WO2001049273A2 - Pharmaceutical composition for transdermally administering hormones with an additive that enhances permeation - Google Patents

Abstract

The invention relates to a pharmaceutical composition which is provided for transdermally administering one or more hormones, is adhesively applied to the skin, comprises at least one matrix layer that contains hormones, and which contains an additive that enhances skin permeation. The inventive composition is characterized in that said additive comprises a 1,4-dioxane-2,5-dione base structure of general formula (I), whereby the radicals R1 and R2 are hydrocarbon groups or substituted hydrocarbon groups or functional groups.

Description

Pharmaceutical composition for the transdermal administration of hormones with a permeation-improving additive.

The invention relates to a pharmaceutical composition which is suitable for the transdermal administration of hormones. In particular, the invention relates to active substance patches which are suitable for the transdermal administration of estrogens or gestagens, or a combination of such hormones, the hormone or the hormones being in a matrix layer, together with an additive which improves skin penetration. The invention further comprises a method for producing such compositions and their use for the prophylaxis or therapeutic treatment of climacteric complaints.

Estrogens and progestogens are the two large groups of female sex hormones, which include, for example, the natural hormones estradiol and estrone and progesterone. On the one hand, these sex hormones from the group of steroid hormones cause the development of primary and secondary sexual characteristics by influencing growth, body structure, and the water and mineral balance. On the other hand, they are also responsible for the course of the menstrual cycle in women and for the maintenance of pregnancy.

The natural sex hormones (estradiol and estrone or progesterone), their derivatives and structural analogs are used for hormonal contraception, for substitution therapy or for the treatment of various diseases.

Oral administration of steroid hormones such as estrogens or progestogens is disadvantageous for various reasons. Because of the poor water solubility, these hormones only partially absorbed. In addition, the absorbed fraction is subject to a high first-pass effect, i.e. a relatively large proportion of active substance is already metabolized by the mucous membranes of the gastrointestinal tract and by the liver during the first passage after oral administration, with numerous metabolites being formed no longer have the original hormonal effects and can lead to side effects. Overall, the bioavailability of the orally administered hormones is reduced. In addition, there is an unphysiological fluctuation in the hormone level when administered orally, because relatively high hormone doses have to be administered because of the first pass effect. This fluctuation causes further side effects. In principle, slow intravenous infusion would be considered an ideal route of administration, but it is not practical.

Transdermal hormone administration offers a number of advantages over oral administration. Bypassing the digestive tract, the pre-systemic elimination (through first-pass effect) is greatly reduced, which results in a relatively high bioavailability. In addition, the hormone effect is independent of the gastric emptying rate and intestinal motility. The fluctuations in hormone intake are also much lower than in oral administration, since absorption via the skin takes place continuously over a longer period of time. The plasma concentration can be set without peaks and valleys in the therapeutic range, ie pulsating blood levels are avoided. Due to the higher bioavailability, the applied dose amount - as compared to oral dosage forms - can generally be reduced, so that dose-dependent side effects are also reduced or even avoided and overall a higher level of therapy results. Another advantage of transdermal administration is that possible irritation of the gastric or intestinal mucosa is avoided. Transdermal administration should also be considered if oral administration is not possible, for example due to tumors in the area of the gastrointestinal tract or because of difficulty swallowing. The transdermal application route is especially for highly effective substances, e.g. B. hormones, because in this case the required plasma concentrations can be achieved despite the limited permeability of the skin. This generally applies to active substances whose daily dose is less than 10 mg.

For the transdermal administration of active substances, for example also of estrogens and gestagens, active substance patches are particularly suitable which are capable of delivering the active substance or substances to the skin continuously at a predetermined rate over a certain period of time, in order thereby to give one cause systemic effect in the organism. Active ingredient preparations of this type are generally characterized by an exact treatment program, which is why they are referred to as "transdermal therapeutic systems" (TTS). TTS are characterized by exact drug loading. The dosage form according to the invention is also a TTS in the sense described.

When administering active substances or hormones with the aid of TTS, it is also advantageous that the frequency of application is greatly reduced in comparison to conventional oral dosage forms. As a result, like the preparations according to the invention, TTS is distinguished by a high level of patient acceptance (so-called “co pliance”), ie by a high level of reliability with regard to the patient's adherence to the therapy plan. Another advantage is that the treatment can easily be stopped at any time if necessary by removing the active substance patch from its place of application.

5 Active substances from TTS or from the hormone-containing active substance patches according to the invention are released to the skin by passive diffusion into the underlying skin areas. For this, the active substance loading of the TTS must be high enough to create a clear diffusion gradient. The defined active ingredient release of a TTS is related to the length of time it is worn and depends, among other things, on the size of the diffusion-active contact surface on the skin.

In the transdermal absorption of active ingredients, the _first 5 skin, in particular the cornea, represents a barrier. In order to ensure that the corneal layer is switched off as a quantity-determining or speed-determining layer, the area of skin in question can be treated with agents which relate to the permeation of the skin in relation to the particular skin Lighten active ingredient. In TTS this is often done by combining the active ingredient with a permeation enhancing substance.

25 The hormone-containing TTS according to the invention are so-called

"Matrix systems", i. H. they have at least one polymer matrix layer, which on the one hand serves as a reservoir for the active ingredient (s) and on the other hand has an adhesive function to attach the TTS to the skin and one

30 to allow close contact. The manufacture of such systems is relatively simple compared to TTS, in which the active ingredient is in a bag-shaped reservoir. In a matrix-type TTS, the active ingredients are finely divided, i.e. H. dissolved or dispersed, in a

35 ner polymer matrix, which acts as a reservoir takes over .

TTS with a bag-shaped reservoir usually requires a control membrane that regulates the transdermal drug delivery. Such a membrane is not required for TTS of the matrix type, since the function of the

Control membrane in this case is taken over by the skin itself. This simplifies the manufacture of these TTS.

Adhesion of the TTS to the application area is ensured by an adhesive. Generally, adhesives are highly viscous, permanently adhesive structures. A distinction is made between the quality characteristics of initial tack ("tack"), adherence (adhesion) and the internal strength (cohesion) of the pressure sensitive adhesive. Polyacrylics, polyisobutylenes, styrene-isoprene block copolymers or polysilicones are customary as polymeric adhesives.

Examples of simply structured matrix systems for the transdermal application of estradiol in combination with a gestagen are described in EP 0 695 177 B1. WO 96/40087 describes a matrix system based on a crosslinked acrylate polymer for the transdermal application of estradiol.

To ensure high permeation rates over a longer period of time, high permeation enhancer concentrations are often required. In this way, sufficient transdermal active ingredient intake is made possible and the therapeutic effectiveness is guaranteed. For example, US Pat. No. 5,676,968 describes the use of 1,2-propanediol and isopropyl myristate to increase the permeation of estradiol through the skin. EP 0 811 381 AI discloses the use of fatty alcohols in combination with a diethylene glycol monoalkyl ether as an enhancer for estradiol and norethisterone acetate. According to U.S. Patent 5,686,097 the use of monoglycerides and lactate esters can promote the penetration of an estrogen-progestogen combination. To improve estradiol performance, the addition of monoisopropylidene glycerol or diglycerol has been described in US Pat. No. 5,686,098. U.S. Patent 5,122,383 discloses sorbitan esters as penetration enhancers.

However, the use of permeation-promoting substances, especially in higher concentrations, often leads to a reduction in the cohesion of the system in TTS matrix systems. This manifests itself by an increased "tack" (initial stickiness), an increased "cold flow", or a transfer of adhesive to the protective film or a residue of adhesive residues on the skin after removal of the system. A general solution to this problem is provided by US Pat. No. 5,306,503, according to which so-called film formers are to be added to systems with a high content of liquid or plasticizing components. However, this introduces an additional excipient into the system, which under certain circumstances can adversely affect the stability of the active ingredient, for example in the case of incompatibility reactions.

A main area of application of estrogens and progestogens is in the field of postmenopausal hormone substitution, which 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. Such a combined gift is Monotherapy with estradiol is preferable, since in the latter case there is a risk of hyperstimulation of the endometrium, combined with an increased risk of hyperplasia or degeneration. In addition, menstrual disorders occur more frequently with estradiol monotherapy. In order to avoid these risks, it makes sense to give estradiol in combination with a progestogen.

Due to the circumvention of the "first pass" effect, estradiol plasma concentrations corresponding to the physiological hormone blood level of a premenopausal woman (40-60 pg / ml) can be achieved by transdermal administration. Another advantage of transdermal administration over oral administration is that the daily dose can be reduced to 50 μg / day. When a progestogen is administered in combination (norethisterone acetate or an equivalent) to avoid hyperplasia, 0.7-1 mg / day is required for oral administration (Wiseman, LR and McTavish, D.: Transdermal Estradiol / Norethisterone: A review of its pharmacological properties and clinical use in postmenopausal women. Drug & Aging, Vol. 4 No. 3, 1994, 238-256). With transdermal administration, the daily administration of 200-300 μg norethisterone acetate (or equivalent) is sufficient to avoid hyperplasia.

The object of the present invention was to provide a pharmaceutical composition for the transdermal administration of hormones to the skin, which has the general advantages of a transdermal therapeutic system, can be prepared in a simple manner and enables an active ingredient release rate suitable for therapeutic purposes without the addition of the Permeation enhancers lead to a reduction in system cohesion. The addition of a film former should be avoided as far as possible. In particular, the task was to To provide ster of the type mentioned, which is suitable for the combined delivery of an estrogen with a progestogen in postmenopausal hormone substitution.

Surprisingly, the object is achieved in that, in the case of a pharmaceutical composition for transdermal administration with the features of the preamble of claim 1, an additive with a 1,4-dioxane-2,5-dione basic structure of the general formula

als die Hautpermeation verbessernder Zusatzstoff eingesetzt wird, wobei die Reste R^ und R2 Kohlenwasserstoffgruppen oder substituierte Kohlenwasserstoffgruppen oder funktio- nelle Gruppen sind. Ein erfindungsgemäßer Permeationsenhan- cer ermöglicht eine Steigerung der Hautpermeation von Ste- roidhormonen, insbesondere von Estrogenen und Gestagenen, ohne die Kohäsion der Wirkstoffmatrix zu beeinträchtigen. Ein Zusatz von filmbildenden Polymeren zur Wirkstoffmatrix zum Zwecke der Kohäsionsverbesserung ist nicht erforderlich.

is used as an additive to improve skin permeation, the radicals R 1 and R 2 being hydrocarbon groups or substituted hydrocarbon groups or functional groups. A permeation enhancer according to the invention enables an increase in the skin permeation of steroid hormones, in particular of estrogens and gestagens, without impairing the cohesion of the active substance matrix. It is not necessary to add film-forming polymers to the active substance matrix for the purpose of improving cohesion.

The residues Rj. And R2 of the permeation-promoting additive according to the invention (enhancer) are preferably alkyl groups, particularly preferably methyl, ethyl, propyl, isopropyl, butyl and isobutyl groups, where 3, 6- Dimethyl-1,4-dioxane-2,5-dione (dilactide) is particularly preferred. The R ^ and R2 radicals are usually identical, but they can also be different from one another. Furthermore, the radicals can also be functional groups or contain functional groups, e.g. B. functional groups containing oxygen, sulfur, nitrogen or phosphorus pen. Halogen-containing radicals R ^ or R2 are also possible. The

Residues R 1 and R 2 can also be cyclic hydrocarbons, in particular aromatic hydrocarbons or also heterocyclic compounds, or contain such groups.

The proportion of the permeation-improving additive according to the invention can be 0.1-10%, preferably the proportion is in the range of 0.5-5%, in each case based on the mass of the matrix layer.

The hormone-containing plasters according to the invention for transdermal administration have the structure of transdermal therapeutic systems of the matrix type. They have a layered structure with at least one matrix layer which is based on a base polymer or polymer mixture and which contains the hormone or hormones and the permeation enhancer in dissolved or dispersed form. The matrix layer has adhesive properties so that it can allow the system to be permanently attached to the skin. Acrylate polymers or acrylate copolymers, polyisobutylenes, styrene-isoprene block copolymers or polysilicones, or else suitable mixtures of polymers, are preferably used as pressure-sensitive adhesive base polymers for the matrix layer (s). If necessary, a system according to the invention can also contain two or more matrix layers.

In addition to the matrix layers, the TTS according to the invention have two film-like layers which cover the matrix layer (s) on both sides. It is a backing layer that is impermeable to active substances and a protective layer to be removed before the patch is applied. A protective plastic film is preferably used as the protective layer, for example silicon butted polyester film. The backing layer serves to seal off the matrix layers from the outside during the application time. A wide variety of skin-compatible plastic films are also suitable for this, e.g. B. polyester film.

In general, the compositions according to the invention are suitable for the transdermal administration of steroid hormones, preferably for the administration of estrogens and / or gestagens. The compositions can contain both individual estrogens or individual progestogens, or combinations of different estrogens, or combinations of different progestogens, or combinations of at least one estrogen with at least one progestogen. Compositions according to the invention which each contain an estrogen or a gestagen are particularly preferred. Furthermore, compositions are particularly preferred which contain a combination of at least one estrogen, preferably estradiol, with a progestogen, preferably norethisterone acetate, for example for use in postmenopausal hormone substitution.

In the hormone patches according to the invention, 17-ß-estradiol is preferably used as estrogen. Furthermore, estrogens or estrogen derivatives can also be used, for example selected from the group consisting of 17-α-

Estradiol, 17-ß-estradiol cypionate, 17-ß-ethinyl estradiol, 3,17-ß-estradiol dienanthate, 17-ß-estradiol yalerate, 17-ß-estradiol benzoate, 17-ß-estradiolundecylate, 17-deacetyl-norgestate, Quinestrol includes. The estrogens mentioned are characterized by an aromatic hydroxyl group or its ether. Among the gestagens, norethisterone acetate is preferred for the production of the transdermal active substance patches according to the invention. Furthermore, progestogens or gestagen derivatives can also be used, which are selected, for example, from the group consisting of 19-norprogesterone, norethisterone, ethisterone, melengestrol, norgestrel, levonorgestrel, gestodene, hydroxyprogesterone capronate, medroxyprogesteronate acetate, ethynodiol diacetate, 17-α-hydroxypro Megestrol acetate, Lynestrenol, Desogestrel, Allylestrenol, Chlormadinon and Chlormadinonacetate includes. typical

The structural feature of most compounds is a 3-keto-4-en structure.

The hormone concentration in the formulations according to the invention is in the range from 0.1-5, preferably in the range from 0.2-2%, based on the mass of the matrix layer.

With the compositions according to the invention, it was possible to achieve in vitro permeation rates which are comparable to those which are achieved with a commercially available preparation of the bag-reservoir type (cf. Examples 1 and 3). However, it must be taken into account here that the systems according to the invention are based on the matrix principle and are therefore much easier and cheaper to manufacture than the preparations of the bag-reservoir type used for comparison. A comparison of a composition according to the invention containing estradiol with a commercial preparation of the matrix type, which also contained estradiol, showed that the estradiol skin permeation achieved with the system according to the invention was significantly higher than that of the comparison preparation and that after a test period of 48 h skin permeation was twice as high (see Example 2). With a system according to the invention, which contained a combination of an estrogen with a progestogen (Example 1), in vitro release results were achieved which are comparable to those obtained with a commercial preparation of the "reservoir type" (cf. Tab 1 and 2), which - as mentioned - is more complex to manufacture. In any case, by using the additive according to the invention as a permeation enhancer, a significant improvement in the in vitro permeation could be demonstrated.

The permeation values achieved with the systems according to the invention show that these hormone-containing plasters are suitable for the purposes of hormone replacement therapy. In addition, compared to transdermal systems based on a bag-shaped reservoir, they are much easier and cheaper to manufacture. An impairment of the cohesion of the active substance matrix could not be found in the patch preparations according to the invention.

The hormone-containing preparations according to the invention are therefore suitable for carrying out hormone substitution and in particular for the prophylactic and therapeutic treatment of climacteric complaints. Embodiments according to the invention which contain a combination of an estrogen with a gestagen are particularly suitable for this. Due to the transdermal mode of administration, the use is associated with fewer side effects than is the case with oral administration, and the patient acceptance is, as expected, better than with oral administration forms.

The invention is explained in more detail below with the aid of examples. example 1

Composition with an estrogen in combination with a progestogen.

0.24 g estradiol, 1.2 g norethisterone acetate, 57.3 g solution of an acrylate adhesive (Durotak ^® 387-2353) and 1.2 g 3,6-dimethyl-1,4-dioxane-2,5-dione were mixed until a homogeneous mass was obtained. The resulting mass was then coated with a wet layer thickness of 400 .mu.m applied by doctor blade onto a siliconized polyester film (eg. As Hostaphan ^®). The result was an even, clear line. The moist film was dried for 30 minutes at 50 ° C. and then laminated with a transparent polyester film (e.g. Hostaphan ^® ). The weight per unit area of an adhesive film produced in this way (weight of the matrix without films) was approximately 90 gm ^. Patches of an appropriate size were punched out of the laminate and evaluated by in vitro skin permeations over a period of 72 hours. The results are summarized in Tables 1 and 2 below.

The permeation experiments were carried out using Franz diffusion cells. Here, the acceptor compartment was filled with 9 ml of a 0.9% NaCl solution and heated to 37 ° C. by means of a water bath. The acceptor medium was stirred continuously during the test period. Human epidermis was clamped between the acceptor and donor compartments. The area available for permeation was 1.54 cm ^. The corresponding TTS die cuts were glued to the epidermis. Subsequently, samples were taken from the acceptor medium at the times indicated in the tables and their active substance content was determined analytically by means of HPLC. Finally, the flux calculated. The same measurement method was also used in Examples 2 and 3.

Table 1: In vitro skin permeation of norethisterone acetate through human epidermis.

a) beuteiförmiges Reservoir

a) bag-shaped reservoir

Case 2; In vitro skin permeation of estradiol through human epidermis.

a) beuteiförmiges Reservoir

a) bag-shaped reservoir

Example 2

Composition with an estrogen.

0.22 g estradiol, 55.4 g solution of an acrylate adhesive

(Durotak® 387-2353) and 1.2 g of 3,6-dimethyl-1,4-dioxane-2,5-dione were mixed until a homogeneous mass was obtained. The resulting mass was then coated with a Naßschichtdik- ke of 450 .mu.m coating knife onto a siliconized polyester film (z. B. Hostaphan ^®) applied. The result was an even, clear line. The moist film was dried for 30 min at 50 ° C. and then laminated with a matt polyester film (e.g. Hostaphan ^® ). The weight per unit area of an adhesive film produced in this way (weight of the matrix without films) was approximately 110 g / m ² . Patches of an appropriate size were punched out of the laminate and in vitro permeated by skin permeations over a period of time. rated by 72 hours. The results are summarized in Table 3 below.

Table 3: In vitro skin permeation of estradiol through human epidermis.

Example 3 Composition with a progestogen

0.11 g norethisterone acetate, 53.1 g solution of an acrylate adhesive (Durotak ^® 387-2353) and 1.1 g 3,6-dimethyl-1,4-dioxan-2,5-dione were mixed until a homogeneous mass was received. The resulting mass was then coated with a wet layer thickness of 400 .mu.m applied by doctor blade onto a siliconized polyester film (eg. As Hostaphan ^®). The result was an even, clear line. The moist film was dried for 30 min at 50 ° C. and then laminated with a matt polyester film (e.g. Hostaphan ^® ). The weight per unit area of an adhesive film produced in this way (weight of the matrix without films) was approximately 94 g / m ² . Patches were made from the laminate in a reasonable manner Die cut out and evaluated by in vitro skin permeations over a period of 72 hours. The results are summarized in Table 4 below.

Table 4: In vitro skin permeation of norethisterone acetate through human epidermis.

a) beuteiförmiges Reservoir

a) bag-shaped reservoir

A negative influence of the added enhancer on the cohesive properties of the active substance matrix could not be found in the compositions according to the invention in Examples 1 to 3.

Claims

claims 1. Pharmaceutical composition for the transdermal administration of one or more hormones, to be attached to the skin with a pressure-sensitive adhesive, with at least one hormone-containing matrix layer, containing an additive that improves skin permeation, characterized in that the additive mentioned contains a 1,4-dioxane-2,5- dion basic structure of the general formula

, wherein the radicals R _x and 2 are hydrocarbon groups or substituted hydrocarbon groups or functional groups. 2. Composition according to claim 1, characterized in that the radicals R ^ and R2 are aliphatic hydrocarbons, preferably alkyl radicals, particularly preferably methyl groups. 3. Composition according to claim 1 or 2, characterized in that the radicals R ^ and R2 are identical. , Composition according to one of the preceding claims, characterized in that the radicals R ^ and / or 2 have oxygen, sulfur, nitrogen, phosphorus or halogen-containing functional groups. 5. Composition according to one of the preceding claims, characterized in that the proportion of the permeation-improving additive is 0.1-10%, preferably 0.5-5%, in each case based on the mass of the matrix layer. 6. Composition according to one of the preceding claims, characterized in that it contains at least one steroid hormone, preferably an estrogen or a progestogen. 7. The composition according to claim 6, characterized in that the estrogen is selected from the group consisting of 17-ß- Estradiol, 17-α-estradiol, 17-β-estradiol cypionate, 17-β-ethinyl estradiol, 3, 17-β-estradiol dienanthate, 17-β-estradiol diol valerate, 17-β-estradiol benzoate, 17-β-estradiol benzoate, 17-deacetyl norgestimate, norgestimate, mestranol and quinestrol, with 17-ß-estradiol being particularly preferred. 8. The composition according to claim 6, characterized in that the gestagen is selected from the group consisting of norethisterone acetate, 19-norprogesterone, norethisterone, ethiesterone, melengestrol, norgestrel, levonorgestrel, gestodene, hydroxyprogesterone capronate, medroxyprogesterone acetate, ethynodiol diacetate, 17-α Hydroxyprogesterone, megestrolacetate, lynestrenol, desogestrel, allylestrenol, chlormadinone and chlormadinone acetate, with norethisterone acetate being particularly preferred. 9. Composition according to one or more of the preceding claims, characterized in that it contains at least one estrogen, preferably estradiol, in combination with at least one gestagen, preferably norethisterone acetate. 10. Composition according to one or more of the preceding claims, characterized in that the hormone concentration in the matrix layer is in the range of 0.1-5%, preferably in the range of 0.2-2%, based on the mass of the matrix layer. 11. The composition according to one or more of the preceding claims, characterized in that the pressure-sensitive adhesive matrix layer is based on a polymer or polymer mixture, preferably on one or more acrylate polymers or acrylate copolymers. 12. A method for producing a composition according to one of the preceding claims, characterized by the following steps: a) preparing a solution which contains the acrylate adhesive and the hormone (s) and adding a 1,4-dioxane-2,5 -dione derivative as a penetration-enhancing additive; b) coating this mass on a carrier film, which is preferably siliconized; c) drying, preferably with heating; d) laminating a film as a backing layer; e) punching out plasters of suitable size. 13. Use of a composition according to one or more of claims 1 to 11 for hormone substitution, preferably for the prophylaxis and therapeutic treatment of climacteric complaints. 14. Use of compositions according to one or more of claims 1 to 11 for the production of transdermal dosage forms for hormone substitution, preferably for the prophylaxis and therapeutic treatment of climatic complaints. 15. Method for the prophylaxis or therapeutic treatment of climacteric complaints, characterized by repeated application of a composition according to one or more of claims 1 to 11 to the skin.