HK1186968B - Low-dose transdermal patches with high drug release - Google Patents

Description

Low dose transdermal patch with high drug release

Technical Field

The invention relates to the technical field of pharmaceutical preparations. The present invention provides a low dose pharmaceutical composition for transdermal delivery of hormones, preferably a progestin (such as a gestodene) and an estrogen (preferably ethinyl estradiol), to achieve a plasma concentration profile effective in inhibiting ovulation in a female.

Background

Transdermal delivery of estrogens and progestins for contraception is a known concept (Sitruk-Ware, transduction applications of stereo hormones for contraception, J Steroid biochem Molecul Biol, Vol. 53, p. 247-2511). It is also known that estrogens and progestogens generally have poor skin penetration properties, for which reason substances with a skin penetration enhancing effect are often introduced into the transdermal system.

ORTHO Is the first transdermal contraceptive patch to gain acceptance by market agencies. It was first marketed in 2002 in the united states. ORTHOIs a once-a-week transdermal contraceptive system having a length of 20cm²And comprises 6mg of methyl progesterone (norelgestromin) and 0.75mg of ethinyl estradiol.

ORTHO Is a matrix type thin transdermal contraceptive patch consisting of three layers. The back lining layer is composed of a beige elastic film, and the beige elastic film is composed of a low-density colored polyethylene outer layer and a polyester inner layer. Which provides structural support and protects the intermediate adhesive layer from the environment. The middle layer contains polyisobutylene/polybutene binder, crospovidone, non-woven polyester fabric and lauryl lactate as inactive ingredients. The active ingredients in this layer are hormones, norelgestromin and ethinyl estradiol. The third layer is a release liner that protects the adhesive layer during storage and is removed prior to application. It is a transparent polyethylene terephthalate (PET) film with a polydimethylsiloxane coating on the side in contact with the intermediate adhesive layer.

AG200-15 (the first contraceptive patch developed by Agile Therapeutics) is now in the third study stage of evaluating efficacy and safety. AG200-15 was designed to deliver effectively 25-30 μ g estrogen (ethinylestradiol) and 100-120 μ g levonorgestrel for 21 days on a once weekly schedule. The patch was administered once a week for three weeks, followed by a one week rest period.

Transdermal contraceptive patches comprising a combination of gestodene and estrogen are not yet available on the market.

However, there have been many publications describing compositions for transdermal delivery of gestodenes.

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

US5,512,292 relates to compositions comprising a contraceptively effective amount of a gestodene and an estrogen (e.g. ethinylestradiol) together with a suitable penetration enhancer. The amount of estrogen co-delivered is maintained at a constant and contraceptively effective rate, while the amount of gestodene co-delivered is dependent on the phase of the menstrual cycle.

US5,376,377 discloses a comparative study between transdermal systems with and without penetration enhancers. The study included an adhesive layer made of ethylene vinyl acrylate and as active ingredients gestodene and estrogen (ethinyl estradiol). The results of the study indicate that a permeation enhancer needs to be incorporated into the adhesive layer to achieve a contraceptively effective amount. A maximum plasma concentration of about 0.8ng/ml was achieved.

WO90/04397 also discloses examples of compositions for transdermal delivery of gestodene optionally in combination with an estrogen such as ethinyl estradiol, wherein the composition may further comprise a penetration enhancer such as 1, 2-propanediol or isopropyl myristate. Various polymers are mentioned as adhesive layers. Examples of polar polymers (polyacrylates and silicones) in combination with penetration enhancers are specifically disclosed. The resulting plasma level of gestodene under steady state conditions was about 250-337 pg/mL.

US6,521,250 discloses an adhesive layer comprising a mixture of a styrene-isoprene block copolymer and a hydrogenated resin acid or a derivative thereof, the amount of resin being 55-92%. Such an adhesive layer appears to be suitable for transdermal delivery of estradiol in combination with a progestogen because such a system has a suitable adhesive contact with the skin for long term application and prevents crystallization of the hormone.

US5,904,931 relates to a transdermal therapeutic system comprising a steroid (such as gestodene) and dimethyl isosorbide in a drug-containing layer. Isosorbide dimethyl ether enhances the solubility of the steroid in the drug-containing layer. The concentration of gestodene in the drug-containing layer may be 1-40% by weight of the layer, and the drug-containing layer may be composed of an adhesive such as polyacrylate, silicone, styrene-butadiene copolymer, and polyisobutylene. Particularly suitable are polar polymers such as polyacrylates.

DE 19906152 relates to a transdermal drug delivery system in which gestodene is embedded in polar polymers such as polyvinylpyrrolidone, methylcellulose, ethylcellulose and hydroxypropylcellulose before being added to an adhesive polymer such as polyisobutylene. Thus, the transdermal drug delivery system is a two-phase system and due to the content of polar polymer, the drug-containing layer is opaque, which when exposed to water results in the presence of milky-white spots. The amount of gestodene in the drug-containing layer was 5.1% by weight of the drug-containing layer.

WO02145701 describes TTS (transdermal therapeutic system) suitable for steroids (gestodenes). The gestodene may be incorporated into the adhesive layer in an amount that substantially reaches or approaches or even exceeds its saturation concentration in the carrier composition, rather than being substantially in a sub-saturation state. Preferably, the amount of steroid is from about 0.1 wt% to about 0.6 wt% of the dry weight of the total carrier composition. The adhesive layer may comprise all non-toxic natural and synthetic polymers known and suitable for use in transdermal systems, such as polyacrylates, polysiloxanes, polyisobutylene, styrene block copolymers, and the like.

WO92/07590 discloses a composition containing a penetration enhancer for transdermal delivery of gestodene and estrogen to achieve a maximum plasma level of gestodene of about 0.9 ng/mL. The amount of estrogen and gestodene present in the therapeutic device and required to achieve a contraceptive effect is described, which depends on many factors, such as the minimum necessary dosage of each drug; permeability of the matrix, adhesive layer, and rate controlling membrane (if present); and the time the device is secured to the skin.

Since the drug will be released over a period of more than one day, there is virtually no upper limit for the maximum amount of drug in the device. The minimum amount of each drug is determined by the requirement that a sufficient amount of drug must be present in the device to maintain the desired release rate over the specified administration time.

No mention is made in WO92/07590 of the amount or range of amounts of drug.

The minimum amounts of each drug (i.e. gestodene and estrogen) to maintain the desired release rate over a defined administration period have not been clearly known to date.

EP 1541137 describes a pharmaceutical composition for transdermal delivery comprising a drug-containing layer comprising a gestodene or an ester thereof and a carrier selected from polyisobutylene, polybutene, polyisoprene, polystyrene, styrene-isoprene-styrene block polymers, styrene-butadiene-styrene block polymers and mixtures thereof, wherein the drug-containing layer has a solubility of the gestodene of not more than 3% by weight of the drug-containing layer, and wherein the gestodene or ester thereof is present in an amount of 0.5-3% by weight of the drug-containing layer.

In 10cm containing 0.9mg ethinylestradiol and 1.9mg gestodene²The drug plasma level of gestodene following patch composition is 2082pg/mL (C)_max) And 10cm containing 0.67mg ethinylestradiol and 1.33mg gestodene when administered in a single dose²The patch reaches 1995pg/mL (C)_max)。

EP 1541137 also demonstrates that in order to achieve the desired high release rate, a drug-containing layer of a polar polymer (polyacrylate) requires a concentration of gestodene of 3.9% by weight of the layer. Furthermore, a concentration of 1.9 wt.% gestodene in a drug-containing layer comprising a low polarity polymer (e.g. polyisobutylene) has been shown to achieve the same high release rate.

EP 1541137 does not disclose minimum amounts of the respective drugs, i.e. gestodene and estrogen, for maintaining a desired release rate over a determined administration time.

Summary of The Invention

The present invention relates to compositions suitable for formulating for transdermal delivery of hormones to achieve contraceptively effective levels. The actual hormone is preferably a steroid hormone, such as a progestin (e.g., a gestodene), which may optionally be used in combination with an estrogen. The preferred estrogen is ethinyl estradiol. The transdermal systems provided contain a limited number of ingredients. For example, no permeation enhancers and/or permeation enhancers are needed to achieve a high release rate and therapeutically effective plasma levels.

Thus, the present invention unexpectedly found that the use of a small but constant amount of ethinylestradiol in combination with varying amounts of gestodene in a transdermal patch resulted in an increasing daily release rate of ethinylestradiol, which was positively correlated with decreasing amounts of gestodene in the transdermal delivery composition, as demonstrated herein in a series of experiments using a constant amount of ethinylestradiol in combination with decreasing amounts of gestodene. Gestodene release is also increased relative to its concentration in the formulation. This results in an increased plasma level of ethinylestradiol and a substantially constant plasma level of gestodene for a particular formulation with a constant ethinylestradiol content and a reduced gestodene content.

It is well known that the solubility of steroid hormones (i.e. gestodenes) is critical for achieving therapeutically effective levels of the hormone in the blood successfully. It is also known that drug-containing adhesive layers containing polymer types with a higher degree of non-polarity (e.g. polyisobutylene over polyacrylate) are better in terms of achieving high plasma AUC (EP 1541137, example 4).

It has been found that transdermal therapeutic systems having a drug-containing layer preferably containing a non-polar polymer, such as polyisobutylene, and characterized by a limited gestodene solubility of not more than 3 wt.%, have a high gestodene release rate even with a low actual loading of gestodene in the drug-containing layer.

It is therefore an object of the present invention to provide a transdermal composition comprising a small amount of gestodene and ethinylestradiol in an adhesive matrix comprising polyisobutylene and having a drug release rate sufficient to achieve therapeutically effective plasma levels (i.e. inhibiting ovulation in healthy women).

This object is achieved by a novel transdermal composition comprising ethinylestradiol in an amount of about 0.5% by weight of the drug-containing layer and varying amounts of gestodene in an adhesive matrix comprising polyisobutylene. The gestodene is present in the adhesive matrix comprising polyisobutylene in an amount from about 0.4 to about 1.95% by weight of the drug-containing layer, preferably from about 0.9 to about 1.5% by weight of the drug-containing layer.

This means that the novel transdermal composition delivers ethinylestradiol at a higher release rate by using a matrix containing a constant amount of ethinylestradiol and a smaller amount of gestodene.

The present invention is an option in EP 15141137, EP 15141137 discloses compositions for transdermal delivery wherein the amount of gestodene is about 0.5-3% by weight of the drug-containing layer, preferably 1-2% by weight of the drug-containing layer.

EP 15141137 discloses that the composition may optionally comprise an estrogen. The estrogen is present in an amount of about 0.5-10% by weight of the drug-containing layer, preferably 0.75-5% by weight of the drug-containing layer, more preferably 1-3% by weight of the drug-containing layer, and most preferably 1-2% by weight of the drug-containing layer.

According to EP 15141137, the term "estrogen" includes natural 17 β -estradiol and semisynthetic estrogen derivatives, such as esters of natural estrogens and 17-alkylated estrogens. Semi-25 synthetic esters of natural estrogens include: such as estradiol-17-beta-heptanoate, estradiol-17-beta-valerate, estradiol-17-beta-benzoate, estradiol-17-beta-undecanoate, estradiol-16, 17-hemisuccinate or estradiol-17-beta-cypionate (cyplonate). Examples of 17-alkylated estrogens are ethinyl estradiol, ethinyl estradiol-3-isopropyl sulfonate, ethinyl estradiol, mestranol or mestranol. The term "estrogen" may also include non-steroidal compounds with estrogenic activity, such as diethylstilbestrol, dienestrol, clomiphene, clostilbestrol (chlorotrianesene) or cyclofenib. In a preferred embodiment, the estrogen is ethinyl estradiol.

EP 15141137 discloses that gestodene and optionally an estrogen are present in a pharmaceutically acceptable carrier comprising at least one polymer selected from the group consisting of polyisobutylene, polybutene, polyisoprene, polystyrene, styrene-isoprene-styrene block polymers, styrene-butadiene-styrene block polymers and mixtures thereof.

After administration of the transdermal therapeutic system of the present invention comprising a small amount of gestodene as defined above in combination with a small and constant amount of ethinylestradiol, plasma levels of gestodene observed from the drug release amount of the drug-containing layer are unexpectedly almost in the same range as in the 1.9% transdermal composition embodiment described in EP 15141137 by weight of the drug-containing layer.

At the same time, the plasma levels of ethinylestradiol increased significantly after administration of the transdermal therapeutic system of the invention.

This is clearly superior to previously known transdermal therapeutic systems in terms of reducing the risk of skin irritation, reducing exposure of the hormone to the user and the environment, and saving the cost of preparing such transdermal compositions with lower amounts of active agent.

Accordingly, a first aspect of the invention relates to a composition for transdermal delivery of gestodene and ethinylestradiol. The composition comprises a drug-containing layer comprising the gestodene and ethinylestradiol in a polyisobutylene-containing adhesive matrix, and the drug-containing layer has a gestodene solubility of no more than 3% by weight of the drug-containing layer.

In one particular aspect, the present invention relates to a composition comprising gestodene and ethinyl estradiol in polyisobutylene, wherein the polyisobutylene is present in an amount from about 15% to about 99% by weight of the drug-containing adhesive layer.

In another particular aspect of the invention, the invention relates to a composition comprising: a drug-containing adhesive layer containing gestodene and ethinylestradiol; polyisobutylene in an amount from about 15% to about 99% by weight of the drug-containing layer; a tackifier (such as rosin) in an amount of up to 85% (e.g., 1-85%) by weight of the drug-containing layer.

In yet another particular aspect, the present invention relates to a composition for transdermal delivery comprising an adhesive matrix comprising polyisobutylene, said adhesive matrix comprising 0.3-2.5mg of gestodene, preferably 0.5-2.3mg of gestodene, more preferably 1-2.1mg of gestodene. Particular compositions include, for example.

In another particular aspect, the invention relates to a composition for transdermal delivery comprising an adhesive matrix comprising polyisobutylene, the adhesive matrix comprising 0.1 to 0.9mg ethinylestradiol, preferably 0.3 to 0.6mg ethinylestradiol, most preferably 0.55mg ethinylestradiol.

It has been unexpectedly found that relatively high plasma levels of gestodene can be maintained over an extended period of time by administering varying amounts of gestodene using the formulations of the invention. Plasma profiles and plasma levels of gestodene obtained by administration of gestodene and ethinylestradiol are effective in inhibiting ovulation in women.

Thus, the composition of the present invention can be used for inhibiting ovulation or for treating endometriosis, premenstrual syndrome, climacteric disorders, preventing osteoporosis, regulating or stabilizing the menstrual cycle.

When the composition is administered, a plasma concentration-time profile of gestodene is obtained that is characterized by: plasma levels of gestodene and ethinylestradiol were 10cm in size over a patch based on 1.9% gestodene and 0.9% ethinylestradiol in a polymer matrix²The preparation of (a) thus having a content of 1.9mg gestodene and 0.9mg ethinylestradiol, and a concentration of the value predicted by a linear extrapolation of the plasma levels achieved. In connection therewith, the present invention relates to the inhibition of females such as femalesMethods of sexual ovulation.

Similar findings were observed when the formulations were studied in an in vitro dissolution test. The formulations of the present invention unexpectedly provide a non-linear relationship between drug content and the resulting in vitro release rate when the concentration of gestodene in the polymer matrix is reduced. More specifically, a decrease in the gestodene content also leads to an increased in vitro release of ethinylestradiol, even if the ethinylestradiol concentration in all preparations is kept constant. For gestodene, contrary to the expected linear relationship, only a slight decrease in vitro release was observed.

When studying patches with different gestodene drug content, it is expected that a decrease in the gestodene content in the patch matrix will proportionally decrease the amount of gestodene released, but the amount of ethinyl estradiol released will remain unchanged, since the ethinyl estradiol content in the patch matrix remains constant. The theoretically expected and actually found release rates of ethinylestradiol and gestodene from different patch formulations are summarized in table 3 and fig. 2.

Thus, the person skilled in the art is able to deduce from table 3 the size and active ingredient content required to achieve a specific desired in vitro release rate and thus a desired plasma profile.

The dosage unit comprises a drug-containing adhesive layer made of polyisobutylene and comprising a combination of gestodene and ethinylestradiol in an amount within the range as defined above and one or more pharmaceutically acceptable excipients or carriers, wherein the drug-containing adhesive layer has a gestodene solubility of no more than 3% by weight of the drug-containing layer.

Detailed Description

The present invention provides compositions for transdermal delivery of hormones (transdermal therapeutic systems) which, when topically applied to the skin or mucosa, result in therapeutically effective amounts, such as contraceptively effective amounts, of the hormones gestodene and ethinylestradiol. There is no need to incorporate a skin penetration enhancer into the drug-containing layer.

As used herein, the term "topical" or "topically" means that the composition is in direct contact with the surface area (including skin) of a mammal. The compositions of the present invention may be designed for several different forms of administration, provided that the composition comprises a drug-containing adhesive layer adapted to be located adjacent to or in direct contact with the skin or mucosa upon topical administration of the composition.

Thus, in a preferred form of administration, the composition (e.g., transdermal therapeutic system) consists essentially of:

a) a backing layer;

b) at least one drug-containing layer comprising gestodene and ethinylestradiol in a polyisobutylene-containing adhesive matrix and a pharmaceutically acceptable ingredient; and

c) optionally a removable release liner or protective layer.

In yet another embodiment, a preferred embodiment consists essentially of:

a) a backing layer;

b) an additional adhesive layer, optionally further comprising a UV absorber;

c) an intermediate layer which is impermeable to the UV absorber or a drug such as a steroid hormone;

d) a polyisobutylene-containing adhesive matrix comprising gestodene and ethinylestradiol as active ingredients;

e) optionally a removable release liner or protective layer.

Preferably, the backing layer, the polyisobutylene-containing adhesive matrix comprising gestodene and ethinylestradiol and the removable release liner (or protective layer) are transparent, which means that the skin is visible. The same applies to the additional adhesive layer and the intermediate layer, which are also transparent.

In case the drug-containing polyisobutylene layer does not exhibit sufficient self-adhesiveness (self-adhesiveness) to the skin, an additional pressure-sensitive adhesive layer or a pressure-sensitive adhesive edge or a pressure-sensitive adhesive ring may be provided to ensure that the composition adheres to the skin throughout the application. 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.

The size of the drug-containing polyisobutylene layer is selected from different reasonable sizes. As used herein, reasonable size means about 3-20cm²Preferably about 5-15cm²Most preferably about 7-12cm²E.g. 10cm²Or 11cm²Surface area of (a). It should be noted that the surface area is the area in contact with or in close proximity to the skin or mucosa.

The composition comprises a drug-containing layer comprising polyisobutylene and one or more pharmaceutically acceptable excipients or carriers, and the drug-containing layer has a solubility of gestodene as defined in EP 1541137 (the disclosure of which is incorporated herein) of not more than 3% by weight of the drug-containing layer, and wherein the gestodene is present in an amount of 0.5-2% by weight of the drug-containing layer.

The phrase "solubility of gestodene not exceeding 3% by weight of the drug-containing layer" is intended to characterize the amount of gestodene that can be dissolved in a particular drug-containing layer that produces a visually clear polymer matrix.

The term "gestodene" as used herein means gestodene (13 β -ethyl-17 α -ethynyl-17 β -hydroxy-4, 15-estrene (gonadien) -3-one).

The term "solubility" should not be understood to mean the actual concentration of gestodene in the drug-containing layer. As described below, the total concentration of hormones in the drug-containing layer may be higher or lower than 3% by weight of the drug-containing layer. Further, the total concentration of hormone in the drug-containing layer may result in a drug-containing layer that contains a saturated or sub-saturated level of hormone.

The term "drug-containing layer" means the part of the transdermal composition or system in which the steroid hormones gestodene and ethinyl estradiol are present. The drug-containing layer may be in a semi-solid or solid form and contains the hormone formulated directly in the layer. The hormone of the invention may be dispersed, partially dissolved or completely dissolved in the drug-containing layer, depending on the concentration of the hormone and its physico-chemical properties. The drug-containing layer is not meant to be in gel or liquid form. The drug-containing layer is intended to be in direct contact with the skin or mucosa. However, in some embodiments, there is an additional layer between the drug-containing layer and the skin or mucosa, referred to as a non-drug-containing layer.

As mentioned above, the compositions of the present invention need not contain a skin penetration enhancer. Thus, in some embodiments of the present invention, the skin permeation rate enhancing agent is not present in the drug-containing layer, meaning that the drug-containing layer consists essentially of ingredients that do not include a skin permeation rate enhancing agent. This means that for example less than 2%, such as less than 1%, preferably less than 0.5%, such as less than 0.2%, such as less than 0.1% by weight of the drug-containing layer is comprised of a skin penetration enhancer.

Suitable drug-containing layers are preferably made of polyisobutylene or a mixture of polyisobutylene with other polymers. These polymers may or may not have significant adhesive properties. In some embodiments, the drug-containing layer is a so-called pressure sensitive adhesive layer.

In principle, any polymer mixture which leads to the solubility of the gestodene can be administered. Thus, in one embodiment of the present invention, the drug-containing layer additionally comprises at least one polymer which may or may not have adhesive properties. Generally, such polymers are biologically acceptable lipophilic polymers of the type of hydrocarbon polymers, polysiloxanes, polyacrylates or mixtures thereof. Preferably, the polymer may be selected from those hydrocarbon polymers, polysiloxanes and/or polyacrylates that form a drug-containing layer having a solubility of gestodene of no more than 3% by weight of the drug-containing layer.

The amount of polyisobutene is a key parameter to some extent. Suitable amounts may depend on the actual type of additional polymer and steroid hormone used. Generally, the amount of polyisobutylene is at least 1%, such as at least 5%, 10%, 15% or 20% by weight of the drug-containing layer. Preferably, however, the polyisobutylene is present in the drug-containing layer in an amount of at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or at least 80% by weight of the drug-containing layer. In other words, the polyisobutylene may be used in an amount from about 1% to about 99%, such as from about 5% to about 99%, from about 10% to about 99%, from about 15% to about 99%, or from about 20% to about 99% by weight of the drug-containing layer. Preferably, the polyisobutylene is present in the drug-containing layer in an amount of about 15-99%, such as about 15-90%, 15-85% or 15-80%, such as about 20-85%, 20-75%, such as about 25-85%, 25-75% by weight of the drug-containing layer.

That is, the present invention relates to a composition for transdermal delivery of gestodene and ethinylestradiol comprising a drug-containing layer comprising:

-gestodene and one or more pharmaceutically acceptable ingredients or carriers;

-polyisobutylene or a mixture of polyisobutylene with other polymers, preferably in an amount of about 15-99% by weight of the drug-containing layer, wherein the polymers are selected from hydrocarbon polymers and mixtures thereof that form a drug-containing layer having a solubility of gestodene of no more than 3% by weight of the drug-containing layer.

The drug-containing layer may comprise a hydrocarbon polymer as an additional polymer, the hydrocarbon polymer being selected from the group consisting of polybutene, polyisoprene, polystyrene, styrene-isoprene-styrene block polymer, styrene-butadiene-styrene block polymer and/or mixtures thereof.

As described above, in some embodiments of the present invention, the drug-containing layer has adhesiveness. Preferably, the polymer of the drug-containing layer has suitable adhesive properties such that no further adhesive (sticking agent) such as a tackifier (tack) is required. Whenever it is considered that the adhesive strength of the drug-containing layer needs to be improved, the layer further contains a tackifier.

The term "tackifier" means an agent that improves the adhesive strength of an adhesive layer to skin or mucous membranes.

Examples of tackifiers are selected from hydrocarbon resins, rosin resins and terpene resins. Examples of hydrocarbon resins may be given by the trade namePurchased from ExxonMobil; to be provided withAndfrom Eastman orPurchased from BP. Examples of rosin esters suitable for use in the transdermal systems of the present invention include esters of hydrogenated wood rosin such as the pentaerythritol ester of hydrogenated wood rosin, esters of partially hydrogenated wood rosin such as the pentaerythritol ester of partially hydrogenated wood rosin, esters of modified wood rosin (modified wood rosin), esters of partially dimerized rosin, esters of tall oil rosin, esters of dimerized rosin, and the like, and combinations and mixtures thereof. Such rosin may be given a brand nameAndand (4) obtaining the product.

In a preferred embodiment of the invention, the drug-containing layer comprises a tackifier in the form of a rosin ester (e.g. pentaerythritol ester).

It is generally contemplated that the viscosity enhancing agent may be present in any suitable amount so long as the critical solubility of the gestodene in the drug-containing layer is not significantly affected. Thus, the tackifier may be present in the drug-containing layer in an amount of about 0.1-95%, such as 0.5-95%, such as 1-95% by weight of the drug-containing layer. In other words, the binder may be present in an amount of about 1-85%, 1-75%, 1-65%, 1-55%, 1-50%, 1-45%, 1-40%, or more preferably about 1-35%, such as preferably 1-30%, more preferably 1-25%. It is clear that the amount of tackifier in the drug-containing layer is important for the solubility of the gestodene in the drug-containing layer. Thus, in other embodiments of the invention, the tackifier is present in the drug-containing layer in an amount of up to 35%, such as up to 30%. Preferably, the tackifier is present in an amount of up to 25%, such as up to 20% or 15% by weight of the drug-containing layer.

Another particular aspect of the invention relates to a composition for transdermal delivery of gestodene and ethinylestradiol, the composition comprising a drug-containing layer consisting essentially of:

-gestodene and one or more pharmaceutically acceptable ingredients and/or carriers;

-polyisobutylene or a mixture of polyisobutylene with other polymers, preferably in an amount of about 15-99% by weight of the drug-containing layer. As described above, the drug-containing layer has the solubility of gestodene as described above; and

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

As mentioned above, the drug-containing layer is composed of ingredients that form a layer that meets the solubility criteria for gestodene. Preferably, this criterion is met when the drug-containing layer consists essentially of gestodene and ethinylestradiol in combination with polyisobutylene and optionally a tackifier.

Furthermore, in some embodiments, the drug-containing layer does not comprise, or at least comprises only a limited amount of, a crystallization inhibitor, such as polyvinylpyrrolidone, a cellulose polymer, such as methylcellulose or ethylcellulose derivatives or hydroxypropylmethylcellulose, or a mixture thereof.

And in some embodiments, a solubilizing agent such as isosorbide dimethyl ether is not present in the drug-containing layer or is present at least only in a limited amount.

The term "limited amount" means that the polymer or solubilizer in question is present in the layer at a concentration of less than 10%, such as less than 8%, 5%, 3%, 2%, 1%, 0.5% or 0.2% by weight of the drug-containing layer.

As described above, the steroid hormones gestodene and ethinylestradiol can be sufficiently permeated into the skin without incorporation of a skin permeation enhancer and/or an permeation enhancer. That is, in interesting embodiments of the present invention, the skin penetration enhancer and/or the penetration enhancer is not present in the drug-containing layer or is present in a limited amount of less than 5% by weight of the drug-containing layer, such as less than 4%, 3%, 2%, 1%, 0.5% or 0.2%.

The terms "skin penetration enhancer" and "penetration enhancer" are terms used interchangeably herein and refer to a compound that enhances skin penetration/penetration of an active drug when administered to the skin of a user along with the drug. Penetration enhancers in transdermal formulations alter the thermodynamic activity of the drug in the drug-containing layer and thereby cause a positive or negative "push" action. In addition, 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 lipid acyl chain mobility, thereby providing a "traction" effect.

Any skin penetration/penetration enhancement of a substance can be understood when testing the same formulation with and without a penetration enhancer, such as by using nude mouse skin or the like. Such testing methods are known to those skilled in the art.

Common penetration/permeation enhancers include the following compounds:

alcohols, such as monohydric alcohols having about 2 to 10 carbon atoms, such as ethanol, isopropanol, butanol, pentanol, octanol, decanol and/or benzyl alcohol; glycols, such as 1, 2-propanediol; polyols, such as glycerol, sorbitol and/or polyethylene glycol; saturated and unsaturated fatty alcohols having 8 to 18 carbon atoms, such as octanol, decanol, lauryl alcohol, 2-lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol, linoleyl alcohol and linolenyl alcohol.

Fatty acids, such as saturated or unsaturated fatty acids which may contain from 8 to 18 carbon atoms, for example dodecanoic acid, tetradecanoic acid, stearic acid, oleic acid, linoleic acid, linolenic acid and hexadecanoic acid, triacetin, ascorbic acid, panthenol, butylated hydroxytoluene, tocopherol acetate, tocopherol linoleate. Other fatty acids include, but are not limited to, valeric acid, caproic acid, caprylic acid, pelargonic acid (pelargonic acid), capric acid (caprin acid), isovaleric acid (isovalerian acid), pivalic acid (neopentanan acid), neoheptanoic acid (neoheptan acid), and/or isostearic acid.

Esters, e.g. aliphatic esters, e.g. ethyl acetate, lower (C) of lactic acid₁-C₄) Alkyl esters of the general formula CH₃(CH₂)_nFatty acid esters of COOR (where n is a number from 1 to 18 and R is an alkyl residue having up to 6 carbon atoms) (for example fatty acid esters of lauric, myristic, stearic and palmitic acids, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl esters of these acids), or of the general formula R' OCO (CH)₂)_mDicarboxylic acid diesters of COOR '(where m is a number from 4 to 8 and R' in each case denotes an alkyl residue having up to 6 carbon atoms) (such as propyl oleate, decyl oleate, isopropyl palmitate, ethylene laurate, dodecyl myristate, isopropyl myristate and ethylene stearate, suitable dicarboxylic acid diesters being, for example, diisopropyl adipate, diisobutyl adipate and diisopropyl sebacate).

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

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

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

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

-an amino acid.

Aminoacetate, such as aminoacetate derivatives, such as 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-dimethylamino) phenylacetate.

-azone derivatives, such as 1-dodecylazacycloheptane-2-one derivatives, azacycloalkanone derivatives and/or hexamethylene lauramide derivatives.

Cyclodextrins, such as alpha-, beta-and gamma-cyclodextrins.

Glycerol esters, 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).

Diols, such as ethylene glycol, diethylene glycol, propylene glycol, dipropylene glycol and/or 1, 3-propanediol.

Oils, such as mineral, vegetable, animal and fish fats and oils, such as cottonseed oil, corn oil, safflower oil, olive oil and castor oil, 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-pyrrolidone, N-lauryl-pyrrolidone, 4-carboxy-pyrrolidone, 4-carboxycarbocation 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 methyloctyl-sulfoxide, dimethyl sulfoxide (DMSO), hexylmethylsulfoxide (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; anionic surfactants such as sulfates, including but not limited to compounds such as sodium lauryl sulfate and/or sodium dodecyl sulfate; and nonionic surfactants such as esters of sorbitol and sorbitan including, but not limited to, polysorbates, sorbitan monopalmitates and/or sorbitan polyoleates.

Terpenes, ketones and oxides.

In addition to the steroid hormones gestodene and ethinylestradiol, polymeric polyisobutylene or a mixture of polyisobutylene with other polymers, one or more tackifiers, the drug-containing layer or other parts of the composition may also contain stabilizers, dyes, pigments, inert fillers, anti-aging agents, antioxidants, elastomers, thermoplastics and other conventional components of transdermal compositions known in the art. Preferably, the composition or at least the drug-containing layer comprises no or only a limited amount (less than 1%, 0.8%, 0.5%, 0.2% or 0.1% by weight of the drug-containing layer) of polyvinylpyrrolidone, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose and/or isosorbide dimethyl ether.

It will be appreciated that the compositions of the present invention are transparent or at least in highly interesting embodiments transparent, which means that the skin can be visually inspected through the drug delivery system. That is, the drug-containing layer is a single phase system in which the drug (here, gestodene) is completely dissolved in the drug-containing layer.

The drug-containing layer is further characterized as being homogeneous. The term "homogeneous" is used to describe a single phase system in which the matrix consists of one polymer phase. These systems can be distinguished from multiphase systems consisting of at least two polymer phases. In most cases, the multi-phase system can be visually detected by its opaque appearance. The opaque appearance is caused by light diffraction due to differences in the diffraction indices of the polymer phases. Other methods of detecting single-phase systems are microscopy (microscopic method) or rheology or by mechanical stretching of polymer films. As determined visually, during mechanical stretching, the polymer film consisting of the multiphase system becomes opaque.

Thus, in summary, it should be understood that meaningful embodiments of the present invention include:

a drug-containing layer comprising:

i) gestodene and ethinyl estradiol,

ii) polyisobutylene, and

iii) the drug-containing layer comprises gestodene in an amount of 0.4-1.95%, preferably about 0.9-1.5% by weight of the drug-containing layer, and ethinyl estradiol in an amount of about 0.5% by weight of the drug-containing layer.

In a further interesting embodiment thereof, the drug-containing layer is characterized by the following parameters, which can be present as single parameters or as a combination of parameters:

the drug-containing layer does not contain isosorbide dimethyl ether or contains isosorbide dimethyl ether in an amount of less than 0.5% by weight of the layer;

the drug-containing layer does not comprise polyvinylpyrrolidone, methylcellulose, ethylcellulose and/or hydroxypropylmethylcellulose, or comprises polyvinylpyrrolidone, methylcellulose, ethylcellulose and/or hydroxypropylmethylcellulose in an amount of less than 2% by weight of the layer;

the drug-containing layer comprises gestodene and ethinylestradiol 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 contains no skin penetration enhancer or a skin penetration enhancer in an amount of less than 2% by weight of the layer;

the drug-containing layer comprises polyisobutylene in an amount of about 15-99% by weight of the layer;

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

In another embodiment of the invention, an additional adhesive layer comprising a UV radiation absorber is provided between the backing layer and the drug-containing adhesive matrix comprising polyisobutylene and the active ingredients gestodene and ethinyl estradiol.

The UV absorber is a Tinosorb or Tinuvin UV absorber, preferably Tinosorb S.

An intermediate or separation layer is provided between the additional adhesive layer containing the UV absorber and the drug-containing layer. The separating or intermediate layer is impermeable to the active ingredient and the UV absorber. Preferably, the intermediate or separating layer is impermeable to gestodene and ethinylestradiol.

Due to this structure, no contact between the active ingredient and the UV absorber occurs. The advantage of this arrangement is that the UV absorber is only contained in the thin adhesive layer between the backing layer and the intermediate layer, thereby allowing a lower amount of UV absorber to be required in the formulation than in systems where the UV absorber is distributed throughout the drug-containing adhesive matrix. Furthermore, the UV absorber can be prevented from directly contacting the skin, thereby preventing potential side effects such as allergy of the skin.

Thus, one embodiment of the present invention is arranged according to fig. 1.

Fig. 1 shows a cross-section of a patch having a backing layer a, an adhesive layer B comprising a UV absorber, an intermediate layer or separation layer C, a drug-containing adhesive matrix D and a release liner E.

As noted above, the compositions of the present invention are characterized by the delivery of a therapeutically effective contraceptive amount of a combination of gestodene and ethinyl estradiol. In other words, the composition may be characterized as having a drug-containing layer that delivers gestodene in an amount of 0-700 μ g over 24 hours, preferably in an amount of 130-665 μ g, preferably 200-520 μ g, most preferably 360-520 μ g over 24 hours, and ethinylestradiol in an amount of 40-220 μ g over 24 hours, preferably in an amount of 70-190 μ g, preferably 100-165 μ g, most preferably 135-140 μ g over 24 hours.

As can also be seen from table 3, the compositions of the present invention are characterized by having a drug-containing layer that delivers:

600-650. mu.g, for example 600. mu.g or 630. mu.g or 660. mu.g of gestodene, and 120-135. mu.g, for example 120. mu.g or 130. mu.g or 135. mu.g of ethinylestradiol, or

520. mu.g of gestodene and 140. mu.g of ethinylestradiol, or

350-380. mu.g gestodene and 160-165. mu.g ethinylestradiol, or

200-210. mu.g, e.g. 205. mu.g, of gestodene and 175-190. mu.g, e.g. 180. mu.g, of ethinylestradiol, or

210. mu.g, e.g. 215. mu.g or 230. mu.g, of gestodene and 90-100. mu.g, e.g. 95. mu.g or 100. mu.g, of ethinylestradiol, or

290. mu.g, e.g. 295. mu.g or 350. mu.g, of gestodene and 60-70. mu.g, e.g. 65. mu.g, of ethinyl estradiol.

The above amounts are measured in an in vitro dissolution test as described under pharmacokinetic results.

As noted above, the composition is effective in inhibiting ovulation in healthy women.

The second steroid hormone ethinylestradiol is incorporated into the same drug-containing layer with the gestodene or into a separate drug-containing layer devoid of gestodene.

The actual drug concentration in the drug-containing layer may be adjusted in order to obtain a therapeutically effective amount of hormone in the blood. Generally, the drug-containing layer should contain an amount of hormone in excess of that absorbed to obtain a therapeutically effective amount of hormone. According to the invention, the degree of excess is small, e.g. the amount of hormone is less than 10 times, preferably less than 5 times the amount of desired/required hormone. For example, it is also important to limit the amount of hormone to reduce the overall exposure of the hormone to the user (e.g., when contacting the skin or mucous membranes). Thus, a suitable concentration of gestodene in the drug-containing layer is 0.4-1.95% by weight of the drug-containing layer, and the concentration of ethinyl estradiol is about 0.5% by weight of the drug-containing layer. As mentioned above, the total concentration of the hormone (e.g., gestodene) may result in a drug-containing layer that contains the hormone at a saturated or sub-saturated level. In a highly interesting embodiment, the concentration of gestodene in the drug-containing layer is about 0.4-1.95%, preferably about 0.9-1.5% by weight of the drug-containing layer.

Ethinyl estradiol is present in the drug-containing layer in an amount of 0.5% by weight of the adhesive layer.

In addition, the mass ratio of gestodene to ethinyl estradiol is about 4:1 to 1:1, for example a ratio of about 4:1, about 3:1, about 2:1 or about 1: 1.

The following combinations illustrate the compositions of the present invention, but the invention is not limited thereto:

TABLE 1

It has been unexpectedly found that by administering small amounts of gestodene formulated in the compositions of the present invention, relatively high plasma levels of gestodene can be maintained over an extended period of time. Furthermore, it has been unexpectedly found that the plasma profile and plasma levels of gestodene obtained from the administration of gestodene and ethinylestradiol from the above formulation are effective in inhibiting ovulation in women.

Thus, the use of the compositions of the invention for inhibiting ovulation in a female (e.g. a woman) is further described. When the drug is administered, a plasma concentration-time profile of gestodene is obtained that is characterized by: it has a mean gestodene plasma level (C) over a period of 7 days of a concentration of at least 0.5ng/ml, as measured under steady state conditions_av). A method of inhibiting ovulation in a female, such as a female, comprising topically administering to the skin or mucosa an effective amount of a combination of gestodene and ethinylestradiol such that, upon administration of said gestodene alone, a plasma concentration-time profile of gestodene characterized by: it has a plasma level of gestodene at a concentration of at least 1.0ng/ml as measured under steady state conditions.

It should be noted that the terms "plasma level" and "serum level" are used interchangeably. There was no difference measured in serum or plasma with respect to the drug concentration of steroid hormones. When the term "plasma" is used, the same applies to "serum".

Alternatively, the use and method are for the treatment of other symptoms, disorders or conditions that are typically treated by administration of gestodene and ethinylestradiol.

Thus, it is generally understood that the use and method are useful for treating endometriosis pain, premenstrual syndrome, menopausal disorders, regulating and/or stabilizing the menstrual cycle.

Gestodene is administered in combination with ethinylestradiol for the treatment of menopausal disorders, such as symptoms and diseases associated with menopause, e.g., hot flashes, sweating, palpitations, sleep disturbances, mood changes, stress, anxiety, poor memory, loss of confidence, loss of libido, poor attention, weakness (demisted energy), reduced power (demisted drive), irritability, urogenital atrophy, atrophy of the breast, cardiovascular disease, changes in hair distribution and thickness, changes in skin condition, and/or osteoporosis. Most notably, the treatment is directed to the prevention or treatment of hot flashes, sweating, palpitations, sleep disturbances, mood changes, stress, anxiety, urogenital atrophy and atrophy of the breasts, or to osteoporosis.

According to the invention, the plasma concentration-time profile of gestodene under steady state conditions is characterized by a mean gestodene plasma level (C) of 0.5-7.0ng/mL, preferably 2.0-6.0ng/mL, most preferably 3.5-6.0ng/mL_av) While individual concentrations in the preferred range are 1-12 ng/mL. Accordingly, the mean maximum gestodene plasma level (C) over multiple dosing periods_max) About 0-10nl/mL, preferably 3-9nl/mL, and a minimum gestodene plasma level (C)_min) Is about 0.5-4.5ng/mL, preferably 2-4.0 ng/mL.

In a preferred embodiment, the plasma concentration-time profile of gestodene under steady state conditions is characterized as having a concentration of about 4.2ng/mL (C)_av) E.g., about 4.9ng/mL (C)_max) Or about 3.2ng/mL (C)_min) Plasma levels of gestodene at concentration. In other interesting embodiments, the plasma concentration-time profile of gestodene under steady state conditions is characterized by an average gestodene concentration of 5.0ng/mL, preferably 4.0-6.0ng/mL, after the first 6 days after a single administration of a composition of gestodene or a derivative thereof, preferably in the form of a composition according to the invention.

The plasma concentration-time profile of gestodene under steady state conditions is characterized by a maximum plasma level of gestodene during the 18-60 hours after repeated administration of the drug and/or by a plasma level under steady state conditions during the 5-7 days after a single administration of the drug that is at least 50% of the maximum plasma level of gestodene obtained during the first 18-60 hours after administration.

Preferably, the gestodene/ethinylestradiol composition is administered repeatedly over a 28 day cycle such that during each 28 day cycle, the gestodene/ethinylestradiol composition is administered at 7 day intervals for 21 days (3 weeks), followed by no administration of the gestodene/ethinylestradiol composition for the subsequent 7 days (1 week). That is, the gestodene/ethinylestradiol composition is administered on days 1, 8, and 15 of each 28-day cycle. Preferably, the day 1 may be the day of onset of menstruation, or any other suitable day, such as day 1,2, 3, 4, 5 or 6 after the day of onset of menstruation. In another embodiment, the gestodene/ethinylestradiol composition is administered repeatedly over a 12-week period, such that during each 12-week period, the gestodene/ethinylestradiol composition is administered at 7-day intervals over 11 consecutive week periods, followed by no administration of gestodene or derivative thereof for the subsequent 7 days (one week).

As will be appreciated, the use and method of the invention comprises administration of the gestodene/ethinylestradiol composition in the form of a composition as defined herein. Thus, the term "drug" includes compositions as defined herein. Furthermore, the term "medicament" is intended to include the kits of the present invention.

In yet another aspect, the invention relates to a kit comprising 1-52, 1-26, 1-13 dosage units for administration to the skin over a period of 52 weeks, 26 weeks, or 13 weeks plus a 7 day rest period (no patch). The dosage unit is one patch for 7 days or one week. The patch is always applied on day 1 or on day 2, 3, 4, 5 or 6 of menstruation. The next patch application is administered 7 days after the first patch application, i.e. at day 8, 9, 10, 11, 12 or 13 after day 1 of menstruation. The patch of the present invention may be administered for a period of three 7 days (i.e., 21 days) and then discontinued for 7 days. This means that three patches are applied within three weeks and the patch is deactivated for one week.

For example, administration may be carried out continuously over a period of 1-52, 1-26, and 1-13 weeks. Other periods within the range are also possible. After administering a large number of patches over a long period of time, the interruption was 7 days.

Each dosage unit contains a dosage of about 0.38-2.3mg, preferably 0.525-2.1mg, more preferably 1.05-1.575mg of gestodene.

It is further understood that the kit further comprises ethinyl estradiol in a dose of about 0.15-0.6mg, preferably 0.35-0.55 mg. Ethinyl estradiol is combined with gestodene in the same dosage unit or provided in separate dosage units.

A possible combination of these two hormones is illustrated in table 1.

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

Example 1

Preparation of Patches

The compositions of the invention were prepared as described in example 1 of EP 1541137, except that tetrahydrofuran was used to solubilize the gestodene and ethinyl estradiol.

The patch thus obtained had 11cm²The following composition:

gestodene: 1.05mg

Ethinyl estradiol: 0.55mg

Polymer (b): 108.4mg (as polyisobutylene with tackifier (e.g.)) Form of combination)

An intermediate layer: 11cm²

UV absorber: 0.825mg

Polymer (b): 32.175mg

And (3) release liner: 11cm²

Backing layer: 11cm²

Further examples can be obtained accordingly based on the compositions of gestodene and ethinylestradiol and patch size given in tables 1 and 3.

Example 2

Pharmacokinetic Properties

The effect of the patch of the present invention on ovulation inhibition, serum drug concentration and safety were studied in selected female populations. The study design was based on the requirements of the EMEA guidelines for clinical studies on contraceptive steroids (Committee for pro prioral Medicinal Products, CPMP/EWP 519/98).

Design of research

The study was divided into three phases: the pretreatment phase, which includes a wash cycle and an additional cycle to ensure that the selected woman is ovulating. Finally, the second phase is a three cycle treatment phase followed by a third phase consisting of one cycle of post-treatment phases.

The women selected for this study had to have a weight of 18-30kg/m²Healthy, non-pregnant, non-smoking, non-lactating 18-35 year old female volunteers of normal body mass index. Only women with light skin were selected so that the application site could be easily and consistently evaluated.

Test Patch C is a patch containing a drug-containing layer containing 0.55mg of ethinylestradiol and 2.1mg of gestodene andhaving a width of 11cm²The size of (c).Is a polyisobutylene-based Adhesive from Adhesive Research. Test patch D was identical to patch C, but contained 0.55mg of ethinylestradiol and 1.05mg of gestodene.

During the study, blood was drawn to assay for endogenous hormones such as estradiol, progesterone, follicle stimulating hormone, sex hormone binding protein, ethinylestradiol, gestodene. Transvaginal ultrasonography was performed to assess the development of the oothecal structure. Patch adhesion, skin reactions and general health of the women were evaluated at the site of application. Vaginal bleeding was also evaluated.

During the pretreatment cycle, normal and spontaneous ovulation is determined by evaluating serum progesterone values, and then only women with a preovulatory cycle and progesterone serum level above 5nmol/l are included in the treatment phase. The treatment phase comprises three menstrual cycles. The first treatment in the first cycle was the volunteer applying the patch to the lower abdomen starting the first day after menstruation started within this cycle. The patch is applied to clean, dry intact and preferably hairless skin with the lower abdomen under the navel, starting with the right side in the first treatment cycle, and then changing to the other side. A total of three test patches are administered at 7 day intervals, for example on days 1, 8 and 15 of the first cycle. Each patch was applied for 7 days and subsequently replaced with a new patch for a total of 21 consecutive days. This is followed by a 7 day drug withdrawal interval followed by the next treatment period beginning with the application of a total of three patches, each applied at 7 day intervals. If the patch is shed or shed more than 50%, a new patch is applied.

Determination of pharmacokinetic variables

Serum concentrations of estrogen and progestin (including ethinylestradiol and gestodene) were measured throughout the study to evaluate the pharmacokinetic properties of the patch. The sampling time points were day 24 of the pretreatment cycle and approximately every 3 rd day during treatment cycles 2 and 3. In addition, samples were taken daily during treatment cycle 3 of 3 weeks.

The concentration of ethinylestradiol and gestodene is determined by conventional methods known in the art. Specifically, the concentrations of ethinylestradiol and gestodene were determined by liquid chromatography using mass spectrometry as the detection method. The lower limit of quantitation for ethinylestradiol and gestodene was 2.5pg/ml and 50pg/ml, respectively.

Analysis of pharmacokinetics collected during the study using a nonlinear mixed effects modelTo learn the data. A mixed-effect or population-type pharmacokinetic model describes the relationship between dose and practice and variables such as drug plasma concentration. The relationship relates to structural effects and random effects. Drug concentration was used as a dependent variable to build a population pharmacokinetic compartment model. Parameters during steady state, such as AUC, are calculated based on the population pharmacokinetic zone compartment model. In addition, parameters during cycle 3 of cycle 3, such as C, are calculated by a atrioventricular method_maxAUC (0-168 hr) and C_min. Results

The primary pharmacokinetic variable is the proportion of women with ovulation inhibition.

No ovulation was observed in both treatment groups throughout the study. Ovulation inhibition, defined as a Hoogland score below 6 (ovulation), was sufficient for all volunteers in each protocol throughout the study.

The progesterone concentration was sufficiently suppressed to be below 2.5nmol/l during each treatment cycle. The mean estradiol level in the blood was less than 20pg/ml on all days the patch was applied.

The Hoogland score is a method known to those skilled in the art to assess ovulation inhibition. For example, a detailed description of this method can be found in database BioMed Central: (B)www.biomedcentral.com) The publication in (1) is Doris Heger-Mahn, "Use of a generic speech and hormonesearch in gynecological tris".

With transvaginal ultrasonography, the internal female genitalia (uterus, ovaries and blood vessels) can be visualized in a harmless and easy way. Closed-cell examination (e.g., every 3 days) is performed throughout the cycle to assess follicle size, ovulation, luteal phase, and endometrial conversion. Using doppler ultrasound imaging, changes in blood flow under the influence of hormones can be assessed. Estradiol and progesterone are the major hormones tested. Estradiol is produced by constantly growing follicles, and progesterone is associated with corpus luteum development and degeneration during half of the second cycle. In addition, FSH and LH can be assessed. Especially inhibin A and B, prolactin, testosterone or DHEAS are to be evaluated. In principle, the major hormones can be determined by RIA techniques and immunoassays (e.g., ECLIA = electrochemiluminescence immunoassay). The variability of hormone values depends mainly on the blood sampling interval, the release conditions of these hormones and the specificity and reliability of the test system.

The data from both methods can be summarized using the so-called Hoogland score, and the activity of follicular structures observed by TVS can be ranked.

Pharmacokinetic results

Serum concentrations of ethinylestradiol and gestodene were quantified in all individuals after administration of the study drug. See the results in table 2.

Table 2: summary of patch formulations and resulting plasma data

C_max: maximum concentration during observation

C_av: average concentration during observation

C_min: minimum concentration during observation

SD: single dose, MD = multiple doses (steady state)

Plasma concentrations of gestodene obtained after administration of formulations a and B may be slightly overestimated, since a brief wash-out period prior to administration of these formulations may lead to residual (carry-over) effects of gestodene from the previous treatment period.

The residue was associated with SHBG (sex hormone binding globulin), which declined to the starting point within 7 days.

The gestodene concentration is maintained at a high level.

Comparable plasma levels were obtained when formulations AA and a were administered in a single dose. For formulation B with reduced ethinylestradiol and gestodene content (about 70%) relative to formulations AA and a, slightly lower plasma levels of gestodene and ethinylestradiol were obtained when administered as a single dose than for formulations AA and a (table 2). This is not beyond the expectations of the skilled person who generally thinks that the plasma levels of individual compounds administered transdermally using formulations with similar compositions are related to the amount of such compounds. Furthermore, it is desirable that the plasma levels of two compounds administered simultaneously do not interfere with each other.

It is assumed that the formulation AA of example 3 of EP 1541137 is a patch containing 1.9mg (instead of 1.0g as described in example 3) of gestodene. No description is found in EP 1541137 about the preparation of a patch with 1.0mg of gestodene. In addition, at the web sitewww.clinicaltrials.govThe above search did not yield a suggestion for a clinical trial with a patch containing 1.0mg gestodene and 0.9mg ethinylestradiol, but information on the trial with 1.9mg gestodene and 0.9mg ethinylestradiol is given. Thus, it is assumed that the amount of gestodene in example 3 of EP 1541137 is wrong.

The results of these previously published data relating to formulations AA and a as described in EP 1541137 in examples 3 and 4 are clearly demonstrated by the results obtained with formulation C having a gestodene content of about 110% and an ethinyl estradiol content of only about 60% relative to formulation AA. This is also reflected in plasma levels: after multiple dosing, plasma levels of formulation C increased approximately 10% compared to those obtained with formulation AA, while ethinyl estradiol was only 65-70% (table 2). Furthermore, these results are fully in line with the expectations of the skilled person, i.e. the plasma levels are related to the drug content and the plasma levels of the two compounds administered simultaneously do not interfere.

Compared to formulation C, formulation D had only a 50% gestodene content, but the same ethinyl estradiol content.

Unexpectedly, although the gestodene content in patch preparation D was 50% lower than preparation C, both preparations obtained almost the same plasma of gestodeneAnd (4) horizontal. Furthermore, although the ethinylestradiol content was the same in both preparations C and D, preparation D obtained ethinylestradiol plasma levels almost twice as high as preparation C (C)_max(C) The method comprises the following steps 32pg/ml vs. C_max(D)：55pg/ml).

Without wishing to be bound by a particular theory, the inventors of the present invention have unexpectedly discovered a method of combining the levels of gestodene and ethinylestradiol in a manner that achieves high plasma levels of both compounds with relatively low levels of gestodene and ethinylestradiol in the patch.

Plasma levels expected in clinical studies can be assessed by in vitro methods. Even in the pharmacopoeia, in vitro dissolution methods have been established for the release of drugs from formulations. The transdermal patches were subjected to dissolution testing as described in USP <724> or ph.eur.2.9.4, method 1, in a paddle over disk set-up (paddle over disks). Dioxane (HPLC-quality)/water purified in a ratio of 30+70 was used as dissolution medium (1000ml) at 50rpm at 32+/-0.5 ℃. At predetermined time points (1, 4, 8 and 24 hours) 1ml of each sample was taken and analyzed on a reverse phase column for the drug content of gestodene and ethinylestradiol by standard HPLC methods.

Thus, the drug release rates in the in vitro dissolution test of the different patch formulations were investigated and compared to the drug release rates of formulations AA, a and C and D (table 3).

The results show that a wide range of drug release rates can be achieved by adjusting the ethinylestradiol and gestodene concentrations in the patch matrix. The ratio of ethinyl estradiol to gestodene in the patch preparation can be selected in such a way that a desired drug release rate from the patch preparation and thus a desired plasma level of both drugs is obtained.

Table 3: release rates of different patch formulations in vitro dissolution

Formulation A/AA

Preparation D

Preparation C

The data in the gray shade grid is for comparison only.

In an in vitro dissolution test, the drug release rate of ethinylestradiol in combination with different amounts of gestodene in a transdermal patch resulted in a directly proportional increase in the ethinylestradiol release rate with decreasing amounts of gestodene, even with constant amounts of ethinylestradiol in the formulation (fig. 1). In addition, the rate of release of gestodene is also increased relative to its concentration in the formulation.

FIG. 2 shows the relationship between drug release from the patch and varying concentrations of gestodene and a constant concentration of ethinylestradiol in the patch matrix (concentration of gestodene 0-1.9%, concentration of ethinylestradiol 0.5%. The data is for a patch having 11cm²Size of suitable patch obtained after 24 hours of in vitro drug release).

Claims (14)

1. A transdermal therapeutic system comprising, in order:

a) a backing layer;

b) at least one drug-containing adhesive layer comprising the active ingredients gestodene and ethinylestradiol in a polyisobutylene-containing matrix and optionally other pharmaceutically acceptable ingredients; and

c) a release liner;

wherein the transdermal therapeutic system comprises 1.05mg of gestodene and 0.55mg of ethinylestradiol, or 0.525mg of gestodene and 0.55mg of ethinylestradiol, and has a size of 11cm²。

2. Transdermal therapeutic system according to claim 1, wherein the transdermal therapeutic system comprises an additional layer with a UV absorber between the backing layer and the drug-containing adhesive layer.

3. Transdermal therapeutic system according to claim 2, wherein the UV absorber is a Tinuvin or Tinosorb UV absorber.

4. Transdermal therapeutic system according to claim 3, wherein the UV absorber is Tinosorb S.

5. Transdermal therapeutic system according to claim 2, wherein the transdermal therapeutic system comprises an additional intermediate or separation layer between the additional layer with UV absorber and the drug-containing adhesive layer.

6. Transdermal therapeutic system according to claim 1, comprising in succession:

a) a backing layer;

b) an adhesive layer comprising a UV absorber;

c) an intermediate layer which is impermeable to the UV absorber and/or the active ingredients gestodene and ethinyl estradiol;

d) at least one adhesive layer comprising polyisobutylene, which comprises the active ingredients gestodene and ethinylestradiol and pharmaceutically acceptable ingredients; and

e) a release liner.

7. Transdermal therapeutic system according to claim 1, comprising less than 5% of penetration enhancers.

8. The transdermal therapeutic system according to claim 1, comprising isosorbide dimethyl ether in an amount of less than 0.5% (w/w) of the weight of the drug-containing layer.

9. Transdermal therapeutic system according to claim 1, which is a dosage unit for continuous administration over 7 days.

10. Transdermal therapeutic system according to claim 9, wherein the dosage unit has a size of 11cm²Comprises 0.525 or 1.05mg of gestodene and 0.55mg of ethinyl estradiol per dosage unit.

11. Transdermal therapeutic system according to claim 10, wherein the dosage unit comprises 0.825mg of Tinosorb S.

12. Transdermal therapeutic system according to claim 10, wherein the dosage unit contains 1.05mg of gestodene.

13. Use of a transdermal therapeutic system according to claim 1 for the preparation of a medicament for female contraception.

14. A kit comprising 1-52 dosage units as defined in claim 9.