SK21997A3 - Transdermal therapeutic system and a method for producing same - 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

Transdermal therapeutic system and process for its manufacture

Technical field

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, an active ingredient-containing matrix layer and optionally a release protective layer overlaying the matrix layer . The invention also relates to a process for the manufacture of this transdermal system.

BACKGROUND OF THE INVENTION

Transdermal Therapy Systems (TTS) are already in the market for medical therapy for many diseases.

The term estradiol further refers to the anhydrous 17-β-estradiol substance 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 " saturating the flux even by many galenical measures in the construction of TTS (deployment of multilayer 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 rejection work, e.g. T. Higuchi: Psyhical Chemical Analysis of Percutaneous Processes from Creams and Ointments, J. Soc. Cosmetic Chem. 11, p. 85-97 (1960).

The systems described in EP 0 421 454 contain estradiol in an acylate polymer with the addition of crystallization inhibitors and sticky resins. Swellable substances are included to prevent premature loss of tack. In addition, there is the possibility of adding a number of active ingredients to the TTS during production to enhance efficiency. As a rule, these are liquid additives which improve the resorptive properties of human skin and thus allow the active substance to be taken up from a sufficiently small area of the TTS. Particularly easily volatile substances, such as ethanol used for the active substance estradiol, appear to be problematic due to the considerable softening of the sticky TTS layers. Therefore, additional spatial interventions need to be made in the TTS system, rendering the TTS unacceptably rude. Finally, with each additional non-polymeric additive there is a risk of skin intolerance, possibly also sensitivity to the additive. However, the addition of other, less volatile and mostly least active substances (e.g. glycerine esters, cyclic amides, eucalyptol) makes it possible to produce a matrix system containing the active ingredient and resorption enhancing components in one or more monolithic layers.

U.S. Pat. No. 4,863,738 represents one of many examples in which the application of active substances, e.g. oestradiol, together with a certain potency enhancer (here glycerin monooleate) in any TTS matrix at any concentration.

According to the prior art, even such TTS cannot be satisfactorily administered because the enhancer is or is not readily tolerated by the enhancer or the systems require unacceptably large areas due to the still low flow through the skin.

Another possibility to increase the active substance flow through the skin is that more active substance can be dissolved in the molecular dispersion of the TTS than corresponds to the solubility at saturation. 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 saturation flow level, thereby losing a large portion of the initial available therapeutic activity according to the starting concentration. This procedure is especially for estradiol.

does not exist at room temperature and normal air humidity (20-60% relative humidity) of known crystalline anhydrous but as a semihydrate

B28,560).

the stabilized bundle can be a semihydrate up to 170 ° C Winkler (1976) Scientia 177-190]. By micronization, a crystalline surface can be obtained at about 120 ° C.

both (I and II), Acta Cryst. 1972, by hydrogen bridges of crystalline strength without decomposition

Estradiol relative in no modification

Hospital, layered diffuse short-term [Kuhnert-Brandstätter and Pharmaceutics 44 (3), increasing quantitatively anhydrous form, slow heating (0.2-1 K / min) substance conversion even at about 90 (Busetta due to structure)

On the other hand, estradiol does not show greater solubility in some polymers, especially polyacrylates, as the water vapor partial pressure decreases. Since, 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 semi-hydrate is sufficient to initiate a gradual re-crystallization as estradiol semi-hydrate 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 by 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 loss 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 anhydrous estradiol, an amount of 66.1 μg of water is sufficient to precipitate completely. It is therefore very difficult to eliminate access to such low humidity over several years in conventional packaging materials.

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

It is therefore an object of the present invention to provide a transdermal therapeutic system with estradiol. which, in the package during the shelf life, protects the system against estradiol semi-hydrate loss and, as appropriate, is suitable for a matrix containing more active substances dispersed in molecular dispersion than corresponds to the saturation solubility.

SUMMARY OF THE INVENTION

This object is solved by the transdermal therapeutic system of the invention. It is based on the fact that the water binding additive is part of the matrix.

The transport of water-binding mineral constituents to 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 terms of 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 provide such a low equilibrium moisture that estradiol semi-hydrate is not lost.

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 for estradiol, also 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 in that it contains in all cases in the matrix mineral water-binding components. It is necessary to select the exact proportion of these additives in the matrix sufficiently large, as this will increase the total moisture binding in the system. The precise amount of additives will be apparent to those skilled in the art from the ability of the components to bind water. Since the water-binding capacity is generally above estradiol value for most of the exemplified examples, 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 the flowability of the matrix, its tackiness and processability; it is usually sought to use a proportion of 10 to 50% by weight, preferably 20 to 35%.

As the mineral binding agents, 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 taken into account that chemical reactive processes such as the reaction of magnesium oxide to magnesium hydroxide, as well as physical transitions such as the closure of crystal water in anhydrous sodium sulphate, calcium sulphate or calcium chloride, or even pure, non-stoichiometric hygroscopy or adsorptivity. These circumstances are well known to those skilled in the art.

Substances which 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 hydrates of alkaline-earth and alkali metal salts, such as calcium and magnesium carbonate, calcium sulfate, sodium and magnesium sulfate, 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 a system according to the invention

2.0 - [beta] -estradiol semihydrate, micronized

60.0 g Cariflex ^R TR 1107 (styrene-isoprene-styrene block copolymer),

120.0 g of Staybelite Ester 5E (thermoplastic ester resin from rosin derivatives), g of thick liquid paraffin and g of calcium sulfate dihydrate are melted in an evacuated kneader at 130 ° C and mixed for 10 hours to an externally homogeneous form. 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 [deg.] C. and then a 100 micron thick siliconized polyester foil is applied to a 100 micron thick continuous coating apparatus to achieve a layer weight of 200 g / m &^lt; ^{2 &gt};.

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

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

Example 2: Production of a system according to the invention

3.0 micronized 17-β-estradiol semihydrate

400.0 g of acrylic ester copolymer solution (50% g / g solids content) and

70.0 g of anhydrous calcium sulphate is stirred at room temperature in a cylindrical glass vessel until a uniform suspension is obtained, which is then applied in a width of 500 microns to 100 microns thick siliconized polyester film. The coating is dried for 10 minutes at 25 ° C, at 50 ° C, at 80 ° C and 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 that 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 (13)

Transdermal estradiol and, optionally, a layered active ingredient, an effective therapeutic and, optionally, water-binding back and moisture-building agent, and optionally is found to be anhydrous. K Y with active substance active substances substance system additional additional χα, sides impervious to the matrix layer containing a release liner by the matrix containing estradiol together with water which provides an equilibrium in the effective binding moisture The transdermal therapeutic system of claim 1, wherein the matrix has multiple layers containing the active ingredient, and at least one of these layers comprises a pharmaceutically acceptable, water-binding mineral additive. and wherein the substance is an additive preventing the estradiol semihydrate from falling out. therapeutic system by: 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. The transdermal therapeutic system of any one of claims 1 to 3, wherein the water-binding additive is a mineral. The transdermal therapeutic system of any one of claims 1 to 4, wherein 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 a calcium sulfate semihydrate or anhydride (anhydride). 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 estradiol 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 is soluble under anhydrous conditions 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 a water-binding additive is prepared in a solution, dispersion or melt of the matrix base material, the suspension is applied in a layer to the foil carrier material, and - conversion of estradiol semihydrate to anhydrous estradiol is carried out in the deposited layer by heating to 90-175 ° C. 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 has been converted into its anhydrous form. Method according to either of Claims 12 and 13, characterized in that the transdermal therapeutic system is packaged in a vapor-proof packaging agent, optionally with the addition of a drying agent.