DE19834006A1 - Estradiol-containing patch for the transdermal application of hormones - Google Patents

Abstract

The invention relates to a patch containing an active substance for controlling the release of estradiol or pharmaceutically acceptable derivatives thereof on its own or combined with gestagens into the human or animal skin, consisting of a back layer, a reservoir connected thereto containing an active substance and suitable for combined release thereof and having adhesive means and a removable protective layer. The invention is characterized in that the adhesive used contains cholesterol or corn starch.

Description

The invention relates to an active substance-containing plaster for controlled release of estradiol or its pharmazeu table-safe derivatives alone or in combination with progestogens on human or animal skin.

Patches containing estrogen and / or gestagen are already there known. However, they have the disadvantages that they ent neither contain ethanol nor pose a potential danger, that the active ingredient recrystallizes over time.

It is known from DE-OS 32 05 258 and EP 0 285 563 Estradiol and ethanol at the same time in one patch administration. The production of this patch is however very complex and the comfort according to Appli cation due to the lack of flexibility.

EP 0 285 563 describes a transdermal therapeuti system for the combined application of Qestroge and gestagens. The reservoir receives the active ingredient form mulation and optionally a membrane and ethanol as percutaneous absorption enhancing agent. Because the freeset tion of the active ingredient mainly controlled by the membrane this transdermal therapeutic differs System basically from the active substance patch according to the present invention. The adhesive has been there written patch only the function, the patch to attach to the skin. That he made a contribution to tax It is not possible to release the active ingredient his main job, but only one - possibly even undesirable - side effect. It is about this a so-called "pouch patch" because the active ingredient preparation in a bag consisting of impermeable Backing layer and membrane with adhesive layer is located. As a result  its complicated structure is the production of the Pfla sters very expensive because the individual components are made separately and then in a further work step to a Patches must be put together.

EP 0 275 716 describes a - in contrast to that he inventive one-layer system - two-layer transdermal system for the simultaneous administration of one or several estrogens dissolved in the polymer layer or are microdispersed. The adhesive layer contains in addition to the active substances, substances that transdermal Ab improve sorption. Polymer and adhesive layers can be made from Polyaxylates, silicones or polyisobutylenes exist.

EP 0 328 806 describes a membrane-free transdermal therapeutic system, the matrix of which is made of a polyacrylic lat adhesive, a solvent, a penetration enhancer and estrogens, their derivatives and combinations thereof consists.

In WO 87/07138 there is an estradiol patch with a Backing layer, a matrix containing the active ingredient and a pressure sensitive adhesive that comes with a removable protection layer is covered. The production of Ma Trix and pressure sensitive adhesive are technologically very complex end processes by homogenizing, degassing, loading layering, drying and separating. In an execution form the backing must even be with a pressure sensitive adhesive be layered, which requires a further operation. The individual parts are put together in one se separate operation. So the manufacture of the patch is overall very complex and complex.

Systems are known from US Pat. No. 4,624,665 which are in the reservoir contain the active ingredient in microencapsulated form. The Re servoir is embedded between the backing and a meme  bran. The outside edge of the system is covered with a pressure sensitive adhesive equipped. The construction and manufacture of this system is very complicated because the active ingredient is microencapsulated and must be distributed homogeneously in a liquid phase, the then in further operations between the back layer and Membrane is embedded. In addition, the system must then provided with an adhesive edge and with a protection layer to be covered.

Active ingredient plasters are also known from EP 0 186 019 known in which a rubber / adhesive resin composition in water swellable polymers are added and from which estradiol can be released. However, it has been shown that the release of estradiol from these patches is far too low and does not meet the therapeutic requirement nits corresponds.

In DE-OS 20 06 969 is a plaster or a Haftver band described with system effect, at the conception herbal substances in the adhesive component or the Glue film are incorporated. The adhesive film can be a Be acrylate.

It is therefore an object of the present invention, the above to avoid the disadvantages listed and a stable that is called recrystallization-free estrogen and / or gesta Genetic plaster with sufficient drug release to make available, the release of which is controlled by La not changed.

Surprisingly, it has been shown that the task by one Pressure sensitive adhesive containing estrogen and / or progestin, the chole contains sterol or corn starch.

The above task is therefore an active ingredient plaster containing dissolved according to the main claim. The Unteran  sayings relate to particularly preferred embodiments of the subject of the invention.

Cholesterol is known as a pharmaceutical raw material and described as such in the Pharmacopoeia. Cholesterol acts as a swelling regulator and protective substance. It will used because of its good skin tolerance because it makes the epidermis soft and tender. It also increases the water absorption capacity.

Corn starch is also described in the pharmacopoeias. Corn Starch is used because of its adherence and absorbency and their swelling power.

The active ingredient-containing plaster can for cosmetic and therapeutic purposes in human and Veterinary medicine can be used.

The recrystallization-free estrogen and / or gestagen plaster with sufficient active ingredient release contains estradiol and its pharmaceutically un questionable derivatives alone or in combination with Gesta genes in a total concentration of 1-20 wt .-%, be moved to the entirety of the reservoir components, and in a molar ratio of 1: 1 to 1:10.

The estradiol-containing reservoir can have at least one loading included in the group, which age protection with tel, plasticizers, antioxidants and absorption enhancers includes. Suitable plasticizers are known to the person skilled in the art and described for example in DE 37 43 946. The estra diol-containing reservoir usually contains plasticizers in up to 5% by weight.

There are also old people in the active substance-containing reservoir antioxidants in a concentration of up to 1% by weight  contain. These are known to the expert and z. B. in the DE 37 43 946 described.

The materials for the impermeable backing and the Removable protective layers are also known to the person skilled in the art knows.

The estradiol-containing reservoir can be from solution, from disper sion and also be produced from the melt.

The reservoir can consist of several layers.

In the event that the reservoir is insufficient own has stickiness to the skin, this can with a too additional active ingredient-free adhesive layer or with be provided with an all-round adhesive border. On this ensures that the transdermal Pfla over the entire application period on the skin is liable.

A particularly preferred structure of the transdermal estra diol-containing patch is a matrix system in which be The matrix is known to be the control for the active ingredient-free takes over and obeys the √t law according to Higuchi. However, that does not mean that not in special cases a membrane system is also an advantage. Here is between The reservoir and PSA layer are the active ingredient release control membrane attached.

The thickness of the transdermal patch depends on the therapeutic requirements and can accordingly be fit. It is usually in the range of 0.03- 0.6 mm.

The invention is explained below with reference to exemplary embodiments play explained.

EXAMPLE 1

131.91 g Durotak 387-2287 solution (67.8 g solid)
3.2 g cholesterol
55.89 g of ethanol / ethyl acetate (2: 1 g / g) are homogenized by stirring at room temperature.
Then be
2.0 g of estradiol hemihydrate and
7.0 g of norethindrone acetate were added and the mixture was stirred for about 2 hours.
The adhesive substance obtained in this way is coated on the removable protective layer (Hosta phan RN 100, coated on one side with silicone - Hoechst-Diafoil) in such a way that an active substance-containing reservoir with a weight per unit area of approx. 80 g / m ²

results. The impermeable backing layer (polyester film, 19 µm thick) is laminated on from this reservoir. Then who the 16 cm ²

large active substance patches are punched out.

EXAMPLE 2

131.91 g Durotak 387-2287 solution (67.8 g solid)
3.2 g corn starch
55.89 g of ethanol / ethyl acetate (2: 1 g / g) are homogenized by stirring at room temperature.
Then be
2.0 g of estradiol hemihydrate and
7.0 g of norethindrone acetate were added and the mixture was stirred for about 2 hours.
The adhesive substance obtained in this way is coated on the removable protective layer (Hosta phan RN 100, coated on one side with silicone - Hoechst-Diafoil) in such a way that an active substance-containing reservoir with a weight per unit area of approx. 80 g / m ²

results. The impermeable backing layer (polyester film, 19 µm thick) is laminated on from this reservoir. Then who the 16 cm ²

large active substance patches are punched out.

To measure human skin penetration, the skin is clamped in the Franz cell. An estrogen- and / or gestagen-containing patch with an area of 1.539 cm ² is applied to the skin and the active ingredient release is measured at 37 ° C. (acceptor medium: 0.9% saline + 0.1% NaN ₃ ).

The check for recrystallization is visual performed against the light.

The results are shown in Table 1.

TABLE 1

Analytical results

As the table shows, one obtains with the invention Patch a significantly increased penetration by the human skin compared to the comparative product. At the same time found that the recrystallization at which he Examples according to the invention are omitted.

Claims (14)

1. Active substance-containing plaster for the controlled release of estradiol or its pharmaceutically acceptable derivatives alone or in combination with gestagens to the human or animal skin, from a backing layer, an associated active substance-containing reservoir suitable for the combined active substance release, which using Pressure-sensitive adhesives is produced, and a removable protective layer, characterized in that the pressure-sensitive adhesive contains cholesterol or corn starch. 2. Active substance-containing plaster according to claim 1, characterized characterized in that the reservoir 1-30 wt .-% cholesterol or contains 1-20% by weight of corn starch. 3. Active substance-containing plaster according to claim 1 or 2, since characterized in that the reservoir is estradiol or ne pharmaceutically acceptable derivatives alone or in Combination with gestagens in a proportion of 1-20% by weight, preferably 1.5-15% by weight. 4. Active substance-containing plaster according to one of claims 1 to 3, characterized in that the reservoir estradiol or its pharmaceutically acceptable derivatives alone or in combination with gestagens in a molar ver ratio of 1: 1 to 1:10. 5. Active substance-containing patch after one or more of claims 1 to 4, characterized in that the Pressure sensitive adhesives tackifying resins in a concentration of Contains 1-50 wt .-%. 6. Active substance-containing patch after one or more of claims 1 to 5, characterized in that the Re servoir at least one component from the group of Al  preservatives, plasticizers, antioxidants and ab contains sorption improvers. 7. Active substance-containing patch after one or more of claims 1 to 6, characterized in that the Pressure sensitive adhesive a solvent pressure sensitive adhesive, dispersion pressure sensitive adhesive or hot melt pressure sensitive adhesive. 8. Active substance-containing patch after one or more of claims 1 to 7, characterized in that the Back layer for the components of the reservoir impermeable sig is. 9. Active substance-containing patch after one or more of claims 1 to 8, characterized in that the Re servoir consists of several layers and one additional active ingredient-free adhesive layer is. 10. Active substance-containing patch after one or more of claims 1 to 9, characterized in that between Reservoir and adhesive layer that releases the active ingredient zung control membrane is attached. 11. Active substance-containing patch after one or more of claims 1 to 10, characterized in that the Re servoir with a circumferential adhesive border is. 12. Active substance-containing patch after one or more of claims 1 to 11, characterized in that the Thickness of the active substance-containing patch in the range of 0.03- 0.6 mm. 13. Use of the active ingredient-containing patch according to Claims 1 to 12 for cosmetic purposes.   14. Use of the active ingredient-containing patch after a of claims 1 to 12 as a preparation for therapeutic Purposes in human and veterinary medicine.