NO341989B1 - Transdermal administration of hormones without the need for penetration enhancers. - Google Patents

Abstract

The present invention relates to a patch comprising a low-hormone drug-containing layer, such as the gestod, and optionally an estrogen (e.g., ethinylestradiol). When administering the patch to a woman, plasma levels of at least 1.0 ng / ml of the gestode are achieved under steady-state conditions without the need for incorporation of penetration enhancers or permeation enhancers into the drug-containing layer. Satisfactory plasma levels of the hormones are also achieved over a period of at least 1 week, the patch being made usable for use in contraception in women with a principle of administering the patches once weekly.

Description

Transdermal administration of hormones without the need for penetration enhancers.

Field of the invention

The present invention relates to the field of pharmaceutical formulation techniques. The invention provides a low-dose pharmaceutical preparation for transdermal administration of at least one hormone, preferably a progestin, as a gestodene, and optionally an estrogen, to achieve plasma concentration profiles effective in preventing ovulation in a woman.

The background of the invention

Transdermal administration of estrogens and progestins to provide contraception is a known principle (Sitruk-Ware, Transdermal application of steroid hormones for contraception, J Steroid Biochem Molecul Biol, Volume 53, p 247-251). Estrogens and progestins, however, generally penetrate the skin poorly, for which reason it is common in transdermal systems to incorporate agents with enhanced skin penetrating action.

The following documents describe a number of 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 preparations with penetration enhancers for transdermal administration of the gestode and an estrogen to achieve maximum plasma levels of the gestode of approx. 0.9 ng/ml.

WO 97/397443 relates to a transdermal system containing between 30 and 60% penetration enhancers for administering an amount of an estrogen and a progestin in an amount effective for pregnancy prevention.

WO 01/37770 relates to transdermal systems containing between 10 and 60% penetration enhancers for the administration of ethinylestradiol and levonorgestrel in amounts effective for pregnancy prevention.

US 5512292 relates to preparations comprising a gestodene and an estrogen in an amount effective for pregnancy prevention, such as ethinylestradiol, together with a suitable permeation enhancer. The amount of co-administered estrogen is kept at a constant and pregnancy-preventing amount, while the co-administered amount of gestogen varies depending on the phase of the menstrual cycle.

In US 5376377, comparable studies are shown between transdermal systems with and without penetration enhancers. The investigations include an adhesive layer of ethylene vinyl arylate and the gestodene and an estrogen (ethinyl estradiol) as active ingredient. The results of the investigation show the need to incorporate penetration enhancers in the adhesive layer to achieve amounts that are effective for pregnancy prevention. Maximum plasma levels of approx. 0.8 ng/ml.

Finally, WO 90/04397 also describes examples of preparations for transdermal administration of the gestode, possibly in combination with an oestrogen, such as ethinylestradiol, where the preparation may further comprise a penetration enhancer, such as 1,2-propanediol or isopropyl myristate. A number of different polymers are mentioned as adhesive layers. Examples of polar polymers (polyacrylates and silicones) in combination with a penetration enhancer are specifically described. The resulting plasma levels of the gestode at steady-state conditions were approx. 250 to 337 pg/ml.

In addition to penetration enhancers, it has also been proposed to add solubilizers or the like to the drug-containing layer to increase the amount of dissolved drug or to add agents that prevent crystallization of the drug in the layer.

In US 6521250, for example, an adhesive layer is described which comprises a mixture of styrene isoprene block copolymer and a hydrogenated resin acid or derivatives thereof, the amount of resin being 55-92%. Such an adhesive layer seems suitable for transdermal administration of estradiol in combination with a progestin, in that such systems have a correct adhesive contact with the skin during long-term use and prevent crystallization of the hormones.

US 5904931 relates to TTS systems which in the drug-containing layer comprise a steroid (such as gestodene) and dimethylisosorbide. The latter promotes the solubility of the steroid in the drug-containing layer. The concentration of the gestode in the drug-containing layer can vary from 1-40 percent by weight of the layer, and the drug-containing layer can consist of adhesives such as polyacrylates, silicones, styrene-butadiene copolymers and polyisobutylenes. Particularly polar polymers such as polyacrylates are suitable.

DE 19906152 relates to a transdermal drug administration system where the gestode is encapsulated in a polar polymer, such as polyvinylpyrrolidone, methylcellulose, ethylcellulose and hydroxypropylcellulose, before being added to an adhesive polymer, such as polyisobutylene. Thus, this transdermal drug administration system is a two-phase system, and the drug-containing layer is not transparent due to the content of the polar polymers, which on exposure to water will result in the presence 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 the addition of a resin ester to an adhesive layer in an amount of up to 25% by weight can sufficiently counteract crystal formation of active agents such as hormones. The adhesive layer may include all known non-toxic natural and synthetic polymers suitable for use in transdermal systems, for example polyacrylates, polysiloxanes, polyisobutylenes, styrene block copolymers and the like. Polyacrylates are particularly highlighted. TTS systems are suitable for steroids (the gestodene) which can be incorporated into the adhesive layer in an amount substantially at or near or even above saturation relative to their concentration in the carrier preparation rather than substantially under saturation. It is preferred that the amount of steroids is from approx. 0.1 to approx. 6 percent by weight, based on the total dry weight of the carrier preparation.

Unfortunately, penetration enhancers can adversely affect the skin, such as skin irritation, which to some extent makes transdermal systems unacceptable to the user. In addition, it is generally known that penetration enhancers can negatively affect the stability of active substances, which makes long-term storage problematic. Furthermore, it is also known that the viscosity is reduced by the incorporation of penetration enhancers, which results in the risk of formation of dark rings along the edges of the patch.

Therefore, there is a need for transdermal systems without the above disadvantages, such as transdermal systems that do not require penetration enhancers to achieve therapeutically effective amounts of a steroid hormone, such as gestodene.

Gestode is a known orally active synthetic progestin with a progesterone-like activity profile (see US Patent No. 4081537). It is used as an oral contraceptive in combination with certain estrogens.

Brief description of the invention

This invention relates to preparations which are formulated appropriately for transdermal administration of hormones, so that pregnancy prevention effective levels are achieved without the need for the incorporation of penetration enhancers in the hormone-containing adhesive layer. The actual hormones are gestodene or an ester thereof, which can possibly be used in combination with an oestrogen. Contrary to the general knowledge in the art, the inventors have provided transdermal systems comprising a limited number of ingredients. For example, penetration enhancers and/or permeation enhancers are not required to achieve high release rates and therapeutically effective plasma levels.

The inventors of the present invention have found that the selection of a drug-containing layer that has a solubility for the steroid hormone (eg, the gestode) is very important for successfully achieving therapeutically effective levels of a hormone in the blood. Example 2 herein shows the comparison between two gestode containing layers with regard to their release rate of the gestode. It has been clearly demonstrated that a drug-containing layer of a polar polymer (polyacrylate) requires a concentration of the gestode of 3.9% by weight of this layer to achieve the desired release rate. Surprisingly, and contrary to what has been 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 polyisobutylene, even without the use of a penetration enhancer . Also, in-vivo studies have revealed that drug-containing layers containing the more non-polar polymer type, such as the polyisobutylene rather than the polyacrylate, are better in achieving high plasma AUC (Example 4).

The inventors have thus found, contrary to what might be expected, that the use of drug-containing layers which preferably contain an apolar polymer, such as polyisobutylenes, and which are characterized by having limited solubility in relation to the gestode of no more than 3% by weight, has a high release rate of the gestode despite the fact that the actual amount of gestode in the drug-containing layer is small. This is clearly an advantage compared to the previously known TTS systems when it comes to reducing the risk of skin irritation, reducing the exposure of hormones to the user and the environment.

A further advantage is that the drug-containing layer is a monophase system and contains the drug evenly distributed throughout the layer. This means 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. The invention has thus provided a transparent preparation where the skin can be examined visually through the drug administration system. The fact that a transdermal drug administration system is transparent is a clear advantage for the user, because non-transparent systems are visible and thus indicate disease, which is not the purpose of a contraceptive patch.

Consequently, a first aspect of the invention relates to preparations for transdermal administration of the gestode or an ester thereof, and optionally an estrogen. The preparation according to claim 1 comprises a drug-containing layer comprising the hormone 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, where the drug-containing layer has a solubility for the hormones (such as gestode) of no more than 3 percent by weight of the drug-containing layer, and where the gestode or an ester thereof is present in an amount that lies in the range between 0.5 and 3 percent by weight of the drug-containing layer.

In a particular aspect thereof, the invention relates to a preparation comprising a progestin, such as gestodene or an ester thereof, and a polymer in an amount of from approx. 15 to 99 percent by weight of the drug-containing layer, the polymer being selected from the group consisting of polyisobutylenes, polybutenes, polyisoprenes, polystyrenes, styrene-isoprene-styrene block polymers, styrene-butadiene-styrene block polymers and mixtures thereof, which form a drug-containing layer having a solubility for the gestode of not more than 3% by weight of the drug-containing layer.

In another particular aspect thereof, the invention relates to preparations comprising a drug-containing layer which essentially consists of the gestode or an ester thereof, a polymer in an amount of from approx. 15 to 99 percent by weight of the drug-containing layer, a tackifier, such as a resin ester in an amount up to 85 percent by weight, such as in an amount in the range of 1-85 percent by weight of the drug-containing layer, and optionally an estrogen.

In yet another further aspect, the invention relates to a transparent preparation according to claim 1 for transdermal administration.

It has surprisingly been shown that relatively high plasma levels of the gestode can be maintained for a longer period by administering a gestode which is formulated in a preparation according to the invention. The gestodene plasma profile and plasma levels, which result from the administration of a gestodene and optionally an estrogen, are effective in inhibiting ovulation in a woman.

Therefore, preparations according to the invention can be used to inhibit ovulation or alternatively for the treatment of endometriosis, premenstrual syndrome, climacteric disorders, prevention of osteoporosis, regulation of the menstrual cycle or stabilization of the menstrual cycle.

When the preparation is administered individually, a plasma concentration time curve of the gestode is obtained which is characterized by having plasma levels of the gestode at a concentration of at least 1.0 ng/ml, as determined under steady-state conditions. In connection with this, the invention relates to a method for inhibiting ovulation in a female, such as a woman. The method comprises topical administration on the skin or mucous membrane of an effective amount of the gestodene or a derivative, an ester thereof, possibly in combination with an oestrogen, so that after individual administration of the gestodene a time curve is obtained for the concentration of the gestodene in plasma which is characterized by having plasma levels of the gestodene at a concentration of at least 1.0 ng/ml, as determined under steady-state conditions.

Finally, the invention relates to a set comprising 1 to 11 dose units, such as 9 or 3 dose units, depending on the length of the treatment period, formulated in a form for transdermal administration of the gestode or an ester thereof, as in the form of a preparation as described here. The dosage form comprises a drug-containing layer comprising the gestode and one or more pharmaceutically acceptable excipients or carriers, where the drug-containing layer has a solubility in relation to the gestode of no more than 3% by weight of the drug-containing layer.

Detailed description

The invention provides preparations for the transdermal administration of hormones (transdermal treatment system) which, when applied topically to the skin or a mucous membrane, result in therapeutically effective amounts, such as pregnancy prevention effective amounts of the hormones, although skin penetration enhancers are not necessarily incorporated in the drug-containing layer.

As used herein, the term "topical" denotes the direct contact of preparations with a surface area of a mammal, including skin and mucous membranes.

The term "mucosa" means any surface membrane of a mammal that is not skin, such as the surface found in the buccal cavity, vagina, rectum, nose or eye. The mucosa can thus be buccal, vaginal, rectal, nasal or ophthalmic mucosa.

The preparations according to the invention can be designed in a number of different ways of application, provided that the preparation comprises a drug-containing layer which is adapted to be placed near or in direct contact with skin or mucous membrane during topical administration of the preparation.

Therefore, the preparation, i.e. the transdermal treatment system, in a preferred application form essentially consists of

a) a backing layer;

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

c) possibly a removable release liner or a protective layer.

It is preferred that the backing layer, the drug-containing layer and the removable release liner (or protective layer) are transparent, meaning that the skin is visible.

In the event that the drug-containing layer cannot exhibit sufficient adhesive ability to the skin or mucous membrane, it can be equipped with an additional layer of a pressure-sensitive adhesive layer or with a pressure-sensitive adhesive edge or ring to ensure the preparation's adhesion to the skin throughout the period of use. The pressure-sensitive adhesive layer can be placed between the drug-containing layer and the skin, and the adhesive ring can be placed around or on the edge of the drug-containing layer. Optionally, the preparation may further comprise one or more membranes or adhesive layers. For example, a membrane for controlling hormone release can be placed 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 number of reasonable sizes. As used herein, a reasonable size means a surface area of from approx. 5 to 20 cm<2>, preferably from approx. 7 to 15 cm<2>, preferably from approx. 8 to 12 cm<2>, such as 10 cm<2>. The surface area is especially the area that is in contact with or very close to the skin or mucous membrane.

According to the invention, it has been found that a drug-containing layer with minimized solubility for the hormone provides sufficient skin penetration of a steroid hormone. In the present invention, the drug-containing layer is characterized by defining its solubility for the gestode. The skin penetration rate is particularly sufficient without the need for the incorporation of a skin penetration enhancer. For example, it has surprisingly been found that the skin penetration of a steroid hormone according to the invention results in therapeutically effective amounts of the steroid hormone in the circulating blood, such as effective pregnancy-preventing amounts of the hormone.

Accordingly, the invention relates in a first aspect to a preparation for transdermal administration of the gestode or an ester thereof. The preparation comprises a drug-containing layer and one or more pharmaceutically acceptable excipients or carriers according to claim 1, and the drug-containing layer has a solubility for the gestodene of no more than 3 weight percent of the drug-containing layer and where the gestodene or an ester thereof is present in an amount which lies in the range between 0.5 and 3 percent by weight of the drug-containing layer. The preparation may optionally include an oestrogen.

In some embodiments thereof, the solubility of the drug-containing layer for the gestode is no more than 2.5 weight percent of the drug-containing layer, preferably no more than 2.0 weight percent, such as no more than 1.8 weight percent. In principle, the solubility can be very low, but it is assumed that the critical level in relation to the lowest level of solubility is approx. 0.1% by weight, such as approx. 0.2, 0.3, 0.5, 0.7, 0.8, 0.9 or 1% by weight of the gestode in the drug-containing layer. It is generally assumed that the solubility of the drug-containing layer for the gestode is in the range between approx. 0.1 and 3, such as approx. 0.2 and 3, 0.4 and 3, 0.5 and 3, 0.8 and 3 or 1 and 3 weight percent. In further embodiments thereof, the upper limit of the range is not 3 weight percent, but lower, such as 2.5, 2.2, or 2.0 weight percent.

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

In preferred embodiments according to the invention, an ester of gestodene is gestodene propionate, gestodene valerate and/or gestodenecapronate, which is described in US5858394.

As mentioned, the inventors have found that a suitable drug-containing layer according to the invention is one which has a solubility for the steroid hormone (gestode) of no more than 3% by weight of the drug-containing layer.

The phrase "a solubility for a steroid hormone, such as a solubility for the gestode of not more than 3 percent by weight of the drug-containing layer" is intended to characterize the amount of the steroid hormone, such as the gestode, that can be dissolved in a particular drug-containing layer that provides a visual clear solution. The term (a solubility for) should not be understood as meaning the actual concentration of the gestode, in the drug-containing layer. As described above, the total concentration of hormone in the drug-containing layer may be above or below 3 percent by weight of the drug-containing layer. Furthermore, the total concentration of hormone in the drug-containing layer can give rise to a drug-containing layer that includes the hormone at saturated or undersaturated levels.

To select drug-containing layers having the indicated solubility for which the gestode can be used, the following test can be performed to determine whether the hormone is completely dissolved and the resulting drug-containing layer is visually clear.

One test method is to determine whether the hormone is completely dissolved, as the solid particles cannot be detected visually or using a microscope that has a magnification of 25X.

Another method is actually to determine the solubility of the drug-containing layer for the hormone by the following method. The method is based on determining the hormone's release rate constants from a drug-containing layer that comprises the hormone in completely dissolved form, and from a drug-containing layer where the hormone is partially dissolved.

The procedure includes the following steps:

First, identical drug-containing layers of the hormone must be prepared, but with different amounts, such as increasing amounts. As a rule, at least three of the different drug-containing layers must contain the hormone in a completely dissolved form in the drug-containing layer, and at least three drug-containing layers must contain the hormone as partially dissolved, i.e. 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 the production of adhesive layers may also be suitable:

- The medicinal substance is dissolved or suspended in a suitable solvent.

- The polymer, possibly the tackifier and other excipients are dissolved in a suitable solvent.

- The two solutions are combined while stirring, with a view to obtaining a homogeneous mixture.

- A release liner is coated with the mixture to a suitable thickness and dried under heat to evaporate the solvents.

- The resulting laminate is covered with the backing foil.

Second, the release rate of the drug from the drug-containing layer is tested using the equipment and test conditions specified in the relevant section of the European Pharmacopoeia (Ph.Eur. 2.9.4. Dissolution test for transdermal patches) or the United States Pharmacopoeia (USP 26, <724> DRUG RELEASE, apparatus (Paddle over Disk).

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

- After removing the release liner, the sample is placed in a container (as described in the above-mentioned pharmacopoeia) which has been previously filled with a suitable dissolution medium equilibrated at 32°C ± 0.5°C. The drug-containing layer must be in 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 can be chosen from among those that ensure sinking conditions. Suitable solvents are e.g. water solutions containing up to 30% by weight of organic solvents, such as ethanol, isopropanol and dioxane.

Third, the hormone release rate from the two types of drug-containing layers is determined as follows:

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

- each drug-containing layer's release rate is determined as the slope obtained by the linear regression analysis of the last three data points on the amount of hormone per unit area in relation to the square root of time.

- The release rate constant for each of the drug-containing layers is plotted against the concentration of hormone in the drug-containing layer. Linear regression analysis is then carried out separately for the drug-containing layers with completely dissolved hormone and for drug-containing layers with partially dissolved hormone, i.e. with solid particles of hormone present. The two regression lines will cross each other at a point. The concentration of the hormone which can then be read off at the intersection of the two regression lines denotes the hormone's solubility in the drug-containing layers.

The expression "drug-containing layer" is intended to denote the part of the transdermal preparation or system where the steroid hormone is present. The drug-containing layer can be in semi-solid or solid form and includes the hormone that is formulated directly in the layer. The hormone according to the invention can be dispersed, partially dispersed, partially dissolved or completely dissolved in it, depending on the concentration and the hormone's physico-chemical properties. The drug-containing layer is not intended to be in the form of a gel or a liquid. The drug-containing layer is deliberately intended to be in direct contact with the skin or mucous membrane. In some embodiments, however, there is a further layer, a so-called non-drug-containing layer, which is placed between the drug-containing layer and the skin or mucous membrane.

As mentioned, preparations according to the invention do not necessarily include a skin penetration enhancer. In some embodiments according to the invention, the drug-containing layer thus excludes the presence of a skin penetration rate enhancer, which means that the drug-containing layer essentially consists of ingredients that do not include a skin penetration rate enhancer. This means that, for example, less than 2% by weight, such as less than 1% by weight, preferably less than 0.5% by weight, such as less than 0.2% by weight, such as less than 0.1% by weight of the drug-containing layer is made up of a skin penetration enhancer .

According to the present invention, the choice of the suitable drug-containing layer affects the skin penetration. The suitable drug-containing layer is preferably made from a polymer or mixtures of polymers. The polymers may have adhesive properties or may have no appreciable adhesive properties. In some embodiments, the drug-containing layer is a so-called pressure-sensitive adhesive layer.

In principle, any mixture of polymers that results in the solubility of the gestode can be used. In one embodiment according to the invention, the drug-containing layer thus comprises at least one polymer which may optionally have adhesive properties. Such polymers are typically biologically acceptable lipophilic polymers of the types of a hydrocarbon polymer, a polysiloxane, a polyacrylate or mixtures thereof. It is preferred that the polymers are selected from hydrocarbon polymers, polysiloxanes and/or polyacrylates which form a drug-containing layer which has a solubility for the gestode of no more than 3% by weight of the drug-containing layer.

The amount of the polymer is to some extent a critical parameter. The appropriate amount may depend on the actual polymer type and steroid hormone used. Generally, the amount of the polymer is at least 1 percent by weight of the drug-containing layer, such as at least 5, 10, 15, or 20 percent by weight. However, the polymer is preferably 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 percent by weight of the drug-containing layer. In other words, the polymer can be used in an amount of from approx. 1 to 99 percent by weight of the drug-containing layer, such as from approx. 5 to 99% by weight, 10 to 99% by weight, 15 to 99% by weight or 20 to 99% by weight. The polymer is preferably present in the drug-containing layer in an amount ranging from approx. 15 to 99 percent by weight, such as from approx.

15 to 90% by weight, 15 to 85% by weight or 15 to 80% by weight, such as from approx. 20 to 85% by weight, 20 to 75% by weight, such as from approx. 25 to 85 percent by weight, 25 to 75 percent by weight of the drug-containing layer.

It should also be said that a particular aspect of the invention is directed towards a preparation for transdermal administration of the gestode or an ester thereof, and possibly an oestrogen, as the preparation comprises a drug-containing layer comprising

- at least one steroid hormone, such as a gestodene or an ester thereof and one or more pharmaceutically acceptable ingredients or carriers;

- a polymer or a mixture of polymers, preferably in an amount of from approx. 15 to 99 percent by weight of the drug-containing layer,

where the polymer is selected from the group consisting of hydrocarbon polymers and mixtures thereof which form a drug-containing layer with a solubility in relation to the steroid hormone of no more than 3% by weight of the drug-containing layer.

As mentioned, it has been found that adhesive layers comprising the more non-polar types of polymers, such as the hydrocarbon polymers, have been found to be better than the polar types of polymers, such as polyacrylates (Example 2). In a preferred embodiment of the invention, the drug-containing layer therefore comprises as the polymer a hydrocarbon polymer which may preferably include polyisobutylenes, polybutenes, polyisoprenes, polystyrenes, styrene isoprene-styrene block polymers, styrene butadiene-styrene block polymers and/or mixtures thereof.

As mentioned above, the drug-containing layer is adhesive in some embodiments according to the invention. The drug-containing layer's polymer preferably has suitable adhesive properties, so that an additional adhesive agent, such as a tackifier, is not required. When it seems necessary to improve the drug-containing layer's adhesive strength, the layer further comprises a tackifier.

The term "tackifier" denotes an agent which improves the adhesive strength of the adhesive layer against the skin or mucous membrane.

Examples of tackifiers are selected from hydrocarbon resins, rosin resins and terpene resins. Examples of hydrocarbon resins are commercially available under the trade name Escorez® from ExxonMobil; Regalite®, Piccotac® and Picco® from Eastman or Indopol® from BP. Examples of rosin esters suitable for transdermal systems according to the present invention include esters of hydrogenated trirosin, e.g. pentaerythritol esters of hydrogenated tree rosin, esters of partially hydrogenated tree rosin, e.g. pentaerythritol esters of partially hydrogenated wood rosin, esters of wood rosin, esters of modified wood rosin, esters of partially dimerized rosin, esters of tall oil rosin, esters of dimerized rosin and similar rosins, and combinations and mixtures thereof. Such rosin masters are commercially available under the trade names Foral®, Foralyn®, Pentalyn®, Permalyn® and Staybelite®.

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

In general, it is believed that the tackifier may be present in any suitable amount as long as the critical solubility of the steroid hormone in the drug-containing layer is not appreciably affected. A tackifier can thus be present in the drug-containing layer in an amount of from approx. 0.1 to 95% by weight, such as 0.5 to 95% by weight, such as 1 to 95% by weight of the drug-containing layer. That is to say, the tackifier can be present in an amount of from approx. 1 to 85% by weight, 1 to 75% by weight, 1 to 65% by weight, 1 to 55% by weight, 1 to 50% by weight, 1 to 45% by weight, 1 to 40% by weight or preferably approx. 1 to 35% by weight, such as preferably 1 to 30% by weight, most preferably 1 to 25% by weight. It is obvious that the amount of tackifier in the drug-containing layer can be critical for the solubility of the steroid hormone in the drug-containing layer. In further other embodiments according to the invention, the tackifier is thus present in the drug-containing layer in an amount of up to 35 percent by weight, such as up to 30 percent by weight. It is particularly preferred that the amount of tackifier is up to 25% by weight, such as up to 20% by weight or 15% by weight, preferably up to 10, 7, 5% by weight of the drug-containing layer.

It follows that a further particular aspect of the invention relates to a preparation for transdermal administration of the gestode or an ester thereof, and possibly an oestrogen, the preparation comprising a drug-containing layer which essentially consists of:

- at least one steroid hormone, such as a gestodene, and one or more pharmaceutically acceptable ingredients and/or carriers;

- a polymer or a mixture of polymers, preferably in an amount of from approx. 15 to 99 percent by weight of the drug-containing layer, the polymer being preferably selected from the group consisting of hydrocarbon polymers, polysiloxanes, polyacrylates and mixtures thereof, preferably hydrocarbon polymers (polyisobutylenes, polybutenes, polyisoprenes, polystyrenes, styrene-isoprene-styrene block polymers, styrene-butadiene-styrene block polymers and/or mixtures thereof ). As mentioned, the drug-containing layer has a solubility for the gestode as mentioned above; and

- a tackifier in an amount of up to 85% by weight of the drug-containing layer; and

- possibly an estrogen.

As said, the drug-containing layer must consist of ingredients that form a layer where the dissolution criterion for the gestode is met. This criterion is preferably met when the drug-containing layer mainly consists of the hormones according to the invention together with a polymer or a mixture of polymers and possibly a tackifier.

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 high molecular weight polymers (at least relative to polyisobutylene) is usually in the range of 500,000 to 2,000,000 Da, whereas the molecular weight of the low molecular weight is in the range of about 20,000 to 100,000 Da. Such polymers typically comprise a mixture of high molecular weight polymers and low molecular weight polymers where the amount of low molecular weight polyisobutylene in the overall mixture is at least 50%.

In preferred embodiments, the hydrocarbon polymer is a polyisobutylene, polybutene, polyisoprene, preferably polyisobutylene.

In some embodiments of the invention, the polymer excludes isoprene copolymers.

However, exclusion of other polymers from the drug-containing layer does not prevent the use of such polymers in other layers or parts of the preparation.

Furthermore, the drug-containing layer in some embodiments does not comprise, or comprises at least only a limited amount of, a hydrophilic polymer, such as crystallization inhibitors such as polyvinylpyrrolidone, cellulose polymers, such as methyl or ethyl cellulose derivatives or hydroxypropylmethylcellulose, or mixtures thereof.

In some embodiments, a solubility enhancer, such as dimethyl isosorbide, is not present in the drug-containing layer or at least only present in a limited amount.

By the term "limited amount" it is meant that the polymer or the appropriate solubilizer is present in a concentration in the drug-containing layer of less than 10 percent by weight, such as less than 8, 5, 3, 2, 1, 0.5 or 0, 2 weight percent of the layer.

As mentioned, it has been possible to provide sufficient skin penetration of a steroid hormone without the incorporation of a skin penetration enhancer and/or permeation enhancer. That is, in interesting embodiments according to the invention, a skin penetration enhancer and/or permeation enhancer is omitted in the drug-containing layer or present in the drug-containing layer in a limited amount, this amount being less than 5 percent by weight, such as less than 4, 3, 2, 1, 0.5 or 0.2 percent by weight of the drug-containing layer.

The terms "skin penetration enhancers" and "permeation enhancers" are intended in the present invention to be interchangeable terms, and denote compounds that provide enhanced skin penetration/permeation to the active drugs when administered together with the drugs on the user's skin. Penetration/permeation enhancers in transdermal formulations will change the drug's thermodynamic activity in the drug-containing layer, thus leading to a positive or negative "push" effect. Furthermore, some penetration/permeation enhancers can be thought to penetrate into the highly ordered intercellular lipid structure of the stratum corneum and reduce its resistance by increasing the lipid acyl chain mobility and thus providing a "pull" effect.

Any skin penetration/skin permeation enhancing effect of a substance can be recognized by testing identical preparations with and without penetration enhancers, e.g. by using naked mouse skin or the like. Those skilled in the art are familiar with such test procedures.

Typical penetration/permeation enhancers are included in the group of compounds listed below:

- Alcohols, such as monohydric alcohols with approx. 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, stearyl, oleyl, linoleyl and linolenyl alcohol.

- Fatty acids, such as saturated and unsaturated fatty acids which may include 8-18 carbon atoms, e.g. 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 valeric acid, capronic acid, caprylic acid, pelargonic acid, capric acid, isovaleric acid, neopentanoic acid, neoheptanoic acid and/or isostearic acid.

- Esters such as aliphatic esters, ethyl acetate, lower (C1-C4) alkyl esters of lactic acid, fatty acid esters according to the general formula CH3--(CH2)n--COOR, where n is a number from 8 to 18 and R is an alkyl residue of maximum 6 carbon atoms, such as fatty acid esters, e.g. those of lauric acid, myristic acid, stearic acid and palmitic acid, e.g. methyl esters, ethyl esters, propyl esters, isopropyl esters, butyl esters, sec-butyl esters, isobutyl esters of these acids, or dicarboxylic acid diesters of the general formula R'OCO(CH2)mCOOR', where m is a number from 4 to 8 and R' in each case means an alkyl residue with 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, suitable dicarboxylic acid diesters are e.g. diisopropyl 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 with chain lengths of 6 to 17 carbon atoms.

- Amides, such as dimethylacetamide, dimethylformamide, dimethyllauramide, dimethyllaurylamide and/or fatty acid amides and their derivatives.

- Amides, such as amides with long aliphatic chains, 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-N,N-dimethylaminoacetate and dodecyl-2-methyl-2-(N,N-methylaminoacetate), decyl-2-(N,Ndimethylamino)-propionate, decyl-2- (N,N-dimethylamino)-butyrate, octyl-2-(N,N-dimethylamino)-propionate and/or docecyl-(N,N-dimethylaminophenylacetate).

- Azone derivatives, such as 1-dodecyl azacycloheptan-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 monolinoleate, polyethylene glycol-3-lauramide (PEG LR), polyethylene glycol monolaurate (PGML), glycerol monooleate (GMO), glycerol monolinoleate and/or glycerol monolaurate (GML).

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

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

- Polyols, such as propylene glycol.

- Pyrrolidones, such as 2-pyrrolidone, N-methyl-2-pyrrolidone, dodecyl-pyrrolidone, 2-pyrrolidone-5-carboxylic acid, N-hexyl-, N-lauryl-, 4-carboxy-, 4-carboxycarbon derivatives, 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 sulfoxide derivatives, such as methyloctylsulfoxide, dimethylsulfoxide (DMSO), hexylmethylsulfoxide (hexyl-MSO) and/or decylmethylsulfoxide (decyl-MSO).

- Surfactants, such as cationic surfactants such as cetyltrimethylammonium bromide, octadecyltrimethylammonium chloride, cetylpyridinium chloride and/or equivalent cationic compounds, anionic surfactants, such as sulphate salts including but not limited to compounds such as sodium lauryl sulphate and/or sodium dodecyl sulphate and non-ionic surfactants, such as esters of sorbitol and sorbitol anhydride including but not limited to polysorbate, sorbitan monopalmitate and/or sorbitan polyoleate.

- Terpenes, ketones and oxides.

In addition to the steroid hormone, such as a progestin, the one or more polymer(s), the one or more tackifier(s), and the possible estrogen, the drug-containing layer or other parts of the preparation also contain stabilizers, dyes, pigments, inert fillers, antiaging agents, antioxidants, elastomers, thermoplastic materials and other conventional components of transdermal preparations known in the art. It is preferred that the preparation, or at least the drug-containing layer, does not contain or only contains in a limited amount (less than 1, 0.8, 0.5% by weight, 0.2 or 0.1% by weight of the drug-containing layer) polyvinylpyrrolidone , methylcellulose, ethylcellulose, hydroxypropylmethylcellulose and/or dimethylisosorbide.

It is clear that the preparations according to the invention are transparent or at least in very interesting embodiments transparent, which means that the skin can be inspected visually through the drug administration system. This means that the drug-containing layer is a monophasic system where the drug (here progestin) dissolves completely in the drug-containing layer. The property as a monophasic system can be identified by mechanical stretching of the drug-containing layer using a test procedure described below.

The drug-containing layer is further characterized by being homogeneous. The term "homogeneous" is used to describe a monophase system where the matrix consists of one polymer phase. These systems can be distinguished from multiphase systems, which consist 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 light diffraction due to differences in the diffraction index of the polymer phases. Other methods for detecting monophase systems are microscopic or rheological methods or by mechanical stretching of thin polymer films. During mechanical stretching, the thin polymer film consisting of multiphase systems becomes opaque, as visually demonstrated.

Briefly, it is thus clear that embodiments according to claim 1 according to the invention include:

a drug-containing layer comprising:

i) 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, and

iii) the drug-containing layer comprises the gestodene or an ester thereof is present in an amount of 0.5-3% by weight of the drug-containing layer.

In further interesting embodiments thereof, the drug-containing layer is characterized by the following parameters, which may be present as a single parameter or as a mixture of parameters;

• The drug-containing layer excludes dimethylisosorbide or contains an amount of dimethylisosorbide of less than 0.5% by weight of the layer;

• The drug-containing layer excludes polyvinylpyrrolidone, methylcellulose, ethylcellulose and/or hydroxypropylcellulose or contains an amount of polyvinylpyrrolidone, methylcellulose, ethylcellulose and/or hydroxypropylcellulose of less than 2% by weight of the layer;

• The drug-containing layer contains the progestin (gestode or an ester thereof) completely dissolved in the 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 skin penetration enhancer or contains an amount of less than 2 percent by weight of the layer;

• The drug-containing layer comprises the polymer in an amount of from approx. 15 to 99 percent by weight of the layer;

• The drug-containing layer comprises a tackifier, such as a resin ester, in an amount of up to 85 percent by weight of the drug-containing layer;

As mentioned above, the preparations according to the invention are characterized by releasing an effective pregnancy-preventive amount of the gestode or an ester thereof, possibly in combination with an oestrogen. The preparation can be characterized by providing a permeation rate of the gestode or an ester thereof on in-vitro naked mouse skin of at least 25 µg/cm²*24h. In other words, the preparation can be characterized by having a drug-containing layer that emits the gestode or an ester thereof in an amount of from approx. 49 to 70 µg per day. ;;Not only the gestodene or an ester thereof can be used as a drug in the preparation according to the invention. Other progestins may be included in the drug-containing layer together with the gestode or instead of a gestode, such as dienogest, drospirenone, levornorgestrel, cyproterone acetate, tetrahydrodienogest, norethisterone, norethisterone acetate, desogestrel, 3-keto-desorgestrel, norgestimate, lynestrenol, medroxyprogesterone acetate, norgestrel, norethisterone enanthate, trimegestone or alpha and beta progesterone receptor ligands. As mentioned, the preparation is effective in inhibiting ovulation. In some cases, the preparation further comprises an estrogen. The estrogen can be incorporated together with the progestin in the same drug-containing layer or incorporated in a separate drug-containing layer free of progestin. ;;The term "estrogen" includes both the natural 17-β-estradiol and the semi-synthetic estrogen derivatives, such as esters of natural estrogen and 17-alkylated estrogens. Semisynthetic esters of natural estrogen include, for example, estradiol-17-β-enanthate, estradiol-17-β-valerate, estradiol-17-β-benzoate, estradiol-17-β-undecanoate, estradiol-16,17-hemisuccinate or estradiol- 17-β-cypionate. Examples of 17-alkylated estrogens are ethinylestradiol, ethinylestradiol-3-isopropylsulphonate, quinestrol, mestranol or methylestradiol. The term "estrogen" may also include a non-steroidal compound with estrogenic activity, such as diethylstilbestrol, dienestrol, clomiphene, chlorotrianese or cyclophenyl. ;;In a preferred embodiment, the estrogen is ethinylestradiol. ;;In order to achieve the therapeutically effective amount of hormone in the blood, the actual concentration of drug in the drug-containing layer can be adjusted. In general, the drug-containing layer should contain excess hormone in addition to the amount of hormone to be absorbed, in order to achieve the therapeutically effective amount of the hormone. Normally this excess amount is small, so that the amount of hormone is less than 10 times the desired/required amount of hormone, preferably less than 5 times, such as less than 2 times. For example, it is also considered important to limit the amount of hormones with a view to reducing the overall hormone exposure the user is exposed to. Suitable concentrations of the gestode or an ester thereof in the drug-containing layer are therefore from 0.5 to 3 weight percent of the drug-containing layer. As mentioned, the overall concentration of hormone, such as the gestode, can result in drug-containing layers comprising the hormone in saturated or undersaturated levels. In a very interesting embodiment, the concentration of a steroid hormone, such as gestodene or a derivative thereof, in the drug-containing layer is from approx. 1 to 3 weight percent, such as 1 to 2 weight percent. Similarly, in some embodiments according to the invention which further comprise an estrogen, the estrogen is present in the drug-containing layer in an amount of from approx. ;0.5 to 10 percent by weight of the adhesive layer, preferably from approx. 0.75 to 5 percent by weight, preferably from approx. 1 to 3 weight percent, such as 1 to 2 weight percent. ;;Furthermore, the progestin, such as the gestode or an ester thereof, is in a mass ratio in relation to the estrogen in the range of from approx. 4 to 0.5, preferably 2 to 0.5, such as 1:1. ;;It has surprisingly been shown that relatively high plasma levels of the gestode can be maintained for a longer period by administering the gestode or an ester thereof which is formulated in a preparation according to the invention. It has also surprisingly been shown that the gestode's plasma profile and plasma levels, which are the result of the administration of a gestode or a derivative thereof and possibly an oestrogen, are effective in inhibiting ovulation in a woman. Therefore, further aspects according to the invention relate to the use of a preparation according to the invention, possibly in combination with an oestrogen, to inhibit ovulation in a female, such as a woman. When the drug is administered individually, a plasma concentration-time curve of the gestode is obtained which is characterized by having plasma levels of the gestode at a concentration of at least 1.0 ng/ml, as determined under steady-state conditions. As follows, one aspect according to the invention relates to a method for inhibiting ovulation in a female, such as a woman, which method comprises topically administering to the skin or mucous membrane an effective amount of gestodene or an ester thereof, optionally in combination with an estrogen, so that after individual administration of the gestodene, a time curve is obtained for the concentration of the gestodene in plasma which is characterized by having plasma levels of the gestodene in a concentration of at least 1.0 ng/ml, as determined under steady-state conditions. ;;Alternatively, the applications and methods according to the invention are for the treatment of other symptoms, disorders or symptoms which are normally treated by administration of a progestin, such as a gestodene or an ester thereof or a combination of a progestin and an oestrogen. Therefore, it should be generally understood that in some embodiments according to the invention, the applications and methods are intended for the treatment of endometriosis, premenstrual syndrome, climacteric disorders, regulation of the menstrual cycle and/or stabilization of the menstrual cycle. ;;For example, administration of a progestin without concomitant treatment with an estrogen can treat irregular bleeding and abnormal bleeding. As used herein, the term "irregular bleeding" refers to any uterine bleeding outside of the regular monthly menstrual periods of non-pregnant women. Uterine bleeding is irregular if menstrual cycles or menstrual periods are too short, too long, too frequent, too infrequent, or occur at irregular intervals that fall outside the normal 26-30 day menstrual cycle. The menstrual period is classified as being too long when it is delayed by 15 to 50 days or more in relation to the expected onset of bleeding. The term "abnormal bleeding" characterizes major bleeding that typically bleeds through sanitary protection products to an extent that requires changing more often than hourly or every two hours for a period of more than seven days. Abnormal bleeding does not include bleeding in women who have already reached menopause, abnormal uterine bleeding due to side effects of estrogen replacement therapy, abnormal bleeding as a symptom of cancer of the uterus, as a consequence of abnormal blood clotting normally, congenital bleeding disorder or due to medical disease that affects platelet levels. ;;Progestins are administered in combination with an estrogen by administering a drug according to the invention comprising the combination of the gestode or an ester thereof, and an estrogen for the treatment of climacteric disorders, such as symptoms and disorders associated with menopause, such as hot flashes, sweating, palpitations, sleep disorders, mood swings, nervousness, anxiety, poor memory, low self-esteem, loss of libido, poor concentration, reduced energy, reduced drive, irritability, urogenital atrophy, breast atrophy, cardiovascular disorder, changes in hair distribution, hair thickness, changes in skin condition and/ or osteoporosis. The treatment is particularly aimed at hot flushes, sweating, palpitations, sleep disorders, mood swings, nervousness, anxiety, urogenital atrophy, breast atrophy and to prevent or manage osteoporosis. In connection with the treatment of climacteric disorders, the estrogen can be selected from natural estrogens, such as estradiol and esters thereof, such as estradiol valerate, estradiol benzoate. Natural estrogens further include estrone, estriol, estriol succinate and conjugated oestrogens, including conjugated equine estrogen such as estrone sulfate, 17β-estradiol sulfate, 17αestradiol sulfate, equilin sulfate, 17β-dihydroequilin sulfate, 17α-dihydroequilin sulfate, equilenin sulfate, 17β-dihydroequilenin sulfate and 17α-dihydroequilenin sulfate or mixtures thereof. ;;The plasma concentration-time curve of the gestode at steady-state conditions is characterized by having plasma levels of the gestode at a 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 interesting embodiments, the time curve for concentration of the gestode in plasma at steady-state conditions is characterized by having plasma levels of the gestode in the range from 1 to 8 ng/ml, preferably in the range from 1.5 to 6 ng/ml after the first 6 days after simple administration of a preparation of the gestode or a derivative thereof, preferably in the form of a preparation according to the invention. ;;The time curve for the concentration of the gestode in plasma at steady-state conditions is characterized by having plasma levels of the gestode in the period of 18 to 60 hours after single administration of the drug and/or by having plasma levels of the gestode at steady-state conditions in the period in 5 to 7 days after single administration of the drug in the order of at least 50% of the maximum plasma levels of the gestode achieved during the first 18 to 60 hours after administration. ;;The gestodene is preferably administered repeatedly in cycles of 28 days, so that within each 28-day cycle the gestodene/preparation is administered at an interval of 7 days for a period of 21 days (3 weeks) followed by no administration of the gestodene or a derivative hence for 7 days (one week). This means that the gestodene/preparation is administered on days 1, 8 and 15 within each cycle of 28 days. It is preferred that day 1 is the day on which menstruation begins, or any other suitable day, such as the first, second, third, fourth, fifth or sixth day after the day of onset of menstruation. In another embodiment, the gestodenet, optionally in combination with an estrogen, is administered repeatedly in cycles of 12 weeks, so that within each cycle of 12 days the gestodenet/preparation is administered with an interval of 7 days for a continuous period of 11 weeks after no administration of the gestode or a derivative thereof for 7 days (one week). ;;To improve the contraceptive effectiveness and safety, an estrogen can be administered at the same time as the gestodene. The estrogen can be selected from the above-mentioned estrogens. It is clear that the applications and methods according to the invention include application of the gestode or an ester thereof, which may be in the form of a preparation as defined herein. The term "drug" thus includes a preparation as defined herein. Furthermore, the term "medicine" shall include a kit according to the invention. ;;In yet a further aspect, the invention relates to a kit comprising 1 to 11 dose units intended for a treatment period of 12 weeks, formulated in a form for transdermal administration of a progestin, such as gestode or an ester thereof, the dose units comprising a drug-containing layer comprising the gestodene and one or more pharmaceutically acceptable excipients or carriers, and the drug-containing layer has a solubility in relation to the gestodene of no more than 3% by weight of the drug-containing layer. The dosage unit may comprise a preparation as described herein. It will be understood that in one embodiment thereof, 11 dosage units are administered continuously once weekly for a period of 11 weeks, followed by one week without administration of a dosage unit or administration of a placebo. ;;In other embodiments, the kit is intended for a treatment period of 12 weeks, but the kit comprises 1 to 9 dose units. In one embodiment, 3 dose units are administered weekly for a period of 3 weeks, followed by a week without administration of a dose unit or administration of a placebo. This means that the set is intended for a treatment period of 4 weeks, and the set includes 1-3 dose units. ;;The dose of progestin, such as of gestodene or an ester thereof in each dosage unit, corresponds to a dose selected from a six-day dose, seven-day dose, eight-day dose, 14-day dose and 21-day dose. In one embodiment thereof, each dose unit comprises the gestodene or a derivative thereof in a dose of from approx. 0.5 to 5 mg, preferably 1 to 3 mg, most preferably 1.5 to 2.5 mg. ;;It should also be clear that the set can further comprise an estrogen as mentioned above. The estrogen may be combined with the gestodene or an ester thereof, in the same dosage unit or provided in separate dosage units. The set can e.g. further comprising 1 to 30 dosage units comprising an estrogen and no gestodene. The estrogen can 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 oral administration of an estrogen, such as in the form of a tablet, pill, capsule, powder, paste or granule. The preparations according to the invention can be prepared using methods known in the art. An example is included here. ;;Figures ;;Figure 1. Mean serum levels of the gestodene (GSD) during two treatment cycles, week 1 and week 3, respectively. The texts are as follows: ;cycle 1, week 1 ;cycle 2, week 1 ;cycle 1, week 2 ; cycle 2, week 2 ;Examples ;;Example 1 ;;Preparation of a plaster ;;A preparation according to the invention is prepared as follows. ;;In a first step, 380 g of gestodene and possibly 180 g of ethinylestradiol are dissolved in a suitable solvent, such as 16.8 kg of dioxane. In a second step, approx. 57 kg of a mixture of polyisobutylene and resin ester in heptane (Arcare<®>MA 24A). The hormone solution according to the first step is transferred to the polymer solution while stirring, and stirring is continued until a homogeneous solution is obtained. The drug-containing solution thus obtained is coated on a release liner (such as FL 2000 75µm PET 1S; Fa Loparex) and dried under suitable conditions. The dried drug-containing layer is then laminated with a backing foil/layer, such as Cotran<®>, 9720, 3M. The laminate thus obtained is divided into patches with a size of 10 cm<2> and the resulting patch has the following composition: ;; Gestode: 1.9 mg ; Any ethinyl estradiol: 0.9 mg ; Polymer 97.2 mg ; (i form of polyisobutylene in combination with a tackifier, e.g. ;MA-24A®) ;Release liner: 10 cm<2>;Back layer: 10 cm<2>;;In another example, the resulting patch corresponds to the above , but the amount of ethinylestradiol is 0.6 mg. ;In yet another example, the resulting patch corresponds to the above, but the adhesive is Duro-tak<®>, 10711, which consists of a hydrocarbon polymer. ;;Example 2 ;;Skin penetration rates for preparations with different polymers. ;;Six preparations (A-F) were prepared with acrylate vinyl acetate polymers as the polymer in the drug-containing layer. Furthermore, preparation G was prepared using polyisobutylene as the polymer in the drug-containing layer. The preparation was carried out according to the method described in example 1. None of the preparations comprise a skin penetration enhancer. ;;Each of the preparations was tested in an in-vitro permeation test on mouse skin. The test is performed using skin preparations from nude mouse skin (HsdCpb: NMRI-nu) which can be obtained from Harlan Bioservice for Science GmbH, Walsrode, Germany. The test formulation is attached to the outside of a skin sample. Both are placed into the permeation cell with the inside in contact with the receptor media. HEPES-buffered water solution is used as receptor media. Sodium azide is added to prevent microbial growth. The receptor solution is kept at 32°C. Samples are taken from the receptor solution at specific time intervals, and the concentration of gestodene (GSD) and ethinylestradiol (EE) in the receptor media was analyzed by HPLC. The flux rate was then calculated as the amount of released drug per unit area and time [µg/cm²*24h] during application of the calculated amounts of active substances.

Results on skin penetration rate in vitro:

Table 1.

The results indicate that both gestodene and ethinylestradiol's permeation rate from preparation G (polyisobuylene) is better than that from preparations A-F.

Example 3

Contraceptive effect and pharmacokinetic profile

The effect on inhibition of ovulation, drug concentration in serum and the safety of a patch according to the invention was investigated in a selected population of women. The design of the study was based on the requirements of the EMEA guideline for clinical studies with contraceptive steroids (Committee for Proprietary Medicinal Products, CPMP/EWP 519/98).

The survey's design

The study has three phases, a pretreatment phase that includes two washout cycles and a further cycle to ensure that the selected women were ovulating. Finally, the second phase is a treatment phase of two cycles, which was followed by a third phase consisting of a post-treatment phase of one cycle.

It was required that the women who were to take part in the survey were healthy, non-pregnant, non-smoking, non-lactating volunteer women between the ages of 18 and 35 with a normal body mass index of 18-26 kg/m<2> and a normal menstrual cycle length, such as 28 days ± 4 days. Only women with fair skin were included, so that the application sites could be assessed easily and uniformly.

The test patch is a patch comprising a drug-containing layer of 0.9 mg ethinylestradiol and 1.0 mg gestodene and Arcare MA-24A<®>, and the drug-containing layer has a size of 10 cm<2>. Arcare MA-24A<®>is a polyisobutylene-based adhesive from Adhesive Research.

During the examination, blood was taken for the determination of endogenous hormones, such as estradiol, progesterone, follicle-stimulating hormone, sex hormone-binding protein, ethinyl estradiol, gestodene. A transvaginal ultrasound examination was carried out to assess the development of follicle-like structures in the uterus. Patch adhesion, skin reaction at the application site and the woman's general state of health were assessed. Vaginal bleeding was also evaluated.

During the pre-treatment cycle, normal and spontaneous ovulation was determined by assessment of serum progesterone values by only women with ovulatory pre-cycle and progesterone serum levels above 5 nmol/l being included in the treatment phase.

The treatment phase includes a period of two menstrual cycles. The first treatment in the first cycle began one day after the volunteers began menstruating in that cycle, by applying a patch. In total, three test patches were applied at intervals of 7 intervening days, such as application at days 1, 8 and 15 of the first cycle, each at different application sites, during each treatment cycle. Each patch was worn for 7 days, then replaced with a new patch to complete a total continuous application of 21 days. This was followed by a treatment-free interval of 7 days before the next treatment period began with a combined application of three patches, each applied at an interval of 7 days. If the patches were lost or loosened more than 40%, a new patch was applied.

The patches were applied to clean, dry, undamaged and preferably hairless skin on the lower abdomen, below the navel, starting on the right side for the first treatment cycle, then alternating sides.

Determination of pharmacodynamic variables

The primary pharmacodynamic variable is the proportion of women with inhibited ovulation. According to the so-called Hoogland method, ovulation requires follicle growth above 13 mm and subsequent ovarian rupture, plus a serum progesterone concentration > 5 nmol/l that occurs with the follicle rupture. It follows that ovulation is inhibited when the follicle is below 13 mm and the serum progesterone concentration is below 5 nmol/l at the time of follicle rupture.

Determination of pharmacokinetic variables

Pharmacokinetic parameters, such as the area under the drug concentration-time curve during the patch-bearing period AUC(0-168h), Cmax, tmax, and accumulation factors within each cycle, as determined by AUC(0-168h) of third patch/AUC(0-168h) ) of first patch within cycle 1 or 2, or accumulation factors between two cycles, such as AUC(0-168h) of third patch in cycle 2/ AUC(0-168h) of third patch in cycle 1. AUC was calculated according to the linear trapezoid rule.

Serum concentrations of the estrogen and progestin, including ethinylestradiol and gestodene, were determined through the examination to assess the patch's pharmacokinetic characteristics. Sample points were on day 18 of the last cycle before treatment and days 1, 2, 3, 4, 5, 6, 7, 8, 15, 16, 17, 18, 19, 20, 21 and 22 of cycle 1 as well as day 1 (before application of new patch), 2, 3, 4, 5, 6, 7, 8, 15, 16, 17, 18, 19, 20, 21 and 22 of cycle 2.

The concentrations of ethinylestradiol and gestodene were determined using conventional methods in the art. Specifically, the concentration of ethinylestradiol was determined by gas chromatography using mass spectrometry in the chemical ionization mode as the detection method after extraction of ethinyl estradiol from acidified serum and consecutive derivatization. Gestodene concentrations were determined by radioimmunoassay using a rabbit antiserum and 3H-labeled gestodene. After incubation and centrifugation, the resulting precipitate was redissolved with NaOH. The assay has a lower quantification limit of approx. 250 pg/ml.

Results

The primary pharmacodynamic variable was the proportion of women with inhibited ovulation.

Ovarian activity was effectively suppressed ie;

No ovarian activity: cycle 1: 78%, cycle 2: 56%.

Potential activity: cycle 1: 15%, cycle 2: 22%.

Non-active FLS: cycle 1: 4%, cycle 2: none;

Active FLS: cycle 1: 4%, cycle 2: 22%

No cases of ovulation were found during the examination. Inhibition of ovulation, defined as a Hoogland score of less than 6 (ovulation), was sufficient for all volunteers in the per-protocol data set during the study.

Progesterone concentrations were appropriately suppressed below 2.5 nmol/l in each of the treatment cycles. Average blood estradiol levels were below 20 pg/ml on all days where a patch was applied.

Pharmacokinetic results

In all predose samples, the serum concentrations of ethinylestradiol (EE) and gestodene (GSD) were below the limit of quantification (LOQ: 10 pg/ml for EE, 250 pg/ml for GSD). After administration of the study drug, serum concentrations of EE and GSD became quantifiable for at least 168 hours in all subjects. See results in tables 2 and 3 and in figure 1.

Example 4

Comparison of polyisobutylene adhesive and acrylic formulation in humans.

A randomized cross-over study to determine the mean daily release of ethinylestradiol (EE) and gestodene (GSD) from three different transdermal patch formulations (A-C) in healthy postmenopausal volunteers after single administration was conducted. The aim was also to compare the transdermal application with that from the intravenous injection.

The test formulations were as follows:

Formulation A (Polyisobutylene)

Formulation B (polyisobutylene, 70% of formulation A)

Formulation C (Acrylate)

The survey was conducted according to the following parameters:

The patches were administered by simple transdermal administration with a wearing period per test of seven days. A week of washout was carried out after removal of the plaster at each test treatment. A dose of 60 µg EE and 75 µg GSD was administered intravenously once.

Blood sampling for kinetic measurements was at 72 hours after intravenous administration and during a period of 12 days after transdermal administration as described in Example 3. Determination of blood levels for GSD and EE was carried out according to Example 3.

Results:

The maximum concentrations of the gestode are given in the following table which indicates the difference between the polyisobutylene formulations A and B and the acrylic formulation. The figure shows the time course of the average serum levels of the gestodene.

The results indicate that the drug release of formulation C, which included a drug-containing layer of an acrylate in combination with a penetration enhancer, is significantly lower than the drug release from formulations A and B.

Example 5

Drug-containing layers containing 1.9 mg of gestodene and 0.9 mg of ethinylestradiol and consisting of different mixtures of polymers are shown (A to M).

Claims (22)

Patent requirements 1. Preparation for transdermal administration comprising a drug-containing layer comprising the 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 the gestodene of no more than 3 percent by weight of the drug-containing layer, and where the gestodene or an ester thereof is present in an amount that lies in the range between 0.5 and 3 percent by weight of the drug-containing layer. 2. Preparation according to claim 1, wherein the drug-containing layer further comprises a tackifier selected from the group consisting of hydrocarbon resins, rosin resins and terpene resins. 3. Preparation according to claim 2, where the tackifier is a rosin ester. 4. Preparation according to any one of the preceding claims, where the gestodene or an ester thereof is completely dissolved in the drug-containing layer. 5. Preparation according to any one of the preceding claims, wherein the drug-containing layer comprises less than 2 percent by weight of polyvinylpyrrolidone, methylcellulose, ethylcellulose and hydroxypropylcellulose. 6. Preparation according to any one of the preceding claims, wherein the drug-containing layer comprises less than 0.5 percent by weight of dimethyl isosorbide. 7. Preparation according to any one of the preceding claims, wherein the drug-containing layer is transparent. 8. A preparation according to any one of the preceding claims, wherein the drug-containing layer comprises less than 2 percent by weight of a skin penetration enhancer or a skin permeation enhancer. 9. Preparation according to any one of the preceding claims further comprising an estrogen. 10. Preparation according to claim 9, where the estrogen is present in the drug-containing layer in an amount of from 0.5 to 10 percent by weight of the drug-containing layer. 11. Preparation according to claim 10, where the estrogen is present in the drug-containing layer in an amount of from 0.75 to 5 percent by weight of the drug-containing layer. 12. Preparation according to any one of claims 9-11, where the estrogen is ethinylestradiol. 13. Preparation according to any one of the preceding claims, where the gestodene or an ester thereof is present in an amount that lies in the range between 1 and 2 percent by weight of the drug-containing layer. 14. Transdermal treatment system consisting essentially of a) a backing layer; b) at least one drug-containing layer as defined in any of claims 1-13; and c) optionally a removable release liner or protective layer. 15. Transdermal treatment system according to claim 14, where the gestodene or ester thereof is present in a dose of from 1 to 3 mg. 16. Transdermal treatment system according to claim 15, where the gestodene or ester thereof is present in a dose of from 1.5 to 2.5 mg. 17. Transdermal treatment system according to any one of claims 14-16, which further comprises an estrogen, where the mass ratio between the gestodene or ester thereof and the estrogen is in the range of from 4 to 0.5. 18. Transdermal treatment system according to any one of claims 14-17, wherein the gestodene or ester thereof is the gestodene. 19. Transdermal treatment system according to claim 17 or 18, where the estrogen is ethinylestradiol. 20. Transdermal treatment system according to claim 19 which comprises a dose of gestodene of 1.9 mg, a dose of ethinylestradiol of 0.9 mg and 97.2 mg of polyisobutylene in combination with a tackifier. 21. Transdermal treatment system according to claim 19 which comprises a dose of gestodene of 1.9 mg, a dose of ethinylestradiol of 0.6 mg and 97.2 mg of polyisobutylene in combination with a tackifying agent. 22. Kit comprising 1 to 11 dosage units, the dosage unit comprising a preparation as defined in any one of claims 1-13.