WO2001089488A1

WO2001089488A1 - Plaster containing estrogen, with an active agent reservoir based on ethylcellulose, polyoxyethylene lauryl alcohol and an ethylene-vinylacetate-vinylpyrrolidone copolymer

Info

Publication number: WO2001089488A1
Application number: PCT/EP2001/005439
Authority: WO
Inventors: Reinhold Meconi; Robert-Peter Klein; Frank Seibertz
Original assignee: Lts Lohmann Therapie-Systeme Ag
Priority date: 2000-05-25
Filing date: 2001-05-12
Publication date: 2001-11-29
Also published as: AR029664A1; DE10025970C2; DE10025970A1; AU2001267435A1

Abstract

The invention relates to a transdermal therapeutic system in the form of a plaster, for the controlled release of oestradiol, alone or combined with progestogens, to human or animal skin. Said system comprises a back layer, a reservoir containing the active agent, said reservoir being connected to said back layer and a removable protective layer. The inventive plaster is characterized in that the reservoir containing the active agent contains ethylcellulose, ethylene-vinylacetate-vinylpyrrolidone-copolymer, polyoxyethylene lauryl alcohol and at least one substance which improves skin permeation.

Description

ESTROGEN-BASED PLASTER WITH AN ACTIVE SUBSTANCE RESERVOIR BASED ON ETHYLCELLULOSE, POLYOXYETHYLENE LAURYL ALCOHOL AND AN ETHYLENE VINYL ACETATE VINYL PYRROLIDONE COPOLYMER

Plaster containing estrogen with an active substance reservoir based on ethyl cellulose and an ethylene-vinyl acetate-vinyl pyrrolidone copolymer.

The present invention relates to a transdermal therapeutic system (TTS) in plaster form containing an estrogen, optionally in combination with a gestagen, which enables a controlled release of these active substances to human or animal skin and especially for contraception and hormone substitution suitable is.

Estradiol, estrone (estrogen) and progesterone (progestogen) are the natural female sex hormones. The sex hormones serve to develop the primary and secondary sexual characteristics. They have an influence on growth and body structure as well as on the water and mineral balance. Sex hormones also shape the course of the menstrual cycle in women.

The natural sex hormones, their derivatives and structural analogues are used for hormonal contraception, for substitution therapy or for the treatment of various diseases.

A main area of application of sex hormones is in the field of postmenopausal hormone substitution. The substitution serves to prevent climacteric complaints (hot flashes, dizziness, tachycardia, sweating, anxiety, irritability, poor concentration, sleep disorders, etc.). Furthermore, changes to the urinary and genital organs, cardiovascular changes due to hyperlipoproteinemia, skin atrophies or osteoporosis and other pathological symptoms are to be prevented. For this purpose, an estrogen is administered in combination with a progestogen.

Estradiol-containing plasters or transdermal therapeutic systems which allow the delivery of estradiol and other steroid hormones to the skin are already known. However, the number of such application systems that are already available on the market is still relatively small. The reason for this lies in the fact that various problems appear in the development and production of skin patches containing horon, which are able to meet the demands placed on them, which have hitherto been insufficiently solved.

For example, a patch containing hormones must enable the active substance to be released as evenly as possible over a longer period of time, with the highest possible active substance release rates (flux rates) having to be achieved through the skin in order to ensure the desired therapeutic or contraceptive effect. If the achievable delivery rate is too low, the area of the steroid hormone-containing active substance patch over which the active substance is delivered to the skin must be increased accordingly in order to enable the administration of effective doses. On the other hand, the enlargement of the delivery area is a disadvantage because there is a risk with large-area systems that complete skin contact is not achieved and the active ingredient delivery is thus restricted. In addition, small patches are preferred by the users.

The rate of release of active substance depends on the one hand on the permeability properties of the skin for the active substances in question and on the other hand on the concentration of the active substance in the matrix of the transdeπrtal therapeutic system. The permeability properties of the skin can be improved by permeation enhancers; substances suitable for this are known in principle to the person skilled in the art.

Particularly in the case of skin plasters containing estradiol, the active substance easily recrystallizes in the active substance atrix during storage or during the application period as a result of the saturation concentration being exceeded. Due to the recrystallization, the thermodynamic activity of the active substance decreases sharply, and as a result, the active substance release rate. For this reason, various solutions have been proposed in the prior art with which high active substance concentrations in the active substance reservoir of the plaster can be achieved and at the same time the recrystallization of the active substance should be prevented.

For example, systems are known from US Pat. No. 4,624,665 which contain the active substance in microencapsulated form in the reservoir. The construction and manufacture of this system is very complicated since the active ingredient has to be microencapsulated and homogeneously distributed in a liquid phase, which is then embedded between the backing layer and the membrane in further operations. EP 0 186 019 AI describes active ingredient plasters in which polymers which are swellable in water are added to a rubber / adhesive resin composition and from which estradiol can be released. However, it has been shown that the release of estradiol from these active substance patches is far too low and does not meet the therapeutic requirements. DE-OS 39 33 460 describes active ingredient plasters based on homopolymers and copolymers with at least one derivative of acrylic or methacrylic acid, which are said to additionally contain water-swellable substances. DE-OS 195 00 662 describes a transdermal therapeutic system with an estradiol-containing active substance reservoir based on ethyl cellulose with a high proportion of rosin esters as a tackifying resin, together with up to 20 wt. -5s lauric acid, which recrystallize the active substance and to counteract a decrease in its release rate.

Various other substances have been described in the literature which act as crystallization inhibitors and are intended to prevent the crystallization in particular of estradiol, for example silicon dioxide (US Pat. No. 5,676,968) or anhydrous glycerol (WO 96/05814). The addition of such substances is often associated with disadvantages, e.g. For example, the mechanical properties (cohesion) of the patch may be impaired, or problems may arise in the manufacture of these patches.

The object of the present invention was therefore to provide a transdermal therapeutic system which has a simple structure and is inexpensive to produce, and which is able to deliver estradiol or estradiol in combination with a progestogen to the skin, Permeation rates are to be achieved which are far above the perception rates achievable by known systems, but are in any case sufficient for therapeutic purposes or for contraception, without the surface area of the plasters becoming unacceptably large.

Surprisingly, it has been found that transdermal therapeutic systems (TTS) in plaster form, which have the structure described in the preamble of claim 1 and which contain estradiol, alone or in combination with a progestogen, very high skin permeation allow rates for the active substances mentioned if the active substance-containing reservoir of the patch contains ethyl cellulose, an ethylene-vinyl acetate-vinyl pyrrolidone copolymer, polyoxyethylene lauryl alcohol as emulsifier, and at least one substance which improves skin permeation. Further advantageous embodiments of the transemeral therapeutic systems according to the invention are described in the subclaims.

With the transdermal therapeutic system according to the invention, skin perforation rates were achieved which are several times higher than those of the reference product Evorel Conti. Values were determined for both the estradiol permeation and the norethindrone acetate permeation, each corresponding to four times the value achieved with the reference product Evorel Conti.

This increase in skin permeation makes it possible to produce skin patches containing estradiol with a very small area. Furthermore, it also makes it possible to produce combination plasters which contain estradiol and norethindrone acetate (or another progestogen) and which have small area dimensions. Such combination plasters can advantageously be used for contraception and for hormone replacement therapy.

The systems according to the invention are notable for a certain water absorption capacity, which is preferably at least 15% by weight. An active substance reservoir which can absorb or contains at least 20% by weight of water is particularly preferred.

The active substance content, based on the active substance-containing reservoir is in the case of estradiol, preferably 0.5 to 10.0 wt -. ° s, particularly preferably 1 to 2.5 wt ⁰ ". In the case of TTS according to the invention, which in a preferred embodiment approximate shape estradiol in combination with at least one gestagen, the progestin concentration in the active substance reservoir preferably 0.7 to 20 wt ⁰ ", more preferably 2 to 5 wt -.%.

17-beta-estradiol is preferably used as the estradiol. In addition, the following estrogens can also be used: 17-alpha-estradiol, 17-beta-estradiol cypionate, 17-beta-ethinylestradiol, 3,17-beta-estradiol dienanthate, 17-beta-estradiol valerate, 17-beta-estradiol benzoate, 17-beta-estradiol undecylate, 17-deacetyl norgestimate, norgestimate, mestranol and quinestrol.

The preferred progestogen is norethindrone acetate (norethisterone acetate). Furthermore, the gestagen (s) can also be selected from the group consisting of 19-norprogesterone, norethisterone acetate, norethisterone, ethisterone, melengestrol, norgestel, levonorgestrel, gestodene, hydroxyprogesterone capronate, medroxyprogesterone acetate, ethynodiol diacetate, 17- -Hydroxyprogesteron, Megestrolaσetat, Lynestrenol, De-sogestrel, Allylestrenol, Chlormadinon and Chlormadinon acetate includes.

The polymer matrix of the active ingredient reservoir of the TTS according to the invention has an ethyl cellulose content; ethyl cellulose is preferably present in a concentration of 5 to 40% by weight, based on the active substance reservoir. With regard to the ethylene-vinyl acetate-vinyl pyrrolidone copolymer, a content of 5 to 50% by weight is preferred.

The active substance-containing reservoir of the plasters according to the invention also contains polyoxyethylene lauryl alcohol (Brij®30) or other polyethoxylated fatty alcohols as emulsifier. The concentration of the polyoxyethylene lauryl alcohol is preferably 0.1 to 15% by weight. If necessary. further emulsifiers and / or plasticizers and / or antioxidants can be added to the active substance-containing reservoir in a concentration of up to 10% by weight, preferably from 0.1 to 5% by weight.

Furthermore, the active substance-containing reservoir has a content of at least one enhancer, whereby an enhancer is understood to be a substance that improves the skin permeation of the active substances to be administered. The enhancer (s) is / are added in a concentration of 0.5 to 50 wt. -5s, based on the reservoir containing the active ingredient. The enhancer (s) can be selected from the group which contains the following substances: lauric acid diethanolamide (eg Comperlan LD), oleic acid diethanolamide (eg Comperlan OD), coconut fatty acid diethanolamide (eg Comperlan COD), D-alpha-tocopherol (e.g. copherol), hexyl laurate (e.g. cetiol A), 2-octyldodocanol (e.g. eutanol) and dexpanthenol.

In further embodiments, provision is made for the active substance-containing reservoir to be added with tackifying or tackifying resins and / or fillers. Substances suitable for this are known in principle to the person skilled in the art.

It can prove to be particularly advantageous if the active substance-containing reservoir is made up of two or more layers. In this case, the individual layers can contain different active substances or active substance concentrations, or have a different polymer composition, or otherwise differ in their composition. Furthermore, a sheet-like structure can be introduced between individual layers of the active substance-containing reservoir, which is, for example, a membrane, a film, a textile fabric or a textile. til matter can act. Another embodiment is that the TTS according to the invention is provided with an additional pressure-sensitive adhesive layer and / or a pressure-sensitive edge; this is particularly useful if the stickiness of the matrix containing the active ingredient does not appear to be sufficient.

The TTS according to the invention are characterized by a small layer thickness; the layer thickness of the active substance-containing reservoir is preferably 0.02 mm to 0.5 mm, particularly preferably 0.03 to 0.2 mm.

In addition to an active substance reservoir, the structure of the TTS according to the invention comprises an active substance-impermeable backing layer as well as a likewise active substance-impermeable, removable protective layer. Particularly suitable as a backing layer are polyesters, which are notable for their particular strength, but moreover almost any other skin-compatible plastics, such as. B. polyvinyl chloride, ethylene vinyl acetate, vinyl acetate, polyethylene, polypropylene, cellulose derivatives or combinations of different films and many others. In individual cases, the backing layer can be provided with an additional layer, e.g. B. by vapor deposition with metals or other diffusion-blocking additives such as silicon dioxide, aluminum oxide or similar substances which are known to the person skilled in the art. The same materials can be used for the removable protective layer as for the backing layer, provided that they can be treated by suitable surface treatment, such as. B. siliconization, is removable. However, other removable protective layers, such as paper treated with polytetrafluoroethylene, cellophane, polyvinyl chloride, or the like, can also be used. \ The TTS according to the invention are advantageously suitable for the purposes of contraception and for hormone substitution for the purposes of prophylaxis and therapy of climacteric complaints, in particular for osteoporosis prophylaxis.

The following examples describe TTS, which have a composition according to claim 1, and the skin perforation rates achieved therewith.

example 1

30.8 g of ethylene-vinyl acetate-vinylpyrrolidone copolymer (Plastic S 630, from International Specialty Products) and 1.9 g of the emulsifier polyoxyethylene (4) lauryl alcohol (Brij 30, from ICI) are initially introduced and stirred in Ethanόl solved. Then 30.8 g of the film former ethyl cellulose are slowly added with stirring. Then 14.5 g of the permeation enhancer oleic acid diethanolamide and 14.5 g of the permeation enhancer lauric acid hexyl ester are added and homogenized; 2.5 g of estradiol and 5.0 g of norethindrone acetate are added to the homogenized mass. The mixture is then stirred until the active ingredients have dissolved. The solids content is adjusted to 50.0% by adding ethanol.

The adhesive solution obtained in this way is coated on the backing layer (Hostaphan RN 23, Mitsubishi), so that after drying an active substance-containing reservoir with a weight per unit area of 80-90 g / m 2 results. This layer is covered with the removable protective layer (host phan RN 100, coated on one side with aluminum and siliconized on both sides).

Individual plasters are punched out of the laminate thus obtained.

Examples 2 and 3

Examples 2 and 3 were also prepared in the manner described above, the composition of which, like the composition of Example 1, can be seen from Table 1.

Table 1

Explanation of the used abbreviations:

Oes = estradiol

NeA = norethindrone acetate

OD = Comperlan OD = lauric acid diethanolamide

COD = Comperlan COD = coconut fatty acid diethanolamide

Cetiol A = hexyl laurate

Eutanol G = 2-octyldodecanol

Ethylcell. = Ethyl cellulose Examples 4, 5 and 6

were produced in a corresponding manner and have the following composition:

* The hormone content in Examples 4 to 6 corresponds to that in Examples 1 to 3 (Oes / NeA combination; 2.5% by weight -5s Oes and 5.0% by weight NeA; see Table 1).

Durotak 387-2287: acrylate / methacrylate vinyl acetate

Copolymer.

To measure the human skin permeatxon, the skin is clamped in a Franz cell. An estrogen- and / or gestagen-containing patch with an area of

1.539 cm ^{2 was} glued on and the active substance release measured at 37 ° C (acceptor medium: 0.9% saline solution with 0.15s NaJS.3; filling volume 9 ml).

The results are shown in Table 2 (Examples 1-3) and in Table 3 (Examples 4-6). Compared to Evorel Conti, the estradiol flux can

[μg / cm ² «h] in Examples 2 and 3 were increased by 3.6 and 3.9 times and the norethindrone acetate flux by 3.2 and 3.9 times, respectively. This means that the TTS area, which is 16 cm ² in the Evorel Conti, can be reduced to approximately 4 cm ² in the TTS according to the invention.

In addition, the transdermal therapeutic systems according to the invention are completely free from recrystallization phenomena, while Evorel Conti tends to crystallize the active ingredient.

The water absorption capacity of Examples 1 and 2 and the commercial product Evorel Conti was measured as follows. The TTS were weighed and hung in a thin layer chromatography chamber in a saturated water vapor atmosphere for one week. After removal, the water content of the TTS was determined by coulometric titration according to Karl Fischer. The results are shown in Table 4.

As the results from Table 4 show, the water absorption of the TTS produced according to Example 1 or 2 is 28.25 s or 36.7 5≤, while Evorel Conti only absorbs 10.0 wt. 5s water and increases under these conditions increased active ingredient crystallization tends. In contrast, the samples according to Examples 1 and 2 show no signs of crystallization even under moist conditions.

Table 4

Obviously, the increased water absorption of the TTS according to the present invention leads to an increase in the solubility of the active substance (s) in the active substance-containing reservoir and thus an unexpectedly increased active substance release.

N

Table 2

Flux: tμg / cm ² «h3

Table 3 &

(0 H H ffl ω

* Verglexchsbexspiele

Claims

Expectations

1. Transdermal therapeutic system in plaster form for the controlled release of estradiol, alone or in combination with gestagens, to human or animal skin, the system having a backing layer, an associated active substance-containing reservoir and a removable protective layer, characterized in that the active substance-containing Reservoir contains ethyl cellulose, ethylene-vinyl acetate-vinyl pyrrolidone copolymer, polyoxyethylene lauryl alcohol and at least one substance which improves skin permeation.

2. Transdermal therapeutic system according to claim 1, characterized in that the active substance-containing reservoir has a water absorption capacity of at least 15 wt. -5≤, preferably of at least 20 wt. -5s.

3. Transdermal therapeutic system according to claim 1 or 2, characterized in that the active substance-containing reservoir contains estradiol in combination with at least one gestagen.

4. Transdermal therapeutic system according to one or more of the preceding claims, characterized in that the estradiol concentration in the active substance-containing reservoir is 0.5 to 10.0 wt. -5s, preferably 1 to 2.5 wt. -5s and, if the drug reservoir contains gestagen (e), the gestagen concentration in the drug reservoir is 0.7 to 20 wt. -5s, preferably 2 to 5 wt. -5s.

5. Transdermal therapeutic system according to one or more of the preceding claims, characterized in that the content of ethyl cellulose in the drug-containing reservoir is 5 to 40 wt .-%.

6. Transdermal therapeutic system according to one or more of the preceding claims, characterized in that the content of ethylene-vinyl acetate-vinyl pyrrolidone copolymer in the active substance-containing reservoir is 5 to 50 wt.

7. Transdermal therapeutic system according to one or more of the preceding claims, characterized in that the active substance-containing reservoir contains polyoxyethylene lauryl alcohol in a concentration of 0.1 to 15% by weight.

8. Transdermal therapeutic system according to one or more of the preceding claims, characterized in that the active substance-containing reservoir contains one or more substances which improve the permeation of the active substance (s) through the skin in a concentration of 0.5 to 50% by weight. -5s, the said substance (s) preferably being selected from the group containing benzyl alcohol, lauric acid diethanolamide, oleic acid diethanolamide, coconut fatty acid diethanolamide, D-alpha-tocopherol, lauric acid hexyl ester, 2-octyldodecanol and dexpanthenol.

9. Transdermal therapeutic system according to one or more of the preceding claims, characterized in that the active substance-containing reservoir contains emulsifiers and / or plasticizers and / or antioxidants in a concentration of up to 10% by weight, preferably of

10. Transdermal therapeutic system according to one or more of the preceding claims, characterized in that the active substance-containing reservoir contains the tackifying resins.

11. Transdermal therapeutic system according to one or more of the preceding claims, characterized in that the active substance-containing reservoir contains fillers.

12. Transdermal therapeutic system according to one or more of the preceding claims, characterized in that the active substance-containing reservoir is constructed from two or more layers.

13. Transdermal therapeutic system according to claim 12, characterized in that the individual layers contain different active substances and / or differ with regard to the active substance concentration and / or the polymer composition.

14. Transdermal therapeutic system according to claim 12, characterized in that a sheet-like structure, preferably a membrane, a film, a textile material, a nonwoven material or a textile fabric, is inserted between the layers of the active substance-containing reservoir.

15. Transdermal therapeutic system according to one or more of the preceding claims, characterized in that the active substance-containing reservoir has a Schiσhtdiσke of 0.02 mm to 0.5 mm, preferably from 0.03 to 0.2 mm.

16. Transdermal therapeutic system according to one or more of the preceding claims, characterized in that the active substance-containing reservoir is provided with an additional pressure-sensitive adhesive layer and / or a pressure-sensitive edge.

17. Use of the transdermal therapeutic system according to one or more of claims 1 to 16 for therapeutic purposes in human medicine, preferably for hormone substitution for the prophylaxis and treatment of climacteric complaints and for osteoporosis prophylaxis.

18. Use of the transdermal therapeutic system according to one or more of claims 1 to 16 for hormonal contraception.