MXPA97001301A - Transdermal therapeutic system containing estradiol comprising additives higrofili - Google Patents

Abstract

The present invention relates to a transdermal therapeutic system containing estradiol as active substance and optionally also active substances as well as a hydrophilic additive. The therapeutic system has a layered structure comprising a reinforcement that is impermeable to active substances and moisture, a matrix layer containing active substance and, depending on the case, a removable protective layer. The system is characterized in that the hydrophilic additive is a component of the matr

Description

TRANSDERMAL THERAPEUTIC SYSTEM CONTAINING ESTRADIOL COMPRISING HYGROFILIC ADDITIVES FIELD OF THE INVENTION The invention relates to a transdermal therapeutic system, with the active ingredient estradiol, and optionally other active ingredients, as well as an additional substance that binds to water, with a layered construction of a backing layer impermeable to the active principle and moisture, a matrix layer containing the active ingredient and optionally a protective layer that covers the matrix layer.

BACKGROUND OF THE INVENTION Transdermal therapeutic systems (STT) have already been introduced in the market for medicinal therapy of a number of diseases. The term "estradiol" represents the water-free substance of 17-beta-estradiol in dissolved or crystalline form (anhydrate). STTs containing the active ingredient estradiol are already on the market as therapeutic agents for the treatment of menopause discomfort, recently also against osteoporosis, they have been shown to be effective in such therapy. A drawback of the systems corresponding to the state of the art is the insufficient permeation capacity of the active principle through the skin, which has not been able to be increased by numerous galenic measures of the construction of the STT (application of systems formed by several layers , use of directing membranes, variation of the concentration of the active principle, modification of the base polymers, etc.), beyond the determined limit, the so-called "saturation flow". This verification, that the transdermal flow of an active ingredient from a solid phase, finely divided also by means of the application of more soluble vehicles, can basically not be further increased, was already pointed out in the extensive works of Higuchi, for example, T. Higuchi; Physical Chemical Analysis of Percutaneous Process from Creams and Ointments, J. Soc. Cosmetic Chem. 11, page 85-97 (1960). Those systems described in European patent EP 0 4121 454 contains estradiol in an acrylate polymer with incorporation of "crystallization inhibitors" and sticky resins. These systems contain expandable substances to protect against an anticipated loss of adhesive strength. In addition, for many active ingredients there is the possibility of incorporating the so-called enhancers ("enhancer") into the STT during its manufacture. These are generally liquid auxiliary substances that allow improving the resorption capacity of human skin, thus allowing the recovery of the active principle, from a surface of the STT sufficiently small. Particularly volatile enhancers, such as ethanol, used in the case of the active principle estradiol, contain problems derived from a marked softening of the adhesive layers of the STT and make necessary other bulky compartments in the system, which increase the thickness of the STT in an unacceptable way. Finally, each auxiliary, non-polymeric substance contains the risk of producing intolerance in the skin, possibly also a sensitized skin. By incorporating certain less volatile, but generally less active enhancers or "enhancer" (eg, glycerin ester, cyclic amides, eucalyptol) it is possible to manufacture the matrix systems, which contain the active ingredient and the reinforcing component of the resorption in one or several monolithic layers. The patent of E.U.A. 4 863 738 represents an example among many, in which the application of the active principles, for example, estradiol, together with a certain enhancer or "enhancer" (in this case the glycerin monooleate), is claimed in any matrix. STT in varying concentrations. According to the prior art, these STTs do not allow to achieve a satisfactory therapy, because the effective breeders present a tolerance by the skin, or because the systems, due to the reduced flow through the skin, require unacceptably large surfaces. Another possibility to increase the flow of the active ingredient, through the skin, consists of dissolving a greater quantity of active ingredient in dispersed form, molecularly, in the STT, than that amount equivalent to the solubility of saturation. By supersaturation of such systems, the skin's permeation rate increases to the same extent. Because such states are thermodynamically unstable, these forms of medications are not stable during storage; there is an unforeseeable recrystallization over time of the particles of active principle, in such a way that the flow velocity, through the skin, falls more and more to the level of saturation and with it, depending on the initial concentration, Most of the therapeutic activity initially present is lost. This phenomenon is a characteristic of estradiol. At room temperature and at the usual relative humidity (20-60% relative humidity), estradiol is not present in one of the free crystallization water modifications (I and II) but as a hemihydrate (Busetti and Hospital, Acta Cryst, 1972 , B28, 560). Due to the structure stratified and stabilized through hydrogen bonds and the diffusional compaction of the crystalline bonds, it is possible to briefly heat the hemihydrate without decomposing it until temperatures of around 170 ° C (Kuhnert-Brandstádter and Winkler (1976), Scientia Pharmaceutica 44 (3), 177-190). By means of a micronization, it is possible to achieve, through an increase in the crystalline surface, at a temperature of 120 ° C, quantitatively the free form of water. According to own observations, it takes place with a very slow heating (0.2-1 K / min) and a particularly fine crystalline substance, the conversion to the temperature of only 90 ° C. On the other hand, estradiol has, as the partial pressure of water vapor is reduced, greater solubilities in some polymers, especially polyacrylates. Because as the concentration increases, keeping the other conditions constant, the diffusional flow through the skin increases according to Fick's law, this increase in concentration is very convenient in the case of transdermal therapeutic systems. However, the amount of water incorporated with the estradiol-hemihydrate is sufficient to successively trigger a recrystallization in the form of estradiol-hemihydrate from the solution (Kuhnert-Brandstdter and Winkler (1976), Scientia Pharmaceutica 44 (3), 177 -190). After crystallization, as the concentration decreases, the flow from the system to the skin is also markedly reduced. Taking these circumstances into account, transdermal systems have been known that offer a satisfactory pharmaco-therapeutic solution through a precise adjustment of the concentration slightly below the saturation solubility of the estradiol-anhydrate (DE 42 37 453) or by the use of a partially undissolved or dispersed estradiol-anhydrate (DE 42 23 360). Also, when taking this state of the art, it is important to maintain, during the manufacture and storage of an STT of estradiol, a sufficiently low level of air humidity, in order to avoid a precipitation over a large area of the estradiol-hemihydrate of low solubility. For this purpose, it is basically possible to use a water-tight package with reduced permeability to water vapor. However, with the reduced concentration of estradiol, contained in the current TTS, only very small amounts of moisture are sufficient to produce a precipitation of the estradiol-hemihydrate. If, for example, you have 2 mg of free estradiol of water dissolved in a STT, then 66.1 micrograms are enough to produce a complete precipitation. Consequently, with conventional packages it is difficult to avoid, during storage periods of several years, the entry of small amounts of moisture. German patent DE 42 37 453 suggested the use of drying agents in the package prepared for storage. But it does not indicate data about the use of the water-neutralizing substance as a component of the matrix.

OBJECTS AND DESCRIPTION OF THE INVENTION For this reason, the present invention has as an object to provide a transdermal therapeutic system with estradiol, which provides the container during the storage period, with a protection of the system against a precipitation of the estradiol-hemihydrate and, which optionally, is suitable for a matrix, which contains dissolved, in a molecularly dispersed form, a greater amount of active principle than that corresponding to saturation solubility. This object has been achieved by a transdermal therapeutic system of the type indicated in the preamble of claim 1, in the present invention, in which the moisture pick-up or neutralizing substance is a compound of the matrix. The incorporation of the moisture neutralizing mineral components, according to the present invention, into the matrix, can be performed in different ways in a STT. The simplest form consists of a matrix system formed of a single layer, whose matrix, from the point of view of its function, is at the same time adhesive under pressure and thus avoids the use of an additional adhesive layer. With the aid of dissolved or generally dispersed solid mineral components in the matrix, it is possible to ensure, during the storage period, such low equilibrium moisture, that a precipitation of estradiol-hemihydrate is impossible. In case it is necessary to avoid a direct contact of the mineral particles with the skin, then the mineral components neutralizing the humidity in the matrix are introduced, applying by means of lamination, an adhesive layer directed towards the skin, which does not contain estradiol in particles. In the case that between a matrix of this type, which contains estradiol and mineral components that neutralize the water, and the adhesive layer is placed a membrane of low permeability for estradiol, then a modified delivery of the active principle is achieved. As the base material, it is possible to use, other than the acrylic acid ester copolymers, which are well known and suitable for estradiol, other polymers, such as polyisobutylene, polyvinyl acetate and copolymers, synthetic rubber, silicones, etc. A feature of the transdermal therapeutic system, according to the present invention, is, in all cases, the presence of mineral neutralizing components of the water in the matrix. Here, it is necessary to choose the exact amount of these auxiliary substances in the matrix at a sufficient level, because this increases the total neutralization of moisture in the system. The exact quantity of the auxiliary substances is, according to what can be determined by a specialist, of the neutralization capacity of the components against water. Because the neutralization capacity of most of the following substances, in general, is greater for water than for estradiol, the minimum amount can be an auxiliary quantity of the order of magnitude of the estradiol contained around 1 to 2% . The upper limit is defined by mechanical variables, such as the fluidity of the matrix, the adhesive force and the ease of absorption; Generally, an amount of 10 to 50% by weight, preferably between 20 and 35% by weight, is sought. As mineral neutralizing components of the water, for example, zinc oxide, silicon dioxide, silica gel (also in a modified form, for example hydrophobic), talc, phosphorus pentoxide, sodium oxide, etc. can be applied. aluminum, aluminum phosphate, magnesium oxide and hydroxide, calcium oxide and calcium hydroxide, kaolin, molecular filters, sodium oxide, calcium and magnesium carbonate, magnesium sulfate, calcium sulfate, copper sulfate, manganese oxide , silicates, aluminates or magnesium perchlorate. Here it should be kept in mind that it is possible to take advantage of reactive chemical processes, for example, the reaction of magnesium oxide to deliver magnesium hydroxide, as well as physical processes, such as, for example, the inclusion of crystallization water in water-free sodium sulfate, calcium sulfate or calcium chloride , or one can take advantage of the non-stoichiometric and pure hygroscopicity, or the adsorption capacity, phenomena known to the person skilled in the art. Preferably, those substances which, under conditions of reduced atmospheric humidity (in the range of approximately 5% relative humidity), have a high water neutralizing capacity are applied. On the other hand, a high physiological tolerance is desired. Fortunately, these conditions are met in the case of numerous hydrates of salts of the alkali and alkaline earth metals, as for example, in the case of calcium and magnesium carbonates, the sulfates of calcium, sodium and magnesium, or also numerous silicates, aluminates, borates and phosphates of the alkali metals (preferably sodium, potassium and lithium) and alkaline earth metals (calcium and magnesium). Other embodiments of the present invention have been considered according to the subclaims.

EXAMPLES EXAMPLE 1 This example relates to the preparation of a system according to the invention. They were melted, at a temperature of 130 ° C, in an evacuated kneader mixer, 2.0 g of 17-beta-estradiol-hemihirate, micronized, 60.0 g of Cariflex (MR) TR 1107 (styrene-isoprene-styrene copolymer), 120.0 g of Ester Stabilite (ester of the thermoplastic resin of the rosin derivatives), 50 g of viscous paraffin, 50 g of calcium sulfate-dihydrate, and by kneading, were taken within 10 hours, to a homogeneous exterior form. Under vacuum conditions (less than 0.02 bar), heat for one hour to 165 ° C, and with a kneading, the crystallization water is evacuated from the active principle and calcium sulphate. The melt was cooled to 120 ° C, and then, applied in a continuous operation coating plant, on a siliconised polyester sheet, 100 microns thick, in such a way that it resulted in a surface weight of 100 g. / m. Next, a laminate of a polyester sheet of 15 microns thick is incorporated with air bubbles under the pressure of the rollers on the still hot layer. By means of a stamping, with perforated matrices of Henkel, transdermal systems of a6 cm2 are obtained.

EXAMPLE 2 Next, the preparation of a system according to the invention is presented. 3.0 g of 7-beta-estradiol-hemihydrate, micronized, 400.0 g of an acrylic acid ester copolymer solution (solid content of 50% w / w), 70.0 g of calcium sulfate, free of moisture were stirred. ("Anhydrite"), at room temperature, in a glass container, cylindrical, until a uniform suspension was reached and then applied with a slit width of 500 microns on a siliconised polyester sheet 100 microns thick. The spreader or the layer was dried for 10 minutes at 25 ° C, at 50 ° C, 80 ° C and at 95 ° C. A polyester film 15 microns thick was applied immediately on the dry layer, free of air bubbles, under the application of pressure (surface lamination). By stamping with a perforated Henkel matrix, transdermal systems of 10 cm were obtained, which were packed in a paper / aluminum foil packaging material (thermal seal layer with the incorporation of a drying tablet containing 0.3 g of sulphate of calcium, previously dried at a temperature of 180 ° C).

Claims (4)

1. - A transdermal therapeutic system with the active ingredient estradiol and possibly other active substances, as well as, where appropriate, water-binding additives, with a stratified structure of a back layer that is impermeable to the active principle and moisture, with a matrix layer containing the active principle, and depending on the case, a removable protective layer, wherein the matruz contains the active principle in the form of an anhydrous estradiol together with a water-binding additive, thanks to which a balance in the moisture preventing the precipitation of estradiol-hemihydrate. 2.- The transdermal therapeutic system of the claim 1, wherein the matrix has several layers, which contain the active principle and at least one of these layers contains a pharmaceutically acceptable, water-neutralizing mineral auxiliary substance. 3. The transdermal therapeutic system of any of claims 1 or 2, wherein the matrix material contains the neutralizing auxiliary substance of water in a finely dispersed suspension. 4 - The transdermal therapeutic system of any of claims 1 to 3, wherein the neutralizing substance of water is a mineral. 5. The transdermal therapeutic system of any of claims 1 to 4, wherein the water-neutralizing auxiliary substance is an anhydrate of an alkaline or alkaline-earth salt. 6. The transdermal therapeutic system of any of claims 1 to 4, wherein the water-neutralizing auxiliary substance is the hemihydrate or the anhydrate ("anhydrite") of calcium sulfate. 7. The transdermal therapeutic system of any of claims 1 to 6, wherein the estradiol is present in the form of a dispersion of a water-free crystallization. 8. The transdermal therapeutic system of any of claims 1 to 7, wherein a larger amount of estradiol dispersed molecularly than that corresponding to the saturation solubility is contained in the base material of the matrix. 9 - The transdermal therapeutic system of any of claims 1 to 8, wherein the proportion of the neutralizing mineral auxiliary substance of water, with respect to the total material of the matrix, is from 1 to 40% by weight, preferably 20% by weight. % in weigh. 10. The transdermal therapeutic system of any of claims 1 to 9, wherein the base material of the matrix is a polymer, which under the conditions free of moisture, has a solubility for the active principle estradiol between 0.4 and 3.0 % (p / p). 11. The transdermal therapeutic system of claim 10, wherein the base material of the matrix is a polyacrylate polymer. 1

2. A process for manufacturing a transdermal therapeutic system according to any of the preceding claims, which comprises the following steps of operation: - in a solution, dispersion or fusion of the base material of the matrix, a suspension of estradiol is prepared -hemihydrate and a mineral auxiliary substance neutralizing the water, - the suspension is applied on a carrier material, in the form of a sheet, a layer, - in the layer is carried out, by heating 90 to 175 ° C, a conversion of estradiol -hemihydrate, in water-free estradiol. 1

3. The process of claim 12, wherein the dried layer is heated from 90 to 200 ° C, for so long until the conversion of the hydrated form of the neutralizing mineral auxiliary substance from the water to its water-free form occurs. 1

4. The method of any of claims 12 or 13, wherein the transdermal therapeutic system is packaged in a water vapor tight packaging material, optionally containing an additional drying product.