EA011160B1 - A composition for transdermal delivery of hormones without penetration enhancers and its use - Google Patents

Abstract

The present invention relates to a composition for transdermal delivery comprising a drug-containing layer that comprises gestodene or an ester thereof and a carrier selected from the group consisting of polyisobutylenes, polybutenes, polyisoprenes, polystyrenes, styrene isoprene styrene block polymers, styrene butadiene styrene block polymers and mixtures thereof, wherein the drug-containing layer has a solubility for said gestodene of no more than 3% by weight of the drug-containing layer. The gestodene or an ester thereof is in an amount ranging between 0.5 and 3% by weight of the drug-containing layer. A patch comprising a drug-containing layer with low content of hormones, such as gestodene, and optionally an estrogen (e.g. ethinyl estradiol) is the most representative. Upon administering the patch to a woman, plasma levels of at least 1.0 ng/ml of gestodene is achieved at steady state conditions without the need of incorporating penetration enhancers or permeation enhancers in the drug-containing layer. Satisfactorily plasma levels of the hormones is also achieved throughout a period of at least 1 week, making the patch applicable for being used in female contraception with the concept of administering the patch ones weekly.

Description

The present invention relates to the field of technology of pharmaceutical compositions. The invention provides a low dosage pharmaceutical composition for transdermal delivery of at least one hormone, preferably progestin, such as gestodene, and optionally estrogen, in order to achieve plasma concentration profiles effective to inhibit ovulation in women.

BACKGROUND OF THE INVENTION

Transdermal delivery of estrogens and progestins to ensure contraception is a well-known direction (8tyk- ^ age, Tgap8bigta1 arrysiop oG yogo and yogtopek Gog sop1tacer1yup, 1 81go1b Vusyet Mo1esi1 Vyu1, Uo1ite 53, p 247-251). However, estrogens and progestins generally poorly penetrate the skin, and therefore it is generally accepted to introduce agents into the transdermal system that have the effect of enhancing penetration into the skin.

The following documents describe a number of transdermal systems with progestin and estrogen present in the adhesive layer, where special attention is paid to the use of penetration enhancing agents.

XVO 92/07590 describes compositions with penetration enhancing agents for transdermal delivery of gestodene and estrogen to achieve maximum plasma levels of gestodene of approximately 0.9 ng / ml.

νθ 97/397443 relates to a transdermal system containing 30 to 60% penetration enhancing agents in order to deliver a contraceptively effective amount of estrogen and progestin.

νθ 01/37770 relates to transdermal systems containing from 10 to 60% penetration enhancing agents for the delivery of ethinyl estradiol and levonorgestrel in contraceptive effective amounts.

υδ 5512292 is directed to compositions containing a contraceptively effective amount of gestodene and estrogen, such as ethinyl estradiol, together with an acceptable penetration enhancing agent. The amount of co-delivered estrogen is maintained at a constant and contraceptive effective rate, while the amount of co-delivered gestogen varies depending on the phase of the menstrual cycle.

Ϋδ 5376377 shows comparative studies conducted between transdermal systems containing penetration enhancing agents and those not containing. Test systems include an adhesive layer made of ethylene vinyl acrylate, as well as gestodene and estrogen (ethinyl estradiol) as the active ingredient. The results of the study show the need to introduce penetration enhancing agents into the adhesive layer in order to achieve contraceptive effective amounts. Maximum plasma levels are reached, which are approximately 0.8 ng / ml.

In conclusion, νθ 90/04397 also discloses examples of compositions for transdermal delivery of gestodene, optionally in combination with estrogen, such as ethinyl estradiol, where the composition may further include a penetration enhancing agent such as 1,2-propanediol or isopropyl myristate. As an adhesive layer, a number of different polymers are mentioned. In particular, examples of polar polymers (polyacrylates and silicones) in combination with a penetration enhancing agent are disclosed. The resulting plasma levels of gestodene at steady state ranged from about 250 to 337 pg / ml.

In addition to penetration enhancing agents, it is also proposed to add solubilizing agents or the like to the drug containing layer in order to increase the amount of dissolved drug or to add agents that inhibit crystallization of the drug in this layer.

For example, an adhesive layer is disclosed in I8 6521250, which comprises a mixture of styrene-isoprene block copolymers and hydrogenated resin acid or its derivatives, wherein the amount of resin is 55-92%. Such an adhesive layer was found to be suitable for transdermal delivery of estradiol in combination with progestin, since such systems have their own adhesive contact with the skin for long-term use and prevent the crystallization of hormones.

υδ 5904931 refers to ΤΤδ systems containing in the layer comprising a drug, a steroid (such as gestodene) and dimethyl isosorbide. The latter enhances the solubility of the steroid in the drug-containing layer. The concentration of gestodene in the drug-containing layer may vary from 1 to 40% by weight of the layer, and the drug-containing layer may consist of adhesives such as polyacrylates, silicones, styrene-butadiene copolymers and polyisobutylene. In particular, polar polymers such as polyacrylates are acceptable.

ΌΕ 19906152 relates to a transdermal drug delivery system in which gestodene is embedded in a polar polymer such as polyvinylpyrrolidone, methyl cellulose, ethyl cellulose and hydroxypropyl cellulose, which is pre-added to an adhesive polymer such as

- 1 011160 polyisobutylene. Thus, this transdermal drug delivery system is a two-phase system and the drug containing layer is opaque due to the presence of polar polymers which, when exposed to water, will result in milky white spots. The amount of gestodene in the drug-containing layer is 5.1% of the weight of the drug-containing layer.

In \ νϋ 02/45701 it is emphasized that the addition of resin acids in an amount of up to 25 wt.% To the adhesive layer can significantly inhibit the formation of crystals of active agents, such as, for example, hormones. The adhesive layer may include all known non-toxic natural and synthetic polymers that are suitable for use in transdermal systems, for example polyacrylates, polysiloxanes, polyisobutylenes, styrene block copolymers and the like. In particular, polyacrylates are preferred. TT8 system is acceptable for steroids (gestodene), which can be introduced into the adhesive layer in an amount substantially equal to, or close to, or even higher than saturation in relation to their concentration in the carrier composition, which is more preferable than substantially at the level of sub-saturation . Preferably, the amount of steroid is from about 0.1 to about 6% by weight based on the dry weight of the total carrier composition.

Unfortunately, penetration enhancing agents can have harmful effects on the skin, such as skin irritation, which to some extent makes transdermal systems unacceptable to the user. In addition, it is well known that penetration enhancing agents can adversely affect the stability of active substances, which makes long-term storage problematic. In addition, it is also recognized that the viscosity decreases with the introduction of agents that enhance penetration, which leads to the risk of the formation of dark rings along the edge of the patch.

Thus, there is a need for transdermal systems that do not have the above disadvantages, such as transdermal systems that do not require penetration enhancing agents, to achieve therapeutically effective amounts of a steroid hormone such as gestodene.

Gestoden is known as an active synthetic progestin with an activity profile similar to progesterone (see I8 4081537). It is used as an oral contraceptive in combination with certain estrogens.

Summary of the invention

This invention relates to compositions for transdermal delivery of hormones such that contraceptive effective levels are achieved without the need for introducing penetration enhancing agents into the adhesive layer containing the hormone. Such hormones are preferably steroid hormones, such as progestins, such as gestoden, which may optionally be used in combination with estrogen. In contrast to the general knowledge of the prior art, the inventors of the present invention provide transdermal systems comprising a limited amount of ingredients. For example, absorption promoting agents and penetration enhancing agents are not required in order to achieve a high degree of release and therapeutically effective plasma levels.

The inventors of the present invention have found that the choice of a drug-containing layer that has a solubility for steroid hormone (e.g. gestodene) is critical for successfully achieving therapeutically effective levels of the hormone in the blood. Example 2 in this application is a comparison of two layers containing gestodene in relation to the rate of release of gestodene. It is clearly shown that the polar polymer layer (polyacrylate) containing the drug requires a gestodene concentration of 3.9% of the weight of this layer to achieve the desired high release rate. Unexpectedly and in contrast to what was previously known, it was found that a similar high release rate can be achieved with a gestodene concentration of 1.9% by weight in a layer comprising a drug that contains a polar polymer such as polyisobutylene, even without the use of an agent penetration enhancing. Ίη νίνο studies have found that drug-containing layers that include a more non-polar type of polymer, such as polyisobutylene, are more preferred than those containing polyacrylates for achieving high plasma LIS (Example 4).

Thus, the inventors found that, unlike what might be expected, the use of drug-containing layers, which preferably contain an apolar polymer, such as polyisobutylenes, and are characterized by the presence of a limited dissolving ability with respect to gestodene in an amount of not more than 3% by weight, have a high rate of gestoden release, despite the fact that the actual amount of gestodene in the drug-containing layer is low. This represents a clear advantage compared to the known TT8 systems in terms of reducing the risk of skin irritation, reducing the effects of the hormone on the user and the environment.

Another advantage is that the drug-containing layer is a monophasic system and contains the drug evenly distributed in

- 2 011 160 layer. In other words, the drug containing layer is homogeneous. In the absence of polar polymers or other excipients with a tendency to absorb water or retain water, the drug-containing layer is transparent. Thus, a transparent composition, by using which the skin can be visually viewed through the delivery system, is provided by the present invention. The transparency of the transdermal drug delivery system is a clear benefit for the user, since the opaque systems are visible, and thus indicate the presence of a disease, which is not the purpose of the contraceptive patch.

SUMMARY OF THE INVENTION

In accordance with its first aspect, the invention relates to compositions for transdermal delivery, comprising a drug-containing layer that includes gestodene or its ester and a carrier selected from the group consisting of polyisobutylenes, polybutenes, polyisoprenes, polystyrenes, styrene block copolymers styrene isoprene, styrene butadiene styrene block copolymers and mixtures thereof, while gestodene or its ester are present in an amount that ranges from 0.5 to 3% by weight of the layer, soda zhaschego medicament.

The drug-containing layer may further include tackifiers selected from the group consisting of hydrocarbon resins, rosin-based resins and terpene resins. Preferably, the tackifier is a rosin ester.

Gestoden or its ester is preferably completely dissolved in the layer containing the drug.

The drug-containing layer comprises less than 2% by weight of polyvinylpyrrolidone, methyl cellulose, ethyl cellulose and hydroxypropyl cellulose, less than 0.5% by weight of dimethyl isosorbide, less than 2% by weight of a skin absorption agent or penetration enhancing agent skin, and is transparent.

The composition may further include estrogen, which is present in the drug-containing layer in an amount of from 0.5 to 10% by weight of the drug-containing layer, preferably in an amount of 0.75 to 5% of the weight of the drug-containing layer. Preferably, the estrogen is ethinyl estradiol.

Surprisingly, it has been found that relatively high plasma levels of gestodene can be maintained for a long period of time by administration of gestodene incorporated into the composition of the invention. The plasma profile and plasma gestoden levels obtained with the administration of gestoden and optionally estrogen are effective in inhibiting ovulation in women.

Therefore, the compositions in accordance with the invention can be used to inhibit ovulation or, alternatively, to treat endometriosis, premenstrual syndrome, menopause, prevent osteoporosis, regulate the menstrual cycle or stabilize the menstrual cycle.

Thus, in further aspects, the invention relates to the use of a composition as described herein, optionally in combination with estrogen, to inhibit ovulation in females. When the composition is administered on its own, the time-dependent plasma concentration of gestodene in the blood plasma is characterized by the presence of plasma levels of gestodene at least 1.0 ng / ml, as determined under steady state conditions. In this regard, the invention relates to a method for inhibiting ovulation in females, such as a female. The method provides for the local administration through the skin or mucous membrane of an effective amount of gestodene or its derivative, optionally in combination with estrogen, so that with the self-administration of the indicated gestodene, the time-dependent plasma concentration of gestodene in the blood plasma is characterized by the presence of levels of plasma gestodene at least 1.0 ng / ml as determined under steady state conditions.

The invention also relates to a transdermal therapeutic system, consisting of:

a) a substrate layer;

b) at least one drug-containing layer as defined above; and

c) an optional removable release liner or protective layer.

In said transdermal therapeutic system, gestodene or its ester is present in a dose of 1 to 3 mg, preferably in a dose of 1.5 to 2.5 mg.

If the above system further includes estrogen, then the mass ratio of gestodene or its ester to said estrogen, preferably such as ethinyl estradiol, is in the range from 4 to 0.5. Preferred is a system that contains a dose of gestodene 1.9 mg, a dose of ethinyl estradiol 0.9 mg and 97.2 mg of polyisobutylene in combination with a tackifier. Particularly preferred is a system that contains a dose of gestodene of 1.9 mg, a dose of ethinyl estradiol 0.6 and 97.2 mg of polyisobutylene in combination with a tackifier.

- 3 011160

In conclusion, the invention relates to a kit comprising 1-11 unit doses, for example, 9 or 3 unit doses, depending on the length of the treatment period entered into the transdermal delivery form of gestodene or a derivative thereof, such as the composition described in this application. The dosage form contains a layer comprising a drug containing gestodene, as well as one or more pharmaceutically acceptable excipients or carriers, wherein the layer containing the drug has a solubility with gestodene of not more than 3% by weight of the layer containing the drug.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides compositions for transdermal delivery of hormones (transdermal therapeutic system), which when applied topically to the skin or mucous membrane leads to therapeutically effective amounts, such as contraceptively effective amounts of hormones, although it is not necessary to introduce into the layer containing the drug penetration enhancing agents.

As used in this application, the term "local" or "local" means direct contact of the composition with a specific surface area, including skin and mucous membrane.

The term “mucous membrane” means a surface membrane of a mammal that is not skin, such as a surface present in the oral cavity, vagina, rectum, nose, or eyes. Thus, the mucous membrane can be buccal, vaginal, rectal or ocular mucosa.

Compositions in accordance with the invention can be created in various forms of application so that the composition includes a layer containing a medicinal product, which is adapted to be placed near or in direct contact with the skin or mucous membrane with local administration of the composition.

Thus, in its preferred form of use, a composition, for example a transdermal therapeutic system, consists of:

a) a substrate layer;

b) at least one drug-containing layer comprising said hormone or mixture of said hormones and one or more pharmaceutically acceptable ingredients; and

c) optionally removable coating film or protective layer.

Preferably, when the substrate layer, the drug containing layer, and the removable coating film (or protective layer) are transparent, which means that the skin is visible.

In the case where the layer containing the drug does not sufficiently demonstrate the property of self-adhesion to the skin or mucous membrane, it can be provided with an additional adhesive layer that sticks together under pressure, or with an adhesive edge or ring that sticks together under pressure, so that the composition sticks to skin during the entire period of application. The pressure-sensitive adhesive layer can be placed between the drug-containing layer and the skin, and the adhesive ring can be located around or along the edge of the drug-containing layer. Optionally, the composition may also further include one or more shells or adhesive layers. For example, a shell for controlling hormone release may be located between the drug-containing layer and the pressure-sensitive layer, or between the drug-containing layer and the skin.

The size of the drug containing layer is selected from a variety of acceptable sizes. As used herein, an acceptable size means a surface area of from about 5 to 20 cm ² , preferably from about 7 to 15 cm ² , most preferably from about 8 to 12 cm ² , such as 10 cm ² . It should be noted that the surface area is the surface that is in contact with or is in close proximity to the skin or mucous membrane.

In accordance with the invention, it was found that a layer containing a drug having a minimized solubility for the hormone provides sufficient penetration of the steroid hormone into the skin. In the present invention, the drug-containing layer is characterized by a determinant dissolving power for gestodene. It is noteworthy that the rate of penetration into the skin is sufficient without the need for the introduction of an agent that enhances penetration into the skin. For example, it was unexpectedly discovered that penetration into the skin of a steroid hormone in accordance with the invention leads to a therapeutically effective amount of a steroid hormone in the circulatory system, such as contraceptively effective amounts of the hormone.

Accordingly, the invention relates in a first aspect to a composition for transdermal delivery of a steroid hormone such as a progestin, for example gestoden or its ester. The composition includes a layer containing the drug and one or more pharmaceutically acceptable excipients or carriers, the layer containing the drug has a solubility for gestodene of not more than 3% by weight of the layer containing the drug. Compo

- 0120160 Zitsia may optionally include estrogen.

In some embodiments of the invention, the solvent capacity of the drug-containing layer for gestodene is not more than 2.5% by weight of the drug-containing layer, preferably not more than 2.0%, for example, not more than 1.8% . In principle, the dissolving power may be very low, but it is believed that the critical level with respect to the lowest levels of the indicated dissolving power is approximately 0.1%, for example approximately 0.2, 0.3, 0.5, 0.7, 0 , 8, 0.9 or 1% by weight of gestodene in the drug-containing layer. In the General case, it is believed that the solubility of the layer containing the drug for gestoden is in the range from about 0.1 to 3%, for example from about 0.2 to 3%, from 0.4 to 3%, from 0.5 up to 3%, from 0.8 to 3% or from 1 to 3%. In additional embodiments of the invention, the upper limit in the range is not equal to 3% by weight, but is lower, for example 2.5, 2.2% or 2.0%.

As used herein, the term "gestodene" refers to gestodene (13b-ethyl-17a-ethynyl17b-hydroxy-4,15-gonadiene-3-one), a derivative thereof, or a mixture thereof, such as a mixture of derivatives or a mixture of gestodene and derivative. The derivative may be a derivative of a 17b hydroxy group, such as an ether, ester, acetal, or a pharmaceutically acceptable salt thereof. For example, an ester with 2-12 carbon atoms in the acyl radical, including alkanoates with 2-8 carbon atoms in the alkanoyl radical.

In preferred embodiments of the invention, the gestodene ester is gestodenpropionate, gestodenvalerate and / or gestodencapronate, which are described in US patent No. 5858394.

As mentioned above, the inventors have found that the drug-containing layer according to the invention is a layer that has a solubility for steroid hormone (e.g. gestodene) of not more than 3% by weight of the drug-containing layer.

The phrase “solubility for steroid hormone,” such as “solubility for gestodene, which is not more than 3% of the weight of the drug containing layer” is intended to characterize the amount of steroid hormone, such as gestodene, that can be dissolved in an individual layer containing the drug upon receipt of a visually clear solution. The term “solubility for” is not to be understood as meaning the actual concentration of a hormone, such as gestodene, in a drug-containing layer. As described below, the total concentration of the hormone in the drug-containing layer may be higher or lower than 3% of the weight of the drug-containing layer. In addition, the total concentration of the hormone in the drug-containing layer can lead to the formation of a drug-containing layer comprising the hormone at saturation and sub-saturation levels.

In order to select drug-containing layers that have the indicated solubility for a hormone, such as gestodene, the following analysis can be performed to determine if the hormone is completely dissolved and whether the drug-containing layer is visually transparent.

One analysis method to determine if a hormone is completely dissolved is that solid particles can be detected visually or using a microscope that has a magnification of 25X.

Another method for actually determining the solubility of a drug-containing layer for a hormone is the following method. The method is based on determining the rate constant of hormone release from the drug-containing layer and including the hormone in fully dissolved form, and from the drug-containing layer and including the partially dissolved hormone.

The method includes the following steps:

Firstly, identical layers are prepared containing the drug, but with different, for example, increasing concentrations of the hormone. Typically, at least 3 different layers containing the drug will contain the hormone in a fully dissolved form, and at least 3 layers containing the drug will contain the hormone in a partially dissolved form, for example with a hormone in the form of solid particles substances.

Regarding the preparation method, it should be said that the following steps can be carried out. Any other method known in the art for preparing adhesive layers may also be acceptable:

The drug substance is dissolved or suspended in an acceptable solvent.

The polymer, optionally a tackifier and other excipients, are dissolved in an acceptable solvent.

The two solutions are combined with stirring to obtain a homogeneous mixture.

The mixture is coated with a coating film of acceptable thickness and dried by heat to evaporate the solvents. The resulting laminate is coated with a protective foil.

- 5 011160

Secondly, the release rate of the drug from the drug-containing layer is analyzed using equipment and analysis conditions that are given in the relevant section of the European Pharmacopoeia (Pb. Eig. 2,9,4. E | 55o1i1yup 1sz1 ίοτ 1gapz6egta1 ra1e11sz) or in the United States Pharmacopeia (И8Р 26, <724> ЭКИС КЕБЕА8Е, Arraga 5 (Ra661e ueeg Escchk).

A sample with a specific area is cut from the drug containing layer.

After removing the coating film, the sample is placed in a test tube (as described in the pharmacopoeias mentioned above), which is pre-filled with an acceptable dissolution medium equilibrated at 32 ° C ± 0.5 ° C. The drug-containing layer must be brought into contact with the dissolution medium. Samples of the dissolution medium are taken at predetermined time intervals, and the amount of hormone dissolved in the dissolution medium is measured using HPLC or other suitable quantification methods. The dissolution medium may be selected from those which provide immersion conditions. For example, suitable dissolution media are aqueous solutions containing up to 30% by weight of organic solvents such as ethanol, isopropanol and dioxane.

Thirdly, the rate of release of hormones from two types of drug-containing layers is determined as described below:

The amount of hormone released per unit area for each drug-containing layer is calculated from the dissolution data mentioned above and the specific area of the drug-containing layer.

The release rate constants for each drug-containing layer are defined as the slope obtained by linear regression analysis of the last three data points relative to the amount of hormone per unit area against the square root of time.

A release rate constant for each drug containing layer is applied against the concentration of the hormone in the drug containing layer. Then a linear regression analysis is carried out separately for each layer containing the drug, with a completely dissolved hormone, and for each layer containing the drug, with a partially dissolved hormone, that is, with the solid particles of the hormone. Two regression lines will intersect at one point. The concentration of the hormone that can be read at the intersection of the two regression lines means the "solubility" of the hormone in the layers containing the drug.

The term “drug-containing layer” is intended to mean a portion of a transdermal composition or system in which a steroid hormone is present. The drug-containing layer may be in semi-solid or solid form and includes a hormone contained directly in the layer. The hormone in accordance with the invention can be dispersed, partially dispersed, partially or completely dissolved in the layer, depending on the concentration and physicochemical properties of the hormone. The drug containing layer is not intended to be in the form of a gel or liquid. To this end, a drug-containing layer is understood to be one which is in direct contact with the skin or mucous membrane. However, in some embodiments, there is an additional layer, the so-called “drug-free layer”, which is located between the drug-containing layer and the skin or mucous membrane.

As noted previously, the compositions of the invention do not necessarily include a skin penetration enhancing agent. Therefore, in some embodiments of the invention, the drug-containing layer excludes the presence of an agent that increases the rate of penetration into the skin, which means that the drug-containing layer essentially consists of ingredients that do not include an agent to increase the rate of penetration of the skin. This means that, for example, less than 2%, for example less than 1%, preferably less than 0.5%, for example less than 0.2%, for example less than 0.1% of the weight of the layer containing the drug consists from an agent that enhances penetration into the skin.

In accordance with the present invention, the selection of a specific drug-containing layer affects penetration into the skin. The specific drug-containing layer is preferably made of a polymer or a mixture of polymers. The polymers may have adhesive properties or may not have noticeable adhesive properties. In some embodiments, the drug-containing layer is a so-called self-adhesive adhesive layer.

In principle, any polymer mixture can be used that results in the indicated dissolution ability for gestodene. Thus, in one embodiment according to the invention, the drug-containing layer comprises at least one polymer which may or may not have adhesive properties. Typically, such polymers are biologically acceptable lipophilic polymers such as a hydrocarbon polymer, polysiloxane, polyacrylate, or mixtures thereof. Preferably, when the polymers can be selected from those including hydrocarbon polymers, polysiloxanes and / or polyacrylates, which

- 6 011160 which form a layer containing a drug having a solubility for gestodene, not more than 3% by weight of the layer containing the drug.

The amount of polymer is to some extent a critical parameter. The specific amount may depend on the particular type of polymer and steroid hormone that are used. In general, the amount of polymer is at least 1% of the weight of the layer containing the drug, for example at least 5, 10, 15, or 20%. However, it is preferred that the polymer is present in the drug containing layer in an amount of at least 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75%, or at least 80% of the layer weight containing the drug. In other words, the polymer can be used in an amount of from about 1 to 99% by weight of the layer containing the drug, such as from about 5 to 99%, from 10 to 99%, from 15 to 99%, or from 20 to 99%. Preferably, when the polymer is present in the drug-containing layer in an amount that ranges from about 15 to 99%, such as from about 15 to 90%, from 15 to 85%, or from 15 to 80%, such as from about 20 up to 85%, from 20 to 75%, such as from about 25 to 85%, from 25 to 75% of the weight of the layer containing the drug.

It is indicated that a specific aspect in accordance with the invention relates to a composition for transdermal delivery of a steroid hormone such as gestoden or a derivative thereof, and optionally estrogen, wherein the composition comprising the drug-containing layer contains at least one steroid hormone, such as gestodene or a derivative thereof, and one or more pharmaceutically acceptable ingredients or carriers; a polymer or mixture of polymers, preferably in an amount of from about 15 to 99% by weight of the layer containing the drug, where the polymer is selected from the group consisting of hydrocarbon polymers, polysiloxanes, polyacrylates and mixtures thereof, which form a layer containing a drug having the solubility in relation to the specified steroid hormone is not more than 3% by weight of the layer containing the drug.

As mentioned above, it has been found that adhesive layers comprising more non-polar types of polymers, such as hydrocarbon polymers, have shown their advantage over polar types of polymers such as polyacrylates (Example 2). Thus, in a preferred embodiment of the invention, the drug-containing layer comprises a hydrocarbon polymer as a polymer, which preferably may include polyisobutylenes, polybutenes, polyisoprenes, polystyrenes, styrene butadiene styrene block copolymers, styrene butadiene block copolymers and / or mixtures thereof.

As mentioned above, in some embodiments of the invention, the drug-containing layer is adhesive. It is preferred that the polymer of the drug-containing layer has acceptable adhesive properties so that no additional adhesive agent, such as tackifiers, is required. Whenever it is considered necessary to improve the adhesive properties of a drug-containing layer, the layer further includes tackifiers.

The term “tackifier” means an agent that improves the adhesive strength of the adhesive layer with respect to the skin or mucous membrane.

Examples of tackifiers are selected from hydrocarbon resins, rosin-based resins and terpene resins. Examples of hydrocarbon resins are commercially available under the trade names Exogeh® from ExxoMoY1; Veda®e®, Ryusoac® and P1sso® from Eak1shap or 1pyoro1® from BP. Examples of rosin esters for transdermal systems in accordance with the present invention include hydrogenated rosin esters, for example hydrogenated rosin pentaerythritol ester, partially hydrogenated rosin ester, for example partially hydrogenated rosin pentaerythritol esters, partially rosin esters, partially rosin esters, modified esters dimerized rosin, tall oil resin esters, dimerized canine esters foley, as well as similar resins, their combinations and mixtures. Such rosin esters are commercially available under the trade names Horn1®, Horn1uy®, Rei1auy®, Regta1up®, and 81aue6e®.

In a preferred embodiment of the present invention, the drug-containing layer comprises tackifiers in the form of a rosin ester, such as pentaerythritol ester.

In the general case, it is believed that the tackifier may be present in any acceptable amount until the indicated critical solubility of the steroid hormone in the drug-containing layer is significantly affected. Thus, the tackifier may be present in the drug-containing layer in an amount of about 0.1 to 95%, such as 0.5 to 95%, such as 1 to 95% by weight of the drug-containing layer means. That is, a tackifier may be present

- 7011160 in an amount of from about 1 to 85%, from 1 to 75%, from 1 to 65%, from 1 to 55%, from 1 to 50%, from 1 to 45%, from 1 to 40% or more preferably from about 1 to 35%, such as preferably from 1 to 30%, more preferably from 1 to 25%. It is apparent that the amount of tackifier in the drug-containing layer may be critical for the solubility of the steroid hormone in the drug-containing layer. Thus, in yet another embodiment of the invention, the tackifier is present in the drug-containing layer in an amount of up to 35%, such as up to 30%. More preferably, when the amount of tackifier is up to 25%, such as up to 20% or 15%, more preferably up to 10, 7, 5% of the weight of the drug containing layer.

It follows that an additional specific aspect of the invention relates to a composition for transdermal delivery of gestodene or its ester, as well as optional estrogen, the composition comprising a layer containing a drug, which essentially consists of

- at least one steroid hormone, such as gestodene, and one or more pharmaceutically acceptable ingredient (s) and / or carrier (s);

a polymer or mixture of polymers, preferably in an amount of from about 15 to 99% by weight of the layer containing the drug, the polymer being preferably selected from the group consisting of hydrocarbon polymers, polysiloxanes, polyacrylates and mixtures thereof, most preferably hydrocarbon polymers (polyisobutylene) , polybutenes, polyisoprenes, polystyrenes, block copolymers of styrene isoprene styrene, block copolymers of styrene butadiene styrene and / or mixtures thereof). The drug-containing layer has a solubility for gestodene such as that mentioned above,

- substances to increase the stickiness in an amount up to 85% by weight of the layer containing the drug, and

- optional estrogen.

As noted previously, the drug-containing layer consists of ingredients that form a layer that meets the solubility criterion for gestodene. Preferably, this correspondence is achieved when the layer containing the drug mainly consists of hormones in accordance with the invention together with a polymer or mixture of polymers and optionally a tackifier.

In some embodiments, it was found that an acceptable polymer in accordance with the invention is lipophilic, which is substantially free of free hydrophilic groups. Thus, any suitable hydrocarbon polymer, polysiloxane or polyacrylate are selected from those polymers that have a limited number of functional groups in the side chains, such as free hydrophilic functional groups such as carboxyl groups, ester groups, hydroxy, amino groups, amide groups , halogen or sulfo group. Accordingly, in some embodiments, the polymer substantially excludes polyacrylates, some of which include free carboxyl and / or hydroxyl groups.

In a preferred embodiment, the polymer is a hydrocarbon polymer, polysiloxane, or a mixture of these two types of polymers. As mentioned earlier, the type of hydrocarbon polymers is a non-polar type of polymers substantially free of free hydrophilic functional groups, such as carboxyl groups, ester, hydroxy, amino, amide, halogen or sulfo groups in the side chains. Therefore, in its most preferred embodiment, the polymer is a hydrocarbon polymer.

There are a variety of hydrocarbon polymers with both high molecular weight and low molecular weight, or mixtures thereof. Typically, hydrocarbon polymers are in the form of polyisobutylenes, polybutenes, polyisoprenes, polystyrenes, styrene isoprene styrene block copolymers, styrene butadiene styrene block copolymers or mixtures thereof. The molecular weight of high molecular weight polymers (at least in relation to polyisobutylene) is usually in the range of 500,000 to 2,000,000 Da, while that for low molecular weight polymers ranges from about 20,000 to 100,000 Da. Typically, such polymers include a mixture of high molecular weight polymers and low molecular weight polymers, wherein the amount of low molecular weight polyisobutylene in the total mixture is at least 50%.

In preferred embodiments of the invention, the hydrocarbon polymer is polyisobutylene, polybutene, polyisoprene, most preferably polyisobutylene.

In some embodiments in accordance with the invention, the polymer excludes isoprene copolymers.

Polysiloxanes are typically high molecular weight polydimethylsiloxane with free silanol groups or terminal silanol groups (Βίο-ΡδΆ®).

Typical examples of polyacrylates, which, as mentioned above, can either be excluded or can be used in a minimal amount in some embodiments, include polymers selected from homopolymers of acrylic esters, copolymers of two or more types of units

- 8 011160 acrylic esters or copolymers of acrylic esters, or other functional monomers. Acrylic esters include, but are not limited to, butyl methacrylate, pentyl methacrylate, hexyl methacrylate, heptyl methacrylate, octyl methacrylate, nonyl methacrylate, decyl methacrylate, for example ethylene / ethyl acrylate copolymers, polymethacrylate polymers and polymethoxylate copolymers. As mentioned above, functional monomers containing a hydrophilic functional group can be excluded as acceptable polymers, they are, such as hydroxyethyl methacrylate, hydroxypropyl methacrylate, etc., as well as monomers containing an amide group, such as methacrylate, dimethyl methacrylamide.

In addition, based on this, polymers such as polyalkylenes (polyethylene, polypropylene, ethylene / propylene copolymers, chlorinated polyethylene, polytetrafluoroethylene), polyacetates (ethylene / vinyl acetate copolymers, vinyl chloride-vinyl acetate copolymer), polyvylene (polyvinylidene chloride, ethylene-vinyl alcohol copolymer ethylene-vinyloxyethanol copolymer, polyvinylpyrrolidone), polycarbonates, cellulose polymers (methyl or ethyl cellulose derivatives, hydroxypropyl methylcellulose and cellulose esters) may not be acceptability polymers according to the invention and are excluded or at least used in a restricted amount in some embodiments of the invention. However, such an exception does not preclude the use of such polymers in other layers or parts of the composition.

In addition, in some embodiments, the drug-containing layer does not include, or at least include, only a limited amount of a hydrophilic polymer, such as crystallization inhibitors like polyvinylpyrrolidone, cellulose polymers such as methyl or ethyl cellulose derivatives or hydroxypropyl methylcellulose, or mixtures.

Also in some embodiments, the solubilizer, such as dimethyl isosorbide, is present in the drug-containing layer, or at least is present in a limited amount only.

The term "limited amount" means that the polymer or solubilizer in question is present in the layer containing the drug in a concentration of less than 10%, such as less than 8, 5, 3, 2, 1, 0.5 or 0, 2% of the weight of the layer.

As mentioned above, it is possible to provide sufficient penetration into the skin of a steroid hormone without the introduction of an agent that promotes absorption in the skin and / or an agent that enhances penetration into the skin. That is, in a preferred embodiment of the invention, an agent that promotes absorption into the skin and / or an agent that enhances penetration into the skin are excluded in the drug-containing layer or are present in a limited amount in the drug-containing layer, this amount is less than less than 5%, such as less than 4, 3, 2, 1, 0.5%, or 0.2% of the weight of the layer containing the drug.

The terms “absorption enhancing agents” and “penetration enhancing agents” are used interchangeably in this invention and mean compounds that provide improved absorption / penetration into the skin of active drugs when they are used together with drugs to the skin of the user. Absorption enhancing / penetration enhancing agents in transdermal compositions will alter the thermodynamic activity of the drug in the drug containing layer, and thus will result in a positive or negative “push” effect. In addition, some absorption / penetration enhancing agents can suitably penetrate the highly ordered intercellular lipid structures of the stratum corneum and lower their stability by increasing the mobility of the lipid acyl chain, thereby providing a “push” effect.

Any effect of enhancing the absorption / penetration of a substance can be established by analyzing identical compositions containing or not containing a penetration enhancing agent, for example, using bare mouse skin or the like. Such methods are known to those skilled in the art.

Typical absorption / penetration enhancing agents are included in the group of compounds below.

Alcohols, such as monohydric alcohols containing from 2 to 10 carbon atoms, such as ethyl, isopropyl, butyl, pentyl, octanyl, decanyl and / or benzyl alcohols; dihydric alcohols, such as 1,2-propanediol polyhydric alcohols, such as glycerin, sorbitol and / or polyethylene glycol; saturated and unsaturated fatty alcohols with 8-18 carbon atoms, such as caprylic, decyl, lauryl, 2-lauryl, myristyl, cetyl, sterile, oleyl, linoleyl, linolenyl.

Fatty acids, such as saturated or unsaturated fatty acids, which may include 8-18 carbon atoms, for example lauric acid, myristic acid, stearic acid, oleic acid, linoleic acid, linolenic acid and palmitic acid, triacetin, ascorbic acid, panthenol, butylated hydroxytoluene, tocopherol, tocopherol acetate, tocopheryl linoleate. Other fatty acids include, but are not limited to, valerianic acid, capro

- 9 011160 new acid, caprylic acid, pelargonic acid, capric acid, isovalerianic acid, neopentanoic acid, neoheptanoic acid and / or isostearic acid.

Esters, such as aliphatic esters, ethyl acetate, lower (C ₁ -C ₄ ) alkyl esters of lactic acid, fatty acid esters of the general formula CH ₃ - (CH ₂ ) _p -COOB, where n is a number from 8 to 18a, B is an alkyl residue containing at most 6 carbon atoms, such as fatty acid esters, for example, such as lauric acid, myristic acid, stearic acid and palmitic acid, for example methyl esters, ethyl esters, propyl esters isopropyl esters, butyl esters, sec-butyl esters, isobutyl esters of these acids, or dicarboxylic acid esters of the general formula B'OCO (CH ₂ ) _t COOB ', where t is a number from 4 to 8, and B 'in each case means an alkyl residue containing a maximum of 6 carbon atoms, such as propyl oleate, decyl oleate, isopropyl palmitate, glycol palmitate, glycol laurate, dodecyl myristate, isopropyl myristate and glycol stearate, acceptable dicarboxylic acid esters are, for example, di isopropyl adipate, diisobutyl adipate and diisopropyl sebacate.

Ethers such as polyethylene glycol ethers of aliphatic alcohols (such as cetyl, lauryl, oleyl and stearyl), including polyoxyethylene (4) lauryl ether, polyoxyethylene (2) oleyl ether and polyoxyethylene (10) oleyl ether.

Alkanes, such as alkanes having a chain length of 6 to 17 carbon atoms.

Amides such as dimethylacetamide, dimethylformamide, dimethyl lauramide, dimethyl lauryl amide and / or fatty acid amides and their derivatives.

Amides, such as long aliphatic amides, or aromatic amides, urea and urea derivatives, such as cyclic urea, dodecylurea, diphenylurea and / or allantoin.

Amino acids.

Aminoacetates such as derivatives of aminoacetates such as dodecyl-Y, Y-dimethylaminoacetate and dodecyl-2-methyl-2- (M, Y-methylaminoacetate), decyl-2- (S, Y-dimethylamino) propionate, decyl-2- (S, Y-dimethylamino) butyrate, octyl-2- (S, Y-dimethylamino) propionate and / or dodecyl (S, Y-dimethylamino) phenylacetate.

Aza derivatives, such as 1-dodecylazacycloheptan-2-one derivatives, azacycloalkanone derivatives and / or hexamethylene lauramide derivatives.

Cyclodextrins such as alpha, beta and gamma cyclodextrins.

Glycerides, such as monoglycerides, including glycerol monooleate, glycerol monolaurate and glycerol monolinoate, polyethylene glycol-3-lauramide (PEC LB), polyethylene glycol monolaurate (PCMB) glycerol monol oleate (CMO), glycerol / glycerol.

Glycols such as ethylene glycol, diethylene glycol or propylene glycol, dipropylene glycol and / or trimethylene glycol.

Oils, such as mineral, vegetable, animal and fish oils and oils, such as cottonseed oil, corn oil, safflower oil, olive and castor oil, squalene and / or lanolin.

Polyols such as propylene glycol.

Pyrrolidones, such as 2-pyrrolidone, Y-methyl-2-pyrrolidone, dodecylpyrrolidone, 2pyrrolidone-5-carboxylic acid, derivatives of Ν-hexyl-, Ν-lauryl-, 4-carboxy-, 4-carboxycarbon, 3-hydroxy-Y -methyl-2-pyrrolidone, Y-farnesyl-2-pyrrolidone, Y- (2 (decylthio) ethyl) -2-pyrrolidone and / or Y- (2-hydroxyethyl) -2-pyrrolidone.

Sulfoxides, such as sulfoxide derivatives, such as methyloctyl sulfoxide, dimethyl sulfoxide (DMSO), hexyl methyl sulfoxide (hexyl-MCO) and / or decyl methyl sulfoxide (decyl MCO).

Surfactants such as cationic surfactants like cetyltrimethylammonium bromide, octadecyltrimethylammonium chloride, cetylpyridinium chloride. and / or equivalent cationic compounds, anionic surfactants such as sulfate salts, which include, but are not limited to, compounds such as sodium lauryl sulfate and / or sodium dodecyl sulfate, and nonionic surfactants such as sorbitol esters and sorbitol anhydride, which include, but are not limited to, polysorbate, sorbitol monopalmitate and / or sorbitol polyoleate.

Terpenes, ketones and oxides.

In addition to a steroid hormone, such as progestin, one or more polymers, one or more tackifiers and optional estrogen, the drug layer or other parts of the composition also contain colorants, pigments, inert fillers, anti-aging agents, antioxidants, elastomers, thermoplastics and other traditional components of the transdermal composition that are known in the art. Preferably, when the composition or at least the layer containing the drug does not contain or contain only a limited amount (less than 1, 0.8, 0.5, 0.2 or 0.1% by weight of the layer containing the drug) polyvinylpyrrolidone, methyl cellulose, ethyl cellulose, guide

- 10 011160 roxypropylmethyl cellulose and / or dimethyl isosorbide.

It is understood that the compositions in accordance with the invention are transparent or, at least in particularly preferred embodiments, are transparent, which means that the skin can be visually controlled through the drug delivery system. That is, this means that the drug-containing layer is a monophasic system in which the drug (progestin in this application) is completely dissolved in the drug-containing layer. The property of the composition can be a monophasic system, can be identified by mechanical stretching of the layer containing the drug, using the methods described below.

The drug containing layer is further characterized in that it is homogeneous. The term “homogeneous” is used to describe a monophasic system in which the matrix consists of a single polymer phase. Such systems may differ from multiphase systems, which consist of at least two polymer phases. In most cases, multiphase systems can be visually determined using their opaque appearance. The opaque appearance is caused by light diffraction due to differences in the diffraction coefficients of the polymer phases. Other methods for determining monophasic systems are microscopic and rheological methods, either by mechanical stretching of thin polymer films. In the process of stretching a thin polymer film, which consists of multiphase systems, it becomes opaque, which is determined visually.

Thus, it is understood that preferred embodiments in accordance with the invention include:

a drug containing layer, which includes:

ί) progestin, such as gestodene or its ester; and ίί) a polymer selected from the group consisting of polyisobutylenes, polybutenes, polyisoprenes, polystyrenes, styrene block copolymers, styrene isoprene, styrene butadiene styrene block copolymers and mixtures thereof.

In further preferred embodiments of the invention, the drug-containing layer is characterized by the following parameters, which may be present as single parameters or in a combination of parameters;

the drug-containing layer has a solubility for gestodene of not more than 3% by weight of the drug-containing layer;

the drug containing layer excludes dimethyl isosorbide or contains dimethyl isosorbide in an amount of less than 0.5% by weight of the layer;

the drug-containing layer excludes the content of polyvinylpyrrolidone, methyl cellulose, ethyl cellulose and / or hydroxypropyl cellulose or contains polyvinyl pyrrolidone, methyl cellulose, ethyl cellulose and / or hydroxypropyl cellulose in an amount of less than 2% by weight of the layer;

the drug containing layer contains progestin (gestodene or its ester), which is completely dissolved in the layer;

the layer containing the drug includes gestodene or its ester in an amount of 0.5-3% by weight of the layer containing the drug;

the drug containing layer is transparent;

the drug containing layer is homogeneous;

the drug containing layer is monophasic;

the layer containing the drug excludes the use of an agent that enhances penetration into the skin, or contains less than 2% of the weight of the layer;

the drug-containing layer comprises said polymer in an amount of from about 15 to 99% by weight of the layer;

the drug-containing layer includes a tackifier, such as rosin ester, in an amount up to 85% of the weight of the drug-containing layer.

As mentioned above, the compositions in accordance with the invention are characterized by the delivery of a contraceptive effective amount of a steroid hormone such as progestin, in particular such as gestoden, optionally in combination with estrogen. In an embodiment in which the progestin is gestodene or a derivative thereof, the composition may be characterized by the ίη νίΐΓΟ penetration rate of gestodene and / or its derivative into the exposed skin of the mice, which is at least 25 μg / cm ² -24 hours. In other words , the composition can be characterized by the content of a layer containing a drug that delivers gestodene and / or its derivative in an amount of from about 40 to 70 μg per day.

Not only gestodene or its derivative can be used as a medicine in the composition in accordance with the invention. Other progestins may be included in the drug layer together with gestoden or in place of gestoden, such as dienogest, drospirenone, levonorgestrel, cyproterone acetate, tetrahydrodienogest, nortisterone, nortisterone acetate, desogestrel, 3-ketodesogestrel, norgestrogestol, norgestrogestol, norgestrogen

- 11 011160 steronenanthate, trimegestone or ligands of the alpha and beta progesterone receptor.

As mentioned above, the composition is effective in inhibiting ovulation. In some cases, the composition further includes estrogen. Estrogen can be introduced along with progestin in the same layer containing the drug, or can be introduced in a separate layer containing the drug that does not contain progestin.

The term “estrogen” includes both natural 17b-estradiol and semi-synthetic derivatives of estrogen, such as natural estrogen esters and 17-alkyl estrogens. Semi-synthetic esters of natural estrogen include, for example, estradiol-17-b-enanthate, estradiol-17-b-valerate, estradiol-17-b-benzoate, estradiol-17-b-undecanoate, estradiol-16,17-hemisuccinate or estradiol -17-in-cypionate. Examples of 17-alkylated estrogens are ethinyl estradiol, ethinyl estradiol-3-isopropyl sulfonate, quinestrol, mestranol or methyl estradiol. The term “estrogen” may also include a non-steroidal compound having estrogen activity, such as diethylstilbestrol, dienestrol, clomiphene, chlorotrienesene or cyclophenyl.

In a preferred embodiment, the estrogen is ethinyl estradiol.

In order to achieve a therapeutically effective amount of the hormone in the blood, the actual concentration of the drug in the layer containing the drug can be selected. Generally speaking, a drug-containing layer will contain some hormone in excess of the amount of hormone absorbed to achieve a therapeutically effective amount of the hormone. Normally, this excess is negligible, such as the amount of the hormone that is 10 times lower than the desired / required amount of the hormone, preferably one that is 5 times lower, such as 2 times lower. For example, it is also considered important to limit the amount of the hormone in order to reduce the overall effect of the hormone on the user. Acceptable concentrations of a steroid hormone, such as progestin, in particular such as gestodene or a derivative thereof, in the drug-containing layer thus comprise from about 0.5 to 10% by weight of the drug-containing layer. In even more preferred embodiments, the concentration of said hormone is from about 0.5 to 10%, for example from about 0.75 to 5%. As mentioned, the total concentration of a hormone, such as gestodene, can result in drug-containing layers and including the hormone at saturation and sub-saturation levels. In a most remarkable embodiment, the concentration of a steroid hormone, such as gestodene or a derivative thereof, in the drug-containing layer is from about 1 to 3%, for example from 1 to 2%.

Similarly, in some embodiments in accordance with the invention, which further comprise estrogen, estrogen is present in the drug-containing layer in an amount of from about 0.5 to 10% by weight of the adhesive layer, preferably from about 0.75 to 5% more preferably from about 1 to 3%, for example from 1 to 2%.

Moreover, said progestin, such as gestodene or a derivative thereof, are in a weight ratio to said estrogen in the range of from about 4 to 0.5, preferably from 2 to 0.5, such as 1: 1.

Surprisingly, it has been found that relatively high levels of gestodene in blood plasma can be maintained for a long period of time with the administration of gestodene or its derivative, administered as a composition in accordance with the invention. It was also unexpectedly discovered that the plasma profile of gestodene and its levels resulting from the administration of gestodene or its derivative and optionally estrogen are effective for inhibiting ovulation in women.

Thus, further aspects of the invention relate to the use of the composition of the invention, optionally in combination with estrogen, to inhibit ovulation in a female, such as a female. When a drug is administered on its own, the time course of the achieved concentration of gestodene in the blood plasma is characterized by the presence of gestodene in the blood plasma at a concentration level of at least 1.0 ng / ml, as determined under steady state conditions. Another aspect of the invention relates to a method for inhibiting ovulation in a female individual, such as a woman, comprising topical application of an effective amount of gestodene or its derivative on the skin or mucous membrane, optionally in combination with estrogen, so that with the self-administration of said gestodene an achieved concentration dependence curve plasma gestodene with time is characterized by the presence of plasma levels of gestodene of at least 1.0 ng / ml, as determined in a stable condition and I.

Alternatively, the uses and methods of the invention are acceptable for the treatment of other symptoms, disorders or symptoms that are normally treated by the administration of a progestin such as gestodene or a derivative thereof, or a combination of progestin and estrogen.

Thus, it is generally understood that in some embodiments of the invention, the uses and methods are for the treatment of endometriosis, premenstrual syndrome, cli

- 12 011160 of macrotic disorders, regulation of the menstrual cycle and / or stabilization of the menstrual cycle.

For example, by administering progestin in the absence of competitive therapy with estrogen, irregular bleeding and abnormal bleeding can be treated. As used in this application, the term "irregular bleeding" refers to any uterine bleeding that goes beyond the regular monthly menstrual periods in non-pregnant women. Uterine bleeding is irregular if the menstrual cycles or menstrual periods are too short, too long, too frequent, too rare, or occur at irregular intervals that go beyond the regular 26-30 days of the menstrual cycle. The menstrual period is classified as too long if there is a delay within 15-50 days or more from the expected onset of the indicated bleeding. The term “abnormal bleeding” refers to severe bleeding, which causes the soaking of a sufficient number of sanitary protective products so that they need to be changed more often than every hour or every two hours, which at the same time lasts for a period of time over 7 days. Abnormal bleeding does not include bleeding in women who have already reached menopause, abnormal uterine bleeding due to side effects of hormone replacement therapy based on estrogen, abnormal bleeding as a symptom of uterine cancer, bleeding resulting from abnormal coagulation, hereditary bleeding disorder or bleeding due to a medical condition that affects blood platelet levels.

In other embodiments, the progestin is administered in combination with estrogen, for example, by administering a medicament in accordance with the invention, comprising a combination of a progestin, such as gestodene or a derivative thereof, and estrogen for the treatment of menopausal disorders, such as symptoms and diseases associated with menopause, such like hot flashes, sweating attacks, palpitations, sleep disorders, mood swings, nervousness, anxiety, weak memory, loss of confidence, loss of libido, weak concentration of extra mania, decreased energy, decreased excitability, irritability, urinary tract atrophy, atrophy of the breasts, cardiovascular disease, changes in hair distribution on the body and hair thickness, changes in skin condition and / or osteoporosis. In particular, the treatment is aimed at hot flashes, sweating attacks, palpitations, sleep disorders, mood swings, nervousness, anxiety, urinary tract atrophy, mammary atrophy, or is used to prevent or treat osteoporosis.

In connection with the treatment of menopausal disorders, estrogen can be selected from natural estrogens, such as estradiol and its esters, such as estradiolvalerate, estradiol benzoate. In addition, natural estrogens include estrone, estriol, estriolsuccinate and conjugated estrogens, including conjugated equine estrogens, such as estronsulfate, 17b-estradiol sulfate, 17a-estradiol sulfate, equilinsulfate, 17v-dihydroequylate sulfate-equilibrium sulfate, 17c-dihydroequylate sulfate equilibrium sulfate 17a-dihydroequileninsulfate or mixtures thereof.

In some embodiments of the invention, the time-dependent plasma curve of gestodene concentration under steady state conditions is characterized by a gestodene concentration of at least 1.5 ng / ml, such as at least 2.0 ng / ml or at least 2.5 ng / ml In other noteworthy embodiments, the time-dependent plasma curve of gestodene concentration under steady state conditions is characterized by the presence of gestodene concentration levels in the range from 1 to 8 ng / ml, preferably in the range from 1.5 to 6 ng / ml, 6 days after a single injection the composition of gestodene or its derivative, preferably in the form of a composition in accordance with the invention.

In other additional embodiments, the curve of the concentration of gestodene in blood plasma versus time under steady state conditions is characterized by the presence of maximum levels of gestodene in plasma in the period from 18 to 60 hours after a single injection of the drug and / or the presence of levels of gestodene in plasma in the period from 5 to 7 days after a single injection of the drug, at least 50% of the maximum levels of gestoden in the blood plasma obtained during the first 18-60 hours after administration.

Gestoden is preferably reintroduced in 28-day cycles, so that within each 28-day cycle, Gestoden / composition is administered with an interval of 7 days for a period of 21 days (3 weeks), after which there is no administration of gestodene or its derivative for 7 days (one week) . That is, gestodene / composition is administered on day 1, 8 and 15 within each cycle of 28 days. Preferably, when said day 1 may be a day of the onset of menstruation or any other suitable day, such as the first, second, third, fourth, fifth or sixth day from the day the menstruation begins. In another embodiment, gestodene, optionally in combination with estrogen, is reintroduced in 12 week cycles, so that within each 12-week gestoden / composition cycle, is administered at intervals of 7 days for a continuous period of 11 weeks, after which gestodene or it is not administered. derivative within 7 days (one week).

- 13 011160

To improve contraceptive effectiveness and safety, estrogen can be administered in combination with gestoden. Estrogen may be selected from the estrogens mentioned above.

As you can understand, the applications and methods in accordance with the invention include the use of gestodene or its derivative, which may be in the form of a composition, as defined in this application. Thus, the term “drug” includes a composition as defined herein. In addition, the term "drug" is intended to include a kit in accordance with the invention.

In yet another aspect, the invention relates to a kit comprising from 1 to 11 unit doses intended for a treatment period of 12 weeks, formulated for transdermal delivery of a progestin such as gestodene or a derivative thereof, said unit doses including a layer containing a drug comprising gestodene and one or more pharmaceutically acceptable excipients or carriers, wherein the drug-containing layer has a solvent capacity of no more than said gestodene less than 3% of the weight of the layer containing the drug. A unit dose may include a composition as described herein. It is understood that in one embodiment, 11 unit doses are administered continuously once a week for a period of 11 weeks, after which a unit dose is not administered or a placebo is administered.

In other embodiments, the kit is also intended for a treatment period of 12 weeks, but the kit includes from 1 to 9 unit doses. In one embodiment, 3 unit doses are administered over a period of 3 weeks every week, after which a unit dose is not administered or a placebo is administered. That is, the kit is intended for a treatment period of 4 weeks and this kit includes 1-3 unit doses.

The dose of a progestin, such as gestodene or its derivative, in each unit dose corresponds to a dose selected from a dose of 6 days, from a dose of 7 days, a dose of 8 days, a dose of 14 days or a dose of 21 days. In one embodiment, each unit dose includes gestodene or a derivative thereof in a dose of from about 0.5 to 5 mg, preferably from 1 to 3 mg, more preferably from 1.5 to 2.5 mg.

It is also understood that the kit may further include estrogen, as mentioned above. Estrogen may be combined with a progestin, such as gestodene or a derivative thereof, in the same unit dose, or provided in separate unit doses. The kit may, for example, additionally include from 1 to 30 unit doses containing estrogen and not contain gestodene. Estrogen may be contained in a dosage form formulated for transdermal delivery, vaginal delivery, or the like. Alternatively, estrogen may be in the form of unit doses formulated for oral delivery of estrogen, such as in the form of tablets, pills, capsules, powders, pastes or granules.

Compositions in accordance with the invention can be made using procedures known in the art. One example is included in this application.

Figures

The drawing shows the average level of gestodene (Ο8Ό) in blood serum during two treatment cycles, week 1 and week 3, respectively. Signatures are as follows:

cycle 1, week 1 ° cycle 2, week 1 and cycle 1, week 2 ^Δ cycle 2, week 2

Examples

Example 1. The manufacture of the patch

The composition in accordance with the invention was prepared as described below.

In a first step, 380 g of gestodene and optionally 180 g of ethinyl estradiol were dissolved in an acceptable solvent, such as 16.8 kg of dioxane. At the second stage, approximately 57 kg of a mixture of polyisobutylene and resin ester in heptane (Agsage MA 24A) were weighed. The hormone solution obtained in the first step was added with stirring to the polymer solution and stirring was continued until a homogeneous solution was obtained. The drug-containing solution thus obtained was coated with a coating film (such as E 2000 75 μm PET 18; Ea Lorahech) and dried under acceptable conditions. The dried drug-containing layer was then laminated with a protective foil / layer such as Co1gap®, 9720, 3M. Thus obtained laminate was divided into patches with a size of 10 cm ^{2 the} resulting patch had the following composition:

- 14 011160

Gestoden: 1.9 mg

Optional ethinyl estradiol: 0.9 mg

97.2 mg polymer (in the form of polyisobutylene in combination with a tackifier, e.g. MA-24A®)

Cover film: 10 cm ²

Substrate Layer: 10 cm ²

In another example, the resulting patch was similar to the one mentioned above, but the amount of ethinyl estradiol was 0.6 mg.

In another example, the resulting patch was similar to the one mentioned above, but the adhesive was Oigo-1Ac®. 10711, which consists of a hydrocarbon polymer.

Example 2. The penetration rate into the skin of a composition with various polymers.

Six compositions (AE) were prepared with acrylate-vinyl acetate polymers as the polymer for the drug-containing layer. In addition, composition C was prepared using polyisobutylene as the polymer for the drug-containing layer. The preparation was carried out in accordance with the process described in example 1. None of the compositions included an agent that enhances penetration into the skin.

Each composition was analyzed in a ίη νίίτο mouse penetration test. The analysis was performed using preparations of exposed mouse skin (HkbSbb: S-pi), which were obtained from Nag1ap VyukeMse for Zaepse STN, No. a1kgo6e, Segtapu. The test composition was attached on the outside of the sample. The skin sample and composition were placed so that the cells into which the drug penetrates were placed on the inside in contact with the receptor medium. HEPE8 buffered aqueous solution was used as a receptor medium. Sodium azide was added to prevent microbial growth. The receptor solution was maintained at a temperature of 32 ° C. Samples were taken from the receptor solution at regular intervals and the concentrations of gestodene (SEC) and ethinyl estradiol (EE) in the receptor medium were analyzed by HPLC. The outflow rate was then calculated as the amount of drug released through the unit area per unit time [μg / cm ² -24 h] using the calculated amounts of active substances.

Ιη νίίτο skin penetration rate results:

Table 1

Composition BUT IN FROM ϋ E R FROM 080 (wt.%) 1.9 3.9 2.1 4.2 1.9 3.8 1.9 EE (wt.%) 1,0 2.0 1,1 2.1 1,0 1.9 0.9 Polymer Acrylate vinyl acetate, e.g. Oigotac® 387-2051 Acrylate vinyl acetate, e.g. RigSack 387-2051 Acrylate vinyl acetate, e.g. Oigoik 387-2825 Acrylate vinyl acetate, e.g. Oigoik 387-2825 Acrylate VINYL acetate, e.g. Pipyaak 87-2097 Acrylate vinyl acetate, e.g. Vigo1ac 87-2097 ΡΙΒ, for example. MA24 A Penetration Ο8ϋ mcg / cm ^g * 24 hours 14.8 32.8 12.6 14.3 13.5 16.7 30.9 Penetration EE m kg / cm ² * 24 hours 2.6 6.5 1,5 2,8 1.3 1.9 8.1

The results indicate that the penetration rate of gestodene, as well as ethinyl estradiol from composition C (polyisobutylene) is superior to those with respect to compositions AE.

Example 3. Contraceptive effect and pharmacokinetic profile

The effect with respect to inhibition of ovulation, drug concentrations and safety in accordance with the invention was studied in a selected female population. The study model was based on the requirements of the EMEA guidelines for clinical research with contraceptive steroids (Committee on Patented Medical Products, CPPM / E No. 519/98).

- 15 011160

Study model

The study included three phases; The preliminary phase included two dropout cycles and one additional cycle to ensure that the selected women were ovulatory. The second phase was the treatment phase, which consisted of two cycles, after which the third phase was carried out, which was the phase after the treatment and included one cycle.

The women who were included in the study had to be healthy, non-pregnant, non-smokers, non-lactating female volunteers aged 18 to 35 years, with a normal body mass ratio of 18-26 kg / m and with a normal menstrual cycle such as 28 days ± 4 days. Only women with fair skin were included in the study, since sites of use should be easily and unequivocally evaluated.

The studied patch was a patch containing a layer containing a drug, 0.9 mg of ethinyl estradiol and 1.0 mg of gestodene, as well as Agsage MA-24A®, which is an adhesive based on polyisobutylene from Abyeuye Eekeagsy.

During the study, blood was taken to determine endogenous hormones such as estradiol, progesterone, follicle-stimulating hormone, sex hormone-binding protein, ethinyl estradiol, gestodene. Transvaginal ultrasound was performed to evaluate the development of follicle-like structures of the ovaries. The patch adhesion, skin reactions at the site of application, and the general health status of women were evaluated. Vaginal bleeding was also evaluated.

During the preliminary cycle, normal and spontaneous ovulation was established by assessing the value of serum progesterone, since only those women who had an ovulatory previous cycle and serum progesterone levels higher than 5 nmol / L were taken to participate in the treatment phase.

The treatment phase included a period of two menstrual cycles. The first treatment in the first cycle was started a day after the onset of menstruation in volunteers in this cycle by applying a patch. In general, 3 test patches were used at intervals of 7 days between applications, for example, on days 1, 8 and 15 of the first cycle, each patch was applied at different sites of application during each treatment cycle. Each patch was worn for 7 days, then replaced with a new patch to complete a 21-day period of continuous use. This was followed by a 7-day treatment-free interval, before the next treatment period, during which 3 patches were used, each of which was applied with an interval of 7 days. If the patches were lost or the patch was peeled off by more than 40%, a new patch was used.

The patches were applied to clean, dry, intact skin, preferably hairless, lower abdomen, below the navel, starting from the right side in the first treatment cycle and then changing sides.

Definition of pharmacodynamic variables

The primary pharmacodynamic variable was the quantitative ratio of women with inhibited ovulation. According to the so-called Gugland method, ovulation requires a follicle size of more than 13 mm followed by follicle rupture, plus serum progesterone concentration must be> 5 nmol / L, which coincides with follicle rupture. From this it follows that we can say that ovulation is inhibited if the follicle has a size of less than 13 mm and the concentration of progesterone in the blood serum is less than 5 nmol / L during follicle rupture.

Definition of pharmacokinetic variables

The following pharmacokinetic parameters were used, such as the area under the curve of the drug concentration versus time during the period of wearing the AIS patch ( ₀ 1 _{68 h} ), C _max , 1 _t , _{| X.} and accumulation factors in each cycle, as determined by the AIS _(0- 1 _{h 68)} of the third patch / AIS _(0- 1 ₆₈ n) of the first patch in cycle 1 or 2, or accumulation factors between two cycles, such as AIS _{(0 -} 1 _{68 h} ) of the third patch in cycle 2 / AIS ( _{0-168 h} ) of the third patch in cycle 1. The value of AIS was calculated in accordance with the linear rule of the trapezoid.

Serum concentrations of estrogen and progestin, including ethinyl estradiol and gestodene, were determined by studying the pharmacokinetic characteristics of the patch. The time points when sampling was carried out were on day 18 of the last cycle before treatment and on days 1, 2, 3, 4, 5, 6, 7, 8, 15, 16, 17, 18, 19, 20, 21 and 22 cycles 1, as well as on days 1 (before applying a new patch), 2, 3, 4, 5, 6, 7, 8, 15, 16, 17, 18, 19, 20, 21, and 22 cycles 2.

The concentrations of ethinyl estradiol and gestodene were determined using conventional methods known in the art. In particular, the concentration of ethinyl estradiol was determined by gas chromatography using mass spectrometry in chemical ionization mode as a determination method, followed by extraction of acidified serum ethinyl estradiol and sequential derivatization. Gestoden concentrations were determined by radioimmunoassay using rabbit antiserum and 3H-labeled gestoden. After incubation and centrifugation, the obtained precipitate was re-dissolved in ΝαΟΗ. The assay has a lower quantification limit of approximately 250 pg / ml.

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results

The primary pharmacodynamic variable was the ratio of women to inhibition of ovulation.

Ovarian activity was effectively suppressed, that is;

Lack of ovarian activity: cycle

Potential Activity:

cycle

Inactive Pb8:

cycle

1: 78%, cycle 2: 56%.

1: 15%, cycle 2: 22%.

1: 4%, cycle 2: absent;

1: 4%, cycle 2: 22%

Active Pb8: cycle

No cases of ovulation were detected during the study period. Ovulation inhibition, defined by the Gugland scale below 6 (ovulation), was sufficient for all volunteers in the prescription data obtained from the study.

Progesterone concentrations were adequately suppressed below 2.5 nmol / L in each of the treatment cycles. The average serum estradiol levels were below 20 pg / ml on all days when the patch was used.

Pharmacokinetic results

In all samples taken before the dose, the concentrations of ethinyl estradiol (EE) and gestodene (Ο8Ό) in the blood serum were below the limit of quantification (LOO: 10 pg / ml for EE, 250 pg / ml for Ο8Ό). After applying the study treatment, the concentrations of EE and Ο8Ό in the blood serum were such that it was possible to measure at least 168 hours in all individuals. See table results. 2 and 3, as well as FIG. one.

Table 2. The average value of the pharmacokinetic parameters of ethinyl estradiol (EE)

Pharmacokinetic parameter Unit Cycle 1 Cycle 2 Week I Week 3 Week 1 Week 3 Stah pg / ml 45.6 50,4 45,2 48.0 Ttah hour. 48 24 48 48 ATsS (0-168ch) ng x h / ml 5.3 6.1 5.1 5.8

Table 3. The average pharmacokinetic parameters of gestodene (ена8Ό)

Pharmacokinetic parameter Unit Cycle 1 Cycle 2 Week 1 Week 3 Week 1 Week 3 Stah pg / ml 1564 3896 Ttah hour. 144 48 ATsS (0-168ch) NG X h / ml 194 524

Example 4. Comparison of polyisobutylene adhesive and acrylic composition in humans

A randomized, crossover study of the average daily delivery of ethinyl estradiol (EE) and gestodene (Ο8Ό) from three different transdermal patch formulations (A-C) in healthy menopausal volunteers after a single administration was performed. The aim of the study was to compare transdermal administration with that of intravenous injection.

The studied compositions were as follows:

Composition A (Polyisobutylene)

No. Ingredient name 2 Quantity per 10 cm patch Comments one Ethinyl estradiol 0.95 mg 2 Mr. estoden 1.9 mg 3 Polyisobutylene adhesive 97.15 mg MA-24A

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Composition B (Polyisobutylene, 70% of composition A)

No. Ingredient name Quantity per 10 cm ² patch Comments one Ethinyl estradiol 0.67 mg 2 Mr. estoden 1.33 mg 3 Polyisobutylene Adhesive 98.00 mg MA-24A

Composition C (Acrylate)

No. Ingredient name 2 Quantity per 10 cm patch Comments one Ethini lestr adiol 0.67 mg 2 Mr. estoden 1.33 mg 3 Acrylic adhesive 73.5 mg OECA® 7883 4 Isopropyl myristate 5.0 mg Penetration enhancer 5 Οορονίάοηε 15.0 mg Crystallization Inhibitor (CoPIop UA64, VA8R, Segtapu)

The study was carried out in accordance with the following parameters.

The patches were used by single use with a patch wearing period of 7 days during the study. After removing the patch, one week of screening was performed for each treatment studied. A dose of 60 μg EE and 75 μg 68Ό was administered once intravenously.

Blood samples for kinetic measurements were taken 72 hours after intravenous administration and for a period of 12 days after transdermal administration, as described in example 3. Determination of blood levels 68Ό and EE was carried out in accordance with example 3.

Results:

The maximum concentrations of gestodene are presented in the following table, they demonstrate the difference between polyisobutylene compositions A and B from acrylic compositions. The figure shows the average serum gestoden levels versus time.

Parameter Composition A Composition B Composition C S _ta x [pg / ml]: 2082 1995 1277 Matchmaker [hour]: 168 144 156 A11C (0-7 days): [hour * ng / ml] 243 257 155

These results indicate that the drug delivery of composition C, which includes a drug-containing layer that includes acrylate in combination with a penetration enhancing agent, is significantly lower than drug delivery from compositions A and B.

Example 5

Presented are drug-containing layers that include 1.9 mg of gestodene and 0.9 mg of ethinyl estradiol and are composed of various polymer blends (AM).

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Polymer trademark The chemical name of the polymer BUT ^IN G 3 Horns! 85E® Pentaerythritol ester hydrogenated rosin 20,0 Horns1 105E® Hydrogenated rosin glycerin ester 20,0 s 0,0 Orrapo1 B10 N / 8ΡΝ® Polyisobutylene (MV approximately 40,000 daltons) 57.2 57.2 57.2 15,2 Orrapo! AT 11 8ΡΝ® Polyisobutylene (MV approximately 49,000 Daltons) 62,2 Orrapo1 B12 8ΡΝ® Polyisobutylene (MV approximately 55,000 Daltons) 62,2 62,2 Orrapo! WZO 8ΡΝ® Polyisobutylene (MV approximately 200.00 C Daltons) Orrapo1 V100 Polyisobutylene (MV approximately 1,000,000 daltons) 20,0 20,0 12.0 12.0 20,0 12.0 15.0 Orrapo1 B150 Polyisobutylene (ME approximately 2,600,000 Daltons) Ιηάοροί NZOO Synthetic Polybutene (ME approximately 1,300 Dalton) 10.0 Ιηάοροί Η1900 Synthetic Polybutene (MV approximately 2,500 Dalton) 23.0 Ιηάοροί Η2100 Synthetic Polybutene (MV approximately 2,500 Dalton) 23.0 Josogeg 5300 Cyclic aliphatic hydrocarbon coumaronondene resin 20,0 81aue1e ZE ester Ester hydrogenated resin 81au Complicated ether 5E K) Glycerol ester partially hydrogenated resin Kga (op οιΐόΐΝυ Styrene-Isoprene-Styrene Block Polymer

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Yoga1 85E® Pentaerythritol 10.0 complex hydrogenated rosin other ether Yoga1 105E® Hydrogenated rosin glyceryl ester 10.0 > 5.0 Errapo1 ΒΙΟ E '8ΡΝ® Polyisobutylene approximately Daltons) (MV 40,000 67.2 67.2 75.7 75.7 Orrapo! AT 11 8ΡΝ® Polyisobutylene approximately Daltons) (MV 49,000 Orrapo1 B12 8ΡΝ® Polyisobutylene approximately Daltons) (MV 55,000 57.2 Orrapo1 VZO 8ΡΝ® Polyisobutylene approximately Daltons) (MV 200,000 10.0 10.0 Orrapo1 V100 Zoliisobutylene (MV approximately 1,000,000 daltons) 10.0 10.0 15.0 Orrapo1 B150 Zoliisobutylene (MV approximately 2,600,000 Daltons) 10.8 10.8 Ιηάοροί ΡΙ300 Synthetic polybutene approximately Daltons) (MV 1,300 Ιηάοροί H1900 Synthetic polybutene approximately Daltons) (MV 2,500 [ηάοροί H2100 Synthetic polybutene approximately Daltons) (MV 2,500 Josogeg 5300 Cyclic aliphatic hydrocarbon coumaronoindene resin 81au Ester ZE Ester hydrogenated resin 10.8 81au Ester 5E K) Glycerol ester partially hydrogenated resin 25.0 10.8 Kga1op epbshi Styrene-Isoprene-Styrene Block Polymer 32,2

CLAIM

Claims (25)

1. Composition for transdermal delivery, comprising a drug-containing layer that includes gestodene or its ester and a carrier selected from the group consisting of polyisobutylenes, polybutenes, polyisoprenes, polystyrenes, block copolymers of styrene isoprene styrene, block copolymers of styrene styrene butadiene and mixtures thereof, wherein the drug-containing layer has a solubility for said gestodene of not more than 3% of the weight of the drug-containing layer, wherein the gestodene or its ester is present in an amount that ranges from 0.5 to 3% by weight of the layer containing the drug. 2. The composition according to claim 1, in which the layer containing the drug further comprises tackifiers selected from the group consisting of hydrocarbon resins, rosin-based resins and terpene resins. 3. The composition of claim 2, wherein the tackifiers are ether ka - 20 011160 nifoli. 4. The composition according to any one of the preceding paragraphs, in which gestodene or its ester is completely dissolved in the layer containing the drug. 5. The composition according to any one of the preceding paragraphs, in which the layer containing the drug comprises less than 2% by weight of polyvinylpyrrolidone, methyl cellulose, ethyl cellulose and hydroxypropyl cellulose. 6. The composition according to any one of the preceding paragraphs, in which the layer containing the drug comprises less than 0.5% by weight of dimethyl isosorbide. 7. The composition according to any one of the preceding paragraphs, in which the layer containing the drug is transparent. 8. The composition according to any one of the preceding paragraphs, in which the layer containing the drug comprises less than 2% by weight of an agent that promotes absorption in the skin, or an agent that enhances penetration into the skin. 9. The composition according to any one of the preceding paragraphs, further comprising estrogen. 10. The composition according to claim 9, in which estrogen is present in the layer containing the drug in an amount of from 0.5 to 10% by weight of the layer containing the drug. 11. The composition of claim 10, in which estrogen is present in the layer containing the drug in an amount of from 0.75 to 5% by weight of the layer containing the drug. 12. The composition according to any one of paragraphs.9-11, in which the estrogen is ethinyl estradiol. 13. The use of a composition according to any one of claims 1 to 12 for inhibiting ovulation in a female individual. 14. A method of inhibiting ovulation in a female individual, comprising topical application to the skin or mucous membrane of a female individual of the composition according to any one of claims 1-12. 15. Transdermal therapeutic system, consisting of: a) a substrate layer; b) at least one layer containing the drug according to any one of claims 1 to 12; and c) an optional removable release liner or protective layer. 16. The transdermal therapeutic system according to clause 15, in which gestodene or its ester is present in a dose of from 1 to 3 mg. 17. The transdermal therapeutic system according to clause 16, in which gestodene or its ester is present in a dose of from 1.5 to 2.5 mg. 18. The transdermal therapeutic system according to any one of paragraphs.15-17, which further includes estrogen, where the mass ratio of gestodene or its ester to estrogen is in the range from 4 to 0.5. 19. The transdermal therapeutic system according to any one of claims 15-18, wherein the gestodene or its ester is gestodene. 20. The transdermal therapeutic system according to claim 18 or 19, wherein the estrogen is ethinyl estradiol. 21. The transdermal therapeutic system according to claim 20, which contains a dose of gestodene 1.9 mg, a dose of ethinyl estradiol 0.9 mg and 97.2 mg of polyisobutylene in combination with a tackifier. 22. The transdermal therapeutic system according to claim 20, which contains a dose of gestodene 1.9 mg, a dose of ethinyl estradiol 0.6 mg and 97.2 mg of polyisobutylene in combination with a tackifier. 23. A kit comprising from 1 to 11 unit doses, where the specified unit dose includes a composition according to any one of claims 1 to 12. 24. The use of the transdermal therapeutic system according to any one of claims 15-22 for inhibiting ovulation in a female individual. 25. A method for inhibiting ovulation in a female individual, comprising topical application to the skin or mucous membrane of a female individual of the transdermal therapeutic system according to any one of claims 15-22.