NO970553L - Ostradiol-containing transdermal therapeutic systems comprising hydrophilic additives - Google Patents

Abstract

The invention concerns a transdermal therapeutic system which contains oestradiol as active substance and optionally further active substances as well as a hydrophylic additive. The therapeutic system has a layered structure comprising a backing which is impervious to the active substances and moisture, an active substance-containing matrix layer and, depending on the case, a separable protective layer. The system is characterized in that the hydrophylic additive is a component of the matrix.

Description

The present invention relates to a transdermal therapeutic system with the active substance estradiol and possibly further active substances as well as a water-binding additive with a layered structure of an active substance and a moisture-impermeable backing layer, a matrix layer containing the active substance and optionally a removable protective layer covering the matrix.

Transdermal therapeutic systems (TTS) have already been introduced to the market in drug therapy for a number of diseases.

In the following, the term "estradiol" is to be understood as the anhydrous substance of 17-B-estradiol in dissolved or crystalline (anhydrate) form.

TTS with the active ingredient estradiol is on the market as a therapeutic for problems with changing seasons, as well as for osteoporosis, and shows results in the therapy.

A disadvantage of similar systems, according to the state of the art, is the unsatisfactory penetrability of the active substance through the skin, which also through numerous galenic measures in the TTS structure (use of several layer systems, use of control membranes, variation of the active substance concentration, modification of the base polymers, etc. .), cannot get over a certain limit, the so-called "saturation flow". This conclusion, that the transdermal flow of an active substance from the solid, finely divided phase, even when using a strongly dissolving carrier cannot in principle be further increased, can be found in the seminal work of Higuchi, e.g. T. Higuchi: Physical Chemical Analysis of percutaneous processes from creams and ointments. J. Soc. Cosmetic Chem. 11, pp. 85-97 (1960).

The system described in EP 0,421,454 contains estradiol in an acrylate polymer with the addition of "crystallization inhibitors" and adhesive resins. Humectants are contained to protect against short-term loss of adhesion. In addition, for several active substances it is possible to add TTS in the so-called "enhancer" of the preparation. This usually involves liquid additives, which improve the resorption properties of the human skin, thereby enabling detection of the active substance on a sufficiently small TTS surface. Particularly easily volatile enhacers, such as estradiol used for the active substance estradiol, cause problems with strong softening of the adhesive layer in TTS and also necessitate large, space-consuming containers in the system which make TTS unacceptably thick. Finally, further non-polymeric additives also present a risk of incompatibility with the skin under certain circumstances and also of sensitisation. However, with the addition of the specific less volatile, mostly also less active, enhancer (e.g. glyceryl ester, cyclic amide, eucalyptol), the production of matrix systems is possible which contain the active substance and the resorption-enhancing components in one or more monolithic layers.

US 4,863,738 is one example of several where the application of active substances, e.g. estradiol, is made together with a specific enhancer (here glycerin mono-oleate) in a desired TTS matrix with the desired concentration.

According to the state of the art, a satisfactory therapy is not possible with such TTS systems either, as the effective enhancer is either too poorly compatible with the skin, or the system, due to insufficient circulation, uses an excessively large and unacceptable area of the skin .

Another possibility for increasing the flow of active substances in the skin consists in dissolving more TTS molecularly dispersed corresponding to the saturation solution. With oversaturation of such systems, the rate of penetration into the skin rises to the same extent. As such systems are thermodynamically unstable, such drug forms are not storage stable; an unpredictable recrystallization of the active substance takes place over time, so that the flow rate through the skin falls towards the saturation flow level, and thereby, depending on the initial concentration, a large part of the initially present therapeutic activity is lost.

This process is specific to estradiol.

Estradiol exists at room temperature and normal relative humidity (20-60% relative humidity) not in any of the known crystalline water-free modifications (I and II), but as a semihydrate (Busetti u. Hospital, Acta Cryst. 1972, B28, 560). Due to the layer-like structure stabilized by hydrogen bridges and the diffusion density of the crystals, the semihydrate can be heated in a short time to temperatures of approx. 170°C without decomposition (Kuhnert-Branståter and Winkler (1976) Scientia Pharmaceutica 44 (3), 177-190). With micronisation, however, due to the increase in crystal surface area, the anhydrous form can already be achieved at approx. 120°C. According to my own observations, with slow heating (0.2-1 K/min.) and particularly finely crystallized material, the transformation already takes place at around 90°C.

On the other hand, estradiol with a low water vapor partial pressure present has a higher solubility in some polymers, especially also polyacrylates. As the diffusion current through the skin according to Fickschen's theorem increases with higher concentration under otherwise equal conditions, such a concentration increase in transdermal therapeutic systems is highly desirable. However, the water introduced with estradiol hemihydrate already covers to trigger a renewed crystallization as estradiol hemihydrate from the solution (Kuhnert-Brand-statter and Winkler (1976) Scientia Pharmaceutica 44 (3), 177-190). After crystallization, with a lower concentration present, the rate of flow from the system to the skin also drops sharply.

These circumstances are taken into account in transdermal systems, which provide a satisfactory pharmacotherapeutic solution by carefully setting the concentration barely below the saturation solubility of the estradiol anhydrate (DE-PS 42.37.453) or by using partially undissolved, dispersed estradiol anhydrate (DE-PS 42.23 .360).

Also taking into account the state of the art, it is important during the manufacture and storage of an estradiol TTS to maintain a sufficiently low humidity in order to thereby avoid a large-scale precipitation of the poorly soluble estradiol semihydrate. For this purpose, however, a waterproof package with low water vapor permeability can be used. At a low concentration of estradiol, which today's TTS contains, however, very low amounts of moisture are sufficient for precipitation of the estradiol hemihydrate. If, for example, 2 mg of estradiol (anhydrous) is present dissolved in a TTS, there is already a complete precipitation at an amount of 66.1 ug of water. Similarly, with conventional packaging materials it is very difficult to exclude access to such low amounts of moisture with storage times over several years.

DE 42.37.453 already suggests the use of desiccants in the ready-to-storage package. However, there is no reference to the use of the water-binding additive as a component of the matrix.

The aim of the present invention is thus to provide a transdermal therapeutic system with estradiol, which in the package during storage provides a protection of the system against precipitation of the estradiol hemihydrate and is suitable for a matrix in which several active substances contain molecularly dispersed dissolved corresponding to the saturation solubility. This task is solved by a transdermal therapeutic system according to the type mentioned in the preamble in claim 1, which according to the invention is solved by the water-binding additive being a component of the matrix.

The invention's incorporation of water-binding mineral dental parts into the substance of the matrix can be realized in different ways in a TTS: The simplest form is a single-layer matrix system, whose matrix function is at the same time adhesive and thereby makes an additional adhesive layer redundant.

With the dissolved, or usually solid-phase dispersed mineral components contained in the matrix, such a low equilibrium humidity is ensured over the storage period that a precipitation of estradiol hemihydrate is impossible.

If the direct contact of the skin with mineral particles is to be avoided, only mineral-binding mineral components are applied to the matrix, and when cased, an adhesive surface facing the skin is applied, which is free of particulate estradiol.

If a membrane that is poorly permeable to estradiol is introduced between such a matrix containing estradiol and water-binding mineral components and the adhesive layer, a modified release of the active substance is achieved.

As a base material, in addition to the widely used, and for estradiol well-usable, acrylic acid ester copolymers, other polymers such as polyisobutylene, polyvinyl acetate and copolymers, synthetic rubber and silicone can also be used.

Characteristic of the invention's transdermal therapeutic system is in all cases the presence of water-binding mineral components in the matrix. Hereby, the exact proportion of this additive in the matrix can be chosen sufficiently high, as thereby the total moisture binding in the system increases. The exact amount of additives is determined in ways that are demonstrable to the person skilled in the art from the binding capacity of the components for water. As the binding capacity in most of the substances mentioned below, for example, for water, is generally above that for estradiol, an addition in the same order of magnitude as the contained estradiol can be used as a minimum amount - about 1 to 1 percent. The upper limit is given by mechanical parameters such as the matrix's fluidity, adhesive strength and workability; as a rule, a proportion of from 10 to 50% by weight is aimed for, preferably between 20 and 35% by weight.

As water-binding mineral components, e.g. be used zinc oxide, silicon dioxide, silica gel (also in modified, e.g. hydrophobicized form) talc, phosphorus pentaoxide, aluminum oxide, aluminum phosphate, magnesium oxide and -hydroxide, calcium oxide and -hydroxide, kaolin, molecular sieves, sodium oxide, calcium and magnesium carbonate, magnesium sulphate, calcium sulphate, copper sulphate, manganese oxide, silicate, aluminate or magnesium perchlorate.

Here it must be noted that both chemically reactive processes, for example the reaction of magnesium oxide to magnesium hydroxide, as well as physical transitions, such as the inclusion of crystal water in initially anhydrous sodium sulfate, calcium sulfate or calcium chloride, can be used, or also pure non-stoichiometric hydroscopy or adsorptivity, which is known to the person skilled in the art as such.

Preferably, substances are used which, at lower humidity (in the area below about 5% relative humidity), have a high binding capacity for water. In addition, a high degree of physiological acceptance is desired.

These conditions are satisfactorily met for numerous hydrates of salts of alkaline earth and alkali metals, such as for example calcium and magnesium carbonate, calcium, sodium and magnesium sulphate or also several silicates, aluminates, borates and phosphates of alkali (preferably sodium, potassium and lithium) and alkaline earth metals (calcium and magnesium).

Further features of the invention are indicated in the independent claims.

EXAMPLES

Example 1: Production of a system according to the invention

2.0 g 17-B-estradiol hemihydrate, micronized

60.0 g Cariflex<R>TR 1107 (styrene-isoprene-styrene block copolymer)

120.0 g Staybelite Ester 5E (thermoplastic ester resin of rosin derivatives)

50 g viscous paraffin

50 g of calcium sulfate dihydrate was melted in an evacuating kneader at 130°C, and was brought into a fairly homogeneous form by kneading over the course of 10 hours. Under vacuum (less than 0.02 bar) it was then heated for one hour to 165°C, and crystal water was then driven out of the active substance and calcium sulphate during kneading.

The melt was cooled to 120°C and is subsequently coated on a continuously working coating substrate of 100 micrometer thick, siliconized polyester foil, so that it resulted in a layer surface weight of 200 g/m<2>.

Then, 15 micrometer thick polyester foil was applied without air bubbles under roller pressure on the still warm layer (cased).

By punching with a hole punch, transdermal systems of 16 cm<2> were obtained.

Example 2: Production of a system according to the invention

3.0 g 17-0-estradiol hemihydrate, micronized

400.00 g acrylic acid ester copolymer solution (solids content 50% g/g)

70.0 g calcium sulfate, anhydrous ("anhydrite")

was stirred at room temperature in a cylindrical glass shard to obtain a homogeneous suspension and then coated on 100 micrometer thick micronized polyester foil with a gap width of 500 micrometers. The smear was dried for 10 minutes at 25°C, at 50°C, at 80°C and at 95°C. A 15-micrometer-thick polyester foil was then immediately applied without air bubbles under roller pressure on the dried layer (cased).

By punching with a hole punch, transdermal systems of 10 cm<2> were obtained which were packed in wrapping material of paper/aluminium foil/heat sealing layer with the addition of a drying tablet, containing 0.3 calcium sulfate (which had previously been dried at 180°C).

Claims (14)

1. Transdermal therapeutic system with the active substance estradiol and possibly further active substances and any water-binding additives, with a layered structure of an active substance and moisture-impermeable back layer, a matrix layer containing the active substance and possibly a dissolvable protective layer, characterized in that the matrix contains the active substance as anhydrous estradiols together with a water-binding additive, by means of which an equilibrium humidity is maintained which prevents the precipitation of estradiol hemihydrate. 2. Transdermal therapeutic system according to claim 1, characterized in that the matrix has several active substance-containing layers, and at least one of these layers contains a pharmaceutically acceptable, water-binding mineral additive. 3. Transdermal therapeutic system according to claim 1 or 2, characterized in that the matrix material contains the water-binding additive in finely dispersed suspension. 4. Transdermal therapeutic system according to one or more of claims 1 to 3, characterized in that the water-binding additive is a mineral. 5. Transdermal therapeutic system according to one or more of claims 1 to 4, characterized in that the water-binding additive is anhydrate of an alkaline earth or alkali metal salt. 6. Transdermal therapeutic system according to one or more of claims 1 to 4, characterized in that the water-binding additive is semihydrate or anhydrate ("anhydrite") of the calcium sulfate. 7. Transdermal therapeutic system according to one or more of claims 1 to 6, characterized in that estradiol is present as a dispersion of an anhydrous crystallisate. 8. Transdermal therapeutic system according to one of claims 1 to 7, characterized in that the matrix base material contains dissolved more molecularly dispersed estradiol than that which corresponds to the saturation solubility. 9. Transdermal therapeutic system according to one or more of claims 1 to 8, characterized in that the proportion of mineral water-binding additive of the total matrix material is between 1 and 40% by weight and preferably 20% by weight. 10. Transdermal therapeutic system according to one or more of claims 1 to 9, characterized in that the matrix base material is a polymer which under anhydrous conditions has a solubility for the active substance for estradiol between 0.4 and 3.0% (w/w). 11. Transdermal therapeutic system according to claim 10, characterized in that the matrix base material is a polyacrylate polymer. 12. Method for producing the trandermal therapeutic system according to one or more of the preceding claims, characterized by the method steps: - in a solution, dispersion or melt of the matrix base material, a suspension of estradiol hemihydrate and water-binding mineral additive is produced, - with the suspension, a layer is applied to a foil-like carrier material, - in the layer, by heating to 90 to 175°C, a conversion of estradiol hemihydrate to anhydrous estradiol is carried out. 13. Method according to claim 12, characterized in that the dried layer is heated to 90 to 200°C for so long that a conversion of the water-containing form of the mineral water-binding additive to its anhydrous form occurs. 14. Method according to one of claims 12 or 13, characterized in that the transdermal therapeutic system is packaged in a water vapor-tight packaging material where the package optionally contains an additional desiccant.