KR101168449B1 - Transdermal delivery system of hormones without penetration enhancers - Google Patents

Abstract

The present invention relates to a patch comprising a gestodene and optionally a drug-containing layer having a low content of hormones such as estrogen (eg ethynyl estradiol). When the patch is administered to a female, a plasma level of gastodene of at least 1.0 ng / ml is obtained at steady state conditions without the need to introduce a penetration enhancer or a penetration enhancer into the drug-containing layer. Satisfactory plasma levels of the hormone are also obtained over a period of at least one week, making the patch applicable for use in the concept of female contraception in which the patch is administered weekly.

Transdermal delivery, patches, hormones, penetration enhancers, contraception, gestesen, estrogens, progestins

Description

Transdermal delivery system for hormones that do not require penetration enhancers {TRANSDERMAL DELIVERY SYSTEM OF HORMONES WITHOUT PENETRATION ENHANCERS}

The present invention relates to the field of pharmaceutical preparation techniques. The present invention provides a low dose medicament for transdermal delivery of at least one hormone, preferably a progestin such as gestostene, and optionally estrogen, to obtain a plasma concentration profile that is effective in inhibiting ovulation in women. To provide a pharmaceutical composition.

Transdermal delivery of estrogens and progestins to provide contraception is a known concept (Sitruk-Ware, Transdermal application of steroid hormones for contraception, J Steroid Biochem Molecul Biol, Volume 53, p 247-251). However, estrogens and progestins generally do not penetrate the skin well, and for that reason, it is common to introduce substances having a skin penetration enhancing effect in the transdermal system.

The following documents describe a number of transdermal systems with progestins and estrogens present in the adhesive layer and in which the need for penetration enhancers is emphasized:

WO 92/07590 describes a composition having a penetration enhancer for transdermal delivery of gestodene and estrogen to obtain a gestododen maximum plasma level of about 0.9 ng / ml.

WO 97/397443 relates to a transdermal system containing a penetration enhancer between 30 and 60% to deliver a contraceptive effective amount of estrogen and progestin.

WO 01/37770 relates to transdermal systems containing a penetration enhancer between 10 and 60% to deliver ethynylestradiol and levonorgestrel in an effective contraceptive amount.

US 5,512,292 relates to compositions comprising an effective contraceptive enhancer with an estrogen, such as contraceptive effective amounts of gestodene and ethynylestradiol. The amount of estrogen delivered together is maintained at a constant and contraceptive effective rate, while the amount of gasogen delivered together varies with the phase of the menstrual cycle.

US 5,376,377 shows comparative studies between transdermal systems with or without penetration enhancers. The study includes an adhesive layer made of ethylene vinyl acrylate and estrogen and estrogen (ethynylestradiol) as active ingredients. The findings indicate the need to introduce penetration enhancers into the adhesive layer to obtain an effective contraceptive amount. Maximum plasma levels of about 0.8 ng / ml were obtained.

Finally, WO 90/04397 also discloses an example of a composition for transdermal delivery of gestoden, optionally in combination with an estrogen such as ethynylestradiol, wherein the composition is 1,2-propanediol or iso It may further comprise a penetration enhancer, such as propyl myristate. Many different polymers are mentioned as adhesive layers. Examples of polar polymers (polyacrylates and silicones) in combination with penetration enhancers are specifically disclosed. The obtained plasma levels of gestodene at steady state conditions were about 250 to 337 pg / ml.

In addition to penetration enhancers, it is also proposed to add solubilizers or the like to the drug-containing layer to increase the amount of drug dissolved, or to add substances that inhibit crystallization of the drug in the layer.

For example, US Pat. No. 6,521,250 discloses an adhesive layer comprising a mixture of styrene-isoprene block copolymers and hydrogenated resin acids or derivatives thereof, wherein the amount of resin is 55-92%. Such an adhesive layer seems suitable for transdermal delivery of estradiol in combination with progestin in that the system has adequate adhesive contact with the skin for prolonged application and prevents the crystallization of hormones.

U. S. Patent No. 5,904, 931 relates to a TTS system containing steroids (guestene and the like) and dimethyl isosorbide in the drug-containing layer. The latter enhances the solubility of steroids in the drug-containing layer. The concentration of gestodene in the drug-containing layer can vary from 1 to 40% by weight of the layer, wherein the drug-containing layer is an adhesive such as polyacrylate, silicone, styrene-butadiene copolymer and polyisobutylene It can be configured as. In particular, polar polymers such as polyacrylates are suitable.

DE 199 06 152 describes transdermal drug delivery embedded in polar polymers, such as polyvinylpyrrolidone, methylcellulose, ethylcellulose and hydroxypropylcellulose, before gestoden is added to an adhesive polymer such as polyisobutylene. It is about the world. Thus, the transdermal drug delivery system is a two-phase system and the drug-containing layer is not transparent due to the content of the polar polymer, which results in the presence of milky spots upon exposure to water. The amount of gestoden in the drug-containing layer is 5.1% by weight of the drug-containing layer.

In WO 02/45701 it is emphasized that adding rosin esters in amounts of up to 25% by weight to the adhesive layer can sufficiently inhibit the crystal formation of active substances such as, for example, hormones. The adhesive layer can include all non-toxic natural and synthetic polymers known and suitable for use in transdermal systems such as polyacrylates, polysiloxanes, polyisobutylenes, styrene block copolymers, and the like. In particular, polyacrylate is emphasized. The TTS system is suitable for steroids (guestene), which can be introduced into the adhesive layer in an amount substantially saturated or near or above its concentration in the carrier composition, rather than in a substantially saturated state. Preferably, the amount of steroid is from about 0.1% to about 6% by weight based on the dry weight of the total carrier composition.

Unfortunately, penetration enhancers can adversely affect the skin, such as skin irritation, which causes the percutaneous system to some extent to be unacceptable to the user. In addition, it is generally known that penetration enhancers can negatively affect the stability of the active material, making long-term storage difficult. It is also recognized that the viscosity is reduced by the introduction of penetration enhancers, resulting in the formation of dark rings along the edges of the patch.

Therefore, there is a need for a transdermal system that does not have the above-mentioned disadvantages, for example, a transdermal system that does not require a penetration enhancer to obtain a therapeutically effective amount of a steroid hormone such as gestodene.

Gestodene is a known orally active synthetic progestin with a progesterone-like activity profile (see US Pat. No. 4,081,537). It is used as an oral contraceptive in combination with certain estrogens.

Summary of the Invention

The present invention relates to a composition suitably formulated for transdermal delivery of hormones such that a contraceptive effective level is obtained without the need to introduce a penetration enhancer into the hormone-containing adhesive layer. The actual hormone is preferably a steroidal hormone such as progestin such as gestodene, which is optionally used in combination with estrogen. Contrary to the general knowledge in the art, the present inventors have provided a transdermal system comprising a limited number of components. For example, no penetration enhancer or permeation enhancer is needed to obtain high release rates and therapeutically effective plasma levels.

The inventors have found that the selection of a drug-containing layer having solubility for steroidal hormones (e.g., Gestogen) is critical for successfully obtaining a therapeutically effective level of blood hormones. Example 2 herein shows a comparison of two gestodene-containing layers in the release rate of gestodene. It is clearly shown that a drug-containing layer of polar polymer (polyacrylate) requires a concentration of gustodene of 3.9% by weight of the layer in order to obtain the desired high release rate. Surprisingly, in the pharmaceutical-containing layer comprising a less polar polymer such as polyisobutylene, the same high release rate was obtained at 1.9% by weight of Gestodene concentration without the use of penetration enhancers as opposed to what was previously known. can do. In vivo studies also showed that drug-containing layers containing polymers of a more nonpolar type, such as polyisobutylene, rather than polyacrylates are better in terms of obtaining high plasma AUC (Example 4).

Accordingly, the present invention, contrary to what could be expected, employs a medicament-containing layer, which preferably contains a nonpolar polymer such as polyisobutylene and is characterized by a limited solubility in gestodene of up to 3% by weight. It was found that it has a high release rate of Gestoden, although the actual load of Gestodene in the drug-containing layer is low. This is an obvious advantage over conventionally known TTS systems in that it reduces the risk of skin irritation and reduces the exposure of hormones to users and the environment.

A further advantage is that the drug-containing layer is a single phase system and contains medicines evenly distributed across the layers. In other words, the drug-containing layer is homogeneous. In the absence of polar polymers or other polar additives that tend to absorb water or retain water, the drug-containing layer is transparent. Thus, provided by the present invention is a clear composition in which the skin can be visually inspected through the drug delivery system. Transparency is an obvious advantage because non-transparent systems are noticeable and represent pain not intended as a contraceptive patch.

Accordingly, the first aspect of the invention relates to a composition for transdermal delivery with progestins such as steroid hormones, preferably gestodenes or derivatives (esters) thereof, and optionally estrogens. The composition comprises a medicament-containing layer comprising the hormone and one or more pharmaceutically acceptable excipients or carriers, wherein the medicament-containing layer is less than or equal to 3 weight percent of the medicament-containing layer Soluene).

In certain aspects, the present invention relates to a composition comprising a progestin, such as gestoden or derivatives thereof, and a polymer in an amount of about 15 to 99% by weight of the drug-containing layer, wherein the polymer is formed of the drug-containing layer 3 wt% or less, selected from the group consisting of hydrocarbon polymers, polysiloxanes, poly-acrylates, and mixtures thereof, which form a drug-containing layer having solubility in gestodene.

In another particular aspect, the present invention relates to progestins, such as gestoden or derivatives thereof, to polymers in an amount of about 15 to 99% by weight of the drug-containing layer, to 85 weights in an amount ranging from 1 to 85% of the drug-containing layer. A composition comprising a tackifier, such as rosin ester, in an amount of up to%, and optionally a medicament-containing layer consisting primarily of estrogen.

In another particular aspect, the invention

i) derivatives such as progestins, preferably gestodenes or esters thereof; And

ii) transdermal delivery comprising a pharmaceutical-containing layer comprising a polymer selected from the group consisting of polyisobutylene, polybutene, polyisoprene, polystyrene, styrene isoprene styrene block polymer, styrene butadiene styrene block polymer and mixtures thereof It relates to a composition.

In another particular aspect, the present invention relates to a transparent composition for transdermal delivery, wherein the composition comprises a medicament-containing layer comprising a progestin, preferably a gastodene or a derivative thereof (such as an ester thereof), The containing layer has a gestoden solubility of not more than 3% by weight of the drug-containing layer.

It has been surprisingly found that by administering gestodene formulated with the compositions of the present invention, relatively high plasma levels of gestodene can be maintained for a sustained time. Plasma profile and plasma levels of gestodene resulting from administration of gestodene and optionally estrogen are effective in suppressing ovulation in women.

Accordingly, the compositions of the present invention can be used for the inhibition of ovulation or optionally for the treatment of endometriosis, premenstrual syndrome, menopausal disorders, prevention of osteoporosis, regulation of the menstrual cycle or stabilization of the menstrual cycle.

In another aspect, the invention relates to the use of the composition described herein for inhibiting female ovulation, optionally in combination with estrogen. When the composition is administered alone, the plasma concentration-time curve of the obtained gastodene is characterized as having a plasma level of gastoden at a concentration of at least 1.0 ng / ml when measured under steady state conditions. In addition, the present invention relates to a method for suppressing ovulation in females such as women. The method comprises topically administering to the skin or mucous membranes an effective amount of gestodene or a derivative thereof, optionally in combination with estrogen, the plasma concentration of gestodene obtained upon a single administration of the gestodene- The time curve is characterized as having Gestodene plasma levels at a concentration of at least 1.0 ng / ml as measured under steady state conditions.

Finally, the invention relates to 1 to 11 dosage units, for example 9 or 9, formulated in a form for transdermal delivery of gestodene or derivatives thereof, such as in the form of a composition as described herein, depending on the length of the treatment period. A kit comprising three dosage units. The dosage form comprises a medicament-containing layer comprising gestoden and one or more pharmaceutically acceptable excipients or carriers, wherein the medicament-containing layer is up to 3% by weight of the medicament-containing layer Has solubility in stodene.

The present invention provides a composition for transdermal delivery of a hormone (transdermal therapeutic system) that results in a therapeutically effective amount such as a contraceptive effective amount of hormone upon topical application to the skin or mucous membranes, even if a skin penetration enhancer is not necessarily introduced into the drug-containing layer. do.

The term "locally" or "locally" as used herein refers to direct contact of the composition with the surface of a mammal, including the skin and mucous membranes.

The term "mucosa" refers to any surface membrane of a mammal that is not skin, such as the surface present in the oral cavity, vagina, rectum, nose or eye. That is, the mucosa may be a mucous membrane of the oral cavity, vagina, rectum, nose or eyes.

The compositions of the present invention may be devised in a variety of different application forms, as long as they comprise a medicament-containing layer adapted to be placed in close contact with or in direct contact with the skin or mucous membranes when topically administered.

Therefore, in a preferred application form, the composition, for example a transdermal therapeutic system,

a) a backing layer;

b) at least one drug-containing layer comprising said hormone or a mixture of said hormone and at least one pharmaceutically acceptable ingredient; And

c) consisting predominantly of an optionally removable release liner or protective layer.

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

If the drug-containing layer does not exhibit sufficient self-adhesion to the skin or mucosa, it may have a pressure sensitive adhesive layer or additional layers of pressure sensitive adhesive edges or rings to ensure adhesion of the composition to the skin over the entire application period. Can be. The pressure sensitive adhesive layer may be located between the drug-containing layer and the skin, and the adhesive ring may be located around or at the edge of the drug-containing layer. Optionally, the composition may also include one or more membrane or adhesive layers. For example, a membrane for controlling the release of hormones may be located between the drug-containing layer and the pressure-sensitive layer or between the drug-containing layer and the skin.

The size of the drug-containing layer is selected from a variety of reasonable sizes. As used herein, a reasonable size means a surface area of about 8 to 12 cm ² , such as about 5 to 20 cm ² , preferably about 7 to 15 cm ² , most preferably 10 cm ² . In particular, the surface area is the area in contact with or close to the skin or mucous membranes.

According to the present invention, it has been found that a drug-containing layer with minimized solubility for hormones provides sufficient skin penetration of steroidal hormones. In the present invention, the drug-containing layer is characterized by defining its solubility in gestodene. In particular, the skin penetration rate is sufficient without the need to introduce skin penetration enhancers. For example, it has surprisingly been found that skin penetration of steroidal hormones of the present invention results in a therapeutically effective amount of steroidal hormones in the circulating blood, such as a contraceptive effective amount of hormones.

Accordingly, the present invention relates to a composition for transdermal delivery of a steroidal hormone, such as progestin, such as, for example, gestoden or derivatives thereof in the first aspect. The composition comprises a medicament-containing layer and one or more pharmaceutically acceptable excipients or carriers, wherein the medicament-containing layer has a solubility in gestoden up to 3% by weight of the medicament-containing layer. The composition optionally comprises estrogen.

In some embodiments, the solubility of the drug-containing layer in the gastodene is 2.5% by weight or less, preferably 2.0% or less, for example 1.8% or less of the drug-containing layer. In principle, the solubility may be very low, but at the lowest level of solubility the critical level is about 0.1%, for example about 0.2%, 0.3%, 0.5%, 0.7% of the gastodene in the drug-containing layer. , 0.8%, 0.9% or 1% by weight. The solubility of the drug-containing layer in gastodene is about 0.1% to 3%, for example about 0.2% to 3%, 0.4% to 3%, 0.5% to 3%, 0.8% to 3% or 1% It is generally considered to be in the range of 3%. In another embodiment, the upper limit of the range is not 3% by weight and is lower, such as 2.5%, 2.2% or 2.0%.

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

In a preferred embodiment of the present invention, the esters of gestodene are gestodeden propionate, gestodene valerate, and / or gestodeden capronate, which are described in US Pat. No. 5,858,394.

As mentioned, the inventors have found that a suitable drug-containing layer of the present invention has solubility in steroid-based hormones (e.g., Gestoden) up to 3% by weight of the drug-containing layer.

The phrase "solubility in steroidal hormones such as solubility in gestododen up to 3% by weight of the drug-containing layer" may be dissolved in a particular drug-containing layer that produces a visually clear solution. It is meant to characterize the amount of steroid-based hormones such as stodene, solubility in is not to be understood as meaning the actual concentration of hormones such as gestodene in the drug-containing layer. As such, the total concentration of hormones in the drug-containing layer may be at least 3 weight percent or less of the drug-containing layer, and the total concentration of hormones in the drug-containing layer may be at a saturated or saturated level. A drug-containing layer containing hormones can be brought.

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

One test method is to determine whether the hormone is completely dissolved so that the solid particles are not detected visually or using a microscope with a magnification of 25 ×.

Another method is to actually measure the solubility of the drug-containing layer in hormones by the following method. The method is based on determining the release rate constant of the hormone from the drug-containing layer containing the hormone in fully dissolved form and from the drug-containing layer in which the hormone is partially dissolved.

The method includes the following steps:

First, prepare the same drug-containing layer with various, for example, increasing amounts of hormones. In general, at least three different drug-containing layers should contain the hormone in a fully dissolved form within the drug-containing layer, and at least three drug-containing layers may be, for example, in the form of solid particles. It should contain partially dissolved hormones.

With regard to the manufacturing method, the following steps may be followed. Any other methods known in the art may be suitable for preparing the adhesive layer:

Dissolve or suspend the pharmaceutical substance in a suitable solvent.

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

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

The mixture is coated on a release liner to a suitable thickness and dried under heating to evaporate the solvent.

The laminate obtained is covered with a backing foil.

Secondly, the device given in the relevant part of the European Pharmacopoeia (Ph. Eur 2.9.4 Dissolution Test for Transdermal Patch) or US Pharmacopeia (USP 26, Drug Release, Device 5 (paddles on the disc)) and Test conditions are used to test the rate of release of the drug from the drug-containing layer.

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

After removal of the release liner, the sample is placed in a container prefilled with a suitable dissolution medium equilibrated at 32 ° C. ± 0.5 ° C. (as described above in the Pharmacopoeia mentioned above). The drug-containing layer must be in contact with the dissolution medium. Samples of the solvent 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 method. The dissolution medium may be selected from those which ensure the settling conditions. For example, a suitable dissolution medium is an aqueous solution containing up to 30% by weight of organic solvents such as ethanol, isopropanol and dioxane.

Third, the rate of release of hormones from the two drug-containing layers is measured as follows:

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

The release rate constant for each drug-containing layer is determined by the slope obtained by linear regression analysis of the square root of at least three data points versus time for the amount of hormone per unit of area.

The release-rate constants for each drug-containing layer are plotted against the concentration of hormones in the drug-containing layer. Next, a linear regression analysis is performed separately for the drug-containing layer with the fully dissolved hormone and for the drug-containing layer in which the partially dissolved hormone, ie, the solid particles of the hormone, is present. The two regression lines will intersect each other at one point. The concentration of a hormone that can be read at the intersection of the two regression lines indicates "solubility" in the drug-containing layer of the hormone.

The term "medicament-containing layer" is meant to denote a transdermal composition or part of a system in which steroidal hormones are present. The drug-containing layer may be in semi-solid or solid form and comprises a hormone formulated directly in the layer. Hormones of the present invention may be dispersed, partially dispersed, partially dissolved or completely dissolved therein, depending on the concentration and physicochemical properties of the hormone. The drug-containing layer is not meant to be in the form of a gel or a liquid. Intentionally, the drug-containing layer means direct contact with the skin or mucous membranes. However, in some embodiments, there is an additional layer called the drug-free layer, located between the drug-containing layer and the skin or mucous membranes.

As mentioned, the compositions according to the invention do not necessarily comprise skin penetration enhancers. Thus, in some embodiments of the invention, the medicament-containing layer excludes the presence of a skin penetration rate enhancer, which means that the medicament-containing layer consists mainly of ingredients that do not include a skin penetration rate enhancer. it means. This means for example that less than 2%, ie less than 1%, preferably less than 0.5%, ie less than 0.2%, less than 0.1% by weight of the drug-containing layer consists of skin penetration enhancers.

According to the invention, the selection of a suitable drug-containing layer performs skin penetration. Said suitable drug-containing layer is preferably made of a polymer or a mixture of polymers. The polymer may or may not have noticeable adhesion properties. In some embodiments, the drug-containing layer is a so-called pressure sensitive adhesive layer.

In principle any mixture of polymers which results in the solubility in gestodene can be applied. That is, in one embodiment of the invention the drug-containing layer comprises at least one polymer that may or may not have adhesive properties. Typically, such polymers are biologically acceptable lipophilic polymers of the kind of hydrocarbon polymers, polysiloxanes, poly-acrylates or mixtures thereof. Preferably, the polymer may be selected from hydrocarbon polymers, polysiloxanes and / or polyacrylates which form a drug-containing layer having a solubility in gestodene of up to 3% by weight of the drug-containing layer.

The amount of polymer is a somewhat decisive variable. Appropriate amounts may depend on the actual type of polymer and steroidal hormone used. In general, the amount of polymer is at least 1% by weight of the drug-containing layer, for example at least 5%, 10%, 15% or 20%. However, preferably the polymer is at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or at least 80 weight of the drug-containing layer. Present in the drug-containing layer in an amount of%. In other words, the polymer may be used in an amount of about 1 to 99% by weight of the drug-containing layer, for example about 5 to 99%, 10 to 99%, 15 to 99% or 20 to 99%. Preferably, the polymer is about 15 to 99%, for example about 15 to 90%, 15 to 85% or 15 to 80%, for example about 20 to 85%, 20 to 75 of the drug-containing layer %, For example about 25 to 85%, 25 to 75% by weight of the drug-containing layer.

As mentioned, certain aspects of the invention relate to compositions for transdermal delivery of steroidal hormones, such as gestodene or derivatives thereof, and optionally estrogens, wherein the compositions

Steroidal hormones, such as at least one gestodene or derivative thereof, and at least one pharmaceutically acceptable component or carrier;

Preferably a medicament-containing layer comprising a polymer or polymer mixture in an amount of about 15 to 99% by weight of the medicament-containing layer,

Wherein the polymer consists of hydrocarbon polymers, polysiloxanes, poly-acrylates, and mixtures thereof, which form a drug-containing layer having solubility in the steroidal hormone, up to 3% by weight of the drug-containing layer. Selected from the group.

As mentioned, it has been found that adhesive layers comprising more non-polar types of polymers, such as hydrocarbon polymers, are superior to polymers of polar type, such as polyacrylates (Example 2). Thus, in a preferred embodiment of the invention, the medicament-containing layer is a polymer, preferably polyisobutylene, polybutene, polyisoprene, polystyrene, styrene isoprene styrene block polymer, styrene butadiene styrene block polymer and / or their Hydrocarbon polymers, which may include mixtures.

As mentioned, in some embodiments of the present invention, the drug-containing layer is an adhesive. Preferentially, the polymer of the drug-containing layer has suitable adhesive properties such that no additional sticky material such as a tackifier is needed. If it is deemed necessary to improve the adhesive strength of the drug-containing layer, the layer further comprises a tackifier.

The term "tackifier" refers to a substance that improves the adhesive strength of the adhesive layer to the skin or mucous membranes.

Examples of tackifiers are selected from hydrocarbon resins, rosin resins and terpene resins. Examples of hydrocarbon resins are from ExxonMobil under the trade name Escorez ^(R) ; Commercially available from Eastman under the trade names Regalite ^(R) , Piccotac ^(R ) and Picco ^(R) or under the trade name Indopol ^(R) from BP. Examples of rosin esters suitable for the transdermal system according to the invention are esters of hydrogenated wood rosin, for example pentaerythritol ester of hydrogenated wood rosin, esters of partially hydrogenated wood rosin, for example partially hydrogenated wood. Pentaerythritol ester of rosin, ester of wood rosin, ester of modified wood rosin, ester of partially dimerized rosin, ester of deoiled rosin, ester of dimerized rosin and similar rosin, and combinations and mixtures thereof It includes. Such rosin esters are trade names such as Foral ^(R) , Foralyn ^(R) , Pentalyn ^(R ), Permalyn ^(R ) and Staybelite ^(R) . It is marketed under.

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

The tackifier may be present in any suitable amount so long as the critical solubility of steroid hormones in the drug-containing layer is not significantly affected. That is, the tackifier may be present in the drug-containing layer in an amount of about 0.1 to 95%, for example 0.5 to 95%, for example 1% to 95% by weight of the drug-containing layer. That is, the tackifier is about 1 to 85%, 1 to 75%, 1 to 65%, 1 to 55%, 1 to 50%, 1 to 45%, 1 to 40% or more preferably about 1 to It may be present in an amount of 35%, for example preferably 1 to 30%, more preferably 1 to 25%. Clearly, the amount of tackifier in the drug-containing layer can be critical for the solubility of steroidal hormones in the drug-containing layer. Thus, in another embodiment of the present invention, the tackifier is present in the drug-containing layer in an amount of up to 35%, for example up to 30%. More preferably, the amount of tackifier is present in an amount of up to 25%, for example up to 20% or up to 15%, more preferably up to 10%, 7%, up to 5% of the weight of the drug-containing layer.

Another particular aspect of the invention relates to a composition for transdermal delivery of gestodene or its esters and optionally estrogen, wherein the composition

At least one steroidal hormone such as gestodene and one or more pharmaceutically acceptable component (s) and / or carrier (s);

-A polymer or polymer mixture, preferably in an amount of about 15 to 99% by weight of the drug-containing layer (the polymer is preferably a hydrocarbon polymer, polysiloxane, poly-acrylate and mixtures thereof, most preferably a hydrocarbon polymer) Polyisobutylene, polybutene, polyisoprene, polystyrene, styrene isoprene styrene block polymer, styrene butadiene styrene block polymer and / or mixtures thereof) As mentioned, the medicament-containing layer is mentioned above. Has solubility in gestoden as such); And

Tackifiers in an amount of up to 85% by weight of the drug-containing layer; And

Optionally comprises a drug-containing layer consisting predominantly of estrogen.

As mentioned, the drug-containing layer should consist of ingredients that form a layer that meets solubility criteria for gestodene. Preferably, the criterion is met if the drug-containing layer consists predominantly of the hormone of the invention together with a polymer or a mixture of polymers and optionally a tackifier.

In some embodiments, suitable polymers of the present invention are lipophilic and substantially free of any free hydrophilic groups. That is, any suitable hydrocarbon polymer, polysiloxane or poly-acrylate may contain a limited amount of free hydrophilic functional groups such as carboxyl-, ester-, hydroxy-, amino-, amide, halogen- or sulfo- groups. It is selected from the polymer which has a functional group in a side chain. Therefore, in some embodiments, the polymer predominantly excludes poly-acrylates, some of which include free carboxyl and / or hydroxyl groups.

In a preferred embodiment, the polymer is a hydrocarbon polymer, poly-siloxane or a mixture of two kinds of polymers. As mentioned, the hydrocarbon type polymer is a non-polar kind of polymer that is substantially free of hydrophilic functional groups such as carboxyl-, ester-, hydroxy-, amino-, amide, halogen- or sulfo- groups in the side chain. Therefore, in the most preferred embodiment, the polymer is a hydrocarbon polymer.

Excess hydrocarbon polymer is present in both high molecular weight and low molecular weight or mixtures thereof. Typically, the hydrocarbon polymer is in the form of polyisobutylene, polybutene, polyisoprene, polystyrene, styrene isoprene styrene block polymer, styrene butadiene styrene block polymer or mixtures thereof. The molecular weight (at least for polyisobutylene) of the high molecular weight polymer is typically in the range of 500,000 to 2,000,000 Da, while the low molecular weight is in the range of about 20,000 to 100,000 Da. Typically such polymers comprise a mixture of a high molecular weight polymer and a low molecular weight polymer, wherein the amount of low molecular weight polyisobutylene in the total mixture of the total mixture is at least 50%.

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

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

Poly-siloxanes are typically high molecular weight polydimethylsiloxanes having free silanol groups or endcapped silanol groups (Bio-PSA ^(R) ).

As mentioned above, poly-acrylates which may be excluded in some embodiments or used in minimal amounts are typical examples of homopolymers of acrylic esters, copolymers of two or more types of acrylic ester units or of acrylic esters or other functional monomers. Polymers selected from copolymers. Acrylic esters include, but are not limited to, butyl methacrylate, pentyl methacrylate, hexyl methacrylate, heptyl methacrylate, octyl methacrylate, nonyl methacrylate, decyl methacrylate. For example, ethylene / ethylacrylate copolymers, polymethacrylate polymers and polysiloxane-polymethacrylate copolymers. As mentioned, functional monomers containing hydrophilic functional groups such as hydroxyethyl methacrylate, hydroxypropyl methacrylate and the like, and monomers containing amide groups such as methacrylate, dimethylmethacrylamide are suitable May be excluded as a polymer.

Also for the same reasons polyalkylenes (polyethylene, polypropylene, ethylene / propylene copolymers, chlorinated polyethylene, polytetrafluoroethylene), polyacetates (ethylene / vinyl acetate copolymers, vinyl chloride-vinyl acetate copolymers), poly Vinylene (polyvinylidene chloride, ethylene-vinyl alcohol copolymer, ethylene-vinyloxyethanol copolymer, polyvinylpyrrolidone) polycarbonate, cellulose polymer (methyl or ethyl cellulose derivative, hydroxypropyl methyl cellulose and cellulose ester) May not be a suitable polymer according to the present invention and is used in some embodiments of the present invention or at least in limited amounts. However, this exclusion does not prevent the use of the polymer in other layers or portions of the composition.

Furthermore, in some embodiments, the medicament-containing layer does not include or at least have a limited amount of crystallization inhibitors such as polyvinylpyrrolidone, cellulose polymers such as methyl or ethyl cellulose derivatives or hydroxypropyl methyl cellulose or mixtures thereof Include only as.

Also in some embodiments, solubilizers such as dimethyl-isosorbide are not present in the drug-containing layer or are present only at least in limited amounts.

The term “limited amount” means that the polymer or solubilizing agent in question is present at a concentration of less than 10%, for example less than 8, 5, 3, 2, 1, 0.5 or 0.2% by weight of the drug-containing layer. Means.

As mentioned, it was possible to provide sufficient skin penetration of steroidal hormones without introducing skin penetration enhancers and / or penetration enhancers. That is, in an interesting embodiment of the present invention, skin penetration enhancers and / or penetration enhancers are present in the drug-containing layer in an amount excluded or limited from the drug-containing layer, which amount is equal to 5 weight of the drug-containing layer weight. Less than%, for example, less than 4%, 3%, 2%, 1%, 0.5% or 0.2%.

The terms "skin penetration enhancer" and "permeation enhancer" are interchangeable terms in the present invention and refer to compounds that provide improved skin penetration / permeation for the active medicament when administered with the medicament to the user's skin. Indicates. Penetration / permeation enhancers in transdermal compositions will change the thermodynamic activity of the drug in the drug-containing layer, thereby leading to a positive or negative “push” action. In addition, some penetration / permeation enhancers can be thought to penetrate into the highly ordered intercellular lipid structures of the stratum corneum to increase lipid acyl chain mobility, thereby reducing its resistance and thus providing a “pull” action. have.

Any skin penetration / permeation enhancement effect of the material can be recognized by testing the same composition with or without penetration enhancers, for example using hairless mouse skin and the like. Those skilled in the art know such test methods.

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

Alcohols such as monohydric alcohols having about 2 to 10 carbon atoms, for example ethyl, isopropyl, butyl, pentyl, octanyl decanyl and / or benzyl alcohol; Dihydric alcohols such as 1,2-propanediol, polyhydric alcohols such as glycerin, sorbitol and / or polyethylene glycol; Saturated or unsaturated fatty alcohols having 8 to 18 carbon atoms, for example capryl-, decyl-, lauryl-, 2-lauryl-, myristyl-, cetyl-, stearyl-, oleyl-, Linoleyl- and linolenyl alcohol.

Fatty acids such as saturated or unsaturated fatty acids which may contain from 8 to 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, valerian acid, capronic acid, caprylic acid, pelargon acid, caprinic acid, isovaleric acid, neopentanoic acid, neoheptanoic acid and / or isostearic acid. do.

Esters, for example aliphatic esters ethyl acetate, lower (C1-C4) alkyl esters of lactic acid, fatty acid esters of the formula CH _3- (CH ₂ ) _n -COOR, wherein n is from 8 to 18 Is an alkyl moiety having up to six carbon atoms), for example lauric acid, myristic acid, stearic acid and palmitic acid, for example methyl esters, ethyl esters, propyl esters, isopropyl esters of these acids , Butyl esters, sec-butyl esters, fatty acid esters such as isobutyl esters, or the formula R'OCO (CH ₂ ) _m COOR 'wherein m is a number from 4 to 8 and R' is at most 6 in each case Dicarboxylic acid diesters, such as propyl oleate, decyl oleate, isopropyl palmitate, glycol palmitate, glycol laurate, dodecyl myristate, isopropyl myristate Glycol stearate. Suitable dicarboxylic acid diesters are, for example, diisopropyl adipate, diisobutyl adipate and diisopropyl sebacate.

Aliphatic alcohols such as polyoxyethylene (4) lauryl ether, polyoxyethylene (2) oleyl ether and polyoxyethylene (10) oleyl ether (for example cetyl, lauryl, oleyl) Polyethylene glycol ether).

Alkanes, for example alkanes having a chain length of 6 to 17 carbon atoms.

Amides such as dimethyl acetamide, dimethyl formamide, dimethyl laurylamide, dimethyl laurylamide and / or fatty acid amides and derivatives thereof.

Amides, for example amides with long aliphatic chains, such as cyclic ureas, dodecyl-urea, diphenyl-urea and / or allantoin, or aromatic amides, ureas and urea derivatives.

- amino acid.

Amino acetates such as derivatives of amino acetates, for example dodecyl-N, N-dimethylaminoacetate and dodecyl-2-methyl-2- (N, N-methylaminoacetate), 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 1-dodecylazacycloheptan-2-one derivatives, azacycloalkanone derivatives and / or hexamethylenelauramid derivatives.

Cyclodextrins such as alpha, beta and gamma cyclodextrins.

Glycerides, for example monoglycerides including glycerol monooleate, glycerol monolaurate and glycerol monolinoleate, polyethylene glycol-3-lauamide (PEG LR), polyethylene glycol monolaurate (PGML), glycerol mono Oleate (GMO), glycerol monolinoleate and / or glycerol monolaurate (GML).

Glycols, for example ethylene glycol, diethylene glycol, or propylene glycol dipropylene glycol and / or trimethylene glycol.

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

Polyols, such as propylene glycol.

Pyrrolidones, for example 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 (decyl Thio) ethyl) -2-pyrrolidone and / or N- (2-hydroxyethyl) -2-pyrrolidone.

Sulfoxides such as sulfoxide derivatives, for example methyloctyl-sulfoxide, dimethyl-sulfoxide (DMSO), hexylmethyl-sulfoxide (hexyl-MSO) and / or decylmethyl-sulfoxide (decyl-MSO) .

Surfactants such as cationic surfactants such as cetyltrimethylammonium bromide, octadecyltrimethylammonium chloride, cetylpyridinium chloride and / or equivalent cationic compounds, sodium lauryl sulfate and / or sodium dodecyl sulfate Anionic surfactants such as but not limited to sulfates, and nonionic interfaces such as sorbitol esters and sorbitol anhydrides including, but not limited to, polysorbates, sorbitan-monopalmitates and / or sorbitan-polyoleates Active agent.

Terpenes, ketones and oxides.

In addition to steroidal hormones such as progestins, one or more polymers, one or more tackifiers and optionally estrogens, drug-containing layers or other parts of the composition may be stabilizers, dyes, pigments, inert fillers, antioxidants, antioxidants, elastomers It also contains conventional components of thermoplastics and other transdermal compositions known in the art. Preferably, the composition or at least the medicament-containing layer contains no or limited amounts of polyvinylpyrrolidone, methylcellulose, ethyl cellulose, hydroxypropyl methylcellulose, and / or dimethyl-isosorbide (the medicament- Less than 1%, 0.8%, 0.5%, 0.2% or 0.1% of the weight of the containing layer).

The compositions of the present invention are transparent or at least in very interesting embodiments, it should be understood to mean that the skin can be visually examined through the medicament delivery system. That is, the drug-containing layer refers to a single phase system in which a drug (here progestin) is completely dissolved in the drug-containing layer. The properties of the single phase system can be confirmed by the mechanical stretching of the drug-containing layer by the test method described below.

The drug-containing layer is also characterized as being homogeneous. The term "homogeneous" is used to express a system of single phases whose matrix consists of one polymer phase. The system can be distinguished from a multiphase system consisting of at least two polymer phases. In most cases polyphase systems can be visually perceived by their opaque appearance. The opaque appearance is caused by the diffraction of light due to the difference in the diffraction index on the polymer. Other methods for detecting single phase systems are by microscopic or rheological methods or by mechanically stretching the polymer thin film. During mechanical stretching, the polymer thin film consisting of a multiphase system becomes opaque as visually judged.

In short, an interesting embodiment of the invention

i) progestins, such as gestoden or derivatives thereof; And

ii) a pharmaceutical-containing layer comprising a polymer selected from the group consisting of polyisobutylene, polybutene, polyisoprene, polystyrene, styrene isoprene styrene block polymer, styrene butadiene styrene block polymer and mixtures thereof do.

In another interesting embodiment thereof, the drug-containing layer is characterized by the following variables, which may exist as a single variable or in a combination of variables;

? The drug-containing layer has a solubility in gestoden of not more than 3% by weight of the drug-containing layer;

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

? The drug-containing layer excludes polyvinylpyrrolidone, methylcellulose, ethylcellulose and / or hydroxypropylcellulose or polyvinylpyrrolidone, methylcellulose, ethylcellulose and / or in an amount less than 2% of the layer weight. Or hydroxypropylcellulose;

? The drug-containing layer contains progestin (gestoden or ester thereof) completely dissolved in the layer;

? The drug-containing layer comprises gestoden or an ester thereof in an amount of 0.5 to 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 a single phase;

? The drug-containing layer excludes or contains less than 2% by weight of the skin penetration enhancer;

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

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

As mentioned, the compositions of the present invention are characterized by delivering a contraceptive effective amount of a steroidal hormone, such as progestin, such as gestostene, optionally in combination with estrogen. In embodiments wherein progestin is gestodene or a derivative thereof, the composition may be characterized by providing an in vitro hairless mouse skin penetration rate of at least 25 μg / cm ² * 24h of gestodene and / or its derivatives. . In other words, the composition may be characterized as having a medicament-containing layer that delivers gestodene and / or its derivatives in an amount of about 40 to 70 μg per day.

Gestodene or a derivative thereof may not be used as a medicament in the composition of the present invention. Dienoguest, drospirenone, levororgestrel, cyproterone acetate, tetrahydrodienoguest, noretysterone, noretysterone acetate, desogestrel, 3-keto-desorgstrel, norgesti Other progestins such as mate, linestrenol, methoxy-progesterone acetate, norgestrel, noestyrone enanthate, trimegstone or alpha and beta-progesterone receptor ligands, together with gestodene or gestodene Instead it may be included in the drug-containing layer.

As mentioned, the composition is effective in suppressing ovulation. In some cases, the composition further comprises estrogen. Estrogens can be introduced with progestins in the same drug-containing layer or in separate drug-containing layers without progestins.

The term "estrogen" includes both natural 17β-estradiol and semi-synthetic estrogen derivatives such as esters of natural estrogens and 17-alkylated estrogens. Semi-synthetic esters of natural estrogens are, for example, estradiol-17-β-enanthate, estradiol-17-β-valerate, estradiol-17-β-benzoate, estradiol-17-β-undecano Ate, estradiol-16,17-hemisuccinate or estradiol-17-β-cifionate. Examples of 17-alkylated estrogens are ethynylestradiol, ethynylestradiol-3-isopropylsulfonate, quinestrol, mestranol or methyl estradiol. The term "estrogen" may also include non-steroidal compounds with estrogen activity, such as diethylstilbestrol, dienestrol, clomiphene, chlorotriacene or cyclofenil.

In a preferred embodiment, the estrogen is ethynylestradiol.

To obtain a therapeutically effective amount of a hormone in the blood, the actual concentration of the drug in the drug-containing layer can be adjusted. Generally speaking, the drug-containing layer should contain certain hormones in excess of the amount of hormone absorbed to obtain a therapeutically effective amount of the hormone. Typically, the excess is small, for example the amount of hormone is less than 10 times, preferably less than 5 times, for example less than 2 times the desired / needed amount of hormone. For example, it is also contemplated that it is important to limit the amount of hormone in order to reduce the overall exposure of the hormone to the user. Therefore, suitable concentrations in the drug-containing layer of steroidal hormones such as progestin, such as gestodene or derivatives thereof, are about 0.5 to 10% by weight of the drug-containing layer. In even more preferred embodiments, the concentration of the hormone is about 0.5 to 10%, for example about 0.75 to 5%. As mentioned, the total concentration of a hormone, such as gestodene, may result in a drug-containing layer comprising the hormone in saturated or sub-saturated levels. In a very interesting embodiment, the concentration in the medicament-containing layer of steroidal hormone, such as gestoden or derivatives thereof, is about 1 to 3%, for example 1 to 2%.

Likewise, in some embodiments of the present invention further comprising estrogen, the estrogen is about 0.5-10% by weight of the adhesive layer, preferably about 0.75-5%, more preferably about 1-3%, for example 1 Present in the drug-containing layer in an amount of from 2%.

In addition, progestins, such as gestoden or derivatives thereof, have a mass ratio to the estrogen in the range of about 4 to 0.5, preferably 2 to 0.5, for example 1: 1.

It has surprisingly been found that relatively high plasma levels of gestodene can be maintained for a prolonged period of time by administering gestodene or a derivative thereof formulated with the composition of the present invention. Surprisingly, it has also been found that the plasma profile and plasma levels of the gastrodens are effective in inhibiting ovulation in women, as a result of the administration of the gastodene or derivatives thereof and optionally estrogen.

Therefore, another aspect of the invention relates to the use of the composition of the invention, optionally in combination with estrogen, for the inhibition of ovulation in a female, such as a female. When the medicament is administered alone, a plasma concentration-time curve of Gestöden is obtained which is characterized by having Gestöden plasma levels of at least 1.0 ng / ml when measured under steady state conditions. As follows, aspects of the present invention include a topical administration of an effective amount of gestodene or a derivative thereof, optionally in combination with estrogen, to the skin or mucous membranes, thus providing a stable state of A method for inhibiting ovulation in females, such as females, which results in obtaining a plasma concentration-time curve of gastodens characterized by having a gastodensian plasma level of at least 1.0 ng / ml when measured at .

Otherwise, the uses and methods of the present invention are for the treatment of disorders or conditions that can be conventionally treated by administering other symptoms, progestin or a combination of progestin and estrogen, such as gestodene or derivatives thereof.

Therefore, in some embodiments of the present invention, it is generally to be understood that the use and method is for the treatment of endometriosis, premenstrual syndrome, menopausal disorders, control of the menstrual cycle and / or stabilization of the menstrual cycle.

For example, administering progestin without simultaneous treatment with estrogens can treat irregular and abnormal bleeding. As used herein, the term "irregular bleeding" means any uterine bleeding outside the regular monthly menstrual period of a woman who is not pregnant. Uterine bleeding is irregular when the menstrual cycle or menstrual period is too short, too long, too frequent, too moist, or at irregular intervals that appear outside the regular 26-30 day menstrual cycle. Menstrual cycles are classified as too long if they are delayed by 15 to 50 days or more than the expected start date of the bleeding. The term "abnormal bleeding" refers to severe bleeding that typically lasts through a sanitary protective product that has a duration that lasts more than seven days and is sufficient to require more than one hour or two hours of exchange. Abnormal bleeding affects 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 uterine cancer, usually as a result of abnormal coagulation, inherited bleeding disorders, or levels of platelets. Does not include bleeding in women due to medical conditions.

In another embodiment, the progestin is progestin, such as gestodene or a derivative thereof, and symptoms and diseases associated with menopause, such as hot flashes, sweating, palpitations, sleep disorders, changes in planting, nervousness, anxiety, Menopausal periods such as memory loss, loss of confidence, loss of libido, loss of concentration, loss of energy, force reduction, irritability, genitourinary atrophy, breast atrophy, cardiovascular disease, hair distribution, changes in hair thickness, changes in skin condition and / or osteoporosis It is administered in combination with estrogen, for example, by administering a medicament of the present invention comprising a combination of estrogens for the treatment of disorders. Most notably, the treatment relates to the prevention or management of hot flashes, sweating, palpitations, sleep disorders, changes in planting, nervousness, anxiety, genitourinary atrophy, breast atrophy or osteoporosis.

In connection with the treatment of menopausal disorders, estrogens may be selected from natural estrogens such as estradiol and its esters, for example estradiol valerate, estradiol benzoate. Natural estrogens also include conjugated estrogens including estrogen, estriol, estriol succinate and conjugated equine estrogens, such as estrogen sulfate, 17β-estradiol sulfate, 17α-estradiol sulfate, equilin sulfate, 17β -Dihydroequiline sulfate, 17α-dihydroequiline sulfate, equilenin sulfate, 17β-dihydroequilenin sulfate and 17α-dihydroequilenin sulfate or mixtures thereof.

In some embodiments of the invention, the plasma concentration-time curve of gestodene at steady state conditions is at a concentration of at least 1.5 ng / ml, for example at least 2.0 ng / ml or at least 2.5 ng / ml. It is characterized by having. In another interesting embodiment, the plasma concentration-time curve of gastoden at steady state conditions, preferably on the first 6 days after a single administration of the composition of gestoden or its derivatives in the form of a composition of the present invention, 1 It is characterized by having a gastodene plasma level in the range of from 8 ng / ml, preferably in the range of 1.5 to 6 ng / ml.

In another embodiment, the plasma concentration-time curve of Gestöden under steady state conditions has a Gestöden maximum plasma concentration for 18 to 60 hours after a single dose of the medicament and / or 5 to 5 after a single dose of the medicament At steady state conditions for 7 days, it is characterized by having at least about 50% of the maximum plasma level of gestodene obtained during the first 18 to 60 hours after administration.

Gestodene is administered within 28 days so that the Gestodene / composition is administered 7 days apart for 21 days (3 weeks) followed by no administration of Gestodene or its derivatives for 7 days (1 week). It is preferred to be administered repeatedly in cycles. That is, the gestodene / composition is administered on days 1, 8 and 15 within each 28 day cycle. Preferably, the first day is the start date of menstruation or any other suitable day, such as the first, second, third, fourth, fifth or sixth day from the start of menstruation. In another embodiment, the Gestogen, optionally in combination with Estrogen, is administered for 7 days (1 week) following administration of the Gestogen / Composition at 7 day intervals for 11 consecutive weeks within each 12 week cycle. Administration is repeated at 12-week cycles such that no den or derivatives thereof are administered.

To improve the contraceptive effect and safety, estrogen may be administered simultaneously with gestodene. Estrogens may be selected from the estrogens mentioned above.

As can be appreciated, the uses and methods of the present invention include the application of gestodene or derivatives thereof, which can be in the form of a composition as defined herein. Thus, the term "medicament" includes compositions as defined herein. The term "medicament" is also meant to include kits of the invention.

In another aspect, the invention relates to a kit comprising 1 to 11 dosage units intended for a 12 week treatment period formulated in the form for transdermal delivery of progestin, such as gestodene or a derivative thereof, wherein the dosage unit Comprises a medicament-containing layer comprising gestoden and at least one pharmaceutically acceptable excipient or carrier, wherein the medicament-containing layer is less than or equal to 3% by weight of the medicament-containing layer, Has solubility. The dosage unit may comprise the composition described herein. In one embodiment, the 11 dosage units are administered once weekly consecutively for a period of 11 weeks, followed by 1 week without administering the dosage unit or placebo.

In another embodiment, the kit is intended for a 12 week treatment period, but the kit comprises 1 to 9 dosage units. In one embodiment, the three-dose unit is administered weekly for three weeks, then one week does not administer the dosage unit or administers a placebo. That is, the kit is intended for a 4 week treatment period and the kit includes 1-3 dosage units.

The dosage of progestin, such as gestodene or a derivative thereof, in each dosage unit is a dosage selected from a 6-day dosage, a 7-day dosage, an 8-day dosage, a 14-day dosage or a 21-day dosage. Corresponds to In one embodiment, each dosage unit comprises gestoden or a derivative thereof in a dosage of about 0.5 to 5 mg, preferably 1 to 3 mg, more preferably 1.5 to 2.5 mg.

It should also be understood that the kit may further comprise estrogens such as those mentioned above. Estrogens may be combined in the same dosage unit or provided in separate dosage units with progestins such as gestodene or derivatives thereof. The kit may further comprise, for example, 1 to 30 dosage units that contain estrogen and no gastodene. Estrogens can be in dosage forms formulated for transdermal delivery, vaginal delivery, and the like. Otherwise, estrogens may be in the form of dosage units formulated for oral delivery of estrogens, such as in the form of tablets, pills, capsules, powders, pastes or granules.

The compositions of the present invention can be prepared using methods known in the art. One embodiment is included here.

1. Mean serum levels of Gestodene (GSD) during two treatment cycles, one week and three weeks, respectively. The signs are as follows:

■ Cycle 1, 1 week

□ Cycle 2, 1 week

▲ Cycle 1, 2 weeks

△ cycle 2, 2 weeks

Example  One

Manufacture of patches

The composition of the present invention was prepared as follows.

In the first step, 380 g of gastodene and optionally 180 g of ethynylestradiol were dissolved in a suitable solvent, for example in 16.8 kg of dioxane. In the second step, about 57 kg of a mixture of rosin ester (Arcare ^(R) MA 24A) in polyisobutylene and heptane were weighed. The hormonal solution of the first step was transferred to the polymer solution under agitation and stirring continued until a homogeneous solution was obtained. The drug-containing solution so obtained was coated on a release liner (FL 2000 75 μm PET 1S; Fa Loparex) and dried under appropriate conditions. The dried drug-containing layer was then laminated to a backing foil / layer such as Cotran ^(R ) 9720 (3M). When the laminate thus obtained is divided into 10 cm ² patches, the resulting patch has the following composition:

Gustoden: 1.9 mg

Alternatively ethynylestradiol: 0.9 mg

97.2 mg of polymer

(For example in the form of polyisobutylene in combination with a tackifier such as MA-24A ^(R) )

Release Liner: 10 cm ²

Backing layer: 10 cm ²

In another example, the patch obtained was similar to that mentioned above but with an amount of ethynylestradiol of 0.6 mg.

In another embodiment, the patch obtained was similar to that mentioned above, but the Duro-tak ^(R ) 10711, the adhesive consisting of a hydrocarbon polymer.

Example  2

Skin Penetration Rate of Compositions with Various Polymers

Six compositions (A-F) were prepared with the acrylate-vinylacetate polymer as the polymer in the drug-containing layer. In addition, composition G was prepared using polyisobutylene as the polymer in the drug-containing layer. Preparation was carried out according to the method described in Example 1. None of the compositions contained skin penetration enhancers.

Each composition was tested by an in vitro mouse skin permeation test. The test was performed using a skin preparation of hairless mouse skin (HsdCpb: NMRI-nu) available from Harlan Bioservice for Science GmbH, Walsrode, Germany. The test composition was attached on the outside of the skin swatch. Both were placed in the permeation cell with the inside in contact with the receptor medium. HEPES buffered aqueous solution was used as the receptor medium. Sodium azide was added to prevent microbial growth. The receptor solution was kept at 32 ° C. Samples were taken from the receptor solution at defined time intervals and the concentration in the receptor medium of Gestodene (GSD) and ethynylestradiol (EE) was analyzed by HPLC. The runoff rate was then calculated using the calculated amount of active substance in the amount of drug released per area and time unit [μg / cm ² * 24h].

Results for in vitro rate of skin penetration:

Composition A B C D E F G GSD
(% W / w) 1.9 3.9 2.1 4.2 1.9 3.8 1.9 EE
(% W / w) 1.0 2.0 1.1 2.1 1.0 1.9 0.9 polymer Acrylate-
Vinyl acetate, eg
Durotak ^(R ) 387-2051 Acrylate-
Vinyl acetate, e.g.
Durotech ^(R)
387-2051 Acrylate-
Vinyl acetate, e.g.
Durotech ^(R)
387-2825 Acrylate-
Vinyl acetate, e.g.
Durotech ^(R)
387-2825 Acrylate-
Vinyl acetate, e.g.
Durotech ^(R)
87-2097 Acrylate-
Vinyl acetate, e.g.
Durotech ^(R)
87-2097 PIB
Yes:
MA-24A GSD penetration
μg / cm ² * 24h 14.8 32.8 12.6 14.3 13.5 16.7 30.9 EE transmission
μg / cm ² * 24h 2.6 6.5 1.5 2.8 1.3 1.9 8.1

The results show that the permeation rate of not only ethynyl estradiol as well as gestodene from composition G (polyisobutylene) is better than that from compositions A-F.

Example  3

Contraceptive Effects and Pharmacokinetic Profiles

The effects on ovulation inhibition, serum drug concentrations and the safety of the patch of the invention were studied in women of the selected population. The study design was based on the requirements of the EMEA Guidelines for Clinical Studies with Contraceptive Steroids (Committee for Proprietary Medicinal Products, CPMP / EWP 519/98).

Research Design

The study has three phases: one pre-treatment comprising two wash cycles and one additional cycle to confirm that the selected women are ovulatory. Finally, the second phase is a two-cycle treatment phase, which leads to a third phase consisting of a one-cycle postprocessing phase.

Women enrolled in this study are healthy, not pregnant, and not smokers, with a normal weight index of 18-26 kg / m ² and a normal menstrual cycle of 28 days ± 4 days, ages 18 to 35 years. The female volunteer was not breastfeeding. Only women with light skin color were included so that the site of application could be easily and uniformly evaluated.

The test patch was a patch comprising a drug-containing layer of 0.9 mg of ethynylestradiol and 1.0 mg of gestodene and arcare (Arcare MA-24A ^(R) ), wherein the drug-containing layer was 10 cm ^2. Had the size of. Arcare MA-24A ^(R) is a polyisobutylene-based adhesive manufactured by Adhesive Research.

During the study, blood was drawn for measurement of endogenous hormones such as estradiol, progesterone, follicle stimulating hormone, sex hormone binding protein, ethynylestradiol, gestodene. Hard ultrasound examinations were performed to evaluate the development of follicle-like structures in the ovary. Patch adhesion, skin response at the site of application and the general state of health of the women were evaluated. Vaginal bleeding was also evaluated.

During the pre-treatment cycle, evaluation of serum progesterone values normally resulted in autogenous ovulation, in that only women with ovulation pre-cycle and progesterone serum levels above 5 nmol / l were allowed for the treatment step.

The treatment phase included two menstrual cycles. The first treatment of the first cycle was started by applying the patch one day after the volunteer's menstruation began in that cycle. A total of three test patches were applied at different application sites-during each treatment cycle-at intervals of seven days, for example, on days 1, 8 and 15 of the first cycle. Each patch was worn for 7 days and then replaced with a new patch for a total of 21 days of complete use. This was followed by a 7-day treatment-free interval, before the next treatment cycle, each beginning with a total of 3 patches applied at 7-day intervals. If a patch was lost or more than 40% was removed, a new patch was applied.

The patch was applied to the clean, dry, intact, preferably hairless skin under the navel, the lower abdomen, starting to the right and then alternating in the first treatment cycle.

Measurement of Pharmacokinetic Variables

The main pharmacokinetic variable is the proportion of women whose ovulation is suppressed. According to the so-called Hoogland method, ovulation requires serum progesterone concentrations in excess of 5 nmol / l, which coincide with follicular rupture, with follicular growth exceeding 13 mm and subsequent ovarian rupture. Ovulation was suppressed when the follicle was less than 13 mm and the serum progesterone concentration was less than 5 nmol / l upon follicular rupture.

Determination of Pharmacokinetic Variables

Pharmacokinetic variables AUC _(0-168h) , C _max , t _max , and cumulative factors within each cycle, such as the area under the drug concentration time curve during the patch-wear period, for example, a third patch within cycle 1 or cycle 2. _Measured by AUC _(0-168h) / AUC _of first patch _(0-168h) , or cumulative factor between two cycles, eg AUC _(0-168h) / cycle of third to third patch AUC of the third patch from 1 _(0-168h) . The AUC was calculated according to the linear rhombus rule.

Serum concentrations of estrogens and progestins, including ethynylestradiol and gestodene, were measured through studies for pharmacokinetic evaluation of patches. Sampling time points are at day 18 of the preprocessing cycle, and 1, 2, 3, 4, 5, 6, 7, 8, 15, 16, 17, 18, 19, 20, 21, and 22 of cycle 1 and 1 of cycle 2. Days (prior to application of the new patch), 2, 3, 4, 5, 6, 7, 8, 15, 16, 17, 18, 19, 20, 21 and 22 days.

The concentrations of ethynylestradiol and gestoden were measured by conventional methods known in the art. Specifically, the concentration of ethynylestradiol was determined by gas chromatography using mass spectral measurements in a chemical ionization manner as a detection method following extraction from acidified serum and subsequent derivatization. Gestodene concentrations were determined by radioimmunoassay using rabbit antiserum and 3H-labeled gestodene. After incubation and centrifugation, the resulting precipitate was redissolved with NaOH. The assay has a lower limit of quantification of about 250 pg / ml.

result

The main pharmacokinetic variable was the proportion of women suppressed ovulation.

Ovulation was effectively suppressed. In other words,

No ovulation action: cycle 1: 78%, cycle 2: 56%.

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

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

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

Ovulation was not found throughout the study. Ovulation inhibition, defined as Hugland score below 6 (ovulation), was sufficient for all volunteers per fixed protocol data throughout the study.

Progesterone concentrations were adequately suppressed below 2.5 nmol / l at each treatment cycle. Mean estradiol levels in blood were below 20 pg / ml on all days of patch application.

Pharmacokinetic Results

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

-Average pharmacokinetic parameters of ethynyl estradiol (EE) Pharmacokinetic Variables unit
Cycle 1 Cycle 2 1 week 3 weeks 1 week 3 weeks C _max pg / ml 45.6 50.4 45.2 48.0 T _max h 48 24 48 48 AUC (0-168h) ng x h / ml 5.3 6.1 5.1 5.8

-Average pharmacokinetic parameters of Gestode (GSD) Pharmacokinetic Variables unit
Cycle 1 Cycle 2 1 week 3 weeks 1 week 3 weeks 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 Polyisobutylene Adhesives and Acrylic Compositions in Human Body

A randomized crossover study was conducted to measure the average daily delivery of ethynylestradiol (EE) and gestodene (GSD) from three different transdermal patch compositions (AC) following a single dose in healthy postmenopausal volunteers. Was performed. The aim is also to compare the transdermal application with that of intravenous injection.

The test composition was as follows:

Composition A (Polyisobutylene)

No.1 Ingredients Quantity per 10 cm ² patch Remarks One Ethynylestradiol 0.95 mg 2 Guest House 1.9 mg 3 Polyisobutylene adhesive 97.15 mg MA-24A

Composition B (Polyisobutylene, 70% of Composition A)

No. Ingredients Quantity per 10 cm ² patch Remarks One Ethynylestradiol 0.67 mg 2 Guest House 1.33 mg 3 Polyisobutylene adhesive 98.00 mg MA-24A

Composition C (acrylate)

No. Ingredients Quantity per 10 cm ² patch Remarks One Ethynylestradiol 0.67 mg 2 Guest House 1.33 mg 3 Acrylic adhesive 73.5 mg Gelva ^(R) 7883 4 Isopropyl myristate 5.0 mg Penetration enhancer 5 Copovidone 15.0 mg Crystallization inhibitor
(Kollidon VA64, BASF, Germany)

This study was conducted with the following variables:

Patches were administered by one transdermal administration in a 7-day wear cycle / test. Washing was performed for 1 week after removal of the patch in each test treatment. Doses of 60 μg EE and 75 μg GSD were administered once intravenously.

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

result:

The maximum concentration of gestodene is given in the following table showing the difference between the polyisobutylene compositions A and B and the acrylic composition. The numbers represent the time course of the Gestogen average serum levels.

variable Composition A Composition B Composition C C _max [pg / ml] 2082 1995 1277 t _max [h] 168 144 156 AUC (0-7d): [h * ng / ml] 243 257 155

The results indicate that drug delivery of composition C comprising a drug-containing layer of acrylate in combination with penetration enhancer is significantly lower than that of compositions A and B.

Example  5

A drug-containing layer containing 1.9 mg of gestodene and 0.9 mg of ethynylestradiol and consisting of various mixtures of polymers is shown (A-M).

polymer
Brand name polymer
Chemical name A B C D E F G Foral 85E ^(R) Hydrogenated rosin
Pentaerythritol ester 20.0 Foral 105E ^(R) Hydrogenated rosin
Glycerol ester 20.0 30.0 Oppanol
B10 N / SFN ^(R) Polyisobutylene
(MW approximately 40.000 Dalton) 57.2 57.2 67.2 55.2 Opanol B11 SFN ^(R) Polyisobutylene
(MW approximately 49.000) 62.2 Opanol B12 SFN ^(R) Polyisobutylene
(MW approximately 55.000 Dalton) 62.2 62.2 Opanol B30 SFN ^(R) Polyisobutylene
(MW approximately 200.000 Dalton) Opanol B100 Polyisobutylene
(MW approximately 1.000.000 Dalton) 20.0 20.0 12.0 12.0 20.0 12.0 15.0 Opanol B150 Polyisobutylene
(MW approximately 2.600.000 Dalton) Indopole H300 Synthetic polybutene
(MW approximately 1.300 Dalton) 10.0 Indopole H1900 Synthetic polybutene
(MW approximately 2.500 Dalton) 23.0 Indopole H2100 Synthetic polybutene
(MW approximately 2.500 Dalton) 23.0 Escores 5300 Cycloaliphatic petroleum hydrocarbon resin 20.0 Stay light
Ester 3E Esters of hydrogenated resins Stay light
Ester 5E JQ Partially hydrogenated rosin
Glycerol ester Kraton D1161NU Styrene-isoprene-styrene
Block polymer

polymer
Brand name polymer
Chemical name H I J K L M Foral 85E ^(R) Hydrogenated rosin
Pentaerythritol ester 10.0 Foral 105E ^(R) Hydrogenated rosin
Glycerol ester 10.0 65.0 Oppanol
B10 N / SFN ^(R) Polyisobutylene
(MW approximately 40.000 Dalton) 67.2 67.2 75.7 75.7 Opanol B11 SFN ^(R) Polyisobutylene
(MW approximately 49.000) Opanol B12 SFN ^(R) Polyisobutylene
(MW approximately 55.000 Dalton) 57.2 Opanol B30 SFN ^(R) Polyisobutylene
(MW approximately 200.000 Dalton) 10.0 10.0 Opanol B100 Polyisobutylene
(MW approximately 1.000.000 Dalton) 10.0 10.0 15.0 Opanol B150 Polyisobutylene
(MW approximately 2.600.000 Dalton) 10.8 10.8 Indopole H300 Synthetic polybutene
(MW approximately 1.300 Dalton) Indopole H1900 Synthetic polybutene
(MW approximately 2.500 Dalton) Indopole H2100 Synthetic polybutene
(MW approximately 2.500 Dalton) Escores 5300 Cycloaliphatic petroleum hydrocarbon resin Stay light
Ester 3E Esters of hydrogenated resins 10.8 Stay light
Ester 5E JQ Partially hydrogenated rosin
Glycerol ester 25.0 10.8 Kraton D1161NU Styrene-isoprene-styrene
Block polymer 32.2

Claims (40)

A medicament-containing layer comprising a gastodene and a carrier selected from the group consisting of polyisobutylenes, wherein the medicament-containing layer is 3% by weight of the medicament-containing layer relative to the gastodene. A composition for transdermal delivery, having a solubility of less than or equal to, wherein the gastodene is present in an amount ranging from 0.5 to 3% by weight of the drug-containing layer. The composition of claim 1, wherein the drug-containing layer further comprises a tackifier selected from the group consisting of hydrocarbon resins, rosin resins, and terpene resins. The composition of claim 2 wherein the tackifier is a rosin ester. The composition of any one of claims 1 to 3, wherein the gestoden is completely dissolved in the drug-containing layer. The composition of claim 1, wherein the drug-containing layer comprises less than 2% by weight of polyvinylpyrrolidone, methylcellulose, ethylcellulose and hydroxypropylcellulose. The composition of claim 1, wherein the drug-containing layer comprises less than 0.5% by weight of dimethylisosorbide. The composition of claim 1, wherein the drug-containing layer is transparent. The composition of claim 1, wherein the drug-containing layer comprises less than 2% by weight of a skin penetration enhancer or a skin permeation enhancer. The composition according to any one of claims 1 to 3, further comprising estrogen. 10. The composition of claim 9, wherein the estrogen is present in the drug-containing layer in an amount of 0.5 to 10% by weight of the drug-containing layer. The composition of claim 9, wherein the estrogen is present in the drug-containing layer in an amount of 0.75 to 5% by weight of the drug-containing layer. The composition of claim 9 wherein the estrogen is ethynylestradiol. 4. The composition of claim 1, wherein the gestoden is present in an amount in the range of 1 to 2 wt% of the drug-containing layer. The composition of any one of claims 1 to 3, wherein the carrier is one polyisobutylene present in an amount of at least 30% by weight. The composition of claim 1, wherein the carrier is substantially free of isoprene copolymer. The composition according to any one of claims 1 to 3, for suppressing ovulation in a female. a) a backing layer; b) at least one drug-containing layer as defined in any one of claims 1 to 3; And c) optionally, a removable release liner or protective layer Transdermal therapeutic system consisting essentially of. 18. The transdermal therapeutic system according to claim 17, wherein the gestoden is present at a dosage of 1-3 mg. 18. The transdermal therapeutic system according to claim 17, wherein the gestoden is present at a dose of 1.5 to 2.5 mg. 18. The transdermal therapeutic system according to claim 17, further comprising estrogen, wherein the mass ratio of the gastoden to the estrogen is in the range of 4 to 0.5. 21. The transdermal therapeutic system according to claim 20, wherein the estrogen is ethynylestradiol. 22. The transdermal therapeutic system according to claim 21, which contains a 1.9 mg of gestodene dose, a 0.9 mg of ethynylestradiol dose, and 97.2 mg of polyisobutylene in combination with a tackifier. 23. The transdermal therapeutic system according to claim 21, which contains a 1.9 mg of gestodene dose, a 0.6 mg of ethynylestradiol dose, and 97.2 mg of polyisobutylene in combination with a tackifier. 22. The transdermal therapeutic system according to claim 21, which contains 1.9% by weight of gastodene and 0.9% by weight of ethynyl estradiol and wherein the carrier is polyisobutylene. A kit comprising 1 to 11 dosage units comprising a composition as defined in claim 1. The kit of claim 25, which is formulated in a form for transdermal delivery of Gestoden and for use during a 12 week treatment period. The kit of claim 26 comprising 1 to 9 dosage units and for use for a 12 week treatment period. The kit of claim 26 comprising 11 dosage units and for use for a 12 week treatment period. 29. The kit of claim 28, wherein the 11 dosage units are administered once weekly consecutively for a period of 11 weeks, then no dosage units are administered or placebo is administered. The kit of claim 26 comprising 9 dosage units and for use for a 12 week treatment period. A kit comprising 1-3 dosage units, formulated in the form for transdermal delivery of gestodene and for use during a 4-week treatment period, wherein the dosage unit is in the group consisting of gestodene, and polyisobutylenes. A transdermal delivery composition comprising a medicament-containing layer comprising a selected carrier, wherein the medicament-containing layer has a solubility of 3% or less based on the weight of the medicament-containing layer relative to the gastodene, Wherein the stodene is present in an amount ranging from 0.5 to 3% by weight of the drug-containing layer. 32. The kit of claim 31 comprising three dosage units and for use during a four week treatment period. 33. The kit of claim 32, wherein the three dosage units are administered weekly for a three week period and then one week is not administered or the placebo is administered. 32. The kit of claim 25 or 31, wherein each dosage unit comprises gestoden at a dosage of 0.5 to 5 mg. 32. The kit of claim 25 or 31, wherein the drug-containing layer further comprises a tackifier selected from the group consisting of hydrocarbon resins, rosin resins, and terpene resins. 36. The kit of claim 35, wherein the tackifier is a rosin ester. 32. The kit of claim 25 or 31, wherein the dosage unit further comprises estrogen. 38. The kit of claim 37, wherein the estrogen is ethynyl estradiol. 32. The unit of claim 25 or 31, wherein the dosage unit is a) backing foil / layer; b) a drug-containing layer; And c) removable release liner It consists of a patch consisting essentially of, And the drug-containing layer comprises 1.9% by weight of gestodene and 0.9% by weight of ethynyl estradiol, and polyisobutylene as polymer. 18. The transdermal therapeutic system according to claim 17, which is for suppressing ovulation in a female.

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