylene glycol, 2-octyldocecyl myristate and mixtures thereof.

7. Use of a VA / VP copolymer according to claim 1, characterized in that the active principle of the matrix is chosen from estrogenic components, progestogen components and their mixtures.

8. Use of a VA / VP copolymer according to claim 7, characterized in that said active principle is chosen from 17β-estradiol, norethisterone acetate and their mixtures.

9. Use of a VA / VP copolymer according to claim 1, characterized in that the active principle of the matrix is a non-steroidal anti-inflammatory, preferably ibuprofen.

10. Use of a VA / VP copolymer according to claim 1, characterized in that said matrix consists, for 100 parts by total weight, of a mixture of

(α) 1 to 12 parts by weight of VA / VP copolymer having a vinyl acetate content of between 35 and 45% by weight relative to the total weight of said copolymer,

(β) 20 to 40 parts by weight of poly (styrene-isoprene-styrene) block copolymer,

(y) 35 to 65 parts by weight of tackifying resin,

(δ) 2 to 10 parts by weight of N-alkyl-2-pyrrolidone in which the alkyl group contains from 8 to 12 carbon atoms, the preferred N-alkyl-2-pyπolidone being

N-octy 1-2-pyrrolidone,

(ε) 5 to 20 parts by weight of pegicol 5-oleate, and

(ζ) 0.1 to 5 parts by weight of 17β-estradiol.