MXPA98002327A - Transderm matrix system - Google Patents

Abstract

The present invention relates to a novel system of transdermal matrix for the percutaneous administration of a hormone, the system, comprising a support and an adhesive matrix, is characterized in that the matrix comprises: (a) from 39 to 61 parts by weight of ethylene vinyl acetate copolymer, (b) from 12 to 17 parts by weight of 2-octyldodecyl myristate, (c) from 5 to 17 parts by weight of diethyl phthalate, (d) from 10 to 16 parts by weight, weight of a compound selected from the N-alkyl-2-pyrrolidones, in which the alkyl group is a group of 4 to 15 carbon atoms, (e) from 1 to 12 parts by weight of at least one hormone selected from the group constituted by the estrogen compounds and the progestin compounds. The invention also relates to a process for the preparation of this transdermal matrix system, and to its use in therapeutics.

Description

SYSTEM. OF TRANSDERMIC MATRIX FIELD OF THE INVENTION The present invention has for its object a novel matrix system for the percutaneous administration of an estrogen compound and / or a progestogen compound, the system is formed of a support and an adhesive matrix which is composed of an ethylene copolymer and of vinyl acetate (EVA) and of the specific association of three compounds: diethyl phthalate, 2-actyldodecyl myristate, and N-alkyl-2-pyrrolidone, and in which the estrogen compound is dissolved and / or the progestogen compound. The invention also relates to a process for the preparation of the matrix system and its use in therapy.

BACKGROUND OF THE INVENTION Numerous systems of percutaneous administration of a hormone, in particular of an estrogen-only compound, for the treatment of the symptoms of menopause and osteoporosis in the context of treatments qualified as "hormone-deficit replacement therapy" are today available. Among these are today so-called "deposit" systems, in which the active principle is dissolved in a solvent that serves as a transport vector through a microporous membrane towards the skin. Such is the case of the device based on 17ß-estradiol marketed by the company CIBA-GEIGY under the name ESTRADERM "TTS." In parallel, there are systems called "matrices", in which the active ingredients are dissolved or dispersed within the body. an adhesive matrix based on polymers such as copolymers of EVA, acrylics, poly (styrene-isoprene-styrene), etc. Such is the case of the device based on 17β-estradiol, marketed under the name OESCLIM® by the company LABORATOIRES FOURNIER SCA On the other hand, the implementation of percutaneous administration systems of an estrogen compound and a progestogen compound in these matrix systems still poses many problems, since it is known that estrogens and progestogens are products that are little soluble in the polymers used in the formulation of the matrix system.Also, each of these active principles can be partially or totally incompatible with certain constituents of the formulation (resins, solvents, plasticizers, polymers, cutaneous absorption promoters). They may have different solubilities and stability temperatures, and one of the two may recrystallize with time, be degraded during the application, or not be usable in the compositions only at very low concentrations to obtain the desired therapeutic effect. Likewise, there is no universal cutaneous absorption promoter for all active ingredients, in order to increase their percutaneous flows. Thus, to administer different active ingredients, often several promoters and / or solvents must be used. 0, the introduction of any novel substance could cause or cause novel problems of irritation and of cohesion or adhesion in the system. In the same way, the set of these difficulties (compatibility, solubility) also acts between the different constituents of the formulation different from the active principles, and thus increases the difficulties to be solved. In addition to these requirements for skin tolerance, adhesion and cohesion of the system, dosing difficulties are added. In general, the active principles have different skin permeabilities, which thus impose different absorption fluxes for each active ingredient. The preparation of a formulation that allows the administration of the desired therapeutic dose for each active ingredient becomes very complex. In practice, this preparation is very often not feasible, and leads to a dead end, or to unsatisfactory systems, and thus economically unprofitable. This explains why no system of this type is still marketed.

In fact, the only transdermal system of administration of two hormones already available is a system of "deposit" based on 17β-estradiol and norethisterone acetate, which is marketed by the company CIBA-GEIGY under the name ESTRAGEST ^ TTS. It is also known to the person skilled in the art that estrogens and / or progestagens are molecules that traverse the cutaneous barrier. Thus, the amounts released from these active ingredients to obtain the desired therapeutic effect are generally small in relation to the initial amounts present in the transdermal devices, whatever their type, which results in obtaining poor yields. Although matrix systems [where the matrix is based on a copolymer of ethylene and vinyl acetate (EVA)] administration of an estrogen compound and / or a progestogen compound have already been described in published patent applications FR -A-2 612 785, EP-A-0 279 982, OA-92/07589 and EP-A-055 360, none of these publications disclose, nor suggest the specific formulations of the invention that allow to solve the drawbacks described above.

OBJECTS OF THE INVENTION According to the invention, it is proposed to realize systems of matrices based on EVA for the simultaneous administration of an estrogen compound and a progestogen compound to solve the problems mentioned above, and which also present excellent yields. It is also proposed to perform such matrix systems for the administration of an estrogen-only compound, or a progestogen-only compound that exhibit excellent yields. According to a second aspect of the invention, it is proposed to provide a method of preparing these matrix systems. According to yet another aspect of the invention, it is proposed to provide a use of such a system of matrices in the treatment of menopause and osteoporosis.

OBJECT OF THE INVENTION The aforementioned objects are obtained thanks to a novel technical solution, according to which the matrix of the matrix system, which contains an estrogen compound and / or a progestogen compound, consists essentially of EVA and of the specific association of three compounds, Diethyl phthalate, 2-octyldodecyl myristate and N-alkyl-2-pyrrolidone. More precisely, according to the invention, a transdermal matrix system for the percutaneous administration of at least one hormone is recommended, the system, comprising a support and an adhesive matrix, is characterized in that the matrix comprises: (a) from 39 to 61 parts by weight of ethylene vinyl acetate copolymer, (b) from 12 to 17 parts by weight of 2-octyldodecyl myristate, (c) from 5 to 17 parts by weight of diethyl phthalate, (d) from 10 to 16 parts by weight of a compound selected from the N-alkyl-2-pyrrolidones, in which the alkyl group is a group of 4 to 15 carbon atoms, (e) from 1 to 12 parts by weight of at least a hormone selected from the group consisting of estrogen compounds and progestin compounds. According to a second aspect of the invention, a transdermal matrix system is also recommended for the percutaneous administration of at least one hormone, the system comprising a support and an adhesive matrix is characterized in that the matrix comprises: (a) 39 to 61 parts by weight of ethylene vinyl acetate copolymer, (b) from 12 to 17 parts by weight of 2-octyldodecyl myristate, (c) from 5 to 17 parts by weight of diethyl phthalate, (d) ) from 10 to 16 parts by weight of a compound selected from the N-alkyl-2-pyrrolidones, in which the alkyl group is a group of 4 to 15 carbon atoms, (e) from 1 to 12 parts by weight of at least one hormone selected from the group consisting of the estrogen compounds and the progestagen compounds, and (f) from 1 to 10 parts by weight of a copolymer of vinyl acetate and N-vinyl-2-pyrrolidone (abbreviated VA / VP). According to the invention, a process for the preparation of the transdermal matrix system is also recommended, the method is characterized in that they comprise the steps consisting of: (a) successively incorporating in a reactor, at a temperature lower than the boiling point of the solvent or of the system of solvent used, diethyl phthalate, N-alkyl-2-pyrrolidone, 2-octyldodecyl myristate, the hormone selected from the group consisting of the estrogen compounds, the progestin compounds, and their mixtures, the VA copolymer / VP if present in the formulation, and the EVA, and shake the obtained mixture; (ß) then incorporate the solvent or the solvent system, and stir the assembly always at the same temperature, until the total dissolution of the EVA and the complete homogenization of the mixture; (?) depositing the homogeneous mixture resulting from stage (ß) on a non-stick temporary support, at a temperature comprised between 50 and 70 ° C, to obtain a deposit of 50 to 300 g / m2 of support; (6) heating the coating obtained, to evaporate the solvent or the system of solvents, at a temperature comprised between 40 and 80 ° C, depending on the boiling point of the latter; and (e) transferring the dry matrix thus obtained onto a final support. The use of a transdermal matrix system is also recommended for obtaining a medicament intended for therapeutic use against the symptoms of menopause or osteoporosis.

BRIEF DESCRIPTION OF THE DRAWINGS In the appended drawings, Figure 4 represents the amount (Q), expressed in μg / cm2, of 17β-estradiol released as a function of time (t), expressed in hours, and Figures 1 to 3 represent the yield (R) , expressed as a percentage, of 17β-estradiol or NETA (norethisterone acetate) as a function of time (t), expressed in hours.

More precisely in these drawings, - Figure 1 allows to compare (in the system R / t) curves 3, 6 and Ei relative to the yield of the release of 17β-estradiol and obtained respectively with the products of examples 3 to 6 according to the invention, and a transdermal reference product known under the name ESTRAGEST TTS and marketed by the company CIBA-GE1GY (referenced in Ei herein); - Figure 2 allows comparing (in the R / t system) the curves 3, 6 and E2 relative to the yield of the NETA release, and obtained respectively with the products of the examples 3 and 6 according to the invention, and the ESTRAGEST ™ TTS (with reference in the present of Ez); Figure 3 allows to compare (in the R / t system) curves 2, 8 and E3 relative to the yield of the release of 17β-estradiol, and obtained respectively with the products of examples 2 and 8 according to the invention and a product transdermal reference known under the name OESCLIM ^ and marketed by the company LABORATOIRES FOURNIER SCA (with reference in the present of E3); Figure 4 allows to compare (in the system Q / t) curves 3, 6 and E4 relative to the release of 17β-estradiol, and obtained respectively with the products of examples 3 and 6 according to the invention, and OESCLIM ™ ( with reference to the present of E4).

DETAILED DESCRIPTION OF THE INVENTION Preferably, a copolymer of ethylene and vinyl acetate having a vinyl acetate content of between 30 and 75% by weight, in particular of the order of 45 to 60% by weight, based on the weight of the copolymer of ethylene / vinyl acetate. An EVA mixture such as having different molecular weights or different contents of vinyl acetate could be used if necessary. The N-alkyl-2-pyrrolidones here comprise substances in which the alkyl group is a group formed from 4 to 15 carbon atoms, such as for example N-dodecyl-2-pyrrolidone and N-octyl-2 -pyrrolidone. In the present invention, N-dodecyl-2-pyrrolidone will be particularly preferred. By "hormone" is meant in the context of the present invention the estrogen compounds and / or the progestogen compounds. Among the estrogen compounds which are suitable according to the invention, mention may be made in particular of 17β-estradiol and estradiol derivatives, in particular the mono- and di-esters of estradiol, such as, for example, 17-estradiol acetate, 3.17. - estradiol diacetate, estradiol 3-benzoate, estradiol 17-undecanoate, alkylated derivatives at position 17 of estradiol such as ethinylestradiol, ethinylestradiol 3-isopropylsulfonate, ethylestradiol, quinestrol, mestranol and, if necessary, their mixtures.

Among the progestogen compounds which are suitable according to the invention, mention may be made in particular of progesterone, edrogesterone and its derivatives (in particular 17-hydroxyprogesterone acetate, medroxyprogesterone acetate, norethisterone and its derivatives (particularly 17-norethisterone acetate). ), norpregnane, nomegestrol acetate and levonorgestrol According to the invention, 17β-estradiol is preferably used as an estrogen compound, and 17-norethisterone acetate (NETA) as a progestogen compound. and N-vinyl-2-pyrrolidone, it is understood herein a copolymer having a content of vinyl acetate comprised between 30 and 70% by weight relative to the weight of the copolymer, such products are well known for their use as agents film formers in aerosols, and are for example marketed under the name "PVP / VA" by the company GAF CORPORATION, in the form of powder for the series PVP / VA-S, or solution in ethanol or in isopropanol respectively for the series PVP / VA- E and PVP / VA-I, or by BASF under the name Kollidon VA. Among these, the VA / VP copolymer marketed under the name PVP / VA-S-630, which contains 40% by weight of vinyl acetate, and the VA / VP copolymer marketed under the name Kollidon VA 64, will be particularly preferred. It contains 37.7% by weight of vinyl acetate.

The support received by the matrix may be any support used generally in occlusive transdermal systems or not, and impermeable to the constituents of the matrix. For example, a support which is in the form of a film of polyethylene, polypropylene, polyester, a complex or compound consisting of polyethylene and a copolymer of vinyl acetate and ethylene, or foams, will be preferred. If necessary, a supplementary adhesive strip, for example peripheral, in the form of an aureole, may be added to the system to optimize its adhesion properties. Practically, the surface of the matrix that is not attached to the support may be coated with a layer of release protective film prior to the use of the device. The device can itself be packaged in a waterproof protection, such as polyethylene-aluminum complexes. Thanks to the excellent yields of hormonal release it provides, the matrix system according to the invention has numerous advantages, which will be explained in the following. An advantage is that of the cost price, very clearly diminished in relation to the devices already commercialized, thanks to the use of a smaller amount of hormone (s), whose price is high. The risks of contamination of the environment by these hormones are also diminished, when the product is thrown after the period of treatment. Only the formulations according to the invention in which an EVA copolymer is associated with the three specific compounds: N-alkyl-2-pyrrolidone, diethyl phthalate and 2-octyldodecyl myristate make it possible to obtain these results. In addition, the fact of using less estrogen and / or progestogens, obtaining more important liberated quantities, simplifies the preparation and the realization of the formulations that form the matrix of the devices. In effect, the solubility problems of the hormones in the EVA are minimized or suppressed, as well as the risks of chemical or physical incompatibility with the other constituents of the matrix. It is the same for the problems of crystallization of hormones, and instability of the devices over time, these latter phenomena are unacceptable for the validation and commercialization of products with a therapeutic objective, such as transdermal systems. Thanks to all these advantages, it is finally reached to obtain an acceptable and marketable matrix system for the administration of an estrogen compound and a progestogen compound, and which presents excellent yields. If necessary, the cohesion of the device can be optimized by the use of a mixture of EVA of different molecular weights. Likewise, the addition of VA / VP copolymer allows to optimize the adhesion properties and the solubility of the hormones in the matrix. Surprisingly, it also allows minimizing the skin irritation phenomena that certain devices can present. The transdermal systems according to the invention are made following the techniques generally employed by the person skilled in the art: coating in solvent phase or according to the so-called "hot melt" technique, that is, in the absence of solvent. In both cases, in the framework of an industrial production, large surfaces are coated, which are cut immediately, to bring the devices to the dimensions adapted to the dose of active principle that is going to be administered during a certain time. Within the framework of the so-called "solvent phase" technique, a process for the preparation of an adhesive matrix system process according to the invention is recommended, which comprises the following steps: (a) they are successively incorporated in a mixer, a temperature below the boiling point of the solvent or solvent system used, such as for example ethyl acetate, or a mixture of ethyl acetate / ethanol, diethyl phthalate, N-alkyl-2-pyrrolidone, 2-octyldodecyl myristate, the hormone selected from the group consisting of the estrogen compounds, the progestin compounds, and their mixtures, the VA / VP copolymer if present in the formulation, and the EVA, and the mixture is stirred obtained; (ß) the solvent or solvent system is incorporated and the whole is stirred always at the same temperature, until the total dissolution of the EVA and the complete homogenization of the mixture; (?) the homogenous mixture thus obtained is deposited, at a temperature comprised between 50 and 70 ° C, on a temporary non-stick intermediate support, particularly a silicone-coated polyester film, at a rate of 50 to 300 g / m2 of support; (d) the solvent or solvent system is evaporated, heating to a temperature comprised between 40 and 80 ° C, preferably 60 to 80 ° C, as a function of the boiling point of the solvent or system of solvents; and (e) the dry matrix thus obtained is transferred to stage 4 on the selected final support. The novel adhesive matrix device according to the invention is particularly useful for the treatment of osteoporosis, the symptoms of menopause and the cardiovascular risks that are derived, within the framework of a therapy called "deficit hormone replacement", as well as for any treatment based on the administration of estrogens and / or progestogens transdermally.

BEST WAY TO CARRY OUT THE INVENTION The best mode of application of the invention consists in resorting to a transdermal matrix system, whose matrix contains, for a total of 100 parts by weight: (a) 54 parts by weight of copolymer of ethylene and vinyl acetate, (b) 17 parts by weight of 2-octyldodecyl myristate, (c) 5 parts by weight of diethyl phthalate, (d) 16 parts by weight of N-dodecyl-2-pyrrolidone, (ei) 2 parts by weight of 17β-estradiol, (e2) 5 parts by weight of norethisterone, and (f) 1 part by weight of a copolymer of vinyl acetate and of N-vinyl-2-pyrrolidone (VA / VP), on the one hand, or (a) 62 parts by weight of copolymer of ethylene and acetate of vinyl, (b) 13 parts by weight of 2-octyldodecyl myristate, (c) 10 parts by weight of diethyl phthalate, (d) 10 parts by weight of N-dodecyl-2-pyrrolidone, (e) 3 parts by weight of 17β-estradiol, and (f) 2 parts by weight of a copolymer of vinyl acetate and N-vinyl-2-pyrrolidone (VA / VP), on the other hand, or (a) 53 parts by weight of ethylene vinyl acetate copolymer, (b) 17 parts by weight of myristate 2-octyldodecyl, (c) 10 parts by weight of diethyl phthalate, (d) 13 parts by weight of N-dodecyl-2-pyrrolidone, (e) 6 parts by weight of norethisterone acetate, and (f) 1 part by weight of a copolymer of vinyl acetate and N-vinyl-2-pyrrolidone (VA / VP). In these formulations, the EVA used advantageously has a content of vinyl acetate of 60% by weight relative to the weight of the copolymer of ethylene and vinyl acetate. The VA / VP copolymer advantageously has a vinyl acetate content of 35 to 40% by weight relative to the weight of the VA / VP copolymer. Other advantages and features of the invention will be better understood on reading the following description of the exemplary embodiments and comparative tests. Of course, the set of these elements is not in any way limiting, but is given by way of illustration. For convenience, the following abbreviations have been used in the following: EVA: copolymer of ethylene and vinyl acetate Es: 17β-estradiol NETA: norethisterone acetate VA / VP: copolymer of vinyl acetate and N-vinyl-2- pyrrolidone.

Example 1 Into a 250 ml flask, 0.62 grams of 17β-estradiol, 1.2 grams of NETA, 3 grams of SURFADONE® LP 300 (N-dodecyl-2-pyrrolidone (marketed by GAF CORPORATION), 3.9 grams of myristate were successively introduced. 2-octyldodecyl marketed by the company GATTEFOSSE (hereinafter abbreviated as "MOD"), 3 grams of diethyl phthalate, and 40.5 grams of ethyl acetate.The mixture obtained was heated to a temperature between 65 and 75 ° C 18.3 grams of LEVAPREN ™ 600 HV (EVA copolymer having a content of 60% by weight in vinyl acetate, and marketed by the company BAYER), were then introduced in fractions, and the mixture obtained was stirred by heating always between 65 and 75 ° C for about 50 minutes, until the complete dissolution of the EVA copolymer The dry extract is re-adjusted to 50% by weight, and the obtained mixture is allowed to degas. form e a deposit of (100 + 10) g / m2 on a temporary support of polyester with a silicone coating, at a temperature between 65 and 75 ° C. The coating thus obtained is heated to 70 ° C. for at least 15 minutes, in order to evaporate the solvent. The matrix thus obtained is then transferred onto a final polyester support. It is cut to the desired size, and the products thus cut are conditioned in the thermoweldable envelopes.

Example 2 The procedure is analogous to Example 1, but 0.83 g of Es, 1.6 g of NETA, 4 g of SURFADONE ™ LP 300, 6 g of MOD, 6 g of diethyl phthalate, 54 g of acetate, are used in this case. ethyl acetate and 21.6 g of LEVAPREN ** 600 HV (EVA copolymer having a content of 60% by weight in vinyl acetate grounds, and marketed by the company BAYER).

Example 3 The procedure is analogous to Example 1, but in this case 0.62 g of Es, 1.2 g of NETA, 4.8 g of SURFADONE LP 300, 5.1 g of MOD, 3 g of diethyl phthalate, 40.5 g of ethyl acetate are used. and 15.3 g of LEVAPREN ™ 600 HV.

Example 4 The procedure is analogous to Example 1, but a mixture of EVA copolymers is used in this case. Incorporate 0.62 g of Es, 1.5 g of NETA, 3 g of SURFADONE ™ LP 300, 4.5 g of MOD, 3 g of diethyl phthalate, 40.5 g of ethyl acetate, and a mixture of 14.4 g of LEVAPREN 6Q0 HV and 3 g of LEVAPREN ™ 400 (EVA copolymer having a content of 40% by weight in vinyl acetate grounds, and marketed by the company BAYER).

Example 5 In a reactor they are incorporated at room temperature 201. 6 g of diethyl phthalate, 101.3 g of SURFADONE LP 300, 100.8 g of MOD, 20.7 g of Es, 40 g of NETA, and 539.9 g of LEVAPREN * 500 HV (EVA copolymer having a content of 50% by weight in motifs of vinyl acetate, and marketed by the company BAYER), and the whole is shaken. 1003.7 g of ethyl acetate are then incorporated, and heated to about 75 ° C under stirring, until the complete dissolution of the EVA copolymer. The obtained mixture is allowed to degas. The latter is deposited so as to form a deposit of (100 + 10) g / m2, at a temperature of 50 ° C, on a temporary support in polyester with silicone coating. The coated product is then placed in a drying tunnel, whose temperature varies from 70 to 80 ° C, in order to evaporate the solvent, and the matrix thus obtained is transferred onto a final polyester support. It is cut to the desired size, and the products thus cut are conditioned in thermoweldable envelopes.

Example 6 In a reactor, 130.5 g of M.O.D. are incorporated at 75 ° C, 130. 9 g of diethyl phthalate, 10 Q.9 g of SURFADQNE "LP 300, 20.7 g of Es, 40 g of NETA, 570.3 g of LEVAPREN ™ 600 HV, 10.1 g of PVP / VA-S-630 (acetate copolymer of vinyl and N-vinyl-2-pyrrolidone containing 40% by weight of vinyl acetate, marketed by GAF CORPORATION), and the whole is stirred for 5 minutes, then 989.9 g of ethyl acetate and 10.1 g are incorporated. The mixture is always stirred at 75 ° C until the complete dissolution of the EVA copolymer, and the obtained mixture is allowed to degas The latter is deposited at a temperature of 50 ° C to form a deposit of (100 + 10) g / m2 on a temporary silicone-coated polyester support The coated product is then placed in a drying tunnel whose temperature varies from 60 to 80 ° C, in order to evaporate the solvents, and the matrix is transferred obtained on a final polyester support, cut to the desired size and the products thus cut are conditioned in thermoweldable envelopes.

Example 7 In a reactor, 201.4 g of diethyl phthalate, 201.1 g of SURFADONE ™ LP 300, 340.1 g of MOD, 40 g of Es, 80 g of NETA, 60 g of PVP / VA-S-630 are incorporated in a reactor at 75 ° C. and 1080.2 g of LEVAPREN 500 HV, and the mixture obtained is stirred. 1999.8 g of ethyl acetate are then incorporated, and the mixture is stirred, always around 75 ° C for at least 4 hours, until the complete dissolution of the EVA copolymer. The obtained mixture is allowed to degas. The latter is deposited, at a temperature of 50 ° C, to form a deposit of (100 + 10) g / m2 on a temporary support of polyester with silicone coating. The coated product is then placed in a drying tunnel whose temperature varies from 60 to 80 ° C, in order to evaporate the solvents, and the matrix thus obtained is transferred onto a final polyester support. It is cut to the desired size and the products thus cut are conditioned in thermoweldable envelopes.

Example 8 In a 250 ml flask, 0.62 g of Es, 1.5 g of NETA, 3 g of SURFADONE ™ LP 300, 4.5 g of MOD, 3 g of diethyl phthalate, 0.3 g of PVP / VA-S-630, 10 are introduced. g of ethanol and 40.5 g of ethyl acetate. The mixture obtained is heated, stirring at a temperature between 65 and 75 ° C, until the complete dissolution of VA / VP polymer. Then, 17.1 g of LEVAPREN * 600 HV are introduced by fractions, and the obtained mixture is stirred, always heating between 65 and 75 ° C for about 50 minutes, until the complete dissolution of the EVA polymer. The dry extract is again adjusted to 50% by weight, and the obtained mixture is allowed to degas. The latter is deposited to form a deposit of (100 + 10) g / m2 on a temporary silicone-coated polyester support at a temperature comprised between 65 to 75 ° C. The coating thus obtained is heated at 70 ° C during a minimum of 15 minutes, in order to evaporate the solvents, and transfer the matrix thus obtained onto a final polyester support. It is cut to the desired size, and the products thus cut are conditioned in thermoweldable envelopes.

Example 9 The procedure is analogous to Example 1, but in this case a single hormone is incorporated: the NETA. In this example, 1.2 g of NETA, 3 g of SURFADONEMR LP 300, 7.5 g of M.O.D., 1.5 g of diethyl phthalate, 40.5 g of ethyl acetate and 16.8 g of LEVAPREtf 500 HV are used in this example.

Example 10 The procedure is analogous to Example 9, but in this case 4.8 g of NETA, 19.2 g of SURFADQNE "LP 300, 20.4 g of MOD, 6 g of diethyl phthalate, 162 g of ethyl acetate and 69.6 g of LEVAPREN 600 HV.

Example 11 In a 250 ml flask, 1.8 g of NETA are introduced, 4. 8 grams of SURFADONE ™ LP 300, 5.2 g of M.O.D., 3 g of diethyl phthalate, and 40.5 g of ethyl acetate, and the whole is heated to about 75 ° C with stirring. 12 g of LEVAPREN ™ 600 HV and 3 g of LEVAPREN ^ 400 are then introduced into small fractions and stirred at 75 ° C for about 1 hour until the complete dissolution of the EVA copolymer. The dried extract is again adjusted to 50% by weight, and 0.6 g of PVP / VA-S-630 is introduced in 50% ethanolic solution by weight. The whole is stirred, and the obtained mixture is allowed to degas. The latter is deposited to form a deposit of (100 + 10) g / m2 on a temporary silicone-coated polyester support, at a temperature comprised between 65 to 75 ° C. The coating thus obtained is heated at 70 ° C during a minimum of 15 minutes, in order to evaporate the solvents. The matrix thus obtained is then transferred onto a final polyester support. It is cut to the desired size, and the products thus cut are conditioned in thermoweldable envelopes.

Example 12 In a 250 ml flask, 0.93 g of Es, 3 g of SURFADONE ™ LP 300, 3.9 g of MOD, 3 g of diethyl phthalate, 0.6 g of KOLLIDQN VA-64 (copolymer of vinyl acetate and N) are introduced. vinyl-2-pyrrolidone having 37.7% by weight of vinyl acetate, marketed by BASF), 37.5 g of ethyl acetate and 3 g of ethanol. The whole is heated to 75 ° C under agitation, until the complete dissolution of KOLLIDON VA-64. 18.6 g of LEVAPREN "600 HV are then introduced into small fractions and stirred for about 1 hour until the complete dissolution of the EVA copolymer. The dry extract is re-adjusted to 50% by weight and the mixture is allowed to degas. obtained mixture, the latter is deposited to form a deposit of (100 + 10) g / m2 on a temporary support of polyester with silicone coating, at a temperature comprised between 65 and 75 ° C. The coating thus obtained is then heated to 70 ° C for a minimum of 15 minutes, in order to evaporate the solvents, the matrix thus obtained is transferred onto a final polyester support, cut to the desired size, and the products thus cut are conditioned in thermoweldable envelopes.

Example 13 The procedure is analogous to Example 12, but in this case a second hormone is added: the NETA. In this example, 1.5 g of NETA, 0.62 g of Es, 4.8 g of SURFADONE "^ LP 300, 5.1 g of MOD, 1.5 g of diethyl phthalate, 0.3 g of KOLLIDON VA-64, 37.5 g of ethyl acetate are used in this example. ethyl, 3 g of ethanol and 16.2 g of LEVAPREIST 600.

Example 14 The procedure is analogous to Example 11, but a single solvent, ethyl acetate; In this case 1.8 g of NETA, 3.9 g of SURFADONE ™ LP 300, 5.1 g of M.O.D., 3 g of diethyl phthalate, 40.5 g of ethyl acetate, . 9 g of LEVAPREN ™ 600 HV and 0.6 g of PVP / VA-S-630.

Assays The performances of the devices according to the invention were determined from measurements of amounts of hormone (s) released in 24 hours on an ex vivo skin model. For this, ex-vivo permeation tests were performed on male "naked" mouse abdominal skin according to the following protocol. The measurement of the amounts of hormone (s) released by a transdermal device from a surface of 2.54 cm2, previously cut with a punch, and deposited on a 3.14 cm2 disc of abdominal skin of "naked" male mouse, was carried out in a static glass cell with thermostat at 37 ° C, and having a receiver compartment with a volume of 11.5 ml, this receptor compartment contained as a receptor phase a mixture of physiological saline / PEG 400 (75/25 v / v). Taking into account the variability of the results linked to the intrinsic permeability of the skin samples, each permeation test for a transdermal device sample was performed on a minimum number of 3 to 5 skin samples. The result that is given is the average obtained for each device, from these tests. The relationship between this average value of the amounts of hormone (s) released at the end of the kinetics in 24 hours, and the initial amount of hormone (s) contained in the device allows the performance to be evaluated in 24 hours the transdermal systems according to the invention. With a comparative objective, the quantities of hormones released after 24 hours of a single product that is already available, which comprises both an estrogen and a progestagen, namely the device marketed under the brand ESTRAGEST *, were determined in the same way. TTS by the company CIBA-GEIGY. It is also the only commercial transdermal system that contains a progestogen compound. The ESTRAGEST TTS device consists of two bonded tanks containing a total of 10 mg of 17β-estradiol and 30 mg of NETA, each deposit containing a mixture of 5 mg of 17β-estradiol and 15 mg of NETA. Cutaneous permeation measurements were made following the same protocol on only one of the two deposits placed on a 3.14 cm2 skin sample. The initial amounts of hormones contained in this deposit were subtracted from the initial amount of hormone per unit area expressed in μg / cm2. The ratio of the average value of the amounts of 17ß-estradiol or NETA released in 24 hours at the initial amount contained in the deposit allows obtaining the yields in 24 hours of Es or of NETA. The results obtained were reported in Table I for the devices according to the invention containing an estrogen and a progestogen, and in Table II for the devices containing only one progestogen. The yields obtained in 24 hours were also compared by a device according to the invention for 17β-estradiol in relation to the only EVA copolymer based matrix device already marketed, namely the LIM ™ product. For this, ex-vivo permeation tests were carried out according to the same protocol on the abdominal skin of the male "naked" mouse with the help of 2.54 cm2 samples of LIM ™. With this matrix device, according to several series of tests, an initial value of 17β-estradiol was found on average per unit area of 452.7 μg / cm2, and an amount of 17β-estradiol was released after 24 hours on this model. of skin of 14.2 μg / cm2. Table III shows the calculated yields for the devices according to the invention of examples 1, 2, 3, 6 and 12, and only 17β-estradiol and the product LIM ™ are taken into account. In the case of a matrix containing both 17β-estradiol and NETA, Table I illustrates the advantages of the systems according to the invention against the ESTRAGEST ™ TTS product mentioned above. It was found in this case, as shown by curves 3 and 6 of Figures 1 and 2, that there are always yields for the devices according to the invention for 17β-estradiol and for NETA that are significantly higher than those of the ESTRAGEST system. ™ TTS, this with lower initial quantities, respectively 8 and 12 times lower. In addition, as shown in Table 1, in 1 case of 17ß-estradiol, yields are on average 25 to 80 times higher than that of ESTRAGEST ™ TTS, and in the case of NETA, yields 20 to 50 times higher than that of ESTRAGEST1"0 * TTS More precisely, we have in relation to ESTRAGEST" 1 TTS: - for Example 1, a performance 47 times higher for Es and 29 times higher for NETA, - for Example 2, a performance 55 times higher for Es and 32 times higher for NETA, - for Example 3, an 81 times higher performance for Es and 52 times higher for NETA, - for Example 4, a performance 36 times higher for Es and 29 times higher for NETA, - for Example 5, a performance 26 times higher for Es and 18 times higher for NETA, - for Example 6, a yield 48 times higher for Es and 31 times higher for NETA, - for Example 7, a performance 23 times higher for Is and 18 times higher for NETA, - for Example 8, a performance 38 v eces superior for Es and 23 times higher for NETA, - for Example 13, a 75 times higher performance for Es and 50 times higher for NETA. These important differences again demonstrate the advantages of the invention, namely to allow it to be realized with significant cost savings, and by using less product in the desired therapeutic objective, to avoid the possible problems of crystallization and incompatibility in the matrix, as well as to simplify the preparing the systems, and in particular manufacturing matrix systems for administration of an efficient and commercially acceptable estrogen compound and progestogen compound.

The VA / VP copolymer, which intervenes in examples 6-8 and 13, is following the case, useful to improve the adherence of the devices, the solubility of the hormones in the matrix, or surprisingly the phenomena of skin irritation that may appear with use. According to the invention, and considering the amounts used, the presence of the VA / VP copolymer dnot interfere with obtaining good yields. Also, in the case of the mixture of two EVA having different vinyl acetate contents (example 4), you also have good results. Similarly, analogous results are obtained in the case of systems containing either alone or NETA alone, as illustrated by Figures 3 and 4, on the one hand, and Tables II and III on the other hand. The results of Table II show that there are always liberated amounts of NETA higher than those of the ESTRAGEST ™ TTS device, and this despite the 12 times lower concentrations. The analysis of the performances of Table II shows that, in relation to the ESTRAGEST ™ TTS device, there are respectively yields for NETA 26 times, 39 times and 25 times and 48 times higher for the products of Examples 9, , 11 and 14. The results of Table III also demonstrate the advantages of the devices according to the invention in relation to the product OESCLIM ™ in the case of 17β-estradiol. Regarding the product of OESCLIM1 *, which is the only EVA-based matrix system already marketed, it is found again that the performances of the devices according to the invention that are for examples 1, 2, 3 and 6 containing 17β -estradiol and NETA, or for Example 12 which contains as OESCLIM ^ only 17β-estradiol, are always superior 3 to 5 times in the best of cases. This result is also illustrated by curves 2 and 8 (relating to Examples 2 and 8) of Figure 3. Likewise, curves 3 and 6 of Figure 4 show that there are always amounts of 17β-estradiol released by the devices according to the invention which are significantly superior to that of the OESCLIM ™ product, this with amounts 2.3 times lower. The conclusions drawn from Table I, in the case of the administration of two hormones, on the advantages of the devices according to the invention are thus, in the case of the administration of a single hormone, again evident and identical.

TABLE I TABLE III It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.

Having described the invention as above, property is claimed as contained in the following:

Claims (13)

1. Transdermal matrix system for the percutaneous administration of at least one hormone, the system, comprising a support and an adhesive matrix, is characterized in that the matrix comprises: (a) from 39 to 61 parts by weight of ethylene copolymer and of vinyl acetate, (b) from 12 to 17 parts by weight of 2-octyldodecyl myristate, (c) from 5 to 17 parts by weight of diethyl phthalate, (d) from 10 to 16 parts by weight of a compound selected from the N-alkyl-2-pyrrolidones, in which the alkyl group is a group of 4 to 15 carbon atoms, (e) from 1 to 12 parts by weight of at least one hormone selected from the group consisting of estrogen compounds and the progestin compounds.

2. Transdermal matrix system according to claim 1, characterized in that the adhesive matrix further comprises from 1 to 10 parts by weight of a copolymer of vinyl acetate and N-vinyl-2-pyrrolidone (VA / VP)

3. Transdermal matrix system according to claim 2, characterized in that the copolymer of vinyl acetate and N-vinyl-2-pyrrolidone has a content of vinyl acetate comprised between 30 and 70% by weight with respect to the weight of the copolymer.

4. Transdermal matrix system according to any of claims 1 to 3, characterized in that the N-alkyl-2-pyrrolidone is N-dodecyl-2-pyrrolidone.

5. Transdermal matrix system according to any of claims 1 to 3, characterized in that the copolymer of ethylene and vinyl acetate has a content of vinyl acetate comprised between 30 and 75% by weight with respect to the weight of the copolymer, preferably 60% by weight. %.

6. Transdermal matrix system according to any of claims 1 to 3, characterized in that the hormone is an estrogen compound, preferably 17β-estradiol.

7. Transdermal matrix system according to any of claims 1 to 3, characterized in that the hormone is a pragestagen compound, preferably norethisterone acetate.

8. Transdermal matrix system according to any of claims 1 to 3, characterized in that the system contains a mixture consisting of an estrogen compound and a progestogen compound, preferably a mixture of 17β-estradiol and norethisterone acetate.

9. Process for the preparation of a transdermal matrix system according to any of claims 1 to 8, the method is characterized in that it comprises the steps consisting of: (a) successively incorporating in a reactor, at a temperature lower than the temperature of boiling of the solvent or solvent system used, diethyl phthalate, N-alkyl-2-pyrrolidone, 2-octyldodecyl myristate, at least one hormone selected from the group consisting of the estrogen compounds, the progestogen compounds, and its mixtures, the VA / VP copolymer if present in the formulation, and the EVA, and stir the mixture obtained; (ß) then incorporate the solvent or the solvent system, and stir the assembly always at the same temperature, until the total dissolution of the EVA and the complete homogenization of the mixture; (?) deposit the homogeneous mixture resulting from the stage (ß) on a non-stick temporary support, at a temperature between 50 and 70 ° C to obtain a deposit of 50 to 300 g / m2 of support; (d) heating the coating obtained to evaporate the solvent or solvent system, at a temperature comprised between 40 and 80 ° C, as a function of the boiling point of the latter; and (e) transferring the dry matrix thus obtained onto a final support.

10. Use of a transdermal matrix system according to any of claims 1 to 8, characterized in that it is for the preparation of a medicament intended for therapeutic use against the symptoms of menopause or osteoporosis.

11. System according to claim 2, characterized in that its matrix comprises, for a total of 100 parts by weight: (a) 54 parts by weight of copolymer of ethylene and vinyl acetate, (b) 17 parts by weight of myristate of 2 -octildodecyl, (c) 5 parts by weight of diethyl phthalate, (d) 16 parts by weight of N-dodecyl-2-pyrrolidone, (ei) 2 parts by weight of 17β-estradiol, (e2) 5 parts by weight of norethisterone, and (f) 1 part by weight of a copolymer of vinyl acetate and N-vinyl-2-pyrrolidone (VA / VP).

12. System according to claim 2, characterized in that its matrix comprises, for a total of 100 parts by weight: (a) 62 parts by weight of ethylene and vinyl acetate copolymer, (b) 13 parts by weight of myristate 2-octyldodecyl, (c) 10 parts by weight of diethyl phthalate, (d) 10 parts by weight of N-dodecyl-2-pyrrolidone, (e) 3 parts by weight of 17β-estradiol, and (f) 2 parts by weight of a vinyl acetate copolymer and N-vinyl-2-pyrrolidone (VA / VP).

13. System according to claim 2, characterized in that its matrix comprises, for a total of 100 parts by weight: (a) 53 parts by weight of ethylene and vinyl acetate copolymer, (b) 17 parts by weight of myristate 2-octyldodecyl, (c) 10 parts by weight of diethyl phthalate, (d) 13 parts by weight of N-dodecyl-2-pyrrolidone, (e) 6 parts by weight of norethisterone acetate, and (f) 1 part by weight of a copolymer of vinyl acetate and N-vinyl-2-pyrrolidone (VA / VP).