SK280299B6 - Transdermal therapeutic system and a method of its production - Google Patents

Abstract

A transdermal therapeutic system contains estradiol as an active substance and optionally further active substances. The system has a laminated structure positioned on a backing layer which is essentially impermeable to active substance and moisture. A matrix layer contains the active substance, an anhydrous auxiliary substance and, optionally, an adhesive protection layer.

Description

The invention relates to a transdermal therapeutic system comprising both the active ingredient estradiol and, optionally, other active ingredients as well as water-binding additives, with a layered, moisture-impermeable backsheet construction, a matrix layer containing the active ingredient and optionally a release layer overlaying the matrix layer. . The invention also relates to a process for the manufacture of this transdermal system.

BACKGROUND OF THE INVENTION

Transdermal therapeutic systems (TTS) are already on the market for medical therapy for many diseases.

The term "estradiol" is further understood to mean the anhydrous substance of 17-13-estradiol in dissolved or crystalline (anhydrate) form.

Meanwhile, TTSs with estradiol as an active ingredient are commercially available as therapeutics for the problems associated with hormonal transition, most recently for osteoporosis, and have been successful in therapy.

A drawback of the prior art system is the lack of the ability of the active substance to penetrate the skin, which cannot be increased beyond a certain level, the so-called " 'Saturation flow', or by many galenical measures in the construction of TTS (deployment of multi-layer systems, use of control membranes, variation of active substance concentration, modification of base polymers, etc.). This finding that the transdermal flow of the active substance from the solid, finely divided phase cannot be further increased, in principle even with the use of strong soluble carriers, is already evident from the TTS dispersions than corresponds to the saturation solubility. With the supersaturation of such systems, the rate of penetration of the skin increases in direct proportion. Because such conditions are thermodynamically unstable, these dosage forms are not always in storage; there is a time-unpredictable recrystallization of the active agent particles, so that the flow rate gradually decreases to the flux level at saturation, thereby losing much of the initial available therapeutic activity by initial concentration.

This procedure is especially for estradiol.

Estradiol does not exist at room temperature and the usual relative air humidity (20-60% relative humidity) in either of the two known blood-free clueless modifications (I and II), but as a semihydrate (Busetta and Hospital, Acta Cryst. 1972, B28, 560). ). Due to the layered, hydrogen-bonded structure and the diffusion strength of the crystalline beam, the semihydrate can be heated to 170 ° C for a short time without decomposition [Kuhnert-Brandstätter and Winkler (1976) Scientia Pharmaceutica 44 (3), 177-190]. by increasing the crystalline surface, a quantitative anhydrous form can be obtained already at about 120 ° C. According to the observations, the conversion occurs even at about 90 ° C with slow heating (Q2 - 1 K / min) and especially with the fine crystalline substance.

On the other hand, estradiol has no greater solubility in some polymers, especially polyacrylates, as the water vapor partial pressure decreases. Because with increasing concentration under otherwise identical conditions, the diffuse flux through the skin according to Ficksch's law increases, such an increase in concentration in transdermal therapeutic systems is very welcome. However, only water introduced with estradiol semihydrate is sufficient to initiate a gradual re-crystallization as estradiol semihydrate from solution [Kuhnert-Brandstätter and Winkler (1976) Scientia Pharmaceutica 44 (3), 177-190]. After crystallization, the intensity of the flow from the system to the skin decreases as the concentration decreases considerably.

Transdermal systems are known in which these circumstances are taken into account. By precisely adjusting the concentration just below the saturation solubility of estradiol anhydrate (DE-PS 42 37 453) or using partially undissolved, dispersed estradiol anhydrate (DE-PS 42 23 360), a pharmacotherapeutically satisfactory solution is achieved.

Taking this state of the art into account, it is important to maintain sufficiently low air humidity during production and storage of estradiol TTS to prevent the large-scale depletion of sparingly soluble estradiol semihydrate. For this purpose, a substantially waterproof package with low water vapor permeability can be used. However, at low concentrations of estradiol containing today's TTS, very low humidity is sufficient to precipitate estradiol semihydrate. For example, if some TTS contains 2 mg of helpless estradiol, 66.1 pg of water is enough to precipitate completely. It is therefore very difficult to exclude access to such low humidity over a period of several years in conventional packaging materials.

DE 42 37 453 already suggests the use of desiccants in ready-to-store packages. However, there are no data on the use of water-binding additives as part of the matrix.

SUMMARY OF THE INVENTION It is therefore an object of the present invention to provide a transdermal therapeutic system with estradiol which provides, during shelf-life, protection of the system against estradiol semisolid loss during storage and is desirably suitable for a matrix containing more active substances molecularly dispersed than corresponding to solubility.

SUMMARY OF THE INVENTION

This object is achieved by the transdermal therapeutic system of the invention. Its essence is that the water binding additive is part of the matrix.

The transport of water-binding mineral components into the matrix substance can be accomplished in various ways in TTS: the simplest form is a single-layer matrix system whose matrix is also sticky in function and therefore an additional sticky layer is unnecessary. The mineral constituents which the matrix contains as dissolved or generally dispersed in the solid phase ensure such a low equilibrium moisture that estradiol semihydrate precipitation is not possible.

To avoid direct contact of the skin with the mineral particles, only the matrix is provided with the water-binding mineral components and a laminated, non-particulate oestradiol-coated sticky layer is laminated.

If a estradiol-poorly permeable membrane is introduced between such a matrix containing estradiol and water-binding mineral components and a sticky layer, a modified administration of the active ingredient is achieved.

As the base material, besides the widely used acrylic esters copolymers which are widely used and suitable for estradiol, other polymers such as polyisobutylene, polyvinyl acetate and their copolymers, synthetic rubber and silicones can be used.

The transdermal therapeutic system according to the invention is characterized by the fact that it contains in all cases in the matrix mineral water-binding components. The exact proportion of these additives in the matrix must be chosen sufficiently large, since this will increase the binding of the total moisture in the system. The precise amount of additives will be apparent to those skilled in the art from the ability of the component to bind water. Since the water-binding capacity of most other substances exemplified above is generally above the value for estradiol, about 1 to 2% of the estradiol contained may be added as the smallest amount. The upper limit is given by mechanical values such as matrix flowability, tackiness and processability; it is generally sought to use a proportion of 10 to 50% by weight, preferably 20 to 35%.

As the water-binding mineral constituents, e.g. use zinc oxide, silica, silica gel (also in modified eg hydrophobised form), talc, phosphorus pentoxide, aluminum oxide, aluminum phosphate, magnesium oxide and hydroxide, calcium oxide and hydroxide, kaolin, molecular sieves, sodium oxide, calcium carbonate, and magnesium, magnesium sulfate, calcium sulfate, copper sulfate, manganese oxides, silicates, aluminates or magnesium perchlorate.

It should be noted that chemical reactive processes, such as the reaction of magnesium oxide to magnesium hydroxide, can also be utilized, as well as physical transitions, such as the closure of crystalline water in anhydrous sodium, calcium or calcium chloride, or even pure , non-stoichiometric hygroscopy or adsorptivity. These circumstances are well known to those skilled in the art.

It should be noted here that chemical reactive processes, such as the reaction of magnesium oxide to magnesium hydroxide, can also be used, as well as physical transitions, such as the closure of crystal water in anhydrous sodium sulphate, calcium sulphate or calcium chloride, or pure, non-stoichiometric hygroscopy or adsorptivity. These circumstances are well known to those skilled in the art.

Substances that have a high water binding capacity at low air humidity (in the range below about 5% relative air humidity) are preferred. Furthermore, a high level of physiological tolerance is required.

These conditions are favorably met for many alkaline earth and alkali metal salt hydrates, such as calcium and magnesium carbonate, calcium sulfate, sodium and magnesium, or even many alkali metal silicates, aluminates, borates and phosphates (especially sodium, potassium and lithium) ) and alkaline earth metals (calcium and magnesium).

Further embodiments of the invention will be apparent from the dependent claims and the specific embodiments of the following examples.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Production of the system according to the invention

2.0 micronized 17-β-estradiol semihydrate, 60.0 g Cariflex® TR 1107 (styrene-isoprene-styrene block copolymer), 120.0 g Staybelite Ester 5E (thermoplastic ester resin from rosin derivatives), 50 g thick liquid paraffin and 50 g of calcium sulfate dihydrate is melted in an evacuated kneader at 130 ° C and converted to an externally homogeneous form by mixing for 10 hours. In a vacuum (less than 0.02 bar), the melt is heated at 165 ° C for one hour, whereby crystalline water is expelled from the active ingredient and calcium sulfate by mixing.

The melt is cooled to 120 ° C and then a 100 micron thick siliconized polyester foil is applied to a 100 micron thick continuous-layer laminator to achieve a layer weight of 200 g / m ² .

Then, a 15 micron thick polyester film is rolled onto the still warm layer to form air bubbles.

By embossing with Henkeloy punches, 16 cm ² transdermal systems are obtained.

Example 2

Production of the system according to the invention

3.0 17- [i-estradiol semi-hydrate, micronized 400.0 g acrylic ester copolymer solution (solids content 50% g / g) and 70.0 g anhydrous calcium sulphate are stirred at room temperature in a cylindrical glass container until a uniform suspension is obtained, which is then applied at a width of 500 microns per 100 microns thick siliconized polyester film at 95 ° C. Immediately, a 15 micron thick polyester film is applied to the dried layer by compressing the rollers without causing air bubbles.

Henkel punches yield 10 cm ² transdermal systems which are packaged in paper / aluminum foil / hot seal layers with the addition of one tablet containing 0.3 g of calcium sulfate (which has been previously dried at 180 ° C) ).

Claims (14)

PATENT CLAIMS Transdermal therapeutic system with the active ingredient estradiol and optionally other active ingredients and optionally water-binding additives, with a layered, moisture-permeable backsheet construction, an active ingredient-containing matrix layer and, optionally, a release liner, characterized in that the matrix contains an active ingredient such as anhydrous estradiol together with a water binding additive that provides an equilibrium moisture to prevent the estradiol semihydrate from falling out. Transdermal therapeutic system according to claim 1, characterized in that the matrix has a plurality of layers containing the active ingredient, and at least one of these layers comprises a pharmaceutically acceptable water-binding mineral additive. Transdermal therapeutic system according to claim 1 or 2, characterized in that the matrix material comprises a water-binding additive in a finely dispersed suspension. Transdermal therapeutic system according to any one of claims 1 to 3, characterized in that the water-binding additive is a mineral. Transdermal therapeutic system according to any one of claims 1 to 4, characterized in that the water-binding additive is an alkali earth or alkali metal salt anhydrate. Transdermal therapeutic system according to any one of claims 1 to 5, characterized in that the water-binding additive is calcium sulfate anhydride, semihydrate or anhydrate. Transdermal therapeutic system according to any one of claims 1 to 6, characterized in that the estradiol is in the form of an anhydrous crystal dispersion. Transdermal therapeutic system according to any one of claims 1 to 7, characterized in that the matrix base material contains more es3 of tradiol molecularly dispersed than corresponds to the saturation solubility. Transdermal therapeutic system according to one of Claims 1 to 8, characterized in that the proportion of mineral water-binding additives in the total matrix material is 1 to 40% by weight, preferably 20% by weight. Transdermal therapeutic system according to any one of claims 1 to 9, characterized in that the matrix base material is a polymer which, under anhydrous conditions, is soluble for estradiol as active ingredient in the range of 0.4 to 3.0% (g / g). . 11. The transdermal therapeutic system of claim 10, wherein the matrix base material is a polyacrylate polymer. A method for producing a transdermal therapeutic system according to one or more of the preceding claims, comprising the steps of: - a suspension, estradiol semi-hydrate and water-binding additive is prepared in the solution, dispersion or melt of the matrix base material, the suspension is applied in a layer to the foil carrier material, and converting estradiol semihydrate into anhydrous estradiol by heating to 90 to 175 ° C in the deposited layer. The method according to claim 12, characterized in that the dried layer is heated to 90 to 200 ° C until the water-containing form of the water-binding mineral additive is converted into its anhydrous form. Method according to either of Claims 12 or 13, characterized in that the transdermal therapeutic system is packaged in a vapor-proof packaging agent, optionally with the addition of a drying agent.