FI118721B - Estradiol-TTS with water-binding 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

118721

Estradiol-TTS with water-binding additives

The present invention relates to a transdermal therapeutic system comprising the active ingredient estradiol and optionally other active ingredients and a water-binding additive and having an active substance and a moisture impermeable backing layer, a matrix layer containing an active ingredient and a release liner covering a matrix layer. structure.

Transdermal therapeutic systems (TTSs) have already been marketed for the treatment of certain diseases.

The term "estradiol" as used herein refers to the anhydrous component of 17β-estradiol, dissolved or crystallized (anhydrate).

TTSs, which contain the active ingredient estradiol, have already been marketed for the treatment of menopausal disorders, now including osteoporosis, and have been successfully treated.

The disadvantage of prior art systems is the inadequate skin permeability of the active ingredient, which could not be increased beyond a certain limit, the so-called "saturation current", even through numerous galenic measures (· multilayer Φ · * * ... · 25 use of systems, use of control membranes, alteration of active substance concentration, conversion of base polymers, etc.) This finding that trans-

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the dermal flow from the solid, finely divided phase can no longer be increased, even by using more intensively Φ 30 soluble diluents, has already been disclosed in Higuch's derivative works, for example in T. Higuchi: Physical Analysis of Percutaneous Process from Creams " * and ointments, J. Soc. Cosmetic Chem. 11, 85-97 (1960).

• ·

In the systems described in EP 0 421 454 *: **: 35, estradiol is present in an acrylate polymer with the addition of 2 118721 "crystallization inhibitors" and adhesive resins. Swellers are included to protect against premature gluing. In addition, for many active ingredients, it is possible to add so-called "Enhancer" agents to the TTS during manufacture. These are usually liquid additives which improve the resorption properties of the human skin and thus allow the binding of the active ingredient from a sufficiently small TTS surface. In particular, the highly volatile enhancers, such as ethanol used as an active ingredient for estradiol, mask the problems of strong softening of the TTS adhesive layers and require, above all, other bulking components which render the TTS unsuitable for packing. In the end, every other non-polymeric additive may be unsuitable for the skin, and sensitizations are also possible. However, with the addition of certain less volatile, in most cases also less active, enhancers (e.g., glycerol esters, cyclic amides, euka-20 lyptol), it is possible to prepare matrix systems in which the active ingredient and resorption enhancing component are present in one or more monolithic layers. US 4,863,738 discloses one example of the many cases in which active substances, such as oestradiol, are used in combination with a particular • ·: 1 ·· agent (herein glycerol monooleate) ) in an arbitrary concentration of M1 ί.,. ϊ matrix.

Also, according to the state of the art, satisfactory treatment with such TTSs is not possible because either the skin is intolerant to the over-effective healers or the systems require; due to too little flow through the skin • t ·] ··., too large areas.

Another opportunity to increase the flow of the active ingredient through the skin is to dissolve more active ingredients - *: ** in TTS 35 in molecular distribution in response to saturation solubility. As the superabundance of such systems increases, so does the rate of skin penetration. However, since such additives are thermodynamically unstable, such dosage forms are not storage stable; over time, unpredictable recrystallization of the active ingredient particles so that flow rates through the skin gradually decrease to saturation levels, and thus, at baseline, much of the therapeutic effect initially lost.

10 This phenomenon is a special feature of estradiol.

Estradiol is not at room temperature and normal humidity (20-60% relative humidity) of either of the known anhydrous forms (I and II) but as a semihydrate (Busetti and Hospital, Acta IB Cryst. 1972, B28, 560). Because of the layered structure stabilized by hydrogen bridges and the diffusion rate of the crystal combination, the semihydrate can be heated briefly without decomposition to temperatures of about 170 ° C (Kuhnert-Brandstätter and Winkler (1976) Scientia Pharmaceutics 44 20 (3), 177-190). By micronisation, however, by increasing the crystal surface, a crystalline-free form can be obtained quantitatively already at a temperature of about 120 ° C. Your own observations. . On the basis of these, very slow heating (0.2 - 1 • ♦ · ** # / K / min) and very fine crystalline material, the change already occurs at about 90 ° C.

On the other hand, estradiol, having a decreasing water vapor pressure, has higher solubilities in some polymers, especially polyacrylates. Because at higher concentrations of ΓΓ, otherwise under the same conditions, the diffusion flow through the skin increases according to Fick's law, sel-: *. _ There is a concentration increase in transdermal therapists. ···. highly desirable in those systems. However, the water already present with the estra- • * • * # diol hemihydrate is sufficient to trigger *. * Σ gradual recrystallization from a solution of estradiol ***** 35 mihydrate (Kuhnert-Brandstätter and Winkler (1976))

Scientia Pharmaceutica 44 (3) 177-190). After crystallization, with decreasing concentration, the flow rate from the systems to the skin is also greatly reduced.

Under these circumstances, transdermal systems are known which, by the effect of precise length adjustment, provide a barely pharmacotherapeutically satisfactory solution with estradiol anhydrate saturation solubility (DE-PS 4 237 453) or when using partially insoluble, dispersed estradiol 4 223,360).

Also, taking into account this state of the art, it is important to maintain a sufficiently low humidity during the preparation and storage of estradiol TTS to avoid excessive precipitation of sparingly soluble estradiol semis hydrate. However, for this purpose, in principle, a watertight packaging having a low water vapor permeability can be used. With the low concentration of estradiol present in the present TTS I, even very small amounts of moisture are sufficient to precipitate estradiol semihydrate. For example, if 2 mg of wa-oestradiol (anhydrous) is dissolved in TTS, an amount of 66.1 µg of water is sufficient for complete precipitation. Similarly, when using conventional packing materials, it is very difficult to avoid such small amounts of water when stored for several years.

• ·! DE 4 237 453 already proposes the use of drying agents in packaged storage, but there is no information on the use of a water-binding additive as a constituent of rice.

It is therefore an object of the present invention to provide an estradiol-containing transdermal therapeutic sys-. • a pack with a shelf-life protection system for the precipitation and • V * of the oestradiol hemihydrate, if needed, fits in a matrix containing more active ingredient. solubilized as the saturation solubility corresponds.

This object is solved by the invention by means of the transdermal therapeutic system 5 according to the upper concept of claim 1, wherein the water-binding additive is an ingredient of the matrix.

The incorporation of water-binding mineral constituents according to the invention into the matrix material can be accomplished in various ways: The simplest form is a single-layer matrix system whose matrix is simultaneously adhesive and thus eliminates the need for an additional air layer. The soluble or normally dispersed mineral constituents of the matrix provide a low equilibrium moisture content during storage which makes it impossible to precipitate estradiol semihydrate. If direct skin contact with mineral particles can be avoided, only water-binding mineral ingredients are applied to the matrix and applied by laminating a skin-facing adhesive layer that does not contain Erik-20 to estradiol.

If a matrix and a layer of air containing the estradiol and water-binding mineral constituents are colored with an estradiol-impermeable membrane, a modified release of the active ingredient is achieved.

In addition to the widely used acrylic acid ··· · ·, · poester copolymers which are widely used and are very useful for estradiol, other polymers such as: polyisobutylene, polyvinyl acetate and copolymers, synthetic rubber .

In any case, the transdermal therapeutic system according to the invention is characterized by a hydrogen · 1 ···. the presence of binding minerals in the matrix. In this case, the exact proportion of these additives in the matrix 2 · · * .2: must be chosen sufficiently as this will increase the total * 2 · 35 teudine bonding in the system. The exact amount of the additives is obvious to one skilled in the art as to the water-binding capacity of the ingredients. Since the water-binding capacity of most of the substances mentioned in the following examples exceeds the value of estradiol, an increase of the order of about 1% to about 2% of the amount of estradiol present can be used as a minimum. The upper limit is determined by mechanical quantities such as matrix fluidity, bonding ability and workability; a proportion of 10 to 50% by weight, preferably 20 to 35% by weight, is usually sought.

Zinc oxide, silica, silica gel (also modified, for example in hydrophobic form), talc, phosphorus pentoxide, alumina, aluminum phosphate, magnesium oxide and sodium hydroxide, calcium hydroxide, calcium oxide, , calcium and magnesium carbonate, magnesium sulfate, calcium sulfate, copper sulfate, manganese oxides, silicates, aluminates or magnesium perchlorate.

It should be noted, however, that both chemically reactive processes, for example the reaction of magnesium oxide with magnesium hydroxy, can be utilized here. . because physical changes, such as the incorporation of Ki · deve first into anhydrous sodium sulfate, t · * ··· * 25 calcium sulfate or calcium chloride, or pure ***, non-stoichiometric hygroscopy or adsorption known to the person skilled in the art.

··; *. Preferably, substances having a low water-humidity (in the range less than about 5% relative humidity) high water-binding capacity are used. In addition, broad physiological compatibility is considered. These conditions, ···, are satisfactorily fulfilled by numerous hydrates of alkaline earth and alkali metals, such as calcium *. *: and magnesium carbonate, calcium, sodium, and magnesium "" · 35 sulfate, or many alkali metals (preferably sodium, potassium, and lithium). ) and silicates, aluminates, borates and phosphates of alkaline earth metals (calcium and magnesium).

Other embodiments of the invention have been designed in accordance with the claims.

5 Examples

Example 1

Preparation of the System of the Invention 2.0 g 17-β-estradiol semihydrate, micronized 60.0 g Cariflex® TR 1107 (styrene-isoprene-styrene block copolymer) 120.0 g Staybelite Ester 5E (thermoplastic ester resin) rosin 50 g of calcium sulfate dihydrate 15 are thawed at 130 ° C in an evacuation mixer and brought to a homogeneous shape by stirring for ten hours. Under reduced pressure (less than 0.02 bar), the mixture is now heated to 165 ° C for one hour, whereupon the water is removed with stirring and the active ingredient and calcium sulfate.

The melt is cooled to 120 ° C and subsequently deposited in a continuously operating supernatant. . 100 μτη for thickening silicone polyester film to give a layer weight of 25 200 g / m. Then a 15 µπι thick polyester film is applied • ·! ** air-free in the roll printing to a warm layer (glued). By punching with a hole punch · ·! * ·· Account provides transdermal systems with an area of 16 cm2.

Example 2; * · Preparation of system according to the invention, ···, 3.0 g of 17-β-estradiol semihydrate, micronized • · * “400.0 g of acrylic acid ester copolymer solution (solids content 50% g). / g) * · ** · 35 70.0 g of calcium sulphate, anhydrous ("anhydrite") 8 118721 is stirred at room temperature in a cylindrical glass dish until a uniform suspension is obtained, and then layered using a slit width 500 μπι 100 μτη on a thick, siliconized polyester film Sample-5 is each dried for 10 minutes at 25 ° C, 50 ° C, 80 ° C and 95 ° C Immediately, a 15 μm thick polyester film is air-bubbled onto a roll dried layer (glued). additional punch 10-cm transdermal systems are packaged in a combination pack of paper / aluminum foil / heat seal layer ämällä drying the tablet, containing 0.3 g of calcium sulfate (which was dried in advance at 180 ° C).

t · * · • · * * · · m m m m m «m m m« «« «« «« ««. ♦ • · · · * * * «** ** m m m mm mm mm mm mm mm

Claims (14)

118721 Patent Applications for Suction et A transdermal therapeutic system comprising the active ingredient estradiol and optionally other active ingredients and possibly water-binding additives and having a layer structure comprising an active substance and a moisture impermeable backing layer, an active matrix layer and a release liner, the matrix contains the active ingredient in the form of anhydrous estradiol, together with a water-binding additive, which acts to ensure equilibrium moisture content to prevent precipitation of estradiol semihydrate. A transdermal therapeutic system according to claim 1, characterized in that the matrix comprises a plurality of active ingredient-containing layers and at least one of these layers contains a pharmaceutically-acceptable, water-binding mineral additive. Transdermal therapeutic system according to claim 1 or 2, characterized in that the matrix material contains a water-binding additive in the form of a fine suspension. . . Transdermal therapeutic system according to one or more of claims 1 to 3, characterized in that the water-binding additive is mineral. The transdermal therapeutic system according to one or more of claims 1 to 4, characterized in that the water-binding additive is an alkaline earth metal or an anhydrate salt. A transdermal therapeutic system according to one or more of claims 1 to 4, characterized in that the water-binding additive is calcium sulphate or anhydrate ("anhydrite"). • · • i * • M • f «···· • · • • • •••••• 118721 Transdermal therapeutic system according to one or more of claims 1 to 6, characterized in that the oestradiol is in the form of a dispersion of anhydrous crystalline product. A transdermal therapeutic system according to one or more of claims 1 to 7, characterized in that the matrix base material contains more estradiol in molecular weight than the saturation solubility. Transdermal therapeutic system according to one or more of claims 1 to 8, characterized in that the proportion of the mineral water-binding additive in the total matrix material is from 1 to 40% by weight and preferably 20% by weight. 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, dissolves the active ingredient estradiol 0.4-3.0% (g / g). The transdermal therapeutic system according to claim 10, characterized in that the matrix base material is a polyacrylate polymer. ,. A process for the preparation of one or more transdermal therapeutic · ... * 25 systems according to one or more of the above claims, characterized in that «a: ** · has the following steps: ··· Σ <ϊ # ί - a suspension of oestradiol semis hydrate and water-binding mineral additive in a solution, dispersion or melt of matrix base material is applied using a suspension of 30 to the membrane ··, aa aa to the carrier - heating to 90-175 ° C in a layer of estradiol anhydrous V *; estradiol. ·: ··: 35 a a a a a a a a a a a a a a a 118721 13. A process according to claim 12, characterized in that the dried layer is heated to a temperature of 90 to 200 ° C until the aqueous form of the mineral water-binding additive is converted to its anhydrous form. A method according to claim 12 or 13, characterized in that the transdermal therapeutic system is packaged in a water vapor-proof packaging material, optionally containing an additional desiccant. • • a • · • ♦ • ♦ ♦ a a a a a a a • • • • • • • • • • • • • • • • • 118721