MXPA06006682A

MXPA06006682A - Transdermal delivery of hormones without the need of penetration enhancers.

Info

Publication number: MXPA06006682A
Application number: MXPA06006682A
Authority: MX
Inventors: Dirk Schenk
Original assignee: Schering Ag
Priority date: 2003-12-12
Filing date: 2004-12-10
Publication date: 2006-08-11
Also published as: CN1913878B; IL176112A; JP4965263B2; WO2005058287A2; NO341989B1; AU2004298930A1; EA200601089A1; BRPI0417530B1; KR101168449B1; ZA200605713B; ECSP066694A; NO20062594L; EA011160B1; KR20060128910A; JP2007513938A; NZ548091A; BRPI0417530A; BRPI0417530B8; CA2549916C; CU23868B1

Abstract

The present invention relates to a patch comprising a drug-containing layer with low content of hormones, such as gestodene, and optionally an estrogen (e.g. ethinyl estradiol). 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

TRANSDERMAL ADMINISTRATION HORMONES THAT DO NOT NEED PENETRATION ENHANCERS FIELD OF THE INVENTION The present invention relates to the field of pharmaceutical formulation techniques. The invention provides a low dosage pharmaceutical composition for transdermal administration of at least one hormone, preferably a progestin, such as a gestodene, and optionally an estrogen, in order to achieve plasma concentration profiles that are effective in inhibiting Ovulation in a woman.

PREVIOUS ART The transdermal administration of estrogens and progestins as contraceptives is a well-known concept (Sitruk-Ware, "Transdermal application of steroidal hormones for contraception", J. Steroidal Biochem.Molecul. Biol., Vol. 53, p 247-251 ). However, generally estrogens and proges-tubins penetrate little through the skin, and because of that, in transdermal systems it is common to incorporate agents with a penetration enhancing effect through the skin. The following documents describe various transdermal systems with a progestin and an estrogen present in the adhesive layer and where the need for penetration enhancers is emphasized: WO 92/07590 describes compositions with penetration enhancers for the transdermal administration of gestodene and a estrogen so as to achieve maximum plasma levels of gestodene of about 0 9ng / ml. WO 97/397443 is related to a transdermal system containing between 30 and 60% penetration enhancers so as to administer an amount of an estrogen and an effective progestin as a contraceptive. WO 01/37770 relates to transdermal systems containing between 10 and 60% penetration enhancers for administration of ethinylestradiol and levonorgestrel in an effective amount as a contraceptive. US 5,512,292 relates to compositions comprising an effective amount as a contraceptive of gestodene and an estrogen, such as ethinylestradiol, together with an appropriate permeation enhancer. The amount of estrogen that is coadministered is maintained in a constant and effective proportion as a contraceptive while the amount of gestagen that is coadministered varies depending on the phase of the menstrual cycle. Similar studies between transdermal systems with penetration enhancers and without them are shown in US 5,376,377. These studies include an adhesive layer made of ethylene vinyl acrylate and gestodene and an estrogen (ethinyl estradiol) as active ingredients. The results of the study indicate the need to incorporate penetration enhancers in the adhesive layer in order to achieve effective amounts as a contraceptive. Maximum plasma levels of approximately 0.8ng / ml were achieved. Finally, WO 90/04397 also discloses examples of compositions for transdermal administration of gestodene, optionally in combination with an estrogen, such as, for example, ethinylestradiol, where the composition can further comprise a penetration enhancer, such as, for example, 1,2-propanediol or isopropyl myristate. As the adhesive layer, several different polymers are mentioned. Specifically disclosed are examples of polar polymers (polyacrylates and silicones) in combination with a penetration enhancer. The plasma levels of gestodene causing steady-state conditions were approximately between 250 and 337 pg / ml. In addition to the penetration enhancers, it is also suggested to add solubilizing or similar agents to the drug-containing layer to increase the amount of drug released or to add agents that inhibit the crystallization of the drug in said layer. For example, in US Pat. No. 6,521,250 an adhesive layer is disclosed which comprises a mixture of styrene-isoprene block copolymer and a hydrogenated acid resin or its derivatives, where the amount of the resin is 55-92%. . A Cape of adhesive with these characteristics seems appropriate for the transdermal administration of estradiol in combination with a progestin because said systems have a correct adhesive contact with the skin for long-term application and prevent the crystallization of hormones. US 5,904,931 relates to TTS systems containing a spheroid in the drug-containing layer (such as gestodene) and dimethyl isosorbide. The latter improves the solubility of the spheroid in the drug-containing layer. The concentration of gestodene in the drug-containing layer may vary between 1-40% by weight of the layer and the drug-containing layer may consist of adhesives such as polyacrylates., silicones, styrene-butadiene copolymers and polyisobutylenes. Polar polymers, such as polyacrylates, are especially suitable. DE 199 06 152 relates to a transdermal drug administration system where the gestodene is included in a polar polymer, such as polyvinylpyrrolidone, methylcellulose, ethylcellulose, and hydroxypropylcellulose, before being added to an adhesive polymer, such as, for example, polyisobutile-no. Therefore, said transdermal drug delivery system is a two-phase system and the drug-containing layer is not transparent due to the content of polar polymers, which when exposed to water cause the appearance of milky white spots. The amount of gestodene in the drug-containing layer is 5.1% by weight of the drug-containing layer. In WO 02/45701 it is emphasized that by adding a rosin ester in an amount of up to 25% by weight to a layer of adhesive, the formation of crystals of active agents such as, for example, hormones can be suppressed sufficiently. The adhesive layer may include all known natural and synthetic non-toxic polymers and which are suitable for use in transdermal systems, eg polyacrylates, polysiloxanes, polyisobutylenes, styrene block copolymers and the like. In particular, emphasis is placed on polyacrylates. The TTS system is appropriate for steroids (gestodene), which can be incorporated into the adhesive layer in a substantially saturating amount or close to or even greater than the same with respect to its concentration in the composition of the vehicle more than substantially sub-saturation. Preferably, the amount of the spheroid is between about 0.1% and about 6% by weight, based on the dry weight of the total composition of the vehicle. Unfortunately, penetration enhancers can adversely affect the skin, for example by irritating the skin, and to some extent that transdermal systems are unacceptable to the user. Furthermore, it is generally known that penetration enhancers can adversely affect the stability of the active substances making long-term storage problematic. In addition, it is also recognized that the incorporation of penetration enhancers reduces the viscosity causing the risk of dark ring formation at the edges of the patch. Therefore, there is a need for transdermal systems that do not have the aforementioned disadvantages, such as for example transdermal systems that do not require penetration enhancers to reach the effective amounts for the therapeutic use of a steroid hormone, as per example the gesturedeno. The gestodene is a known synthetic active progestin in oral form with an activity profile similar to that of progesterone (see, US Pat. No. 4,081,537). The same is used as an oral contraceptive in combination with certain estrogens.

SUMMARY OF THE INVENTION The present invention relates to compositions formulated appropriately for the transdermal administration of hormones, in such a way as to reach effective levels as a contraceptive without the need to incorporate penetration enhancers in the layer of adhesive containing the hormone. The present hormones are preferably steroid hormones, such as, for example, progestins, eg a gestodene, which can optionally be used in combination with an estrogen. Unlike general knowledge in the art, the present inventors provide transdermal systems comprising a limited amount of ingredients. For example, no penetration enhancers or permeation enhancers are required to achieve a high release rate and effective plasma levels for therapeutic use. The inventors hereby discovered that the selection of a drug-containing layer in which the spheroid hormone (eg gestodene) has some solubility is critical to successfully achieving blood levels of a hormone that are effective for therapeutic use. Example 2 of the present documentation shows the comparison of gestodene release rates of two layers containing gestodene. It clearly demonstrates that a drug-containing layer of a polar polymer (polyacrylate) requires a gestodene concentration of 3.9% by weight of said layer to achieve the high release rate that is desired. Surprisingly, and in contradiction with what was previously known, the same high release rate can be achieved with a concentration of 1.9% by weight of gestodene in a drug-containing layer comprising a less polar polymer, such as example polyisobutylene, even without the use of a penetration enhancer. In addition, in vivo studies revealed that drug-containing layers containing the less polar type of polymer such as for example polyisobutylene-not in preference to polyacrylates are better for achieving high AUC in plasma (example 4). Therefore, the present inventors discovered, unlike what would be expected, that the use of drug containing layers preferably containing an apolar polymer, such as for example polyisobutylenes, and characterized by a limited solubility of gestodene in them not greater than 3% in Weight have a high rate of gestodene release despite the fact that the actual load of gestodene in the drug-containing layer is low. This is clearly an advantage with respect to the TTS systems that were previously known in terms of decreasing the risk of skin irritation and decreasing the exposure of the hormone to the user and the environment. An additional advantage is that the drug-containing layer is a monophasic system and contains the drug distributed evenly throughout the entire layer. That is to say that the drug-containing layer is homogeneous. In the absence of polar polymers or other polar additives with a tendency to absorb water or retain water, the drug-containing layer is transparent. Therefore, the present invention provides a transparent composition, wherein the skin can be visually inspected through the drug delivery system. The transparency of a transdermal drug administration system is a clear advantage for the user because non-transparent systems are visible and therefore indicate disease, which is not the intention of a contraceptive patch. Therefore, a first aspect of the invention relates to compositions for transdermal administration of a spheroid hormone, preferably a progestin, such as Gestodene or an instance derivative thereof (ester thereof), and optionally an estrogen composition co -prende a layer containing drug comprising said hormone and one or more excipients or vehicles for pharmaceutical use, and wherein said hormones (such as gestodene) have a solubility in the drug-containing layer is not greater than 3% by weight of the layer that contains drugs. In a particular aspect thereof, the invention relates to a composition comprising a progestin, such as gestodene or a derivative thereof, and a polymer in an amount between about 15 and 99% by weight of the layer containing drug, wherein the polymer is is-lecciona from the group consisting of hydrocarbon polymers, polysiloxanes, polyacrylates and mixtures thereof that form a drug-containing layer having a solubility of gestodene in the same not more than 3% weight of the drug-containing layer. In another particular aspect thereof, the invention relates to compositions comprising a drug-containing layer consisting essentially of a progestin such as for example gestodene or a derivative thereof, a polymer in an amount between about 15 and 99% in weight of the drug-containing layer, an adhesive, such as an ester of rosin in an amount of up to 85% by weight, such as, for example, in an amount within the range of 1-85% of the layer containing drug, and optionally an estrogen. In yet another particular aspect, the invention relates to a composition for transdermal administration comprising a drug-containing layer comprising: i) a progestin, preferably a gestodene or derivative thereof, such as, for example, an ester thereof; and ii) a polymer selected from the group consisting of polyisobutylenes, polybutenes, polyisoprenes, polystyrenes, styrene-isoprene-styrene block polymers, styrene-butadiene-styrene block polymers and mixtures thereof. Still another aspect of the invention relates to a transparent composition for transdermal administration, wherein said composition comprises a drug-containing layer comprising a progestin, preferably a gestodene or derivative thereof (such as an ester thereof) ) and the gestodene has a solubility in the drug-containing layer that is not more than 3% by weight of the drug-containing layer. Surprisingly, it has been found that relatively high levels of gestodene plasma can be maintained for a prolonged period of time by administering a ges-todeno formulated in a composition of the invention. The plasma profile and the plasma levels of gestodene, such as obtained by the administration of a gestodene and optionally an estrogen, are effective in inhibiting ovulation in a woman. Therefore, the compositions of the invention can be used to inhibit ovulation or as an alternative for the treatment of endometriosis, premenstrual syndrome, climacteric disorders, prevention of osteoporosis, regulate the menstrual cycle or stabilize the menstrual cycle. Therefore, in still further aspects, the invention relates to the use of a composition as described herein optionally in combination with an estrogen, to inhibit ovulation in a woman. When the composition is administered alone, a plasma gestodene concentration curve is achieved with respect to time characterized by levels of gestodene plasma concentration of at least 1.0ng / ml, as determined under steady-state conditions. Associated with the above, the invention is re-laced with a method to inhibit ovulation in a female subject, such as a female. The method comprises administering topically on the skin or mucosa an effective amount of gestodene or a derivative thereof, optionally in combination with an estrogen, such that by said single administration of gestodene, a plasma concentration of gestodene curve is achieved. with respect to the time characterized by levels of gestodene plasma concentration of at least l, 0ng / ml, as determined under steady-state conditions. Finally, the invention relates to a set of elements comprising between 1 and 11 dosage units, such as for example 9 or 3 dosage units, depending on the duration of the treatment period, formulated in a form of transdermal gesture administration -dede or a derivative thereof, as for example in the form of a composition as described herein. The dosage form comprising a drug-containing layer comprising gestodene and one or more excipients or vehicles acceptable for pharmaceutical use, wherein the gestodene has a solubility in the drug-containing layer not greater than 3% by weight of the layer containing drug. DETAILED DESCRIPTION OF THE INVENTION The invention provides compositions for the transdermal administration of hormones (transdermal therapeutic system) that when applied topically on the skin or on a mucosa causes quantities of the hormones effective for therapeutic use, for example, to be obtained. Effective amounts as a contraceptive, although in the drug-containing layer do not necessarily incorporate penetration enhancers through the skin. As used herein, the term "topical" or "topically" denotes direct contact of the composition with a surface area of a mammal that includes skin and mucosa. The term "mucosa" means any superficial membrane of a mammal, which is not skin, such as a surface present in the oral cavity., vagina, rectum, nose or eye. Therefore, the mucosa can be the buccal, vaginal, rectal, nasal or ophthalmic mucosa. The compositions of the invention can be designed in several different application forms as long as the composition comprises a drug-containing layer, which is adapted to be placed close to the skin or mucosa or in direct contact to topically administer the composition. Therefore, in a preferred application form, the composition, for example the transdermal therapeutic system, consists essentially of a) a supporting layer; b) at least one drug-containing layer comprising said hormone or a mixture of said hormones and one or more ingredients acceptable for pharmaceutical use; and c) optionally a separable coating or a protective layer. Preferably, the support layer, the drug-containing layer and the separable coating (or protective layer) are transparent, which means that the skin is visible. In the event that the drug-containing layer is not sufficiently adhesive to the skin or mucosa, it may be provided with an additional layer of a layer of pressure sensitive adhesive or a pressure-sensitive adhesive edge or ring in order to ensure the adherence of the composition to the skin during the entire period of application. The layer of pressure-sensitive adhesive may be placed between the drug-containing layer and the skin and the adhesive ring may be placed around the edge of the drug-containing layer or on it. Optionally, the composition may additionally further comprise one or more membranes or adhesive layers. For example, a membrane can be placed to control the release of hormones 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 reasonable sizes. As used herein, a reasonable size means a surface area of between about 5 and 20cm2, preferably between about 7 and 15cm2, more preferably between about 8 and 12cm2, such as 10cm2. It is notable that the surface area is the area that is in contact with or close to the skin or mucous membrane. In accordance with the invention, it has been discovered that a drug-containing layer that has minimized the hormone's solubility provides sufficient penetration of a spheroid hormone through the skin. In the present invention, the drug-containing layer is characterized by defining the solubility of gestodene therein. It is notable that the rate of penetration through the skin is sufficient without the need to incorporate a penetration enhancer through the skin. For example, it was surprisingly discovered that the penetration of a spheroid hormone of the invention through the skin causes quantities of the spheroid hormone to be obtained in the bloodstream that are effective for therapeutic use, such as, for example, effective amounts of the hormone. as a contraceptive. Therefore, in a first aspect the invention relates to a composition for transdermal administration of a spheroid hormone, such as for example a progestin, for example gestodene or a derivative thereof. The composition comprises a drug-containing layer and one or more excipients or vehicles acceptable for pharmaceutical use and the gesture-deno has a solubility in the drug-containing layer that is not more than 3% by weight of the drug-containing layer. The composition may optionally comprise an estrogen. In some embodiments thereof, the solubility of gestodene in the drug-containing layer is not more than 2.5% by weight of the drug-containing layer, preferably not greater than 2.0%, such as, for example, no greater of 1.8%. In principle, the solubility could be very low, but it is considered that the critical level with respect to the lower level of said solubility is approximately 0.1%, as for example about 0.2%, 0.3%, 0.5% , 0.7%, 0.8%, 0.9% or 1% by weight of gestodene in the drug-containing layer. It is generally considered that the solubility of gestodene in the drug-containing layer is within the range between about 0.1% and 3%, such as between about 0.2% and 3%, 0.4% and 3%. %, 0.5% and 3%, 0.8% and 3% or 1% and 3%. In further embodiments of the invention, the upper limit of the range is not 3% by weight but less, such as 2.5% 2.2% or 2.0%. As used here, the term "a gestodene" means gestodene (13β-ethyl-17a-ethynyl-17β-hydroxy-4,15-gona-dien-3-one), a derivative thereof or a mixture thereof, as for example mixtures of the derivatives or a mixture of gestodene and a derivative. The derivative can be a derivative of the 17β-hydroxy group, such as for example ether, ester, acetal or a salt thereof acceptable for pharmaceutical use. For example an ester with between 2 and 12 carbon atoms in the acyl radical, including alkanoates with 2 to 8 carbon atoms in the alkanoyl radical. In preferred embodiments of the invention, a gestodene ester is gestodene propionate, gestodene valerate, and / or gestodene capronate, which are described in US 5,858,394. As mentioned, the inventors discovered that a drug-containing layer of the appropriate invention has a solubility for the spheroid hormone (eg gestodene) no greater than 3% by weight of the drug-containing layer. The phrase "a solubility for a spheroid hormone", such as "a solubility for gestodene no greater than 3% by weight of the drug-containing layer" characterizes the amount of the spheroid hormone, such as gestodene, which can be Dissolve in a layer containing particular drug that gives a visually crystalline solution. It should not be understood that the term "a solubility for" refers to the actual concentration of hormone, such as gestodene, in the drug-containing layer. As described below, the total concentration of hormone in the drug-containing layer may be greater than or less than 3% by weight of the drug-containing layer. In addition, the total hormone concentration in the drug-containing layer can result in a drug-containing layer comprising the hormone at saturation or subsaturation levels. To select drug-containing layers with the solubility specified for a hormone, such as gestodene, the following assay can be performed to determine whether the hormone is completely dissolved and the drug-containing layer obtained is visually crystalline. A test method is to determine if the hormone is completely dissolved since the solid particles can not be detected visually or using a 25-fold microscope. Another method is to effectively determine the solubility of the hormone in the drug-containing layer by the following method. The method is based on the determination of the rate constants of release of the hormone from a drug-containing layer comprising the hormone in completely dissolved form and from a drug-containing layer with the hormone partially dissolved. The method includes the following steps; First of all, identical layers are made that contain drugs, but with different amounts of the hormone, (for example, floods). As a rule, at least 3 of the different drug-containing layers should contain the hormone in a completely dissolved form in the drug-containing layer and at least 3 drug-containing layers should contain the hormone partially dissolved, for example with the hormone in the form of solid particles. With regard to the manufacturing process, the following steps can be followed. Any other method known in the art for making adhesive coatings may also be appropriate: dissolving or suspending the drug substance in an appropriate solvent. - dissolving the polymer, optionally the adhesive and other excipients in a suitable solvent. - combine the two solutions while stirring, in such a way as to obtain a homogeneous mixture. - use the mixture to coat a protective sheet in an appropriate thickness and dry it with heat to evaporate the solvents. - coating the laminate obtained with the support sheet. Secondly, measure the release rate of the drug from the drug-containing layer using the equipment and the test conditions given in the relevant section of the European Pharmacopoeia (Ph. Eur. 2.9.4 Dissolution test for transdermal patches ) or in the US Pharmacopoeia (ÜSP 26, <724> DRUG RELAY, apparatus 5 (Paddle over Disk)). - Cut a sample from a certain area of the drug-containing layer. - after removing the protective sheet, place the sample in a container (as described in the Pharmacopoeias mentioned above) that was previously filled with an appropriate dissolution medium equilibrated at 32 ° C + 0.5 ° C. The drug-containing layer should be in contact with the solution medium. Samples of the dissolution medium are taken at defined time intervals and the amount of dissolved hormone in the dissolution medium is measured using HPLC or other appropriate quantization methods. The dissolution medium can be selected from those that ensure sedimentation conditions. For example, aqueous solutions containing up to 30% by weight of organic solvents, such as, for example, ethanol, isopropanol and dioxane, are suitable dissolution media. Thirdly, the rate of "release of hormones from the two types is determined. of layers containing drug as follows: - calculate the amount of hormone released per unit area of each of the drug-containing layers from the dissolution data mentioned above and the specific area of the drug-containing layer. - determine the constant of the release rate for each drug-containing layer as the slope obtained by linear regression analysis of at least three data points on the amount of hormone per unit area versus square root weather. - graph the constant of the release rate for each of the drug-containing layers against the concentration of hormone in the drug-containing layer. Then the linear regression analysis is carried out separately for the drug-containing layers with completely dissolved hormone and for the drug-containing layers with partially dissolved hormone, that is, with the presence of solid hormone particles. The two regression lines will intersect at one point. The concentration of the hormone that can be read at the point of intersection of the two regression lines denotes the "solubility" of the hormone in the drug-containing layers. The term "drug-containing layer" means that part of the composition or transdermal system where the spheroid hormone is present. The drug-containing layer may be in semisolid or solid form and comprises the hormone formulated directly in the layer. The hormone of the invention may be dispersed, partially dispersed, partially dissolved or completely dissolved therein, depending on the concentration and physicochemical properties of the hormone. It is not necessary that the drug-containing layer should be in the form of a gel or a liquid. Intentionally, the drug-containing layer should come into direct contact with the skin or mucosa. However, in some embodiments, there is an additional layer, a so-called non-drug-containing layer, disposed between the drug-containing layer and the skin or mucosa. As said, the compositions according to the invention do not necessarily comprise a penetration enhancer through the skin. Therefore, in some embodiments of the invention, the drug-containing layer excludes the presence of a penetration rate enhancer through the skin, which means that the drug-containing layer consists essentially of ingredients that do not they include a skin penetration rate improver. This means that for example less than 2%, such as for example less than 1%, preferably less than 0.5%, such as for example less than 0.2%, such as for example less than 0.1% by weight of the layer Containing drug consists of a penetration enhancer through the skin. In accordance with the present invention, the selection of the correct drug-containing layer affects the penetration through the skin. The layer containing the correct drug is preferably made of a polymer or mixtures of polymers. The polymers may have adhesive properties or may lack perceptible adhesive properties. In some embodiments, the drug-containing layer is a layer of adhesive that is referred to as a pressure-sensitive layer. In principle, any mixture of polymers with which the solubility of gestodene is obtained therein can be applied. Therefore, in one embodiment of the invention the drug-containing layer comprises at least one polymer which may have adhesive properties or non-typically, said polymers are lipophilic polymers acceptable for biological applications of the types of a hydrocarbon polymer, a polysiloxane, a polyacrylate, or mixtures thereof. Preferably, the polymers can be selected from those polymers of hydrocarbons, polysiloxanes and / or polyacrylates that form a drug-containing layer with a solubility of gestodene therein no greater than 3% by weight of the drug-containing layer. To some extent, the amount of the polymer is a critical parameter. The correct amount may depend on the type of polymer and the spheroid hormone that is being used. In general, the amount of the polymer is at least 1% by weight of the drug-containing layer, such as at least 5%, 10%, 15% or 20%. However, preferably, 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% by weight of the drug-containing layer. In other words, the polymer can be used in an amount between about 1 and 99% by weight of the drug-containing layer, such as between about 5 and 99%, 10 and 99%, 15 and 99% or 20 and 99% . Preferably, the polymer is present in the drug-containing layer in an amount that varies within the range between about 15 and 99%, such as between about 15 and 90%, 15 and 85% or 15 and 80% , such as, for example, between about 20 and 85%, 20 and 75%, such as, for example, between about 25 and 85%, 25 and 75% by weight of the drug-containing layer. Having said this, a particular aspect of the invention has as its object a composition for transdermal administration of a spheroid hormone, such as for example a gestodene or a derivative thereof, and optionally a estrogen, wherein said composition comprises a layer containing drug comprising - at least one spheroid hormone, such as a gestodene or a derivative thereof and one or more ingredients or vehicles acceptable for pharmaceutical use; - a polymer or a mixture of polymers, preferably in an amount between about 15 and 99% by weight of the drug-containing layer, wherein the polymer is selected from the group consisting of polymers of hydrocarbons, polysiloxanes, polyacrylates and mixtures of which form a drug-containing layer with a solubility therein of said spheroidal hormone not greater than 3% by weight of the drug-containing layer. As mentioned, it has been found that adhesive layers comprising less polar types of polymers, such as hydrocarbon polymers, have been shown to be superior to polar type polymers, such as polyacrylates ( example 2). Therefore, in a preferred embodiment of the invention, the drug-containing cap comprises as a polymer a hydrocarbon polymer, which preferably may include polyisobutylenes, polybutenes, polyisoprenes, polystyrenes, styrene-isoprene-styrene block polymers, styrene butadiene styrene block polymers and / or mixtures thereof. As mentioned before, in some embodiments of the invention, the drug-containing layer is adhesive. Preferably, the polymer of the drug-containing layer has appropriate adhesive properties, so that an additional tackifier, such as, for example, an adhesive is not required. Whenever it is considered necessary to improve the strength of the adhesive of the drug-containing layer, the layer may further comprise an adhesive. The term "adhesive" denotes an agent that improves the strength with which the adhesive layer adheres to the skin or mucosa. Examples of adhesives are selected from hydrocarbon resins, rosin resins and terpeN resins. Examples of commercially available hydrocarbon resins are those with the Escorez® trademarks of Exxon Mobil; Regalite®, Piccotac® and Picco® from Eastman or Indopol® from BP. Examples of rosin esters which are suitable for the transdermal systems according to the present invention include hydrogenated wood rosin esters for example hydrogenated wood rosin ester with pentaerythritol, partially hydrogenated wood rosin esters eg esters of partially hydrogenated wood rosin with pentaerythritol, wood rosin esters, modified wood rosin esters, partially dimerized rosin esters, resin oil rosin esters, dimerized rosin esters, and similar rosins, and combinations and blends thereof. Such rosin esters can be obtained commercially under the trademarks Fo-ral®, Foralyn®, Pentalyn®, Permalyn® and Staybelite®. In a preferred embodiment of the invention, the drug-containing layer comprises an adhesive in the form of a rosin ester such as, for example, pentaerythritol ester. It is generally considered that the adhesive can be present in any suitable amount as long as the above critical solubility of the spheroid hormone in the drug-containing layer is not noticeably affected. Therefore, an adhesive may be present in the drug-containing layer in an amount between about 0.1 and 95%, such as 0.5% and 95%, such as 1% and 95% by weight, for example. of the drug-containing layer. That is, the adhesive can be present in an amount between about 1% and 85%, 1 and 75%, 1 and 65%, 1 and 55%, 1 and 50%, 1 and 45%, 1 and 40% or more preferably between about 1 and 35%, for example preferably between 1 and 30%, more preferably between 1 and 25%. Obviously, the amount of adhesive in the drug-containing layer can be critical to the solubility of the spheroid hormone in the drug-containing layer. Therefore, in still other embodiments of the invention, the adhesive is present in the drug-containing layer in an amount of up to 35%, such as up to 30%. More preferably, the amount of adhesive is up to 25%, such as up to 20% or 15%, more preferably up to 10%, 7%, 5% by weight of the drug-containing layer. It follows that another particular aspect of the invention relates to a composition for transdermal administration of gestodene or an ester thereof, and optionally an estrogen, wherein said composition comprises a drug-containing layer consisting essentially of: - at least one hormone spheroid, such as a gestodene, and one or more ingredient (s) and / or carrier (s) acceptable for pharmaceutical use; - a polymer or a mixture of polymers, preferably in an amount between about 15 and 99% by weight of the drug-containing layer, wherein the polymer is preferably selected from the group consisting of polymers of hydrocarbons, polysiloxanes, polyacrylates and mixtures of them, more preferably polymers of hydrocarbons (polyisobutylenes, polybutenes, polyisoprenes, polystyrenes, styrene-isoprene-styrene block polymers, styrene-butadiene-styrene block polymers and / or mixtures thereof). As mentioned, gestodene has a solubility in the drug-containing layer as mentioned above; and - an adhesive in an amount of up to 85% by weight of the drug-containing layer; and - optionally an estrogen. According to what was said, the drug-containing layer must be composed of ingredients that form a layer where the solubility criterion of gestodene is satisfied therein. Preferably, said criterion is satisfied when the drug-containing layer is composed mainly of the hormones of the invention together with a polymer or a mixture of polymers and optionally an adhesive. In some embodiments, it has been found that an appropriate polymer of the invention is lipophilic and essentially free of the presence of free hydrophilic groups. Therefore, any suitable hydrocarbon, polysiloxane or polyacrylate polymer is selected from those polymers with a limited amount of functional groups in the side chains, such as, for example, free hydrophilic functional groups, such as, for example, carboxylic- , ester-, hydroxy-, amino-, amide-, halogen- or sulfo-. Therefore, in some embodiments, the polymer essentially excludes polyacrylates, some of which comprise free carboxylic and / or hydroxyl groups. In preferred embodiments, the polymer is a hydrocarbon polymer, a polysiloxane or a mixture of the two types of polymers. As mentioned, polymers of the hydrocarbon type are polymers of the non-polar type essentially free of free hydrophilic functional groups, such as, for example, carboxylic-, ester-, hydroxy-, amino-, amide-, halogeno- or sulfo- groups in the chains lateral Therefore, in a more preferred embodiment, the polymer is a hydrocarbon polymer. There is a plethora of hydrocarbon polymers of both high molecular weight and low molecular weight or mixtures thereof. Typically, the hydrocarbon polymers are in the form of polyisobutylenes, polybutenes, polyisoprenes, polystyrenes, styrene-isoprene-styrene block polymers, styrene-butadiene-styrene block polymers or mixtures thereof. The molecular weight of the high molecular weight polymers (at least with respect to polyisobutylene-no) is usually within the range between 500,000 and 2,000,000 Da, while those of low molecular weight are within the range between about 20,000 and 10,000. .OOODa. Typically, said polymers comprise a mixture of high molecular weight polymers and low molecular weight polymers wherein the amount of the low molecular weight polyisobutylene in the total mixture is at least 50%. In preferred embodiments, the hydrocarbon polymer is a polyisobutylene, polybutene, polyisoprene, more preferably polyisobutylene. In some embodiments of the invention the polymer excludes isoprene copolymers. The polysiloxanes are typically high molecular weight polydimethylsiloxanes with free silanol groups or silanol end groups (Bio-PSA®). Typical examples of polyacrylates, which as mentioned above may be excluded or used in minimal amounts in some embodiments, include polymers that are selected from acrylic ester homopolymers, copolymers of two or more types of acrylic ester units or ester copolymers acrylics or other functional monomers. Acrylic esters include, but not limited to, butyl methacrylate, pentyl methacrylate, hexyl methacrylate, heptyl methacrylate, octyl methacrylate, nonyl methacrylate, decyl methacrylate. For example, ethylene / ethylacrylate copolymer, polymethacrylate polymers and polysiloxane-polymethacrylate copolymers. As mentioned, functional monomers containing a hydrophilic functional group can be excluded as suitable polymers, such as for example hydroxyethyl methacrylate, hydroxypropyl methacrylate, etc. and monomers containing an amide group such as methacrylate, dimethyl methacrylamide. Moreover, due to the same reason, polymers such as polyalkylenes (polyethylene, polypropylene, ethylene / propylene copolymers, chlorinated polyethylene, polytetrafluoroethylene), polyacetates (ethylene / vinyl acetate copolymers, vinyl chloride-acetate copolymers) vinyl), polyvinylidenes (polyvinylidene chloride, ethylene-vinyl alcohol copolymer, ethylene-vinyloxy-ethanol copolymer, polyvinyl pyrrolidone) polycarbonates, cellulose polymers (methyl or ethyl cellulose derivatives, hydroxypropyl methyl cellulose and cellulose esters) may not be suitable polymers according to the invention and should be excluded or at least should be used in a restricted amount in some embodiments of the invention. However, said exclusion does not prevent the use of said polymers in other layers or parts of the composition. Furthermore, in some embodiments, the drug-containing layer does not comprise a hydrophilic polymer, such as crystallization inhibitors such as polyvinyl pyrrolidone, cellulose polymers, such as, for example, methyl or ethylcellulose derivatives or hydroxypropyl methylcellulose, or mixtures thereof. same; or at least comprises only a restricted amount thereof. In addition, in some embodiments there is no solubilizer, such as dimethyl isosorbide, present in the drug-containing layer or at least only in a restricted amount. The term "restricted amount" means that the polymer or solubilizer in question is present in a concentration in the drug-containing layer of less than 10%, such as, for example, less than 8.5, 3, 2, 1, 0. , 5 or 0.2% by weight of the layer. As mentioned, it has been possible to provide sufficient penetration of a spheroid hormone through the skin without incorporating a penetration enhancer through the skin and / or permeation enhancer. That is, in interesting embodiments of the invention, a penetration enhancer through the skin and / or permeation enhancer of the drug-containing layer is excluded or is present in the drug-containing layer in a restricted amount, where said amount is less than 5%, such as, for example, less than 4%, 3%, 2%, 1%, 0.5%, or 0.2% by weight of the drug-containing layer. In the present invention, the meaning of the terms "penetration enhancers through the skin" and "permeation enhancers" is interchangeable and denotes compounds, which provide an enhanced penetration / permeation through the skin for active drugs. when it is administered together with the drugs on the skin of a user. Penetration / permeation enhancers in transdermal formulations will change the thermodynamic activity of the drug in the drug-containing layer, and in that way will produce a positive or negative "driving" effect. Furthermore, it is conceivable that some penetration / permeation enhancers can penetrate into the highly ordered structure of the intercellular lipids of the stratum corneum and reduce their resistance by increasing the mobility of the lipid acyl chain, thereby providing a "driving" effect . Any penetration / permeation enhancing effect through the skin of a substance can be recognized by testing identical formulations with and without penetration enhancer, e.g. using athymic mouse skin or similar. The experienced person knows such test methods. Typical penetration / permeation enhancers are included in the group of compounds listed below: Alcohols, such as for example monohydric alcohols with between about 2 and 10 carbon atoms, such as p. ex. ethyl, isopropyl, butyl, pentyl, octanyl, decanyl and / or benzyl alcohols; dihydric alcohols such as, for example, 1,2-propanediol, polyhydric alcohols such as, for example, glycerin, sorbitol and / or polyethylene glycol; saturated and unsaturated fatty alcohols with 8-18 carbon atoms, such as, for example, caprylic, decyl, lauryl, 2-lauryl, myristyl, cetyl, stearyl, oleyl, linoyl and linolenyl alcohol. - Fatty acids, such as for example saturated or unsaturated fatty acids which can 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, capric acid, caprylic acid, pelargonic acid, goat acid, isovaleric acid, neopenthane acid, neoheptanic acid and / or isostearin. - Esters such as for example aliphatic esters ethyl acetate, lower alkyl ester (Cl-C4) lactic acid, fatty acid esters of the general formula CH3- (CH2) n-COOR, where n is a number between 8 and 18 and R is an alkyl residue having a maximum of 6 carbon atoms, such as, for example, fatty acid esters, for example, those of lauric acid, myristic acid, stearic acid and palmitic acid, for example, methyl estersethyl esters, propyl esters, isopropyl esters, butyl esters, sec-butyl esters, isobutyl esters of said acids, or diesters of dicarboxylic acid of the general formula R'OCO (CH2) m COORA where m is a number of 4 and 8 and R 'in each case means an alkyl residue having a maximum of 6 carbon atoms, such as, for example, propyl oleate, decyl oleate, isopropyl palmitate, glycol palmitate, glycol laurate, dodecyl myristate, myristates of isopropyl and glycol stearate, the diesters of suitable dicarboxylic acid are, for example, diisopropyl adipate, diisobutyl adipate and diisopropyl sebacate. - Ethers, such as, for example, 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 for example alkanes with chain lengths of between 6 and 17 carbon atoms. Amides, such as, for example, dimethyl acetamide, dimethyl formamide, dimethyl lauramide, dimethyl laurylamide and / or fatty acid amides and their derivatives. Amides, such as, for example, amides with long aliphatic chains, or aromatic amides, urea and urea derivatives, for example. cyclic urea, dodecyl-urea, diphenyl-urea and / or allantoin.

- Amino acids . - Aminoacetates, such as, for example, derivatives of aminoacetates, such as, for example, dodecyl N, N-dimethylaminoacetate and 2- methyl-2- (N, N-methylaminoacetate) of dodecyl, decyl 2- (N, N-dimethylamino) propionate , Decyl 2- (N, N-dimethylamino) butyrate, octyl 2- (N, N-dimethylamino) propionate, and / or dodecyl N, N-dimethylaminophenylacetate. - Azone derivatives, such as, for example, 1-dodecyl-azacycloheptane-2-one derivatives, azacycloalkanone derivatives and / or hexamethylenelauramide derivatives. - Cyclodextrins such as alpha, beta, and gamma cyclodextrins. - Glycerides, such as for example monoglycerides, which include glycerol monooleate, glycerol monolaurate and glycerol monolindoleate, polyethylene glycol 3-lauramide (PEG LR), polyethylene glycol monolaurate (PGML), glycerol monooleate (GMO), monolinoleate glycerol and / or glycerol monolaurate (GML). - Glycols such as for example ethylene glycol, diethylene glycol, or propylene glycol, dipropylene glycol and / or trimethylene glycol.

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

- Polyols such as propylene glycol. - Pyrrolidones, such as, for example, 2-pyrrolidone, N-methyl-2-pyrrolidone, dodecylpyrrolidone, 2-pyrrolidone-5-carboxylic acid, N-hexyl-, N-lauryl-, 4-carboxy-, 4- derivatives. carboxy-carbon, 3-hydroxy-N-methyl-2-pyrrolidone, N-farnesyl-2-pyrrolidone, N- (2- (decylthio) ethyl) -2-pyrrolidone and / or N- (2-hydroxyethyl) -2-pyrrolidone. Sulfoxides, such as, for example, sulphoxide derivatives, such as methyloctyl sulfoxide, dimethyl sulfoxide (DMSO), hexylmethylsulphoxide (hexyl-MSO) and / or decylmethylsulfoxide (decyl-MSO). Surfactants, such as, for example, cationic surfactants such as cetyltrimethylammonium bromide, octadecyltrimethylammonium chloride, cetylpyridinium chloride and / or equivalent cationic compounds, anionic surfactants such as, for example, sulfate salts, including but not limited to compounds such as lauryl. sodium sulfate and / or sodium dodecyl sulfate, and nonionic surfactants such as for example sorbitol esters and sorbitol anhydride which include but are not limited to polysorbate, sorbitan monopalmitate and / or sorbitan polyoleate. - Terpenes, ketones and oxides. In addition to the spheroid hormone, such as a progestin, said one or more polymers, said one or more adhesives and the optional estrogen, the drug-containing layer or other parts of the composition also contain stabilizers, dyes, pigments, fillers inerts, anti-aging agents, antioxidants, elastomers, thermoplastics and other conventional components of the transdermal compositions that are known in the art. Preferably, the composition, or at least the drug-containing layer, does not comprise or comprise only a restricted amount (less than 1%, 0.8%, 0.5%, 0.2% or 0.1% by weight of the drug-containing layer) polyvinylpyrrolidone, methylcellulose, ethylcellulose, hydroxypropyl methylcellulose, and / or dimethyl-isosorbide. It should be understood that the compositions of the invention are transparent or at least in interesting embodiments are very transparent, which means that the skin can be visually inspected through the drug delivery system. That is, the drug-containing layer is a monophasic system where the drug (here progestin) is completely dissolved in the drug-containing layer. The property by which a single phase system can be identified by mechanical stretching of the drug containing layer using a test method is described below. The drug-containing layer is also characterized as being homogeneous. The term "homogeneous" is used to describe a single-phase system, where the matrix is composed of a polymer phase. These systems can be distinguished from multiphase systems, which are composed of at least two polymer phases. In most cases multiphase systems can be detected visually by their opaque appearance. The opaque appearance is caused by the diffraction of the light due to differences in the diffraction indices of the polymer phases. Other methods to detect single-phase systems are microscopic or rheological methods or by mechanical stretching of thin polymer films. During mechanical stretching, thin polymer films composed of multiphase systems become opaque, as can be visually determined. Therefore, in summary, it should be understood that the interesting embodiments of the invention include: a drug-containing layer comprising: i) a progestin such as gestodene or an ester thereof; and ii) a polymer selected from the group consisting of polyisobutylenes, polybutenes, polyisoprenes, polystyrenes, styrene-isoprene-styrene block polymers, styrene-butadiene-styrene block polymers and mixtures thereof. In other interesting embodiments of the invention the drug-containing layer is characterized by the following parameters, and may be present as a single parameter or as a combination of parameters; • The gestodene has a solubility in the drug-containing layer that is not more than 3% by weight of the drug-containing layer; • The drug-containing layer excludes dimethylisosorbide or contains an amount of dimethylisosorbide less than 0.5% by weight of the layer; • The drug-containing layer excludes polyvinylpyrrolidone, methylcellulose, ethylcellulose and / or hydroxypropylcellulose or contains less than 2% by weight of the layer of polyvinylpyrrolidone, methylcellulose, ethylcellulose and / or hydroxypropylcellulose; • The drug-containing layer contains the progestin (Gestodene or an ester thereof) completely dissolved in the layer; • The layer that. The drug comprises the gestodene or an ester thereof in an amount of 0.5-3% by weight of the drug-containing layer; • The drug-containing layer is transparent; • The drug-containing layer is homogeneous; • The drug-containing layer is monophasic; • The drug-containing layer excludes a penetration enhancer through the skin or contains less than 2% by weight of the layer; • The drug-containing layer comprises said polymer in an amount between about 15 and 99% by weight of the layer; • The drug-containing layer comprises an adhesive, such as an ester of rosin, in an amount of up to 85% by weight of the drug-containing layer; As mentioned above, the compositions of the invention are characterized by providing an amount of a spheroid hormone, such as for example a progestin, such as for example a gestodene, which is effective as a contraceptive, optionally in combination with an estrogen. In the embodiment, where the progestin is gestodene or a derivative thereof the composition can be characterized in that it provides an in vitro permeation rate in the athymic mouse skin of gestodene and / or a derivative thereof of at least 25μg / cm2 * 24h In other words, the composition can be characterized by having a drug-containing layer that provides gestodene and / or a derivative thereof in an amount between about 40 and 70 μg per day. In the composition of the invention can be used as a drug not only gestodene or a derivative thereof. Other progestins may be included in the drug-containing layer together with gestodene or in place of gestodene, such as dienogest, drospirenone, levonorgestrel, cyproterone acetate, tetrahydrodienogest, norethisterone, norethisterone acetate, desogestrel, 3-keto-desorgestrel, norgestimate. -to, linestrenol, medroxy-progesterone acetate, norgestrel, norethisterone enanthate, trimegestone, or alpha- and beta-progesterone receptor ligands. As mentioned, the composition is effective to inhibit ovulation. In some cases, the composition also comprises an estrogen. Estrogen can be incorporated along with the progestin in the same drug-containing layer or can be incorporated into another separate layer containing drug that is progestin-free. The term "estrogen" includes both natural 17β-estradiol and semisynthetic derivatives of estrogen, such as, for example, natural estrogen esters and 17-alkylated estrogens. Natural semisynthetic esters of estrogen include, for example, 17β-estradiol enanthate, 17β-estradiol estradiol, 17β-estradiol benzoate, 17β-estradiol undecanoate, 16-estradiol, 17-hemisuccinate or 17β-estradiol cipronate. Examples of 17-alkylated estrogens are ethinylestradiol, ethynylestradiol 3-isopropylsulfonate, qui-nestrol, mestranol or methylestradiol. The term "estrogen" can also include a non-spheroidal compound with estrogenic activity, such as, for example, diethylstilbestrol, die-nestrol, clomiphene, chlorotrianesene or cyclophenyl. In a preferred embodiment, the estrogen is ethinylestradiol. The actual concentration of the drug in the drug-containing layer can be adjusted to achieve an effective amount of blood hormone for therapeutic use. Talking in general, the drug-containing layer should contain some excess hormone with respect to the amount of hormone that must be absorbed to get the effective amount for the therapeutic use of the hormone. Normally, said excess is small, as for example the amount of hormone is less than 10 times the amount of hormone that is desired / required, preferably less than 5 times, as for example less than 2 times. For example, it is also considered important to limit the amount of hormone in such a way as to reduce the total exposure of the user to the hormone. Appropriate concentrations of a spheroid hormone, such as a progestin, such as gestodene or a derivative thereof, in the drug-containing layer are between about 0.5 and 10% by weight of the drug-containing layer. . In embodiments that are even more preferred, the concentration of said hormone is between about 0.5 and 10%, such as between about 0.75 and 5%. As mentioned, the total hormone concentration, such as eg gestodene, can result in drug-containing layers comprising the hormone at saturation or subsaturation levels. In a very interesting embodiment, the concentration of a spheroid hormone, such as eg gestodene or a derivative thereof, in the drug-containing layer is between about 1 and 3%, as p. ex. between 1 and 2%.

In the same way, in some embodiments of the invention also comprising an estrogen, estrogen is present in the drug-containing layer in an amount between about 0.5 and 10% by weight of the adhesive layer, preferably between about 0.75 and 5%, more preferably between about 1 and 3%, as p. ex. between 1 and 2%. Moreover, said progestin, such as gestodene or a derivative thereof, is in a mass ratio to di-cha estrogen in the range between about 4 and 0.5, preferably between 2 and 0.5, such as 1: 1. . Surprisingly, it has been found that relatively high levels of gestodene plasma can be maintained for a prolonged period of time by administering gestodene or a derivative thereof formulated in a composition of the invention. Furthermore, surprisingly, it has been discovered that the plasma profile and the plasma levels of gestodene, such as those obtained by the administration of gestodene or a derivative thereof and optionally an estrogen, are effective in inhibiting ovulation in a woman . Therefore, there are additional aspects of the invention that relate to the use of a composition of the invention, optionally in combination with an estrogen, to inhibit ovulation in a female subject, such as a female. When the drug is administered alone, a plasma gestodene concentration curve is achieved over time which is characterized by levels of gestodene plasma concentration of at least 1.0ng / ml, as determined under steady-state conditions. As follows, one aspect of the invention relates to a method of inhibiting ovulation in a female subject, such as a female, which comprises topically administering to the skin or mucosa an effective amount of gestodene or a derivative thereof, optionally in combination with an estrogen, such that by said single administration of gestodene, a plasma gestodene concentration curve is achieved with respect to time which is characterized by concentration levels in gestodene plasma of minus l, 0ng / ml, as determined under steady-state conditions. Alternatively, the uses and methods of the invention are for the treatment of other symptoms, disorders or symptoms that are normally treated by administering a progestin, such as gestodene or a derivative thereof or a combination of a progestin and an estrogen. Therefore, in general it should be understood that in some embodiments of the invention, the uses and methods are for the treatment of endometriosis, premenstrual syndrome, climacteric disorders, regulating the menstrual cycle and / or for stabilizing and menstrual cycle. For example, administering a progestin without concurrent therapy with an estrogen can treat irregular bleeding and abnormal bleeding. As used herein, the term "irregular bleeding" characterizes any bleeding from the uterus, outside the normal monthly menstrual periods of non-pregnant women. Bleeding from the uterus is irregular if menstrual cycles or menstrual periods are too short, too long, too frequent, too infrequent, or occur at irregular intervals outside the normal menstrual cycle of 26-30 days. The menstrual period is classified as too long when it is delayed between 15 and 50 days or more of the expected beginning of such bleeding. The term "abnormal bleeding" characterizes an abundant bleeding that typically soaks up through the products of intimate hygiene until it requires changing them more than every one or two hours, during a period that lasts more than seven days. Abnormal bleeding does not include bleeding in women who have already reached menopause, abnormal bleeding from the uterus due to side effects of estrogen replacement therapy, abnormal bleeding as a symptom of uterine cancer, as a result of a normal abnormal blood clotting, an inherited bleeding disorder, or due to a medical condition that affects blood platelet levels.

In other embodiments, the progestin is administered in combination with an estrogen, for example by administering a medicament of the invention comprising the combination of a progestin, such as gestodene or a derivative thereof, and an estrogen for the treatment of climacteric disorders, such as symptoms and discomforts associated with menopause, such as flushing, sweating, palpitations, sleep disturbances, changes in mood, nerves, anxiety, lack of memory , loss of confidence, loss of libido, poor concentration, decreased energy, decreased impulses, irritability, urogenital atrophy, atrophy of the breast, cardiovascular disease, changes in hair distribution, hair thickness, changes in hair condition of the skin and / or osteoporosis. Fundamentally, the treatment is aimed at hot flashes, sweat attacks, palpitations, sleep disorders, changes in mood, nerves, anxiety, urogenital atrophy, atrophy of the breast or for the prevention or management of osteoporosis. In connection with the treatment of climacteric disorders, estrogen can be selected from natural estrogens, such as estradiol and esters thereof, such as, for example, estradiol valerate, estradiol benzoate. In addition, natural estrogens include estrone, estriol, estriol succinate and conjugated estrogens, including conjugated equine estrogens such as, for example, estrone sulfate, 17β-estradiol sulfate, 17α-estradiol sulfate, equilin sulfate, 17β-dihydroequiline sulfate. , 17-dihydroequilin sulfate, equilenin sulfate, 17β-dihydroequilenin sulfate and 17a-dihydroequilenin sulfate or mixtures thereof. In some embodiments of the invention, the plasma gestodene concentration curve with respect to time under steady-state conditions is characterized by levels of gestodene plasma concentration of at least 1.5ng / ml, e.g. eg at least 2.0ng / ml or at least 2.5ng / ml. In other interesting embodiments, the plasma gestodene concentration curve with respect to time under steady state conditions is characterized by levels of gestodene plasma within the range between 1 and 8ng / ml, preferably within the range of 1 , 5 to 6ng / ml after the first 6 days after a single administration of a gestodene composition or a derivative thereof, preferably in the form of a composition of the invention. In still further embodiments, the plasma gestodene concentration curve with respect to time under steady-state conditions is characterized by maximal plasma levels of gestodene for a period of between 18 and 60 hours after a single administration of the drug and / or by plasma levels of gestodene under steady state conditions in the period of 5 and 7 days after a single administration of the drug in the order of at least 50% of the maximum plasma levels of gestodene obtained during the first 18 to 60 hours after administration. The gestodene is preferably administered repeatedly in cycles of 28 days such that within each 28-day cycle, the gestodene / composition is administered at a 7-day interval for a period of 21 days (3 weeks) followed of a period without administration of gestodeno or a derivative thereof for 7 days (one week). That is, the gesture / composition is administered on days 1, 8 and 15 within each cycle of 28 days. Preferably, said day 1 may be the day of the beginning of menstruation, or any other appropriate day, such as the first, second, third, fourth, fifth or sixth day following the day of the beginning of menstruation. In another embodiment, the gestodene, optionally in combination with an estrogen, is administered repeatedly in cycles of 12 weeks such that within each 12-day cycle, the gestodene / composition is administered at a 7-day interval during a continuous period of 11 weeks followed by a period without administration of gestodene or a derivative thereof for 7 days (one week).

To improve the effectiveness and safety of the contraceptive, an estrogen can be administered concomitantly with gestodene. Estrogen can be selected from the estrogens mentioned above. As can be understood, the uses and methods of the invention include the application of gestodene or a derivative thereof, which may be in the form of a composition as defined herein. Therefore, the term "medicament" includes a composition as defined herein. In addition, the term "medicament" includes a set of elements of the invention. In a still further aspect, the invention relates to a set of elements comprising between 1 and 11 dosage units for a treatment period of 12 weeks formulated in a transdermal administration form of a progestin, such as for example gestodene or a derivative thereof, wherein said dosage units comprise a drug-containing layer comprising gestodene and one or more excipients or vehicles acceptable for pharmaceutical use and the drug-containing layer has a solubility with respect to said gestodene which is not greater than 3%. % by weight of the drug-containing layer. The dosage unit may comprise a composition as described herein. It should be understood that in one embodiment thereof, 11 dosage units are administered continuously once a week for a period of 11 weeks followed by one week without administration of any dosage unit or placebo administration. In other embodiments, the set of elements serves for a treatment period of 12 weeks, but the set of elements comprises between 1 and 9 dosage units. In one embodiment, 3 dosage units are administered weekly during a period of 3 weeks, followed by one week without administration of any dosage unit or placebo administration. That is to say that the set of elements serves for a treatment period of 4 weeks and the set of elements comprises 1-3 dosage units. The dose of the progestin, such as, for example, gestodene or a derivative thereof in each dosage unit corresponds to a dose selected from a dose for 6 days, a dose for 7 days, a dose for 8 days, a dose for 14 days or a dose for 21 days. In one embodiment thereof, each dosage unit comprises gestodene or a derivative thereof in a dose between about 0.5 and 5 mg, preferably between 1 and 3 mg, more preferably 1.5 and 2.5 mg. It should be further understood that the set of elements may further comprise an estrogen as mentioned above. The estrogen may be combined together with the progestin, such as gestodene or a derivative thereof, in the same dosage unit or may be provided in separate dosage units. For example, the set of elements may further comprise between 1 and 30 dosage units comprising an estrogen and no gestodene. The estrogen may be in a dosage form formulated for transdermal administration, vaginal administration or the like. Alternatively, the estrogen may be in the form of dosage units formulated for the peroral administration of an estrogen, such as, for example, in the form of a tablet, pill, capsule, powder, paste or granules. The compositions of the invention can be manufactured using methods known in the art. Here is an example. Figures Figure 1. Mean serum levels of gestodene (GSD) during two treatment cycles, week 1 and week 3, respectively. The legends are the following: cycle 1, week 1 cycle 2, week 1 cycle 1, week 3? cycle 2, week 3 Examples Example 1 Manufacture of a patch A composition of the invention was prepared as follows. In a first step, 380 g of gestodene, and optionally 180 g of ethinyl estradiol, were dissolved in a suitable solvent, such as, for example, 16.8 kg of dioxane. In a second step, approximately 57 kg of a mixture of polyisobutylene and rosin ester in heptane (Arcare® MA 24A) were weighed. The first step hormone solution was transferred with agitation to the polymer solution and stirring was continued until a homogeneous solution was achieved. The solution containing the drug obtained in this way was used to coat a protective sheet (such as, for example, FL 2000 75μm PET 1S; Fa Loparex) and dried under appropriate conditions. The dried drug-containing layer was then laminated with a backing sheet / layer, such as, for example, Cotran®, 9720, 3M. The laminate obtained in this way was divided into patches with a size of 10cm2 and the patches that were obtained had the following composition: Gestodeno: l, 9mg Optional ethinylestradiol: 0.9mg Polymer 97.2mg (in the form of polyisobutylene in combination with an adhesive, for example MA-24A®) Protective film: 10cm2 Support layer: 10cm2 In another example, the patch obtained was similar to that mentioned above but the amount of ethinylestradiol was 0.6mg. In yet another example, the patch obtained was similar to that mentioned above but the adhesive was Durotak®, 10711, which is composed of a hydrocarbon polymer. EXAMPLE 2 Penetration rates through the skin of compositions with different polymers. Six compositions (A-F) were made with acrylate-vinyl acetate polymers as the polymer of the drug-containing layer. In addition, composition G was made using polyisobutylene as the polymer in the drug-containing layer. The manufacture was carried out according to the process described in Example 1. None of the compositions comprised a penetration enhancer through the skin. Each of the compositions was tested in the in vitro permeation assay in mouse skin. The assay was carried out using athymic mouse skin preparations (HsdCpb: NMRI-nu) obtainable from Harian Bioservice for Science GmbH, Walsrode, Germany. The test formulation was adhered to the outside of a skin sample. Both were placed inside the permeation cell with the interior in contact with the receiving medium. A pH buffering solution of HEPES was used as the receiving medium. Sodium azide was added to prevent microbial growth. The receptor solution was maintained at 32 ° C. Samples of the receptor solution were taken at defined time intervals and the concentration of gestodene (GSD) and ethinylestradiol (EE) in the recipient medium was analyzed by HPLC. Then the flow rate was calculated as the amount of drug released per area and unit of time [μg / cm2 * 24h] using the calculated amounts of active substances. In vitro results of the penetration rate through the skin: Table 1 The results indicate that the permeation rate of gestodene as well as that of ethinylestradiol from composition G (polyisobutylene) were higher than the same from compositions A-F. Example 3 Contraceptive effect and pharmacokinetic profile The effect on ovulation inhibition, serum drug concentrations and the safety of a patch of the invention in a population of selected women were investigated. The design of the study was based on the requirements of the EMEA guidelines for clinical studies with steroid contraceptives (Commitee for Proprietary Medical Products, CPMP / EWP 519/98). Study design The study had three phases; a pretreatment phase that included two cycles of purification and an additional cycle to ensure that the women who were selected were ovulatory. Finally, the second phase was a phase of treatment of two cycles, which was followed by a third phase that consisted of a post-treatment phase of a cycle. Women who were enrolled in the study were required to be healthy, non-pregnant, non-smoking, non-breastfeeding female volunteers, ages 18 to 35, with a normal body mass index of 18-26 kg / m2 and a normal menstrual cycle length such as, for example, 28 days ± 4 days. Only white-skinned women were included, so that application sites could be easily and uniformly evaluated. The test patch was a patch comprising a drug-containing layer with 0.9 mg of ethinylestradiol and 1.0 mg of gestodene and Arcare MA-24A®, the drug-containing layer having a size of 10 cm2. The Arcare MA-24A® is a polyisobutylene-based adhesive from Adhesive Research. During the study, blood was drawn for the determination of endogenous hormones, such as estradiol, progesterone, follicle-stimulating hormone, protein that binds to the sex hormone, ethinylestradiol, gestodene. Transvaginal ultrasound examinations were carried out to evaluate the development of ovarian structures similar to follicles. The adherence of the patch, the skin reactions at the application site and the general state of health of the woman were evaluated. Vaginal bleeding was also evaluated. During the pretreatment cycle, normal and spontaneous ovulation was established, estimating serum progesterone values in such a way that only women with an ovulatory pre-cycle and serum progesterone levels greater than 5nmol were admitted for the treatment phase. / l. The treatment phase includes a period of two menstrual cycles. The first treatment in the first cycle began one day after the volunteers started menstruating in that cycle by applying a patch. A total of three test patches were applied at 7-day intervals between them, such as application on days 1, 8 and 15 of the first cycle - each at different application sites - during each treatment cycle. Each patch was used for 7 days, then replaced with a new patch to complete a total of 21 days of continuous use. This was followed by an untreated interval of 7 days before beginning the next treatment period with application of a total of three patches, each applying a 7-day interval. If the patches were lost or detached by more than 40%, a new patch was applied. The patches were applied on the clean, dry skin intact and preferably without hair of the lower abdomen, below the navel, starting with the right side in the first treatment cycle, then alternating the sides. Determination of pharmacodynamic variables The primary pharmacodynamic variable is the proportion of women with their ovulation inhibited. According to the so-called Hoogland method, ovulation requires a follicular growth greater than 13mm and the subsequent rupture of the ovary, plus a concentration of progesterone in serum >; 5nmol / l that coincides with the rupture of the follicle. As follows, it is said that ovulation is inhibited when the follicle is less than 13mm and the concentration of progesterone in serum is less than 5nmol / l at the time of the follicle rupture. Determination of pharmacokinetic variables Pharmacokinetic parameters were for example the area under the drug concentration curve over time during the period during which the AUC patch (0-i68h), Cmax, tmax, and the accumulation factors within each cycle, such as those determined by the AUC (o-i68n of the 3rd patch / AUC (o-ißßh) of the 1st patch within cycle 1 or 2, or accumulation factors between two cycles, such as example the AÜC (0-i68h) of the 3rd patch in cycle 2 / AUC (o-i68h) of the 3rd patch in cycle 1. The AUC were calculated according to the linear trapezoidal rule, the serum concentrations of estrogen and progestin, including ethinylestradiol and gestodene, throughout the study to evaluate the pharmacokinetic characteristics of the patch. The sampling points were on day 18 of the last pretreatment cycle and on days 1, 2, 3, 4, 5, 6, 7, 8, 15, 16, 17, 18, 19, 20, 21 and 22 of cycle 1 thus co or on days 1 (before applying the new patch), 2, 3, 4, 5, 6, 7, 8, 15, 16, 17, 18, 19, 20, 21 and 22 of cycle 2.

Ethinylestradiol and gestodene concentrations were determined using conventional methods known in the art. Specifically, the concentration of ethinylestradiol was determined by gas chromatography using mass spectrometry in the chemical ionization mode as a detection method after the extraction of ethinylestradiol from acidified serum and consecutive derivatization. The concentrations of gestodene were determined by radioimmunoassay using a rabbit antiserum and gestodene labeled with 3H. After incubation and centrifugation, the precipitate obtained was redissolved with NaOH. The assay has a lower detection limit of approximately 250pg / ml. Results The primary pharmacodynamic variable was the proportion of women with inhibition of ovulation. The activity of the ovaries was effectively suppressed, that is; Without activity of the ovaries: cycle 1: 78%, cycle 2: 56%. Potential activity: cycle 1: 15%, cycle 2: 22%. FLS not active: cycle 1: 4%, cycle 2: no; Active FLS: cycle 1: 4%, cycle 2: 22% Throughout the study there were no cases of ovulation. Inhibition of ovulation, defined as a Hoo-gland score below 6 (ovulation), was sufficient for all volunteers in the data set per protocol throughout the study. The progesterone concentrations were suitably suppressed to less than 2.5nmol / l in each of the treatment cycles. Mean blood estradiol levels were less than 20pg / ml every day when a patch was applied. Pharmacokinetic results In all samples prior to dosing, serum concentrations of ethinylestradiol (EE) and gestodene (GSD) were lower than the limit of detection (LOQ: lOpg / ml for EE, 250pg / ml for GSD). After administering the test medication, serum concentrations of EE and GSD could be measured for at least 168 hours in all subjects. See the results in tables 2 and 3 as well as in figure 1. Table 2. Mean pharmacokinetic parameters of ethinylestradiol (EE) Cycle 1 Cycle 2 Parameter far¬ Unit Week Week Week Macokinetic Week 1 3 1 3 Cmax pg / ml 45.6 50.4 45.2 48.0 Tmax h 48 24 48 48 AUC (0-168h) ng x h / ml 5.3 6.1 5.1 5.8 Table 3. Mean pharmacokinetic parameters of gestodene (GSD) Cycle 1 Cycle 2 Parameter pharma¬ Unit Week Week Week Cook week 1 3 1 3 Cmax pg / ml 1564 3896 2219 4416 Tmax h 144 48 96 48 AUC (0-168h) ng x h / ml 194 524 302 598 Example 4 Comparison of formulation of polyisobutylene and acrylic adhesive in humans. A randomized cross-over study was conducted to determine the average daily administration of ethinylestradiol (EE) and gestodene (GSD) from three different transdermal patch formulations (A-C) in healthy postmenopausal volunteers after a single administration. Another goal was to compare the transdermal application with that of intravenous injection. The test formulations were as follows: Formulation A (Polyisobutylene) Polyisobutylene Adhesive 97,15mg MA-24A Formulation B (Polyisobutylene, 70% formulation A) Formulation C (Acrylate) The study was carried out according to the following parameters: The patches were administered by a single transdermal application with a period of use of 7 days per test. After removing the patch in each treatment trial, a week of purification was left. A dose of 60μg EE and 75μg of GSD was administered intravenously at one time. A blood sample was taken for the kinetic measurements 72 hours after the intravenous administration and for a period of 12 days after the transdermal application as described in example 3. The determination of blood levels of GSD and EE was performed according to example 3. Results: The highest concentrations of gestodene are given in the following table which indicates the difference of the polyisobutylene formulations A and B and the acrylic formulation. The figure shows the time course of the average serum levels of gestodene.

Parameter Formulation Formulation Formulation A B C Cmax [pg / ml]: 2082 1995 1277 tmax [h]: 168 144 156 AUC (0-7d): 243 257 155 [h * ng / ml] The results indicate that the drug administration of formulation C, which included a layer containing drug of an acrylate in combination with a penetration enhancer is significantly lower than the administration of the drug from formulations A and B. Example 5 Layers containing drug with 1, 9 mg of gestodene and 0 are shown. , 9mg of ethinylestradiol and composed of different polymer mixtures (A to M)

Claims

CLAIMS 1. A composition for transdermal administration comprising a drug-containing layer consisting of gestodene or an ester thereof and a vehicle selected from the group consisting of polyisobutylenes, polybutenes, polyisoprenes, polystyrenes, styrene block polymers. isoprene styrene, styrene butadiene styrene block polymers and mixtures thereof, wherein said gestodene or an ester thereof is present in an amount ranging between 0.5% and 3% by weight of the drug-containing layer and wherein the layer containing drug comprises less than 0.5% by weight of dimethylisosorbide.
2. The composition according to claim 1, wherein the drug-containing layer further comprises an adhesive which is selected from the group consisting of hydrocarbon resins, rosin resins and terpene resins.
3. The composition according to claim 2, wherein the adhesive is an ester of rosin.
4. The composition according to any of the preceding claims, wherein the gestodene (or an ester thereof) is completely dissolved in the drug-containing layer.
5. The composition according to any of the preceding claims, wherein the drug-containing layer comprises less than 2% by weight of polyvinylpyrrolidone, methylcellulose, ethylcellulose and hydroxypropylcellulose.
6. The composition according to any of the preceding claims, wherein the drug-containing layer is transparent.
The composition according to any of the preceding claims, wherein the drug-containing layer comprises less than 2% by weight of a penetration enhancer through the skin or a permeation enhancer through the skin.
8. The composition according to any of the preceding claims, further comprising an estrogen.
9. The composition according to the claim 8, where estrogen is present in the drug-containing layer in an amount ranging from 0.5% to 10% by weight of the drug-containing layer.
10. The composition according to the claim 9, where estrogen is present in the drug-containing layer in an amount ranging from 0.75% to 5% by weight of the drug-containing layer.
11. The composition according to one of claims 8 to 10, wherein the estrogen is ethinylestradiol.
12. The use of a composition as defined in any of claims 1 to 11, to inhibit ovulation in a woman.
13. A method for inhibiting ovulation in a woman comprising topical administration to the skin or mucosa of the female of a composition as defined in one of claims 1 - 11.
14. A transdermal therapeutic system consisting essentially of ) a support layer; e) at least one drug-containing layer as defined in claims 1-11; and f) optionally a separable coating or a protective layer
15. The transdermal therapeutic system according to claim 14, wherein the gestodene or an ester of the mimic is present in a dose of 1 to 3 mg.
16. The transdermal therapeutic system according to claim 15, wherein the gestodene or ester of the mimmo is present in a dose of 1.5 to 2.5 mg.
17. The transdermal therapeutic system according to one of claims 14-16 and further comprising an estrogen, wherein the mass ratio of such gestodene or an ester thereof to such an estrogen is in the range of 4 to 0.5. .
18. The transdermal therapeutic system according to one of claims 14-17, wherein the gestodene or an ester thereof is gestodene.
19. The transdermal therapeutic system according to one of claims 17 or 18, wherein the estrogen is ethinylestradiol.
20. The transdermal therapeutic system according to claim 19, which contains a dose of 1.9 mg gestodene, a dose of 0.9 mg ethinylestradiol and 97 mg., 2 mg of polyisobutylene combined with an adhesive.
The transdermal therapeutic system according to claim 19, which contains a dose of 1.9 mg of gestodene, a dose of 0.6 mg of ethinylestradiol and 97.2 mg of polyisobutylene combined with an adhesive.
22. An assembly comprising 1 to 11 dosage units, wherein the dosage unit comprises a composition as defined in claims 1-11.
23. Use of a transdermal therapeutic system as defined in one of claims 14-21 in the inhibition of ovulation in a woman.
24. A method for inhibiting ovulation in a woman comprising topical administration to the skin or mucosa of a woman of the transdermal therapeutic system as defined in one of the claims 14-21.